Patent EA-002769-B1 (EA)
Title: Substituted 6,5-hetero-bicyclic derivatives
Inventor: CHEN YUHPYNG LIANG
IPC: A61P13/02
Filed: 1997-07-25
Abstract: 1. A compound of the formula   or a pharmaceutically acceptable salt thereof, wherein the dashed lines represent optional double bonds; A is nitrogen or CR<7>; B is -NR<1>R<2>, -CR<1>R<2>R<10>, -C(=CR<2>R<11>)R<1>, -NHCR<1>R<2>R<10>, -OCR<1>R<2>R<10>, -SCR<1>R<2>R<10>, -CR<2>R<10>NHR<1>, -CR<2>R<10>OR<1>, -CR<2>R<10>SR<1> or -COR<2>; J and K are each independently nitrogen or carbon and both J and K are not nitrogens; D and E are each selected, independently, from nitrogen, CR<4>, C=O, C=S, sulfur, oxygen, CR<4>R<6> and NR<8>; G is nitrogen or carbon; the ring containing D, E, G, K, and J in formula I may be a saturated or unsaturated 5-membered ring and may optionally contain one or two double bonds and may optionally contain from one to three heteroatoms in the ring and may optionally have one or two C=O or C=S groups; R<1> is C1-C6 alkyl optionally substituted with one or two substituents independently selected from hydroxy, fluoro, chloro, bromo, iodo, -O-(C1-C4 alkyl), CF3, -C(=O)O-(C1-C4alkyl), -OC(=O)(C1-C4 alkyl), -OC(=O)N(C1-C4 alkyl)(C1-C2 alkyl), -NHCO(C1-C4 alkyl), -COOH, -COO(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CON(C1-C4 alkyl)(C1-C2 alkyl), -S(C1-C4 alkyl), -CN, -NO2, -SO(C1-C4 alkyl), -SO2(C1-C4 alkyl), -SO2NH(C1-C4 alkyl) and -SO2N(C1-C4 alkyl)(C1-C2 alkyl), wherein each of the C1-C4 alkyl groups in the foregoing R<1> groups may optionally contain one or two double or triple bonds; R<2> is C1-C12 alkyl which may optionally contain from one to three double or triple bonds, aryl or (C1-C4 alkylene)aryl, wherein said aryl and the aryl moiety of said (C1-C4 alkylene)aryl is selected from phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidinyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl and benzoxazolyl; C3-C8 cycloalkyl or (C1-C6 alkylene)(C3-C8 cycloalkyl), wherein one or two of the carbon atoms of said cycloalkyl and the 5 to 8 membered cycloalkyl moieties of said (C1-C6 alkylene)(C3-C8 cycloalkyl) may optionally and independently be replaced by an oxygen or sulfur atom or by NZ<2> wherein Z<2> is selected from hydrogen, C1-C4 alkyl, benzyl and C1 -C4 alkanoyl, and wherein each of the foregoing R<2> groups may optionally be substituted with from one to three substituents independently selected from chloro, fluoro, hydroxy and C1-C4 alkyl, or with one substituent selected from bromo, iodo, C1-C6 alkoxy, -OC(=O)(C1-C6 alkyl), -OC(=O)N(C1-C4 alkyl)(C1-C2 alkyl), -S(C1-C6 alkyl), amino, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)(C1-C4 alkyl), -N(C1-C4 alkyl)-CO-(C1-C4 alkyl), -NHCO(C1-C4 alkyl), -COOH, -COO(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CON(C1-C4 alkyl)(C1-C2 alkyl), -SH, -CN, -NO2, -SO(C1-C4 alkyl), -SO2(C1-C4 alkyl), -SO2NH(C1-C4 alkyl) and -SO2N(C1-C4 alkyl)(C1-C2 alkyl); -NR<1>R<2> or CR<1>R<2>R<10> may form a saturated 3 to 8 membered carbocyclic ring which may optionally contain from one to three double bonds and wherein one or two of the ring carbon atoms of such 5 to 8 membered rings may optionally and independently be replaced by an oxygen or sulfur atom or by NZ<3> wherein Z<3> is hydrogen, C1-C4 alkyl, benzyl or C1-C4 alkanoyl; R<3> is C1-C4 alkyl, -O(C1-C4 alkyl), or -S(C1-C4 alkyl); each R<4> is, independently, hydrogen, (C1-C6 alkyl), fluoro, chloro, bromo, iodo, hydroxy, cyano, amino, (C1-C2 alkylene)-OH, CF3, CH2SCH3, nitro, -O(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C2 alkyl), -S(C1-C4 alkyl), -CO(C1-C4 alkyl), -C(=O)H or -C(=O)O(C1-C4alkyl); R<6> is hydrogen, methyl or ethyl; R<8> is hydrogen or C1-C4 alkyl; R<5> is phenyl, substituted with from one to three substituents R<13>, independently, selected from fluoro, chloro, C1-C6 alkyl and -O(C1-C6 alkyl), bromo, iodo, -S(C1 -C6 alkyl); R<7> is hydrogen, C1-C4 alkyl, halo (e.g., chloro, fluoro, iodo or bromo), hydroxy, -O(C1-C4 alkyl), -C(=O)(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -OCF3, -CF3, -CH2OH or -CH2O(C1-C2 alkyl); R<10> is hydrogen, hydroxy, methoxy or fluoro; R<11> is hydrogen or C1-C4 alkyl; and with the proviso that: a) when both J and K are carbons and D is CR<4> and E is nitrogen, then G can not be nitrogen; (b) when both J and K are carbons and D and G are nitrogens, then E can not be CR<4>, CR<4>R<6>, C=O or C=S; (c) when both J and K are carbons and D and E are carbons, then G can not be nitrogen; (d) when G is carbon, it must be double banded to E; and (e) in the ring containing J, K, D, E and G, there can not be two double bonds adjacent to each other; and the pharmaceutically acceptable salts of such compounds. 2. Compounds according to Claim 1 wherein B is -NR<1>R<2>, -NHCHR<1>R<2>, -OCHR<1>R<2>, and R<1> is C1-C6 alkyl, which may optionally be substituted with one fluoro, or C1-C4 alkoxy group and which may optionally contain one double or triple bond; and R<2> is C1-C4 alkyl or (C1-C2 alkyl)-CO-(C1-C2 alkyl) which may optionally contain one double or triple bond. 3. Compounds according to Claim 1, wherein B is --CHR<1>R<2>, -NR<1>R<2>, -NHCHR<1>R<2>, -OCHR<1>R<2>, -SCHR<1>R<2>, and R<1> is C1-C6 alkyl, which may optionally be substituted with one hydroxy, fluoro, CF3, cyclopropyl or C1-C4 alkoxy group and which may optionally contain one double or triple bond; and R<2> is benzyl or C1-C6 alkyl, which may optionally contain one double or triple bond, wherein said C1-C6, alkyl and the phenyl moiety of said benzyl may optionally be substituted with one fluoro, hydroxy, CF3, cyclopropyl, C1-C2 alkyl, C1-C2 alkoxy or chloro group. 4. Compounds according to Claim 1 wherein R<3> is methyl. 5. Compounds according to Claim 1 wherein R<4>, R<6>, R<8> are hydrogen or methyl. 6. Compounds according to Claim 1 wherein R<5> is di- or tri-substituted phenyl in which the two or three substitutents are independently selected from C1-C4 alkyl, O-(C1-C4 alkyl), chloro, fluoro, bromo and iodo. 7. Compounds according to Claim 1 wherein R<3> is methyl, ethyl, or methoxy; and each of R<4>, R<6>, and R<8> is, independently, hydrogen, methyl or ethyl. 8. Compounds according to Claim 1 wherein A is N, CH or CCH3. 9. Compounds according to Claim 1 wherein A is CH, J and K are carbon and D, E, and G are nitrogen. 10. Compounds according to Claim 1 wherein J and D are nitrogen, and K and G are carbon, and E is CH, CCH3 or CC2H5. 11. Compounds according to Claim 1 wherein J and K are carbon, and D=EG is O-C(CH3)=C, O-CH=C, S-C(CH3)=C, S-CH=C, N(CH3)-C(CH3)=C, NHC(CH3)=C, NHC(CH3CH2)=C, N(CH3)-CH=C, O-N=C, S-N=C, N(CH3)-N=C, O-CH2N or S-CH2N. 12. A compound according to Claim 1 wherein B is -CHR<1>R<2>, -NCHR<1>R<2> or -OCHR<1>R<2>, and the CHR<1>R<2> group of B is a cyclopentane ring, a tetrahydrofuran ring or a tetrahydrothienyl ring. 13. A compound according to Claim 1 wherein the NR<1>R<2> group of B is a five membered saturated or unsaturated heterocyclic ring. 14. A compound according to Claim 13 wherein the NR<1>R<2> is a pyrrolo ring, a pyrrolidino ring, a thiazolidino ring or a morpholino ring. 15. A pharmaceutical composition for the treatment, prevention or inhibition of a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in particular, a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, mood disorders associated with premenstrual syndrome, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; chronic fatigue syndrome; stress-induced headache; cancer; irritable bowel syndrome, Crohn's disease; spastic colon; post operative ileus; ulcer; diarrhea; stress-induced fever; human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; chemical dependencies and addictions (dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.a., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis; hypertension; tachycardia; congestive heart failure; osteoporosis; premature birth; and hypoglycemia in a mammal, comprising an amount of a compound according to Claim 1 that is effective in the treatment of such disorder, and a pharmaceutically acceptable carrier. 16. A method for the treatment, prevention or inhibition of a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression,