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IL-8 receptor antagonists

  • US 6,262,113 B1
  • Filed: 08/14/1998
  • Issued: 07/17/2001
  • Est. Priority Date: 03/20/1996
  • Status: Expired due to Fees
First Claim
Patent Images

1. A compound of the formula:

  • whereinX is oxygen;

    X1 is oxygen or sulfur;

    R1 is independently selected from hydrogen;

    halogen;

    nitro;

    cyano;

    C1-10 alkyl;

    halosubstituted C1-10 alkyl;

    C2-10 alkenyl;

    C1-10 alkoxy;

    halosubstituted C1-10alkoxy;

    azide;

    S(O)tR4;

    (CR8R8)q S(O)tR4;

    hydroxy;

    hydroxy substituted C1-4alkyl;

    aryl;

    aryl C1-4 alkyl;

    aryl C2-10 alkenyl;

    aryloxy;

    aryl C1-4 alkyloxy;

    heteroaryl;

    heteroarylalkyl;

    heteroaryl C2-10 alkenyl;

    heteroaryl C1-4 alkyloxy;

    heterocyclic, heterocyclic C1-4alkyl;

    heterocyclicC1-4alkyloxy;

    heterocyclicC2-10 alkenyl;

    (CR8R8)q NR4R5;

    (CR8R8)q C(O)NR4R5;

    C2-10 alkenyl C(O)NR4R5;

    (CR8R8)q C(O)NR4R10;

    S(O)3R8;

    (CR8R8)q C(O)R11;

    C2-10 alkenyl C(O)R11;

    C2-10 alkenyl C(O)OR11;

    (CR8R8)q C(O)OR11;

    (CR8R8)q OC(O)R11;

    (CR8R8)qNR4C(O)R11;

    (CR8R8)q C(NR4)NR4R5;

    (CR8R8)q NR4C(NR5)R11;

    (CR8R8)q NHS(O)2R13;

    (CR8R8)q S(O)2NR4R5;

    or two R1 moieties together may form O—

    (CH2)sO—

    or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, and heterocyclic moieties are substituted;

    or unsubstituted t is 0, or an integer having a value of 1 or 2;

    s is an integer having a value of 1 to 3;

    R4 and R5 are independently hydrogen, substituted or unsubstituted C1-4 alkyl, substituted aryl, substituted aryl C1-4alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl C1-4 alkyl, heterocyclic, heterocyclic C1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which does or does not contain an additional heteroatom selected from O, N or S;

    Y is hydrogen;

    halogen;

    nitro;

    cyano;

    halosubstituted C1-10 alkyl;

    C1-10 alkyl;

    C2-10 alkenyl;

    C1-10 alkoxy;

    halosubstituted C1-10 alkoxy;

    azide;

    (CR8R8)qS(O)tR4;

    (CR8R8)qOR4;

    hydroxy;

    hydroxy substituted C1-4alkyl;

    aryl, aryl C1-4 alkyl;

    aryloxy;

    arylC1-4 alkyloxy;

    aryl C2-10 alkenyl;

    heteroaryl;

    heteroarylalkyl;

    heteroaryl C1-4 alkyloxy;

    heteroaryl C2-10 alkenyl;

    heterocyclic, heterocyclic C1-4alkyl;

    heterocyclicC2-10 alkenyl;

    (CR8R8)qNR4R5;

    C2-10 alkenyl C(O)NR4R5;

    (CR8R8)qC(O)NR4R5;

    (CR8R8)q C(O)NR4R10;

    S(O)3R8;

    (CR8R8)qC(O)R11;

    C2-10 alkenylC(O)R11;

    (CR8R8)qC(O)OR11;

    C2-10alkenylC(O)OR11;

    (CR8R8)qOC(O) R11;

    (CR8R8)qNR4C(O)R11;

    (CR8R8)q NHS(O)2Rb;

    (CR8R8)q S(O)2NR4R5, (CR8R8)qC(NR4)NR4R5;

    (CR8R8)q NR4C(NR5)R11;

    or two Y moieties together may form O—

    (CH2)sO—

    or a 5 to 6 membered unsaturated ring; and

    wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups are substituted;

    or unsubstituted q is 0 or an integer having a value of 1 to 10;

    n is an integer having a value of 1 to 3;

    m is an integer having a value of 1 to 3;

    R6 and R7 are independently hydrogen or a C1-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring does or does not contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;

    R8 is hydrogen or C1-4 alkyl;

    R10 is C1-10 alkyl C(O)2R8;

    R11 is hydrogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl C1-4alkyl, substituted or substituted heteroaryl, substituted heteroaryl C1-4alkyl, substituted or substituted heterocyclic, or substituted or unsubstituted heterocyclicC1-4alkyl;

    R12 is hydrogen, C1-1alkyl, substituted or substituted aryl or substituted or substituted arylalkyl;

    R13 is C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl;

    Rb is NR6R7, alkyl, aryl, aryl C1-4 alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl C1-4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4 alkyl, heterocyclic C2-4 alkenyl, or camphor, all of which groups are optionally substituted;

    provided that when n=1 than Y is substituted in the 2- or 3-position;

    when n=2 than Y is di-substituted in the 2′

    -3′

    -position, the 2′

    -5′

    -position, the 2′

    -6′

    position, the 3′

    -5′

    or the 3′

    -6′

    position;

    when n=3 than Y is trisubstituted in the 2′

    -3′

    -5′

    or the 2′

    -3′

    -6′

    -positions;

    further provided that when X1 is O, m=2, R1 is 2-t-butyl, 4-methyl, and n=3 than Y is not 2′

    -OH, 3′

    -t-butyl, 5′

    -methyl;

    when X1 is O, m=1, R1 is 4-methyl, and n=2 than Y is not 2′

    -OH, 5′

    -methyl;

    when X1 is O, m=1, R1 is hydrogen, and n=2 than Y is not 2′

    -6′

    -diethyl;

    when X1 is O, m=1, R1 is 6—

    OH, and n=2 than Y is not 2′

    -5′

    -methyl;

    when X1 is S, m=1, R1 is 4-ethyl, and n=1 than Y is not 2-methoxy;

    when X1 is O, m=1, R1 is 5-nitro, and, n=2 than Y is not 2-fluoro-5-nitro, or 2-methyl-5-nitro, or 2,3,-dichloro, or 2-methyl-6-chloro, or 2,5-dimethoxy, or 2-methyl-3-chloro;

    when X1 is O, m=1, R1 is 3-nitro, and n=1, than Y is not hydrogen;

    when X1 is O, m=1, R1 is 3-nitro, and n=2, than Y is not 2,5-dichloro;

    when X1 is O, m=1, R1 is hydrogen, and n=2, than Y is not 2-methyl-5-chloro;

    when X1 is O, m=1, R1 is 5-chloro, and n=1, than Y is not hydrogen;

    when X1 is O, m=1, R1 is 5-chloro, and n=2, than Y is not 2-fluoro-5-nitro, or 3,4,-dichloro, or 2-methyl-5-nitro;

    when X1 is O, m=1, R1 is 4-amino, and n=1, than Y is not hydrogen;

    or a pharmaceutically acceptable salt thereof.

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