Patent ID: 6384039
Filing Date: 2002-05-07
Classification: A61K,A61P

Abstract:
A method of reducing the incidence of sudden death in an animal comprising administering to said animal a therapeutically effective amount of a corticotropin releasing factor antagonist, wherein the risk of sudden death is related to the presence of a disease state in said animal, wherein said disease state is diabetes, neurological disorders, brain damage, Guillain-Barre syndrome, sudden infant death syndrome, congenital hypoventilation syndrome, or uremic neuropathy; and further wherein said corticotropin releasing factor antagonist is a compound of Formula I or II: or a pharmaceutically acceptable salt thereof, whereinthe dashed line represents an optional double bond; A is â€”CR7or N; B is â€”NR1R2, â€”CR1R2R11, â€”C(&boxH;CR1R12)R2, â€”NHCR11R1R2, â€”OCR11R1R2, â€”SCR11R1R2, â€”CR11R2OR1, â€”CR11R2SR1, â€”C(S)R2, â€”NHNR1R2, â€”CR2R11NHR1 or â€”C(O)R2; D is N or â€”CR10 when a double bond connects E and D and E is â€”CR4; â€”CR10 when a double bond connects E and D and E is N; or â€”CR8R9, â€”CHR10, â€”C&boxH;O, â€”C&boxH;S, â€”C&boxH;NH, or â€”C&boxH;NCH3 when a single bond connects E and D; E is â€”CR4 or N when a double bond connects E and D, and E is â€”CR4R6 or â€”NR6 when a single bond connects E and D; Y is N or â€”CH; Z is NH, O, S, â€”N(C1-C2 alkyl), or â€”CR12R13, wherein R12 and R13 are each, independently, hydrogen, trifluoromethyl, or methyl, or one of R12 and R13 is cyano and the other is hydrogen or methyl; R1 is hydrogen or C1-C6 alkyl which is optionally substituted with up to two substituents independently selected from hydroxy, cyano, nitro, fluoro, chloro, bromo, iodo, CF3, C1-C4 alkoxy, â€”Oâ€”COâ€”(C1-C4 alkyl), â€”Oâ€”COâ€”NH(C1-C4 alkyl), â€”Oâ€”COâ€”N(C1-C4 alkyl)(C1-C2 alkyl), â€”NH(C1-C4 alkyl), â€”N(C1-C2 alkyl)(C1-C4 alkyl), â€”S(C1-C4 alkyl), â€”N(C1-C4alkyl)CO(C1-C4 alkyl), â€”NHCO(C1-C4 alkyl), â€”CO2(C1-C4 alkyl), â€”CONH(C1-C4 alkyl), â€”CON(C1-C4 alkyl)(C1-C2 alkyl), (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, and (C1-C4 alkyl)sulfanyl, and wherein said C1-C6 alkyl, C1-C4 alkoxy, and C1-C4 alkyl moieties in the foregoing R1 groups optionally contain one double or triple bond; R2 is C1-C6 alkyl, heteroaryl, aryl, heteroaryl (C1-C4 alkyl), or aryl (C1-C4 alkyl), wherein said aryl and the aryl moiety of said (aryl)C1-C4 alkyl are selected from the group consisting of phenyl and naphthyl, and said heteroaryl and the heteroaryl moiety of said (heteroaryl)C1-C4 alkyl is selected from the group consisting of thienyl, benzothienyl, pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, and benzoxazolyl; or R2 is C3-C8 cycloalkyl or (C3-C8 cycloalkyl)C1-C6 alkyl, wherein one or two of the ring carbons of said cycloalkyl having at least 4 ring members and the cycloalkyl moiety of said (C3-C8 cycloalkyl)C1-C6 alkyl having at least 4 ring members is optionally replaced by an oxygen or sulfur atom or by â€”NR4 wherein R14 is hydrogen or C1-C4 alkyl; and wherein each of the foregoing R2 groups is optionally substituted by up to three substituents independently selected from chloro, fluoro, and C1-C4 alkyl, or by one substituent selected from bromo, iodo, cyano, nitro, C1-C6 alkoxy, â€”Oâ€”COâ€”(C1-C4 alkyl), â€”Oâ€”COâ€”N(C1-C4 alkyl)(C1-C2 alkyl), â€”CO2(C1-C4 alkyl), (C1-C4 alkyl)sulfanyl, (C1-C4 alkyl)sulfinyl, and (C1-C4 alkyl)sulfonyl, and wherein said C1-C4 alkyl and C1-C6 alkyl moieties of the foregoing R2 groups optionally contain one carbon-carbon double or triple bond; or R1 and R2 of said â€”NR1R2 and said â€”CR1R2R11 are taken together to form a saturated or partially saturated 5- to 8-membered ring, wherein said ring optionally contains one or two carbon-carbon double bonds, and wherein one or two of the ring carbons is optionally replaced by a heteroatom selected from O, S, and N; R3is hydrogen, C1-C6 alkyl, fluoro, chloro, bromo, iodo, hydroxy, amino, SH, â€”NH(C1-C4 alkyl), â€”N(C1-C4 alkyl)(C1-C2 alkyl), â€”CH2OH, â€”CH2OCH3, â€”O(C1-C4 alkyl), (C1-C4 alkyl)sulfanyl, (C1-C4 alkyl)sulfonyl, or (C1-C4 alkyl)sulfinyl, wherein said C1-C6 alkyl and C1-C4 alkyl moieties of the foregoing R3 groups optionally contain one double or triple bond and are optionally substituted by from one to three substituents independently selected from hydroxy, amino, C1-C3 alkoxy, â€”NH(C1-C2 alkyl), â€”N(C1-C2 alkyl)2, â€”NHCOCH3, fluoro, chloro, and C1-C3 thioalkyl; R4 is hydrogen, C1-C6 alkyl, fluoro, chloro, bromo, iodo, C1-C6 alkoxy, formyl, trifluoromethoxy, â€”CH2OCH3, â€”CH2OCH2CH3, â€”CH2CH2OCH3, â€”CH2CF3, CF3, amino, nitro, â€”NH(C1-C4 alkyl), â€”N(CH3)2, â€”NHCOCH3, â€”NHCONHCH3, (C1-C4 alkyl)sulfanyl, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, cyano, hydroxy, â€”CO(C1-C4 alkyl), â€”CHO, or â€”CO2(C1-C4 alkyl), wherein said C1-C6 alkyl, C1-C6 alkoxy, and C1-C4 alkyl moieties of the foregoing R4 groups optionally contain one double or triple bond and are optionally substituted with one substituent selected from hydroxy, amino, â€”NHCOCH3, â€”NH(C1-C2 alkyl), â€”N(C1-C2 alkyl)2, â€”CO2(C1-C4 alkyl), â€”CO(C1-C4 alkyl), C1-C3 alkoxy, (C1-C3 alkyl)sulfanyl, fluoro, chloro, cyano, and nitro; R5 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or a 3- to 8-membered cycloalkyl ring or a 9- to 12-membered bicycloalkyl ring system, wherein said cycloalkyl ring and said bicycloalkyl ring system optionally contain one or two of O, S, or â€”Nâ€”G wherein G is hydrogen, C1-C4 alkyl, C1-C4 alkanoyl, phenyl, or benzyl, wherein each of the above R5 groups is optionally substituted by up to three substituents independently selected from fluoro, chloro, C1-C6 alkyl, C1-C6 alkoxy, and trifluoromethyl, or one substituent selected from bromo, iodo, cyano, nitro, amino, â€”NH(C1-C4 alkyl), â€”N(C1-C4 alkyl)(C1-C2 alkyl), â€”CO2(C1-C4 alkyl), â€”CO(C1-C4 alkyl), â€”SO2NH(C1-C4 alkyl), â€”SO2N(C1-C4 alkyl)(C1-C2 alkyl), â€”SO2NH2, â€”NHSO2(C1-C4 alkyl), â€”S(C1-C4 alkyl), and â€”SO2(C1-C4 alkyl), wherein said C1-C4 alkyl and C1-C6 alkyl moieties of the foregoing R5 groups optionally contain one double or triple bond and are optionally substituted by one or two substituents independently selected from fluoro, chloro, hydroxy, amino, methylamino, dimethylamino, and acetyl; R6 is hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted by a single hydroxy, methoxy, ethoxy, or fluoro group; R7 is hydrogen, C1-C4 alkyl, fluoro, chloro, bromo, iodo, cyano, hydroxy, C1-C4 alkoxy, â€”CO(C1-C4 alkyl), â€”CO2(C1-C4 alkyl), â€”OCF3, CF3, â€”CH2OH, â€”CH2OCH3, or â€”CH2OCH2CH3; R8 and R9 are each, independently, hydrogen, hydroxy, methyl, ethyl, methoxy, or ethoxy; or R8 and R9 together form an oxo (&boxH;O) group; R10 is hydrogen, C1-C6 alkyl, fluoro, chloro, bromo, iodo, C1-C6 alkoxy, formyl, amino, â€”NH(C1-C4 alkyl), â€”N(C1-C4 alkyl)(C1-C2 alkyl), cyano, carboxy, amido, or â€”SOn(C1-C4 alkyl) wherein n is 0, 1, or 2, wherein said C1-C6 alkyl and C1-C4 alkyl moieties of the foregoing R10 groups are optionally substituted by one of hydroxy, trifluoromethyl, amino, carboxy, amido, â€”NHCO(C1-C4 alkyl), â€”NH(C1-C4 alkyl), â€”N(C1-C4 alkyl)(C1-C2 alkyl), â€”CO2(C1-C4 alkyl), C1-C3 alkoxy, C1-C3 thioalkyl, fluoro, bromo, chloro, iodo, cyano, or nitro; and R11 is hydrogen, hydroxy, fluoro, or methoxy.