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Inhibitors of prenyl-protein transferase

  • US 6,172,076 B1
  • Filed: 06/14/1999
  • Issued: 01/09/2001
  • Est. Priority Date: 06/15/1998
  • Status: Expired due to Fees
First Claim
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1. A compound illustrated by the formula I:

  • wherein;

    R1a and R1b are independently selected from;

    a) hydrogen, or b) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O—

    , R9S(O)m

    , R8C(O)NR8

    , CN, (R8)2N—

    C(NR8)—

    , R8C(O)—

    , R8OC(O)—

    , N3, —

    N(R8)2, or R9OC(O)—

    NR8

    ;

    R1 is selected from;

    a) unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—

    , R9S(O)m

    , R8C(O)NR8

    , CN, NO2, R82N—

    C(NR8)—

    , R8C(O)—

    , R8OC(O)—

    , N3, —

    N(R8)2, or R9OC(O)NR8

    , and b) C1-C6 alkyl unsubstituted or substituted by aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—

    , R9S(O)m

    , R8C(O)NH—

    , CN, H2N—

    C(NH)—

    , R8C(O)—

    , R8OC(O)—

    , N3, —

    N(R8)2, or R8OC(O)NH—

    ;

    R2 is independently selected from;

    a) hydrogen, b) unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, ClBr, R8O—

    , R9S(O)m

    , R8C(O)NR8

    , CN, NO2, R82N—

    C(NR8)—

    , R8C(O)—

    , R8OC(O)—

    , N3, —

    N(R8)2, or R9OC(O)NR8

    , and c) C1-C6 alkyl unsubstituted or substituted by aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—

    , R9S(O)m

    , R8C(O)NH—

    , CN, H2N—

    C(NH)—

    , R8C(O)—

    , R8OC(O)—

    , N3, —

    N(R8)2, or R8OC(O)NH—

    ;

    R3 is selected from;

    a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R8O—

    , R9S(O)m

    , R8C(O)NR8

    , CN, NO2, (R8)2N—

    C—

    (NR8)—

    , R8C(O)—

    , R8OC(O)—

    , N3, —

    N(R8)2, or R9OC(O)NR8

    , and c) C1-C6 alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R8O—

    , R9S(O)m

    , R8C(O)NR8

    , CN, (R8)2N—

    C(NR8)—

    , R8C(O)—

    , R8OC(O)—

    , N3, —

    N(R8)2, or R9OC(O)NR8

    ;

    R4a and R4b independently are selected from;

    H, ═

    O, unsubstituted or substituted C1-8 alkyl, or unsubstituted or substituted aryl;

    R4c and R5 independently are selected from;

    H, ═

    O, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted aryl,

    and —

    S(O)2R6, wherein the substituted group is substituted with one or more of;

    1) aryl, unsubstituted or substituted with one or two groups selected from;

    a) C1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) C1-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6, S(O)R6, SO2R6, 5) —

    NR6R715) C1-8 alkyl, 16) C1-8 perfluoroalkyl, or 17) halo;

    R6, R7 and R7a are independently selected from;

    H, C1-4 alkyl, C3-6 cycloalkyl, aryl, C1-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from;

    a) C1-4 alkoxy, b) substituted or unsubstituted aryl, c) halogen, d) HO, g) —

    S(O)mR9, or h) N(R8)2;

    or R8 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;

    R9 is independently selected from C1-C6 alkyl and aryl;

    A1 and A2 are bonds;

    X1 and X3 are N(H)w;

    X2 and X5 are C(H)y;

    X4 is selected from;

    C(H)y, N(H)w, O, C═

    O, S(O)2, and PO(OMe);

    u is 0;

    V is an aryl, W is an imidazolyl;

    m is 0, 1 or 2;

    n is 0, 1, 2, 3 or 4;

    p is 0 1, 2, 3 or 4;

    r is independently 0 to 5;

    s is 1 or 2;

    t is 1;

    w is 0 or 1; and

    y is 1 or 2;

    dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof.

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