WO2007138431A2 - Azabicyclic ether histamine-3 antagonists - Google Patents

Azabicyclic ether histamine-3 antagonists Download PDF

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Publication number
WO2007138431A2
WO2007138431A2 PCT/IB2007/001367 IB2007001367W WO2007138431A2 WO 2007138431 A2 WO2007138431 A2 WO 2007138431A2 IB 2007001367 W IB2007001367 W IB 2007001367W WO 2007138431 A2 WO2007138431 A2 WO 2007138431A2
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WO
WIPO (PCT)
Prior art keywords
methyl
octahydro
lsopropyl
azabicyclo
pyridin
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PCT/IB2007/001367
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French (fr)
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WO2007138431A3 (en
Inventor
Helen Berke
Harry Ralph Howard, Jr.
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Pfizer Products Inc.
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Publication of WO2007138431A2 publication Critical patent/WO2007138431A2/en
Publication of WO2007138431A3 publication Critical patent/WO2007138431A3/en

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    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention is directed to compounds of formula I described herein, to a pharmaceutical composition comprising such compounds, and to methods of treatment of disorders or conditions that may be treated by antagonizing histamine-3 (H 3 ) receptors using such compounds.
  • the histamine-3 (H 3 ) receptor antagonists of the invention are useful for treating anxiety disorders, including, for example, generalized anxiety disorder, panic disorder, PTSD, and social anxiety disorder; mood adjustment disorders, including depressed mood, mixed anxiety and depressed mood, disturbance of conduct, and mixed disturbance of conduct and depressed mood; age-associated learning and mental disorders, including Alzheimer's disease; attention adjustment disorders, such as attention-deficit disorders, or other cognitive disorders due to general medical conditions; attention-deficit hyperactivity disorder; psychotic disorders including schizoaffective disorders and schizophrenia; sleep disorders, including narcolepsy and enuresis; obesity; dizziness, epilepsy, and motion sickness.
  • the H 3 receptor antagonists of the invention are also useful for treating, for example, allergy, allergy-induced airway (e.g., upper airway) responses, congestion (e.g., nasal congestion), hypotension, cardiovascular disease, diseases of the Gl tract, hyper- and hypo-motility and acidic secretion of the gastrointestinal tract, sleeping disorders (e.g., hypersomnia, somnolence, and narcolepsy), attention deficit hyperactivity disorder ADHD), hypo- and hyper-activity of the central nervous system (for example, agitation and depression), and other CNS disorders (such as schizophrenia and migraine).
  • allergy allergy-induced airway responses
  • congestion e.g., nasal congestion
  • hypotension e.g., cardiovascular disease
  • diseases of the Gl tract e.g., hyper- and hypo-motility and acidic secretion of the gastrointestinal tract
  • sleeping disorders e.g., hypersomnia, somnolence, and narcolepsy
  • attention deficit hyperactivity disorder ADHD e.g., hypo- and hyper
  • Histamine is a well-known mediator in hypersensitive reactions (e.g. allergies, hay fever, and asthma) that are commonly treated with antagonists of histamine or "antihistamines.” It has also been established that histamine receptors exist in at least two distinct types, referred to as H 1 and H 2 receptors.
  • H 3 receptor A third histamine receptor (H 3 receptor) is believed to play a role in neurotransmission in the central nervous system, where the H 3 receptor is thought to be disposed presynaptically on histaminergic nerve endings (Nature. (1983) 302, S32- 837).
  • the existence of the H 3 receptor has been confirmed by the development of selective H 3 receptor agonists and antagonists (Nature, (1987), 327, 117-123) and has subsequently been shown to regulate the release of the neurotransmitters in both the central nervous system and peripheral organs, particularly the lungs, cardiovascular system and gastrointestinal tract.
  • H 3 histamine-3
  • the H 3 ligand may be an antagonist, agonist or partial agonist, see: (Imamura et al., Circulation Res., (1996) 78, 475-481 ); (Imamura et al., Circ. Res.. (1996) 78, 863-869); (Lin et al., Brain Res. (1990) 523, 325-330); (Monti et al., Neuropsvchopharmacology (1996) 15, 31-35); (Sakai et al., Life Sci.
  • Such diseases or conditions include cardiovascular disorders such as acute myocardial infarction; memory processes, dementia and cognition disorders such as Alzheimer's disease and attention deficit hyperactivity disorder; neurological disorders such as Parkinson's disease, schizophrenia, depression, epilepsy, and seizures or convulsions; cancer such as cutaneous carcinoma," medullary thyroid carcinoma and melanoma; respiratory disorders such as asthma; sleep disorders such as narcolepsy; vestibular dysfunction such as Meniere's disease; gastrointestinal disorders, inflammation, migraine, motion sickness, obesity, pain, and septic shock.
  • cardiovascular disorders such as acute myocardial infarction
  • memory processes dementia and cognition disorders such as Alzheimer's disease and attention deficit hyperactivity disorder
  • neurological disorders such as Parkinson's disease, schizophrenia, depression, epilepsy, and seizures or convulsions
  • cancer such as cutaneous carcinoma," medullary thyroid carcinoma and melanoma
  • respiratory disorders such as asthma
  • sleep disorders such as narcolepsy
  • vestibular dysfunction such as Meniere's disease
  • gastrointestinal disorders inflammation
  • H 3 receptor antagonists have also been previously described in, for example, WO 03/050099, WO 02/0769252, and WO 02/12224.
  • the histamine H 3 receptor (H 3 R) regulates the release of histamine and other neurotransmitters, including serotonin and acetylcholine.
  • H 3 R is relatively neuron specific and inhibits the release of certain monoamines such as histamine.
  • Selective antagonism of H 3 R raises brain histamine levels and inhibits such activities as food consumption while minimizing non-specific peripheral consequences.
  • Antagonists of the receptor increase synthesis and release of cerebral histamine and other monoamines. By this mechanism, they induce a prolonged wakefulness, improved cognitive function, reduction in food intake and normalization of vestibular reflexes.
  • EP 978512 and EP 982300 disclose non-imidazole alkyamines as histamine H 3 receptor antagonists.
  • WO 02/12190 Organic McNeil Pharmaceuticals
  • EP 1275647 Les Laboratoires Servier
  • novel octahydro-2H-pyrido[1 ,2-a]pyrazines that are selective H 3 receptor antagonists.
  • Other receptor antagonists have been described in WO 02/32893 and WO 02/06233.
  • the present invention is directed to histamine-3 (H 3 ) receptor antagonists useful for treating the conditions listed in the preceding paragraphs.
  • the compounds of this invention are highly selective for the H 3 receptor (vs.
  • the compounds of this invention selectively distinguish H 3 R from the other receptor subtypes H-iR, H 2 R.
  • novel compounds that interact with the histamine H 3 receptor would be a highly desirable contribution to the art.
  • the present invention provides such a contribution -A-
  • L is CR 3 R 4 ;
  • X is a halogen, CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 thioalkyl;
  • E is a 7-13 member bicyclic heterocycloalkyl group, containing at least one secondary nitrogen atom and up to 3 additional heteroatoms selected from N, O and S, up to two carbon-carbon double bonds and optionally substituted at available C and N positions with hydrogen, OH, CN, CF 3 , C 1 -C 6 alkyl, aryl, (C 1 -C 6 alkyl)-aryl or heteroaryl;
  • R 1 and R 2 are independently selected from hydrogen, C 1 -C 6 alkyl, aryl, (C 1 -C 6 alkyl)- aryl, heteroaryl, (C 1 -C 6 alkyl)-heteroaryl;
  • R 3 , R 4 , R 5 and R 6 are independently selected from C 1 -C 6 alkyl, optionally substituted at available positions with H, OH, F or C 1 -C 6 alkyl; or
  • R 3 and R 4 together with the carbon to which they are attached form a 3-7 member carbocyclic ring;
  • m is O, 1 , 2 or 3; and
  • n is 0, 1 , 2, 3 or 4.
  • alkyl refers to straight or branched chains of carbon atoms.
  • exemplary alkyl groups are C 1 -C 6 alkyl groups which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and the like, including all regioisomeric forms thereof, and straight and branched chain forms thereof.
  • alkyl is also used to denote straight or branched chains of carbon atoms having one or more carbon-carbon double bonds, such as vinyl, allyl, butenyl, and the like, as well as straight or branched chains of carbon atoms having one or more carbon-carbon triple bonds, such as ethynyl, propargyl, butynyl, and the like.
  • aryl denotes a cyclic, aromatic hydrocarbon. Examples of aryl groups include phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like.
  • alkoxy and aryloxy denote “O-alkyl” and "O-aryl", respectively.
  • cycloalkyl is also intended to denote a cyclic group comprising at least two fused rings, such as adamantanyl, decahydronaphthalinyl, norbornanyl, where the cyclic group may also have one or more carbon-carbon double bonds in one or both rings, such as in bicyclo[4.3.0]nona-3,6(1)-dienyl, dicyclopentadienyl, 1 ,2,3,4-tetrahydronaphthalinyl (tetralinyl), indenyl, and the like.
  • halogen represents chloro, fluoro, bromo, and iodo.
  • heteroaryl denotes a monocyclic or bicyclic aromatic group wherein one or more carbon atoms are replaced with heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Preferred heteroaryl groups are five- to fourteen- member rings that contain from one to three heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • heteroaryl groups include benzo[b]thienyl, chromenyl, furyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinolizinyl, quinolyl, quinoxalinyl, thiazolyl, thienyl, triazinyl, triazolyl, and xanthenyl.
  • heterocycloalkyl denotes a cycloalkyl system, wherein “cycloalkyl” is defined above, in which one or more of the ring carbon atoms are replaced with a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur.
  • heterocycloalkyl groups examples include azabicycloheptanyl, azetidinyl, benzazepinyl, 1 ,3- dihydroisoindolyl, indolinyl, tetrahydrofuryl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, and, tetrahydro-2H-1 ,4-thiazinyl.
  • a cyclic group may be bonded to another group in more than one way. If no particular bonding arrangement is specified, then all possible arrangements are intended.
  • the term "pyridyl” includes 2-, 3-, or 4-pyridyl
  • thienyl includes 2- or 3-thienyl.
  • C 0 -C/ includes the embodiment where there are no carbons in a chain.
  • the groups "C 3 -C 7 cycloalkyl-C 0 -C 4 alkyl,” “C 6 -Ci 4 aryl-C 0 -C 4 alkyl,” “5-10- membered heteroaryl-C 0 -C 4 alkyl,” and "C 6 -Ci 4 aryl-C 0 -C 4 alkylene-O-C 0 -C 4 alkyl" include C 3 -
  • CrC 4 dialkylamino refers to a dialkylamino group in which each alkyl group is independently a C r C 4 alkyl group.
  • This invention is also directed to: a pharmaceutical composition for treating, for example, a disorder or condition that may be treated by antagonizing histamine-3 (H 3 ) receptors, the composition comprising a compound of formula I as described above, and optionally a pharmaceutically acceptable carrier; a method of treatment of a disorder or condition that may be treated by antagonizing histamine-3 (H 3 ) receptors, the method comprising administering to a mammal in need of such treatment a compound of formula I as described above; and a pharmaceutical composition for treating, for example, a disorder or condition selected from the group consisting of depression, mood disorders, schizophrenia, anxiety disorders, Alzheimer's disease, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergy, allergy-induced airway responses, allergic rhinitis, nasal congestion, allergic congestion, congestion, hypotension, cardiovascular disease, diseases of the Gl tract, hyper and hypo motility and acidic secretion of the gastrointestinal
  • This invention is also directed to a method of treatment of a disorder or condition selected from the group consisting of the disorders or conditions listed in the preceding paragraph, the method comprising administering to a mammal in need of such treatment a compound of formula I as described above.
  • the histamine-3 (H 3 ) receptor antagonists of the invention are useful for treating, in particular, ADD, ADHD, obesity, anxiety disorders and respiratory diseases.
  • Respiratory diseases that may be treated by the present invention include adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis.
  • the pharmaceutical composition and method of this invention may also be used for preventing a relapse in a disorder or condition described in the previous paragraphs. Preventing such relapse is accomplished by administering to a mammal in need of such prevention a compound of formula I as described above.
  • the disclosed compounds may also be used as part of a combination therapy, including their administration as separate entities or combined in a single delivery system, which employs an effective dose of a histamine H 3 antagonist compound of general formula I and an effective dose of a histamine H 1 antagonist, such as cetirizine (ZyrtecTM), for the treatment of allergic rhinitis, nasal congestion and allergic congestion.
  • a histamine H 3 antagonist compound of general formula I an effective dose of a histamine H 1 antagonist, such as cetirizine (ZyrtecTM)
  • the disclosed compounds may also be used as part of a combination therapy, including their administration as separate entities or combined in a single delivery system, which employs an effective dose of a histamine H 3 antagonist compound of general formula I and an effective dose of a neurotransmitter reuptake blocker.
  • neurotransmitter reuptake blockers will include the serotonin-selective reuptake inhibitors (SSRI's) like sertraline (ZoloftTM), fluoxetine (ProzacTM), and paroxetine (PaxilTM), or non-selective serotonin, dopamine or norepinephrine reuptake inhibitors for treating depression and mood disorders.
  • SSRI's serotonin-selective reuptake inhibitors
  • ZoloftTM sertraline
  • fluoxetine ProzacTM
  • paroxetine PaxilTM
  • non-selective serotonin, dopamine or norepinephrine reuptake inhibitors for treating depression and mood disorders.
  • the compounds of the present invention may have optical centers and therefore may occur in different enantiomeric configurations.
  • Formula I as depicted above, includes all enantiomers, diastereomers, and other stereoisomers of the compounds depicted in structural formula I, as well as racemic and other mixtures thereof. Individual isomers can be obtained by known methods, such as optical resolution, optically selective reaction, or chromatographic separation in the preparation of the final product or its intermediate.
  • the present invention also includes isotopically labeled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 0, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • lsotopicaily labeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • H 3 histamine-3 receptors
  • a "unit dosage form” as used herein is any form that contains a unit dose of the compound of formula I.
  • a unit dosage form may be, for example, in the form of a tablet or a capsule.
  • the unit dosage form may also be in liquid form, such as a solution or suspension.
  • compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pre-gelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate).
  • binding agents e.g., pre-gelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato star
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • the composition may take the form of tablets or lozenges formulated in conventional manner.
  • the active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • a proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
  • Aerosol formulations for treatment of the conditions referred to above are preferably arranged so that each metered dose or "puff' of aerosol contains 20 ⁇ g to 1000 ⁇ g of the compound of the invention.
  • the overall daily dose with an aerosol will be within the range 100 ⁇ g to 100 mg.
  • Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • an active compound of this invention with a histamine H 1 antagonist, preferably cetirizine, for the treatment of subjects possessing any of the above conditions
  • these compounds may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages.
  • the active combination can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes.
  • the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage and a histamine H-i antagonist, preferably cetirizine, is present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
  • a proposed daily dose of an active compound of this invention in the combination formulation is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.
  • a proposed daily dose of a histamine H-i antagonist, preferably cetirizine, in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the histamine H 1 antagonist per unit dose which could be administered, for example, 1 to 4 times per day.
  • a preferred dose ratio of cetirizine to an active compound of this invention in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.00005 to about 20,000, preferably from about 0.25 to about 2,000.
  • Aerosol combination formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff' of aerosol contains from about 0.01 ⁇ g to about 100 mg of the active compound of this invention, preferably from about 1 ⁇ g to about 10 mg of such compound. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time. Aerosol formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff of aerosol contains from about 0.01 mg to about 2000 mg of a histamine H 1 antagonist, preferably cetirizine, preferably from about 1 mg to about 200 mg of cetirizine.
  • Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • a histamine H-i antagonist, preferably cetirizine in combination with compounds of formula I are readily adapted to therapeutic use as antiallergy agents.
  • these antiallergy compositions containing a histamine H 1 antagonist, preferably cetirizine, and a compound of formula I are normally administered in dosages ranging from about 0.01 mg to about 100 mg per kg of body weight per day of a histamine H 1 antagonist, preferably cetirizine, preferably from about 0.1 mg. to about 10 mg per kg of body weight per day of cetirizine; with from about 0.001 mg.
  • an active compound of this invention with a 5-HT re- uptake inhibitor, preferably sertraline, for the treatment of subjects possessing any of the above conditions
  • these compounds may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages.
  • the active combination can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes.
  • the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage and a 5-HT re-uptake inhibitor, preferably sertraline, is present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
  • a proposed daily dose of an active compound of this invention in the combination formulation is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.
  • a proposed daily dose of a 5-HT re-uptake inhibitor, preferably sertraline, in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the 5-HT re-uptake inhibitor per unit dose which could be administered, for example, 1 to 4 times per day.
  • a preferred dose ratio of sertraline to an active compound of this invention in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.00005 to about 20,000, preferably from about 0.25 to about 2,000.
  • Aerosol formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff' of aerosol contains from about 0.01 mg to about 2000 mg of a 5-HT re-uptake inhibitor, preferably sertraline, preferably from about 1 mg to about 200 mg of sertraline. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • a 5-HT re-uptake inhibitor preferably sertraline
  • Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • a 5-HT re-uptake inhibitor preferably sertraline
  • these antidepressant compositions containing a 5-HT reuptake inhibitor, preferably sertraline, and a compound of formula I are normally administered in dosages ranging from about 0.01 mg to about 100 mg per kg of body weight per day of a 5-HT re-uptake inhibitor, preferably sertraline, preferably from about 0.1 mg. to about 10 mg per kg of body weight per day of sertraline; with from about 0.001 mg.
  • Anxiety disorders include, for example, generalized anxiety disorder, panic disorder, PTSD, and social anxiety disorder.
  • Mood adjustment disorders include, for example, depressed mood, mixed anxiety and depressed mood, disturbance of conduct, and mixed disturbance of conduct and depressed mood.
  • Attention adjustment disorders include, for example, in addition to ADHD, attention deficit disorders or other cognitive disorders due to general medical conditions.
  • Psychotic disorders include, for example, schizoaffective disorders and schizophrenia; sleep disorders include, for example, narcolepsy and enuresis.
  • disorders or conditions which may be treated by the compound, composition and method of this invention are also as follows: depression, including, for example, depression in cancer patients, depression in Parkinson's patients, post-myocardial Infarction depression, depression in patients with human immunodeficiency virus (HIV), Subsyndromal Symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, post partum depression, DSM-IV major depression, treatment-refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic depressive illness, including manic depressive illness with mixed episodes and manic depressive illness with depressive episodes, seasonal affective disorder, bipolar depression BP I, bipolar depression BP II, or major depression with dysthymia; dysthymia; phobias, including, for example, agoraphobia, social phobia or simple phobias; eating disorders, including, for example, anorexia nervosa or bulimia
  • the mammal in need of the treatment or prevention may be a mammal other than a human.
  • a compound of formula I which is basic in nature, is capable of forming a wide variety of different salts with various inorganic and organic acids.
  • the acid addition salts are readily prepared by treating the base compounds with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
  • the acids which are used to prepare the pharmaceutically acceptable acid salts of the active compound used in formulating the pharmaceutical composition of this invention that are basic in nature are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions.
  • Non-limiting examples of the salts include the acetate, benzoate, beta-hydroxybutyrate, bisulfate, bisulfite, bromide, butyne-1 ,4-dioate, caproate, chloride, chlorobenzoate, citrate, dihydrogenphosphate, dinitrobenzoate, fumarate, glycollate, heptanoate, hexyne-1 ,6-dioate, hydroxybenzoate, iodide, lactate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, naphthalene-1 -sulfonate, naphthalene-2-sulfonate, oxalate, phenyl butyrate, phenyl propionate, phosphate, phthalate, phenylacetate, propanesulfonate, propiolate, propionate, pyr
  • A is a phenyl ring
  • the most preferred embodiment of the present invention includes the compounds of formula I in which A is a heteroaryl ring and E is either 3-aza-bicyclo[3.1.0]hexane or octahydro-indole.
  • Preferred compounds of formula I in accordance with the present invention are the following:
  • the most preferred examples of compounds according to the present invention include: 6-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-quinoline;
  • a suitably protected alcohol of the general formula Il is reacted with a phenol of the general formula III to give an ether intermediate of general formula IV, as shown in step a.
  • the reaction is most efficiently conducted using conditions often referred to as a Mitsunobu reaction, wherein the alcohol Il and the phenol III are combined to form an ether bond through the elimination of water.
  • This reaction is generally performed in the presence of a reagent like diethylazodicarboxylate (DEAD) and triphenylphosphine (Ph 3 P), in a reaction inert solvent such as THF or dichloromethane and at temperatures in the range of about 0 °C to about 40 0 C.
  • the intermediate aryl ether of formula IV so obtained may be purified (e.g., by chromatography on silica gel or alumina) or used without purification in the next step.
  • the starting reagents Il used in step a are commercially available or may be prepared according to procedures described in the chemical literature.
  • a suitable protecting group (P) for this reagent will include carboxybenzyl (CBZ) or tert-butoxycarbonyl (BOC) groups, and the like, which can prevent further reaction at the secondary nitrogen atom of the bicyclic heterocycloalkyl group E.
  • Such protecting groups would be unreactive under the conditions employed in the ether formation yet readily removed prior to replacement of the group P by a group R 1 as previously defined.
  • Recommended protecting groups for the amine nitrogen may be found in such references as T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, (Third Edition), John Wiley and Sons, Inc., NY (1999) and
  • phenols of formula III which contain a reactive group Z, are commercially available or prepared by methods described in the chemical literature.
  • step b the intermediate of general formula IV (described above) is reacted with an aryl or heteroaryl halide of general formula A-HaI, wherein A is as defined previously and Hal is a halogen (e.g., Cl, Br, I).
  • Hal a halogen
  • this step are generally referred to in the literature as the Suzuki reaction and are described in a number of publications including, e.g., M. Sato, N. Miyaura and A. Suzuki, Chemistry Letters (1989) 1405-1408; T. lihama, J. Fu, M.
  • step c of the process the protecting group (i.e., P) is removed from the intermediate of general formula V to give the intermediate amine of general formula Vl.
  • This transformation can be effected using one or more methods as disclosed in the chemical literature and known to one skilled in the art, depending on the nature of the group P. Efficient conditions for removal of a wide variety of amine protecting groups can be found in the Wuts and Greene reference listed above.
  • the secondary amine intermediate of formula Vl so derived may be used with or without prior purification in step d of the current process, wherein the intermediate of formula Vl can be converted to the title compound(s) of general formula I.
  • This conversion can be effected in a variety of manners, and the choice of procedure may be influenced by the nature and reactivity of any substituents present on the intermediate of formula Vl.
  • reaction inert solvent e.g., THF, dichloromethane, methanol, ethanol
  • Suitable reducing agents for this step may include one or more of the following: sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like.
  • Mass spectral (micromassZO) conditions Capillary(kV): 3.0; Cone (V): 20; Extractor (V): 3.0; RF Lens (V): 0; Source temp. ( 0 C): 120A/150P; Desolvation temp. ( 0 C): 150A/300P; Desolvation gas flow (L/hr): 500; Cone gas flow (L/hr): 100; LM Resolution: 15; HM Resolution: 15; Ion Energy: 0.2; Multiplier: 600. Splitter; Acurate by LC Packings, 1/10,000; Upchurch needle valve setting: 14; Make up pump (Waters 515) Flow (ml/min.): 1. PDA (Waters 996) Settings; Start/End wavelength (nm): 200/600; Resolution: 1.2; Sample Rate: 1 ; Channels: TIC, 254 nm and 220 nm.
  • the first eluting component (5 ⁇ -0H) was isolated as a pale yellow viscous oil.
  • 1 H-nmr 500 MHz, CDCI 3 ) ⁇ 1.00 (s, 3H), 1.10-1.27 (m, 2H), 1.28-1.35 (m, 1 H), 1.35-
  • 1 H-nmr 500 MHz, CDCI 3 ) ⁇ 1.05 (s, 3H), 1.45 (s, 9H), 1.30-1.70 (m, 7H), 1.80 (m, 1 H), 2.20 and 2.48 (2 bs, 1 H) 1 3.19 (bs, 1 H), 3.35 (m, 1 H), 3.45 (bs, 1 H) 1 3.82 (bs, 1 H).
  • 6-r4-(4,4,5,5-Tetram ⁇ thyl-ri,3,21dioxaborolan-2-yl)-phenoxymethvn-3-azabicy- clof3.1.01hexane-3-carboxylic acid tert-butyl ester Under N 2 , 6.0 g (28.0 mmol) of 6-hydroxymethyl-3-azabicyclo[3.1.0]hexane-3- carboxylic acid tert-butyl ester (prepared according to the method of J. Young and N.
  • the flask was then sealed and immersed in an oil bath preheated to 145-150 °C for 4 hr and allowed to cool to rt overnight.
  • the yellow mixture was filtered through a d.e. pad, washing the pad with additional ethanol.
  • the solvent was removed in vacuo to give a yellow waxy solid, which was chromatographed on a Biotage silica gel column (40x75 mm) eluting with 0.5% TEA in CH 2 CI 2 .
  • the major product band fractions were combined, concentrated in vacuo to a yellow solid and dried under vacuum, 0.311 g.
  • the dihydrochloride salt was prepared as above; m.p. 256.0-256.6 0 C.
  • the in vitro affinity of the compounds in the present invention at the rat or human histamine H 3 receptors can be determined according to the following procedure. Frozen rat frontal brain or frozen human post-mortem frontal brain is homogenized in 20 volumes of cold 50 mM Tris»HCI containing 2 mM MgCI 2 (pH to 7.4 at 4°C). The homogenate is then centrifuged at 45,000 G for 10 minutes. The supernatant is decanted and the membrane pellet re-suspended by Polytron in cold 50 mM Tris»HCI containing 2 mM MgCI 2 (pH to 7.4 at 4 0 C) and centrifuged again.
  • the final pellet is re-suspended in 50 mM Tris HCI containing 2 mM MgCI 2 (pH to 7.4 at 25 0 C) at a concentration of 12 mg/mL Dilutions of compounds are made in 10% DMSO / 50 mM Tris buffer (pH 7.4) (at 10 x final concentration, so that the final DMSO concentration is 1 %). Incubations are initiated by the addition of membranes (200 microliters) to 96-well V-bottom polypropylene plates containing 25 microliters of drug dilutions and 25 microliters of radioligand (1 nM final concentration 3 H-N-methylhistamine).

Abstract

This invention is directed to compounds of the formula (I) as defined herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical composition containing a compound of formula (I), a method of treatment of a disorder or condition that may be treated by antagonizing histamine H3 receptors, the method comprising administering to a mammal in need of such treatment a compound of formula (I) as described above, and a method of treatment of a disorder or condition selected from the group consisting of depression, mood disorders, schizophrenia, anxiety disorders, Alzheimer's disease, attention-deficit disorder (ADD), attention-deficit hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergy, allergy-induced airway responses, allergic rhinitis, nasal congestion, allergic congestion, congestion, hypotension, cardiovascular disease, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastro-intestinal tract, the method comprising administering to a mammal in need of such treatment a compound of formula (I) as described above.

Description

AZABICYCLIC ETHER HISTAMINE-3 ANTAGONISTS BACKGROUND OF THE INVENTION
This invention is directed to compounds of formula I described herein, to a pharmaceutical composition comprising such compounds, and to methods of treatment of disorders or conditions that may be treated by antagonizing histamine-3 (H3) receptors using such compounds. The histamine-3 (H3) receptor antagonists of the invention are useful for treating anxiety disorders, including, for example, generalized anxiety disorder, panic disorder, PTSD, and social anxiety disorder; mood adjustment disorders, including depressed mood, mixed anxiety and depressed mood, disturbance of conduct, and mixed disturbance of conduct and depressed mood; age-associated learning and mental disorders, including Alzheimer's disease; attention adjustment disorders, such as attention-deficit disorders, or other cognitive disorders due to general medical conditions; attention-deficit hyperactivity disorder; psychotic disorders including schizoaffective disorders and schizophrenia; sleep disorders, including narcolepsy and enuresis; obesity; dizziness, epilepsy, and motion sickness. The H3 receptor antagonists of the invention are also useful for treating, for example, allergy, allergy-induced airway (e.g., upper airway) responses, congestion (e.g., nasal congestion), hypotension, cardiovascular disease, diseases of the Gl tract, hyper- and hypo-motility and acidic secretion of the gastrointestinal tract, sleeping disorders (e.g., hypersomnia, somnolence, and narcolepsy), attention deficit hyperactivity disorder ADHD), hypo- and hyper-activity of the central nervous system (for example, agitation and depression), and other CNS disorders (such as schizophrenia and migraine).
Histamine is a well-known mediator in hypersensitive reactions (e.g. allergies, hay fever, and asthma) that are commonly treated with antagonists of histamine or "antihistamines." It has also been established that histamine receptors exist in at least two distinct types, referred to as H1 and H2 receptors.
