Antagonists of gonadotropin releasing hormone

A compound of the formula ##STR294## wherein A is C.sub.1 -C.sub.6 alkyl optionally substituted with one or more halogen, C.sub.3 -C.sub.7 cycloalkyl, substituted C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.6 alkenyl, substituted C.sub.3 -C.sub.6 alkenyl, C.sub.3 -C.sub.6 alkynyl, substituted C.sub.3 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, or C.sub.0 -C.sub.5 alkyl-S(O).sub.n -C.sub.0 -C.sub.5 alkyl, C.sub.0 -C.sub.5 alkyl-O-C.sub.0 -C.sub.5 alkyl, C.sub.0 -C.sub.5 alkyl-NR.sub.18 -C.sub.0 -C.sub.5 alkyl where R.sub.18 and the C.sub.0 -C.sub.5 alkyl do not form a ring, or a single bond;

• R.sub.0 is hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, wherein the substituents are as defined below;
• aryl, substituted aryl, aralkyl or substituted aralkyl, wherein the substituents are as defined for R.sub.3, R.sub.4 and R.sub.5 ;
• R.sub.1 is ##STR295## R.sub.2 is hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, alkyl --OR.sub.11, C.sub.1 -C.sub.6 (NR.sub.11 R.sub.12), C.sub.1 -C.sub.6 (CONR.sub.11 R.sub.12) or C(NR.sub.11 R.sub.12)NH;
• R.sub.2 and A taken together form a ring of 5-7 atoms;
• R.sub.3, R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, substituted C.sub.2 -C.sub.6 alkenyl, CN, nitro, or halogen;
• R.sub.6 is hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, aryl, substituted aryl, C.sub.1 -C.sub.3 perfluoroalkyl, CN, NO.sub.2, halogen, R.sub.11 O(CH.sub.2).sub.p --, NR.sub.12 C(O)R.sub.11, NR.sub.12 C(O)NR.sub.11 R.sub.12 or SO.sub.n R.sub.11 ;
• R.sub.7 is hydrogen, C.sub.1 -C.sub.6 alkyl, or substituted C.sub.1 -C.sub.6 alkyl, unless X is hydrogen or halogen, then R.sub.7 is absent;
• R.sub.8 is hydrogen, C(O)OR.sub.9, C(O)NR.sub.11 R.sub.12, C(O)R.sub.11, NR.sub.12 C(O)R.sub.11, NR.sub.12 C(O)NR.sub.11 R.sub.12, NR.sub.12 S(O).sub.2 R.sub.11, NR.sub.12 S(O).sub.2 NR.sub.11 R.sub.12, OC(O)R.sub.11, OC(O)NR.sub.11 R.sub.12, OR.sub.11, SO.sub.n R.sub.11, S(O).sub.n NR.sub.11 R.sub.12, C.sub.1 -C.sub.6 alkyl or substituted C.sub.1 -C.sub.6 alkyl, unless X is hydrogen or halogen, then R.sub.8 is absent;
• or
• R.sub.7 and R.sub.8 taken together form a carbocyclic ring of 3-7 atoms;
• R.sub.9 and R.sub.9a are independently hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl;
• aryl or substituted aryl, aralkyl or substituted aralkyl when m.notident.0;
• or
• R.sub.9a and A taken together form a ring containing 3-7 carbon atoms when m.notident.0;
• or
• R.sub.10 and R.sub.10a are independently hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl;
• R.sub.11 and R.sub.12 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, a carbocyclic ring of 3-7 atoms or a substituted carbocyclic ring containing 3-7 atoms;
• R.sub.11 and R.sub.12 taken together can form an optionally substituted ring of 3-7 atoms;
• R.sub.13 is hydrogen, OH, NR.sub.20 R.sub.21, NR.sub.11 SO.sub.2 (C.sub.1 -C.sub.6 alkyl), NR.sub.11 SO.sub.2 (substituted C.sub.1 -C.sub.6 alkyl), NR.sub.11 SO.sub.2 (aryl), NR.sub.11 SO.sub.2 (substituted aryl), NR.sub.11 SO.sub.2 (C.sub.1 -C.sub.3 perfluoroalkyl);
• SO.sub.2 NR.sub.11 (C.sub.1 -C.sub.6 alkyl), SO.sub.2 NR.sub.11 (substituted C.sub.1 -C.sub.6 alkyl), SO.sub.2 NR.sub.11 (aryl), SO.sub.2 NR.sub.11 (substituted aryl), SO.sub.2 NR.sub.11 (C.sub.1 -C.sub.3 perfluoroalkyl);
• SO.sub.2 NR.sub.11 (C(O)C.sub.1 -C.sub.6 alkyl);
• SO.sub.2 NR.sub.11 (C(O)-substituted C.sub.1 -C.sub.6 alkyl);
• SO.sub.2 NR.sub.11 (C(O)-aryl);
• SO.sub.2 NR.sub.11 (C(O)-substituted aryl);
• S(O).sub.n (C.sub.1 -C.sub.6 alkyl);
• S(O).sub.n (substituted C.sub.1 -C.sub.6 alkyl), S(O).sub.n (aryl), S(O).sub.n (substituted aryl), C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.1 -C.sub.3 perfluoroalkoxy, C.sub.1 -C.sub.6 alkoxy, substituted C.sub.1 -C.sub.6 alkoxy, COOH, halogen, NO.sub.2 or CN;
• R.sub.14 and R.sub.15 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, substituted C.sub.2 -C.sub.6 alkenyl, CN, nitro, C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.1 -C.sub.3 perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, R.sub.11 O(CH.sub.2).sub.p --, R.sub.11 C(O)O(CH.sub.2).sub.p --, R.sub.11 OC(O)(CH.sub.2).sub.p --, --(CH.sub.2).sub.p S(O).sub.n R.sub.17, --(CH.sub.2).sub.p C(O)NR.sub.11 R.sub.12 or halogen;
• wherein R.sub.17 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.3 perfluoroalkyl, aryl or substituted aryl;
• or
• R.sub.13 and R.sub.14 taken together form an oxo group;
• R.sub.18 is hydrogen;
• R.sub.19 is either the definition of R.sub.13 or R.sub.14 ;
• R.sub.20 and R.sub.21 are independently hydrogen, C.sub.1 -C.sub.6 alkyl or substituted C.sub.1 -C.sub.6 alkyl;
• X is hydrogen, halogen, N, O, S(O).sub.n, C(O), (CR.sub.11 R.sub.12).sub.p ;
• when X is hydrogen or halogen, R.sub.7 and R.sub.8 are absent;
• when X is O, S(O)n, C(O), or CR.sub.11 R.sub.12 only one of R.sub.7 or R.sub.8 is present;
• Z is O, S, or NR.sub.11 ;
• with the proviso that if only one heterocyclic atom is present it must be N;
• m is 0-3;
• n is 0-2;
• p is 0-;
• and the alkyl, alkenyl and alkynyl substituents are selected from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, hydroxy, oxo, cyano, C.sub.1 -C.sub.6 alkoxy, fluoro, COOH, C(O)O(C.sub.1 -C.sub.6)alkyl, aryl C.sub.1 -C.sub.3 alkoxy, substituted aryl C.sub.1 -C.sub.3 alkoxy, and the aryl substituents are as defined for R.sub.3, R.sub.4 and R.sub.5 ;
• or a pharmaceutically acceptable addition salt and/or hydrate thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof.