Pegylated interferon alfa-CCR5 antagonist combination HIV therapy

A method of treating pediatric patients having HIV-1 infections which comprises administering a therapeutically effective amount of pegylated interferon-alfa in association with a therapeutically effective amount of Highly Active Antiretroviral Therapy and a therapeutically effective amount of a CCR5 antagonist represented by the structural formula I or II or III or IV:

• or a pharmaceutically acceptable salt of I or II or II or IV;
• sufficient to lower HIV-1RNA levels;
• wherein in the CCR5 antagonist compounds represented by structural formula I:
• X is —C(R13)2—, —C(R13)(R19)—, —C(O)—, —O—, —NH—, —N((C1-C6)alkyl)-,
• R is R6-phenyl, R6-pyridyl, R6-thiophenyl or R6-naphthyl;
• R1 is hydrogen, (C1-C6) alkyl or (C2-C6) alkenyl;
• R2 is R7, R8, R9-phenyl;
• R7, R8, R9-substituted 6-membered heteroaryl;
• R7, R8, R9-substituted 6-membered heteroaryl N-oxide;
• R10, R11-substituted 5-membered heteroaryl;
• naphthyl;
• fluorenyl;
• diphenylmethyl
• or
• R3 is R6-phenyl, R6-heteroaryl or R6-naphthyl;
• R4 is hydrogen, (C1-C6) alkyl, fluoro-(C1-C6) alkyl, cyclopropylmethyl, —CH2CH2OH, —CH2CH2—O—(C1-C6)alkyl, —CH2C(O)—O—(C1-C6)alkyl, —CH2C(O)NH2, —CH2C(O)—NH(C1-C6)alkyl or —CH2C(O)—N((C1-C6)alkyl)2;
• R5 and R11 are independently selected from the group consisting of hydrogen and (C1-C6)-alkyl;
• R6 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)—,
• —NH2, —NHCOCF3, —NHCONH(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHSO2(C1-C6 alkyl), 5-membered heteroaryl and
• wherein Xb is —O—, —NH— or —N(CH3)—;
• R7 and R8 are independently selected from the group consisting of (C1-C6)alkyl, halogen, —NR20R21, —OH, —CF3, —OCH3, —O-acyl, and —OCF3;
• R9 is R7, hydrogen, phenyl, —NO2, —CN, —CH2F, —CHF2, —CHO, —CH═NOR20, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, —N(R20)CONR21R22, —NHCONH(chloro-(C1-C6)alkyl), —NHCONH((C3-C10)-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, —SR23, —SOR23, —SO2R23, —SO2NH(C1-C6 alkyl), —OSO2(C1-C6)alkyl, —OSO2CF3, hydroxy(C1-C6)alkyl, —CON R20R21, —CON(CH2CH2—O—CH3)2, —OCONH(C1-C6)alkyl, —CO2R20, —Si(CH3)3 or —B(OC(CH3)2)2;
• R10 is (C1-C6)alkyl, —NH2 or R12-phenyl;
• R12 is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C1-C6) alkyl, —CF3, —CO2R20, —CN, (C1-C6)alkoxy and halogen;
• R13, R14, R15 and R16 are independently selected from the group consisting of hydrogen and (C1-C6)alkyl;
• R17 and R18 are independently selected from the group consisting of hydrogen and (C1-C6) alkyl, or R17 and R18 together are a C2-C5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms;
• R19 is R6-phenyl, R6-heteroaryl, R6-naphthyl, C3-C10 cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkyl;
• R20, R21 and R22 are independently selected from the group consisting of H and C1-C6 alkyl;
• and
• R23 is (C1-C6) alkyl or phenyl;
• and wherein in the CCR5 antagonist compounds represented by the structural formula II:
• or a pharmaceutically acceptable salt thereof, wherein
• (1)
• Xa is —C(R13)2—, —C(R13)(R19)—, —C(O)—, —O—, —NH—, —N((C1-C6)alkyl)-,
• Ra is R6a-phenyl, R6a-pyridyl, R6a-thiophenyl or R6-naphthyl;
• R1 is hydrogen, (C1-C6) alkyl or (C2-C6)alkenyl;
• R2 is R7, R8, R9-phenyl;
• R7, R8, R9-substituted 6-membered heteroaryl;
• R7, R8, R9-substituted 6-membered heteroaryl N-oxide;
• R10, R11-substituted 5-membered heteroaryl;
• naphthyl;
• fluorenyl;
• diphenylmethyl
• or
• R3 is R10-phenyl, pyridyl, pyrimidyl, pyrazinyl or thiazolyl;
• R4 is hydrogen, C1-C6 alkyl, fluoro-C1-C6 alkyl, cyclopropylmethyl, —CH2CH2OH, —CH2CH2—O—(C1-C6)alkyl, —CH2C(O)—O—(C1-C6)alkyl, —CH2C(O)NH2, —CH2C(O)—NH(C1-C6)alkyl or —CH2C(O)—N((C1-C6)alkyl)2;
• R5 and R11 are independently selected from the group consisting of hydrogen and (C1-C6)-alkyl;
• R6a is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, —CF3, CF3O—, —CN, —CF3SO2—, R12-phenyl, —NHCOCF3, 5-membered heteroaryl and
• wherein Xb is —O—, —NH— or —N(CH3)—;
• R6 is independently selected from the group consisting of R6a and CH3SO2—;
• R7 and R8 are independently selected from the group consisting of (C1-C6)alkyl, halogen, —NR20R21, —OH, —CF3, —OCH3, —O-acyl, and —OCF3;
• R9 is R7, hydrogen, phenyl, —NO2, —CN, —CH2F, —CHF2, —CHO, —CH═NOR20, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, —N(R20)CONR21R22, —NHCONH(chloro-(C1-C6)alkyl), —NHCONH((C3-C10)-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, —SR23, —SOR23, —SO2R23, —SO2NH(C1-C6 alkyl), —OSO2(C1-C6)alkyl, —OSO2CF3, hydroxy(C1-C6)alkyl, —CON R20R21, —CON(CH2CH2—O—CH3)2, —OCONH(C1-C6)alkyl, —CO2R20, —Si(CH3)3 or —B(OC(CH3)2)2;
• R10 is (C1-C6)alkyl, —NH2 or R12-phenyl;
• R12 is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C1-C6) alkyl, —CF3, —CO2R20, —CN, (C1-C6)alkoxy and halogen;
• R13, R14, R15 and R16 are independently selected from the group consisting of hydrogen and (C1-C6) alkyl;
• R17 and R18 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R17 and R18 together are a C2-C5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms;
• R19 is R6-phenyl, R6-heteroaryl, R6-naphthyl, C3-C10 cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkyl;
• R20, R21 and R22 are independently selected from the group consisting of H and (C1-C6) alkyl;
• and
• R23 is (C1-C6) alkyl or phenyl;
• or
• (2):
• Xa is —C(R13)(R19)—, —C(O)—, —O—, —NH—, —N((C1-C6)alkyl)-,
• Ra is R6b-phenyl, R6b-pyridyl or R6b-thiophenyl;
• R4a is fluoro-C1-C6 alkyl, cyclopropylmethyl, —CH2CH2OH, —CH2CH2—O—(C1-C6)alkyl, —CH2C(O)—O—(C1-C6)alkyl, —CH2C(O)NH2, —CH2C(O)—NH—(C1-C6)alkyl or —CH2C(O)—N((C1-C6)alkyl)2;
• R6b is CH3SO2—;
• and
• R1, R2, R3, R5, R14, R15, R16 and R19 are as defined in II(1);
• and wherein in the CCR5 antagonist compounds represented by the structural formula III:
• R is R8-phenyl, R8-pyridyl, R8-thiophenyl or R8-naphthyl;
• R1 is hydrogen or (C1-C6) alkyl;
• R2 is R9, R10, R11-phenyl;
• R9, R10, R11-substituted 6-membered heteroaryl;
• R9, R10, R11-substituted 6-membered heteroaryl N-oxide;
• R12, R13-substituted 5-membered heteroaryl;
• naphthyl;
• fluorenyl;
• diphenylmethyl
• or
• R3 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),
• —NH2, —NHCOCF3, —NHCONH(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHSO2(C1-C6 alkyl), 5-membered heteroaryl and
• wherein Xb is —O—, —NH— or —N(CH3)—;
• 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 spiro 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;
• and wherein in the CCR5 antagonist compounds represented by the structural formula IV:
• or 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 R9, R10, R11-phenyl;
• R9, R10, R11-substituted 6-membered heteroaryl;
• R9, R10, R11-substituted 6-membered heteroaryl N-oxide;
• R12, R13-substituted 5-membered heteroaryl;
• naphthyl;
• fluorenyl;
• diphenylmethyl,
• or
• R3 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),
• —NH2, —NHCOCF3, —NHCONH(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHSO2(C1-C6 alkyl), 5-membered heteroaryl and
• wherein Xb 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
• wherein Xb 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—, R14-benzyl, CH3C(═NOCH3), CH3C(═NOCH2CH3),
• —NHCOCF3, 5-membered heteroaryl and
• wherein Xb 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 spiro 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,
• or
• 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 IV(1).