WO2005053663A2 - Norepinephrine reuptake inhibitors useful for treatment of cognitive failure - Google Patents

Norepinephrine reuptake inhibitors useful for treatment of cognitive failure Download PDF

Info

Publication number
WO2005053663A2
WO2005053663A2 PCT/US2004/037195 US2004037195W WO2005053663A2 WO 2005053663 A2 WO2005053663 A2 WO 2005053663A2 US 2004037195 W US2004037195 W US 2004037195W WO 2005053663 A2 WO2005053663 A2 WO 2005053663A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
optionally substituted
formula
phenyl
substituents
Prior art date
Application number
PCT/US2004/037195
Other languages
French (fr)
Other versions
WO2005053663A3 (en
Inventor
Alan Kramer Hatfield
Franklin Porter Bymaster
David Lee Mckinzie
Tina Marie Tucker
Kirk Matthew Keaffaber
Calvin Russell Sumner
Paula Terese Trzepacz
Albert John Allen
Douglas Kenneth Kelsey
David Michelson
Donald Richard Gehlert
Charles Renkin Yang
Original Assignee
Eli Lilly And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Publication of WO2005053663A2 publication Critical patent/WO2005053663A2/en
Publication of WO2005053663A3 publication Critical patent/WO2005053663A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
    • C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
    • C04B35/632—Organic additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the fields of pharmaceutical chemistry and central nervous system medicine. More particularly, the present invention provides pharmaceutical formulations and methods of treatment for cognitive failure due to a wide variety of different etiologies, or associated with a number of different conditions or disorders.
  • Cognitive failure also variously referred to as “cognitive insufficiency,” “cognitive deficit,” “cognitive impairment,” “cognitive dysfunction,” and the like, refers to the dysfunction, diminution, or loss of one or more cognitive functions, the processes by which knowledge is acquired, retained, and used.
  • Cognitive dysfunction includes cognitive changes associated with ageing ("age-associated memory impairment"), as well as changes due to other causes. Cognitive impairment is most commonly due to a delirium or dementia, but can also occur in association with a number of other medical or neuropsychiatric disorders.
  • More focal cognitive deficits are diagnosed using the criteria disclosed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TRTM, 2000), American Psychiatric Association, Washington, D.C., as either amnestic disorders (affecting memory) or cognitive disorder not otherwise specified (NOS), which includes executive dysfunction, visuospatial/visuocontructional impairment, attentional deficits, disorientation, etc.
  • DSM-IV-TRTM Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TRTM, 2000), American Psychiatric Association, Washington, D.C.
  • NOS cognitive disorder not otherwise specified
  • These more focal cognitive disorders also have a wide variety of causes, some of which are of unknown etiology.
  • a delerium is characterized by a disturbance of consciousness with a reduced ability to focus, sustain, or shift attention and a change in cognition that develops over a short period of time. Delirium is very common, and occurs on average in about a fifth of general hospital inpatients, and is even more common in nursing home patients and those with terminal illnesses.
  • the disorders included in the "Delirium" section of the DSM-IV- TRTM are listed according to presumed etiology: Delirium Due to a General Medical Condition, Substance-Induced Delirium (i.e., due to a drug of abuse, a medication, or toxin exposure), Delirium Due to Multiple Etiologies, or Delirium Not Otherwise Specified (if the etiology is indeterminate).
  • exemplary etiological bases of delirium include, but are not limited to, infection, withdrawal from alcohol and drugs, acute metabolic conditions, trauma of various types, CNS pathologies, hypoxia, vitamin deficiencies, endocrinopathies, acute
  • a dementia is a chronic condition, usually with a more gradual deterioration of memory and other intellectual functioning and other cognitive skills severe enough to interfere with the ability to perform activities of daily living. Although dementia may occur at any age, it primarily affects the elderly, presenting in more than 15% of persons
  • Alzheimer's disease Dementia due to Alzheimer's disease is particularly common. It affects four million Americans, at an annual cost of about $90 billion, including medical and nursing home care, social services, lost productivity, and early death. Alzheimer's disease
  • . 0 accounts for more than 65% of the dementias in the elderly.
  • Non- Alzheimer's cognitive impairments and/or dementias include, for example, those caused by or associated with: vascular diseases; Parkinson's disease; Lewy body disease (diffuse Lewy body disease); HIN/AIDS; mild cognitive impairments; mild nuerocognitive disorders; age-associated memory impairments; neurologic and/or
  • psychiatric conditions including epilepsy and epilepsy treatments; brain tumors, cysts, lesions, or other inflammatory brain diseases; multiple sclerosis; Down's syndrome; Rett's syndrome; progressive supranuclear palsy; frontal lobe dementia syndromes; schizophrenia and related psychiatric disorders; antipsychotic medications; traumatic brain injury (closed head injury), dementia pugilistica, and other head traumas; normal-
  • the dementias are also listed in the "Dementia" section of the DSM-IV-TRTM according to presumed etiology: Dementia of the Alzheimer's Type, Vascular Dementia, Dementia Due to Other General Medical Conditions (e.g., human immunodeficiency virus [HIV] disease, head trauma, Parkinson's disease, Huntington's disease), Substance- 5 Induced Persisting Dementia (i.e., due to a drug of abuse, a medication, or toxin exposure), Dementia Due to Multiple Etiologies, or Dementia Not Otherwise Specified (if the etiology is indeterminate).
  • HAV human immunodeficiency virus
  • exemplary etiological bases of principal dementia syndromes include, but are not limited to, degenerative disorders (cortical and subcortical), vascular disorders, myelinoclastic disorders, traumatic conditions, neoplastic disorders, hydrocephalic disorders, inflammatory conditions, infections, toxic conditions, metabolic disorders, and
  • amnestic disorder is characterized by memory impairment in the absence of other significant accompanying cognitive impairments.
  • the disorders in the "Amnestic Disorders" section of the DSM-IV-TRTM are also listed according to presumed etiology: Amnestic Disorder Due to a General Medical Condition, Substance-Induced Persisting
  • DSM-IV-TRTM Cognitive Disorder Not Otherwise Specified in the DSM-IV-TRTM covers presentations that are characterized by cognitive dysfunction presumed to be due to either a general medical condition or substance use that do not meet criteria for any of the disorders listed elsewhere in the section of the DSM-IV-TRTM entitled "Delirium, 5 Dementia, and Amnestic and Other Cognitive Disorders.”
  • Dementia, amnestic disorders, and cognitive disorders NOS occur in patients with a wide variety of other disorders including, but not limited to, Huntington's disease (chorea); Pick's disease; spinocerebellar ataxias (types 1-11); corticobasalganglionic degeneration; neuroacanthocytosis; dentatorubropallidoluysian atropy (DRPLA); systemic 0 lupus erythematosus; heavy metal intoxication; alcoholic dementia (Wernicke's encephalopathy); fetal alcohol syndrome; single or multiples strokes, including small vessels (Binswanger's dementia: subcortical arteriosclerotic encephalopathy) and large vessels (multi-infarct dementia); anoxic encephalopathy; tumors; birth anoxia; premature birth; inborn errors of metabolism; neurofibromatosis (Type I); tuberous sclerosis; Hallervorden Spatz disease; Wilson's disease; post-infectious sequel
  • Hydergine therapy may require six
  • the FDA has recently approved the noncompetitive NMDA antagonist memantine for the treatment of moderate to late-stage Alzheimer's disease. Noted side effects include hallucinations, confusion, dizziness, headache, and tiredness.
  • the present invention provides the use of a selective norepinephrine reuptake inhibitor for the preparation of a medicament for the treatment or prevention of
  • the selective norepinephrine reuptake inhibitor can be used alone, or in combination with a conventional Alzheimer's or Parkinson's agent, for the treatment of cognitive failure associated with the particular disease.
  • the present invention provides methods for the treatment of cognitive failure, which may occur due to a wide variety of different causes, or in conjunction with a number of different disorders or conditions.
  • cognitive failure refers to the dysfunction, diminution, or loss of one or more cognitive functions, and includes the spectrum of cognitive dysfunctions ranging from mild cognitive impairment to deterioration of intellectual function and other cognitive skills severe enough to interfere with the ability to perform activities of daily living.
  • cognitive function is a multidimensional concept that refers to the processes by which knowledge is acquired, retained, and used, and includes, but is not limited to, any one or more of the processes of attention, concentration, learning, memory, thinking, organization, problem-solving ability, visuospatial abilities, mental flexibility, psychomotor efficiency, and manual dexterity.
  • the methods for the prevention or treatment of cognitive failure encompassed by the present invention rely on a novel mechanism of action, i.e., selective inhibition of norepineprhine reuptake, and comprise administering to a mammal in need of such prophylactic or therapeutic treatment an effective amount of a selective norepinephrine reuptake inhibitor.
  • This mechanism is operative in mammals, with the preferred mammal being a human.
  • norepinephrine reuptake inhibitors are selective norepinephrine reuptake inhibitors, and no doubt many more will be identified in the future.
  • it is intended to include reuptake inhibitors which show 50% effective concentrations of about 1000 nM or less, in the protocol described by Wong et al, Drug Development Research, 6, 397 (1985).
  • the norepinephrine reuptake inhibitors useful for the method of the present invention are characterized in being selective for the inhibition of neurotransmitter reuptake relative to their ability to act as direct agonists or antagonists at other receptors.
  • the compounds useful for the method of the present invention are selective for the inhibition of norepinephrine reuptake relative to direct agonist or antagonist activity at other receptors by a factor of at least ten.
  • compounds useful for the method of the present invention are selective for the inhibition of norepinephrine reuptake relative to direct agonist or antagonist activity at other receptors by a factor of at least one hundred.
  • Norepinephrine reuptake inhibitors useful in the compositions and methods of the present invention include, but are not limited to,:
  • Atomoxetine (formerly known as tomoxetine), (R)-(-)-N-methyl-3-(2-methyl- phenoxy)-3-phenylpropylamine, is usually administered as the hydrochloride salt. Atomoxetine was first disclosed in U.S. Patent No. 4,314,081. The term “atomoxetine” will be used here to refer to any acid addition salt or the free base of the molecule. See, for example, Gehlert et al. (1993) Neuroscience Letters 157:203-206, for a discussion of atomoxetine's activity as a norepinephrine reuptake inhibitor;
  • Reboxetine (EdronaxTM; ProliftTM; VestraTM; NoreboxTM), 2-[ ⁇ -(2- ethoxy)phenoxy-benzyl]morpholine, first disclosed in U.S. Patent 4,229,449 for the treatment of depression, is usually administered as the racemate.
  • Reboxetine is a selective norepinephrine reuptake inhibitor.
  • the term "reboxetine” as used herein refers to any acid addition salt or the free base of the molecule existing as the racemate or either enantiomer, i.e., (S,S)-reboxetine or (R,R)-reboxetine.
  • (S,S)-reboxetine as a preferred selective norepinephrine reuptake inhibitor is disclosed in PCT International Publication No. WO 01/01973.
  • n 1, 2 or 3
  • Ci -C4alko y 5 0, 1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alko y
  • R3 is H, C1-C4 alkyl (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkyl-S(O) x - wherein x is 0, 1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkoxy (optionally substituted with from 1 to 7
  • halogen atoms cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, C ⁇ -G alkyl and C ⁇ -C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, C ⁇ -C4alkyl and Ci -C4alkoxy) or -CO2(Ci -C4alkyl), or together with R2 or R4 forms a further benzene ring (optionally substituted with from 1 to 3 substituents 0 each independently selected from halogen, Ci -G4alkyl and Ci -C4alkoxy); R4 is H, Ci -
  • C4alkyl (optionally substituted with from 1 to 7 halogen atoms), C ⁇ -C4alkyl-S(O) x - wherein x is 0, 1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -
  • R5 is H, Cj ⁇ alkyl (optionally substituted with from 1 to 7 halogen atoms), C ⁇ alkoxy (optionally substituted with from 1 to 7 halogen atoms) or, halogen;
  • R6 is H, Ci -C4alkyl (optionally substituted with from 1 to 7 halogen atoms),
  • Ci -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms) or halogen; R7 is
  • R8 is H or Ci ⁇ alkyl
  • R9 is H, halogen, hydroxy, cyano, Cj ⁇ alkyl or Ci -C4alkoxy
  • RIO is H, halogen, hydroxy, cyano, Cj ⁇ alkyl or C ⁇ -C4alkoxy; or a pharmaceutically acceptable salt thereof, with the proviso that the compound N-ethyl- N-benzyl-4-piperidinamine is excluded.
  • C2-C ⁇ oalkyl means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 2 to 10 carbon atoms.
  • C2-C ⁇ oalkenyl means a monovalent unsubstituted unsaturated straight-chain or branched-chain hydrocarbon radical having from 2 to 10 carbon atoms and containing at least one carbon-carbon double bond.
  • C3-Cgcycloalkyl means a monovalent unsubstituted saturated cyclic hydrocarbon radical having from 3 to 8 carbon atoms.
  • C4-C ⁇ ocycloalkylalkyl means a monovalent unsubstituted saturated cyclic hydrocarbon radical having from 3 to 9 carbon atoms linked to the point of substitution by a divalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having at least 1 carbon atom.
  • RI groups encompassed by this phrase include but are not limited to:
  • halo or halogen means F, Cl, Br or I.
  • C ⁇ -C4alkoxy means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 carbon atoms linked to the point of substitution by an O atom.
  • phenoxy means a monovalent unsubstituted phenyl radical linked to the point of substitution by an O atom.
  • n 1 or 2. More preferably, n is 1.
  • Preferred compounds of formula (IA) are those wherein R7 is H or methyl. More preferably R7 is H.
  • Preferred compounds of formula (IA) are those wherein R8 is H.
  • Preferred compounds of formula (IA) are those wherein R9 is H or fluoro. More preferably, R9 is H.
  • Preferred compounds of formula (IA) are those wherein R10 is H or fluoro. More preferably, R10 is H.
  • Preferred compounds of formula (IA) are those wherein RI is C2-C6alkyl, C2- C5alkenyl, C3-Cgcycloalkyl or C4-C7cycloalkylalkyl, each of which is optionally substituted with from 1 to 3 halogen atoms or a methoxy radical. More preferably, RI is C2-Cgalkyl (optionally substituted with from 1 to 3 halogen atoms or a methoxy radical),
  • Suitable C2-Cgalkenyl groups include, for example, 2-methyl-2-propenyl.
  • Suitable C3-Cgcycloalkyl groups include, for example, cyclopentyl.
  • Suitable C4-C7cycloalkylalkyl groups include, for example, cyclohexylmethyl or cyclopropylmethyl.
  • Pref erred compounds of formula (IA) are those wherein RI is a C2-C ⁇ oalkyl group optionally substituted with from 1 to 7 halogen substituents and/or with from 1 to 3 substituents each independently selected from hydroxy, cyano and C ⁇ -C4alko y. More preferably, RI is a C2-C ⁇ o lkyl group optionally substituted with from 1 to 3 substituents each independently selected from halogen, hydroxy and C j-C4alkoxy. More preferably
  • RI is C2-C alkyl optionally substituted with from 1 to 3 halogen atoms or a methoxy radical. Still more preferably RI is C2-C6alkyl. Still more preferably, RI is selected from ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, 3-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, 3,3-dimethylbutyl and 2-ethylbutyl. Most preferably RI is selected from n- propyl, n-butyl and isobutyl.
  • Preferred compounds of formula (IA) are those wherein R2 is H, Cj-C4alkyl
  • C4 lkyl and C[-C4alkoxy) or phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj-C4alkyl and Cj-C4alko ), or together with R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, C j-C4alkyl and Ci -C4alkoxy).
  • R2 is H, Ci -C2alkyl (optionally substituted with from 1 to 5 halogen atoms), Ci -C4alkyl-S(O) x - wherein x is 0 or 2 (optionally substituted with from 1 to 5 halogen atoms), Cj -C2al oxy (optionally substituted with from 1 to 5 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C2al yl and Cj -C2alkoxy) or phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj -C2alkyl and C ⁇ -C2alkoxy), or together with R3 forms a further benzene ring
  • R2 is H, methyl, trifluoromethyl, methylthio, tert-butylthio, trifluoromethylthio, methylsulfonyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyano, fluoro, chloro, bromo, phenyl or phenoxy, or together with R3 forms a further benzene ring.
  • Preferred compounds of formula (IA) are those wherein R2 is not H. More preferably, R2 is Cj -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), C ⁇ - 5 C4alkyl-S(O) x - wherein x is 0 or 2 (optionally substituted with from 1 to 7 halogen atoms), C ⁇ -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, C ⁇ -C4alkyl and C ⁇ C4alko y) or phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and
  • R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, C ⁇ -Q4alkyl and
  • R2 is C ⁇ -C2alkyl (optionally substituted with from 1 to
  • L5 halogen atoms L5 halogen atoms
  • cyano halogen
  • phenyl optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj -C2 lkyl and Cj-C2al oxy
  • phenoxy optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C2alkyl and C ⁇ -C2 l oxy
  • R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently 20 selected from halogen, Ci -C2alkyl and C ⁇ -C2alkoxy).
  • R2 is methyl, trifluoromethyl, methylthio, tert-butylthio, trifluoromethylthio, methylsulfonyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyano, fluoro, chloro, bromo, phenyl or phenoxy, or together with R3 forms a further benzene ring.
  • Preferred compounds of formula (IA) are those wherein R3 is H, C ⁇ -C4alkyl 5 (optionally substituted with from 1 to 7 halogen atoms), Ci-C ⁇ alkyl-S- (optionally substituted with from 1 to 7 halogen atoms), Cj-C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj-C4 l yl and C ⁇ -C4alko y), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj ⁇ alkyl and Ci -C4alkoxy) or -CO2(Ci -C4alkyl), or together with R2 or R4 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl
  • R3 is H, C ⁇ -C2alkyl (optionally substituted with from 1 to 5 halogen atoms), Ci -C2alkyl-S- (optionally substituted with from 1 to 5 halogen atoms), C ⁇ -C2alkoxy
  • R3 is H, methyl, trifluoromethyl, trifluoromethylthio, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyano, fluoro, chloro, bromo, phenyl, phenoxy or CO2CH3, or together with R2 or R4 forms a further benzene ring.
  • Preferred compounds of formula (IA) are those wherein R4 is H, C ⁇ -C4alkyl
  • Ci -C4alkyl-S- (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkyl-S- (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj -COalkyl and Ci -C4alkoxy), or -CO2(Ci -C4alkyl), or together with R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -
  • R4 is H, C ⁇ alkyl (optionally substituted with from 1 to 5 halogen atoms), Ci -C2alkyl-S- (optionally substituted with from 1 to 5 halogen atoms), C ⁇ C2alkoxy (optionally substituted with from 1 to 5 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C2alkyl and Cj-C2alkoxy), or -CO2(C ⁇ -
  • R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, C ⁇ -C2alkyl and C - C2alkoxy).
  • R4 is H, methyl, trifluoromethyl, methylthio, methoxy, trifluoromethoxy, cyano, fluoro, chloro, phenyl or CO2CH3, or together with R3 forms a further benzene ring.
  • Preferred compounds of formula (IA) are those wherein R5 is H, Ci -C4alkyl (optionally substituted with from 1 to 5 halogen atoms), Ci -C4alkoxy (optionally substituted with from 1 to 5 halogen atoms) or halogen. More preferably, R5 is H, Ci -
  • R5 is H, methyl, methoxy, fluoro or chloro.
  • Preferred compounds of formula (IA) are those wherein R6 is H, C ⁇ -C4alkyl (optionally substituted with from 1 to 5 halogen atoms) or halogen. More preferably, R6 is H, Cj-C4alkyl or halogen. Still more preferably, R6 is H, methyl, fluoro or chloro.
  • Preferred compounds of formula (IA) are those wherein the group
  • phenyl is phenyl, 2-methylphenyl, 2-(trifluoromethyl)phenyl, 2-(methylthio)phenyl, 2- (tertbutylthio)phenyl, 2-(trifluoromethylthio)phenyl, 2-(methylsulfonyl)phenyl, 2- methoxyphenyl, 2-ethoxyphenyl, 2-(difluoromethoxy)phenyl, 2- (trifluoromethoxy)phenyl, 2-cyanophenyl, 2-fluorophenyl, 2-chlorophenyl, 2- bromophenyl, 2-biphenyl, 2-phenoxyphenyl, 3-methylphenyl, 3-(trifluoromethyl)phenyl, 3-(trifluoromethylthio)phenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3- (difluoromethoxy)phenyl, 3-(trifluoiOmethoxy)phenyl, 3-cyanophenyl, 3-flu
  • a further embodiment provides a group (Group A) of compounds of formula (IA) 5 above, wherein R2, R3, R4, R5 and R6 are all H.
  • a further embodiment provides a group (Group B) of compounds of formula (IA) above, wherein one of R2, R3, R4, R5 and R6 is not H and the others are H.
  • Compounds of Group B include those (Group B2) wherein R3, R4, R5 and R6 are all H and R2 is C ⁇ -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Ci -
  • Compounds of Group B also include those (Group B3) wherein R2, R4, R5 and R6 are all H and R3 is Ci -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), C ⁇ -C4alkyl-S(O) x - wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms),
  • cyano halogen
  • phenyl optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and Ci -C4alkoxy
  • phenoxy optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -
  • Compounds of Group B also include those (Group B4) wherein R2, R3, R5 and 15 R6 are all H and R4 is Ci -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkyl-S(O) x - wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Cj ⁇ alko y (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj ⁇ alkyl and Ci -C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci - C4alkyl and Ci-C ⁇ alkoxy) or -CO2(Ci -COalkyl).
  • a further embodiment provides a group (Group C) of compounds of formula (IA) above, wherein two of R2, R3, R4, R5 and R6 are not H and the others are H.
  • 5 Compounds of Group C include those (Group C2,3) wherein R4, R5 and R6 are all H; R2 is C ⁇ -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Ci -
  • Ci -C4alkoxy or -CO2(Cj-C4alkyl), or together with R3 forms a further benzene ring
  • R3 is C] -C4alkyl (optionally substituted
  • Compounds of Group C also include those (Group C2,4) wherein R3, R5 and R6 are all H; R2 is Cj-C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Cj-
  • Compounds of Group C also include those (Group C2,5) wherein R3, R4 and R6 are all H; R2 is Cj-C4alkyl (optionally substituted with from 1 to 7 halogen atoms), C ⁇ - C4alkyl-S(O) x - wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and C;[-C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, C ⁇ -C4alkyl and C ⁇ -C4alkoxy) or -CO2(Ci-C4alkyl); and R5 is C ⁇ -C4alkyl (optionally substituted with from 1 to
  • Compounds of Group C also include those (Group C2,6) wherein R3, R4 and R5 are all H;
  • R2 is Ci -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), C - C4alkyl-S(O) x - wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), C ⁇ -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj-C4alkyl and Cj-C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and C ⁇ -C4alkoxy) or -CO2(C ⁇ -C4alkyl) ; and R6 is C 1 -C4alkyl (
  • Compounds of Group C also include those (Group C3,4) wherein R2, R5 and R6 are all H; R3 is Cj -C4 alkyl (optionally substituted with from 1 to 7 halogen atoms), C ⁇ - C4alkyl-S(O) x - wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), C1 -C4 alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj -C4alkyl and Ci -C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj -C4alkyl and
  • R4 is C ⁇ -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), C ⁇ -C4alkyl-S(O) x - wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), C ⁇ -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and C ⁇ -C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, C ⁇ C4alkyl and Ci -C4alkoxy) or -CO2(Ci -C4alkyl), or together with R3 forms
  • Compounds of Group C also include those (Group C3,5) wherein R2, R4 and R6 are all H; R3 is Ci -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), C -
  • Ci -C4alkoxy or -CO2(Ci -C4alkyl); and R5 is C ⁇ -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), C ⁇ -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms) or halogen.
  • n is preferably 1 or 2, more preferably 1.
  • R7 is preferably H or methyl, more preferably H.
  • R8 is preferably H.
  • R9 is preferably H or fluoro, more preferably H.
  • RIO is preferably H or fluoro, more preferably H.
  • RI is preferably a C2-
  • C1 ⁇ alkyl group optionally substituted with from 1 to 7 halogen substituents and/or with from 1 to 3 substituents each independently selected from hydroxy, cyano and C ⁇ -
  • n is preferably 1
  • R7, R8, R9 and RIO are preferably H and RI is preferably a C2-CiQalkyl group optionally substituted with from 1 to 7 halogen substituents and/or with from 1 to 3 substituents each independently selected from hydroxy, cyano and Ci -C4alkoxy.
  • Rx is H; Ry is H or C ⁇ -C 4 alkyl; each Rz is independently H or C ⁇ -C 4 alkyl; X represents O; Y represents OH or OR; R is C1-Q alkyl; Ari is a phenyl ring or a 5- or 6- membered heteroaryl ring each of which may be substituted with 1, 2, 3, 4 or 5 substituents (depending upon the number of available substitution positions) each independently selected from Ci -C4 alkyl, O(C ⁇ -C4 alkyl), S(Cj-C4 alkyl), halo, hydroxy, pyridyl, thiophenyl and phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci -C4 alkyl, or O(C ⁇ -C4 alkyl); and
  • Ar2 is a phenyl ring or a 5- or 6-membered heteroaryl ring each of which may be substituted with 1, 2, 3, 4 or 5 substituents (depending upon the number of available substitution positions) each independently selected from C1 -C4 alkyl, O(C ⁇ -C4 alkyl) and halo; wherein each above-mentioned C1-C4 alkyl group is optionally substituted with one or more halo atoms; or a pharmaceutically acceptable salt thereof.
  • Preferred compounds of formula (IB) above are those wherein Arj is phenyl, pyridyl, pyrimidyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiophenyl, furanyl, imidazolyl, triazolyl, oxadiazolyl or thiadiazolyl, each of which may be substituted with 1, 2, 3, 4 or 5 substituents (depending upon the number of available substitution positions) each independently selected from C1-C4 alkyl, O(C ⁇ -C4 alkyl), S(C- -C4 alkyl), halo, hydroxy, pyridyl, thiophenyl and phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci -C4 alkyl, or O(C ⁇ -C4 alkyl); and Ar2 is phenyl, pyridyl, pyrimid
  • Ari is a phenyl ring or a 5- or 6-membered heteroaryl ring substituted with 1, 2, 3, 4 or 5 substituents, more preferably with 1 or 2 substituents.
  • Preferred compounds of formula (IB) above are those wherein Ari includes a substituent attached at the 2- ⁇ osition. That is, the substituent is attached to the atom adjacent to that which forms the point of attachment of Ari to the methylene group connecting Ari to the rest of the molecule.
  • Ari is phenyl, it is preferably ortho-substituted.
  • Rx is H; Ry is H or C ⁇ -C 4 alkyl; each Rz is independently H or C ⁇ -C 4 alkyl; X represents O; Y represents OH or OR; R is C ⁇ -C 4 alkyl; and Ari and Ar2 are each independently selected from the group consisting of phenyl, and substituted phenyl; and pharmaceutically acceptable salts thereof.
  • the group Ar! may be substituted or unsubstituted phenyl.
  • Ari may be unsubstituted phenyl or, preferably phenyl substituted with 1, 2, 3, 4 or 5 substituents, preferably with 1 or 2, for example 1, substituent.
  • the substituted phenyl group When disubstituted, the substituted phenyl group is preferably substituted at the 2- and 5- positions. When monosubstituted, the substituted phenyl group is preferably substituted in the 2- position. Suitable substituents include Ci -C4 alkyl, O(C ⁇ -C4 alkyl), S(C ⁇ -C4 alkyl), halo, and phenyl, optionally substituted with, for example, halo, C1-C4 alkyl, or O(C]-C4 alkyl). In this further preferred embodiment, the group Ar 2 may be substituted or unsubstituted phenyl.
  • Ar 2 may be phenyl substituted with 1, 2, 3, 4 or 5 substituents, preferably with 1 substituent.
  • Suitable substituents include Ci -C4 alkyl, O(C ⁇ -C4 alkyl), and especially, halo.
  • Ci -C4 alkyl as used in respect of compounds of formula (IB) includes straight and branched chain alkyl groups of 1, 2, 3 or 4 carbon atoms, and may be unsubstituted or substituted. Ci -C2 alkyl groups are preferred. Suitable substituents include halo, especially Cl and/or F. Thus the term “Ci -C4 alkyl” includes haloalkyl. A particularly preferred substituted C j -C4 alkyl group is trifluoromethyl. Similar terms defining different numbers of C atoms (e.g. "Ci -C3 alkyl”) take an analogous meaning. When Ry is Ci -C4 alkyl it is preferably unsubstituted. When Rz is C1-C4 alkyl it is preferably unsubstituted. When R is C1-C4 alkyl it is preferably unsubstituted.
  • 5-membered heteroaryl ring as used in respect of compounds of formula (IB) means a 5-membered aromatic ring including at least one heteroatom independently selected from N, O and S. Preferably there are not more than three heteroatoms in total in the ring. More preferably there are not more than two heteroatoms in total in the ring. More preferably there is not more than one heteroatom in total in the ring.
  • the term includes, for example, the groups thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, triazolyl, oxadiazolyl and thiadiazolyl.
  • 6-membered heteroaryl ring as used in respect of compounds of formula (IB) means a 6-membered aromatic ring including at least one heteroatom independently selected from N, O and S. Preferably there are not more than three heteroatoms in total in the ring. More preferably there are not more than two heteroatoms in total in the ring. More preferably there is not more than one heteroatom in total in the ring.
  • the term includes, for example, the groups pyridyl, pyrimidyl, pyrazinyl, pyridazinyl and triazinyl.
  • Halo as used in respect of compounds of formula (IB) includes F, Cl, Br and I, and is preferably F or Cl.
  • “Pyridyl” as used in respect of compounds of formula (IB) includes 2-pyridyl, 3-pyridyl and 4-pyridyl.
  • “Pyrimidyl” as used in respect of compounds of formula (IB) includes 2- pyrimidyl, 4-pyrimidyl and 5- ⁇ yrimidyl.
  • “Pyridazinyl” as used in respect of compounds of formula (IB) includes 3- pyridazinyl and 4-pyridazinyl.
  • Pyrazinyl as used in respect of compounds of formula (IB) includes 2- pyrazinyl and 3- ⁇ yrazinyl.
  • Triazinyl as used in respect of compounds of formula (IB) includes 2-(l,3,5- triazinyl), 3-, 5- and 6-(l,2,4-triazinyl) and 4- and 5-(l,2,3-triazinyl).
  • Thiazolyl as used in respect of compounds of formula (IB) includes 2- thiazolyl, 4-thiazolyl and 5-thiazolyl.
  • Isothiazolyl as used in respect of compounds of formula (IB) includes 3- isothiazolyl, 4-isothiazolyl, and 5-isothiazolyl.
  • Oxazolyl as used in respect of compounds of formula (LB) includes 2- oxazolyl, 4-oxazolyl and 5-oxazolyl.
  • Isoxazolyl as used in respect of compounds of formula (IB) includes 3- isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl.
  • Thiophenyl as used in respect of compounds of formula (IB) includes 2- thiophenyl and 3-thiophenyl.
  • “Furanyl” as used in respect of compounds of formula (IB) includes 2-furanyl and 3-furanyl.
  • “Pyrrolyl” as used in respect of compounds of formula (IB) includes 2-pyrrolyl and 3-pyrrolyl.
  • Imidazolyl as used in respect of compounds of formula (IB) includes 2- imidazolyl and 4-imidazolyl.
  • Triazolyl as used in respect of compounds of formula (IB) includes 1- triazolyl, 4-triazolyl and 5-triazolyl.
  • Oxadiazolyl as used in respect of compounds of formula (IB) includes 4- and 5-(l,2,3-oxadiazolyl), 3- and 5-(l,2,4-oxadiazolyl), 3-(l,2,5-oxadiazolyl), 2-(l,3,4- oxadiazolyl).
  • Thiadiazolyl as used in respect of compounds of formula (IB) includes 4- and 5-(l,2,3-thiadiazolyl), 3- and 5-(l,2,4-thiadiazolyl), 3-(l,2,5-thiadiazolyl), 2-(l,3,4- thiadiazolyl).
  • Ry is preferably H or Me. More preferably Ry is H.
  • each Rz is preferably H or Me with
  • Rz being Me. More preferably only 1 Rz is Me. Most preferably all Rz are H.
  • Y is preferably OH or OMe. More preferably, Y is OH.
  • a preferred group of compounds of formula (IB) is represented by the formula (HB)
  • Ri and R2 are each independently selected from H, Ci -C4 alkyl, O(C ⁇ -C4 alkyl), S(C ⁇ -C4 alkyl), halo and phenyl; and R3 is selected from H, C1-C4 alkyl and halo; and pharmaceutically acceptable salts thereof.
  • Ri is preferably Ci -C3 alkyl
  • R2 is preferably H.
  • R2 is also preferably F.
  • R3 is preferably H.
  • Especially preferred compounds of formula (IB) are l-morpholin-2-yl-l-phenyl-2- (2-trifluoromethoxy-phenyl)-ethanol and 2-(5-fluoro-2-mefhoxy-phenyl)- 1 -morpholin-2- yl-1-phenyl-ethanol.
  • the (S,R) stereoisomer is preferred.
  • the preferred salt form is the hydrochloride salt.
  • C4 alkyl group a C3-C6 cycloalkyl group or a CH 2 (C3-C6 cycloalkyl) group.
  • A is S.
  • Ar is phenyl substituted with 1, 2, 3, 4 or 5 substituents, more preferably with 1 or 2 substituents.
  • Ar is a substituted phenyl, it is preferred that not more than one of those substituents is a pyridyl, thiophenyl or optionally substituted phenyl group.
  • Preferred compounds of formula (IC) above are those wherein Ar is ortho-substituted. Further preferred compounds of formula (IC) above are those of formula (ICa)
  • R 1 is independently H or Ci -C4 alkyl; and pharmaceutically acceptable salts thereof.
  • the group Ar may be substituted or unsubstituted phenyl.
  • Ar may be unsubstituted phenyl or, preferably phenyl substituted with 1, 2, 3, 4 or 5 substituents, preferably with 1 or 2, for example 1, substituent.
  • the substituted phenyl group is preferably substituted at the 2- and 5- positions
  • the substituted phenyl group is preferably substituted in the 2- position.
  • Suitable substituents include Ci -C4 alkyl, O(C ⁇ -G4 alkyl), S(C ⁇ -C4 alkyl), halo, and phenyl optionally substituted with, for example, halo, C1-C4 alkyl, or O(C ⁇ -C4 alkyl).
  • the group X may be substituted or unsubstituted phenyl.
  • X may be phenyl substituted with 1, 2, 3, 4 or 5 substituents, preferably with 1 substituent.
  • Suitable substituents include Ci -C4 alkyl,
  • C1 -C4 alkyl as used in respect of compounds of formula (IC) includes straight and branched chain alkyl groups of 1, 2, 3 or 4 carbon atoms, and may be unsubstituted or substituted. Ci -C2 alkyl groups are preferred. Suitable substituents include halo. Thus the term “Ci -C4 alkyl” includes haloalkyl. Similar terms defining different numbers of C atoms (e.g. "C1-C3 alkyl”) take an analogous meaning. When R' is Ci -C4 alkyl it is preferably unsubstituted. When R 1 is C ⁇ -C4 alkyl it is preferably unsubstituted.
  • C3-C6 cycloalkyl as used in respect of compounds of formula (IC) includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Halo as used in respect of compounds of formula (IC) includes F, Cl, Br and I, and is preferably F or Cl.
  • “Pyridyl” as used in respect of compounds of formula (IC) includes 2-pyridyl, 3- pyridyl and 4-pyridyl.
  • “Thiophenyl” as used in respect of compounds of formula (IC) includes 2- thiophenyl and 3 -thiophenyl.
  • R ' is preferably H or Me. More preferably R ' is H.
  • each R 1 is preferably H or Me with 0, 1, 2 or 3 of R 1 being Me. More preferably only 1 R 1 is Me. Most preferably all R 1 are H.
  • R' and all R 1 are H.
  • -C4 alkyl group for the group Ar is trifluoromethyl.
  • a preferred group of compounds of formula (IC) is represented by the formula
  • R2 and R3 are each independently selected from H, C1 -C4 alkyl, O(C ⁇ -C4 alkyl), S(C ⁇ -C4 alkyl), halo and phenyl; and R4 is selected from H and C1-C4 alkyl; and pharmaceutically acceptable salts thereof.
  • R2 is preferably Ci -C3 alkyl (especially trifluoromethyl), O(C ⁇ -C3 alkyl) (especially methoxy or trifluoromethoxy), F or Ph.
  • R3 is preferably H.
  • R3 is also preferably F.
  • R4 is preferably H.
  • -X- is -C(R 4 R 5 )-, -O- or -S-; n is 2 or 3; R 1 is H or C C 4 alkyl; R 3 is H, halo, - C alkyl, O(C ⁇ -C 4 alkyl), nitrile, phenyl or substituted phenyl; R 4 and R 5 are each independently selected from H or C ⁇ -C 4 alkyl; Ar- is selected from the group consisting of
  • R 2a is H, halo, methyl or ethyl
  • R 2b is H, halo or methyl
  • R 2c is H, halo, methyl, trifluoromethyl, nitrile, or methoxy
  • R 2d is H, halo, methyl or ethyl
  • R 2e is H, halo, methyl, trifluoromethyl, nitrile, or methoxy
  • R 2f is H, or fluoro
  • -Y- is -O-, -S- or -N(R 6 )-
  • R 6 is H or methyl and pharmaceutically acceptable salts thereof.
  • Ci -C4 alkyl as used in respect of compounds of formula (TD) includes straight and branched chain alkyl groups of 1, 2, 3 or 4 carbon atoms.
  • Ci -C4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl and tert-butyl.
  • Ci -C2 alkyl groups are preferred.
  • a particularly preferred Ci -C4 alkyl group is methyl or ethyl.
  • halo as used in respect of compounds of formula (ID) includes F, Cl, Br and I, and is preferably F or Cl.
  • substituted phenyl as used in respect of compounds of formula (ID) means phenyl substituted with 1, 2, 3, 4 or 5 substituents, preferably with 1 or 2, for example 1, substituent. Suitable substituents include C1 -C4 alkyl, O(C ⁇ -C4 alkyl), S(C ⁇ -
  • C4 alkyl C4 alkyl
  • halo C1-C4 alkyl
  • phenyl optionally substituted with, for example, C1-C4 alkyl, O(C ⁇ -
  • O(C ⁇ -C4 alkyl) or S(C ⁇ -C4 alkyl) as used in respect of compounds of formula (ID) mean a C1-C4 alkyl group as defined above linked to the point of substitution via an oxygen or a sulphur atom.
  • An O(C ⁇ -C4 alkyl) or S(C ⁇ -C4 alkyl) group includes for example methoxy, ethoxy, thiomethyl or thioethyl.
  • Another group of preferred compounds of formula (ID) or (IDa) are compounds wherein Ar is (ii) and -Y- is -S-. More preferably Ar is 2-thiophenyl or 3-thiophenyl.
  • a further preferred group of compounds of formula (ID) is represented by the formula (DD)
  • n 2 or 3;
  • R 1 is H or - alkyl;
  • R 3 is H, halo, phenyl or substituted phenyl;
  • R 2a is H, halo, methyl or ethyl;
  • R 2b is H, halo or methyl; and pharmaceutically acceptable salts thereof.
  • Preferred compounds of formulae (ID), (IDa) and (HD) are those wherein n is 3, or wherein R 1 is H, methyl, ethyl or n-propyl, or wherein R 3 is H or halo.
  • R 1 is C ⁇ -C 6 alkyl (optionally substituted with 1, 2 or 3 halo substituents and/or with 1 substituent selected from -S-(C ⁇ -C 3 alkyl), -O-(C ⁇ -C 3 alkyl) (optionally substituted with 1, 2 or 3 F atoms), -O-(C 3 -C 6 cycloalkyl), -SO 2 -(C ⁇ -C 3 alkyl), -CN, -COO-(d-C 2 alkyl) and -OH); C 2 -C 6 alkenyl; -(CH 2 ) q -Ar 2 ; or a group of formula (i) or (ii)
  • R 2 , R 3 and R 4 are each independently selected from hydrogen or C ⁇ -C 2 alkyl;
  • R 5 , R 6 , R 7 and R are at each occurrence independently selected from hydrogen or C ⁇ -C alkyl;
  • -Y- is a bond, -CH 2 - or -O-;
  • -Z is hydrogen, -OH or -O-(C ⁇ -C 3 alkyl);
  • p is 0, 1 or 2;
  • q is 0, 1 or 2;
  • r is 0 or 1;
  • s is 0, 1, 2 or 3;
  • t is 0, 1, 2 or 3;
  • Ar 2 is naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl, wherein said naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl may be substituted with 1, 2 or 3 substituents each independently selected from halo, C ⁇ -C alkyl
  • C2-Cg alkenyl means a monovalent unsubstituted unsaturated straight-chain or branched-chain hydrocarbon radical having from 2 to 6 carbon atoms and containing at least one carbon-carbon double bond.
  • C3-C6 cycloalkyl means a monovalent unsubstituted saturated cyclic hydrocarbon radical having from 3 to 6 carbon atoms.
  • Ci -Cg alkylene means a divalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from
  • halo or halogen means F, Cl, Br or I.
  • Ci -C4 difluoroalkyl means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 carbon atoms wherein two hydrogen atoms are substituted with two fluoro atoms.
  • the two fluoro atoms are attached to the same carbon atom.
  • C1-C4 trifluoroalkyl means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 carbon atoms wherein three hydrogen atoms are substituted with three fluoro atoms. Preferably the three fluoro atoms are attached to the same carbon atom.
  • phenoxy means a monovalent unsubstituted phenyl radical linked to the point of substitution by an O atom.
  • pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl.
  • furyl includes 2-furyl and 3-furyl. 2-furyl is preferred.
  • thiophenyl includes 2-thiophenyl and 3- thiophenyl.
  • thiazolyl includes 2-thiazolyl, 4-thiazolyl and 5-thiazolyl.
  • pyrazole includes 1 -pyrazole, 3-pyrazole and 4-pyrazole. 1 -pyrazole is preferred.
  • benzothiophenyl includes 2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b] thiophenyl and 7-benzo[b]thiophenyl.
  • naphthyl includes 1 -naphthyl, and 2- naphthyl. 1 -naphthyl is preferred.
  • Ci -C4 alkyl and C1-C3 alkyl mean a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 and 1 to 3 carbon atoms respectively.
  • the term "Ci -C4 alkyl” includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.
  • C1-C3 alkyl includes methyl, ethyl, n-propyl and iso-propyl.
  • each R 5 and/or each R 6 can be different.
  • each R 7 and/or each R 8 can be different.
  • Preferred compounds of formula (IE) are those wherein R 1 is C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, -(CH 2 ) m -CF 3 , -(CH 2 ) compassion-S-(C,-C 3 alkyl), ⁇ CH 2 -COO-(d-C 2 alkyl), -(d-C 5 alkylene)-O-(d-C 3 alkyl), -(C 1 -C 5 alkylene)-O-(C 3 -C 6 cycloalkyl), -(d-C 5 alkylene)- SO 2 -(d-C 3 alkyl), -(Q-C 5 alkylene)-OCF 3 , -(Ci- alkylene)-OH, -(C1-C 5 alkylene)-CN,
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , -X-, -Y-, p, q, r and s have the values defined above; m is 1, 2 or 3; n is 1, 2 or 3; t is 2, 3 or 4; -Ari is phenyl, pyridyl, thiazolyl or naphthyl; wherein said phenyl, pyridyl or thiazolyl group may be substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl, cyano, C ⁇ -C 4 alkyl, -O-(C ⁇ -C 4 alkyl), - O-(C C 4 difluoroalkyl), -O-(C C 4 trifluoroalkyl), -S-(C C 4 alkyl), -S-(d-C 2 trifluoroalkyl
  • Preferred compounds of formula (IE) are those wherein R is hydrogen.
  • R 3 and R 4 are hydrogen. More preferably R 2 , R 3 and R 4 are hydrogen.
  • Preferred compounds of formula (IE) are those wherein each R 5 and R 6 is
  • each R and R is hydrogen. More preferably
  • R 5 , R 6 , R 7 and R 8 are hydrogen.
  • Preferred compounds of formula (IE) are those wherein R 1 is C ⁇ -C 6 alkyl. More preferably R 1 is n-propyl, 1-methylethyl, 2-methylpropyl, 3,3-dimethylpropyl.
  • Preferred compounds of formula (IE) are those wherein R 1 is -(C 4 -C 5 alkylene)- OH. More preferably R 1 is 2,2-dimethyl-2-hydroxyethyl or 3,3-dimethyl-3- hydroxypropyl.
  • Preferred compounds of formula (IE) are those wherein R is a group of formula (i) and each R and R is hydrogen. More preferably each R , R , R and R is hydrogen.
  • Preferred compounds of formula (IE) are those wherein R 1 is a group of formula (ii) and each R and R is hydrogen. More preferably each R , R , R and R is hydrogen.
  • Preferred compounds of formula (IE) are those wherein R 1 is a group of formula (i), r is 0, s is 2, t is 2, -Z is hydrogen and -X- is -O-, -S- or -SO 2 -. More preferably R 1 is a group of formula (i), r is 0, s is 2, t is 1 or 2, -Z is hydrogen and -X- is -O-.
  • Preferred compounds of formula (IE) are those wherein R 1 is a group of formula (i), r is 0, s is 1, 2 or 3, t is 1, -Z is hydrogen and -X- is -CH 2 -.
  • Preferred compounds of formula (IE) are those wherein R 1 is a group of formula (i), r is 1, s is 0, 1, 2 or 3, t is 1, -Z is hydrogen and -X- is -CH 2 -.
  • Preferred compounds of formula (IE) are those wherein R 1 is a group of the formula (ia). More preferably R 1 is a group of the formula (ia) and each R 5 , R 6 , R 7 and R 8 is hydrogen.
  • Preferred compounds of formula (IE) are those wherein R 1 is a group of the formula (ib). More preferably R 1 is a group of the formula (ib), r is 1, t is 3, and each
  • R 7 and R 8 is hydrogen.
  • Preferred compounds of formula (IE) are those wherein R 1 is -(CH 2 ) m -CF 3 . More preferably R 1 is -(CH 2 ) m -CF 3 and m is 1, 2, or 3.
  • Preferred compounds of formula (IE) are those wherein R 1 is -(CH 2 ) n -S-(C ⁇ -C 3 alkyl). More preferably R 1 is -(CH 2 ) 3 -S-CH 3 .
  • Preferred compounds of formula (IE) are those wherein R 1 is -CH 2 -COO-(C ⁇ -C 2 alkyl). More preferably R 1 is -CH 2 -COOCH 3 .
  • Preferred compounds of formula (IE) are those wherein R 1 is -(C1-C 5 alkylene)-O-(C ⁇ -C 3 alkyl). More preferably R 1 is -(C3-C4 alkylene)-OCH 3 . Preferred compounds of formula (IE) are those wherein R 1 is -(C 1 -C 5 alkylene)-O-(C 3 -C 6 cycloalkyl). More preferably R 1 is -CH 2 -CH 2 -O-cyclobutyl.
  • Preferred compounds of formula (IE) are those wherein R 1 is -(C 1 -C 5 alkylene)-SO 2 -(C ⁇ -C 3 alkyl).
  • Preferred compounds of formula (IE) are those wherein R 1 is -(C 1 -C 5 alkylene)-OCF 3 . More preferably R 1 is -CH 2 -CH 2 -OCF 3 .
  • Preferred compounds of formula (IE) are those wherein R 1 is -(C 1 -C 5 alkylene)-CN. More preferably R 1 is -(C -C 4 alkylene)-CN. Most preferably -CH 2 -CH 2 -CN or -CH 2 -C(CH 3 ) 2 -CN.
  • Preferred compounds of formula (IE) are those wherein R 1 is -(CH 2 ) q -Ar 2 , and q is 1. More preferably R 1 is -(CH 2 ) q -Ar 2 , q is 1 and -Ar 2 is pyridyl, phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl or C ⁇ -C 4 alkyl.
  • Preferred compounds of formula (IE) are those wherein -Ari is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and C ⁇ -C 4 alkyl and/or with 1 substituent selected from phenyl, phenyl substituted with 1, 2 or 3 halo substituents, pyridyl, pyrazole, phenoxy and phenoxy substituted with 1, 2 or 3 halo substituents; pyridyl; or pyridyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and d-Q alkyl and/or with 1 substituent selected from phenyl and phenyl substituted with 1, 2 or 3 halo substituents.
  • More preferably -Ar ! is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and C ⁇ -C 4 alkyl and/or with 1 substituent selected from phenyl, phenyl substituted with 1, 2 or 3 halo substituents, pyridyl, pyrazole, phenoxy and phenoxy substituted with 1, 2 or 3 halo substituents.
  • -Ari is phenyl substituted with 1 or 2 substituents each independently selected from halo, trifluoromethyl and C ⁇ -C 4 alkyl and/or with 1 substituent selected from phenyl, phenyl substituted with 1, 2 or 3 halo substituents, pyridyl, pyrazole, phenoxy and phenoxy substituted with 1, 2 or 3 halo substituents.
  • Suitable -Ari groups include, for example, 2-methylthiophenyl, 2-methylphenyl,
  • Preferred compounds of formula (IE) are those wherein -Ari is pyridyl or pyridyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and C ⁇ -C 4 alkyl and/or with 1 substituent selected from phenyl and phenyl substituted with 1, 2 or 3 halo substituents. More preferably -Ari is pyridyl substituted with 1 or 2 substituents each independently selected from halo, trifluoromethyl and C ⁇ -C 4 alkyl and/or with 1 substituent selected from phenyl and phenyl substituted with 1, 2 or 3 halo substituents.
  • Suitable -Ari groups include, for example, 3-phenyl-2-pyridyl. In general when -Ari s a substituted pyridyl, substituted 2-pyridyl is preferred. 9. A compound of formula (IF)
  • R 1 is C ⁇ -C 6 alkyl (optionally substituted with 1, 2 or 3 halo substituents and/or with 1 substituent selected from -S-(C ⁇ -C 3 alkyl), -O-(C ⁇ -C 3 alkyl) (optionally substituted with 1, 2 or 3 F atoms), -O-(C 3 -C 6 cycloalkyl), -SO 2 -(C C 3 alkyl), -CN, -COO-(C ⁇ C 2 alkyl) and -OH); C 2 -C 6 alkenyl; -(CH 2 ) q -Ar 2 ; or a group of formula (i) or (ii)
  • R 2 , R 3 and R 4 are each independently selected from hydrogen or C ⁇ -C 2 alkyl;
  • R 5 , R 6 , R 7 and R 8 are at each occurrence independently selected from hydrogen or C ⁇ -C 2 alkyl;
  • -Y- is a bond, -CH 2 - or -O-;
  • -Z is hydrogen, -OH or -O-(C ⁇ -C 3 alkyl);
  • p is 0, 1 or 2;
  • q is 0, 1 or 2;
  • r is 0 or 1;
  • s is 0, 1, 2 or 3;
  • t is 0, 1, 2 or 3;
  • Ari is phenyl, pyridyl, thiazolyl, benzothiophenyl or naphthyl; wherein said phenyl, pyridyl or
  • C2-Cg alkenyl means a monovalent unsubstituted unsaturated straight-chain or branched-chain hydrocarbon radical having from 2 to 6 carbon atoms and containing at least one carbon-carbon double bond.
  • C3-C6 cycloalkyl means a monovalent unsubstituted saturated cyclic hydrocarbon radical having from 3 to 6 carbon atoms.
  • C ⁇ -Cg alkylene means a divalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 6 carbon atoms.
  • halo or “halogen” means F, Cl, Br or I.
  • C1-C4 difluoroalkyl means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 carbon atoms wherein two hydrogen atoms are substituted with two fluoro atoms. Preferably the two fluoro atoms are attached to the same carbon atom.
  • C1-C4 trifluoroalkyl means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 carbon atoms wherein three hydrogen atoms are substituted with three fluoro atoms. Preferably the three fluoro atoms are attached to the same carbon atom.
  • phenoxy means a monovalent unsubstituted phenyl radical linked to the point of substitution by an O atom.
  • pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl.
  • furyl includes 2-furyl and 3-furyl. 2-furyl is preferred.
  • thiophenyl includes 2-thiophenyl and 3- thiophenyl.
  • thiazolyl includes 2-thiazolyl, 4-thiazolyl and 5 -thiazolyl.
  • pyrazole includes 1 -pyrazole, 3-pyrazole and 4-pyrazole. 1 -pyrazole is preferred.
  • benzothiophenyl includes 2- benzo[b]thiophenyl, 3 -benzo[b] thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl and 7-benzo[b]thiophenyl.
  • naphthyl includes 1 -naphthyl, and 2- naphthyl. 1 -naphthyl is preferred.
  • C1-C4 alkyl and “Ci -C3 alkyl” mean a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 and 1 to 3 carbon atoms respectively.
  • the term “C1-C4 alkyl” includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.
  • Ci -C3 alkyl includes methyl, ethyl, n-propyl and iso-propyl.
  • each R and/or each R can be different. In the same way when t is 2 or 3, then each R and/or each R 8 can be different.
  • Preferred compounds of formula (IF) are those of formula (IF')
  • Preferred compounds of formula (IF) are those wherein R 1 is C ⁇ -C 6 alkyl, C -C 6 alkenyl, -(CH 2 ) m -CF 3 , -(CH 2 ) n -S-(C C 3 alkyl), -CH 2 -COO-(C ⁇ -C 2 alkyl), -(C ⁇ -C 5 alkylene)-O-(C ⁇ -C 3 alkyl), -(C ⁇ -C 5 alkylene)-O-(C 3 -C 6 cycloalkyl), -(C ⁇ -C 5 alkylene)- SO 2 -(C ⁇ -C 3 alkyl), -(d-C 5 alkylene)-OCF 3 , -(d-C 6 alkylene)-OH, -(d-C 5 alkylene)-CN, -(CH 2 ) q -Ar 2 or a group of formula (ia), (ib) or (ii)
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , -X-, -Y-, p, q, r and s have the values defined above; m is 1, 2 or 3; n is 1, 2 or 3; t is 2, 3 or 4; -Ari is phenyl, pyridyl, thiazolyl or naphthyl; wherein said phenyl, pyridyl or thiazolyl group may be substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl, cyano, C 1 -C alkyl, -O-(C ⁇ -C 4 alkyl), - O-(d-C 4 difluoroalkyl), -O-(C!-C 4 trifluoroalkyl), -S-(d-C 4 alkyl), -S-(C C 2 trifluoro
  • Preferred compounds of formula (IF) are those wherein R 2 is hydrogen.
  • R 3 and R 4 are hydrogen. More preferably R 2 , R 3 and R 4 are hydrogen.
  • Preferred compounds of formula (IF) are those wherein each R 5 and R 6 is hydrogen. In another preferred embodiment each R 7 and R 8 is hydrogen. More preferably R 5 , R 6 , R 7 and R 8 are hydrogen.
  • Preferred compounds of formula (IF) are those wherein R 1 is C ⁇ -C 6 alkyl. More preferably R 1 is n-propyl, 1-methylethyl (i-propyl), 2-methylpropyl (i-butyl), 2- methylbutyl, 2,2-dimethylbutyl.
  • Preferred compounds of formula (IF) are those wherein R 1 is -(C -C 5 alkylene)- OH. More preferably R 1 is 2,2-dimethyl-2-hydroxyethyl or 3,3-dimethyl-3- hydroxypropyl. Preferred compounds of formula (IF) are those wherein R 1 is a group of formula
  • each R 5 and R 6 is hydrogen. More preferably each R 5 , R 6 , R 7 and R 8 is hydrogen.
  • Preferred compounds of formula (IF) are those wherein R 1 is a group of formula (ii) and each R 5 and R 6 is hydrogen. More preferably each R 5 , R 6 , R 7 and R 8 is hydrogen.
  • Preferred compounds of formula (IF) are those wherein R 1 is a group of formula (i), r is 0 or 1, s is 2, t is 1 or 2, -Z is hydrogen and -X- is -O-, -S- or -SO 2 -. More preferably R 1 is a group of formula (i), r is 0 or 1, s is 2, t is 1 or 2, -Z is hydrogen and - X- is -O-, for example tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl or (tetrahydrofuran-3-yl)methyl.
  • R 1 is a group of formula (i), r is 0, s is 2, t is 1 or 2, -Z is hydrogen and -X- is -O-, for example tetrahydro-2H-pyran-4-yl or tetrahydrofuran-3-yl.
  • Preferred compounds of formula (IF) are those wherein R 1 is a group of formula (i), r is 0, s is 1, 2 or 3, t is 1, -Z is hydrogen and -X- is -C ⁇ 2 -, for example cyclobutyl, cyclopentyl or cyclohexyl.
  • Preferred compounds of formula (IF) are those wherein R 1 is a group of formula (i), r is 1, s is 0, 1, 2 or 3, t is 1, -Z is hydrogen and -X- is -CH 2 -.
  • Preferred compounds of formula (IF) are those wherein R 1 is a group of the formula (ia). More preferably R 1 is a group of the formula (ia) and each R 5 , R 6 , R 7 and R 8 is hydrogen.
  • Preferred compounds of formula (IF) are those wherein R 1 is a group of the formula (ib). More preferably R 1 is a group of the formula (ib), r is 1, t is 3, and each R 7 and R 8 is hydrogen. Preferred compounds of formula (IF) are those wherein R 1 is -(CH 2 ) m -CF 3 . More preferably R 1 is -(CH ) m -CF 3 and m is 1, 2, or 3.
  • Preferred compounds of formula (IF) are those wherein R 1 is -(CH 2 ) n -S-(C ⁇ -C alkyl). More preferably R 1 is -(CH 2 ) 3 -S-CH 3 .
  • Preferred compounds of formula (IF) are those wherein R 1 is -CH 2 -COO-(d-C 2 alkyl). More preferably R 1 is -CH 2 -COOCH 3 .
  • Preferred compounds of formula (IF) are those wherein R 1 is -(C 1 -C 5 alkylene)-O- (d-C 3 alkyl). More preferably R 1 is -(C 3 -C 4 alkylene)-OCH 3 .
  • Preferred compounds of formula (IF) are those wherein R 1 is -(C1-C 5 alkylene)-O- (C 3 -C 6 cycloalkyl). More preferably R 1 is -CH 2 -CH 2 -O-cyclobutyl. Preferred compounds of formula (IF) are those wherein R 1 is -(C1-C 5 alkyl ene)-
  • Preferred compounds of formula (IF) are those wherein R 1 is -(C1-C 5 alkylene)- OCF 3 . More preferably R 1 is -CH 2 -CH 2 -OCF 3 .
  • Preferred compounds of formula (IF) are those wherein R 1 is -(C1-C 5 alkylene)- CN. More preferably R 1 is -(C 2 -C 4 alkylene)-CN. Most preferably -CH 2 -CH 2 -CN or
  • Preferred compounds of formula (IF) are those wherein R 1 is -(CH 2 ) q -Ar 2 , and q is 1. More preferably R 1 is -(CH 2 ) q -Ar 2 , q is 1 and -Ar 2 is pyridyl, phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl, d-C 4 alkyl or O-(d-C 4 alkyl).
  • Preferred compounds of formula (IF) are those wherein -An is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and C ⁇ -C 4 alkyl and/or with 1 substituent selected from phenyl, phenyl substituted with 1, 2 or 3 halo substituents, pyridyl, pyrazole, phenoxy and phenoxy substituted with 1, 2 or 3 halo substituents; pyridyl; or pyridyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and C ⁇ -C 4 alkyl and/or with 1 substituent selected from phenyl and phenyl substituted with 1, 2 or 3 halo substituents.
  • -Ari is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and C]-C 4 alkyl and/or with 1 substituent selected from phenyl, phenyl substituted with 1, 2 or 3 halo substituents, pyridyl, pyrazole, phenoxy and phenoxy substituted with 1, 2 or 3 halo substituents.
  • -Ari is phenyl substituted with 1 or 2 substituents each independently selected from halo, trifluoromethyl and C ⁇ -C 4 alkyl and/or with 1 substituent selected from phenyl, phenyl substituted with 1, 2 or 3 halo substituents, pyridyl, pyrazole, phenoxy and phenoxy substituted with 1, 2 or 3 halo substituents.
  • Suitable -Ari groups include, for example, 2-methylthiophenyl, 2-methylphenyl, 2- fluorophenyl, 2-chlorophenyl, 2-isopropoxyphenyl, 2-trifluoromethylphenyl, 2- difluoromethoxyphenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-(l,l'-biphenyl), 2- phenoxyphenyl, 2-benzylphenyl, 3-trifiuoromethoxyphenyl, 3-chlorophenyl, 3- trifluoromethylphenyl, 3-methylphenyl, 3-trifluorothiomethoxyphenyl, 3-methoxyphenyl, 4- trifluoromethylphenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-dichlorophenyl, 3,5- dimethylphenyl, 3-trifluoromethyl-5-fluorophenyl, 3,5-difluorophenyl, 2,3- dichloropheny
  • Preferred compounds of formula (IF) are those wherein -Ari is pyridyl or pyridyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and C ⁇ -C 4 alkyl and/or with 1 substituent selected from phenyl and phenyl substituted with 1, 2 or 3 halo substituents. More preferably -Ari is pyridyl substituted with 1 or 2 substituents each independently selected from halo, trifluoromethyl and C ⁇ -C 4 alkyl and/or with 1 substituent selected from phenyl and phenyl substituted with 1, 2 or 3 halo substituents.
  • Suitable -Ari groups include, for example, 3-phenyl-2-pyridyl. In general when -Ari is a substituted pyridyl, substituted 2-pyridyl is preferred. 10.
  • a compound of formula (IG) is preferred.
  • IG wherein -X- is -S- or -O-; each R is independently selected from H or C ⁇ -C 4 alkyl; R 1 is H,
  • R is C ⁇ -C 4 alkyl, phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C ⁇ -C 4 alkyl, C ⁇ -C 4 alkoxy, nitro, hydroxy, cyano, halo, trifluoromethyl, trifluoromethoxy, benzyl, benzyloxy, -NR >6° ⁇ Rj7', -CONR 6° n Rl', COOR°, -SO 2 NR >6°Rr>7' and -SO 2 R°;
  • R 5 is selected from C ⁇ -C 4 alkyl, C ⁇ -C alkoxy, carboxy, nitro, hydroxy, cyano, halo, trifluoromethyl, trifluoromethoxy, benzyl, benzyloxy, -NR 8 R 9 , -CONR 8 R 9 , -SO NR 8 R 9 and - SO 2 R 8 ;
  • C C 4 alkyl means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 carbon atoms.
  • d-C 4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • d-C 4 alkoxy means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 carbon atoms linked to the point of substitution by an O atom.
  • C4 alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec- butoxy.
  • halo or halogen means F, Cl, Br or I.
  • Preferred compounds of formula (IG) are those wherein -X- is -S-.
  • Preferred compounds of formula (IG) are those wherein -X- is -O-.
  • Preferred compounds of formula (IG) are those wherein R 2 is phenyl.
  • Preferred compounds of formula (IG) are those wherein all R groups are hydrogen.
  • Preferred compounds of formula (IG) are those represented by the formula (UG)
  • R 1 is H, C 1 -C 4 alkyl, C1-C4 alkoxy, halo, cyano, trifluoromethyl, trifluoromethoxy, NR 3 R 4 , -CONR 3 R 4 , -COOR 3 or a group of the formula (i)
  • R 5 is selected from d-C alkyl, C ⁇ -C 4 alkoxy, carboxy, nitro, hydroxy, cyano, halo, trifluoromethyl, trifluoromethoxy, benzyl, benzyloxy, -NR 8 R 9 , -CONR 8 R 9 , -SO 2 NR 8 R 9 and - SO 2 R 8 ;
  • R 3 , R 4 , R 8 and R 9 are each independently selected from H or Q- C 4 alkyl; -Z- is a bond, -CH 2 -, or -O-; or a pharmaceutically acceptable salt thereof.
  • Preferred compounds of formula (IG) or (EG) are those wherein the substituent R 1 is in the three position of the pyridine ring as numbered in formula (IG) above. More preferably said substituent R 1 is H, d-C 4 alkyl, halo, cyano, -CONR 3 R 4 , trifluoromethyl or a group of the formula (i). When R 1 is -CONR 3 R 4 , then R 3 and R 4 are both preferably H. When R 1 is Q- C 4 alkyl, then it is preferably methyl. Preferred compounds of formula (IG) or (EG) are those wherein the substituent R 1 is a group of the formula (i).
  • Preferred compounds of formula (IG) or (UG) are those wherein R 1 is a group of the formula (i), -Z- is a bond, and R 5 is H or halo.
  • Preferred compounds of formula (IG) or (EG) are those wherein R 1 is a group of the formula (i), -Z- is -CH 2 - or -O-, and R 5 is H.
  • Preferred compounds of formula (IG) or (EG) are those wherein the substituent R 1 is in the five position of the pyridine ring as numbered in formula (IG) above. More preferably said substituent R 1 is selected from bromo, chloro or iodo.
  • Formulae (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above are selective inhibitors of norepinephrine reuptake.
  • Biogenic amine transporters control the amount of biogenic amine neurotransmitters in the synaptic cleft. Inhibition of the respective transporter leads to a rise in the concentration of that neurotransmitter within the synaptic cleft.
  • Formulae (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above and their pharmaceutically acceptable salts preferably exhibit a Kj value less than 500nM at the norepinephrine transporter as determined using the scintillation proximity assay as described below. More preferred compounds of Formulae (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above and their pharmaceutically acceptable salts exhibit a Kj value less than lOOnM at the norepinephrine transporter.
  • these compounds selectively inhibit the norepinephrine transporter relative to the serotonin and dopamine transporters by a factor of at least five, more preferably by a factor of at least ten.
  • the compounds of Formulae (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above of the present invention are preferably acid stable.
  • they have a reduced interaction (both as substrate and inhibitor) with the liver enzyme Cytochrome P450 (CYP2D6). That is to say, they preferably exhibit less than 75% metabolism via the liver enzyme Cytochrome P450 (CYP2D6). That is to say, they preferably exhibit less than 75% metabolism via the
  • CYP2D6 pathway according to the CYP2D6 substrate assay described below and they preferably exhibit an IC50 of >6 ⁇ M according to the CYP2D6 inhibitor assay described below.
  • norepinephrine reuptake inhibitor is selective for the reuptake of norepinephrine over the reuptake of other neurotransmitters. It is also preferred that the norepinephrine reuptake inhibitor does not exhibit signigicant direct agonist or antagonist activity at other receptors.
  • the norepinephrine reuptake inhibitor be selected from atomoxetine, reboxetine, (S,S)-reboxetine, (R)-N-methyl-3-(2-methyl-thiophenoxy)-3-phenylpropylamine, and compounds of Formulae (I), (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above.
  • the present invention encompasses pharmaceutical compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutically acceptable carrier diluent, or excipient.
  • most or all of the compounds used in the present invention are capable of forming salts, and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free bases.
  • the use of the pharmaceuticals described above as salts is contemplated in the description herein, and often is preferred, and the pharmaceutically acceptable salts of all of the compounds are included in the names of them.
  • Many of the compounds used in this invention are amines, and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts.
  • acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p_- toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p_- toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
  • salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-
  • 1,6-dioate benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, b-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate and the like.
  • Preferred pharmaceutically acceptable salts are those formed with hydrochloric acid.
  • salts of the compounds of Formulae (IA), (TB), (IC), (ID) (IE), (IF) and (IG) above include acid addition salts, including salts formed with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic or organic sulphonic acids, for example, acetoxybenzoic, citric, glycolic, o- mandelic-1, mandelic-dl, mandelic d, maleic, mesotartaric monohydrate, hydroxymaleic, fumaric, lactobionic, malic, methanesulphonic, napsylic, naphtalenedisulfonic, naphtoic, oxalic, palmitic, phenylacetic, propionic, pyridyl hydroxy pyruvic, salicylic, stearic, succinic, sulphanilic, tartaric, 2-hydroxyethane sulphonic
  • the present invention encompasses the administration of a composition that exhibits (preferably selective) norepinephrine reuptake inhibitor activity.
  • the composition can comprise one or more agents that, individually or together, inhibit norepinephrine reuptake preferably in a selective manner.
  • the dosages of the drugs used in the present invention must, in the final analysis, be set by the physician in charge of the case using knowledge of the drugs, the properties of the drugs in combination as determined in clinical trials, and the characteristics of the patient including diseases other than that for which the physician is treating the patient.
  • General outlines of the dosages, and some preferred dosages, are: Atomoxetine: In adults and older adolescents: from about 5 mg/day to about 200 mg/day; preferably in the range from about 60 to about 150 mg/day; more preferably from about 60 to about 130 mg/day; and still more preferably from about 50 to about 120 mg/day;
  • Racemic reboxetine can be administered to an individual in an amount in the range of from about 2 to about 20 mg per patient per day, more preferably from about 4 to about 10 mg/day, and even more preferably from about 6 to about 10 mg/day. Depending on the formulation, the total daily dosage can be administered in smaller amounts up to two times per day.
  • a preferred adult daily dose of optically pure (S,S) reboxetine can be in the range of from about 0.1 mg to about 10 mg, more preferably from about 0.5 mg to about 8 to 10 mg, per patient per day.
  • the effective daily dose of reboxetine for a child is smaller, typically in the range of from about 0.1 mg to about 4 to about 5 mg/day.
  • compositions containing optically pure (S,S)-reboxetine are about 5 to about 8.5 times more effective in inhibiting the reuptake of norepinephrine than compositions containing a racemic mixture of (R,R)- and (S,S)-reboxetine, and therefore lower doses can be employed.
  • PCT international Publication No. WO 01/01973 contains additional details concerning the dosing of (S,S) reboxetine.
  • Compounds of formula I from about 0.01 mg/kg to about 20 mg/kg; preferred daily doses will be from about 0.05 mg/kg to 10 mg/kg; ideally from about 0.1 mg/kg to about 5 mg/kg;
  • the present invention includes the use of a norepinephrine reuptake inhibitor to treat cognitive failure presenting alone, or where cognitive failure is associated with another disorder.
  • Schizophrenic patients for example, commonly exhibit symptoms that include cognitive failure.
  • An embodiment of the present invention is the use of a norepinephrine reuptake inhibitor to treat cognitive failure associated with schizophrenia.
  • Patients suffering from schizophrenia also frequently exhibit negative symptoms such as flat affect, asociality, anergia, avolition, and anhedonia.
  • a further embodiment of the present invention is the use of a norepinephrine reuptake inhibitor to treat the negative symptoms of schizophrenia, or abulia and apathy related to other disorders such as dementia of the frontal lobe type.
  • the invention further provides a method for treating a patient suffering from or susceptible to psychosis, comprising administering to said patient an effective amount of a first component which is an antipsychotic, in combination with an effective amount of a second component which is a norepinephrine reuptake inhibitor.
  • the invention also provides a pharmaceutical composition that comprises a first component that is an antipsychotic, and a second component that is a norepinephrine reuptake inhibitor.
  • the first component is a compound that acts as an antipsychotic.
  • the antipsychotic may be either a typical antipsychotic, such as haloperidol, or an atypical antipsychotic.
  • the essential feature of an atypical antipsychotic is less acute extrapyramidal symptoms, especially dystonias, associated with therapy as compared to a typical antipsychotic such as haloperidol.
  • Clozapine the prototypical atypical antipsychotic, differs from the typical antipsychotics with the following characteristics: (1) greater efficacy in the treatment of overall psychopathology in patients with schizophrenia nonresponsive to typical antipsychotics; (2) greater efficacy in the treatment of negative symptoms of schizophrenia; and (3) less frequent and quantitatively smaller increases in serum prolactin concentrations associated with therapy (Beasley, et al., Neuropsychopharma- cologv, 14(2), 111-123 , (1996)). Although both typical and atypical antipsychotics are useful for these methods and formulations of the present invention, it is preferred that the first component compound is an atypical antipsychotic.
  • Typical antipsychotics include, but are not limited to:
  • Chlorpromazine 2-chloro-10-(3-dimethylaminoprop-yl)phenothiazine
  • Citron-Crismon 2-chloro-10-(3-dimethylaminoprop-yl)phenothiazine
  • Trifluoperazine 10-[3-(4-methyl-l-piperazinyl)-propyl]-2- trifluoromethylphenthiazine hydrochloride, is described in U.S. Patent 2,921,069.
  • Atypical antipsychotics include, but are not limited to:
  • Olanzapine 2-methyl-4-(4-methyl- 1 -piperazinyl)- 1 OH-thieno [2,3- b][l,5]benzodiazepine, is a known compound and is described in U.S. Patent No.
  • 5,229,382 as being useful for the treatment of schizophrenia, schizophreniform disorder, acute mania, mild anxiety states, and psychosis;
  • Clozapine 8-chloro-l l-(4-methyl-l-piperazinyl)-5H- dibenzo[b,e][l,4]diazepine, is described in U.S. Patent No. 3,539,573. Clinical efficacy in the treatment of schizophrenia is described (Hanes, et al., Psychopharmacol. Bull.. 24,
  • Sertindole l-[2-[4-[5-chloro-l-(4-fluorophenyl)-lH-indol-3-yl]-l- piperidinyl]ethyl]imidazolidin-2-one, is described in U.S. Patent No. 4,710,500. Its use in the treatment of schizophrenia is described in U.S. Patent Nos. 5,112,838 and 5,238,945;
  • Quetiapine 5-[2-(4-dibenzo[b,f][l,4]thiazepin-l 1-yl-l- piperazinyl)ethoxy]ethanol, and its activity in assays which demonstrate utility in the treatment of schizophrenia are described in U.S. Patent No. 4,879,288.
  • Quetiapine is typically administered as its (E)-2-butenedioate (2:1) salt;
  • Ziprasidone 5-[2-[4-(l,2-benzoisothiazol-3-yl)-l-piperazinyl]ethyl]-6- chloro-l,3-dihydro-2H-indol-2-one, is typically administered as the hydrochloride monohydrate.
  • the compound is described in U.S. Patent Nos. 4,831,031 and 5,312,925. Its activity in assays which demonstrate utility in the treatment of schizophrenia are described in U.S. Patent No. 4,831,031.
  • Aripiprazole (AbilityTM), 7-[4-[4-(2,3-dichlorophenyl)-l- piperazinyl]butoxy]-3,4-dihydrocarbostyril (U.S. Patents 4,734,416 and 5,006,528) is a new antipsychotic indicated for the treatment of schizophrenia.
  • the second component compound is a compound that functions as a norepinephrine reuptake inhibitor as described above.
  • first and second component compounds While all combinations of first and second component compounds are useful and valuable, certain combinations are particularly valued and are preferred, as follows: olanzapine/atomoxetine olanzapine/reboxetine olanzapine/(R)-N-methyl-3-(2-methylthiophenoxy)-3- phenylpropylamine clozapine/atomoxetine risperidone/atomoxetine sertindole/atpmoxetine quetiapine/atomoxetine ziprasidone/atomoxetine aripiprazole/atomoxetine In general, combinations and methods of treatment using olanzapine as the first component are preferred.
  • combinations and methods of treatment using atomoxetine as the second component are preferred.
  • Especially preferred are combinations and methods of treatment using olanzapine as the first component and atomoxetine as the second component. It is especially preferred that when the first component is olanzapine, it will be the Form E olanzapine as described in U.S. Patent
  • Form E olanzapine polymorph will be administered as the substantially pure Form E olanzapine polymorph.
  • substantially pure refers to Form E associated with less than about 5% Form I, preferably less than about 2% Form I, and more preferably less than about 1% Form I.
  • substantially pure Form E will contain less than about 0.5% related substances, wherein “related substances” refers to undesired chemical impurities or residual solvent or water.
  • substantially pure Form E should contain less than about 0.05% content of acetonitrile, more preferably, less than about 0.005% content of acetonitrile.
  • the polymorph of the invention should contain less than 0.5% of associated water.
  • olanzapine embraces all solvate and polymorphic forms unless specifically indicated.
  • the present invention also encompasses the use of one or more SNRIs such as atomoxetine, racemic reboxetine, S,S-reboxetine, or any of the other SNRI compounds disclosed herein, in combination with one or more conventional Alzheimer's agents for the prevention or treatment of cognitive dysfunction in patients suffering from Alzheimer's disease.
  • Alzheimer's agents include inhibitors of acetylcholine degradation (i.e., cholinesterase or acetylcholinesterase inhibitors) within synapses, e.g., donepezil (Aricept®), rivastigmine (Exelon®), galantamine (Reminyl®), and tacrine (Cognex®); the selective monoamine oxidase inhibitor selegiline
  • the present invention also encompasses the use of one or more SNRIs such as atomoxetine, racemic reboxetine, S,S-reboxetine, or any of the other SNRI compounds disclosed herein, in combination with one or more conventional Parkinson's agents for the treatment of cognitive dysfunction in Parkinson's disease.
  • one or more SNRIs such as atomoxetine, racemic reboxetine, S,S-reboxetine, or any of the other SNRI compounds disclosed herein, in combination with one or more conventional Parkinson's agents for the treatment of cognitive dysfunction in Parkinson's disease.
  • Parkinson's agents include levodopa; levodopa/carbidopa (Sinemet®); Stalevo (carbidopa/levodopa/entacapone); dopamine agonists, e.g., bromocriptine; pergolide; Mirapex® (pramipexole), Permax® (pergolide), and Requip® (ropinirole); COMT inhibitors, e.g., tolcapone, and entacapone; Selegiline (Deprenyl®; Eldepryl®); propranolol; primidone; anticholinergics, e.g., Cogentin®, Artane®, Akineton®, Disipal®, and Kemadrin®; and amantadine.
  • dopamine agonists e.g., bromocriptine
  • pergolide Mirapex® (pramipexole), Permax® (pergolide), and Requip®
  • the dosages of the component drugs used in the combination therapy aspects of the present invention must, in the final analysis, be set by the physician in charge of the case using knowledge of the drugs, the properties of the drugs in combination as determined in clinical trials, and the characteristics of the patient, including diseases other than that for which the physician is treating the patient. Dosage guidelines for some of the antipsychotic drugs are first given separately. In order to create a guideline for any desired combination, one would choose the guidelines for each of the component drugs.
  • Chlorpromazine from about 25-75 mg daily to about 75-150 mg daily;
  • Droperidol about 5 mg by injection
  • Haloperidol from about 1-15 mg/day to about 100 mg/day administered orally or by injection;
  • Thioridazine about 75-150 mg daily
  • Trifluoperazine from about 4-10 mg/day to about 15-20 mg/day;
  • Olanzapine from about 0.25 to 50 mg, once/day; preferred, from 1 to 30 mg, once/day; and most preferably 1 to 25 mg once/day;
  • Clozapine from about 12.5 to 900 mg daily; preferred, from about 150 to 450 mg daily;
  • Risperidone from about 0.25 to 16 mg daily; preferred from about 2-8 mg daily; Sertindole: from about .0001 to 1.0 mg/kg daily;
  • Quetiapine from about 1.0 to 40 mg/kg given once daily or in divided doses;
  • Ziprasidone from about 5 to 500 mg daily; preferred from about 50 to 100 mg daily; Aripiprazole: from about 10 to 30 mg/day, preferably from about 10 to 15 mg/day, given once daily.
  • Dosage guidelines for conventional Alzheimer's and Parkinson's agents are well known in the art, and can be found, for example, in the package inserts accompanying each drug.
  • one can create an initial combination of the present invention by choosing a dosage of first and second component compounds according to the spirit of the above guidelines. Based on the response of the patient, the physician or other medical professional can then adjust the doses as appropriate.
  • the adjunctive therapy aspect of the present invention is carried out by administering a first component together with the second component in any manner that provides effective levels of the compounds in the body at the same time.
  • Oral administration of the adjunctive combination is preferred. Both components can be administered together, in a single dosage form, or administered separately.
  • oral administration is not the only route or even the only preferred route.
  • transdermal administration may be very desirable for patients who are forgetful or petulant about taking oral medicine.
  • Administration by the percutaneous, intravenous, intramuscular, intranasal, or intrarectal route may be prudent in particular circumstances.
  • the route of administration can be varied in any way, limited by the physical properties of the drugs, the convenience of the patient and the caregiver, and other relevant circumstances (Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990)).
  • the adjunctive combination can be administered as a single pharmaceutical composition, and so pharmaceutical compositions incorporating both compounds are important embodiments of the present invention.
  • Such compositions can take any physical form that is pharmaceutically acceptable, but orally usable pharmaceutical compositions are particularly preferred.
  • Such adjunctive pharmaceutical compositions contain an effective amount of each of the compounds, which effective amount is related to the daily dose of the compounds to be administered.
  • Each adjunctive dosage unit can contain the daily doses of all compounds, or can contain a fraction of the daily doses, such as one-third of the doses.
  • each dosage unit can contain the entire dose of one of the compounds, and a fraction of the dose of the other compounds. In such case, the patient would daily take one of the combination dosage units, and one or more units containing only the other compounds.
  • the amounts of each drug to be contained in each dosage unit depends on the identity of the drugs chosen for the therapy, and other factors such as the indication for which the adjunctive therapy is being given.
  • the pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art.
  • the carrier or excipient can be a solid, semi-solid, or liquid material that can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art.
  • the pharmaceutical composition can be adapted for oral, inhalation, parenteral, or topical use, and can be administered to the patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solutions, suspensions, or the like.
  • the compounds useful for the methods of the present invention can be administered orally, for example, with an inert diluent or capsules or compressed into tablets.
  • the compounds can be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, and the like.
  • compositions and preparations useful for the methods of the present invention should contain at least 4% of the compound of the present invention, the active ingredient, but can be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit.
  • the amount of the compound present in compositions is such that a suitable dosage will be obtained.
  • Preferred compositions and preparations useful for the methods of the present invention can be determined by a person skilled in the art.
  • the tablets, pills, capsules, troches, and the like can also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or
  • the dosage unit form When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms can contain other various materials that modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills can be coated with sugar, shellac, or other coating agents.
  • a syrup can contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • a formulation useful for the administration of R-(-)-N-methyl 3-((2- methylphenyl)oxy)-3-phenyl-l-aminopropane hydrochloride comprises a dry mixture of R-(-)-N-methyl 3-((2-methylphenyl)oxy)-3-phenyl-l-aminopropane hydrochloride with a diluent and lubricant.
  • a starch such as pregelatinized corn starch, is a suitable diluent and a silicone oil, such as dimethicone, a suitable lubricant for use in hard gelatin capsules.
  • Suitable formulations are prepared containing about 0.4 to 26% R- (-)-N-methyl 3-((2-methylphen-yl)oxy)-3-phenyl-l-aminopropane hydrochloride, about 73 to 99% starch, and about 0.2 to 1.0% silicone oil.
  • the following tables illustrate particularly preferred atomoxetine formulations:
  • the compounds of the present invention can be incorporated into a solution or suspension.
  • These preparations typically contain at least 0.1% of a compound of the invention, but can be varied to be between 0.1 and about 90% of the weight thereof.
  • the amount of the compound of formula I present in such compositions is such that a suitable dosage will be obtained.
  • the solutions or suspensions can also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetra-acetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Preferred compositions and preparations can be determined by one skilled in the art.
  • Norepinephrine Reuptake The ability of compounds to inhibit the reuptake of norepinephrine can be measured by the general procedure of Wong, et al., supra.
  • Cerebral cortices are homogenized in 9 volumes of a medium containing 0.32 M sucrose and 10 mM glucose. Crude synaptosomal preparations are isolated after differential centrifugation at 1000 x g for 10 minutes and
  • Synaptosomal uptake of 3 H-norepinephrine is determined as follows. Cortical synaptosomes (equvalent to 1 mg of protein) are incubated at 37°C for 5 minutes in 1 mL Krebs-bicarbonate medium containing also 10 mM glucose, 0.1 mM iproniazide,
  • the present invention provides methods for the treatment of cognitive failure.
  • cognitive failure may present in patients suffering from a number of disorders, including dementia or delirium, or due to a wide variety of other causes.
  • the methods of the present invention are useful for the treatment or prevention of cognitive failure associated with, or due to, the disorders or etiologies discussed above, including disorders formally classified in the DSM-IV-TRTM.
  • the DSM-IV-TRTM code numbers or descriptions are supplied below .
  • ICD-9-CM codes refers to codes for, e.g., selected general medical conditions and medication-induced disorders contained in the International Classification of Diseases, 9 th Revision, Clinical Modification.
  • Substance-Induced Delirium including:
  • Coding note Use multiple codes based on specific dementias and specific etiologies, e.g., 294.10 Dementia of the Alzheimer's Type, With Late Onset, Without Behavioral Disturbance; 290.40 Vascular Dementia, Uncomplicated. Dementia Not Otherwise Specified 294.8
  • Non-limiting examples of cognitive disorders due to various etiologies, or associated with various disorders, of particular interest that can be prevented or treated according to the methods of the present invention include: Enhancing cognitive functions and executive functioning (ability to plan, initiate, organize, carry out, monitor, and correct one's own behavior) in normal subjects or in subjects exhibiting cognitive dysfunction;
  • Cognitive and attentional deficits are associated with prenatal exposure to substances of abuse including, but not limited to, nicotine, alcohol, methamphetamine, ***e, and heroin.
  • Children born to addicted mothers often exhibit life-long cognitive deficits, often including diagnoses of attention deficit disorder (with and without hyperactivity (ADHD)).
  • ADHD attention deficit disorder
  • Besides attentional abnormalities, such children often exhibit psychomotor developmental delay and intellectual impairments;
  • SNRIs Treatment of deficits in normal memory functioning comorbid with major depressive and bipolar disorders.
  • Patients in need of treatment with SNRIs as disclosed herein include those that suffer from major depressive and bipolar disorders, and who also exhibit deficits in normal memory functioning. The latter can be ascertained using tests conventional in the art;
  • SNRIs Treatment of cognitive impairment associated with depression, mental retardation, bipolar disorder, or schizophrenia.
  • Patients in need of treatment with SNRIs as disclosed herein include those that suffer from depression, mental retardation, bipolar disorder, or schizophrenia, and who also exhibit cognitive deficits. Such deficits can be ascertained using tests conventional in the art;
  • problems of attention can occur in the absence of dementia, while the converse is not necessarily true, i.e., dementia includes problems with attention;
  • the present invention relates to the field of psychooncology, including methods for preventing or treating cognitive impairments, including dementias and deliriums, due to cancers per se in child, adolescent, and adult patients, or due to the therapies employed to treat cancers in such patients.
  • cognitive impairments including dementias and deliriums
  • conventional cancer therapies can have negative effects on cognitive function
  • patients with tumors of the CNS are also particularly prone to cognitive dysfunction.
  • both cancers themselves, and the treatments for these diseases can lead to cognitive deficits in this patient population.
  • Cognitive deficits associated with cancer treatment can be temporarily associated with the administration of anti-cancer therapies and therefore transitory or short term, or more long lasting. Such deficits dramatically affect a patient's quality of life including, for example, memory, concentration, the ability to remain focused or organized, etc.
  • Cognitive deficits are associated with a variety of cancer treatments, including cranial radiation, conventional (standard-dose) chemotherapy, high-dose chemotherapy and hematopoietic (bone-marrow) transplantation, and biologic agents.
  • cancer has many definitions. According to the American Cancer Society, cancer is a group of diseases characterized by uncontrolled growth (and sometimes spread) of abnormal cells. Although often referred to as a single condition, it actually consists of more than 200 different diseases. Cancerous growths can kill when such cells prevent normal function of vital organs, or spread throughout the body, damaging essential systems.
  • Non-limiting examples of different types of cancers include: carcinomas, such as neoplasms of the central nervous system, including glioblastoma multiforme, astrocytoma, oligodendroglial tumors, ependymal and choroid plexus tumors, pineal tumors, neuronal tumors, medulloblastoma, schwannoma, meningioma, and meningeal sarcoma; neoplasms of the eye, including basal cell carcinoma, squamous cell carcinoma, melanoma, rhabdomyosarcoma, and retinoblastoma; neoplasms of the endocrine glands, including pituitary neoplasms, neoplasms of the thyroid, neoplasms of the adrenal cortex, neoplasms of the neuroendocrine system, neoplasms of the gastroenteropancreatic endocrine system, and n
  • cancer therapy refers to treatments including, but not limited to, surgery, radiation therapy (including photodynamic therapy), chemotherapy (including hormonal therapy), and biologic therapy (including immunotherapy, differentiating agents, and agents targeting cancer cell biology).
  • radiation therapy including photodynamic therapy
  • chemotherapy including hormonal therapy
  • biologic therapy including immunotherapy, differentiating agents, and agents targeting cancer cell biology.
  • Such therapies are often used in combination, and agents in a single category can act by several different mechanisms.
  • cancer chemotherapy agents can induce differentiation, and antibodies, which are a form of immunotherapy, can be used to deliver radiation therapy.
  • Surgery and radiation therapy are considered local treatments, although their effects can influence the behavior of tumors at remote sites.
  • Chemotherapy and biologic therapy are usually systemic treatments.
  • the many types of therapies used in cancer treatment are well known to practitioners in the art, and are summarized, for example, in Sausville and Longo ((2001) Harrison's Principles Of Internal Medicine, 15th Edition, Eugene Braunwald et al., Eds., Chapter 84, The McGraw-Hill Companies, Inc.); Calabresi et al. (2001) in Goodman & Gilman's The Pharmacological Basis of Therapeutics, Tenth Edition, Hardman et al., Eds., McGraw-Hill, New York, pp. 1381-1388; Chabner et al.
  • the compounds disclosed herein can be used either to prevent or treat cognitive dysfunction in patients due to cancer or the cancer therapy they receive.
  • changes in mental status of cancer patients can be due to the presence of cancer in the CNS per se, or metastases to the central nervous system of tumors from other areas of the body, for example lung cancer, breast cancer, kidney cancer, metastatic melanoma, renal cancer, etc.
  • a metastatic tumor appears to be isolated, surgical resection is considered. Otherwise, the treatment is whole-brain irradiation.
  • Delirium in patients with cancer can also be caused by distant, non-metastatic effects of tumors.
  • Such paraneoplastic syndromes are most common in patients with small cell carcinoma of the lung, but can also occur due to breast, stomach, uterine, renal, testicular, thyroid, and colon cancers (Minotti et al. (1994) Am. J. Otolaryngology 15:336-343; Peterson et al. (1994) J. Neurooncol. 21:159-170; Schiller et al. (1993) Curr. Opin. Oncol. 5:335-342).
  • Neurological insults frequently associated with delirium and dementia include subacute cerebellar degeneration, encephalomyopathy, and Eaton-
  • hypercalcemia often secondary to bone metastases
  • hypomagnesemia often associated with cisplatin therapy
  • hyperviscosity syndrome often occurring in patients with lymphoma, Waldenstrom's macroglobulinemia, or myeloma (Crawford et al. (1985) Am. J. Med. 79:13-22).
  • Psychotic conditions that can be treated by the adjunctive therapy aspect of the present invention include schizophrenia, schizophreniform diseases, acute mania, and schizoaffective disorders.
  • the titles given these conditions represent multiple disease states. The following list illustrates a number of these disease states, many of which are classified in the DSM-IV-TRTM.
  • the DSM-IV-TRTM code numbers for these disease states are supplied below, when available, for the convenience of the reader.
  • a child is considered to be a patient below the age of puberty
  • an adolescent is considered to be a patient from the age of puberty up to about 18 years of age
  • an adult is considered to be a patient 18 years or older.
  • Compounds of formula (IA) may be prepared by conventional organic chemistry techniques and also by solid phase synthesis.
  • boc refers to the N-protecting group t-butyloxycarbonyl.
  • TFA trifluoroacetic acid.
  • DMF dimethylformamide.
  • SPE solid phase extraction.
  • ACE-C1 refers to ⁇ -chloroethyl chloroformate.
  • a boc-protected 4-piperidone (IIA) is reductively aminated with an amine to provide a 4-amino-piperidine (EIAa or EIAb).
  • EIAa or EIAb 4-amino-piperidine
  • a second reductive amination with an aldehyde or ketone provides a boc-protected compound of formula (IA) (WA).
  • the boc group is removed under acidic conditions to provide a compound of formula (IA) (where R8 is H).
  • the compound of formula (IA) (where R8 is H) may be converted to a suitable salt by addition of a suitable quantity of a suitable acid.
  • N-protecting group is used in the above illustration, it will be appreciated that other N-protecting groups (for example acetyl, benzyl or benzoxycarbonyl) could also be used together with a deprotection step appropriate for the N-protecting group used.
  • other reducing agents for example NaBH4 or
  • LiAlH4 may be used in the reductive amination steps and other acids (for example HCI) may be used in the deprotection step.
  • compound EIAa or EIAb may be subjected to an alkylation step as shown in Scheme IB below (L represents a suitable leaving group - for example Br or tosyl).
  • N-protection other than boc may also be used together with a suitable deprotection step.
  • bases other than potassium carbonate e.g NaH
  • bases other than potassium carbonate e.g NaH
  • the compounds of formula (IA) (where R8 is H) may also be prepared by a solid phase parallel synthesis technique as outlined in Scheme IC shown below.
  • a piperidone hydrate is attached to a polystyrene resin to provide a resin bound piperidone (VA). Aliquots are reductively aminated to provide a resin bound secondary amine (VIA) that can undergo a further reductive amination with an aldehyde or ketone to give the tertiary amine (VEA). Acidic cleavage from the resin and SPE provides compounds of formula (IA) (where R8 is H) which may be purified by ion exchange methods using, for example, the SCX-2 ion exchange resin.
  • NaBH(OAc) 3 is used in the above illustration, it will be appreciated that other reducing agents (for example NaBH4 or LiAlH4) may be used in the reductive amination steps and other acids (for example HCI) may be used in the deprotection step.
  • Solid phase resins other than the p-nitrophenylcarbonate-polystyrene resin illustrated above may also be employed.
  • Scheme ID A benzyl-protected 4-piperidone (VIEA) is alkylated with an alkyllithium reagent to provide a 4-amino-pi ⁇ eridinol (I A).
  • a secondary amide (XA) which may be deprotected, boc-protected and reduced to provide a secondary amine (XIA).
  • Alkylation of the secondary amine (XIA) followed by removal of the boc group provides a compound of formula (IA) (where R8 is Ci -C4alkyl).
  • N-protecting groups are used in the above illustration, it will be appreciated that other N-protecting groups could also be used in their place together with deprotection steps appropriate for those N-protecting groups.
  • other reducing agents may be used in the amidecarbonyl reduction step and other organometallics or bases may be used in the respective alkylation steps.
  • the deprotection can be done using catalytic palladium hydrogenolysis, or carbamate exchange with ACE-C1 (1-Chloroethyl chloroformate), giving intermediates of type 7B, followed by methanolysis as shown in Scheme 3B.
  • the intermediates 3B can be further elaborated using for example organometallic type couplings between an ortho bromide derivative of type 8B and an arylboronic acid as shown in Scheme 4B.
  • Av and its substituent R are shown as phenyl and substitution occurs at the 2-position.
  • analogous methods could be applied for other possible identities of Ari and Ri and other possible substitution positions. This approach can also be carried out by solid phase synthetic methods as described in more detail in the specific examples below.
  • An alternative route for the preparation of the compounds of Formulae (IB) is method B (see Scheme IB).
  • Formation of the intermediate epoxides of type 2B from racemic N-benzyl-ketomorpholines of type IB can be done using for example trimethyl sulfoxonium iodide and a suitable base, for example sodium hydride.
  • Condensation of 2B with a commercially available aryl organometallic, or an aryl organometallic prepared from the corresponding halo aryl derivative gives the intermediates of type 3B, as mixtures of diastereoisomers.
  • Final deprotections can be done as described above (see Scheme 3B).
  • Final compounds made using method B can be purified using chiral HPLC.
  • IC Compounds of formula (IC) may be prepared by conventional organic chemistry techniques from N-benzyl-cyanomorpholine IC (Route A) or N-benzyl-morpholinone 2C (Route B) as outlined in Scheme IC below: For clarity, X is shown as phenyl and R' and R 1 are shown as H. It will be appreciated that analogous methods could be applied for other possible identities of X, R' and R 1 .
  • the amino alcohol 4Ca can be obtained by reaction of N-benzyl-cyanomorpholine IC with a Grignard reagent, followed by acid hydrolysis to give racemic phenyl ketone 3C which may be separated on chiral HPLC. (2S)-Phenyl ketone 3Ca may then be reduced with DIP-Cl to give 4Ca in high diastereomeric excess.
  • the amino alcohol 4Ca is converted into benzyl bromide 5Ca, to give the desired N-substituted aryl thio morpholines after displacement with the requisite aryl thiol.
  • N-substituted aryloxy morpholines may be obtained in an analogous manner by displacement with the requisite hydroxyaryl compound.
  • N-substituted aryloxy morpholines may be obtained by addition of a strong base, such as sodium hydride, to the amino alcohol 4Ca to form a nucleophilic alkoxide followed by an S N A ⁇ reaction with an Ar group substituted with a suitable leaving group (e.g. F). Deprotection of the tertiary amine gives the final products.
  • a strong base such as sodium hydride
  • N-benzyl morpholinone 2C Treatment of N-benzyl morpholinone 2C with a strong base such as lithium diisopropylamide at low temperature followed by addition of benzaldehyde gives aldol adducts 6Ca-6Cd as a 2:1 mixture of diastereomer pairs 6Ca,6Cb and 6Cc,6Cd, which may be separated using conventional chromatographic techniques. Reduction with a borane reagent at elevated temperatures gives diasteremeric amino alcohol pairs 4Ca,4Cb and 4Cc,4Cd respectively.
  • a strong base such as lithium diisopropylamide
  • benzaldehyde Treatment of N-benzyl morpholinone 2C with a strong base such as lithium diisopropylamide at low temperature followed by addition of benzaldehyde gives aldol adducts 6Ca-6Cd as a 2:1 mixture of diastereomer pairs 6Ca,6Cb and 6Cc,
  • Amino alcohol pair 4Ca,4Cb may be converted to bromide 5Ca,5Cb and further to racemic aryl thio morpholines as outlined in Scheme 4C.
  • Amino alcohol pair 4Cc,4Cd may be converted into the corresponding mesylate. Displacement with the requisite thiol, followed by removal of the nitrogen protecting group furnishes aryl thiol morpholines as racemic mixtures of two diastereomers.
  • the racemic aryl thiol morpholines may be separated into enantiomerically pure products using chiral HPLC technology. ⁇ - substituted aryloxy morpholines may be obtained in an analogous manner by displacement with the requisite hydroxyaryl compound.
  • Aryl-substituted morpholines 33C, 35C, 37C may be obtained from morpholinone 2C as outlined in Scheme 5C:
  • Compounds of formula (TD) may be prepared using the following methods. General schemes outlining the synthetic routes used to prepare racemic products are given below. All active racemates may be separated into single enantiomers using chiral HPLC and may be readily converted into suitable salts.
  • Quinolin-2-one ID or its corresponding 4-oxo and 4-thio derivatives can be N- arylated using modified conditions to those reported by Buchwald, (J. Am. Chem. Soc, 123, 2001, p. 7727).
  • the quinolin-2-one ID is reacted with 3 equivalents of Ar-Br wherein Ar is (i) and R 2c is H, 0.2 equivalents of trans-cyclohexanediamine, 0.2 equivalent of copper iodide (Cul), 2.1 equivalents of potassium carbonate (K 2 CO 3 ), in an organic solvent such as 1,4-dioxane at a temperature of 125°C overnight.
  • the resulting N- arylated quinolin-2-one 2D can be alkylated by treatment with a strong base such as lithium hexamethyldisilazide (LiHMDS) at temperatures of -78°C in a suitable organic solvent such as tetrahydrofuran (THF), followed by the addition of an alkyl halide such as alkyl iodide to give the corresponding 3-alkylated-N-arylated quinolin-2-one derivative 3D.
  • a strong base such as lithium hexamethyldisilazide (LiHMDS)
  • THF tetrahydrofuran
  • a 1,2-dihaloethane such as 1- bromo-2-chloroethane, or a 1,3-dihalopropane, such as l-bromo-3-chloropropane
  • alkylating agents provides 4D or 5D wherein n is 2 or 3 respectively.
  • halo analogues were chosen as ideal precursors to the desired amine products.
  • treatment of 4D or 5D with aqueous methylamine in the presence of a catalytic amount of a suitable iodide, such as potassium iodide (Kl), in ethanol at 100°C provided the racemic amine products 6D and 7D respectively, in moderate yields.
  • Kl potassium iodide
  • the alcohols were cleanly converted into their mesylates, by reaction of a mesyl halide such as mesyl chloride in the presence of a suitable base such as triethylamine in a suitable solvent such as THF at a suitable temperature such as 0°C to room temperature.
  • the resulting mesylates are used directly in the amination step described above in Scheme ID to provide good yields of the final racemic targets 13D.
  • the protection reaction can be carried out for example using a suitable base, such as sodium hydride in a suitable solvent, such as dimethylformamide, followed by reaction with a 4- methoxybenzyl halide, such as 4-methoxybenzyl chloride, to give the corresponding N- protected derivative 14D in good yield.
  • a suitable base such as sodium hydride in a suitable solvent, such as dimethylformamide
  • 4- methoxybenzyl halide such as 4-methoxybenzyl chloride
  • quinolin-2-one ID in Scheme 2D can be halogenated using N- chlorosuccinimide in a suitable solvent such as DMF at a suitable temperature such as room temperature to give the corresponding 6-chloro-quinolin-2-one ID wherein R 3 is Cl.
  • Schemes ID to 4D above relate to methods for the preparation of compounds of formula (ED) wherein Ar is (i) and R 2c is hydrogen.
  • Compounds of formula (ED) wherein Ar is (i) and R 2c can be other than hydrogen can be prepared using any of the general methods mentioned above, starting from the corresponding N-arylated quinolin-2-one 27D.
  • a general method for preparing said intermediates is illustrated in Scheme 5D.
  • 3-(2-Bromo-phenyl)- propionic acids 25D can be converted to amide 26D using standard amide coupling conditions and converted to the N-arylated quinolin-2-ones 27D by an intramolecular, palladium catalysed cyclisation according to the method of Buchwald et al (Tetrahedron, 1996, 52, p. 7525).
  • Compounds of formula (IE) may be prepared by conventional organic chemistry techniques and also by solid phase synthesis.
  • Compounds of formula (TE) can be prepared via the 3-aminopyrrolidine intermediate of formula (IVE) as illustrated in the Scheme IE below:
  • 3-hydroxypyrrolidine of formula (INK) wherein R 2 is hydrogen can be protected using a suitable nitrogen-protecting group such as those described in T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1991, hereafter referred to as "Greene”.
  • a suitable nitrogen-protecting group such as those described in T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1991, hereafter referred to as "Greene”.
  • 3-R- hydroxypyrrolidine (ETfi) can be protected with a tert-butoxycarbonyl group, (boc).
  • the protection reaction can be carried out for example using Boc anhydride in a suitable solvent such as for example tetrahydrofuran (THF) or dichloromethane (DCM) in the presence of a base such as tryethylamine (TEA) or 4-(dimethylamino)pyridine (DMAP).
  • THF tetrahydrofuran
  • DCM dichloromethane
  • TAA tryethylamine
  • DMAP 4-(dimethylamino)pyridine
  • the hydroxy group of the N-protected-3-hydroxypyrrolidine can be converted into a suitable leaving group (L) such as for example chloride, bromide, iodide or mesylate.
  • L a suitable leaving group
  • the N- protected-hydroxypyrrolidine can be converted to the mesylate in the presence of mesyl chloride and a suitable base such as triethylamine in a solvent such as DCM.
  • Said mesylate is subsequently displaced with the corresponding azide in a suitable solvent such as dimethylformamide (DMF) or dimethylsulphoxide (DMSO).
  • This azide intermediate can be converted to the corresponding N-protected-aminopyrrolidine of formula (IVE) via hydrogenation in the presence of a suitable catalyst such as Palladium on charcoal and in a suitable solvent such as methanol or ethanol.
  • intermediate (IVE) can be alkylated via reductive alkylation with a ketone of formula R 3 -CO-Ari wherein R 3 and A ⁇ ⁇ have the values for formula (IE) above.
  • the reductive alkylation can be carried out for example as a hydrogenation reaction in the presence of a suitable catalyst such as
  • the reductive alkylation can be carried out in the presence of a ketone of formula An-CO-R 3 wherein Ari and R 3 have the values defined for formula (IE) above.
  • Initial condensation of the amino pyrrolidine with the ketone is undertaken in the presence of a suitable acid such as p-toluenesulphonic acid, in a suitable solvent such as toluene.
  • the resultant imino pyrrolidine intermediate can then be protected with for example a boc group.
  • the reaction can be carried out in the presence of boc anhydride and a suitable base such as DMAP, in a suitable solvent such as DCM.
  • Said imine is reduced via hydrogenation in the presence of a suitable catalyst such as palladium on charcoal, in a suitable solvent such as ethanol to give the corresponding amine of formula (VE).
  • the reductive alkylation can be carried out using standard methods, for instance as those mentioned above with the ketone ArrCO-R 3 .
  • a compound of formula (VE) can be alkylated with R 9 -CHO in the presence of a suitable borane, such as ⁇ aBH(OAc) 3 , optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE).
  • a suitable borane such as ⁇ aBH(OAc) 3
  • an acid such as acetic acid
  • a suitable solvent such as dichloroethane (DCE).
  • Compounds of formula (IE) wherein R is -CH 2 -COO-(C ⁇ -C 2 alkyl) can be prepared by reacting intermediate (NE) with a compound of formula L 2 -CH 2 -COO-(C 1 -C alkyl) wherein L 2 is a suitable leaving group such as for example bromo, chloro or iodo. Said reaction can be carried out in the presence of a suitable base such as sodium hydride, in a suitable solvent such as dimethylformamide.
  • Compounds of formula (IE) wherein R 1 is -(CH 2 ) m -CF 3 can be prepared by reacting intermediate (VE) with a compound of formula HOOC-(CH 2 ) m ⁇ -CF 3 , wherein ⁇ i ! is 0, 1 or 2.
  • the acid may be activated as its anhydride or acyl chloride, and is reacted in the presence of a suitable base such as triethylamine and a catalytic amount of DMAP, in a suitable solvent such as DCM.
  • the resulting amide can be reduced to the amine of formula (VIEE) C in the presence of a suitable borane.
  • a suitable borane for example, for compounds wherein m is 1, the reduction can be carried out in the presence of BH 3 -Me S borane- dimethyl sulphide complex, in a suitable solvent such as THF.
  • Compounds of formula (JE) wherein R 1 is -( - alkylene)-OH can be prepared by reacting intermediate (VE) with an epoxide.
  • intermediate (VE) for example, compounds wherein R 1 is -CH 2 -C(CH 3 ) 2 -OH, the intermediate of formula (VE) is reacted with 2,2- dimethyloxirane, in a suitable solvent such as aqueous ethanol.
  • Alternatively compounds of formula (IE) wherein Ri is -(C ⁇ -Cgalkylene)-OH can be prepared by reacting intermediate (VE) with an w-haloalkanoate, such as methylbromoacetate, in the presence of a base such a sodium hydrogen carbonate in a solvent such as acetonitrile.
  • a base such as sodium hydrogen carbonate
  • a solvent such as acetonitrile.
  • the intermediate ester is then reacted with 2 equivalents of methyl magnesium bromide in THF to yield the tertiary alcohol(VIEE)d:
  • R is -C 2 -C 6 alkenyl, -(CH 2 ) n -S-(C 1 -C 3 alkyl), -(C C 5 alkylene)-O-(C 1 -C 3 alkyl), -(C 1 -C 5 alkylene)-O-(C 3 -C 6 cycloalkyl), -( -
  • C 5 alkylene)-SO 2 -(C 1 -C 3 alkyl), -(C 1 -C 5 alkylene)-OCF 3 , or -(C1-C 5 alkylene)-CN can be prepared via alkylation of intermediate (VE) with a compound of formula L 2 -C -C 6 alkenyl, LHCHz S-Cd- alkyl), L 2 -(C 1 -C 5 alkylene)-O-(C 1 -C 3 alkyl), L 2 -(C r C 5 alkylene)-O-(C 3 -C 6 cycloalkyl), L 2 -(C ⁇ -C 5 alkylene)-SO 2 -(C!-C 3 alkyl), LHC .
  • intermediate (VE) can be prepared via alkylation of intermediate (VE) with a compound of formula L 2 -C -C 6 alkenyl, LHCHz S-Cd- alkyl), L 2 -(C 1 -C 5
  • L is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (VETE) e .
  • compound of formula (IVE) can be alkylated with 4-tetrahydropyranone in the presence of a suitable borane, such as sodium borohydride or NaBH(OAc) 3 , optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE).
  • DCE dichloroethane
  • the secondary amine can be alkylated with a compound of formula Ar ⁇ CH 2 L;[ wherein ⁇ is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (VIEE)f.
  • a suitable borane such as sodium borohydride or NaBH(OAc) 3
  • an acid such as acetic acid
  • a suitable solvent such as dichloroethane (DCE).
  • the secondary amine can be alkylated
  • the coupling reaction can be carried out using standard methods known in the art.
  • the reduction of the amide bond can also be carried by general methods known in the art for example using the same reduction conditions as those used in Scheme 6, such as in the presence of BH 3 -Me S (borane-dimethyl sulphide complex), in a suitable solvent such as THF.
  • compounds of formula (IE) wherein R is a group of formula (i) wherein r is 0 can be prepared by a process illustrated in Scheme 12E for compounds wherein -Z is hydrogen, s isl, t is 2, each are hydrogen and -X- is - O-, (i.e. R is 2-tetrahydrofuranyl).
  • the compound of formula (IVE) can be alkylated with a compound of formula: wherein L 4 is a suitable leaving group such as chloro, bromo, iodo, mesylate or tosylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding secondary amine which can be subsequently alkylated with a compound of formula is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (NEJE)f.
  • L 4 is a suitable leaving group such as chloro, bromo, iodo, mesylate or tosylate
  • a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile
  • compound of formula (IVE) can be alkylated with oxabicyclo[3,2,l]octan-3-one in the presence of a suitable borane, such as sodium borohydride or ⁇ aBH(OAc) 3 , optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE).
  • a suitable borane such as sodium borohydride or ⁇ aBH(OAc) 3
  • an acid such as acetic acid
  • DCE dichloroethane
  • the secondary amine can be alkylated with a compound of formula Ar ⁇ CH L ⁇ wherein L ⁇ is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (VlllH) ⁇ .
  • L ⁇ is a suitable leaving group such as chloro, bromo, iodo or mesylate
  • a suitable base such as potassium carbonate
  • a suitable solvent such as acetonitrile
  • the secondary amine can be alkylated using the geheral methods described above for the incorporation of R 1 .
  • the intermediate aldehyde can be prepared via reduction of readily available methyl 3-phenyl picolinate to the corresponding alcohol and subsequent oxidation to the aldehyde as shown in Scheme 16E below.
  • the reduction step can be carried out in the presence of a suitable reducing agent such as lithium borohydride in a suitable solvent such as tetrahydrofuran.
  • a suitable reducing agent such as lithium borohydride
  • a suitable solvent such as tetrahydrofuran.
  • the oxidation to the aldehyde can be carried out under Swern conditions such as oxalyl chloride and DMSO in DCM.
  • the compound of formula (IVE) can be alkylated via reductive alkylation using standard methods, as those mentioned above with the ketone An-CO-R 3 .
  • compound of formula (IVE) can be alkylated with an aldehyde of formula:
  • the intermediate aldehyde can be prepared from the commercially available 2-formyl phenyl boronic acid via palladium coupling in the presence of 3-bromopyridine, a suitable palladium catalyst such as Pd(PPh 3 ) 4 and a suitable base such as potassium carbonate in a suitable solvent such as acetonitrile, as shown in Scheme 18E below.
  • the pyrazole group can be incorporated by reacting a compound of formula (VETE) m ' ; wherein L 5 is a suitable leaving group such as bromo, chloro or iodo, with pyrazole in the presence of a suitable base such as potassium carbonate and a catalytic amount of copper iodide in a suitable solvent such as for example DMF.
  • a suitable base such as potassium carbonate
  • a catalytic amount of copper iodide in a suitable solvent such as for example DMF.
  • the compound of formula (VEJE) m > can be prepared by any of the methods mentioned above for compounds wherein Ari is a phenyl group substituted with a halogen atom such as chloro, bromo or iodo.
  • any of the intermediates (VIEE), (VEffi) a-m are then deprotected using suitable deprotecting conditions such as those discussed in Greene, to give the corresponding compounds of formula (IE).
  • suitable deprotecting conditions such as those discussed in Greene
  • the protecting group is a boc group
  • the deprotection reaction can be carried out in trifluoroacetic acid in a suitable solvent such as DCM.
  • the reaction can be carried out in ethanolic hydrochloric acid.
  • the sequence is preferably performed on a polystyrene resin.
  • R 1 and A have the values defined above for formula (IE).
  • the sequence is performed without characterisation of the resin-bound intermediates.
  • 3- trifluoroacetamido-pyrrolidine is bound to a solid support by reaction with 4-nitrophenyl carbonate activated polystyrene resin in the presence of a base, such as N,N- diisopropylethylamine, in a solvent such as DMF.
  • the trifluoroacetamido protecting group is cleaved by hydrolysis with a base such as aqueous lithium hydroxide.
  • step (iii) the primary amine is then condensed with a substituted benzaldehyde in the presence of a dehydrating agent, such as trimethylorthoformate, to form the intermediate imine.
  • a dehydrating agent such as trimethylorthoformate
  • the imine is reduced with a borane reducing agent, such as sodium cyanoborohydride, in a solvent such as DMF, containing acetic acid.
  • step (v) the resultant secondary amine is then reductively alkylated with an aldehyde in the presence of a reducing agent such as sodium triacetoxyborohydride in a solvent, such as DMF.
  • a reducing agent such as sodium triacetoxyborohydride in a solvent, such as DMF.
  • the desired product is finally cleaved from the resin with acid, such as aqueous trifluoroacetic acid.
  • Compounds of formula (IF) may be prepared by conventional organic chemistry techniques and also by solid phase synthesis.
  • Compounds of formula (IF') can be prepared by the general methods illustrated below. It will be appreciated that the same methods can be used for compounds of formula (E 7 ") with the only difference that the nitrogen atom of the quinuchdines does not need to be protected as it is already a tertiary amine as it is explained in more detail below with reference to Scheme IF.
  • the protection reaction can be carried out for example using Boc anhydride in a suitable solvent such as for example tetrahydrofuran (THF) or dichloromethane (DCM) in the presence of a base such as triethylamine (TEA) or 4-(dimethylamino)pyridine (DMAP).
  • THF tetrahydrofuran
  • DCM dichloromethane
  • a base such as triethylamine (TEA) or 4-(dimethylamino)pyridine (DMAP).
  • the hydroxy group of the N-protected-3-hydroxypiperidine can be converted into a suitable leaving group (L) such as for example chloride, bromide, iodide or mesylate.
  • L a suitable leaving group
  • the N-protected-hydroxypiperidine can be converted to the mesylate in the presence of mesyl chloride and a suitable base such as triethylamine in a solvent such as DCM.
  • Said mesylate is subsequently displaced with the corresponding azide in a suitable solvent such as dimethylformamide (DMF) or dimethylsulphoxide (DMSO).
  • This azide intermediate can be converted to the corresponding N-protected-aminopiperidine of formula (TV) via hydrogenation in the presence of a suitable catalyst such as Palladium on charcoal and in a suitable solvent such as methanol or ethanol.
  • intermediate (FvT) can be alkylated via reductive alkylation with a ketone of formula R 3 -CO-Ar 1 wherein R 3 and Ari have the values for formula (IF) above.
  • the reductive alkylation can be carried out for example as a hydrogenation reaction in the presence of a suitable catalyst such as Palladium on charcoal and a suitable solvent such as for example ethanol.
  • a suitable catalyst such as Palladium on charcoal
  • a suitable solvent such as for example ethanol.
  • said reductive alkylation can be carried out in the presence of a suitable borane such as sodium triacetoxyborohydride, NaBH(OAc) 3 and optionally in the presence of a suitable acid such as acetic acid, in a suitable solvent such as for example dichoroethane (DCE).
  • DCE dichoroethane
  • intermediate of formula (VF) wherein R 4 is H can be prepared as shown in Scheme 2F below by reductive alkylation of readily available 3- aminopiperidine of formula (VIF) wherein R 2 has the values defined for formula (TF) above, followed by the protection of the nitrogen in the piperidine ring using a suitable protecting group such as those defined in Greene.
  • the reductive alkylation can be carried out in the presence of a ketone of formula An-CO-R 3 wherein An and R 3 have the values defined for formula (IF) above.
  • Initial condensation of the amino piperidine with the ketone is undertaken in the presence of a suitable acid such as p-toluenesulphonic acid, in a suitable solvent such as toluene.
  • the resultant imino piperidine intermediate can then be protected with for example a boc group.
  • the reaction can be carried out in the presence of boc anhydride and a suitable base such as DMAP, in a suitable solvent such as DCM.
  • Said imine is reduced via hydrogenation in the presence of a suitable catalyst such as palladium on charcoal, in a suitable solvent such as ethanol to give the corresponding amine of formula (VF).
  • the reductive alkylation can be carried out using standard methods, for instance as those mentioned above with the ketone An-CO-R 3 .
  • a compound of formula (VF) can be alkylated with R >9 -CHO in the presence of a suitable borane, such as NaBH(OAc) 3 , optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE).
  • a suitable borane such as NaBH(OAc) 3
  • an acid such as acetic acid
  • a suitable solvent such as dichloroethane (DCE).
  • DCE dichloroethane
  • R 3 and R 4 are hydrogen
  • the alkylation of intermediate (VF) can be carried out with a compound of formula AnCH 2 Li wherein L is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (VIEF) a .
  • a suitable base such as potassium carbonate
  • Compounds of formula (IF) wherein R is -CH -COO-(C 1 -C 2 alkyl) can be prepared by reacting intermediate (VF) with a compound of formula L 2 -CH 2 -COO-(C 1 -C 2 alkyl) wherein L 2 is a suitable leaving group such as for example bromo, chloro or iodo. Said reaction can be carried out in the presence of a suitable base such as sodium hydride, in a suitable solvent such as dimethylformamide.
  • Compounds of formula (IF) wherein R 1 is -(CH ) m -CF 3 can be prepared by reacting intermediate (VF) with a compound of formula HOOC-(CH )( m- i)-CF 3 .
  • the acid may be activated as its anhydride or acyl chloride, and is reacted in the presence of a suitable base such as triethylamine and a catalytic amount of DMAP, in a suitable solvent such as DCM.
  • the resulting amide can be reduced to the amine of formula (VIEF) C in the presence of a suitable borane.
  • a suitable borane for compounds wherein m is 1, the reduction can be carried out in the presence of BH 3 -Me 2 S borane-dimethyl sulphide complex, in a suitable solvent such as THF.
  • Compounds of formula (IF) wherein R 1 is -(C ⁇ -C 6 alkylene)-OH can be prepared by reacting intermediate (NF) with an epoxide.
  • intermediate (NF) for example, compounds wherein R 1 is -CH 2 -C(CH 3 ) 2 -OH, the intermediate of formula (NF) is reacted with 2,2- dimethyloxirane, in a suitable solvent such as aqueous ethanol.
  • Scheme 7F Alternatively compounds of formula (BF) wherein R* is -(Ci -Cgalkylene ⁇ OH can be prepared by reacting intermediate (VF) with an co-haloalkanoate, such as methylbromoacetate, in the presence of a base such a sodium hydrogen carbonate in a solvent such as acetonitrile. The intermediate ester is then reacted with 2 equivalents of methyl magnesium bromide in THF to yield the tertiary alcohol (VTEF)d:
  • VTEF tertiary alcohol
  • a compound of formula (TVF) can be alkylated with 4-tetrahydropyranone in the presence of a suitable borane, such as sodium borohydride or ⁇ aBH(OAc) 3 , optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE).
  • a suitable borane such as sodium borohydride or ⁇ aBH(OAc) 3
  • an acid such as acetic acid
  • a suitable solvent such as dichloroethane (DCE).
  • the secondary amine can be alkylated with a compound of formula Ar 1 CH 2 L ⁇ wherein Li is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (NlHF ' ) f .
  • a suitable base such as potassium carbonate
  • a suitable solvent such as acetonitrile
  • the coupling reaction can be carried out using standard methods known in the art.
  • the reduction of the amide bond can also be carried out by general methods known in the art for example using the same reduction conditions as those used in Scheme 6F, such as in the presence of BH 3 -Me 2 S (borane-dimethyl sulphide complex), in a suitable solvent such as THF.
  • the compound of formula (TVF) can be alkylated with a compound of formula: wherein L is a suitable leaving group such as chloro, bromo, iodo, mesylate or tosylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding secondary amine which can be subsequently alkylated with a compound of formula A CH 2 Li wherein Li is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (VIEF) f .
  • L is a suitable leaving group such as chloro, bromo, iodo, mesylate or tosylate
  • a suitable base such as potassium carbonate
  • a suitable solvent such as acetonitrile
  • compound of formula (TVF) can be alkylated with oxabicyclo[3,2,l]octan-3-one in the presence of a suitable borane, such as sodium borohydride or ⁇ aBH(OAc) 3 , optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE).
  • a suitable borane such as sodium borohydride or ⁇ aBH(OAc) 3
  • an acid such as acetic acid
  • a suitable solvent such as dichloroethane (DCE).
  • the secondary amine can be alkylated with a compound of formula AnCH ⁇ wherein L] is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (NEBF) j .
  • L is a suitable leaving group such as chloro, bromo, iodo or mesylate
  • a suitable base such as potassium carbonate
  • a suitable solvent such as acetonitrile
  • Scheme 15F The compound of formula (INF) can be alkylated via reductive alkylation using standard methods, as those mentioned above with the ketone An-CO-R .
  • compound of formula (INF) can be alkylated with an aldehyde of formula:
  • the secondary amine can be alkylated using the general methods described above for the incorporation of R 1 .
  • the intermediate aldehyde can be prepared via reduction of readily available methyl 3-phenyl picolinate to the corresponding alcohol and subsequent oxidation to the aldehyde as shown in Scheme 16F below.
  • the reduction step can be carried out in the presence of a suitable reducing agent such as lithium borohydride in a suitable solvent such as tetrahydrofuran.
  • a suitable reducing agent such as lithium borohydride
  • a suitable solvent such as tetrahydrofuran.
  • the oxidation to the aldehyde can be carried out under Swern conditions such as oxalyl chloride and DMSO in DCM.
  • the compound of formula (TVF) can be alkylated via reductive alkylation using standard methods, as those mentioned above with the ketone An-CO-R 3 .
  • compound of formula (INF) can be alkylated with an aldehyde of formula:
  • the intermediate aldehyde can be prepared from the commercially available 2-formyl phenyl boronic acid via palladium coupling in the presence of 3-bromopyridine, a suitable palladium catalyst such as Pd(PPh 3 ) 4 and a suitable base such as potassium carbonate in a suitable solvent such as acetonitrile, as shown in Scheme 18F below.
  • the pyrazole group can be incorporated by reacting a compound of formula (VETF) m ' ⁇ wherein L 5 is a suitable leaving group such as bromo, chloro or iodo, with pyrazole in the presence of a suitable base such as potassium carbonate and a catalytic amount of copper iodide in a suitable solvent such as for example DMF.
  • a suitable base such as potassium carbonate
  • a catalytic amount of copper iodide in a suitable solvent such as for example DMF.
  • the compound of formula (NIEF) m > can be prepared by any of the methods mentioned above for compounds wherein Ari is a phenyl group substituted with a halogen atom such as chloro, bromo or iodo.
  • any of the intermediates (VEBF), (VETF) a-m are then deprotected using suitable deprotecting conditions such as those discussed in Greene, to give the corresponding compounds of formula (BF).
  • suitable deprotecting conditions such as those discussed in Greene
  • the protecting group is a boc group
  • the deprotection reaction can be carried out in trifluoroacetic acid in a suitable solvent such as DCM.
  • the reaction can be carried out in ethanolic hydrochloric acid.
  • the sequence is preferably performed on a polystyrene resin.
  • R 1 and Ar ! have the values defined above for formula (BF).
  • the sequence is performed without characterisation of the resin-bound intermediates.
  • 3- trifluoroacetamido-piperidine is bound to a solid support by reaction with 4-nitrophenyl carbonate activated polystyrene resin in the presence of a base, such as N,N- diisopropylethyl amine, in a solvent such as DMF.
  • the trifluoroacetamido protecting group is cleaved by hydrolysis with a base such as aqueous lithium hydroxide.
  • step (iii) the primary amine is then condensed with a substituted benzaldehyde in the presence of a dehydrating agent, such as trimethylorthoformate, to form the intermediate imine.
  • a dehydrating agent such as trimethylorthoformate
  • the imine is reduced with a borane reducing agent, such as sodium cyanoborohydride, in a solvent such as DMF, containing acetic acid.
  • step (v) the resultant secondary amine is then reductively alkylated with an aldehyde in the presence of a reducing agent such as sodium triacetoxyborohydride in a solvent, such as DMF.
  • a reducing agent such as sodium triacetoxyborohydride in a solvent, such as DMF.
  • the desired product is finally cleaved from the resin with acid, such as aqueous trifluoroacetic acid.
  • Compounds of formula (IG) may be prepared by conventional organic chemistry techniques from N-protected-2-cyanomorpholines as outlined in Error! Reference source not found.G below, wherein R and R 2 have the values defined for formula (IG) above and P is a suitable nitrogen protecting group such as those described in T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1991, hereafter referred to as "Greene”.
  • a suitable nitrogen protecting group is a benzyl group:
  • the ketone is stereoselectively reduced to the corresponding (2S) or (2R) alcohol of formula (TVG) or (IVG) a using standard methods known in the art. For example it can be reduced in the presence of [(-)-B-chlorodiisopinocampheylborane] in a suitable solvent such as tetrahydrofuran (THF) to provide the (2S) alcohol.
  • a suitable solvent such as tetrahydrofuran (THF)
  • Suitable leaving groups include halo groups, such as bromo, chloro or iodo and sulfonate groups, such as mesylate.
  • L is a halo group
  • the alcohol used will be the (2S) enantiomer (TVG) and it will be reacted with inversion of stereochemistry.
  • the bromination reaction can be carried out in the presence of a brominating agent such as triphenylphosphine dibromide, in a suitable solvent such as chloroform.
  • the alcohol used will be the (2R) enantiomer (IVG) a and it will be reacted with retention of stereochemistry in the presence of mesylate chloride and a suitable base.
  • the resulting intermediate of formula (VG) can then be converted into the corresponding methylethanethioate of formula (VIG) via displacement of the leaving group with a suitable thiolacetate salt such as potassium thiolacetate in the presence of a suitable solvent such as a mixture of dimethylformamide (DMF) and tetrahydrofuran (THF).
  • a suitable thiolacetate salt such as potassium thiolacetate
  • a suitable solvent such as a mixture of dimethylformamide (DMF) and tetrahydrofuran (THF).
  • the methanethiol intermediate of formula (VEG) can be prepared via reaction of the methylethanethioate (VIG) with a suitable thiomethoxide such as sodium thiomethoxide in the presence of a suitable solvent such as methanol (one can use a variety of bases but thiomethoxide is preferred because it also acts as a reducing agent and prevents oxidation of thiol hence inhibiting dimerisation; Ref: O.B.Wallace & D.M.Springer, Tetrahedron Letters, 1998, 39 (18), pp2693-2694).
  • a suitable thiomethoxide such as sodium thiomethoxide
  • a suitable solvent such as methanol
  • the pyridyl portion of the molecule is incorporated via general methods known in the art.
  • a particularly useful method is the reaction of the methanethiol (VEG) with a compound of the formula
  • R 1 has the values defined above and Li is a suitable leaving group such as fluoro, bromo, chloro, iodo or mesylate, in the presence of suitable base such as sodium hydride, cesium fluoride or sodium methoxide, in a suitable solvent such as DMF.
  • suitable base such as sodium hydride, cesium fluoride or sodium methoxide
  • the final step for the preparation of compounds of formula (IG) comprises deprotection of the morpholine ring.
  • Conditions for the deprotection depend on the protecting group chosen. Suitable deprotecting conditions can be found in Greene.
  • the deprotection reaction can be carried out in the presence of polymer supported diisopropylamine (PS-DIEA) and 1-chloroethyl chloroformate (ACE-C1) in a suitable solvent such as dichloromethane, followed by reaction with methanol to give compounds of formula (IG).
  • PS-DIEA polymer supported diisopropylamine
  • ACE-C1 1-chloroethyl chloroformate
  • Compounds of formula (IG) can alternatively be prepared by the derivatisation of a suitable substituent in the pyridyl ring to give the desired substituent R 1 as shown in Scheme 3G below.
  • compounds of formula (IG) wherein -R 1 is -CF 3 can be prepared via reaction of the intermediate (KG)' wherein z is introduced into the molecule in place of R 1 in formula (VIEG) as shown in Error! Reference source not found.G above.
  • the group L 2 is a suitable leaving group such as for example iodo, bromo, chloro or fluoro.
  • the leaving group is converted into a trifluoromethyl group via reaction in the presence of copper iodide, a suitable base such as for example potassium fluoride, and a suitable source of a trifluoromethyl group such as for example (trifluoromethyl)trimethylsilane, in a suitable solvent such as for example a mixture of DMF and N-methyl-pyrrolidinone (NMP).
  • a suitable solvent such as for example a mixture of DMF and N-methyl-pyrrolidinone (NMP).
  • reaction can be carried out via general methods known in the art.
  • the intermediate (VIG) can be reacted with a compound of formula (VIEG), wherein R 1 and Li have the values defined above, in the presence of a suitable base such as sodium methoxide, in a suitable solvent such as for example DMF.
  • intermediates of formula (VEIG) wherein R 1 is a group of formula (i) and -Z- is a bond can be prepared via palladium coupling as illustrated in Error! Reference source not found.G below.
  • the reaction is carried out via reaction of readily available pyridines of formula (XEG) wherein Li has the values mentioned above and L 3 is a suitable leaving group such as for example a halogen group such as bromo or chloro, with the corresponding phenylboronic acid of formula (XEIG), in the presence of a suitable palladium catalyst such as for example palladium acetate, a suitable ligand such as triphenylphosphine, in a suitable solvent such as acetonitrile.
  • a suitable palladium catalyst such as for example palladium acetate
  • a suitable ligand such as triphenylphosphine
  • O- can be prepared by the method illustrated below in Error! Reference source not found.G.
  • Scheme 8G Readily available pyridinols of formula (XVEG), wherein Li has the values mentioned above react with phenylboronic acids of formula (XEIG) in the presence of copper(E)acetate, powdered 4 ⁇ molecular sieves, and a suitable base such as triethylamine, in a suitable solvent such as for example dichloromethane to give intermediates of formula (VEIG) wherein R* is a group of formula (i) and -Z- is -O-.
  • compounds of formula (IG) wherein -X- is -O- may alternatively be prepared by the reaction of the (2S) alcohol (TVG) with a pyridine of the formula (NIEG), where Li is preferably chloro and R 1 has the values defined for formula
  • IG IG
  • a suitable base such as potassium hydroxide
  • a suitable solvent such as benzene or toluene
  • a suitable phase transfer catalyst such as 18- Crown-6 as described by A.J.S. Duggan et al, in Synthesis, 1980, 7, p573.
  • the resultant oil was dissolved in dichloromethane (5 ml), and trifluoroacetic acid (2 ml) added. Reaction was monitored by thin layer chromatography (100% ethyl acetate; reactant. r.f. 0.4, product r.f. 0.0). After 2 hours, reaction was concentrated in vacuo, azeotroped with dichloromethane (c.a. 25 ml), taken up in methanol (c.a. 5 ml), and passed through an SCX-2 column. The resultant colourless oil was purified using reverse phase chromatography, concentrated in vacuo, taken up in 5 M hydrochloric acid (10 ml), and heated to 90°C for 3 hours.
  • This oil was further purified by automated flash chromatography using an ISCO Combiflash system (SiO 2 (120 g); ethyl acetate gradient elution over 40 minutes) to give 1,1- dimethylethyl 4-[( ⁇ 2-biphenyl ⁇ methyl)(3,3-dimethylbutyl)amino]piperidine-l- carboxylate as a yellow oil (0.549 g, 82%).
  • TFA trifluoromethanesulfomc acid
  • the chlorinated organic layer was then run through a hydrophobic frit then diluted with methanol (10 ml) and loaded onto an SCX-2 (10 g) column.
  • the column was washed with methanol (50 ml) then basic material eluted with 2N ammonia in methanol.
  • the ammonia/methanol solution was concentrated in vacuo to give a pale yellow oil (1.2 g).
  • the dichloromethane layer was passed through a hydrophobic frit then diluted with methanol (10 ml). This solution was loaded onto an SCX-2 (10 g) column. The column was washed with methanol (50 ml) then basic material was eluted using 2N ammonia in methanol (50 ml). Concentration of the ammonia/methanol solution under vacuum yielded a colourless oil (0.344 g, 90%). To a solution of this oil (0.344 g, 0.74 mmole, 1.0 eq.) in dichloromethane (10 ml) was added trifluoroacetic acid (TFA) (0.83 ml, 11.2 mmole, 15 eq).
  • TFA trifluoroacetic acid
  • Example 6A N-(3-methylbutyl)-N-r(2-phenoxyphenyl)methyIlpiperidin-4-amine difumarate (i) To 10% Pd/C (1.0 g, 10%wt), under nitrogen, was added a solution of the 1-
  • Boc-4-piperidone (10.0 g, 50.1 mmole, 1.0 eq.) and isoamylamine (4.46 g, 51.2 mmole, 1.02 eq.) in ethanol (60 ml). This was hydrogenated overnight, at 60 psi using a Parr hydrogenator. The catalyst was removed by filtration through Celite. Solvent was removed under vacuum to give 1,1-dimethylethyl 4-[(3-methylbutyl)amino]piperidine-l- carboxylate as a colourless, slightly cloudy, oil (13.59 g, 100%).
  • the aqueous layer (176 kg) was separated after 35 minutes of post-stirring allowing the mixture to reach 15 °C and the toluene layer was washed with ultra pure water (142.5 L) and the aqueous layer (162 kg) was separated.
  • the organic layer was then concentrated under reduced pressure (150 mbars) maintaining Tmass ⁇ 60 °C in order to distill 162 kg of toluene.
  • the filtrates were then diluted with toluene (114 L) and treated with SiO 2 (Merck silica gel 60, 0.063-0.1 mm, 74.1 kg) under agitation at room temperature for 1.25 h. SiO was filtered and rinsed with toluene (2x114 L). Then, the filtrates were concentrated under reduced pressure (150 mbars) maintaining Tmass ⁇ 60 °C in order to distill 351.8 kg of toluene (KF : 0.01 % w/w H 2 O).
  • the toluene layer was cooled to 0°C and a 5 N NaOH aqueous solution (420.1 kg) was slowly added maintaining the temperature at - 2.4 °C ⁇ Tmass ⁇ 11 °C.
  • the reaction mixture was post-stirred for lh and the aqueous layer (494.8 kg) was extracted.
  • the toluene layer was concentrated under reduced pressure (50 mbars) maintaining Tmass ⁇ 60 °C in order to distill 356.2 kg of toluene and isopropanol (180.4 kg) was added.
  • the toluene was stripped off under reduced pressure (100 mbars) maintaining Tmass ⁇ 60 °C in order to distill 186.4 kg of toluene and isopropanol (135 kg) was added again to the mixture.
  • a last distillation of toluene was performed under reduced pressure (50 mbars) maintaining Tmass ⁇ 60 °C in order to distill 131 kg of toluene and isopropanol (49.4 kg) was finally added to the mixture and the solution was stirred at RT until crystallization (17 minutes).
  • Ultra pure water was added (125.4 L) and the mixture was stirred overnight at RT and cooled down to about 0 °C for 1 hour.
  • Neat (5-Fluoro-2-methoxy-phenyl)-methanol (19.587g, 1 equiv.) was added to neat SOCl (42.2 mL, 4.6 equiv.) at -78°C under a nitrogen atmosphere and the solution was then allowed to warm to room temperature and stirred until evolution of gas had ceased.
  • An equivalent volume of anhydrous toluene was added to the flask and the solution heated to 60°C On cooling the reaction solution was poured onto ice water. The toluene layer was separated and dried (MgSO 4 ) and the solvent removed under reduced pressure.
  • Example IB (S, R)-2-(2-Methoxy-phenyl)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride.
  • Example 2B (S, R) 2-(2-Ethoxy-phenyl)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride.
  • Example 3B S, R) 2-(2-Isopropoxy-phenyI)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride.
  • Example 4B (S, R) l-(3-Fluoro-phenyl)-2-(2-methoxy-phenyl)-l-morpholin-2-yl- ethanol hydrochloride
  • the active enantiomer was obtained after a further preparative chiral HPLC separation.
  • the active enantiomer, a white solid, was next taken up in ethanol and hydrogen chloride was added (large excess of 2M solution in diethyl ether) and the mixture was stirred until it became a clear solution. Then all the volatiles were evaporated in vacuo, to give 447mg of the title compound as white solid.
  • PrOH 375 mL
  • 5% Pd/C (30 g, 50% water, Johnson & Matthey type 440).
  • the heterogeneous reaction mixture was then purged 5 times with 25 psi nitrogen then purged 5 times with 50 psi hydrogen, and the hydrogenation was performed at RT.
  • the initial Tmass was 22°C and the maximum Tmass during the hydrogenation was 23°C.
  • the reactor was stirred vigorously. In-process analysis after 2 hours indicated complete hydrogenolysis. The hydrogenation was stopped after 3 hours.
  • the nitrogen purged reaction mixture was then filtered at RT through an hyflo filter (56 g), impregnated beforehand with 75 mL of a 50/50 v/v isopropanol/water mixture and washed with 300 mL of a 50/50 v/v isopropanol/water mixture.
  • the filtrates were stored overnight at RT.
  • the filtrates were concentrated at 40-50°C under reduced pressure (typical 622 g distilled).
  • the reaction mixture was cooled to RT and post-agitated. After 3 hours, 1 mL of the solution was taken and cooled to 0°C to initiate crystallization. These seeds were added to the reaction mixture and precipitation was observed within a few minutes.
  • the mixture was post-agitated at RT for 2 hours.
  • the crystals were filtered and rinsed with H 2 O (30 mL).
  • the precipitate was dried under reduced pressure (400 mmHg) with a nitrogen flow (0.1 bar) for 4 hours affording the title compound as the hydrate polymorph (103.5 g, 81% yield).
  • Example 8B (S , R) 2 - ( 5 -Fluoro-2 -methoxy-phenyl ) -1-morpholin- 2 -yl - 1 -phenyl - ethanol hydrochloride
  • a glass hydrogenation flask was loaded with methanol (1.55 L), Pd/C (10%, 31 g,

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Manufacturing & Machinery (AREA)
  • Ceramic Engineering (AREA)
  • Neurosurgery (AREA)
  • Medicinal Chemistry (AREA)
  • Materials Engineering (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Structural Engineering (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Selective norepinephrine reuptake inhibitors are used to treat cognitive failure.

Description

TREATMENT OF COGNITIVE FAILURE
Background of the Invention
Field of the Invention
The present invention relates to the fields of pharmaceutical chemistry and central nervous system medicine. More particularly, the present invention provides pharmaceutical formulations and methods of treatment for cognitive failure due to a wide variety of different etiologies, or associated with a number of different conditions or disorders.
Description of Related Art
Cognitive failure, also variously referred to as "cognitive insufficiency," "cognitive deficit," "cognitive impairment," "cognitive dysfunction," and the like, refers to the dysfunction, diminution, or loss of one or more cognitive functions, the processes by which knowledge is acquired, retained, and used. Cognitive dysfunction includes cognitive changes associated with ageing ("age-associated memory impairment"), as well as changes due to other causes. Cognitive impairment is most commonly due to a delirium or dementia, but can also occur in association with a number of other medical or neuropsychiatric disorders. More focal cognitive deficits are diagnosed using the criteria disclosed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR™, 2000), American Psychiatric Association, Washington, D.C., as either amnestic disorders (affecting memory) or cognitive disorder not otherwise specified (NOS), which includes executive dysfunction, visuospatial/visuocontructional impairment, attentional deficits, disorientation, etc. These more focal cognitive disorders also have a wide variety of causes, some of which are of unknown etiology.
A delerium is characterized by a disturbance of consciousness with a reduced ability to focus, sustain, or shift attention and a change in cognition that develops over a short period of time. Delirium is very common, and occurs on average in about a fifth of general hospital inpatients, and is even more common in nursing home patients and those with terminal illnesses. The disorders included in the "Delirium" section of the DSM-IV- TR™ are listed according to presumed etiology: Delirium Due to a General Medical Condition, Substance-Induced Delirium (i.e., due to a drug of abuse, a medication, or toxin exposure), Delirium Due to Multiple Etiologies, or Delirium Not Otherwise Specified (if the etiology is indeterminate). As disclosed by Wise et al. ((2002) Delirium (Confusional States), In Wise and Rundell, Eds., The American Psychiatric Publishing 5 Textbook of Consultation-Liaison Psychiatry, Psychiatry in the Medically III, Second
Edition, American Psychiatric Publishing, Inc., Washington, D.C., Chapter 15, pp. 257- 272, Table 15-4), exemplary etiological bases of delirium include, but are not limited to, infection, withdrawal from alcohol and drugs, acute metabolic conditions, trauma of various types, CNS pathologies, hypoxia, vitamin deficiencies, endocrinopathies, acute
L 0 vascular conditions, toxins or drugs, and heavy metals.
A dementia is a chronic condition, usually with a more gradual deterioration of memory and other intellectual functioning and other cognitive skills severe enough to interfere with the ability to perform activities of daily living. Although dementia may occur at any age, it primarily affects the elderly, presenting in more than 15% of persons
L 5 over 65 years of age and in as many as 40% of persons over 80 years old. Dementia accounts for more than half of nursing home admissions.
Dementia due to Alzheimer's disease is particularly common. It affects four million Americans, at an annual cost of about $90 billion, including medical and nursing home care, social services, lost productivity, and early death. Alzheimer's disease
. 0 accounts for more than 65% of the dementias in the elderly.
Non- Alzheimer's cognitive impairments and/or dementias include, for example, those caused by or associated with: vascular diseases; Parkinson's disease; Lewy body disease (diffuse Lewy body disease); HIN/AIDS; mild cognitive impairments; mild nuerocognitive disorders; age-associated memory impairments; neurologic and/or
15 psychiatric conditions including epilepsy and epilepsy treatments; brain tumors, cysts, lesions, or other inflammatory brain diseases; multiple sclerosis; Down's syndrome; Rett's syndrome; progressive supranuclear palsy; frontal lobe dementia syndromes; schizophrenia and related psychiatric disorders; antipsychotic medications; traumatic brain injury (closed head injury), dementia pugilistica, and other head traumas; normal-
> 0 pressure hydrocephalus; surgery (including coronary artery by-pass graft surgery) and anaesthesia, electroconvulsive shock therapy, and cancer and cancer therapies. The dementias are also listed in the "Dementia" section of the DSM-IV-TR™ according to presumed etiology: Dementia of the Alzheimer's Type, Vascular Dementia, Dementia Due to Other General Medical Conditions (e.g., human immunodeficiency virus [HIV] disease, head trauma, Parkinson's disease, Huntington's disease), Substance- 5 Induced Persisting Dementia (i.e., due to a drug of abuse, a medication, or toxin exposure), Dementia Due to Multiple Etiologies, or Dementia Not Otherwise Specified (if the etiology is indeterminate). As disclosed by Gray and Cummings ((2002) Dementia, In Wise and Rundell, Eds., The American Psychiatric Publishing Textbook of Consultation-Liaison Psychiatry, Psychiatry in the Medically III, Second Edition,
L 0 American Psychiatric Publishing, Inc., Washington, D.C., Chapter 16, pp. 273-306, Table
16-1), exemplary etiological bases of principal dementia syndromes include, but are not limited to, degenerative disorders (cortical and subcortical), vascular disorders, myelinoclastic disorders, traumatic conditions, neoplastic disorders, hydrocephalic disorders, inflammatory conditions, infections, toxic conditions, metabolic disorders, and
L5 psychiatric disorders.
An amnestic disorder is characterized by memory impairment in the absence of other significant accompanying cognitive impairments. The disorders in the "Amnestic Disorders" section of the DSM-IV-TR™ are also listed according to presumed etiology: Amnestic Disorder Due to a General Medical Condition, Substance-Induced Persisting
20 Amnestic Disorder, or Amnestic Disorder Not Otherwise Specified.
Cognitive Disorder Not Otherwise Specified in the DSM-IV-TR™ covers presentations that are characterized by cognitive dysfunction presumed to be due to either a general medical condition or substance use that do not meet criteria for any of the disorders listed elsewhere in the section of the DSM-IV-TR™ entitled "Delirium, 5 Dementia, and Amnestic and Other Cognitive Disorders."
Dementia, amnestic disorders, and cognitive disorders NOS occur in patients with a wide variety of other disorders including, but not limited to, Huntington's disease (chorea); Pick's disease; spinocerebellar ataxias (types 1-11); corticobasalganglionic degeneration; neuroacanthocytosis; dentatorubropallidoluysian atropy (DRPLA); systemic 0 lupus erythematosus; heavy metal intoxication; alcoholic dementia (Wernicke's encephalopathy); fetal alcohol syndrome; single or multiples strokes, including small vessels (Binswanger's dementia: subcortical arteriosclerotic encephalopathy) and large vessels (multi-infarct dementia); anoxic encephalopathy; tumors; birth anoxia; premature birth; inborn errors of metabolism; neurofibromatosis (Type I); tuberous sclerosis; Hallervorden Spatz disease; Wilson's disease; post-infectious sequelae (e.g., tuberculosis, viral encephalitis, bacterial meningitis); subdural hematoma; subcortical dementia; 5 Creutzfeldt- Jakob disease; Gerstmann-Straussler-Scheinker disease; general paresis; and syphilis.
Current treatments for cognitive failure include compounds that enhance cholinergic transmission such as donepezil, rivastigmine, galantamine, and tacrine. The use of these agents is limited by side effects including changes in vision or balance,
L 0 diarrhea, dizziness, fainting spells or falls, increase in frequency of passing urine or incontinence, nervousness, agitation, increased confusion, skin rash or hives, slow heartbeat or palpitations, stomach pain, sweating, uncontrollable movements, unusual bleeding or bruising, red or purple spots on the skin, vomiting, and weight loss. Another therapy is the administration of the ergot hydergine. Hydergine therapy may require six
L 5 months to determine whether the drug has been effective, and side effects include nausea.
The FDA has recently approved the noncompetitive NMDA antagonist memantine for the treatment of moderate to late-stage Alzheimer's disease. Noted side effects include hallucinations, confusion, dizziness, headache, and tiredness.
Additional therapies are needed for the treatment of cognitive failure that are more
! 0 efficacious and better tolerated than treatments that are currently available.
Summary of the Invention
Accordingly, the present invention provides the use of a selective norepinephrine reuptake inhibitor for the preparation of a medicament for the treatment or prevention of
5 cognitive failure.
In the case of Alzheimer's disease and Parkinson's disease, the selective norepinephrine reuptake inhibitor can be used alone, or in combination with a conventional Alzheimer's or Parkinson's agent, for the treatment of cognitive failure associated with the particular disease.
0 Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the present invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
Detailed Description of the Invention
The following detailed description of the invention is provided to aid those skilled in the in practicing the present invention. Even so, the following detailed description should not be construed to unduly limit the present invention as modifications and variations in the embodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.
The contents of each of the references cited herein are herein incorporated by reference in their entirety.
The present invention provides methods for the treatment of cognitive failure, which may occur due to a wide variety of different causes, or in conjunction with a number of different disorders or conditions.
The term "cognitive failure," or equivalents such as "cognitive insufficiency," "cognitive deficit," "cognitive impairment," "cognitive dysfunction," and the like, as used herein refers to the dysfunction, diminution, or loss of one or more cognitive functions, and includes the spectrum of cognitive dysfunctions ranging from mild cognitive impairment to deterioration of intellectual function and other cognitive skills severe enough to interfere with the ability to perform activities of daily living. The term "cognitive function" as used herein is a multidimensional concept that refers to the processes by which knowledge is acquired, retained, and used, and includes, but is not limited to, any one or more of the processes of attention, concentration, learning, memory, thinking, organization, problem-solving ability, visuospatial abilities, mental flexibility, psychomotor efficiency, and manual dexterity.
The methods for the prevention or treatment of cognitive failure encompassed by the present invention rely on a novel mechanism of action, i.e., selective inhibition of norepineprhine reuptake, and comprise administering to a mammal in need of such prophylactic or therapeutic treatment an effective amount of a selective norepinephrine reuptake inhibitor. This mechanism is operative in mammals, with the preferred mammal being a human. Norepinephrine Reuptake Inhibitors Useful in the Present Invention
Many compounds, including those discussed at length below, are selective norepinephrine reuptake inhibitors, and no doubt many more will be identified in the future. In the practice of the present invention, it is intended to include reuptake inhibitors which show 50% effective concentrations of about 1000 nM or less, in the protocol described by Wong et al, Drug Development Research, 6, 397 (1985). The norepinephrine reuptake inhibitors useful for the method of the present invention are characterized in being selective for the inhibition of neurotransmitter reuptake relative to their ability to act as direct agonists or antagonists at other receptors. It is preferred that the compounds useful for the method of the present invention are selective for the inhibition of norepinephrine reuptake relative to direct agonist or antagonist activity at other receptors by a factor of at least ten. Preferably, compounds useful for the method of the present invention are selective for the inhibition of norepinephrine reuptake relative to direct agonist or antagonist activity at other receptors by a factor of at least one hundred. Norepinephrine reuptake inhibitors useful in the compositions and methods of the present invention include, but are not limited to,:
1. Atomoxetine (formerly known as tomoxetine), (R)-(-)-N-methyl-3-(2-methyl- phenoxy)-3-phenylpropylamine, is usually administered as the hydrochloride salt. Atomoxetine was first disclosed in U.S. Patent No. 4,314,081. The term "atomoxetine" will be used here to refer to any acid addition salt or the free base of the molecule. See, for example, Gehlert et al. (1993) Neuroscience Letters 157:203-206, for a discussion of atomoxetine's activity as a norepinephrine reuptake inhibitor;
2. Reboxetine (Edronax™; Prolift™; Vestra™; Norebox™), 2-[α-(2- ethoxy)phenoxy-benzyl]morpholine, first disclosed in U.S. Patent 4,229,449 for the treatment of depression, is usually administered as the racemate. Reboxetine is a selective norepinephrine reuptake inhibitor. The term "reboxetine" as used herein refers to any acid addition salt or the free base of the molecule existing as the racemate or either enantiomer, i.e., (S,S)-reboxetine or (R,R)-reboxetine. The use of (S,S)-reboxetine as a preferred selective norepinephrine reuptake inhibitor is disclosed in PCT International Publication No. WO 01/01973.
3. Compounds of formula I:
Figure imgf000009_0001
(D wherein X is Cι-C4 alkylthio, and Y is Cι-C alkyl or a pharmaceutically acceptable salt thereof. The compounds of formula I have been described in U.S. Patent 5 No. 5,281,624, and in Gehlert et al. (1995) Life Sciences, 55(22): 1915-1920. These compounds are disclosed as being inhibitors of norepinephrine reuptake in the brain. It should be noted that these compounds exist as stereoisomers, and accordingly include not only the racemates, but also the isolated individual isomers as well as mixtures of the individual isomers. For example, the compounds of formula I include the following L 0 exemplary species:
N-ethyl-3-phenyl-3-(2-methylthiophenoxy)propyl-amine benzoate; (R)-N-methyl-3-phenyl-3-(2-propylthiophenoxy)-propylamine hydrochloride;
(S)-N-ethyl-3-phenyl-3-(2-butylthiophenoxy)propyl-amine; L 5 N-methyl-3-phenyl-3-(2-ethylthiophenoxy)propyl-amine malonate;
(S)-N-methyl-3-phenyl-3-(2-tert-butylthiophenoxy)-propylamine naphthalene-2-sulfonate; and
(R)-N-methyl-3-(2-methylthiophenoxy)-3-phenyl-propylamine. 4. A compound of formula (IA)
Figure imgf000009_0002
(IA) wherein n is 1, 2 or 3; RI is C2-CiQalkyl, C2-Cιoalkenyl, C3-Cgcycloalkyl or C4- CiQcycloalkylalkyl, wherein one C-C bond within any cycloalkyl moiety is optionally substituted by an O-C or C=C bond and wherein each group is optionally substituted with from 1 to 7 halogen substituents and/or with from 1 to 3 substituents each independently selected from hydroxy, cyano, Cj-C4alkyl and Cι~C4alkoxy; R2 is H, Ci -C4alkyl
(optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkyl-S(O)x- wherein x is
5 0, 1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alko y
(optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and Ci -C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι-C4alkyl and C -G^alkoxy) or
L 0 -CO2(Ci -C4alkyl), or together with R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -
C4alkyl and C;[-C4alkoxy); R3 is H, C1-C4 alkyl (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkyl-S(O)x- wherein x is 0, 1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkoxy (optionally substituted with from 1 to 7
.5 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι-G alkyl and Cι-C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι-C4alkyl and Ci -C4alkoxy) or -CO2(Ci -C4alkyl), or together with R2 or R4 forms a further benzene ring (optionally substituted with from 1 to 3 substituents 0 each independently selected from halogen, Ci -G4alkyl and Ci -C4alkoxy); R4 is H, Ci -
C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Cι-C4alkyl-S(O)x- wherein x is 0, 1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -
C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl
(optionally substituted with from 1 to 3 substituents each independently selected from 5 halogen, C- -C4alkyl and Cj^alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj^alkyl and Cj^alkoxy) or
-CO2(Ci -C4alkyl), or together with R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, C -
C4alkyl and Ci -C4alkoxy); R5 is H, Cj^alkyl (optionally substituted with from 1 to 7 halogen atoms), C^^alkoxy (optionally substituted with from 1 to 7 halogen atoms) or, halogen; R6 is H, Ci -C4alkyl (optionally substituted with from 1 to 7 halogen atoms),
Ci -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms) or halogen; R7 is
H or Cι-C4alkyl; R8 is H or Ci^alkyl; R9 is H, halogen, hydroxy, cyano, Cj^alkyl or Ci -C4alkoxy; and RIO is H, halogen, hydroxy, cyano, Cj^alkyl or Cι-C4alkoxy; or a pharmaceutically acceptable salt thereof, with the proviso that the compound N-ethyl- N-benzyl-4-piperidinamine is excluded.
With respect to compounds of formula (IA), the term "C2-Cιoalkyl" means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 2 to 10 carbon atoms.
With respect to compounds of formula (IA), the term "C2-Cιoalkenyl" means a monovalent unsubstituted unsaturated straight-chain or branched-chain hydrocarbon radical having from 2 to 10 carbon atoms and containing at least one carbon-carbon double bond. With respect to compounds of formula (IA), the term "C3-Cgcycloalkyl" means a monovalent unsubstituted saturated cyclic hydrocarbon radical having from 3 to 8 carbon atoms.
With respect to compounds of formula (IA), the term "C4-Cιocycloalkylalkyl" means a monovalent unsubstituted saturated cyclic hydrocarbon radical having from 3 to 9 carbon atoms linked to the point of substitution by a divalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having at least 1 carbon atom.
With respect to compounds of formula (IA), the phrase "wherein one C-C bond within any cycloalkyl moiety is optionally substituted by an O-C or C=C bond" means that either (i) any two adjacent carbon atoms within a cycloalkyl ring may be linked by a double bond rather than a single bond (with the number of substituents on each carbon atom being reduced accordingly), or that (ii) one of any two adjacent C atoms within a cycloalkyl ring (and any substituents thereon) may be replaced by an oxygen atom.
Examples of RI groups encompassed by this phrase include but are not limited to:
Figure imgf000011_0001
With respect to compounds of formula (IA), the term "halo" or "halogen" means F, Cl, Br or I.
With respect to compounds of formula (IA), the term "Cι-C4alkoxy" means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 carbon atoms linked to the point of substitution by an O atom.
With respect to compounds of formula (IA), the term "phenoxy" means a monovalent unsubstituted phenyl radical linked to the point of substitution by an O atom.
With respect to compounds of formula (IA), in the above definitions, similar terms specifying different numbers of C atoms take an analogous meaning. Preferred compounds of formula (IA) are those wherein n is 1 or 2. More preferably, n is 1.
Preferred compounds of formula (IA) are those wherein R7 is H or methyl. More preferably R7 is H.
Preferred compounds of formula (IA) are those wherein R8 is H. Preferred compounds of formula (IA) are those wherein R9 is H or fluoro. More preferably, R9 is H.
Preferred compounds of formula (IA) are those wherein R10 is H or fluoro. More preferably, R10 is H.
Preferred compounds of formula (IA) are those wherein RI is C2-C6alkyl, C2- C5alkenyl, C3-Cgcycloalkyl or C4-C7cycloalkylalkyl, each of which is optionally substituted with from 1 to 3 halogen atoms or a methoxy radical. More preferably, RI is C2-Cgalkyl (optionally substituted with from 1 to 3 halogen atoms or a methoxy radical),
C2-Cgalkenyl, C3-C6cycloalkyl or C4-C7cycloalkylalkyl. Suitable C2-Cgalkyl groups
(optionally substituted with from 1 to 3 halogen atoms or a methoxy radical) include, for example, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, 3-methylbutyl, 1,2- dimethylpropyl, 1-ethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and 2-methoxyethyl. Suitable C2-Cgalkenyl groups include, for example, 2-methyl-2-propenyl. Suitable C3-Cgcycloalkyl groups include, for example, cyclopentyl. Suitable C4-C7cycloalkylalkyl groups include, for example, cyclohexylmethyl or cyclopropylmethyl. Pref erred compounds of formula (IA) are those wherein RI is a C2-Cιoalkyl group optionally substituted with from 1 to 7 halogen substituents and/or with from 1 to 3 substituents each independently selected from hydroxy, cyano and C^-C4alko y. More preferably, RI is a C2-Cιo lkyl group optionally substituted with from 1 to 3 substituents each independently selected from halogen, hydroxy and C j-C4alkoxy. More preferably
RI is C2-C alkyl optionally substituted with from 1 to 3 halogen atoms or a methoxy radical. Still more preferably RI is C2-C6alkyl. Still more preferably, RI is selected from ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, 3-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, 3,3-dimethylbutyl and 2-ethylbutyl. Most preferably RI is selected from n- propyl, n-butyl and isobutyl.
Preferred compounds of formula (IA) are those wherein R2 is H, Cj-C4alkyl
(optionally substituted with from 1 to 7 halogen atoms), Cι-C4alkyl-S(O)x- wherein x is
0 or 2 (optionally substituted with from 1 to 7 halogen atoms), Cι-C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, C^-
C4 lkyl and C[-C4alkoxy) or phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj-C4alkyl and Cj-C4alko ), or together with R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, C j-C4alkyl and Ci -C4alkoxy). More preferably, R2 is H, Ci -C2alkyl (optionally substituted with from 1 to 5 halogen atoms), Ci -C4alkyl-S(O)x- wherein x is 0 or 2 (optionally substituted with from 1 to 5 halogen atoms), Cj -C2al oxy (optionally substituted with from 1 to 5 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C2al yl and Cj -C2alkoxy) or phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj -C2alkyl and Cι-C2alkoxy), or together with R3 forms a further benzene ring
(optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι-C2alkyl and C^-C2 lko y). Still more preferably, R2 is H, methyl, trifluoromethyl, methylthio, tert-butylthio, trifluoromethylthio, methylsulfonyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyano, fluoro, chloro, bromo, phenyl or phenoxy, or together with R3 forms a further benzene ring.
Preferred compounds of formula (IA) are those wherein R2 is not H. More preferably, R2 is Cj -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Cι - 5 C4alkyl-S(O)x- wherein x is 0 or 2 (optionally substituted with from 1 to 7 halogen atoms), Cι-C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cχ-C4alkyl and Cι~C4alko y) or phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and
.0 C -C4alkoxy), or together with R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι -Q4alkyl and
C1-C4 alkoxy). More preferably, R2 is Cι -C2alkyl (optionally substituted with from 1 to
5 halogen atoms), Ci -C2alkyl-S(0)x- wherein x is 0 or 2 (optionally substituted with from 1 to 5 halogen atoms), Cj-C2alkoxy (optionally substituted with from 1 to 5
L5 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj -C2 lkyl and Cj-C2al oxy) or phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C2alkyl and Cι-C2 l oxy), or together with R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently 20 selected from halogen, Ci -C2alkyl and Cι-C2alkoxy). Still more preferably, R2 is methyl, trifluoromethyl, methylthio, tert-butylthio, trifluoromethylthio, methylsulfonyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyano, fluoro, chloro, bromo, phenyl or phenoxy, or together with R3 forms a further benzene ring.
Preferred compounds of formula (IA) are those wherein R3 is H, Cι-C4alkyl 5 (optionally substituted with from 1 to 7 halogen atoms), Ci-C^alkyl-S- (optionally substituted with from 1 to 7 halogen atoms), Cj-C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj-C4 l yl and Cι-C4alko y), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj^alkyl and Ci -C4alkoxy) or -CO2(Ci -C4alkyl), or together with R2 or R4 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and Cι-C4alkoxy). More preferably, R3 is H, Cι -C2alkyl (optionally substituted with from 1 to 5 halogen atoms), Ci -C2alkyl-S- (optionally substituted with from 1 to 5 halogen atoms), Cι -C2alkoxy
(optionally substituted with from 1 to 5 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι -C2alkyl and Cj-C2alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C2alkyl and Ci -C2alkoxy) or -CO2(Ci -C2alkyl), or together with R2 or R4 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, C -
C2alkyl and Ci -C2alkoxy). Still more preferably, R3 is H, methyl, trifluoromethyl, trifluoromethylthio, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyano, fluoro, chloro, bromo, phenyl, phenoxy or CO2CH3, or together with R2 or R4 forms a further benzene ring.
Preferred compounds of formula (IA) are those wherein R4 is H, Cι -C4alkyl
(optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkyl-S- (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj -COalkyl and Ci -C4alkoxy), or -CO2(Ci -C4alkyl), or together with R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -
C4alkyl and Cι-C4alkoxy). More preferably, R4 is H, C^^alkyl (optionally substituted with from 1 to 5 halogen atoms), Ci -C2alkyl-S- (optionally substituted with from 1 to 5 halogen atoms), Cι~C2alkoxy (optionally substituted with from 1 to 5 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C2alkyl and Cj-C2alkoxy), or -CO2(C^-
C2alkyl), or together with R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι-C2alkyl and C - C2alkoxy). Still more preferably, R4 is H, methyl, trifluoromethyl, methylthio, methoxy, trifluoromethoxy, cyano, fluoro, chloro, phenyl or CO2CH3, or together with R3 forms a further benzene ring.
Preferred compounds of formula (IA) are those wherein R5 is H, Ci -C4alkyl (optionally substituted with from 1 to 5 halogen atoms), Ci -C4alkoxy (optionally substituted with from 1 to 5 halogen atoms) or halogen. More preferably, R5 is H, Ci -
C4alkyl, Cι -C4alkoxy or halogen. Still more preferably, R5 is H, methyl, methoxy, fluoro or chloro.
Preferred compounds of formula (IA) are those wherein R6 is H, Cι -C4alkyl (optionally substituted with from 1 to 5 halogen atoms) or halogen. More preferably, R6 is H, Cj-C4alkyl or halogen. Still more preferably, R6 is H, methyl, fluoro or chloro.
Preferred compounds of formula (IA) are those wherein the group
Figure imgf000016_0001
is phenyl, 2-methylphenyl, 2-(trifluoromethyl)phenyl, 2-(methylthio)phenyl, 2- (tertbutylthio)phenyl, 2-(trifluoromethylthio)phenyl, 2-(methylsulfonyl)phenyl, 2- methoxyphenyl, 2-ethoxyphenyl, 2-(difluoromethoxy)phenyl, 2- (trifluoromethoxy)phenyl, 2-cyanophenyl, 2-fluorophenyl, 2-chlorophenyl, 2- bromophenyl, 2-biphenyl, 2-phenoxyphenyl, 3-methylphenyl, 3-(trifluoromethyl)phenyl, 3-(trifluoromethylthio)phenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3- (difluoromethoxy)phenyl, 3-(trifluoiOmethoxy)phenyl, 3-cyanophenyl, 3-fluorophenyl, 3- chlorophenyl, 3-bromophenyl, 3-biphenyl, 3-phenoxyphenyl, 3-(methoxycarbonyl)phenyl, 4-methylphenyl, 4-(trifluoromethyl)phenyl, 4-(methylthio)phenyl, 4-methoxyphenyl, 4- (trifluoromethoxy)phenyl, 4-cyanophenyl, 4-fluorophenyl, 4-chloroρhenyl, 4-biphenyl, 4- (methoxycarbonyl)phenyl, 2,3-dichlorophenyl, 2,4-dimethylphenyl, 2,4- bis(trifluoromethyl)phenyl, 2,4-dimethoxyphenyl, 2,4-difluoroρhenyl, 2,4-dichlorophenyl,
2,5-dimethylphenyl, 2,6-dimethylphenyl, 2,6-dichlorophenyl, 2-chloro-6-fluorophenyl, 2- fluoro-6-(trifluoromethyl)phenyl, 3,4-dichlorophenyl, 3,5-dimethylphenyl, 3,5- dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3-fluoro-5- (trifluoromethyl)phenyl, 5-fluoro-2-(trifluoromethylphenyl), 5-fluoro-2-methoxyphenyl, 4-fluoro-2-(trifluoromethyl)ρhenyl, 1 -naphthyl or 2-naphthyl.
A further embodiment provides a group (Group A) of compounds of formula (IA) 5 above, wherein R2, R3, R4, R5 and R6 are all H.
A further embodiment provides a group (Group B) of compounds of formula (IA) above, wherein one of R2, R3, R4, R5 and R6 is not H and the others are H.
Compounds of Group B include those (Group B2) wherein R3, R4, R5 and R6 are all H and R2 is Cι -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Ci -
10 C4alkyl-S(O)x- wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, C\ -COalkyl and Cj-C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj-C4alkyl and
L 5 C -C4alkoxy) or -CO2(C i -C4alkyl) .
Compounds of Group B also include those (Group B3) wherein R2, R4, R5 and R6 are all H and R3 is Ci -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Cι-C4alkyl-S(O)x- wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms),
.0 cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and Ci -C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -
C4alkyl and Ci -C4alkoxy) or -CO2(Ci -C4alkyl).
Compounds of Group B also include those (Group B4) wherein R2, R3, R5 and 15 R6 are all H and R4 is Ci -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkyl-S(O)x- wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Cj^alko y (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj^alkyl and Ci -C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci - C4alkyl and Ci-C^alkoxy) or -CO2(Ci -COalkyl).
A further embodiment provides a group (Group C) of compounds of formula (IA) above, wherein two of R2, R3, R4, R5 and R6 are not H and the others are H. 5 Compounds of Group C include those (Group C2,3) wherein R4, R5 and R6 are all H; R2 is Cι -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Ci -
C4alkyl-S(O)x- wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Cι -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently 10 selected from halogen, C]-C4alkyl and Cι -C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι-C4alkyl and
Ci -C4alkoxy) or -CO2(Cj-C4alkyl), or together with R3 forms a further benzene ring
(optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι -C4alkyl and Cι -C4alkoxy); and R3 is C] -C4alkyl (optionally substituted
L5 with from 1 to 7 halogen atoms), Cι-C4alkyl-S(O)x- wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -G4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and Ci -C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected > 0 from halogen, Ci -C4alkyl and Ci -C4alkoxy) or -CO2(Ci -C4alkyl), or together with R2 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and Cj-C4alkoxy).
Compounds of Group C also include those (Group C2,4) wherein R3, R5 and R6 are all H; R2 is Cj-C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Cj-
!5 C4alkyl-S(O)x- wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), C1-C4 alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι -G4alkyl and Cι-C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci-Cψalkyl and Cι-C4alkoxy) or -CO2(Ci -C4alkyl); and R4 is Ci -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Cι -C4alkyl-S(O)x- wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Cj-C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj-C4alkyl and Cι-C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι-C4alkyl and Ci -C4alkoxy) or -CO2(Ci -C4alkyl).
Compounds of Group C also include those (Group C2,5) wherein R3, R4 and R6 are all H; R2 is Cj-C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Cι - C4alkyl-S(O)x- wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and C;[-C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι-C4alkyl and Cι-C4alkoxy) or -CO2(Ci-C4alkyl); and R5 is Cι-C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms) or halogen.
Compounds of Group C also include those (Group C2,6) wherein R3, R4 and R5 are all H; R2 is Ci -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), C - C4alkyl-S(O)x- wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Cι -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj-C4alkyl and Cj-C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and C ι -C4alkoxy) or -CO2(C \ -C4alkyl) ; and R6 is C 1 -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Ci -Gψalkoxy (optionally substituted with from 1 to 7 halogen atoms) or halogen.
Compounds of Group C also include those (Group C3,4) wherein R2, R5 and R6 are all H; R3 is Cj -C4 alkyl (optionally substituted with from 1 to 7 halogen atoms), C\- C4alkyl-S(O)x- wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), C1 -C4 alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj -C4alkyl and Ci -C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj -C4alkyl and
Cι-C4alkoxy) or -CO2(Ci -C4alkyl), or together with R4 forms a further benzene ring
(optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι -C4alkyl and Cι-G4alkoxy); and R4 is Cι -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Cι -C4alkyl-S(O)x- wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Cι -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and Cι-C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι~C4alkyl and Ci -C4alkoxy) or -CO2(Ci -C4alkyl), or together with R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj-C4alkyl and Ci -C4alkoxy).
Compounds of Group C also include those (Group C3,5) wherein R2, R4 and R6 are all H; R3 is Ci -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), C -
C4alkyl-S(O)x- wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj-C4alkyl and Cι -C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and
Ci -C4alkoxy) or -CO2(Ci -C4alkyl); and R5 is Cι-C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Cι-C4alkoxy (optionally substituted with from 1 to 7 halogen atoms) or halogen.
For compounds of Formula (IA) falling within any one of groups A, B, B2, B3, B4, C, C2,3, C2,4, C2,5, C2,6, C3,4 and C3,5 described above, n is preferably 1 or 2, more preferably 1. For compounds of Formula (IA) falling within any one of groups A, B, B2, B3, B4, C, C2,3, C2,4, C2,5, C2,6, C3,4 and C3,5 described above, R7 is preferably H or methyl, more preferably H.
For compounds of Formula (IA) falling within any one of groups A, B, B2, B3, B4, C, C2,3, C2,4, C2,5, C2,6, C3,4 and C3,5 described above, R8 is preferably H.
For compounds of Formula (IA) falling within any one of groups A, B, B2, B3, B4, C, C2,3, C2,4, C2,5, C2,6, C3,4 and C3,5 described above, R9 is preferably H or fluoro, more preferably H.
For compounds of Formula (IA) falling within any one of groups A, B, B2, B3, B4, C, C2,3, C2,4, C2,5, C2,6, C3,4 and C3,5 described above, RIO is preferably H or fluoro, more preferably H.
For compounds of Formula (IA) falling within any one of groups A, B, B2, B3, B4, C, C2,3, C2,4, C2,5, C2,6, C3,4 and C3,5 described above, RI is preferably a C2-
C1 øalkyl group optionally substituted with from 1 to 7 halogen substituents and/or with from 1 to 3 substituents each independently selected from hydroxy, cyano and C\-
C4alkoxy.
For compounds of Formula (IA) falling within any one of groups A, B, B2, B3, B4, C, C2,3, C2,4, C2,5, C2,6, C3,4 and C3,5 described above, n is preferably 1, R7, R8, R9 and RIO are preferably H and RI is preferably a C2-CiQalkyl group optionally substituted with from 1 to 7 halogen substituents and/or with from 1 to 3 substituents each independently selected from hydroxy, cyano and Ci -C4alkoxy.
5. A compound of formula (IB)
Figure imgf000021_0001
(IB) wherein Rx is H; Ry is H or Cι-C4 alkyl; each Rz is independently H or Cι-C4 alkyl; X represents O; Y represents OH or OR; R is C1-Q alkyl; Ari is a phenyl ring or a 5- or 6- membered heteroaryl ring each of which may be substituted with 1, 2, 3, 4 or 5 substituents (depending upon the number of available substitution positions) each independently selected from Ci -C4 alkyl, O(Cι -C4 alkyl), S(Cj-C4 alkyl), halo, hydroxy, pyridyl, thiophenyl and phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci -C4 alkyl, or O(Cι -C4 alkyl); and
Ar2 is a phenyl ring or a 5- or 6-membered heteroaryl ring each of which may be substituted with 1, 2, 3, 4 or 5 substituents (depending upon the number of available substitution positions) each independently selected from C1 -C4 alkyl, O(Cι -C4 alkyl) and halo; wherein each above-mentioned C1-C4 alkyl group is optionally substituted with one or more halo atoms; or a pharmaceutically acceptable salt thereof.
Preferred compounds of formula (IB) above are those wherein Arj is phenyl, pyridyl, pyrimidyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiophenyl, furanyl, imidazolyl, triazolyl, oxadiazolyl or thiadiazolyl, each of which may be substituted with 1, 2, 3, 4 or 5 substituents (depending upon the number of available substitution positions) each independently selected from C1-C4 alkyl, O(Cι -C4 alkyl), S(C- -C4 alkyl), halo, hydroxy, pyridyl, thiophenyl and phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci -C4 alkyl, or O(Cι -C4 alkyl); and Ar2 is phenyl, pyridyl, pyrimidyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiophenyl, furanyl, imidazolyl or triazolyl each of which may be substituted with 1, 2, 3, 4 or 5 substituents (depending upon the number of available substitution positions) each independently selected from C1 -C4 alkyl, O(Cι -C4 alkyl) and halo; wherein each above-mentioned C1 -C4 alkyl group is optionally substituted with one or more halo atoms.
For the compounds of formula (IB) above, it is preferred that Ari is a phenyl ring or a 5- or 6-membered heteroaryl ring substituted with 1, 2, 3, 4 or 5 substituents, more preferably with 1 or 2 substituents.
For the compounds of formula (IB) above, when Ar] is a substituted phenyl ring or a substituted 5- or 6-membered heteroaryl ring, it is preferred that not more than one of those substituents is a pyridyl, thiophenyl or optionally substituted phenyl group.
Preferred compounds of formula (IB) above are those wherein Ari includes a substituent attached at the 2-ρosition. That is, the substituent is attached to the atom adjacent to that which forms the point of attachment of Ari to the methylene group connecting Ari to the rest of the molecule. For example, when Ari is phenyl, it is preferably ortho-substituted.
Further preferred compounds of formula (IB) above are those wherein Rx is H; Ry is H or Cι-C4 alkyl; each Rz is independently H or Cι-C4 alkyl; X represents O; Y represents OH or OR; R is Cι-C4 alkyl; and Ari and Ar2 are each independently selected from the group consisting of phenyl, and substituted phenyl; and pharmaceutically acceptable salts thereof. In this further preferred embodiment, the group Ar! may be substituted or unsubstituted phenyl. For example, Ari may be unsubstituted phenyl or, preferably phenyl substituted with 1, 2, 3, 4 or 5 substituents, preferably with 1 or 2, for example 1, substituent. When disubstituted, the substituted phenyl group is preferably substituted at the 2- and 5- positions. When monosubstituted, the substituted phenyl group is preferably substituted in the 2- position. Suitable substituents include Ci -C4 alkyl, O(Cι -C4 alkyl), S(Cι-C4 alkyl), halo, and phenyl, optionally substituted with, for example, halo, C1-C4 alkyl, or O(C]-C4 alkyl). In this further preferred embodiment, the group Ar2 may be substituted or unsubstituted phenyl. For example, Ar2 may be phenyl substituted with 1, 2, 3, 4 or 5 substituents, preferably with 1 substituent. Suitable substituents include Ci -C4 alkyl, O(Cι -C4 alkyl), and especially, halo.
"Ci -C4 alkyl" as used in respect of compounds of formula (IB) includes straight and branched chain alkyl groups of 1, 2, 3 or 4 carbon atoms, and may be unsubstituted or substituted. Ci -C2 alkyl groups are preferred. Suitable substituents include halo, especially Cl and/or F. Thus the term "Ci -C4 alkyl" includes haloalkyl. A particularly preferred substituted C j -C4 alkyl group is trifluoromethyl. Similar terms defining different numbers of C atoms (e.g. "Ci -C3 alkyl") take an analogous meaning. When Ry is Ci -C4 alkyl it is preferably unsubstituted. When Rz is C1-C4 alkyl it is preferably unsubstituted. When R is C1-C4 alkyl it is preferably unsubstituted.
"5-membered heteroaryl ring" as used in respect of compounds of formula (IB) means a 5-membered aromatic ring including at least one heteroatom independently selected from N, O and S. Preferably there are not more than three heteroatoms in total in the ring. More preferably there are not more than two heteroatoms in total in the ring. More preferably there is not more than one heteroatom in total in the ring. The term includes, for example, the groups thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, triazolyl, oxadiazolyl and thiadiazolyl.
"6-membered heteroaryl ring" as used in respect of compounds of formula (IB) means a 6-membered aromatic ring including at least one heteroatom independently selected from N, O and S. Preferably there are not more than three heteroatoms in total in the ring. More preferably there are not more than two heteroatoms in total in the ring. More preferably there is not more than one heteroatom in total in the ring. The term includes, for example, the groups pyridyl, pyrimidyl, pyrazinyl, pyridazinyl and triazinyl.
"Halo" as used in respect of compounds of formula (IB) includes F, Cl, Br and I, and is preferably F or Cl.
"Pyridyl" as used in respect of compounds of formula (IB) includes 2-pyridyl, 3-pyridyl and 4-pyridyl.
"Pyrimidyl" as used in respect of compounds of formula (IB) includes 2- pyrimidyl, 4-pyrimidyl and 5-ρyrimidyl. "Pyridazinyl" as used in respect of compounds of formula (IB) includes 3- pyridazinyl and 4-pyridazinyl.
"Pyrazinyl" as used in respect of compounds of formula (IB) includes 2- pyrazinyl and 3-ρyrazinyl.
"Triazinyl" as used in respect of compounds of formula (IB) includes 2-(l,3,5- triazinyl), 3-, 5- and 6-(l,2,4-triazinyl) and 4- and 5-(l,2,3-triazinyl).
"Thiazolyl" as used in respect of compounds of formula (IB) includes 2- thiazolyl, 4-thiazolyl and 5-thiazolyl.
"Isothiazolyl" as used in respect of compounds of formula (IB) includes 3- isothiazolyl, 4-isothiazolyl, and 5-isothiazolyl. "Oxazolyl" as used in respect of compounds of formula (LB) includes 2- oxazolyl, 4-oxazolyl and 5-oxazolyl.
"Isoxazolyl" as used in respect of compounds of formula (IB) includes 3- isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl.
"Thiophenyl" as used in respect of compounds of formula (IB) includes 2- thiophenyl and 3-thiophenyl.
"Furanyl" as used in respect of compounds of formula (IB) includes 2-furanyl and 3-furanyl. "Pyrrolyl" as used in respect of compounds of formula (IB) includes 2-pyrrolyl and 3-pyrrolyl.
"Imidazolyl" as used in respect of compounds of formula (IB) includes 2- imidazolyl and 4-imidazolyl. "Triazolyl" as used in respect of compounds of formula (IB) includes 1- triazolyl, 4-triazolyl and 5-triazolyl.
"Oxadiazolyl" as used in respect of compounds of formula (IB) includes 4- and 5-(l,2,3-oxadiazolyl), 3- and 5-(l,2,4-oxadiazolyl), 3-(l,2,5-oxadiazolyl), 2-(l,3,4- oxadiazolyl). "Thiadiazolyl" as used in respect of compounds of formula (IB) includes 4- and 5-(l,2,3-thiadiazolyl), 3- and 5-(l,2,4-thiadiazolyl), 3-(l,2,5-thiadiazolyl), 2-(l,3,4- thiadiazolyl).
For the compounds of formula (IB) above, Ry is preferably H or Me. More preferably Ry is H. For the compounds of formula (IB) above, each Rz is preferably H or Me with
0, 1, 2 or 3 of Rz being Me. More preferably only 1 Rz is Me. Most preferably all Rz are H. For the compounds of formula (IB) above, Y is preferably OH or OMe. More preferably, Y is OH.
For the compounds of formula (IB) above, it is preferred that Ry and all Rz are H and Y is OH.
For the compounds of formula (IB) above, the preferred stereochemistry is shown below:
Ar,
Figure imgf000025_0001
A preferred group of compounds of formula (IB) is represented by the formula (HB)
Figure imgf000026_0001
(ΠB) wherein Ri and R2 are each independently selected from H, Ci -C4 alkyl, O(Cι -C4 alkyl), S(Cι -C4 alkyl), halo and phenyl; and R3 is selected from H, C1-C4 alkyl and halo; and pharmaceutically acceptable salts thereof.
For the compounds of formula (IB) or (HB) above, Ri is preferably Ci -C3 alkyl
(especially trifluoromethyl), O(Cι -C3 alkyl) (especially methoxy or trifluoromethoxy), F or phenyl (Ph). R2 is preferably H. R2 is also preferably F. R3 is preferably H.
Especially preferred compounds of formula (IB) are l-morpholin-2-yl-l-phenyl-2- (2-trifluoromethoxy-phenyl)-ethanol and 2-(5-fluoro-2-mefhoxy-phenyl)- 1 -morpholin-2- yl-1-phenyl-ethanol. For both of these compounds the (S,R) stereoisomer is preferred. For both of these compounds the preferred salt form is the hydrochloride salt.
6. A compound of formula (IC)
Figure imgf000026_0002
(IC) wherein: A is S or O; R is H; Ar is a phenyl group optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from Ci -C4 alkyl, O(Cι -C4 alkyl), S(Cj-C4 alkyl), halo, hydroxy, CO2(Cι -C4 alkyl), pyridyl, thiophenyl and phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, C1-C4 alkyl, or O(Cι -C4 alkyl); X is a phenyl group optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci -C4 alkyl, or O(Cι-C4 alkyl); a Ci -C4 alkyl group; a C3-C6 cycloalkyl group or a CH2(C3-Cg cycloalkyl) group; R' is H or Ci -C4 alkyl; each R1 is independently H or Cj -C4 alkyl; wherein each above- mentioned C1-C4 alkyl group is optionally substituted with one or more halo atoms; or a pharmaceutically acceptable salt thereof; with the proviso that, when A is O, X is a C\-
C4 alkyl group, a C3-C6 cycloalkyl group or a CH2(C3-C6 cycloalkyl) group.
For the compounds of formula (IC) above, it is preferred that A is S. For the compounds of formula (IC) above, it is preferred that Ar is phenyl substituted with 1, 2, 3, 4 or 5 substituents, more preferably with 1 or 2 substituents. When Ar is a substituted phenyl, it is preferred that not more than one of those substituents is a pyridyl, thiophenyl or optionally substituted phenyl group.
Preferred compounds of formula (IC) above are those wherein Ar is ortho-substituted. Further preferred compounds of formula (IC) above are those of formula (ICa)
Figure imgf000027_0001
(ICa) wherein: R is H; Ar is a phenyl group; X is a phenyl group; R' is H or C1-C4 alkyl; each
R1 is independently H or Ci -C4 alkyl; and pharmaceutically acceptable salts thereof. For these further preferred compounds, the group Ar may be substituted or unsubstituted phenyl. For example, Ar may be unsubstituted phenyl or, preferably phenyl substituted with 1, 2, 3, 4 or 5 substituents, preferably with 1 or 2, for example 1, substituent. When disubstituted, the substituted phenyl group is preferably substituted at the 2- and 5- positions When monosubstituted, the substituted phenyl group is preferably substituted in the 2- position. Suitable substituents include Ci -C4 alkyl, O(Cι-G4 alkyl), S(Cι -C4 alkyl), halo, and phenyl optionally substituted with, for example, halo, C1-C4 alkyl, or O(Cι -C4 alkyl). For these further preferred compounds, the group X may be substituted or unsubstituted phenyl. For example, X may be phenyl substituted with 1, 2, 3, 4 or 5 substituents, preferably with 1 substituent. Suitable substituents include Ci -C4 alkyl,
O(Cι -C4 alkyl), and halo.
"C1 -C4 alkyl" as used in respect of compounds of formula (IC) includes straight and branched chain alkyl groups of 1, 2, 3 or 4 carbon atoms, and may be unsubstituted or substituted. Ci -C2 alkyl groups are preferred. Suitable substituents include halo. Thus the term "Ci -C4 alkyl" includes haloalkyl. Similar terms defining different numbers of C atoms (e.g. "C1-C3 alkyl") take an analogous meaning. When R' is Ci -C4 alkyl it is preferably unsubstituted. When R1 is C\ -C4 alkyl it is preferably unsubstituted.
"C3-C6 cycloalkyl" as used in respect of compounds of formula (IC) includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
"Halo" as used in respect of compounds of formula (IC) includes F, Cl, Br and I, and is preferably F or Cl.
"Pyridyl" as used in respect of compounds of formula (IC) includes 2-pyridyl, 3- pyridyl and 4-pyridyl. "Thiophenyl" as used in respect of compounds of formula (IC) includes 2- thiophenyl and 3 -thiophenyl.
For the compounds of formula (IC) above, R ' is preferably H or Me. More preferably R ' is H.
For the compounds of formula (IC) above, each R1 is preferably H or Me with 0, 1, 2 or 3 of R1 being Me. More preferably only 1 R1 is Me. Most preferably all R1 are H.
For the compounds of formula (IC) above, it is preferred that R' and all R1 are H.
A particularly preferred substituted C| -C4 alkyl group for the group Ar is trifluoromethyl. A preferred group of compounds of formula (IC) is represented by the formula
(πc);
Figure imgf000029_0001
(πc) wherein R2 and R3 are each independently selected from H, C1 -C4 alkyl, O(Cι -C4 alkyl), S(Cι -C4 alkyl), halo and phenyl; and R4 is selected from H and C1-C4 alkyl; and pharmaceutically acceptable salts thereof. R2 is preferably Ci -C3 alkyl (especially trifluoromethyl), O(Cι -C3 alkyl) (especially methoxy or trifluoromethoxy), F or Ph. R3 is preferably H. R3 is also preferably F. R4 is preferably H.
7. A compound of formula (ID)
Figure imgf000029_0002
(ID) wherein -X- is -C(R4R5)-, -O- or -S-; n is 2 or 3; R1 is H or C C4 alkyl; R3 is H, halo, - C alkyl, O(Cι-C4 alkyl), nitrile, phenyl or substituted phenyl; R4 and R5 are each independently selected from H or Cι-C4 alkyl; Ar- is selected from the group consisting of
Figure imgf000029_0003
in which R2a is H, halo, methyl or ethyl; R2b is H, halo or methyl; R2c is H, halo, methyl, trifluoromethyl, nitrile, or methoxy; R2d is H, halo, methyl or ethyl; R2e is H, halo, methyl, trifluoromethyl, nitrile, or methoxy; R2f is H, or fluoro; -Y- is -O-, -S- or -N(R6)- ; and R6 is H or methyl and pharmaceutically acceptable salts thereof.
The term "Ci -C4 alkyl" as used in respect of compounds of formula (TD) includes straight and branched chain alkyl groups of 1, 2, 3 or 4 carbon atoms. Thus the term "Ci -C4 alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl and tert-butyl. Ci -C2 alkyl groups are preferred. A particularly preferred Ci -C4 alkyl group is methyl or ethyl.
The term "halo" as used in respect of compounds of formula (ID) includes F, Cl, Br and I, and is preferably F or Cl. The term "substituted phenyl" as used in respect of compounds of formula (ID) means phenyl substituted with 1, 2, 3, 4 or 5 substituents, preferably with 1 or 2, for example 1, substituent. Suitable substituents include C1 -C4 alkyl, O(Cι -C4 alkyl), S(Cι-
C4 alkyl), halo, and phenyl optionally substituted with, for example, C1-C4 alkyl, O(Cι -
C4 alkyl), S(Cι -C4 alkyl), or halo. The terms "O(Cι-C4 alkyl)" or "S(Cι -C4 alkyl)" as used in respect of compounds of formula (ID) mean a C1-C4 alkyl group as defined above linked to the point of substitution via an oxygen or a sulphur atom. An O(Cι -C4 alkyl) or S(C^-C4 alkyl) group includes for example methoxy, ethoxy, thiomethyl or thioethyl.
Preferred compounds of formula (ID) are represented by the formula (IDa)
Figure imgf000030_0001
(IDa) wherein -X-, n, R1, R3 and Ar have the values as defined for formula (ID) above.
Compounds of formula (ID) or (IDa) wherein -X- is -C(R4R5)- are preferred. Even more preferred are compounds of formula (ID) or (IDa) wherein -X- is -C(R4R5)- and R4 and R5 are both H or R4 and R5 are both the same -C alkyl.
Compounds of formula (ID) or (IDa) wherein Ar is (i) are also preferred. Preferably Ar is (i) and R2c is H. Even more preferred are compounds of formula (ID) or (IDa) wherein Ar is (i), R >2c c . is H, and (a) R a is H or methyl, R 2bD is H and R >2fI i ;s H or (b) R2a is H, R2b is halo, preferably fluoro or chloro and R2f is H or fluoro.
Another group of preferred compounds of formula (ID) or (IDa) are compounds wherein Ar is (ii) and -Y- is -S-. More preferably Ar is 2-thiophenyl or 3-thiophenyl.
A further preferred group of compounds of formula (ID) is represented by the formula (DD)
Figure imgf000031_0001
wherein n is 2 or 3; R1 is H or - alkyl; R3 is H, halo, phenyl or substituted phenyl; R2a is H, halo, methyl or ethyl; R2b is H, halo or methyl; and pharmaceutically acceptable salts thereof.
Preferred compounds of formulae (ID), (IDa) and (HD) are those wherein n is 3, or wherein R1 is H, methyl, ethyl or n-propyl, or wherein R3 is H or halo.
8. A compound of formula (IE)
Figure imgf000031_0002
(IE) wherein R1 is Cι-C6 alkyl (optionally substituted with 1, 2 or 3 halo substituents and/or with 1 substituent selected from -S-(Cι-C3 alkyl), -O-(Cι-C3 alkyl) (optionally substituted with 1, 2 or 3 F atoms), -O-(C3-C6 cycloalkyl), -SO2-(Cι-C3 alkyl), -CN, -COO-(d-C2 alkyl) and -OH); C2-C6 alkenyl; -(CH2)q-Ar2; or a group of formula (i) or (ii)
Figure imgf000032_0001
(i) (ϋ)
R2, R3 and R4 are each independently selected from hydrogen or Cι-C2 alkyl; R5, R6, R7 and R are at each occurrence independently selected from hydrogen or Cι-C alkyl; -X- is a bond, -CH2-, -CH=CH-, -O-, -S-, or -SO2-; -Y- is a bond, -CH2- or -O-; -Z is hydrogen, -OH or -O-(Cι-C3 alkyl); p is 0, 1 or 2; q is 0, 1 or 2; r is 0 or 1; s is 0, 1, 2 or 3; t is 0, 1, 2 or 3; Ar! is phenyl, pyridyl, thiazolyl, benzothiophenyl or naphthyl; wherein said phenyl, pyridyl or thiazolyl group may be substituted with 1, 2 or 3 substituents each independently selected from halo, cyano, Cι-C alkyl (optionally substituted with 1, 2 or 3 F atoms), ~O-(d-C alkyl) (optionally substituted with 1, 2 or 3 F atoms) and -S-(CrC4 alkyl) (optionally substituted with 1, 2 or 3 F atoms) and/or with 1 substituent selected from pyridyl, pyrazole, phenyl (optionally substituted with 1 , 2 or 3 halo substituents) and phenoxy (optionally substituted with 1, 2 or 3 halo substituents); and wherein said benzothiophenyl or naphthyl group may be optionally substituted with 1, 2 or 3 substituents each independently selected from halo, cyano, Cι-C alkyl (optionally substituted with 1, 2 or 3 F atoms), -O-(Cι-C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms), and -S-(C!-C alkyl) (optionally substituted with 1, 2 or 3 F atoms); Ar2 is naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl, wherein said naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl may be substituted with 1, 2 or 3 substituents each independently selected from halo, Cι-C alkyl
(optionally substituted with 1, 2 or 3 F atoms) and -O-(Cι-C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms); and pharmaceutically acceptable salts thereof; provided that (a) the cyclic portion of the group of formula (i) must contain at least three carbon atoms and not more than seven ring atoms; (b) when -X- is -CH=CH-, then the cyclic portion of the group of formula (i) must contain at least five carbon atoms; and (c) when -Z is -OH or -O-(C C3 alkyl), then -X- is -CH2-; (d) when -Y- is -O- then p cannot be 0; and (e) the compound 3-[(phenylmethyl)-(3S)-3-pyrrolidinylamino]- propanenitrile is excluded. With respect to formula (IE) the term "Ci -C alkyl" means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 6 carbon atoms.
With respect to formula (IE) the term "C2-Cg alkenyl" means a monovalent unsubstituted unsaturated straight-chain or branched-chain hydrocarbon radical having from 2 to 6 carbon atoms and containing at least one carbon-carbon double bond.
With respect to formula (IE) the term "C3-C6 cycloalkyl" means a monovalent unsubstituted saturated cyclic hydrocarbon radical having from 3 to 6 carbon atoms. With respect to formula (IE) the term "Ci -Cg alkylene" means a divalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from
1 to 6 carbon atoms.
With respect to formula (IE) the term "halo" or "halogen" means F, Cl, Br or I. With respect to formula (IE) the term "Ci -C4 difluoroalkyl" means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 carbon atoms wherein two hydrogen atoms are substituted with two fluoro atoms.
Preferably the two fluoro atoms are attached to the same carbon atom.
With respect to formula (IE) the term "C1-C4 trifluoroalkyl" means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 carbon atoms wherein three hydrogen atoms are substituted with three fluoro atoms. Preferably the three fluoro atoms are attached to the same carbon atom.
With respect to formula (IE) the term "phenoxy" means a monovalent unsubstituted phenyl radical linked to the point of substitution by an O atom.
With respect to formula (IE) the term "pyridyl" includes 2-pyridyl, 3-pyridyl and 4-pyridyl. With respect to formula (IE) the term "furyl" includes 2-furyl and 3-furyl. 2-furyl is preferred.
With respect to formula (IE) the term "thiophenyl" includes 2-thiophenyl and 3- thiophenyl.
With respect to formula (IE) the term "thiazolyl" includes 2-thiazolyl, 4-thiazolyl and 5-thiazolyl. With respect to formula (IE) the term "pyrazole" includes 1 -pyrazole, 3-pyrazole and 4-pyrazole. 1 -pyrazole is preferred.
With respect to formula (IE) the term "benzothiophenyl" includes 2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b] thiophenyl and 7-benzo[b]thiophenyl.
With respect to formula (IE) the term "naphthyl" includes 1 -naphthyl, and 2- naphthyl. 1 -naphthyl is preferred.
With respect to formula (IE), similar terms specifying different numbers of C atoms take an analogous meaning. For example the terms "Ci -C4 alkyl" and "C1-C3 alkyl" mean a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 and 1 to 3 carbon atoms respectively. The term "Ci -C4 alkyl" includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. The term "C1-C3 alkyl" includes methyl, ethyl, n-propyl and iso-propyl.
With respect to formula (IE) it will be appreciated that when s is 2 or 3, then each R5 and/or each R6 can be different. In the same way when t is 2 or 3, then each R7 and/or each R8 can be different.
Preferred compounds of formula (IE) are those wherein R1 is Cι-C6 alkyl, C2-C6 alkenyl, -(CH2)m-CF3, -(CH2)„-S-(C,-C3 alkyl), ~CH2-COO-(d-C2 alkyl), -(d-C5 alkylene)-O-(d-C3 alkyl), -(C1-C5 alkylene)-O-(C3-C6 cycloalkyl), -(d-C5 alkylene)- SO2-(d-C3 alkyl), -(Q-C5 alkylene)-OCF3, -(Ci- alkylene)-OH, -(C1-C5 alkylene)-CN,
-(CH2)q-Ar2 or a group of formula (ia), (ib) or (ii)
Figure imgf000034_0001
(ia) (ib) (ii) R2, R3, R4, R5, R6, R7, R8, -X-, -Y-, p, q, r and s have the values defined above; m is 1, 2 or 3; n is 1, 2 or 3; t is 2, 3 or 4; -Ari is phenyl, pyridyl, thiazolyl or naphthyl; wherein said phenyl, pyridyl or thiazolyl group may be substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl, cyano, Cι-C4 alkyl, -O-(Cι-C4 alkyl), - O-(C C4 difluoroalkyl), -O-(C C4 trifluoroalkyl), -S-(C C4 alkyl), -S-(d-C2 trifluoroalkyl) and/or with 1 substituent selected from pyridyl, pyrazole, phenyl (optionally substituted with 1, 2 or 3 halo substituents) and phenoxy (optionally substituted with 1, 2 or 3 halo substituents); and wherein said naphthyl group may be optionally substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl, cyano, C C4 alkyl, -O-(C C4 alkyl), -O-(Cι-C4 difluoroalkyl), -O-(d-C4 trifluoroalkyl), -S-(C C alkyl), -S-(Cι-C2trifluoroalkyl); Ar2 is naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl, wherein said naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl may be substituted with 1, 2 or 3 substituents each independently selected from halo, d-C4 alkyl, trifluoromethyl and -O- (Cι-C4 alkyl); and pharmaceutically acceptable salts thereof.
Preferred compounds of formula (IE) are those wherein R is hydrogen. In another preferred embodiment R3 and R4 are hydrogen. More preferably R2, R3 and R4 are hydrogen.
Preferred compounds of formula (IE) are those wherein each R5 and R6 is
7 R hydrogen. In another preferred embodiment each R and R is hydrogen. More preferably
R5, R6, R7 and R8 are hydrogen.
Preferred compounds of formula (IE) are those wherein R1 is Cι-C6 alkyl. More preferably R1 is n-propyl, 1-methylethyl, 2-methylpropyl, 3,3-dimethylpropyl.
Preferred compounds of formula (IE) are those wherein R1 is -(C4-C5 alkylene)- OH. More preferably R1 is 2,2-dimethyl-2-hydroxyethyl or 3,3-dimethyl-3- hydroxypropyl.
Preferred compounds of formula (IE) are those wherein R is a group of formula (i) and each R and R is hydrogen. More preferably each R , R , R and R is hydrogen.
Preferred compounds of formula (IE) are those wherein R1 is a group of formula (ii) and each R and R is hydrogen. More preferably each R , R , R and R is hydrogen.
Preferred compounds of formula (IE) are those wherein R1 is a group of formula (i), r is 0, s is 2, t is 2, -Z is hydrogen and -X- is -O-, -S- or -SO2-. More preferably R1 is a group of formula (i), r is 0, s is 2, t is 1 or 2, -Z is hydrogen and -X- is -O-.
Preferred compounds of formula (IE) are those wherein R1 is a group of formula (i), r is 0, s is 1, 2 or 3, t is 1, -Z is hydrogen and -X- is -CH2-.
Preferred compounds of formula (IE) are those wherein R1 is a group of formula (i), r is 1, s is 0, 1, 2 or 3, t is 1, -Z is hydrogen and -X- is -CH2-. Preferred compounds of formula (IE) are those wherein R1 is a group of the formula (ia). More preferably R1 is a group of the formula (ia) and each R5, R6, R7and R8 is hydrogen.
Preferred compounds of formula (IE) are those wherein R1 is a group of the formula (ib). More preferably R1 is a group of the formula (ib), r is 1, t is 3, and each
R7and R8 is hydrogen.
Preferred compounds of formula (IE) are those wherein R1 is -(CH2)m-CF3. More preferably R1 is -(CH2)m-CF3 and m is 1, 2, or 3.
Preferred compounds of formula (IE) are those wherein R1 is -(CH2)n-S-(Cι-C3 alkyl). More preferably R1 is -(CH2)3-S-CH3.
Preferred compounds of formula (IE) are those wherein R1 is -CH2-COO-(Cι-C2 alkyl). More preferably R1 is -CH2-COOCH3.
Preferred compounds of formula (IE) are those wherein R1 is -(C1-C5 alkylene)-O-(Cι-C3 alkyl). More preferably R1 is -(C3-C4 alkylene)-OCH3. Preferred compounds of formula (IE) are those wherein R1 is -(C1-C5 alkylene)-O-(C3-C6 cycloalkyl). More preferably R1 is -CH2-CH2-O-cyclobutyl.
Preferred compounds of formula (IE) are those wherein R1 is -(C1-C5 alkylene)-SO2-(Cι-C3 alkyl).
Preferred compounds of formula (IE) are those wherein R1 is -(C1-C5 alkylene)-OCF3. More preferably R1 is -CH2-CH2-OCF3.
Preferred compounds of formula (IE) are those wherein R1 is -(C1-C5 alkylene)-CN. More preferably R1 is -(C -C4 alkylene)-CN. Most preferably -CH2-CH2-CN or -CH2-C(CH3)2-CN.
Preferred compounds of formula (IE) are those wherein R1 is -(CH2)q-Ar2, and q is 1. More preferably R1 is -(CH2)q-Ar2, q is 1 and -Ar2 is pyridyl, phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl or Cι-C4 alkyl.
Preferred compounds of formula (IE) are those wherein -Ari is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and Cι-C4 alkyl and/or with 1 substituent selected from phenyl, phenyl substituted with 1, 2 or 3 halo substituents, pyridyl, pyrazole, phenoxy and phenoxy substituted with 1, 2 or 3 halo substituents; pyridyl; or pyridyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and d-Q alkyl and/or with 1 substituent selected from phenyl and phenyl substituted with 1, 2 or 3 halo substituents. More preferably -Ar! is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and Cι-C4 alkyl and/or with 1 substituent selected from phenyl, phenyl substituted with 1, 2 or 3 halo substituents, pyridyl, pyrazole, phenoxy and phenoxy substituted with 1, 2 or 3 halo substituents. Most preferably -Ari is phenyl substituted with 1 or 2 substituents each independently selected from halo, trifluoromethyl and Cι-C4 alkyl and/or with 1 substituent selected from phenyl, phenyl substituted with 1, 2 or 3 halo substituents, pyridyl, pyrazole, phenoxy and phenoxy substituted with 1, 2 or 3 halo substituents. Suitable -Ari groups include, for example, 2-methylthiophenyl, 2-methylphenyl,
2-fluorophenyl, 2-chlorophenyl, 2-isopropoxyphenyl, 2-trifluoromethylphenyl, 2- difluoromethoxyphenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-(l,l'-biphenyl), 2- phenoxyphenyl, 2-benzylphenyl, 3-trifluoromethoxyphenyl, 3 -chlorophenyl, 3- trifluoromefhylphenyl, 3-methylphenyl, 3-trifluorothiomethoxyphenyl, 3-methoxyphenyl, 4- trifluoromethylphenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-dichlorophenyl, 3,5- dimethylphenyl, 3-trifluoromethyl-5-fluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 2,3-dimethylphenyl, 2-chloro-3-trifluoromethylphenyl, 2-chloro-3-methylphenyl, 2-methyl-3- chlorophenyl, 2,4-dichlorophenyl, 2,4-dimethyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-trifluoromethyl-4-fluorophenyl, 2-fluoro-4-trifluoromethylphenyl, 2-methyl-4- chlorophenyl, 2-methoxy-4-fluorophenyl, 2-trifluoromethyl-5-fluorophenyl, 2,5- dimethylphenyl, 4-fluoro-[l,l'-biphenyl]-2-yl, 2-chloro-5-fluorophenyl, 2-(trifluoromethyl)- 6-fluorophenyl, 2-chloro-6-fluorophenyl, 3,4-dichlorophenyl, and 3-chloro-4-fluorophenyl. In general when -Arj is phenyl substituted with pyridyl, 3-pyridyl is preferred.
Preferred compounds of formula (IE) are those wherein -Ari is pyridyl or pyridyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and Cι-C4 alkyl and/or with 1 substituent selected from phenyl and phenyl substituted with 1, 2 or 3 halo substituents. More preferably -Ari is pyridyl substituted with 1 or 2 substituents each independently selected from halo, trifluoromethyl and Cι-C4 alkyl and/or with 1 substituent selected from phenyl and phenyl substituted with 1, 2 or 3 halo substituents. Suitable -Ari groups include, for example, 3-phenyl-2-pyridyl. In general when -Ari s a substituted pyridyl, substituted 2-pyridyl is preferred. 9. A compound of formula (IF)
Figure imgf000038_0001
(IF) wherein
is a group of formula (a) or (b)
Figure imgf000038_0002
Figure imgf000038_0003
(a) (b)
R1 is Cι-C6 alkyl (optionally substituted with 1, 2 or 3 halo substituents and/or with 1 substituent selected from -S-(Cι-C3 alkyl), -O-(Cι-C3 alkyl) (optionally substituted with 1, 2 or 3 F atoms), -O-(C3-C6 cycloalkyl), -SO2-(C C3 alkyl), -CN, -COO-(Cι~C2 alkyl) and -OH); C2-C6 alkenyl; -(CH2)q-Ar2; or a group of formula (i) or (ii)
Figure imgf000038_0004
(i) (ϋ)
R2, R3 and R4 are each independently selected from hydrogen or Cι-C2 alkyl; R5, R6, R7 and R8 are at each occurrence independently selected from hydrogen or Cι-C2 alkyl; -X- is a bond, -CH2-, -CH=CH-, -O-, -S-, or -SO2~; -Y- is a bond, -CH2- or -O-; -Z is hydrogen, -OH or -O-(Cι-C3 alkyl); p is 0, 1 or 2; q is 0, 1 or 2; r is 0 or 1; s is 0, 1, 2 or 3; t is 0, 1, 2 or 3; Ari is phenyl, pyridyl, thiazolyl, benzothiophenyl or naphthyl; wherein said phenyl, pyridyl or thiazolyl group may be substituted with 1, 2 or 3 substituents each independently selected from halo, cyano, Cι-C alkyl (optionally substituted with 1, 2 or 3 F atoms), -O-(Cι-C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms) and -S-(Cι-C alkyl) (optionally substituted with 1, 2 or 3 F atoms) and/or with 1 substituent selected from pyridyl, pyrazole, phenyl (optionally substituted with 1, 2 or 3 halo substituents), benzyl and phenoxy (optionally substituted with 1, 2 or 3 halo substituents); and wherein said benzothiophenyl or naphthyl group may be optionally substituted with 1, 2 or 3 substituents each independently selected from halo, cyano, Cι-C4 alkyl (optionally substituted with 1, 2 or 3 F atoms), -O-(Cι-C alkyl) (optionally substituted with 1, 2 or 3 F atoms), and -S-(Cι-C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms); Ar2 is naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl, wherein said naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl may be substituted with 1, 2 or 3 substituents each independently selected from halo, Cι-C alkyl (optionally substituted with 1, 2 or 3 F atoms) and -O-(Cι-C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms); or a pharmaceutically acceptable salt thereof; provided that (a) the cyclic portion of the group of formula (i) must contain at least three carbon atoms and not more than seven ring atoms; (b) when -X- is -CH=CH-, then the cyclic portion of the group of formula (i) must contain at least five carbon atoms; and (c) when -Z is -OH or -O-(Cι-C3 alkyl), then -X- is -CH2-; and (d) when -Y- is -O- then p cannot be 0. With respect to formula (IF) the term "Ci -Cg alkyl" means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 6 carbon atoms.
With respect to formula (IF) the term "C2-Cg alkenyl" means a monovalent unsubstituted unsaturated straight-chain or branched-chain hydrocarbon radical having from 2 to 6 carbon atoms and containing at least one carbon-carbon double bond.
With respect to formula (IF) the term "C3-C6 cycloalkyl" means a monovalent unsubstituted saturated cyclic hydrocarbon radical having from 3 to 6 carbon atoms. With respect to formula (IF) the term "C^-Cg alkylene" means a divalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 6 carbon atoms.
With respect to formula (IF) the term "halo" or "halogen" means F, Cl, Br or I. With respect to formula (IF) the term "C1-C4 difluoroalkyl" means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 carbon atoms wherein two hydrogen atoms are substituted with two fluoro atoms. Preferably the two fluoro atoms are attached to the same carbon atom. With respect to formula (IF) the term "C1-C4 trifluoroalkyl" means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 carbon atoms wherein three hydrogen atoms are substituted with three fluoro atoms. Preferably the three fluoro atoms are attached to the same carbon atom.
With respect to formula (IF) the term "phenoxy" means a monovalent unsubstituted phenyl radical linked to the point of substitution by an O atom.
With respect to formula (IF) the term "pyridyl" includes 2-pyridyl, 3-pyridyl and 4-pyridyl.
With respect to formula (IF) the term "furyl" includes 2-furyl and 3-furyl. 2-furyl is preferred. With respect to formula (IF) the term "thiophenyl" includes 2-thiophenyl and 3- thiophenyl.
With respect to formula (IF) the term "thiazolyl" includes 2-thiazolyl, 4-thiazolyl and 5 -thiazolyl.
With respect to formula (IF) the term "pyrazole" includes 1 -pyrazole, 3-pyrazole and 4-pyrazole. 1 -pyrazole is preferred.
With respect to formula (IF) the term "benzothiophenyl" includes 2- benzo[b]thiophenyl, 3 -benzo[b] thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl and 7-benzo[b]thiophenyl.
With respect to formula (IF) the term "naphthyl" includes 1 -naphthyl, and 2- naphthyl. 1 -naphthyl is preferred.
With respect to formula (IF), similar terms specifying different numbers of C atoms take an analogous meaning. For example the terms "C1-C4 alkyl" and "Ci -C3 alkyl" mean a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 and 1 to 3 carbon atoms respectively. The term "C1-C4 alkyl" includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. The term "Ci -C3 alkyl" includes methyl, ethyl, n-propyl and iso-propyl. With respect to formula (IF), it will be appreciated that when s is 2 or 3, then each
S 7
R and/or each R can be different. In the same way when t is 2 or 3, then each R and/or each R8 can be different.
Preferred compounds of formula (IF) are those of formula (IF')
Figure imgf000041_0001
(IF') wherein R1, R2, R3, R4 and Ari have the values defined in formula (IF) above. Preferred compounds of formula (IF) are those of formula (IF")
Figure imgf000041_0002
(IF") wherein R1, R2, R3, R4 and Ari have the values defined in formula (IF) above.
Preferred compounds of formula (IF) are those wherein R1 is Cι-C6 alkyl, C -C6 alkenyl, -(CH2)m-CF3, -(CH2)n-S-(C C3 alkyl), -CH2-COO-(Cι-C2 alkyl), -(Cι-C5 alkylene)-O-(Cι-C3 alkyl), -(Cι-C5 alkylene)-O-(C3-C6 cycloalkyl), -(Cι-C5 alkylene)- SO2-(Cι-C3 alkyl), -(d-C5 alkylene)-OCF3, -(d-C6 alkylene)-OH, -(d-C5 alkylene)-CN, -(CH2)q-Ar2 or a group of formula (ia), (ib) or (ii)
Figure imgf000041_0003
(ia) (ib) (ii) R2, R3, R4, R5, R6, R7, R8, -X-, -Y-, p, q, r and s have the values defined above; m is 1, 2 or 3; n is 1, 2 or 3; t is 2, 3 or 4; -Ari is phenyl, pyridyl, thiazolyl or naphthyl; wherein said phenyl, pyridyl or thiazolyl group may be substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl, cyano, C1-C alkyl, -O-(Cι-C4 alkyl), - O-(d-C4 difluoroalkyl), -O-(C!-C4 trifluoroalkyl), -S-(d-C4 alkyl), -S-(C C2 trifluoroalkyl) and/or with 1 substituent selected from pyridyl, pyrazole, phenyl (optionally substituted with 1, 2 or 3 halo substituents) and phenoxy (optionally substituted with 1, 2 or 3 halo substituents); and wherein said naphthyl group may be optionally substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl, cyano, C C4 alkyl, -O-(Cι-C4 alkyl), -O-(C C4 difluoroalkyl), -O-(Cι-C4 trifluoroalkyl), -S-(Cι-C4 alkyl), -S-(Cι-C2 trifluoroalkyl); Ar2 is naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl, wherein said naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl may be substituted with 1 , 2 or 3 substituents each independently selected from halo, Cι-C4 alkyl, trifluoromethyl and -O- (C1-C4 alkyl).
Preferred compounds of formula (IF) are those wherein R2 is hydrogen. In another preferred embodiment R3 and R4 are hydrogen. More preferably R2, R3 and R4 are hydrogen.
Preferred compounds of formula (IF) are those wherein each R5 and R6 is hydrogen. In another preferred embodiment each R7 and R8 is hydrogen. More preferably R5, R6, R7 and R8 are hydrogen.
Preferred compounds of formula (IF) are those wherein R1 is Cι-C6 alkyl. More preferably R1 is n-propyl, 1-methylethyl (i-propyl), 2-methylpropyl (i-butyl), 2- methylbutyl, 2,2-dimethylbutyl.
Preferred compounds of formula (IF) are those wherein R1 is -(C -C5 alkylene)- OH. More preferably R1 is 2,2-dimethyl-2-hydroxyethyl or 3,3-dimethyl-3- hydroxypropyl. Preferred compounds of formula (IF) are those wherein R1 is a group of formula
(i) and each R5 and R6 is hydrogen. More preferably each R5, R6, R7 and R8 is hydrogen.
Preferred compounds of formula (IF) are those wherein R1 is a group of formula (ii) and each R5 and R6 is hydrogen. More preferably each R5, R6, R7 and R8 is hydrogen.
Preferred compounds of formula (IF) are those wherein R1 is a group of formula (i), r is 0 or 1, s is 2, t is 1 or 2, -Z is hydrogen and -X- is -O-, -S- or -SO2-. More preferably R1 is a group of formula (i), r is 0 or 1, s is 2, t is 1 or 2, -Z is hydrogen and - X- is -O-, for example tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl or (tetrahydrofuran-3-yl)methyl. Most preferably R1 is a group of formula (i), r is 0, s is 2, t is 1 or 2, -Z is hydrogen and -X- is -O-, for example tetrahydro-2H-pyran-4-yl or tetrahydrofuran-3-yl.
Preferred compounds of formula (IF) are those wherein R1 is a group of formula (i), r is 0, s is 1, 2 or 3, t is 1, -Z is hydrogen and -X- is -CΗ2-, for example cyclobutyl, cyclopentyl or cyclohexyl.
Preferred compounds of formula (IF) are those wherein R1 is a group of formula (i), r is 1, s is 0, 1, 2 or 3, t is 1, -Z is hydrogen and -X- is -CH2-.
Preferred compounds of formula (IF) are those wherein R1 is a group of the formula (ia). More preferably R1 is a group of the formula (ia) and each R5, R6, R7and R8 is hydrogen.
Preferred compounds of formula (IF) are those wherein R1 is a group of the formula (ib). More preferably R1 is a group of the formula (ib), r is 1, t is 3, and each R7and R8 is hydrogen. Preferred compounds of formula (IF) are those wherein R1 is -(CH2)m-CF3. More preferably R1 is -(CH )m-CF3 and m is 1, 2, or 3.
Preferred compounds of formula (IF) are those wherein R1 is -(CH2)n-S-(Cι-C alkyl). More preferably R1 is -(CH2)3-S-CH3.
Preferred compounds of formula (IF) are those wherein R1 is -CH2-COO-(d-C2 alkyl). More preferably R1 is -CH2-COOCH3.
Preferred compounds of formula (IF) are those wherein R1 is -(C1-C5 alkylene)-O- (d-C3 alkyl). More preferably R1 is -(C3-C4 alkylene)-OCH3.
Preferred compounds of formula (IF) are those wherein R1 is -(C1-C5 alkylene)-O- (C3-C6 cycloalkyl). More preferably R1 is -CH2-CH2-O-cyclobutyl. Preferred compounds of formula (IF) are those wherein R1 is -(C1-C5 alkyl ene)-
SO2-(d-C3 alkyl).
Preferred compounds of formula (IF) are those wherein R1 is -(C1-C5 alkylene)- OCF3. More preferably R1 is -CH2-CH2-OCF3.
Preferred compounds of formula (IF) are those wherein R1 is -(C1-C5 alkylene)- CN. More preferably R1 is -(C2-C4 alkylene)-CN. Most preferably -CH2-CH2-CN or
-CH2-C(CH3)2-CN. Preferred compounds of formula (IF) are those wherein R1 is -(CH2)q-Ar2, and q is 1. More preferably R1 is -(CH2)q-Ar2, q is 1 and -Ar2 is pyridyl, phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl, d-C4 alkyl or O-(d-C4 alkyl). Preferred compounds of formula (IF) are those wherein -An is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and Cι-C4 alkyl and/or with 1 substituent selected from phenyl, phenyl substituted with 1, 2 or 3 halo substituents, pyridyl, pyrazole, phenoxy and phenoxy substituted with 1, 2 or 3 halo substituents; pyridyl; or pyridyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and Cι-C4 alkyl and/or with 1 substituent selected from phenyl and phenyl substituted with 1, 2 or 3 halo substituents. More preferably -Ari is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and C]-C4 alkyl and/or with 1 substituent selected from phenyl, phenyl substituted with 1, 2 or 3 halo substituents, pyridyl, pyrazole, phenoxy and phenoxy substituted with 1, 2 or 3 halo substituents. Most preferably -Ari is phenyl substituted with 1 or 2 substituents each independently selected from halo, trifluoromethyl and Cι-C4 alkyl and/or with 1 substituent selected from phenyl, phenyl substituted with 1, 2 or 3 halo substituents, pyridyl, pyrazole, phenoxy and phenoxy substituted with 1, 2 or 3 halo substituents. Suitable -Ari groups include, for example, 2-methylthiophenyl, 2-methylphenyl, 2- fluorophenyl, 2-chlorophenyl, 2-isopropoxyphenyl, 2-trifluoromethylphenyl, 2- difluoromethoxyphenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-(l,l'-biphenyl), 2- phenoxyphenyl, 2-benzylphenyl, 3-trifiuoromethoxyphenyl, 3-chlorophenyl, 3- trifluoromethylphenyl, 3-methylphenyl, 3-trifluorothiomethoxyphenyl, 3-methoxyphenyl, 4- trifluoromethylphenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-dichlorophenyl, 3,5- dimethylphenyl, 3-trifluoromethyl-5-fluorophenyl, 3,5-difluorophenyl, 2,3- dichlorophenyl, 2,3-dimethylphenyl, 2-chloro-3 -trifluoromethylphenyl, 2-chloro-3- methylphenyl, 2-methyl-3-chlorophenyl, 2,4-dichlorophenyl, 2,4-dimethyl, 2,4- difluorophenyl, 2-chloro-4-fluorophenyl, 2-trifluoromethyl-4-fluorophenyl, 2-fluoro-4- trifluoromethylphenyl, 2-methyl-4-chlorophenyl, 2-methoxy-4-fluorophenyl, 2- trifluoromethyl-5-fluorophenyl, 2,5-dimethylphenyl, 4-fluoro-[l,l'-biphenyl]-2-yl, 2- chloro-5-fluorophenyl, 2-(trifluoromethyl)-6-fluorophenyl, 2-chloro-6-fluorophenyl, 3,4- dichlorophenyl, and 3-chloro-4-fluorophenyl. In general when -Ari is phenyl substituted with pyridyl, 3-pyridyl is preferred.
Preferred compounds of formula (IF) are those wherein -Ari is pyridyl or pyridyl substituted with 1, 2 or 3 substituents each independently selected from halo, trifluoromethyl and Cι-C4 alkyl and/or with 1 substituent selected from phenyl and phenyl substituted with 1, 2 or 3 halo substituents. More preferably -Ari is pyridyl substituted with 1 or 2 substituents each independently selected from halo, trifluoromethyl and Cι-C4 alkyl and/or with 1 substituent selected from phenyl and phenyl substituted with 1, 2 or 3 halo substituents. Suitable -Ari groups include, for example, 3-phenyl-2-pyridyl. In general when -Ari is a substituted pyridyl, substituted 2-pyridyl is preferred. 10. A compound of formula (IG)
Figure imgf000045_0001
(IG) wherein -X- is -S- or -O-; each R is independently selected from H or Cι-C4 alkyl; R1 is H,
Cι-C4 alkyl, d-C4 alkoxy, halo, cyano, trifluoromethyl, trifluoromethoxy, -NR 3 Rr>4
CONR >3JrR>4, -COOR' or a group of the formula (i)
Figure imgf000045_0002
(i)
R is Cι-C4 alkyl, phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from Cι-C4 alkyl, Cι-C4 alkoxy, nitro, hydroxy, cyano, halo, trifluoromethyl, trifluoromethoxy, benzyl, benzyloxy, -NR >6°τRj7', -CONR 6°nRl', COOR°, -SO2NR >6°Rr>7' and -SO2R°; R5 is selected from Cι-C4 alkyl, Cι-C alkoxy, carboxy, nitro, hydroxy, cyano, halo, trifluoromethyl, trifluoromethoxy, benzyl, benzyloxy, -NR8R9, -CONR8R9, -SO NR8R9 and - SO2R8; R3, R4, R6, R7, R8 and R9 are each independently selected from H or Q- C4 alkyl; and XL- is a bond, -CH2-, or -O-; or a pharmaceutically acceptable salt thereof.
With respect to formula (IG) the term "C C4 alkyl" means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 carbon atoms. Thus the term "d-C4 alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
With respect to formula (IG) the term "d-C4 alkoxy" means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 carbon atoms linked to the point of substitution by an O atom. Thus the term "C -
C4 alkoxy" includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec- butoxy.
With respect to formula (IG) the term "halo" or "halogen" means F, Cl, Br or I.
Preferred compounds of formula (IG) are those wherein -X- is -S-.
Preferred compounds of formula (IG) are those wherein -X- is -O-.
Preferred compounds of formula (IG) are those wherein R2 is phenyl.
Preferred compounds of formula (IG) are those wherein all R groups are hydrogen.
Preferred compounds of formula (IG) are those represented by the formula (UG)
Figure imgf000046_0001
(ΠG) wherein R1 is H, C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, trifluoromethyl, trifluoromethoxy, NR3R4, -CONR3R4, -COOR3 or a group of the formula (i)
Figure imgf000046_0002
(i) R5 is selected from d-C alkyl, Cι-C4 alkoxy, carboxy, nitro, hydroxy, cyano, halo, trifluoromethyl, trifluoromethoxy, benzyl, benzyloxy, -NR8R9, -CONR8R9, -SO2NR8R9 and - SO2R8; R3, R4, R8 and R9 are each independently selected from H or Q- C4 alkyl; -Z- is a bond, -CH2-, or -O-; or a pharmaceutically acceptable salt thereof. Preferred compounds of formula (IG) or (EG) are those wherein the substituent R1 is in the three position of the pyridine ring as numbered in formula (IG) above. More preferably said substituent R1 is H, d-C4 alkyl, halo, cyano, -CONR3R4, trifluoromethyl or a group of the formula (i). When R1 is -CONR3R4, then R3 and R4 are both preferably H. When R1 is Q- C4 alkyl, then it is preferably methyl. Preferred compounds of formula (IG) or (EG) are those wherein the substituent R1 is a group of the formula (i).
Preferred compounds of formula (IG) or (UG) are those wherein R1 is a group of the formula (i), -Z- is a bond, and R5 is H or halo.
Preferred compounds of formula (IG) or (EG) are those wherein R1 is a group of the formula (i), -Z- is -CH2- or -O-, and R5 is H.
Preferred compounds of formula (IG) or (EG) are those wherein the substituent R1 is in the five position of the pyridine ring as numbered in formula (IG) above. More preferably said substituent R1 is selected from bromo, chloro or iodo.
Compounds within the scope of Formulae (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above are inhibitors of norepinephrine reuptake. Certain compounds within the scope of
Formulae (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above are selective inhibitors of norepinephrine reuptake.
Biogenic amine transporters control the amount of biogenic amine neurotransmitters in the synaptic cleft. Inhibition of the respective transporter leads to a rise in the concentration of that neurotransmitter within the synaptic cleft. Compounds of
Formulae (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above and their pharmaceutically acceptable salts preferably exhibit a Kj value less than 500nM at the norepinephrine transporter as determined using the scintillation proximity assay as described below. More preferred compounds of Formulae (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above and their pharmaceutically acceptable salts exhibit a Kj value less than lOOnM at the norepinephrine transporter. More preferred compounds of Formulae (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above and their pharmaceutically acceptable salts exhibit a Kj value less than 50nM at the norepinephrine transporter. Especially preferred compounds of Formulae (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above and their pharmaceutically acceptable salts exhibit a K{ value less than 20nM at the norepinephrine transporter.
Preferably, these compounds selectively inhibit the norepinephrine transporter relative to the serotonin and dopamine transporters by a factor of at least five, more preferably by a factor of at least ten.
In addition, the compounds of Formulae (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above of the present invention are preferably acid stable. Advantageously, they have a reduced interaction (both as substrate and inhibitor) with the liver enzyme Cytochrome P450 (CYP2D6). That is to say, they preferably exhibit less than 75% metabolism via the
CYP2D6 pathway according to the CYP2D6 substrate assay described below and they preferably exhibit an IC50 of >6μM according to the CYP2D6 inhibitor assay described below.
While all compounds exhibiting norepinephrine reuptake inhibition are useful for the methods of the present invention, certain are preferred. It is preferred that the norepinephrine reuptake inhibitor is selective for the reuptake of norepinephrine over the reuptake of other neurotransmitters. It is also preferred that the norepinephrine reuptake inhibitor does not exhibit signigicant direct agonist or antagonist activity at other receptors. It is especially preferred that the norepinephrine reuptake inhibitor be selected from atomoxetine, reboxetine, (S,S)-reboxetine, (R)-N-methyl-3-(2-methyl-thiophenoxy)-3-phenylpropylamine, and compounds of Formulae (I), (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above.
The present invention encompasses pharmaceutical compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier, diluent, or excipient. It will be understood by the skilled reader that most or all of the compounds used in the present invention are capable of forming salts, and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free bases. In all cases, the use of the pharmaceuticals described above as salts is contemplated in the description herein, and often is preferred, and the pharmaceutically acceptable salts of all of the compounds are included in the names of them. Many of the compounds used in this invention are amines, and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Since some of the free amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration, since the latter are routinely solid at room temperature. Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p_- toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-
1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, b-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable salts are those formed with hydrochloric acid.
Pharmaceutically acceptable salts of the compounds of Formulae (IA), (TB), (IC), (ID) (IE), (IF) and (IG) above include acid addition salts, including salts formed with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic or organic sulphonic acids, for example, acetoxybenzoic, citric, glycolic, o- mandelic-1, mandelic-dl, mandelic d, maleic, mesotartaric monohydrate, hydroxymaleic, fumaric, lactobionic, malic, methanesulphonic, napsylic, naphtalenedisulfonic, naphtoic, oxalic, palmitic, phenylacetic, propionic, pyridyl hydroxy pyruvic, salicylic, stearic, succinic, sulphanilic, tartaric, 2-hydroxyethane sulphonic, toluene-p-sulphonic, and xinafoic acids. In addition to the pharmaceutically acceptable salts, other salts can serve as intermediates in the purification of compounds, or in the preparation of other, for example pharmaceutically acceptable, acid addition salts, or are useful for identification, characterization, or purification.
The present invention encompasses the administration of a composition that exhibits (preferably selective) norepinephrine reuptake inhibitor activity. The composition can comprise one or more agents that, individually or together, inhibit norepinephrine reuptake preferably in a selective manner.
Dosages
The dosages of the drugs used in the present invention must, in the final analysis, be set by the physician in charge of the case using knowledge of the drugs, the properties of the drugs in combination as determined in clinical trials, and the characteristics of the patient including diseases other than that for which the physician is treating the patient. General outlines of the dosages, and some preferred dosages, are: Atomoxetine: In adults and older adolescents: from about 5 mg/day to about 200 mg/day; preferably in the range from about 60 to about 150 mg/day; more preferably from about 60 to about 130 mg/day; and still more preferably from about 50 to about 120 mg/day;
In children and younger adolescents: from about 0.2 to about 3.0 mg/kg/day; preferably in the range from about 0.5 to about 1.8 mg/kg/day;
Reboxetine: Racemic reboxetine can be administered to an individual in an amount in the range of from about 2 to about 20 mg per patient per day, more preferably from about 4 to about 10 mg/day, and even more preferably from about 6 to about 10 mg/day. Depending on the formulation, the total daily dosage can be administered in smaller amounts up to two times per day. A preferred adult daily dose of optically pure (S,S) reboxetine can be in the range of from about 0.1 mg to about 10 mg, more preferably from about 0.5 mg to about 8 to 10 mg, per patient per day. The effective daily dose of reboxetine for a child is smaller, typically in the range of from about 0.1 mg to about 4 to about 5 mg/day. Treatments using compositions containing optically pure (S,S)-reboxetine are about 5 to about 8.5 times more effective in inhibiting the reuptake of norepinephrine than compositions containing a racemic mixture of (R,R)- and (S,S)-reboxetine, and therefore lower doses can be employed. PCT international Publication No. WO 01/01973 contains additional details concerning the dosing of (S,S) reboxetine.
Compounds of formula I: from about 0.01 mg/kg to about 20 mg/kg; preferred daily doses will be from about 0.05 mg/kg to 10 mg/kg; ideally from about 0.1 mg/kg to about 5 mg/kg;
Compounds of formulae (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above: from about 5 to about 500 mg, more preferably from about 25 to about 300 mg, of the active ingredient per patient per day.
Cognitive failure presents in patients suffering from a number of other disorders. The present invention includes the use of a norepinephrine reuptake inhibitor to treat cognitive failure presenting alone, or where cognitive failure is associated with another disorder. Schizophrenic patients, for example, commonly exhibit symptoms that include cognitive failure. An embodiment of the present invention, therefore, is the use of a norepinephrine reuptake inhibitor to treat cognitive failure associated with schizophrenia. Patients suffering from schizophrenia also frequently exhibit negative symptoms such as flat affect, asociality, anergia, avolition, and anhedonia. A further embodiment of the present invention is the use of a norepinephrine reuptake inhibitor to treat the negative symptoms of schizophrenia, or abulia and apathy related to other disorders such as dementia of the frontal lobe type. The invention further provides a method for treating a patient suffering from or susceptible to psychosis, comprising administering to said patient an effective amount of a first component which is an antipsychotic, in combination with an effective amount of a second component which is a norepinephrine reuptake inhibitor. The invention also provides a pharmaceutical composition that comprises a first component that is an antipsychotic, and a second component that is a norepinephrine reuptake inhibitor.
In the general expressions of this aspect of the present invention, the first component is a compound that acts as an antipsychotic. The antipsychotic may be either a typical antipsychotic, such as haloperidol, or an atypical antipsychotic. The essential feature of an atypical antipsychotic is less acute extrapyramidal symptoms, especially dystonias, associated with therapy as compared to a typical antipsychotic such as haloperidol. Clozapine, the prototypical atypical antipsychotic, differs from the typical antipsychotics with the following characteristics: (1) greater efficacy in the treatment of overall psychopathology in patients with schizophrenia nonresponsive to typical antipsychotics; (2) greater efficacy in the treatment of negative symptoms of schizophrenia; and (3) less frequent and quantitatively smaller increases in serum prolactin concentrations associated with therapy (Beasley, et al., Neuropsychopharma- cologv, 14(2), 111-123 , (1996)). Although both typical and atypical antipsychotics are useful for these methods and formulations of the present invention, it is preferred that the first component compound is an atypical antipsychotic.
Typical antipsychotics include, but are not limited to:
Chlorpromazine, 2-chloro-10-(3-dimethylaminoprop-yl)phenothiazine, is described in U.S. Patent 2,645,640. Its pharmacology has been reviewed (Crismon,
Psychopharma-col. Bui., 4, 151 (October 1967):
Droperidol, l-(l-[3-(p-fluorobenzoyl)propyl]-l,2,3,6-tetrahydro-4- pyridyl)-2-benzimidazolinone, is described in U.S. Patent 3,141,823;
Haloperidol, 4-[4-(4-chlorophenyl)-4-hydroxy-l-piperidinyl]-l-(4- fluorophenyl)- 1-butanone, is described in U.S. Patent 3,438,991. Its therapeutic efficacy in psychosis has been reported (Beresford and Ward, Drugs, 33, 31-49 (1987);
Thioridazine, 1 -hydroxy- 10-[2-( 1 -methyl-2-pyridinyl)ethyl]-2- (methylthio)phenothiazine hydrochloride, was described by Bourquin, et al.(Helv. Chim. Acta. 41, 1072 (1958)). Its use as an antipsychotic has been reported (Axelsson, et al., Curr. Ther. Res.. 21, 587 (1977)); and
Trifluoperazine, 10-[3-(4-methyl-l-piperazinyl)-propyl]-2- trifluoromethylphenthiazine hydrochloride, is described in U.S. Patent 2,921,069.
Atypical antipsychotics include, but are not limited to:
Olanzapine, 2-methyl-4-(4-methyl- 1 -piperazinyl)- 1 OH-thieno [2,3- b][l,5]benzodiazepine, is a known compound and is described in U.S. Patent No.
5,229,382 as being useful for the treatment of schizophrenia, schizophreniform disorder, acute mania, mild anxiety states, and psychosis;
Clozapine, 8-chloro-l l-(4-methyl-l-piperazinyl)-5H- dibenzo[b,e][l,4]diazepine, is described in U.S. Patent No. 3,539,573. Clinical efficacy in the treatment of schizophrenia is described (Hanes, et al., Psychopharmacol. Bull.. 24,
62 (1988)); Risperidone, 3-[2-[4-(6-fluoro- 1 ,2-benzisoxazol-3-yl)piperidino]ethyl]-2- methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-4-one, and its use in the treatment of psychotic diseases are described in U.S. Patent No. 4,804,663;
Sertindole, l-[2-[4-[5-chloro-l-(4-fluorophenyl)-lH-indol-3-yl]-l- piperidinyl]ethyl]imidazolidin-2-one, is described in U.S. Patent No. 4,710,500. Its use in the treatment of schizophrenia is described in U.S. Patent Nos. 5,112,838 and 5,238,945;
Quetiapine, 5-[2-(4-dibenzo[b,f][l,4]thiazepin-l 1-yl-l- piperazinyl)ethoxy]ethanol, and its activity in assays which demonstrate utility in the treatment of schizophrenia are described in U.S. Patent No. 4,879,288. Quetiapine is typically administered as its (E)-2-butenedioate (2:1) salt; and
Ziprasidone, 5-[2-[4-(l,2-benzoisothiazol-3-yl)-l-piperazinyl]ethyl]-6- chloro-l,3-dihydro-2H-indol-2-one, is typically administered as the hydrochloride monohydrate. The compound is described in U.S. Patent Nos. 4,831,031 and 5,312,925. Its activity in assays which demonstrate utility in the treatment of schizophrenia are described in U.S. Patent No. 4,831,031.
Aripiprazole (Ability™), 7-[4-[4-(2,3-dichlorophenyl)-l- piperazinyl]butoxy]-3,4-dihydrocarbostyril (U.S. Patents 4,734,416 and 5,006,528) is a new antipsychotic indicated for the treatment of schizophrenia. Similarly, when this aspect of the invention is regarded in its broadest sense, the second component compound is a compound that functions as a norepinephrine reuptake inhibitor as described above.
It will be understood that while the use of a single antipsychotic as a first component compound is preferred, combinations of two or more antipsychotics may be used as a first component if necessary or desired. Similarly, while the use of a single norepinephrine reuptake inhibitor as a second component compound is preferred, combinations of two or more norepinephrine reuptake inhibitors may be used as a second component if necessary or desired.
While all combinations of first and second component compounds are useful and valuable, certain combinations are particularly valued and are preferred, as follows: olanzapine/atomoxetine olanzapine/reboxetine olanzapine/(R)-N-methyl-3-(2-methylthiophenoxy)-3- phenylpropylamine clozapine/atomoxetine risperidone/atomoxetine sertindole/atpmoxetine quetiapine/atomoxetine ziprasidone/atomoxetine aripiprazole/atomoxetine In general, combinations and methods of treatment using olanzapine as the first component are preferred. Furthermore, combinations and methods of treatment using atomoxetine as the second component are preferred. Especially preferred are combinations and methods of treatment using olanzapine as the first component and atomoxetine as the second component. It is especially preferred that when the first component is olanzapine, it will be the Form E olanzapine as described in U.S. Patent
5,736,541.
It is further preferred that the Form E olanzapine polymorph will be administered as the substantially pure Form E olanzapine polymorph. As used herein "substantially pure" refers to Form E associated with less than about 5% Form I, preferably less than about 2% Form I, and more preferably less than about 1% Form I.
Further, "substantially pure" Form E will contain less than about 0.5% related substances, wherein "related substances" refers to undesired chemical impurities or residual solvent or water. In particular, "substantially pure" Form E should contain less than about 0.05% content of acetonitrile, more preferably, less than about 0.005% content of acetonitrile. Additionally, the polymorph of the invention should contain less than 0.5% of associated water.
Although Form E olanzapine is preferred it will be understood that as used herein, the term "olanzapine" embraces all solvate and polymorphic forms unless specifically indicated. The present invention also encompasses the use of one or more SNRIs such as atomoxetine, racemic reboxetine, S,S-reboxetine, or any of the other SNRI compounds disclosed herein, in combination with one or more conventional Alzheimer's agents for the prevention or treatment of cognitive dysfunction in patients suffering from Alzheimer's disease. Conventional Alzheimer's agents include inhibitors of acetylcholine degradation (i.e., cholinesterase or acetylcholinesterase inhibitors) within synapses, e.g., donepezil (Aricept®), rivastigmine (Exelon®), galantamine (Reminyl®), and tacrine (Cognex®); the selective monoamine oxidase inhibitor selegiline
(Eldepryl®); and memantine (Namenda ™), a newly FDA-approved NMDA receptor antagonist for the treatment of moderate to severe Alzheimer's disease. Modafinil (Provigil®) is also used in the treatment of Alzheimer's disease.
The present invention also encompasses the use of one or more SNRIs such as atomoxetine, racemic reboxetine, S,S-reboxetine, or any of the other SNRI compounds disclosed herein, in combination with one or more conventional Parkinson's agents for the treatment of cognitive dysfunction in Parkinson's disease. Conventional Parkinson's agents include levodopa; levodopa/carbidopa (Sinemet®); Stalevo (carbidopa/levodopa/entacapone); dopamine agonists, e.g., bromocriptine; pergolide; Mirapex® (pramipexole), Permax® (pergolide), and Requip® (ropinirole); COMT inhibitors, e.g., tolcapone, and entacapone; Selegiline (Deprenyl®; Eldepryl®); propranolol; primidone; anticholinergics, e.g., Cogentin®, Artane®, Akineton®, Disipal®, and Kemadrin®; and amantadine.
It will be understood by the skilled reader that most or all of the compounds used in the present invention are capable of forming salts, and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free bases. In all cases, the use of the pharmaceuticals described above as salts is contemplated in the description herein, and often is preferred, and the pharmaceutically acceptable salts of all of the compounds are included in the names of them. Especially preferred pharmaceutically acceptable salts are those formed with hydrochloric acid.
The dosages of the component drugs used in the combination therapy aspects of the present invention must, in the final analysis, be set by the physician in charge of the case using knowledge of the drugs, the properties of the drugs in combination as determined in clinical trials, and the characteristics of the patient, including diseases other than that for which the physician is treating the patient. Dosage guidelines for some of the antipsychotic drugs are first given separately. In order to create a guideline for any desired combination, one would choose the guidelines for each of the component drugs.
Chlorpromazine: from about 25-75 mg daily to about 75-150 mg daily;
Droperidol: about 5 mg by injection; Haloperidol: from about 1-15 mg/day to about 100 mg/day administered orally or by injection;
Thioridazine: about 75-150 mg daily;
Trifluoperazine: from about 4-10 mg/day to about 15-20 mg/day;
Olanzapine: from about 0.25 to 50 mg, once/day; preferred, from 1 to 30 mg, once/day; and most preferably 1 to 25 mg once/day;
Clozapine: from about 12.5 to 900 mg daily; preferred, from about 150 to 450 mg daily;
Risperidone: from about 0.25 to 16 mg daily; preferred from about 2-8 mg daily; Sertindole: from about .0001 to 1.0 mg/kg daily;
Quetiapine: from about 1.0 to 40 mg/kg given once daily or in divided doses;
Ziprasidone: from about 5 to 500 mg daily; preferred from about 50 to 100 mg daily; Aripiprazole: from about 10 to 30 mg/day, preferably from about 10 to 15 mg/day, given once daily.
Dosage guidelines for conventional Alzheimer's and Parkinson's agents are well known in the art, and can be found, for example, in the package inserts accompanying each drug. In general terms, one can create an initial combination of the present invention by choosing a dosage of first and second component compounds according to the spirit of the above guidelines. Based on the response of the patient, the physician or other medical professional can then adjust the doses as appropriate.
The adjunctive therapy aspect of the present invention is carried out by administering a first component together with the second component in any manner that provides effective levels of the compounds in the body at the same time. Oral administration of the adjunctive combination is preferred. Both components can be administered together, in a single dosage form, or administered separately. However, oral administration is not the only route or even the only preferred route. For example, transdermal administration may be very desirable for patients who are forgetful or petulant about taking oral medicine. Administration by the percutaneous, intravenous, intramuscular, intranasal, or intrarectal route may be prudent in particular circumstances.
The route of administration can be varied in any way, limited by the physical properties of the drugs, the convenience of the patient and the caregiver, and other relevant circumstances (Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990)). The adjunctive combination can be administered as a single pharmaceutical composition, and so pharmaceutical compositions incorporating both compounds are important embodiments of the present invention. Such compositions can take any physical form that is pharmaceutically acceptable, but orally usable pharmaceutical compositions are particularly preferred. Such adjunctive pharmaceutical compositions contain an effective amount of each of the compounds, which effective amount is related to the daily dose of the compounds to be administered. Each adjunctive dosage unit can contain the daily doses of all compounds, or can contain a fraction of the daily doses, such as one-third of the doses. Alternatively, each dosage unit can contain the entire dose of one of the compounds, and a fraction of the dose of the other compounds. In such case, the patient would daily take one of the combination dosage units, and one or more units containing only the other compounds. The amounts of each drug to be contained in each dosage unit depends on the identity of the drugs chosen for the therapy, and other factors such as the indication for which the adjunctive therapy is being given. The pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art. The carrier or excipient can be a solid, semi-solid, or liquid material that can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition can be adapted for oral, inhalation, parenteral, or topical use, and can be administered to the patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solutions, suspensions, or the like. The compounds useful for the methods of the present invention can be administered orally, for example, with an inert diluent or capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compounds can be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, and the like. These preparations should contain at least 4% of the compound of the present invention, the active ingredient, but can be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit. The amount of the compound present in compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations useful for the methods of the present invention can be determined by a person skilled in the art.
The tablets, pills, capsules, troches, and the like can also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or
Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms can contain other various materials that modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills can be coated with sugar, shellac, or other coating agents. A syrup can contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
A formulation useful for the administration of R-(-)-N-methyl 3-((2- methylphenyl)oxy)-3-phenyl-l-aminopropane hydrochloride (atomoxetine) comprises a dry mixture of R-(-)-N-methyl 3-((2-methylphenyl)oxy)-3-phenyl-l-aminopropane hydrochloride with a diluent and lubricant. A starch, such as pregelatinized corn starch, is a suitable diluent and a silicone oil, such as dimethicone, a suitable lubricant for use in hard gelatin capsules. Suitable formulations are prepared containing about 0.4 to 26% R- (-)-N-methyl 3-((2-methylphen-yl)oxy)-3-phenyl-l-aminopropane hydrochloride, about 73 to 99% starch, and about 0.2 to 1.0% silicone oil. The following tables illustrate particularly preferred atomoxetine formulations:
Figure imgf000060_0001
Figure imgf000060_0002
For the purpose of parenteral therapeutic administration, the compounds of the present invention can be incorporated into a solution or suspension. These preparations typically contain at least 0.1% of a compound of the invention, but can be varied to be between 0.1 and about 90% of the weight thereof. The amount of the compound of formula I present in such compositions is such that a suitable dosage will be obtained. The solutions or suspensions can also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetra-acetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Preferred compositions and preparations can be determined by one skilled in the art.
Inhibition of Norepinephrine Reuptake The ability of compounds to inhibit the reuptake of norepinephrine can be measured by the general procedure of Wong, et al., supra.
Male Sprague-Dawley rats weighing 150-250 gm are decapitated and brains are immediately removed. Cerebral cortices are homogenized in 9 volumes of a medium containing 0.32 M sucrose and 10 mM glucose. Crude synaptosomal preparations are isolated after differential centrifugation at 1000 x g for 10 minutes and
17,000 x g for 28 minutes. The final pellets are suspended in the same medium and kept in ice until use within the same day.
Synaptosomal uptake of 3H-norepinephrine is determined as follows. Cortical synaptosomes (equvalent to 1 mg of protein) are incubated at 37°C for 5 minutes in 1 mL Krebs-bicarbonate medium containing also 10 mM glucose, 0.1 mM iproniazide,
1 mM ascorbic acid, 0.17 mM EDTA and 50 nM 3H-norepinephrine. The reaction mixture is immediately diluted with 2 mL of ice-chilled Krebs-bicarbonate buffer and filtered under vacuum with a cell harvester (Brandel, Gaithersburg, MD). Filters are rinsed twice with approximately 5 mL of ice-chilled 0.9% saline and the uptake of 3H- norepinephrine assessed by liquid scintillation counting. Accumulation of 3H- norepinephrine at 4°C is considered to be background and is subtracted from all measurements. The concentration of the test compound required to inhibit 50% of the H-norepinephrine accumulation (IC50 values) are determined by linear regression analysis.
The present invention provides methods for the treatment of cognitive failure. As discussed in detail above, cognitive failure may present in patients suffering from a number of disorders, including dementia or delirium, or due to a wide variety of other causes. The methods of the present invention are useful for the treatment or prevention of cognitive failure associated with, or due to, the disorders or etiologies discussed above, including disorders formally classified in the DSM-IV-TR™. For the convenience of the reader, the DSM-IV-TR™ code numbers or descriptions are supplied below . "ICD-9-CM codes" refers to codes for, e.g., selected general medical conditions and medication-induced disorders contained in the International Classification of Diseases, 9th Revision, Clinical Modification.
Delirium Due to a General Medical Condition 293.0
Substance-Induced Delirium, including:
Substance Intoxication Delirium:
Code [Specific Substance] intoxication Delirium: (291.0 Alcohol; 292.81 Amphetamine [or Amphetamine-Like Substance]; 292.81
Cannabis; 292.81 Cocaine; 292.81 Hallucinogen; 292.81 Inhalant; 292.81 Opioid; 292.81 Phencyclidine [or Phencyclidine-Like Substance]; 292.81 Sedative, Hypnotic, or Anxiolytic; 292.81 Other [or Unknown] Substance [e.g., cimetidine, digitalis, benztropine])
Substance Withdrawal Delirium:
Code [Specific Substance] Withdrawal Delirium:
(291.0 Alcohol; 292.81 Sedative, Hypnotic, or Anxiolytic; 292.81 Other [or
Unknown] Substance) Delirium Due to Multiple Etiologies: Multiple codes are used, reflecting the specific delirium and specific etiologies, e.g., 293.0 Delirium Due to Niral Encephalitis; 291.0 Alcohol Withdrawal Delirium
Delirium Not Otherwise Specified 780.09 Dementia of the Alzheimer's Type 294. lx* (*ICD-9-CM code)
Subtypes:
With Early Onset (onset of the dementia is age 65 years or under)
With Late Onset (onset of the dementia is after age 65 years)
Without Behavioral Disturbance 294.10 With Behavorial Disturbance 294.11
Vascular Dementia 290.4x
Subtypes:
With Delirium 290.41
With Delusions 290.42 With Depressed Mood 290.43
With Behavioral Disturbance Uncoded
Uncomplicated 290.40
Dementia Due to HIV Disease 294. lx* (*ICD-9-CM code)
Dementia Due to Head Trauma 294. lx* (*ICD-9-CM code) Dementia Due to Parkinson's Disease 294. lx* (*ICD-9-CM code)
Dementia Due to Huntington's Disease 294. lx* (*ICD-9-CM code)
Dementia Due to Pick's Disease 290. lx* (*ICD-9-CM code)
Dementia Due to Creutzfeldt- Jakob Disease 290. lx* (*ICD-9-CM code)
Dementia Due to Other General Medical Conditions 294. lx* (*ICD-9-CM code) Code based on presence or absence of a clinically significant behavioral disturbance:
Without Behavioral Disturbance 294.10 With Behavioral Disturbance 294.11
Substance-Induced Persisting Dementia Code [Specific Substance]-Induced Persisting Dementia:
(291.2 Alcohol; 292.82 Inhalant; 292.82 Sedative, Hypnotic, or Anxiolytic; 292.82 Other [or Unknown] Substance) Dementia Due to Multiple Etiologies
Coding note: Use multiple codes based on specific dementias and specific etiologies, e.g., 294.10 Dementia of the Alzheimer's Type, With Late Onset, Without Behavioral Disturbance; 290.40 Vascular Dementia, Uncomplicated. Dementia Not Otherwise Specified 294.8
Amnestic Disorder Due to a General Medical Condition 294.0
Transient or Chronic Substance-Induced Persisting Amnestic Disorder Code [Specific Substance] -Induced Persisting Amnestic Disorder:
291.1 Alcohol; 292.83 Sedative, Hypnotic, or Anxiolytic; 292.83 Other [or Unknown] Substance Amnestic Disorder Not Otherwise Specified 294.8
Cognitive Disorder Not Otherwise Specified 294.9 Age-Related Cognitive Decline 780.9
Schizophrenia
Paranoid Type Schizophrenia 295.30
Disorganized Type Schizophrenia 295.10 Catatonic Type Schizophrenia 295.20
Undifferentiated Type Schizophrenia 295.90
Residual Type Schizophrenia 295.60
Schizophreniform Disorder 295.40
Schizoaffective Disorder 295.70
The skilled artisan will appreciate that the disorders listed above are only illustrative of those indications where cognitive failure may appear, and are not intended to limit the scope of the present invention in any way.
Non-limiting examples of cognitive disorders due to various etiologies, or associated with various disorders, of particular interest that can be prevented or treated according to the methods of the present invention include: Enhancing cognitive functions and executive functioning (ability to plan, initiate, organize, carry out, monitor, and correct one's own behavior) in normal subjects or in subjects exhibiting cognitive dysfunction;
Treatment of cognitive and attentional deficits associated with prenatal exposure to substances of abuse. Cognitive and attentional deficits are associated with prenatal exposure to substances of abuse including, but not limited to, nicotine, alcohol, methamphetamine, ***e, and heroin. Children born to addicted mothers often exhibit life-long cognitive deficits, often including diagnoses of attention deficit disorder (with and without hyperactivity (ADHD)). Besides attentional abnormalities, such children often exhibit psychomotor developmental delay and intellectual impairments;
Treatment of cognitive impairment caused by chronic alcohol and drug abuse (substance-induced persisting dementia), medicament side effects, and treatment of dmg craving and withdrawal; Treatment of cognitive deficits in Down' s Syndrome patients;
Treatment of deficits in normal memory functioning comorbid with major depressive and bipolar disorders. Patients in need of treatment with SNRIs as disclosed herein include those that suffer from major depressive and bipolar disorders, and who also exhibit deficits in normal memory functioning. The latter can be ascertained using tests conventional in the art;
Treatment of cognitive impairment associated with depression, mental retardation, bipolar disorder, or schizophrenia. Patients in need of treatment with SNRIs as disclosed herein include those that suffer from depression, mental retardation, bipolar disorder, or schizophrenia, and who also exhibit cognitive deficits. Such deficits can be ascertained using tests conventional in the art;
Treatment of dementia syndromes associated with mania, conversion disorder, and malingering;
Treatment of problems of attention, prefrontal executive function, or memory due to head trauma or stroke. It should be noted that problems of attention can occur in the absence of dementia, while the converse is not necessarily true, i.e., dementia includes problems with attention;
Treatment of cognitive dysfunction in menopausal and post-menopausal women; Treatment of cognitive deficits and fatigue due to, or associated with, cancer and cancer therapies. In this context, the present invention relates to the field of psychooncology, including methods for preventing or treating cognitive impairments, including dementias and deliriums, due to cancers per se in child, adolescent, and adult patients, or due to the therapies employed to treat cancers in such patients. While conventional cancer therapies can have negative effects on cognitive function, patients with tumors of the CNS are also particularly prone to cognitive dysfunction. Thus, both cancers themselves, and the treatments for these diseases, can lead to cognitive deficits in this patient population. Virtually all cancer patients and survivors will suffer some effect on cognitive function due either to their cancer or therapy, including deliriums, characterized by temporary disturbances of consciousness and changes in cognition that develop over a short period of time, and long-term complications related to learning, academic, psychological, and social functioning ("cognitive late effects" or dementias) that had previously been irrelevant due to the high mortality rate in this patient population. The etiologies of these conditions can vary.
Cognitive deficits associated with cancer treatment can be temporarily associated with the administration of anti-cancer therapies and therefore transitory or short term, or more long lasting. Such deficits dramatically affect a patient's quality of life including, for example, memory, concentration, the ability to remain focused or organized, etc.
Cognitive deficits are associated with a variety of cancer treatments, including cranial radiation, conventional (standard-dose) chemotherapy, high-dose chemotherapy and hematopoietic (bone-marrow) transplantation, and biologic agents.
Taken together, a number of other studies support the hypothesis that cognitive deficits, particularly in the areas of memory and concentration, are associated with cancer chemotherapy regimens during treatment, in the short-term after treatment, and up to ten years after treatment (van Dam et al. (1998) J. Natl. Cancer Inst. 90: 210-218; Schagen et al. (1999) Cancer 85: 640-650; Brezden et al. (2000) J. Clin. Oncol. 18:2695-2701; Ahles et al. (2002) J. Clin. Oncol 20(2):485-493). Other studies suggest that these cognitive problems may persist for many years after treatment (Ferrell et al. (1997)
Oncology 11: 565-576; Whedon et al. (1995) Oncol. Nurs. Forum 22:1527-1537). In a report of cognitive defects in patients approximately ten years after chemotherapy, Ahles et al. ((2002) J. Clin. Oncol. 20(2):485-493) suggests that cognitive defects can persist long after treatment, and perhaps indefinitely.
The term "cancer" has many definitions. According to the American Cancer Society, cancer is a group of diseases characterized by uncontrolled growth (and sometimes spread) of abnormal cells. Although often referred to as a single condition, it actually consists of more than 200 different diseases. Cancerous growths can kill when such cells prevent normal function of vital organs, or spread throughout the body, damaging essential systems. Non-limiting examples of different types of cancers include: carcinomas, such as neoplasms of the central nervous system, including glioblastoma multiforme, astrocytoma, oligodendroglial tumors, ependymal and choroid plexus tumors, pineal tumors, neuronal tumors, medulloblastoma, schwannoma, meningioma, and meningeal sarcoma; neoplasms of the eye, including basal cell carcinoma, squamous cell carcinoma, melanoma, rhabdomyosarcoma, and retinoblastoma; neoplasms of the endocrine glands, including pituitary neoplasms, neoplasms of the thyroid, neoplasms of the adrenal cortex, neoplasms of the neuroendocrine system, neoplasms of the gastroenteropancreatic endocrine system, and neoplasms of the gonads; neoplasms of the head and neck, including head and neck cancer, neoplasms of the oral cavity, pharynx, and larynx, and odontogenic tumors; neoplasms of the thorax, including large cell lung carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, malignant mesothelioma, thymomas, and primary germ cell tumors of the thorax; neoplasms of the alimentary canal, including neoplasms of the esophagus, stomach, liver, gallbladder, the exocrine pancreas, the small intestine, veriform appendix, and peritoneum, adneocarcinoma of the colon and rectum, and neoplasms of the anus; neoplasms of the genitourinary tract, including renal cell carcinoma, neoplasms of the renal pelvis, ureter, bladder, urethra, prostate, penis, testis; and female reproductive organs, including neoplasms of the vulva and vagina, cervix, adenocarcinoma of the uterine corpus, ovarian cancer, gynecologic sarcomas, and neoplasms of the breast; neoplasms of the skin, including basal cell carcinoma, squamous cell carcinoma, dermatofibrosarcoma, Merkel cell tumor, and malignant melanoma; neoplasms of the bone and soft tissue, including osteogenic sarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, primitive neuroectodermal tumor, and angiosarcoma; neoplasms of the hematopoietic system, including myelodysplastic sydromes, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, HTLV-1 and 5 T-cell leukemia/lymphoma, chronic lymphocytic leukemia, hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphomas, and mast cell leukemia; and neoplasms of children, including acute lymphoblastic leukemia, acute myelocytic leukemias, neuroblastoma, bone tumors, rhabdomyosarcoma, lymphomas, and renal tumors.
The term "cancer therapy" refers to treatments including, but not limited to, surgery, radiation therapy (including photodynamic therapy), chemotherapy (including hormonal therapy), and biologic therapy (including immunotherapy, differentiating agents, and agents targeting cancer cell biology). Such therapies are often used in combination, and agents in a single category can act by several different mechanisms.
For example, cancer chemotherapy agents can induce differentiation, and antibodies, which are a form of immunotherapy, can be used to deliver radiation therapy. Surgery and radiation therapy are considered local treatments, although their effects can influence the behavior of tumors at remote sites. Chemotherapy and biologic therapy are usually systemic treatments. The many types of therapies used in cancer treatment are well known to practitioners in the art, and are summarized, for example, in Sausville and Longo ((2001) Harrison's Principles Of Internal Medicine, 15th Edition, Eugene Braunwald et al., Eds., Chapter 84, The McGraw-Hill Companies, Inc.); Calabresi et al. (2001) in Goodman & Gilman's The Pharmacological Basis of Therapeutics, Tenth Edition, Hardman et al., Eds., McGraw-Hill, New York, pp. 1381-1388; Chabner et al.
(2001) in Goodman & Gilman's The Pharmacological Basis of Therapeutics, Tenth Edition, Hardman et al., Eds., McGraw-Hill, New York, Chapter 52, pp. 1389-1459; and other references, to which the reader is referred. Fawzy et al. ((2002) Oncology and Psychooncology, In Wise and Rundell, Eds., The American Psychiatric Publishing Textbook of Consultation-Liaison Psychiatry, Psychiatry in the Medically III, Second
Edition, American Psychiatric Publishing, Inc., Washington, D.C., Chapter 29, pp. 657- 678, Table 29-5) summarize neuropsychiatric side effects, including delirium and dementia, of chemotherapeutic agents.
The compounds disclosed herein can be used either to prevent or treat cognitive dysfunction in patients due to cancer or the cancer therapy they receive. Regarding the former, changes in mental status of cancer patients can be due to the presence of cancer in the CNS per se, or metastases to the central nervous system of tumors from other areas of the body, for example lung cancer, breast cancer, kidney cancer, metastatic melanoma, renal cancer, etc. When a metastatic tumor appears to be isolated, surgical resection is considered. Otherwise, the treatment is whole-brain irradiation.
Delirium in patients with cancer can also be caused by distant, non-metastatic effects of tumors. Such paraneoplastic syndromes are most common in patients with small cell carcinoma of the lung, but can also occur due to breast, stomach, uterine, renal, testicular, thyroid, and colon cancers (Minotti et al. (1994) Am. J. Otolaryngology 15:336-343; Peterson et al. (1994) J. Neurooncol. 21:159-170; Schiller et al. (1993) Curr. Opin. Oncol. 5:335-342). Neurological insults frequently associated with delirium and dementia include subacute cerebellar degeneration, encephalomyopathy, and Eaton-
Lambert syndrome. Limbic encephalopathy can result in a prominent memory defect, the mechanism perhaps being autoimmune, and associated with antineuronal antibodies (Cornelius et al. (1986) Biol Psychiatry 21:686-690; Moll et al. (1990) J. Neurol Neurosurg. Psychiatry 53:940-943; Newman et al. (1990) Biol. Psychiatry 27:529-540; Posner (1989) Neurology 39 (suppl. l):244-245). Ectopic production of hormone by tumors can also alter mental status. Other causes of delirium in cancer patients include hypercalcemia often secondary to bone metastases; hypomagnesemia, often associated with cisplatin therapy (Schilsky et al. (1979) Ann. Intern. Med. 90:929-931); hyperviscosity syndrome, often occurring in patients with lymphoma, Waldenstrom's macroglobulinemia, or myeloma (Crawford et al. (1985) Am. J. Med. 79:13-22).
Psychotic conditions that can be treated by the adjunctive therapy aspect of the present invention include schizophrenia, schizophreniform diseases, acute mania, and schizoaffective disorders. The titles given these conditions represent multiple disease states. The following list illustrates a number of these disease states, many of which are classified in the DSM-IV-TR™. The DSM-IV-TR™ code numbers for these disease states are supplied below, when available, for the convenience of the reader.
Paranoid Type Schizophrenia 295.30
Disorganized Type Schizophrenia 295.10 Catatonic Type Schizophrenia 295.20
Undifferentiated Type Schizophrenia 295.90
Residual Type Schizophrenia 295.60 Schizophreniform Disorder 295.40
Schizoaffective Disorder 295.70
It should be noted that the methods of the present invention are effective in the treatment of children, adolescents, and adults. For purposes of the present invention, a child is considered to be a patient below the age of puberty, an adolescent is considered to be a patient from the age of puberty up to about 18 years of age, and an adult is considered to be a patient 18 years or older.
Preparation of Compounds of Formula (IA)
Compounds of formula (IA) may be prepared by conventional organic chemistry techniques and also by solid phase synthesis. In the present specification the abbreviation "boc" refers to the N-protecting group t-butyloxycarbonyl. In the present specification the abbreviation "TFA" refers to trifluoroacetic acid. In the present specification the abbreviation "DMF" refers to dimethylformamide. In the present specification the abbreviation "SPE" refers to solid phase extraction. In the present specification the abbreviation "ACE-C1" refers to α-chloroethyl chloroformate.
When R8 is H, a suitable three-step conventional synthesis is outlined in Scheme IA shown below.
Figure imgf000071_0001
IIA
Figure imgf000071_0002
IVA
Figure imgf000071_0003
IA (where R8 = H)
Scheme IA
A boc-protected 4-piperidone (IIA) is reductively aminated with an amine to provide a 4-amino-piperidine (EIAa or EIAb). A second reductive amination with an aldehyde or ketone provides a boc-protected compound of formula (IA) (WA). The boc group is removed under acidic conditions to provide a compound of formula (IA) (where R8 is H). If desired, the compound of formula (IA) (where R8 is H) may be converted to a suitable salt by addition of a suitable quantity of a suitable acid. In the schemes above (and below) RI to R7, R9, RIO and n are as previously defined, m is 0, 1 or 2 and RI 1 and R12 are chosen such that R11-CH-R12 = RI.
Although the boc N-protecting group is used in the above illustration, it will be appreciated that other N-protecting groups (for example acetyl, benzyl or benzoxycarbonyl) could also be used together with a deprotection step appropriate for the N-protecting group used. Similarly, other reducing agents (for example NaBH4 or
LiAlH4) may be used in the reductive amination steps and other acids (for example HCI) may be used in the deprotection step.
As an alternative to the second reductive amination step, compound EIAa or EIAb may be subjected to an alkylation step as shown in Scheme IB below (L represents a suitable leaving group - for example Br or tosyl).
Figure imgf000073_0001
IIIAa IIIAb
Figure imgf000073_0002
IVA
Figure imgf000073_0003
IA (where R8 = H)
Scheme IB
Once again, N-protection other than boc may also be used together with a suitable deprotection step. Similarly, bases other than potassium carbonate (e.g NaH) may be used for the alkylation step
Using essentially the same chemical reactions as in the first scheme above, the compounds of formula (IA) (where R8 is H) may also be prepared by a solid phase parallel synthesis technique as outlined in Scheme IC shown below.
Figure imgf000074_0001
Figure imgf000074_0002
IA (where R8 = H)
Scheme IC
A piperidone hydrate is attached to a polystyrene resin to provide a resin bound piperidone (VA). Aliquots are reductively aminated to provide a resin bound secondary amine (VIA) that can undergo a further reductive amination with an aldehyde or ketone to give the tertiary amine (VEA). Acidic cleavage from the resin and SPE provides compounds of formula (IA) (where R8 is H) which may be purified by ion exchange methods using, for example, the SCX-2 ion exchange resin.
Although NaBH(OAc)3 is used in the above illustration, it will be appreciated that other reducing agents (for example NaBH4 or LiAlH4) may be used in the reductive amination steps and other acids (for example HCI) may be used in the deprotection step. Solid phase resins other than the p-nitrophenylcarbonate-polystyrene resin illustrated above may also be employed.
When R8 is Cι-C4alkyl, a conventional synthetic route is outlined in Scheme ID shown below.
Figure imgf000075_0001
VIIIA IXA
Figure imgf000075_0002
IA (where Rg is C C4alkyl)
Scheme ID A benzyl-protected 4-piperidone (VIEA) is alkylated with an alkyllithium reagent to provide a 4-amino-piρeridinol (I A). Treatment with an alkylnitrile or alkylamide under strongly acidic conditions provides a secondary amide (XA) which may be deprotected, boc-protected and reduced to provide a secondary amine (XIA). Alkylation of the secondary amine (XIA) followed by removal of the boc group provides a compound of formula (IA) (where R8 is Ci -C4alkyl). In the scheme above L is a leaving group as previously defined and R13 is chosen such that R13-CH2 = RI.
Although the benzyl and boc N-protecting groups are used in the above illustration, it will be appreciated that other N-protecting groups could also be used in their place together with deprotection steps appropriate for those N-protecting groups. Similarly, other reducing agents may be used in the amidecarbonyl reduction step and other organometallics or bases may be used in the respective alkylation steps.
Preparation of Compounds of Formula (IB)
A general scheme outlining the synthetic routes to compounds of Formulae (IB) wherein Y is OH is shown below (Scheme IB). For clarity, Ar2 is shown as phenyl and Ry and Rz are shown as H. It will be appreciated that analogous methods could be applied for other possible identities of Ar2, Ry and Rz.
Figure imgf000076_0001
2B Scheme IB Compounds of Formulae (BB) can be prepared by conventional organic chemistry techniques from an N-benzyl-ketomorpholine of type IB by addition of a suitable organometallic derivative (method A), or via the addition of a suitable organometallic reagent to an epoxide of type 2B (method B), as outlined in Scheme IB. The racemic intermediates of type IB can be obtained as outlined in Scheme 2B by condensation of an N-benzyl cyanomorpholine 5B (J. Med. Chem. 1993, 36, pp 683 - 689) with a suitable aryl organometallic reagent followed by acid hydrolysis. Chiral HPLC separations of the racemic N-benzyl-aryl-ketomorpholine of type IB gives the required single enantiomer, i.e., the (2S)- N-benzyl-aryl-ketomorpholine of type 6B (Scheme 2B).
CHIRAL HPLC separation
Figure imgf000077_0002
Figure imgf000077_0001
Scheme 2B
Condensation of a chiral (2S)-N-benzyl-aryl-ketomorpholine of type 6B with a commercially available benzylic magnesium halide or a benzylic magnesium halide prepared using standard Grignard techniques from the corresponding halo-benzylic derivative gives a tertiary alcohol of type 3B without any observed epimerisation of the existing asymmetric center (ee's/de's determinations can be carried out using chiral HPLC) and with very high overall diastereoisomeric excesses (see Scheme 3B). The final compounds of type 4B can be obtained after cleavage of the N-benzyl protecting group on a compound of type 3B. The deprotection can be done using catalytic palladium hydrogenolysis, or carbamate exchange with ACE-C1 (1-Chloroethyl chloroformate), giving intermediates of type 7B, followed by methanolysis as shown in Scheme 3B.
Figure imgf000078_0001
Scheme 3B
The intermediates 3B can be further elaborated using for example organometallic type couplings between an ortho bromide derivative of type 8B and an arylboronic acid as shown in Scheme 4B. For clarity, Av and its substituent (R are shown as phenyl and substitution occurs at the 2-position. It will be appreciated that analogous methods could be applied for other possible identities of Ari and Ri and other possible substitution positions. This approach can also be carried out by solid phase synthetic methods as described in more detail in the specific examples below.
Figure imgf000078_0002
Scheme 4B
An alternative route for the preparation of the compounds of Formulae (IB) is method B (see Scheme IB). Formation of the intermediate epoxides of type 2B from racemic N-benzyl-ketomorpholines of type IB, can be done using for example trimethyl sulfoxonium iodide and a suitable base, for example sodium hydride. Condensation of 2B with a commercially available aryl organometallic, or an aryl organometallic prepared from the corresponding halo aryl derivative, gives the intermediates of type 3B, as mixtures of diastereoisomers. Final deprotections can be done as described above (see Scheme 3B). Final compounds made using method B can be purified using chiral HPLC.
Compounds of Formula (IB) of the present invention wherein Y is OR and R is C1 -C4 alkyl, can be synthesized by standard alkylation of intermediates of type 3B prior to deprotection of the morpholine N-atom as shown in Scheme 5B. Suitable strong bases will be known to the person skilled in the art and include, for example, sodium hydride. Similarly, suitable alkylating agents will be known to the person skilled in the art and include, for example, C1-C4 alkyl halides such as methyl iodide.
Figure imgf000079_0001
Scheme 5B
Preparation of Compounds of Formula (IC) Compounds of formula (IC) may be prepared by conventional organic chemistry techniques from N-benzyl-cyanomorpholine IC (Route A) or N-benzyl-morpholinone 2C (Route B) as outlined in Scheme IC below: For clarity, X is shown as phenyl and R' and R1 are shown as H. It will be appreciated that analogous methods could be applied for other possible identities of X, R' and R1.
Route
Figure imgf000080_0001
Figure imgf000080_0002
Scheme IC
More detail of Route A is given in Scheme 2C:
Figure imgf000080_0003
Scheme 2C
The amino alcohol 4Ca can be obtained by reaction of N-benzyl-cyanomorpholine IC with a Grignard reagent, followed by acid hydrolysis to give racemic phenyl ketone 3C which may be separated on chiral HPLC. (2S)-Phenyl ketone 3Ca may then be reduced with DIP-Cl to give 4Ca in high diastereomeric excess. The amino alcohol 4Ca is converted into benzyl bromide 5Ca, to give the desired N-substituted aryl thio morpholines after displacement with the requisite aryl thiol. N-substituted aryloxy morpholines may be obtained in an analogous manner by displacement with the requisite hydroxyaryl compound. Alternatively, N-substituted aryloxy morpholines may be obtained by addition of a strong base, such as sodium hydride, to the amino alcohol 4Ca to form a nucleophilic alkoxide followed by an SNAΓ reaction with an Ar group substituted with a suitable leaving group (e.g. F). Deprotection of the tertiary amine gives the final products.
Detail of route B is given in Scheme 3C:
Figure imgf000081_0001
Scheme 3C
Treatment of N-benzyl morpholinone 2C with a strong base such as lithium diisopropylamide at low temperature followed by addition of benzaldehyde gives aldol adducts 6Ca-6Cd as a 2:1 mixture of diastereomer pairs 6Ca,6Cb and 6Cc,6Cd, which may be separated using conventional chromatographic techniques. Reduction with a borane reagent at elevated temperatures gives diasteremeric amino alcohol pairs 4Ca,4Cb and 4Cc,4Cd respectively.
Amino alcohol pair 4Ca,4Cb may be converted to bromide 5Ca,5Cb and further to racemic aryl thio morpholines as outlined in Scheme 4C. Amino alcohol pair 4Cc,4Cd may be converted into the corresponding mesylate. Displacement with the requisite thiol, followed by removal of the nitrogen protecting group furnishes aryl thiol morpholines as racemic mixtures of two diastereomers. The racemic aryl thiol morpholines may be separated into enantiomerically pure products using chiral HPLC technology. Ν- substituted aryloxy morpholines may be obtained in an analogous manner by displacement with the requisite hydroxyaryl compound.
Figure imgf000082_0001
Scheme 4C
Aryl-substituted morpholines 33C, 35C, 37C may be obtained from morpholinone 2C as outlined in Scheme 5C:
Figure imgf000082_0002
38Ca,38Cb: R = meta-F 41Ca,41Cb: R = meta-F 44Ca,44Cb: R = meta-F 39Ca,39Cb: R = para-CI 42Ca,42Cb: R = para-CI 45Ca,45Cb: R = para-CI 40Ca,40Cb: R = ortho-F 43Ca,43Cb: R = ortho-F 46Ca,46Cb: R = ortho-F
Figure imgf000082_0003
32Ca,32Cb: R = meta-F, R' = CF3 33C: R = meta-F, R' = CF3 34Ca,34Cb: R = para-CI, R' = CF3 35C: R = para-CI, R' = CF3 36Ca,36Cb: R = ortho-F, R' = Cl 37C: R = ortho-F, R' = Cl
Scheme 5C
An alternative route to 9C is outlined in Scheme 6C. This route makes use of a chiral auxiliary and gives 9C in enantiomerically pure form.
Figure imgf000083_0001
51C
52C 9C: (2S,2'S): R1 = orttrø-CF3
Scheme 6C
Preparation of Compounds of Formula (ID)
Compounds of formula (TD) may be prepared using the following methods. General schemes outlining the synthetic routes used to prepare racemic products are given below. All active racemates may be separated into single enantiomers using chiral HPLC and may be readily converted into suitable salts.
Compounds of formula (ID) wherein Ar is (i) and R2c is H may be prepared as shown in Scheme ID below:
Figure imgf000084_0001
Scheme ID Quinolin-2-one ID or its corresponding 4-oxo and 4-thio derivatives can be N- arylated using modified conditions to those reported by Buchwald, (J. Am. Chem. Soc, 123, 2001, p. 7727). For example the quinolin-2-one ID is reacted with 3 equivalents of Ar-Br wherein Ar is (i) and R2c is H, 0.2 equivalents of trans-cyclohexanediamine, 0.2 equivalent of copper iodide (Cul), 2.1 equivalents of potassium carbonate (K2CO3), in an organic solvent such as 1,4-dioxane at a temperature of 125°C overnight. The resulting N- arylated quinolin-2-one 2D can be alkylated by treatment with a strong base such as lithium hexamethyldisilazide (LiHMDS) at temperatures of -78°C in a suitable organic solvent such as tetrahydrofuran (THF), followed by the addition of an alkyl halide such as alkyl iodide to give the corresponding 3-alkylated-N-arylated quinolin-2-one derivative 3D. Using the same alkylating conditions above with a 1,2-dihaloethane, such as 1- bromo-2-chloroethane, or a 1,3-dihalopropane, such as l-bromo-3-chloropropane, as alkylating agents provides 4D or 5D wherein n is 2 or 3 respectively. These halo analogues were chosen as ideal precursors to the desired amine products. For instance, treatment of 4D or 5D with aqueous methylamine, in the presence of a catalytic amount of a suitable iodide, such as potassium iodide (Kl), in ethanol at 100°C provided the racemic amine products 6D and 7D respectively, in moderate yields.
Compounds of formula (ID) wherein Ar is (i), R2c is H and n is 3 may be prepared using alternative chemistry as shown in Scheme 2D.
Figure imgf000085_0001
Scheme 2D Quinolin-2-ones 2D and 3D can be alkylated using the aforementioned alkylating procedure using an allyl halide e.g. allyl bromide as the alkylating agent to give the corresponding 3-allyl-N-arylated-quinolin-2-ones 11D. Said allyl analogues could then be converted to the corresponding primary alcohols 12D by a hydroboration procedure involving a suitable borane, such as 9-BBN in a suitable solvent such as THF. Oxidative work up using for example reaction conditions such as aqueous hydrogen peroxide in a solvent such as ethanol, in the presence of a suitable base, such as sodium hydroxide, gave moderate to good yields of alcohol products after column chromatography purification. The alcohols were cleanly converted into their mesylates, by reaction of a mesyl halide such as mesyl chloride in the presence of a suitable base such as triethylamine in a suitable solvent such as THF at a suitable temperature such as 0°C to room temperature. The resulting mesylates are used directly in the amination step described above in Scheme ID to provide good yields of the final racemic targets 13D.
In order to prepare a range of N-arylated analogues advanced intermediates were prepared that could undergo N-arylations with a range of substituted aryl halides, such as aryl bromides or iodides, 2 and 3-halothiophenes, 2 and 3-halofurans or 2 and 3- halopyrroles. The synthetic route used to prepare intermediates 19D is shown below in Scheme 3D.
Figure imgf000086_0001
Scheme 3D
Compounds of formula (ID) wherein n is 3 may be prepared as shown in Scheme 3D. This method is particularly suitable for compounds wherein Ar is (i) and R2c is H or Ar is (ii), wherein -Y- is -S-. Quinolin-2-one ID can be protected using a suitable amide-protecting group such as those described in T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1991, hereafter referred to as "Greene". For example quinolin-2-one ID can be protected with a 4-methoxybenzyl group. The protection reaction can be carried out for example using a suitable base, such as sodium hydride in a suitable solvent, such as dimethylformamide, followed by reaction with a 4- methoxybenzyl halide, such as 4-methoxybenzyl chloride, to give the corresponding N- protected derivative 14D in good yield. This intermediate can be converted directly to the allyl analogue 16Da, wherein R1 = H, in a manner described earlier or converted into the alkyl analogue 15D which can be subsequently alkylated with a allyl halide to give the allyl analogue 16Db, wherein R1 is -C alkyl. Using the same hydroboration, mesylation and amination sequence described in Scheme 2D provided both amines 18Da- b. Deprotection of protected quinolin-2-one could be achieved using any suitable deprotection conditions as those shown in Greene. For example, the 4-methoxybenzyl group could be cleaved cleanly using trifluoroacetic acid and anisole at 65°C. The resultant product could be selectively protected on the secondary amine with a suitable nitrogen protecting group as those described in Greene. For example, the secondary amine can be protected with a Boc group. The reaction can be carried out with Boc anhydride in a suitable solvent such as THF to provide multi gram quantities of 19Da-b. Reaction of 19Da-b with various aryl bromides using the previously described N- arylation conditions, deprotection using suitable deprotecting conditions such as those described in Greene gave a range of final racemic targets 21Da-b or 22Da-b. For example, for compounds protected with a Boc group they can be deprotected in the presence of trifluoroacetic acid (TFA) in a suitable organic solvent such as dichoromethane (DCM).
Intermediates 19Da-b wherein R3 is a halo group, for example chloro or bromo, can be used to provide compounds of formula (ID) wherein R3 is a phenyl group, such as compound 24D, via a Suzuki coupling, see Scheme 4D below.
Figure imgf000088_0001
24D
Scheme 4D
Intermediates 19Da-b, wherein R is for example bromo can be N-protected with a suitable amide protecting group for example 4-methoxybenzyl as described in Scheme 3D above and then coupled with phenylboronic acid under Suzuki conditions to provide the phenyl analogues 23D. Deprotection of the 4-methoxybenzyl group with TFA, followed by protection of the resulting secondary amine with a suitable nitrogen protecting group such as Boc followed by subsequent N-arylation and Boc deprotection using the previously described methodology gave the final target 24D. It will be appreciated that compounds of formula (IDa) wherein R3 is bromo or chloro can be prepared as shown in Schemes ID to 4D above starting from the corresponding haloquinolin-2-ones. Alternatively, they can be prepared from the corresponding quinolin-2-one ID wherein R3 is hydrogen as mentioned above including an extra step comprising the halogenation of a suitable intermediate at some stage of the synthesis. For example quinolin-2-one ID in Scheme 2D can be halogenated using N- chlorosuccinimide in a suitable solvent such as DMF at a suitable temperature such as room temperature to give the corresponding 6-chloro-quinolin-2-one ID wherein R3 is Cl.
Alternatively intermediates (19Da-b) wherein R3 is H in Scheme 3D can be halogenated in the presence of N-chloro and N-bromosuccinimide in a suitable solvent such as DMF to give the corresponding 6-chloro and 6-bromoquinolin-2-ones (20Da-c).
Figure imgf000089_0001
20Da-c
It will be appreciated that Schemes ID to 4D above relate to methods for the preparation of compounds of formula (ED) wherein Ar is (i) and R2c is hydrogen. Compounds of formula (ED) wherein Ar is (i) and R2c can be other than hydrogen, can be prepared using any of the general methods mentioned above, starting from the corresponding N-arylated quinolin-2-one 27D. A general method for preparing said intermediates is illustrated in Scheme 5D. Commercially available 3-(2-Bromo-phenyl)- propionic acids 25D can be converted to amide 26D using standard amide coupling conditions and converted to the N-arylated quinolin-2-ones 27D by an intramolecular, palladium catalysed cyclisation according to the method of Buchwald et al (Tetrahedron, 1996, 52, p. 7525).
Figure imgf000089_0002
25D 26D
Figure imgf000089_0003
Scheme 5D
Preparation of Compounds of Formula (IE)
Compounds of formula (IE) may be prepared by conventional organic chemistry techniques and also by solid phase synthesis. Compounds of formula (TE) can be prepared via the 3-aminopyrrolidine intermediate of formula (IVE) as illustrated in the Scheme IE below:
Figure imgf000090_0001
(HIE)
Figure imgf000090_0003
Figure imgf000090_0002
Figure imgf000090_0004
(VEffi) (IE)
Scheme IE
Commercially available 3-hydroxypyrrolidine of formula (INK) wherein R2 is hydrogen, can be protected using a suitable nitrogen-protecting group such as those described in T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1991, hereafter referred to as "Greene". For example 3-R- hydroxypyrrolidine (ETfi) can be protected with a tert-butoxycarbonyl group, (boc). The protection reaction can be carried out for example using Boc anhydride in a suitable solvent such as for example tetrahydrofuran (THF) or dichloromethane (DCM) in the presence of a base such as tryethylamine (TEA) or 4-(dimethylamino)pyridine (DMAP). It will be appreciated that for compounds of formula (IE) wherein R2 is Cι-C2 alkyl, the 3-hydroxypyrrolidine of formula (TEE) can be prepared from the readily available 3- pyrrolidinone via addition of the appropriate C1-C2 alkyl organometallic. The hydroxy group of the N-protected-3-hydroxypyrrolidine can be converted into a suitable leaving group (L) such as for example chloride, bromide, iodide or mesylate. For example the N- protected-hydroxypyrrolidine can be converted to the mesylate in the presence of mesyl chloride and a suitable base such as triethylamine in a solvent such as DCM. Said mesylate is subsequently displaced with the corresponding azide in a suitable solvent such as dimethylformamide (DMF) or dimethylsulphoxide (DMSO). This azide intermediate can be converted to the corresponding N-protected-aminopyrrolidine of formula (IVE) via hydrogenation in the presence of a suitable catalyst such as Palladium on charcoal and in a suitable solvent such as methanol or ethanol.
For compounds of formula (IE) wherein R4 is H, intermediate (IVE) can be alkylated via reductive alkylation with a ketone of formula R3-CO-Ari wherein R3 and AΓΪ have the values for formula (IE) above. The reductive alkylation can be carried out for example as a hydrogenation reaction in the presence of a suitable catalyst such as
Palladium on charcoal and a suitable solvent such as for example ethanol. Alternatively, said reductive alkylation can be earned out in the presence of a suitable borane such as sodium triacetoxyborohydride, NaBH(OAc)3 and optionally in the presence of a suitable acid such as acetic acid, in a suitable solvent such as for example dichoroethane (DCE). Alternatively, intermediate of formula (NE) wherein R4 is H can be prepared as shown in Scheme 2E below by reductive alkylation of readily available 3- aminopyrrolidine of formula (VIE) wherein R has the values defined for formula (IE) above, followed by the protection of the nitrogen in the pyrrolidine ring using a suitable protecting group such as those defined in Greene.
Figure imgf000091_0001
(VIE) (VEE) (NE)
Scheme 2E For example the reductive alkylation can be carried out in the presence of a ketone of formula An-CO-R3 wherein Ari and R3 have the values defined for formula (IE) above. Initial condensation of the amino pyrrolidine with the ketone is undertaken in the presence of a suitable acid such as p-toluenesulphonic acid, in a suitable solvent such as toluene. The resultant imino pyrrolidine intermediate can then be protected with for example a boc group. The reaction can be carried out in the presence of boc anhydride and a suitable base such as DMAP, in a suitable solvent such as DCM. Said imine is reduced via hydrogenation in the presence of a suitable catalyst such as palladium on charcoal, in a suitable solvent such as ethanol to give the corresponding amine of formula (VE).
Intermediate of formula (VE) can be converted to compounds of formula (NETE) via reductive alkylation with an aldehyde of formula R9-CHO, wherein R9 is chosen such that R9-CH2 = R1 and R1 has the values defined for formula (IE) above. The reductive alkylation can be carried out using standard methods, for instance as those mentioned above with the ketone ArrCO-R3.
Figure imgf000092_0001
(VE) (VEJE)
Scheme 3E For example a compound of formula (VE) can be alkylated with R9-CHO in the presence of a suitable borane, such as ΝaBH(OAc)3, optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE).
For compounds of formula (IE) wherein R and R are hydrogen the alkylation of intermediate (VE) can be carried out with a compound of formula AriQHkLi wherein L] is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (VEIE)a. It will be appreciated that the same reaction can be carried out using Ar1-CR3R4-L1 wherein R3 and R4are -C2 alkyl. -91-
Figure imgf000093_0001
Scheme 4E
Compounds of formula (IE) wherein R is -CH2-COO-(Cι-C2 alkyl) can be prepared by reacting intermediate (NE) with a compound of formula L2-CH2-COO-(C1-C alkyl) wherein L2 is a suitable leaving group such as for example bromo, chloro or iodo. Said reaction can be carried out in the presence of a suitable base such as sodium hydride, in a suitable solvent such as dimethylformamide.
Figure imgf000093_0002
(VE) (VEffi)b
Scheme 5E
Compounds of formula (IE) wherein R1 is -(CH2)m-CF3 can be prepared by reacting intermediate (VE) with a compound of formula HOOC-(CH2)mι-CF3, wherein πi! is 0, 1 or 2. The acid may be activated as its anhydride or acyl chloride, and is reacted in the presence of a suitable base such as triethylamine and a catalytic amount of DMAP, in a suitable solvent such as DCM. The resulting amide can be reduced to the amine of formula (VIEE)C in the presence of a suitable borane. For example, for compounds wherein m is 1, the reduction can be carried out in the presence of BH3-Me S borane- dimethyl sulphide complex, in a suitable solvent such as THF.
Figure imgf000094_0001
(NE) (NEffi)c
Scheme 6E
Compounds of formula (JE) wherein R1 is -( - alkylene)-OH can be prepared by reacting intermediate (VE) with an epoxide. For example for compounds wherein R1 is -CH2-C(CH3) 2-OH, the intermediate of formula (VE) is reacted with 2,2- dimethyloxirane, in a suitable solvent such as aqueous ethanol.
Figure imgf000094_0002
(VE) (VIEE)d Scheme 7E
Alternatively compounds of formula (IE) wherein Ri is -(Cι -Cgalkylene)-OH can be prepared by reacting intermediate (VE) with an w-haloalkanoate, such as methylbromoacetate, in the presence of a base such a sodium hydrogen carbonate in a solvent such as acetonitrile. The intermediate ester is then reacted with 2 equivalents of methyl magnesium bromide in THF to yield the tertiary alcohol(VIEE)d:
Figure imgf000094_0003
Scheme 8E
It will be appreciated that the Scheme 8E above applies to alkylene chains longer than -CH2-.
Compounds of formula (IE) wherein R is -C2-C6 alkenyl, -(CH2)n-S-(C1-C3 alkyl), -(C C5 alkylene)-O-(C1-C3 alkyl), -(C1-C5 alkylene)-O-(C3-C6 cycloalkyl), -( -
C5 alkylene)-SO2-(C1-C3 alkyl), -(C1-C5 alkylene)-OCF3, or -(C1-C5 alkylene)-CN, can be prepared via alkylation of intermediate (VE) with a compound of formula L2-C -C6 alkenyl, LHCHz S-Cd- alkyl), L2-(C1-C5 alkylene)-O-(C1-C3 alkyl), L2-(CrC5 alkylene)-O-(C3-C6 cycloalkyl), L2-(Cι-C5 alkylene)-SO2-(C!-C3 alkyl), LHC.-Cs alkylene)-OCF3, or L2-( -C5 alkylene)-CN respectively, wherein L is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (VETE)e.
Figure imgf000095_0001
(VE) (VEIE)e
Scheme 9E
Compounds of formula (IE) wherein R is a group of formula (i) can be prepared using the synthesis illustrated in Scheme 10E for compounds wherein R is 4- tetrahydropyranyl. The compound of formula (IVE) can be alkylated via reductive alkylation using standard methods, as those mentioned above with the ketone An-CO-R3.
For example compound of formula (IVE) can be alkylated with 4-tetrahydropyranone in the presence of a suitable borane, such as sodium borohydride or NaBH(OAc)3, optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE). Then, the secondary amine can be alkylated with a compound of formula ArιCH2L;[ wherein \ is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (VIEE)f. It will be appreciated that as mentioned above the same reaction can be carried out using Ar1-CR3R4-L1 wherein R3 and R4are -C2 alkyl.
Figure imgf000096_0001
(IVE) (VIEE)f
Scheme 10E
It will be appreciated that for compounds of formula (IE) wherein R is a group of formula (i) and r is 1 then the reductive amination can be carried out using the same reaction conditions but using the corresponding homologous aldehyde of formula
Figure imgf000096_0002
instead of the corresponding 4-tetrahydropyranone. Alternatively, compounds of formula
(IE) wherein R is a group of formula (i) and r is 1 can be prepared via formation of an amide, followed by reduction of this amide bond to the corresponding amine as shown in Scheme HE below:
Figure imgf000096_0003
(NπτE)g Scheme HE
The coupling reaction can be carried out using standard methods known in the art. The reduction of the amide bond can also be carried by general methods known in the art for example using the same reduction conditions as those used in Scheme 6, such as in the presence of BH3-Me S (borane-dimethyl sulphide complex), in a suitable solvent such as THF.
Alternatively, compounds of formula (IE) wherein R is a group of formula (i) wherein r is 0 can be prepared by a process illustrated in Scheme 12E for compounds wherein -Z is hydrogen, s isl, t is 2, each
Figure imgf000097_0001
are hydrogen and -X- is - O-, (i.e. R is 2-tetrahydrofuranyl). The compound of formula (IVE) can be alkylated with a compound of formula:
Figure imgf000097_0002
wherein L4 is a suitable leaving group such as chloro, bromo, iodo, mesylate or tosylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding secondary amine which can be subsequently alkylated with a compound of formula
Figure imgf000097_0003
is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (NEJE)f. It will be appreciated that as mentioned above the same reaction can be carried out using Ar1-CR3R4-L1 wherein R3 and R4are - alkyl.
Figure imgf000097_0004
(IVE) (vm)h
Scheme 12E The tetrahydrofuranyl intermediates can be prepared from the corresponding 3- hydroxytetrahydrofuran, wherein the hydroxy group is converted into the leaving group using standard methods.
Compounds of formula (IE) wherein R is a group of formula (i) and -X- is -SO2- can be prepared from the corresponding intermediates (NTTTE)f wherein the thioether is oxidized to the corresponding sulphoxide as shown in Scheme 13E below:
Figure imgf000098_0001
Scheme 13E
Compounds of formula (IE) wherein R1 is a group of formula (ii) can be prepared using the synthesis illustrated in Scheme 14E for compounds wherein R1 is oxabicyclo[3,2,l]octan-3-yl. The compound of formula (IVE) can be alkylated via reductive alkylation using standard methods, as those mentioned above with the ketone Ar^CO-R3. For example compound of formula (IVE) can be alkylated with oxabicyclo[3,2,l]octan-3-one in the presence of a suitable borane, such as sodium borohydride or ΝaBH(OAc)3, optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE). Then, the secondary amine can be alkylated with a compound of formula ArιCH Lι wherein L\ is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (VlllH)ι. It will be appreciated that as mentioned above the same reaction can be carried out using Ar1-CR3R4-L1 wherein R3 and R4are Q- C2 alkyl.
Figure imgf000099_0001
(IVE) (VfflE)j
Scheme 14E
The oxabicyclo[3,2,l]octan-3-one intermediate is prepared according to the method described in A E Hill, G Greenwood and H M R Hoffmann JACS 1973, 95,
1338. It will be appreciated that for compounds of formula (IE) wherein R is a group of formula (i) and r is 1 then the reductive amination can be carried out using the same reaction conditions but using the corresponding homologous aldehyde of formula
Figure imgf000099_0002
instead of the corresponding oxabicyclo[3,2,l]octan-3-one.
Compounds of formula (IE) wherein An is a substituted or unsubstituted pyridyl
3 group can be prepared by a process illustrated in Scheme 15E for compounds wherein R
4 and R are hydrogen and At\ is 3-phenylpyrid-2-yl.
Figure imgf000099_0003
(IVE) (VETE)k
Scheme 15E The compound of formula (IVE) can be alkylated via reductive alkylation using standard methods, as those mentioned above with the ketone Ar CO-R3. For example compound of formula (IVE) can be alkylated with an aldehyde of formula:
Figure imgf000100_0001
in the presence of a suitable borane, such as sodium borohydride or NaBH(OAc)3, optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE). Then, the secondary amine can be alkylated using the geheral methods described above for the incorporation of R1. The intermediate aldehyde can be prepared via reduction of readily available methyl 3-phenyl picolinate to the corresponding alcohol and subsequent oxidation to the aldehyde as shown in Scheme 16E below.
Figure imgf000100_0002
Scheme 16E The reduction step can be carried out in the presence of a suitable reducing agent such as lithium borohydride in a suitable solvent such as tetrahydrofuran. The oxidation to the aldehyde can be carried out under Swern conditions such as oxalyl chloride and DMSO in DCM.
Compounds of formula (IE) wherein Ari is a substituted or unsubstituted phenyl
3 group can be prepared by a process illustrated in Scheme 17E for compounds wherein R and R are hydrogen and
Figure imgf000100_0003
is 2-(3-pyridyl)phenyl.
Figure imgf000101_0001
(IVE) (vmE)ι
Scheme 17E
The compound of formula (IVE) can be alkylated via reductive alkylation using standard methods, as those mentioned above with the ketone An-CO-R3. For example compound of formula (IVE) can be alkylated with an aldehyde of formula:
Figure imgf000101_0002
in the presence of a suitable borane, such as sodium borohydride or NaBH(OAc)3, optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE). Then, the secondary amine can be alkylated using the general methods described above for the incorporation of R1. The intermediate aldehyde can be prepared from the commercially available 2-formyl phenyl boronic acid via palladium coupling in the presence of 3-bromopyridine, a suitable palladium catalyst such as Pd(PPh3)4 and a suitable base such as potassium carbonate in a suitable solvent such as acetonitrile, as shown in Scheme 18E below.
Figure imgf000101_0003
Scheme 18E
Compounds of formula (IE) wherein Ar! is a phenyl group substituted with a 1- pyrazole group can be prepared by a process illustrated in Scheme 19E.
Figure imgf000102_0001
(VETE)n (VEffi)n
Scheme 19E
The pyrazole group can be incorporated by reacting a compound of formula (VETE)m'; wherein L5 is a suitable leaving group such as bromo, chloro or iodo, with pyrazole in the presence of a suitable base such as potassium carbonate and a catalytic amount of copper iodide in a suitable solvent such as for example DMF. The compound of formula (VEJE)m> can be prepared by any of the methods mentioned above for compounds wherein Ari is a phenyl group substituted with a halogen atom such as chloro, bromo or iodo.
It will be appreciated that any of the intermediates (VIEE), (VEffi)a-m are then deprotected using suitable deprotecting conditions such as those discussed in Greene, to give the corresponding compounds of formula (IE). For example if the protecting group is a boc group, the deprotection reaction can be carried out in trifluoroacetic acid in a suitable solvent such as DCM. Alternatively the reaction can be carried out in ethanolic hydrochloric acid.
Figure imgf000102_0002
(IE)
Scheme 20E
Compounds of formula (IE) wherein R3 and R4 are both hydrogen may also be prepared by solid phase synthesis by the route shown below in Scheme 21E below.
Figure imgf000103_0001
Figure imgf000103_0002
Scheme 21E
The sequence is preferably performed on a polystyrene resin. The process may be run in a combinatorial fashion such that all possible compounds from sets of precursors An CHO and R9CHO may be prepared, wherein R9 is chosen such that R9-CH2 = R1, and
R1 and A have the values defined above for formula (IE). The sequence is performed without characterisation of the resin-bound intermediates. In step (i) 3- trifluoroacetamido-pyrrolidine is bound to a solid support by reaction with 4-nitrophenyl carbonate activated polystyrene resin in the presence of a base, such as N,N- diisopropylethylamine, in a solvent such as DMF. In step (ii), the trifluoroacetamido protecting group is cleaved by hydrolysis with a base such as aqueous lithium hydroxide. In step (iii) the primary amine is then condensed with a substituted benzaldehyde in the presence of a dehydrating agent, such as trimethylorthoformate, to form the intermediate imine. In step (iv) the imine is reduced with a borane reducing agent, such as sodium cyanoborohydride, in a solvent such as DMF, containing acetic acid. In step (v) the resultant secondary amine is then reductively alkylated with an aldehyde in the presence of a reducing agent such as sodium triacetoxyborohydride in a solvent, such as DMF. In step (vi) the desired product is finally cleaved from the resin with acid, such as aqueous trifluoroacetic acid.
Preparation of Compounds of Formula (IF) Compounds of formula (IF) may be prepared by conventional organic chemistry techniques and also by solid phase synthesis. Compounds of formula (IF') can be prepared by the general methods illustrated below. It will be appreciated that the same methods can be used for compounds of formula (E7") with the only difference that the nitrogen atom of the quinuchdines does not need to be protected as it is already a tertiary amine as it is explained in more detail below with reference to Scheme IF.
Compounds of formula (W) can be prepared via the 3-aminopiperidine intermediate of formula (INF) as illustrated in Scheme IF below:
Figure imgf000104_0001
(IΠF)
Figure imgf000104_0002
(NIIIF)
(IF')
Scheme IF Commercially available 3-hydroxypiperidine of formula (lEF) wherein R" is hydrogen, can be protected using a suitable nitrogen-protecting group such as those described in T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1991, hereafter referred to as "Greene". For example 3-R- hydroxypiperidine (Hit) can be protected with a tert-butoxycarbonyl group, (boc). The protection reaction can be carried out for example using Boc anhydride in a suitable solvent such as for example tetrahydrofuran (THF) or dichloromethane (DCM) in the presence of a base such as triethylamine (TEA) or 4-(dimethylamino)pyridine (DMAP). It will be appreciated that for compounds of formula (BF) wherein R is Cι-C2 alkyl, the 3- hydroxypiperidine of formula (IEF) can be prepared from the readily available 3- pyrrolidinone via addition of the appropriate Cj -C2 alkyl organometallic.
The hydroxy group of the N-protected-3-hydroxypiperidine can be converted into a suitable leaving group (L) such as for example chloride, bromide, iodide or mesylate. For example the N-protected-hydroxypiperidine can be converted to the mesylate in the presence of mesyl chloride and a suitable base such as triethylamine in a solvent such as DCM. Said mesylate is subsequently displaced with the corresponding azide in a suitable solvent such as dimethylformamide (DMF) or dimethylsulphoxide (DMSO). This azide intermediate can be converted to the corresponding N-protected-aminopiperidine of formula (TV) via hydrogenation in the presence of a suitable catalyst such as Palladium on charcoal and in a suitable solvent such as methanol or ethanol.
For compounds of formula (TF) wherein R4 is H, intermediate (FvT) can be alkylated via reductive alkylation with a ketone of formula R3-CO-Ar1 wherein R3 and Ari have the values for formula (IF) above. The reductive alkylation can be carried out for example as a hydrogenation reaction in the presence of a suitable catalyst such as Palladium on charcoal and a suitable solvent such as for example ethanol. Alternatively, said reductive alkylation can be carried out in the presence of a suitable borane such as sodium triacetoxyborohydride, NaBH(OAc)3 and optionally in the presence of a suitable acid such as acetic acid, in a suitable solvent such as for example dichoroethane (DCE).
Alternatively, intermediate of formula (VF) wherein R4 is H can be prepared as shown in Scheme 2F below by reductive alkylation of readily available 3- aminopiperidine of formula (VIF) wherein R2 has the values defined for formula (TF) above, followed by the protection of the nitrogen in the piperidine ring using a suitable protecting group such as those defined in Greene.
Figure imgf000106_0001
(VIE) (VEF) (VF)
Scheme 2F
For example the reductive alkylation can be carried out in the presence of a ketone of formula An-CO-R3 wherein An and R3 have the values defined for formula (IF) above. Initial condensation of the amino piperidine with the ketone is undertaken in the presence of a suitable acid such as p-toluenesulphonic acid, in a suitable solvent such as toluene. The resultant imino piperidine intermediate can then be protected with for example a boc group. The reaction can be carried out in the presence of boc anhydride and a suitable base such as DMAP, in a suitable solvent such as DCM. Said imine is reduced via hydrogenation in the presence of a suitable catalyst such as palladium on charcoal, in a suitable solvent such as ethanol to give the corresponding amine of formula (VF).
Intermediate of formula (VF) can be converted to compounds of formula (Vl i ) via reductive alkylation with an aldehyde of formula R9-CHO, wherein R9 is chosen such that R9-CH = R1 and R1 has the values defined for formula (IF) above. The reductive alkylation can be carried out using standard methods, for instance as those mentioned above with the ketone An-CO-R3.
Figure imgf000106_0002
(VF) (VIEF)
Scheme 3F
For example a compound of formula (VF) can be alkylated with R >9 -CHO in the presence of a suitable borane, such as NaBH(OAc)3, optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE). For compounds of formula (IF) wherein R3 and R4 are hydrogen the alkylation of intermediate (VF) can be carried out with a compound of formula AnCH2Li wherein L is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (VIEF)a. It will be appreciated that the same reaction can be carried out using Ar1-CR3R4-L1 wherein R3 and R4are Cι-C2 alkyl.
Figure imgf000107_0001
Scheme 4F
Compounds of formula (IF) wherein R is -CH -COO-(C1-C2 alkyl) can be prepared by reacting intermediate (VF) with a compound of formula L2-CH2-COO-(C1-C2 alkyl) wherein L2 is a suitable leaving group such as for example bromo, chloro or iodo. Said reaction can be carried out in the presence of a suitable base such as sodium hydride, in a suitable solvent such as dimethylformamide.
Figure imgf000107_0002
(VF) (vππ b
Scheme 5F
Compounds of formula (IF) wherein R1 is -(CH )m-CF3 can be prepared by reacting intermediate (VF) with a compound of formula HOOC-(CH )(m-i)-CF3. The acid may be activated as its anhydride or acyl chloride, and is reacted in the presence of a suitable base such as triethylamine and a catalytic amount of DMAP, in a suitable solvent such as DCM. The resulting amide can be reduced to the amine of formula (VIEF)C in the presence of a suitable borane. For example, for compounds wherein m is 1, the reduction can be carried out in the presence of BH3-Me2S borane-dimethyl sulphide complex, in a suitable solvent such as THF.
Figure imgf000108_0001
(VF) (vππ c
Scheme 6F
Compounds of formula (IF) wherein R1 is -(Cι-C6 alkylene)-OH can be prepared by reacting intermediate (NF) with an epoxide. For example for compounds wherein R1 is -CH2-C(CH3) 2-OH, the intermediate of formula (NF) is reacted with 2,2- dimethyloxirane, in a suitable solvent such as aqueous ethanol.
Figure imgf000108_0002
(NF) (VEDF)d
Scheme 7F Alternatively compounds of formula (BF) wherein R* is -(Ci -Cgalkylene^OH can be prepared by reacting intermediate (VF) with an co-haloalkanoate, such as methylbromoacetate, in the presence of a base such a sodium hydrogen carbonate in a solvent such as acetonitrile. The intermediate ester is then reacted with 2 equivalents of methyl magnesium bromide in THF to yield the tertiary alcohol (VTEF)d:
Figure imgf000108_0003
(VF) (vmF)d Scheme 8F
It will be appreciated that the Scheme 8F above applies to alkylene chains longer than -CH2-.
Compounds of formula (IF) wherein R is -C2-C6 alkenyl, -(CH2)n-S-(C1-C3 alkyl), -(C1-C5 alkylene)-O-(d-C3 alkyl), -( -C5 alkylene)-O-(C3-C6 cycloalkyl), -(C C5 alkylene)-SO2-(d-C3 alkyl), -(Cι-C5 alkylene)-OCF3, or -( -C5 alkylene)-CN, can be prepared via alkylation of intermediate (VF) with a compound of formula L2-C2-C6 alkenyl, L2-(CH2)n-S-(C1-C3 alkyl), L2-(Cι-C5 alkylene)-O-(C1-C3 alkyl), L2-(C1-C5 alkylene)-O-(C3-C6 cycloalkyl), LH -Cs alkylene)-SO2-(C1-C3 alkyl), L2-(C!-C5 alkylene)-OCF3, or La-CCi-Cs alkylene)-CN respectively, wherein 2 is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (NlUh)e.
Figure imgf000109_0001
(VF) (VEJP)e
Scheme 9F
Compounds of formula (IF) wherein R is a group of formula (i) can be prepared
1 using the synthesis illustrated in Scheme 10F for compounds wherein R is 4- tetrahydropyranyl. The compound of formula (TVF) can be alkylated via reductive alkylation using standard methods, as those mentioned above with the ketone An-CO-R3.
For example a compound of formula (TVF) can be alkylated with 4-tetrahydropyranone in the presence of a suitable borane, such as sodium borohydride or ΝaBH(OAc)3, optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE). Then, the secondary amine can be alkylated with a compound of formula Ar1CH2Lι wherein Li is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (NlHF')f. It will be appreciated that as mentioned above the same reaction can be carried out using Ar1-CR3R4-L1 wherein R3 and R4are -C2 alkyl.
Figure imgf000110_0001
(TVF) (VEfF)f
Scheme 10F
It will be appreciated that for compounds of formula (IF) wherein R is a group of formula (i) and r is 1 then the reductive amination can be carried out using the same reaction conditions but using the corresponding homologous aldehyde of formula
Figure imgf000110_0002
instead of the corresponding 4-tetrahydropyranone. Alternatively, compounds of formula
(TF) wherein R is a group of formula (i) and r is 1 can be prepared via formation of an amide, followed by reduction of this amide bond to the corresponding amine as shown in Scheme 11F below:
Figure imgf000110_0003
(vmF)g
Scheme 11F
The coupling reaction can be carried out using standard methods known in the art. The reduction of the amide bond can also be carried out by general methods known in the art for example using the same reduction conditions as those used in Scheme 6F, such as in the presence of BH3-Me2S (borane-dimethyl sulphide complex), in a suitable solvent such as THF.
Alternatively, compounds of formula (IF) wherein R is a group of formula (i) wherein r is 0 can be prepared by a process illustrated in Scheme 12F for compounds wherein -Z is hydrogen, s isl, t is 2, each R^, R6, R7 and R^ are hydrogen and -X- is -
O-, (i.e. R is tetrahydrofuran-3-yl). The compound of formula (TVF) can be alkylated with a compound of formula:
Figure imgf000111_0001
wherein L is a suitable leaving group such as chloro, bromo, iodo, mesylate or tosylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding secondary amine which can be subsequently alkylated with a compound of formula A CH2Li wherein Li is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (VIEF)f. It will be appreciated that as mentioned above the same reaction can be carried out using Ar1-CR3R4-L1 wherein R3 and R4are Cι-C2 alkyl.
Figure imgf000111_0002
(INF) (vmF)h
Scheme 12F The tetrahydrofuranyl intermediates can be prepared from the corresponding 3- hydroxytetrahydrofuran, wherein the hydroxy group is converted into the leaving group using standard methods.
Compounds of formula (BF) wherein R is a group of formula (i) and -X- is -SO - can be prepared from the corresponding intermediates (NETF)f wherein the thioether is oxidized to the corresponding sulphoxide as shown in Scheme 13F below:
Figure imgf000112_0001
(NIEF)f (VIEF);
Scheme 13F
Compounds of formula (BF) wherein R1 is a group of formula (ii) can be prepared using the synthesis illustrated in Scheme 14F for compounds wherein R1 is oxabicyclo[3,2,l]octan-3-yl. The compound of formula (INF) can be alkylated via reductive alkylation using standard methods, as those mentioned above with the ketone An-CO-R3. For example compound of formula (TVF) can be alkylated with oxabicyclo[3,2,l]octan-3-one in the presence of a suitable borane, such as sodium borohydride or ΝaBH(OAc)3, optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE). Then, the secondary amine can be alkylated with a compound of formula AnCH^ wherein L] is a suitable leaving group such as chloro, bromo, iodo or mesylate, in the presence of a suitable base such as potassium carbonate and a suitable solvent such as acetonitrile, to give the corresponding intermediate of formula (NEBF)j. It will be appreciated that as mentioned above the same reaction can be carried out using Ar1-CR3R4-L1 wherein R3 and R4are - C2 alkyl.
Figure imgf000113_0001
Scheme 14F
The oxabicyclo[3,2,l]octan-3-one intermediate is prepared according to the method described in A E Hill, G Greenwood and H M R Hoffmann JACS 1973, 95,
1338. It will be appreciated that for compounds of formula (IF) wherein R is a group of formula (i) and r is 1 then the reductive amination can be carried out using the same reaction conditions but using the corresponding homologous aldehyde of formula
Figure imgf000113_0002
instead of the corresponding oxabicyclo[3,2,l]octan-3-one.
Compounds of formula (IF) wherein Ari is a substituted or unsubstituted pyridyl
3 group can be prepared by a process illustrated in Scheme 15F for compounds wherein R
4 and R are hydrogen and Ari is 3-phenylpyrid-2-yl.
Figure imgf000113_0003
(TVF) (VIEF)k
Scheme 15F The compound of formula (INF) can be alkylated via reductive alkylation using standard methods, as those mentioned above with the ketone An-CO-R . For example compound of formula (INF) can be alkylated with an aldehyde of formula:
Figure imgf000114_0001
in the presence of a suitable borane, such as sodium borohydride or ΝaBH(OAc)3, optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE). Then, the secondary amine can be alkylated using the general methods described above for the incorporation of R1. The intermediate aldehyde can be prepared via reduction of readily available methyl 3-phenyl picolinate to the corresponding alcohol and subsequent oxidation to the aldehyde as shown in Scheme 16F below.
Figure imgf000114_0002
Scheme 16F
The reduction step can be carried out in the presence of a suitable reducing agent such as lithium borohydride in a suitable solvent such as tetrahydrofuran. The oxidation to the aldehyde can be carried out under Swern conditions such as oxalyl chloride and DMSO in DCM.
Compounds of formula (IF) wherein Ari is a substituted or unsubstituted phenyl
3 group can be prepared by a process illustrated in Scheme 17F for compounds wherein R and R are hydrogen and Ari is 2-(3-pyridyl)phenyl.
Figure imgf000115_0001
(INF) (VIEF)!
Scheme 17F
The compound of formula (TVF) can be alkylated via reductive alkylation using standard methods, as those mentioned above with the ketone An-CO-R3. For example compound of formula (INF) can be alkylated with an aldehyde of formula:
Figure imgf000115_0002
in the presence of a suitable borane, such as sodium borohydride or ΝaBH(OAc)3, optionally in the presence of an acid such as acetic acid, in the presence of a suitable solvent such as dichloroethane (DCE). Then, the secondary amine can be alkylated using the general methods described above for the incorporation of R1. The intermediate aldehyde can be prepared from the commercially available 2-formyl phenyl boronic acid via palladium coupling in the presence of 3-bromopyridine, a suitable palladium catalyst such as Pd(PPh3)4 and a suitable base such as potassium carbonate in a suitable solvent such as acetonitrile, as shown in Scheme 18F below.
Figure imgf000115_0003
Scheme 18F
Compounds of formula (IF) wherein An is a phenyl group substituted with a 1- pyrazole group can be prepared by a process illustrated in Scheme 19F.
Figure imgf000116_0001
(vmF)n (NEBF)r
Scheme 19F
The pyrazole group can be incorporated by reacting a compound of formula (VETF)m'ι wherein L5 is a suitable leaving group such as bromo, chloro or iodo, with pyrazole in the presence of a suitable base such as potassium carbonate and a catalytic amount of copper iodide in a suitable solvent such as for example DMF. The compound of formula (NIEF)m> can be prepared by any of the methods mentioned above for compounds wherein Ari is a phenyl group substituted with a halogen atom such as chloro, bromo or iodo.
It will be appreciated that any of the intermediates (VEBF), (VETF)a-m are then deprotected using suitable deprotecting conditions such as those discussed in Greene, to give the corresponding compounds of formula (BF). For example if the protecting group is a boc group, the deprotection reaction can be carried out in trifluoroacetic acid in a suitable solvent such as DCM. Alternatively the reaction can be carried out in ethanolic hydrochloric acid.
Figure imgf000116_0002
(IF) Scheme 20F
Compounds of formula (B?) wherein R3 and R4 are both hydrogen may also be prepared by solid phase synthesis by the route shown below as Scheme 21F.
Figure imgf000117_0001
Scheme 21F
The sequence is preferably performed on a polystyrene resin. The process may be run in a combinatorial fashion such that all possible compounds from sets of precursors Ari CHO and R9CHO may be prepared, wherein R9 is chosen such that R9-CH2 = R1, and
R1 and Ar! have the values defined above for formula (BF). The sequence is performed without characterisation of the resin-bound intermediates. In step (i) 3- trifluoroacetamido-piperidine is bound to a solid support by reaction with 4-nitrophenyl carbonate activated polystyrene resin in the presence of a base, such as N,N- diisopropylethyl amine, in a solvent such as DMF. In step (ii), the trifluoroacetamido protecting group is cleaved by hydrolysis with a base such as aqueous lithium hydroxide. In step (iii) the primary amine is then condensed with a substituted benzaldehyde in the presence of a dehydrating agent, such as trimethylorthoformate, to form the intermediate imine. In step (iv) the imine is reduced with a borane reducing agent, such as sodium cyanoborohydride, in a solvent such as DMF, containing acetic acid. In step (v) the resultant secondary amine is then reductively alkylated with an aldehyde in the presence of a reducing agent such as sodium triacetoxyborohydride in a solvent, such as DMF. In step (vi) the desired product is finally cleaved from the resin with acid, such as aqueous trifluoroacetic acid.
Preparation of Compounds of Formula (IG) Compounds of formula (IG) may be prepared by conventional organic chemistry techniques from N-protected-2-cyanomorpholines as outlined in Error! Reference source not found.G below, wherein R and R2 have the values defined for formula (IG) above and P is a suitable nitrogen protecting group such as those described in T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1991, hereafter referred to as "Greene". For example a suitable nitrogen protecting group is a benzyl group:
Figure imgf000118_0001
(IIIG) (HIG)a
Scheme IG The phenyl ketone (EJG) can be obtained by reaction of N-protected-2- cyanomorpholine with a Grignard reagent, followed by acid hydrolysis to give the racemic phenyl ketone which may be separated on chiral HPLC.
Compounds of formula (IG) can be prepared from the N-protected morpholine ketone intermediate of formula (BIG), as illustrated in Error! Reference source not found.G below:
Figure imgf000119_0001
(IG) Scheme 2G
The ketone is stereoselectively reduced to the corresponding (2S) or (2R) alcohol of formula (TVG) or (IVG)a using standard methods known in the art. For example it can be reduced in the presence of [(-)-B-chlorodiisopinocampheylborane] in a suitable solvent such as tetrahydrofuran (THF) to provide the (2S) alcohol.
The resulting alcohol is then transformed into a suitable leaving group L. Suitable leaving groups include halo groups, such as bromo, chloro or iodo and sulfonate groups, such as mesylate. When L is a halo group, the alcohol used will be the (2S) enantiomer (TVG) and it will be reacted with inversion of stereochemistry. For example, when L is bromo, the bromination reaction can be carried out in the presence of a brominating agent such as triphenylphosphine dibromide, in a suitable solvent such as chloroform. When L is a mesylate group, the alcohol used will be the (2R) enantiomer (IVG)a and it will be reacted with retention of stereochemistry in the presence of mesylate chloride and a suitable base. The resulting intermediate of formula (VG) can then be converted into the corresponding methylethanethioate of formula (VIG) via displacement of the leaving group with a suitable thiolacetate salt such as potassium thiolacetate in the presence of a suitable solvent such as a mixture of dimethylformamide (DMF) and tetrahydrofuran (THF). The methanethiol intermediate of formula (VEG) can be prepared via reaction of the methylethanethioate (VIG) with a suitable thiomethoxide such as sodium thiomethoxide in the presence of a suitable solvent such as methanol (one can use a variety of bases but thiomethoxide is preferred because it also acts as a reducing agent and prevents oxidation of thiol hence inhibiting dimerisation; Ref: O.B.Wallace & D.M.Springer, Tetrahedron Letters, 1998, 39 (18), pp2693-2694).
The pyridyl portion of the molecule is incorporated via general methods known in the art. A particularly useful method is the reaction of the methanethiol (VEG) with a compound of the formula
Figure imgf000120_0001
(VIIIG) wherein R1 has the values defined above and Li is a suitable leaving group such as fluoro, bromo, chloro, iodo or mesylate, in the presence of suitable base such as sodium hydride, cesium fluoride or sodium methoxide, in a suitable solvent such as DMF.
Compounds of formula (IG) wherein -X- is -O- can be prepared in an analogous fashion by reaction of the (2S) alcohol of formula (IVG) with a compound of formula (VETO) above.
The final step for the preparation of compounds of formula (IG) comprises deprotection of the morpholine ring. Conditions for the deprotection depend on the protecting group chosen. Suitable deprotecting conditions can be found in Greene. For example when the nitrogen protecting group is a benzyl group, the deprotection reaction can be carried out in the presence of polymer supported diisopropylamine (PS-DIEA) and 1-chloroethyl chloroformate (ACE-C1) in a suitable solvent such as dichloromethane, followed by reaction with methanol to give compounds of formula (IG).
Compounds of formula (IG) can alternatively be prepared by the derivatisation of a suitable substituent in the pyridyl ring to give the desired substituent R1 as shown in Scheme 3G below. For example compounds of formula (IG) wherein -R1 is -CF3 can be prepared via reaction of the intermediate (KG)' wherein z is introduced into the molecule in place of R1 in formula (VIEG) as shown in Error! Reference source not found.G above. The group L2 is a suitable leaving group such as for example iodo, bromo, chloro or fluoro. The leaving group is converted into a trifluoromethyl group via reaction in the presence of copper iodide, a suitable base such as for example potassium fluoride, and a suitable source of a trifluoromethyl group such as for example (trifluoromethyl)trimethylsilane, in a suitable solvent such as for example a mixture of DMF and N-methyl-pyrrolidinone (NMP). The resulting compound of formula (XG) is deprotected using the methodology described above.
Figure imgf000121_0001
(IG) wherein R] =CF3
(IXG)' (XG)
Scheme 3G
Compounds of formula (IG) wherein -X- is -S- can alternatively be prepared directly from the intermediate methylethanethioate of formula (NIG) as illustrated in Error! Reference source not found.G below.
Figure imgf000122_0001
(vm)
(VI) (IX) wherein -X- is -S- (I) wherein -X- is -S- Scheme 4G The reaction can be carried out via general methods known in the art. For example, the intermediate (VIG) can be reacted with a compound of formula (VIEG), wherein R1 and Li have the values defined above, in the presence of a suitable base such as sodium methoxide, in a suitable solvent such as for example DMF.
The resulting compound of formula (IXG) wherein -X- is -S- is then deprotected using the methods described above for Error! Reference source not found.G to give a compound of formula (IG) wherein -X- is -S-. This method is particularly useful when Li and R1 are halogen groups such as for example fluoro and bromo respectively. Alternatively, the reaction can be carried out in the presence of a suitable base such as sodium hydroxide in a suitable solvent such as a mixture of ethanol and water. This method is particularly useful when Li is a halogen group and - R1 is -CN or -CONR3R4, wherein R3 and R4 have the values defined for formula (IG) above.
Compounds of formula (IG) wherein -X- is -S- can also be prepared via an alternative method using the intermediate of formula (VG) as illustrated below in Error! Reference source not found.G.
Figure imgf000122_0002
(XIG)
(VG) (IXG) wherein -X- is -S- (IG) wherein -X- is -S- Scheme 5G The leaving group of intermediate (VG) is displaced with a suitable thiol of formula (XIG) wherein R1 has the values defined for formula (IG) above, in the presence of a suitable base such as potassium carbonate, in a suitable solvent such as DMF. The resulting intermediate of formula (KG) wherein -X- is -S- is then deprotected as described in Error! Reference source not found.G above.
The intermediate of formula (NIEG) above (including analogs wherein L2 is introduced in place of R*) often commercially available. This is the case for intermediates wherein Li is a halogen group and R1 (or L2) has the values selected from
H, methyl, halo, cyano, trifluoromethyl, ΝH2, CO2H, CONH2, SO2H, SO2NHCH3, NCOCCl3 and NSO2Ph.
Intermediates of formula (VEIG) wherein R1 is a group of formula (i) can readily be prepared via methods known in the art. We illustrate below 3 methods for the preparation of compounds of formula (VEIG) wherein R1 is a group of formula (i) and - Z- has the value of a bond (Error! Reference source not found.G), -CH2- (Error!
Reference source not found.G) or -O- (Error! Reference source not found.G). It will be appreciated that these methods are only illustrative as there are many other alternative methods known in the art which can be used.
As mentioned above, intermediates of formula (VEIG) wherein R1 is a group of formula (i) and -Z- is a bond can be prepared via palladium coupling as illustrated in Error! Reference source not found.G below.
Figure imgf000123_0001
(XπG) (XDIG) (VEIG) wherein R1 is a group of formula (i) and -Zr is a bond
Scheme 6G
The reaction is carried out via reaction of readily available pyridines of formula (XEG) wherein Li has the values mentioned above and L3 is a suitable leaving group such as for example a halogen group such as bromo or chloro, with the corresponding phenylboronic acid of formula (XEIG), in the presence of a suitable palladium catalyst such as for example palladium acetate, a suitable ligand such as triphenylphosphine, in a suitable solvent such as acetonitrile. Alternative palladium catalysts are known in the art, for example bis(benzonitrile)palladium(E)dichloride can be used in the presence of a suitable ligand such as for example bis(diphenylphosphine)butane and a suitable base such as sodium carbonate in a suitable solvent such as for example ethanol, to give good yields of intermediate of formula (VEIG) wherein R1 is a group of formula (i) and -Z- is a bond.
Intermediates of formula (VEIG) wherein R* is a group of formula (i) and -Z- is - CH2- can be prepared by the method illustrated in Error! Reference source not found.G below.
Figure imgf000124_0001
(XIVG) (XVG) (XVIG) (VIIIG) wherein Rl is a groi p of formula (i) and -Z- is ■ CH2-
Scheme 7G
Readily available pyridine compounds of formula (XIVG) wherein Li has the values mentioned above (preferably fluoro) are reacted with suitable benzaldehydes of formula (XNG), wherein R5 has the value defined for formula (IG) above, in the presence of a suitable base such as for example n-butyllithium or lithium diwøpropylamide, in a suitable solvent such as THF, to give the alcohol of formula (XVIG). Said alcohol is then reduced to give the corresponding benzyl derivative (VEIG) wherein Rl is a group of formula (i) and -Z- is -CH2- via hydrogenation, in the presence of a suitable catalyst such as for example palladium on charcoal, in a suitable solvent such as for example ethanol. Intermediates of formula (VEIG) wherein R* is a group of formula (i) and -Z- is -
O- can be prepared by the method illustrated below in Error! Reference source not found.G.
Figure imgf000124_0002
(XIΠG) (VEIG) wherein R1 is a group of formula (i) and -Z- is -O-
Scheme 8G Readily available pyridinols of formula (XVEG), wherein Li has the values mentioned above react with phenylboronic acids of formula (XEIG) in the presence of copper(E)acetate, powdered 4Λ molecular sieves, and a suitable base such as triethylamine, in a suitable solvent such as for example dichloromethane to give intermediates of formula (VEIG) wherein R* is a group of formula (i) and -Z- is -O-.
Compounds of formula (IG) wherein -X- is -O- may also be prepared by conventional chemistry techniques from the (2R) alcohol (ING)a using standard methods known in the art. For example as shown in Scheme 9G by reaction of said alcohol with a pyridine of the formula (XVIEG) or the ketone tautomer of this pyridine wherein R1 has the values defined for formula (IG) above, in the presence of a suitable phosphine such as triphenyl phosphine and diethyl azodicarboxylate, using an appropriate solvent such as THF, dimethoxyethane, (DME), or chloroform (CHC13), as described by D.L. Comins and G. Jianhua, in Tetrahedron Letters, 1994, 35 (18), pp2819-2822. This reaction is usually carried out with inversion of the stereocentre to (2S)
Figure imgf000125_0001
(XVIIIG)
(IVG)a (IG) wherein -X- is -O-
Scheme 9G
As previously mentioned, compounds of formula (IG) wherein -X- is -O- may alternatively be prepared by the reaction of the (2S) alcohol (TVG) with a pyridine of the formula (NIEG), where Li is preferably chloro and R1 has the values defined for formula
(IG) above, using a suitable base such as potassium hydroxide, in a suitable solvent such as benzene or toluene, in the presence of a suitable phase transfer catalyst such as 18- Crown-6 as described by A.J.S. Duggan et al, in Synthesis, 1980, 7, p573. in
Figure imgf000126_0001
Scheme 10G
Compounds of formula (IG) wherein -X- is -O- may alternatively be prepared by the reaction of intermediate (VG) wherein L is Br with a pyridine of the formula (VEIG) wherein -Li is -OAg and R1 has the values defined for formula (IG) above, in a non-polar solvent such as benzene, as described by U. Schollkopf et al, in Liebigs Ann. Chem. 1972, 765, pp 153- 170 and G.C. Hopkins et al, in J. Org. Chem. 1967, 32, pp4040.
It will be appreciated that compounds of Formulae (IA), (IB), (IC), (ED), (IE), (BF) and (IG) above possess one or more asymmetric carbon atoms, and that in the present invention specific individual stereoisomers are preferred. In the present specification, where a structural formula does not specify the stereochemistry at one or more chiral centres, it encompasses all possible stereoisomers and all possible mixtures of stereoisomers (including, but not limited to, racemic mixtures), which can result from stereoisomerism at each of the one or more chiral centers.
The following examples illustrate compounds of of Formula (IA) above and methods for their preparation.
Example IA: N-(2-methylpropyI)-N-r(2-fluorophenyl)methvnpiperidin-4-amine fumarate
To a dry boiling tube (50 ml), under nitrogen, was added tert-butyl-4-(2-methyl- propylamino)-piperidine-l-carboxylate (0.200g, 0.780 mmol), 2-fluorobenzaldehyde
(0.087 ml, 0.102g, 0.819 mmol), and titanium isopropoxide (0.268 ml, 0.937 mmol) to give a yellow/orange solution. This was heated to 90°C for 2 hours. Solution cooled, and ethanol (5 ml) added. Sodium borohydride (0.030g, 0.780 mmol) was then added and allowed to stir for 2 days. Further sodium borohydride (0.300g, 7.80 mmol) was added, and after 6 hours, this was diluted with methanol (10 ml) with stirring for 20 hours. This was concentrated in vacuo, dissolved in dichloromethane (5 ml), and acetic anhydride (0.371 ml, 39.00 mmol) added with stirring for 30 minutes. Solution was diluted with methanol (10 ml), and passed through an SCX-2 column to give an oil (0.150g, 0.412 mmol).
The resultant oil was dissolved in dichloromethane (5 ml), and trifluoroacetic acid (2 ml) added. Reaction was monitored by thin layer chromatography (100% ethyl acetate; reactant. r.f. 0.4, product r.f. 0.0). After 2 hours, reaction was concentrated in vacuo, azeotroped with dichloromethane (c.a. 25 ml), taken up in methanol (c.a. 5 ml), and passed through an SCX-2 column. The resultant colourless oil was purified using reverse phase chromatography, concentrated in vacuo, taken up in 5 M hydrochloric acid (10 ml), and heated to 90°C for 3 hours. This solution was freeze dried to give an oil (0.049g, 0.185 mmol). Resultant oil was passed through an SCX-2 column, dissolved in aqueous acetonitrile (c.a. 20 ml), and fumaric acid (0.0214g, 0.1850 mmol) added. After 5 minutes, this was freeze dried to give a white solid (0.070g, 0.185 mmol) as the title compound. δH (300 MHz, MeOD) 7.47 (IH, t, Ar), 7.25 (IH, m, Ar), 7.13 (IH, t, Ar), 7.02 (IH, t, Ar), 6.70 (2H, s, fumarate), 3.21 (2H, s, NCH2Ar), 3.45 (2H, d, CH), 2.95 (2H, t, CH), 2.82 (IH, t, CH), 2.29 (2H, d, NCH2), 2.00 (2H, d, CH), 1.80 (2H, t, m),
1.68 (IH, t, CH), 0.85 (6H, d, CHMe2). LCMS 12 minute gradient, Rt = 1.99 mins, (M++l) = 265.2
Example 2A: N-(3,3-dimethylbutyl)-N-r(2-biphenyl)methv]1piperidin-4-amine fumarate
To a 100 ml round bottomed flask, under nitrogen, was added the 1,1- dimethylethyl 4-[(2-bromophenylmethyl)( 3,3-dimethylbutyl)amino]piperidine-l- carboxylate (0.675 g, 1.49 mmole, l.Oeq.), phenylboronic acid (0.363 g, 2.98 mmole, 2.0 eq.), dichlorobis(triphenylphosphine)palladium(E) (0.104 g, 0.15 mmole, 0.1 eq.), sodium carbonate (0.158 g, 2.98 mmole,2.0 eq.) and a 1 : 1 mixture of tetrahydrofuran : water (50 ml). The mixture was heated at 90°C for two hours. The reaction mixture was allowed to cool then poured into diethyl ether (100 ml). This organic mixture was washed with a solution of sodium hydroxide (2M, aqueous, 80 ml) then concentrated in vacuo to give a dark yellow oil (1.18 g). This oil was purified by automated flash chromatography using an ISCO Combiflash system (SiO2 (120 g); 0-10% methanol (+5% 7M NH3 MeOH) in dichloromethane gradient elution over 40 minutes) to give a yellow oil (0.683 g). This oil was further purified by automated flash chromatography using an ISCO Combiflash system (SiO2 (120 g); ethyl acetate gradient elution over 40 minutes) to give 1,1- dimethylethyl 4-[({2-biphenyl}methyl)(3,3-dimethylbutyl)amino]piperidine-l- carboxylate as a yellow oil (0.549 g, 82%). To a solution of this oil (0.549 g, 1.22 mmole, 1.0 eq.) in dichloromethane (10 ml) was added trifluoromethanesulfomc acid (TFA) (1.36 ml, 18.27 mmole, 15 eq). The solution was stirred for one hour at room temperature.
Solvent and TFA were removed in vacuo. The resulting oil was taken up in methanol and loaded onto an SCX-2 (10 g) column. The column was washed with methanol (50 ml). Basic material was then eluted using 2N ammonia in methanol (50 ml). Removal of solvent from the ammonia/methanol mixture under vacuum, gave a colourless oil (0.27 g). This oil was purified on the Biotage Parallel Flex Purification System (UV-guided
HPLC) followed by SCX-2 treatment (to obtain the free base) to give a colourless oil (0.132 g). To a solution of this oil in methanol was added a solution of fumaric acid (0.044 g g, 0.38 mmole, 1 eq) in methanol. The mixture was left to stir for a couple of minutes, ethyl acetate and cyclohexane were then added. The resulting precipitate was collected by filtration to give the title compound as a white solid (0.121 g, 17%). 5H (300
MHz, MeOD) 7.50-7.47 (IH, m, ArH), 7.35-7.18 (7H, m, ArH), 7.10-7.07 (IH, m, ArH), 6.61 (3H, s, fumarate CH), 3.58 (2H, s, CH2Ar), 3.25-3.24 (2H, m, NCH2), 2.74 (2H, dt, NCH2), 2.67-2.57 (IH, m, NCH), 2.34-2.29 (2H, m, NCH2), 1.65-1.45 (4H, m, CCH2), 1.13-1.08 (2H, m, CH2tBu), 0.70 (9H, s, CH3); LCMS 12 min, Rt = 4.3 min, (M++l) = 351.
Example 3A: N-(2-ethylbutyl)-N-r(2-biphenyl)methyllpiperidin-4-amine fumarate
As method previously described for Example 2A, using 1,1-dimethylethyl 4-[(2- bromophenylmethyl)(2-ethylbutyl)amino]piρeridine-l-carboxylate. Isolation of the fumarate salt from methanol, diethyl ether, cyclohexane yielded the title compound as a white solid (0.238 g, 34%). 6H (300 MHz, MeOD) 7.59-7.57 (IH, m, ArH), 7.45-7.27 (7H, m, ArH), 7.19-7.16 (IH, m, ArH), 6.69 (1.5H, s, fumarate CH), 3.62 (2H, s, CH2Ar), 3.34-3.32 (2H, m, NCH2), 2.79 (2H, dt, NCH2), 2.66-2.57 (IH, m, NCH), 2.21 (2H, d, NCH2), 1.64-1.50 (4H, m, CCH2), 1.38-1.17 (5H, m, CH(CH2Me)2), 0.78 (6H, t, CH3); LCMS 12 min, Rt = 5.1 min, (M++l) = 351.
Example 4A: N-(cyclohexyImethyl)-N-r(2-biphenyl)methyllpiperidin-4-amine fumarate
(i) To a solution of cyclohexylmethylamine (0.461 g, 4.08 mmole, 1.02 eq.) in 1,2-dichloroethane (10 ml) was added l-Boc-4-piperidone (0.797 g ml, 4.00 mmole, 1.0 eq.). To this was added a solution of sodium triacetoxyborohydride (0.865 g, 4.08 mmole, 1.02 eq.) in dimethylformamide (2 ml). This mixture was left to stir under nitrogen, at room temperature, over the weekend. To the reaction mixture was then added water (10 ml) and the mixture stirred vigorously for several minutes. The chlorinated organic layer was then run through a hydrophobic frit then diluted with methanol (10 ml) and loaded onto an SCX-2 (10 g) column. The column was washed with methanol (50 ml) then basic material eluted with 2N ammonia in methanol. The ammonia/methanol solution was concentrated in vacuo to give a pale yellow oil (1.2 g). This was purified by automated flash chromatography using an ISCO Combiflash system (SiO2 (40 g); 0-10% methanol in ethyl acetate gradient elution over 40 minutes) to give 1,1-dimethylethyl 4- [(cyclohexylmethyl)amino]piperidine-l-carboxylate as a colourless oil (0.98 g, 83%). δπ (300 MHz, CDC13) 4.03-4.00 (2H, m, NCH2), 2.83-2.75 (2H, m, NCH2), 2.60-2.49 (IH, m, NCH), 2.45 (2H, d, NCH2), 1.18-0.83 (15H, m, CCH2), 1.45 (9H, s, OC(CH3)3); LCMS 6 min, Rt = 2.7 min, (M++l) = 297.
(ii) To a solution of 1,1-dimethylethyl 4-[(cyclohexylmethyl)amino]piperidine-l- carboxylate (0.245 g, 0.840 mmole, 1.0 eq.), 2-phenylbenzyl bromide (0.185 ml, 1.01 mmole, 1.2 eq.) in dry acetonitrile (5 ml) was added anhydrous potassium carbonate (0.19 g, 1.35 mmole, 1.6 eq.). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to give a white solid. The white solid was taken up in dichloromethane (10 ml) and this washed with water (10 ml). The dichloromethane layer was passed through a hydrophobic frit then diluted with methanol (10 ml). This solution was loaded onto an SCX-2 (10 g) column. The column was washed with methanol (50 ml) then basic material was eluted using 2N ammonia in methanol (50 ml). Concentration of the ammonia/methanol solution under vacuum yielded a colourless oil (0.344 g, 90%). To a solution of this oil (0.344 g, 0.74 mmole, 1.0 eq.) in dichloromethane (10 ml) was added trifluoroacetic acid (TFA) (0.83 ml, 11.2 mmole, 15 eq). The solution was stirred overnight at room temperature. Solvent and TFA were removed in vacuo. The resulting oil was taken up in methanol and loaded onto an SCX-2 (10 g) column. The column was washed with methanol (50 ml). Basic material was then eluted using 2N ammonia in methanol (50 ml). Removal of solvent from the ammonia/methanol mixture under vacuum, gave a colourless oil (0.298 g, 99%). The oil was taken up in methanol. To this solution was added a solution of fumaric acid (0.095 g, 0.08 mmole, 1 eq) in methanol followed by diethyl ether and cyclohexane. The resulting precipitate was collected by filtration to give the title compound as a white solid
(0.302 g, 76 %). δH (300 MHz, MeOD) 7.58 (IH, d, ArH), 7.45-7.29 (7H, m, ArH), 7.18 (IH, d, ArH), 6.70 (2H, s, fumarate CH), 3.64 (2H, s, CH2Ar), 3.33-3.32 (2H, m, NCH2), 2.79 (2H, dt, NCH2), 2.65-2.54 (IH, m, NCH), 2.17 (2H, d, NCH2), 1.74-1.47 (9H, m, CCH2), 1.28-1.11 (4H, m, CH, CCH2), 0.78-0.67 (2H, m, CH2); LCMS 12 min, Rt = 5.0 min, (M++l) = 363.
Example 5A : N-(cvclopropylmethyl)-N-r(2-biphenyl)methyllpiperidin-4-amine fumarate
As method previously described for Example 4A, using 1,1-dimethylethyl 4- [(cyclopropylmethyl)amino]piperidine-l-carboxylate and 2-phenylbenzyl bromide.
Isolation of the fumarate salt from methanol and diethyl ether yielded the title compound as a white solid (0.485 g, 74%). δH (300 MHz, MeOD) 7.68 (IH, dd, ArH), 7.47-7.29 (7H, m, ArH), 7.21 (IH, d, ArH), 6.72 (2H, s, fumarate CH), 3.76 (2H, s, CH2Ar), 3.38- 3.34 (2H, m, NCH2), 2.92-2.82 (3H, m, NCH, NCH2), 2.32 (2H, d, NCH2), 1.79-1.57 (4H, m, CCH2), 0.77-0.66 (IH, m, CH), 0.46-0.40 (2H, m, CH2), 0.03-O.02 (2H, m,
CH2); LCMS 12 min, Rt = 3.5 min, (M++l) = 321.
Example 6A: N-(3-methylbutyl)-N-r(2-phenoxyphenyl)methyIlpiperidin-4-amine difumarate (i) To 10% Pd/C (1.0 g, 10%wt), under nitrogen, was added a solution of the 1-
Boc-4-piperidone (10.0 g, 50.1 mmole, 1.0 eq.) and isoamylamine (4.46 g, 51.2 mmole, 1.02 eq.) in ethanol (60 ml). This was hydrogenated overnight, at 60 psi using a Parr hydrogenator. The catalyst was removed by filtration through Celite. Solvent was removed under vacuum to give 1,1-dimethylethyl 4-[(3-methylbutyl)amino]piperidine-l- carboxylate as a colourless, slightly cloudy, oil (13.59 g, 100%). δH (300 MHz, CDC13) 4.05-4.02 (2H, m, NCH2), 2.82-2.75 (2H, m, NCH2), 2.66-2.54 (3H, m, NCH, NCH2), 1.86-1.82 (2H, m, CCH2), 1.62 (IH, septet, CHMe2), 1.45 (9H, s, OC(CH3)3), 1.41-1.17
(4H, m, CCH2), 0.90 (6H, d, C(CH3)2); LCMS 6 min, Rt = 2.7 min, (M++l) = 271.
(ii) To a solution of 1,1-dimethylethyl 4-[(3-methylbutyl)amino]piperidine-l- carboxylate in 1 ,2-dichloroethane (10 ml) was added 2-phenoxybenzaldehyde. To this was added a solution of sodium triacetoxyborohydride (3.0 eq.) in dimethylformamide (2 ml). This mixture was left to stir for 3 days under nitrogen, at room temperature. To the reaction mixture was added water (10 ml) and the mixture stirred vigorously for several minutes. The chlorinated organic layer was run through a hydrophobic frit to remove water, diluted with methanol (10 ml) and loaded onto an SCX-2 (10 g) column. The column was washed with methanol (50 ml) then basic material eluted with 2N ammonia in methanol. The ammonia/methanol solution was concentrated in vacuo to give 1,1- dimethylethyl 4-[(2-phenoxyphenylmethyl)( 3-methylbutyl)amino]piperidine-l- carboxylate as a colourless oil. To a solution of this oil in dichloromethane (10 ml) was added trifluoroacetic acid (TFA) (15 eq). The solution was stirred overnight at room temperature. Solvent and TFA were removed in vacuo. The resulting oil was taken up in methanol and loaded onto an SCX-2 (10 g) column. The column was washed with methanol (50 ml). Basic material was then eluted using 2M ammonia in methanol (50 ml). Removal of solvent from the ammonia/methanol mixture under vacuum, gave a colourless oil. The oil was taken up in methanol. To this solution was added a solution of fumaric acid (1 eq) in methanol . The mixture was left to stir for a couple of minutes, then ethyl acetate and cyclohexane were added. The resulting precipitate was collected by filtration to give the title compound as a white solid (0.264 g, 30%). δn (300 MHz, MeOD) 7.46 (IH, dd, ArH), 7.26-7.16 (3H, m, ArH), 7.10-7.04 (IH, m, ArH), 7.00-6.95 (IH, m, ArH), 6.86-6.79 (3H, m, ArH), 6.61 (4H, s, fumarate CH), 3.68 (2H, s, CH2Ar), 3.33-3.28 (2H, m, NCH2), 3.04-2.96 (3H, m, NCH, NCH2), 2.56-2.51 (2H, m, NCH2), 1.91-1.87 (2H, m, CCH2), 1.76-1.62 (2H, m, CCH2), 1.52-1.41 (IH, m, CH), 1.30-1.23
(2H, m, CH2), 0.74 (6H, d, CH3); LCMS 12 min, Rt = 4.2 min, (M++l) = 353. Example 7A: N-(3-methylbutyl)-N-r(2-biphenyl)methvnpiperidin-4-amine difumarate
As method previously described for Example 4A, using 1,1-dimethylethyl 4-[(3- methylbutyl)amino]piperidine-l-carboxylate and 2-phenylbenzyl bromide. Isolation of the fumarate salt from methanol and diethyl ether yielded the title compound as a white solid (0.239 g, 24%). δH (300 MHz, MeOD) 7.49 (IH, dd, ArH), 7.35-7.18 (7H, m, ArH), 7.10 (IH, dd, ArH), 6.61 (4H, s, fumarate CH), 3.62 (2H, s, CH2Ar), 3.25 (2H, m, NCH2), 2.78-2.59 (3H, m, NCH, NCH2), 2.36-2.31 (2H, m, NCH2), 1.64-1.45 (4H, m, CCH2), 1.42-1.31 (IH, m, CH), 1.13-1.05 (2H, m, CH2), 0.69 (6H, d, CH3); LCMS 12 min, Rt = 4.1 min, (M++l) = 337.
The following examples illustrate compounds of of Formula (BB) above and methods for their preparation.
Synthesis of Intermediates.
Preparation of (4-Benzyl-morpholin-2-yl)-phenyl-methanone.
A 1600 L GL reactor under N2 was successively loaded with 2-chloroacrylonitrile
(33.2 kg, 379 moles) and toluene (114 L) at 21°C. Then, N-benzylethanolamine (57 kg, 377 moles) was added and the reaction mixture was post-agitated at room temperature for about 17 h. Then, the mixture was diluted with toluene (336 L), cooled down to - 12.4 °C and potassium t-butoxide (42.3 kg, 377 moles) was added in portions (10) maintaining - 13.7 °C < Tmass < -2.8 °C. The mixture was post-agitated at about 0°C for 2.5 h, quenched by adding ultra pure water (142.5 L) maintaining 2.1 °C < Tmass < 8.7 °C. The aqueous layer (176 kg) was separated after 35 minutes of post-stirring allowing the mixture to reach 15 °C and the toluene layer was washed with ultra pure water (142.5 L) and the aqueous layer (162 kg) was separated. The organic layer was then concentrated under reduced pressure (150 mbars) maintaining Tmass < 60 °C in order to distill 162 kg of toluene. The filtrates were then diluted with toluene (114 L) and treated with SiO2 (Merck silica gel 60, 0.063-0.1 mm, 74.1 kg) under agitation at room temperature for 1.25 h. SiO was filtered and rinsed with toluene (2x114 L). Then, the filtrates were concentrated under reduced pressure (150 mbars) maintaining Tmass ≤ 60 °C in order to distill 351.8 kg of toluene (KF : 0.01 % w/w H2O).
The solution of 4-Benzyl-morpholine-2-carbonitrile (169.2 kg) was diluted with toluene (157 L) and was cooled to 0°C and phenylmagnesiumchloride (25 wt. % solution in THF, 213 kg, 389 moles,.1.36 molar equiv.) was slowly added (over 3.5 h) to the reaction mixture, maintaining the temperature at - 3 °C < Tmass < 7 °C. The reaction mixture was post-stirred for 2 hours at Tmass = 0°C. Then, the quench was performed by adding acetic acid (8.55 L, Tmass = 5 → 17.2 °C), post stirring 10 minutes and cooling to 5 °C before adding an acetic acid / water mixture (229 L, 33/67 v/v). During the quench, addition was performed at such a rate that Tmass did not exceed 20°C (typical Tmass = 4.6 °C to 10.4 °C). The mixture was post-agitated overnight at RT and the aqueous layer (285.8 kg) was extracted.
The toluene layer was cooled to 0°C and a 5 N NaOH aqueous solution (420.1 kg) was slowly added maintaining the temperature at - 2.4 °C < Tmass < 11 °C. The reaction mixture was post-stirred for lh and the aqueous layer (494.8 kg) was extracted. The toluene layer was concentrated under reduced pressure (50 mbars) maintaining Tmass < 60 °C in order to distill 356.2 kg of toluene and isopropanol (180.4 kg) was added. The toluene was stripped off under reduced pressure (100 mbars) maintaining Tmass < 60 °C in order to distill 186.4 kg of toluene and isopropanol (135 kg) was added again to the mixture. A last distillation of toluene was performed under reduced pressure (50 mbars) maintaining Tmass < 60 °C in order to distill 131 kg of toluene and isopropanol (49.4 kg) was finally added to the mixture and the solution was stirred at RT until crystallization (17 minutes). Ultra pure water was added (125.4 L) and the mixture was stirred overnight at RT and cooled down to about 0 °C for 1 hour. The precipitate was filtered and rinsed with a cooled water/isopropanol 50/50 v/v solution (76.6 kg). The wet precipitate was dried under vacuum at Tjack = 35°C for 96 hours to obtain the title compound as an off-white powder with 59 % overall yield. The title compound can be resolved by the fractional crystallisation process described above. Preparation of (4-Benzyl-morpholin-2-yl)-(3-fluoro-phenyl)-methanone.
Figure imgf000134_0001
To a solution of 4-Benzyl-morpholine-2-carbonitrile (lOg, 50 mmol) in dry diethyl ether (100 ml) at -10 °C under an atmosphere of nitrogen was added (time of addition 30 minutes) a solution of 3-fluorophenylmagnesium bromide (0.5N solution in tetrahydrofuran, 120 ml, 60 mmol, 1.2 equivalents, available from Aldrich Chemical Company or Rieke Metals) and the reaction mixture was further stirred at -10 °C for 30 minutes. Then the reaction was allowed to warm to room temperature and stirred for one hour. The reaction was then cooled to 0 °C and quenched by addition of hydrochloric acid (2N aqueous solution, 50 ml) and the resulting mixture was stirred for 30 minutes at 0 °C.
Then the solution was concentrated in vacuo and the residue was taken-up by sodium hydroxide (2N aqueous solution, 60 ml). The aqueous solution was extracted with diethyl ether, the organics fractions were collected and dried (MgSO4) and the solvent removed under reduced pressure to give the title compound as a brown oil (15g, 100%). FIA [M+H]+=300.1.
Preparation of 2-ChIoromethyl-4-fIuoro-l-methoxy-benzene.
a) (5-Fluoro-2-methoxy-phenyl)-methanol.
Figure imgf000134_0002
To a solution of 2-Methoxy-5-fluorobenzaldehyde (11.093g, 1 equiv.- available from Aldrich Chemical Company) in methanol at -10 °C under nitrogen atmosphere was added NaBH4 (7.515g, 2.7 equiv.) portionwise. The solution was allowed to warm to room temperature and after 30 minutes the reaction solvent was removed under reduced pressure and replaced with dichloromethane. This solution was poured onto ice water and further extracted with dichloromethane. The organic fractions were collected and dried (MgSO4) and the solvent removed under reduced pressure to give the title compound as an oil (9.794g, 87%).1H NMR (300MHz, CDC13): 62.58 (m, IH), 3.81 (s, 3H), 4.63 (d, 2H, J = 6.3 Hz), 6.78 (dd, IH, 7 = 8.9 and 4.3 Hz), 6.94 (td, IH, 7= 8.5 and 3.1Hz), 7.04 (dd, IH, 7 = 8.7 and 3.1Hz).
b) 2-Chloromethyl-4-fluoro-l-methoxy-benzene.
Figure imgf000135_0001
Neat (5-Fluoro-2-methoxy-phenyl)-methanol (19.587g, 1 equiv.) was added to neat SOCl (42.2 mL, 4.6 equiv.) at -78°C under a nitrogen atmosphere and the solution was then allowed to warm to room temperature and stirred until evolution of gas had ceased. An equivalent volume of anhydrous toluene was added to the flask and the solution heated to 60°C On cooling the reaction solution was poured onto ice water. The toluene layer was separated and dried (MgSO4) and the solvent removed under reduced pressure. The crude material was sublimed (60-80°C/0.05 mBarr) to give the title compound as a white solid (13.40 g, 61%). 1H NMR (300MHz, CDC13): 5 3.87 (s, 3H), 4.60 (s, 2H), 6.79-7.20 (m, 3H).
Preparation of l-Chloromethyl-2-isopropoxy-benzene.
a) (2-Isopropoxy-phenyl)-methanol.
Figure imgf000135_0002
A mixture of 2-hydroxybenzyl alcohol (21.04g, 1 equiv., available from Aldrich Chemical Company), 2-isopropyl iodide (32.3 mL, 1.9 equiv., available from Aldrich Chemical Company) and K2CO3 (71.42g, 3 equiv.) in ethanol was refluxed for 3 hours. On cooling the reaction mixture was filtered and the solvent removed under reduced pressure and replaced with dichloromethane, and then filtered and the solvent removed to give the title compound as an oil (27.75 lg, 99%). 1H NMR (300MHz, CDC13): δ 1.37 (d, 6H, J = 6.0Hz), 3.55 (bs, IH), 4.50-4.70 (m, 3H), 6.78-6.90 (m, 2H), 7.15-7.25 (m, 2H).
b) l-Chloromethyl-2-isopropoxy-benzene.
Figure imgf000136_0001
The title compound was prepared using the general procedure outlined above for the preparation of 2-Chloromethyl-4-fluoro- 1 -methoxy-benzene followed by the following treatment:
The crude reaction material was chromatographed on silica gel and eluted 1:9 ethyl acetate/heptane prior to distillation (40-60 °C/0.05 mBar). 1H NMR (300MHz, CDC13): 6 1.37 (d, 6H, J = 6.0Hz), 4.50-4.70 (m, 3H), 6.80-7.00 (m, 2H), 7.23-7.30 (m, 2H).
Synthesis of Compounds of Formula (IB).
Example IB: (S, R)-2-(2-Methoxy-phenyl)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride.
a) l-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-l-phenyl-ethanoϊ.
Figure imgf000136_0002
Solid magnesium turnings (9.5 g, 28 equiv.) under nitrogen atmosphere at room temperature were stirred vigorously with a magnetic stirring bar overnight. The magnesium was then covered with dry diethyl ether and to the suspension was added 1,2- dibromoethane (50 μL). A cold bath was then applied followed by dropwise addition of l-chloromethyl-2-methoxy-benzene (18.18 g, 5 equiv. available from Aldrich Chemical
Company) in diethyl ether (71 mL) which maintained the temperature at up to 15 °C. The resulting black suspension was stirred at room temperature for 30 minutes and cooled down at -20 °C. A solution of (4-Benzyl-morpholin-2-yl)-phenyl-methanone (4g, 1 equiv.) in diethyl ether (50 mL) was then added dropwise via canula. The reaction mixture was left to warm to room temperature over two hours and then quenched by addition of aqueous saturated solution of NaHCO3 (50 mL). The aqueous solution was extracted with diethyl ether, the organic phase dried with MgSO4, evaporated in vacuo to give 7 g of a yellow amorphous solid. The compound was taken without further purification in the next step. FIA [M+H]+=404.
b) 2-(2-Methoxy-phenyl)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride.
Figure imgf000137_0001
CIH To a solution of l-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-l-phenyl- ethanol (1 g, 1 equiv.) in ethyl acetate (100 mL) at room temperature under nitrogen atmosphere was added ammonium formate (3.9 g, 25 equiv.) followed by addition of palladium on charcoal (10 %, lg.). The reaction mixture was heated to reflux for 1 hour, cooled to room temperature and then filtered through Celite. All volatiles were evaporated under vacuum, and the resulting solid was purified via preparative HPLC. The isolated white solid was taken up in ethanol. Hydrogen chloride was added (large excess of 2M solution in diethyl ether) and the mixture was stirred until it became a clear solution. Then all the volatiles were evaporated in vacuo, to give 650 mg of the title compound as white solid (75 %). 1H NMR (300MHz, DMSO D6) δ: 2.43-2.51 (m, 2H), 2.77-2.92 (m, 2H), 3.15-3.23 (m, 3H), 3.41 (s, 3H), 4.10-4.19 (m, 2H), 6.66-6.72 (m, 2H), 6.98-7.07 (m, 2H), 7.13-7.20 (m, 5H), 9.32 (bs, 2H). LCMS (12 minute method) [M+H]+=314 @ Rt 3.96 min. single major peak.
Example 2B: (S, R) 2-(2-Ethoxy-phenyl)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride.
a) l-(4-Benzyl-morpholin-2-yl)-2-(2-ethoxy-phenyl)-l-phenyl-ethanol.
Figure imgf000138_0001
The procedure for the synthesis of example IBa, l-(4-Benzyl-morpholin-2-yl)-2-
(2-methoxy-phenyl)-l -phenyl -ethanol, was followed using commercially available 2- ethoxybenzylmagnesium bromide (available from Rieke-Metals) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+=418.
b) 2-(2-Ethoxy-phenyl)-l-morphoIin-2-yl-l-phenyl-ethanol hydrochloride.
Figure imgf000138_0002
CIH The procedure for the synthesis of example lBb, 2-(2-Methoxy-phenyl)-l- morpholin-2-yl-l-phenyl-ethanol hydrochloride was followed making non-critical variations, to yield the title compound. 1H NMR (300MHz, DMSO D6) S: 1.11 (t, 3H, J=6.97Hz), 2.43-2.56 (m, IH), 2.81-2.96 (m, 2H), 3.17-3.27 (m, 3H), 3.55-3.67 (m, 2H), 3.84-3.92 (m, IH), 4.05-4.20 (m, 2H), 6.68-6.74 (m, 2H), 7.01-7.18 (m, 8H), 8.92 (bs, 2H) ppm. LCMS (12 minute method) [M+H]+=328 @ Rt 4.57 min. single major peak.
Example 3B: S, R) 2-(2-Isopropoxy-phenyI)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride.
a) l-(4-Benzyl-morpholin-2-yl)-2-(2-isopropoxy-phenyl)-l-phenyl-ethanol.
Figure imgf000139_0001
Solid magnesium turnings (4.6 g, 48 equiv.) under nitrogen atmosphere at room temperature were stirred vigorously with a magnetic stirring bar overnight. The magnesium was then covered with dry tetrahydrofuran. A cold bath was then applied followed by dropwise addition of l-chloromethyl-2-isopropoxy-benzene (3.0 g, 4 equiv. prepared as described above) in tetrahydrofuran (40 mL). During slow addition of the electrophile no exotherm was observed so on completion of addition 3 crystals of Iodine were added to promote initiation of the reaction. After this addition the reaction temperature was allowed to spike to 50 °C then cooled rapidly to 8 °C before being left to warm to room temperature for one hour. The resulting black suspension was cooled down to -10 °C and a solution of (4-Benzyl-morpholin-2-yl)-phenyl-methanone (1.2 g, 1 equiv.) in tetrahydrofuran (10 mL) was then added dropwise. The reaction mixture was left to warm to room temperature over thirty minutes and then quenched by addition of aqueous saturated solution of NaHCO3 (50 mL) prior to filtration through Celite. The aqueous solution was extracted with diethyl ether, the organic phase dried with MgSO4, evaporated in vacuo to give 3 g of a yellow amorphous solid. The compound was taken without further purification in the next step. LCMS (6 minutes method) [M+H]+=432 @ Rt 3.25 min. major peak.
b) 2-(2-Isopropoxy-phenyI)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride.
Figure imgf000140_0001
The procedure for the synthesis of example lBb, 2-(2-Methoxy-phenyl)-l- morpholin-2-yl-l-phenyl-ethanol hydrochloride was followed making non-critical variations, to yield the title compound. 1H NMR (300MHz, MeOH D3) δ: 1.12-1.16 (m, 6H), 2.51-2.55 (m, IH), 2.89-3.14 (m, 4H), 3.56-3.60 (m, IH), 3.82-3.92 (m, IH), 3.99-
4.03 (m, IH), 4.17-4.22 (m, IH), 4.36-4.44 (m, IH), 6.50-6.55 (m, IH), 6.66-6.73 (m, 2H), 6.92-6.98 (m, IH), 7.07-7.20 (m, 5H) ppm. LCMS (12 minutes method) [M+H]+= 342 @ Rt 4.90 min. major peak.
Example 4B: (S, R) l-(3-Fluoro-phenyl)-2-(2-methoxy-phenyl)-l-morpholin-2-yl- ethanol hydrochloride
a) l-(4-Benzyl-morpholin-2-yl)-l-(3-fluoro-phenyl)-2-(2-methoxy-phenyl)- ethanol.
Figure imgf000140_0002
A magnetically stirred 0.25M tetrahydrofuran solution of commercially available 2-methoxybenzylmagnesium bromide (available from Rieke-Metals) (80ml, 3equiv.) under nitrogen atmosphere was cooled to -10 °C and to this was added neat (4-Benzyl- morpholin-2-yl)-l-(3-fluoro-phenyl)-methanone (2.1g, lequiv.). The solution was allowed to warm to room temperature and reaction progress followed using mass spectrometry. After 1.5 hours 2-methoxybenzylmagnesium bromide solution (14ml, 0.5equiv.) was again added to the reaction and after a further 0.5 hours an aqueous saturated solution of NaHCO3 (50 mL) was added to halt the reaction. The aqueous solution was extracted with diethyl ether, the organic phase dried with MgSO4, evaporated in vacuo to give 2.8 g of a yellow amorphous solid. The compound was taken without further purification in the next step. LCMS (6 minutes method) [M+H]+=422 @ Rt 3.03 and 2.86 min. major peaks.
b) (S, R )-l-(3-Fluoro-phenyl)-2-(2-methoxy-phenyl)-l-morphoIin-2-yl-ethanoI hydrochloride.
Figure imgf000141_0001
To a solution of l-(4-Benzyl-morpholin-2-yl)-l-(3-fluoro-phenyl)-2-(2-methoxy- phenyl)-ethanol (2.8 g, 1 equiv.) in ethyl acetate (100 mL) at room temperature under nitrogen atmosphere was added ammonium formate (4.3 g, 10 equiv.) followed by addition of palladium on charcoal (10 %, 2.7g.). The reaction mixture was heated to reflux for 1 hour, cooled to room temperature and then filtered through Celite. All volatiles were evaporated under vacuum, and the resulting solid was purified via preparative HPLC to give the desired diastereoisomers. The active enantiomer was obtained after a further preparative chiral HPLC separation. The active enantiomer, a white solid, was next taken up in ethanol and hydrogen chloride was added (large excess of 2M solution in diethyl ether) and the mixture was stirred until it became a clear solution. Then all the volatiles were evaporated in vacuo, to give 447mg of the title compound as white solid. 1H NMR (300MHz, DMSO D6) δ: 2.49-2.53 (m, IH), 2.80- 2.93 (m, 2H), 3.12-3.33 (m, 4H), 3.41 (s, 3H), 3.85-3.92 (m, IH), 4.07-4.20 (m, 2H), 6.70-6.75 (m, 2H), 6.92-7.10 (m, 5H), 7.20-7.27 (m, IH), 9.08 (bs, 2H). LCMS (12 minutes method) [M+H]+=332. Rt 4.1 lmin. Example 5B: (S. R) l-Morpholin-2-yl-l-phenyl-2-(2-trifluoromethoxy-phenyι)-ethanol hydrochloride
a) l-(4-Benzyl-morpholin-2-yl)-l-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanol.
Figure imgf000142_0001
Magnesium turnings (24.2 g, 0.935 mole, 2 eq.) and diethyl ether (300 ml) were loaded in a reactor under N2. A solution of 2-trifluoromethoxybenzyl bromide (165 g, 0.647 mole, 1.3 eq.) in diethyl ether (300 ml) was loaded in an addition funnel. Iodine crystals and a small amount of the 2-trifluoromethoxybenzyl bromide solution were added and the reaction mixture was stirred to initiate the reaction. The remainder of the 2- trifluoromethoxybenzyl bromide solution was then added drop-wise maintaining the temperature of the reaction mixture below 35°C. The mixture was stirred for another 5 minutes at 23°C after completion of the addition. A solution of (4-Benzyl-morpholin-2- yl)-phenyl-methanone (140 g, 0.498 mole) in diethyl ether (2.1 L) was added drop-wise, maintaining the temperature of the reaction mixture below 25°C. The solution obtained was stirred for 1 hour at 20°C. The reaction mixture was quenched through the addition of a saturated aqueous NaHCO3 solution (700 ml) and water (700 ml). The solids were filtered and washed with diethyl ether (200 ml). The filtrates were loaded into a separation funnel and the layers were separated. The aqueous layer was extracted with diethyl ether (1 L). The organic layers were combined and the filtrates were concentrated under vacuum to about 2 liters. The solution was dried over MgSO , filtered and the filter cake was washed with diethyl ether (200 ml). The filtrate was concentrated under vacuum to orange oil. The residue was twice dissolved in toluene (500 ml) and concentrated to a solid product. The yield of crude title compound was 235 g (103%). 1H-NMR (CDC13):
6.80-7.07 ppm, 11 H, mp; 7.04-7.01 ppm, IH, mp; 7.01-6.86 ppm, IH, dt; 6.84-6.80 ppm, IH, d; 3.98-4.03 ppm, IH, dt; 3.86-3.89 ppm, IH, dd; 3.70-3.60 ppm, IH, dt; 3.52- 3.58 ppm, IH, d; 3.37-3.42 ppm, IH, d; 3.13-3.37 ppm, IH, d; 3.05-3.08 ppm, IH, d; 2.44-2.45 ppm, IH, d; 2.30-2.00 ppm, 3H, mp.
b) (S, R) l-Morpholin-2-yl-l-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanol hydrochloride.
Figure imgf000143_0001
CIH A stainless steel Buchi hydrogenation reactor was loaded with l-(4-Benzyl- morpholin-2-yl)-l-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanol (230 g, 0.503 mole), methanol (1 L), a suspension of Pd/C (10%, 46 g, 20% loading) in methanol (500 ml), and methanol (500 ml) from equipment rinses. A solution of HCI in ethanol (1.6N, 460 ml, 0.736 mole, 1.5 eq.) was added and the reactor was pressurized with H2 (3 Bar). The reaction mixture was heated to 40°C and stirred for 3 hours. The reaction mixture was cooled to 20°C and flushed with N2. The catalyst was filtered off and washed with methanol (0.5 L). The filtrates were concentrated under vacuum to a yellow solid. The yield of crude title compound was 198 g (97.5%). A reactor was loaded with crude title compound (190 g, 0.47 mole) and toluene (6.65 L) under N2. The suspension was heated under reflux and toluene (150 ml) was added until all solid dissolved. The solution was stirred for 15 minutes more under reflux and then cooled slowly to 20°C. The suspension was stirred for 1 hour at 20°C. The solid was filtered, washed with toluene (680 ml), and dried at 40°C under vacuum. The yield of pure anhydrous title compound was 158.5 g
(83.4%).
Alternatively, the following method can be used. In a glass-lined nitrogen purged hydrogenator are charged l-(4-Benzyl-morpholin-2-yl)-l-phenyl-2-(2-trifluoromethoxy- phenyl)-ethanol hydrochloride (150g, 303.7 mmol), demineralized water (352 mL), i-
PrOH (375 mL) and 5% Pd/C (30 g, 50% water, Johnson & Matthey type 440). The heterogeneous reaction mixture was then purged 5 times with 25 psi nitrogen then purged 5 times with 50 psi hydrogen, and the hydrogenation was performed at RT. The initial Tmass was 22°C and the maximum Tmass during the hydrogenation was 23°C. The reactor was stirred vigorously. In-process analysis after 2 hours indicated complete hydrogenolysis. The hydrogenation was stopped after 3 hours. The nitrogen purged reaction mixture was then filtered at RT through an hyflo filter (56 g), impregnated beforehand with 75 mL of a 50/50 v/v isopropanol/water mixture and washed with 300 mL of a 50/50 v/v isopropanol/water mixture. The filtrates were stored overnight at RT. The filtrates were concentrated at 40-50°C under reduced pressure (typical 622 g distilled). The reaction mixture was cooled to RT and post-agitated. After 3 hours, 1 mL of the solution was taken and cooled to 0°C to initiate crystallization. These seeds were added to the reaction mixture and precipitation was observed within a few minutes. The mixture was post-agitated at RT for 2 hours. The crystals were filtered and rinsed with H2O (30 mL). Then, the precipitate was dried under reduced pressure (400 mmHg) with a nitrogen flow (0.1 bar) for 4 hours affording the title compound as the hydrate polymorph (103.5 g, 81% yield).
Example 6B: (S, R) 2-Biphenyl-2-yl-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride
a) l-(4-Benzyl-morpholin-2-yl)-2-biphenyl-2-yl-l-phenyI-ethanol.
Figure imgf000144_0001
l-(4-Benzyl-morpholin-2-yl)-2-(2-bromo-phenyl)-l-phenyl-ethanol (0.50 g, 1.0 equiv. prepared according to Example 15Ba below) and phenylboronic acid (0.402 g, 3.0 equiv., available from Aldrich Chemical Company) were suspended in a mixture ethanol/water (2/1, 7.5 mL) and Pd(Ph3)4 (0.022 g, 0.04 equiv.), then K2CO3 (0.654 g, 4.30 equiv.) were added. The mixture was heated to 80°C under nitrogen atmosphere.
After 16 hours, the reaction was cooled down to room temperature and filtered through Celite, then extracted with ethyl acetate. The organic layers were combined, dried with MgSO4, filtered and concentrated in vacuo yielding a yellow oil, which was purified by column chromatography on silica gel (10% EtOAc:Hexane) to give 0.49 lg (98%) of the title compound as a white solid.
b) (S, R) 2-Biphenyl-2-yl-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride.
Figure imgf000145_0001
CIH The procedure for the synthesis of example lBb, 2-(2-methoxy-phenyl)-l- morpholin-2-yl-l-phenyl-ethanol hydrochloride, was followed making non-critical variations, to yield the title compound.1H NMR (300MHz, DMSO D6) 6: 2.16-2.20 (m,
IH), 2.54-2.62 (m, IH), 2.67-2.76 (m, IH), 2.85-2.89 (m, IH), 3.24 (s, 2H), 3.61-3.69 (m, 2H), 3.93-3.98 (m, IH), 5.14 (bs, IH), 6.80-6.92 (m, 5H), 7.04-7.17 (m, 5H), 7.27-7.30 (m, 3H), 7.36-7.39 (m, IH). LCMS (12 minutes method) [M+H]+=360 @ Rt 5.15 min. single major peak.
Example 7B: (S, R) 2-(2-Chloro-phenyl)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride
a) l-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-phenyl)-l-phenyl-ethanol.
Figure imgf000145_0002
The procedure for the synthesis of example IBa, l-(4-Benzyl-morpholin-2-yl)-2-
(2-methoxy-phenyl)-l-phenyl-ethanol, was followed using 2-chlorobenzyl chloride (available from Aldrich Chemical Company) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+=408 and 410.
b) (S, R) 2-(2-Chloro-phenyl)-l-morpholin-2-yI-l-phenyI-ethanol hydrochloride
Figure imgf000146_0001
The procedure for the synthesis of example 5Bb, (S, R) l-Morpholin-2-yl-l- phenyl-2-(2-trifluoromethoxy-phenyl)-ethanol hydrochloride, was followed making non- critical variations, to yield the title compound.1H NMR (300MHz, DMSO D6) 6: 2.45- 2.54 (m, IH), 2.84-2.93 (m, 2H), 3.17-3.22 (m, IH), 3.33-3.38 (m, 3H), 3.89-3.97 (m, IH), 4.14-4.18 (m, 2H), 7.06-7.11 (m, 2H), 7.15-7.26 (m, 7H), 9.24 (bs, 2H) ppm. LCMS
(12 minutes method) [M+H]+=318-320 @ Rt 4.36 min. single peak.
Example 8B : (S , R) 2 - ( 5 -Fluoro-2 -methoxy-phenyl ) -1-morpholin- 2 -yl - 1 -phenyl - ethanol hydrochloride
a) l-(4-Benzyl-morpholin-2-yI)-2-(5-fIuoro-2-methoxy-phenyl)-l-phenyI- ethanol.
Figure imgf000146_0002
Magnesium turnings (21.6 g, 0.888 mole, 2 eq.) and diethyl ether (300 ml) were loaded in a reactor under N2. A solution of 5-fluoro-2~methoxybenzyl chloride (116 g,
0.664 mole, 1.5 eq.) in diethyl ether (200 ml) was loaded in an addition funnel. Iodine crystals and a small amount of the 5-fluoro-2-methoxybenzyl chloride solution were added and the reaction mixture was stirred to initiate the reaction. The remainder of the 5- fluoro-2 methoxybenzyl chloride solution was then added drop-wise maintaining the temperature of the reaction mixture below 28 °C. The mixture was stirred for another 5 minutes at 19 °C after completion of the addition and a white suspension was formed. A solution of (4-Benzyl-morpholin-2-yl)-phenyl-methanone (125 g, 0.444 mole) in diethyl ether (1.8 L) was added drop-wise, maintaining the temperature of the reaction mixture below 25 °C. The suspension obtained was stirred for 2 hours. The reaction mixture was quenched through the addition of a saturated aqueous NaHCO3 solution (625 ml) and water (500 ml), maintaining the temperature below 20 °C. The mixture was stirred for 30 minutes and the solids were filtered, washed with water (125 ml) and diethyl ether (200 ml). The filtrates were loaded into a separation funnel and the layers were separated. The aqueous layer was extracted with diethyl ether (1 L). The organic layers were combined and dried over MgSO , filtered and the filter cake was washed with diethyl ether (100 ml). The filtrates were concentrated under vacuum. The yield of title compound was 201 g as a yellow solid (107%). Title compound (200 g, 0.474 mole) was then suspended in isopropanol (400 ml) under N2. The suspension was heated under reflux until all solids were dissolved. The solution is allowed to cool to 20 °C over 4 hours under stirring. The solid is filtered, washed with isopropanol (100 ml) and dried at 40°C under vacuum. The yield of pure title compound is 158 g (79%). 1H-NMR (CDC13): 6.99-7.26 ppm, 10H, mp; 6.60-6.71 ppm, IH, dt; 6.49-6.60 ppm, IH, dd; 6.31-6.44 ppm, IH, dd; 3.92-4.01 ppm, IH, dt; 3.80-3.90 ppm, IH, dd; 3.64-3.73 ppm, IH, dd; 3.59-3.64 ppm, IH, d; 3.52- 3.59 ppm, 3+1 H, 2s; 3.37-3.45 ppm, IH, d; 3.07-3.17 ppm, IH, d; 2.84-2.92 ppm, IH, d;
2.43-2.53 ppm, IH, d; 2.20-2.28 ppm, IH, d; 1.98-2.11 ppm, 2H, mp.
b) (S, R) 2-(5-Fluoro-2-methoxy-phenyl)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride
Figure imgf000147_0001
CIH
A glass hydrogenation flask was loaded with methanol (1.55 L), Pd/C (10%, 31 g,
20% loading), l-(4-benzyl-morpholin-2-yl)-2-(5-fluoro-2-methoxy-phenyl)-l-phenyl- ethanol (155 g, 0.368 mole) and a solution of HCI in ethanol (2.5N, 233 ml, 0.582 mole, 1.6 eq.). The reactor was mounted on a Parr instrument and pressurized with H2 (49 Psi). The reaction mixture was shaken overnight between 20°C and 15°C. The catalyst was filtered off and washed with methanol (0.5 L). The filtrates were concentrated under vacuum. The yield of crude title compound was 109.5 g (81%). The catalyst was washed again with methanol (2 x 500 ml). The filtrates were combined and concentrated under vacuum. The yield of the second crop of crude title compound was 21.7 g (16%). A reactor was loaded with crude title compound (131 g, 0.356 mole) and isopropanol (1,3 L) under N2. The suspension was heated under reflux for 4 hours. The mixture was cooled to 20°C and the solid was filtered, washed with isopropanol (130 ml), and dried at 50°C under vacuum. The yield of pure title compound was 115.9 g (88.5% yield).
Example 9B : (S, R) l-Morpholin-2-yl-l-phenyl-2- (2- trifluoromethylsulfanyl-phenyl) -ethanol acetate
a) l-(4-Benzyl-morpholin-2-yl)-l-phenyl-2-(2-trifluoromethylsulfanyl-phenyl)- ethanol.
Figure imgf000148_0001
The procedure for the synthesis of example IBa, l-(4-benzyl-morpholin-2-yl)-2- (2-methoxy-phenyl)-l-phenyl-ethanol, was followed using l-bromomethyl-2- trifluoromethylsulfanyl-benzene (available from Fluorochem Ltd.) as starting material and making non-critical variations, to yield the title compound. 1H NMR (300MHz, CDC13) 6: 2.05-2.33 (m, 3H), 2.49-2.65 (m, IH), 3.10-3.35 (m, 2H), 3.43-3.55 (m, IH), 3.67-3.89 (m, 2H), 3.91-4.08 (m, 2H), 4.09-4.22 (m, IH), 6.91-7.05 (m, IH), 7.10-7.42 (m, 12H), 7.50-7.63 (m, IH) ppm.
b) (S, R) l-Morpholin-2-yl-l-phenyl-2-(2-trifluoromethylsulfanyl-phenyl)- ethanol acetate
Figure imgf000149_0001
To a solution of l-(4-benzyl-morpholin-2-yl)-l-phenyl-2-(2- trifluoromethylsulfanyl-phenyl)-ethanol (218 mg g, 1 equiv.) and solid supported Hunig's base (available from Argonaut, lg, 5 equiv.) in dry tetrahydrofuran (4 mL) at 0 °C under nitrogen atmosphere was added ACE-C1 (502 μL, 10 equiv.). The reaction mixture was left to warm to room temperature for 48 hours. All volatiles were evaporated under vacuum, and the resulting solid was taken-up with methanol (50 mL) and stirred at room temperature overnight. The solution was filtered through acid ion exchange column and the required fractions evaporated to dryness. The resulting solid was purified via preparative HPLC to give 62 mg of the title compound as a colourless oil. 1H NMR
(300MHz, CDC13) 6: 2.01 (s, 3H), 2.43-2.47 (m, IH), 2.63-2.70 (m, IH), 2.81-2.94 (m, 2H), 3.24 (d, IH, J=13.57Hz), 3.85-3.96 (m, 2H), 4.01-4.05 (m, lH), 4.09-4.13 (m, IH), 4.45 (bs, 4H), 6.90-6.93 (m, IH), 7.13-7.26 (m, 7H), 7.55-7.58 (m, IH) ppm. LCMS (12 minute method) [M+H]+=384 @ Rt 5.13 min. single peak.
Example 10B: (S, R) l-Morpholin-2-yl-l-phenyl-2- (2- trifluoromethyl-phenyl) -ethanol
a) 4-Benzyl-2-(2-phenyl-oxiranyl)-morpholine.
Figure imgf000149_0002
To a mixture of trimethylsulfoxonium iodide (783 mg, lequiv.) and sodium hydride (142 mg, 1 equiv.) in dimethylformamide (17 mL) at 0 °C under nitrogen atmosphere was added dimethylsulfoxide (251 μL, 1 equiv.) and the resulting suspension was stirred for 30 minutes. A solution of (4-Benzyl-morpholin-2-yl)-phenyl-methanone (1 g, 1 equiv.) in dimethylformamide (10 mL) was then added dropwise. Stirring was continued for 30 minutes and the reaction was stopped by addition of water (50 mL). The aqueous solution was extracted with diethyl ether, the organic phase dried with MgSO4, and evaporated in vacuo. The crude material was purified using a column chromatography on silica gel eluting with a mixture of ethyl acetate/heptane (20/80) to give 825 mg of the title compound as a colourless oil (78 %), mixture of two diastereoisomers. LCMS (6 minute method) [M+H]+=296 @ Rt 1.88 min. single peak.
b) l-(4-Benzyl-morpholin-2-yl)-l-phenyl-2-(2-trifluoromethyl-phenyl)-ethanol.
Figure imgf000150_0001
To a suspension of magnesium turnings in tetrahydrofuran (2mL) at room temperature under nitrogen atmosphere was added a solution of l-bromo-2-trifluoromethyl- benzene (7.6g, 5equiv., available from Acros) in tetrahydrofuran (32 mL) and the mixture was stirred for an hour. The solution was cooled to -78 °C and copper iodide (646 mg) was added followed by dropwise addition of a solution of 4-Benzyl-2-(2-phenyl-oxiranyl)- morpholine (2g, 1 equiv.) in tetrahydrofuran (10 mL). The resulting mixture was warmed to room temperature over 2 hours and then treated with water (10 mL). The solution was extracted with diethyl ether, the organic phase dried with MgSO4, arid evaporated in vacuo. The crude material was purified using a column chromatography on silica gel eluting with a mixture of ethyl acetate/heptane (10/90) to give 352 mg of the title compound as a colourless oil (12 %). LCMS (6 minutes method) [M+H]+=442 @ Rt 3.05 min. major peak.
c) (S, R) l-Morpholin-2-yl-l-phenyl-2-(2-trifluoromethyl-phenyl)-ethanol
Figure imgf000150_0002
To a solution of l-(4-Benzyl-morpholin-2-yl)-l-phenyl-2-(2-trifluoromethyl- phenyl)-ethanol (352 mg, 1 equiv.) in ethanol (15 mL) at room temperature under nitrogen atmosphere was added ammonium formate (507 mg g, 10 equiv.) followed by addition of palladium on charcoal (10 %, 355 mg.). The reaction mixture was heated to reflux for 1 hour, cooled to room temperature and then filtered through Celite. All volatiles were evaporated under vacuum to give 265 mg of the title compound as white solid (94 %). The enantiomeric mixture was resolved using chiral HPLC, to give the title compound as a single enantiomer. 1H NMR (300MHz, CDC13) 8: 2.25-2.30 (m, IH), 2.56-2.64 (m, IH), 2.75-2.87 (m, 2H), 3.18 (d, IH, J=14.88Hz), 3.71-3.81 (m, 2H), 3.89 (d, IH, J=14.88Hz), 4.02-4.05 (m, IH), 6.83-6.86 (m, IH), 7.09-7.34 (m, 7H), 7.53-7.55
(m, IH) ppm. LCMS (12 minute method) [M+H]+=352 @ Rt 4.73 min. single peak.
Example 11B: (S, R) 2- (2-Chloro-phenyl) -1- (3-fluoro-phenyl) -1- morpholin-2-yl-ethanol hydrochloride
a) l-(4-BenzyI-morpholin-2-yI)-2-(2-chloro-phenyl)-l-(3-fluoro-phenyl)-ethanol.
Figure imgf000151_0001
The procedure for the synthesis of 4Ba, l-(4-Benzyl-morpholin-2-yl)-l-(3-fluoro- phenyl)-2-(2-methoxy-phenyl)-ethanol was followed using 2-chorobenzyl chloride (available from Aldrich Chemical Company) as starting material, and making non-critical variations, to yield the title compound which was taken without further purification in the next step. LCMS (6 minutes method) [M+H]+=426 @ Rt 2.85 min. major peak.
b) (S, R) 2-(2-Chloro-phenyl)-l-(3-fluoro-phenyl)-l-morpholin-2-yl-ethanol hydrochloride
Figure imgf000152_0001
To a solution of l-(4-Benzyl-morpholine-2-yl)-2-(2-chloro-phenyl)-l-(3-fluoro- phenyl)-ethanol. (3.2g, 1 equiv.) in dry 1,2-dichloroethane (40 mL) under nitrogen atmosphere was added ACE-C1 (20.33 g, 5 equiv.). The reaction mixture was stirred at room temperature overnight then refluxed until completion. All volatiles were evaporated under vacuum, and the resulting residue redissolved in acetonitrile. This solution was filtered through an ion exchange column and the filtrate taken-up with methanol (50 mL) and refluxed for 3h. The solution was again filtered through acid ion exchange column and the required fractions evaporated to dryness. The resulting solid was next purified via preparative HPLC followed by chiral HPLC. The purified active enantiomer was taken up in ethanol and hydrogen chloride was added (large excess of 2M solution in diethyl ether) and the mixture stirred. Then all the volatiles were evaporated in vacuo, to give 519mg of the title compound as a white solid (18 %). 1H NMR (300MHz, DMSO D6) 8: 2.43-2.54 (m, IH), 2.81-2.95 (m, 2H), 3.16-3.23 (m, IH), 3.30-3.44 (m, 2H), 3.54 (bs, IH), 3.92- 4.00 (m, IH), 4.15-4.23 (m, 2H), 6.96-7.29 (m, 8H), 9.32-9.45 (m, 2H). LCMS (12minute method) [M+H]+=336.
Example 12B: (S, R) l-Morpholin-2-yl-l-phenyl-2-o-tolyl- ethanol hydrochloride
a) l-(4-Benzyl-morphoIin-2-yl)-l-phenyl-2-ø-tolyl-ethanol.
Figure imgf000152_0002
The procedure for the synthesis of example IBa, l-(4-benzyl-morpholin-2-yl)-2- (2-methoxy-phenyl)-l-phenyl-ethanol, was followed using commercially available 2- methylbenzylmagnesium bromide (available from Rieke-Metals) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+= 388.
b) (S, R) l-Morpholin-2-yl-l-phenyl-2-ø-tolyl-ethanol hydrochloride
Figure imgf000153_0001
CIH The procedure for the synthesis of example lBb, 2-(2-methoxy-phenyl)-l- morpholin-2-yl-l-phenyl-ethanol hydrochloride was followed making non-critical variations, to yield the title compound. 1H NMR (300MHz, DMSO D6) δ: 1.62 (s, 3H),
2.40-2.58 (m, IH), 2.78-3.01 (m, 2H), 3.03-3.09 (m, IH), 3.15-3.31 (m, 2H), 3.90-4.05 (m, IH), 4.15-4.25 (m, 2H), 6.89-7.28 (m, 9H), 9.21-9.55 (m, 2H). LCMS (12 minute method) [M+H]+= 298 single peak.
Example 13B: (S, R) l-Morpholin-2-yl-l, 2-diphenyl-ethanol hydrochloride .
a) l-(4-Benzyl-morpholin-2-yl)-l,2-diphenyl-ethanol.
Figure imgf000153_0002
The procedure for the synthesis of example IBa, l-(4-benzyl-morpholin-2-yl)-2-
(2-methoxy-phenyl)-l-phenyl-ethanol, was followed using commercially available benzylmagnesium bromide (available from TCI America) as starting material and making non-critical variations, to yield the title compound. LCMS [M+H]+= 374.1 major single peak @ 3.82 min.
b) (S, R) l-Morpholin-2-yl-l,2-diphenyI-ethanol hydrochloride
Figure imgf000154_0001
CIH
The procedure for the synthesis of example lBb, 2-(2-methoxy-phenyl)-l- morpholin-2-yl-l-phenyl-ethanol hydrochloride was followed making non-critical variations, to yield the title compound. 1H NMR (300MHz, CDC13) 8: 2.36-2.41 (m, IH), 2.64-2.71 (m, IH), 2.78-2.91 (m, 3H), 3.16-3.32 (m, 2H), 3.73-3.82 (m, 2H), 4.08-4.11 (m, IH), 6.80-6.83 (m, 2H), 7.07-7.12 (m, 3H), 7.16-7.27 (m, 6H). LCMS [M+H]+=284.1 single peak @ 3.82 minutes.
Example 14B: (S, R) 2- (2-Fluoro-phenyl) -l-morpholin-2-yl-l- phenyl-ethanol hydrochloride
a) l-(4-Benzyl-morpholin-2-yl)-2-(2-fluoro-phenyl)-l-phenyl-ethanol.
Figure imgf000154_0002
The procedure for the synthesis of example IBa, l-(4-benzyl-morpholin-2-yl)-2- (2-methoxy-phenyl)-l-phenyl-ethanol, was followed using commercially available 2- fluoro-benzylmagnesium chloride (available from Rieke Metals) as starting material and making non-critical variations, to yield the title compound. FLA [M+H]+=392.1. b) (S, R) 2-(2-Fluoro-phenyl)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride
Figure imgf000155_0001
CIH The procedure for the synthesis of example lBb, 2-(2-methoxy-phenyl)-l- morpholin-2-yl-l-phenyl-ethanol hydrochloride was followed making non-critical variations, to yield the title compound. 1H NMR (300MHz, DMSO D6) 6: 2.40-2.56 (m,
IH), 2.78-2.97 (m, 2H), 3.17-3.29 (m, 3H), 3.89-3.96 (m, IH), 4.14-4.19 (m, 2H), 5.47 (bs, IH), 6.82-6.94 (m, 2H), 7.01-7.25 (m, 7H), 9.28-9.38 (m, 2H). LCMS [M+H]+=302.1 single major peak @ 3.82 minutes.
Example 15B : (S , R) 2 - (2 -bromo-phenyl ) - l -phenyl - l-morpholin-2 - yl - ethanol .
a) l-(4-Benzyl-morphoIin-2-yl)-2-(2-bromo-phenyl)-l-phenyl-ethanol.
Figure imgf000155_0002
The procedure for the synthesis of example IBa, l-(4-Benzyl-morpholin-2-yl)-2-
(2-methoxy-phenyl)-l-phenyl-ethanol, was followed using commercially available 2- bromobenzylmagnesium bromide (available from Rieke-Metals) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+= 452/454.
b) (S, R) l-Morpholin-2-yl-2-(2-bromo-phenyl)-l-phenyl-ethanol.
Figure imgf000156_0001
The procedure for the synthesis of example 5Bb, (S, R) l-Mo holin-2-yl-l- phenyl-2-(2-trifluoromethoxy-phenyl)-ethanol, was followed making non-critical variations, to yield the title compound.1H NMR (300MHz, CDC13) 8: 2.64-2.68 (m, IH), 3.02-3.21 (m, 2H), 3.27-3.33 (m, 3H), 3.45-3.50 (m, IH), 3.63-3.68 (m, IH), 3.99-4.09
(m, IH), 4.20-4.24 (m, IH), 4.29-4.34 (m, IH), 4.87 (s, IH), 6.98-7.21 (m, 2H), 7.24- 7.59 (m, 7H) ppm. LCMS (6 minutes method) [M+H]+= 362.3 @ Rt 2.85 min. single peak.
Example 16B: (S, R) 2- (2 ' -chloro [1-1' biphenyl] -2-yl) -1- morpholin-2-yl-1-phenyl-ethanol hydrochloride
a) 2-(2'-chloro[l-l'biphenyl]-2-yl)-l-phenyl-l-[4-(phenylmethyl)morpholin-2- yl]ethanol.
Figure imgf000156_0002
The procedure for the synthesis of example 6Ba, was followed using 2-chloro phenyl boronic acid (available from Aldrich Chemical Company) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+= 485
b) (S, R) 2-(2'-chloro[l-l'biphenyl]-2-yl)-l-morpholin-2-yl-l-phenyl-ethanoI hydrochloride
Figure imgf000157_0001
HCI
The procedure for the synthesis of example 6Bb, was followed making non- critical variations, to yield the title compound. 1H NMR (300MHz, CDC13) S: 2.10-2.21 (m, IH), 2.57-2.65 (m, IH), 2.62-2.75 (m, IH), 2.83-2.87 (m, IH), 3.20 (s, 2H), 3.63-3.70 (m, 2H), 3.95-3.97 (m, IH), 5.12 (bs, IH), 6.80-6.92 (m, 5H), 7.04-7.17 (m, 5H), 7.27-
7.37 (m, 3H). LCMS (12 minutes method) [M+H]+=393 @ Rt 4.75 min. single major peak.
Example 17B: 4-Fluoro-2- (2-morpholin-2-yl-2- phenylpropyl) phenol hydrochloride
a) 4-Fluoro-2- (2-morphoIin-2-yl-2-phenylpropyl)phenol hydrochloride
Figure imgf000157_0002
Sodium thiomethoxide (13 eq, 186 mg) was added at once to a solution of 2-{2- [5-fluoro-2-(methyloxy)phenyl]-l -methyl- 1 -phenylethyl} morpholine hydrochloride (75.2 mg, 0.204 mmol, synthesized as described in Example 8 above) in anydrous DMF (3 ml) in a microwave vessel. Upon addition, the reaction vessel was sealed and heated up in a CEM-Discovery microwave at 150 Watts, reaching 110 °C in 5 minutes and maintaining this temperature 6 minutes. The reaction vessel was cooled to room temperature and the reaction mixture taken into methanol (5 ml) and purified by SCX-2 chromatography to obtain the free base as clear oil (50 mg). The hydrochloride salt was obtained following general procedures as a white solid (52 mg, 72 % after salt formation.). MW 353.83; C18H22NO3FCI; 1H NMR (CD3OD): 7.29-7.26 (2H, m), 7.20-7.08 (2H, m), 6.53-6.50 (2H, m), 6.30-6.26 (IH, m), 4.18 (IH, dd, 12.6 Hz, 2.6 Hz), 4.02 (IH, dd, 10.9 Hz, 2.3 Hz), 3.86 (IH, td, 12.6 Hz, 2.6 Hz), 3.60 (IH, lΛ AB), 3.16 (IH, d, 12.6 Hz), 3.08-2.90
(3H, m), 2.5 588 (IH, m); 19F NMR (CD3OD) -128.4; LCMS: (12 min method) m z 318.1 [M-HC1+H]+ @ Rt 3.954 min.
Example 18B : 2 - (2 -Fluoro- 6 -chloro-phenyl ) - l -rtιorpholin- 2 -yl - 1 -phenyl -ethanol hydrochloride .
a) l-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluόro -phenyl)-l-phenyl-ethanol.
Figure imgf000158_0001
To a stirred solution of 2-chloro-6-fluorobenzyl magnesium chloride (12.8mL,
3.20 mmol, 3 equiv., available from Rieke Metals) in anhydrous tetrahydrofuran (15 ml) at 0 °C under nitrogen was added a solution of (4-Benzyl-morpholin-2-yl)-phenyl- methanone (300mg, 1.07mmol, 1 equiv.) in tetrahydrofuran (5ml) dropwise over 15 minutes. The reaction was then stirred at 0 °C for one hour. The reaction mixture was allowed to warm to room temperature over two hours and stirred for a further 18h. The solvent was then evaporated "in vacuo " and the residue redissolved in dichloromethane (30mL). The organic solution was washed with aqueous saturated solution of NaHCO3 (50 mL). The aqueous solution was extracted with dichloromethane using a hydrophobic phase separator. The dichloromethane was evaporated "in vacuo" and redissolved in methanol (2 mL). The sample was bound to SCX-2 (5g) and washed with methanol
(30mL). The sample was eluted using 2M ammonia in methanol (30mL). The solvent was then evaporated using a reacti-therm blow down station to give 450 mg of a yellow amorphous solid. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+ = 426 @ Rt 3.27 min. major peak.
b) 2-(2-Fluoro-6-chloro-phenyl)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride.
Figure imgf000159_0001
To a solution of l-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro -phenyl)- 1-phenyl- ethanol (450mg, 1 equiv.) in ethyl acetate (15mL) at room temperature under nitrogen atmosphere was added ammonium formate (1.69 g, 25 equiv.) followed by addition of palladium on charcoal (10 %, 450g.). The reaction mixture was heated to reflux for 1.5 hours, cooled to room temperature and then filtered through Celite. All volatiles were evaporated under vacuum, and the resulting solid was purified via preparative HPLC. The isolated white solid was taken up in ethanol. Hydrogen chloride was added (large excess of 2M solution in diethyl ether) and the mixture was stirred until it became a clear solution. Then all the volatiles were evaporated "in vacuo", to give 147 mg of the title compound as white solid. 1H NMR (300MHz, CD3OD D4) 8: 2.51-2.61 (d, IH), 2.79- 2.91 (t, IH), 2.96-3.09 (m, IH), 3.09-3.16 (m, IH), 3.32-3.54 (q, 2H), 3.82-3.97 (t, IH), 4.09-4.24 (t, 2H), 6.73-6.84 (t, IH), 6.93-7.08 (m, 2H), 7.08-7.21 (m, 5H). LCMS (12 minutes method) [M+H]+ = 336 @ Rt 4.44 min. single major peak.
Example 19B: 2- (2, 5-Di ethoxy-phenyl) -l-morpholin-2-yl-l- phenyl-ethanol hydrochloride
a) l-(4-Benzyl-morpholin-2-yl)-2-(2,5-dimethoxy-phenyl)-l-phenyl-ethanol.
Figure imgf000159_0002
The procedure for the synthesis of example 18Ba, l-(4-Benzyl-morpholin-2-yl)-2- (2-chloro-6-fluoro -phenyl)- 1-phenyl-ethanol, using 2,5-dimethoxybenzyl magnesium chloride as starting material (available from Rieke Metals) was followed making non- critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+ = 434 @ Rt 3.10min. major peak.
b) 2-(2,5-Dimethoxy-phenyl)-l-morpholin-2-yl-l-phenyl-ethanoI hydrochloride.
Figure imgf000160_0001
HCI
The procedure for the synthesis of example 18Bb, 2-(2-Fluoro-6-chloro-phenyl)- l-moφholin-2-yl-l-phenyl-ethanol hydrochloride, was followed making non-critical variations, to yield the title compound.1H NMR (300MHz, CD3OD D4) 8: 2.53-2.62 (d, IH), 2.86-3.10 (m, 3H), 3.13-3.27 (m, 2H), 3.36-3.51 (m, 6H), 3.81-3.93 (t, IH), 4.02- 4.08 (d, IH), 4.15-4.25 (d, IH), 6.28-6.33 (s, IH), 6.49-6.64 (m, 2H), 7.06-7.22 (m, 5H). LCMS (12 minutes method) [M+H]+=344 @ Rt 4.15 min. single major peak.
Example 20B; 2- (2 , 4-Difluoro-phenyl) -l-morpholin-2-yl-l- phenyl-ethanol hydrochloride
a) l-(4-Benzyl-morpholin-2-yl)-2-(2,4-difluoro-phenyl)-l-phenyl-ethanol.
Figure imgf000160_0002
The procedure for the synthesis of example 18Ba, l-(4-Benzyl-morpholin-2-yl)-2- (2-chloro-6-fluoro -phenyl)- 1-phenyl-ethanol, using 2,4-difluorobenzyl magnesium bromide as starting material (available from Rieke Metals) was followed making non- critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+= 410 @ Rt 3.19 min. major peak.
b) 2-(2,4-Difluoro-phenyl)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride.
Figure imgf000161_0001
HCI The procedure for the synthesis of example 18Bb, 2-(2-Fluoro-6-chloro-phenyl)- l-morpholin-2-yl-l-phenyl-ethanol hydrochloride, was followed making non-critical variations to yield the title compound. 1H NMR (300MHz, CD3OD D4) 6: 2.48-2.59 (d,
IH), 2.87-3.09 (m, 2H), 3.11-3.17 (m, 2H), 3.26-3.38 (m, IH), 3.81-3.95 (t, IH), 4.02- 4.11 (d, IH), 4.13-4.25 (d, IH), 6.48-6.60 (m, 2H), 7.70-6.98 (m, IH) 7.08-7.28 (m, 5H). LCMS (12 minutes method) [M+H]+= 320 @ Rt 4.20 min. major peak.
Example 21B: Preparation of 2- (2, 6 -Dichloro-phenyl) -1- morpholin-2 -yl-1-phenyl-ethanol hydrochloride
a) l-(4-Benzyl-morpholin-2-yl)-2-(2,6-dichloro-phenyl)-l-phenyl-ethanol.
Figure imgf000161_0002
The procedure for the synthesis of example 18Ba, l-(4-Benzyl-morpholin-2-yl)-2-
(2-chloro-6-fluoro -phenyl)- 1-phenyl-ethanol, using 2,6-dichlorobenzyl magnesium chloride as starting material (available from Rieke Metals) was followed making non- critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+ = 442 @ Rt 3.49 min. major peak.
b) 2-(2,6-Dichloro-phenyl)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride.
Figure imgf000162_0001
C1H
To a solution of l-(4-Benzyl-morpholin-2-yl)-2-(2,6-dichloro-phenyl)-l-phenyl- ethanol (450mg, 1 equiv.) in ethyl acetate (15mL) at room temperature under nitrogen atmosphere was added ammonium formate (1.69 g, 25 equiv.) followed by addition of palladium on charcoal (10 %, 45mg.). The reaction mixture was heated to reflux for 3 hour, cooled to room temperature and then filtered through Celite. All volatiles were evaporated under vacuum, and the resulting solid was purified via preparative HPLC. The isolated white solid was taken up in ethanol. Hydrogen chloride was added (large excess of 2M solution in diethyl ether) and the mixture was stirred until it became a clear solution. Then all the volatiles were evaporated "in vacuo", to give 60 mg of the title compound as white solid^H NMR (300MHz, CD3OD D4) 5: 2.52-2.61 (d, IH), 2.79-2.96
(t, IH), 2.98-3.13 (t, IH), 3.15-3.19 (s, IH), 3.56-3.71 (q, 2H), 3.88-4.02 (t, IH), 4.10- 4.21 (d, IH), 4.29-4.39 (d, IH), 6.97-7.08 (m, IH), 7.10-7.21 (m, 7H). LCMS (12 minutes method) [M+H]+=352 @ Rt 4.63 min. single major peak.
Example 22B; Preparation of 2- (2, 5-Dichloro-phenyl) -1- morpholin-2 -yl-1-phenyl-ethanol hydrochloride
a) l-(4-Benzyl-morpholin-2-yl)-2-(2,5-dichloro-phenyl)-l-phenyl-ethanol.
Figure imgf000163_0001
The procedure for the synthesis of example 18Ba, l-(4-Benzyl-morpholin-2-yl)-2- (2-chloro-6-fluoro -phenyl)- 1-phenyl-ethanol, using 2,5-dichlorobenzyl magnesium chloride as starting material (available from Rieke Metals) was followed making non- critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+ = 442 @ Rt 3.48 min. major peak.
b) 2-(2,5-Dichloro-phenyl)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride.
Figure imgf000163_0002
HCI
The procedure for the synthesis of example 21Bb, l-(4-Benzyl-morpholin-2-yl)-2- (2,6-dichloro-phenyl)- 1-phenyl-ethanol, was followed making non-critical variations to the title compound. 1H NMR (300MHz, CD3OD D4) 8: 2.49-2.61 (d, IH), 2.88-3.1 l(m, 2H), 3.12-3.24 (m, IH), 3.24-3.35 (m, IH), 3.41-3.53 (d, IH), 3.82-3.96 (m, IH), 4.04-4.25 (m, 2H), 6.90-7.00 (m, IH), 7.02-7.29 (m, 7H). LCMS (12 minutes method) [M+H]+ = 352@ Rt
4.86 min. major peak
Example 23B: Preparation of 2-(2,5-Difluoro-phenyl)-l-nιorpholin-2-yl-l-phenyI- ethanol hydrochloride
a) l-(4-Benzyl-morpholin-2-yl)-2-(2,5-difluoro -phenyl)-l-phenyl-ethanol.
Figure imgf000164_0001
The procedure for the synthesis of example 18Ba, l-(4-Benzyl-morpholin-2-yl)-2- (2-chloro-6-fluoro -phenyl)-l-phenyl-ethanol, using 2,5-difluorobenzyl magnesium bromide as starting material (available from Rieke Metals) was followed making non- critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+= 410 @ Rt 3.11 min. major peak.
b) 2-(2,5-Difluoro-phenyl)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride.
Figure imgf000164_0002
CIH
The procedure for the synthesis of example 18Bb, 2-(2-Fluoro-6-chloro-phenyl)- l-morpholin-2-yl- 1-phenyl-ethanol hydrochloride, was followed making non-critical variations, to yield the title compound.1H NMR (300MHz, CD3OD D4) 8: 2.48-2.59 (d,
IH), 2.87-3.09 (m, 2H), 3.11-3.17 (m, IH), 3.26-3.38 (m, 2H), 3.81-3.95 (t, IH), 4.02- 4.11 (d, IH), 4.13-4.25 (d, IH), 6.62-6.77 (m, 3H), 7.08-7.28 (m, 5H). LCMS (12 minutes method) [M+H]+ = 320 @ Rt 4.20 min. single major peak.
Example 24B; Preparation of 2 - (2-Fluoro-5 -phenyl-phenyl) -1- morpholin-2 -yl- 1-phenyl-ethanol hydrochloride
a) l-(4-BenzyI-morpholin-2-yl)-2-(-2-biphenyl-5-flouro-phenyl)-l-phenyl- ethanol.
Figure imgf000165_0001
The procedure for the synthesis of example 18Ba, l-(4-Benzyl-morpholin-2-yl)-2- (2-chloro-6-fluoro -phenyl)- 1-phenyl-ethanol, using 2-phenyl-5-fluorobenzyl magnesium bromide as starting material was followed making non-critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+ = 468 @ Rt 3.62 min. major peak.
b) 2-(2-Fluoro-5-phenyl-phenyl)-l-morpholin-2-yl-l-phenyl-ethanol hydrochloride.
Figure imgf000165_0002
HCI
The procedure for the synthesis of example 18Bb, 2-(2-Fluoro-6-chloro-phenyl)- l-morpholin-2-yl- 1-phenyl-ethanol hydrochloride, was followed making non-critical variations to the title compound. 1H NMR (300MHz, CD3OD D4) 8: 2.35-2.48 (d, IH), 2.77-2.91 (t, IH), 2.91-3.04 (m, IH), 3.04-3.16 (m, IH), 3.22-3.28 (m, IH), 3.30-3.42 (m, IH), 3.66-3.87 (m, 2H), 4.01-4.14 (d, IH), 6.70-6.89 (m, 5H), 6.98-7.11 (m, 4H), 7.14-
7.25 (m, 4H). LCMS (12 minutes method) [M+H]+= 378 @ Rt 5.22 min. major peak.
Solid Phase Synthesis of Compounds of Formulae (IB)
Compounds of the invention wherein Ari is substituted with an aromatic group (i.e., pyridyl, thiophenyl, and optionally substituted phenyl) can be prepared by solid phase synthesis using the route shown below (the black dot represents polystyrene resin).
Figure imgf000166_0001
Figure imgf000166_0002
The sequence is preferably performed on a polystyrene resin, without characterization of the resin-bound intermediates.
i) Aliquots (52 mg, 0.05 mmoles) of p-nitrophenyl carbonate resin (Novabiochem) were dispensed into 4.5 ml MiniBlock reaction tubes (Mettler-Toledo). To each resin was added DMF (0.5 ml) followed by a 0.2M solution of 2-(2-bromo-phenyl)-l- morpholin-2-yl- 1-phenyl-ethanol in DMF (0.5 ml, 0.1 mmoles). The tubes were
L0 sealed and agitated by orbital shaking for 24 hrs. The resins were then filtered and washed with DMF (3 x 1.0 ml), a solution of diisopropylethylamine (0.25 ml) in DMF (1.0 ml) and finally DMF (4 x 1.0 ml), ii) To each resin was added a 2M solution of an optionally substituted aryl boronic acid in DMF (0.5 ml, 1.0 mmoles), a 0.5M solution of triphenylphosphine in DMF (0.2 ml,
15 0.1 mmoles), a 0.25M solution of Pd(H) acetate in DMF (0.2 ml, 0.05 mmoles) and a
1.25M solution of caesium carbonate in water (0.1 ml, 0.125 mmoles). The tubes were sealed, agitated by orbital shaking and heated at 80° for 20 hrs. The reactions were then cooled to ambient temperature and the resins washed with DMF (2 x 1.0 ml), MeOH (3 x 1.0 ml) and DCM (4 x 1.0 ml). iii) To each resin was added a TFA H2O mixture (95:5 v/v, 1 ml). The tubes were sealed and agitated by orbital shaking for 6 hrs. The reactions were filtered and washed with DCM (2 x 2 ml). Appropriate filtrates and washings were combined and volatile components removed by vacuum evaporation. Each residue was dissolved in MeOH
(1 ml) and the solutions applied to MeOH-washed SCX-2 cartridges (0.5 g/3.0 ml) (Jones Chromatography). After draining under gravity the cartridges were washed with MeOH (2.5 ml) and the products then eluted using a 2M solution of ammonia in MeOH (2.5 ml). Removal of volatile components by vacuum evaporation gave the desired products which were purified by preparative LCMS.
By this means were prepared:
Example 25B 2-(4'-methyl-biphenyl-2-yl)-l-morpholin-2-yl- 1-phenyl-ethanol, RT (6 min gradient) 3.11 min, [M+H]+ 374.2
Example 26B
2-(4'-chloro-biphenyl-2-yl)-l-morpholin-2-yl- 1-phenyl-ethanol, RT (6 min gradient) 3.36 min, [M+H]+ 394.2
Example 27B
2-(4'-methoxy-biphenyl-2-yl)-l-morpholin-2-yl- 1-phenyl-ethanol, RT (6 min gradient) 3.37 min, [M+H]+ 390.2
Example 28B
2-(3'-fluoro-biphenyl-2-yl)-l-morpholin-2-yl-l-phenyl-ethanol, RT (6 min gradient) 3.39 min, [M+H]+ 378.4
Example 29B
2-(3'-chloro-biphenyl-2-yl)-l-morpholin-2-yl- 1-phenyl-ethanol, RT (6 min gradient) 3.53 min, [M+H]+ 394.4 Example 30B
2-(3'-methoxy-biphenyl-2-yl)-l-morpholin-2-yl-l-phenyl-ethanol, RT (6 min gradient) 3.31 min, [M+H]+ 390.4
Example 31B
2-(3'-methyl-biphenyl-2-yl)-l-morpholin-2-yl-l-phenyl-ethanol, RT (6 min gradient) 3.45 min, [M+H]+ 374.4
Example 32B
2-(3',5'-dichloro-biphenyl-2-yl)-l-morpholin-2-yl- 1-phenyl-ethanol, RT (6 min gradient) 3.71 min, [M+H]+ 428.3
Example 33B 2-(2', 4 '-dimethyl -biphenyl-2-yl)-l-morpholin-2-yl- 1-phenyl-ethanol, RT (6 min gradient)
3.59 min, [M+H]+ 388.4
Example 34B
2-(2',4'-dimethoxy-biphenyl-2-yl)-l-morpholin-2-yl- 1-phenyl-ethanol, RT (6 min gradient) 3.33 min, [M+H]+ 420.4
Example 35B l-morpholin-2-yl-l-phenyl-2-(2-pyridin-3-yl-phenyl)-ethanol, RT (6 min gradient) 2.17 min, [M+H]+ 361.4
Example 36B l-morpholin-2-yl-l-phenyl-2-(2-thiophen-3-yl-phenyl)-ethanol, 3.25 min, [M+H]+ 366.4
Example 37B 2-(3',4'-dichloro-biphenyl-2-yl)-l-morpholin-2-yl-l-phenyl-ethanol, RT (6 min gradient)
3.56 min, [M+H]+ 428.1 The following examples illustrate compounds of of Formulae (IC) above and methods for their preparation.
General Synthetic Procedures for the preparation of Examples 1C-17C
The numbers included in the following Sections refer to the compounds illustrated in Schemes 2C to 6C herein.
General Procedure IC: Preparation of racemic IV-substituted aryl thiols
To a solution of 5Ca,5Cb (0.02 g, 0.52 mmol) and the requisite aryl thiol (1.1 eq) in anhydrous dimethylformamide (1 ml) at room temperature under nitrogen was added cesium carbonate (1.1 eq, 0.19 g, 0.57 mmol). The reaction mixture was heated to 95°C for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, then washed sequentially with water, brine, dried over magnesium sulphate and finally concentrated in vacuo.
General Procedure 2Ca : Deprotection of iV-substituted aryl thiols
To a solution of the requisite N-benzyl aryl thiol in anhydrous dichloromethane (5ml) was added solid supported Hunig's base (Argonaut, 3.56 mmol/g, 2 eq) and α- chloroethyl chloroformate (3 to 10 eq) at room temperature under nitrogen. The reaction mixture was heated to 40°C and followed by LCMS analysis. After completion the reaction mixture was filtered, and the resin washed with dichloromethane. The combined organic phases were concentrated in vacuo. Methanol (HPLC grade, 25 ml) was added and the solution heated to 60°C for 1.5 to 4 hours. After complete consumption of starting material the methanol solution was evaporated to give a solid which was further purified as detailed for individual compounds. General Procedure 2Cb : Deprotection of JV-substituted aryl thiols
To a solution of the requisite N-benzyl aryl thiol (1 eq) in ethyl acetate at room temperature was added phenylchloroformate (3 eq). The mixture was warmed under reflux for 2 hours. The mixture was then cooled to room temperature and 30% ΝaOH with water was added over 1 hour. The biphasic system was stirred for 1.5 hours at room temperature and the organic layer was separated. The organic layer was washed with water, dried over MgSO , filtered and rinsed with ethyl acetate.
To the mixture of carbamate and benzylchloride in ethyl acetate was added 5.6M dimethylamine in ethanol. The solution was warmed under reflux (70-72°C) for 2 hours.
After cooling at room temperature, water and 12Ν HCI were added and the mixture was stirred for 10 minutes. The layers were separated and the organic phase was washed twice with water. Then the organic layer was concentrated (T=50°C) until crystallization.
MeOH was added and approx. 40% of solvent was then removed under reduce pressure, this operation was repeated. The heterogeneous mixture was stirred for 0.5 hours at room temperature and filtered. The precipitate was washed twice with MeOH and dried under reduce pressure at 40°C to yield the carbamate.
To a biphasic mixture of 30% NaOH and isopropanol warmed to 65°C, was added the carbamate. The heterogeneous mixture was warmed under reflux for 4 hours and then cooled to room temperature and post-agitated overnight. The organic layer was concentrated under reduce pressure and the yellow solid obtained was added to a mixture of AcOEt and IN NaOH. After separation of the layers, the organic one was washed with IN NaOH. The aqueous layers were combined and extracted with AcOEt. The combined organic layers were dried over MgSO4, filtered and concentrated under reduce pressure to dryness to obtain the free amine.
General Procedure 3C: Conversion of amines into hydrochloride salts
To a solution of the requisite amine in dry diethyl ether (1 ml) was added hydrochloric acid (500 μl of a IM solution in diethyl ether). A white precipitate immediately formed. The suspension was then sonicated for 5 minutes. Ether was blown off with a stream of nitrogen and the samples were dried under high vacuum for several hours to give the hydrochloride salts in near quantitative yield as white solids.
General Procedure 4C: Aldoladdition with substituted benzaldehydes
Preparation of 38Ca,38Cb; 39Ca,39Cb; 40Ca,40Cb
N-Benzylmorpholinone (1.0 eq) and the requisite aldehyde (1.1 eq) were dissolved in anhydrous tetrahydrofuran (25 ml) under nitrogen and the reaction cooled to -78°C. Then, lithium diisopropylamide (1.1 eq of a 2M solution in heptane/tetrahydrofuran/ethylbenzene) was added over approximately 20 minutes, whilst maintaining the reaction temperature below -78°C. The resulting yellow solution was stirred at -78°C for 1 hour and then allowed to warm to room temperature. The reaction was quenched with saturated ammonium chloride solution (25 ml) and extracted into ethyl acetate. The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo, to give a yellow oil which was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 70/100 [v/v]).
General Procedure 5C: Reduction of substituted aldol adducts Preparation of 41Ca,41Cb; 42Ca,42Cb; 43Ca,43Cb To a solution of the requisite amide 38Ca,38Cb, 39Ca,39Cb or 40Ca,40Cb (1.1 mmol) in anhydrous tetrahydrofuran under nitrogen at room temperature was slowly added borane (4 eq of a IM solution in tetrahydrofuran). The solution was stirred at 60°C for 2 hours. The reaction was cooled to room temperature; dry methanol (excess) was slowly added, followed by aqueous hydrochloric acid solution (IM, excess). The reaction mixture was heated to 60°C for 1 hour and quenched with aqueous potassium carbonate solution (IM, excess) and extracted with diethyl ether. The combined organic layers were washed with brine, dried with magnesium sulphate, filtered and concentrated in vacuo yielding a yellow oil which was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 10/100 [v/v]). Preparation of intermediates for the synthesis of Examples
1C-17C 4-Benzylmorpholin-3-one (2C)
Figure imgf000172_0001
A solution of N-benzyl-N-(2-hydroxyethyl) chloroacetamide (627.7 g, 2.76 mol) in tert-butanol (0.9 1) was stirred under nitrogen while warming to 25-30°C. Potassium tert-butoxide (2.897 1 of a IM solution in tert-butanol, 2.90 mol, 1.05 eq) was added over 2 hours. The reaction mixture was then stirred at room temperature for 90 minutes. Ice- cold water (6 1) was added and the resultant cloudy solution extracted with ethyl acetate.
The combined organic layers were washed with brine, dried over magnesium sulphate and evaporated in vacuo to give a light brown oil (441 g, 84%), which was used in the next stage without further purification; MW 191.23; CπH13ΝO2; 1H NMR (CDC13): 7.29- 7.40 (5H, m), 4.67 (2H, s), 4.28 (2H, s), 3.87 (2H, t, 5 Hz), 3.31 (2H, t, 5 Hz); LCMS: (12 min method) m/z 192 [M+H]+ @ Rt 1.00 min.
(2S)-(4-Benzyl-morpholin-2-yl)-phenyl-methanone (3Ca) and (2R)-(4-Benzyl- morpholin-2-yl)-phenyl-methanone (3Cb)
Figure imgf000172_0002
Described above under the "Synthesis of Intermediates" section for compounds of
Formula (IB).
(5)-Phenyl[(25)-4-(phenylmethyl)morpholin-2-yl]methanol (4Ca)
Figure imgf000173_0001
To a stirred solution of [(-)-B-chlorodisopinocampheylborane] (45 g, 140 mmol) in dry tetrahydrofuran (300 ml) under nitrogen was added 3Ca (7.97 g, 28.4 mmol) in one portion. The reaction mixture was stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and extracted from 2M aqueous sodium hydroxide solution into ethyl acetate. The combined organic extracts were washed with brine, dried, filtered and evaporated. The crude product was taken up in chloroform methanol (1:1 [v/v]) and absorbed onto 150g SCX-2 ion exchange resin. After elution of borane residues with methanol the product was eluted with 2M ammonia in methanol. Removal of solvent in vacuo yielded the product as yellow oil. This was further purified by flash chromatography (eluent: ethyl acetate/isohexane 80/20 [v/v]). After removal of solvents, the product crystallised on standing (6.73g, 84%); MW 283.37; C18H21NO2; 1H NMR (CDC13): 7.32-7.45 (10H, m), 4.67 (IH, d, 7 Hz), 4.03 (IH, dt, 11 Hz and 2 Hz), 3.86- 3.73 (2H, m), 3.64 (IH, d, 13 Hz), 3.39 (IH, d, 13 Hz), 3.30 (IH, br, s), 2.68 (IH, d, 12 Hz), 2.56 (IH, d, 10 Hz), 2.28-2.15 (2H, m); LCMS: m/z 284 [M+H]+ @ Rt 0.95 min.
(2S)-2-[(R)-bromo(phenyl)methyl]-4-(phenyImethyI)morpholine (5Ca)
Figure imgf000173_0002
To a solution of 4Ca (4.71 g, 16.6 mmol) in anhydrous chloroform (200 ml) under nitrogen was added triphenylphosphine dibromide (14.04 g, 33.26 mmol). The reaction mixture was heated at 60°C overnight. The mixture was allowed to cool to room temperature then washed with saturated aqueous sodium carbonate solution, dried over sodium sulphate and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica (eluent: ethyl acetate/isohexane gradient 10/90 to 30/70 [v/v]) to give 5Ca as a white solid (4.63 g, 81%); MW 346.27; C18H20BrNO; 1H NMR (CDC13): 7.14-7.39 (10H, m), 4.83 (IH, d, 7 Hz), 4.01 (IH, br, t, 8 Hz), 3.73 (IH, br, d, 11 Hz), 3.60-3.48 (2H, m), 3.39 (IH, d, 12 Hz), 3.20 (IH, d, 11 Hz), 2.50 (IH, d, 10 Hz), 2.07 (2H, t, 10 Hz); LCMS: (6 min method) m/z 346 [M]+ @ Rt 2.51 min.
(25)-2-[(S)-Hydroxy(phenyl)methyl]-4-(phenyImethyl)morpholin-3-one (6Ca) and (2S)-2-[(R)-Hydroxy(phenyl)methyl]-4-(phenylmethyl)morpholin-3-one (6Cb) and (2R)-2-[(S)-Hydroxy(phenyl)methyl]-4-(phenylmethyl)morpholin-3-one (6Cc) and (2R)-2-[(R)-Hydroxy(phenyl)methyl]-4-(phenylmethyl)morpholin-3-one (6Cd)
Figure imgf000174_0001
To a stirred solution of 2C (5.02 g, 26 mmol) in anhydrous tetrahydrofuran (25 ml) under nitrogen at -78°C was added lithium diisopropylamide (1.5 eq, 39 mmol, 19.5 ml of a 2M solution in heptane/tetrahydrofuran/ethylbenzene) over approximately 20 minutes, whilst maintaining the reaction temperature below -75°C. The resulting brown solution was stirred for a further 30 minutes at -78°C, before being added over approximately 30 minutes to a solution of benzaldehyde (1.2 eq, 3.29 g, 31 mmol) in anhydrous tetrahydrofuran (15 ml) under nitrogen at -78°C, whilst again maintaining the reaction temperature below -75°C. The resulting yellow solution was stirred at -78°C for 1 hour, before being allowed to warm to room temperature slowly over 1 hour. The reaction mixture was cautiously quenched by addition of saturated ammonium chloride solution (50 ml) and the tetrahydrofuran was evaporated in vacuo. The resulting cloudy aqueous solution was extracted with dichloromethane, and the organic extracts were combined, washed with brine, dried over sodium sulphate and the dichloromethane evaporated in vacuo to give a thick brown oil (9.2 g), which partially crystallised on standing. After purification by flash column chromatography (eluent: ethyl acetate/dichloromethane ,10/90 to 20/80 gradient [v/v]) 6Ca,6Cb was obtained as light red crystals (2.46 g, 32%); MW 297.36; C18H19NO3; 1H NMR (CDC13): 7.36-7.41 (2H, m), 7.16-7.31 (6H, m), 6.86- 6.91 (2H, m), 5.14 (IH, d, I 3 Hz), 4.71 (IH ,d, 14 Hz), 4.48 (IH, d, J 3 Hz), 4.25 (IH, d, 14 Hz), 4.20 (IH, br, s), 3.89 (IH, ddd, 12 Hz, 3 Hz, 2 Hz), 3.67 (IH, dt, 11 Hz, 3 Hz), 3.16 (IH, dt, 12 Hz and 4 Hz), 2.86 (IH, br, d, 12 Hz); LCMS: m/z 298 [M+H]+ @ Rt 1.24 min. 6Cc, 6Cd was isolated as a brown solid (1.42 g) contaminated with 2C.
Trituration with ethyl acetate afforded pure 6Cc,6Cd as a white solid (0.484 g, 6%); MW 297.36; C18H19NO3; 1H NMR (CDC13): 7.55-7.61 (2H, m), 7.36-7.50 (6H, m), 7.25-7.31 (2H, m), 5.21 (IH, d, 2 Hz), 5.09 (IH, d, J 7 Hz and 2 Hz), 4.73 (2H, s), 4.37 (IH, d, J 8 Hz), 4.01 (IH, ddd, 12 Hz, 3 Hz, 2 Hz), 3.77 (IH, dt, 11 Hz, 4 Hz), 3.50 (IH, dt, 12 Hz, 4 Hz), 3.16 (IH, br, d, 12 Hz); LCMS: m/z 298 [M+H]+ @ Rt 1.24 min.
(S)-Phenyl[(25)-4-(phenylmethyl)morpholin-2-yl]methanol (4Ca) and
(R)-Phenyl[(2R)-4-(phenyImethyl)morphoIin-2-yl]methanol (4Cb)
Figure imgf000175_0001
To a solution of 6Ca,6Cb (0.033 g, 1.1 mmol) in anhydrous THF (5 ml) under nitrogen at room temperature was slowly added borane (4 eq, 4.4 ml of a IM solution in tetrahydrofuran, 4.4 mmol). The solution was stirred at 60°C for 2 hours. After cooling down to room temperature, dry methanol (2 ml) was slowly added to quench excess borane reagent. After addition of aqueous hydrochloric acid solution (2 ml of a IM solution) the reaction mixture was heated to 60°C for 1 hour. The organic solvents were evaporated in vacuo and the concentrated solution was poured onto aqueous potassium carbonate solution (10 ml of a IM solution) and extracted with diethyl ether (2 x 20 ml). The combined organic layers were washed with brine, water, dried over magnesium sulphate and concentrated in vacuo. Purification by flash column chromatography (eluent: hexane/ethyl acetate/triethylamine 90/9/1 [v/v/v]) gave a viscous oil (0.19 g, 60%); MW 283.37; C18H21NO2; 1H NMR (CDC13): 7.45-7.32 (10H, m), 4.67 (IH, d, 7 Hz), 4.03 (1H, dt, 11 Hz, 2.7 Hz), 3.86-3.73 (2H, m), 3.64 (IH, d, 13 Hz), 3.39 (IH, d, 13 Hz), 3.30 (IH, br, s), 2.68 (IH, d, 13 Hz), 2.56 (IH, d, 11 Hz), 2.28-2.15 (2H, m); LCMS: m/z 284 [M+H]+ @ Rt 0.95 min.
(R)-[(2S)-4-Benzylmorpholinyl](phenyI)methanol (4Cc) and (5)-[(2R)-4-Benzylmorpholinyl](phenyl)methanoI (4Cd)
Figure imgf000176_0001
Using the procedure described for the preparation of 4Ca,4Cb starting from 6Cc,6Cd (0.14 g, 0.45 mmol) 4Cc,4Cd was obtained as a viscous oil (0.098 g, 68%);
MW 283.37; C18H21NO2; 1H NMR (CDC13): 7.17-7.28 (10H, m), 4.80 (IH, d, 4 Hz), 3.88 (IH, dt, 11 Hz, 3 Hz), 3.72 (IH, m), 3.61-3.68 (IH, m), 3.50 (IH, d, 13 Hz), 3.25 (IH, d, 13 Hz), 2.52 (2H, br, t, 12 Hz), 2.17 (IH, t, 11 Hz), 2.08 (IH, td, 11 Hz, 3 Hz); LCMS: m/z 284 [M+H]+ @ Rt 0.98 min.
(25)-2-[(R)-Bromo(phenyI)methyl]-4-(phenylmethyl)morphoIine (5Ca) and
(2R)-2-[(S)-Bromo(phenyl)methyl]-4-(phenylmethyl)morphoIine (5Cb)
Figure imgf000176_0002
To a solution of 4Ca,4Cb (10.27 g, 36.29 mmol) in anhydrous dichloromethane
(150 ml) under nitrogen at room temperature was added freshly recrystallised triphenylphosphine (13.32 g, 50.80 mmol, 1.4 eq) followed by carbon tetrabromide (16.85 g, 50.8 mmol, 1.4 eq) as a solution in anhydrous dichloromethane (50 ml). After 15 minutes the reaction mixture was diluted with dichloromethane (100 ml) and washed with saturated aqueous solution of sodium hydrogencarbonate, brine, dried over magnesium sulphate and concentrated in vacuo to give an orange oil (42.0 g). To the orange oil was added diethyl ether (200 ml) and the resulting suspension was sonicated for 30 minutes. The solvent was decanted and the process repeated with a further portion of diethyl ether. The combined organic extracts were concentrated in vacuo to yield an orange solid (22.0 g) which was purified by flash column chromatography (eluent: ethyl acetate/hexane/triethylamine 10/89.5/0.5 [v/v/v]) 5Ca,5Cb was otained as a white solid (7.20 g, 57%). Alternative Work-up: The reaction mixture was poured onto a silica (160 g) filtration pad which was washed with dichloromethane (14 x 250 ml). After removal of solvents in vacuo and purification by flash column chromatography (eluent: ethyl acetate/hexane/triethylamine gradient 5/94.5/0.5 to 10/89.5/0.5 [v/v/v]) to give a white solid (6.05 g, 48%); MW 346.27; C18H20BrNO; 1H NMR (CDC13): 7.14-7.39 (10H, m), 4.83 (IH, d, 7 Hz), 4.01 (IH, br, t, 8 Hz), 3.73 (IH, br, d, 11 Hz), 3.48-3.60 (2H, m), 3.39 (IH, d, 12 Hz), 3.20 (IH, d, 11 Hz), 2.50 (IH, d, 10 Hz), 2.07 (2H, t, 11 Hz); LCMS: m/z 348/346 [M+H]+ @ Rt 1.20 min.
4- [ (IR) -1-Phenylethyl] morpholine- (2S) -carbonitrile (47Ca) and 4- [ ( IR) -1-Phenylethyl] morpholine- (2R) -carbonitrile (47Cb)
Figure imgf000177_0001
To (R)-(-)-2-hydroxyethyl- -phenethylamine (1.65 g, 10.0 mmol) in diethyl ether (10ml) was added at room temperature 2-chloroacrylonitrile (0.80 ml, 10.0 mmol) with stirring. The mixture was stirred at room temperature for 4.5 days when additional 2- chloroacrylonitrile (0.8 ml, 10.0 mmol) was added. After stirring another 3.5 days, the reaction mixture was concentrated in vacuo to give an oil. The oil was dissolved in dry tetrahydrofuran (30 ml), cooled under nitrogen to 0°C and potassium tert-butoxide (1.23 g, 11.0 mmol) added. The solution was stirred at 0°C for 2 hours then at reflux for 1.5 hours, cooled, diluted with diethyl ether and washed with aqueous saturated sodium bicarbonate. The organic phase was extracted with 2N hydrochloric acid and the aqueous made basic by addition of solid sodium bicarbonate and extracted with diethyl ether. The organic phase was dried over magnesium sulphate, filtered and evaporated to a brown oil. The crude product was purified by flash chromatography (eluent: ethyl acetate/hexane gradient 100%; ethyl acetate to 50/50 [v/v]) to give 47Ca,47Cb as a colourless oil (0.58g, 27%%); MW 216.29; C13H16N2O; 1H NMR (CDC13) 7.25-7.38 (5H, m), 4.6 (IH, dd), 4.54 (IH, dd), 3.91-4.06 (2H, m), 3.66-3.82 (2H, m), 3.39-3.49 (2H, m), 2.30 -2. 89 (4H, m), 1.39 (3H, d). m/z [M+H]+ 217.
Phenyl{(25)-4-[(lΛ)-l-phenylethyI]morpholin-2-yI}methanone (48Ca) and
Phenyl{(2R)-4-[(lR)-l-phenylethyl]morpholin-2-yl}methanone (48Cb)
Figure imgf000178_0001
To a stirred solution of 47Ca,47Cb (0.57 g, 2.64 mmol) in dry tetrahydrofurane (10 ml) at 0°C under nitrogen was added a solution of phenylmagnesium chloride in tetrahydrofurane (2.0 M, 2.67 ml) dropwise over 2 minutes. The pale yellow solution was stirred at 0°C for 30 minutes and then allowed to warm to room temperature. After 2 hours the mixture was cooled, quenched with 2M hydrochloric acid and was stirred vigorously for 1 hour at room temperature. After addition of water and extraction with ethyl acetate, the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and evaporated to give an oil (0.63 g). After purification by column chromatography (eluent: ethyl acetate/hexane gradient 0/100 to 20/80 [v/v]) 48Ca was obtained as an oil (0.15 g, 19%%); MW 295.38; C19H21NO2; 1H NMR (CDC13) 8.00 (2H, d), 7.60 (IH, t), 7.50 (2H, t), 7.20-7.35 (5H, m), 4.96 (IH, d), 3.93-4.00 (IH, m), 3.70- 3.80 (IH, m), 3.41 (IH, q), 3.25 (IH, br, d), 2.59 (IH, br, d), 2.13 -2. 36 (2H, m), 1.38 (3H, d). m/z [M+H]+ 296 followed by 48Cb as an oil (0.27 g, 35%%) 1H NMR (CDC13) 7.90 (2H, d), 7.54 (IH, t), 7.45 (2H, t), 7.20-7.38 (5H, m), 4.85 (IH, d), 4.05-4.12 (IH, m), 3.80-3.92 (IH, m), 3.43 (IH, q), 2.86-3.00 (2H, m), 2.29-2.40 (IH, m), 2.21 (IH, t), 1.38 (3H, d). m/z [M+H]+ 296.
(R)-Phenyl{(25)-4-[(lR)-l-phenylethyl]morpholin-2-yl}methanol (50C)
Figure imgf000179_0001
To a stirred solution of 48Ca (0.08 g, 0.26 mmol) and triphenylsilane (0.34 g, 1.31 mmol) in dichloromethane (4 ml) cooled to 0°C was added boron trifluoride etherate (0.09 g, 0.66 mmol) followed by trifluoroacetic acid (0.36 ml, 63 mmol). The reaction mixture was allowed to warm to room temperature and diluted after three hours with dichloromethane (20 ml) and neutralised with aqueous sodium bicarbonate. The organic phase was dried over magnesium sulphate, filtered and evaporated to give the required product. This was purified as its hydrochloric acid salt crystallising from isopropanol and diethyl ether (0.05 g, 69%%); MW 297.4; C19H23NO2; 1H NMR (CDC13) on free base 7.08-7.29 (10H, m), 4.78 (IH, d), 3.90-4.00 (IH, m), 3.57-3.68 (2H, m), 3.33 (IH, q),
2.53-2.64 (IH, m), 2.37-2.47 (IH, m), 2.09-2.26 (2H, m), 1.29 (3H, d). m/z [M+H]+ 298.
(R)-Phenyl{(2S)-4-[(lR)-l-phenylethyl]morpholin-2-yl}methyl methanesulphonate
(51C)
Figure imgf000179_0002
To a solution of 50C (0.05 g, 0.17 mmol) in dichloromethane (1 ml) at room temperature was added polymer supported Hunig's base ((Argonaut, 3.56 mmol/g, 0.089 g, 0.32 mmol, 1.9 eq) and methanesulphonyl chloride (0.02 g, 0.19 mmol). The mixture was stirred under nitrogen for 6 hours then filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (eluent: ethyl acetate/heptane 33/67 [v/v]) to give 51C as a colourless oil (0.035 g, 55%%); MW 375.49; C20H25NO4S 1H NMR (CDC13) 7.20-7.35 (10H, m), 5.46 (IH, d), 3.79-3.88 (2H, m), 3.59 (lH,td), 3.4 (IH, q), 2.68-2.78 (2H, m), 2.68 (3H, s), 2.03-2.24 (2H, m), 1.34 (3H, d). m/z [M+H]+ 376.
(2S)-4-[(lR)-l-Phenylethyl]-2-((S)-phenyl{[2- (trifluoromethyl)phenyl]thio}methyl)morpholine (52C)
Figure imgf000180_0001
A mixture of 51C (0.035 g, 0.093 mmol), potassium carbonate (0.026 g, 0.19 mmol) and 2-trifluoromethylbenzenethiol (0.084 g, 0.47 mmol) in dry, degassed dimethylformamide (0.5 ml) was stirred under nitrogen at room temperature for 3 days. The reaction mixture was diluted with water and extracted with diethyl ether. The extracts was washed with water and brine, dried over magnesium sulphate, filtered and evaporated to give a colourless oil (0.03 g, 71%). Purification by flash column chromatography
(eluent: ethyl acetate/heptane 20/80 [v/v]) gave 52C as a colourless oil (0.03 g, 71%); MW 457.56; C26H26F3NOS 1H NMR (CDC13) 7.53 (IH, d), 7.10-7.28 (13H, m), 4.39 (IH, d), 3.85-4.04 (2H, m), 3.8 (IH, td), 3.35 (IH, q), 2.70 (IH, d), 2.40 (IH, d), 2.30 (IH, td), 2.10-2.20 (IH, m), 1.29 (3H, d). m/z [M+H]+458.
Example IC: (2S)-2-((S)-PhenvUr2-(trifluoromethyl)phenvπ thiolmethyD morpholine (9C)
(5)-Phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl 2-trifluoromethyl)phenyl sulfide (8C)
Figure imgf000181_0001
Compound 8C was obtained from 5Ca (4.00 g, 11.55 mmol), 2-trifluoromethyl thiophenol (2.47 g, 13.86 mmol, 1.2 eq) and caesium carbonate (4.95 g, 15.24 mmol, 1.1 eq) in dimethylformamide (60 ml) as a brown oil following a modification of General Procedure IC in which the reaction was carried out over 1 hour (6.04 g). The oil was purified by flash column chromatography (eluent: hexane/ethyl acetate gradient 100 to 90/10 [v/v]) to give a yellow oil (4.83 g, 94%); MW 443.54; C25H24F3NOS; 1H NMR (CDC13): 7.60 (IH, dd, 7 Hz, 1 Hz), 7.17-7.39 (13H, m), 4.50 (IH, d, 7 Hz), 3.97-4.12 (2H, m), 3.73 (IH, dt, 10 Hz, 2 Hz), 3.59 (IH, d, 13 Hz), 3.37 (IH, d, 13 Hz), 2.57-2.68 (2H, m); 2.18-2.38 (2H, m); LCMS (2.5 minute method): m/z 445 [M+H]+ @ Rt 1.50 min.
(2S)-2-((5)-Phenyl{[2-(trifluoromethyl)phenyl]thio}methyl)morpholine (9C)
Figure imgf000181_0002
Compound 9C (Example IC) was obtained from 8C (5.25 g, 11.84 mmol), solid supported Hunig's base (Argonaut, 3.56 mmol/g, 6.64 g, 23.67 mmol, 2 eq) and α- chloroethyl chloroformate (3.83 ml, 35.51 mmol, 3 eq) in anhydrous dichloromethane (75 ml) following General Procedure 2Ca. After evaporation of solvents a light brown solid (5.60 g) was obtained which was recrystallised from iso-propanol. The solid was suspended in ethyl acetate and washed with an aqueous solution of sodium hydroxide (50 ml of a IM solution). The organic layer was washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield the free amine as a colourless oil (3.10 g, 74%); MW 353.41; C18H18F3NOS; 1H NMR (CDC13): 7.46 (IH, d, 8 Hz), 7.24 (IH, d, 7 Hz), 7.05-7.2 (7H, m), 4.28 (IH, d, 8 Hz), 3.92 (IH, d, 11 Hz), 3.80 (IH, q, 7 Hz), 3.58 (IH, dt, 2 Hz and 11 Hz), 2.69-2.87 (2H, m), 2.59 (2H, d, 6 Hz), 2.13-1.90 (IH, br s); LCMS (10 minute method): m z 354 [M+H]+ @ Rt 5.26 min. The hydrochloride salt of 9 was obtained following General Procedure 3C.
An alternative method for the preparation of compound 9C (Example IC), according to Scheme 6C, is as follows:
To a suspension of polymer supported Hunig's base (0.11 g, 0.40 mmol) and 52C (0.03 g, 0.066 mmol) in dry dichloromethane (1 ml) was added α-chloroethyl chloroformate (0.09 g, 0.066 mmol) at room temperature under nitrogen. The mixture was stirred at room temperature over the weekend then filtered and concentrated in vacuo. This was taken up in methanol, heated at 70°C for 2 hours, cooled, and purified by SCX chromatography (eluent: ammonia/methanol 1/1 [v/v]) to give 9C as a colourless oil (0.01 g, 43%). The spectroscopic data for 9C obtained by the route outlined here was identical to the data for 9C obtained as described above.
Example 2C; (25)-2-((S)-Phenyl{[2-(thiomethyl)phenyllthio]methyl) morpholine no
(2S)-2-[(S)-{[2-(methylthio)phenyl]thio}(phenyl)methyI]-4- (phenylmethyl)morpholine (10C)
Figure imgf000182_0001
Compound 10C was obtained from 5Ca (4.0 g, 11.55 mmol), 2-methylsulphenyl- thiophenol (2.17 g, 13.86 mmol, 1.2 eq) and caesium carbonate (4.42 g, 13.63 mmol, 1.18 eq) in dimethylformamide (35 ml) following a modification of General Procedure IC in which the mixture was heated at 50°C for 1.5 hours, allowed to cool to room temperature, taken up in methanol and treated with SCX-2 (100 g). The SCX-2 was washed with methanol. 10C was obtained as a white solid (4.92 g) after SCX chromatography (eluent: ammonia/methanol 1/1 [v/v]) and removal of solvents in vacuo. Purification by flash column chromatography (eluent: ethyl acetate/isohexane gradient 10/90 to 30/70 [v/v]) gave 10C as a white solid (4.04 g, 83%); MW 421.63; C27H27NOS2; 1H NMR (CDC13): 7.03-7.15 (6H, m), 6.93-6.99 (2H, m), 6.74 (IH, td, 7 Hz, 1 Hz), 4.31 (IH, d, 8 Hz), 3.95 (IH, br, d, 12 Hz), 3.83 (IH, td, 8 Hz, 3.8 Hz), 3.59 (IH, td, 11 Hz and 3 Hz), 2.82 (IH, td, 12 Hz and Hz), 2.61-2.75 (3H, m), 2.35 (3H, s), 1.73 (IH, br, s); LCMS (6 minute method): m/z 422 [M+H]+ @ Rt 3.36 min.
(2S)-2-((S)-Phenyl{[2-(trifluoromethyl)phenyl]thio}methyl)morpholine (llC)
Figure imgf000183_0001
Compound IIC (Example 2C) was obtained from 10C (4.02 g, 9.53 mmol), solid supported Hunig's base (Argonaut, 3.56 mmol/g, 5.02 g, 17.87 mmol, 2 eq) and α- chloroethyl chloroformate (3.09 ml, 28.6 mmol, 3 eq) in anhydrous dichloromethane (75 ml) following General Procedure 2Ca. The mixture was heated at 40°C for 1.5 hours then left to stir at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo to give a pale orange liquid. This was taken up in methanol (70 ml) and heated at 40°C for 2 hours. A white solid crashed out of the solution which was taken up in methanol and purified by SCX chromatography (eluent: ammonia/methanol 1/1 [v/v]). After evaporation in vacuo IIC was obtained as a pale yellow oil (3.13 g, 99%); MW 331.50; C18H21NOS2; 1H NMR (CDC13): 7.03-7.15 (6H, m), 6.93-6.99 (2H, m), 6.74
(IH, td, 7 Hz, 2 Hz), 4.31 (IH, d, 8 Hz), 3.95 (IH, br, d, 12 Hz), 3.83 (IH, td, 8 Hz, 4 Hz), 3.59 (IH, td, 11 Hz, 3 Hz), 2.82 (IH, td, 12 Hz, 3 Hz), 2.61-2.75 (3H, m), 2.35 (3H, s), 1.73 (IH, br, s). Compound IIC was converted into its hydrochloride salt following a modification of General Procedure 3C in which the pale yellow oil was taken up in isopropanol (-200 ml) and filtered. Addition of hydrogen chloride (19 ml of a IM solution in diethyl ether, 19 mmol) gave a white precipitate to which further diethyl ether (-50 ml) was added. The solid was isolated by filtration and washed with diethyl ether to give the hydrochloride salt of IIC as a white solid (3.03 g, 78%); MW 367.96; C18H22ClNOS2; 1H NMR (CDC13): 9.94 (2H, br, s), 7.06-7.18 (6H, m), 6.94-7.03 (2H, m), 6.78 (IH, t, 7 Hz), 4.24-4.32 (IH, m), 4.20 (IH, d, 6 Hz), 3.89-4.06 (2H, m), 3.18 (2H, br, t, 12 Hz), 2.99 (2H, br, s), 2.37 (3H, s); LCMS (10 minute method): m/z 332 [M- HC1]+ @ Rt 5.07 min.
Example 3C : ( 2S) -2 - [ (S) - { [2 - ( 1 - methyl ethyl ) phenyl] thio) (phenyl ) methylmorpholine ( 13C) (25)-2-[(S)-{[2-(l-methylethyl)phenyl]thio}(phenyl)methyl]-4- (phenylmethyl)morpholine (12C)
Figure imgf000184_0001
Compound 12C was obtained from 5Ca (4.04 g, 11.66 mmol), 2- isopropylsulphenyl-thiophenol (2.35 ml, 14 mmol, 1.2 eq) and caesium carbonate (4.56 g, 14 mmol, 1.2 eq) in dimethylformamide (35 ml) following a modification of General Procedure IC in which the mixture was heated at 90°C for 20 minutes, allowed to cool to room temperature, taken up in ethyl acetate (50 ml), washed with water and brine, dried over sodium sulphate, filtered and reduced in vacuo to give a yellow oil which was purified by SCX chromatography (eluent: ammonia/methanol 1/1 [v/v]). Removal of solvents in vacuo gave 12C as a white solid (4.45, 91%); MW 417.62; C27H31NOS; 1H NMR (CDC13): 7.14-7.26 (7H, m), 7.03-7.1 (6H, m), 6.86-6.92 (IH, m), 4.10 (IH, d, 8
Hz), 3.88-3.94 (2H, m), 3.62 (IH, td, 11 Hz, 2 Hz), 3.37-3.47 (2H, m), 3.22 (IH, d, 13 Hz), 2.50 (2H, d, 11 Hz), 2.12-2.29 (2H, m), 1.05 (3H, d, 7 Hz), 0.92 (3H, d, 7 Hz); LCMS (6 minute method): m/z 418 [M+H]+ @ Rt 3.72 min.
(25)-2-[(S)-{[2-(l-methylethyl)phenyl]thio}(phenyl)methyl]morpholine (13C)
Figure imgf000185_0001
Compound 13C (Example 3C) was obtained from 12C (4.44 g, 10.65 mmol), solid supported Hunig's base (Argonaut, 3.56 mmol/g, 6.05 g, 21.54 mmol, 2 eq) and α- chloroethyl chloroformate (3.30 ml, 32.0 mmol, 3 eq) in anhydrous dichloromethane (50 ml) following General Procedure 2Ca. The mixture was heated at 40°C for 1.5 hours then left to stir at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo to give a pale yellow liquid. This was taken up in methanol (50 ml) and heated at 60°C for 1.5 hours. The reaction mixture was allowed to cool to room temperature and purified by SCX chromatography (eluent: ammonia/methanol 1/1 [v/v]) to give 13C as a pale yellow oil; MW 327.49; C20H25NOS; 1H NMR (CDC13): 7.22 (IH, d, 8 Hz), 7.03-7.13 (7H, m), 6.87-6.92 (IH, m), 4.04 (IH, d, 8 Hz), 3.94-3.99 (IH, m), 3.79 (IH, td, 9 Hz, 3 Hz), 3.61 (IH, td, 11 Hz, 3 Hz), 3.41 (IH, sept, 7 Hz), 2.82 (IH, td, 12 Hz and 3 Hz), 2.72 (IH, br, d, 12 Hz), 2.52-2.63 (2H, m), 1.70 (IH, br, s), 1.05 (3H, d, 7 Hz), 0.91 (3H, d, 7 Hz). Compound 13C was converted into its hydrochloride salt following a modification of General Procedure 3C in which the pale yellow oil was taken up in ether (50 ml), and filtered. Addition of hydrogen chloride in dry diethyl ether (19 ml of a IM solution in diethyl ether) gave a white precipitate to which further diethyl ether (50 ml) was added. The reaction mixture was concentrated and the residue washed with diethyl ether to give a white solid (2.76 g, 69% overall yield from 5Ca); MW 363.95; C20H25NOS.HC1; 1H NMR (CDC13): 9.91 (2H, br, s), 7.05-7.22 (7H, m), 6.91-
6.96 (2H, m), 4.23-4.31 (IH, m), 4.08-3.90 (3H, m), 3.31-3.41 (IH, m), 3.04-3.21 (2H, br, m), 2.91-2.99 (2H, br, m), 1.06 (3H, d, 7 Hz), 0.93 (3H, d, 7 Hz); LCMS (10 minute method): m/z 327 [M-HC1]+ @ Rt 5.7 min. Example 4C: ( 2S) -2- [ ( S) - ( [1, 1 ' -Biphenyl] -2- ylthio) (phenyl) methyl] orpholine (15C) (25)-2-[(5)-([l,l'-Biphenyl]-2-ylthio)(phenyI)methyl]-4-(phenylmethyl)morpholine (14C)
Figure imgf000186_0001
Compound 14C was obtained from 5Ca (2.16 g, 6.24 mmol), 2-phenylsulphenyl- thiophenol (2.35 ml, 14 mmol, 1.2 eq) and caesium carbonate (2.43 g, 7.5 mmol, 1.2 eq) in dimethylformamide (50 ml) following a modification of General Procedure IC in which the mixture was heated at 90°C for 20 minutes, allowed to cool to room temperature, taken up in ethyl acetate (50 ml), washed with water and brine, dried over sodium sulphate, filtered and reduced in vacuo to give a yellow oil. Purification by SCX- chromatography (eluent: ammonia/methanol 1/1 [v/v]) followed by evaporation in vacuo gave 14C as a white solid (0.59 g, 90%); MW 451.64; C30H29NOS; 1H NMR (CDC13): 6.93-7.34 (19H, m), 3.92 (IH, br, d, 6 Hz), 3.63-3.76 (2H, m), 3.45 (IH, t, 10 Hz), 3.33
(IH, d, 13 Hz), 3.17 (IH, d, 12 Hz), 2.39 (IH, d, 12 Hz), 2.20 (IH, d, 11 Hz), 1.97-2.07 (IH, m), 1.82-1.92 (IH, m); LCMS (6 minute method): m/z 452 [M+H]+ @ Rt 3.69 min.
(25)-2-[(5)-([l,l'-Biphenyl]-2-ylthio)(phenyI)methyl]morpholine (15C)
Figure imgf000186_0002
Compound 15C (Example 4C) was obtained from 14C (2.95 g, 6.54 mmol), solid supported Hunig's base (Argonaut, 3.56 mmol/g, 13.06 g, 21.54 mmol, 2 eq) and α- chloroethyl chloroformate (2.0 ml, 19.6 mmol, 3 eq) in anhydrous dichloromethane (50 ml) following General Procedure 2Ca. The reaction mixture was concentrated in vacuo to give a pale yellow liquid. This was taken up in methanol (70 ml) and heated at 40°C for
2 hours. A white solid crashed out of the solution which was taken up in methanol and purified by SCX-chromatography (eluent: ammonia/methanol 1/1 [v/v]). After removal of solvents in vacuo 15C was obtained as a pale yellow oil; MW 361.51; C23H23NOS; 1H NMR (CDC13): 7.0-7.45 (14H, m), 3.95 (IH, d, 8 Hz), 3.65-3.85 (2H, m), 3.35 (IH, d, 12 Hz), 3.2 (IH, d, 12 Hz), 2.45 (IH, d, 10 Hz), 2.20 (IH, d, 10 Hz), 2.0-2.15 (IH, m), 1.8-
2.0 (IH, m); LCMS (12 minute method): m/z 363 [M+H]+ @ Rt 3.00 min. 15C was converted into its hydrochloride salt following a modification of General Procedure 3C in which the pale yellow oil was taken up in isopropanol (-200 ml), and filtered. Addition of hydrogen chloride (19 ml of a IM solution in diethyl ether) gave a white precipitate to which further diethyl ether (-50 ml) was added. The solid was isolated by filtration and washed with diethyl ether to give the hydrochloride salt of 15C as a white solid (1.95 g, 75% overall yield from 5Ca); MW 397.97; C23H23NOS.HCl; 1H NMR (CDCI3): 9.80 (2H, br, s), 7.38-7.03 (12H, m), 6.90-6.96 (2H, m), 3.85-4.00 (2H, m), 3.72-3.82 (IH, m), 3.66 (IH, d, 5 Hz), 2.98-3.10 (IH, m), 2.81 (IH, br, s), 2.62 (2H, br, s); LCMS (12 minute method): m/z 362 [M+H]+ @ Rt 2.99 min.
Example 5C : (25) -2 - [ (S) - [ (2 - Fluorophenyl ) thio] (phenyl ) methyl] morpholine (17C) (2S)-2-[(S)-[(2-Fluorophenyl)thio](phenyl)methyl]-4-phenylmethyl)morpholine (16Ca) and
(2R)-2-[(R)-[(2-Fluorophenyl)thio](phenyI)methyl]-4-phenylmethyl)morpholine (16Cb)
Figure imgf000188_0001
Compounds 16Ca,16Cb were obtained from 5Ca,5Cb (0.114 g, 0.33 mmol), 2- fluorothiophenol (0.045 g, 0.36 mmol, 1.2 eq) and caesium carbonate (0.12 g, 0.36 mmol, 1.2 eq) in dimethylformamide (50 ml) following General Procedure IC as a pale yellow oil (0.14 g, 65%); MW 393.53; C24H24FNOS; 1H NMR (CDC13): 7.12-7.36 (12H, m), 6.87-6.99 (2H, m), 4.48 (IH, d, 8 Hz), 4.00-4.11 (2H, m), 3.77 (IH, td, 11 Hz, 2 Hz), 3.60 (IH, d, 13 Hz), 3.37 (IH, d, 13 Hz); 2.63 (2H, t, 10 Hz), 2.16-2.31 (2H, m); LCMS (2.5 minute method): m/z 394 [M+H]+ @ Rt 1.41 min.
(2S)-2-[(S)-[(2-Fluorophenyl)thio](phenyl)methyl]morpholine (17C)
Figure imgf000188_0002
Compound 17C (Example 5C) was obtained from 16Ca,16Cb (0.72 g, 0.18 mmol), solid supported Hunig's base (Argonaut, 3.56 mmol/g, 2.0 g, 0.56 mmol, 3 eq) and α-chloroethyl chloroformate (0.62 ml, 0.56 mmol, 3 eq) in anhydrous dichloromethane (5 ml) following General Procedure 2Ca as a viscous yellow oil (0.046 g, 82%) from which 17C was obtained as a single isomer after separation by chiral HPLC (0.016 g); Chiral LC (AD): 10.83 min. LC purity = 91% (UV254nm) / 98% (ELS); LCMS (10 minute method): m/z 304 [M+H]+ @ Rt 5.82 min; HPLC purity = 84% (UV215nm) / 98% (ELS); MW 303.41; C17H18FNOS; 1H NMR (CDC13): 7.13-7.00 (7H, m), 6.87-6.76 (2H, m), 4.29 (IH, d, 9 Hz), 3.98-3.93, (IH, m), 3.78 (IH, td, 9 Hz and 4
Hz), 3.60 (IH, td, 11 Hz and 3 Hz), 2.82 (IH, td, 12 Hz, 3 Hz), 2.76-2.70 (IH, m), 2.57- 2.53, (2H, m), NH signal not observed; LCMS (10 minute method): m/z 304 [M+H]+ @ Rt 5.84 min; HPLC purity = 100%% (ELS). Compound 17C was converted into its hydrochloride salt following General Procedure 3C.
Example 6C: (2S) -2- [ (g) - [ (2- Ethylphenyl) thio] (phenyl) methyl] morpholine (19C)
(25)-2-[(5)-[(2-Ethylphenyl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine (18Ca) and
(2R)-2-[(R)-[(2-EthyIphenyl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine (18Cb)
Figure imgf000189_0001
Compounds 18Ca,18Cb were obtained from 5Ca,5Cb (0.2 g, 0.58 mmol), 2- ethyl-thiophenol (0.16 g, 1.16 mmol, 2 eq) and caesium carbonate (0.23 g, 0.7 mmol, 1.2 eq) in dimethylformamide (5 ml) following modification of General Procedure IC in which the reaction mixture was heated to 95°C for 2 hours. After purification by flash column chromatography (eluent: ethyl acetate/hexane 9/1 [v/v]) 18Ca,18Cb was obtained as a white solid (0.15 g, 65%%); MW 403.59; C26H29NOS; 1H NMR (CDC13): 6.96-7.40 (14H, m), 4.22 (IH, d, 7 Hz), 3.96-4.01 (2H, m), 3.72 (IH, td, 11 Hz and 2 Hz), 3.52 (IH, d, 13 Hz), 3.32 (IH, d, 13 Hz), 2.68 (2H, q, 8 Hz), 2.59 (2H, br d, 12 Hz), 2.06-2.21 (2H, m), 1.12 (3H, t, 7 Hz); LCMS (2.5 minute method) m/z 404 [M+H]+ @ Rt 1.49 min.
(25)-2-[(5)-[(2-Ethylphenyl)thio](phenyl)methyl]morpholine (19C)
Figure imgf000190_0001
Compound 19C (Example 6C) was obtained from 18Ca,18Cb (0.18 g, 0.52 mmol), solid supported Hunig's base (Argonaut, 3.56 mmol/g, 3.7 g, 1.04 mmol, 2 eq) and α-chloroethyl chloroformate (0.34 ml, 3.12 mmol, 3 eq) in anhydrous dichloromethane (5 ml) following General Procedure 2Ca as a viscous yellow oil (0.21 g, 86%) from which 19C was obtained after separation by chiral HPLC on chiral OD semi-preparative column; chiral LC (OD): 15.95 min. LC purity = 100% (UN254nm) / 100% (ELS); MW 313.47; C19H23ΝOS; 1H NMR (CDC13): 7.17 (IH, d, 8 Hz), 7.12-7.05 (5H, m), 7.01 (2H, d, 4 Hz), 6.87-6.93 (IH, m), 4.07 (IH, d, 8 Hz), 3.92-3.97 (IH, m), 3.74-3.80 (IH, m), 3.59 (IH, td, 11 Hz, 3 Hz), 2.80 (IH, td, 12 Hz and 3 Hz), 2.71 (IH, br, d, 12 Hz), 2.63-2.54 (4H, m), 1.64 (IH, br, s), 1.04 (3H, t, 8 Hz); LCMS (10 minute method): m/z 314 [M+H]+ @ Rt 5.92 min. 19C was converted into its hydrochloride salt following General Procedure 3C; MW 349.93; C19H23NOS.HCl; 1H NMR (CDC13): 10.10 (2H, br, s), 7.13-7.28 (8H, m), 7.02-7.08 (IH, m), 4.36 (IH, br, s), 4.01-4.17 (3H, br, m), 3.16-3.31 (2H, br, m), 2.92-3.09 (2H, br, m), 2.71 (2H, q, 8 Hz), 1.15 (3H, t, 7
Hz).
Example 7C : (25) -2 - [ (5) - { [2 - (Methyloxy) phenyl] thio } (phenyl ) methyl] morpholine (21C) (2S)-2-[(S)-{[2-(MethyIoxy)phenyl]thio}(phenyl)methyI]-4-
(phenylmethyl)morpholine (20Ca) and
(2R)-2-[(R)-{[2-(MethyIoxy)phenyl]thio}(phenyl)methyl]-4- (phenylmethyl)morpholine (20Cb)
Figure imgf000191_0001
Compounds 20Ca,20Cb were obtained from 5Ca,5Cb (0.18 g, 0.52 mmol), 2- methoxy thiophenol (0.074 ml, 0.57 mmol, 1.2 eq) and caesium carbonate (0.17 g, 0.52 mmol, 1.2 eq) in dimethylformamide (5 ml) following modification of General Procedure IC in which the reaction was heated at 95°C for 2.5 hours. After purification by flash column chromatography (eluent: ethyl acetate/hexane gradient 15/85 to 25/75 [v/v]) 20Ca,20Cb was obtained as a viscous yellow oil (0.17 g, 83%); MW 405.56; C25H27NO2S; 1H NMR (CDC13): 7.01-7.26 (12H, m), 6.58-6.63 (2H, m), 4.39 (IH, d, 7 Hz), 3.86-3.91 (2H, m), 3.71 (3H, s), 3.56-3.62 (IH, m), 3.42 (IH, d, 11 Hz); 3.21 (IH, d, 11 Hz), 2.46-2.52 (2H, m), 2.01-2.11 (2H, m); LCMS (10 minute method): m/z 406 [M+H]+ @ Rτ 6.09 min.
(2S)-2-[(5)-{[2-(Methyloxy)phenyl]thio}(phenyl)methyI]morpholine (21C)
Figure imgf000191_0002
Compound 21C (Example 7C) was obtained from 20Ca,20Cb (0.1 g, 0.25 mmol), solid supported Hunig's base (Argonaut, 3.56 mmol/g, 1.78 g, 0.5 mmol, 2 eq) and α-chloroethyl chloroformate (0.16 ml, 1.5 mmol, 3 eq) in anhydrous dichloromethane (5 ml) following General Procedure 2Ca as a viscous yellow oil (0.06 g, 77%) from which 21C was obtained after separation by chiral HPLC on a Chiralcel O semi- preparative column. Chiral LC: 11.45 min. LC purity = 100%; MW 315.44; C18H21NO2S;
1H NMR (CDC13): 7.14-7.34 (7H, m), 6.74-6.84 (2H, m), 4.50 (IH, d, 8 Hz), 4.10 (IH, d, 11 Hz), 3.85-4.00 (4H, m), 3.74 (IH, dt, 1 Hz, 11 Hz), 2.82-3.02 (2H, m), 2.66-3.02 (3H, m); LCMS (10 minute method): m/z 316 [M+H]+ @ Rt 4.87 min. 21C was converted its hydrochloride salt following General Procedure 3C.
Example 8C : (2S) -2 - [ (S) - ( { 2 - [ ( 1-
Methylethyl ) oxy] phenyl } thio) (phenyl ) methyl] morpholine (23C) (2S)-2-[(S)-({2-[(l-Methylethyl)oxy]phenyl}thio)(phenyl)methyl]-4- (phenylmethyl)morpholine (22Ca) and (2R)-2-[(R)-({2-[(l-Methylethyl)oxy]phenyl}thio)(phenyl)methyl]-4-
(phenylmethyl)morpholine (22Cb)
Figure imgf000192_0001
Compounds 22Ca,22Cb were obtained from 5Ca,5Cb (0.57 g, 1.7 mmol), 2- isopropoxy-thiophenol (0.94 g, 5.61 mmol) and caesium carbonate (2.18 g, 6.72 mmol, 1.2 eq) in dimethylformamide (15 ml) following modification of General Procedure IC in which the reaction mixture was heated to 95°C for 3 hours. After purification by SCX chromatography (eluent: ammonia/methanol 1/1 [v/v]) 22Ca,22Cb was obtained as a dark yellow oil (0.56 g, 76%%); MW 433.62; C27H3ιNO2S; 1H NMR (CDC13): 7.01-7.24 (7H, m), 6.94-7.09 (5H, m), 6.64 (IH, d, 8 Hz), 6.56 (IH, td, 8 Hz, 1 Hz), 4.42-4.51 (2H, m), 3.83-3.92 (2H, m), 3.56 (IH, td, 11 Hz and 3 Hz), 3.42 (IH, d, 13 Hz), 3.24 (IH, d,
13 Hz), 2.52 (IH, d, 11 Hz), 2.46 (IH, d, 11 Hz), 2.05-2.17 (2H, m), 1.29 (3H, d, 6 Hz), 1.27 (3H, d, 6 Hz); LCMS (2.5 minute method): m/z 434 [M+H]+ @ Rτ 1.44 min.
(2S)-2-[(S)-({2-[(l-Methylethyl)oxy]phenyl}thio)(phenyl)methyl]morpholine (23C)
Figure imgf000193_0001
Compound 23C (Example 8C) was obtained from 22Ca,22Cb (0.56 g, 1.3 mmol), solid supported Hunig's base (Argonaut, 3.56 mmol/g, 0.73 g, 2.6 mmol, 2 eq) and α-chloroethyl chloroformate (0.16 ml, 1.5 mmol, 3 eq) in anhydrous dichloromethane (5 ml) following General Procedure 2Ca as a viscous yellow oil (0.41 g, 93%) after separation using chiral HPLC on a OD semi-preparative column. Chiral LC (OD): 12.51 min. LC purity = 100% (UV254nm) / 100% (ELS); MW 343.49; C2oH25NO2S; 1H NMR (CDC13): 7.13-7.20 (IH, m), 6.96-7.12 (6H, m), 6.67 (IH, d, 8 Hz), 6.59 (IH, td, 7 Hz, 1 Hz), 4.48 (IH, sept, 6 Hz), 4.38 (IH, d, 7 Hz), 3.90-3.95 (IH, m), 3.73 (IH, td, 8 Hz, 4 Hz), 3.54 (IH, td, 11 Hz and 3 Hz), 2.79 (IH, td, 12 Hz and 3 Hz), 2.62-2.72 (3H, m),
1.55 (IH, br, s), 1.32 (3H, d, 6 Hz), 1.29 (3H, d, 6 Hz); LCMS (10 minute method): m/z 344 [M+H]+ @ Rt 6.19 min; HPLC purity = 92% (UV215nm). 23C was converted into its hydrochloride salt following General Procedure 3C; MW 379.95; C20H25NO2S.HC1; 1H NMR (CDC13): 9.81-10.04 (2H, br, m), 7.03-7.25 (7H, m), 6.71 (IH, d, 8 Hz), 6.63 (IH, t, 7 Hz), 4.51 (IH, sept., 6 Hz), 4.31 (IH, d, 6 Hz), 4.15-4.23 (IH, m), 3.83-4.03
(2H, m), 3.05-3.18 (2H, m), 2.80-3.03 (2H, m), 1.31 (3H, d, 6 Hz), 1.29 (3H, d, 6 Hz).
Example 9C: 2- { [ (S) - (2S) -Morpholin-2- yl (phenyl) methyl] thio}phenyl trifluoromethyl ether (25C) (25)-4-(Phenylmethyl)-2-[(S)-phenyI({2-
[(trifluoromethyl)oxy]phenyl}thio)methyl]morpholine (24Ca) and
(2S)-4-(Phenylmethyl)-2-[(S)-phenyI({2- [(trifluoromethyl)oxy]phenyl}thio)methyl]morpholine (24Cb)
Figure imgf000194_0001
Compounds 24Ca,24Cb were obtained from 5Ca,5Cb (0.011 g, 0.33 mmol), 2- trifluoromethoxythiophenol (1.2 eq, 0.077g, 0.39 mmol) and caesium carbonate (0.15 g, 0.47 mmol, 1.2 eq) in dimethylformamide (15 ml) following modification of General 5 Procedure IC in which the reaction was heated at 95°C for 1.5 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (20 ml), washed sequentially with water and brine, dried over sodium sulphate and finally concentrated in vacuo to give a pale yellow oil (0.14 g, 92%); MW 459.53; C25H2 F3NO2S; 1H NMR (CDC13): 7.13-7.41 (13H, m), 7.08-7.13 (IH, m), 4.51 (IH, d, 8 L0 Hz), 3.99-4.07 (2H, m), 3.73 (IH, td, 9 Hz, 2.5 Hz), 3.57 (IH, d, 13 Hz), 3.37 (IH, d, 13
Hz); 2.57-2.66 (2H, m), 2.20-2.31 (2H, m); LCMS (10 minute method): m/z 460 [M+H]+ @ Rt 6.69 min.
2-{[(S)-(2S)-Morpholin-2-yl(phenyl)methyl]thio}phenyl trifluoromethyl ether (25C)
Figure imgf000194_0002
Compound 25C (Example 9C) was obtained from 24Ca,24Cb (0.06 g, 0.13 mmol), solid supported Hunig's base (Argonaut, 3.56 mmol/g, 0.073 g, 0.026 mmol, 2 eq) and α-chloroethyl chloroformate (0.04 ml, 0.39mmol, 3 eq) in anhydrous dichloromethane (5 ml) following General Procedure 2Ca as a viscous yellow oil (0.021 20 g, 44%) from which 25C was obtained after separation using chiral HPLC on a OD semi- preparative column. Chiral LC (OJ): 12.60 min. LC purity = 98% (UV254nm) / 100% (ELS); MW 369.41; C18H18F3NO2S; 1H NMR (CDC13): 7.02-7.21 (8H, m), 6.91-6.96 (1H, m), 4.28 (IH, d, 8 Hz), 3.93 (IH, br, d 11 Hz), 3.75-3.81 (IH, ), 3.60 (IH, td, 11 Hz and 3 Hz), 2.71-2.86 (2H, m), 2.61 (2H, d, 6 Hz), 1.90 (IH br, s); LCMS (10 minute method): m/z 370 [M+H]+ @ Rt 5.86 min.
Example IOC : (2S) -2 - [ (S) - [ (2 -
Methylphenyl) thio] (phenyl) methyl] morpholine (27C) (2S)-2-[(5)-[(2-Methylphenyl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine (26Ca) and (2R)-2-[(R)-[(2-Methylphenyl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine (26Cb)
Figure imgf000195_0001
Compounds 26Ca,26Cb were obtained from 5Ca,5Cb (0.1 g, 0.29 mmol), 2- methyl thiophenol (0.04 ml, 0.31 mmol) and caesium carbonate (0.125 g, 0.37 mmol, 1.2 eq) in dimethylformamide (15 ml) following General Procedure IC as a colourless oil
(0.13 g, 85%); MW 389.56; C25H27NOS; 1H NMR (CDC13): 6.84-7.24 (14H, m), 4.14 (IH, d, 8 Hz), 3.85-3.95 (2H, m), 3.60 (IH, dt, 10 Hz, 3 Hz), 3.42 (IH, d, 13 Hz); 3.21 (IH, d, 13 Hz), 2.46-2.54 (2H, m), 2.18 (3H, s), 1.97-2.13 (2H, m); LCMS (2.5 minute method): m/z 390 [M+H]+ @ Rτ 1.49 min.
(25)-2-[(S)-[(2-Methylphenyl)thio](phenyl)methyl]morpholine (27C)
Figure imgf000195_0002
Compound 27C (Example IOC) was obtained from 26Ca,26Cb (0.04 g, 0.12 mmol), solid supported Hunig's base (Argonaut, 3.56 mmol/g, 0.89 g, 0.24 mmol, 2 eq) and -chloroethyl chloroformate (0.04 ml, 0.36mmol, 3 eq) in anhydrous dichloromethane (5 ml) following General Procedure 2Ca as a viscous yellow oil (0.03 g, 75%) from which 27C was obtained after chiral separation. Chiral LC (OJ): 15.84 min. LC purity = 98.57% (UN254nm); MW 299.44; C18H21ΝOS; 1H NMR (CDC13): 6.86-7.21 (9H, m), 4.08 (IH, d, 7 Hz), 3.75 (IH, br s), 3.58 (IH, br s), 2.34-3.1 (4H, m), 2.20 (3H, s); 1.41-2.04 (2H, m); LCMS (10 minute method): m/z 300 [M+H]+ @ Rτ 5.08 min. 27C was converted into its hydrochloride salt following General Procedure 3C.
Example I C : (25) - 2 - { (S) -Phenyl [ (2 - propylphenyl ) thio] methyl } morpholine (29C) (5)-Phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl-2-propylphenyl sulfide (28Ca) and
(J?)-Phenyl[(2R)-4-(phenylmethyl)morpholin-2-yl]methyl-2-propylphenyl suIfide (28Cb)
Figure imgf000196_0001
Compounds 28Ca,28Cb were obtained from 5Ca (0.53 g, 1.50 mmol), 2-n-propyl thiophenol (0.025 g, 1.65 mmol) and caesium carbonate (0.59 g, 1.8 mmol, 1.2 eq) in dimethylformamide (5 ml) following a modification of General Procedure IC in which the reaction was heated at 95°C for 3 hours. After purification by SCX column chromatography (eluent: ammonia/methanol 1/1 [v/v]) 28Ca,28Cb was obtained as a dark yellow oil (0.56 g, 90%%); MW 417.62; C27H31NOS; 1H NMR (CDC13): 7.23-7.12 (6H, m), 7.06-7.11 (5H, m), 6.97-6.99 (2H, m), 6.87-6.92 (IH, m), 4.13 (IH, d, 8 Hz),
3.86-3.94 (2H, m), 3.61 (IH, td, 11 Hz, 2 Hz), 3.44 (IH, d, 13 Hz), 3.23 (IH, d, 13 Hz), 2.46-2.59 (4H, m), 2.01-2.14 (2H, m), 1.34-1.52 (2H, m), 0.83 (3H, t, 7 Hz); LCMS (2.5 minute method): m/z 418 [M+H]+ @ Rt 1.55 min.
(2S)-2-{(S)-Phenyl[(2-propylphenyl)thio]methyl}morpholine (29C)
Figure imgf000197_0001
Compound 29C (Example IIC) was obtained from 28Ca,28Cb (0.56 g, 1.35 mmol), solid supported Hunig's base (Argonaut, 3.56 mmol/g, 0.75 g, 2.7 mmol, 2 eq) and α-chloroethyl chloroformate (0.44 ml, 4.05 mmol, 3 eq) in anhydrous dichloromethane (5 ml) following General Procedure 2Ca as a viscous yellow oil (0.41 g, 93%); MW 327.49; C20H25NOS; 1H NMR (CDC13): 7.17 (IH, br, d, 7 Hz), 7.07-7.12
(5H, m), 6.96-7.00 (2H, m), 6.88-6.93 (IH, m), 4.07 (IH, d, 8 Hz), 3.93-3.98 (IH, m), 3.74-3.80 (IH, m), 3.60 (IH, td, 11 Hz, 3 Hz), 2.81 (IH, td, 12 Hz and 3 Hz), 2.72 (IH, br, d, 12 Hz), 2.48-2.62 (4H, m), 1.36-1.59 (3H, m), 0.83 (3H, t, 7 Hz); LCMS (2.5 minute method): m/z 328 [M+H]+ @ Rt 1.40 min (single major peak).
Example 12C : Methyl 2 - { [ (S) - (2S) -morpholin-2 - yl (phenyl ) methyl] thio }benzoate (31C) Methyl-2-({(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl}thio)benzoate (30Ca) and
Methyl-2-({(R)-phenyl[(2i?)-4-(phenylmethyl)morpholin-2-yl]methyl}thio)benzoate (30Cb)
Figure imgf000198_0001
Compounds 30Ca,30Cb were obtained from 5Ca,5Cb (0.5 g, 1.45 mmol), methyl thiosalicylate (0.49 g, 2.89 mmol) and potassium carbonate (0.21 g, 1.52 mmol) in dry tetrahydrofurane (5 ml) following modification of General Procedure IC in which the solvents were degassed and purged with nitrogen before the addition of methyl thiosalicylate. The reaction mixture was stirred at room temperature for 18 hours after which time the reaction mixture was poured onto water and extracted twice with diethyl ether. The organic layers were washed with water, dried and evaporated in vacuo. After purification by SCX column chromatography (eluent: ammonia/methanol 1/1 [v/v]) 30Ca,30Cb was obtained as a colourless solid (0.18 g, 29%%); MW 433.57;
C26H27NO3S; 1H NMR (CDC13): 8.65-8.85 (IH, m), 6.95-7.45 (13H, m), 4.45 (IH, d, 8 Hz), 3.85-4.05 (IH, m), 3.8 (3H, s), 3.65 (IH, dt, 1 Hz and 7 Hz), 3.55 (IH, d, 11 Hz), 3.25 (IH, d, 11 Hz), 2.5-2.6 (2H, m); 2.0-2.15 (2H, m); FIA: m/z 462 [M+H]+.
Methyl 2-{[(5)-(25)-morpholin-2-yl(phenyl)methyl]thio}benzoate (31C)
Figure imgf000198_0002
Compound 31C (Example 12C) was obtained from 30Ca,30Cb (0.2 g, 0.46 mmol), solid supported Hunig's base (Argonaut, 3.56 mmol/g, 0.08 g, 2.77 mmol, 6 eq) and α-chloroethyl chloroformate (0.5 ml, 4.62 mmol, 10 eq) in anhydrous dichloromethane (5 ml) following General Procedure 2Ca as a white solid (0.16 g,
91%) from which 31C was obtained after separation using chiral HPLC on chiral OJ semi-preparative column. Chiral LC (OJ): 12.32 min. LC purity = 100% (UN254nm); MW 343.45. 31 was converted into its hydrochloride salt following General Procedure 3C; 1H ΝMR (d6-DMSO): 9.30-9.5 (IH, m), 7.75-7.80 (IH, m), 7.1-7.55 (8H, m), 4.82 (IH, d, 8 Hz), 3.95-4.15 (2H, m), 3.65.3.9 (3H, m), 3.55 (3H, s), 2.80-3.25 (2H, m).
Example 13C : ( 2S) -2 - ( (S) - (3 -Fluorophenyl ) { [2 - (trifluoromethyl ) phenyl] thio } methyl ) morpholine (33C) (25)-2-((S)-(3-Fluorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)-4- (phenylmethyl)morpholine (32Ca) and
(2R)-2-((R)-(3-FIuorophenyI){[2-(trifluoromethyl)phenyI]thio}methyl)-4- (phenylmethyl)morpholine (32Cb)
Figure imgf000199_0001
Compounds 32Ca,32Cb were obtained as outlined in Scheme 5C from 38Ca,38Cb (0.33 g, 0.91 mmol) following General Procedure 4C as a white solid after column chromatography (0.28 g, 67%); MW 461.53; C25H23F4ΝOS; 1H NMR (CDC13 ) 6.75-7.65 (IH, m), 6.85-7.33 (12H, m), 4.45 (2H, d, 8 Hz), 3.6-3.75 (2H, m), 3.45 (IH, d 12 Hz), 3.3 (IH, d 12 Hz), 2.45-2.7 (2H, br, m), ), 2.1-2.3 (2H, br, m); FIA: m/z 462 [M+H]+.
(25)-2-((S)-(3-Fluorophenyl){[2-(trifIuoromethyl)phenyl]thio}methyl)morpholine
(33C)
Figure imgf000200_0001
Compound 33C (Example 13C) was obtained from 32Ca,32Cb (0.28 g, 0.615 mmol), solid supported Hunig's base (Argonaut, 3.56 mmol/g, 0.19 g, 0.68 mmol, 1.1 eq) and α-chloroethyl chloroformate (0.07 ml, 0.68 mmol, 1.1 eq) in anhydrous dichloromethane (5 ml) following General Procedure 2Ca as a colourless oil (0.22 g,
95%) from which 33C was obtained after chiral chromatography on a Chiralcel OJ semi- preparative column. Chiral LC (OJ): 13.33 min. LC purity = 98.37% (UV254nm); MW 371.4; C18H17F4NOS. LCMS (12 minute method): m/z 372 [M+H]+ @ Rt 5.2 min. 33C was converted into its hydrochloride salt following General Procedure 3C; MW 407.86; C18H17F4NOS.HCl; 1H NMR (CDC13 ) 9.8-10.2 (IH, br), 7.4-7.6 (IH, m), (6.85-7.45 (8H, m), 4.05-4.45 (4H, br, m), 2.90-3.41 (4H, br, m).
Example 14C : ( 2ff) -2 - ( (S) - (4 -Chlorophenyl ) { [2 - ( trifluoromethyl ) phenyl] thio }methyl ) morpholine ( 35C) (25)-2-((5)-(4-ChlorophenyI){[2-(trifIuoromethyl)phenyl]thio}methyl)-4-
(phenylmethyl)morpholine (34Ca) and
(2R)-2-((R)-(4-Chlorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)-4- (phenylmethyl)morpholine (34Cb)
Figure imgf000200_0002
Compounds 34Ca,34Cb were obtained as outlined in Scheme 5C from 39Ca,39Cb (0.4 g, 1.06 mmol, 1.1 eq), cesium carbonate (0.33 g, 1.0 mmol, 1.1 eq), and 2-trifluoromethyl benzene thiol (0.19 g, 1.06 mmol, 1.1 eq) following a modification of General Procedure IC in which the reaction was stirred at room temperature for 1.5 hours as a white solid after column chromatography (eluent: gradient hexane/ethyl acetate 10/90 to 25/75[v/v]) (0.409g, 80%); MW 477.98; C25H23F3ClNOS; 1H NMR (CDC13 ) 7.1-7.65 (13H, m), 4.45 (IH, d, 8 Hz), 3.85-4.0 (2H, m), 3.55 (IH, m), 3.3 (IH, d 12 Hz), 3.3 (IH, d 12 Hz), 2.45-2.65 (2H, br), ), 2.1-2.3 (2H, br, m); FIA: m/z 478 [M+H]+.
(25)-2-((S)-(4-Chlorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)morphoIine
(35C)
Figure imgf000201_0001
Compound 35C (Example 14C) was obtained from 34Ca,34Cb (0.41 g, 0.86 mmol), solid supported Hunig's base (Argonaut, 3.56 mmol/g, 0.27 g, 0.94 mmol, 1.1 eq) and α-chloroethyl chloroformate (0.10 ml, 0.94 mmol, 1.1 eq) in anhydrous dichloromethane (5 ml) following General Procedure 2Ca as a colourless oil (0.28 g, 84% yield) from which 35C was obtained after separation using chiral HPLC on a
ChiralPak-AD OJ semi-preparative column; MW 387.85; C18H17ClF3NOS; LCMS (12 minute method): m/z 372 [M+H]+ @ Rt 5.2 min. 35C was converted into its hydrochloride salt following General Procedure 3C; MW 423.96; C18H17C1F3N0S.HC1; 1H NMR (CDC13): 9.8-10.2 (IH, br), 7.4-7.6 (IH, m), 7.07-7.35 (7H, m), 3.8-4.45 (4H, br, m), 2.85-3.45 (4H, br, m).
Example 15C : (2S) -2 - ( (S) - ( 2 -Fluorophenyl ) { [2 - (methyloxy) phenyl] thio } methyl ) morpholine (37C)
(25)-2-((5)-(2-Fluorophenyl){[2-(methyloxy)phenyl]thio}methyl)-4- (phenylmethyl)morpholine (36Ca) and
(2R)-2-((R)-(2-Fluorophenyl){[2-(methyloxy)phenyl]thio}methyl)-4-
(phenylmethyl)morpholine (36Cb)
Figure imgf000202_0001
Compounds 36Ca,36Cb were obtained from 7Ca,7Cb (0.45 g, 1.17 mmol), cesium carbonate (0.42 g, 1.29 mmol, 1.1 eq), and 2-methoxy-thiophenol (0.82 g, 5.87 mmol) following a modification of General Procedure IC in which the reaction mixture was heated to 95°C for 2 hours and then stirred at room temperature for 18 hours. After purification by flash column chromatography (eluent: heptane/ethyl acetate 80/20 [v/v]) 36Ca,36Cb was obtained as a colourless oil (0.36 g, 72%%); MW 423.55; C25H26FNOS; 1H NMR (CDC13): 6.65-7.5 (13H, m), 4.9 (IH, d, 7 Hz), 3.9-4.05 (2H, m), 3.8 (3H, s), 3.6 (IH, dt, 8 Hz and 1 Hz), 3.45 (IH, d, 13 Hz), 3.15 (IH, d, 13 Hz), 2.60 (2H, t, 8 Hz), 2.05-2.2 (2H, m); FIA: /z 424 [M+H]+.
(2S)-2-((S)-(2-Fluorophenyl){[2-(methyIoxy)phenyl]thio}methyl)morpholine (37C)
Figure imgf000202_0002
CIH Compound 37C (Example 15C) was obtained from 36Ca,36Cb (0.43 g, 1.02 mmol), solid supported Hunig's base (Argonaut, 3.56 mmol/g, 0.37 g, 1.12 mmol, 1.1 eq) and α-chloroethyl chloroformate (1.08 ml, 10.12 mmol, 10 eq) in anhydrous dichloromethane (5 ml) following General Procedure 2Ca as a colourless oil (0.34 g, 99%) after separation by chiral HPLC on a ChiralPak-AD semi-preparative column. Chiral LC: 12.86 min. LC purity = 99.1 (UV254nm); MW 369.89; C18H20FNOS; FIA: m/z 334 [M+H]+. 37C was converted into its hydrochloride salt following General
Procedure 3C; MW 333.43; C18H20FNOS; 1H NMR (CDC13): 7.2-7.3 (IH, m), 6.85-7.2 (8H, m), 4.85 (IH, d, 8 Hz), 3.95-4.15 (2H, m), 3.85.3.9 (3H, m), 3.7 (IH, dt, 1 Hz and 7 Hz), 2.6-3.0 (4H, m). Example 16C; 2-r2-Methyl-l-(2-trifluoromethyl-phenylsulfanvD-propyll- morpholine (56C) 4-Benzyl-2-(l-hydroxy-2-methyl-propyl)-morpholin-3-one (53C)
Figure imgf000203_0001
To a stirred solution of 2C (5.05 g, 26.4 mmol) in tetrahydrofuran (25 ml) at - 78°C under nitrogen was added lithium diisopropylamide (14.5 ml of a 2M solution, 29.0 mmol) dropwise over 40 minutes. The reaction mixture was stirred at the same temperature over 30 minutes after which time a solution of isobutyraldehyde (2.63 ml, 29.0 mmol) in tetrahydrofuran (15 ml) was added dropwise over 30 minutes. After one hour, the reaction mixture was allowed to warm to room temperature and quenched by addition of saturated ammonium chloride solution. Extraction with dichloromethane and drying over magnesium sulphate gave 53C as a mixture of diastereomers. Upon concentration in vacuo one diastereomer precipitated as a white solid (53Ca: 0.99 g). The remaining mother liquors were purified by column chromatography (30% ethyl acetate in hexane [v/v]) to give 53C (2.06 g). MW 263.34; C15H21NO3; LCMS (6 min method): m/z 286 [M+Na]+; RT = 2.748.
l-(4-Benzyl-morpholin-2-yI)-2-methyl-propan-l-ol (54C)
Figure imgf000203_0002
To a stirred solution of 53C (1.97 g, 7.47 mmol) in tetrahydrofuran (50 ml) at room temperature under nitrogen was added borane-tetrahydrofuran complex (30 ml of a IM solution, ca 4 eq.). The reaction was heated to 60°C and followed by TLC-analysis. When all starting material had been consumed a few drops of methanol were added followed by a similar amount of IN hydrochloric acid and heating was continued for another hour. Organic solvents were removed in vacuo and the remaining solution was poured onto IM potassium carbonate solution (30 ml), extracted with diethyl ether. The organic layers were dried over magnesium sulphate and purified by column chromatography (gradient from 15% ethyl acetate in hexane [v/v]) gave 54C (1.8 g, 97%). MW 249.36; C15H23NO2; LCMS (6 min method): m/z 250 [M+H]+; RT = 0.838.
4-Benzyl-2-[2-methyl-l-(2-trifluoromethyl-phenylsulfanyl)-propyl]-morpholine
(55C)
Figure imgf000204_0001
Compound 55C was obtained from 54C in a two-step procedure. To a stirred solution of 54C (1.8 g, 7.2 mmol) in dichloromethane (50 ml) at room temperature was added solid solid supported Hϋnig's base (Argonaut, 3.56 mmol/g, 6.2 g, 22 mmol, 3 eq) followed methanesulphonyl chloride (1.12 ml, 14 mmol). After stirring for one hour, the reaction mixture was filtered and the filtrates washed with brine and dried over magnesium sulphate to give the intermediate mesylate as a yellow oil (2.93 g of isolated crude product). The crude product was taken up in dry dimethylformamide (50 ml), 2- trifluoromethyl benzenethiol (2.1 ml, 14 mmol) and solid supported Hϋnig's base
(Argonaut, 3.56 mmol/g, 0.55 g, 1.95 mmol) were added and the mixture heated to 70°C and stirred for 72 hours. The reaction was quenched by addition of water (50 ml) and sodium hydroxide solution (70 ml of a 2N solution). The aqueous layer was extracted with diethyl ether (3x50 ml), washed with brine and dried over magnesium sulphate. Purification by ion-exchange chromatography followed by preparative HPLC gave 55C.
MW 409.52; C22H26F3NOS; LCMS (6 min method): m/z 410 [M+H]+; RT = 3.398.
2-[2-MethyI-l-(2-trifluoromethyl-phenylsulfanyl)-propyl]-morpholine (56C)
Figure imgf000204_0002
,H Compound 56C (Example 16C) was obtained from 55C (0.8 g, 1.95 mmol), solid supported Hϋnig's base (Argonaut, 3.56 mmol/g, 1.65 g, 5.85 mmol, 3 eq) and α- chloroethyl chloroformate (0.4 ml, 3.9 mmol, 2 eq) in anhydrous dichloromethane (20 ml) following General Procedure 2Ca as a colourless oil (0.5 g, 85% yield). Chiral HPLC on a ChiralCel-OD(3671) column using 50% heptane in ethanol [v/v] gave 2 fractions (Rt = 8.793 min and 10.443 min). Conversion into fumarate salt 56C was carried out by dissolving in diethyl ether and addition of small amount of methanol. Data for 56C derived from fraction with Rt = 8.793 min: MW 435.46; C19H24F3NO5S; 1H NMR (d3-MeOD): 6.2-6.3 (2H, m), 6.1-6.2 (IH, m), 5.2 (IH, s), 2.6-2.7 (2H, m), 2.2-2.4 (IH, m), 1.6-1.9 (4H, m), 1.6-1.7 (IH, m), -0.4- -0.5 (6H, m).
Example 17C; 2-[2-Methyl-l-(2-trifluoromethyl-phenoxy)-propyll-morpholine (58C) 4-Benzyl-2-[2-methyl-l-(2-trifluoromethyl-phenoxy)-propyl]-morpholine (57C)
Figure imgf000205_0001
To a solution of 53Ca (0.146 g, 0.585 mmol) in dry dimethylformamide (2 ml) under nitrogen and ice-cooling was added sodium hydride (26 mg of a 60% dispersion in oil, 0.644 mmol) portionwise. The reaction was allowed to warm to room temperature for 30 minutes before addition of 2-fluoro-benzotriflouride (0.07 ml, 0.66 mmol). After stirring for 12 hours, another 0.5 equivalents of reagents were added and the reaction mixture heated to 40°C for 30 minutes and then to 60°C for another 2 hours. The crude reaction mixture was purified by ion-exchange column chromatography followed by preparative HPLC to give 57C (0.208 g, 92% yield) MW 393.45; C22H26F3NO2; LCMS (6 min method): m/z 394 [M+H]+; RT = 3.150.
2-[2-Methyl-l-(2-trifluoromethyl-phenoxy)-propyl]-morpholine (58C)
Figure imgf000206_0001
Compound 58C (Example 17C) was obtained from 57C (0.21 g, 0.53 mmol), solid supported Hϋnig's base (Argonaut, 3.56 mmol/g, 0.45 g, 1.5 mmol, 3 eq) and α-chloroethyl chloroformate (0.11 ml, 1.06 mmol, 2 eq) in anhydrous dichloromethane (10 ml) following General Procedure 2C as a colourless oil (0.147 g, 92% yield) MW 303.33; C15H20F3NO2;
1H NMR (CDCI3): 7.5-7.6 (IH, m), 7.2-7.4 (IH, m), 7.0-7.1 (IH, m), 6.8-6.95 (IH, m), 4.15- 4.25 (IH, m), 3.6-3.9 (2H, m), 3.4-3.6 (IH, m), 2.6-2.9 (4H, m), 2.15 (IH, br, s)1.8-2.1 (IH, m), 1.1-1.2 (6H, m); LCMS (12 min method): m/z 304 [M+H]+; RT = 4.862.
The following examples illustrate compounds of of Formulae (ID) above and methods for their preparation.
Scheme ID - Preparation of Intermediates l-Phenyl-3,4-dihydro-2#-quinolin-2-one (2Da)
A stirred mixture of 3,4-Dihydro-iH-quinolin-2-one (IDa) (1.47 g. 10 mmol), K2CO3 (2.9 g, 21 mmol), trαns-cyclohexane-l,2-diamine (240 μL, 2 mmol) and bromobenzene (3.16 mL, 30 mmol) in 1,4-dioxane (10 mL) was heated under a nitrogen atmosphere at 125°C for 5 min to deoxygenate the reaction mixture. Copper (I) iodide (380 mg, 2 mmol) was added in one portion and the reaction mixture was refluxed overnight at 125°C. After cooling to rt, the reaction mixture was poured into ethyl acetate (100 mL) and extracted with water. The organic layer was separated, dried over MgSO and concentrated. Treatment of the residue with ether (100 mL) and cooling (ice bath) gave the product as a white solid after filtration (1.77 g, 79%).
6-Fluoro-l-p-tolyl-3,4-dihydro-IΗ-quinolin-2-one (2Db)
This was prepared using the method described for (2Da) using 6-Fluoro-3,4-dihydro-iH- quinolin-2-one (lDb) (617 mg, 3.7 mmol) and 4-bromotoluene (1.91 g, 11 mmol) to give the crude product, which was purified using automated chromatography (silica) (0 to -60% ethyl acetate\cyclohexane gradient) to provide the product as a light brown solid (880 mg, 92%).
3-Methyl-l-phenyl-3,4-dihydro-i#-quinoIin-2-one (3Da) To a soln of (2Da) (892 mg, 4 mmol) in anhydrous THF (40 mL) at -78°C under nitrogen was added LiHMDS (4.4 mL, IM soln in hexanes, 4.4 mmol) dropwise over 10 min. The reaction mixture was left at -78°C for 30 min and then a solution of methyl iodide (298 μL, 4.8 mmol) in THF (1 mL) was added dropwise. The reaction mixture was warmed slowly to rt, quenched with water (2 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated, dried over MgSO4 and concentrated. The residue was purified by column chromatograpy (silica, gradient 100% hexane to ethyl acetate\hexane 3:10) giving the product as an oil (667 mg, 70%).
3-Ethyl-l-phenyl-3,4-dihydro-IH-quinolin-2-one (3Db) This was prepared in a similar manner to (3Da) on a 1.5 mmol scale using 1 -iodoethane
(125 μL, 1.1 eq.) as the alkylating agent. The crude product (378 mg) was used directly in the next step.
3-(3-Chloro-propyI)-l-phenyl-3,4-dihydro-iH-quinolin-2-one (4Da) To a soln of (2Da) (892 mg, 4 mmol) in anhydrous THF (40 mL) at -78°C under nitrogen was added LiHMDS (4.4 mL, IM soln in hexanes, 4.4 mmol) dropwise over 10 min. The reaction mixture was left at -78°C for 30 min and then a solution of l-bromo-3- chloropropane (405 μL, 4.4 mmol) in THF (1 mL) was added dropwise. The reaction mixture was warmed slowly to rt, quenched with water (2 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated, dried over MgSO4 and concentrated.
The crude product (1.2 g) was used directly in the next step.
3-(3-Chloro-propyl)-6-fluoro-l-p-tolyl-3,4-dihydro-I^-quinolin-2-one (4Db)
This was prepared from (2Db) (300 mg, 1.17 mmol) using the method described for (4Da) using l-bromo-3-chloropropane (140 μL, 1.4 mmol) as the alkylating agent. The crude product (399 mg) was used directly in the next step.
3-(2-Chloro-ethyl)-l-phenyl-3,4-dihydro-2i-T-quinolin-2-one (4Dc) This was prepared from (2Da) (892 mg, 4.0 mmol) using the method described for (4Da) using l-bromo-2-chloroethane (365 μL, 4.4 mmol) as the alkylating agent. The crude product (1 g) was used directly in the next step.
3-(3-Chloro-propyl)-3-methyl-l-phenyI-3,4-dihydro-IH-quinolin-2-one (5Da)
This was prepared from (3Da) (462 mg, 1.95 mmol) using the method described for (4Da) using l-bromo-3-chloropropane (270 μL, 2.7 mmol) as the alkylating agent. The crude product (650 mg) was used directly in the next step.
3-(3-Chloro-propyl)-3-ethyl-l-phenyl-3,4-dihydro-i -quinolin-2-one (5Db)
This was prepared from (3Db) (378 mg, 1.5 mmol) using the method described for (4Da) using l-bromo-3-chloropropane (179 μL, 1.8 mmol) as the alkylating agent. The crude product (528 mg) was used directly in the next step.
Scheme ID - Examples
Example ID; 3-(3-Methylamino-propyl)-l-phenyl-3.4-dihvdro-lH-quinolin-2-one (6Da)
A soln of (4Da) (1.2 g, 4 mmol), potassium iodide (200 mg, 1.2 mmol) and aqueous 40% methylamine (12 mL) in ethanol (30 mL) was refluxed at 100°C under nitrogen for 3 h.
The reaction mixture was cooled, poured into water and extracted with ethyl acetate (100 mL). The organic layer was separated, dried over MgSO4 and concentrated. The product was purified by preparative LCMS to give 500 mg of the racemate. The racemate was separated into its individual enantiomers using chiral HPLC. 1H NMR (300 MHz, CDC13) (racemate & isomer) 5 1.5-1.73 (m, 4H), 1.88-1.97 (m, IH), 2.43 (s, 3H), 2.62 (t, J= 6.69
Hz, 2H), 2.70-2.79 (m, IH), 2.84-2.92 (m, IH), 3.15 (dd, J= 15.45, 5.28 Hz, IH), 6.33 (d, J= 7.73 Hz, IH), 6.95-7.06 (m, 2H), 7.19-7.22 (m, 3H), 7.38-7.43 (m, IH), 7.47-7.52 (m, 2H). LCMS (12 minute method) [M+H]+ = 295 @ Rt 4.0 min (100%).
Example 2D: 6-Fluoro-3-(3-methylamino-propyl)-l-p-tolyl-3,4-dihvdro-iHr-quinolin-
2-one (6Db) This was prepared in an identical manner to (6Da) using crude (4Db) (399 mg) to give the crude product, which was purified by preparative LCMS to give the product (35 mg). 1H NMR (300 MHz, CDC13) (racemate) δ 1.40-1.70 (m, 3H), 1.75-1.90 (m, 4H), 2.34 (s, 3H), 2.36 (s, 3H), 2.50-2.83 (m, 2H), 3.01-3.08 (m, IH), 6.21-6.26 (m, IH), 6.62-6.68 (m, IH), 6.82-6.86 (m, IH), 6.99 (d, J= 8.1 Hz, 2H), 7.22 (d, J= 8.1 Hz, 2H). LCMS (12 minute method) [M+H]+ = 327 @ Rt 4.8 min (100%).
Example 3D: 3-(2-Methylamino-ethyl)-l-phenyl-3.4-dihydro-lH-quinolin-2-one (6Dc) This was prepared in an identical manner to (6Da) using crude (4Dc) (lg) to give the racemate (80 mg). The racemate was separated into its individual enantiomers using chiral HPLC. 1H NMR (300 MHz, CDC13) (racemate & isomer) δ ppm 1.64-1.76 (m, IH), 1.79 (br, IH), 2.03-2.18 (m, IH), 2.44 (s, 3H), 2.71-2.82 (m, 2H), 2.82-2.94 (m, 2H), 3.09-3.21 (m, IH), 6.33 (dd, J= 7.91, 1.32 Hz, IH), 6.94-7.07 (m, 2H), 7.18-7.24 (m, 3H), 7.37-7.44 (m, IH), 7.47-7.54 (m, 2H). LCMS (12 minute method) [M+H]+ = 281 @Rt
3.82 min (100%).
Example 4D: 3-Methyl-3-(3-methylamino-propyl)-l-phenyl-3,4-dihydro-i/7- quinolin-2-one (7Da) This was prepared in an identical manner to (6Da) using crude (5Da) (650 mg) to give the crude product (198 mg), which was purified by preparative LCMS. The purified racemate was then separated into its individual enantiomers using chiral HPLC. 1H NMR (300 MHz, CDC13) (isomer) δ ppm 1.27 (s, 3H), 1.43 (br, IH), 1.53-1.66 (m, 4H), 2.39 (s, 3H), 2.54 (t, J= 6.12 Hz, 2H), 2.91 (d, J= 15.64 Hz, IH), 2.98 (d, J= 15.64 Hz, IH), 6.28 (dd, J= 7.91, 1.32 Hz, IH), 6.97 (td, J= 7.21, 1.41 Hz, IH), 7.03 (td, J= 7.68, 1.98 Hz, IH), 7.14-7.22 (m,
3H), 7.36-7.44 (m, IH), 7.46-7.53 (m, 2H). LCMS (12 minute method) [M+H]+ = 309 @Rt 4.21 min (100%).
Example 5D: 3-Ethyl-3-(3-methylamino-propyl)-l-phenyI-3,4-dihydro-jfH-quinolin- 2-one (7Db) This was prepared in an identical manner to (6Da) using crude (5Db) (528 mg) to give the crude product (105 mg), which was purified by preparative LCMS. The purified racemate was then separated into its individual enantiomers using chiral HPLC. 1H NMR (300 MHz, CDC13) (racemate) δ 0.93 (t, J= 7.53 Hz, 3H), 1.56-1.75 (m, 6H), 1.91 (bs, IH), 2.41 (s, 3H), 2.55-2.60 (m, 2H), 2.91 (d, J= 15.82, IH), 3.02 (d, J= 15.82,
IH), 6.25-6.28 (m, IH), 6.94-7.05 (m, 2H), 7.16-7.19 (m, 3H), 7.38-7.43 (m, IH), 7.4- 7.52 (m, 2H). 1H NMR (300 MHz, MeOD-d4) (isomer D-tartrate salt) δ 0.85 (t, J= 7.53 Hz, 3H), 1.45-1.75 (m, 6H), 2.57 (s, 2H), 2.83-2.89 (m, 2H), 3.01-3.06 (d, J= 16.01, IH), 4.32 (s, 2H), 6.11-6.14 (m, IH), 6.89-6.97 (m, 2H), 7.09 (d, J= 7.16 Hz, 2H), 7.15-7.18 (m, IH), 7.37 (t, J= 7.35 Hz, IH), 7.46 (t, J= 7.35 Hz, 2H). LCMS (12 minute method)
[M+H]+ = 323 @ Rt 4.9 min (98%).
Scheme 2D - Preparation of Intermediates
l-/ -Tolyl-3,4-dihydro-2H-quinolin-2-one (2Dc)
A stirred mixture of 3,4-Dihydro-iH-quinolin-2-one (IDa) (4.41 g. 30 mmol), K CO3 (8.7 g, 63 mmol), tran.s-cyclohexane-l,2-diamine (720 μL, 2 mmol) and 4-bromotoluene (15.4 g, 90 mmol) in 1,4-dioxane (30 mL) was heated under a nitrogen atmosphere at 125°C for 5 min to deoxygenate the reaction mixture. Copper (I) iodide (1.14 g, 2 mmol) was added in one portion and the reaction mixture was refluxed overnight at 125°C. After cooling to rt, the reaction mixture was filtered through celite, poured into ethyl acetate (100 mL) and extracted with water. The organic layer was separated, dried over MgSO and concentrated. Treatment of the residue with ether (200 mL) and cooling (ice bath) gave the product as a white solid after filtration (6.2 g, 87%).
l-PhenyI-3-propyl-3,4-dihydro-I T-quinoIin-2-one (3Dc)
This was prepared from (2Da) (669 mg, 3 mmol) and 1-iodopropane (352 μl, 1.2 eq.) as the alkylating agent. The crude product (780 mg) was used directly in the next step.
3-Ethyl-l-/?-tolyl-3,4-dihydro-i#-quinolin-2-one (3Dd)
This was prepared from (2Dc) (711 mg, 3 mmol) and 1 -iodoethane (265 μl, 1.2 eq.) as the alkylating agent. The crude product (800 mg) was used directly in the next step. 3-Propyl-l-p-tolyl-3,4-dihydro-iiϊ-quinolin-2-one (3De)
This was prepared from (2Dc) (711 mg, 3 mmol) and l-iodopropane (352 μl, 1.2 eq.) as the alkylating agent. The crude product (840 mg) was used directly in the next step.
3-Butyl-l-p-tolyl-3,4-dihydro-IJH-quinolin-2-one (3Df)
This was prepared from (2Dc) (711 mg, 3 mmol) and l-iodobutane (354 μl, 1.1 eq.) as the alkylating agent. The crude product (790 mg) was used directly in the next step.
3-Isopropyl-l-p-tolyl-3,4-dihydro-JH-quinolin-2-one (3Dg)
This was prepared from (2Dc) (711 mg, 3 mmol) and 2-iodopropane (330 μl, 1.1 eq.) as the alkylating agent. The crude product (806 mg) was used directly in the next step.
3-AllyI-3-ethyl-l- ?-tolyl-3,4-dihydro-IH-quinolin-2-one (llDb) To a soln of (3Dd) (800 mg, 2.7 mmol) in anhydrous THF (30 mL) at -78°C under nitrogen was added LiHMDS (3 mL, IM soln in hexanes, 3 mmol) dropwise over 10 min. The reaction mixture was left at -78°C for 30 min and then a solution of allyl bromide (280 μL, 3.2 mmol) in THF (1 mL) was added dropwise. The reaction mixture was warmed slowly to rt, quenched with water (2 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated, dried over MgSO4 and concentrated. The crude product (920 mg) was used directly in the next step.
3-Ethyl-3-(3-hydroxypropyl)-l-/?-tolyl-3,4-dihydro-2H-quinolin-2-one (12Db) To a soln of (HDb) (732 mg, 2.4 mmol) in anhydrous THF (25 mL) at 0°C under nitrogen was added 9-BBN (12 mL, 0.5M soln in THF, 6 mmol, 2.5 eq.) dropwise over
10 min. The reaction mixture was warmed to rt and left to stir overnight. The resultant yellow soln was cooled to 0°C and then quenched carefully with ethanol (3 mL), followed by aq. NaOH (1.8 mL, 3N soln). Finally, aq. H2O2 (1.8 mL, 37% soln) was added dropwise maintaining the internal reaction mixture temp between 5 and 10 °C. The reaction mixture was warmed to rt and then refluxed for 90 min. The reaction mixture was cooled to rt, poured into ethyl acetate and water and extracted. The organic layer was separated, dried over MgSO and concentrated. The crude product was purified using automated chromatography (silica) (0 to 60% ethyl acetate\cyclohexane gradient) to provide (12Db) as a clear oil (540 mg, 70%).
Scheme 2D - Examples
Example 6D: 3-EthvI-3-(3-methylamino-propyl)-l-p-tolyl-3,4-dihvdro-iH-quinolin- 2-one (13Db)
To a soln of (12Db) (540 mg, 1.67 mmol) and triethylamine (350 μL, 2.5 mmol) in anhydrous THF (20 mL) at 0°C under nitrogen was added dropwise a soln of methanesulfonyl chloride (142 μL, 1.8 mmol) in THF (1 mL). The reaction mixture was warmed to rt and stirred for 3 h. The reaction mixture was poured into ethyl acetate and water and extracted. The organic layer was separated, dried over MgSO4 and concentrated. The crude mesylate (670 mg, 100%) was dissolved in ethanol (10 mL) and aqueous 40% methylamine (5 mL) and heated at 65°C under nitrogen for 2 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate (100 mL). The organic layer was separated, dried over MgSO4 and concentrated. The product was purified by SCX-2 to give 384 mg of the racemate. The racemate was separated into its individual enantiomers using chiral HPLC. Each enantiomer was dissolved in CH2C12 (2 mL) and treated with 1 equivalent of D-tartaric acid dissolved in a minimum volume of warm methanol. The resultant soln was concentrated and the solid was dried under vacuo to provide the D- tartrate salt of the amine. 1H NMR (300 MHz, CDC13) (racemate) δ 0.92 (t, J= 7.44 Hz, 3H), 1.49-1.75 (m, 6H), 1.81 (br, IH), 2.40 (s, 6H), 2.57 (t, J= 6.59 Hz, 2H), 2.89 (d, J= 15.82 Hz, IH), 3.00 (d, J= 15.82 Hz, IH), 6.29 (d, J= 7.91 Hz, IH), 6.92-7.08 (m, 4H), 7.16 (d, J= 7.16 Hz, IH), 7.29 (d, J= 7.91 Hz, 2H). 1H NMR (300 MHz, MeOD-d4) (isomer D- tartrate salt) δ 0.93 (t, J= 7.44 Hz, 3H), 1.54-1.84 (m, 6H), 2.42 (s, 3H), 2.66 (s, 3H), 2.91-
3.00 (m, 3H), 3.11 (d, J= 15.83 Hz, IH), 4.41 (s, 2H), 6.22-6.27 (m, IH), 6.80-7.07 (m,
4H), 7.21-7.27 (m, IH), 7.36 (d, J= 7.91 Hz, 2H). LCMS (12 minute method) [M+H]+ = 337 @Rt 5.21 min (100%).
Example 7D: 3-(3-Methylamino-propyl)-l-phenyl-3-propyl-3,4-dihvdro-2Hr- quinolin-2-one (13Da) This was prepared from (3Dc) (780 mg, 2.9 mmol) using the same synthetic sequence described above (3Dd to 13Db) to give 233 mg of the racemate. The racemate was separated into its individual enantiomers using chiral HPLC and each enantiomer was converted into its D-tartrate salt as described for (13Db). 1H NMR (300 MHz, CDC13) (racemate) δ 0.88 (t, J= 7.16 Hz, 3H), 1.26-1.48 (m, 2H), 1.50-1.78 (m, 7H), 2.40 (s, 3H),
2.56 (t, J= 6.59 Hz, 2H), 2.92 (d, J= 15.83 Hz, IH), 3.01 (d, J= 15.83 Hz, IH), 6.25-6.28 (m, IH), 6.94-7.05 (m, 2H), 7.16-7.19 (m, 3H), 7.37-7.42 (m, IH), 7.47-7.52 (m, 2H). 1H NMR (300 MHz, MeOD-d4) (isomer D-tartrate salt) δ 0.77-0.82 (t, J= 7.06 Hz, 3H), 1.24-1.35 (m, 2H), 1.44-1.51 (m, 2H), 1.69 (bs, 3H), 2.56 (s, 3H), 2.84-2.89 (m, 3H), 3.01-3.06 (d, J= 15.83 Hz, IH), 3.20-3.22 (q, J=1.55 Hz, 2H), 4.30 (s, 2H), 6.11-6.14 (dd,
J= 7.72, 2.26 Hz, IH), 6.89-6.97 (m, 2H), 7.07-7.10 (m, 2H), 7.14-7.17 (m, IH), 7.34- 7.39 (t, J= 7.35 Hz, IH), 7.43-7.48 (t, J= 7.35 Hz, 2H). LCMS (12 minute method) [M+H]+ = 337 @ Rt 5.2 min (100%).
Example SD^-Q-Methylamino-propyD-S-propyl-l-p-tolyl-S^-dihvdro-ig- quinolin-2-one (13Dc)
This was prepared from (3De) (840 mg, 2.6 mmol) using the same synthetic sequence described above (3Dd to 13Db) to give 393 mg of the racemate. The racemate was separated into its individual enantiomers using chiral HPLC and each enantiomer was converted into its D-tartrate salt as described for (13Db). 1H NMR (300 MHz, CDC13)
(racemate) δ 0.88 (t, J= 7.16 Hz, 3H), 1.20-1.75 (m, 11H), 2.39 (s, 3H), 2.40 (s, 3H), 2.90 (d, J= 15.64 Hz, IH), 2.99 (d, J= 15.64 Hz, IH), 6.29 (d, J= 7.72 Hz, IH), 6.93-7.07 (m, 4H), 7.14-7.16 (m, IH), 7.25-7.31 (m, 2H). 1H NMR (300 MHz, MeOD-d4) (isomer D- tartrate salt) δ 0.91 (t, J= 7.06 Hz, 3H), 1.28-1.85 (m, 8H), 2.44 (s, 3H), 2.68 (s, 3H), 2.94-2.99 (m, 3H), 3.14 (d, J= 15.82 Hz, IH), 4.41 (s, 2H), 6.25-6.28 (m, IH), 7.02-7.07
(m, 4H), 7.25-7.28 (m, IH), 7.38 (d, J= 7.91 Hz, 2H). LCMS (12 minute method) [M+H]+ = 351 @ Rt 5.6 min (100%).
Example 9D: 3-Butyl-3-(3-methyIamino-propyl)-l-p-tolvI-3,4-dihvdro-iH-quinolin- 2-one (13Dd)
This was prepared from (3Df) (790 mg, 2.7 mmol) using the same synthetic sequence described above (3Dd to 13Db) to give 334 mg of the racemate. The racemate was separated into its individual enantiomers using chiral HPLC and each enantiomer was converted into its D-tartrate salt as described for (13Db). 1H NMR (300 MHz, CDC13) (racemate) δ 0.87 (t, J= 6.97 Hz, 3H), 1.20-1.40 (m, 4H), 1.55-1.74 (m, 6H), 2.40 (s, 3H), 2.40 (s, 3H), 2.55 (t, J= 6.78 Hz, 3H), 2.91 (d, J= 15.63 Hz, IH), 2.99 (d, J= 15.63 Hz, IH), 6.28-6.31 (m, IH), 6.93-7.00 (m, 2H), 7.02-7.06 (m, 2H), 7.14-7.16 (m, IH), 7.29
(d, J= 8.07 Hz, 2H). 1H NMR (300 MHz, MeOD-d4) (isomer D-tartrate salt) δ 0.90 (t, J= 6.97 Hz, 3H), 1.20-1.85 (m, 10H), 2.44 (s, 3H), 2.68 (s, 3H), 2.94-2.99 (m, 3H), 3.14 (d, J= 15.82 Hz, IH), 4.42 (s, 2H), 6.25-6.28 (m, IH), 7.00-7.07 (m, 4H), 7.25-7.28 (m, IH), 7.38 (d, J= 7.91 Hz, 2H). LCMS (12 minute method) [M+H]+ = 365 @ Rt 5.9 min (100%).
Example 10D: 3-Isopropyl-3-(3-methylamino-propyl)-l-p-tolyl-3.4-dihvdro-lH- quinolin-2-one (13De)
This was prepared from (3Dg) (806 mg, 2.89 mmol) using the same synthetic sequence described above (3Dd to 13Db) to give 307 mg of the racemate. 1H NMR (300 MHz,
CDC13) (racemate) δ ppm 0.92 (dd, J= 8.95, 6.88 Hz, 6H), 1.39-1.88 (m, 5H), 2.12-2.23 (m, IH), 2.39 (s, 3H), 2.40 (s, 3H), 2.56 (t, J= 6.78 Hz, 2H), 2.94 (d, J= 15.92 Hz, IH), 3.00 (d, J= 15.92 Hz, IH), 6.28 (dd, J= 7.82, 1.04 Hz, IH), 6.92-7.06 (m, 4H), 7.16 (dd,
J= 6.97, 1.13 Hz, IH), 7.29 (d, J= 7.91 Hz, 2H). LCMS (12 minute method) [M+H]+ = 351 @Rt 5.55 min (100%o).
Example IIP: ό-Chloro-S-ethyl-S-O-methylamino-propyD-l-p-tolyl-S^-dihvdro-lg- quinolin-2-one (13Df)
This was prepared from (lDc) using the same synthetic sequence described above to give 205 mg of the racemate. The racemate was separated into its individual enantiomers using chiral
HPLC and each enantiomer was converted into its D-tartrate salt as described for (13Db). 1H NMR (300 MHz, CDC13) (racemate) D ppm 0.91 (t, J= 7.44 Hz, 3H), 1.50-1.75 (m, 6H), 2.15 (br, IH), 2.40 (s, 3H), 2.41 (s, 3H), 2.55-2.64 (m, 2H), 2.85 (d, J= 16.01 Hz, IH), 2.97 (d, J= 16.01 Hz, IH), 6.23 (d, J= 8.85 Hz, IH), 6.97 (dd, J= 8.67, 2.45 Hz, IH), 7.02 (d, J= 8.29 Hz, 2H), 7.14 (d, J= 2.26 Hz, IH), 7.29 (d, J= 8.10 Hz, 2H). 1H NMR (300 MHz,
MeOD-d4) (isomer, D-tartrate salt) D ppm 0.84 (t, J= 7.35 Hz, 3H), 1.40-1.75 (m, 6H), 2.32 (s, 3H), 2.57 (s, 3H), 2.80-2.92 (m, 3H), 3.01 (d, J= 16.20 Hz, IH), 4.31 (s, 2H), 6.13 (d, J= 8.67 Hz, IH), 6.92-6.98 (m, 3H), 7.19 (d, J= 2.26 Hz, IH), 7.26 (d, J= 7.91 Hz, 2H). LCMS (12 minute method) [M+H]+ = 371/373 @Rt 5.75 min (100%).
Example 12D: 6-Chloro-l-(4-chloro-phenyl)-3-ethyl-3-(3-methylamino-propyl)-3.4- dihydro-ig-quinolin-2-one (13Dg)
This was prepared from (IDc) using the same synthetic sequence described above to give 222 mg of the racemate, which was purified by preparative LCMS. 1H NMR (300 MHz, CDC13) (racemate) δ ppm 0.84 (t, J= 7.44 Hz, 3H), 1.40-1.70 (m, 6H), 2.35 (br, 4H), 2.49-2.56 (m, 2H), 2.80 (d, J= 16.01 Hz, IH), 2.90 (d, J= 16.01 Hz, IH), 6.14 (d, J= 8.67 Hz, IH), 6.93 (dd, J= 8.67, 2.26 Hz, IH), 7.04 (ddd, J= 9.04, 2.83, 2.45 Hz, 2H), 7.09 (d,
J= 2.26 Hz, IH), 7.36-7.43 (m, 2H). LCMS (12 minute method) [M+H]+ = 391/393 @Rt 5.67 min (92%).
Scheme 3D - Preparation of intermediates
l-(4-Methoxy-benzyl)-3,4-dihydro-IH-quinolin-2-one (14D)
A 5 litre flange-neck flask equipped with an air stirrer and paddle, thermometer, nitrogen bubbler and pressure equalising dropping funnel was charged with sodium hydride (25.5g, 60% oil dispersion, 0.637 mol) and 40-60 pet. ether (100 ml). The mixture was stirred briefly and then allowed to settle under nitrogen. After decanting the supernatant liquid, the vessel was charged with dimethylformamide (2 litres). The well stirred suspension was cooled to 7-8°C using an external ice-bath. Then a soln of 3,4-dihydro- lH-quinolin-2-one (la) (73.6g, 0.5 mole) in anhydrous dimethylformamide (500 ml) was added dropwise over 25 min. The mixture was stirred at 7-8°C for 30 min. then 4- methoxybenzyl chloride (102 g, 0.65 mole, 1.3 eq.) was added over 10 min. The reaction mixture was left to stir for 2 h. at <10°C then allowed to warm-up to room temperature and stirred overnight. The stirred reaction mixture was quenched with ice/water (2.5 litres) and cooled to 15 °C using an external ice-bath. The white solid was isolated by filtration and washed with water. After drying in vacuo at 40°C overnight the product was obtained (113.4g, 85%). 1- (4 -Methoxy-benzyl) -3 -methyl-3 , 4 -dihydro- 22ϊ-quinolin-2 -one ( 15D)
To a soln of (14) (20 g, 75 mmol) in anhydrous THF (400 mL) at -78°C under nitrogen was added LiHMDS (78.6 mL, IM soln in hexanes, 78.6 mmol) dropwise over 10 min. The reaction mixture was left at -78°C for 30 min and then a solution of methyl iodide (5.13 mL, 83 mmol) in THF (5 mL) was added dropwise. The reaction mixture was warmed slowly to rt, quenched with water (50 mL) and extracted with ethyl acetate (400 mL). The organic layer was separated, dried over MgSO4 and concentrated to give the product as a yellow solid (21 g, 100%) that was used directly in the next step.
3-Allyl-l-(4-methoxy-benzyl)-3-methyl-3,4-dihydro-iH-quinolin-2-one (16Db)
To a soln of (15D) (20.5 g, 73 mmol) in anhydrous THF (400 mL) at -78°C under nitrogen was added LiHMDS (80 mL, IM soln in hexanes, 80 mmol) dropwise over 10 min. The reaction mixture was left at -78°C for 30 min and then a solution of allyl bromide (7.6 mL, 87 mmol) in THF (5 mL) was added dropwise. The reaction mixture was warmed slowly to rt, quenched with water (100 mL) and extracted with ethyl acetate (400 mL). The organic layer was separated, dried over MgSO4 and concentrated to give the product as an orange oil (23.9 g, 100%) that was used directly in the next step.
3-(3-Hydroxy-propyl)-l-(4-methoxy-benzyl)-3-methyl-3,4,4a,8a-tetrahydro-i^- quinoϊin-2-one (17Db)
To a soln of (16Db) (23.9 g, 74 mmol) in anhydrous THF (400 mL) at 0°C under nitrogen was added 9-BBN (370 mL, 0.5M soln in THF, 185 mmol, 2.5 eq.) dropwise over 10 min. The reaction mixture was warmed to rt and left to stir overnight. The resultant yellow soln was cooled to 0°C and then quenched carefully with ethanol (95 mL), followed by aq. NaOH (60 mL, 3N soln). Finally, aq. H2O2 (60 mL, 37% soln) was added dropwise maintaining the internal reaction mixture temp between 5 and 10 °C. The reaction mixture was warmed to rt and then refluxed for 90 min. The reaction mixture was cooled to rt, poured into ethyl acetate and water and extracted. The organic layer was separated, dried over MgSO4 and concentrated. The crude product was purified using automated chromatography (silica) (0 to 80% ethyl acetate\cyclohexane gradient) to provide the product as a clear oil (21.3 g, 84%). l-(4-Methoxy-benzyl)-3-methyl-3-(3-methylamino-propyl)-3,4,4a,8a-tetrahydro-IH- quinolin-2-one (18Db)
To a soln of (17Db) (18 g, 53 mmol) and triethylamine (11.1 mL, 79 mmol) in anhydrous THF (450 mL) at 0°C under nitrogen was added dropwise a soln of methanesulfonyl chloride (4.52 mL, 58 mmol) in THF (50 mL). The reaction mixture was warmed to rt and stirred for 3 h. The reaction mixture was poured into ethyl acetate and water and extracted. The organic layer was separated, dried over MgSO4 and concentrated. The crude mesylate (22 g, 99%) was dissolved in ethanol (500 mL) and aqueous 40% methylamine (200 mL) and heated at 65°C under nitrogen for 2 h. The reaction mixture was cooled, concentrated and then extracted with ethyl acetate (300 mL). The organic layer was washed with water, brine, dried over MgSO4 and concentrated to give the crude product (17.8 g, 96%).
Methyl-[3-(3-methyl-2-oxo-l,2,3,4,4a,8a-hexahydro-quinolin-3-yl)-propyl]-carbamic acid tert-butyl ester (19Db)
A mixture of (18Db) (17.8 g, 50.5 mmol) and anisole (5.5 mL, 50.5 mmol) in trifluoroacetic acid (250 mL) was heated at 65°C under nitrogen for 2 h. The reaction mixture was concentrated under vacuo and the residue was dissolved in methanol (10 mL). The methanol soln was applied to an SCX-2 column (300 g, pre-washed with methanol) and the column washed with methanol (approx 1 litre) until the soln became colourless. The product was eluted with 2N NH3 in methanol (500 mL) and the basic soln was concentrated to provide 3-Methyl-3-(3-methylamino-propyl)-3,4-dihydro-lH- quinolin-2-one (9 g, 77%). To a soln of this amine (8.6 g, 37 mmol) in anhydrous THF (350 mL) at 0°C was added a soln of di-tert-butyl dicarbonate (8.34 g, 97%, 50.5 mmol) in THF (20 mL) dropwise. The reaction mixture was warmed to rt and stirred for 3 h. The reaction mixture was poured into ethyl acetate (400 mL) and water (200 mL) and extracted. The organic layer was separated, dried over MgSO4 and concentrated to give the product as a yellow solid (12.26 g, 100%). This material was used without further purification. Methyl-[3-(2-oxo-l,2,3,4-tetrahydro-quinolin-3-yl)-propyI]-carbamic acid tert-butyl ester (19Da)
This was prepared from (14D) using the same synthetic sequence described above.
r3-(6-Chloro-l,2,3,4-tetrahydro-quinolin-3-yl)-propyll-methyl-carbamic acid fert- butyl ester (20Da)
To a soln of (19Da) (2.75 g, 8.6 mmol) in anhydrous DMF (25 mL) at 0°C was added dropwise a soln of N-chlorosuccinimide (1.17 g, 8.7 mmol) in anhydrous DMF (3 mL). The reaction mixture was warmed to rt, stirred overnight and then poured into ethyl acetate (100 mL) and water (50 mL) and extracted. The organic layer was separated, dried over MgSO4 and concentrated to provide the product as a yellow oil 3 g, 98%) that was used without further purification.
Scheme 3D - Examples
Example 13D: 3-(3-Methylamino-propyl)-l-p-tolyl-3,4-dihvdro-iH-quinolin-2-one (21Da)
A stirred mixture of (19Da) (100 mg. 0.31 mmol), K2CO3 (92 mg, 0.66 mmol), trans- cyclohexane-l,2-diamine (8 μL, 0.06 mmol) and 4-bromotoluene (162 mg, 0.94 mmol) in 1,4-dioxane (0.5 mL) was heated under a nitrogen atmosphere at 125°C for 5 min to deoxygenate the reaction mixture. Copper (I) iodide (12 mg, 0.06 mmol) was added in one portion and the reaction mixture was refluxed overnight at 125°C. After cooling to rt, the reaction mixture was poured into ethyl acetate (100 mL) and extracted with water. The organic layer was separated, dried over MgSO4 and concentrated. The crude product was purified using automated chromatography (silica) (0 to 80% ethyl acetate\cyclohexane gradient) to provide the Boc protected product (70 mg, 54%). To a soln of this material (70 mg, 0.17 mol) in DCM (2 mL), was added trifluoroacetic acid (197 μL, 2.55 mmol, 15 eq.). The reaction mixture was left to stir at room temperature for 90 min, concentrated under vacuo poured into ethyl acetate (50 mL) and aq. NaHCO3 (20 mL) and extracted. The organic layer was separated, dried over MgSO , concentrated and the crude product was purified by SCX-2 to provide the racemate (40 mg, 75%). The racemate was separated into its individual enantiomers using chiral HPLC. 1H NMR (300 MHz, CDCI3) (racemate) δ 1.49-1.77 (m, 3H), 1.86-1.96 (m, IH), 2.34 (bs, IH), 2.40 (s, 3H), 2.43 (s, 3H), 2.61-2.66 (t, J= 6.88 Hz, 2H), 2.68-2.78 (m, IH), 2.83-2.90 (m, IH), 3.09-3.17 (m, IH), 6.36 (dd, J= 7.7 Hz, 1.0 Hz, IH), 6.94-7.03 (m, 2H), 7.08 (d, J= 8.2 Hz, 2H), 7.13-7.17 (m, IH), 7.29 (d, J= 8.1 Hz, 2H); 1H NMR (300 MHz, MeOD-d4) (isomer, D-tartrate salt) δ 1.64 (bs, IH), 1.89 (bs, 3H), 2.41(s, 3H), 2.70 (s, 3H), 2.75- 2.87 (m, IH), 2.91-3.06 (m, 3H), 3.20 (dd, J= 5.9, 15.26 Hz, IH), 4.45 (s, 2H), 6.32-6.35 (m, IH), 7.00-7.12 (m, 4H), 7.28-7.30 (m, IH), 7.37 (d, J= 8.1 Hz, 2H). LCMS (12 minute method) [M+H]+ = 309 @ Rt 4.7 min (100%).
Example 14D : 6 -Chloro- 3 - (3 -methylamino-propyl ) - 1 -p-tolyl - 3 , 4 -dihydro- lfl-quinolin-2 -one ( 21Dn) This was prepared from (20Da) (132 mg, 0.29 mmol) using the same methods described for (21Da) to provide the racemate (86 mg). 1H NMR (300 MHz, CDCI3) (racemate & isomer) δ 1.50-1.57 (m, IH), 1.62-1.90 (m, 3H), 2.34 (s, 3H), 2.41 (s, 3H), 2.63-2.82 (m,
5H), 3.00-3.07 (m, IH), 6.22 (d, J= 8.6 Hz, IH), 6.92 (dd, J= 2.45, 8.66 Hz, IH), 6.99 (d, J= 8.1 Hz, 2H), 7.11 (d, J= 2.25 Hz, IH), 7.23 (d, J= 8.1 Hz, 2H). LCMS (12 minute method) [M+H]+ = 343/345 @ Rt 5.2 min (96%).
Example 15D : 1 - ( 3 -Fluorophenyl ) -3 - ( 3 -methylamino-propyl ) -
3 , 4 -dihydro- lH-quinolin-2 -one ( 21Db) This was prepared from (19Da) (200 mg, 0.63 mmol) using the same two-step procedure described for (21Da) to provide the racemate (83 mg). 1H NMR (300 MHz, CDC13) (racemate) δ 1.60-1.70 (m, IH), 1.92 (br, 3H), 2.64 (bs, 3H), 2.72-2.74 (m, IH), 2.86- 3.09 (m, 4H), 6.35 (dd, J= 7.72, 1.510 Hz, IH), 6.94-7.23 (m, 6H), 7.43-7.51 (m, IH).
LCMS (12 minute method) [M+H]+ = 313 @ Rt 4.4 min (100%).
Example 16D: 1- (4 -Chlorophenyl) -3- (3-methylamino-propyl) - 3 , 4-dihydro-lE-quinolin-2-one (2IDc) This was prepared from (19Da) (122 mg, 0.38 mmol) using the same two-step procedure described for (21Da) to provide the crude product, which was purified by SCX-2 to give the racemate (70 mg). 1H NMR (300 MHz, CDC13) (racemate) δ 1.49-1.73 (m, 3H), 1.89 (m, 2H), 2.43 (s, 3H), 2.62 (t, J= 6.79, 7.15 Hz, 2H), 2.68-2.78 (m, IH), 2.83-2.93 (m, IH), 3.14 (dd, J= 15.43, 5.37 Hz, IH), 6.34 (dd, J= 7.73, 1.14 Hz, IH), 6.96-7.09 (m, 2H), 7.14-7.21 (m, 3H), 7.45-7.48 (m, 2H). LCMS (12 minute method) [M+H]+ = 329/331 @ Rt 5.1 min (90%).
Example 17D : 1 - ( 3 , 4 -Dichlorophenyl ) -3 - (3 -methylamino- propyl ) -3 , 4 -dihydro-lIf-quinolin-2 -one ( 21Dd) This was prepared from (19Da) (150 mg, 0.47 mmol) using the same two-step procedure described for (21Da) to provide the crude product, which was purified by. SCX-2 to give the racemate (111 mg). 1H NMR (300 MHz, CDC13) (racemate) δ 1.49-1.75 (m, 3H), 1.83
(bs, IH), 1.85-1.97 (m, IH), 2.43 (s, 3H), 2.63 (t, J= 13.56, 6.59 Hz, 2H), 2.68-2.77 (m, IH), 2.83-2.94 (m, IH), 3.13 (dd, J= 15.45, 5.28 Hz, IH), 6.36 (dd, J= 7.73, 0.93 Hz, IH), 6.99-7.11 (m, 3H), 7.20-7.21 (m, IH), 7.35 (d, J= 2.26 Hz, IH), 7.57 (d, J= 8.48 Hz, IH). LCMS (12 minute method) [M+H]+ = 363/365 @Rt 5.4 min (92%).
Example 18D : 1 - ( 3 -Chlorophenyl ) -3 - (3 -methylamino-propyl ) - 3 , 4 -dihydro- lff-quinolin-2 -one (21De) This was prepared from (19Da) (200 mg, 0.63 mmol) using the same two-step procedure described for (21Da) to provide the crude product, which was purified by SCX-2 to give the racemate (138 mg). 1H NMR (300 MHz, CDC13) (racemate) δ 1.50-1.77 (m, 3H),
1.89-1.96 (m, 2H), 2.44 (s, 3H), 2.64 (t, J= 6.89 Hz, 2H), 2.69-2.78 (m, IH), 2.84-2.93 (m, IH,), 3.10-3.17 (m, IH), 6.33-6.36 (m, IH), 6.97-7.10 (m, 2H), 7.11-7.15 (m, IH), 7.21-7.24 (m, 2H), 7.37-7.47 (m, 2H). LCMS (12 minute method) [M+H]+ = 329/331 @ Rt 5.01 min (90%).
Example 19D: 1- (4-Fluorophenyl) -3- (3-methylamino-propyl) -
3,4-dihydro-lH-quinolin-2-one (21Df)
This was prepared from (19Da) (200 mg, 0.63 mmol) using the same two-step procedure described for (21Da) to provide the crude product, which was purified by SCX-2 to give the racemate (48 mg). 1H NMR (300 MHz, CDC13) (racemate) δ 1.26-1.28 (m, IH), 1.92
(m, 2H), 2.63 (bs, IH), 2.72 (m, IH), 2.85-3.08 (m, 2H), 3.48-3.51 (m, 5H), 6.32-6.34 (d, J= 7.91 Hz, IH), 7.01-7.70 (m, 2H), 7.16-7.19 (d, J= 7.16 Hz, 5H), 9.46 (bs, IH). LCMS (12 minute method) [M+H]+ = 313 @ Rt 4.5 min (100%).
Example 20D: 1- (4-Ethylphenyl) -3- (3-methylamino-propyl) -3 , 4- dihydro-lH-quinolin-2-one (21Dg)
This was prepared from (19Da) (148 mg, 0.46 mmol) using the same two-step procedure described for (21Da) to provide the racemate (61 mg). 1H NMR (300 MHz, CDC13) (racemate) δ 1.25-1.30 (m, IH), 1.52-1.67(m, IH), 1.69-1.80 (m, 2H), 1.87-1.98 (m, IH), 2.46 (s, 3H), 2.67-2.92 (m, 9H), 3.11-3.16 (m, IH), 6.34-6.37 (m, IH), 6.94-7.06 (m, 2H), 7.09-7.11 (d, J= 8.1 Hz, 2H), 7.17-7.20 (d, J= 7.35 Hz, IH), 7.30-7.33 (d, J= 8.28 Hz,
2H). LCMS (12 minute method) [M+H]+ = 323 @ Rt 5.4 min (98%).
Example 21D : 3 -Methyl -3 - ( 3 -methylamino-propyl ) - 1 -p-tolyl - 3 , 4-dihydro- lH-quinolin-2 -one ( 21Dh) This was prepared from (19Db) (806 mg, 2.89 mmol) using the same methods described for (21Da) to provide the racemate. The racemate was separated into its individual enantiomers using chiral HPLC. 1H NMR (300 MHz, CDCI3) (racemate & isomer) δ 1.24 (s, 3H), 1.60-1.65 (m, 4H), 2.40 (s, 3H), 2.43 (s, 3H), 2.60-2.65 (m, 2H), 2.87 (d, J= 15.73 Hz, IH), 2.98 (d, J= 15.73 Hz, IH), 3.46 (br, IH), 6.30 (dd, J= 7.91, 1.13 Hz, IH), 6.90-7.05 (m, 2H), 7.05 (d, J= 8.29 Hz, 2H), 7.10-7.20 (m, IH), 7.29 (d, J= 7.91 Hz, 2H).
LCMS (12 minute method) [M+H]+ = 323 @Rt 5.06 min (100%).
Example 22D : 1 - (4 -Chlorophenyl ) - 3 -methyl -3 - ( 3 -methylamino- propyl ) -3 , 4 -dihydro- lH-quinolin-2 -one (21Di ) This was prepared from (19Db) (100 mg, 0.30 mmol) using the same methods described for (21Da) to provide the racemate (97 mg). IH NMR (300 MHz, CDC13) (racemate) δ ppm 1.25 (s, 3H), 1.55-1.65 (m, 4H), 2.41 (s, 3H), 2.58 (m, 2H), 2.89 (d, J= 15.82 Hz, IH), 2.98 (d, J= 15.82 Hz, IH), 3.12 (br, IH), 6.29 (dd, J= 7.91, 0.94 Hz, IH) , 6.95-7.10 (m, 2H) , 7.14 (d, J= 8.67 Hz, 2H), 7.15 (m, IH), 7.45 (d, J= 8.67 Hz, 2H). LCMS (12 minute method) [M+H]+ = 343/345 @Rt 5.09 min (100%). Example 23D : 1 - (3 , 4 -Dif luorophenyl ) -3 -methyl -3 - ( 3 - methylamino-propyl ) -3 , 4 -dihydro- lH-quinolin-2 -one (21Dj ) This was prepared from (19Db) (100 mg, 0.30 mmol) using the same two-step procedure described for (21Da) to provide the crude product, which was purified by SCX-2 to give the racemate (100 mg). 1H NMR (300 MHz, CDC13) (racemate) δ ppm 1.25 (s, 3H), 1.55- 1.65 (m, 4H), 2.41 (s, 3H), 2.50-2.60 (m, 2H), 2.89 (d, J= 15.45 Hz, IH), 2.90 (s, IH), 2.98 (d, J= 15.45 Hz, IH), 6.30 (dd, J= 7.91, 1.13 Hz, IH), 6.90-7.10 (m, 4H), 7.18 (dd,
J= 7.16, 1.32 Hz, IH), 7.22-7.35 (m, IH). LCMS (12 minute method) [M+H]+ = 345 @Rt 4.85 min (97%).
Example 24D : 3 -Methyl -3 - (3 -methylamino-propyl ) -1 -m-tolyl - 3 , 4 -dihydro- l.H'-quinolin-2 -one ( 21Dk) This was prepared from (19Db) (100 mg, 0.30 mmol) using the same two-step procedure described for (21Da) to provide the crude product, which was purified by SCX-2 to give the racemate (90 mg). 1H NMR (300 MHz, CDC13) (racemate) δ ppm 1.26 (s, 3H), 1.50-
1.70 (m, 4H), 1.75 (s, IH), 2.38 (s, 3H), 2.39 (s, 3H), 2.50-2.60 (m, 2H), 2.89 (d, J= 15.64 Hz, IH), 2.98 (d, J= 15.64 Hz, IH), 6.30 (dd, J= 7.82, 1.04 Hz, IH), 6.90-7.07 (m, 4H) , 7.18 (dd, J= 13.66, 7.63 Hz, 2H), 7.37 (t, J= 7.63 Hz, IH). LCMS (12 minute method)
[M+H]+ = 323 @Rt 5.09 min (98%).
Example 25D: 1- (3 , 5-Difluorophenyl) -3-methyl-3- (3- methylamino-propyl) -3 , 4-dihydro-lff-quinolin-2-one (21D1)
This was prepared from (19Db) (100 mg, 0.30 mmol) using the same two-step procedure described for (21Da) to provide the crude product, which was purified by SCX-2 to give the racemate (95 mg). 1H NMR (300 MHz, CDCI3) (racemate) δ ppm 1.26 (s, 3H), 1.50-
1.65 (m, 4H), 2.40 (s, 3H), 2.50-2.60 (m, 2H), 2.82 (br, IH), 2.89 (d, J= 15.82 Hz, IH), 2.97 (d, J= 15.82 Hz, IH), 6.34 (dd, J= 8.01, 1.04 Hz, IH), 6.74-6.83 (m, 2H), 6.83-6.92 (m, IH), 6.97-7.13 (m, 2H), 7.19 (dd, J= 7.06, 1.22 Hz, IH). LCMS (12 minute method) [M+H]+ = 345 @ Rt 4.87 min, (97%). Example 26D: 6-Chloro-3- (3-methylamino-propyl) -1-phenyl-3 , 4- dihydro- lH-quinolin-2 -one (21Dm) This was prepared from (20Da) (285 mg, 0.8 mmol) using the same two-step procedure described for (21Da) to provide the crude product, which was purified by preparative LCMS to give the racemate (62 mg). 1H NMR (300 MHz, CDC13) (racemate) δ 1.49-1.76 (m, 3H), 1.86-1.95 (m, IH), 2.33 (bs, IH), 2.44 (s, 3H), 2.61-2.95 (m, 4H), 3.09-3.16 (m, IH), 6.24-6.27 (d, J= 8.67 Hz, IH), 6.99 (dd, J= 8.67, 2.26 Hz, IH), 7.17-7.19 (m, 3H), 7.39-7.44 (m, IH), 7.47-7.52 (m, 2H). LCMS (12 minute method) [M+H]+ = 329/331 @ Rt 5.04 min (93%).
Example 27D : 6 -Chloro- l- (4 -chlorophenyl ) -3 - ( 3 -methylamino- propyl ) -3 , -dihydro- lH-quinolin-2 -one (21Do) This was prepared from (20Da) (160 mg, 0.45 mmol) using the same two-step procedure described for (21Da) to provide the crude product, which was purified by preparative LCMS to give the racemate (52 mg). 1H NMR (300 MHz, CDC13) (racemate) δ 1.57-1.67
(m, IH), 1.73-1.75 (m, 2H), 1.87-1.9 (m, IH), 2.47 (s, 2H), 2.64 (s, IH), 2.68-2.73 (m, 2H), 2.81-2.89 (m, IH), 3.07-3.13 (m, 3H), 6.27 (d, J= 8.48 Hz, IH), 7.02 (d, J= 8.48 Hz, IH), 7.14 (d, J= 8.29 Hz, 2H), 7.19 (s, IH), 7.47 (d, J= 8.29 Hz, 2H). LCMS (12 minute method) [M+H]+ = 363/365 @ Rt 5.4 min (72%).
Example 28D: 6-Chloro-3-methyl-3- (3-methylamino-propyl) -1-p- tolyl -3 , 4 -dihydro- lH-quinolin-2 -one (21Dp) This was prepared from (20Db) (490 mg, 1.34 mmol) using the same methods described for (21Da) to provide the racemate (470 mg). The racemate was separated into its individual enantiomers using chiral HPLC. 1H NMR (300 MHz, CDC13) (racemate) δ
1.25 (s, 3H), 1.50-1.65 (m, 4H), 2.39 (s, 3H), 2.40 (s, 3H), 2.50-2.60 (m, 3H), 2.86 (d, J= 16.01 Hz, IH), 2.94 (d, J= 16.01 Hz, IH), 6.24 (d, J= 8.67 Hz, IH), 6.97 (dd, J= 8.76, 2.35 Hz, IH), 7.03 (d, J= 8.10 Hz, 2H), 7.14 (d, J= 2.26 Hz, IH), 7.29 (d, J= 7.91 Hz, 2H); 1H NMR (300 MHz, MeOD-d4) (isomer hemi-D-tartrate salt) δ 1.15 (s, 3H), 1.50- 1.75 (m, 4H), 2.32 (s, 3H), 2.51 (s, 3H), 2.78 (br, 2H), 2.84 (d, J= 16.20 Hz, IH), 2.98
(m, IH), 3.15-3.25 (m, 2H), 4.22 (s, IH), 6.14 (d, J= 8.85 Hz, IH), 6.90-6.70 (m, 3H), 7.19 (d, J= 2.26 Hz, IH), 7.25 (d, J= 7.91 Hz, 2H). LCMS (12 minute method) [M+H]+ = 357/359 @Rt 5.43 min (100%).
Example 29D: 6-Chloro-l- (4-chlorophenyl) -3-methyl-3- (3- methylamino-propyl) -3 , -dihydro-lH-quinolin-2-one (21Dq)
This was prepared from (20Db) (490 mg, 1.34 mmol) using the same methods described for (21Da) to provide the racemate (425 mg). 1H NMR (300 MHz, CDC13) (racemate) δ ppm 1.25 (s, 3H), 1.50-1.65 (m, 4H), 2.39 (s, 3H), 2.40 (br, IH), 2.50-2.60 (m, 2H), 2.87 (d, J= 16.20 Hz, IH), 2.95 (d, J= 16.20 Hz, IH), 6.23 (d, J= 8.85 Hz, IH), 7.00 (dd, J= 8.57, 2.35 Hz, IH), 7.05-7.20 (m, 3H), 7.40-7.50 (m, 2H). LCMS (12 minute method)
[M+H]+ = 377/379 @Rt 5.26 min (94%).
Example 30D: 3-Methyl-3-(3-methylamino-propyI)-l-thiophen-2-yl-3,4-dihydro-lH- quinolin-2-one (22Da) This was prepared from (19Db) (200 mg, 0.60 mmol) using the same two-step procedure described for (21Da) to provide the crude product, which was purified by SCX-2 to give the racemate (125 mg). 1H NMR (300 MHz, CDC13) (racemate) δ ppm 1.25 (s, 3H), 1.50- 1.65 (m, 4H), 2.39 (s, 3H), 2.50-2.60 (br, 2H), 2.88 (d, J= 16.20 Hz, IH), 2.97 (d, J= 16.20 Hz, IH), 3.17 (br, IH), 6.58 (dd, J= 8.01, 0.85 Hz, IH), 6.89 (dd, J= 3.58, 1.32 Hz, IH), 6.95-7.15 (m, 3H), 7.16 (d, J= 7.16 Hz, IH), 7.32 (dd, J= 5.65, 1.32 Hz, IH). LCMS (12 minute method) [M+H]+ = 315 @Rt 4.35 min (98%).
Example 31D: 3-Methyl-3-(3-methylamino-propyl)-l-thiophen-3-yl-3,4-dihydro-lH- quinolin-2-one (22Db) This was prepared from (19Db) (200 mg, 0.60 mmol) using the same two-step procedure described for (21Da) to provide the crude product, which was purified by SCX-2-2 to give the racemate (128 mg). 1H NMR (300 MHz, CDC13) δ 1.24 (s, 3H), 1.50-1.65 (m, 4H), 2.40 (s, 3H), 2.50-2.60 (m, 2H), 2.87 (d, J= 15.82 Hz, IH), 2.96 (d, J= 15.82 Hz, IH), 3.07 (br, IH), 6.45 (dd, J= 8.10, 0.94 Hz, IH), 6.92 (dd, J= 5.09, 1.32 Hz, IH), 6.98 (td, J= 7.35, 1.13 Hz, IH), 7.07 (td, J= 7.77, 1.60 Hz, IH), 7.16 (d, J= 7.35 Hz, IH), 7.22 (dd, J= 3.20, 1.32 Hz, IH), 7.41 (dd, J= 5.09, 3.20 Hz, IH). LCMS (12 minute method) [M+H]+ = 315 @Rt 4.29 min (100%).
Scheme 4D - Preparation of intermediates
{3-[l-(4-Methoxy-benzyl)-3-methyl-2-oxo-6-phenyl-l,2,3,4-tetrahydro-quinolin-3-yI]- propyl}-methyl-carbamic acid tert-butyl ester (23D) Step (i)
Sodium hydride (340 mg, 60% dispersion in mineral oil, 8.55 mmol, 1.3 eq.) was added portionwise to a soln of (20Dc) (2.7 g. 6.57 mmol) in DMF (40 mL) at 0°C. The reaction mixture was left for 30 min at this temperature and then 4-methoxybenzyl chloride (1.16 mL, 8.55 mmol, 1.3 eq.) in DMF (1 mL) was added dropwise over 10 min. The reaction mixture was warmed to rt slowly and after 1 h was poured into ethyl acetate (200 mL) and extracted with water (3 x 50 mL). The organic layer was separated, dried over MgSO4 and concentrated under vacuo. The crude product was purified using automated chromatography (silica) (0 to 80% ethyl acetate\cyclohexane gradient) to provide the 4- methoxybenzyl protected 6-bromo precursor (2.2 g, 63%). Step (ii)
The product from Step (i) (100 mg, 0.23 mmol), phenylboronic acid (85 mg, 0.70 mmol, 3 eq.), K2CO3 (138 mg, 1 mmol, 4.3 eq.) and Pd(PPh3) (11 mg, 0.009 mmol, 0.04 eq.) were suspended in ethanol (1 mL) and water (0.6 mL). The reaction mixture was heated at 80°C overnight, cooled to rt and filtered through celite. The filtrate was poured into ethyl acetate (100 mL) and water (50 mL) and extracted. The organic layer was separated, dried over MgSO4 and concentrated to provide the product (23D) (120 mg, 98%) that was used without further purification.
Methyl-[3-(3-methyl-2-oxo-6-phenyl-l,2,3,4-tetrahydro-quinolin-3-yl)-propyl]- carbamic acid tert-butyl ester Step (iii) & (iv) A mixture of (23D) (120 mg, 0.23 mmol) and anisole (25 μL, 0.23 mmol) in trifluoroacetic acid (2.3 mL) was heated at 65°C under nitrogen for 4 h. The reaction mixture was concentrated under vacuo and the residue was dissolved in methanol (2 mL). The methanol soln was applied to an SCX-2 column (5g) and the column washed with methanol (50 mL). The product was eluted with 2N Et3N in methanol (50 mL) and the basic soln was concentrated to provide 3-Methyl-3-(3-methylamino-propyl)-6-phenyl-3,4-dihydro-iH- quinolin-2-one (72 mg, 100%). To a soln of this amine (72 mg, 0.23 mmol) in anhydrous TΗF (2 mL) at 0°C was added di-tert-butyl dicarbonate (53 mg, 97%, 0.24 mmol) in one portion. The reaction mixture was warmed to rt and stirred for 3 h. The reaction mixture was poured into ethyl acetate (25 mL) and water (10 mL) and extracted. The organic layer was separated, dried over MgSO4 and concentrated to give the Boc protected precursor (95 mg, 100%). This material was used without further purification.
Scheme 4D - Examples
Example 32D: 3-Methyl-3-(3-methylamino-propyl)-6-phenyl-l-p-tolyl-3,4-dihvdro- lΗ-quinolin-2-one (24D) This was prepared from the above Boc protected precursor (95 mg, 0.23 mmol) using the same two-step procedure described above (19Da to 21Da) to provide the crude product, which was purified by SCX-2 to give the racemate (53 mg). 1H NMR (300 MHz, CDC13) (racemate) δ 1.29 (s, 3H), 1.50-1.70 (m, 4H), 2.42 (s, 6H), 2.55-2.65 (m, 2H), 2.94 (d, J= 15.64 Hz, IH), 3.04 (d, J= 15.64 Hz, IH), 3.18 (br, IH), 6.38 (d, J= 8.29 Hz, IH), 7.09 (d, J= 8.10 Hz, 2H), 7.29 (m, 4H), 7.41 (m, 3H), 7.54 (m, 2H). LCMS (12 minute method) [M+H]+
= 399 @Rt 6.06 min (100%).
The following examples illustrate compounds of of Formulae (IE) above and methods for their preparation.
Preparation of Intermediates
1,1-DimethyIethyl (3S)-3-aminopyrrolidine-l-carboxylate
a) 1,1-Dimethylethyl (3R)-3-hydroxypyrrolidine-l-carboxylate
Solid ditert-butyldicarbonate (38.8g, 178mmol) was added in portions over 15 minutes to a stirred solution of (3R)-pyrrolidin-3-ol hydrochloride (20g, 162mmol), triethylamine (24.8mL, 178mmol) and 4-(dimethylamino)-pyridine (20mg) in dry dichloromethane (300mL). After stirring for 2 hours at room temperature, the mixture was washed with aqueous citric acid, then brine. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (20:80 to 60:40), to give the title compound as a solid.
b) 1,1-Dimethylethyl (3R)-3-[(methylsulfonyl)oxy]-pyrrolidine-l-carboxylate Methanesulfonyl chloride (5.26mL, 68mmol) was added dropwise over 5 minutes to a stirred solution of 1,1-dimethylethyl (3R)-3-hydroxypyrrolidine-l-carboxylate (10.6g,
56.7mmol) and triethylamine (11.8mL, 85mmol) in dichloromethane (250mL) at -10°C. After stirring for 1 hour at 0°C, the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (25:75 to 50:50), to give the title compound as an oil.
c) 1,1-Dimethylethyl (3S)-3-azidopyrrolidine-l-carboxylate
Sodium azide (4.4g, 67.4mmol) was added to a solution of 1,1-dimethylethyl (3R)-3- [(methylsulfonyl)oxy] -pyrrolidine- 1-carboxylate (14.3g, 54mmol) in dry dimethylformamide (75mL) and the resultant suspension heated at 65°C for 8 hours.
After cooling to room temperature, the reaction mixture was diluted with water and extracted into diethyl ether. The organic phase was washed two further times with water, then brine. The organic extracts were dried (MgSO ), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with diethyl ether/cyclohexane (20:80 to 40:60), to give the title compound as an oil.
d) 1,1-Dimethylethyl (3S)-3-aminopyrrolidine- 1-carboxylate
A mixture of 1,1-dimethylethyl (3S)-3-azidopyrrolidine- 1-carboxylate (9.0g, 2.97mmol) and 5% palladium-on-carbon (0.70g) in methanol (150mL) was hydrogenated in a Parr apparatus at 65 p.s.i. for 4 hours. The catalyst was removed by filtration through
Celite and the solvent evaporated in vacuo to give an oil. The resultant title compound was used in subsequent reactions without further purification. 1,1-Dimethylethyl (3R)-3-aminopyrrolidine- 1-carboxylate was similarly prepared as described above, from (3S)-pyrrolidin-3-ol.
1,1-Dimethylethyl (3S)-3-[(l-methylethyl)aminol-pyrrolidine-l-carboxylate
A mixture of 1,1-dimethylethyl (3S)-3-aminopyrrolidine-l-carboxylate (3.0g) and 5% palladium-on-carbon (0.35g) in methanol (75mL) and acetone (15mL) was hydrogenated in a Pan- apparatus at 65 p.s.i. for 3 hours. The catalyst was removed by filtration through Celite and the solvent evaporated in vacuo to give an oil. The resultant title compound was used in subsequent reactions without further purification.
1H NMR (300 MHz, CDC13) δH: 1.11-1.19 (m, 6H), 1.45 (s, 9H), 1.55-1.75 (m, IH), 2.01-2.15 (m, IH), 2.80-2.92 (m, IH), 2.93-3.05 (m, IH), 3.25-3.70 (m, 4H).
The following secondary amines were similarly prepared by reductive alkylation of 1,1-dimethylethyl (3S)-3-aminopyrrolidine- 1-carboxylate with the appropriate aldehyde or ketone:
1,1-Dimethylethyl (3S)-3-(cyclopentylamino)pyrrolidine- 1-carboxylate
1 , 1 -Dimethylethyl (3S)-3-[(cyclohexylmethyl)amino]-pyrrolidine- 1 -carboxylate
1,1-Dimethylethyl (3S)-3-({[2-(trifluoromethyl)phenyll-methyl)amino)pyrrolidine-l- carboxylate
Method A
a)(3S)-N- { (E)-[2-(Trifluoromethyl)phenyl]methylidene ) -pyrrolidin-3 -amine
3(S)-Pyrrolidin-3-amine (0.45g, 5.2mmol) and trifluoromethylbenzaldehyde (0.87g, 5.0mmol), a crystal of 4-toluenesulphonic acid and toluene were refluxed with stirring for one day, using a Dean and Stark apparatus. The solution was evaporated in vacuo to give the title compound as a brown oil (M+H = 243).
b) 1,1-Dimethylethyl (3S)-3-({(E)-[2-(trifluoromethyl)- phenyl]methylidene } amino)pyrrolidine- 1 -carboxylate (3S)-N- { (E)- [2-(Trifluoromethyl)phenyl]methylidene } -pyrrolidin-3-amine ( 1.21 g, 5mmol) was dissolved in dichloromethane (50 mL), and di-tert-butyl dicarbonate (l.lg, 5.05mmol) followed by DMAP (60mg, 0.5mmol) was added. After stirring under nitrogen for 4 hours, the solution was evaporated in vacuo to give the title compound as a brown oil (M + H = 343).
c) 1 , 1 -Dimethylethyl (3S)-3-( { [2-(trifluoromethyl)-phenyl]methyl } amino)pyrrolidine- 1 - carboxylate 1,1 -Dimethylethyl (3S)-3-( { (E)-[2-(trifluoromethyl)- phenyl]methylidene]amino)pyrrolidine- 1-carboxylate (1.71g, 5mmol) was hydrogenated in the presence of 5% palladium on carbon (250mg) at 65psi in ethanol (60mL). After 3.5 hours, the catalyst was filtered off and the filtrate evaporated in vacuo to give an oil. The oil was purified by automated flash chromatography over silica, eluting with 10% ethyl acetate in cyclohexane (10:90 to 50:50), to give the title compound as a colourless oil (l.Og, 58%; M +
H = 345).
Method B
a) (3S)-N- { [2-(Trifluoromethyl)phenyl]methyl } pyrrolidin-3-amine
A mixture of 3(S)-pyrrolidin-3-amine (4g, 46.5mmol), 2-trifluoromethylbenzaldehyde (9.1g, 46.5mmol), 5% palladium on carbon (0.4g) and ethanol (150mL) was hydrogenated at 60psi for 3 hours using a Parr hydrogenator. The catalyst was filtered off and the filtrate evaporated in vacuo to give the title compound as an oil. MS: [M+H] = 245.
b) 1,1-Dimethylethyl (3S)-3-({ [2-(trifluoromethyl)-phenyl]methyl)amino)pyrrolidine-l- carboxylate
(3S)-N-{ [2-(Trifluoromethyl)phenyl]methyl}pyrrolidin-3-amine (12g, 49.2mmol) was dissolved in dichloromethane (120 mL), then di-tert-butyl dicarbonate (10.7g, 49.2mmol) and DMAP (40mg, 0.33mmol) were added. After stirring under nitrogen for 1 day, the solution was evaporated in vacuo to give an oil. The oil was purified by automated flash chromatography over silica, eluting with ethyl acetate in cyclohexane (0:100 to 40:60), to give the title compound as a colourless oil. MS: [M+H] = 345.
l.l-Dimethylethyl (3S)-3-({[4-fluoro-2-(trifluoromethyl)- phenyl]methyl}amino)pyrroIidine-l-carboxylate
1,1-Dimethylethyl (3S)-3-aminopiperidine-l -carboxylate (5g) and 4-fluoro-2- (trifluoromethyl)benzaldehyde (5.15g, 26.8mmol)were allowed to stir in methanol for 16h at room temperature. Sodium borohydride (1.62g, 26.8mmol) was then added portionwise. The resulting solution was further stiπ-ed for 2 h at room temperature. The solvent was evaporated in vacuo, water was added, and the solution extracted with dichloromethane. The organic extracts were absorbed onto a methanol washed cationic ion exchange resin (Isolute ™ SCX-2). The basic components were recovered from the column by elution with 7N ammonia in methanol. The resultant solution was concentrated in vacuo to yield the desired compound as an oil. This was further purified by column chromatography on silica gel, eluting with ethyl acetate/iso-hexane (0:100 to
40:60). The title compound was used in subsequent reactions without further purification.
1H NMR (300 MHz, CDC13) δH: 7.37-7.28 (m, 2H), 7.24-7.20 (m, IH), 3.80 (s, 2H), 3.52-3.48 (m, 2H), 3.32 (m, 3H), 3.12 (m, IH), 2.08-2.0 (m, IH), 1.75 (m, IH), 1.45
(s, 9H).
The following secondary amines were similarly prepared by reductive alkylation of 1,1-dimethylethyl (3S)-3-aminopiperidine- 1-carboxylate with the appropriate benzaldehyde:
1.1 -Dimethylethyl (3S)-3- { F(3 ,5-dichloiO-phenyl)methyl] -amino ) pyrrolidine- 1 - carboxylate. 1,1-Dimethylethyl (3S)-3-{ [(5-fluoro-2-(trifluoromethyl)- phenyl)methyl] amino ) pyrrolidine- 1 -carboxylate.
1 , 1 -Dimethylethyl (3S)-3- { [(2-chloro-4-fluoro-phenyl)-methyl] amino } pyrrolidine- 1 - carboxylate. Example IE: (35) -N- (1-Methylethyl) -N- { [3 , 5-dichlorophenyl] - methyl }pyrrolidin-3 -amine D-tartrate
a) 1,1-Dimethylethyl (3S)-3-((l-methylethyl)-{ [3,5-dichlorophenyl]methyl}amino)- pyrrolidine- 1 -carboxylate
To a solution of 1,1-dimethylethyl (3S)-3-[(l-methylethyl)amino]-pyrrolidine-l- carboxylate (lg, 4.4 mmol) and 3,5-dichlorobenzaldehyde (1.53g, 8.77 mmol) in trimethylorthoformate (10 mL) at room temperature under a nitrogen atmosphere was added portionwise sodium triacetoxyborohydride (1.3g, 6.1 mmol). The reaction was stirred at room temperature for 72 hours, then evaporated to dryness in vacuo. The residue was taken up in aqueous saturated sodium hydrogen carbonate/dichloromethane mixture. The aqueous layer was further extracted with dichloromethane (3X), and the combined organic layers dried (MgSO4) and evaporated to dryness in vacuo. The resulting residue was dissolved in methanol and filtered through a cationic ion exchange resin (Isolute ™
SCX-2). The basic components were recovered from the column by elution with 2N ammonia in methanol. This solution was concentrated in vacuo to yield the desired compound as a yellow oil that was used in the next step without further purification. 1H NMR (300 MHz, CDC13) δH: 0.95-1.04 (m, 6H), 1.45 (s, 9H), 1.56-1.77 (m, IH), 1.8-1.94 (m, IH), 2.9-3.09 (m, 2H), 3.11-3.25 (m, IH), 3.32-3.56 (m, 3H), 3.59 (s, 2H), 7.15-7.27
(m, 3H). MS: [M+H] = 387/389/391.
b)(3S)-N-(l-Methylethyl)-N-{ [3,5-dichlorophenyl]methyl)-pyrrolidin-3-amine D-tartrate 1,1-Dimethylethyl (3S)-3-((l-methylethyl)-{ [3,5- dichlorophenyl]methyl]amino)pyrrolidine-l-carboxylate (1.36g, 3.51 mmol) was dissolved in a mixture of dichloromethane and trifluoroacetic acid (10 mL, 2:1) and stirred at room temperature for 30 minutes. The reaction solution was concentrated in vacuo and redissolved in MeOH. This solution was filtered through a cationic ion exchange resin (Isolute ™ SCX-2). The basic components were isolated by elution with 2Ν ammonia in methanol and further purified by UN guided prep-LC. The desired compound was isolated from the acidic prep-LC mobile phase via a cationic ion exchange resin as described above. After evaporation in vacuo the residue was dissolved in hot cyclohexane (5 mL) and to this was added an equimolar amount of D-tartaric acid (450 mg), dissolved in a minimal amount of hot isopropanol. The solution was evaporated in vacuo to yield the title compound as a solid. 1H NMR (300 MHz, d6-DMSO) δH: 0.95- 0.99 (m, 6H), 1.58-1.71 (m, IH), 1.91-2.00 (m, IH), 2.76-2.91 (m, 2H), 2.97-3.07 (m, IH), 3.18-3.25 (m, 2H), 3.55-3.67 (m, 4H), 3.95 (s, 2H), 7.37-7.38 (m, 2H), 7.43-7.45 (m,
IH). MS: [M+H] = 287/289/291.
The following Examples were similarly prepared as described above for Example IE, by reductive alkylation of 1,1-dimethylethyl (3S)-3-[(l-methylethyl)amino]-pyrrolidine-l- carboxylate with the appropriate substituted benzaldehyde:
Example 2E : ( 35) -N- ( 1-Methylethyl ) -N- { [2 -
(methylthio) phenyl] methyl ) -pyrrolidin- 3 -amine fumarate
1H NMR (300 MHz, CD3OD) δH: 0.99 (s, 6H), 2.06 (m, IH), 2.37 (s, 3H), 3.01-2.85
(m, IH), 3.18-3.06 (m, IH), 3.46-3.19 (m, 4H), 3.67 (dd, 2H), 6.60 (s, 2H), 7.10-7.02 (m, IH), 7.20-7.11 (m, 2H), 7.40 (dd, IH); MS: [M+H] = 265.
The following Examples were similarly prepared as described above for Example IE, by reductive alkylation of 1,1-dimethylethyl (3S)-3-[(cyclohexylmethyl)amino]- pyrrolidine- 1-carboxylate with the appropriate substituted benzaldehyde:
Example 3E: (35) -N- (Cyclohexylmethyl) -N- { [2- (methylthio) henyl] -methyl }pyrrolidin-3-amine fumarate
1H NMR (300 MHz, CD3OD) δH: 0.86-0.69 (s, 3H), 1.22-1.12 (m, 3H), 1.41-1.29 (m, IH), 1.84-1.67 (m, 5H), 2.16-1.95 (m, 2H), 2.34 (d, 2H), 2.38 (s, 3H), 3.23-3.05 (m, IH), 3.44-3.28 (m, 4H), 3.78-3.55 (m, 2H), 6.70 (s, 2H), 7.16 (s, 2H), 7.35-7.32 (m, IH); MS: [M+H] = 319.
Example 4E: (35) -N- (Cyclohexylmethyl) -N- [ (2- fluorophenyl) methyl] -pyrrolidin-3-amine fumarate 1H NMR (300 MHz, CD3OD) δH: 0.83-0.75 (s, 6H), 1.24-1.17 (m, 3H), 1.48-1.42 (m,
IH), 1.85-1.68 (m, 5H), 2.03-1.92 (m, IH), 2.17-2.10 (m, IH), 2.35 (d, 2H), 3.25-3.05
(m, IH), 3.44-3.32 (m, 4H), 3.81-3.62 (m, 2H), 6.71 (s, 2H), 7.20-7.05 (m, 2H), 7.33-7.27
(m, IH), 7.47-7.42 (m, IH); MS: [M+H] = 291.
Example 5E: (35) -N- [ (2-Chlorophenyl) methyl] -N-
(cyclohexylmethyl) -pyrrolidin-3 -amine fumarate
1H NMR (300 MHz, CD3OD) δH: 0.89-0.77 (m, 2H), 1.24-1.13 (m, 3H), 1.36 (d, 6H) , 1.49-1.42 (m, IH), 1.83-1.68 (m, 5H), 2.15-1.93 (m, 2H), 2.35 (d, 2H), 3.20-3.06 (m,
IH), 3.33-3.23 (m, 4H), 3.75-3.42 (m, 2H), 4.69-4.61 (m, IH), 6.70 (s, 2H), 6.98-6.88 (m, 2H), 7.35 (d, IH), 7.50-7.19 (m, IH); MS: [M+H] = 307.
Example 6E : ( 35) -N- (Cyclohexylmethyl ) -N- ( ( 2 - [1 - (methylethyl ) oxy] -phenyl jmethyl ) pyrrolidin-3 -amine fumarate
1H NMR (300 MHz, CD3OD) δH: 0.89-0.77 (m, 2H), 1.24-1.13 (m, 3H), 1.36-1.34 (dd, 6H), 1.49-1.42 (m, IH), 1.83-1.68 (m, 5H), 1.93 (m, 2H, m), 2.35 (d, 2H), 3.20-3.06 3.20-3.06 (m, IH), 3.33-3.23 (m, 4H), 3.75-3.42 (m, 2H), 4.69-4.61 (m, IH), 6.70 (s, 2H), 6.98-6.88 (m, 2H), 7.35 (d, IH), 7.50-7.19 (m, IH); MS: [M+H] = 331.
Example 7E : ( 35) -N- { [5 -Fluoro-2 -
(trif luoromethyl ) phenyl] methyl ) -N- (tetrahydro-2H-pyran-4 - yl ) pyrrolidin-3 -amine P-tartrate
a) 1 , 1-Dimethyleth l (35) -3 - [ ( tetrahydro-2H-pyran-4 - yl) amino] pyrrolidine- 1-carboxylate Neat tetrahydro-4H-pyran-4-one (18.7g, lOOmmol) and 1,1-dimethylethyl (3S)-3- aminopyrrolidine- 1-carboxylate (26.1g, 140.1 mmol) were stirred together for 20 minutes prior to addition of anhydrous dichloroethane (140mL). The solution was then cooled to
0°C under nitrogen and stirred as sodium triacetoxyborohydride ( 59.2g, 281mmol) was added portionwise. The reaction was allowed to warm to room temperature and stirred for 5 days, after which the reaction solution was carefully poured onto ice-cold aqueous sodium hydrogen carbonate solution. The phases were separated and the aqueous phase washed with dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The crude product was purified by automated flash chromatography on silica, eluting with methanol in ethyl acetate (0:100 to 30:70), to provide the title compound as an off-white solid. 1H NMR (300 MHz, d6-DMSO) δH:
1.13-1.29 (m, 2H), 1.39 (s, 9H), 1.55-1.65 (m, IH), 1.68-1.81 (m, 2H), 1.87-2.00 (m, IH), 2.64 (sep, IH), 2.91 (sex, IH), 3.10-3.45 (m, 6H), 3.81 (dt, 2H). MS: [M+H] = 271, [M+H-tBu] = 215.
b) (3S)-N- { [5-Fluoro-2-(trifluoromethyl)phenyl]methyl } -N-(tetrahydro-2H-pyran-4- yl)pyrrolidin-3-amine D-tartrate
To a stirred solution of 1,1-dimethylethyl (3S)-3-[(tetrahydro-2H-pyran-4- yl)amino]pyrrolidine- 1-carboxylate (1.12g, 4.2mmol) and 5-fluoro-2- (trifluoromethyl)benzaldehyde (4.56g, 23.8mmol) in anhydrous dichloroethane (50mL) was added portionwise sodium triacetoxyborohydride (3.86g, 18.3mmol). The reaction mixture was stirred at room temperature under nitrogen and the reaction progress was followed by MS. After 2 days more reagents were added: 5-fluoro-2- (trifluoromethyl)benzaldehyde (0.98g, 5.1mmol) and sodium triacetoxyborohydride (3.00g, 14.2mmol), and after a further 2 days the reaction was found to be complete. The reaction solution was carefully poured onto ice-cold saturated aqueous sodium hydrogen carbonate solution and filtered through a PTFE hydrophobic frit. The organic phase was concentrated in vacuo and the residue redissolved in methanol. The methanolic solution was filtered through a cationic ion exchange resin (Isolute ™ SCX-2) and the basic components isolated by elution with 2Ν ammonia in methanol. After concentrating in vacuo, the residue was redissolved in dichloromethane /trifluoro-acetic acid (2:1) and allowed to stir at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and redissolved in methanol. The methanolic solution was filtered through a cationic ion exchange resin (Isolute ™ SCX-2) and the basic components isolated by elution with 2N ammonia in methanol. The crude product was purified by UV guided prep-LC, and the desired compound collected from the acidic prep-LC mobile phase via a cationic ion exchange resin, as described above. The basic product was dissolved in hot cyclohexane and to this was added an equimolar amount of D-tartaric acid dissolved in a minimal amount of hot isopropanol. The solution was allowed to cool overnight, and the next day the resultant solid was filtered off and dried in vacuo, to yield the title compound as a white crystalline solid. 1H NMR (300 MHz, d6-DMSO) δH: 1.40-1.80 (m, 5H), 1.91- 2.06 (m, IH), 2.61-2.74 (m, IH), 2.81-2.93 (dd, IH), 2.97-3.11 (dt, IH), 3.12-3.31 (m, 4H), 3.69-3.96 (m, 7H), 7.49-7.61 (m, 2H), 7.90-7.99 (m, IH). MS: [M+H] = 347.
The following Examples were similarly prepared from 1,1-dimethylethyl (3S)-3- [(tetrahydro-2H-pyran-4-yl)amino]pyιτolidine- 1-carboxylate and the appropriate benzaldehyde, as described above for Example 7E:
Example 8E : ( 35) -N- { [2 - (Trifluoromethyl ) phenyl] methyl } -N- (tetrahydro-2ff-pyran-4 -yl ) pyrrolidin-3 -amine hemi -D-tartrate
1H NMR (300 MHz, d6-DMSO) δH: 1.35-1.75 (m, 5H), 1.90-2.04 (m,lH), 2.63-2.75 (m, IH), 2.76-2.86 (m, IH), 2.94-3.03 (m, IH), 3.10-3.25 (m, 4H), 3.67-3.90 (m, 6H),
7.43 (t, IH), 7.66 (t, 2H), 7.92 (d, IH); MS: [M+H] = 329.
Example 9E: (3S) -N- (1-Methylethyl) -N- { [2- (trifluoromethyl) - 5- fluorophenyl] ethyl}pyrrolidin-3 -amine fumarate
a) 1,1-Dimethylethyl (3S)-3-((l-methylethyl)-{ [2-(trifluoromethyl)-5- fluorophenyl]methyl } amino)-pyrrolidine- 1 -carboxylate
A solution of 1,1-dimethylethyl (3S)-3-[(l-methylethyl)amino]pyrrolidine-l- carboxylate (0.34g, 1.5mmol) and 2-(trifluoromethyl)-5-fluorobenzyl bromide (0.58g,
2.25mmol) in acetonitrile (5mL) was heated at reflux with anhydrous potassium carbonate (0.4 lg, 3mmol) for 24 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with water. The organic extracts were washed with brine, dried (MgSO ), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (0: 100 to 10:90), to give the title compound as an oil. b) (3S)-N-(l-Methylethyl)-N-{ [2-(trifluoromethyl)-5- fluorophenyl] methyl ) pyrrolidin-3 -amine fumarate
A solution of 1,1-dimethylethyl (3S)-3-((l-methylethyl)-{ [2-(trifluoromethyl)-5- fluorophenyl] -methyl } amino)-pyrrolidine- 1 -carboxylate (0.26g) in a mixture of trifluoroacetic acid (2mL), dichloromethane (8mL) and water (0.2mL) was stirred at room temperature for 3 hours. The reaction mixture was evaporated in vacuo. The crude mixture was taken up in methanol and absorbed onto an SCX-2 ion exchange cartridge. After initially washing with methanol, the product was eluted with 2M methanolic ammonia and the collected fractions evaporated in vacuo. The crude product was taken up in methanol and fumaric acid (1 equiv.) in methanol added. The solvent was removed in vacuo and the resultant gum triturated with diethyl ether. The solid formed was filtered off and dried in vacuo at 50°C to yield the title compound as an off-white microcrystalline solid. 1H ΝMR (300 MHz, CD3OD) δH: 1.09 (d, 3H), 1.10 (d, 3H), 1.87 (m, IH), 2.15 (m, IH), 3.01 (m, 2H), 3.23 (m, IH), 3.38 (m, 2H), 3.81 (m, IH), 3.91 (s,
2H), 6.70 (s, 2H), 7.15 (dt, IH), 7.73 (m, 2H); MS: [M+H] = 305.
The following Examples were similarly prepared as described for Example 9E, using the appropriate substituted benzyl bromide in step b) above:
Example 10E: (3S)-N-([l.l'-Biphenyll-2-ylmethyl)-N-(l-methylethyl)-pyrrolidin-3- amine fumarate
1H ΝMR (300 MHz, CD3OD) δH: 0.95 (d, 6H), 1.75 (m, IH), 1.91 (m, IH), 2.75 (dd, IH), 2.93 (sept, IH), 3.10 (m, 2H), 3.25 (m, IH), 3.60 (m, 3H), 6.70 (s, 2H), 7.17 (dd,
IH), 7.25-7.48 (m, 7H), 7.67 (d, IH); MS: [M+H]= 295.
Example HE: Methyl ((3S)-pyrrolidin-3-yl|[2-(trifluoromethyl)phenyll- methyl)amino)acetate D-tartrate
60% Sodium hydride oil dispersion (39mg, 0.95mmol) was added to 1,1-dimethylethyl (3S)-3-( {[2-(trifluoromethyl)-phenyl]methyl}amino)pyrrolidine-l -carboxylate (250mg, 0.73mmol) in DMF (5mL). After heating at 50°C for 1 hour under nitrogen, methyl bromoacetate (123mg, 0.73mmol) was added. After heating overnight at 50°C overnight, excess water was added and the product was extracted into ether. The ether was washed with water, dried (MgSO ) and evaporated in vacuo to give an oil (460mg). The oil was dissolved in dichloromethane (5mL) and trifluoroacetic acid (0.5mL) was added. After stirring for 1 day, the solution was evaporated in vacuo to give an oil. The oil was purified using preparative LCMS to give the product as the acetate salt, which was converted to the free base by absorption onto a cationic ion exchange resin (Isolute ™ SCX-2) and eluting the basic fractions with 2N ammonia in methanol. The resultant oil was converted to the D- tartaric acid salt (crystallised from ethanol/ diethyl ether) to give the title compound as a white solid. 1H NMR(300 MHz, CD3OD) δH: 1.84-196 (m, IH), 2.06-2.14 (m, IH), 3.06-3.37 (2 x m,6H), 3.57 (s, 3H), 3.77-3.86 quin,lH), 3.91-4.06 (q, 2H), 4.29 (s, 2H), 7.32-7.36 (t, IH), 7.49-7.54 (t, IH), 7.56-7.59 (d, IH), 7.76-7.89 (d, IH); MS: [M+H] = 317.
The following Examples were prepared from 1 , 1 -dimethylethyl (3S)-3- aminopyrrolidine- 1-carboxylate by initial reductive alkylation with 2- methylpropanaldehyde, followed by a second reductive alkylation with the appropriate benzaldehyde and subsequent deprotection.
Example 12E: (3S) -N- [2- (Methoxy) henyl] methyl) -N- (2- methylpropyl) pyrrolidin-3 -amine fumarate
^ NMR (300 MHz, CD3OD) δH: 0.82 (dd, 6H) , 1.66 (sept, IH) , 1.79-1.92 (m, IH) , 1.92-2.06 (m, IH) , 2.19-2.22 (m, 2H) , 2.96- 3.13 (m, 2H) , 3.18-3.31 (m, 2H) , 3.59-3.67 (m, 2H) , 3.74 (s, 3H) , 6.59 (s, 2H) , 6.80-6.87 (m, 2H) , 7.11-7.18 (m, IH) , 7.25 (dd, IH) ; MS: [M+H] = 263.
The following Examples were prepared from 1,1-dimethylethyl (3S)-3-({[2- (trifluoromethyl)phenyl]-methyl } amino)pyrrolidine- 1 -carboxylate by reductive alkylation with the appropriate aldehyde or ketone and subsequent deprotection. Example 13E; (35) -N- (1-Methylethyl) -N- [2- (trifluoromethyl) - phenyl] methyl}pyrrolidin-3 -amine fumarate
1H NMR (300 MHz, CD3OD) δH: 7.98-8.00 (d, IH), 7.60-7.68 (d+t, 2H), 7.38-7.43(t, IH), 6.70 (s, 2H), 3.91 (bs, 2H), 3.74-3.85 (m, IH), 3.17-3.40 (M, 5H), 2.96-3.10 (m,3H), 2.08-2.18 (m, IH), 1.82-1.96 (m,lH), 1.08-1.11 (dd, 6H); MS: [M+H] = 287.
Example 14E: (35) -iV-Ethyl-2^-{ [2-
( trifluoromethyl) phenyl] methyl) -pyrrolidin-3 -amine fumarate
1H NMR (300 MHz, CD3OD) δH: 8.00-8.03 (d, IH), 7.67-7.76 (d+t, 2H), 7.47-7.52 (t, IH), 6.77 (s, 2H), 3.89-4.03 (q, 2H), 3.65-3.75 (quin, 2H), 3.43-3.53 (m, 2H), 3.28-3.41 (m, IH), 3.17-3.23 (m, IH), 2.73-2.84 (q, 2H), 2.19-2.30 (m, 2H), 2.19-2.30 (m, IH), 1.98-2.14 (m, IH), 1.10-1.15 (t, 3H); MS: [M+H] = 273. Example 15E; (35) -iV-Propyl-flf-{ [2- (trifluoromethyl) phenyl] methyl) -pyrrolidin-3 -amine fumarate
2H NMR (300 MHz, CD3OD) δH : 7.92-7.94 (d, IH) , 7.60-7.69) d+t, 2H) , 7.40-7.45 (t, IH) , 6.69-6.73 (s, 2H) , 3.82-3.98 (q, 2H) , 5.59-3.69 (quin, IH) , 3.35-3.45 (m, 2H) , 2.80-3.21 (m, IH) , 3.08-3.15 (m, IH) , 2.54-2.59 (q, 2H) , 2.10-2.21 (m, IH) , 1.90-2.06 (m, IH) , 1.44-1.56 (quin, 2H) , 0.86-0.91 (T, 3H) ; MS: [M+H] = 287.
Example 16E: (35) -ΪV- (Cyclohexylmethyl) -N- { [2 - (trifluoromethyl) -phenyl] methyl)pyrrolidin-3 -amine fumarate XH NMR (300 MHz, CD3OD) δH : 77.89-7.92 (d, IH) , 7.61-7.70 (d+t, 2H) , 7.41-7.49 (t, IH) , 6.70 (s, 2H) , 3.81-3.95 (q, 2H) , 3.56-3.67 (quin, IH) , 3.31-3.43 (m, 2H) , 3.14-3.23 (m, IH) , 3.04-3.11 (m, IH) , 2.39-2.41 (d, 2H) , 2.06-2.13 (m, IH) , 1.70- 2.01 (m, 6H) , 1.34-1.46 (m, IH) , 1.12-1.23 (m, IH) , 0.83-0.89 (m, 2H) ; MS: [M+H] = 341. Example 17E ; (35) -JY-Butyl-Jf- { [2 -
(trifluoromethyl) phenyl] methyl) -pyrrolidin-3 -amine fumarate 1H NMR (300 MHz, CD3OD) δH: 7.91-7.94 (d, IH), 7.60-7.69 (m, 2H), 7.40-7.45 (t, IH), 6.70 (s, 2H), 3.82-3.96 (q, 2H), 3.59-3.69 (quin, IH), 3.32-3.50 (m, 2H), 3.22-3.29 (m, IH), 3.09-3.15 (q, IH), 2.58-2.63 (t, 2H), 2.10-2.21 (m, IH), 1.90-2.04 (m, IH), 1.42- 1.51 (m, 2H), 1.17-1.37 (m, 2H), 0.87-0.91 (t, 3H); MS: [M+H] = 301.
Example 18E; (35) -N- (2-Ethylbutyl) -N- [2- (trifluoromethyl) phenyl] -methyl)pyrrolidin-3 -amine sesquifumarate
1H NMR (300 MHz, CD30D) OH: 7.77-7.80 (d, IH) , 7.49-7.60 (m, 2H) , 7.29-7.34 (t, IH) , 6.60 (s, 1.5H) , 3.70-3.81 (q, 2H) , 3.46-3.57 (quin, IH) , 3.20-3.33 (m, 2H) , 2.94-3.13 (m, 2H) , 2.32-2.34 (d, 2H) , 1.97-2.07 (m IH) , 1.78-1.91 (m, IH) , 1.05-1.40 ( , 5H) , 0.69-0.76 (m, 6H) . MS: [M+H] = 329.
Example 19E: (35) -N- [2- (Trifluorome hyl) phenyl] methyl)-iV- (3,3, 3 - trifluoropropyl) pyrrolidin-3 -amine fumarate
XH NMR (300 MHz, CD30D) δH: 7.76-7.78 (d, IH) , 7.50-7.60 (d+t, 2H) , 7.32-7.37 (t, IH) , 6.58 (s, 2H) , 3.75-3.89 (q, 2H) , 3.48-3.59 (quin, IH) , 3.126-3.22 (m, IH) , 2.98-3.05 (dd, IH) , 2.75-2.80 (t, 2H) , 2.18-2.34 (m, 2H) , 2.02-2.13 (m, IH) , 1.80- 1.93 (m, IH) ; MS: [M+H] = 341.
Example 20E: (35) -N- (Furan-2-ylmethyl) -N- [2-
( trifluoromethyl) phenyl] -methyl)pyrrolidin-3 -amine D-tartrate E NMR (300 MHz, CD3OD) δπ: 7.83-7.86 (d, IH) , 7.49-7.58 (t+s, 2H) , 7.29-7.38 (m, 2H) , 6.23-6.26 (m, IH) , 6.14-6.15 (m, IH) , 4.30 (s, 2H) , 3.78-3.91 (q, 2H) , 3.66-3.67 (m, 2H) , 3.25- 3.55 (m, 3H) , 2.30-3.17 (m, 2H) , 2.05-2.16 (m, IH) , 1.83-1.96 (m, IH) ; MS: [M+H] = 325. Example21E:(3S)-N-r3-(Methylthio)propyll-N-ir2-(trifluoromethylV phenyllmethyl)pyrrolidin-3-amine D-tartrate
XH ΝMR (300 MHz, CD3OD) δ^: 7.90-7.92 (d,lH) , 7.61-7.70 (d+t, 2H) , 7.41-7.46 (t, IH) , 4.42 (s, 2H) , 3.84-3.97 (q, 2H) , 3.59- 3.69 (quin, IH) , 3.38-3.47 (m, 2H) , 3.19-3.29 (m, IH) , 3.09- 3.16 (m, IH) , 2.70-2.77 (dt, 2H) , 2.48-2.52 (t, 2H) , 2.08-2.21 (m, IH) , 1.89-2.08 (s+m, 4H) , 1.69-1.79 (quin, 2H) ; MS: [M+H] = 333.
Example 22E: N- (Phenylmethyl) -N- [ (35) -pyrrolidin-3 -yl] -iV-{ [2 - (trifluoromethyl) phenyl] methyl)amine fumarate
2H ΝMR (300 MHz, CD3OD) δπ: 7.93-7.96 (d, IH) , 7.60-7.68 (q, 2H) , 7.23-7.44 (m, 6H) , 6.69 (s, 2H) , 3.83-3.94 (s,2H) , 3.61-
3.80 (m, 3H) , 3.32-3.44 (m, 2H) , 3.08-3.25 (m, 2H) , 1.99-2.22
(m, 2H) ; MS: [M+H] = 335.
Example 23E; (35) -N- [2- (Methyloxy) phenyl] methyl) -N- [2 -
(trifluoromethyl) phenyl] methyl )pyrrolidin- 3 -amine fumarate 1H ΝMR (300 MHz, CD3OD) δH: 7.85-7.87 (d, IH), 7.61-7.64 (d, IH), 7.52-7.58 (t,
IH), 7.21-7.40 (m, 3H), 6.81-6.97 (m, 2H), 6.69 (s, 2H), 3.61-3.97 (m, 8H), 3.16-3.44 (m,
4H), 1.20-2.21 (m, 2H); MS: [M+H] = 365.
Example 24E: (35) -iV,,.V-bis{ [2- (Trifluoromethyl) phenyl] methyl) - pyrrolidin-3 -amine fumarate
2H ΝMR (300 MHz, CD3OD) δH : 7.90-7.92 (d, 2H) , 7.66-7.69 (d, 2H) ,7.59-7.64 (t, 2H) , 7.40-7.45 (t, 2H) , 6.69 (s, 2H) , 3.91 (s, 4H) , 3.62-3-74 (quin, IH) , 3.36-3.46 (m, 2H) , 3.16-3.26 (m, 2H) , 2.02-2.24 (m, 2H) ; MS: [M+H] = 403.
The following examples illustrate compounds of of Formulae (IF) above and methods for their preparation. Preparation of Intermediates
1,1-Dimethylethyl (3S)-3-aminopiperidine-l-carboxylate
e) 1,1 -Dimethylethyl (3R)-3-hydroxypiperidine- 1 -carboxylate
Solid ditert-butyldicarbonate (26.6g, 122mmol) was added in portions over 15 minutes to a stirred solution of (3R)-piperidin-3-ol hydrochloride (15.25g, lllmmol), triethylamine (30.9mL, 222mmol) and 4-(dimethylamino)-pyridine (50mg) in dry dichloromethane (300mL). After stirring for 18 hours at room temperature, the mixture was washed with aqueous citric acid, then brine. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (20:80 to 80:20), to give the title compound as a solid.
f) 1,1-Dimethylethyl (3R)-3-[(methylsulfonyl)oxy]-piperidine-l-carboxylate Methanesulfonyl chloride (9.56mL, 124mmol) was added dropwise over 10 minutes to a stirred solution of 1,1-dimethylethyl (3R)-3-hydroxypiperidine-l-carboxylate (20.7g, 103mmol) and triethylamine (21.5mL, 154mmol) in dichloromethane (300mL) at 0°C. After stirring for 3 hour at 0°C, the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (20:80 to 50:50), to give the title compound as an oil.
g) 1,1 -Dimethylethyl (3S)-3-azidopiperidine- 1 -carboxylate
Sodium azide (7.65g, 118mmol) was added to a solution of 1,1-dimethylethyl (3R)-3- [(methylsulfonyl)oxy]-piperidine-l-carboxylate (21.9g, 78.5mmol) in dry dimethylformamide (120mL) and the resultant suspension heated at 70°C for 48 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted into ethyl acetate. The organic phase was washed two further times with water, then brine. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (10:90 to 50:50), to give the title compound as an oil.
h) 1,1 -Dimethylethyl (3S)-3-aminopiperidine- 1 -carboxylate
A mixture of 1,1-dimethylethyl (3S)-3-azidopiperidine-l-carboxylate (7.5g) and 10% palladium-on-carbon (0.75g) in methanol (lOOmL) was hydrogenated in a Parr apparatus at 70 p.s.i. for 16 hours. The catalyst was removed by filtration through Celite and the solvent evaporated in vacuo to give an oil. The resultant title compound was used in subsequent reactions without further purification.
2-(TJromomethyl)-4-fluoro-l,l'-biphenyl
a) Methyl 5-fluoro-2-{[(trifluoromethyl)sulfonyl]-oxy}benzoate 5-Fluorosalicylic acid methyl ester (28.2g, 166mmol) was dissolved in dry dimethylformamide (165mL) and stirred as sodium hydride (60% in oil) (7.30g, l.leq) was added portionwise over 30 mins at 0°C. The reaction mixture was stirred for a further 30 mins at room temperature, then N-phenyl trifluoromethanesulfonimide (62.8g, 1.05eq) was added in portions over 30 mins, then left to stir for 3 hours. The mixture was diluted with diethyl ether and washed successively with water, then brine. The organic layers were combined, dried (MgSO4), filtered and the solvent removed in vacuo. The resulting oil was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (10:90 to 40:60), to give the title compound as an oil.
b) Methyl 4-fluoro-[l,l'-biphenyl]-2-carboxylate Palladium acetate (635mg, 0.05eq), tricyclohexyl-phosphine (952mg, 0.06eq), potassium fluoride (10.85g, 3.3eq) and phenyl boronic acid (7.6g, l.leq) were taken up in dry THF (150mL) and the reaction mixture flushed with nitrogen for 5 mins. A solution of methyl 5-fluoro-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (17.12g, 56.7 mmol) in THF (20mL) was added in one portion and the reaction mixture stirred at reflux under nitrogen for 5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, then washed with water, dried (MgSO4), filtered and the solvent removed in vacuo. The resulting oil was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (3:97 to 10:90), to give the title compound as an oil.
c) (4-Fluoro- [1,1' -biphenyl] -2-yl)methanol A solution of methyl 4-fluoro-[l,l'-biphenyl]-2-carboxylate (3g, 13.1mmol) in THF
(20mL) was added at 0°C to a suspension of lithium aluminium hydride pellets (lg, 26mmol) in THF (30mL). Upon addition the reaction mixture was heated at 60°C under nitrogen for 2 h. The reaction was then cooled to 0°C and the excess lithium aluminium hydride destroyed by adding water, then IN sodium hydroxide (2mL). The mixture was extracted into diethyl ether and the organic phase was dried (MgSO4), filtered and the solvent removed in vacuo.
The resulting oil was purified by flash chromatography on silica, eluting with ethyl acetate/heptane (2:98 to 25:75), to give the title compound as an oil.
d) 2-(Bromomethyl)-4-fluoro- 1,1' -biphenyl Triphenylphosphine dibromide (35.5g, 2eq) was added in one portion to a solution of
(4-fluoro-[l,l ' -biphenyl] -2-yl)methanol (8.5g, 42mmol) in chloroform (250mL). The reaction mixture was heated at 60°C and left to stir overnight. The solid was filtered off and the solvent removed in vacuo. The resulting oil was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (0:100 to 30:70), to give the title compound as an oil.
Example IF: (3S)-N-(2-Methylpropyl)-N-j [2-(trifluoromethyl)-phenvHmethyl)piperidin- 3-amine, fumarate
a) 1,1-Dimethylethyl (3S)-3-({ [2-(trifluoromethyl)-phenyl]methyl}amino)piperidine-l- carboxylate
1,1-Dimethylethyl (3S)-3-aminopiperidine- 1-carboxylate (l.Og, 5mmol), 2- trifluoromethylbenzaldehyde (0.87g, 5mmol), 5% palladium on carbon (0.35g) and ethanol (40mL) were hydrogenated at 60psi for 2.5 h. using a Parr hydrogenator. The catalyst was filtered off and the filtrate evaporated in vacuo. The resultant oil was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (0:100 to 75:25), to give the title compound as an oil. b) 1,1-Dimethylethyl (3S)-3-((2-methylpropyl){[2- (trifluoromethyl)phenyl] methyl } amino)piperidine- 1 -carboxylate
