US 6,011,052 AGranted

Pyrazolone derivatives as MCP-1 antagonists

AssigneeWarner-Lambert Company

InventorsJanak Khimchand Padia, Bruce David Roth, John Edward Strode, Bharat Kalidas Trivedi

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Abstract

Pyrazolone derivatives of Formula I or a pharmaceutically acceptable salt thereof are MCP-1 antagonists and are thus useful in the treatment of inflammatory diseases or conditions, atherosclerosis, restenosis, and immune disorders such as arthritis and transplant rejection ##STR1## where: R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 can be independently H, C.sub.1-20 alkyl, C.sub.5-7 cycloalkyl, --(CH.sub.2).sub.n NR.sub.6 R.sub.7 --(CH.sub.2).sub.0-6 CONR.sub.6 R.sub.7, --(CH.sub.2).sub.n OH or --(CH.sub.2).sub.0-6 CO.sub.2 R.sub.11, biphenyl, aryl of from 6 to 10 carbon atoms, or aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, SO.sub.2 lower alkyl, --SO.sub.2 NR.sub.6 R.sub.7 lower alkoxy --C0.sub.2 R.sub.11, --CONR.sub.6 R.sub.7, --NR.sub.6 R.sub.7 or CH.sub.2 OH.

Claims18

Dependent claims

A compound of Formula I ##STR16## where:

R.sub.1, R.sub.2 can be independently H,
C.sub.1-20 alkyl,
C.sub.5-7 cycloalkyl,
--(CH.sub.2).sub.n NR.sub.6 R.sub.7
--(CH.sub.2).sub.0-6 CONR.sub.6 R.sub.7,
--(CH.sub.2).sub.n OH,
--(CH.sub.2)0-6CO.sub.2 R.sub.11 ;
biphenyl,
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7, lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH;
wherein n is an integer from 0-6 providing n is not 1 when the moiety is R.sub.1, R.sub.2, R.sub.4 and/or R.sub.5 and n can not be 0 when the moiety is R.sub.4 or R.sub.5 ;
R.sub.6 and R.sub.7 can be independently
H, lower alkyl of from 1-4 carbon atoms, or
(CH.sub.2).sub.n NR.sub.8 R.sub.9 ;
R.sub.8 and R.sub.9 can independently by H or lower alkyl;
R.sub.10 is H, alkyl of from 1-4 carbon atoms, (CH.sub.2).sub.n Ph, or (CH.sub.2).sub.n CHPH.sub.2 where "Ph" is phenyl;
R.sub.11 is H or lower alkyl of from 1-4 carbon atoms;
R.sub.2 and R.sub.3 or R.sub.3 and R.sub.4 or R.sub.4 and R.sub.5 can independently be taken together to form a ring of 5-7 atoms;
further either one of R.sub.1 or R.sub.2 can independently be
--C(O)R.sub.12,
--C(S)R.sub.12 or,
--CO.sub.2 R.sub.12,
where R.sub.12 is lower alkyl of from 1-4 carbon atoms, phenyl or phenyl substituted up to 3 times with substituents as previously defined above;
R.sub.3 is --C(O)NH(CH.sub.2).sub.n NR.sub.6 R.sub.7,
R.sub.4 can be independently H, or C.sub.1-20 alkyl;
R.sub.5 can be independently H, C.sub.1-20 alkyl, C.sub.5-7 cycloalkyl;
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7, lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH.

37 more elements

A method for the treatment of inflammatory disease or condition, atherosclerosis, restenosis, chronic or acute immune disorders, and transplant rejection in a mammal in need thereof comprising administering to such mammal an effective amount of a compound of Formula I ##STR17## where:

R.sub.1, R.sub.2 can be independently H,
C.sub.1-20 alkyl,
C.sub.5-7 cycloalkyl,
--(CH.sub.2).sub.n NR.sub.6 R.sub.7
--(CH.sub.2).sub.0-6 CONR.sub.7,
--(CH.sub.2).sub.n OH,
--(CH.sub.2).sub.0-6 CO.sub.2 R.sub.11 ;
biphenyl,
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7, lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH;
wherein n is an integer from 0-6 providing n is not 1 when the moiety is R.sub.1, R.sub.2, R.sub.4 and/or R.sub.5 and n can not be 0 when the moiety is R.sub.4 or R.sub.5 ;
R.sub.6 and R.sub.7 can be independently
H, lower alkyl of from 1-4 carbon atoms, or
(CH.sub.2).sub.n NR.sub.8 R.sub.9 ;
R.sub.8 and R.sub.9 can independently by H or lower alkyl;
R.sub.10 is H, alkyl of from 1-4 carbon atoms, (CH.sub.2).sub.n Ph, or (CH.sub.2).sub.n CHPH.sub.2 where "Ph" is phenyl;
R.sub.11 is H or lower alkyl of from 1-4 carbon atoms;
R.sub.2 and R.sub.3 or R.sub.3 and R.sub.4 or R.sub.4 and R.sub.5 can independently be taken together to form a ring of 5-7 atoms;
further either one of R.sub.1 or R.sub.2 can independently be
--C(O)R.sub.12,
--C(S)R.sub.12 or,
--CO.sub.2 R.sub.12,
where R.sub.12 is lower alkyl of from 1-4 carbon atoms, phenyl or phenyl substituted up to 3 times with substituents as previously defined above;
where R.sub.3 can be
H,
C.sub.1-20 alkyl,
C.sub.5-7 cycloalkyl,
--(CH.sub.2).sub.n NR.sub.6 R.sub.7
--(CH.sub.2).sub.0-6 CONR.sub.6 R.sub.7,
--(CH.sub.2).sub.n OH,
--(CH.sub.2).sub.0-6 CO.sub.2 R.sub.11 ;
--CF.sub.3 ;
biphenyl,
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7,
lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH;
R.sub.4 can be independently H, or C.sub.1-20 alkyl;
R.sub.5 can be independently H, C.sub.1-20 alkyl, C.sub.5-7 cycloalkyl;
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7, lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH.

55 more elements

A method for the treatment of atherosclerosis in a mammal in need thereof comprising administering to such mammal an effective amount of a compound of Formula I ##STR18## where:

R.sub.1, R.sub.2 can be independently H,
C.sub.1-20 alkyl,
C.sub.5-7 cycloalkyl,
--(CH.sub.2).sub.n NR.sub.6 R.sub.7
--(CH.sub.2).sub.0-6 CONR.sub.6 R.sub.7,
--(CH.sub.2).sub.n OH,
--(CH.sub.2).sub.0-6 CO.sub.2 R.sub.11 ;
biphenyl,
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7, lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR6R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH;
wherein n is an integer from 0-6 providing n is not 1 when the moiety is R.sub.1, R.sub.2, R.sub.4 and/or R.sub.5 and n can not be 0 when the moiety is R.sub.4 or R.sub.5 ;
R.sub.6 and R.sub.7 can be independently
H, lower alkyl of from 1-4 carbon atoms, or
(CH.sub.2).sub.n NR.sub.8 R.sub.9 ;
R.sub.8 and R.sub.9 can independently by H or lower alkyl;
R.sub.10 is H, alkyl of from 1-4 carbon atoms, (CH.sub.2).sub.n Ph, or (CH.sub.2).sub.n CHPH.sub.2 where "Ph" is phenyl;
R.sub.11 is H or lower alkyl of from 1-4 carbon atoms;
R.sub.2 and R.sub.3 or R.sub.3 and R.sub.4 or R.sub.4 and R.sub.5 can independently be taken together to form a ring of 5-7 atoms;
further either one of R.sub.1 or R.sub.2 can independently be
--C(O)R.sub.12,
--C(S)R.sub.12 or,
--CO.sub.2 R.sub.12,
where R.sub.12 is lower alkyl of from 1-4 carbon atoms, phenyl or phenyl substituted up to 3 times with substituents as previously defined above;
where R.sub.3 can be
H,
C.sub.1-20 alkyl,
C.sub.5-7 cycloalkyl,
--(CH.sub.2).sub.n NR.sub.6 R.sub.7
--(CH.sub.2).sub.0-6 CONR.sub.6 R.sub.7,
--(CH2).sub.n OH,
--(CH.sub.2).sub.0-6 CO.sub.2 R.sub.11 ;
--CF.sub.3 ;
biphenyl,
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7,
lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH;
R.sub.4 can be independently H, or C.sub.1-20 alkyl;
R.sub.5 can be independently H, C.sub.1-20 alkyl, C.sub.5-7 cycloalkyl;
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7, lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH.

