WO2002089848A2 - Methode de traitement du diabete - Google Patents

Methode de traitement du diabete Download PDF

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Publication number
WO2002089848A2
WO2002089848A2 PCT/US2002/011847 US0211847W WO02089848A2 WO 2002089848 A2 WO2002089848 A2 WO 2002089848A2 US 0211847 W US0211847 W US 0211847W WO 02089848 A2 WO02089848 A2 WO 02089848A2
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phenyl
formula
alkyl
ethyl
compound
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PCT/US2002/011847
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WO2002089848A3 (fr
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Emanuele Sher
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Eli Lilly And Company
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Priority to CA002446161A priority Critical patent/CA2446161A1/fr
Priority to EP02769268A priority patent/EP1390072A2/fr
Priority to JP2002586980A priority patent/JP2004530680A/ja
Priority to AU2002307327A priority patent/AU2002307327A1/en
Publication of WO2002089848A2 publication Critical patent/WO2002089848A2/fr
Publication of WO2002089848A3 publication Critical patent/WO2002089848A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • Diabetes is a chronic disease in which the body does not produce or properly use insulin, a hormone that is needed to convert sugar, starches and other food into energy needed for daily life.
  • many people do not become aware that they have diabetes until they develop one of its debilitating or life-threatening complications such as blindness, kidney disease, heart disease, stroke, and nerve disease which often results in lower limb amputations.
  • Type 1 diabetes is an auto-immune disease in which the body does not produce any insulin, most often occurring in children and young adults. People suffering from type 1 diabetes must take daily insulin injections to stay alive. Type 1 diabetes accounts for approximately 5-10 percent of diabetes cases.
  • Type 2 diabetes is a metabolic disorder resulting from the body's inability to make enough insulin, or to properly use insulin. It is the most common form of the disease and accounts for approximately 90-95 percent of diabetes cases.
  • gestational diabetes is a disease that develops in approximately 2 -5 percent of all pregnancies but disappears when the pregnancy is over. It is believed that women who have had gestational diabetes are at increased risk for developing type 2 diabetes later in life.
  • There are also other specific types of diabetes which result from certain genetic syndromes, surgery, drugs, malnutrition, infections, and other illnesses. Effective and convenient treatment of diabetes continues to be a target of active research in the pharmaceutical industry.
  • L-Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system.
  • the receptors that respond to L-glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins & Evans, Ann. Rev. Pharmacol. Toxicol., 21 , 165 (1981); Monaghan, Bridges, and Cotman,
  • excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
  • Excitatory amino acid receptors are classified into two general types, ionotropic and metabotropic. The receptors that are directly coupled to the opening of cation channels in the cell membrane of neurons are termed "ionotropic".
  • the ionotropic receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists ⁇ /-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). It has been disclosed by G. Bertrand, et al., Br. J. Pharmacol, 106. 354-
  • U.S. Patent No. 5,459,138, Pirotte et al. disclose compounds that selectively facilitate the activation of the AMPA receptor. Pirotte, et al. further state that these compounds have proved to be advantageous in the treatment of diabetic-type pathologies, related to dysfunctioning of insulin secretion which was described by G. Bertrand, et al., Br. J. Pharmacol., 106, 354-359 (1992) as regulated by AMPA receptors
  • the present invention provides a method of treating diabetes, comprising administering to a patient an effective amount of a suitable AMPA receptor potentiator.
  • the present invention provides a method of treating type 2 diabetes, comprising administering to a patient an effective amount of a suitable AMPA receptor potentiator.
  • the present invention provides the use of a suitable AMPA receptor potentiator, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating type 2 diabetes.
  • the present invention provides the use of a suitable AMPA receptor potentiator or a pharmaceutically acceptable salt thereof for treating type 2 diabetes.
  • the present invention further provides an article of manufacture comprising packaging material and a suitable AMPA receptor potentiator contained within said packaging material, wherein said packaging material comprises a label which indicates that said suitable AMPA receptor potentiator can be used for treating type 2 diabetes.
  • diabetes refers to and includes type I diabetes, type 2 diabetes, and gestational diabetes.
  • type I diabetes refers to insulin dependent diabetes.
  • type 2 diabetes refers to non-insulin dependent diabetes.
  • (1-10C)alkyl includes (1-8C)alkyl, (1-6C)alkyl and (1-4C)alkyl. Particular values are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.
  • (2-10C)alkenyl includes (3-10C)alkenyl, (2- 8C)alkenyl, (2-6C)alkenyl and (2-4C)alkenyl. Particular values are vinyl and prop-2-enyl.
  • (2-10C)alkynyl includes (3-10C)alkynyl, (2- 8C)alkynyl, (2-6C)alkynyl and (3-4C)alkynyl. A particular value is prop-2-ynyl.
  • Ci-C 6 alkoxy refers to a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom.
  • Typical Ci-C ⁇ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like.
  • Ci-C ⁇ alkoxy includes within its definition the term C 1 -C 4 alkoxy.
  • (3-8C)cycloalkyl includes monocyclic and polycyclic groups. Particular values are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[2.2.2]octane.
  • the term includes (3-6C)cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • integer of from 1 to 4" or integer of from 1 to 3 includes the integers 1 , 2, 3, and 4, or the integers 1 , 2, and 3, respectively.
  • (5-8C)cycloalkyl includes cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • hydroxy(3-8C)cycloalkyl includes hydroxy- cyclopentyl, such as 3-hydroxycyclopentyl.
  • oxo(3-8C)cycloalkyl includes oxocyclopentyl, such as 3-oxocyclopentyl.
  • halogen As used herein the terms "halogen”, “Hal” or “halide” include fluorine, chlorine, bromine and iodine unless otherwise specified.
  • halo(1-10C)alkyl includes fluoro(1-10C)alkyl, such as trifluoromethyl and 2,2,2-trifluoroethyl, and chloro(1-10C)alkyl such as chloromethyl.
  • cyano(2-10C)alkenyl includes 2-cyanoethenyl.
  • (2-4C)alkylene includes ethylene, propylene and butylene. A preferred value is ethylene.
  • thienyl includes thien-2-yl and thien-3-yl.
  • furyl includes fur-2-yl and fur-3-yl.
  • oxazolyl includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl.
  • isoxazolyl includes isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl.
  • oxadiazolyl includes [1 ,2,4]oxadiazol-3-yl and [1 ,2,4]oxadiazol-5- yl.
  • pyrazolyl includes pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl.
  • thiazolyl includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl.
  • thiadiazolyl includes [1 ,2,4]thiadiazol-3-yl, and [1 ,2,4]thiadiazol- 5-yl.
  • isothiazolyl includes isothiazol-3-yl, isothiazol-4-yl and isothiazol- 5-yl.
  • imidazolyl includes imidazol-2-yl, imidazolyl-4-yl and imidazolyl-
  • triazolyl includes [1 ,2,4]triazol-3-yl and [1 ,2,4]triazol-5-yl.
  • tetrazolyl includes tetrazol-5-yl.
  • pyridyl includes pyrid-2-yl, pyrid-3-yl and pyrid-4-yl.
  • pyridazinyl includes pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl and pyridazin-6-yl.
  • pyrimidyl includes pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl and pyrimidin-6-yl.
  • benzofuryl includes benzofur-2-yl and benzofur-3-yl.
  • benzothienyl includes benzothien-2-yl and benzothien-3-yl.
  • benzimidazolyl includes benzimidazol-2-yl.
  • benzoxazolyl includes benzoxazol-2-yl.
  • benzothiazolyl includes benzothiazol-2-yl.
  • indolyl includes indol-2-yl and indol-3-yl.
  • quinolyl includes quinol-2-yl.
  • dihydrothiazolyl includes 4,5-dihydrothiazol-2-yl
  • (1- 4C)alkoxycarbonyIdihydrothiazolyl includes 4-methoxycarbonyl-4, 5- dihydrothiazol-2-yl
  • -(1-4C)alkyl(3-8C)cycloalkyl includes the following:
  • the present invention includes the pharmaceutically acceptable salts of the compounds used herein.
  • the compounds used in this invention can possess a sufficiently acidic group, a sufficiently basic group, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts of the compounds used herein which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
  • Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science. 66. 2-19 (1977), which are known to the skilled artisan.
  • Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and
  • salts examples include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprate, caprylate, acrylate, ascorbate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, propionate, phenylpropionate, salicylate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, mandelate, nicotinate, isonicotinate, cinnamate, hippurate, nitrate, phthalate, teraphthalate, butyne-1 ,4-dioate, butyne-1 ,
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the potassium and sodium salt forms are particularly preferred.
  • any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that the above salts may form hydrates or exist in a substantially anhydrous form.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three- dimensional structures which are not interchangeable. The three-dimensional structures are called configurations.
  • enantiomer refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • chiral center refers to a carbon atom to which four different groups are attached.
  • diastereomers refers to stereoisomers which are not enantiomers.
  • two diastereomers which have a different configuration at only one chiral center are referred to herein as "epimers”.
  • racemate refers to a mixture of equal parts of enantiomers.
  • enantiomeric enrichment refers to the increase in the amount of one enantiomer as compared to the other.
  • a convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee”, which is found using the following equation:
  • E 1 is the amount of the first enantiomer and E 2 is the amount of the second enantiomer.
  • the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%.
  • the final ratio is 90:10, the ee with respect to the first enantiomer is 80%.
  • An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred.
  • Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art.
  • the specific stereoisomers and enantiomers of compounds of formula I can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by J. Jacques, et al., "Enantiomers. Racemates, and Resolutions". John Wiley and Sons, Inc., 1981 , and E.L. Eliel and S.H. Wilen," Stereochemistry of Organic Compounds".
  • R and S are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
  • the term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the term “S” (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice",
  • glutamate receptor function refers to any increased responsiveness of glutamate receptors, for example AMPA receptors, to glutamate or an agonist, and includes but is not limited to inhibition of rapid desensitization or deactivation of AMPA receptors to glutamate.
  • suitable AMPA receptor potentiator refers to a compound which inhibits the rapid desensitization or deactivation of AMPA receptors to glutamate and augments insulin secretion.
  • a preferred suitable AMPA receptor potentiator augments insulin secretion only during high glucose levels.
  • AMPA receptor potentiators examples include the following as described in Sections A through E. It is understood that suitable AMPA receptor potentiators fall within the scope of the compounds described in Sections A through E.
  • R " ! represents an unsubstituted or substituted aromatic or heteroaromatic group
  • R 2 represents (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)fluoroalkyl, (1- 6C)chloroalkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or a group of formula R3R4
  • L represents a (2-4C)alkylene chain which is unsubstituted or substituted by one or two substituents selected independently from (1-6C)alkyl, aryl(1- 6C)alkyl,
  • aromatic group means the same as aryl, and includes phenyl and a polycyclic aromatic carbocyclic ring such as 1- or 2-naphthyl, 1 ,2-dihydronaphthyl, 1 ,2,3,4-tetrahydronaphthyI, and the like. Phenyl is the preferred aromatic group.
  • heteromatic group in formula I includes an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a bicyclic group consisting of a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or another 5-6 membered ring containing one to four atoms selected from oxygen, sulfur and nitrogen.
  • heteroaromatic groups are thienyl, furyl, oxazolyl, isoxazolyl, oxadiazoyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, and quinolyl.
  • substituted as used in the term “substituted aromatic or heteroaromatic group” herein for formula I signifies that one or more (for example one or two) substituents may be present, said substituents being selected from atoms and groups which, when present in the compound of formula I, do not prevent the compound of formula II from functioning as a potentiator of glutamate receptor function.
  • R 1 in formula I represents an unsubstituted or substituted (5-8C)cycloalkyl group
  • mixtures of cis and trans isomers may result which can be separated into the individual cis and trans isomers by one of ordinary skill in the art, using standard techniques and procedures such as reverse phase or normal phase high performance liquid chromatography or flash chromatography, with a suitable stationary phase and a suitable eluent.
  • suitable stationary phases are silica gel, alumina, and the like.
  • suitable eluents are ethyl acetate/hexane, ethyl acetate/toluene, methanol/dichloromethane, and the like.
  • substituents which may be present in a substituted aromatic, heteroaromatic group or (5-8C)cycloalkyl group in formula I include halogen; nitro; cyano; hydroxyimino; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3- 8C)cycloalkyl; hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl;
  • (CH2)yX ' ' R® in which y is 0 or an integer of from 1 to 4, ⁇ 1 represents O, S, NR10, CO, COO, OCO, CONR1 1 , NR 2 CO, NR COCOO, OCONR13, R9 represents hydrogen, (1-10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R 10 > R ⁇ .
  • R ⁇ 2 and R ⁇ 3 each independently represents hydrogen or (1-10C)alkyl, or R 9 and R ⁇ °> R ⁇ > R 12 or
  • R13 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1-4C)alkylpiperazinyl; thienyl; fury!; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (1-4C)alkoxycarbonyl dihydrothiazolyl; (1 -4C)alkoxycarbonyl dimethyl-dihydrothiazolyl; tetrahydrothienyl; tetrahydrofuryl; tetrahydrothiopyranyl;
  • CH CH
  • L a and L D each represent (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and R ⁇ 4 represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen; nitro; cyano; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; 4-(1 ,1-dioxotetrahydro-1 ,2- thiazinyl); halo(1-10C)alkyl; cyano(2-10C)alkenyl; phenyl; and (CH2) Z X 3 R 15 in which z is 0 or an integer of from 1 to 4, X 3 represents O, S, NR 16 , CO, CH(OH),
  • R 15 represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1- 10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl, N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl, (3-10C)alkenyl, (3- 10C)alkynyl, (3-8C)cycloalkyl, camphoryl, or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)alkoxy, and R16 R17, R18 an d R ⁇ 9 each independently represents hydrogen or (1-10C)alkyl, or R ⁇ S and R
  • L preferably represents a group of formula R 8 R 6
  • R ⁇ , R7 and R ⁇ together with the carbon atom or carbon atoms to which they are attached form a (3-8C)carbocyclic ring; and the remainder of R ⁇ , R ⁇ , RJ and R ⁇ represent hydrogen.
  • R8 j n formula I are methyl, ethyl and propyl.
  • An example of an aryl(1-C)alkyl group is benzyl.
  • An example of a (2-6C)alkenyl group is prop-2-enyl.
  • An example of a (3- 8C)carbocyclic ring is a cyclopropyl ring. More preferably R ⁇ and R ⁇ represent hydrogen in formula I.
  • R ⁇ and R ⁇ each independently represents hydrogen or (1-4C)alkyl, or together with the carbon atom to which they are attached form a (3-8C) carbocyclic ring.
  • R ⁇ represents methyl or ethyl, or R ⁇ and R ⁇ together with the carbon atom to which they are attached form a cyclopropyl ring.
  • R ⁇ represents methyl or ethyl
  • R preferably represents hydrogen or methyl.
  • R ⁇ represents methyl and R ⁇ , R ⁇ and R7 represent hydrogen.
  • R ⁇ and R4 each represent methyl.
  • R 2 in formula I examples are methyl, ethyl, propyl, 2-propyl, butyl, 2-methylpropyl, cyclohexyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloromethyl, ethenyl, prop-2-enyI, methoxyethyl, phenyl, 4-fluorophenyl, or dimethylamino.
  • R 2 is ethyl, 2-propyl or dimethylamino with 2-propyl being most preferred.
  • values in formula I for R ⁇ are hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2- pyrrolidinyl, morpholino or 2-tetrahydrofuryl.
  • values in formula I for R15 are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, benzyl, 2,2,2-trifluoroethyl, 2- methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl, 2-fluorophenyl, 3- fluorophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 1-(5-dimethylamino)naphthyl, and 2-thienyl.
  • X 1 preferably represents O, CO, CONH or NHCO in formula I.
  • z is preferably 0 in formula I.
  • R 9 is preferably (1-4C)alkyl, (2-4C)alkenyl, (3-6C)cycloalkyl, pyrrolidinyl, morpholino or tetrahydrofuryl.
  • R 9 particular values for the groups (CH2)yX ⁇ R 9 and
  • (CH2)zX 3 R 15 include (1-10C)alkoxy, including (1-6C)alkoxy and (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy and isobutoxy; (3-10C)alkenyloxy, including (3-6C)alkenyloxy, such as prop-2-enyloxy; (3-10C)alkynyloxy, including (3-6C)alkynyloxy, such as prop-2-ynyloxy; and (1-6C)alkanoyl, such as formyl and ethanoyl.
  • L a and L D preferably each independently represents CH2 in formula I.
  • X 2 preferably represents a bond, O, NH, CO, CH(OH), CONH, NHCONH or OCH2CONH in formula I.
  • group (CH2)yX 1 R 9 represents CHO; COCH3, OCH3;
  • NHCOR 9 in which R 9 represents methyl, ethyl, isopropyl, t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyrolidinyl or morpholino; CONHR 9 in which R 9 represents cyclopropyl or cyclopentyl; NHCOCOOCH3; or 2-tetrahydrofurylmethoxy in formula I.
  • the group (CH2)zX 3 ⁇ represents NH2; CH2NH2; (CH2)2NH2; (CH2)3NH2; CONH2; CONHCH3; CON(CH3)2; N(C2H ⁇ )2; CH2OH; CH(OH)CH3; CH(OH)CH2CH2; CHO; COCH3; COOH; COOCH3; CH2NHCOOC(CH3)3; (CH2)2NHCOOC(CH3)3; NHSO2CH(CH3)2; a group of formula (CH2)2NHSO2R 15 in which R 15 represents CH3, CH2CH3, CH(CH3)2, (CH2)2CH3, (CH3)3CH3, benzyl, CH2CF3, 2-methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl, 2-fluorophenyl, 4-fluorophenyl, 2-trifluoromethylphenyl, 4- trifluoromethylphenyl, 4-methoxyphenyl, 1-(
  • R14 j s preferably an unsubstituted or substituted phenyl, naphthyl, furyl, thienyl, isoxazolyl, thiazolyl, tetrazolyl, pyridyl, pyrimidyl benzothienyl or benzothiazolyl group.
  • Examples of particular values in formula I for R14 are phenyl, 2- fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chloro-phenyl, 3-chlorophenyl, 4- chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 2,3- difluoro-phenyl, 2,4-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 4- cyanophenyl, 3-nitrophenyl, 4-hydroxyiminophenyl, 2-methylphenyl, 4- methylphenyl, 4-ethyl phenyl, 3-propylphenyl, 4-t-butylphenyl, 2-prop-2- enylphenyl, 4-(4-(1 ,1-dioxotetrahydro-1 ,2-thiazinyl)phenyl, 2- tri
  • Examples of an unsubstituted or substituted aromatic or heteroaromatic group represented by R ⁇ are unsubstituted or substituted phenyl, furyl, thienyl (such as 3-thienyl) and pyridyl (such as 3-pyridyl) .
  • R ⁇ preferably represents a naphthyl group or a phenyl, furyl, 20 thienyl or pyridyl group which is unsubstituted or substituted by one or two substituents selected independently from halogen; nitro; cyano; hydroxyimino; (1- 10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; hydroxy(3-
  • CONR 1 1 , NR1 2 C0, NR 12 COCOO, OCONR13, R9 represents hydrogen, (1- 10C)alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolindinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and Rl0> R ⁇ > R ⁇ 2 and R13 each independently represents hydrogen or (1-10C)alkyl, or R 9 and R ⁇ °> R ⁇ .
  • R ⁇ 2 or R 13 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, 30 piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1-
  • CH CH
  • L a and L D each represent (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and R14 represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, nitro, cyano, hydroxyimino, (1-10C)alkyl, (2-10C)alkenyl, (2-10C)alkynyl, (3-8C)cycloalkyl, 4-(1 ,1- dioxotetrahydro-1 ,2-thiazinyl), halo(1-10C)alkyl, cyano(2-10C)alkenyl, phenyl, and (CH2)z* 3 R ⁇ in which z is 0 or an integer of from 1 to 4, X 3 represents O, S, NR 16 , CO, CH(OH), COO, OCO, CONR17, NR 18 CO, NHSO2, NHSO2NR17, NHCONH, OCONR
  • R 1 , R 8 and R1 9 each independently represents hydrogen or (1-10C)alkyl, or R ⁇ and R16, R 1 ?,
  • R18 or R1 9 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group. More preferably in formula I, R ⁇ represents 2-naphthyl or a group of formula in which
  • R 2 ⁇ represents halogen; nitro; cyano; hydroxyimino; (1- 10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cyclo-alkyl; hydroxy(3- 8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1 -10C)alkyl; (CH2)yX 1 R 9 in which y is 0 or an integer of from 1 to 4, X 1 represents O, S, NR 10 , CO, COO, OCO,
  • R 9 represents hydrogen, (1- 10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R10> R1 1 » R1 2 and R13 each independently represents hydrogen or (1-10C)alkyl, or R 9 and R10> R 1 1 .
  • R ⁇ 2 or R ⁇ 3 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1- 4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; tetrazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (1-4C)alkoxycarbonyl- dihydrothiazolyl; (1-4C)alkoxycarbonyldimethyl-dihydrothiazolyl; tetrahydrothienyl; tetrahydrofu
  • R 5 represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, (1- 10C)haloalkyl, (1 -4C)alkoxycarbonyl(1 -4C)alkyl, (1 -4C)alkylsulfonylamino(1 - 4C)alkyl, (N-(1 -4C)alkoxycarbonyl)(1 -4C)alkylsulfonylamino(1 -4C)alkyl, (3- 10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, (1-4C)haloalkyl, di(1-4C)alkylamino and (1-4C)alkoxy, and R " ! 6, R1 ⁇ R18 and R ⁇ each independently represents hydrogen or (1 -
  • R 2 ⁇ represents a hydrogen atom, a halogen atom, a (1- 4C)alkyl group or a (1-4C)alkoxy group.
  • Examples of particular values in formula I for R 2 ⁇ are fluorine, chlorine, bromine, cyano, hydroxyimino, methyl, ethyl, propyl, 2-propyl, butyl, 2- methylpropyl, 1 ,1-dimethylethyl, cyclopentyl, cyclohexyl, 3-hydroxycyclopentyl, 3- oxocyclopentyl, methoxy, ethoxy, propoxy, 2-propoxy, acetyl, acetylamino, ethylcarboxamido, propylcarboxamido, 1 -butanoylamido, t-butylcarboxamido, acryloylamido, 2-pyrrolidinylcarboxamido, 2-tetrahydrofurylmethoxy, morpholinocarboxamido, methyloxalylamido, cyclo-propylcarboxamido, cyclobutylcar
  • hydroxyethyl)phenyl 4-(1-hydroxypropyl)phenyl, 2-aminophenyl, 4-aminophenyl, 4-N,N-diethylaminophenyl, 4-aminomethylphenyl, 4-(2-aminoethyl)-phenyl, 4-(3- aminopropyl)phenyl, 4-(2-acetylaminoethyl)-phenyl, 4-t- butoxycarboxylaminoethyl)phenyl, 4-(2-t-butoxycarboxylaminoethyl)phenyl, benzylsulfonylamino, 4-isopropylsulfonylaminophenyl, 4-(2-methanesulfonyl- aminoethyl)phenyl, 4-(2-ethylsulfonylaminoethyl)phenyl, 4-(2- propylsulfonylaminoethyl)phenyl,
  • R ⁇ examples of particular values in formula I for R ⁇ are hydrogen and chlorine.
  • R 2 ⁇ is preferably ortho to R 2( .
  • Examples of particular values in formula I for R1 are 2-naphthyl, 4- bromophenyl, 4-cyanophenyl, 4-benzamidophenyl, 4-methylphenyl, 4-isopropyl- phenyl, 4-isobutylphenyl, 4-f-butyl phenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-cyclopentylphenyl, 4-cyclohexylphenyl, 4-(2-hydroxymethylphenyl)phenyl, 4-(4- hydroxymethylphenyl)-phenyl, 4-(2-furyl)phenyl, 4-(3-furyl)phenyl, 4-(2-thienyl)- phenyl, 4-(3-thienyl)phenyl, 4-(p " yrrolidin-1-yl)phenyl, 4-(piperidin-l-yl)phenyl, 3- chloro-4-piperidin-1-ylphenyl, 4-benzyl
  • A represents SO 2 , or CONH
  • R a represents (1-6C)alkyl, (2-6C)alkenyl, -(1-4C)alkyl(3-8C)cycloalkyl, or
  • R b represents H, (1-6C)alkyl, (2-6C)alkenyl, -(1-4C)alkyl(3-8C)cycloalkyl, or
  • R 1 represents an unsubstituted or substituted aromatic group, an unsubstituted or substituted heteroaromatic group, or an unsubstituted or substituted (5-
  • R 2 represents (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)fluoroalkyl, (1-6C)chloroalkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or when A represents SO 2 , a group of formula R 3 R 4 N in which R 3 and R 4 each independently represents (1- 4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; or a pharmaceutically acceptable salt thereof as disclosed in International Patent Application WO 00/66546 published November 9, 2000 including the preferred and specific compounds disclosed therein.
  • aromatic group means the same as aryl, and includes phenyl and a polycyclic aromatic carbocyclic ring such as 1- or 2-naphthyl, 1 ,2-dihydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, and the like. Phenyl is the preferred aromatic group.
  • heteromatic group in formula II includes an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a bicyclic group consisting of a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or another 5-6 membered ring containing one 0 to four atoms selected from oxygen, sulfur and nitrogen.
  • heteroaromatic groups are thienyl, furyl, oxazolyl, isoxazolyl, oxadiazoyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, and quinolyl.
  • substituted as used in the term “substituted aromatic or heteroaromatic group” in formula II herein signifies that one or more (for example one or two) substituents may be present, said substituents being selected from atoms and groups which, when present in the compound of formula I, do not prevent the compound of formula II from functioning as a potentiator of glutamate o receptor function .
  • R 1 represents an unsubstituted or substituted (5-8C)cycloalkyl group
  • mixtures of cis and trans isomers may result which can be separated into the individual cis and trans isomers by one of ordinary skill in the art, using standard techniques and procedures such as 5 reverse phase or normal phase high performance liquid chromatography or flash chromatography, with a suitable stationary phase and a suitable eluent.
  • suitable stationary phases are silica gel, alumina, and the like.
  • suitable eluents are ethyl acetate/hexane, ethyl acetate/toluene, methanol/dichloromethane, and the like.
  • Such individual cis and trans isomers o are included within the scope of the present invention.
  • substituents which may be present in a substituted aromatic, heteroaromatic group or (5-8C)cycloalkyl group include halogen; nitro; cyano; hydroxyimino; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; ha!o(1-10C)alkyl; (CH2)yX 1 R 9 in which y is 0 or an integer of from 1 to 4, X 1 represents O, S, NR 10 , CO, COO,
  • R 9 represents hydrogen, (1-10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R10, R11 , R12 an( R13 ea ch independently represents hydrogen or (1-10C)alkyl, or R 9 and R " 10» R1 ⁇ R ⁇ 2 or R ⁇ 3 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1- 4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazo
  • CH CH, l_ a and L D each represent (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and R14 represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen; nitro; cyano; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; 4-(1 ,1 -dioxotetrahydro-1 ,2- thiazinyl); halo(1-10C)alkyl; cyano(2-10C)alkenyl; phenyl; and (CH2)zX 3 R 15 in which z is 0 or an integer of from 1 to 4, X 3 represents O, S, NR 16 , CO, CH(OH),
  • R 5 represents hydrogen, (MOC)alkyl, phenyl(1-4C)alkyl, halo(1- 10C)aIkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl, N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl, (3-10C)alkenyl, (3- 10C)alkynyl, (3-8C)cycloalkyl, camphoryl, or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)alkoxy, and R 16 , R 17 , R 18 and R1 9 each independently represents hydrogen or (1 -10C)alkyl, or R ⁇
  • R a in formula II is methyl, ethyl, propyl, n-butyl, sec-butyl, pentyl, and hexyl with methyl being most preferred.
  • R D in formula II is hydrogen, methyl, ethyl, propyl, n-butyl, sec- butyl, pentyl, and hexyl, with hydrogen being most preferred.
  • R 3 and R4 in formula II each represent methyl.
  • R 2 in formula II examples include methyl, ethyl, propyl, 2-propyl, butyl, 2-methyl propyl, cyclohexyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloromethyl, ethenyl, prop-2-enyl, methoxyethyl, phenyl, 4-fluorophenyl, or dimethylamino.
  • R 2 is ethyl, 2-propyl or dimethylamino with 2-propyl being most preferred.
  • R 9 in formula II examples include hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • R 9 is preferably (1-4C)alkyl, (2- 4C)alkenyl, (3-6C)cycloalkyl, pyrrolidinyl, morpholino or tetrahydrofuryl.
  • R15 jn formula II examples include hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, benzyl, 2,2,2-trifluoroethyl, 2- methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl, 2-fluorophenyl, 3- fluorophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 1-(5-dimethylamino)naphthyl, and 2-thienyl.
  • X 1 preferably represents O, CO, CONH or NHCO in formula II.
  • z is preferably 0 in formula II.
  • formula II particular values for the groups (CH2)yX ' ' R 9 and
  • (CH2) Z X 3 R 15 include (1-10C)alkoxy, including (1-6C)alkoxy and (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy and isobutoxy; (3-10C)alkenyloxy, including (3-6C)alkenyloxy, such as prop-2-enyloxy; (3-10C)alkynyloxy, including (3-6C)alkynyloxy, such as prop-2-ynyloxy; and (1-6C)alkanoyl, such as formyl and ethanoyl.
  • L a and l_ D preferably each independently represents CH2-
  • X 2 preferably represents a bond, O, NH, CO, CH(OH), CONH, NHCONH or OCH2CONH, with a bond, O, and CONH being especially preferred.
  • R 9 represents methyl, ethyl, isopropyl, t- butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyrolidinyl or morpholino; CONHR 9 in which R 9 represents cyclopropyl or cyclopentyl; NHCOCOOCH3; or 2-tetrahydrofurylmethoxy.
  • the group (CH2)zX 3 R ⁇ in formula II represents NH2; CH2NH2; (CH2)2NH2! (CH2)3NH2; CONH2; CONHCH3; CON(CH3)2; N(C2H5)2! CH2OH; CH(OH)CH3; CH(OH)CH2CH2; CHO; COCH3; COOH; COOCH3; CH2NHCOOC(CH3)3; (CH2)2NHCOOC(CH3)3; SO2NH2; NHSO2CH3; NHSO2CH(CH3)2; a group of formula (CH2)2NHSO2R 15 in which
  • R 15 represents CH3, CH2CH3, CH(CH3)2, (CH2)2CH3, (CH3)3CH3.
  • R1 jn formula II is preferably an unsubstituted or substituted phenyl, naphthyl, furyl, thienyl, isoxazolyl, thiazolyl, tetrazolyl, pyridyl, pyrimidyl benzothienyl or benzothiazolyl group.
  • R14 j n formula II examples of particular values for R14 j n formula II are phenyl, 2- fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chloro-phenyl, 3-chlorophenyl, 4- chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 2,3- difluoro-phenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 3,4-dichlorophenyl, 3,5- dichlorophenyl, 4-cyanophenyl, 3-nitrophenyl, 4-hydroxyiminophenyl, 2- methylphenyl, 4-methylphenyl, 4-ethylphenyl, 3-propylphenyl, 4-t-butylphenyl, 2- prop-2-enylphenyl, 4-(4-(1 ,1-dioxotetra
  • Examples of an unsubstituted or substituted aromatic or heteroaromatic group represented by R1 in formula II are unsubstituted or substituted phenyl, furyl, thienyl (such as 3-thienyl) and pyridyl (such as 3-pyridyl).
  • Examples of an unsubstituted or substituted (5-8C)cycloalkyl group represented by R1 are unsubstituted or substituted cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, with cyclohexyl being preferred.
  • R ⁇ represents 2-naphthyl or a group of formula
  • R 2 ⁇ represents halogen; nitro; cyano; hydroxyimino; (1- 10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cyclo-alkyl; hydroxy(3-
  • R 9 represents hydrogen, (1- 10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R ⁇ 0> R ⁇ ⁇ R ⁇ 2 and R ⁇ 3 each independently represents hydrogen or (1-10C)alkyl, or R 9 and R 10 > R11 > R ⁇ 2 or R 13 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1- 4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; tetra
  • R 5 represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1- 10C)alkyl, (1 -4C)alkoxycarbonyl(1 -4C)alkyl, (1 -4C)alkylsulfonylamino(1 -4C)alkyl, (N-(1 -4C)alkoxycarbonyl)(1 -4C)alkylsulfonylamino(1 -4C)alkyl, (3-10C)alkenyl, (3- 10C)alkynyl, (3-8C)cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)alkoxy, and R 16 , R 17 , R 18 and R ⁇ each independently represents hydrogen or (1-10C)alkyl
  • R 2 ⁇ represents a hydrogen atom, a halogen atom, a (1- 4C)alkyl group or a (1-4C)alkoxy group.
  • R 2 ⁇ in formula II examples include fluorine, chlorine, bromine, cyano, hydroxyimino, methyl, ethyl, propyl, 2-propyl, butyl, 2- methylpropyl, 1 ,1-dimethylethyl, cyclopentyl, cyclohexyl, 3-hydroxycyclopentyl, 3- oxocyclopentyl, methoxy, ethoxy, propoxy, 2-propoxy, acetyl, acetylamino, ethylcarboxamido, propylcarboxamido, 1 -butanoylamido, t-butylcarboxamido, acryloylamido, 2-pyrrolidinylcarboxamido, 2-tetrahydrofurylmethoxy, morpholinocarboxamido, methyloxalylamido, cyclo-propylcarboxamido, cyclobutylcarbox
  • Ri in formula II examples of particular values for Ri in formula II are 2-naphthyl, 4- bromophenyl, 4-cyanophenyl, 4-benzamidophenyl, 4-methyIphenyl, 4-isopropyI- phenyl, 4-isobutylphenyl, 4-f-butylphenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-cyclopentylphenyl, 4-cyclohexylphenyl, 4-(2-hydroxymethylphenyl)phenyl, 4-(4- hydroxymethylphenyl)-phenyl, 4-(2-furyl)phenyl, 4-(3-furyl)phenyl, 4-(2-thienyl)- phenyl, 4-(3-thienyl)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(piperidin-l-yl)phenyl, 3- chloro-4-piperidin-1-ylphenyl, 4-benzy
  • R 4 represents (1-6C)alkyl, (2-6C)alkenyl, or NR 8 R 9 ;
  • R 5 represents (1-6C)alkyl, CF 3 , or phenyl which is unsubstituted or substituted by one, two, or three substituents selected from the group consisting of halogen,
  • R 6 represents (1 -4C)alkyl or phenyl
  • R 7 represents hydrogen or (1-4C)alkyl
  • R 8 and R 9 each independently represent hydrogen or
  • R 10 and R 11 each independently represent hydrogen or (1-4C)alkyl; and n is O, 1 , 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
  • step A the cyclopentene of structure (1) is converted to the borane of structure (2) under standard conditions.
  • cyclopentene (1 ) is dissolved in a suitable organic solvent, such as dry methylene chloride under an atmosphere of nitrogen and cooled to about 0°C
  • a suitable organic solvent such as dry methylene chloride under an atmosphere of nitrogen and cooled to about 0°C
  • the solution is treated with about 0.5 equivalents of monochloroborane-methyl sulfide.
  • the reaction mixture is allowed to warm to room temperature and stirred for about 8 to 16 hours.
  • the solvent is removed under vacuum under a nitrogen atmosphere to provide borane (2).
  • step B borane (2) is methylated to provide the methylborane of structure (3).
  • a suitable organic solvent such as dry hexanes under an atmosphere of nitrogen.
  • the solution is cooled to about 0°C and treated with about 0.3 equivalents of trimethylaluminum in hexanes.
  • the reaction mixture is allowed to warm to room temperature and stirred for about 1.5 hours.
  • a precipitate results and the supernatant is transferred via cannula to a nitrogen flushed separatory funnel containing saturated aqueous ammonium chloride.
  • the organic phase is then transferred via cannula to a flask containing anhydrous sodium sulfate.
  • the organic solution is then transferred via cannula to a dry, nitrogen flushed flask and the solvent is removed under vacuum in the presence of a nitrogen atmosphere to provide the methylated borane (3).
  • step C the methylated borane (3) is hydrolyzed to the trans- cyclopentylamine of structure (4).
  • methylated borane (3) is dissolved in a suitable organic solvent, such as dry tetrahydrofuran and cautiously treated in small portions with a slight excess of hydroxylamine-O- sulfonic acid (referred to herein as "HAS") dissolved in tetrahydrofuran.
  • HAS hydroxylamine-O- sulfonic acid
  • the mixture is stirred at room temperature for about 30 minutes.
  • the layers are separated, the organic phase is washed with water and the water wash is combined with the aqueous phase.
  • the aqueous phase is cooled to about 0°C, diethyl ether is added and the aqueous is made basic with sodium hydroxide.
  • the organic phase is separated and the aqueous phase is extracted with diethyl ether and ethyl acetate.
  • the organic phase and organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the cyclopentylamine (4).
  • step D the cyclopentene of structure (1) is nitrated under standard conditions to provide the compound of structure (5).
  • step E the nitrated compound of structure (5) is reduced under standard conditions to provide the amine of structure (6).
  • compound (5) is dissolved in a suitable organic solvent, such as ethanol, treated with a suitable hydrogenation catalyst, such as palladium on carbon, the solution is placed under hydrogen at about 413.69 kPa (60 psi). After about 8 to 16 hours, the reaction mixture is filtered and the filtrate is concentrated under vacuum to provide the compound (6).
  • the compound of structure (6) can be prepared by the alternative procedures set forth in Schemes IA and IB below.
  • the reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.
  • step A the cyclopentanone of structure (7) is converted to the corresponding oxime of structure (8) under conditions well known in the art.
  • cyclopentanone (7) is dissolved in a suitable organic solvent, such as ethanol, treated with about 2 equivalents of aqueous sodium hydroxide and about 1.5 equivalents of hydroxylamine hydrochloride.
  • the reaction mixture is stirred for about 8 to 16 hours at room temperature. It is then diluted with water and the precipitated oxime (8) is collected by filtration and dried under vacuum at about 35°C
  • step B oxime (8) is hydrogenated under standard conditions to provide the amine of structure (6).
  • oxime (8) is dissolved in a suitable organic solvent, such as ethanol, treated with a suitable catalyst, such as palladium on carbon, and placed under hydrogen at about 413.69 kPa (60 psi).
  • the hydrogenation is carried out at about 40°C for about 8 to 16 hours.
  • the reaction mixture is then filtered and the filtrate concentrated under vacuum to provide the amine (8).
  • step A the epoxide (9) is coupled with the Grignard reagent to provide the alcohol (11 ).
  • Grignard (10) is dissolved in a suitable organic solvent, such as tetrahydrofuran and treated with a catalytic amount of copper iodide.
  • a suitable organic solvent such as tetrahydrofuran
  • copper iodide copper iodide
  • To this solution is slowly added the epoxide (9) dissolved in tetrahydrofuran.
  • the reaction is exothermic.
  • the reaction is stirred until the temperature reaches room temperature and it is quenched with aqueous ammonium chloride.
  • the quenched reaction is extracted with a suitable organic solvent, such as diethyl ether.
  • the organic extracts are combined, washed with aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide alcohol (11 ).
  • step B alcohol (11) is converted to the compound of structure (12) under standard conditions well known in the art.
  • a suitable organic solvent such as tetrahydrofuran.
  • the solution is cooled to about 0°C and a solution of about one equivalent of diisopropyl azodicarboxylate in tetrahydrofuran is added dropwise to the solution with stirring.
  • reaction mixture is added about one equivalent of phthalimide followed by addition of about one equivalent of alcohol (11) dissolved in tetrahydrofuran maintaining the temperature between about 5°C and 0°C
  • alcohol (11) dissolved in tetrahydrofuran maintaining the temperature between about 5°C and 0°C
  • the reaction is then stirred at about 0°C for about 4 hours, warmed to room temperature, and stirred for 4 to 12 hours.
  • the reaction is then quenched with water and extracted with a suitable organic solvent, such as chloroform.
  • the organic extracts are combined, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide compound (12).
  • step C compound (12) is converted to compound (6) in an exchange reaction well known in the art.
  • compound (12) is dissolved in a suitable organic solvent, such as toluene, and an excess of anhydrous hydrazine is added dropwise over about 15 minutes with stirring.
  • the reaction mixture is stirred for about one hour at room temperature and then heated at about 90-95°C for about 6 hours.
  • the reaction mixture is then cooled to room temperature, filtered, the precipitate rinsed with toluene, the filtrates combined, concentrated under vacuum to provide compound (6).
  • step D compound (11 ) oxidized to the ketone of structure (7) under standard conditions well known in the art.
  • compound (11) is added dropwise to a suspension of an excess of pyridinium chlorochromate in a suitable organic solvent, such as methylene chloride. The reaction is stirred for about 8 to 48 hours at room temperature.
  • step E compound (11) is subjected to Mitsunobu conditions to provide the cis-benzoate derivative. More specifically, compound (11) is dissolved in a suitable organic solvent, such as THF and combined with about 1.05 equivalents of diethyl azodicarboxylate (referred to herein as "DEAD"), about 1.2 equivalents of benzoic acid and about 1.2 equivalents of triphenylphosphine at about 0°C The reaction is stirred for about 2 hours, allowed to warm to room temperature and then concentrated under vacuum. The crude residue can be purified by chromatography on silica gel with a suitable eluent, such as hexanes/methylene chloride to provide the cis-benzoate derivative.
  • a suitable organic solvent such as THF
  • step F the cis-benzoate is hydrolyzed under standard conditions to provide the cis-alcohol.
  • the cis-benzoate is combined with 5% NaOH/methanol and stirred at room temperature for about 3 hours.
  • the reaction mixture is then concentrated under vacuum, the residue dissolved in a suitable organic solvent, such as diethyl ether, which is washed with water.
  • the organic phase is then dried over potassium carbonate, filtered, and concentrated under vacuum.
  • the residue can be purified by chromatography on silica gel with a suitable eluent, such as hexanes/methylene chloride to provide the cis-alcohol.
  • step G the cis-alcohol is converted to the phthalimide derivative in a manner analogous to the procedure described above in Scheme IB, step B.
  • step H the phthalimide derivative is converted to the trans- amine (4) in a manner analogous to the procedure described above in Scheme IB, step C
  • the compound (11) is subjected to an enzymatic resolution to provide the unreacted optically active alcohol (11a) and the optically active acetate (11 b).
  • a suitable organic solvent such as tert-butyl methyl ether
  • a suitable enzyme such as Candida antartctica B lipase.
  • Y represents Br or I.
  • step A compound (4) or (6) is sulfonylated with sulfonyl chloride (13) under conditions well known in the art to provide the sulfonamide of formula (Ilia).
  • compound (4) or (6) is dissolved in a suitable organic solvent, such as methylene chloride and cooled to about 0°C under an atmosphere of nitrogen.
  • a suitable organic solvent such as methylene chloride
  • DBU and sulfonyl chloride (9) may optionally be added in equivalent amounts as necessary in order to drive the reaction to completion.
  • the reaction may be stirred for an additional 8 to 48 hours after additional amounts of DBU and sulfonyl chloride (13) are added.
  • the reaction mixture is then diluted with a suitable organic solvent, such as methylene chloride and washed with 1 N HCI.
  • the organic phase is dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude compound of formula III.
  • This crude material can be purified by standard techniques, such as flash chromatography or radial chromatography on silica gel with a suitable eluent, such as methylene chloride/ethyl acetate.
  • step B the compound of formula III wherein R 1 , R 2 and R 3 represent hydrogen, can be converted to the compound of formula Ilia wherein Y represents iodine.
  • compound of formula III is dissolved in a suitable solvent, such as glacial acetic acid.
  • a suitable solvent such as glacial acetic acid.
  • concentrated sulfuric acid followed by about 0.5 equivalents of iodine and about 0.4 equivalents of diiodine pentoxide.
  • the reaction mixture is protected from light and heated at about 90°C for about 22 hours.
  • the reaction mixture is then treated slowly with 10% aqueous sodium bisulfite, cooled to 0°C for about one hour and the precipitate collected by filtration.
  • R 1 , R 2 or R 3 may represent Br in Scheme II, step A.
  • the reaction is conveniently performed in the presence of a tetrakis (triarylphosphine)palladium(O) catalyst, such as tetrakis (triphenylphosphine)palladium(O) and a base such as potassium carbonate.
  • Suitable solvents for the reaction include aromatic hydrocarbons, such as toluene.
  • the temperature at which the reaction is conducted is conveniently in the range of from 0 to 150°C, preferably 75 to 120°C.
  • the coupling reaction may be carried out using palladium diacetate with a suitable organic solvent, such as n-propanol or acetone.
  • the boronic acid (14) used as a starting material may be prepared by reacting a trialkyl borate, such as triisopropyl borate with an appropriate organolithium compound at reduced temperature.
  • a trialkyl borate such as triisopropyl borate
  • 2-fluoro- benzeneboronic acid may be prepared by reacting 2-fluorobromobenzene with butyllithium in tetrahydrofuran at about -78°C to afford 2-fluorophenyl lithium, and then reacting this organolithium compound with triisopropyl borate. This is followed by hydrolysis with aqueous HCI.
  • compounds of formula 1Mb can be prepared under Suzuki-type reaction conditions as appreciated by one of ordinary skill in the art, from a compound of formula Ilia" and a compound of structure (14b).
  • a compound of formula Ilia is dissolved in a suitable organic solvent, such as DMSO and treated with about 3 equivalents of potassium acetate.
  • the reaction mixture is degassed and treated with about 1.1 equivalents of bis(pinacolato)diboron followed by addition of a catalytic amount of a suitable palladium catalyst, such as [1 ,1'-bis(diphenylphosphino)-ferrocene] dichloropalladium (II), complex with dichloromethane 1 :1.
  • a suitable palladium catalyst such as [1 ,1'-bis(diphenylphosphino)-ferrocene] dichloropalladium (II), complex with dichloromethane 1 :1.
  • reaction mixture is then heated at about 80°C under nitrogen with stirring for about 1 to about 4 hours.
  • the reaction mixture is then cooled to room temperature and about one equivalent of the compound (14b) is added followed by addition of about 3 equivalents of sodium carbonate, water, and a catalytic amount of a suitable palladium catalyst, such as [1 ,1'-bis(diphenylphosphino)-ferrocene] dichloropalladium (II), complex with dichloromethane 1 :1.
  • a suitable palladium catalyst such as [1 ,1'-bis(diphenylphosphino)-ferrocene] dichloropalladium (II), complex with dichloromethane 1 :1.
  • the reaction mixture is then heat at about 105°C for about 10 to about 20 hours. It is then allowed to cool and is diluted with a suitable organic solvent, such as methylene chloride.
  • step A compound of formula 1Mb' wherein R 10 and R 12 each independently represent hydrogen, halogen, CF 3 , (1-6C)alkyl, or (1-6C)alkoxy and m is 0, 1 , 2, or 3, is reduced under conditions well known in the art to provide the amine of formula lllc.
  • compound of formula lb' is dissolved in a suitable organic solvent, such as dry tetrahydrofuran and treated with a suitable reducing agent, such as borane dimethyl sulfide. The reaction is heated at reflux for about 4 hours and then concentrated under vacuum. The residue is treated with diethyl ether:concentrated HCI:water:methanol (6:3:2:1 )and stirred for about 30 minutes.
  • the aqueous layer is then separated and the organic layer washed with water.
  • the aqueous phases are combined, cooled to about 0°C, made basic with a suitable base, such as sodium hydroxide, and extracted with a suitable organic solvent, such as diethyl ether or ethyl acetate.
  • a suitable base such as sodium hydroxide
  • a suitable organic solvent such as diethyl ether or ethyl acetate.
  • the organic extracts are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the amine of formula lllc.
  • step B the amine of formula lllc is converted to the amide of formula Hid under standard coupling conditions as is well known in the art of peptide chemistry.
  • a suitable organic solvent such as dry methylene chloride.
  • a suitable organic base such as triethylamine is added followed by addition of about one equivalent of acetyl chloride.
  • the reaction is stirred at room temperature for about 8 to 72 hours and then concentrated under vacuum to provide the crude amide of formula Hid.
  • This crude material is then purified by standard techniques, such as flash chromatography or radial chromatography on silica gel with a suitable eluent, such as methylene chloride:methanol.
  • step C the amine of formula lllc is readily converted to the sulfonamide of formula Hie under standard conditions well known in the art, for example in a manner analogous to the procedure previously described in Scheme II, step A.
  • the compounds of formulas lllg, lllh, lllj and lllk can be prepared following the procedures set forth in Scheme IV below.
  • the reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.
  • step A the compound of formula lllf, wherein R 1 and R 3 each independently represent hydrogen, halogen, CF 3 , (1-6C)alkyl, or (1- 6C)alkoxy, is nitrated under standard conditions to provide the nitro compound of formula lllg.
  • compound of formula lllf is dissolved in a suitable acid, such as trifluoroacetic acid and an excess of sodium nitrate is added. The reaction mixture is stirred for about 5 hours at room temperature.
  • step B the compound of formula lllg is reduced to the amine of formula lllh under conditions well known in the art.
  • the compound of formula lllg is dissolved in a suitable organic solvent, such as ethanol, treated with a suitable hydrogenation catalyst, such as palladium on carbon and placed under hydrogen at about 413.69 kPa (60 psi).
  • a suitable hydrogenation catalyst such as palladium on carbon
  • the reaction mixture is hydrogenated at room temperature for about 4 to 12 hours, filtered, and concentrated under vacuum to provide the amine of formula lllh.
  • step C the amine of formula lllh is converted to the amide of formula lllj under standard coupling conditions as is well known in the art of peptide chemistry in a manner analogous to the procedure previously described in Scheme III, step B.
  • step D the amine of formula lllh is converted to the sulfonamide of formula lllk under standard conditions well known in the art, for example in a manner analogous to the procedure previously described in Scheme II, step A.
  • step A the compound of formula Ilia' is converted to the compound of formula lllm under standard conditions.
  • compound of formula Ilia' is dissolved in a suitable organic solvent, such as DMF. It is then treated with an excess of ethyl acrylate and an excess of a suitable organic base, such as triethylamine followed by a catalytic amount of palladium acetate and triphenylphosphine. The reaction is then heated at about 80°C under nitrogen for about 8 to 16 hours. The reaction is then allowed to cool and diluted with 75 mL of 10% aqueous sodium bisulfate.
  • the quenched reaction mixture is then extracted with a suitable organic solvent, such as methylene chloride, the organic extracts dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the compound of formula lllm.
  • a suitable organic solvent such as methylene chloride
  • the crude product can be purified by radial chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride.
  • step B the compound of formula lllm is reduced under conditions well known in the art to provide the compound of formula llln.
  • the compound of formula lllm is placed in a Parr bottle and dissolved in a suitable organic solvent, such as ethyl acetate. It is treated with a catalytic amount of 10% palladium on carbon and the mixture is placed under hydrogen at about 275.80 kPa (40 psi) to about 413.69 kPa (60 psi) for about 4 to 16 hours at room temperature.
  • the reaction is then filtered through diatomaceous earth and the filtrate is concentrated under vacuum to provide the compound of formula llln.
  • This material can be further purified, if necessary, for example by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexanes.
  • step C the compound of formula llln is hydrolyzed to the acid of formula lllp under standard conditions.
  • a suitable organic solvent such as methanol with water added.
  • the solution is treated with a suitable base, such as sodium hydroxide and the reaction is allowed to stir for about one to two days.
  • the reaction mixture is then washed with a suitable organic solvent, such as ethyl acetate.
  • the aqueous is cooled with an ice-water bath and made acidic with concentrated HCI.
  • step D the acid of formula lllp is converted to the carbamate of formula II Iq under standard conditions.
  • the acid of formula lllp is dissolved in a suitable organic solvent, such as benzene and is treated with one equivalent of diphenylphosphoryl azide and one equivalent of triethylamine under nitrogen. The reaction is heated at reflux for about 4 hours, cooled to room temperature and stirred for about 8 to 16 hours.
  • step E the carbamate of formula lllq is deprotected under conditions well known in the art such as those conditions described by T.W. Green "Protective Groups in Organic Synthesis,” John Wiley & Sons, 1981 , pages 239-241 , to provide the amine of formula lllr.
  • the carbamate of formula lllq is dissolved in a suitable organic solvent, such as methylene chloride and treated with trifluoroacetic acid. The reaction mixture is allowed to stir at room temperature for about 4 to 16 hours and then the solution is made basic with 2N sodium hydroxide.
  • reaction mixture is then extracted with a suitable organic solvent, such as ethyl acetate, the organic extracts are combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the amine of formula Ir.
  • a suitable organic solvent such as ethyl acetate
  • This material may be further purified by radial chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride.
  • a suitable eluent such as methanol/methylene chloride.
  • the carbamate of formula lllq may be deprotected using hydrogenation conditions well known in the art to provide the amine of formula lllr.
  • step F the amine of formula lllr is converted to the sulfonamide of formula lilt under standard conditions well known in the art, for example, in a manner analogous to the procedure described in Scheme II, step A above.
  • substituent R 4 in formula III compounds wherein R 4 is methyl, ethyl, n-propyl and isopropyl are preferred, with 2-propyl being especially preferred.
  • substituent R 2 in formula III compounds wherein R 2 is hydrogen, fluoro, chloro, bromo, iodo, amino, nitro, -NHSO 2 CH 3 , and (1-6C)alkyl are preferred.
  • substituent R 3 in formula III compounds wherein R 3 is hydrogen, fluoro, chloro, bromo, iodo, amino, nitro, -NHSO 2 CH 3 , and (1-6C)alkyl are preferred.
  • R 1 , R 2 , and R 3 in forumla III compounds wherein R 1 is hydrogen and R 2 and R 3 are fluoro are preferred, and compounds wherein R 1 and R 2 are hydrogen and R 3 is (1-6C)alkyl, amino, nitro, -NHSO 2 CH 3 , fluoro, chloro, bromo and iodo are especially preferred.
  • R 10 , R 10' , R 11 , R 11> , R 12 , and R 12' in formula II compounds wherein R 10 , R 10 , R 12 , and R 12 are hydrogen and R 11 are - NHC( O)R 5 , -NHSO 2 R 5 , -CH 2 NHSO 2 R 5 , -CH 2 CH 2 NHSO 2 R 5 are preferred.
  • R 1 represents an unsubstituted or substituted aromatic group, or an unsubstituted or substituted heteroaromatic group
  • R 2 represents (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl,
  • R 5 represents hydrogen, (1-6C)alkyl; (2-6C)alkenyl; or aryl; and R 6 represents hydrogen, (1-6C)alkyl; (2-6C)alkenyl; or aryl; or a pharmaceutically acceptable salt thereof but excluding the compound
  • step A the compound of structure (15) is O-alkylated with the compound of structure (16).
  • compound (15) is dissolved in a suitable organic solvent, such as N,N-dimethylformamide and added to about 1.0 to about 1.1 equivalents of a suitable base, such as sodium hydride in N,N-dimethylformamide.
  • a suitable organic solvent such as N,N-dimethylformamide
  • a suitable base such as sodium hydride in N,N-dimethylformamide.
  • the reaction mixture is stirred for about 30 minutes to about 2 hours and about one equivalent of compound (16), wherein Hal represents Br or CI and R represents H or (1-10C)alkyl, dissolved in N,N-dimethylformamide is added dropwise to the reaction mixture. This is followed by addition of about 1.2 equivalents of sodium iodide.
  • ether (17) is then isolated and purified by techniques well known in the art, such as extraction techniques and chromatography.
