Monocyte chemoattractant protein-1 inhibitor compounds

Details Monocyte chemoattractant protein-1 inhibitor compounds Monocyte chemoattractant protein-1 inhibitor compounds

2000-02-03

2002-08-27

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S415000, C514S418000, C514S419000, C514S444000, C546S277400, C548S490000, C548S491000

Reexamination Certificate

active

06441004

ABSTRACT:

The present invention relates to anti-inflammatory compounds that act via inhibition of Monocyte Chemoattractant Protein-1 (MCP-1) and especially MCP-1 inhibitor compounds that contain an indole moiety. The invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.
MCP-1 is a member of the chemokine family of pro-inflammatory cytokines which mediate leukocyte chemotaxis and activation. MCP-1 is a C-C chemokine which is one of the most potent and selective T-cell and monocyte chemoattractant and activating agents known. MCP-1 has been implicated in the pathophysiology of a large number of inflammatory diseases including rheumatoid arthritis, glomerular nephritides, lung fibrosis, restenosis (International Patent Application WO 94/09128), alveolitis (Jones et al., 1992,
J. Immunol.,
149, 2147) and asthma. Other disease areas where MCP-1 is thought to play a part in their pathology are atherosclerosis (e.g. Koch et al., 1992,
J. Clin. Invest.,
90, 772-779), psoriasis (Deleuran et al., 1996,
J. Dermatological Science,
13, 228-236), delayed-type hypersensitivity reactions of the skin, inflammatory bowel disease (Grimm et al., 1996,
J. Leukocyte Biol.,
59, 804-812), multiple sclerosis and brain trauma (Berman et al, 1996,
J. Immunol.,
156, 3017-3023). An MCP-1 inhibitor may also be useful to treat stroke, reperfusion injury, ischemia, myocardial infarction and transplant rejection.
MCP-1 acts through the MCP-1 receptor (also known as the CCR2 receptor). MCP-2 and MCP-3 may also act, at least in part, through the MCP-1 receptor. Therefore in this specification, when reference is made to “inhibition or antagonism of MCP-1” or “MCP-1 mediated effects” this includes inhibition or antagonism of MCP-2 and/or MCP-3 mediated effects when MCP-2 and/or MCP-3 are acting through the MCP-1 receptor.
Patent Nos. U.S. 005389650A, U.S. 005290798A, EP 0535926A1, EP 0535923A1, U.S. 005190968A, EP 0535924A1, EP 0419049A1, U.S. Pat. No. 5,308,850, EP 0535925A1, WO 93/16069, WO 93/25546, U.S. 005273980A and U.S. Pat. No. 5,272,145 disclose indole compounds as inhibitors of leukotriene biosynthesis with a benzyl moiety attached to the nitrogen of the indole ring. Similar compounds are also disclosed in WO 93/20078 (severe head injury), EP 0186367 (antiallergy), EP 0275667 (inhibitors of leukotriene biosynthesis), U.S. 4965369A (process patent) WO 94/14434 (antagonizing endothelin receptors), EP 0480659 A2 (treatment of hyperuricemia) and WO 96/03377A1 (allosteric effectors at muscarinic receptors).
The present invention is based on the discovery of a class of compounds containing an indole moiety which have useful inhibitory activity against MCP-1.
Accordingly one aspect of the present invention provides the use of a compound of the formula (I) in the manufacture of a medicament for antagonising an MCP-1 mediated effect in a warm blooded animal, such as man;
wherein:
R
1
is independently selected from trifluoromethyl, C
1-4
alkyl, halo, hydroxy, C
1-4
alkoxy, C
1-4
alkanoyl, C
1-4
alkanoyloxy, carboxy, trifluoromethoxy, amino, cyano, C
1-4
alkylamino, di(C
1-4
alkyl)amino, C
1-4
alkanoylamino, nitro, carbamoyl, C
1-4
alkoxycarbonyl, thiol, C
1-4
alkylsulphanyl, C
1-4
alkylsulphinyl, C
1-4
alkylsulphonyl, sulphonamido, carbamoylC
1-4
alkyl, N—(C
1-4
alkyl)carbamoylC
1-4
alkyl, N—(C
1-4
alkyl)
2
carbamoyl-C
1-4
alkyl, hydroxyC
1-4
alkyl, C
1-4
alkoxyC
1-4
alkyl, morpholino, pyrrolidinyl, carboxyC
1-4
alkylamino, R
3
and —OR
3
(where R
3
is optionally substituted aryl or an optionally substituted 5- or 6- membered heteroaryl ring);
p is 0-4 and R
1
can have the same or different values when p is 2-4 with the proviso that no more than one R
1
can be chosen from the group amino, C
1-4
alkylamino, di(C
1-4
alkyl)amino, morpholino and pyrrolidinyl;
T is of the formula
—(CHR
4
)
m
—,
where
R
4
is independently selected from hydrogen or C
1-4
alkyl and m=1-3 and R
4
can have different values when m is 2 or 3;
X is CO
2
R
4
, SO
3
H, cyano, —SO
2
NHR
4
(where R
4
is as defined above), —SO
2
NHAr (where Ar is an optionally substituted phenyl or optionally substituted 5 or 6 membered heteroaryl ring), —CONHR
5
(where R
5
is H, cyano, C
1-4
alkyl, OH, —SO
2
—C
1-4
alkyl, —SO
2
CF
3
, —SO
2
-phenyl, —(CHR
4
)
r
—COOH, (where r is 1-3 and R
4
(as defined above) can take different values when r is 2-3)), or X is a group of formula (II)
or X represents a group of formula (III)
where the groups defined as R
4
may have different values within the definition of R
4
above;
A is selected from phenyl, naphthyl, furyl, pyridyl and thienyl;
R
2
is independently selected from trifluoromethyl, C
1-4
alkyl, halo, hydroxy, CF
3
O—, C
1-4
alkoxy, C
1-4
alkanoyl, C
1-4
alkanoyloxy, amino, cyano, C
1-4
alkylamino, (C
1-4
alkyl)
2
amino, C
1-4
alkanoylamino, nitro, carboxy, carbamoyl, C
1-4
alkoxycarbonyl, thiol, C
1-4
alkylsulphanyl, C
1-4
alkylsulphinyl, C
1-4
alkylsulphonyl, sulphonamido, carbamoylC
1-4
alkyl, N—(C
1-4
alkyl)carbamoylC
1-4
alkyl, N—(C
1-4
alkyl)
2
carbamoyl-C
1-4
alkyl, hydroxyC
1-4
alkyl, C
1-4
alkoxyC
1-4
alkyl or two R
2
values together may form a divalent radical of the formula —O(CH
2
)
1-4
O— attached to adjacent carbon atoms on ring A;
q is 0-4 and R
2
can have the same or different values when q is 2-4;
Z is hydrogen, fluoro, chloro, bromo, iodo, methyl, trifluoromethyl, hydroxymethyl, acetyl, carboxyC
3-6
cycloalkyl or —(CHR
4
)
r
—NR
6
R
7
(where r is 0-2, R
6
and R
7
are independently selected from H and C
1-4
alkyl or R
6
and R
7
together with the nitrogen to which they are attached form a 5 or 6 membered non-aromatic ring optionally containing one further heteroatom selected from O, N or S);
or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
A further aspect of the present invention provides the use of a compound of the formula (I) in the manufacture of a medicament for antagonising an MCP-1 mediated effect in a warm blooded animal, such as man wherein R
1
is independently selected from trifluoromethyl, C
1-4
alkyl, halo, hydroxy, C
1-4
alkoxy, C
1-4
alkanoyl, C
1-4
alkanoyloxy, amino, cyano, C
1-4
alkylamino, di(C
1-4
alkyl)amino, C
1-4
alkanoylamino, nitro, carbamoyl, C
1-4
alkoxycarbonyl, thiol, C
1-4
alkylsulphanyl, C
1-4
alkylsulphinyl, C
1-4
alkylsulphonyl, sulphonamido, carbamoylC
1-4
alkyl, N—(C
1-4
alkyl)carbamoylC
1-4
alkyl, N—(C
1-4
alkyl)
2
carbamoyl-C
1-4
alkyl, hydroxyC
1-4
alkyl, C
1-4
alkoxyC
1-4
alkyl, morpholino, pyrrolidinyl, carboxyC
1-4
alkylamino, R
3
and —OR
3
(where R
3
is optionally substituted phenyl or an optionally substituted 5- or 6- membered heteroaryl ring);
p is 0-4 and R
1
can have the same or different values when p is 2-4 with the proviso that no more than one R
1
can be chosen from the group amino, C
1-4
alkylamino, di(C
1-4
alkyl)amino, morpholino and pyrrolidinyl; Z is hydrogen, fluoro, chloro, bromo, iodo, methyl, trifluoromethyl, hydroxymethyl, carboxyC
3-6
cycloalkyl or —(CHR
4
)
r
—NR
6
R
7
(where r is 0-2, R
6
and R
7
are independently selected from H and C
1-4
alkyl or R
6
and R
7
together with the nitrogen to which they are attached form a 5 or 6 membered non-aromatic ring optionally containing one further heteroatom selected from O, N or S); and X, T, A, R
2
and q have any of the values defined above; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
In this specification the term ‘alkyl’ includes straight chained, branched structures and ring systems. For example, “C
1-4
alkyl” includes propyl, isopropyl, i-butyl and cyclopropane. However, references to individual alkyl groups such as ‘propyl’ are specific for the straight chained version only, references to individual branched chain alkyl groups such as ‘isopropyl’ are specific for the branched chain version only and references to the cyclo groups such as cyclopropane are specific to the cyclic groups only. A similar convention applies to other radicals, for e

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