Patent EA-000828-B1 (EA)
Title: Antagonists of gonadotropin releasing hormone
Inventor: GOULET MARK
IPC: C07D401/06
Filed: 1996-12-10
Abstract: 1. A compound of the formula:   wherein A is C1-C6 alkyl, substituted C1-C6 alkyl C3-C7 cycloalkyl, substituted C3-C7 cycloalkyl, C3-C6 alkenyl, substituted C3-C6 alkenyl, C3-C6 alkynyl, substituted C3-C6 alkynyl, C1-C6 alkoxy, or C0-C5 alkyl-S(O)n-C0-C5 alkyl, C0-C5 alkyl-O-C0-C5 alkyl, C0-C5 alkyl-NR18- C0-C5 alkyl where R18 and the C0-C5 alkyl can be joined to form a ring,   or a single bond R0 is hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, 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    wherein: Y is B, C or a bond; B is O, S(O)n, C(O), NR18 or C(R11R12)p  C is B(CH2)p-; R2 is hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, 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-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, 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-C6 alkyl, C1-C3 perfluoroalkyl, 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-C6 alkyl, substituted C1-C6 alkyl, aryl, substituted aryl, C1-C3 perfluoroalkyl, CN, NO2, halogen, R11O(CH2)p-, NR21C(O)R20, NR21C(O)NR20R21 or SOnR20; R7 is hydrogen, C1-C6 alkyl, or substituted C1-C6 alkyl, 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-C6 alkyl 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-C6 alkyl, substituted C1-C6 alkyl; aryl or substituted aryl, aralkyl or substituted aralkyl when m#0; or R9 and R9a taken together form a carbocyclic ring of 3-7 atoms or   when m#0 R9 and A taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms when m#0; or R10 and R10a are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; or 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#0; or R9 and R2 taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms when m#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-C6 alkyl, substituted C1-C6 alkyl, 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-C6 alkyl), NR11SO2(aryl), NR11SO2(substituted aryl), NR11SO2(C1-C3 perfluoroalkyl); SO2NR11(C1-C6 alkyl), SO2NR11 (substituted C1-C6 alkyl), SO2NR11(aryl), SO2NR11(substituted aryl), SO2NR11(C1-C3 perfluoroalkyl); SO2NR11(C(O) C1-C6 alkyl); SO2NR11(C(O)-substituted C1-C6 alkyl); SO2NR11(C(O) aryl); SO2NR11(C(O)-substituted aryl); S(O)n(C1-C6 alkyl); S(O)n ( substituted C1-C6 alkyl), S(O)n(aryl), S(O)n(substituted aryl), C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, C1-C6 alkoxy, substituted C1-C6 alkoxy, COOH, halogen, NO2 or CN; R14 and R15 are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, 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-C6 alkyl, C1-C3 perfluoroalkyl, aryl or substituted aryl; R16 is hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, or N(R11R12); R18 is hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C(O)OR11, C(O)NR11R12, C(O)R11, S(O)nR11; R20 and R21 are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, 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-C6-alkyl 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-C6 lkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, or substituted C2-C6 alkynyl; when X is O, S(O)n, C(O), or CR11R12 only R8 is possible; m is 0-3; n is 0-2; p is 0-4; and the alkyl, cycloalkyl, alkenyl and alkynyl substituents are selected from C1-C6 alkyl, C3-C7 cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, hydroxy, oxo, cyano, C1-C6 alkoxy, fluoro, C(O)OR11, aryl C1-C3 alkoxy, substituted aryl C1-C3 alkoxy, 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 thereof. 2. The compound according to claim 1 of the formula:   wherein R1 and X-R8 are as indicated in the table below:     or a pharmaceutically acceptable addition salt and/or hydrate thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof. 3. The compound according to claim 1 of the formula:   wherein X-R7R8 is as indicated in the table below:     or a pharmaceutically acceptable addition salt and/or hydrate thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof. 4. The compound according to claim 1 of the formula:         or a pharmaceutically acceptable addition salt and/or hydrate thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof. 5. The compound according to claim 1 of the formula:   wherein X-R8 is as indicated in the table below:       or a pharmaceutically acceptable addition salt and/or hydrate thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof. 6. The compound according to claim 1 of the formula   or a pharmaceutically acceptable addition salt and/or hydrate thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof. 7. The compound according to claim 1 of the formula   wherein X-R8 is as indicated in the table below:   8. The compound according to claim 1 of the formula:   wherein X-R7R8 is as indicated in the table below:     or a pharmaceutically acceptable addition salt and/or hydrate thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof. 9. The compound according to claim 1 of the formula:   wherein X-R7R8 are as indicated in the table below:     or a pharmaceutically acceptable addition salt and/or hydrate thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof. 10 A pharmaceutical composition which comprises an effective amount of a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefore. 11. 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. 12. A method according to claim 11 wherein the gonadotropin-releasing hormone derived disorder is a sex-hormone related condition. 13. A method according to claim 11 wherein the gonadotropin-releasing hormone derived disorder is a sex hormone dependent cancer, benign prostatic hypertropy or myoma of the uterus. 14. A method according to claim 13 wherein the sex hormone dependent cancer is selected from the group consisting of prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenomas. 15. A method according to claim 12 wherein the sex hormone related condition is selected from the group consisting of endometriosis, polycystic ovarian disease, uterine fibroids and precocious puberty. 16. 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. 17. 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. 18. 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. 19. 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. 20. 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. 21. A me