Patent EA-002607-B1 (EA)
Title: Substituted 6,6-hetero-bicyclic derivatives
Inventor: CHEN YUHPYNG LIANG
IPC: C07D475/02
Filed: 1997-07-21
Abstract: 1. A compound of the formula   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> or -COR<2>; G is nitrogen or CR<4> and is single bonded to all atoms to which it is attached, or G is carbon and is double bonded to K; K is nitrogen or CR<6> when double bonded to G or E, or K is C=O or CR<6>R<12> when single bonded to both adjacent ring atoms; D and E are each independently C=O, oxygen, CR<4>R<6> or NR<8> when single bonded to both adjacent ring atoms, or nitrogen or CR<4> when it is double bonded to an adjacent ring atom; the 6-membered ring that contains D, E, K and G may contain from one to three double bonds, from zero to two heteroatoms selected from oxygen or nitrogen, and from zero to two C=O groups, wherein the carbon atoms of such groups are part of the ring and the oxygen atoms are substituents on the ring; R<1> is C1-C6 alkyl optionally substituted with from one or two substituents independently selected from hydroxy, fluoro-, chloro-, bromo-, iodo-, C1-C4 alkoxy, CF3, -C(=O)(C1-C4alkyl), -C(=O)-O-(C1-C4)alkyl,-OC(=O)(C1-C4 alkyl), -OC(=O)N(C1-C4 alkyl)(C1-C2 alkyl), -NHCO(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CON(C1-C4alkyl)(C1-C2 alkyl), and-SO2(C1-C4 alkyl), wherein each of the C1-C4 alkyl groups in the foregoing R<1> groups may optionally contain one or two double 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, pyridyl, thiazolyl; 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, 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 C1-C6 alkoxy, -OC(=O)(C1-C6 alkyl), -OC(=O)N(C1-C4 alkyl)(C1-C2 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), -CONH(C1-C4 alkyl), -CON(C1-C4 alkyl)(C1-C2 alkyl) and -SO2(C1-C4 alkyl); -NR<1>R<2> or CR<1>R<2>R<10> may form a ring selected from   R<3> is hydrogen, C1-C4 alkyl; each R<8> and R<12> is selected, independently, from hydrogen and C1-C2 alkyl; each R<4> and R<6> that is attached to a carbon atom is selected, independently, from hydrogen and C1-C6 alkyl, chloro-; R<5> is substituted phenyl, wherein said phenyl is substituted with from two to four substituents, said substituents may be selected, independently from C1-C6 alkyl; R<7> is hydrogen or methyl; R<10> is hydrogen, hydroxy, methoxy or fluoro-; and R<11> is hydrogen or C1-C4 alkyl; with the proviso that in the ring containing D, E, K and G of formula I, there can not be two double bonds adjacent to each other; with additional clause, that if (1) B is NR<1>R<2>, and NR<1>R<2 >does not form the ring or forms heteroaryl ring comprising nitrogen, or if (2) B is CR<1>R<2>R<10>, and CR<1>R<2>R<10> does not form the ring or forms aryl or heteroaryl ring or if (3) B is -OCR<1>R<2>R<10>  and CR<1>R<2>R<10> is alkyl, then bicyclic nucleus, comprising A, D, E, K and G, can not be   R<7> is hydrogen, methyl or halo; R<4> or R<6> is hydrogen or alkyl, R<5> is phenyl, pyridyl, pyrimidyl, R<3> is hydrogen or alkyl, and R<8> is hydrogen or alkyl only that the compound of formula I can represent 8-(1-ethyl-propoxy)-6-methyl-4-(2,4,6-trimethyl-phenyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one; 8-(1-ethyl-propoxy)-6-methyl-4-(2,4,6-trimethyl-phenyl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine; 8-(1-ethyl-propoxy)-1,6-dimethyl-4-(2,4,6-trimethyl-phenyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one; 8-(1-ethyl-propoxy)-1,6-dimethyl-4-(2,4,6-trimethyl-phenyl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine; or a pharmaceutically acceptable salt of such compound. 2. A compound according to Claim 1 wherein B is -NR<1>R<2>, -NHCHR<1>R<2> or -OCHR<1>R<2>, R<1> is C1-C6alkyl, which can be optionally subtituted with one fluoro- or C1-C4alkoxy group, and can optionally comprise one double bond, and R<2> is C1-C4alkyl or -(C1-C2 alkyl)-CO-(C1-C2 alkyl), which can optionally comprise one double or triple bond. 3. A compound according to Claim 1, wherein B is -CHR<1>R<2>, -NR<1>R<2>, -NHCHR<1>R<2>, -OCHR<1>R<2> or -SCHR<1>R<2>, R<1> is C1-C6 alkyl, which may optionally be substituted with one hydroxy, cyclopropylfluoro-, CF3 or C1-C4 alkoxy group and may optionally contain one double bond; and R<2> is benzyl or C1-C4 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-, cyclopropyl, hydroxy CF3, C1-C2 alkyl, C1-C2 alkoxy or chloro- group. 4. A compound according to Claim 1 wherein A is N, CH or CCH3. 5. A compound according to Claim 1 wherein G is nitrogen. 6. A compound according to Claim 1 wherein G is carbon and the ring containing D, E, K and G is a benzo ring. 7. A compound according to Claim 1 wherein G is N; and E--K is CH2-CH2, CH=CH, C(O)-CH2, or CH2-C(O). 8. A Compound according to Claim 1 wherein G is N; D--E--K is C(O)-O-CH2, CH2-O-CH2, C(O)-CH2-CH2, C(O)-CH=CH, CH2-CH2-CH2-, CH2-CH2-C(O), CH=CH-C(O), CH=CH-CH2, CH=CH-NH, CH=CH-NCH3. 9. A compound according to Claim 1 wherein R<3> is methyl and each of R<4>, R<6>, R<8> and R<12> is hydrogen. 10. A compound 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. 11. A compound according to Claim 1 wherein R<3> is methyl or ethyl, and each R<4>, R<6>, R<8> and R<12> is, independently, hydrogen or methyl. 12. A compound according to Claim 1 wherein B is -CHR<1>R<2>, -NHCHR<1>R<2> or -OCHR<1>R<2>, and the CHR<1>R<2> group of B is a tetrahydrofuran ring. 13. A pharmaceutical composition for the treatment, prevention or inhibition of (a) a disorder the treatment of which can be effected or facilitated by antagonizing CRF, or (b) 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.n., 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. 14. A method for the treatment, prevention or inhibition of (a) a disorder the treatment of which can be effected or facilitated by antagonizing CRF, or (b) 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; stressinduced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head t