55 more elements

A method of treating inflammation in a mammal in need thereof comprising administrating to such mammal an effective anti-inflammatory a mount of a compound of Formula I ##STR19## where:

R.sub.1, R.sub.2 can be independently H,
C.sub.1-20 alkyl,
C.sub.5-7 cycloalkyl,
--(CH.sub.2).sub.n NR.sub.6 R.sub.7
--(CH.sub.2).sub.0-6 CONR.sub.6 R.sub.7,
--(CH.sub.2).sub.n OH,
--(CH.sub.2).sub.0-6 CO.sub.2 R.sub.11 ;
biphenyl,
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7, lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH;
wherein n is an integer from 0-6 providing n is not 1 when the moiety is R.sub.1, R.sub.2, R.sub.4 and/or R.sub.5 and n can not be 0 when the moiety is R.sub.4 or R.sub.5 ;
R.sub.6 and R.sub.7 can be independently
H, lower alkyl of from 1-4 carbon atoms, or
(CH.sub.2).sub.n NR.sub.8 R.sub.9 ;
R.sub.8 and R.sub.9 can independently by H or lower alkyl;
R.sub.10 is H, alkyl of from 1-4 carbon atoms, (CH.sub.2).sub.n Ph, or (CH.sub.2).sub.n CHPH.sub.2 where "Ph" is phenyl;
R.sub.11 is H or lower alkyl of from 1-4 carbon atoms;
R.sub.2 and R.sub.3 or R.sub.3 and R.sub.4 or R.sub.4 and R.sub.5 can independently be taken together to form a ring of 5-7 atoms;
further either one of R.sub.1 or R.sub.2 can independently be
--C(O)R.sub.12,
--C(S)R.sub.12 or,
--CO.sub.2 R.sub.12,
where R.sub.12 is lower alkyl of from 1-4 carbon atoms, phenyl or phenyl substituted up to 3 times with substituents as previously defined above;
where R.sub.3 can be
H,
C.sub.1-20 alkyl,
C.sub.5-7 cycloalkyl,
--(CH.sub.2).sub.n NR.sub.6 R.sub.7
--(CH.sub.2).sub.0-6 CONR.sub.6 R.sub.7,
--(CH.sub.2).sub.n OH,
--(CH.sub.2).sub.0-6 CO.sub.2 R.sub.11 ;
--CF.sub.3 ;
biphenyl,
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7,
lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH;
R.sub.4 can be independently H, or C.sub.1-20 alkyl;
R.sub.5 can be independently H, C.sub.1-20 alkyl, C.sub.5-7 cycloalkyl;
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7, lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH.

55 more elements

A pharmaceutical composition for the treatment of inflammation, atherosclerosis, restenosis, immune disorders and transplant rejection in a mammal in need thereof comprising administering to such mammal a therapeutically effective amount of a compound of Formula I in combination in admixture with a pharmaceutically acceptable excipient, diluent, or carrier where:

R.sub.1, R.sub.2 can be independently
H,
C.sub.1-20 alkyl,
C.sub.5-7 cycloalkyl,
--(CH.sub.2).sub.n NR.sub.6 R.sub.7
--(CH.sub.2).sub.0-6 CONR.sub.6 R.sub.7,
--(CH.sub.2).sub.n OH,
--(CH.sub.2).sub.0-6 CO.sub.2 R.sub.11 ;
biphenyl,
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7, lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH;
wherein n is an integer from 0-6 providing n is not 1 when he moiety is R.sub.1, R.sub.2, R.sub.4 and/or R.sub.5 and n can not be 0 when the moiety is R.sub.4 or R.sub.5 ;
R.sub.6 and R.sub.7 can be independently
H, lower alkyl of from 1-4 carbon atoms, or
(CH.sub.2).sub.n NR.sub.8 R.sub.9 ;
R.sub.1 and R.sub.9 can independently by H or lower alkyl;
R.sub.10 is H, alkyl of from 1-4 carbon atoms, (CH.sub.2).sub.n Ph, or (CH.sub.2).sub.n CHPH.sub.2 where "Ph" is phenyl;
R.sub.11 is H or lower alkyl of from 1-4 carbon atoms;
R.sub.2 and R.sub.3 or R.sub.3 and R.sub.4 or R.sub.4 and R.sub.5 can independently be taken together to form a ring of 5-7 atoms;
further either one of R.sub.1 or R.sub.2 can independently be
--C(O)R.sub.12,
--C(S)R.sub.12 or,
--CO.sub.2 R.sub.12,
where R.sub.12 is lower alkyl of from 1-4 carbon atoms, phenyl or phenyl substituted up to 3 times with substituents as previously defined above;
where R.sub.3 can be
H,
C.sub.1-20 alkyl,
C.sub.5-7 cycloalkyl,
--(CH.sub.2).sub.n NR.sub.6 R.sub.7
--(CH.sub.2).sub.0-6 CONR.sub.6 R.sub.7,
--(CH.sub.2).sub.n OH,
--(CH.sub.2).sub.0-6 CO.sub.2 R.sub.11 ;
--CF.sub.3 ;
biphenyl,
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7,
lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH;
R.sub.4 can be independently H, or C.sub.1-20 alkyl;
R.sub.5 can be independently H, C.sub.1-20 alkyl, C.sub.5-7 cycloalkyl;
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7, lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH.

