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Piperazine derivatives useful as CCR5 antagonists

  • US 6,391,865 B1
  • Filed: 05/01/2000
  • Issued: 05/21/2002
  • Est. Priority Date: 05/04/1999
  • Status: Expired due to Term
First Claim
Patent Images

1. A compound represented by the structural formula II embedded imageor a pharmaceutically acceptable salt thereof, wherein(1) Ra is R8a-phenyl, R8b-pyridyl, R8b-thiophenyl or R8-naphthyl;

  • R1 is hydrogen or C1-C6 alkyl;

    R2 is 6-membered heteroaryl substituted by R9, R10 and R11;

    6-membered heteroaryl N-oxide substituted by R9, R10 and R11;

    5-membered heteroaryl substituted by R12 and R13;

    naphthyl;

    fluorenyl;

    diphenylmethyl;

    embedded imageR3 is hydrogen, C1-C6 alkyl, (C1-C6)alkoxy(C1-C6)alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl(C1-C6)alkyl, R8-phenyl, R8-phenyl(C1-C6)alkyl, R8-naphthyl, R8-naphthyl(C1-C6)alkyl, R8-heteroaryl or R8-heteroaryl(C1-C6)alkyl;

    R4, R5, R7 and R13 are independently selected from the group consisting of hydrogen and (C1-C6)-alkyl;

    R6 is hydrogen, C1-C6 alkyl or C2-C6 alkenyl;

    R8 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, —

    CF3, CF3O—

    , CH3C(O)—

    , —

    CN, CH3SO2

    , CF3SO2

    , R14-phenyl, R14-benzyl, CH3C(═

    NOCH3), CH3C(═

    NOCH2CH3), embedded image



    NH2, —

    NHCOCF3, —

    NHCONH(C1-C6 alkyl), —

    NHCO(C1-C6 alkyl), —

    NHSO2(C1-C6 alkyl), 5-membered heteroaryl and embedded image

    wherein X is —

    O—

    , —

    NH—

    or —

    N(CH3)—

    ;

    R8a is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, —

    CF3, CF3O—

    , —

    CN, CF3SO2

    , R14-phenyl, —

    NHCOCF3, 5-membered heteroaryl and embedded image

    wherein X is as defined above;

    R8b is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, —

    CF3, CF3O—

    , CH3C(O)—

    , —

    CN, CF3SO2

    , CH3C(═

    NOCH3), CH3C(═

    NOCH2CH3), —

    NHCOCF3, 5-membered heteroaryl and embedded image

    wherein X is as defined above;

    R9 and R10 are independently selected from the group consisting of (C1-C6)alkyl, halogen, —

    NR17R18, —

    OH, —

    CF3, —

    OCH3, —

    O-acyl, —

    OCF3 and —

    Si(CH3)3;

    R11 is R9, hydrogen, phenyl, —

    NO2, —

    CN, —

    CH2F, —

    CHF2, —

    CHO, —

    CH═

    NOR17, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, —

    N(R17)CONR18R19, —

    NHCONH(chloro-(C1-C6)alkyl), —

    NHCONH((C3-C1) -cycloalkyl(C1-C6)alkyl), —

    NHCO(C1-C6)alkyl, —

    NHCOCF3, —

    NHSO2N((C1-C6)-alkyl)2, —

    NHSO2(C1-C6)alkyl, —

    N(SO2CF3)2, —

    NHCO2(C1-C6)alkyl, C3-C10 cycloalkyl, —

    SR20, —

    SOR20, —

    SO2R20, —

    SO2NH(C1-C6)alkyl), —

    OSO2(C1-C6)alkyl, —

    OSO2CF3, hydroxy(C1-C6)alkyl, —

    CON R17R18, —

    CON(CH2CH2

    O—

    CH3)2, —

    OCONH(C1-C6)alkyl, —

    CO2R17, —

    Si(CH3)3 or —

    B(OC(CH3)2)2;

    R12 is (C1-C6)alkyl, —

    NH2 or R14-phenyl;

    R14 is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C1-C6)alkyl, —

    CF3, —

    CO2R17, —

    CN, (C1-C6)alkoxy and halogen;

    R15 and R16 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R15 and R16 together are a C2-C5 alkylene group and with the carbon to which they are attached form a ring of 3 to 6 carbon atoms;

    R17, R18 and R19 are independently selected from the group consisting of H and C1-C6 alkyl; and

    R20 is C1-C6 alkyl or phenyl;

    or (2) Ra is R8-phenyl, R8-pyridyl or R8-thiophenyl;

    R2 is fluorenyl, diphenylmethyl, embedded image

    and R1, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 are as defined in (1);

    wherein heteroaryl is selected from the group consisting of pyridyl, pyrimidyl, pyrazinyl, pyridyl N-oxide, pyrimidyl N-oxide, pyrazinyl N-oxide, thienyl, imidazolyl and isoxazolyl.

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