Piperazine derivatives useful as CCR5 antagonists
View Patent ↗The use of CCR5 antagonists of the formula or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted phenyl, pyridyl, thiophenyl or naphthyl; R 1 is hydrogen or alkyl; R 2 is substituted phenyl, substituted heteroaryl, naphthyl, fluorenyl, diphenylmethyl or optionally substituted phenyl- or heteroaryl-alkyl; R 3 is hydrogen, alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, or optionally substituted phenyl, phenylalkyl, naphthyl, naphthylalkyl, heteroaryl or heteroarylalkyl; R 4 , R 5 and R 7 are hydrogen or alkyl; R 6 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.
1. A method treating solid organ transplant rejection, and graft v. host disease, comprising administering to a human in need of such treatment a therapeutically effective amount of a CCR5 antagonist of the structural formula II
or a pharmaceutically acceptable salt thereof, wherein
(1) R a is R 8a -phenyl, R 8b -pyridyl, R 8b -thiophenyl or R 8 -naphthyl;
R 1 is hydrogen or C 1 -C 6 alkyl;
R 2 is phenyl substituted with R 9 , R 10 , and R 11 ; 6-membered heteroaryl substituted with R 9 , R 10 , and R 11 ; 6-membered heteroaryl N-oxide substituted with R 9 , R 10 , and R 11 ; 5-membered heteroaryl substituted with R 12 , and R 13 ; naphthyl; fluorenyl; diphenylmethyl;
R 3 is hydrogen, C 1 -C 6 alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl(C 1 -C 6 )alkyl, R 8 -phenyl, R 8 -phenyl(C 1 -C 6 )alkyl, R 8 -naphthyl, R 8 -naphthyl(C 1 -C 6 )alkyl, R 8 -heteroaryl or R 8 -heteroaryl(C 1 -C 6 )alkyl;
R 4 , R 5 , R 7 and R 13 are independently selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl;
R 6 is hydrogen, C 1 -C 6 alkyl or C 2 -C 6 alkenyl;
R 8 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —CF 3 , CF 3 O—, CR 3 C(O)—, —CN, CH 3 SO 2 —, CF 3 SO 2 —, R 14 -phenyl, R 14 -benzyl, CH 3 C(═NOCH 3 ), CH 3 C(═NOCR 2 CH 3 ),
—NH 2 , —NHCOCF 3 , —NHCONH(C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), —NHSO 2 (C 1 -C 6 alkyl), 5-membered heteroaryl and
wherein X is —O—, —NH— or —N(CH 3 )—;
R 8a is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, —CF 3 , CF 3 O—, —CN, CF 3 SO 2 —, R 14 -phenyl, —NHCOCF 3 , 5-membered heteroaryl and
wherein X is as defined above;
R 8b is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, —CF 3 , CF 3 O—, CH 3 C(O)—, —CN, CF 3 SO 2 —, R 14 -benzyl, CH 3 C(═NOCH 3 ), CH 3 C(═NOCH 2 CH 3 ),
—NHCOCF 3 , 5-membered heteroaryl and
wherein X is as defined above;
R 9 and R 10 are independently selected from the group consisting of (C 1 -C 6 )alkyl, halogen, —NR 17 R 18 , —OH, —CF 3 , —OCH 3 —O-acyl, —OCF 3 and —Si(CH 3 ) 3 ;
R 11 is R 9 , hydrogen, phenyl, —NO 2 , —CN, —CH 2 F, —CHF 2 , —CHO, —CH═NOR 17 , pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, —N(R 17 )CONR 18 R 19 , —NHCONH(chloro-(C 1 -C 6 )alkyl), —NHCONH((C 3 -C 1 )cycloalkyl(C 1 -C 6 )alkyl), —NHCO(C 1 -C 6 )alkyl, —NHCOCF 3 , —NHSO 2 N((C 1 -C 6 )alkyl) 2 , —NHSO 2 (C 1 -C 6 )alkyl, —N(SO 2 CF 3 ) 2 , —NHCO 2 (C 1 -C 6 )alkyl, C 3 -C 10 cycloalkyl, —SR 20 , —SOR 20 , —SO 2 R 20 , —SO 2 NH(C 1 -C 6 alkyl), —OSO 2 (C 1 -C 6 )alkyl, —OSO 2 CF 3 , hydroxy(C 1 -C 6 )alkyl, —CON R 17 R 18 , —CON(CH 2 CH 2 —O—CH 3 ) 2 , —OCONH(C 1 -C 6 )alkyl, —CO 2 R 17 , —Si(CH 3 ) 3 or —B(OC(CH 3 ) 2 ) 2 ;
R 12 is (C 1 -C 6 )alkyl, —NH 2 or R 14 -phenyl;
R 14 is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, —CF 3 , —CO 2 R 17 , —CN (C 1 -C 6 )alkoxy and halogen;
R 15 and R 16 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or R 15 and R 16 together are a C 2 -C 5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms;
R 17 , R 18 and R 19 are independently selected from the group consisting of H and C 1 -C 6 alkyl; and
R 20 is C 1 -C 6 alkyl or phenyl; or
(2) R a is R 8 -phenyl, R 8 -pyridyl or R 8 -thiophenyl;
R 2 is fluorenyl, diphenylmethyl,
and R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 are as defined in (1).
