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Antagonists of gonadotropin releasing hormone

  • US 6,025,366 A
  • Filed: 03/25/1999
  • Issued: 02/15/2000
  • Est. Priority Date: 04/02/1998
  • Status: Expired due to Fees
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Assignment
First Claim
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1. A compound of the formula ##STR21## 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, ##STR22## 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 ##STR23## the nitrogen atoms contained in the R1 heteroaromatic rings may exist either as drawn or, when chemically allowed, in their oxidized (N→

    O) state;

    R2 is hydrogen, C1 -C6 alkyl, substituted C1 -C6 alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, alkyl --OR11, C1 -C6 (NR11 R12), C1 -C6 (CONR11 R12) or C(NR11 R12)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, R11 O(CH2)p --, R11 C(O)O(CH2)p --, R11 OC(O)(CH2)p --, --(CH2)p S(O)n R17, --(CH2)p C(O)NR11 R12 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, R11 O(CH2)p --, NR12 C(O)R11, NR12 C(O)NR11 R12 or SOn R11 ;

    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)NR11 R12, NR11 R12, C(O)R11, NR12 C(O)R11, NR12 C(O)NR11 R12, NR12 S(O)2 R11, NR12 S(O)2 NR11 R12, OC(O)R11, OC(O)NR11 R12, OR11, SOn R11, S(O)n NR11 R12, C1 -C6 alkyl or substituted C1 -C6 alkyl, unless X is hydrogen or halogen, then R8 is absent;

    orR7 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;

    orR9 and R9a taken together form a carbocyclic ring of 3-7 atoms or ##STR24## 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;

    orR10 and R10a are independently hydrogen, C1 -C6 alkyl, substituted C1 -C6 alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl;

    orR10 and R10a taken together form a carbocyclic ring of 3-7 atoms or ##STR25## 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;

    orR9 and R2 taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms when m≠

    0;

    orR10 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;

    orR11 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, NR7 R8, NR11 SO2 (C1 -C6 alkyl), NR11 SO2 (substituted C1 -C6 alkyl), NR11 SO2 (aryl), NR11 SO2 (substituted aryl), NR11 SO2 (C1 -C3 perfluoroalkyl);

    SO2 NR11 (C1 -C6 alkyl), SO2 NR11 (substituted C1 -C6 alkyl), SO2 NR11 (aryl), SO2 NR11 (substituted aryl), SO2 NR11 (C1 -C3 perfluoroalkyl);

    SO2 NR11 (C(O)C1 -C6 alkyl);

    SO2 NR11 (C(O)-substituted C1 -C6 alkyl);

    SO2 NR11 (C(O)-aryl);

    SO2 NR11 (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, R11 O(CH2)p --, R11 C(O)O(CH2)p --, R11 OC(O)(CH2)p --, --(CH2)p S(O)n R17, --(CH2)p C(O)NR11 R12 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(R11 R12);

    R18 is hydrogen, C1 -C6 alkyl, substituted C1 -C6 alkyl, C(O)OR9, C(O)NR11 R12, C(O)R11, S(O)n R11 ;

    R19 is either the definition of R13 or R14 ;

    X is hydrogen, halogen, N, O, S(O)n, C(O), (CR11 R12)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 CR11 R12 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, 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 acceptible addition salt and/or hydrate thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof.

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