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Inhibitors of farnesyl-protein transferase

  • US 5,756,528 A
  • Filed: 05/23/1996
  • Issued: 05/26/1998
  • Est. Priority Date: 06/06/1995
  • Status: Expired due to Fees
First Claim
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1. A compound which inhibits Ras farnesyl-transferase having the Formula XVI:

  • ##STR18## wherein;

    R2 and R3 are independently selected from;

    a) a side chain of a naturally occurring amino acid,b) an oxidized form of a side chain of a naturally occurring amino acid which is;

    i) methionine, sulfoxide, orii) methionine sulfone, andc) substituted or unsubstituted C1 -C20 alkyl, substituted or unsubstituted C2 -C20 alkenyl, substituted or unsubstituted C3 -C10 cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group,wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, (R10)2 N--C(NR10)--, R10 C(O)--, R10 OC(O)--, N3,-- N(R10)2, R11 OC(O)NR10 -- and C1 -C20 alkyl, andd) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3 -C10 cycloalkyl;

    orR2 and R3 are combined to form --(CH2)s --;

    R4 and R5 are independently selected from;

    a) hydrogen,b) C1 -C6 alkyl unsubstituted or substituted by C2 -C20 alkenyl, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, N3, (R10)2 N-- C(NR10)--, R10 C(O)--, --N(R10)2, or R10 OC((O)NR10 --,c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, halogen, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, NO2, (R10)2 N--C(NR10)--, R10 (O)--, N3,-- N(R10)2, or R11 OC(O)NR10 --, andd) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3 -C10 cycloalkyl;

    R6 is selected from;

    a) hydrogen,b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C1 -C20 perfluoroalkyl, allyloxy, F, Cl, Br, R10 O--, R11 S (O)m --, R10 C(O)NR10 --, CN, NO2, R102 N--C(NR10)--, R10 C(O)--, N3, --N(R10)2, (R12)2 NC(O)-- or R11 OC(O)NR10 --, andc) C1 -C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C2 -C20 perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NH--, CN, H2 N--C(NH)--, R10 C(O)--, N3, --N(R10)2, or R10 OC(O)NH--;

    R7 is independently selected froma) hydrogen,b) unsubstituted or substituted aryl,c) unsubstituted or substituted heterocycle,d) unsubstituted or substituted C3 -C10 cycloalkyl, ande) C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3 -C10 cycloalkyl;

    R8 is selected from;

    a) hydrogen,b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C1 -C20 perfluoroalkyl, allyloxy, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, --S(O)2 NR102, CN, NO2, R102 N-- C(NR10)--, R10 C(O)--, R10 OC(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, andc) C1 -C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C2 -C20 perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NH--, CN, H2 N--C(NH)--, R10 OC(O)--, R10 OC(O)--, N3, --N(R10)2, or R10 OC(O)NH--;

    R10 is independently selected from hydrogen, C1 -C6 alkyl, benzyl and aryl;

    R11 is independently selected from C1 -C6 alkyl and aryl;

    R12 is independently selected from hydrogen, C1 -C6 alkyl and aryl, or (R12)2 forms --(CH2)s --;

    A1 and A2 are independently selected from;

    a bond, --CH═

    CH--, --C.tbd.C--, --C(O)--, --C(O)NR7 --, --NR7 C(O)--, O, --N(R7)--, --S(O)2 N(R7)--, --N(R7)S(O)2 --, or S(O)m ;

    A3 is independently selected from;

    a bond, --CH═

    CH--, --C.tbd.C--, --C(O)NR7 --, --NR7 C(O)--, O, --N(R7)--, --S(O)N(R7)--, --N(R7)S(O)2 --, or S(O)m ;

    A4 is selected from;

    a bond, O, --N(R7)-- or S,V is aryl;

    m is 0, 1 or 2;

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

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

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

    r is 0 to 5, provided that r is 0 when V is hydrogen;

    s is 4 or 5; and

    provided heterocycle is not tetrazolyl; and

    substituted aryl is an aryl group which is substituted with 1 or 2 substitutents selected from F, Cl, Br, CF3, NH2, N(C1 -C6 alkyl)2, NO2, CN, (C1 -C6 alkyl)O--, --OH, (C1 -C6 alkyl)S(O)m --, (C1 -C6 alkyl)C(O)NH--, H2 N--C(NH)--, (C1 -C6 alkyl)C(O)--, (C1 -C6 alkyl)OC(O)--, N3, (C1 -C6 alkyl)OC(O)NH-- and C1 -C20 alkyl;

    or a pharmaceutically acceptable salt thereof.

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