2. The method of claim 1 wherein R a is R 8a -phenyl or R 8 -naphthyl.
3. The method of claim 2 wherein R a is
wherein R 8a is —CF 3 , CF 3 O— or halogen; or R a is
wherein R 8 is C 1 -C 6 alkoxy.
4. The method of claim 1 wherein R 3 is hydrogen, (C 1 -C 6 ) alkyl, R 8 -phenyl, R 8 -benzyl or R 8 -pyridyl.
5. The method of claim 1 wherein R 1 is hydrogen; R 6 is hydrogen or methyl; R 4 is methyl; and R 5 and R 7 are each hydrogen.
6. The method of claim 1 wherein R 2 is phenyl substituted with R 9 , R 10 , and R 11 ; pyridyl substituted with R 9 , R 10 , and R 11 ; pyridyl N-oxide substituted with R 9 , R 10 , and R 11 ; or pyrimidyl substituted with R 9 , R 10 , and R 11 .
7. The method of claim 6 wherein R 2 is selected from the group consisting of
wherein R 9 and R 10 are selected from the group consisting of (C 1 -C 6 )alkyl, halogen, —OH and —NH 2 .
8. The method of claim 1 wherein the CCR5 compound is selected from the group consisting of those represented by the structural formula
wherein R, R 3 , R 6 and R 2 are as defined in the following table:
R
R 3
R 6
R 2
H
—CH 3
H
H
H
H
—CH 3
—CH 3
—CH 3
—CH 3
—CH 3
—CH 3
H
H
—CH 3
—CH 3
—CH 3
—CH 3
—CH 3
H
—CH 3
H
—CH 3
H
—CH 3
H
—CH 3
—CH 3
H
H
H
—CH 3
H
—CH 3
H
H
H
H
—CH 3
H
—CH 3
H
—CH 3
—CH 2 CH 3
—CH 2 CH 3
—CH 2 CH 3
—CH 3
—CH 3
—CH 3
—CH 3
—CH 3
—CH 3
—CH 3
—CH 3
—CH 3
—CH 3
—CH 3
—CH 3
—CH 3
9. A method of treating solid organ transplant rejection, and graft v. host disease, 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 R 8 -phenyl, R 8 -pyridyl, R 8 -thiophenyl or R 8 -naphthyl;
R 1 is hydrogen or C 1 -C 6 alkyl;
R 2 is phenyl substituted with R 9 , R 10 , and R 11 ; 6-membered heteroaryl substituted with R 9 , R 10 , and R 11 ; 6-membered heteroaryl N-oxide substituted with R 9 , R 10 , and R 11 ; 5-membered heteroaryl substituted with R 12 , and R 13 ; naphthyl; fluorenyl; diphenylmethyl;
R 3 is hydrogen, C 1 -C 6 alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl(C 1 -C 6 )alkyl, R 8 -phenyl, R 8 -phenyl(C 1 -C 6 )alkyl, R 8 -naphthyl, R 8 -naphthyl(C 1 -C 6 )alkyl, R 8 -heteroaryl or R 8 -heteroaryl(C 1 -C 6 )alkyl;
R 4 , R 5 , R 7 and R 13 are independently selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl;
R 6 is hydrogen, C 1 -C 6 alkyl or C 2 -C 6 alkenyl;
R 8 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —CF 3 , CF 3 O—, CH 3 C(O)—, —CN, CH 3 SO 2 —, CF 3 SO 2 —, R 14 -phenyl, R 14 -benzyl, CH 3 C(═NOCH 3 ), CH 3 C(═NOCH 2 CH 3 ),
—NH 2 , —NHCOCF 3 , —NHCONH(C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), —NHSO 2 (C 1 -C 6 alkyl), 5-membered heteroaryl and