56 more elements

A method of inhibiting the binding of the MCP-1 receptor in a mammal in need thereof comprising administrating to such mammal an effective inhibiting amount of a compound of Formula I where:

R.sub.1, R.sub.2 can be independently
H,
C.sub.1-20 alkyl,
C.sub.5-7 cycloalkyl,
--(CH.sub.2).sub.n NP.sub.6 R.sub.7
--(CH.sub.2).sub.0-6 CONR.sub.6 R.sub.7,
--(CH.sub.2).sub.n OH,
--(CH.sub.2).sub.0-6 CO.sub.2 R.sub.11 ;
biphenyl,
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7, lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH;
wherein n is an integer from 0-6 providing n is not 1 when the moiety is R.sub.1, R.sub.2, R.sub.4 and/or R.sub.5 and n can not be 0 when the moiety is R.sub.4 or R.sub.5 ;
R.sub.6 and R.sub.7 can be independently
H, lower alkyl of from 1-4 carbon atoms, or
(CH.sub.2).sub.n NR.sub.8 R.sub.9 ;
R.sub.8 and R.sub.9 can independently by H or lower alkyl;
R.sub.10 is H, alkyl of from 1-4 carbon atoms, (CH.sub.2).sub.n Ph, or (CH.sub.2).sub.n CHPH.sub.2 where "Ph" is phenyl;
R.sub.11 is H or lower alkyl of from 1-4 carbon atoms;
R.sub.2 and R.sub.3 or R.sub.3 and R.sub.4 or R.sub.4 and R.sub.5 can independently be taken together to form a ring of 5-7 atoms;
further either one of R.sub.1 or R.sub.2 can independently be
--C(O)R.sub.12,
--C(S)R.sub.12 or,
--CO.sub.2 R.sub.12,
where R.sub.12 is lower alkyl of from 1-4 carbon atoms, phenyl or phenyl substituted up to 3 times with substituents as previously defined above;
where R.sub.3 can be
H,
C.sub.1-20 alkyl,
C.sub.5-7 cycloalkyl,
--(CH.sub.2).sub.n NR.sub.6 R.sub.7
--(CH.sub.2).sub.0-6 CONR.sub.6 R.sub.7,
--(CH.sub.2).sub.n OH,
--(CH.sub.2)0-6CO.sub.2 R.sub.11 ;
--CF.sub.3 ;
biphenyl,
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7,
lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR6R.sub.7, or
--CH.sub.2 OH;
R.sub.4 can be independently H, or C.sub.1-20 alkyl;
R.sub.5 can be independently H, C.sub.1-20 alkyl, C.sub.5-7 cycloalkyl;
aryl of from 6 to 10 carbon atoms, or
aryl of from 6 to 10 carbon atoms substituted up to 3 times by halogen, --CN, lower alkyl of
from 1-4 carbon atoms, --OH, nitro, --SO.sub.2 H, --SO.sub.2 lower alkyl,
--SO.sub.2 NR.sub.6 R.sub.7, lower alkoxy,
--CO.sub.2 R.sub.11,
--CONR.sub.6 R.sub.7,
--NR.sub.6 R.sub.7, or
--CH.sub.2 OH.

56 more elements

Dependencies are inferred from the claim text.