Patent EA-000992-B1 (EA)
Title: Antagonists of gonadotropin releasing hormone
Inventor: GOULET MARK
IPC: A61K31/4545
Filed: 1996-12-10
Abstract: 1. A compound of the formula   wherein A is C1-C6 alkyl, substituted C1-C6alkyl, C3-C7cycloalkyl, substituted C3-C7cycloalkyl, C3-C6alkenyl substituted C3-C6alkenyl, C3-C6alkynyl, substituted C3-C6alkynyl, C1-C6alkoxy, or (C0-C5alkyl)-S(O)n-(C0-C5alkyl), (C0-C5alkyl)-O-(C0-C5alkyl), (C0-C5alkyl)-NR18-(C0-C5alkyl), where R18 and the (C0-C5alkyl) can be joined to form a ring,   or a single bond; R0 is hydrogen, C1-C6alkyl, substituted C1-C6alkyl wherein the substituents are as defined below; aryl, substituted aryl, aralkyl or substituted aralkyl, wherein the substituents are as defined for R3, R4 and R5; R1 is      R2 is hydrogen, C1-C6alkyl, substituted C1-C6alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, alkyl-OR11, C1-C6(NR11R12), C1-C6(CONR11R12) or C(NR11R12)NH; R2 and A taken together form a ring of 5-7 atoms; R3, R4 and R5 are independently hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C2-C6alkenyl, substituted C2-C6alkenyl, CN, nitro, C1-C3perfluoroalkyl, C1-C3perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, R11O(CH2)p-, R11C(O)O(CH2)p-, R11OC(O)(CH2)p-, -(CH2)pS(O)nR17, -(CH2)pC(O)NR11R12 or halogen; wherein R17 is hydrogen, C1-C6alkyl, C1-C3perfluoroalkyl, aryl or substituted aryl;  R3 and R4 taken together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing 1-3 heteroatoms selected from N, O and S; R6 is hydrogen, C1-C6alkyl, substituted C1-C6alkyl, aryl, substituted aryl, C1-C3perfluoroalkyl, CN, NO2, halogen, R11O(CH2)p-, NR21C(O)R20, NR21C(O)NR20R21 or SOnR20; R7 is hydrogen, C1-C6alkyl or substituted C1-C6alkyl, unless X is hydrogen or halogen, then R7 is absent; R8 is C(O)OR20, C(O)NR20R21, NR20R21, C(O)R20, NR21C(O)R20, NR21C(O)NR20R21, NR20S(O)2R21, NR21S(O)2NR20R21, OC(O)R20, OC(O)NR20R21, OR20, SOnR20, S(O)nNR20R21, a heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4 heteroatoms selected from N, O or S which can be optionally substituted by R3, R4 and R5, C1-C6alkyl or substituted C1-C6 alkyl; or R7 and R8 taken together form a heterocyclic ring containing one or more heteroatoms selected from N, O or S which can be optionally substituted by R3, R4 and R5; R9 and R9a are independently hydrogen, C1-C6alkyl, substituted C1-C6alkyl; aryl or substituted aryl, aralkyl or substituted aralkyl when m [not equal] 0; or R9 and R9a taken together form a carbocyclic ring of 3-7 atoms or    when m [not equal] 0;  R10 and R10a taken together form a carbocyclic ring of 3-7 atoms or   R9 and R10 taken together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing one or more heteroatoms when m [not equal] 0; or R9 and R2 taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms when m [not equal] 0; or R10 and R2 taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;  R10 and A taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; or R11 and R12 are independently hydrogen, C1-C6alkyl, substituted C1-C6alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, a carbocyclic ring of 3-7 atoms or a substituted carbocyclic ring containing 3-7 atoms; R11 and R12 taken together can form an optionally substituted ring of 3-7 atoms; R13 is hydrogen, OH, NR7R8, NR11SO2(C1-C6 alkyl), NR11SO2(substituted C1-C6alkyl), NR11SO2(aryl),NR11SO2(substituted aryl), NR11SO2(C1-C3perfluoroalkyl); SO2NR11(C1-C6alkyl), SO2NR11(substituted C1-C6alkyl), SO2NR11(aryl), SO2NR11(substituted aryl), SO2NR11(C1-C3perfluoroalkyl); SO2NR11(C(O) C1-C6alkyl), SO2NR11(C(O)-substituted C1-C6alkyl); SO2NR11(C(O)aryl), SO2NR11(C(O)-substituted aryl); S(O)n(C1-C6alkyl), S(O)n (substituted C1-C6alkyl), S(O)n(aryl), S(O)n(substituted aryl), C1-C3perfluoroalkyl, C1-C3perfluoroalkoxy, C1-C6alkoxy, substituted C1-C6alkoxy, COOH, halogen, NO2 or CN; R14 and R15 are independently hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C2-C6alkenyl, substituted C2-C6alkenyl, CN, nitro, C1-C3perfluoroalkyl, C1-C3perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, R11O(CH2)p-, R11C(O)O(CH2)p-, R11OC(O)(CH2)p-, -(CH2)pS(O)nR17, -(CH2)pC(O)NR11R12 or halogen; wherein R17 is hydrogen, C1-C6alkyl, C1-C3perfluoroalkyl, aryl or substituted aryl; R16 is hydrogen, C1-C6alkyl, substituted C1-C6alkyl, or N(R11R12); R18 is hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C(O)OR11, C(O)NR11R12, C(O)R11, S(O)nR11; R19 is either the definition of R13 or R14; R20 and R21 are independently hydrogen , C1-C6alkyl, substituted C1-C6alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl; a carbocyclic ring of 3-7 atoms, a substituted carbocyclic ring containing 3-7 atoms, a heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4 heteroatoms selected from N, O or S which can be optionally substituted by R3, R4 and R5, C1-C6alkyl substituted by a heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4 heteroatoms selected from N, O or S which can be optionally substituted by R3, R4 and R5; R20 and R21 taken together can form an optionally substituted ring of 3-7 atoms; X is N, O, S(O)n, C(O), (CR11R12)p a single bond to R8, C2-C6alkenyl, substituted C2-C6alkenyl, C2-C6alkynyl, substituted C2-C6alkynyl; when X is O, S(O)n, C(O), or CR11R12 only R8 is possible; Z is O, S or NR11; m is 0-3; n is 0-2; p is 0-4; and the alkyl, cycloalkyl, alkenyl and alkynyl substituents are selected from C1-C6alkyl, C3-C7cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, hydroxy, oxo, cyano, C1-C6alkoxy, fluoro, C(O)OR11, aryl C1-C3alkoxy, substituted aryl C1-C3alkoxy, and the aryl substituents are as defined for R3, R4 and R5; or a pharmaceutically acceptable addition salt and/or hydrate thereof, or where applicable, a geometric or optical isomer or racemic mixture of isomers. 2. The compound according to claim 1 of the formula:   wherein R1 and X-R7, R8 are as indicated in the table below:       3. The compound according to claim 1 of the formula:   wherein R1 and X-R7, R8 are as indicated in the table below:         4. The compound according to claim 1 of the formula:   wherein R1 and X-R7, R8 are as indicated in the table below:     5. The compound according to claim 1 of the formula:   wherein A, R1 and X-R7, R8 are as indicated in the table below:       6. The compound according to claim 1 of the formula:   wherein R1, R2, R9, R9a, R10, R10a, X-R7  R8 and A are as indicated in the table below:   7. The compound according to claim 1 of the formula:   wherein R1, R2, R9, R9a, R10, R10a, X-R7  R8 and A are as indicated in the table below:           8 A pharmaceutical composition which comprises an effective amount of a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor. 9. A method for antagonizing gonadotropin-releasing hormone in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in claim 1 to a subject suffering from a gonadotropin-releasing hormone derived disorder. 10. A method according to claim 9 wherein the gonadotropin-releasing hormone derived disorder is a sex-hormone related condition. 11. A method according to claim 9 wherein the gonadotropin-releasing hormone derived disorder is a sex hormone dependent cancer, benign prostatic hypertropy or myoma of the uterus. 12. A method according to claim 11 wherein the sex hormone dependent cancer is selected from the group consisting of prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenomas. 13. A method according to claim 10 wherein the gonadotropin-releasing hormone derived disorder is selected from the group consisting of endometriosis, polycystic ovarian disease, uterine fibroids and precocious puberty. 14. A method for preventing pregnancy in a subject in need thereof which comprises administering an effective amount of a compound as defined in claim 1.  15. A method for treating lupus erythematosis in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in claim 1. 16. A method for treating irritable bowel syndrome in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in claim 1. 17. A method for treating premenstrual syndrome in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in claim 1. 18. A method for treating hirsutism in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in claim 1. 19. A method for treating short stature or a growth hormone deficiency in a subject in need thereof which comprises administering to said subject an effective amount of a compound which stimulates the endogenous production or release of growth hormone and an effective amount of a compound as defined in claim 1. 20. A method for treating sleep disorders such as sleep apnea in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in claim 1. 21. A pharmaceutical composition which comprises an inert carrier and an effective amount of a compound which stimulates the endogenous production or release of growth hormone in combination with a compound as defined in claim 1. 22. A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier therefor.  23. A process for making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.