A third histamine receptor (H3 receptor) is believed to play a role in neurotransmission in the central nervous system, where the H3 receptor is thought to be disposed presynaptically on histaminergic nerve endings (Nature. (1983) 302, S32- 837). The existence of the H3 receptor has been confirmed by the development of selective H3 receptor agonists and antagonists (Nature, (1987), 327, 117-123) and has subsequently been shown to regulate the release of the neurotransmitters in both the central nervous system and peripheral organs, particularly the lungs, cardiovascular system and gastrointestinal tract.
A number of diseases or conditions may be treated with histamine-3 (H3)receptor ligands wherein the H3 ligand may be an antagonist, agonist or partial agonist, see: (Imamura et al., Circulation Res., (1996) 78, 475-481 ); (Imamura et al., Circ. Res.. (1996) 78, 863-869); (Lin et al., Brain Res. (1990) 523, 325-330); (Monti et al., Neuropsvchopharmacology (1996) 15, 31-35); (Sakai et al., Life Sci. (1991) 48, 2397-2404); (Mazurkiewiez-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. (1989) 67, 75-78); (Panula, P. et al., Neuroscience (1998) 44, 465-481 ); (Wada et al., Trends in Neuroscience (1991 ) 14, 415); (Monti et al., Eur. J. Pharmacol. (1991) 205, 283); (Haas et al., Behav. Brain Res. (1995) 66, 41-44); (De Almeida and Izquierdo, Arch. Int. Pharmacodvn. (1986) 283, 193-198); (Kamei et al., Psychopharmacology (1990) 102, 312-318); (Kamei and Sakata, Japan. J. Pharmacol. (199 1 ) 57, 437-482); (Schwartz et al., Psychopharmacoloqy; The Fourth Generation of Progress, Bloom and Kupfer (eds.), Raven Press, New York, (1995) 3, 97); (Shaywitz et al., Psychopharmacology (1984) 82, 73-77); (Dumery and Blozovski, Exp. Brain Res. (1987) 67, 61-69); (Tedford et al., J. Pharmacol. Exp. Ther. (1995) 275, 598-604); (Tedford et al., Soc. Neurosci. Abstr. (1996) 22, 22); (Yokoyama et al., Eur. J. Pharmacol. (1993) 234, 129); (Yokoyama and linuma, CNS Drugs (1996) 5, 321 ); (Onodera et al., Prog. Neurobiol. (1994) 42, 685); (Leurs and Timmerman, Prog. Drug Res. (1992) 39,127); (The Histamine H3 Receptor, Leurs and Timmerman (ed.), Elsevier Science, Amsterdam, The Netherlands (1998); (Leurs et al., Trends in Pharm. Sci. (1998) 19, 177-183); (Phillips et al., Annual Reports in Medicinal Chemistry (1998) 33, 31-40); (Matsubara et al., Eur. J. Pharmacol. (1992) 224, 145); (Rouleau et al., J. Pharmacol. Exp. Ther. (1997) 281., 1085); (Adam Szelag, "Role of histamine H3-receptors in the proliferation of neoplastic cells in vitro", Med. Sci. Monit., (1998) 4(5}:747- 755); (Fitzsimons, C, H. Duran, F. Labombarda, B. Molinari and E. Rivera, "Histamine receptors signalling in epidermal tumor cell lines with H-ras gene alterations", Inflammation Res., (1998) 47 (Suppl. 1): S50-S51 ); (R. Leurs, R.C. Vollinga and H. Timmerman, "The medicinal chemistry and therapeutic potentials of ligand of the histamine H3 receptor", Progress in Drug Research (1995) 45:170-165); (R. Levi and N. C. E. Smith, "Histamine H3-receptors: A new frontier in myocardial ischemia", J. Pharm. Exp. Ther. (2000) 292:825-830,); (Hatta, E., K Yasuda and R. Levi, "Activation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocardial ischemia", J. Pharm. Exp. Ther., (1997) 283:494-500; (H. Yokoyama and K. linuma, "Histamine and Seizures: Implications for the treatment of epilepsy", CNS Drugs. (1995) 5(5): 321-330); (K. Hurukami, H. Yokoyama, K. Onodera, K. linuma and T. Watanabe, AQ-O 145, "A newly developed histamine H3 antagonist, decreased seizure susceptibility of electrically induced convulsions in mice", Meth. Find. Exp. Clin. Pharmacol.. (1995) 17(0:70-73; (Delaunois A., Gustin P., Garbarg M., and Ansay M., "Modulation of acetylcholine, capsaicin and substance P effects by histamine H3 receptors in isolated perfused rabbit lungs", European Journal of Pharmacology (1995) 277(2-3):243-50); and (Dimitriadou, et al., "Functional relationship between mast cells and C- sensitive nerve fibres evidenced by histamine H3-receptor modulation in rat lung and spleen", Clinical Science (1994) 87(2):151- 63,. Such diseases or conditions include cardiovascular disorders such as acute myocardial infarction; memory processes, dementia and cognition disorders such as Alzheimer's disease and attention deficit hyperactivity disorder; neurological disorders such as Parkinson's disease, schizophrenia, depression, epilepsy, and seizures or convulsions; cancer such as cutaneous carcinoma," medullary thyroid carcinoma and melanoma; respiratory disorders such as asthma; sleep disorders such as narcolepsy; vestibular dysfunction such as Meniere's disease; gastrointestinal disorders, inflammation, migraine, motion sickness, obesity, pain, and septic shock.
H3 receptor antagonists have also been previously described in, for example, WO 03/050099, WO 02/0769252, and WO 02/12224. The histamine H3 receptor (H3R) regulates the release of histamine and other neurotransmitters, including serotonin and acetylcholine. H3R is relatively neuron specific and inhibits the release of certain monoamines such as histamine. Selective antagonism of H3R raises brain histamine levels and inhibits such activities as food consumption while minimizing non-specific peripheral consequences. Antagonists of the receptor increase synthesis and release of cerebral histamine and other monoamines. By this mechanism, they induce a prolonged wakefulness, improved cognitive function, reduction in food intake and normalization of vestibular reflexes. Accordingly, the receptor is an important target for new therapeutics in Alzheimer's disease, mood and attention adjustments, including attention deficit hyperactive disorder (ADHD), cognitive deficiencies, obesity, dizziness, schizophrenia, epilepsy, sleeping disorders, narcolepsy and motion sickness, and various forms of anxiety. The majority of histamine H3 receptor antagonists to date resemble histamine in possessing an imidazole ring that may be substituted, as described, for example, in WO 96/38142. Non-imidazole neuroactive compounds such as beta histamines (Arrang, Eur. J. Pharm. (1985) 111 :72-84) demonstrated some histamine H3 receptor activity but with poor potency. EP 978512 and EP 982300 disclose non-imidazole alkyamines as histamine H3 receptor antagonists. WO 02/12190 (Ortho McNeil Pharmaceuticals) describes non- imidazole bicyclic derivatives as histamine H3 receptor ligands, and EP 1275647 (Les Laboratoires Servier) has disclosed novel octahydro-2H-pyrido[1 ,2-a]pyrazines that are selective H3 receptor antagonists. Other receptor antagonists have been described in WO 02/32893 and WO 02/06233. The present invention is directed to histamine-3 (H3) receptor antagonists useful for treating the conditions listed in the preceding paragraphs. The compounds of this invention are highly selective for the H3 receptor (vs. other histamine receptors), and possess remarkable drug disposition properties (pharmacokinetics). In particular, the compounds of this invention selectively distinguish H3R from the other receptor subtypes H-iR, H2R. In view of the increased level of interest in histamine H3 receptor agonists, inverse agonists and antagonists in the art, novel compounds that interact with the histamine H3 receptor would be a highly desirable contribution to the art. The present invention provides such a contribution -A-
to the art being based on the finding that a novel class of aza-bicyclic ethers exhibits a high and specific affinity to the histamine H3 receptor.
SUMMARY OF THE INVENTION This invention is directed to compounds of the formula I:
Figure imgf000005_0001
I or the pharmaceutically acceptable salt(s) thereof, wherein:
A is an aryl or heteroaryl ring (e.g., pyridine, pyrimidine, pyrazine, indole, quinoline, quinazoline, quinoxaline, benzofuran, benzothiazole, benzoxazole, benzimidazole), optionally substituted by Yn where r is 0 to 3 and each substituent Y is independently selected from the list comprising H, F, Cl, Br, C1-C6 alkyl, C1-C6 alkoxyl, C=O-(C1-C6 alkyl), C=O-(NR4R5), CF3,
OH, NR5R6, SO2NR5R6, (C1-C6 alkyl)-OH, heterocycloalkyl, heteroarl, O-heteroaryl, phenyl;
L is CR3R4;
X is a halogen, CF3, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 thioalkyl; E is a 7-13 member bicyclic heterocycloalkyl group, containing at least one secondary nitrogen atom and up to 3 additional heteroatoms selected from N, O and S, up to two carbon-carbon double bonds and optionally substituted at available C and N positions with hydrogen, OH, CN, CF3, C1-C6 alkyl, aryl, (C1-C6 alkyl)-aryl or heteroaryl;
R1 and R2 are independently selected from hydrogen, C1-C6 alkyl, aryl, (C1-C6 alkyl)- aryl, heteroaryl, (C1-C6 alkyl)-heteroaryl;
R3, R4, R5 and R6 are independently selected from C1-C6 alkyl, optionally substituted at available positions with H, OH, F or C1-C6 alkyl; or
R3 and R4 together with the carbon to which they are attached form a 3-7 member carbocyclic ring; R5 and R6 taken together with the nitrogen to which they are attached form a 4-7 member heterocycloalkyl group, optionally containing up to two additional heteroatoms selected from N, O, S and optionally substituted on available C and N atoms with H, OH, C1- C6 alkyl, aryl, (C1-C6 alkyl)-aryl or heteroaryl; m is O, 1 , 2 or 3; and n is 0, 1 , 2, 3 or 4.
Where cis and trans isomers are possible for an embodiment of the inventive compound of formula I, both cis and trans isomers are to be included within the scope of the invention. The term "alkyl" refers to straight or branched chains of carbon atoms. Exemplary alkyl groups are C1-C6 alkyl groups which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and the like, including all regioisomeric forms thereof, and straight and branched chain forms thereof. The term "alkyl" is also used to denote straight or branched chains of carbon atoms having one or more carbon-carbon double bonds, such as vinyl, allyl, butenyl, and the like, as well as straight or branched chains of carbon atoms having one or more carbon-carbon triple bonds, such as ethynyl, propargyl, butynyl, and the like. The term "aryl" denotes a cyclic, aromatic hydrocarbon. Examples of aryl groups include phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. The terms "alkoxy" and "aryloxy" denote "O-alkyl" and "O-aryl", respectively. The term "cycloalkyl" denotes a cyclic group of carbon atoms, where the ring formed by the carbon atoms may be saturated or may comprise one or more carbon-carbon double bonds in the ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, as well as cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. As used herein, the term "cycloalkyl" is also intended to denote a cyclic group comprising at least two fused rings, such as adamantanyl, decahydronaphthalinyl, norbornanyl, where the cyclic group may also have one or more carbon-carbon double bonds in one or both rings, such as in bicyclo[4.3.0]nona-3,6(1)-dienyl, dicyclopentadienyl, 1 ,2,3,4-tetrahydronaphthalinyl (tetralinyl), indenyl, and the like. The term "halogen" represents chloro, fluoro, bromo, and iodo. The term "heteroaryl" denotes a monocyclic or bicyclic aromatic group wherein one or more carbon atoms are replaced with heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Preferred heteroaryl groups are five- to fourteen- member rings that contain from one to three heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of preferred heteroaryl groups include benzo[b]thienyl, chromenyl, furyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinolizinyl, quinolyl, quinoxalinyl, thiazolyl, thienyl, triazinyl, triazolyl, and xanthenyl. The term "heterocycloalkyl" denotes a cycloalkyl system, wherein "cycloalkyl" is defined above, in which one or more of the ring carbon atoms are replaced with a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of such heterocycloalkyl groups include azabicycloheptanyl, azetidinyl, benzazepinyl, 1 ,3- dihydroisoindolyl, indolinyl, tetrahydrofuryl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, and, tetrahydro-2H-1 ,4-thiazinyl. A cyclic group may be bonded to another group in more than one way. If no particular bonding arrangement is specified, then all possible arrangements are intended. For example, the term "pyridyl" includes 2-, 3-, or 4-pyridyl, and the term "thienyl" includes 2- or 3-thienyl.
The term "C0-C/ includes the embodiment where there are no carbons in a chain. Thus, for example, the groups "C3-C7 cycloalkyl-C0-C4 alkyl," "C6-Ci4 aryl-C0-C4 alkyl," "5-10- membered heteroaryl-C0-C4 alkyl," and "C6-Ci4 aryl-C0-C4 alkylene-O-C0-C4 alkyl" include C3-
C7 cycloalkyl, C6-Ci4 aryl, 5-10-membered heteroaryl, and C6-Ci4 aryl- 0-C0-C4 alkyl, respectively.
The term "CrC4 dialkylamino" refers to a dialkylamino group in which each alkyl group is independently a CrC4 alkyl group.
This invention is also directed to: a pharmaceutical composition for treating, for example, a disorder or condition that may be treated by antagonizing histamine-3 (H3) receptors, the composition comprising a compound of formula I as described above, and optionally a pharmaceutically acceptable carrier; a method of treatment of a disorder or condition that may be treated by antagonizing histamine-3 (H3) receptors, the method comprising administering to a mammal in need of such treatment a compound of formula I as described above; and a pharmaceutical composition for treating, for example, a disorder or condition selected from the group consisting of depression, mood disorders, schizophrenia, anxiety disorders, Alzheimer's disease, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergy, allergy-induced airway responses, allergic rhinitis, nasal congestion, allergic congestion, congestion, hypotension, cardiovascular disease, diseases of the Gl tract, hyper and hypo motility and acidic secretion of the gastrointestinal tract, the composition comprising a compound of formula I as described above, and optionally a pharmaceutically acceptable carrier.
This invention is also directed to a method of treatment of a disorder or condition selected from the group consisting of the disorders or conditions listed in the preceding paragraph, the method comprising administering to a mammal in need of such treatment a compound of formula I as described above.
The histamine-3 (H3) receptor antagonists of the invention are useful for treating, in particular, ADD, ADHD, obesity, anxiety disorders and respiratory diseases. Respiratory diseases that may be treated by the present invention include adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis. The pharmaceutical composition and method of this invention may also be used for preventing a relapse in a disorder or condition described in the previous paragraphs. Preventing such relapse is accomplished by administering to a mammal in need of such prevention a compound of formula I as described above. The disclosed compounds may also be used as part of a combination therapy, including their administration as separate entities or combined in a single delivery system, which employs an effective dose of a histamine H3 antagonist compound of general formula I and an effective dose of a histamine H1 antagonist, such as cetirizine (Zyrtec™), for the treatment of allergic rhinitis, nasal congestion and allergic congestion. The disclosed compounds may also be used as part of a combination therapy, including their administration as separate entities or combined in a single delivery system, which employs an effective dose of a histamine H3 antagonist compound of general formula I and an effective dose of a neurotransmitter reuptake blocker. Examples of neurotransmitter reuptake blockers will include the serotonin-selective reuptake inhibitors (SSRI's) like sertraline (Zoloft™), fluoxetine (Prozac™), and paroxetine (Paxil™), or non-selective serotonin, dopamine or norepinephrine reuptake inhibitors for treating depression and mood disorders.
The compounds of the present invention may have optical centers and therefore may occur in different enantiomeric configurations. Formula I, as depicted above, includes all enantiomers, diastereomers, and other stereoisomers of the compounds depicted in structural formula I, as well as racemic and other mixtures thereof. Individual isomers can be obtained by known methods, such as optical resolution, optically selective reaction, or chromatographic separation in the preparation of the final product or its intermediate.
The present invention also includes isotopically labeled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 11C, 14C, 15N, 180, 17O, 31P, 32P, 35S, 18F, and 36CI, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, lsotopicaily labeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
"Antagonizing histamine-3 (H3) receptors," as used herein, refers to acting as a histamine-3 receptor antagonist.
A "unit dosage form" as used herein is any form that contains a unit dose of the compound of formula I. A unit dosage form may be, for example, in the form of a tablet or a capsule. The unit dosage form may also be in liquid form, such as a solution or suspension.
The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pre-gelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner.
The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., depression) is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
Aerosol formulations for treatment of the conditions referred to above (e.g., attention deficit hyperactivity disorder) in the average human are preferably arranged so that each metered dose or "puff' of aerosol contains 20 μg to 1000 μg of the compound of the invention. The overall daily dose with an aerosol will be within the range 100 μg to 100 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
In connection with the use of an active compound of this invention with a histamine H1 antagonist, preferably cetirizine, for the treatment of subjects possessing any of the above conditions, it is to be noted that these compounds may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages. More particularly, the active combination can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes. In general, the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage and a histamine H-i antagonist, preferably cetirizine, is present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
A proposed daily dose of an active compound of this invention in the combination formulation (a formulation containing an active compound of this invention and a histamine H1 antagonist) for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day. A proposed daily dose of a histamine H-i antagonist, preferably cetirizine, in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the histamine H1 antagonist per unit dose which could be administered, for example, 1 to 4 times per day. A preferred dose ratio of cetirizine to an active compound of this invention in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.00005 to about 20,000, preferably from about 0.25 to about 2,000.
Aerosol combination formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff' of aerosol contains from about 0.01 μg to about 100 mg of the active compound of this invention, preferably from about 1 μg to about 10 mg of such compound. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time. Aerosol formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff of aerosol contains from about 0.01 mg to about 2000 mg of a histamine H1 antagonist, preferably cetirizine, preferably from about 1 mg to about 200 mg of cetirizine. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time. As previously indicated, a histamine H-i antagonist, preferably cetirizine, in combination with compounds of formula I are readily adapted to therapeutic use as antiallergy agents. In general, these antiallergy compositions containing a histamine H1 antagonist, preferably cetirizine, and a compound of formula I are normally administered in dosages ranging from about 0.01 mg to about 100 mg per kg of body weight per day of a histamine H1 antagonist, preferably cetirizine, preferably from about 0.1 mg. to about 10 mg per kg of body weight per day of cetirizine; with from about 0.001 mg. to about 100 mg per kg of body weight per day of a compound of formula I, preferably from about 0.01 mg to about 10 mg per kg of body weight per day of a compound of formula I, although variations will necessarily occur depending upon the conditions of the subject being treated and the particular route of administration chosen.
In connection with the use of an active compound of this invention with a 5-HT re- uptake inhibitor, preferably sertraline, for the treatment of subjects possessing any of the above conditions, it is to be noted that these compounds may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages. More particularly, the active combination can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes. In general, the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage and a 5-HT re-uptake inhibitor, preferably sertraline, is present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
A proposed daily dose of an active compound of this invention in the combination formulation (a formulation containing an active compound of this invention and a 5-HT reuptake inhibitor) for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.
A proposed daily dose of a 5-HT re-uptake inhibitor, preferably sertraline, in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the 5-HT re-uptake inhibitor per unit dose which could be administered, for example, 1 to 4 times per day. A preferred dose ratio of sertraline to an active compound of this invention in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.00005 to about 20,000, preferably from about 0.25 to about 2,000. Aerosol combination formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff of aerosol contains from about 0.01 μg to about 100 mg of the active compound of this invention, preferably from about 1 μg to about 10 mg of such compound. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
Aerosol formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff' of aerosol contains from about 0.01 mg to about 2000 mg of a 5-HT re-uptake inhibitor, preferably sertraline, preferably from about 1 mg to about 200 mg of sertraline. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
As previously indicated, a 5-HT re-uptake inhibitor, preferably sertraline, in combination with compounds of formula I are readily adapted to therapeutic use as antidepressant agents. In general, these antidepressant compositions containing a 5-HT reuptake inhibitor, preferably sertraline, and a compound of formula I are normally administered in dosages ranging from about 0.01 mg to about 100 mg per kg of body weight per day of a 5-HT re-uptake inhibitor, preferably sertraline, preferably from about 0.1 mg. to about 10 mg per kg of body weight per day of sertraline; with from about 0.001 mg. to about 100 mg per kg of body weight per day of a compound of formula I, preferably from about 0.01 mg to about 10 mg per kg of body weight per day of a compound of formula I, although variations will necessarily occur depending upon the conditions of the subject being treated and the particular route of administration chosen.
Anxiety disorders include, for example, generalized anxiety disorder, panic disorder, PTSD, and social anxiety disorder. Mood adjustment disorders include, for example, depressed mood, mixed anxiety and depressed mood, disturbance of conduct, and mixed disturbance of conduct and depressed mood. Attention adjustment disorders include, for example, in addition to ADHD, attention deficit disorders or other cognitive disorders due to general medical conditions. Psychotic disorders include, for example, schizoaffective disorders and schizophrenia; sleep disorders include, for example, narcolepsy and enuresis.
Examples of the disorders or conditions which may be treated by the compound, composition and method of this invention are also as follows: depression, including, for example, depression in cancer patients, depression in Parkinson's patients, post-myocardial Infarction depression, depression in patients with human immunodeficiency virus (HIV), Subsyndromal Symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, post partum depression, DSM-IV major depression, treatment-refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic depressive illness, including manic depressive illness with mixed episodes and manic depressive illness with depressive episodes, seasonal affective disorder, bipolar depression BP I, bipolar depression BP II, or major depression with dysthymia; dysthymia; phobias, including, for example, agoraphobia, social phobia or simple phobias; eating disorders, including, for example, anorexia nervosa or bulimia nervosa; chemical dependencies, including, for example, addictions to alcohol, ***e, amphetamine and other psychostimulants, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's diseases, including, for example, dementia in Parkinson's disease, neuroleptic- induced parkinsonism or tardive dyskinesias; headache, including, for example, headache associated with vascular disorders; withdrawal syndrome; age-associated learning and mental disorders; apathy; bipolar disorder; chronic fatigue syndrome; chronic or acute stress; conduct disorder; cyclothymic disorder; somatoform disorders such as somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated disorder, and somatoform NOS; incontinence; inhalation disorders; intoxication disorders; mania; oppositional defiant disorder; peripheral neuropathy; posttraumatic stress disorder; late luteal phase dysphoric disorder; specific developmental disorders; SSRI "poop out" syndrome, or a patient's failure to maintain a satisfactory response to SSRI therapy after an initial period of satisfactory response; and tic disorders including Tourette's disease. As an example, the mammal in need of the treatment or prevention may be a human.
As another example, the mammal in need of the treatment or prevention may be a mammal other than a human.
A compound of formula I, which is basic in nature, is capable of forming a wide variety of different salts with various inorganic and organic acids. The acid addition salts are readily prepared by treating the base compounds with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
The acids which are used to prepare the pharmaceutically acceptable acid salts of the active compound used in formulating the pharmaceutical composition of this invention that are basic in nature are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions. Non-limiting examples of the salts include the acetate, benzoate, beta-hydroxybutyrate, bisulfate, bisulfite, bromide, butyne-1 ,4-dioate, caproate, chloride, chlorobenzoate, citrate, dihydrogenphosphate, dinitrobenzoate, fumarate, glycollate, heptanoate, hexyne-1 ,6-dioate, hydroxybenzoate, iodide, lactate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, naphthalene-1 -sulfonate, naphthalene-2-sulfonate, oxalate, phenyl butyrate, phenyl propionate, phosphate, phthalate, phenylacetate, propanesulfonate, propiolate, propionate, pyrophosphate, pyrosulfate, sebacate, suberate, succinate, sulfate, sulfite, sulfonate, tartrate, xylenesulfonate, acid phosphate, acid citrate, bitartrate, succinate, gluconate, saccharate, nitrate, methanesulfonate and pamoate [i.e., 1 ,1'-methylene-bis-(2- hydroxy-3-naphthoate)] salts.
Preferred embodiments of the present invention include the compounds of formula I in which
(A): A is a phenyl ring; or
(B): A is a heteroaryl ring; or (C): The group E is 3-aza-bicyclo[3.1.OJhexane; or
(D): The group E is octahydro-indole.
The most preferred embodiment of the present invention includes the compounds of formula I in which A is a heteroaryl ring and E is either 3-aza-bicyclo[3.1.0]hexane or octahydro-indole. Preferred compounds of formula I in accordance with the present invention are the following:
6-[4-(3-Methyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-quinoline;
3-Ethyl-6-(2-fluoro-4-pyridin-3-ylphenoxymethyl)-3-azabicyclo[3.1.0]hexane;
3-tert-Butyl-6-[2-m ethyl-4-(4-m ethyl pyrid i n-3-yl )-phenoxym ethyl]-3-aza bicyclo- [3.1.0]hexane;
7-(2-Methyl-4-pyridin-2-ylphenoxymethyl)-3-azabicyclo[4.1.0]heptane;
6-(2-Fluoro-4-pyridin-2-ylphenoxymethyl)-3-azabicyclo[3.3.1]nonane; δ-^-Pyrimidin^-ylphenoxymethyO-S-azabicycloβ^.iloctane;
6-{1-[4-(4-lsopropyl-pyrimidin-2-yl)-phenoxy]-ethyl}-3-azabicyclo[3.2.1]octane; 4-[4-(4-Cyclopropyl-pyrimidin-2-yl)-phenoxymethyl]-octahydro-cyclopenta[c]pyrrole; δ-^^.β-Dimethyl-pyrimidin^-ylJ-phenoxymethyll-octahydro-cyclopentafblpyrrole;
5-[2-(4-Pyrimidin-4-ylphenoxy)-ethyl]-octahydro-cyclopenta[b]pyrrole;
2-lsopropyl-5-[4-(2-phenyl-pyrimidin-4-yl)-phenoxymethyl]-octahydro-cyclopenta- [c]pyrrole; i-Benzyl-δ-β-^-pyrimidin^-ylphenoxyJ-ethyll-octahydro-cyclopentafbJpyrrole;
2-(2,2-Dimethylpropyl)-4-[4-(4-ethyl-pyrimidin-2-yl)-phenoxymethyl]-octahydro- cyclopenta[c]pyrrole; θ-^S-Fluoro-pyrimidin^-ylJ-phenoxymethylj-S-pyridin^-yl-S-azabicyclotS^.I]- octane;
3-(2-Chlorophenyl)-6-[4-(4-trifluoromethyl-pyridiπ-2-yl)-phenoxymethyl]-3-aza- bicyclo[3.3.1]nonane; 6-(4-Pyrazin-2-ylphenoxymethyl)-octahydro-[2]pyrindine; θ-^-Pyrimidin^-ylphenoxymethyO-δ-oxa-S-azabicycloβ^.iJoctane; β-ti-^S-Methyl-pyrimidin^-yO-phenoxyl-ethylJ-δ-thia-S-azabicyclotS^.iloctane 8- oxide;
S-Methyl-e^i-μ-CS-methyl-pyrimidin^-yO-phenoxyJ-ethylJ-δ-thia-S-azabicyclop^.i]- octane 8,8-dioxide;
2,3,4-Trimethyl-6-[4-(1 -methyl-1 H-pyrrol-3-yl)-phenoxymethyl]-3-azabicyclo[3.1.0]- hexane;
3-{4-[3-(2,2-Dimethylpropyl)-3-azabicyclo[3.1.0]hex-6-ylmethoxy]-phenyl}-1-methyl- 1 H-indole; i-Methyl-S-^S-methyl-S-azabicycloIS.I .Ojhex-e-ylmethoxyVphenyO-I H-pyrroloP.S- bjpyridine;
2-Methyl-3-[4-(2-methyl-octahydro-cyclopenta[b]pyrrol-6-ylmethoxy)-phenyl]-thieno- [2,3-b]pyridine;
6-[4-(2,5-Dimethyl-thiophen-3-yl)-phenoxymethyl]-1-methyl-octahydro-cyclopenta- [b]pyrrole;
7-[4-(1-Methyl-octahydro-indol-5-yloxy)-phenyl]-quinoline;
1-lsopropyl-5-(4-pyridin-3-ylphenoxy)-octahydro-cyclopenta[b]pyrrole; δ-P-Fluoro^^-methyl-pyridin-S-ylJ-phenoxyl^-isopropyl-octahydro-cyclopenta- pyrazole; 2-lsopropyl-6-(4-pyridin-2-ylphenoxy)-octahydro-[2]pyrindine;
2-Methyl-7-[4-(2-methyl-pyrimidin-4-yl)-phenoxy]-decahydro-isoquinoline;
3-Cyclopentyl-8-(4-pyridin-2-ylphenoxy)-3-azabicyclo[4.2.0]octane;
1-lsopropyl-3a-methyl-5-[4-(5-methyl-thiophen-2-yl)-phenoxy]-octahydro-indole;
1-lsopropyl-3a-methyl-5-[4-(2-methyl-thiazol-5-yl)-phenoxy]-octahydro-indole; 5-[4-(2,4-Dimethyl-oxazol-5-yl)-phenoxy]-1-isopropyl-3a-methyl-octahydro-indole; i-lsopropyl-Sa-methyl-δ-^-CS-methyl-CI .S^loxadiazol^-ylJ-phenoxyl-octahydro-indole;
6-[3-Fluoro-4-(5-isopropyl-[1 ,3,4]oxadiazol-2-yl)-phenoxy]-1-methyl-decahydro- quinoline;
6-[4-(1H-Benzoimidazol-2-yl)-2,5-dimethyl-phenoxy]-1-methyl-decahydro-quinoline; 2-[3-Methoxy-4-(1-methyl-octahydro-indol-5-yloxy)-phenyl]-benzoxazole; e-Fluoro^-^-CI-isopropyl-octahydro-indol-δ-yloxyJ-phenyll-benzothiazole;
2-Methyl-4-[4-(5-methyl-[1 ,3,4]thiadiazol-2-yl)-phenoxy]-octahydro-isoindole; 4-[4-(4,6-Dimethyl-pyrimidin-2-yl)-phenoxy]-2-methyl-octahydro-isoindole;
7-[4-(2-Methyl-octahydro-isoindol-4-yloxy)-phenyl]-quinoline;
7-[4-(2-Methyl-octahydro-isoindol-4-yloxy)-phenyl]-2-trifluoromethyl-quinazoline;
5-[4-(1-MethyI-octahydro-[1]pyrindin-4-yloxy)-phenyl]-quinoxaline; 1-[3-(4-Pyridin-2-ylphenoxy)-propyl]-octahydro-[1]pyrindine;
1-{2,2-Dimethyl-3-[4-(6-methyl-pyridin-2-yl)-phenoxy]-propyl}-octahydro-[1]pyrindine;
^{^^-(δ-Fluoro-pyrimidin^-yO-phenoxymethylJ-cyclopropylmethylJ-octahydro- [1]pyrindine;
2-[4-(5-Fluoro-pyrimidin-2-yl)-phenoxy]-octahydro-quinolizine; 5-[4-(5-Fluoro-pyrimidin-2-yl)-phenoxy]-2-methyl-2-azabicyclo[2.2.2]octane; δ-^S-Fluoro-pyrimidin^-ylJ-phenoxyl-S-methyl-S-azabicycloIS^.^octane; and
S-^S-Methyl-pyrimidin^-yO-phenoxymethyπ-i-azabicyclofS^.IJoctane.
The most preferred examples of compounds according to the present invention include: 6-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-quinoline;
3-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-quinoline;
3-lsopropyl-6-(4-pyridin-3-ylphenoxymethyl)-3-azabicyclo[3.1.0]hexane;
1-lsopropyl-3a-methyl-5-(4-pyridin-3-ylphenoxy)-octahydro-indole;
5-[4-(1-lsopropyl-3a-methyl-octahydro-indol-5-yloxy)-phenyl]-2-methyl-benzothiazole; 6-[4-(1-lsopropyl-3a-methyl-octahydro-indol-5-yloxy)-phenyl]-quinoxaline;
4'-(1-lsopropyl-3a-methyl-octahydro-indol-5-yloxy)-biphenyl-4-sulfonic acid amide;
5-[4-(1-lsopropyl-3a-methyl-octahydro-indol-5-yloxy)-phenyl]-2-phenyl-benzoxazole;
1-lsopropyl-3a-methyl-5-(4-pyrimidin-2-ylphenoxy)-octahydro-indole;
I^Z-^i-lsopropyl-Sa-methyl-octahydro-indol-δ-yloxyJ-phenyll-δ-methoxy-benzo- furan-2-yl}-ethanone;
1-lsopropyl-3a-methyl-5-(4'-oxazol-5-ylbiphenyl-4-yloxy)-octahydro-indole; lsopropyl-{1-[4-(1-isopropyl-3a-methyl-octahydro-indol-5-yloxy)-phenyl]-isoquinolin-3- yl}-amine;
Isopropyl^S-^-CI-isopropyl-Sa-methyl-octahydro-indol-S-yloxyJ-phenylJ-β-methyl- pyridin-2-yl}-amine;
4-[4-(1-lsopropyl-3a-methyl-octahydro-indol-5-yloxy)-phenyl]-6-trifluoromethyl-1 H- benzimidazole;
1-lsopropyl-3a-methyl-5-[3'-(1 H-pyrazol-3-yl)-biphenyl-4-yloxy]-octahydro-indole;
1-lsopropyl-3a-methyl-5-[4-(6-trifluoromethyl-pyridin-3-yl)-phenoxy]-octahydro-indole; δ-^-CI-lsopropyl-Sa-methyl-octahydro-indol-δ-yloxyJ-phenylJ^-pyridin-S-yl-benzox- azole;
1-lsopropyl-5-(2'-methoxy-biphenyl-4-yloxy)-3a-methyl-octahydro-indole; 1-lsopropyl-3a-methyl-5-[4-(5-trifluoromethyl-pyridin-2-yl)-phenoxy]-octahydro-indole;
5-[4-(3,5-Dimethyl-1 H-pyrazol-4-yl)-phenoxy]-1-isopropyl-3a-methyl-octahydro-indole;
4'-(1 -Isopropyl-Sa-methyl-octahydro-indol-δ-yloxyJ-biphenyM-sulfonic acid dimethyl- amide; 1-lsopropyl-3a-methyl-5-[4-(5-methyl-pyridin-2-yl)-phenoxy]-octahydro-indole;
5-(Biphenyl-4-yloxy)-1-isopropyl-3a-methyl-octahydro-indole;
5-(2',5'-Difluoro-biphenyl-4-yloxy)-1-isopropyl-3a-methyl-octahydro-indole;
1-lsopropyl-3a-methyl-5-[4-(3-methyl-pyridin-2-yl)-phenoxy]-octahydro-indole;
1-lsopropyl-3a-methyl-5-[4-(4-methyl-pyridin-2-yl)-phenoxy]-octahydro-indole; 5-(2',4'-Dimethyl-biphenyl-4-yloxy)-1 -isopropyl-Sa-methyl-octahydro-indole;
1-lsopropyl-3a-methyl-5-(2'-methyl-biphenyl-4-yloxy)-octahydro-indole;
1-lsopropyl-5-(4'-methoxy-biphenyl-4-yloxy)-3a-methyl-octahydro-indole;
1-lsopropyl-3a-methyl-5-[4-(6-methyl-pyridin-2-yl)-phenoxy]-octahydro-indole;
1-lsopropyl-3a-methyl-5-(4-pyridin-2-ylphenoxy)-octahydro-indole; δ-^S-lsopropyl-S-azabicycloIS.I .Olhex-β-ylmethoxyJ-phenyll^-methyl-benzo- thiazole;
4-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-1H-indole;
6-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-quinoxaline;
3-lsopropyl-6-(4-pyridin-2-ylphenoxymethyl)-3-azabicyclo[3.1.0]hexane; S-lsopropyl-e-^-Cδ-methyl-pyridin^-ylJ-phenoxymethylj-S-azabicyclo^.i .Olhexane; lsopropyl-{6-[4-(3-isopropyl-3-azabicyclo[3.1.0]hex-6-yl-methoxy)-phenyl]-pyridin-2-yl}- amine; δ-^S-lsopropyl-S-azabicyclop.i .Olhex-β-ylmethoxyJ-phenyll-nicotinamide;
6-(3',4'-Dimethyl-biphenyl-4-yloxymethyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane; i^δ-^^S-lsopropyl-S-azabicyciop.i .OJhex-δ-yl-methoxyVphenylJ^.S-dihydro-indol-i- yl}-ethanone;
6-(2',4'-Dimethyl-biphenyl-4-yloxymethyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane;
6-(2',5'-Difluoro-biphenyl-4-yloxymethyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane;
S-lsopropyl-e-^S-trifluoromethyl-pyridin^-yO-phenoxymethyll-S-azabicyclofS.I .O]- hexane;
3-lsopropyl-6-[4-(3-methyl-pyrazin-2-yl)-phenoxymethyl]-3-azabicyclo[3.1.0]hexane;
3-lsopropyl-6-(4'-methoxy-biphenyl-4-yloxymethyl)-3-azabicyclo[3.1.0]hexane;
5-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-1 H-pyrrolo[2,3-b]- pyridine; 4-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-6-trifluoromethyl-1 H- benzimidazole;
7-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-isoquinolin-1-ol; 6-(Biphenyl-4-yloxymethyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane; 3-lsopropyl-6-[4-(5-methyl-pyridin-2-yl)-phenoxymethyl]-3-azabicyclo[3.1.0]hexane; ^[^-(S-lsopropyl-S-azabicyclotS.I .Olhex-θ-ylmethoxyJ-biphenyl-^yπ-pyrrolidin^-one; 1-{7-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-yl-methoxy)-phenyl]-5-methoxy-benzo- furan-2-yl}-ethanone;
3-lsopropyl-6-[4-(4-methyl-pyridin-2-yl)-phenoxymethyl]-3-azabicyclo[3.1.0]hexane; i-^'-β-lsopropyl-S-azabicyclotS.I Olhex-δ-ylmethoxyJ-biphenyl^-ylJ-ethanone; 2-[4'-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-biphenyl-3-y!oxymethyl]- quinoline; 3-lsopropyl-6-[3'-(2-methyl-thiazol-4-yl)-biphenyl-4-yloxymethyl]-3-azabicyclo[3.1.0]- hexane;
3-lsopropyl-6-(2'-methoxy-biphenyl-4-yloxymethyl)-3-azabicyclo[3.1.0]hexane; S-lsopropyl-δ-^S-methyl-pyridin^-yO-phenoxymethyπ-S-azabicyclo^.i .Olhexane; β-^S-lsopropyl-S-azabicydoβ.i Olhex-β-ylmethoxyJ-phenylHH-i-oxa^.δ-diaza- naphthalen-3-one;
4-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-5-methyl-isoxazol-3- ylamine;
2-{4-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-indol-1-yl}-ethanol; 3-lsopropyl-6-[4-(6-methoxy-pyridin-2-yl)-phenoxymethyl]-3-azabicyclo[3.1.0]hexane; 3-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyI]-5-trifluoromethyl- pyrazin-2-ylamine;
6-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-2-methyl-quinoline; 4'-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-biphenyl-4-sulfonic acid dimethyl- amide; 6-{4-[2-tert-Butyl-4-(1-isopropyl-piperidin-4-yl)-pyrimidin-5-yl]-phenoxymethyl}-3-iso- propyl-3-azabicyclo[3.1.0]hexane;
3-lsopropyl-6-[4-(5-methyl-3-trifluoromethyl-1 H-pyrazol-4-yl)-phenoxymethyl]-3-aza- bicyclo[3.1.0]hexane; and
3-lsopropyl-6-[4-(6-phenoxy-pyridin-2-yl)-phenoxymethyl]-3-azabicyclo[3.1.0]hexane.
Detailed Description of the Invention
The compounds of formula I of the present invention may be prepared according to the general procedure shown in Scheme 1. Scheme 1
Figure imgf000020_0001
Thus, a suitably protected alcohol of the general formula Il is reacted with a phenol of the general formula III to give an ether intermediate of general formula IV, as shown in step a. The reaction is most efficiently conducted using conditions often referred to as a Mitsunobu reaction, wherein the alcohol Il and the phenol III are combined to form an ether bond through the elimination of water. This reaction is generally performed in the presence of a reagent like diethylazodicarboxylate (DEAD) and triphenylphosphine (Ph3P), in a reaction inert solvent such as THF or dichloromethane and at temperatures in the range of about 0 °C to about 40 0C. The intermediate aryl ether of formula IV so obtained may be purified (e.g., by chromatography on silica gel or alumina) or used without purification in the next step.
The starting reagents Il used in step a are commercially available or may be prepared according to procedures described in the chemical literature. A suitable protecting group (P) for this reagent will include carboxybenzyl (CBZ) or tert-butoxycarbonyl (BOC) groups, and the like, which can prevent further reaction at the secondary nitrogen atom of the bicyclic heterocycloalkyl group E. Such protecting groups would be unreactive under the conditions employed in the ether formation yet readily removed prior to replacement of the group P by a group R1 as previously defined. Recommended protecting groups for the amine nitrogen may be found in such references as T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, (Third Edition), John Wiley and Sons, Inc., NY (1999) and
Kocienski, P.J., Protecting Groups, Georg Thieme Verlag, Stuttgart (1994).
The phenols of formula III, which contain a reactive group Z, are commercially available or prepared by methods described in the chemical literature. For example, the chloride, bromide or iodide Xl (Hal = Cl, Br, I):
Figure imgf000020_0002
can be converted to the corresponding boronic acid derivative III, wherein Z is a 4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolane group, by procedures like those of M. J. Schulz, S. J. Coats, D. J. Hlasta, Organic Letters (2004) 6(19):3265-8; J. Morgan, JT. Pinhey, Journal of the Chemical Society - Perkin Transactions I (1990) 715; WO-2000/027853 (published May 18, 2000).
In step b, the intermediate of general formula IV (described above) is reacted with an aryl or heteroaryl halide of general formula A-HaI, wherein A is as defined previously and Hal is a halogen (e.g., Cl, Br, I). Conditions for this step are generally referred to in the literature as the Suzuki reaction and are described in a number of publications including, e.g., M. Sato, N. Miyaura and A. Suzuki, Chemistry Letters (1989) 1405-1408; T. lihama, J. Fu, M.
Bourguignon, V. Snieckus, Synthesis (1989) 184-188; G. G. Kublak, P. N. Confalone,
Tetrahedron Letters (1990) 31 :3845-3848, and include the use of a metal ligand (e.g.,
' (PhaP^Pd) and an inorganic base like sodium or potassium carbonate in a reaction inert solvent like toluene or THF. Such reactions can be performed at temperatures in the range of 0° C up to the boiling point of the solvent selected and may be conducted in the presence or absence of microwave activation.
In step c of the process, the protecting group (i.e., P) is removed from the intermediate of general formula V to give the intermediate amine of general formula Vl. This transformation can be effected using one or more methods as disclosed in the chemical literature and known to one skilled in the art, depending on the nature of the group P. Efficient conditions for removal of a wide variety of amine protecting groups can be found in the Wuts and Greene reference listed above.
Depending on the nature of the group P and the conditions employed in step c, the secondary amine intermediate of formula Vl so derived may be used with or without prior purification in step d of the current process, wherein the intermediate of formula Vl can be converted to the title compound(s) of general formula I. This conversion can be effected in a variety of manners, and the choice of procedure may be influenced by the nature and reactivity of any substituents present on the intermediate of formula Vl. For example, the intermediate of formula Vl can be combined with a suitable aldehyde or ketone (i.e., R1- (C=O)-R2), using reductive amination conditions. In this reaction, the appropriate aldehyde or ketone is reacted with an intermediate of general formula Vl in the presence of a reducing agent to generate the corresponding secondary or tertiary amine. The reaction may be conducted in a reaction inert solvent (e.g., THF, dichloromethane, methanol, ethanol) or with an excess of the aldehyde or ketone as co-solvent, at temperatures in the range of -20 0C up to the boiling point of the solvent. Suitable reducing agents for this step may include one or more of the following: sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like. In the examples and descriptions that follow, the abbreviations used are intended to have the following, general meaning: bm: broad multiplet (NMR) bs: broad singlet (NMR) dd: doublet of doublets (NMR) d.e.: diatomaceous earth, filter agent
DMA: dimethylacetamide
DMF: dimethyformamide
DSMO: dimethylsulfoxide LRMS: low resolution mass spectrometry calcd; calculated d; doublet (NMR)
EtOAc: ethyl acetate
J: coupling constant (NMR) LAH: lithium aluminum hydride m: multiplet (in NMR) min: minute(s) m/z: mass to charge ratio (in mass spectrometry) obsd: observed Rf: retention factor (in chromatography)
Rt: retention time (in chromatography) rt: room temperature s: singlet (NMR), second(s) t: triplet THF: tetrahydrofuran tic: thin layer chromatography
Solvents were purchased and used without purification. Yields were calculated for material judged homogenous by thin layer chromatography and NMR. Thin layer chromatography was performed on Merck Kieselgel 60 F 254 plates eluting with the solvents indicated, visualized by a 254 nm UV lamp, and stained with either an aqueous KMnO4 solution or an ethanolic solution of 12-molybdophosphoric acid. Flash column chromatography was performed with using either pre-packed Biotage " or ISCO® columns using the size indicated. Nuclear magnetic resonance (NMR) spectra were acquired on a Unity 400 or 500 at 400 MHz or 500 MHz for 1H, respectively, and 100 MHz or 125 MHz for 13C NMR, respectively. Chemical shifts for proton 1H NMR spectra are reported in parts per million relative to the singlet of CDCI3 at 7.24 ppm. Chemical shifts for 13C NMR spectra are reported in parts per million downfield relative to the centerline of the triplet of CDCI3 at 77.0 ppm. Mass spectra analyses were performed on a APCI Gilson 215, micromass ZMD (50% Acetonitrile / 50% water) spectrometer.
Reactions under microwave conditions were done using 2-5mL round bottom vials, fitted with septa. The vials containing the reactants were inserted into the reaction chamber of a EMRYS™ Creator microwave apparatus (maximum power of 300 W) from Personal Chemistry Inc., 25 Birch St., Bldg C, Suite 304, Milford, MA 01757 and heated to the appropriate temperature for a the prescribed period of time. HPLC was performed according to the following method:
Method: Preparative conditions (Waters 600 & Waters 2767 Sample Manager); Column: Waters Xterra PrepMS Ci8 column, 5μm, 19 x 100 mm steel column; solvent A - water; solvent B - Acetonitrile; modifier - 1 % Trifluoroacetic acid/water; makeup solvent - 2nM ammonium formate in 80% aqueous methanol; volume of injection: 1050 μl_; time 0.0, 95% solvent A, 5% solvent B1 flow 18.0, modifier flow 2.0; time 1.0, 95% solvent A, 5% solvent B, flow 18, modifier flow 2.0; time 7.0, 5% solvent A, 95% solvent B, flow 18, modifier flow 2.0; time 8.5, 5% solvent A, 95% solvent B, flow 18, modifier flow 2.0.
Mass spectral (micromassZO) conditions; Capillary(kV): 3.0; Cone (V): 20; Extractor (V): 3.0; RF Lens (V): 0; Source temp. (0C): 120A/150P; Desolvation temp. (0C): 150A/300P; Desolvation gas flow (L/hr): 500; Cone gas flow (L/hr): 100; LM Resolution: 15; HM Resolution: 15; Ion Energy: 0.2; Multiplier: 600. Splitter; Acurate by LC Packings, 1/10,000; Upchurch needle valve setting: 14; Make up pump (Waters 515) Flow (ml/min.): 1. PDA (Waters 996) Settings; Start/End wavelength (nm): 200/600; Resolution: 1.2; Sample Rate: 1 ; Channels: TIC, 254 nm and 220 nm.
The following preparations, intermediates and examples were prepared by the procedures described above.
Preparation 1
Figure imgf000023_0001
(±)-(3αβ, 5oc, 7αβ)-5-hvdroxy-3a-methyl-octahvdro-indole-1-carboxylic acid tert- butyl ester, and
(±)-(3αβ, 5β, Tαβi-S-hvdroxy-Sa-methyl-octahvdro-indole-i-carboxylic acid tert- butvl ester A solution of 3a-methyl-5-oxo-2, 3, 3a, 4, 5, 6-hexahydroindole-i-carboxylic acid tert- butyl ester (32.3 g, 0.128 mol, prepared according to A. Padwa, M. Brodney and S. Lynch, Organic Synthesis (2002) 78:202) in dry CH2CI2 (550 ml.) was cooled to 00C and treated with triethylsilane (24.5 ml_, 0.154 mol), followed by 26.4 ml_ of trifluoroacetic acid. The maroon colored reaction was stirred and allowed to warm to rt over 3 hr. With ice-bath cooling, 2 M NaOH was added with vigorous stirring until the solution changed to yellow. The organic layer was removed and combined with CH2CI2 extracts of the aqueous layer. After drying over Na2SO4, the solvent was removed in vacuo to give an orange-brown oil. Chromatography (silica gel, 5-30% gradient of EtOAc in petroleum ether) gave 3a-methyl-5-oxo-octahydro- indole-1-carboxylic acid tert-butyl ester as a yellow oil, 26.0 g, which slowly crystallized on standing at rt, m.p. 43.8-45.5 0C.
1 H-nmr (400 MHz, CDCI3) δ 1.12 (s, 3H), 1.45 (s, 9H), 1.60-1.68 (m, 1 H), 1.69-1.72 (m, 1 H), 1.90-2.33 (m, 4H), 2.28 (d, 1 H), 2.39 (d, 1 H), 3.38-3.56 (m, 3H).
Mass spectrum (El1 m/z): calcd. for C14H23NO3: 253.1672; found 253.1676. The preceding ketone (32.05 g, 0.127 mol) in methanol (700 mL) was cooled to 0°C and slowly treated with a fresh solution of NaBH4 (4.80 g, 0.127 mol) in 137 mL water. The bath was removed and the mixture was allowed to warm to rt over 3 hr. The solvent was removed in vacuo and the residue diluted with 800 mL water and extracted with Et2O (3 x 200 mL). The combined extracts were washed with 100 mL of saturated aqueous NaCI and dried over MgSO4, then concentrated in vacuo to a viscous yellow oil, 31.47 g, as a 63:37 mixture of the α- and β-OH diastereomers.
The individual diastereomers were separated using preparative reverse phase chromatography:
The first eluting component (5β-0H) was isolated as a pale yellow viscous oil. 1 H-nmr (500 MHz, CDCI3) δ 1.00 (s, 3H), 1.10-1.27 (m, 2H), 1.28-1.35 (m, 1 H), 1.35-
1.45 (m, 1 H), 1.43 (s, 9H)1 1.45-1.55 (bs, 1 H), 1.80-1.90 (m, 1 H), 1.90-2.01 (m, 2H), 2.02-2.23 (m, 1 H), 3.17-3.45 (m, 3H)1 3.76 (m, 1 H).
Mass spectrum (El, m/z): calcd. for C14H25NO3: 255.1834; found 255.1838.
The second eluting component (5α-0H) was also isolated as a white solid, 97% pure by HPLC analysis.
1 H-nmr (500 MHz, CDCI3) δ 1.05 (s, 3H), 1.45 (s, 9H), 1.30-1.70 (m, 7H), 1.80 (m, 1 H), 2.20 and 2.48 (2 bs, 1 H)1 3.19 (bs, 1 H), 3.35 (m, 1 H), 3.45 (bs, 1 H)1 3.82 (bs, 1 H).
Mass spectrum (El1 m/z): calcd. for C14H25NO3: 255.1834; found 255.1837. lntermediate 1-1
Figure imgf000025_0001
6-r4-(4,4,5,5-Tetramθthyl-ri,3,21dioxaborolan-2-yl)-phenoxymethvn-3-azabicy- clof3.1.01hexane-3-carboxylic acid tert-butyl ester. Under N2, 6.0 g (28.0 mmol) of 6-hydroxymethyl-3-azabicyclo[3.1.0]hexane-3- carboxylic acid tert-butyl ester (prepared according to the method of J. Young and N. Horenstein, Tetrahedron Letters (2004) 45(52):9505-9507), 6.2 g (28.0 mmol) of 4-(4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenol, 11.0 g (42.0 mmol, 1.5 eq, Aldrich Chemical Co.) of triphenylphosphine and 75 ml of anhydrous THF were combined in a 250 ml_ single- neck round-bottom flask fitted with a mechanical stirrer and stirred at rt. To this dark mixture, 7.31 g (42.0 mmol, 1.5 eq, Aldrich Chemical Co.) of diethyl azodicarboxylate (DEAD) was added dropwise via syringe, with external cooling by a cold water bath to control a mild exotherm. The reaction was stirred at rt overnight, after which a tic (2:1 EtOAc: Hexanes, visualized in an iodine chamber) indicated the formation of a new product spot. The crude reaction was treated with ice cold 1 N NaOH, stirred for 1.0 hr at rt and diluted with EtOAc (100 ml_). The organics were washed twice more with cold 1 N NaOH. The organic layer was washed three times with saturated aqueous NaCI and the organic layer was dried over anhydrous MgSO4, filtered and solvent was removed in vacuo to produce an oily residue.
The crude residue was flash chromatographed on a Biotage silica gel column (50 x 250 mm), eluting with 9:1 Hexanes:EtOAc and collecting product fractions which were concentrated in vacuo to a pale oil which slowly crystallized on standing, 7.4 g. LC/MS (m/z): calcd. for C23H34BNO5: 415.34. Found: 416 (M+1 ) 1H-NMR (400 MHz, CDCI3): 51.11 (m, 1 H), 1.31 (s, 12H), 1.42 (s, 9H), 1.53 (bs, 2H), 1.57 (s, 1 H), 3.62 (dd, 2H), 3.77 (dt, 1 H), 3.96 (m, 1 H), 6.85 (d, 2H), 7.72 (d, 2H). In the same manner, the following intermediate was also prepared:
Intermediate 1-2
Figure imgf000025_0002
3a-Methyl-5-r4-(4,4,515-tetramethyl-ri.3,21dioxaborolan-2-yl)-phenoxy1- octahvdro-indole-1-carboxylic acid tert-butyl ester. Prepared from (±)-(3αβ, 5α, 7αβ)-5-hydroxy-3a-methyl-octahydro-indole-1-carboxylic acid tert-butyl ester and 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenol according to the method of intermediate 1-1.
LC/MS (m/z): calcd. for C26H40BNO5: 457.42. Found: 458.2 (M+1) NMR (400 MHz, CDCI3): 51.03 (s, 3H), 1.25 (m, 3H), 1.30 (s, 12H), 1.45 (s+m, 12H),
2.15 (m, 2H), 3.42 (m, 3H), 4.40 (m, 1 H), 6.82 (d, 2H), 7.72 (d, 2H).
Intermediate 2-1
Figure imgf000026_0001
6-(4-Quinolin-6-ylphenoxymethyl)-3-azabicycloF3.1.01hexane-3-carboxylic acid tert-butyl ester.
In a 100-mL round bottom flask fitted with a magnetic stirrer, a mixture of 6-[4- (4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenoxymethyl]-3-azabicyclo[3.1.0]hexane-3- carboxylic acid tert-butyl ester (0.415 g, 1.0 mol, the product of Intermediate 1-1 ), 6-bromo- quinoline (0.312 g, 1.5 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 5 M%, Strem Chemicals Inc., Newburyport, MA) in 15 mL ethanol was degassed with N2 while adding a solution of sodium carbonate (0.53 g, 5.0 mmol) in warm water (5.0 mL). The flask was then sealed and immersed in an oil bath preheated to 145-150 °C for 4 hr and allowed to cool to rt overnight. The yellow mixture was filtered through a d.e. pad, washing the pad with additional ethanol. The solvent was removed in vacuo to give a yellow waxy solid, which was chromatographed on a Biotage silica gel column (40x75 mm) eluting with 0.5% TEA in CH2CI2. The major product band fractions were combined, concentrated in vacuo to a yellow solid and dried under vacuum, 0.311 g.
LC/MS (m/z): calcd. for C26H28N2O3: 416.52. Found: 417.2 (M+1 ); Rt = 2.4 min. NMR (400 MHz, CDCI3): 51.15 (m, 1 H), 1.43 (m, 9H), 1.46 (m, 1 H), 1.57 (s, 2H), 3.38 (m, 2H), 3.61 (m, 2H), 3.60 (d, 1 H), 3.83 (m, 1 H), 3.98 (m, 1 H), 6.99 (d, 2H), 7.41 (dd, 1 H), 7.63 (d, 2H), 7.93 (m, 2H), 8.15 (dd, 2H), 8.88 (d, 1 H).
In the same manner, the following intermediates were also prepared:
Intermediate 2-2:
Figure imgf000026_0002
6-(4-Quinolin-3-ylphenoxymethyl)-3-azabicvclor3.1.0lhexane-3-carboxylic acid tert-butyl ester.
Prepared from Intermediate 1-1 and 3-bromoquinoline, the product was isolated as a pale yellow solid. LC/MS (m/z): calcd. for C26H28N2O3: 416.52. Found: 417.2 (M+1 ); Rt = 2.6 min.
Intermediate 2-3:
Figure imgf000027_0001
6-(4-Pyridin-3-ylphenoxymethyl)-3-azabicvclor3.1.01hexane-3-carboxylic acid tert-butyl ester. Prepared from Intermediate 1-1 and 3-bromo-pyridine, the product was isolated as a pale yellow solid.
LC/MS (m/z): calcd. for C22H26N2O3: 366.42. Found: 367.2 (M+1); Rt = 2.1 min.
Intermediate 3-1 :
Figure imgf000027_0002
6-f4-(3-Azabicvclor3.1.01hex-6-ylmethoxy)-phenvn-quinoline.
A mixture of 6-(4-quinolin-6-ylphenoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carbox- ylic acid tert-butyl ester (0.31 g, 0.75 mmol, the product of Intermediate 2-1 ) in THF (3.0 mL) was treated at rt with 4M HCI in dioxane (4.0 mL, Aldrich Chemical Co.) to give a pale yellow solution which turned cloudy within 5 min. After stirring at rt overnight, the solvent was removed in vacuo to give a yellow solid, which was dried under vacuum at rt for 2 hr. This intermediate, isolated as a dihydrochloride salt, was used without further purification to prepare the title compound of Example 1.
Intermediate 3-2:
Figure imgf000027_0003
3-r4-(3-Azabicvclor3.1.0lhex-6-ylmethoxy)-phenyll-quinoline
Prepared as described for intermediate 3-1 , from 6-(4-quinolin-3-ylphenoxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (the product of Intermediate 2-2) and isolated as a yellow solid; it was used without further purification to prepare the title compound of Example 2.
Intermediate 3-3:
Figure imgf000028_0001
6-(4-Pyridin-3-ylphenoxymethvO-3-azabicvclof3.1.0lhexane.
This was prepared, as described for intermediate 3-1 above, from 6-(4-pyridin-3-yl- phenoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (the product of Intermediate 2-3) and isolated as a yellow solid; it was used without further purification to prepare the title compound of Example 3.
Figure imgf000028_0002
6-f4-(3-lsopropyl-3-azabicvclor3.1.01hex-6-ylmethoxy)-phenvn-quinoline.
A slurry of 6-[4-(3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-quinoline (the title compound of Intermediate 3-1) in dichloroethane (5 mL, DCE) was stirred at rt while adding TEA (365 μl_, 2.65 mmol), followed 30 min later by acetone (742 μL, 10.1 mmol). After 1 hr at rt, triacetoxyborohydride (0.477 g, 2.25 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with water (25 mL) and EtOAc (25 mL) and filtered. The aqueous layer was extracted with additional EtOAc, the organic layers were combined and washed with water and saturated aqueous NaCI. After drying with MgSO4, the solvent was removed in vacuo to a brown gum, 0.133 g. This was chromatographed using a Biotage silica gel column (12 x 50 mm), eluting with CH2CI2 to remove less polar impurities, then adding 5% methanol to. elute the product fractions. Removal of the solvent in vacuo gave a tan solid, 44 mg.
NMR (400 MHz, CDCI3): 51.08 (bm, 6H), 1.50 (m, 2H), 1.79 (bs, 1 H), 2.49 (bs, 3H), 3.20 (bs, 2H), 3.86 (d, 2H), 6.99 (d, 2H), 7.40 (dd, 1 H), 7.62 (m, 2H), 7.94 (m, 2H), 8.11-8.15 (dm, 2H), 8.87 (dd, 1 H).
Mass spectrum (LC/MS, m/z) calcd for C24H26N2O: 358.48; found 359.3 (M+1 ). Retention time (Rt): 1.6 min.
The free base was dissolved in diethyl ether and treated with 0.5 mL of 2.0 M HCI in diethyl ether (Aldrich Chemical Co.). Stirring at rt for 90 min gave a pale yellow solid which was filtered, washed with ether and dried under high vacuum, 27.1 mg; m.p. 244.5-245.5 0C. Example 2
Figure imgf000029_0001
3-r4-(3-lsopropyl-3-azabicvclor3.1.0lhex-6-ylmethoxy)-phenvπ-quinoline
Prepared in the same manner as Example 1 , from 3-[4-(3-azabicyclo[3.1.0]hex-6- ylmethoxy)-phenyl]-quinoline (the product of intermediate 3-2) to give 0.329 g of the title product free base as an off-white solid.
NMR (400 MHz, CDCI3): 51.02 (d, 6H), 1.44 (s, 2H), 1.71 (m, 1 H), 2.41 (bs, 2H), 2.42 (s, 1 H), 3.13 (d, 2H), 3.84 (d, 2H), 7.01 (d, 2H), 7.53 (t, 1 H), 7.60 (d, 1 H), 7.66 (t, 1 H), 7.82 (d, 1 H), 8.10 (d, 1 H), 8.20 (s, 1 H), 9.13 (s, 1 H).
Mass spectrum (LC/MS, m/z) calcd for C24H26N2O: 358.48; found 359.3 (M+1 ).
Retention time (Rt): 1.5 min.
The dihydrochloride salt was prepared as above; m.p. 256.0-256.6 0C.
Example 3
Figure imgf000029_0002
S-lsopropyl-β-fΦpyridin-S-ylphenoxymethvD-S-azabicvclofS.I.OIhexane.
Prepared in the same manner as described above from 6-(4-pyridin-3-yl- phenoxymethyl)-3-azabicyclo[3.1.0]hexane (the product of intermediate 3-3), to produce 0.202 g of free base as a white solid.
NMR (400 MHz, CDCI3): 51.02 (d, 6H), 1.44 (m, 2H), 1.70(bs, 1 H), 2.41 (bs, 1 H), 2.43 (s, 2H), 3.13 (d, 2H), 3.83 (d, 2H), 6.97 (d, 2H), 6.97 (d, 2H), 7.32 (m, 1 H), 7.47 (d, 2H), 7.80 (dd, 1 H), 8.51 (d, 1 H), 8.78 (s, 1 H).
Mass spectrum (LC/MS, m/z) calcd for C20H24N2O: 308.42; found 309.3 (M+1).
Retention time (Rt): 1.2 min.
The free base was converted to the dihydrochloride salt as described above; m.p.179-8-180-6 °C.
In the same manner, the following compounds were also prepared:
Figure imgf000029_0003
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Determination of Biological Activity
The in vitro affinity of the compounds in the present invention at the rat or human histamine H3 receptors can be determined according to the following procedure. Frozen rat frontal brain or frozen human post-mortem frontal brain is homogenized in 20 volumes of cold 50 mM Tris»HCI containing 2 mM MgCI2 (pH to 7.4 at 4°C). The homogenate is then centrifuged at 45,000 G for 10 minutes. The supernatant is decanted and the membrane pellet re-suspended by Polytron in cold 50 mM Tris»HCI containing 2 mM MgCI2 (pH to 7.4 at 4 0C) and centrifuged again. The final pellet is re-suspended in 50 mM Tris HCI containing 2 mM MgCI2 (pH to 7.4 at 25 0C) at a concentration of 12 mg/mL Dilutions of compounds are made in 10% DMSO / 50 mM Tris buffer (pH 7.4) (at 10 x final concentration, so that the final DMSO concentration is 1 %). Incubations are initiated by the addition of membranes (200 microliters) to 96-well V-bottom polypropylene plates containing 25 microliters of drug dilutions and 25 microliters of radioligand (1 nM final concentration 3H-N-methylhistamine). After a 1-hour incubation, assay samples are rapidly filtered through Whatman GF/B filters and rinsed with ice-cold 50 mM Tris buffer (pH 7.4) using a Skatron cell harvester. Radioactivity is quantified using a BetaPlate scintillation counter. The percent inhibition of specific binding can then be determined for each dose of the compound, and an IC50 or Ki value can be calculated from these results. When tested using the above method for determination of binding activity using rat tissue, the compounds of examples 1-68 had Ki values of less than 1 μM.

Claims

1. A compound of formula I:
Figure imgf000036_0001
I or the pharmaceutically acceptable salt(s) thereof, wherein: A is an aryl or heteroaryl ring (e.g., pyridine, pyrimidine, pyrazine, indole, quinoline, quinazoline, quinoxaline, benzofuran, benzothiazole, benzoxazole, benzimidazole), optionally substituted by Yr, where r is O to 3 and each substituent Y is independently selected from the list comprising H, F, Cl, Br, C1-C6 alkyl, C1-C6 alkoxyl, C=O-(C1-C6 alkyl), C=O-(NR4R5), CF3, OH, -NR5R6, SO2NR5R6, (C1-C6 alkyl)-OH, heterocycloalkyl, heteroaryl, O-heteroaryl, phenyl; L iS CR3R4;
X is a halogen, CF3, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 thioalkyl; E is a 7-13 member bicyclic heterocycloalkyl group, containing at least one secondary nitrogen atom and up to 3 additional heteroatoms selected from N, O and S, up to two carbon-carbon double bonds and optionally substituted at available C and N positions with hydrogen, OH, CN, CF3, C1-C6 alkyl, aryl, (C1-C6 alkyl)-aryl or heteroaryl;
R1 and R2 are independently selected from hydrogen, C1-C6 alkyl, aryl, (C1-C6 alkyl)- aryl, heteroaryl, (Ci-C6 alkyl )-heteroaryl;
R3, R4, R5 and R6 are independently selected from C1-C6 alkyl, optionally substituted at available positions with H, OH, F or C1-C6 alkyl; or R3 and R4 together with the carbon to which they are attached form a 3-7 member carbocyclic ring;
R5 and R6 taken together with the nitrogen to which they are attached form a 4-7 member heterocycloalkyl group, optionally containing up to two additional heteroatoms selected from N, O, S and optionally substituted on available C and N atoms with H, OH, C1- C6 alkyl, aryl, (C1-C6 alkyl)-aryl or heteroaryl; m is 0, 1 , 2 or 3; and n is O, 1 , 2, 3 or 4.
2. The compound of Claim 1 , wherein
A is a phenyl or a heteroaryl ring and E is 3-aza-bicyclo [3.1.0] hexane or octahydro- indole.
3. The compound of claim 2 wherein
A is a phenyl ring and E is 3-aza-bicyclo [3.1.0] hexane or octahydro-indole.
4. The compound of claim 2 wherein A is a phenyl ring and E is 3-aza-bicyclo [3.1.0] hexane or octahydro-indole.
5. The compound of claim 1 selected from the group consisting of
6-[4-(3-Methyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-quinoline;
3-Ethyl-6-(2-fluoro-4-pyridin-3-ylphenoxymethyl)-3-azabicyclot3.1.0]hexane; 3-tert-Butyl-6-[2-methyl-4-(4-methylpyridin-3-yl)-phenoxymethyl]-3-azabicyclo-
[3.1.0]hexane;
7-(2-Methyl-4-pyridin-2-ylphenoxymethyl)-3-azabicyclo[4.1.0]heptane;
6-(2-Fluoro-4-pyridin-2-ylphenoxymethyl)-3-azabicyclo[3.3.1]nonane; β^-Pyrimidin^-ylphenoxymethylJ-S-azabicyclofS^.IJoctane; 6-{1-[4-(4-lsopropyl-pyrimidin-2-yl)-phenoxy]-ethyl}-3-azabicyclo[3.2.1]octane;
4-[4-(4-Cyclopropyl-pyrimidin-2-yl)-phenoxymethyl]-octahydro-cyclopenta[c]pyrrole;
6-[4-(4,6-Dimethyl-pyrimidin-2-yl)-phenoxymethyl]-octahydro-cyclopenta[b]pyrrole;
5-[2-(4-Pyrimidin-4-ylphenoxy)-ethyl]-octahydro-cyclopenta[b]pyrrole;
2-lsopropyl-5-[4-(2-phenyl-pyrimidin-4-yl)-phenoxymethyl]-octahydro-cyclopenta- [c]pyrrole;
1-Benzyl-5-[2-(4-pyrimidin-4-ylphenoxy)-ethyl]-octahydro-cyclopenta[b]pyrrole;
2-(2,2-Dimethylpropyl)-4-[4-(4-ethyl-pyrimidin-2-yl)-phenoxymethyl]-octahydro- cyclopenta[c]pyrrole; β-^δ-Fluoro-pyrimidin^-yO-phenoxymethyll-S-pyridin^-yl-S-azabicycloIS^.I]- octane;
3-(2-Chlorophenyl)-6-[4-(4-trifluoromethyl-pyridin-2-yl)-phenoxymethyl]-3-aza- bicyclo[3.3.1]nonane;
6-(4-Pyrazin-2-ylphenoxymethyl)-octahydro-[2]pyrindine;
6-(4-Pyrimidin-2-ylphenoxymethyl)-8-oxa-3-azabicyclo[3.2.1]octane; 6-{1 -^-(S-Methyl-pyrimidin^-yO-phenoxyl-ethylJ-δ-thia-S-azabicyclotS^.iloctane 8- oxide;
3-Methyl-6-{1-t4-(5-methyl-pyrimidin-2-yl)-phenoxy]-ethyl}-8-thia-3-azabicyclo[3.2.1]- octane 8,8-dioxide;
2,3,4-Trimethyl-6-[4-(1-methyl-1 H-pyrroi-3-yl)-phenoxymethyl]-3-azabicyclo[3.1.0]- hexane;
3-{4-[3-(2,2-Dimethylpropyl)-3-azabicyclo[3.1.0]hex-6-ylmethoxy]-phenyl}-1-methyl- 1 H-indole; i-Methyl-S-^S-methyl-S-azabicyclofS.I .Olhex-δ-ylmethoxyJ-phenyll-I H-pyrrolo^.S- b]pyridine; 2-Methyl-3-[4-(2-methyl-octahydro-cyclopenta[b]pyrrol-6-ylmethoxy)-phenyl]-thieno-
[2,3-b]pyridine; 6-[4-(2,5-Dimethyl-thiophen-3-yl)-phenoxymethyl]-1-methyl-octahydro-cyclopenta- [b]pyrrole;
7-[4-(1-Methyl-octahydro-indoi-5-yioxy)-phenyl]-quinoline;
1-lsopropyl-5-(4-pyridin-3-ylphenoxy)-octahydro-cyclopenta[b]pyrrole; 5-[3-Fluoro-4-(4-methyl-pyridin-3-yl)-phenoxy]-2-isopropyl-octahydro-cyclopenta- pyrazole;
2-lsopropyl-6-(4-pyridin-2-ylphenoxy)-octahydro-[2]pyrindine;
2-Methyl-7-[4-(2-methyl-pyrimidin-4-yl)-phenoxy]-decahydro-isoquinoline;
3-Cyclopentyl-8-(4-pyridin-2-ylphenoxy)-3-azabicyclo[4.2.0]octane; 1 -lsopropyl-3a-methyl-5-[4-(5-methyl-thiophen-2-yl)-phenoxy]-octahydro-indole;
1-lsopropyl-3a-methyl-5-[4-(2-methyl-thiazol-5-yl)-phenoxy]-octahydro-indole;
5-[4-(2,4-Dimethyl-oxazol-5-yl)-phenoxy]-1-isopropyl-3a-methyl-octahydro-indole;
1-lsopropyl-3a-methyl-5-[4-(5-methyl-[1 ,3,4]oxadiazo!-2-yl)-phenoxy]-octahydro-indole;
6-[3-Fluoro-4-(5-isopropyl-[1 ,3,4]oxadiazol-2-yl)-phenoxy]-1-methyl-decahydro- quinoline;
6-[4-(1 H-Benzoimidazol-2-yl)-2,5-dimethyl-phenoxy]-1-methyl-decahydro-quinoline;
2-[3-Methoxy-4-(1-methyl-octahydro-indol-5-yloxy)-phenyl]-benzoxazole;
6-Fluoro-2-[4-(1-isopropyl-octahydro-indol-5-yloxy)-phenyl]-benzothiazole;
2-Methyl-4-[4-(5-methyl-[1 ,3,4]thiadiazol-2-yl)-phenoxy]-octahydro-isoindole; 4-[4-(4,6-Dimethyl-pyrimidin-2-yl)-phenoxy]-2-methyl-octahydro-isoindole;
7-[4-(2-Methyl-octahydro-isoindol-4-yloxy)-phenyl]-quinoline;
7-[4-(2-Methyl-octahydro-isoindol-4-yloxy)-phenyl]-2-trifluoromethyl-quinazoline;
5-[4-(1-Methyl-octahydro-[1]pyrindin-4-yloxy)-phenyl]-quinoxaline;
1-[3-(4-Pyridin-2-ylphenoxy)-propyl]-octahydro-[1]pyrindine; 1-{2,2-Dimethyl-3-[4-(6-methyl-pyridin-2-yl)-phenoxy]-propyl}-octahydro-[1]pyrindine;
^{^^-(S-Fluoro-pyrimidin^-yO-phenoxymethyO-cyclopropylmethylJ-octahydro- [1]pyrindine;
2-[4-(5-F!uoro-pyrimidin-2-yl)-phenoxy]-octahydro-quinolizine; δ-^S-Fluoro-pyrimidin^-yO-phenoxyl^-methyl^-azabicyclop^^loctane; 8-[4-(5-Fluoro-pyrimidin-2-yl)-phenoxy]-3-methyl-3-azabicyclo[3.2.1]octane; and
3-[4-(5-Methyl-pyrimidin-2-yl)-phenoxymethyl]-1-azabicyclo[3.2.1]octane.
6. The compounds of claim 1 selected from the group consisting of : β-^S-lsopropyl-S-azabicycloβ.i .Olhex-δ-ylmethoxyVphenyO-quinoline;
3-[4-(3-lsopropyl-3-azabicyclot3.1.0]hex-6-ylmethoxy)-phenyl]-quinoline; 3-lsopropyl-6-(4-pyridin-3-ylphenoxymethyl)-3-azabicyclo[3.1.0]hexane;
1-lsopropyl-3a-methyl-5-(4-pyridin-3-ylphenoxy)-octahydro-indole;
5-[4-(1-lsopropyl-3a-methyl-octahydro-indol-5-yloxy)-phenyl]-2-methyl-benzothiazole; 6-[4-(1-lsopropyl-3a-methyl-octahydro-indol-5-yloxy)-phenyl]-quinoxaline; 4'-(1 -Isopropyl-Sa-methyl-octahydro-indol-δ-yloxyVbiphenyM-sulfonic acid amide; 5-[4-(1-lsopropyl-3a-methyl-octahydro-indol-5-yloxy)-phenyl]-2-phenyl-benzoxazole; 1-lsopropyl-3a-methyl-5-(4-pyrimidin-2-ylphenoxy)-octahydro-indole; 1 -{7-[4-(1 -Isopropyl-Sa-methyl-octahydro-indol-S-yloxyJ-phenyO-δ-methoxy-benzo- furan-2-yl}-ethanone;
1-lsopropyl-3a-methyl-5-(4'-oxazol-5-ylbiphenyl-4-yloxy)-octahydro-indole; Isopropyl-ti-^i-isopropyl-Sa-methyl-octahydro-indol-S-yloxyJ-phenyll-isoquinolin-S- yl}-amine; lsopropyl-{5-[4-(1 -isopropyl-3a-methyl-octahydro-indol-5-yloxy)-phenyl]-6-methyl- pyridin-2-yl}-amine;
4-[4-(1-lsopropyl-3a-methyl-octahydro-indol-5-yloxy)-phenyl]-6-trifluoromethyl-1 H- benzimidazole;
1-lsopropyl-3a-methyl-5-[3'-(1 H-pyrazol-3-yl)-biphenyl-4-yloxy]-octahydro-indole; 1-lsopropyl-3a-methyl-5-[4-(6-trifluoromethyl-pyridin-3-yl)-phenoxy]-octahydro-indole;
5-[4-(1-lsopropyl-3a-methyl-octahydro-indol-5-yloxy)-phenyl]-2-pyridin-3-yl-benzox- azole;
1-lsopropyl-5-(2'-methoxy-biphenyl-4-yloxy)-3a-methyl-octahydro-indole; 1-lsopropyl-3a-methyl-5-[4-(5-trifluoromethyl-pyridin-2-yl)-phenoxy]-octahydro-indole; 5-[4-(3,5-Dimethyl-1 H-pyrazol-4-yl)-phenoxy]-1 -isopropyl-3a-methyl-octahydro-indole;
4'-(1 -Isopropyl-Sa-methyl-octahydro-indol-δ-yloxyJ-biphenyl^-sulfonic acid dimethyl- amide;
1-lsopropyi-3a-methyl-5-[4-(5-methyl-pyridin-2-yl)-phenoxy]-octahydro-indole; 5-(Biphenyl-4-yloxy)-1-isopropyl-3a-methyl-octahydro-indole; 5-(2',5'-Difluoro-biphenyl-4-yloxy)-1-isopropyl-3a-methyl-octahydro-indole;
1-lsopropyl-3a-methyl-5-[4-(3-methyl-pyridin-2-yl)-phenoxy]-octahydro-indole; 1-lsopropyl-3a-methyl-5-[4-(4-methyl-pyridin-2-yl)-phenoxy]-octahydro-indole; 5-(2',4'-Dimethyl-biphenyl-4-yloxy)-1-isopropyl-3a-methyl-octahydro-indole; 1-lsopropyl-3a-methyl-5-(2'-methyl-biphenyl-4-yloxy)-octahydro-indole; 1-lsopropyl-5-(4'-methoxy-biphenyl-4-yloxy)-3a-methyl-octahydro-indole;
1-lsopropyl-3a-methyl-5-[4-(6-methyl-pyridin-2-yl)-phenoxy]-octahydro-indole; 1-lsopropyl-3a-methyl-5-(4-pyridin-2-ylphenoxy)-octahydro-indole; δ-^S-lsopropyl-S-azabicyclotS.I .Olhex-δ-ylmethoxyJ-phenyπ^-methyl-benzo- thiazole; 4-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-1 H-indole;
6-[4-(3-lsopropyl-3-azabicycIo[3.1.0]hex-6-ylmethoxy)-phenyl]-quinoxaline; 3-lsopropyl-6-(4-pyridin-2-ylphenoxymethyl)-3-azabicyclo[3.1.0]hexane; 3-lsopropyl-6-[4-(6-methyl-pyridin-2-yl)-phenoxymethyl]-3-azabicyclot3.1.0]hexane;
Isopropyl^δ-f^S-isopropyl-S-azabicyclofS.I .OJhex-β-yl-methoxyJ-phenyπ-pyridin^-yl}- amine; δ-t^S-lsopropyl-S-azabicyclop.i .Olhex-δ-ylmethoxyJ-phenylj-nicotinamide; 6-(3',4'-Dinnethyl-biphenyl-4-yloxymethyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane;
1-{5-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-yl-methoxy)-phenyl]-2,3-dihydro-indol-1- yl}-ethanone;
6-(2',4'-Dimethyl-biphenyl-4-yloxymethyl)-3-isopropyl-3-azabicyc!o[3.1.0]hexane;
6-(2',5'-Difluoro-biphenyl-4-yloxymethyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane; 3-lsopropyl-6-[4-(5-trifluoromethyl-pyridin-2-yl)-phenoxymethyl]-3-azabicyclo[3.1.0]- hexane;
3-lsopropyl-6-[4-(3-methyl-pyrazin-2-yl)-phenoxymethyl]-3-azabicyclo[3.1.0]hexane;
3-lsopropyl-6-(4'-methoxy-biphenyl-4-yloxymethyl)-3-azabicyclo[3.1.0]hexane;
5-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-1 H-pyrrolo[2,3-b]- pyridine;
4-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-6-trifluoromethyl-1 H- benzimidazole;
Z-^S-lsopropyl-S-azabicyciop.i .Olhex-δ-ylmethoxyJ-phenylJ-isoquinolin-i-ol;
6-(Biphenyl-4-yloxymethyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane; S-lsopropyl-δ-^S-methyl-pyridin^-ylJ-phenoxymethyll-S-azabicyclofS.I .Olhexane;
1-[4'-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-biphenyl-4-yl]-pyrrolidin-2-one;
^{/-^-(S-lsopropyl-S-azabicycloIS.I .Olhex-θ-yl-πnethoxy^phenylJ-S-methoxy-benzo- furan-2-yl}-ethanone;
3-lsopropyl-6-[4-(4-methyl-pyridin-2-yl)-phenoxymethyl]-3-azabicyclo[3.1.0]hexane; 1 -[4'-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-biphenyl-2-yl]-ethanone;
2-[4'-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-biphenyl-3-yloxymethyl]- quinoline;
3-lsopropy!-6-[3'-(2-methyl-thiazol-4-yl)-biphenyl-4-yloxymethyl]-3-azabicyclo[3.1.0]- hexane; 3-lsopropyl-6-(2'-methoxy-biphenyl-4-yloxymethyl)-3-azabicyclo[3.1.0]hexane;
3-lsopropyl-6-[4-(3-methyl-pyridin-2-yl)-phenoxymethyl]-3-azabicyclo[3.1.0]hexane;
6-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-4H-1-oxa-4,5-diaza- naphthalen-3-one;
4-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyI]-5-methyl-isoxazol-3- ylamine;
2-{4-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-indol-1-yl}-ethanol;
3-lsopropyl-6-[4-(6-methoxy-pyridin-2-yl)-phenoxymethyl]-3-azabicyclo[3.1.0]hexane; S-^S-lsopropyl-S-azabicycloβ.i .Olhex-θ-ylmethoxyVphenyll-S-trifluoromethyl- pyrazin-2-ylamine;
6-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-2-methyl-quinoline;
4'-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-biphenyl-4-sulfonic acid dimethyl- amide; β^-P-tert-Butyl^-CI-isopropyl-piperidin^-ylJ-pyrimidin-S-yll-phenoxymethylJ-S-iso- propyl-3-azabicyclo[3.1.0]hexane;
3-lsopropyl-6-[4-(5-methyl-3-trifluoromethyl-1 H-pyrazol-4-yl)-phenoxymethyl]-3-aza- bicyclo[3.1.0]hexane; and 3-lsopropyl-6-[4-(6-phenoxy-pyridin-2-yl)-phenoxymethyl]-3-azabicyclot3.1.0]hexane.
7. The intermediates used to make the compounds of claim 1 selected from the group consisting of
6-[4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenoxymethyl]-3-azabicy- clo[3.1.0]hexane-3-carboxylic acid tert-butyl ester; 3a-Methyl-5-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenoxy]-octahydro- indole-1-carboxylic acid tert-butyl ester;
6-(4-Quinolin-6-ylphenoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert- butyl ester;
6-(4-Quinolin-3-ylphenoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert- butyl ester;
6-(4-Pyridin-3-ylphenoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert- butyl ester;
6-[4-(3-Azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-quinoline; 3-[4-(3-Azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-quinoline; and 6-(4-Pyridin-3-ylphenoxymethyl)-3-azabicyclo[3.1.0]hexane.
8. A pharmaceutical composition for treating a disorder or condition that may be treated by antagonizing histamine-3 receptors, the composition comprising a compound of formula I as described in Claim 1 , and optionally a pharmaceutically acceptable carrier.
9. A method of treatment of a disorder or condition that may be treated by antagonizing histamine-3 receptors, the method comprising administering to a mammal in need of such treatment a compound of formula I as described in Claim 1.
10. A pharmaceutical composition comprising a compound of formula I as described in claim 1 , and optionally a pharmaceutically acceptable carrier.
11. A method of treatment of a disorder or condition selected from the group consisting of depression, mood disorders, schizophrenia, anxiety disorders, Alzheimer's disease, attention-deficit hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergy, allergy- induced airway responses, allergic rhinitis, nasal congestion, allergic congestion, congestion, hypotension, cardiovascular disease, diseases of the Gl tract, hyper and hypo motility and acidic secretion of the gastro- intestinal tract, the method comprising administering to a mammal in need of such treatment a compound of formula I as described in Claim 1.
12. The method of Claim 11 , wherein the disorder or condition is selected from the group consisting of anxiety disorders, attention-deficit hyperactivity disorder, respiratory diseases, and obesity.
13. The method of Claim 11 , wherein the disorder or condition is a respiratory disease selected from the group consisting of adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis.
14. A pharmaceutical composition for treating allergic rhinitis, nasal congestion or allergic congestion comprising: a) an H3 receptor antagonist compound of formula 1; or a pharmaceutically acceptable salt thereof; b) an H1 receptor antagonist such as cetirizine; or a pharmaceutically acceptable salt thereof; and c) a pharmaceutically acceptable carrier; wherein the active ingredients (a) and (b) above are present in amounts that render the composition effective in treating allergy rhinitis, nasal congestion or allergic congestion
15. A pharmaceutical composition for treating depression and mood disorder comprising: a) an H3 receptor antagonist or a pharmaceutically acceptable salt thereof; b) a neurotransmitter uptake blocker; or c) a pharmaceutically acceptable salt thereof; wherein the active ingredients (a) and (b) above are present in amounts that render the composition effective in treating depression and mood disorder.
16. The composition according to claim 15 wherein the H3 receptor antagonist and the neurotransmitter blocker are given simultaneously.
17. The composition according to claim 14 wherein the H3 receptor antagonist and the H1 receptor antagonist are given simultaneously.
18. The pharmaceutical composition of claim 15 wherein the neurotransmitter uptake blocker are selected from SSRI; sertraline, fluoxetine and paroxetine.
PCT/IB2007/001367 2006-05-30 2007-05-18 Azabicyclic ether histamine-3 antagonists WO2007138431A2 (en)

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