wherein X is —O—, —NH— or —N(CH 3 )—;
R 9 and R 10 are independently selected from the group consisting of (C 1 -C 6 )alkyl, halogen, —NR 17 R 18 , —OH, —CF 3 , —OCH 3 , —O-acyl, —OCF 3 and —Si(CH 3 ) 3 ;
R 11 is R 9 , hydrogen, phenyl, —NO 2 , —CN, —CH 2 F, —CHF 2 , —CHO, —CH═NOR 17 , pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, —N(R 17 )CONR 18 R 19 , —NHCONH(chloro-(C 1 -C 6 )alkyl), —NHCONH((C 3 -C 1 )cycloalkyl(C 1 -C 6 )alkyl), —NHCO(C 1 -C 6 )alkyl, —NHCOCF 3 , —NHSO 2 N((C 1 -C 6 )alkyl) 2 , —NHSO 2 (C 1 -C 6 )alkyl, —N(SO 2 CF 3 ) 2 , —NHCO 2 (C 1 -C 6 )alkyl, C 3 -C 10 cycloalkyl, —SR 20 , —SOR 20 , —SO 2 R 20 , —SO 2 NH(C 1 -C 6 alkyl), —OSO 2 (C 1 -C 6 )alkyl, —OSO 2 CF 3 , hydroxy(C 1 -C 6 )alkyl, —CON R 17 R 18 , —CON(CH 2 CH 2 —O—CH 3 ) 2 , —OCONH(C 1 -C 6 )alkyl, —CO 2 R 17 , —Si(CH 3 ) 3 or —B(OC(CH 3 ) 2 ) 2 ;
R 12 is (C 1 -C 6 )alkyl, —NH 2 or R 14 -phenyl;
R 14 is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, —CF 3 , —CO 2 R 17 , —CN, (C 1 -C 6 )alkoxy and halogen;
R 15 and R 16 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or R 15 and R 16 together are a C 2 -C 5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms;
R 17 , R 18 and R 19 are independently selected from the group consisting of H and C 1 -C 6 alkyl; and
R 20 is C 1 -C 6 alkyl or phenyl.
10. The method of claim 9 wherein R is R 8 -phenyl or R 8 -naphthyl.
11. The method of claim 10 wherein R is
12. The method of claim 9 wherein R 3 is hydrogen, (C 1 -C 6 ) alkyl, R 8 -phenyl, R 8 -benzyl or R 8 -pyridyl.
13. The method of claim 9 wherein R 1 is hydrogen and R 6 is hydrogen or methyl.
14. The method of claim 9 wherein R 2 is phenyl substituted with R 9 , R 10 , and R 11 ; pyridyl substituted with R 9 , R 10 , and R 11 ; pyridyl N-oxide substituted with R 9 , R 10 , and R 11 ; or pyrimidyl substituted with R 9 , R 10 , and R 11 .
15. The method of claim 14 wherein R 2 is selected from the group consisting of
wherein R 9 and R 10 are selected from the group consisting of (C 1 -C 6 )alkyl, halogen, —OH and —NR 2 .
16. The method of claim 15 wherein R 2 is selected from the group consisting of
wherein R 11 is hydrogen; and
wherein R 11 is hydrogen, methyl or phenyl.
17. The method of claim 9 , further comprising administering one or more other agents useful in the treatment of said diseases.
18. A method treating solid organ transplant rejection, and graft v. host disease, comprising administering to a human in need of such treatment a therapeutically effective amount of a CCR5 antagonist of the structural formula
or a pharmaceutically acceptable salt thereof.