Sodium triacetoxyborohydride (0.23g, 1.08mmol) was added to a stirred solution of 1 , 1 -dimethylethyl (3S)-3-({ [2-(trifluoromethyl)phenyl]methyl ) amino)piperidine- 1 - carboxylate (0.19g, 0.53mmol), isobutyraldehyde (0.12g, 1.6mmol)and 1,2- dichloroethane (5mL). After stirring under nitrogen at room temperature for 1 day, the reaction mixture was diluted with methanol (6mL) and absorbed onto a cationic ion exchange resin (Isolute ™ SCX-2). After washing the cartridge with methanol (25mL), the basic components were isolated by elution with 2N ammonia in methanol and the eluate evaporated to give an oil.
c) (3S)-N-(2-Methylpropyl)-N- { [2-(trifluoromethyl)-phenyl]methyl } piperidin-3-amine, fumarate
1,1-Dimethylethyl (3S)-3-((2-methylpropyl)[ [2- (trifluoromethyl)phenyl]methyl]amino)piperidine- 1-carboxylate (0.139mg, 0.335mmol), trifluoroacetic acid (4mL) and dichloromethane (lOmL) were stirred at room temperature for 1 day. The solution was evaporated in vacuo to give an oil, which was redissolved in methanol and filtered through a cationic ion exchange resin (Isolute ™ SCX-2). The basic components were isolated by elution with 2Ν ammonia in methanol. The eluate was evaporated in vacuo and the resultant oil converted to the fumaric acid salt (crystallisation from ethanol/ether), to give the title compound as a white solid. 1H NMR (300MHz, CD3OD): δH 7.77-7.74 (d, H), 7.51-7.43 (m, 2H), 7.25-7.22 (t, IH), 4.23 (s, 2H), 3.79- 3.66 (q, 2H), 3.21-3.08 (m, 4H), 2.83-2.61 (m, 3H), 2.28-2.10 (m, 2H), 1.90-1.82 (m, 2H), 1.59-1.37 (m, 3H), 0.77-72 (t, 6H); MS: (M+H) = 315.
The following Examples were similarly prepared as described above for Example IF, by reductive alkylation of 1,1-dimethylethyl (3S)-3-({ [2-(trifluoromethyl)- phenyl]methyl]amino)piperidine-l-carboxylate with the appropriate aldehyde or ketone, and subsequent deprotection: Example 2F: (35) -N- (3 , 3-Dimethylbutyl) -N- { [2- (trifluoromethyl) -phenyl] methyl }piperidin-3-amine, D- tartrate
1HNMR (300MHz, CD3OD): δH 7.79-7.86 (d, IH), 7.47-7.56 (m, 2H), 7.27-7.32 (t,
2H), 4.30 (s, 2H), 3.73-3.84 (t, 2H), 3.16-3.28 (m, 2H), 2.71-2.89 (m, 3H), 2.47-2.52 (t,
2H), 1.84-1.97 (m, 2H), 1.47-1.63 (m, 2H), 1.22-1.33 (m, 2H), 0.75 (s, 9H); MS: [M+H]
= 343.
Example 3F: (35) -iV-Cyclohexyl -JV- { [2- (trifluoromethyl) phenyl] -methyl }piperidin-3 -amine, D- tartrate
1HNMR (300MHz, CD3OD): δH 7.88-7.91 (d, IH), 7.51-7.58 (m, 2H), 7.29-7.34 (t,
IH), 4.29 (s, 2H), 3.68-3.83 (q, 2H), 3.43-3.50 (m, IH), 3.08-3.27 (m, IH), 2.87-3.00 (m,
2H), 2.39-2.45 (dd, IH), 2.22-2.29 (dd, IH), 2.22-2.16 (m, 2H), 1.76-1.90 (m, 2H), 1.58- 1.62 (m, IH), 1.27-1.41 (m, 2H), 1.08-1.22 (m, 2H), 0.97-1.03 (IH), 0.63-0.74 (m, 4H);
MS: [M+H] = 341.
Example 4F: (35) -N- { [5-Fluoro-2-
(trifluoromethyl) phenyl] methyl) -JV-tetrahydro-2H-pyran-4- ylpiperidin-3 -amine, L-tartrate
a) 1 , 1 -Dimethylethyl (3S)-3-(tetrahydro-2H-pyran-4-ylamino)piperidine- 1 -carboxylate l,l-Dimethylethyl-(3S)-3-aminopiperidine-l-carboxylate (2g, l lmmol), 4H- tetrahydropyran-4-one (l.lg, llmmol) and dichloroethane (40mL) were stirred under nitrogen at room temperature for 15 min. Sodium triacetoxyborohydride (2.9g, 14mmol) was added in 3 lots over 30 minutes and stirred overnight. The reaction was diluted with water (50mL) and made basic by addition of 2N NaOΗ solution. After stirring for lh, the mixture was extracted into dichloromethane, and the combined organic extracts washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the title compound as an oil.
b) (3S)-N-{ [5-Fluoro-2-(trifluoromethyl)phenyl]methyl ) -N-tetrahydro-2H-pyran-4- ylpiperidin-3 -amine, L-tartrate
1 , 1 -Dimethylethyl (3S)-3-(tetrahydro-2H-pyran-4-ylamino)piperidine- 1 -carboxylate was reductively alkylated with 5-fluoro-2-(trifluoromethyl)benzaldehyde, then deprotected and crystallised as its L-tartrate salt as described above for Example 1 b) and c), to give the title compound. 1HΝMR (300MΗz, CD3OD): δH 7.74-7.75 (m, 2H), 7.05- 6.98 (t, IH), 4.50 (s, 2H), 3.99-3.85 (m, 4H), 3.43-2.58 (m, 8H), 2.02-1.42 (m, 8H); MS:
[M+H] = 361.
The following Examples were similarly prepared as described above for Example 4F, by reductive alkylation of 1,1-dimethylethyl (3S)-3-(tetrahydro-2H-pyran-4-ylamino)- piperidine- 1-carboxylate with the appropriate benzaldehyde, and subsequent deprotection:
Example 5F : ( 35) -N- [ ( 2 -Chloro- 5 -f luorophenyl ) methyl] -N- tetrahydro-2Η-pyran- 4 -ylpiperidin- 3 -amine , L-tartrate
1ΗNMR (300MHz, CD3OD): δH 7.32-7.24 (m, 2H), 6.92-6.85 (t,lH), 4.30 (s, 2H), 3.90-3.84 (m, 4H), 3.32-3.17 (m, 4H), 3.08-2.97 (m, IH), 2.85-2.67 (m, 3H), 1.98-1.82
(m, 2H), 1.73-1.82 (m,2H), 1.73-1.46 (m, 6H); MS: [M+H] = 327/329.
Example 6F : ( 35) -N- ( [1 , 1 ' -Biphenyl] -2 -ylmethyl ) -N- tetrahydro-2H-pyran- 4 -ylpiperidin-3 -amine , sesqui -L-tartrate
1HNMR (300MHz, CD3OD): δH 7.51-7.48 (d, IH), 7.35-7.17 (m, 7H), 7.08-7.05 (d,
IH), 3.30 (s, 1.5H), 3.79-3.74 (dd, 2H), 3.69 (s, 2H), 3.25-3.10 (m, 9H), 3.20-3.09 (m, 2H), 2.91-2.77 (m, 2H), 2.66-2.51 (m, 3H); MS: [M+H] = 351. Example 7F: (35) -N- [ (2 -Chlorophenyl) methyl] -iV-tetrahydro-2ff- pyran-4 -ylpiperidin-3 -amine, D-tartrate
1HNMR (300MHz, CD3OD): δH 7.52-7.49 (d, IH), 7.26-7.87 (m, 3H), 4.30 (s, 2H), 3.92-3.80 (m, 4H), 3.16-2.34 (m, 4H), 2.92-2.05 (m, IH), 2.90-2.66 (m, 3H), 1.93-187 (m, 2H), 1.68-1.39 (m, 6H); MS: [M+H] = 309/311.
Example 8F : ( 35) -lV-Tetrahydro-2if-pyran-4 -yl --V- { [2 -
(trifluoromethyl) phenyl] methyl }piperidin-3 -amine, D-tartrate
JHNMR (300MHz, CD3OD): δH 7.98-7.95 (d, IH), 7.71-7.62 (q, 2H), 7.47-7.42 (t, IH), 4.44 (s, 2H), 4.14-3.98 (m, 4H), 3.43-3.29 (m, 4H), 3.11-2.82 (m, 4H), 2.06-2.03 (m, 2H), 1.82-1.66 (m, 6H); MS: [M+H] = 343.
Example 9F: (35) -IV-Cyclopentyl-iV~ { [2-
(trifluoromethyl) phenyl] -methyl }piperidin-3 -amine, L- tartrate a) 1, 1-Dimethylethyl (3S) -3- (cyclopentylamino) -piperidine-1- carboxylate
1,1-Dimethylethyl (35) -3-aminopiperidine-l-carboxylate (2.1g, 10.5mmol), cyclopentanone (4.65mL, 52.5mmol), and 10% palladium on carbon (0.2g) in methanol (80mL) were hydrogenated at 60psi overnight in a Parr hydrogenator . The catalyst was filtered off and the filtrate evaporated in vacuo . The resultant oil was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (15:85 to 30:70), to give the title compound as an oil.
b) 1 , 1 -Dimethylethyl (3S)-3-(cyclopentyl { [2- (trifluoromethyl)phenyl]methyl } amino)piperidine- 1 -carboxylate
1 , 1 -Dimethylethyl (3S)-3-(cyclopentylamino)-piperidine- 1 -carboxylate ( 155mg, 0.577mmol), 2-(trifluoromethyl)benzyl bromide (0.105mL, 1.2eq) and anhydrous potassium carbonate (128mg, 1.6eq) in acetonitrile (3mL) were heated at refluxed under nitrogen for 2 days. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water, then brine. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The resulting oil was purified by flash chromatography on silica eluting with ethyl acetate/cyclohexane (0:100 to 30:70), to give the title compound as an oil.
c) (3S)-N-Cyclopentyl-N-{ [2-(trifluoromethyl)phenyl]-methyl}piperidin-3-amine, L- tartrate 1,1 -Dimethylethyl (3S)-3-(cyclopentyl { [2-(trifluoromethyl)phenyl]methyl ) amino)piperidine- 1-carboxylate (160mg, 0.38mmol), trifluoroacetic acid (0.5mL) and dichloromethane (2mL) were stirred at room temperature overnight. The solution was evaporated in vacuo to give an oil, which was redissolved in methanol and filtered through a cationic ion exchange resin (Isolute ™ SCX-2). The basic components were isolated by elution with 2Ν ammonia in methanol. The eluate was evaporated in vacuo and the resultant oil converted to the -tartaric acid salt (freeze drying from acetonitrile/water 1:1), to give the title compound as a white solid. 1H NMR (300MHz, CD3OD): δH 7.89-7.86 (d, IH), 7.54-7.46 (m, 2H), 7.30-7.25 (t, IH), 4.34 (s, 2H), 3.90- 3.78 (q, 2H), 3.30-3.18 (m, 4H), 3.05-2.87 (m, IH), 2.81-2.59 (m, 2H), 1.95-1.79 (m, 2H), 1.68-1.30 (m, 9H); MS: [M+H] = 327.
The following Examples were similarly prepared as described above for Example 9F, by reaction of 1,1-dimethylethyl (3R)-3-(cyclopentylamino)piperidine- 1-carboxylate with the appropriate benzyl bromide and subsequent deprotection:
Example 10F : (35) -N- ( [1 , 1 ' -Biphenyl] -2 -ylmethyl ) -N- cyclopentyl -piperidin-3 -amine , L-tartrate
1H NMR (300MHz, CD3OD): δH 7.57-7.55 (d, IH), 7.35-7.13 (m, 7H), 7.06-7.03 (d, IH), 4.30 (s, 2H), 3.58 (s, 2H), 3.12-2.98 (m, 3H), 2.82-2.73 (m, IH), 2.65-2.42 (m, 2H), 1.79-1.75(m, IH), 1.69-1.65 (m, IH), 1.53-1.19(m, 10H); MS: [M+H] = 335. Example 11F: (35) -JV-Cyclopentyl-JV- ( [5-fluoro-l, 1 ' -biphenyl] - 2-ylmethyl) -piperidin-3 -amine, L-tartrate
XE NMR (300MHz, CD3OD) : δπ 7.35-7.24 (m, 4H) , 7.18-7.15 (m, 2H) , 7.09-7.04 (m, IH) , 6.92-6.85 (m, IH) , 4.28 (s, 2H) , 3.55 (m, 2H) , 3.22-3.06 (m, 3H) , 2.82-2.77 (m, IH) , 2.68-2.58 (m, 2H) , 1.88-1.68 (m, 2H) , 1.57-1.19 (m, 10H) ; MS: [M+H] = 353.
Example 12 F: (35) -N- (Tetrahydrofuran-3 -ylmethyl) -2V- { [2- (trifluoromethyl) phenyl] methyl }piperidin-3 -amine, L-tartrate a) 1,1-Dimethylethyl (3S)-3-[(tetrahydrofuran-3-ylmethyl)amino]piperidine-l-carboxylate
To 5% palladium on carbon (0.05 g) under nitrogen was added a solution of 1,1- dimethylethyl-(3S)-3-aminopiperidine-l -carboxylate (0.50g, 2.5mmol) and tetrahydrofuran-3-carboxaldehyde (50%w/w in water) (0.50g, 2.5mmol) in ethanol (20mL). The reaction mixture was hydrogenated overnight at 60psi in a Parr hydrogenator. The catalyst was removed by filtration through Celite and the solvent removed in vacuo to give 1,1-dimethylethyl (3S)-3-[(tetrahydrofuran-3- ylmethyl)amino]piperidine- 1-carboxylate as a colourless, slightly cloudy oil.
b) (3S)-N-(Tetrahydrofuran-3-ylmethyl)-N- { [2-(trifluoromethyl)phenyl]methyl ) piperidin- 3-amine, L-tartrate
To a solution of 1,1-dimethylethyl (3S)-3-[(tetrahydrofuran-3- ylmethyl)amino] piperidine- 1-carboxylate (0.67g, 2.36 mmol) in 1 ,2-dichloroethane (15 mL) was added 2-(trifluoromethyl)benzaldehyde (0.93mL, 7.07mmol). To this mixture was added a solution of sodium triacetoxyborohydride (1.50g, 7.07mmol) in dimethylformamide (3 mL) and left to stir under nitrogen, at room temperature, over the weekend. To the reaction mixture was added water (10 mL) and the solution stirred vigorously for several minutes. The chlorinated organic layer was absorbed directly onto a silica column and the product eluted with methanol/ethyl acetate (0:100 to 30:70). The resultant pale yellow oil was taken up in methanol and absorbed onto a cationic ion exchange resin (Isolute ™ SCX-2). After washing the cartridge with methanol (25mL), the basic components were isolated by elution with 2Ν ammonia in methanol and the eluate evaporated to give 1,1-dimethylethyl (3S)-3-{(tetrahydrofuran-3-ylmethyl) {[2- (trifluoromethyl)-phenyl]methyl)amino}piperidine-l-carboxylate as a colourless oil.
To a solution of this oil (0.82g, 1.85mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2.06mL, 27.8mmol). The reaction mixture was stirred overnight at room temperature, then the solvent removed in vacuo. The resulting oil was taken up in methanol and absorbed onto a cationic ion exchange resin (Isolute ™ SCX-2). After washing the cartridge with methanol (50mL), the basic components were isolated by elution with 2N ammonia in methanol. The eluate was evaporated in vacuo to give a colourless oil. The diastereomers were separated by hplc (Chiralpak AD-H column; 98% heptane, 2% ethanol and 0.2% diethylamine). The faster eluting isomer was taken up in methanol and to this was added a solution of L-tartaric acid (0.046g, 0.31 mmol) in methanol. Solvent was removed in vacuo and the resulting oil triturated with diethyl ether. Filtration of the resultant suspension gave the title compound as a white solid. 1HNMR (300MHz, CD3OD): δH 7.75 (IH, d), 7.58-7.50 (2H, m), 7.34-7.29 (IH, m), 4.30 (3H, s), 3.83 (2H, s), 3.70-3.53 (3H, m), 3.42-3.31 (2H, m), 3.16 (IH, m), 2.90-2.67
(3H, m), 2.54-2.34 (2H, m), 2.34-2.20 (IH, m), 1.95-1.84 (3H, m), 1.63-1.45 (3H, m); MS: [M+H] = 343.
The following Examples were prepared from racemic 1,1-dimethylethyl 3- aminopiperidine- 1-carboxylate, as described above in Example IF:
Example 13F : N- { [2 - (Methyloxy) phenyl] methyl } -N- { [2 - (trifluoromethyl ) phenyl] methyl }piperidin- 3 -amine
1HNMR (300MHz, CDC13) δH 8.04-7.95 (d, IH), 7.57-7.54 (d, IH), 7.48-7.44 (m, 2H), 7.28-7.11 (m, 2H), 6.93-6.88 (t, IH), 6.83-6.80 (d, IH), 3.94-3.86 (d, 2H), 3.20-3.18
(d, IH), 2.94-2.90 (d, IH), 2.68-2.55 (m, 2H), 2.49-2.40 (dt, IH), 2.08-2.04 (d, IH), 1.76- 1.72 (d, IH), 1.52-1.25 (m, 4H); MS: [M+H] = 379. Example 14F : -Cyclohexyl -iV- { [2 -
(trif luoromethyl) phenyl] methyl ) -piρeridin-3 -amine
!HNMR (300MHz, CDC13) δH 8.01-7.93 (d, IH), 7.59-7.56 (d, IH), 7.51-7.46 (t, IH), 7.30-7.19 (m, IH), 3.91 (s, 2H), 3.15-3.11 (d, IH), 3.02-2.98 (d, IH), 2.88-2.80 (d, IH), 2.55-2.41 (m, 3H), 1.93-1.01 (m, 14); MS: [M+H] = 341.
Example 15F : N- (Phenylmethyl ) -N- { [2 - ( trifluoromethyl ) phenyl] -methyl }piperidin-3 -amine
1HNMR (300MHz, CDC13) δH 7.93-7.96 (d, IH), 7.55-7.61 (d, IH), 7.47-7.51 (t, IH), 7.18-7.35 (m, 6H), 3.77-3.90 (q, 2H), 3.64-3.74 (q, 2H), 3.17-3.20 (d, IH), 2.91-2.95
(d, IH), 2.53-2.67 (m, 2H), 2.39-2.48 (dt, IH), 1.97-2.06 (d, IH), 1.22-1.82 (m,3H); MS: [M+H] = 349.
Example 16F: (35)-N-(2-Methylpropyl)-N-{r2-(trifluoronιethyl)phenyll-methyl)-l- azabicyclo[2.2.21octan-3-amine. sesquifumarate
a) (35)-i\7-{ [2- (Trifluoromethyl) phenyl] methyl }-l- azabicyclo [2.2.2] octan-3 -amine
Sodium triacetoxyborohydride (18.7g, 88.3mmol) was added portionwise over 20 min. to a stirred solution of (3S)-l-azabicyclo[2.2.2]octan-3-amine dihydrochloride (5g,
25.1mmol) and 2-trifluoromethylbenzaldehyde (4.81g, 27.6mmol) in DMF (lOOmL). After stirring under nitrogen for 4 days, the mixture was diluted with excess water, basified with 2Ν sodium hydroxide and stirred for lh. The product was extracted into dichloromethane and evaporated in vacuo to give an oil, which was dissolved in 2N hydrochloric acid. After washing with ether, the aqueous phase was basified with 2N sodium hydroxide and extracted with dichloromethane. The organic phase was dried (MgSO4) and evaporated in vacuo to give an oil. 1HNMR (300 MHz, CD3OD) δH: 7.62- 7.69 (t, 2H), 7.50-7.55 (t, IH), 7.32-7.37 (t, IH), 3.83-3.96 (q, 2H), 3.1-3.19 (m, IH), 2.72-2.93 (m, 5H), 2.42-2.49 (m, IH), 1.85-1.95 (m, IH), 1.63-1.73 (m, IH), 1.32-1.53); MS: [M+H]= 285. b) (3S)-N-(2-Methylpropyl)-N- { [2-(trifluoromethyl)-phenyl]methyl } - 1 - azabicyclo[2.2.2]octan-3-amine, sesquifumarate
(3S)-N-{ [2-(Trifluoromethyl)phenyl]methyl ) -l-azabicyclo[2.2.2]octan-3-amine (0.30g, 1.06mmol), isobutyraldehyde (0.152g, 2.1mmol) and 1,2-dichloroethane (6mL) were stirred under nitrogen at room temperature for 15 min. Sodium triacetoxyborohydride (0.492g, 2.32mmol) was added in two lots over 5 min. TLC after 1 day showed the reaction to be incomplete, so additional sodium triacetoxyborohydride (0.24g, 1.15mmol) was added and the mixture heated at 50°C for 5 days. After cooling to room temperature, methanol was added and the mixture was stirred for lh. This solution was filtered through a cationic ion exchange resin (Isolute ™ SCX-2) and the basic fractions isolated by elution with 2Ν ammonia in methanol to give, after evaporation in vacuo, an oil. The crude product was purified using preparative LCMS to give the product as an acetate salt, which was converted to the free base using cationic ion exchange resin as described above. The free base was converted to the fumarate salt, to give the title compound as a white solid from ethanol/diethyl ether. ]HNMR (300 MHz,
CD3OD) δH: 7.88-7.91 (d, IH), 7.51-7.58 (m, H), 7.30-7.35 (t, IH), 6.60 (s, 3H), 3.71- 3.85 (q, 2H), 3.42-4.50 (m, IH), 2.88-3.26 (m, 6H), 2.25-2.39 (m, IH), 2.09-2.23 (m, 3H), 1.74-1.91 (m, 2H), 1.42-1.63 (m, 2H), 0.78-0.83 (t, 6H); MS: [M+H] = 341.
The following Examples were similarly prepared as described above for Example
16F, from (3S)-N-{ [2-(trifluoromethyl)phenyl]methyl]-l-azabicyclo-[2.2.2]octan-3-amine and the appropriate substituted benzaldehyde:
Example 17F : ( 35) -N- ( [1 , 1 ' -Biphenyl] -2 -ylmethyl ) -N- (2 - methylpropyl ) - 1 -azabicyclo [2 . 2 . 2 ] octan-3 -amine , D-tartrate
1HΝMR (300 MHz, CD3OD) δH: 7.50-7.47 (d, IH), 7.38-7.18 (m, 7H), 7.09-7.06 (dd, IH), 4.29 (s, 2H), 3.58-3.54 (d, IH), 3.43-3.39 (d,lH), 3.25-3.18 (m, IH), 3.09-3.90 (4H), 2.68-2.63 (t,lH), 2.45-2.39 (dq, IH), 2.16-1.98 (m, 3H), 1.83-1.74 (m, 2H), 1.65- 1.61 (m, IH), 1.45-1.42 (m, IH), 1.31-1.22 (quin, IH), 0.65-0.61 (t, 6H); MS: [M+H] = 349. Exa ple 18F; (35) -N- { [4-Fluoro-2- (trif luoromethyl) phenyl] methyl }-N- (2-methylpropyl) -1- azabicyclo [2.2.2] octan-3 -amine, L-tartrate 1HNMR (300 MHz, CD3OD) δH: 7.94-7.89 (t, IH), 7.34-7.27 (m, 2H), 4.29 (s, 4.29), 3.81-3.66 (q, 2H), 3.51-3.44 (t,lH), 3.40-2.89 (m, 6H), 2.37-2.04 (m, 4H), 1.93-1.38 (m,
4H), 0.82-0.76 (dd, 6H); MS: [M+H] = 359.
Example 19F: (35) -N- [ (4-Fluoro [1, 1' -biphenyl] -2-yl) methyl] - N- (2-methylpropyl) -1-azabicyclo [2.2.2] octan-3 -amine, L- tartrate
1HNMR (300 MHz, CD3OD) δH: 7.40-7.08 (m, 7H).6.68-6.91 (dt, IH), 4.29 (s, 2H), 3.56-4.0 (q, 2H), 3.31-2.96 (m, 5H), 2.72-2.67 (t, IH), 2.58-2.52 (dq, IH), 2.18-1.30 (m, 8H), 0.70-0.68 (dd, 6H); MS: [M+H] = 367.
The following examples illustrate compounds of of Formulae (IG) above and methods for their preparation.
Preparation of Intermediates (2S)-(4-Benzyl-morpholin-2-yl)-phenyl-methanone
Figure imgf000253_0001
Described above in section entitled "Preparation of intermediates for the synthesis of Examples 1C-17C".
(S)-Phenyir(2S)-4-(phenylmethyl)morpholin-2-yllmethanol(2)
Figure imgf000254_0001
Described above in section entitled "Preparation of intermediates for the synthesis of Examples 1C-17C".
(2S)-2-[(R)-bromo(phenyl)methyl]-4-(phenyl ethyl) orpholine (3)
Figure imgf000254_0002
To a solution of (S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanol (2) (4.71 g, 16.63 mmole) in chloroform (200 ml) is added the triphenylphosphine dibromide (14.04 g, 33.26 mmole). The mixture is heated at 60°C overnight. The mixture is allowed to cool to room temperature then washed with saturated sodium carbonate solution (aqueous,
-100 ml), dried (Na2SO4) and concentrated in vacuo. The resulting residue is purified by automated flash chromatography (ISCO system: 120 g column, 10-30% EtOAc in isohexane) to give (2S)-2-[(R)-bromo(phenyl)methyl]-4-(phenylmethyl)morpholine (3) as a white solid (4.63 g, 80%). LCMS 6 min gradient method, Rt = 2.5 min, (M+H+) = 346/348
S-|(S)-phenyl[(25)-4-(phenvImethyl)nιorpholin-2-yl] ethyl) ethanethioate (5)
Figure imgf000254_0003
A solution of (2S)-2-[(R)-bromo(phenyl)methyl]-4-(phenylmethyl)morpholine (3) (1.76 g, 5.08 mmole) and potassium thiolacetate (1.16 g, 10.16 mmole) in 1:1 anhydrous
THF:DMF (30 ml), is stirred at 40 °C under nitrogen overnight. The mixture is then taken up in acetonitrile and loaded onto an SC10-2 column (4 x 10 g). The SCI 0-2 columns are washed with further acetonitrile. The target compound is eluted with 4: 1 acetonitrile : Et3N. This is concentrated in vacuo to give an orange oil which is purified by automated flash chromatography (ISCO system: 35 g SiO2 Redisep column, 10-30% EtOAc in isohexane over 40 minutes) to give S-{(S)-phenyl[(2S)-4- (phenylmethyl)morpholin-2-yl] methyl} ethanethioate (5) as an amber coloured crystalline solid (1.54 g, 89%). LCMS 6 min gradient method, Rt = 2.5 min, (M+H+) = 342
(5)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6)
Figure imgf000255_0001
The S-{(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl} ethanethioate (5)
(11.02 g, 32.3 mmole) is taken up in methanol (100 ml, dry, degassed), under nitrogen.
To this is added the sodium thiomethoxide (2.26 g, 32.3 mmole) in one portion (as solid).
The reaction mixture is left to stir at room temperature for 2 hours. The solution is then added to an aqueous solution of HCI (0.1 M). This is extracted with DCM (3 x). The extracts are dried (Na2SO4) and concentrated in vacuo to give (S)-phenyl[(2S)-4-
(phenylmethyl)morpholin-2-yl]methanethiol (6) as a yellow solid (9.59 g, 99%). LCMS 6 min gradient method, Rt = 2.7 min, (M+H+) = 300
Examples
Example IG: (2S)-2-l(S)-phenvir(3-phenylpyridin-2-yl)thio]methyl|morpholine hemifumarate
Figure imgf000255_0002
Fumarate salt i) To palladium acetate (0.026 g, 0.12 mmole) in acetonitrile (3 ml), is added triphenylphosphine (0.122 g, 0.46 mmole), under nitrogen, at room temperature. The mixture is left to stir for 15 minutes. To this mixture is added water (distilled, 1 ml), phenylboronic acid (0.846 g, 6.94 mmole), 3-bromo-2-fluoropyridine (1.02 g, 5.78 mmole) and potassium carbonate (4.80 g, 34.70 mmole). The reaction mixture is heated at 70 °C overnight. After cooling to room temperature, the reaction mixture is loaded directly onto a 40 g Redisep SiO2 column and components isolated by automated flash chromatography (ISCO System, 0 - 30 % ethyl acetate in cyclohexane gradient elution over 40 minutes). This gave 2-fluoro-3-phenylpyridine as a very pale yellow oil (1.00 g, 100 %). LCMS 6 min gradient method, Rt = 3.7 min, (M+H+) = 174.
ii) To a solution of (S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6) (1.50 g, 5.01 mmole) and 2-fluoro-3-phenylpyridine (2.44 g, 14.09 mmole) in dry, degassed DMF (10 ml) is added, under nitrogen, sodium hydride (60 % dispersion in oil, 0.24 g, 6.01 mmole). The mixture is left to stir overnight at room temperature. The reaction mixture is loaded neat onto a 120 g SiO2 Redisep column (preconditioned with cyclohexane). Automated flash chromatography (ISCO System, 0 - 30 % ethyl acetate in cyclohexane gradient elution over 40 minutes at 40 ml/minute flow rate) yielded an orange oil (2.26 g). Chromatography is repeated using chromatography (ISCO System, 40 g column, 0 - 30 % ethyl acetate in cyclohexane gradient elution over 40 minutes at 30 ml/minute flow rate) to give (2S)-2-{(S)-phenyl[(3-phenylpyridin-2-yl)thio]methyl}-4- (phenylmethyl)morpholine as a pale orange oil (1.65 g, 73 %). LCMS 6 min gradient method, Rt = 4.0 min, (M+H+) = 453.
iii) To a suspension of polymer supported dϋsopropylamine (3.78 mmol/g, 0.54 g, 2.03 mmole) and (2S)-2-{(S)-phenyl[(3-phenylpyridin-2-yl)thio]methyl}-4- (phenylmethyl)morpholine (0.184 g, 0.41 mmole) in dry DCM (5 ml) is added 1- chloroethyl chloroformate (0.22 ml, 2.03 mmole) at room temperature and under nitrogen. The mixture is heated at 40°C for 3.75 hours. The reaction mixture is filtered, concentrated in vacuo then taken up in methanol (5 ml). The solution is left to stir at room temperature overnight. After this time, the reaction mixture is loaded directly onto an SClO-2 column. The SClO-2 column is washed with methanol. The title compound is eluted with 2 N NH3/methanol. This is concentrated in vacuo to give (2S)-2-{(S)- phenyl[(3-phenylpyridin-2-yl)thio]methyl] morpholine as white foam (0.148 g, 100 %). The foam is taken up in ethyl acetate. To this is added a solution of fumaric acid (1.1 equiv, 0.052 g) in methanol. The resulting solution is filtered then concentrated in vacuo. To the resulting white solid is added methanol (1.5 ml). This is stirred for a couple of minutes, then the remaining solid collected by filtration to give the hemi-fumarate salt of (2S)-2-{(S)-phenyl[(3-phenylpyridin-2-yl)thio]methyl}morpholine as a white solid (0.127 g). LCMS 12 min gradient method, Rt = 5.5 min, (M+H+) = 363
Example 2G: (2S)-2-r(S)-{r3-(4-fluorophenyl)pyridin-2- yllthioHphenyDmethvIlmorpholine fumarate
Figure imgf000257_0001
Fumarate salt i) To bis(benzonitrile)palladium(IT)dichloride (0.054 g, 0.14 mmole) and 1,4- bis(diphenylphosphine)butane (0.091 g, 0.21 mmole) is added dry toluene (6 ml), under nitrogen, and the mixture stirred for half an hour. To this is added 3-bromo-2- fluoropyridine (0.50 g, 2.83 mmole) in ethanol (1.4 ml) followed by a solution of 4- fluorophenylboronic acid (0.793 g, 5.67 mmole) in ethanol (2.4 ml). To this is added an aqueous solution of sodium carbonate (1 M, 2.83 ml, 2.83 mmole). The mixture is heated at 60°C for 24 hours, then at 75°C for a further 16 hours. The organic layer is loaded directly onto a 40 g Redisep SiO2 column and components isolated by automated flash chromatography (ISCO System, 0 - 30 % ethyl acetate in cyclohexane gradient elution over 40 minutes). This gave 3-(4-fluorophenyl)-2-fluoropyridine as a white solid (0.387 g, 71 %). LCMS 6 min gradient method, Rt = 3.6 min, (M+H+) = 192
ii) To a solution of (S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6)
(0.505 g, 1.69 mmole) and 3-(4-fluorophenyl)-2-fluoropyridine (0.387 g, 2.02mmole) in dry, degassed DMF (3 ml) is added, under nitrogen, cesium fluoride (0.385 g, 2.54 mmole). The mixture is heated at 65°C over the weekend. After this time, the reaction mixture is allowed to cool and loaded directly onto an SClO-2 column. The SClO-2 column is washed with methanol. The (2S)-2-[(S)-{ [3-(4-fluorophenyl)pyridin-2- yl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholine is eluted with 2 N NH /methanol. This is concentrated in vacuo to' give an orange solid (0.649 g). This is purified by automated flash chromatography (ISCO System, 40 g SiO2 Redisep column, 0 - 30 % ethyl acetate in cyclohexane gradient elution over 40 minutes at 30 ml/minute flow rate) to give (2S)-2-[(S)-{ [3-(4-fluorophenyl)pyridin-2-yl]thio}(phenyl)methyl]-4- (phenylmethyl)morpholine as a off -white foam (0.395 g, 50 %). LCMS 6 min gradient method, Rt = 3.3 min, (M+H+) = 471.
iii) Deprotection of the morpholine nitrogen is carried out using the method and work up as described in Example IG, using polymer supported dπsopropylamine (3.78 mmole/g, 1.09 g, 4.14 mmole), (2S)-2-[(S)-{ [3-(4-fluorophenyl)pyridin-2-yl]thio)(phenyl)methyl]- 4-(phenylmethyl)morpholine (0.390 g, 0.83 mmole), dry DCM (20 ml), 1-chloroethyl chloroformate (0.45 ml, 4.14 mmole) and methanol (20 ml). This gave (2S)-2-[(S)-{ [3-(4- fluorophenyl)pyridin-2-yl]thio}(phenyl)methyl]morpholine as a pale yellow oil (0.232 g, 74 %). This oil is taken up in ethyl acetate. To this is added a solution of fumaric acid (1.1 equiv, 0.071 g) in methanol. The resulting solid is collected by filtration to give a white solid (0.115 g). This is recrystallised from MeOH/CHCl3/Et2O to give a white solid (0.061 g). LCMS 12 min gradient method, Rt = 5.4 min, (M+H+) = 381
Example 3G: (2S)-2-r(S)-{[3-(3-chlorophenyl)pyridin-2- yl]thio)(phenyl)methyl1morpholine fumarate
Figure imgf000258_0001
Fumarate salt i) To bis(benzonitrile)palladium(π)dichloride (0.054 g, 0.14 mmole) and 1 ,4- bis(diphenylphosphine)butane (0.091 g, 0.21 mmole) is added dry toluene (6 ml), under nitrogen, and the mixture stirred for half an hour. To this is added 3-bromo-2- fluoropyridine (0.50 g, 2.83 mmole) in ethanol (1.4 ml) followed by a solution of 3- chlorophenylboronic acid (0.887 g, 5.67 mmole) in ethanol (2.4 ml). To this is added an aqueous solution of sodium carbonate (1 M, 2.83 ml, 2.83 mmole). The mixture is heated at 60°C for 24 hours, then at 75°C for a further 16 hours. The organic layer is loaded directly onto a 40 g Redisep SiO2 column and components isolated by automated flash chromatography (ISCO System, 0 - 30 % ethyl acetate in cyclohexane gradient elution over 40 minutes). This gave 3-(3-chlorophenyl)-2-fluoropyridine as an off-white solid (0.333 g, 57 %). LCMS 6 min gradient method, Rt = 4.0 min, (M+H+) = 208.
ii) To a solution of (S)-phenyl[(2S)-4-(phenylmethyl)mo holin-2-yl]methanethiol (6) (0.400 g, 1.34 mmole) and 3-(3-chlorophenyl)-2-fluoropyridine (0.333 g, 1.60 mmole) in dry, degassed DMF (3 ml) is added, under nitrogen, cesium fluoride (0.305 g, 2.00 mmole). The mixture is heated at 65°C over the weekend. After this time, the reaction mixture allowed to cool. The resulting solid is taken up in MeOH/DCM and loaded directly onto an SClO-2 column. The SClO-2 column is washed with methanol. The (2S)- 2-[(S)-{ [3-(3-chlorophenyl)pyridin-2-yl]thio } (phenyl)methyl]-4-
(phenylmethyl)morpholine is eluted with 2 N NH3/methanol. This is concentrated in vacuo to give a white foam (0.555 g). This is purified by automated flash chromatography (ISCO System, 0 - 30 % ethyl acetate in cyclohexane gradient elution over 40 minutes at 40 ml/minute flow rate) to yield (2S)-2-[(S)-{ [3-(3-chlorophenyl)pyridin-2- yl]thio } (phenyl)methyl]-4-(phenylmethyl)morpholine as a white foam (0.258 g, 40 %).
LCMS 6 min gradient method, Rt = 4.2 min, (M+H+) = 487.
iii) Deprotection of the morpholine nitrogen is carried out using the method and work up as described in Example IG, using polymer supported dizsøpropylamine (3.72 mmole/g, 0.70 g, 1.80 mmole), (2S)-2-[(S)-{ [3-(3-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]-
4-(phenylmethyl)morpholine (0.255 g, 0.52 mmole), dry DCM (15 ml), 1-chloroethyl chloroformate (0.29 ml, 2.62 mmole) and methanol (15 ml). This gave a colourless residue (0.211 g). This residue is taken up in ethyl acetate. To this is added a solution of fumaric acid (1.1 equiv, 0.062 g) in methanol. If the resulting solid contains impurities it may be recombined with the mother liquor and purified on a UN Guided PrepHPLC
(Flex) System and treated with SClO-2 to give (2S)-2-[(S)-[[3-(3-chlorophenyl)pyridin-2- yl]thio}(phenyl)methyl]morpholine as a pale yellow oil (0.127 g, 65 %). This oil is taken up in MeOH/DCM. To this is added a solution of fumaric acid (1.1 equiv, 0.0145 g) in methanol, followed by Et2O. The resulting crystals are collected by filtration to give the fumarate salt of (2S)-2-[(S)-{[3-(3-chlorophenyl)pyridin-2- yl]thio}(phenyl)methyl]morpholine (1:1 fumarate salt) as a white solid (0.047 g). LCMS 12 min gradient method, Rt = 5.7 min, (M+H+) = 397
Example 4G: (2S)-2-r|[3-(2-chlorophenyr)pyridin-2- yl1thio}(phenyl)methvHmorpholine fumarate
Figure imgf000260_0001
Fumarate salt i) To palladium acetate (0.0025 g, 0.0011 mmole) in acetonitrile (3 ml), is added triphenylphosphine (0.0119 g, 0.045 mmole), under nitrogen, at room temperature. The mixture is left to stir for 15 minutes. To this mixture is added water (distilled, 1 ml), 2- chlorophenylboronic acid (0.106 g, 0.68 mmole), 3-bromo-2-fluoropyridine (0.10 g, 0.57 mmole) and potassium carbonate (0.470 g, 3.40 mmole). The reaction mixture is heated to 60°C increasing to 75 °C over 5 hours then allowed to cool to room temperature. To the reaction mixture is added MeOH and this is loaded onto an SClO-2 column (10 g) preconditioned with MeOH. The column is washed with MeOH and the resulting solution concentrated in vacuo to give an orange oil (0.196 g). The oil is purified by automated flash chromatography (ISCO System, a 10 g Redisep SiO2 column, 0 - 30 % ethyl acetate in cyclohexane gradient elution over 40 minutes). This gave 2-fluoro-3-(2- chlorophenyl)pyridine as a colourless oil (0.050 g, 42 %). LCMS 6 min gradient method, Rt = 3.3 min, (M+H+) = 208
ii) To a solution of (S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6) (0.288g, 0.96 mmole) and 3-(2-chlorophenyl)-2-fluoropyridine (0.40 g, 1.93 mmole) in dry, degassed DMF (2 ml) is added, under nitrogen, sodium hydride (60% dispersion in oil, 0.0.046 g, 1.15 mmole). The mixture is left to stir at room temperature over the weekend. The reaction mixture is loaded directly onto an a 40 g Redisep SiO2 column. Components are eluted using automated flash chromatography (ISCO System, 0 - 30 % ethyl acetate in cyclohexane gradient elution over 30 minutes at 40 ml/minute flow rate) to give (2S)-2-[{ [3-(2-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]-4- (phenylmethyl)morpholine as a white solid (0.021 g, 5 %). LCMS 6 min gradient method, Rt = 4.3 min, (M+H+) = 487.
iii) Deprotection of the morpholine nitrogen is carried out using the method and work up as described in Example IG, using polymer supported diwopropylamine (3.78 mmole/g, 0.057 g, 0.216 mmole), (2S)-2-[{ [3-(2-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]-4- (phenylmethyl)morpholine (0.021 g, 0.043 mmole), dry DCM (2 ml), 1-chloroethyl chloroformate (0.024 ml, 0.216 mmole) and methanol (2 ml). This gave a colourless residue (0.017 g, 100 %). This residue is taken up in ethyl acetate. To this is added a solution of fumaric acid (1 equiv, 0.005 g) in methanol. This is reduced in volume and Et2O added. The resulting solid is collected by filtration to give the fumarate salt of (2S)- 2-[{ [3-(2-chlorophenyl)pyridin-2-yl]thio](phenyl)methyl]morpholine (1:1 fumarate salt) as a pale green solid (0.012 g). LCMS 12 min gradient method, Rt = 5.4 min, (M+H+) = 397
Example 5G: (2S)-2-((S)-phenvUr3-(trifluoromethyl)pyridin-2- yllthiolmethyDmorpholine
Figure imgf000261_0001
i) Potassium fluoride (0.048 g, 0.84 mmole) and copper (I) iodide (0.159 g, 0.84 mmole) are thoroughly mixed and dried under reduced pressure with a hot air gun for 20 minutes. To the resulting yellow solid, at room temperature is added (2S)-2-[(S)-[(3-iodopyridin-2- yl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine (as prepared in Example 15) (0.190 g, 0.38 mmole) in anhydrous NMP (0.5 ml) followed by anhydrous DMF (0.5 ml) then (trifluoromethyl)trimethylsilane (0.11 ml, 0.76 mmole). After 3 days at room temperature, the temperature is increased to 50 °C. The reaction mixture is heated at 50 °C overnight. After cooling to room temperature, further (trifluoromethyl)trimethylsilane (0.11 ml, 0.76 mmole) is added to the reaction mixture and the mixture is left to stir overnight at room temperature. To the reaction mixture is added MeOH before loading onto an SCI 0-2 column (10 g) preconditioned with MeOH. The column is washed with MeOH. Basic material is eluted with 2 N NH3/methanol. This is concentrated in vacuo to give a pale yellow solid (0.199 g). This is purified by automated flash chromatography (ISCO System, 3 x 4 g Redisep SiO2 columns, in parallel, 0 - 20 % ethyl acetate in cyclohexane gradient elution over 40 minutes) to give the (2S)-2-[(S)-[(3-iodopyridin-2- yl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine as a white foam (0.108 g, 57 % recovery of this starting material) and (2S)-2-((S)-phenyl { [3-(trifluoromethyl)pyridin-2- yl]thio)methyl)-4-(phenylmethyl)morpholine as a colourless oil (0.033 g, 20 %). LCMS 6 min gradient method, Rt = 4.2 min, (M+H+) = 445
ii) To a suspension of polymer supported diwopropylamine (3.72 mmol/g, 0.097 g, 0.36 mmole) and (2S)-2-((S)-phenyl { [3-(trifluoromethyl)pyridin-2-yl]thio } methyl)-4-
(phenylmethyl)morpholine (0.0.032 g, 0.07 mmole) in dry DCM (0.5 ml) is added 1- chloroethyl chloroformate (0.039 ml, 0.36 mmole) at room temperature and under nitrogen. The mixture is heated at 40 °C for 2 hours. The reaction mixture is filtered and concentrated in vacuo then taken up in methanol (0.5 ml). The solution left to stir at room temperature overnight. After this time, the reaction mixture is loaded directly onto an
SClO-2 column. The SC10-2 column is washed with methanol. The target compound is eluted with 2 N NH3/methanol. This is concentrated in vacuo to give a pale yellow oil (0.024 g). The pale yellow oil is purified using an automated PrepLCMS system, then liberated as the free base by treatment with SClO-2 and concentrated under vacuum to give (2S)-2-((S)-phenyl { [3-(trifluoromethyl)pyridin-2-yl]thio } methyl)morpholine as a white solid (0.005 g, 20 %). LCMS 12 min gradient method, Rt = 4.9 min, (M+H+) =354
Example 6G; (25)-2-((S)-phenyl|[3-(phenylmethyl)pyridin-2- yllthiolmethvDmorpholine fumarate
Figure imgf000263_0001
Fumarate salt i) To a 100 ml round-bottomed flask, under nitrogen, containing dry THF (25 ml) is added 72-butyllithium (1.6 M solution in hexanes, 3.99 ml, 6.39 mmole) at 0°C followed by lithium diwopropylamide (2 M solution in THF/«-heptane, 3.19 ml, 6.39 mmole). The reaction mixture is left to stir for 1 hour at 0°C. The mixture is cooled to -70°C then 2- fluoropyridine added. The solution is stirred at -70°C for 4 hours. To the solution is added benzaldehyde (0.71 ml, 6.97 mmole). This is then left to stir for 1 hour at -70°C, after which time water (100 ml) is added. On warming to room temperature the solution is extracted with chloroform (2 x 100 ml). The combined extracts are dried (Na SO4) and concentrated in vacuo to yield a yellow oil (1.58 g). Purification by automated flash chromatography (ISCO System, Redisep 10 g SiO2 column, 0 - 30 % ethyl acetate in cyclohexane gradient elution over 30 minutes at 20 ml/min flow rate) gave 2-fluoro-3- (phenyl-l-hydroxymethyl)pyridine as a yellow oil (0.71 g, 59 %). FIA (M+H+) = 204
ii) To 5 % Pd/C (0.07 g), under nitrogen, is added a solution of 2-fluoro-3-(l-hydroxy-l- phenylmethy pyridine (0.71 g, 3.5 mmole) in ethanol (50 ml). This is then put on a Parr Hydrogenator at 60 psi H2 and left over the weekend. The reaction mixture is filtered through Celite®. Removal of solvent from the resulting solution gave a pale yellow oil. This is purified by automated flash chromatography (ISCO System, 10 g SiO2 Redisep column, 0 - 30 % ethyl acetate in cyclohexane gradient elution over 40 minutes at 20 ml/minute flow rate) to give 2-fluoro-3-(phenylmethyl)pyridine as a colourless oil (0.18 g, 27 %).
iii) To a solution of (S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6) (0.27 g, 0.91 mmole) and 2-fluoro-3-(l -hydroxy- l-phenylmethyl)pyridine (0.17 g, 0.91 mmole) in dry, degassed DMF (1.5 ml) is added, under nitrogen, sodium hydride (60 % dispersion in oil, 0.07 g, 1.82 mmole). The mixture is left to stir overnight at room temperature. A further portion of sodium hydride (605 dispersion in oil, 0.07 g, 1.82 mmole) and DMF (1 ml) is added. After 5 hours at room temperature, the reaction mixture is taken up in MeOH and loaded onto an SClO-2 column. The SClO-2 column is washed with methanol. The (2S)-2-((S)-phenyl{[3-(phenylmethyl)pyridin-2- yl]thio]methyl)-4-(phenylmethyl)morpholine is eluted with 2 N NH3/methanol. This is concentrated in vacuo to give a yellow residue (0.36 g). The residue is purified by automated flash chromatography (ISCO System, 35 g SiO2 Redisep column, 0 - 30 % ethyl acetate in cyclohexane gradient elution over 40 minutes at 40 ml/minute flow rate) which yields (2S)-2-((S)-phenyl{ [3-(phenylmethyl)pyridin-2-yl]thio}methyl)-4- (phenylmethyl)morpholine as a pale yellow oil (0.10 g, 24 %). LCMS 6 min gradient method, Rt = 3.8min, (M+H+) = 467
iv) Deprotection of the morpholine nitrogen is carried out using the method and work up as described in Example IG, using polymer supported dizsopropylamine (3.78 mmole/g, 0.28 g, 1.07 mmole), of (2S)-2-((S)-phenyl{ [3-(phenylmethyl)pyridin-2-yl]thio]methyl)- 4-(phenylmethyl)morpholine (0.092 g, 0.20 mmole), dry DCM (5 ml), 1-chloroethyl chloroformate (0.12 ml, 1.07 mmole) and methanol (5 ml). This gives (2S)-2-((S)- phenyl[ [3-(phenylmethyl)pyridin-2-yl]thio}methyl)morpholine as a colourless residue (0.076 g, 94 %). This oil is taken up in ethyl acetate. To this is added a solution of fumaric acid (1.1 equiv, 0.026 g) in methanol. The resulting solution is concentrated in vacuo and the resulting oil triturated with ethyl acetate. The solid is collected by filtration to give the fumarate salt of (2S)-2-((S)-phenyl{ [3-(phenylmethyl)pyridin-2- yl]thio]methyl)morpholine (1:1 fumarate salt) as a white solid (0.070 g). LCMS 12 min gradient method, Rt = 5.6 min, (M+H+) = 377
Example 7G: (25)-2-((S)-phenyl{r3-(phenyloxy)pyridin-2-yl1thiolmethvI)morpholine fumarate
Figure imgf000264_0001
Fumarate salt i) To a 100 ml round bottomed flask is added 2-chloro-3 -pyridinol (0.50 g, 3.86 mmole), copper (IT) acetate (0.70 g, 3.86 mmole), phenylboronic acid (0.94 g, 7.72 mmole) and powdered 4A molecular sieves. To the mixture is added DCM (39 ml) followed by triethylamine (2.69 ml, 19.30 mmole). This is stirred overnight, under nitrogen, at room temperature. The reaction mixture is poured into water (75 ml) and extracted with ethyl acetate (3 x 75 ml). The combined extracts are concentrated in vacuo to give a brown oil (0.65 g). Purification by automated flash chromatography (ISCO System, Redisep 35 g SiO2 column, 0 - 20 % ethyl acetate in cyclohexane gradient elution over 40 minutes) gives 2-chloro-3-phenoxypyridine as a colourless oil (0.32 g, 41%). LCMS 6 min gradient method, Rt = 3.6min, (M+H+) = 206
ii) To a solution of (S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6) (0.352 g, 1.18 mmole) and 2-chloro-3-phenoxypyridine (0.29 g, 1.41 mmole) in dry, degassed DMF (3 ml) is added, under nitrogen, cesium fluoride (0.179 g, 1.18 mmole). The mixture is left to stir for two days at 55°C. A further portion of cesium fluoride
(0.063 g, 0.41 mmole) is added and the solution heated for 5 hours at 55°C. The reaction mixture is allowed to cool then loaded neat onto a 35 g SiO2 Redisep column (preconditioned with cyclohexane). Automated flash chromatography (ISCO System, 0 - 40 % ethyl acetate in cyclohexane gradient elution over 40 minutes at 30 ml/minute flow rate) yields a yellow oil (2.26 g). This is taken up in MeOH and loaded onto an SClO-2 column. The SClO-2 column is washed with methanol. The title compound is eluted with 2 N NH3/methanol. This is concentrated in vacuo to give (2S)-2-{(S)-phenyl[(3- phenyloxypyridin-2-yl)thio]methyl}-4-(phenylmethyl)morpholine as a pale orange oil (0.092 g, 17 %). LCMS 6 min gradient method, Rt = 3.6 min, (M+H+) = 469
iii) Deprotection of the morpholine nitrogen is carried out using the method and work up as described in Example IG, using polymer supported dizsσpropylamine (3.78 mmole/g, 0.26 g, 0.98 mmole), (2S)-2-{(S)-phenyl[(3-phenyloxypyridin-2-yl)thio]methyl}-4- (phenylmethyl)morpholine (0.092 g, 0.20 mmole), dry DCM (5 ml), 1-chloroethyl chloroformate (0.11 ml, 0.98 mmole) and methanol (5 ml). This gave (2S)-2-((S)- phenyl{[3-(phenyloxy)pyridin-2-yl]thio}methyl)morpholine as a pale yellow oil (0.070 g, 95 %). This oil is taken up in ethyl acetate. To this is added a solution of fumaric acid (1.1 equiv, 0.024 g) in methanol. The resulting solution is concentrated in vacuo and the resulting oil triturated with ethyl acetate. The solid is collected by filtration to give the fumarate salt of (2S)-2-((S)-phenyl{ [3-(phenyloxy)pyridin-2-yl]thio}methyl)morpholine (1:1 fumarate salt) as an off-white solid (0.094 g). LCMS 12 min gradient method, Rt = 5.5 min, (M+H+) = 379
Example 8G: (2S)-2-[(S)-r(3-chloropyridin-2-yl)thiol(phenyl)methyllmorpholine fumarate
Figure imgf000266_0001
Fumarate salt i) To a solution of (S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6)
(0.446 g, 1.49 mmole) and 2,3-dichloropyridine (0.246 g, 1.67 mmole) in dry, degassed DMF (3 ml) is added, under nitrogen, sodium hydride (60 % dispersion in oil, 0.06 lg, 1.53 mmole). The mixture is left to stir overnight at room temperature. The reaction mixture is taken up in MeOH and loaded onto an SClO-2 column. The SClO-2 column is washed with methanol. The (2S)-2-[(S)-[(3-chloropyridin-2-yl)thio](phenyl)methyl]-4-
(phenylmethyl)morpholine is eluted with 2 N NHj/methanol. This is concentrated in vacuo to give (2S)-2-[(S)-[(3-chloropyridin-2-yl)thio](phenyl)methyl]-4- (phenylmethyl)morpholine as a pale yellow oil (0.61 g). LCMS 6 min gradient method, Rt = 3.5 min, (M+H+) = 411
ii) Deprotection of the morpholine nitrogen is carried out using the method and work up as described in Example IG, using polymer supported dizsσpropylamine (3.78 mmole/g, 0.39g, 1.46 mmole), (2S)-2-[(S)-[(3-chloropyridin-2-yl)thio](phenyl)methyl]-4- (phenylmethyl)morpholine (0.120 g, 0.292 mmole), dry DCM (15 ml), 1-chloroethyl chloroformate (0.16 ml, 1.46 mmole) and methanol (15 ml). This gives (2S)-2-[(S)-[(3- chloropyridin-2-yl)thio](phenyl)methyl]morpholine as a pale yellow oil (0.092 g, 98 %). This oil is taken up in ethyl acetate. To this is added a solution of fumaric acid (1 equiv, 0.033 g) in methanol. The resulting solution is concentrated in vacuo to give an oil which is crystallised from IPA. The solid is collected by filtration to give the fumarate salt of (2S)-2-[(S)-[(3-chloropyridin-2-yl)thio](phenyl)methyl]morpholine (1:1 fumarate salt) as a white solid (0.111 g). LCMS 12 min gradient method, Rt = 4.8 min, (M+H+) = 321
Example 9G: (2S)-2-r(S)-r(3-methylpyridin-2-yl)thio1(phenyl)methyllmorpholine fumarate
Figure imgf000267_0001
Fumarate salt i) To a degassed solution of S-{(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl} ethanethioate (5) (0.100 g, 0.293 mmole) and 2-fluoro-3-methylpyridine (0.325 g, 2.93 mmole) in DMF (1 ml) is added sodium methoxide (0.016 g, 0.293 mmole). The reaction mixture is left to stir at room temperature, under nitrogen, overnight. The reaction mixture is diluted with methanol and loaded onto an SClO-2 (5 g) column preconditioned with MeOH. The column is washed with MeOH then basic material is eluted with 2 N NH3/methanol. This ammonia solution is concentrated in vacuo to give an orange oil (0.067 g) which is purified by automated flash chromatography (ISCO System, Redisep
SiO column, 0 - 20 % ethyl acetate in cyclohexane gradient elution over 40 minutes) to give (2S)-2-[(S)-[(3-methylpyridin-2-yl)thio](ρhenyl)methyl]-4- (phenylmethyl)morpholine as a colourless oil (0.055 g, 44%). LCMS 6 min gradient method, Rt = 2.9 min, (M+H+) = 391
ii) To a suspension of polymer supported dizsøpropylamine (3.78 mmol/g, 0.167 g, 0.64 mmole) and (2S)-2-[(S)-[(3-methylpyridin-2-yl)thio](phenyl)methyl]-4- (phenylmethyl)morpholine (0.050 g, 0.13 mmole) in dry DCM (5 ml) is added 1- chloroethyl chloroformate (0.070 ml, 0.64 mmole) at room temperature and under nitrogen. The mixture is heated at 40°C for 1.5 hours. The reaction mixture is filtered and concentrated in vacuo then taken up in methanol (5 ml). The solution is left to stir at room temperature for 2.5 hours. After this time, the reaction mixture is loaded directly onto an SClO-2 column. The SClO-2 column is washed with methanol. The free base of the title compound is eluted with 2 N NH3/methanol. This ammonia solution is concentrated in vacuo to give (2S)-2-[(S)-[(3-methylpyridin-2- yl)thio](phenyl)methyl] morpholine as an orange oil (0.037. g, 97 %). This oil is taken up in methanol. To this is added a solution of fumaric acid (1 equiv, 0.014 g) in methanol.
This is stirred for a couple of minutes, then EtOAc followed by isohexane added. The resulting precipitate is collected by filtration to yield a white solid (0.048 g). This is recrystallised from ethyl acetate and isohexane to give the fumarate salt of (2S)-2-[(S)- [(3 -methylpyridin-2-yl)thio](phenyl)methyl] morpholine (1:1 fumarate salt) as a white solid (0.013 g) LCMS 12 min gradient method, Rt = 4.5 min, (M+H+) = 301
Example 10G: (2S)-2-r(S)-lr3-(4-chlorophenyl)pyridin-2- yllthioHphenvDmethyllmorpholine fumarate
Figure imgf000268_0001
Fumarate salt i) To bis(benzonitrile)palladium(π)dichloride (0.054 g, 0.14 mmole) and 1,4- bis(diphenylphosphine)butane (0.091 g, 0.21 mmole) is added dry toluene (6 ml), under nitrogen, and the mixture stirred for half an hour. To this is added 3-bromo-2- fluoropyridine (0.50 g, 2.83 mmole) in ethanol (1.4 ml) followed by a solution of 4- chlorophenylboronic acid (0.887 g, 5.67 mmole) in ethanol (2.4 ml). To this is added an aqueous solution of sodium carbonate (1 M, 2.83 ml, 2.83 mmole). The mixture is heated at 60°C for 24 hours, then at 75°C for a further 16 hours. The organic layer is loaded directly onto a 40 g Redisep SiO2 column and components isolated by automated flash chromatography (ISCO System, 0 - 30 % ethyl acetate in cyclohexane gradient elution over 40 minutes). This gave 3-(4-chlorophenyl)-2-fluoropyridine as a white solid (0.323 g, 55 %). LCMS 6 min gradient method, Rt = 4.0 min, (M+H+) = 208 ii) To a solution of (S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6) (0.388 g, 1.30 mmole) and 3-(4-chlorophenyl)-2-fluoropyridine (0.323 g, 1.56 mmole) in dry, degassed DMF (3 ml) is added, under nitrogen, cesium fluoride (0.295 g, 1.94 mmole). The mixture is heated at 65°C over the weekend. After this time, the reaction mixture is allowed to cool. The resulting solid is taken up in MeOH/DCM and loaded directly onto an SClO-2 column. The SClO-2 column is washed with methanol followed by 2 N NH3/methanol. The ammonia solution is concentrated in vacuo to give (2S)-2- [(S)-{ [3-(4-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholine as an orange foam (0.514 g). This is purified by automated flash chromatography (ISCO System, 0 - 30 % ethyl acetate in cyclohexane gradient elution over 40 minutes at 40 ml/minute flow rate) to give (2S)-2-[(S)-{[3-(4-chlorophenyl)pyridin-2- yl]thio](phenyl)methyl]-4-(phenylmethyl)morpholine as a white foam (0.178 g, 28 %). LCMS 6 min gradient method, Rt = 4.2 min, (M+H+) = 487
iii) Deprotection of the morpholine nitrogen is carried out using the method and work up as described in Example IG, using polymer supported dizsøpropylamine (3.78 mole/g, 0.48 g, 1.80 mmole), (2S)-2-[(S)-{[3-(4-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]- 4-(phenylmethyl)morpholine (0.175 g, 0.36 mmole), dry DCM (10 ml), 1-chloroethyl chloroformate (0.20 ml, 1.80 mmole) and methanol (10 ml). This gave a colourless residue (0.129 g, 90 %). This residue is taken up in ethyl acetate. To this is added a solution of fumaric acid (1.1 equiv, 0.035 g) in methanol. The resulting solid is recombined with the mother liquor and purified on a UN Guided PrepHPLC (Flex) System and treated with SClO-2 to give a yellow solid. This is further purified by automated flash chromatography (ISCO System, Redisep 4 g SiO2 column, 0 - 5 % methanol in dichloromethane gradient elution over 40 minutes, then 10 minutes at 5 %
Methanol in dichloromethane with 10 ml/min flow rate) to give (2S)-2-[(S)-{[3-(4- chlorophenyl)pyridin-2-yl]thio)(phenyl)methyl]morpholine as a pale yellow oil (0.049 g, 34 %). This oil is taken up in ethyl acetate. To this is added a solution of fumaric acid (1.1 equiv, 0.0145 g) in methanol. The resulting solution is concentrated in vacuo and recrystallised from MeOH and Et2O. The solid is collected by filtration to give the fumarate salt of (2S)-2-[(S)-{[3-(4-chloroρhenyl)pyridin-2- yl]thio](phenyl)methyl]morpholine (1:1 fumarate salt) as a white solid (0.047 g). LCMS 12 min gradient method, Rt = 5.7 min, (M+H+) = 397
Example llG: (2S)-2-r(5)-r(5-bromopyridin-2-yl)thiol(phenvnmethyllmorpholine fumarate
Figure imgf000270_0001
Fumarate salt i) To a solution of S-{(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl] ethanethioate (5) (0.25 g, 0.73 mmole) in dry methanol (2 ml) is added sodium methoxide (0.040 g, 0.73 mmole) under nitrogen. This is left to stir at room temperature for 1 hour. Methanol is removed in vacuo and replaced with DMF (1 ml). To this is then added the 5- bromo-2-fluoropyridine (0.11 ml, 1.02 mmole). The reaction mixture is left to stir at room temperature, under nitrogen, overnight. The reaction mixture is diluted with DCM and loaded directly onto a 35 g Redisep column. Purification by automated flash chromatography (ISCO System, Redisep 35 g SiO2 column, 0 - 20 % ethyl acetate in cyclohexane gradient elution over 40 minutes) gave (2S)-2-[(S)-[(5-bromopyridin-2- yl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine as a colourless oil (0.186 g, 56%). LCMS 6 min gradient method, Rt = 3.6 min, (M+H+) = 455/457
ii) To a suspension of polymer supported diwopropylamine (3.78 mmol/g, 0.108 g, 20.4 mmole) and (2S)-2-[(S)-[(5-bromopyridin-2-yl)thio](phenyl)methyl]-4-
(phenylmethyl)morpholine (0.186 g, 0.408 mmole) in dry DCM (10 ml) is added 1- chloroethyl chloroformate (0.22 ml, 2.04 mmole) at room temperature and under nitrogen. The mixture is heated at 40°C for 2.5 hours. The reaction mixture is then filtered and concentrated in vacuo then taken up in methanol (10 ml). The solution is left to stir at room temperature overnight. After this time, the reaction mixture is loaded directly onto an SClO-2 column (5 g). The SClO-2 column is washed with methanol. The target compound is eluted with 2 N NH3/methanol. This is concentrated in vacuo to give (2S)-2-[(S)-[(5-bromopyridin-2-yl)thio](phenyl)methyl]morpholine as a colourless oil (0.108. g, 72 %). This oil is taken up in ethanol. To this is added a solution of fumaric acid (1.2 equiv, 0.041 g) in ethanol. Solvent is removed in vacuo and the resulting residue triturated with EtOAc. This solid is collected by filtration to give the fumarate salt of (2S)-2-[(S)-[(5-bromopyridin-2-yl)thio](phenyl)methyl]morpholine (1:1 fumarate salt) as a white solid (0.105 g). LCMS 12 min gradient method, Rt = 5.0 min, (M+H+) = 365/367
Example 12G: 2-{r(S)-(2S)-morphoIin-2-virphenyl)methyllthio)pyridine-3- carboxamide fumarate
Figure imgf000271_0001
Fumarate salt i) To a degassed solution of S-{(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl] ethanethioate (5) (0.100 g, 0.293 mmole) and 2-chloronicotinamide (0.046 g, 0.293 mmole) in ethanol (3 ml) is added a solution of sodium hydroxide in water (2 M, 0.293 ml, 0.586 mmole). The resulting solution is stirred at room temperature overnight. An additional portion of 2-chloronicotinamide (0.046 g, 0.293 mmole) is added to the reaction mixture which is then heated at 40 °C overnight. The reaction mixture is diluted with methanol and loaded onto an SClO-2 column preconditioned with MeOH. The column is washed with MeOH then basic material is eluted with 2 N NHs/methanol. This ammonia solution is concentrated in vacuo to give 2-({ [(S)-phenyl[(2S)-4- (phenylmethyl)morpholin-2-yl]methyl }thio)pyridine-3-carboxamide as a pale orange residue (0.124 g, 100%). LCMS 6 min gradient method, Rt = 2.1 min, (M+H+) = 420
ii) To a suspension of polymer supported dizsσpropylamine (3.78 mmol/g, 0.38 g, 1.47 mmole) and 2-({ [(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl}thio)pyridine- 3-carboxamide (0.123 g, 0.29 mmole) in dry DCM (10 ml) is added 1-chloroethyl chloroformate (0.16 ml, 1.47 mmole) at room temperature and under nitrogen. The mixture is heated at 40°C for 2 hours. The reaction mixture is then filtered and concentrated in vacuo to give a pale yellow residue. This is taken up in methanol (10 ml) and the solution left to stir at room temperature for 3 hours. After this time, the reaction mixture is loaded directly onto an SCI 0-2 column. The SCI 0-2 column is washed with methanol then more basic compounds are eluted with 2 N NH3/methanol. The ammonia soluition is concentrated in vacuo to give 2-{ [(S)-(2S)-morpholin-2- yl(phenyl)methyl]thio]pyridine-3-carboxamide as a pale yellow oil (0.097 g, 100 %). The pa]e yellow oil is taken up in methanol. To this is added a solution of fumaric acid (1 equiv, 0.0153 g) in methanol. This is stirred for a couple of minutes, then EtOAc added. The resulting precipitate is collected by filtration to give the fumarate salt of 2-{ [(S)-(2S)- morpholin-2-yl(phenyl)methyl]thio]pyridine-3-carboxamide (1:1 fumarate salt) as a white solid (0.095 g). LCMS 12 min gradient method, Rt = 2.4 min, (M+H+) = 330
Example 13G: 2-ir(5)-(2S)-morpholin-2-vI(phenyl)methyl]thio)pyridine-3- carbonitrile fumarate
Figure imgf000272_0001
Fumarate salt i) To a degassed solution of S-{(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl) ethanethioate (5) (0.050 g, 0.147 mmole) and 2-chloro-3-cyanopyridine (0.020 g, 0.146 mmol) in ethanol (1.5 ml) is added a solution of sodium hydroxide in water (2 M, 0.146 ml, 0.293 mmole). The resulting solution is stirred at room temperature for -17 hours. The reaction mixture is diluted with methanol and loaded onto an SClO-2 column preconditioned with MeOH. The column is washed with MeOH then basic material is eluted with 2 N NH3/methanol. This ammonia solution is concentrated in vacuo to give 2- ({[(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl}thio)pyridine-3-carbonitrile as an off white solid (0.055 g, 93%). LCMS 6 min gradient method, Rt = 2.8 min, (M+H+) = 402 ii) To a suspension of polymer supported di sopropylamine (3.78 mmol/g, 0.181 g, 0.685 mmole) and 2-({ [(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl}thio)pyridine- 3 -carbonitrile (0.055 g, 0.137 mmole) in dry DCM (5 ml) is added 1-chloroethyl chloroformate (0.075 ml, 0.685 mmole) at room temperature and under nitrogen. The mixture is heated at 40°C for 2 hours. The reaction mixture is then filtered and concentrated in vacuo to give a pale orange liquid. This is taken up in methanol (5 ml) and the solution left to stir at room temperature overnight. After this time, the reaction mixture is loaded directly onto an SClO-2 column. The SClO-2 column is washed with methanol then more basic material is eluted with 2 N NH3/methanol. The ammonia solution is concentrated in vacuo to give 2-{ [(S)-(2S)-morpholin-2- yl(phenyl)methyl]thio)pyridine-3-carbonitrile as a pale yellow oil (0.041 g, 95 %). The pale yellow oil is taken up in methanol. To this is added a solution of fumaric acid (1 equiv, 0.0153 g) in methanol. This is stirred for a couple of minutes, then EtOAc followed by cyclohexane added. The resulting precipitate is collected by filtration to give the fumarate salt of 2-{ [(S)-(2S)-morpholin-2-yl(phenyl)methyl]thio }pyridine-3- carbonitrile (1:1 fumarate salt) as a white solid (0.042 g). LCMS 12 min gradient method, Rt = 4.6 min, (M+H+) = 312
Example 14G: (2S)-2-[phenyl(pyridin-2-ylthio)methyl1morpholine hydrochloride
Figure imgf000273_0001
Fumarate salt i) To a stirred solution of (R)-phenyl[(2S)-4-(phenylmethyl)mo holin-2-yl]methyl methanesulfonate (0.70 g, 1.94 mmole) and 2-mercaptopyridine (0.54 g, 4.84 mmole) in anhydrous DMF, at room temperature and under nitrogen, is added potassium carbonate (0.80 g, 5.81 mmole). The reaction is left to stir at room temperature for 6 days. The reaction mixture is diluted with methanol and loaded onto an SClO-2 column preconditioned with MeOH. The column is washed with MeOH then basic material is eluted with 2 N NH3/methanol. This ammonia solution is concentrated in vacuo to give an orange residue (0.881 g). Purification by automated flash chromatography (ISCO System, 0 - 30 % ethyl acetate in isohexane gradient elution over 30 minutes) gave (2S)- 2-[phenyl(pyridin-2-ylthio)methyl]-4-(phenylmethyl)morpholine as a colourless oil (0.245 g, 34 %). LCMS 6 min gradient method, Rt = 2.7 min, (M+H+) = 377.
ii) Deprotection of the morpholine nitrogen is carried out using the method and work up as described in Example IG, using polymer supported di/søpropylamine (3.78 mmole/g, 0.43 g, 1.64 mmole), (2S)-2-[phenyl(pyridin-2-ylthio)methyl]-4- (phenylmethyl)morpholine (0.103g, 0.274 mmole), dry DCM (10 ml), 1-chloroethyl chloroformate (0.15 ml, 1.37 mmole) and methanol (10 ml). This gave a pale yellow oil (0.058 g, 74 %). ). Purification of this residue by automated flash chromatography (ISCO
System, SiO2 Redisep column, 10 % MeOH in DCM) gave a colourless oil (0.044 g, 54 %). This oil is taken up in ethyl acetate. To this is added a solution of hydrochloric acid in dioxane (4 M, 0.1 ml). Concentration in vacuo gave the hydrochloride salt of (2S)-2- [phenyl(pyridin-2-ylthio)methyl] as a white solid (0.045 g). LCMS 6 min gradient method, Rt = 1.8 min, (M+H+) = 287
Example 15G; (2S)-2-r(S)-r(3-iodopyridin-2-yl)thiol(phenyl)methyllmorpholine fumarate
Figure imgf000274_0001
Fumarate salt i) To (S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6) (0.50 g, 1.67 mmole) and 2-chloro-3-iodopyridine (0.48 g, 2.00 mmole) in degassed DMF (3 ml) is added cesium fluoride (0.38 g, 2.50 mmole) at room temperature and under nitrogen. The mixture is heated at between 55-75°C for 3 days. The organic layer is then loaded directly onto a 35 g ISCO column (SiO2) and columned using automated flash chromatography (0 - 30% EtOAc in cyclohexane over 30 minutes) to give a pale yellow crystalline solid
(0.55 g). The solid is taken up in DCM:MeOH (1:1) and loaded onto an SClO-2 column (10 g) preconditioned with MeOH. The column is washed with MeOH to remove 2- chloro-3-iodopyridine, then more basic material is eluted with 2 N NH3/methanol. The ammonia solution is concentrated in vacuo to give (2S)-2-[(S)-[(3-iodopyridin-2- yl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine as a pale yellow solid (0.19 g, 23%). LCMS 6 min gradient method, Rt = 3.8 min, (M+H+) = 503 ii) To a suspension of polymer supported diwøpropyl amine (3.72 mmol/g, 0.285 g, 1.06 mmole) and (2S)-2-[(S)-[(3-iodopyridin-2-yl)thio](phenyl)methyl]-4-
(phenylmethyl)morpholine (0.107 g, 0.21 mmole) in dry DCM (1.5 ml) is added 1- chloroethyl chloroformate (0.116 ml, 1.06 mmole) at room temperature and under nitrogen. The mixture is heated at 40°C for 2 hours. The reaction mixture is then filtered and concentrated in vacuo to give a pale orange liquid. This is taken up in methanol (1.5 ml) and the solution left to stir at room temperature overnight. After stirring overnight at room temperature, the reaction mixture is loaded directly onto an SClO-2 column. The SCI 0-2 column is washed with methanol, then more basic material is eluted with 2 N NH3/methanol. The ammonia solution is concentrated in vacuo to give (2S)-2-[(S)-[(3- iodopyridin-2-yl)thio](phenyl)methyl]morpholine as a pale yellow oil (0.047 g, 53%). This oil is taken up in methanol and to this is added a solution of fumaric acid (1 equiv,
0.013 g) in methanol. This is stirred for a couple of minutes, then EtOAc followed by Et2O added. The resulting precipitate is collected by filtration to give the fumarate salt of (2S)-2-[(S)-[(3-iodopyridin-2-yl)thio](phenyl)methyl]morpholine (1:1 fumarate salt) as a white solid (0.036 g). LCMS 12 min gradient method, Rt = 4.9 min, (M+H+) = 413 The pharmacological profile of the compounds of Formulae (IA), (IB), (IC), (ID),
(IE), (IF) and (IG) can be demonstrated as follows. The preferred exemplified compounds above exhibit a Kj value less than 500nM at the norepinephrine transporter as determined using the scintillation proximity assay described below. Furthermore, the preferred exemplified compounds above selectively inhibit the norepinephrine transporter relative to the serotonin and dopamine transporters by a factor of at least five using the scintillation proximity assays as described below.
Generation of stable cell-lines expressing the human dopamine, norepinephrine and serotonin transporters Standard molecular cloning techniques are used to generate stable cell-lines expressing the human dopamine, norepinephrine, and serotonin transporters. The polymerase chain reaction (PCR) was used in order to isolate and amplify each of the three full-length cDNAs from an appropriate cDNA library. Primers for PCR were designed using the following published sequence data:
Human dopamine transporter: GenBank M95167. Reference: Vandenbergh DI, Persico AM and Uhl GR. A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic Taql RFLPs. Molecular Brain Research (1992) Volume 15, pages 161-166.
Human norepinephrine transporter: GenBank M65105. Reference: Pacholczyk T, Blakely, RD and Amara SG. Expression cloning of a ***e- and antidepressant-sensitive human noradrenaline transporter. Nature (1991) Volume 350, pages 350-354.
Human serotonin transporter: GenBank L05568. Reference: Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V and Blakely RD. Antidepressant- and ***e-sensitivehuman serotonin transporter: Molecular cloning, expression, and chromosomal localization. Proceedings of the National Academy of Sciences of the USA (1993) Volume 90, pages 2542-2546.
The PCR products are cloned into a mammalian expression vector (e.g., pcDNA3.1 (Invitrogen)) using standard ligation techniques. The constructs are then used to stably transfect HEK293 cells using a commercially available lipofection reagent (Lipofectamine™ - Invitrogen) following the manufacturer's protocol.
Scintillation proximity assays for determining the affinity of test ligands at the norepinephrine transporter
The compounds of Formulae (TT) and (TR) of the present invention are norepinephrine reuptake inhibitors, and possess excellent activity in, for example, a scintillation proximity assay (e.g., I. Gobel, D.L. Saussy and A. Goetz, J. Pharmacol. Toxicol. (1999) 42:237-244). Thus, H-nisoxetine binding to norepinephrine re-uptake sites in a cell line transfected with DNA encoding human norepinephrine transporter binding protein has been used to determine the affinity of ligands at the norepinephrine transporter. Membrane Preparation:
Cell pastes from large scale production of HEK-293 cells expressing cloned human norepinephrine transporters were homogenized in 4 volumes 50mM Tris-HCl containing 300mM NaCl and 5mM KCI, pH 7.4. The homogenate was centrifuged twice (40,000g, lOmin, 4°C) with pellet re-suspension in 4 volumes of Tris-HCl buffer containing the above reagents after the first spin and 8 volumes after the second spin. The suspended homogenate was centrifuged (lOOg, lOmin, 4°C) and the supernatant kept and re-centrifuged (40,000g, 20min, 4°C). The pellet was resuspended in Tris-HCl buffer containing the above reagents along with 10%w/v sucrose and 0.1 mM phenylmethylsulfonyl fluoride (PMSF). The membrane preparation was stored in aliquots (1ml) at -80°C until required. The protein concentration of the membrane preparation was determined using a bicinchoninic acid (BCA) protein assay reagent kit (available from Pierce).
[3H] -Nisoxetine Binding Assay :
Each well of a 96 well microtitre plate was set up to contain the following: 50μl 2nM [N-methyl-3H]-Nisoxetine hydrochloride (70-87Ci/mmol, from NEN Life
Science Products) 75μl Assay buffer (50mM Tris-HCl pH 7.4 containing 300mM NaCl and 5mM KCI) 25μl Test compound, assay buffer (total binding) or lOμM Desipramine HCI (nonspecific binding) 50μl Wheatgerm agglutinin coated poly (vinyltoluene) (WGA PVT) SPA Beads
(Amersham Biosciences RPNQ0001) (lOmg/ml) 50μl Membrane (0.2mg protein per ml) The microtitre plates were incubated at room temperature for 10 hours prior to reading in a Trilux scintillation counter. The results were analysed using an automatic spline fitting programme (Multicalc, Packard, Milton Keynes, UK) to provide Ki values for each of the test compounds.
Serotonin Binding Assay
The ability of a test compound to compete with [3H]-citalopram for its binding sites on cloned human serotonin transporter containing membranes has been used as a measure of test compound ability to block serotonin uptake via its specific transporter (Ramamoorthy, S., Giovanetti, E., Qian, Y., Blakely, R., (1998) J. Biol. Chem. 273: 2458).
Membrane Preparation:
Membrane preparation is essentially similar to that for the norepinephrine transporter containing membranes as described above. The membrane preparation was stored in aliquots (1ml) at -70°C until required. The protein concentration of the membrane preparation was determined using a BCA protein assay reagent kit.
[3H]-Citalopram Binding Assay:
Each well of a 96 well microtitre plate was set up to contain the following:
50μl 2nM [3H]-Citalopram (60-86Ci/mmol, Amersham Biosciences) 75μl Assay buffer (50mM Tris-HCl pH 7.4 containing 150mM NaCl and 5mM KCI)
25μl Diluted compound, assay buffer (total binding) or lOOμM Fluoxetine (nonspecific binding)
50μl WGA PVT SPA Beads (40mg/ml)
50μl Membrane preparation (0.4mg protein per ml) The microtitre plates were incubated at room temperature for 10 hours prior to reading in a Trilux scintillation counter. The results were analysed using an automatic spline fitting programme (Multicalc, Packard, Milton Keynes, UK) to provide Ki (nM) values for each of the test compounds.
Dopamine Binding Assay
The ability of a test compound to compete with [3H]-WIN35,428 for its binding sites on human cell membranes containing cloned human dopamine transporter has been used as a measure of the ability of such test compounds to block dopamine uptake via its specific transporter (Ramamoorthy et al 1998 supra).
Membrane Preparation: Is essentially the same as for membranes containing cloned human serotonin transporter as described above.
[3H]-WIN35,428 Binding Assay: Each well of a 96well microtitre plate was set up to contain the following:
50μl 4nM [3H]-WIN35,428 (84-87Ci/mmol, from NEN Life Science Products) 75μl Assay buffer ( 50mM Tris-HCl pH 7 . 4 containing 150mM NaCl and 5mM KCI ) 25μl Diluted compound, assay buffer (total binding) or lOOμM Nomifensine (non- specific binding)
50μl WGA PVT SPA Beads (lOmg/ml)
50μl Membrane preparation (0.2mg protein per ml.)
The microtitre plates were incubated at room temperature for 120 minutes prior to reading in a Trilux scintillation counter. The results were analysed using an automatic spline fitting programme (Multicalc, Packard, Milton Keynes, UK) to provide Ki values for each of the test compounds.
Acid Stability
The acid stability of a compound according to the present invention was determined as a solution in buffer at 6 different pH values (HCI 0. IN, pH 2, pH 4, pH 6, pH 7, and pH 8) at 40°C over a time course of 72 hours. Samples were taken at the beginning of the study and after 3, 6 and 24 hours and analysed by capillary electrophoresis. The original sample used in this study contained 0.8% of the undesired epimer as internal standard. The samples taken at the different time points during the study did not show any significant change in the percentage of the undesired epimer. This assay confirms that compounds of the present invention are chemically and configurationally stable under acidic conditions.
In Nitro Determination of the Interaction of compounds with CYP2D6 in Human Hepatic Microsomes
Cytochrome P450 2D6 (CYP2D6) is a mammalian enzyme which is commonly associated with the metabolism of around 30% of pharmaceutical compounds. Moreover, this enzyme exhibits genetic polymorphism, resulting in the presence of both normal and poor metabolizers in the population. A low involvement of CYP2D6 in the metabolism of compounds (i.e. the compound being a poor substrate of CYP2D6) is desirable in order to reduce any variability from subject to subject in the pharmacokinetics of the compound. Also, compounds with a low inhihibitor potential for CYP2D6 are desirable in order to avoid drug-drug interactions with co-administered drugs that are substrates of CYP2D6. Compounds can be tested both as substrates and as inhibitors of this enzyme by means of the following assays.
CYP2D6 substrate assay
Principle:
This assay determines the extent of the CYP2D6 enzyme involvement in the total oxidative metabolism of a compound in microsomes. Preferred compounds of the present invention exhibit less than 75% total metabolism via the CYP2D6 pathway. For this in vitro assay, the extent of oxidative metabolism in human liver microsomes (HLM) is determined after a 30 minute incubation in the absence and presence of Quinidine, a specific chemical inhibitor of CYP2D6. The difference in the extent of metabolism in absence and presence of the inhibitor indicates the involvement of CYP2D6 in the metabolism of the compound.
Materials and Methods:
Human liver microsomes (mixture of 20 different donors, mixed gender) were acquired from Human Biologies (Scottsdale, AZ, USA). Quinidine and β-NADPH (β-Nicotinamide Adenine Dinucleotide Phosphate, reduced form, tetrasodium salt) were purchased from Sigma (St Louis, MO, USA). All the other reagents and solvents were of analytical grade. A stock solution of the new chemical entity (NCE) was prepared in a mixture of Acetonitrile/Water to reach a final concentration of acetonitrile in the incubation below 0.5%.
The microsomal incubation mixture (total volume 0.1 mL) contained the NCE (4 μM), β-NADPH (1 mM), microsomal proteins (0.5 mg/mL), and Quinidine (0 or 2 μM) in 100 mM sodium phosphate buffer pH 7.4. The mixture was incubated for 30 minutes at 37 °C in a shaking waterbath. The reaction was terminated by the addition of acetonitrile (75 μL). The samples were vortexed and the denaturated proteins were removed by centrifugation. The amount of NCE in the supernatant was analyzed by liquid chromatography /mass spectrometry (LC/MS) after addition of an internal standard. A sample was also taken at the start of the incubation (t=0), and analysed similarly. Analysis of the NCE was performed by liquid chromatography /mass spectrometry. Ten μL of diluted samples (20 fold dilution in the mobile phase) were injected onto a Spherisorb CN Column, 5 μM and 2.1 mm x 100 mm (Waters corp. Milford, MA, USA). The mobile phase consisting of a mixture of Solvent A/Solvent B, 30/70 (v/v) was pumped (Alliance 2795, Waters corp. Milford, MA, USA) through the column at a flow rate of 0.2 ml/minute. Solvent A and Solvent B were a mixture of ammonium formate 5.10"3 M pH 4.5/ methanol in the proportions 95/5 (v/v) and 10/90 (v/v), for solvent A and solvent B, respectively. The NCE and the internal standard were quantified by monitoring their molecular ion using a mass spectrometer ZMD or ZQ (Waters-Micromass corp, Machester, UK) operated in a positive electrospray ionisation. The extent of CYP2D6 involvement (% of CYP2D6 involvement) was calculated comparing the extent of metabolism in absence and in presence of quinidine in the incubation.
The extent of metabolism without inhibitor (%) was calculated as follows:
(NCE response in samples without inhibitor)time Q - (NCE response in samples without inhibitor)time 3Q (NCE response in samples without inhibitor)time Q
The extent of metabolism with inhibitor (%) was calculated as follows:
(NCE response in samples without inhibitor)timeQ - (NCE response in samples with inhibitor)time30 (NCE response in samples without inhibitor)timeO
where the NCE response is the area of the NCE divided by the area of the internal standard in the LC/MS analysis chromatogram, timeO and time30 correspond to the 0 and
30 minutes incubation time.
The % of CYP2D6 involvement was calculated as follows :
(% extent of metabolism without inhibitor) - (% extent of metabolism with inhibitor)
% extent of metabolism without inhibitor CYP2D6 inhibitor assay Principle:
The CYP2D6 inhibitor assay evaluates the potential for a compound to inhibit CYP2D6. This is performed by the measurement of the inhibition of the bufuralol 1 '- hydroxylase activity by the compound compared to a control. The l'-hydroxylation of bufuralol is a metabolic reaction specific to CYP2D6. Preferred compounds of the present invention exhibit an IC50 higher than 6 μM for CYP2D6 activity, the IC50 being the concentration of the compound that gives 50 % of inhibition of the CYP2D6 activity.
Materials and Methods:
Human liver microsomes (mixture of 20 different donors, mixed gender) were acquired from Human Biologies (Scottsdale, AZ). β-NADPH was purchased from Sigma (St Louis, MO). Bufuralol was purchased from Ultrafine (Manchester, UK). All the other reagents and solvents were of analytical grade. Microsomal incubation mixture (total volume 0.1 mL) contained bufuralol 10 μM, β-NADPH (2 mM), microsomal proteins (0.5 mg/mL), and the new chemical entity (NCE) (0, 5, and 25 μM) in 100 mM sodium phosphate buffer pH 7.4. The mixture was incubated in a shaking waterbath at 37 °C for 5 minutes. The reaction was terminated by the addition of methanol (75 μL). The samples were vortexed and the denaturated proteins were removed by centrifugation. The supernatant was analyzed by liquid chromatography connected to a fluorescence detector. The formation of the 1'- hydroxybufuralol was monitored in control samples (0 μM NCE) and in the samples incubated in presence of the NCE. The stock solution of NCE was prepared in a mixture of Acetonitrile/Water to reach a final concentration of acetonitrile in the incubation below 1.0%.
The determination of l'hydroxybufuralol in the samples was performed by liquid chromatograhy with fluorimetric detection as described below. Twenty five μL samples were injected onto a Chromolith Performance RP-18e column (100 mm x 4.6 mm) (Merck KGAa, Darmstadt, Germany). The mobile phase, consisting of a mixture of solvent A and solvent B whose the proportions changed according the following linear gradient, was pumped through the column at a flow rate of 1 ml/min:
Figure imgf000283_0001
Solvent A and Solvent B consisted of a mixture of 0.02 M potassium dihydrogenophosphate buffer pH3/ methanol in the proportion 90/10 (v/v) for solvent A and 10/90 (v/v) for solvent B. The run time was 7.5 minutes. Formation of 1'- hydroxybufuralol was monitored by fluorimetric detection with extinction at λ 252 nm and emission at λ 302 nm.
The IC50 of the NCE for CYP2D6 was calculated by the measurement of the percent of inhibition of the formation of the 1 '-hydroxybufuralol in presence of the NCE compared to control samples (no NCE) at a known concentration of the NCE.
The percent of inhibition of the formation of the 1 '-hydroxybufuralol is calculated as follows:
(1 '-hydroxybufuralol formed without inhibitor) - (1 '-hydroxybufuralol formed with inhibitor) xlOO
(1 '-hydroxybufuralol area formed without inhibitor)
The IC50 is calculated from the percent inhibition of the formation of the 1'- hydroxybufuralol as follows (assuming competitive inhibition):
NCE Concentration x ( l00 - Percent of inhibition ) Percent of inhibition
The IC50 estimation is assumed valid if inhibition is between 20% and 80% (Moody GC, Griffin SI, Mather AN, McGinnity DF, Riley R . (1999) Fully automated analysis of activities catalyzed by the major human liver cytochrome P450 (CYP) enzymes: assessment of human CYP inhibition potential. Xenobiotica 29(1): 53-75). EXAMPLE
The immediate-early gene, c-fos, and its protein products have been increasingly utilized as markers for neuronal activation (Dragunow and Faull, J. Neurosci. Methods. 29, 261-265 (1989); Morgan and Curran, Prog. In Brain Res., 86, 287-294
(1990); Robertson, et a]., J. Pharmacol. Exp. Ther.. 271, 1058-1066 (1994)). C-fos activation is measured as illustrated below for atomoxetine.
Two hours after administration of atomoxetine (3 mg/kg, i.p.), the rats were deeply anesthetized with sodium pentobarbital (60 mg/kg, i.p.) and transcardially perfused with 100 ml of phosphate buffered saline (PBS) followed by 100 ml of 4% paraformaldehyde in PBS. The brain was rapidly removed, postfixed for 90 min in 4% paraformaldehyde and then was transferred to 30% sucrose at 4° C until saturated. After quick freezing, serial 30 μm sections were cut and placed in PBS until processed for immunohistochemistry. In brief, sections were incubated in PBS containing blocking serum and 0.5% Triton-X 100 for 1 hour. Sections were then incubated with anti-Fos antibody (Santa Cruz Biotechnology, Inc.) at 4°C overnight. Visualization of the Fos-like immunoreactivity was performed with a Vectastain ABC Elite Kit (Vector Labs, Burlingame, CA) using the standard protocol supplied with the kit. Nickel-intensified diaminobenzidine (DAB) was used as the chromagen to yield a gray-black precipitation product. Following visualization of the Fos immunoreactivity, the sections were mounted on gelatin-coated glass slides and allowed to dry. The sections were then dehydrated and cover slipped. Fos expressing cells were quantitated using the MCID M2 imaging system (Imaging Research, St. Catherines, Ontario).
Surprisingly, atomoxetine increased the expression of c-fos only in the cortical areas as demonstrated by the data in the following table.
Prefrontal Cortex** Nucleus
Treatment Accumbens** Striatufn**
Vehicle 80±28 129+33 118±26
Atomoxetine 296+26* 152+44 102+35 *=ρ<0.001
** Fos positive cells/mm2
The invention being thus described, it is obvious that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.

Claims

We Claim:
1. A method of treating cognitive failure, comprising administering to a patient in need of such treatment an effective amount of a selective norepinephrine reuptake inhibitor selected from the group consisting of: a compound of formula (IA):
Figure imgf000286_0001
(IA) wherein n is 1, 2 or 3; Rl is C2-Ci Qalkyl, C2-CiQalkenyl, C3-Cgcycloalkyl or C4-C1 Qcycloalkylalkyl, wherein one C-C bond within any cycloalkyl moiety is optionally substituted by an O-C or C=C bond and wherein each group is optionally substituted with from 1 to 7 halogen substituents and/or with from 1 to 3 substituents each independently selected from hydroxy, cyano, Ci -C4alkyl and Ci -C^alkoxy; R2 is H, Ci -C4alkyl
(optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkyl-S(O)x- wherein x is 0, 1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Cι -C4alkoxy
(optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and Ci -C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and Ci -C4alkoxy) or -CO2(Ci -C4alkyl), or together with R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, C1-
C4alkyl and Ci -G4alkoxy); R3 is H, Ci -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Cι-C4alkyl-S(O)x- wherein x is 0, 1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj^al yl and Cι-C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and Ci -C4alkoxy) or -CO2(Ci -C4alkyl), or together with R2 or R4 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and Ci -C4alkoxy); R4 is H, Ci -
C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Ci -G4alkyl-S(O)x- wherein x is 0, 1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -
C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl
(optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι -C4alkyl and Ci -G^alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, C1 -C4 alkyl and Cι-G4alkoxy) or
-CO2(Ci -C4alkyl), or together with R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι-
C4alkyl and Ci -C4alkoxy); R5 is H, Ci -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Cι -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms) or halogen; R6 is H, Ci -COalkyl (optionally substituted with from 1 to 7 halogen atoms),
Ci -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms) or halogen; R7 is
H or Ci -C4alkyl; R8 is H or Ci -C4alkyl; R9 is H, halogen, hydroxy, cyano, Ci -C4alkyl or Ci -C4alkoxy; and R10 is H, halogen, hydroxy, cyano, Ci -C4alkyl or Ci -C4alkoxy; or a pharmaceutically acceptable salt thereof, with the proviso that the compound N-ethyl-
N-benzyl-4-piperidinamine is excluded; a compound of formula (IB):
Figure imgf000287_0001
wherein Rx is H; Ry is H or -C4 alkyl; each Rz is independently H or Cι-C alkyl; X represents O; Y represents OH or OR; R is - alkyl; Ari is a phenyl ring or a 5- or 6-membered heteroaryl ring each of which may be substituted with 1, 2, 3, 4 or 5 substituents (depending upon the number of available substitution positions) each independently selected from Ci -C4 alkyl, O(Cι -C4 alkyl), S(Cι -C4 alkyl), halo, hydroxy, pyridyl, thiophenyl and phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci -C4 alkyl, or O(Cι -C4 alkyl); and Ar2 is a phenyl ring or a 5- or 6-membered heteroaryl ring each of which may be substituted with 1, 2, 3, 4 or 5 substituents (depending upon the number of available substitution positions) each independently selected from C1 -C4 alkyl, O(Cι -C4 alkyl) and halo; wherein each above- mentioned Ci -C4 alkyl group is optionally substituted with one or more halo atoms; or a pharmaceutically acceptable salt thereof; a compound of formula (IC)
^Ar
Figure imgf000288_0001
(IC) wherein: A is S or O; R is H; Ar is a phenyl group optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from C1 -C4 alkyl, O(Cι-C alkyl),
S(Cι -C4 alkyl), halo, hydroxy, CO2(Cι -C4 alkyl), pyridyl, thiophenyl and phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci -C4 alkyl, or O(Cι -C4 alkyl); X is a phenyl group optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci -C4 alkyl, or O(Cι-C4 alkyl); a Ci -C4 alkyl group; a C3-C6 cycloalkyl group or a CH2(C3-C6 cycloalkyl) group; R' is H or Ci -C4 alkyl; each R1 is independently H or C1-C4 alkyl; wherein each above-mentioned Ci -C4 alkyl group is optionally substituted with one or more halo atoms; or a pharmaceutically acceptable salt thereof; with the proviso that, when A is O, X is a Ci -C4 alkyl group, a C3- Cβ cycloalkyl group or a CH (C3-Cg cycloalkyl) group; a compound of formula (ID)
Figure imgf000289_0001
(ID) wherein -X- is -C(R4R5)-, -O- or -S-; n is 2 or 3; R1 is H or CrC4 alkyl; R3 is H, halo, Q- C4 alkyl, O( -C4 alkyl), nitrile, phenyl or substituted phenyl; R4 and R5 are each independently selected from H or -Q alkyl; Ar- is selected from the group consisting of
Figure imgf000289_0002
in which R ,2a is H, halo, methyl or ethyl; R 2b ° is H, halo or methyl; R ,2c is H, halo, methyl, trifluoromethyl, nitrile, or methoxy; R 2d i . s H, halo, methyl or ethyl; R >2e . is H, halo, methyl, trifluoromethyl, nitrile, or methoxy; R2f is H, or fluoro; -Y- is -O-, -S- or - N(R6)-; and R6 is H or methyl or a pharmaceutically acceptable salt thereof; a compound of formula (IE)
Figure imgf000289_0003
(IE) wherein R1 is -G5 alkyl (optionally substituted with 1, 2 or 3 halo substituents and/or with 1 substituent selected from -S-(Cι-C3 alkyl), -O-(CΪ-C3 alkyl) (optionally substituted with 1, 2 or 3 F atoms), -O-(C3-C6 cycloalkyl), -SO2-(C C3 alkyl), -CN, -COO-(Cι-C2 alkyl) and -OH); C2-C6 alkenyl; -(CH2)q-Ar2; or a group of formula (i) or (ii)
Figure imgf000290_0001
(i) (ϋ)
R2, R3 and R4 are each independently selected from hydrogen or -C alkyl; R , R , R and R are at each occurrence independently selected from hydrogen or -C2 alkyl; -X- is a bond, -CH2-, -CH=CH-, -O-, -S-, or -SO2-; -Y- is a bond, -CH2- or -O-; -Z is hydrogen, -OH or -O-(CrC3 alkyl); p is 0, 1 or 2; q is 0, 1 or 2; r is 0 or 1 ; s is 0, 1, 2 or 3; t is 0, 1, 2 or 3;
Figure imgf000290_0002
is phenyl, pyridyl, thiazolyl, benzothiophenyl or naphthyl; wherein said phenyl, pyridyl or thiazolyl group may be substituted with 1, 2 or 3 substituents each independently selected from halo, cyano, - alkyl (optionally substituted with 1, 2 or 3 F atoms), -O-(CrC4 alkyl) (optionally substituted with 1, 2 or 3 F atoms) and -S-(C1-C4 alkyl)
(optionally substituted with 1, 2 or 3 F atoms) and/or with 1 substituent selected from pyridyl, pyrazole, phenyl (optionally substituted with 1, 2 or 3 halo substituents) and phenoxy (optionally substituted with 1, 2 or 3 halo substituents); and wherein said benzothiophenyl or naphthyl group may be optionally substituted with 1, 2 or 3 substituents each independently selected from halo, cyano, C1-C4 alkyl (optionally substituted with 1, 2 or 3 F atoms), -O-(C1-
C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms), and -S-(d-C alkyl) (optionally substituted with 1, 2 or 3 F atoms); Ar2 is naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl, wherein said naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl may be substituted with 1, 2 or 3 substituents each independently selected from halo, -C4 alkyl (optionally substituted with 1, 2 or 3 F atoms) and -O-( -C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms); or a pharmaceutically acceptable salt thereof; provided that (a) the cyclic portion of the group of formula (i) must contain at least three carbon atoms and not more than seven ring atoms; (b) when -X- is -CH=CH-, then the cyclic portion of the group of formula (i) must contain at least five carbon atoms; and (c) when -Z is -OH or -O-(Cι -C3 alkyl), then -X- is -CH -; (d) when -Y- is -O- then p cannot be 0; and (e) the compound 3-[(phenylmethyl)-(3S)-3-pyrrolidinylamino]-propanenitrile is excluded; a compound of formula (IF)
Figure imgf000291_0001
(IF) wherein
is a group of formula (a) or (b)
Figure imgf000291_0002
Figure imgf000291_0003
(a) (b)
R1 is C C6 alkyl (optionally substituted with 1, 2 or 3 halo substituents and/or with 1 substituent selected from -S-(Ci-C3 alkyl), -O- -Cs alkyl) (optionally substituted with 1, 2 or 3 F atoms), -O-(C3-C6 cycloalkyl), -SO2-(C C3 alkyl), -CN, -COO-(C C2 alkyl) and -OH); C2-C6 alkenyl; -(CH2)q-Ar2; or a group of formula (i) or (ii)
Figure imgf000291_0004
(i) (ϋ)
R , R3 and R are each independently selected from hydrogen or Cl-C2 alkyl; R5, R6, R7 and R8 are at each occurrence independently selected from hydrogen or -C alkyl; -X- is a bond, -CH2-, -CH=CH-, -O-, -S-, or -SO2-; -Y- is a bond, -CH2- or -O-; -Z is hydrogen, -OH or -O-(CrC3 alkyl); p is 0, 1 or 2; q is 0, 1 or 2; r is 0 or 1; s is 0, 1, 2 or 3; t is 0, 1, 2 or 3; Ari is phenyl, pyridyl, thiazolyl, benzothiophenyl or naphthyl; wherein said phenyl, pyridyl or thiazolyl group may be substituted with 1, 2 or 3 substituents each independently selected from halo, cyano, -C alkyl (optionally substituted with 1, 2 or 3 F atoms), -O-(CrC alkyl) (optionally substituted with 1, 2 or 3 F atoms) and -S-(Cι-C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms) and/or with 1 substituent selected from pyridyl, pyrazole, phenyl (optionally substituted with 1, 2 or 3 halo substituents), benzyl and phenoxy (optionally substituted with 1, 2 or 3 halo substituents); and wherein said benzothiophenyl or naphthyl group may be optionally substituted with 1, 2 or 3 substituents each independently selected from halo, cyano, Q-C4 alkyl (optionally substituted with 1, 2 or 3 F atoms), -O-(Cι- C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms), and -S-(Cι-C alkyl) (optionally substituted with 1, 2 or 3 F atoms); Ar2 is naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl, wherein said naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl may be substituted with 1, 2 or 3 substituents each independently selected from halo, -C alkyl (optionally substituted with 1, 2 or 3 F atoms) and -O-(CrC4 alkyl) (optionally substituted with 1, 2 or 3 F atoms); or a pharmaceutically acceptable salt thereof; provided that (a) the cyclic portion of the group of formula (i) must contain at least three carbon atoms and not more than seven ring atoms; (b) when -X- is -CH=CH-, then the cyclic portion of the group of formula (i) must contain at least five carbon atoms; and (c) when -Z is -OH or -O-( -C3 alkyl), then -X- is -CH2-; and (d) when -Y- is -O- then p cannot be 0; and a compound of formula (IG)
Figure imgf000292_0001
(IG) wherein -X- is -S- or -O-; each R is independently selected from H or C C4 alkyl; R1 is H, C C4 alkyl, -C4 alkoxy, halo, cyano, trifluoromethyl, trifluoromethoxy, -NR3R4, - CONR3R4, -COOR3 or a group of the formula (i)
Figure imgf000293_0001
(i) R is C C4 alkyl, phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from -C4 alkyl, -C4 alkoxy, nitro, hydroxy, cyano, halo, trifluoromethyl, trifluoromethoxy, benzyl, benzyloxy, -NR6R7, -CONR6R7, COOR6, -SO2NR6R7 and -SO2R6; R5 is selected from Ci-C4 alkyl, - alkoxy, carboxy, nitro, hydroxy, cyano, halo, trifluoromethyl, trifluoromethoxy, benzyl, benzyloxy, -NR8R9, -CONR8R9, -SO2NR8R9 and - SO2R8; R3, R4, R6, R7, R8 and R9 are each independently selected from H or Q- C4 alkyl; and -Z- is a bond, -CH2-, or -O-; or a pharmaceutically acceptable salt thereof.
2. Use of a selective norepinephrine reuptake inhibitor for the manufacture of a medicament for the treatment of cognitive failure, wherein said selective norepinephrine reuptake inhibitor is selected from the group consisting of: a compound of formula (IA):
Figure imgf000293_0002
(IA) wherein n is 1, 2 or 3; Rl is C2-C1 rjalkyl, C2-CiQalkenyl, C3-Cgcycloalkyl or
C4-C1 Qcycloalkylalkyl, wherein one C-C bond within any cycloalkyl moiety is optionally substituted by an O-C or C=C bond and wherein each group is optionally substituted with from 1 to 7 halogen substituents and/or with from 1 to 3 substituents each independently selected from hydroxy, cyano, Cι-C4alkyl and Ci -C4alkoxy; R2 is H, Ci -COalkyl
(optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkyl-S(O)x- wherein x is
0, 1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Cι-C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -G4alkyl and Cj -C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and Ci -C4alkoxy) or -CO2(Ci -C4alkyl), or together with R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci-
C4alkyl and Ci -C4alkoxy); R3 is H, Ci -G4alkyl (optionally substituted with from 1 to 7 halogen atoms), Cι-C4alkyl-S(O)x- wherein x is 0, 1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and Ci -C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and Cι-G4alkoxy) or -CO2(Ci -C4alkyl), or together with R2 or R4 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cι -C4alkyl and Cι -C4alkoxy); R4 is H, Cι -
C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Cι-C4alkyl-S(O)x- wherein x is 0, 1 or 2 (optionally substituted with from 1 to 7 halogen atoms), Ci -
C4alkoxy (optionally substituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl
(optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -C4alkyl and Ci -C4alkoxy), phenoxy (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Cj -C4alkyl and Ci -C4alkoxy) or
-CO2(Ci -C4alkyl), or together with R3 forms a further benzene ring (optionally substituted with from 1 to 3 substituents each independently selected from halogen, Ci -
C4alkyl and Cι -C4alkoxy); R5 is H, Cι -C4alkyl (optionally substituted with from 1 to 7 halogen atoms), Cι-C4alkoxy (optionally substituted with from 1 to 7 halogen atoms) or halogen; R6 is H, Cι-C alkyl (optionally substituted with from 1 to 7 halogen atoms),
Ci -C4alkoxy (optionally substituted with from 1 to 7 halogen atoms) or halogen; R7 is
H or Ci -C4alkyl; R8 is H or Cι-C4alkyl; R9 is H, halogen, hydroxy, cyano, Ci -C4alkyl or Cι-C4alkoxy; and R10 is H, halogen, hydroxy, cyano, Cι-C4alkyl or Cι-C4alkoxy; or a pharmaceutically acceptable salt thereof, with the proviso that the compound N-ethyl- N-benzyl-4-piperidinamine is excluded; a compound of formula (IB):
Figure imgf000295_0001
(IB) wherein Rx is H; Ry is H or -C4 alkyl; each Rz is independently H or -C4 alkyl; X represents O; Y represents OH or OR; R is -C4 alkyl; A is a phenyl ring or a 5- or 6-membered heteroaryl ring each of which may be substituted with 1, 2, 3, 4 or 5 substituents (depending upon the number of available substitution positions) each independently selected from C1-C4 alkyl, O(Cι-C4 alkyl), S(Cι -C4 alkyl), halo, hydroxy, pyridyl, thiophenyl and phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci -C4 alkyl, or O(Cι -C4 alkyl); and Ar2 is a phenyl ring or a 5- or 6-membered heteroaryl ring each of which may be substituted with 1, 2, 3, 4 or 5 substituents (depending upon the number of available substitution positions) each independently selected from C1-C4 alkyl, O(Cι -C4 alkyl) and halo; wherein each above- mentioned Ci -C4 alkyl group is optionally substituted with one or more halo atoms; or a pharmaceutically acceptable salt thereof; a compound of formula (IC)
^Ar
Figure imgf000295_0002
(IC) wherein: A is S or O; R is H; Ar is a phenyl group optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from Ci -C4 alkyl, O(Cι-C4 alkyl), S(Cι -C4 alkyl), halo, hydroxy, CO2(Cι -C4 alkyl), pyridyl, thiophenyl and phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci -C4 alkyl, or O(Cι -C4 alkyl); X is a phenyl group optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci -C4 alkyl, or O(Cι -C4 alkyl); a Ci -C4 alkyl group; a C3-C6 cycloalkyl group or a CH2(C3-Cg cycloalkyl) group; R' is H or Ci -C4 alkyl; each R1 is independently H or Cj -C4 alkyl; wherein each above-mentioned Cj -C4 alkyl group is optionally substituted with one or more halo atoms; or a pharmaceutically acceptable salt thereof; with the proviso that, when A is O, X is a Ci -C4 alkyl group, a C3-
Cβ cycloalkyl group or a CH2(C3-Cg cycloalkyl) group; a compound of formula (ID)
Figure imgf000296_0001
(ID) wherein -X- is -C(R4R5)-, -O- or -S-; n is 2 or 3; R1 is H or C C4 alkyl; R3 is H, halo, Q- C4 alkyl, O( -C4 alkyl), nitrile, phenyl or substituted phenyl; R4 and R5 are each independently selected from H or -C alkyl; Ar- is selected from the group consisting of
Figure imgf000296_0002
in which R >2Δaa . is H, halo, methyl or ethyl; R2b is H, halo or methyl; R2c is H, halo, methyl, trifluoromethyl, nitrile, or methoxy; R 2d is H, halo, methyl or ethyl; R >2ee i. s H, halo, methyl, trifluoromethyl, nitrile, or methoxy; R , 2f i ■s H, or fluoro; -Y- is -O-, -S- or -
N(R )-; and R iiss HH oorr mmeetthhyyll oorr aa pphhaarrmmaacc*eutically acceptable salt thereof; a compound of formula (IE)
Figure imgf000297_0001
(IE) wherein R1 is C!-C6 alkyl (optionally substituted with 1, 2 or 3 halo substituents and/or with 1 substituent selected from -S-(C!-C3 alkyl), -O-(Cι-C alkyl) (optionally substituted with 1, 2 or 3 F atoms), -O-(C3-C6 cycloalkyl), -SO2-( -C3 alkyl), -CN, -COO-(C C2 alkyl) and -OH); C2-C6 alkenyl; -(CH2)q-Ar2; or a group of formula (i) or (ii)
Figure imgf000297_0002
(i) (ϋ)
R2, R3 and R4 are each independently selected from hydrogen or Ci-C alkyl; R5, R6, R7 and R8 are at each occurrence independently selected from hydrogen or -C2 alkyl; -X- is a bond, -CH2-, -CH=CH-, -O-, -S-, or -SO2-; -Y- is a bond, -CH2- or -O-; -Z is hydrogen, -OH or -O-(CrC3 alkyl); p is 0, 1 or 2; q is 0, 1 or 2; r is 0 or 1; s is 0, 1, 2 or 3; t is 0, 1, 2 or 3; Ax\ is phenyl, pyridyl, thiazolyl, benzothiophenyl or naphthyl; wherein said phenyl, pyridyl or thiazolyl group may be substituted with 1, 2 or 3 substituents each independently selected from halo, cyano, -C4 alkyl (optionally substituted with 1, 2 or 3 F atoms), -O-(C1-C alkyl) (optionally substituted with 1, 2 or 3 F atoms) and -S-(Ci-C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms) and/or with 1 substituent selected from pyridyl, pyrazole, phenyl (optionally substituted with 1, 2 or 3 halo substituents) and phenoxy (optionally substituted with 1, 2 or 3 halo substituents); and wherein said benzothiophenyl or naphthyl group may be optionally substituted with 1, 2 or 3 substituents each independently selected from halo, cyano, -C4 alkyl (optionally substituted with 1, 2 or 3 F atoms), -O-( - C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms), and -S-( -C alkyl) (optionally substituted with 1, 2 or 3 F atoms); Ar2 is naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl, wherein said naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl may be substituted with 1, 2 or 3 substituents each independently selected from halo, C C4 alkyl (optionally substituted with 1, 2 or 3 F atoms) and -O-(Cι-C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms); or a pharmaceutically acceptable salt thereof; provided that (a) the cyclic portion of the group of formula (i) must contain at least three carbon atoms and not more than seven ring atoms; (b) when -X- is -CH=CH-, then the cyclic portion of the group of formula (i) must contain at least five carbon atoms; and (c) when -Z is -OH or -O-(Cι-C3 alkyl), then -X- is -CH2-; (d) when -Y- is -O- then p cannot be 0; and (e) the compound 3-[(phenylmethyl)-(3S)-3-pyrrolidinylamino]-propanenitrile is excluded; a compound of formula (IF)
Figure imgf000298_0001
(IF) wherein
is a group of formula (a) or (b)
Figure imgf000298_0002
Figure imgf000298_0003
(a) (b)
R1 is Ci-Cβ alkyl (optionally substituted with 1, 2 or 3 halo substituents and/or with 1 substituent selected from -S-(C1-C alkyl), -O-(C1-C3 alkyl) (optionally substituted with 1, 2 or 3 F atoms), -O-(C3-C6 cycloalkyl), -SO2-(C1-C3 alkyl), -CN,
Figure imgf000298_0004
alkyl) and -OH); C2-C6 alkenyl; -(CH2)q-Ar2; or a group of formula (i) or (ii)
Figure imgf000299_0001
(i) (ϋ)
R2, R3 and R4 are each independently selected from hydrogen or -C2 alkyl; R5, R6, R7 and R8 are at each occurrence independently selected from hydrogen or Cχ-C2 alkyl; -X- is a bond, -CH2-, -CH=CH-, -O-, -S-, or -SO2-; -Y- is a bond, -CH2- or -O-; -Z is hydrogen, -OH or -O-(C!-C3 alkyl); p is 0, 1 or 2; q is 0, 1 or 2; r is 0 or 1; s is 0, 1, 2 or 3; t is 0, 1, 2 or 3; Ar] is phenyl, pyridyl, thiazolyl, benzothiophenyl or naphthyl; wherein said phenyl, pyridyl or thiazolyl group may be substituted with 1, 2 or 3 substituents each independently selected from halo, cyano, -C4 alkyl (optionally substituted with 1, 2 or 3 F atoms), -O-( -C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms) and -S-(C!-C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms) and/or with 1 substituent selected from pyridyl, pyrazole, phenyl (optionally substituted with 1, 2 or 3 halo substituents), benzyl and phenoxy (optionally substituted with 1, 2 or 3 halo substituents); and wherein said benzothiophenyl or naphthyl group may be optionally substituted with 1, 2 or 3 substituents each independently selected from halo, cyano, - alkyl (optionally substituted with 1, 2 or 3 F atoms), -O-(Ci-
C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms), and -S^ - alkyl) (optionally substituted with 1, 2 or 3 F atoms); Ar2 is naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl, wherein said naphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl may be substituted with 1, 2 or 3 substituents each independently selected from halo, -C4 alkyl (optionally substituted with 1, 2 or 3 F atoms) and -O-(C1-C4 alkyl) (optionally substituted with 1, 2 or 3 F atoms); or a pharmaceutically acceptable salt thereof; provided that (a) the cyclic portion of the group of formula (i) must contain at least three carbon atoms and not more than seven ring atoms; (b) when -X- is -CH=CH-, then the cyclic portion of the group of formula (i) must contain at least five carbon atoms; and (c) when -Z is -OH or -O-(C1-C3 alkyl), then -X- is -CH2-; and (d) when -Y- is -O- then p cannot be 0; and a compound of formula (IG)
Figure imgf000300_0001
(IG) wherein -X- is -S- or -O-; each R is independently selected from H or - alkyl; R1 is H, C1-C4 alkyl, -C alkoxy, halo, cyano, trifluoromethyl, trifluoromethoxy, -NR3R4, - CONR3R4, -COOR3 or a group of the formula (i)
Figure imgf000300_0002
(i) R2 is -C4 alkyl, phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C1-C4 alkyl, -C4 alkoxy, nitro, hydroxy, cyano, halo, trifluoromethyl, trifluoromethoxy, benzyl, benzyloxy, -NR6R7, -CONR6R7, COOR6, -SO2NR6R7 and -SO2R6; R5 is selected from - alkyl, C1-C4 alkoxy, carboxy, nitro, hydroxy, cyano, halo, trifluoromethyl, trifluoromethoxy, benzyl, benzyloxy, -NR8R9, -CONR8R9, -SO2NR8R9 and - SO2R8; R3, R4, R6, R7, R8 and R9 are each independently selected from H or d- C4 alkyl; and -Z- is a bond, -CH2-, or -O-; or a pharmaceutically acceptable salt thereof.
PCT/US2004/037195 2003-11-24 2004-11-24 Norepinephrine reuptake inhibitors useful for treatment of cognitive failure WO2005053663A2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US52445003P 2003-11-24 2003-11-24
US60/524,450 2003-11-24
US52478103P 2003-11-25 2003-11-25
US60/524,781 2003-11-25

Publications (2)

Publication Number Publication Date
WO2005053663A2 true WO2005053663A2 (en) 2005-06-16
WO2005053663A3 WO2005053663A3 (en) 2005-08-11

Family

ID=34657156

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/037195 WO2005053663A2 (en) 2003-11-24 2004-11-24 Norepinephrine reuptake inhibitors useful for treatment of cognitive failure

Country Status (1)

Country Link
WO (1) WO2005053663A2 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008093737A1 (en) * 2007-01-31 2008-08-07 Dainippon Sumitomo Pharma Co., Ltd. Amide derivative
US8389511B2 (en) 2007-12-19 2013-03-05 Dainippon Sumitomo Pharma Co., Ltd. Bicyclic heterocyclic derivative
US8658639B2 (en) 2009-06-24 2014-02-25 Dainippon Sumitomo Pharma Co., Ltd N-substituted-cyclic amino derivative

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2370732A1 (en) * 1976-11-16 1978-06-09 Anphar Sa POLYSUBSTITUTE DERIVATIVES OF PIPERIDINE, THEIR METHODS OF PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS
GB2167407A (en) * 1984-11-22 1986-05-29 Erba Farmitalia Enantiomers of phenoxy derivatives of benzyl morpholine and salts thereof
WO2001066521A1 (en) * 2000-03-06 2001-09-13 Acadia Pharmaceuticals, Inc. Azacyclic compounds for use in the treatment of serotonin related diseases
WO2004000808A2 (en) * 2002-06-24 2003-12-31 Acadia Pharmaceuticals Inc. N-substituted piperidine derivatives as serotonin receptor agents
WO2004030668A1 (en) * 2002-10-04 2004-04-15 Ucb, S.A. 4-aminopiperidine derivatives, processes for their preparation and their use as medicaments
WO2004052858A2 (en) * 2002-12-06 2004-06-24 Eli Lilly And Company Inhibitors of monoamine uptake

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2370732A1 (en) * 1976-11-16 1978-06-09 Anphar Sa POLYSUBSTITUTE DERIVATIVES OF PIPERIDINE, THEIR METHODS OF PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS
GB2167407A (en) * 1984-11-22 1986-05-29 Erba Farmitalia Enantiomers of phenoxy derivatives of benzyl morpholine and salts thereof
WO2001066521A1 (en) * 2000-03-06 2001-09-13 Acadia Pharmaceuticals, Inc. Azacyclic compounds for use in the treatment of serotonin related diseases
WO2004000808A2 (en) * 2002-06-24 2003-12-31 Acadia Pharmaceuticals Inc. N-substituted piperidine derivatives as serotonin receptor agents
WO2004030668A1 (en) * 2002-10-04 2004-04-15 Ucb, S.A. 4-aminopiperidine derivatives, processes for their preparation and their use as medicaments
WO2004052858A2 (en) * 2002-12-06 2004-06-24 Eli Lilly And Company Inhibitors of monoamine uptake

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THOMAS RYCKMANS ET AL: "First Dual NK1 Antagonists-Serotonin Reuptake Inhibitors: synthesis and SAR of a New Class of Potential Antidepressants" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 12, no. 2, 2002, pages 261-264, XP002974382 ISSN: 0960-894X *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008093737A1 (en) * 2007-01-31 2008-08-07 Dainippon Sumitomo Pharma Co., Ltd. Amide derivative
US8389511B2 (en) 2007-12-19 2013-03-05 Dainippon Sumitomo Pharma Co., Ltd. Bicyclic heterocyclic derivative
US8658639B2 (en) 2009-06-24 2014-02-25 Dainippon Sumitomo Pharma Co., Ltd N-substituted-cyclic amino derivative

Also Published As

Publication number Publication date
WO2005053663A3 (en) 2005-08-11

Similar Documents

Publication Publication Date Title
AU2003233967B2 (en) Pyrrolidinium derivatives as antagonists of M3 muscarinic receptors
EP2661435B1 (en) 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
CN110234638B (en) Heteroaryl phenoxy benzamide KAPPA opioid ligands
EP1745029A1 (en) Substituted morpholine compounds for the treatment of central nervous system disorders
KR20170053686A (en) Compounds and compositions as raf kinase inhibitors
TW575561B (en) 1-arenesulfonyl-2-aryl-pyrrolidine and piperidine derivatives
EP1729754A2 (en) Selective norepinephrine reuptake inhibitors for the treatment of hot flashes, impulse control disorders and personality change due to a general medical condition
JP2021529775A (en) Compound
EP1638934B1 (en) 3-aminopyrrolidines as inhibitors of monoamine uptake
TWI444376B (en) Prolinamide pyridine compounds, pharmaceutical composition and medical use thereof
WO2005053663A2 (en) Norepinephrine reuptake inhibitors useful for treatment of cognitive failure
US7432280B2 (en) 3-aminopiperidines and 3-aminoquinuclidines as inhibitors of monoamine uptake
WO2005021095A2 (en) Treatment of stuttering and other communication disorders with norepinephrine reuptake inhibitors
WO2005020976A2 (en) Treatment of pervasive developmental disorders with norepinephrine reuptake inhibitors
WO2005020975A2 (en) Treatment of learning disabilities and motor skills disorder with norepinephrine reuptake inhibitors
TWI833773B (en) Compounds
EP4076665B1 (en) Egfr inhibitors
JP2022537301A (en) Novel EGFR inhibitor
JP2022537771A (en) Novel EGFR inhibitor

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase