Piperazine derivatives useful as CCR5 antagonists
First Claim
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1. A compound represented by the structural formula II 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 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;
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 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
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
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,
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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Abstract
The use of CCR5 antagonists of the formula
or a pharmaceutically acceptable salt thereof, wherein
R is optionally substituted phenyl, pyridyl, thiophenyl or naphthyl;
R1 is hydrogen or alkyl;
R2 is substituted phenyl, substituted heteroaryl, naphthyl, fluorenyl, diphenylmethyl or optionally substituted phenyl- or heteroaryl-alkyl;
R3 is hydrogen, alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, or optionally substituted phenyl, phenylalkyl, naphthyl, naphthylalkyl, heteroaryl or heteroarylalkyl;
R4, R5 and R7 are hydrogen or alkyl;
R6 is hydrogen, alkyl or alkenyl; for the treatment of HIV, solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis is disclosed, as well as novel compounds, pharmaceutical compositions comprising them, and the combination of CCR5 antagonists of the invention in combination with antiviral agents useful in the treatment of HIV or agents useful in the treatment of inflammatory diseases.
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Citations
19 Claims
-
1. A compound represented by the structural formula II
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 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;
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 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
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
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,
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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 10, 11)
wherein R8a is CF3, CF3O— - or halogen;
or Ra is
wherein R8 is C1-C6 alkoxy.
-
-
4. A compound of claim 1 wherein R3 is hydrogen, (C1-C6)alkyl, R8-phenyl, R8-benzyl or R8-pyridyl.
-
5. A compound of claim 1 wherein R1 is hydrogen;
- R6 is hydrogen or methyl;
R4 is methyl; and
R5 and R7 are each hydrogen.
- R6 is hydrogen or methyl;
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6. A compound of claim 1 wherein R2 is
-
7. A compound of claim 6 wherein R2 is selected from the group consisting of
wherein R9 and R10 are selected from the group consisting of (C1-C6)alkyl, halogen, — - OH and —
NH2.
- OH and —
-
10. A pharmaceutical composition comprising an effective amount of a CCR5 antagonist of claim 1 in combination with a pharmaceutically acceptable carrier.
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11. A method of treating Human Immunodeficiency Virus comprising administering to a human in need of such treatment a therapeutically effective amount of a CCR5 antagonist of claim 1.
-
8. A compound selected from the group consisting of those represented by the structural formula
wherein R, R3, R6 and R2 are as defined in the following table:
-
9. A compound which is
-
12. A method of treating Human Immunodeficiency Virus comprising administering to a human in need of such treatment a therapeutically effective amount of a CCR5 antagonist of the structural formula I:
-
or a pharmaceutically acceptable salt thereof, wherein R is R8-phenyl, R8-pyridyl, R8-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;
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 X 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 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;
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. - View Dependent Claims (13, 14, 15, 16, 17, 18, 19)
wherein R9 and R10 are selected from the group consisting of (C1-C6)alkyl, halogen, — - OH and —
NH2.
-
19. The method of claim 18 wherein R2 is phenyl or pyridyl and R11 is hydrogen, or wherein R2 is pyrimidyl and R11 is hydrogen, methyl or phenyl.
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Specification
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Current AssigneeMerck Sharp & Dohme Corporation (Merck & Co., Inc.)
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Original AssigneeSchering Corporation (Merck & Co., Inc.)
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InventorsMiller, Michael W., Clader, John W., McKittrick, Brian A., Palani, Anandan, Josien, Hubert B., Smith, Elizabeth M., Neustadt, Bernard R., Steensma, Ruo, Labroli, Marc A., McCombie, Stuart W., Tagat, Jayaram R., Baroudy, Bahige M., Gilbert, Eric, Vice, Susan F.
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Primary Examiner(s)BERNHARDT, EMILY A
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Application NumberUS09/562,814Time in Patent Office750 DaysField of Search544/295, 544/360, 544/364, 544/229, 514/252.18, 514/253.01, 514/253.11, 514/63-64, 514/252.11, 514/253.1, 514/253.09US Class Current514/63CPC Class CodesA61K 2300/00 Mixtures or combinations of...A61K 31/496 Non-condensed piperazines c...A61K 45/06 Mixtures of active ingredie...C07D 211/58 attached in position 4C07D 401/06 linked by a carbon chain co...C07D 401/10 linked by a carbon chain co...C07D 401/12 linked by a chain containin...C07D 405/12 linked by a chain containin...C07D 409/06 linked by a carbon chain co...C07D 413/06 linked by a carbon chain co...