  • the cooled reaction mixture is diluted with water and extracted with a suitable organic solvent, such as ethyl acetate.
  • a suitable organic solvent such as ethyl acetate.
  • the organic extracts are combined, washed with water, dried over potassium carbonate, filtered, and concentrated under vacuum to provide the crude ether (17).
  • This crude material is then purified by silica gel chromatography with a suitable eluent, such as hexane/ethyl acetate (1 :1) to provide the purified ether (17).
  • step B ether (17) is converted to the amide of structure
  • ether (17) is combined with an excess of ammonia (2M solution of ammonia in methanol for example) in a suitable organic solvent, such as tetrahydrofuran and the reaction mixture is stirred for about 24 to about 48 hours at room temperature. The reaction mixture is then concentrated under vacuum to provide the amide (18).
  • a suitable organic solvent such as tetrahydrofuran
  • step C the amide (18) is reduced under conditions well known in the art to provide the amine of structure (19).
  • amide (18) is dissolved in a suitable organic solvent, such as tetrahyrofuran and treated with about 1 equivalent of a suitable reducing agent, such as borane-methyl sulfide complex.
  • a suitable organic solvent such as tetrahyrofuran
  • a suitable reducing agent such as borane-methyl sulfide complex.
  • the reaction mixture is then heated at reflux for about 8 to 16 hours under a nitrogen atmosphere and then cooled to room temperature.
  • the reaction is then quenched by addition of a tetrahydrofuran/methanol (1 :1) mixture until foaming ceases.
  • step D the amine (19) is sulfonylated under conditions well known in the art with a sulfonyl chloride of formula CISO 2 R 2 to provide the compound of formula IV.
  • a suitable organic solvent such as methylene chloride
  • a suitable organic base such as triethylamine under an atmosphere of nitrogen.
  • the solution is cooled to about 0°C and treated slowly with about 1.0 to 1.2 equivalents of a sulfonyl chloride of formula CISO2R 2 , and the reaction mixture is then allowed to warm to room temperature and stirred for about 8 to 16 hours.
  • the compound of formula IV is then isolated and purified by techniques well known in the art.
  • reaction mixture is quenched with water and the organic phase is separated from the aqueous layer.
  • organic phase is then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the crude compound of formula IV.
  • This crude material is then purified by silica gel chromatography with a suitable eluent, such as hexane/ethyl acetate (1 :1) to provide the purified compound of formula IV.
  • R 1 represents a 4-bromophenyl group
  • R 1 represents a 4-substituted alkyl- or cycloalkylphenyl group, such as 4- cyclopentylphenyl by treatment of the corresponding bromide with an appropriate alkyl- or cycloalkyl Grignard reagent, such as cyclopentyl-magnesium bromide, in the presence of a palladium(ll) catalyst, such as [1 ,1'- bis(diphenylphosphino)ferrocene]-dichloropalladium(ll)(PdCl2(dppf)), in an aprotic solvent, such as diethyl ether at temperatures ranging from -78 °C to 25 °C
  • the compounds of formula IV in which R 1 represents a 4- bromophenyl group may be converted to a 4-(trimethylstannyl)phenyl or 4-(tri-n- butylstannyl)phenyl group by treatment of the corresponding bromide with a palladium(O) catalyst, such as tetrakis(triphenylphosphine)-palladium(0) and hexaalkyldistannane, where the alkyl group is methyl or n-butyl, in an aprotic solvent such as toluene in the presence of a tertiary amine base such as triethylamine, at temperatures ranging from 80 to 140°C, preferably from 90 to 110°C.
  • a palladium(O) catalyst such as tetrakis(triphenylphosphine)-palladium(0) and hexaalkyldistannane, where the alkyl group is methyl or n-butyl
  • R 1 represents a 4-(tri- ⁇ - butylstannyl)phenyl group
  • an aryl- or heteroarylbromide such as 2-bromothiophene-5-carboxaldehyde, or an aryl- or heteroaryliodide, or an aryl- or heteroaryltriflate
  • a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(0)
  • a palladium(ll) catalyst such as bis(triphenylphosphine)-palladium(ll) dichloride
  • an aprotic solvent such as dioxane
  • R 1 represents a 4-bromophenyl group
  • R 1 represents a 4-bromophenyl group
  • R 1 represents a 4-bromophenyl group
  • R 1 represents a 4-bromophenyl group
  • R 1 represents a 4-bromophenyl group
  • a palladium(ll) catalyst such as bis(triphenyl-phosphine)palladium(ll) dichloride and sodium formate in an aprotic solvent, such as dimethylformamide at temperatures ranging from 70 to 110°C, preferably at 90 °C
  • the compounds of formula IV in which R 1 represents a 4-hydroxyphenyl group may be converted into other compounds of formula I in which R 1 represents an alkoxy group by treatment of the corresponding hydroxyphenyl group with an appropriate alkyl halide such as benzyl bromide in the presence of sodium hydride in an aprotic solvent such as dimethylformamide at temperatures ranging from 25 to 100°C, preferably from 50 to 90°C More specifically, the compounds of formulas IVa and IVb can be prepared as set forth in Scheme VII.
  • the reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.
  • step A the compound of structure (15a) is O-alkylated with the compound of structure (16) to provide the ether of structure (17a) in a manner analogous to the procedure set forth above in Scheme VI, step A.
  • step B ether (17a) is converted to the amide of structure (18a) in a manner analogous to the procedure set forth above in Scheme VI, step B.
  • step C the amide (18a) is reduced in a manner analogous to the procedure described in Scheme VI, step C above, to provide the amine of structure (19a).
  • step D the amine (19a) is sulfonylated with a sulfonyl chloride of formula CISO 2 R 2 to provide the compound of formula IVa in a manner analogous to the procedure set forth in Scheme VI, step D above.
  • step E the compound of formula IVa is coupled with the boronic acid of structure (20), wherein R 1a and R 1b each independently represent hydrogen, halogen; nitro; cyano; (1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3- 8C)cycloalkyl; 4-(1 ,1-dioxotetrahydro-1 ,2-thiazinyl); halo(1-10C)alkyl; cyano(2-
  • R 15 represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1-10C)alkyl, (1- 4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl, (N-(1- 4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl, (3-10C)alkenyl, (3- 10C)alkynyl, (3-8C)cycloalkyI, camphoryl
  • the compound of formula IVa is combined with about 1.0 to about 1.2 equivalents of a boronic acid (20), a catalytic amount of tetrakis(triphenylphosphine)palladium(0), and an excess of a suitable base, such as aqueous sodium carbonate, in a suitable organic solvent, such as 1 ,4-dioxane under an atmosphere of nitrogen.
  • a suitable base such as aqueous sodium carbonate
  • a suitable organic solvent such as 1 ,4-dioxane
  • the quenched reaction is extracted with a suitable organic solvent, such as methylene chloride, the organic extracts are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide crude compound of formula IVb.
  • a suitable organic solvent such as methylene chloride
  • the organic extracts are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide crude compound of formula IVb.
  • This crude material is then purified by silica gel chromatography with a suitable eluent, such as hexane/ethyl acetate (1 :1) to provide the purified compound of formula IVb.
  • step E the compound of formula IVa is combined with about 1.1 to about 1.2 equivalents of a boronic acid (20), a catalytic amount of dichlorobis(triphenylphosphine)palladium (II), and an excess of a suitable base, such as aqueous sodium carbonate, in a suitable organic solvent, such as 1 ,2-dimethoxyethane under an atmosphere of nitrogen.
  • a suitable base such as aqueous sodium carbonate
  • a suitable organic solvent such as 1 ,2-dimethoxyethane
  • the quenched reaction is extracted with a suitable organic solvent, such as methylene chloride, the organic extracts are combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide crude compound of formula IVb.
  • a suitable organic solvent such as methylene chloride
  • the organic extracts are combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide crude compound of formula IVb.
  • This crude material is then purified by silica gel chromatography with a suitable eluent, such as hexane/ethyl acetate (1 :1 ) to provide the purified compound of formula IVb.
  • the coupling reaction may be carried out using palladium diacetate with a suitable organic solvent, such as n-propanol or acetone.
  • a suitable organic solvent such as n-propanol or acetone.
  • the boronic acid (20) may be prepared, for example, by reacting a trialkyl borate, such as triisopropyl borate with an appropriate organolithium compound at reduced temperature.
  • a trialkyl borate such as triisopropyl borate
  • 2-fluorobenzeneboronic acid may be prepared by reacting 2-fluorobromobenzene with butyllithium in tetrahydrofuran at about -
  • step A the compound of formula IVb' wherein z is 0 or an integer 1 , 2, 3 or 4, is reduced to the amine of formula IVc under conditions well known in the art.
  • a suitable organic solvent such as tetrahydrofuran
  • a suitable reducing agent such as borane-methyl sulfide complex
  • the reaction is treated with a mixture of tetrahydrofuran/methanol (1 :1 ) until foaming ceases.
  • the reaction is then treated with 5N aqueous sodium hydroxide and heated at reflux for about 3 to 6 hours.
  • the reaction is then cooled to room temperature and extracted with a suitable organic solvent, such as methylene chloride.
  • the organic extracts are combined, dried over potassium carbonate, filtered, and concentrated under vacuum to provide the crude amine of formula IVc.
  • the crude material is then purified by techniques well known in the art, such as silica gel chromatography or formation of the corresponding HCI salt and subsequent crystallization.
  • the crude amine of formula lc is dissolved in a suitable organic solvent, such as s diethyl ether and treated with excess anhydrous HCI gas.
  • a suitable organic solvent such as s diethyl ether
  • the mixture is allowed to stir for about 1 to 3 hours and the resulting precipitate is collected by filtration.
  • the precipitate is washed with cold diethyl ether and dried under vacuum to provide the purified amine HCI salt of formula IVc.
  • step B the amine of formula IVc is sulfonylated under standared conditions with a sulfonyl chloride of formula CISO 2 R 15 , wherein R 15 represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1-10C)alkyl, (1- 4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl, (N-(1- 4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl, (3-10C)alkenyl, (3- 10C)alkynyl, (3-8C)cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)
  • the amine of formula IVc is dissolved in a suitable organic solvent, such as methylene chloride under an atmosphere of nitrogen, and treated with an excess of a suitable organic base, such as triethylamine.
  • a suitable organic base such as triethylamine.
  • the solution is cooled to about 0°C and treated with about 1.1 to about 1.5 equivalents of a sulfonyl chloride of formula CISO 2 R 15 .
  • the reaction mixture is allowed to warm to room temperature and stirred for about 8 to 16 hours.
  • the reaction is then quenched with water, the organic layer is separated, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the crude compound of formula Id.
  • This crude material is purified by silica gel chromatography with a suitable eluent, such as ethyl acetate/hexane (1 :1 ) to provide the purified compound of formula IVd.
  • step C the amine of formula IVc is converted to the amide of formula IVe under conditions well known in the art.
  • amide formation can be carried out using standard peptide coupling procedures well known in the art, such as the azide method, the mixed carbonic acid anhydride (isobutyl chloroformate) method, or the carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimide) method.
  • Some of these methods, such as the carbodiimide method can be enhanced by adding 1- hydroxybenzotriazole.
  • the amine of formula lc is dissolved in a suitable organic solvent, such as methylene chloride under an atmosphere of nitrogen, and treated with an excess of a suitable organic base, 5 such as triethylamine.
  • a suitable organic base such as triethylamine.
  • the solution is cooled to about 0°C and treated with about 1.1 to about 1.5 equivalents of an acid chloride of formula CICOR 15 .
  • the reaction mixture is allowed to warm to room temperature and stirred for about 8 to 16 hours.
  • the reaction is then quenched with water and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide 0 the crude amide of formula IVe.
  • This crude material is purified by silica gel chromatography with a suitable eluent, such as ethyl acetate/hexane (1:1) to provide the purified compound of formula IVe.
  • R2 in formula IV examples include methyl, ethyl, propyl, 2-propyl, 5 butyl, 2-methylpropyl, cyclohexyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloromethyl, ethenyl, prop-2-enyl, methoxyethyl, phenyl, 4-fluorophenyl, or dimethylamino.
  • R2 is ethyl, 2-propyl or dimethylamino with 2-propyl being most preferred.
  • R 9 in formula IV examples include hydrogen, methyl, ethyl, 0 propyl, isopropyl, t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • R 9 is preferably (1-4C)alkyl, (2- 4C)alkenyl, (3-6C)cycloalkyl, pyrrolidinyl, morpholino or tetrahydrofuryl.
  • R15 j n formula IV examples include hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, benzyl, 2,2,2-trifluoroethyl, 2- 5 methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl, 2-fluorophenyl, 3- fluorophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 1-(5-dimethylamino)naphthyl, and 2-thienyl.
  • X 1 preferably represents O, CO, CONH or NHCO in formula IV.
  • z is preferably 0 in formula IV. o Particular values for the groups (CH2)yX 1 R 9 and (CH2)zX 3 R 15 in formula
  • IV include (1-10C)alkoxy, including (1-6C)alkoxy and (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy and isobutoxy; (3-10C)alkenyloxy, including (3-6C)alkenyloxy, such as prop-2-enyloxy; (3-10C)alkynyloxy, including (3-6C)alkynyloxy, such as prop-2-ynyloxy; and (1-6C)alkanoyl, such as formyl and ethanoyl. Examples of particular values in formula IV for y are 0 and 1.
  • L a and l ⁇ preferably each independently represents CH2-
  • X 2 preferably represents a bond, O, NH, CO, CH(OH), CONH, NHCONH or OCH2CONH, with a bond, O, and CONH being especially preferred.
  • group (CH2)yX 1 R 9 represents CHO; COCH3,
  • R 9 represents methyl, ethyl, isopropyl, t- butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyrolidinyl or morpholino; CONHR 9 in which R 9 represents cyclopropyl or cyclopentyl; NHCOCOOCH3; or 2-tetrahydrofurylmethoxy.
  • the group (CH2)zX 3 R ⁇ 5 represents NH2;
  • Examples of particular values in formula IV for (L a ) n -X 2 -( b) m are a bond, O, NH, S, SO, SO2, CO, CH2, COCH2, COCONH, CH(OH)CH2, CONH, NHCO, NHCONH, CH2O, OCH2, OCH2CONH, CH2NH, NHCH2 and CH2CH2, with a bond, CONH, and CH2O being especially preferred.
  • R ⁇ 4 js preferably an unsubstituted or substituted phenyl, naphthyl, furyl, thienyl, isoxazolyl, thiazolyl, tetrazolyl, pyridyl, pyrimidyl benzothienyl or benzothiazolyl group.
  • R14 examples of particular values for R14 are phenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-chloro-phenyl, 3-chlorophenyl, 4-chlorophenyl, 2- bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 2,3-difluoro-phenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 4- cyanophenyl, 3-nitrophenyl, 4-hydroxyiminophenyl, 2-methylphenyl, 4- methylphenyl, 4-ethylphenyl, 3-propylphenyl, 4-t-butylphenyl, 2-prop-2- enylphenyl, 4-(4-(1 ,1-dioxotetrahydro-1 ,2-thi
  • Examples of an unsubstituted or substituted aromatic or heteroaromatic group represented by R ⁇ in formula IV are unsubstituted or substituted phenyl, furyl, thienyl (such as 3-thienyl) and pyridyl (such as 3-pyridyl).
  • Examples of an unsubstituted or substituted (5-8C)cycloalkyl group represented by R ⁇ in formula IV are unsubstituted or substituted cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, with cyclohexyl being preferred.
  • R ⁇ represents 2-naphthyl or a group of formula
  • R 20 represents halogen; nitro; cyano; hydroxyimino; (1- 10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cyclo-alkyl; hydroxy(3-
  • CONR11 , NR 2 CO, NRl 2 COCOO, OCONR13, R9 represents hydrogen, (1- 10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R10> R ⁇ > R " ⁇ 2 and R13 each independently represents hydrogen or (1 -10C)alkyl, or R 9 and R 1 °> R 1 1 .
  • R 12 or R 13 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1- 4C)alkyIpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; tetrazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (1-4C)alkoxycarbonyl- dihydrothiazolyl; (1-4C)alkoxycarbonyldimethyl-dihydrothiazolyl; tetrahydrothienyl; tetrahydrofuryl;
  • CONR 17 NR 8 CO, NHSO2 .
  • NHSO2NR 17 NHCONH, OCONRI 9 , N(CO(1-
  • R15 represents hydrogen, (1-10C)alkyl, phenyl(1- 4C)alkyl, halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, (1- 4C)alkylsulfonylamino(1-4C)alkyl, (1-4C)alkylaminosulfonyl(1-4C)alkyl, (N-(1- 4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl, (3-10C)alkenyl, (3- 10C)alkynyl, (3-8C)cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)al
  • R ⁇ represents a hydrogen atom, a halogen atom, a (1- 4C)alkyl group or a (1-4C)alkoxy group.
  • R 2 ⁇ in formula IV are fluorine, chlorine, bromine, cyano, hydroxyimino, methyl, ethyl, propyl, 2-propyl, butyl, 2- methylpropyl, 1 ,1-dimethylethyl, cyclopentyl, cyclohexyl, 3-hydroxycyclopentyl, 3- oxocyclopentyl, methoxy, ethoxy, propoxy, 2-propoxy, acetyl, acetylamino, ethylcarboxamido, propylcarboxamido, 1 -butanoylamido, t-butylcarboxamido, acryloylamido, 2-pyrrolidinylcarboxamido, 2-tetrahydrofuryl
  • R 2 ⁇ in formula IV examples are hydrogen and chlorine.
  • R 2 ⁇ is preferably ortho to R 20 .
  • Ri in formula IV examples of particular values for Ri in formula IV are 2-naphthyl, 4- bromophenyl, 4-cyanophenyl, 4-benzamidophenyl, 4-methylphenyl, 4-isopropyl- phenyl, 4-isobutyIphenyl, 4-f-butylphenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-cyclopentylphenyl, 4-cyclohexylphenyl, 4-(2-hydroxymethylphenyl)phenyl, 4-(4- hydroxymethylphenyl)-phenyl, 4-(2-furyl)phenyI, 4-(3-furyl)phenyl, 4-(2-thienyl)- phenyl, 4-(3-thienyl)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(piperidin-l-yl)phenyl, 3- chloro-4-piperidin-1-ylphenyl, 4-benzyloxyphen
  • z is 0, or an integer 1 , 2, 3 or 4;
  • R 15a represents (1-6C)alkyl, fluoro(1-4C)alkyl, or phenyl which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, and (1- 4C)alkoxy; and R 1a and R 1b each independently represent hydrogen, halogen; nitro; cyano; (1- 10C)alkyl; halo(1-10C)alkyl; phenyl; thienyl; (CH2)zX 3 R 15b in which z is 0 or an integer 1 , 2, 3, or 4, X 3 represents O, S, NR 16 , CO, COO, OCO, R 15b represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1-10C)alkyl, (3- 10C)alkenyl, or phenyl which is unsubstituted or substituted by one or two of halogen, (
  • R ⁇ 6 represents hydrogen or (1-10C)alkyl; or a pharmaceutically acceptable salt thereof; are included within the scope of the present invention and are particularly preferred.
  • R 1a is hydrogen and R 1b is methyl, methoxy, fluoro, chloro, cyano, NH 2 , -CH 2 NH 2 , -CH2CH2NH2, 2-thienyl, 3-thienyl, -CHO, trifluoromethyl, -CH 2 CN, -CO2CH3, or -CO 2 CH 2 CH 3 ; or R 1a and R b are both hydrogen, fluoro, or chloro.
  • R 15a respresents methyl, ethyl, isopropyl, or trifluoromethyl.
  • z represents 0, 1 or 2.
  • R 5 in formula IV represents hydrogen or methyl.
  • R 6 in formula IV represents hydrogen or methyl.
  • R 5 is hydrogen and R 6 is methyl.
  • R 1 represents (1-6C)alkyl, (2-6C)alkenyl, or NR 7 R 8 ;
  • R 2 and R 3 each independently represent hydrogen, F, (1-4C)alkyl, or
  • R 4a and R 4b each independently represent hydrogen, (1-4C) alkyl, (1-4C)alkoxy, I,
  • Q is selected from the following:
  • R 5 represents hydrogen or (1-6C)alkyl
  • Y represents CH 2 CH 2 , CR 10 R 11 , NR 6 , S, or O;
  • Z represents O, S, or NH
  • R 6 represents hydrogen or (1-6C)alkyl
  • R 7 and R 8 each independently represent hydrogen or (1-4C)alkyl
  • R 9 represents hydrogen or (1-4C)alkyl
  • R 10 and R 11 each independently represent hydrogen or (1-4C)alkyl; or a pharmaceutically acceptable salt thereof.
  • the compounds of formula V can be prepared by one of ordinary skill in the art following, for example, the various procedures set forth in the Schemes below.
  • the reagents and starting materials are readily available to one of ordinary skill in the art, for example, see International Patent Application Publications: WO 98/33496 published August 6, 1998, and WO 00/06148 and WO 00/06158, both published February 10, 2000. All substituents, unless otherwise specified are as previously defined.
  • step A the compound of structure (21) is combined with the compound of structure (22) under conditions well known in the art to provide the compound of structure (23). More specifically, for example, the compound (21 ) is dissolved in a suitable organic solvent.
  • suitable organic solvents include methylene chloride, tetrahydrofuran, and the like.
  • the solution is treated with a slight excess of a suitable base, and then cooled to about -78°C to about 0°C.
  • suitable bases include triethylamine, pyridine, 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU),and the like.
  • DBU diazabicyclo[5.4.0]undec-7-ene
  • Lg refers to a suitable leaving group.
  • suitable leaving groups include, CI, Br, and the like.
  • CI is the preferred leaving group.
  • the reaction mixture is stirred at about 0°C to about 50°C for about 0.5 hours to about 16 hours.
  • the compound (23) is then isolated and purified by techniques well known in the art, such as extraction techniques and chromatography. For example, the mixture is washed with 10% sodium bisulfate, the layers separated and the aqueous extracted with several times with a suitable organic solvent, such as methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is then purified by flash chromatography on silica gel with a suitable eluent such as ethyl acetate/hexane to provide the compound (23).
  • step B the compound of structure (23) is fluorinated under conditions well known in the art to provide the compound of formula la.
  • compound (23) is dissolved in a suitable organic solvent, such as methylene chloride and the solution is cooled to about -78°C under an inert atmosphere, such as nitrogen.
  • DAST diethylaminosulfur trifluoride
  • a suitable organic solvent such as methylene chloride with stirring.
  • the reaction is then allowed to warm to room temperature (about 22°C) and the compound of formula la is then isolated and purified using techniques and procedures well known in the art, such as extraction techniques and chromatography.
  • the reaction is diluted with water and methylene chloride.
  • step B' the compound (21 ) is fluorinated in a manner analogous to the procedure described in step B above with DAST to provide the compound of structure (24).
  • step A' compound (24) is converted to the compound of formula Va in a manner analogous to the procedure described in step A above.
  • the compounds of formula Va can be prepared following the procedure described in Scheme X.
  • the reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.
  • step A the compound of structure (25) is coupled with compound of structure (26) under standard Suzuki coupling conditions to provide compound of structure (27). See Suzuki, A., Journal of Organometallic
  • compound (25) is combined with about 1.5 equivalents of compound (26), about 1.5 equivalents of potassium carbonate, and about 0.06 equivalents of tetrakis(triphenyl phosphine)palladium(O) in a suitable solvent or solvent mixture, such as dioxane/water (3:1 ). The mixture is then heated at about 100°C for about 18 hours. The reaction is then cooled and compound (27) is isolated and purified using standard techniques and procedures, such as extraction techniques and chromatography.
  • reaction mixture is extracted with a suitable organic solvent, such as ethyl acetate, the organic extracts are combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum.
  • a suitable eluent such as hexane/ethyl acetate to provide purified compound (25).
  • step B compound (27) is fluorinated under standard conditions to provide the compound of formula la.
  • compound (27) is dissolved in a suitable organic solvent, such as methylene chloride is added to about one equivalent of DAST at about -78°C with stirring under an atmosphere of nitrogen.
  • step B' the compound (25) is fluorinated to provide the compound (28) in a manner analogous to the procedure described above in step B.
  • step A' the compound (28) is converted to the compound of formula Va in a manner analogous to the procedure described above in step A.
  • step A the compound of structure (21) is combined with a compound of formula CISO 2 NR 7 R 8 under standard conditions to provide the compound of structure (29).
  • compound (21 ) is dissolved in a suitable organic solvent, such as tetrahydrofuran and treated with about one equivalent of a suitable base, such as DBU at about 0°C.
  • a suitable base such as DBU at about 0°C.
  • the solution is then treated with about one equivalent of a compound of formula CISO 2 NR 7 R 8 .
  • the reaction is then allowed to warm to room temperature and stirred for about 4 to 16 hours.
  • the reaction is then concentrated under vacuum to provide the crude product (29) which can then be purified by chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane.
  • step B compound (29) is converted to the compound of formula Vb in a manner analogous to the procedure set forth in Scheme IX, step B.
  • step B' the compound (21) is fluorinated in a manner analogous to the procedure described in Scheme IX, step B with DAST to provide the compound of structure (24).
  • step A compound (24) is converted to the compound of formula Vb in a manner analogous to the procedure described above in step A.
  • the compounds of structure (25) can be prepared following the procedure described in Scheme XII.
  • the reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.
  • TMS represents trimethylsilyl
  • step A the compound of structure (30) is converted to the compound of structure (31) under standard conditions.
  • compound (30) is dissolved in a suitable organic solvent, such as dry tetrahydrofuran, containing excess 18-crown-6, and excess potassium cyanide.
  • a suitable organic solvent such as dry tetrahydrofuran, containing excess 18-crown-6, and excess potassium cyanide.
  • To this mixture at room temperature is added dropwise about 1.2 equivalents of cyanotrimethylsilane.
  • the reaction mixture is allowed to stir for about 1 to 4 hours to provide compound (31).
  • Compound (31) is then carried on directly to step B without isolation.
  • step A for example, compound (30) is combined with a catalytic amount of zinc iodide followed by slow addition of excess trimethylsilyl cyanide with the generation of heat.
  • the resulting solution is stirred at room temperature under nitrogen for about 8 to 16 hours.
  • the mixture is then diluted with a suitable organic solvent, such as chloroform, washed with saturated sodium bicarbonate, water, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide compound (31 ).
  • a suitable organic solvent such as chloroform
  • step B compound (31) is converted to compound of structure (32).
  • compound (31) prepared above, still in solution is treated with a solution of about 1.4 equivalents of borane in dimethylsulfide.
  • the reaction mixture is then heated to reflux for about 16 hours and then cooled to room temperature.
  • the reaction mixture is then cautiously treated with anhydrous HCI in methanol and allowed to stir for about one hour.
  • the product (32) is then isolated and purified using standard techniques and procedures. For example, the solvent is removed under vacuum and the residue triturated with a suitable organic solvent, such at methy t-butyl ether and the solid is collected by filtration.
  • the solid is then suspended in methylene chloride/tetrahydrofuran mixture (1 :2.4) and treated with 1 N NaOH until about pH 12.3 is reached.
  • the phases are separated and the organic phase is rinsed with brine.
  • the organic phase is then concentrated under vacuum and the residue triturated with diethyl ether to provide the purified compound (32).
  • step C compound (32) is then sulfonylated to provide compound (25) in a manner analogous to the procedure described in Scheme IX, step A.
  • R 1 compounds of formula V wherein R 1 is methyl, ethyl, isopropyl or N(CH 3 ) 2 are preferred with 2-propyl being most preferred.
  • R 2 compounds of formula V wherein R 2 is hydrogen, methyl or ethyl are preferred, with hydrogen or methyl being most preferred.
  • R 3 compounds of formula V wherein R 3 is hydrogen, methyl or ethyl are preferred, with hydrogen or methyl being most preferred.
  • R 3 is hydrogen
  • R 2 is hydrogen
  • R 3 is methyl
  • R 4a and R 4b compounds of formula V wherein R 4a and R 4b are each independently hydrogen, methyl, ethyl, methoxy, ethoxy, Br, CI or F are preferred, with hydrogen, methyl, methoxy and F being most preferred, and hydrogen be most especially preferred.
  • R 5 compounds of formula V wherein R 5 is hydrogen or methyl are preferred, with hydrogen being most preferred.
  • R 6 compounds of formula V wherein R 6 is hydrogen or methyl are preferred.
  • R 7 and R 8 compounds of formula V wherein R 7 and R 8 are each independently hydrogen, methyl, or ethyl are preferred, with methyl being most preferred.
  • R 9 compounds of formula V wherein R 9 is hydrogen, methyl, or ethyl are preferred, with methyl being most preferred.
  • R 10 and R 11 compounds of formula V wherein R 10 is hydrogen or methyl are preferred, and R 11 is hydrogen or methyl are preferred. It is most preferred that R 10 and R 11 each represent hydrogen.
  • the title compound can be prepared in a manner analogous to the procedures described generally in Schemes I and II, and more specifically as described in examples 2 and 3 below without employing the resolution steps as would be appreciated by one of ordinary skill in the art.
  • reaction was allowed to stir until GC analysis revealed that ((2R)-2- phenylpropyl)[(methylethyl)sulfonyl]amine is less then 1 % (area %). 5
  • the reaction mixture was then diluted with dichloromethane (20 mL) and diionized water (20 mL), and the mixture was transferred to a suitably sized 3- neck bottom outlet round-bottom flask. The mixture was stirred for 10-15 minutes. The aqueous phase was separated, extracted with dichloromethane (1 x 20 mL), and the organic phases were combined. To the organic phase was o added water (15 mL), 10% NaOH (10 mL), and the pH was adjusted to 6.5-7.5 with saturated sodium carbonate. After 10-15 minintes of stirring, the organic layer was separated and concentrated to an oil under reduced pressure (25-35 °C).
  • the oil containing the mixture of [(2R)-2-(4- 5 nitrophenyl)propyl][(methylethyl)sulfonyl]amine, [(2R)-2-(3- nitrophenyl)propyl][(methylethyl)sulfonyl]amine, and [(2R)-2-(2- nitrophenyl)propyI][(methylethyl)sulfonyl]amine, was diluted with ethanol and was transferred to a Parr bottle containing 1.25g of 5% Pd on C (rinsed in with 5 L of THF) under nitrogen (total ethanol 45 mL).
  • reaction mixture was o hydrogenated for 16-20 hours at 20-25 °C until the GC area % of [(2R)-2-(4- aminophenyl)propyl][(methyIethyl)sulfonyl]amine was greater than 70%.
  • the reaction mixture was filtered through Hyflo followed by an ethanol rinse (25 mL).
  • the reaction mixture was washed with deionized water (2 x 100 mL) and 0.1 N HCI (2 x 100 mL).
  • the organic phase was diluted with acetone (50 mL) to ensure complete dissolution of the product and the organic phase was washed with saturated K 2 CO 3 (100 mL), 0.1 N HCI (100 mL), dried (MgSO 4 , 3 g), filtered and co-evaporated with EtOAc to afford an oil.
  • This oil was diluted with diethyl ether (125 mL), which induced crystallization.
  • the solids were collected by filtration, washed with diethyl ether (2 x 20 mL), and dried under reduced pressure at room temperature overnight to afford N-[4-((1R)-1-methyl-2-
  • ⁇ [(methylethyl)sulfonyl]amino ⁇ ethyl)phenyl](3,5-difluorophenyl)carboxamide can be jet milled by one of ordinary skill in the art, for example, with a Model 4 SDM Micronizer by Sturtevant Inc. to provide compound with a mean particle size of about 5.5 microns.
  • Foaming observed during the quench can be controlled by the rate of addition of the carbonate solution.
  • the top organic layer is separated and the aqueous layer back extracted with methylene chloride (130.0 mL).
  • the title compound can be prepared following the procedure disclosed in WO 98/33496 published August 6, 1998, Example 51). More specifically, to a room temperature solution of 0.1 g (0.3 mmol) of N-2-(4-(4-(2- aminoethyl)phenyl)phenyl)propyl 2-propanesulfonamide (prepared following procedure disclosed in WO 98/33496 published August 6, 1998, Example 50) and 0.06 mL (0.4 mmol) of triethylamine in 2 mL of dichloromethane was added 0.03 mL (0.4 mmol) of methanesulfonyl chloride. The mixture was stirred at ambient temperature for 16 hours. Chromatography (10 g silica gel, 50% ethyl acetate/hexane) of the reaction mixture afforded 0.1 g (94%) of the title compound.
  • Heptane 1000 mL was added and the solution was concentrated again at atmospheric pressure to 600 mL using a nitrogen purge to increase the rate of distillation. The final pot temperature was 109 °C.
  • the solution was cooled to room temperature under nitrogen with stirring to give a clear, colorless heptane solution (600 mL) of (2R)-2-phenylpropylamine.
  • 4-dimethylaminopyridine 6.04 g, 0.0494 mol
  • triethylamine 200 g, 1.98 moles
  • CH CI 2 500 mL
  • reaction mixture was cooled to 30° C and a 10% aqueous solution of NaHSO 3 (220 mL) was added dropwise while maintaining the temperature between 25 ° C and 30° C.
  • the mixture crystallized to a solid mass upon cooling to 0-5 °C.
  • the solids were suction filtered and rinsed with H 2 O to afford 61.7 g of crude solids that were redissolved into warm MTBE (500 mL). This solution was extracted with H 2 O (2 x 200 mL) and saturated NaHCO 3 (1 x 200 mL) and the organic phase was dried (MgS0 ), filtered, and concentrated under reduced pressure to -200 mL.
  • Potassium hydroxide pellets (85%, 143 g, 2.16 moles) were added to neutralized the sulfuric acid and then enough saturated aqueous sodium sulfite was added to decolorize the mixture to afford a white suspension.
  • the suspension was cooled to 15 °C and filtered.
  • the filter cake was triturated thoroughly with water and was then dissolved in CH 2 CI 2 (1 L) and extracted with additional water (2 x 200 mL).
  • the organic phase was concentrated under reduced pressure to provide the intermediate title compound, [2-(4-iodophenyl)ethyl](methylsulfonyl)amine, (201 g, 60.2%) as a white powder.
  • the reaction mixture was concentrated to a fluid oil that was partitioned between MTBE (500 mL) and water (500 mL). The organic phase was separated and washed with water (2 x 200 mL) and concentrated to a residue that was partially dissolved with heptane (1 L). The heptane soluble fraction was filtered through Celite ® 521 and concentrated to an oil (95 g). The residue was dissolved in acetone (600 mL) and heptane (600 mL) and filtered through Celite ® 521.
  • potassium formate An aqueous solution of potassium formate was prepared in the following manner. To 15 mL of water was added KOH (85% flakes, 6.73 g, 0.102 mol), then 98% formic acid (4.70 g, 0.102 mol). Alternatively, one may use commercially available potassium formate.
  • potassium formate 112.8 g, 1.34 moles, 5.1 eq
  • water 200 mL
  • Potassium carbonate 72.7g, 0.526 mol, 2.0 eq
  • 4- ⁇ 2-[(methylsulfonyl)amino]ethyl ⁇ benzene boronic acid 60.8 g, 0.250 mol, 0.95 eq
  • 1-propanol 7720 mL
  • the aqueous phase was extracted with CH 2 CI 2 (100 mL) and MTBE (2 x 100 mL).
  • the combined oily product and organic phases were adjusted to pH 12.5 with the addition of 1 N NaOH.
  • the phases were separated, and the organic phase was extracted with 1 N NaOH (100 mL) and water (2 x 100 mL).
  • HPLC analysis (60% CH 3 CN / 40% H 2 0, 2 mL / min, Zorbax C-18, 205 nm) of the organic phase indicated that the product had been removed from this phase.
  • the aqueous phases (containing product) were finally combined and washed with CH 2 CI 2 (100 mL) and MTBE (2 x 100 mL).
  • the aqueous phase was added to CH2CI2 (450 mL) and 1 N H 2 S0 4 was added until the aqueous phase was at pH 3.05.
  • the phases were separated and the aqueous phase was extracted with CH 2 CI 2 (100 mL).
  • the combined organic extracts (containing product) were concentrated to an oil (58.5 g) that crystallized overnight.
  • the aqueous phase was back extracted with EtOAc (300 mL) and the combined organic phases (1500 mL) were dried (MgS0 4 ), filtered, and concentrated to a volume of about 620 mL within a 3 L round-bottom flask.
  • the clear, pale yellow solution was stirred slowly while heating to 60 °C.
  • Heptane 400 mL was added dropwise from a 5 separatory funnel to the stirring EtOAc solution at 60 °C (17 volumes of EtOAc / 11 volumes of heptane). The heptanes were added over a period of 1.5 h and the clear, pale yellow solution was allowed to cool slowly with slow stirring overnight.
  • Example 2b Preparation of ⁇ (2S)-2-r4-(4-f2- f(methylsulfonyl)aminolethyl>phenyl)phenyllpropyl)r(methylethyl)sulfonyllamine.
  • the title compound can be prepared in a manner analogous to the procedure set forth in example 2a starting with, for example, ((2S)-2- phenylpropyl)[(methylethyl)sulfonyl]amine.
  • Example 4 Preparation of r2-fluoro-2-(4- ⁇ 3- [(methylsulfonyl)aminolphenyl)phenyl)propylir(methylethyl)sulfonvnamine.
  • the trimethylsilyl-protected cyanohydrin derivative of 4-iodoacetophenone was prepared in situ following generally the method disclosed by Greenlee and Hangauer, Tetrahedron Lett., 24(42), 4559 (1983). Accordingly, cyanotrimethylsilane (21.4 g, 0.216 mol) was added dropwise over 5 minutes to a dry, room temperature solution containing 4-iodoacetophenone (44.3 g, 0.180 mol), 18-crown-6 (1.6 g, 6.1 mmoles) and KCN (1.17g, 0.018 mol) in THF (100 mL). The resulting solution was allowed to stir for 2.5 h.
  • the free base was prepared by adding 1 N NaOH to a suspension of the HCI salt in CH 2 CI 2 (150 mL) and THF (350 mL) until pH 12.3 was reached. The phases were separated and the organic phase was washed with brine (25 mL). The organic phase containing the free amine was concentrated under reduced pressure and the resulting solids were triturated with diethyl ether (30 mL) to afford 1-amino-2- (4-iodophenyl)propan-2-ol (35.6 g, 71.3%) as an off-white powder after vacuum drying.
  • the resulting semi-solid was purified via silica gel chromatography employing the Prep. LC-2000 and eluting with a solvent of Hexane/EtOAc 3:1 to provide [2-hydroxy-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine (744 mg, 19%) as a solid material.
  • This material was purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor while eluting with a gradient solvent of hexane/ethyl acetate 9:1 to hexane/ethyl acetate 3:1 to yield [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine
  • the desired product was extracted with ethyl acetate and the o organic layer was separated and washed twice with H 2 O, dried over K 2 CO 3 , and concentrated under reduced vacuum to yield the crude material (276 mg) as a dark oil.
  • the resulting oil was purified via silica gel chromatography employing the Chromatotron using a 4000 micron rotor and eluting with a solvent of Hexane/Ethyl Acetate 1 :1 to yield the title compound (164 mg, 90%) as a viscous 5 oil.
  • Example 4a Preparation of r2-Fluoro-2-(4-(3- r(methylsulfonv ⁇ amino1phenyl>phenv ⁇ propyn[(methylethv ⁇ sulfonvnamine (enantiomer 1).
  • the title compound is prepared in a manner analogous to the procedure set forth in WO 98/33496 at example 58 from [(2R)-2-(4- bromophenyl)propyl][(methylethyl)sulfonyl]amine.
  • [(2R)-2-(4- bromophenyl)propyl][(methylethyl)sulfonyl]amine is readily prepared by one of ordinary skill in the art, for example, by resolution of [2-(4- bromophenyl)propyl][(methylethyl)sulfonyl]amine using chiral chromatography.
  • step B A 10M solution of borane in dimethylsulfide (25 mL, 0.25 mol) was added rapidly to the reaction solution and the resulting mixture was heated at reflux for 16 h. The mixture was cooled to room temperature and anhydrous 10% (by wt) HCI in methanol was added slowly over 1 h (GAS)
  • the resulting semi-solid was purified via silica gel chromatography employing the Prep. LC-2000 and eluting with a solvent of Hexane/EtOAc 3:1 to provide the intermediate title compound (744 mg, 19%) as a solid material.
  • This material was purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor while eluting with a gradient solvent of hexane/ethyl acetate 9:1 to hexane/ethyl acetate 3:1 to yield the intermediate title compound (0.906 g) as a white solid.
  • the title compound can be prepared in a manner analogous to the procedure set forth in example 1 from (-)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine and 4-bromo-phenylsulfonamide.
  • step E Into 250 mL 3 neck flask fitted with a stirrer and thermometer was placed 5.00 g (24.7 mmol) of DEAD and 3.50 g (28.7 mmol) benzoic acid in THF (50 mL). 5.78 g (24.0 mmol) of (+)-trans- bromophenylcyclopentyl carbinol and 7.50 g. (28.6 mmol) of triphenylphosphine in THF (50 mL) was added dropwise while stirring at 0°C under a nitrogen atmosphere. After 2 hours at this temperature, TLC showed that the reaction was complete. Solution was let warm to room temperature and then concentrated under reduced vacuum to yield 9.14 g of an oil.
  • This solid was additionally purified by dissolution in 1 N NaOH and extraction into CH 2 CI 2 / THF (1 :1 , 2 x 200 mL).
  • the aqueous phase was acidified with 4N HCI to pH 2.2 and was extracted into CH 2 CI 2 / THF (1 :1 , 500 mL).
  • the combined organic extracts were concentrated to a crude solid (64.6 g) that was triturated with diethyl ether (160 mL) and dried under vacuum to afford the intermediate title compound (44.0 g, 59.9%) as a white powder.
  • the final title compound (128 mg, 60%) is prepared from [2-(4- bromophenoxy)propyl][(methylethyl)sulfonyl]amine (200 mg, 0.595 mmol, prepared in example 1), 4-cyanobenzeneboronic acid (105 mg, 0.715 mmol), 5 tetrakis(triphenylphosphine)palladium(0) (3.7 mg, 0.003 mmol), 2 M sodium carbonate (212 mg in 1 mL water) and 1 ,4-dioxane (4 mL) are combined in a 15 mL round bottom flask, fitted with a condenser, stirbar, and in a temperature regulated oil bath.
  • the reaction mixture is heated at reflux (70° C) under a nitrogen atmosphere overnight.
  • the reaction is quenched with water, extracted 0 three times with 25 mL of methylene chloride, and the organic layer is dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude material is purified via silica gel chromatography, utilizing a Chromatotron ® (the Chromatotron ® is available from Harrison Research Inc., 840 Moana Court, Palo Alto CA 94306) with a 2000 ⁇ m rotor utilizing an eluent of 1 :1 5 hexane:ethyl acetate, to provide the final title compound.
  • 2-(4-Bromophenoxy)propanamide (prepared in example 8) is separated into the (2R)-2-(4-bromophenoxy)propanamide and (2S)-2-(4- bromophenoxy)propanamide enantiomers using standard techniques well known in the art.
  • 2-(4-bromophenoxy)propanamide can be separated into the corresponding enantiomers using chiral chromatography on a Chiralcel OD ® column (Chiral Technologies, Inc., 730 Springdale Drive, Exton, Pennsylvania 19341 , 4.6 X 250 mm) with an eluent of 20% isopropanol/heptane at a flow rate of 1 mL/min.
  • reaction mixture was heated at 55°C for an additional five hours, monitoring occasionally to determine if the borane complexes had been thoroughly broken up. Upon completion, the reaction mixture was cooled to room temperature, and extracted three times with methylene chloride. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding 5.88 g of a viscous yellow oil. This oil was dissolved into 200 mL of diethyl ether, and acidified with concentrated HCI gas, to pH ⁇ 2. The acidic solution was stirred at RT for one hour, then vacuum filtered off white precipitate. The precipitate was heated under vacuum for two hours at 40°C, yielding 2.85 g white solid.
  • the reaction was allowed to cool to room temperature, and quenched with 15 mL of water, and extracted three times with 15 mL ethyl acetate.
  • the organic layer was dried with magnesium sulfate, filtered through Celite ® , and concentrated under reduced pressure, yielding 470 mg viscous black oil.
  • This material was further purified using a 4000 uM rotor on a Chromatotron ® in a 1 :1 hexanes:ethyl acetate solvent system yielding the final title compound (57.5 mg, 18%) as white crystals.
  • Example 9a Preparation of 6-r4-(1 -fluoro-1 -methyl-([(methylethyl)sulfonyl]amino ⁇ ethylphenyl]- indolin-2-one (enantiomer 1).
  • the reaction mixture was allowed to cool to ambient temperature and 6-bromo-1 ,3-dihydro- indol-2-one (6.18 g, 29.14 mmol), PdCI 2 (dppf).CH 2 CI 2 (0.86g, 1.0 mmol.), and 2M Na 2 C0 3 (40.0 mL, 80 mmol) were added respectively.
  • the resulting mixture was stirred and heated at 80° C for 20 hours.
  • the reaction mixture was allowed to cool to ambient temperature and poured into EtOAc and extracted with H 2 O. The aqueous layer was separated and extracted with EtOAc and Et 0. The organic layers were combined and filtered through Celite ® . The purple Celite ® cake was washed repeatedly with EtOAc and Et 2 0.
  • step A' (-)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine (0.345 g, 0.896 mmol).
  • bis(pinacolato)diboron (0.250 g, 0.984 mmol)
  • PdCI 2 (dppf).CH 2 CI 2 (0.024 g, 0.029 mmol) and potassium acetate (0.338 g, 3.44 mmol) were heated and stirred at 80° C in dry DMF (25.0 mL) for 3 hours under N 2 .
  • the reaction mixture was allowed to cool to ambient temperature and 6-bromo-1 ,3-dihydro-indol-2-one (0.209 g, 0.986 mmol), PdCI 2 (dppf).CH 2 CI 2 (0.024 g, 0.029 mmol), and 2M Na 2 C0 3 (2.5 mL, 5.0 mmol) were added respectively.
  • the resulting mixture was stirred and heated at 80° C for 6 hours.
  • the reaction mixture was allowed to cool to ambient temperature and poured into EtOAc and extracted with H 2 0. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, washed with brine and dried (MgS0 4 ).
  • tissue culture medium in the wells is then discarded, and the wells are each washed once with 200 ⁇ l of buffer (glucose, 10mM, sodium chloride, 138mM, magnesium chloride, 1mM, potassium chloride, 5mM, calcium chloride, 5mM, N-[2- hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid], 10mM, to pH 7.1 to 7.3).
  • the plates are then incubated for 60 minutes in the dark with 20 ⁇ M Fluo3-AM dye (obtained from Molecular Probes Inc., Eugene, Oregon) in buffer in each well. After the incubation, each well is washed once with 100 ⁇ l buffer, 200 ⁇ l of buffer is added and the plates are incubated for 30 minutes.
  • Solutions for use in the test are also prepared as follows. 30 ⁇ M, 10 ⁇ M, 3 ⁇ M and 1 ⁇ M dilutions of test compound are prepared using buffer from a 10 mM solution of test compound in DMSO. 100 ⁇ M cyclothiazide solution is prepared by adding 3 ⁇ l of 100 mM cyclothiazide to 3 ml of buffer. Control buffer solution is prepared by adding 1.5 ⁇ l DMSO to 498.5 ⁇ l of buffer.
  • test is then performed as follows. 200 ⁇ l of control buffer in each well is discarded and replaced with 45 ⁇ l of control buffer solution. A baseline fluorescent measurement is taken using a FLUOROSKAN II fluorimeter (Obtained from Labsystems, Needham Heights, MA, USA, a Division of Life
  • test compounds and cyclothiazide solutions are determined by subtracting the second from the third reading (fluorescence due to addition of glutamate in the presence or absence of test compound or cyclothiazide) and are expressed relative to enhance fluorescence produced by 100 ⁇ M cyclothiazide.
  • HEK293 cells stably expressing human GluR4 are used in the electrophysiological characterization of AMPA receptor potentiators.
  • recording pipettes have a resistance of 2-3 M ⁇ .
  • Using the whole-cell voltage clamp technique Hamill et al.(1981)Pfl ⁇ gers Arch., 391 : 85-100), cells are voltage-clamped at -60mV and control current responses to 1 mM glutamate are evoked.
  • Test compounds are then determined in the presence of test compound.
  • Compounds are deemed active in this test if, at a test concentration of 10 ⁇ M or less, they produce a greater than 10% increase in the value of the current evoked by 1 mM glutamate and this effect can be blocked by a specific AMPA receptor antagonist such as NBQX.
  • concentration of the test compound both in the bathing solution and co-applied with glutamate, is increased in half log units until the maximum effect was seen. Data collected in this manner are fit to the Hill equation, yielding an EC50 value, indicative of the potency of the test compound. Reversibility of test compound activity is determined by assessing control glutamate 1 mM responses.
  • the potentiation of these responses by 100 ⁇ M cyclothiazide is determined by its inclusion in both the bathing solution and the glutamate-containing solution. In this manner, the efficacy of the test compound relative to that of cyclothiazide can be determined.
  • Islets of Langerhans are isolated from the pancreata of male Wistar rats weighing 200 to 250 g.
  • the animals are anaesthetized with pentobarbitone and after surgical opening of the abdomen the pancreas is distended by injection of collagenase (17mg/10ml; Serva Bioproducts, Heidelberg, Germany) into the bile duct. After careful removal the distended pancreas is subjected to collagenase digestion in a plastic tube for 15-20 min.
  • Islets are purified on a single layer of ficoll-histopaque 1077 (Sigma, Taufmaschinen, Germany) by centrifugation at 770 x g for 25 min.
  • the islets After centrifugation and washing the islets are transferred into RPMI-1640 (Sigma, Taufkirchen, Germany) supplemented with 2 mM L- glutamine, 10% foetal calf serum, 100 lU/ml penicillin, 100 ⁇ g/ml streptomycin (Life Technologies, Düsseldorf, Germany), and cultured overnight at 37°C in a humidified atmosphere (95% air, 5% C02).
  • Insulin secretion studies are performed in static incubations. Islets are hand-picked into culture dishes and pre-incubated in Earle ' s Balanced Salt Solution (EBSS, Sigma, Taufkirchen, Germany) containing 0.1 % BSA (Sigma, Taufmün, Germany) and supplemented with 3.3 mM glucose for 30 min at 37°C. Batches of 5 islets are hand picked into 24-well tissue culture plates and incubated for 90 min at 37°C in EBSS (+ 0.1 % BSA) supplemented with 3.3 mM or 16.7 mM glucose and the respective test compound is added. Chilling the test plates on ice terminates the incubations. The supernatant is removed and stored at -20°C until it is assayed for insulin.
  • EBSS Earle ' s Balanced Salt Solution
  • the intravenous glucose tolerance test (IVGTT) is performed in overnight fasted anaesthetised male Wistar rats weighing 280-350g. Under pentobarbitone anaesthesia (50 mg/kg ip) polyethylene catheters are placed in the left jugular vein and in the left common carotid artery. Glucose (10% solution) is administered intravenously at a dose of 0.5 g/kg, followed directly by an iv injection of the test compound. Blood samples are drawn before and 3, 6, 10, 15, 30 and 45 min after glucose administration, sampled into 300 ⁇ l heparinized microcuvettes (Sarstedt LH 300, Germany) by tailbleeding, centrifuged and the obtained plasma is stored at -20°C for analysis.
  • IVGTT intravenous glucose tolerance test
  • a reference positive control
  • the protocol of the IVGTT as described above is used except the administration of intravenous glucose.
  • the present invention provides a pharmaceutical composition, which comprises a suitable AMPA receptor potentiator or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
  • the pharmaceutical compositions are prepared by known procedures using well-known and readily available ingredients.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container.
  • the term "active ingredient” refers to a suitable AMPA receptor potentiator.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragcanth, gelatin, calcium silicate, micro-crystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
  • compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 micrograms to about 500 mg, more preferably about 5 micrograms to about 300 mg of the active ingredient.
  • active ingredient refers to the suitable AMPA receptor potentiator.
  • unit dosage form refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.
  • patient refers to a mammal, such as a mouse, guinea pig, rat, dog or human. It is understood that the preferred patient is a human.
  • the terms “treating” or “to treat” each mean to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder.
  • the method of this invention encompasses both therapeutic and prophylactic administration.
  • the term "effective amount” refers to the amount of a suitable AMPA receptor potentiator which is effective, upon single or multiple dose administration to a patient, in treating the patient suffering from the named disorder.
  • an effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. For example, a typical daily dose may contain from about 5 micrograms to about 500 mg of the active ingredient.
  • the compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, bucal or intranasal routes. Alternatively, the compound may be administered by continuous infusion.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Diabetes (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

La présente invention concerne une méthode de traitement du diabète consistant à administrer à un patient une dose efficace d'un potentialisateur approprié du récepteur AMPA.
PCT/US2002/011847 2001-05-04 2002-04-22 Methode de traitement du diabete WO2002089848A2 (fr)

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CA002446161A CA2446161A1 (fr) 2001-05-04 2002-04-22 Methode de traitement du diabete
EP02769268A EP1390072A2 (fr) 2001-05-04 2002-04-22 Methode de traitement du diabete
JP2002586980A JP2004530680A (ja) 2001-05-04 2002-04-22 ２型糖尿病治療薬製造のためのａｍｐａ受容体増強物質の使用
AU2002307327A AU2002307327A1 (en) 2001-05-04 2002-04-22 Use of an ampa receptor potentiator for the manufacture of a medicament for the treatment of type 2 diabetes

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DE102008047461A1 (de) * 2008-09-17 2010-04-15 Dr.Ing.H.C.F.Porsche Aktiengesellschaft Verbindungseinrichtung zum Verbinden von Verkleidungselementen
WO2011049475A1 (fr) * 2009-10-23 2011-04-28 Uniwersytet Jagielloński Nouvelle application de dérivés de 2-pyrrolidone
EP3008167A4 (fr) * 2013-06-13 2017-06-07 VeroScience LLC Compositions et méthodes pour le traitement des troubles métaboliques
WO2018140338A1 (fr) * 2017-01-24 2018-08-02 Alphala Co., Ltd. Composés amide et leur utilisation

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JP5014334B2 (ja) * 2005-10-06 2012-08-29 イーライ リリー アンド カンパニー Ａｍｐａ受容体増強剤

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102008047461A1 (de) * 2008-09-17 2010-04-15 Dr.Ing.H.C.F.Porsche Aktiengesellschaft Verbindungseinrichtung zum Verbinden von Verkleidungselementen
WO2011049475A1 (fr) * 2009-10-23 2011-04-28 Uniwersytet Jagielloński Nouvelle application de dérivés de 2-pyrrolidone
US8686037B2 (en) 2009-10-23 2014-04-01 Uniwersytet Jagiellonski Use of piracetam for treating diabetic nephropathy
EP3008167A4 (fr) * 2013-06-13 2017-06-07 VeroScience LLC Compositions et méthodes pour le traitement des troubles métaboliques
WO2018140338A1 (fr) * 2017-01-24 2018-08-02 Alphala Co., Ltd. Composés amide et leur utilisation
AU2018212473B2 (en) * 2017-01-24 2020-06-11 Alphala Co., Ltd. Amide compounds and use thereof
US10882837B2 (en) 2017-01-24 2021-01-05 Alphala Co., Ltd. Amide compounds and use thereof
EA039455B1 (ru) * 2017-01-24 2022-01-28 Алфала Ко., Лтд. Амидные соединения и их применение

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JP2004530680A (ja) 2004-10-07

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