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Antagonists of gonadotropin releasing hormone

  • US 6,211,224 B1
  • Filed: 10/26/1998
  • Issued: 04/03/2001
  • Est. Priority Date: 10/28/1997
  • Status: Expired due to Fees
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1. A compound of the formula whereinR0 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 and R2 are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C7 cycloalkyl, substituted C3-C7 cycloalkyl, a beterocyclic 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, C3-C6 alkenyl, substituted C3-C6 alkenyl, C3-C6 alkynyl, substituted C3-C6 alkynyl, C0-C5-alkyl-S(O)n—

    C0-C5 alkyl, C2-C6 alkyl(NR11R12), C2-C6 alkyl(OR11), or C1-C6alkyl (CONR11R12);

    with the proviso that R11 and R12 independently or taken together are not aryl, substituted aryl, aralkyl, or substituted aralkyl;

    or R1 and R2 taken together form a non-heteroaromatic ring of 3-8 atoms containing 0,1 or 2 additional heteroatoms selected from S, O or N;

    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, 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;

    R3 and R4 taken together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing 1-3 beteroatoms 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-, NR12C(O)R11, NR12C(O)NR11R12 or SOnR11;

    R7 is hydrogen, C1-C6 alkyl, or substituted C1-C6 alkyl, unless X is hydrogen or halogen, then R7 is absent;

    R8 is hydrogen, C(O)OR9, C(O)NR20R21, N R20R21, C(O)R11, NR20C(O)R11, NR20C(O)N R20R21, NR20S(O)2R11, NR20S(O)2NR20R21, OC(O)R11, OC(O)NR20R21, OR11, SOnR11, S(O)nNR20R21, C1-C6 alkyl or substituted C1-C6 alkyl, unless X is hydrogen or halogen, then R8 is absent;

    or R7 and R8 taken together form a carbocyclic ring of 3-7 atoms;

    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;

    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;

    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;

    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 or a substituted carbocyclic ring containing 3-7 atoms;

    X is hydrogen, halogen, N, O, S(O)n, C(O), (CR11R12)p;

    C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, or substituted C2-C6 alkynyl;

    when X is hydrogen or halogen, R7 and R8 are absent;

    when X is O, S(O)n, C(O), or CR11R12 only R7 or R8 is possible;

    Z is O, S, or NR11;

    m is 0-3;

    n is 0-2;

    p is 0-4; and

    the alkyl, alkenyl and alkynyl substituents are selected from C1-C6 alkyl, C3-C7 cycloalkyl, hydroxy, oxo, cyano, C1-C6 alkoxy, fluoro, C(O)OR11, 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.

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