Bicyclic pyrrole derivatives as MCP-1 inhibitors

Details Bicyclic pyrrole derivatives as MCP-1 inhibitors Bicyclic pyrrole derivatives as MCP-1 inhibitors

2000-07-26

2002-11-12

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S382000, C514S393000, C514S412000, C514S414000, C548S153000, C548S252000, C548S303100, C548S453000

Reexamination Certificate

active

06479527

ABSTRACT:

This application is the national phase of international application PCT/GB99/00335 filed Feb. 2, 1999 which designated the U.S.
The present invention relates to pharmaceutical compositions which comprise anti-inflammatory and immunomodulatory compounds that act via antagonism of the CCR2 receptor, (also known as the MCP-1 receptor), leading inter alia to inhibition of Monocyte Chemoattractant Protein-1 (MCP-1). These compounds contain a bicyclic aromatic moiety. The invention further relates to novel compounds for use in the compositions, to processes for their preparation. to intermediates useful in their preparation and to their use as therapeutic agents.
MCP-1 is a member of the chemokine family of pro-inflammatory proteins 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 CCR2 receptor. MCP-2 and MCP-3 may also act, at least in part, through this 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 MCP2 and/or MCP-3 mediated effects when MCP-2 and/or MCP-3 are acting through the CCR2 receptor.
WO-9631492 describes a range of compounds including bicyclic compounds which are inhibitors of endothelin receptors. JP-3284177 discloses the preparation of certain formyl substituted pyrrolo-pyrroles for use in a range of applications. In addition, U.S. Pat. No.4,751,231 describes the preparation of substituted thienosulphonamides as antiglaucoma agents.
The applicants have found a class of compounds containing a bicyclic moiety which have useful inhibitory activity against MCP-1.
The present invention provides a pharmaceutical composition comprising a compound of formula (I):
or a pharmaceutically acceptable salt or esters of amides thereof, which is an inhibitor of monocyte chemoattractant protein- I and wherein A and B together with the carbon atoms to which they are attached, form an optionally substituted 5 membered aromatic ring which includes at least one heteroatom;
X is CH
2
or SO
2
;
R
1
is an optionally substituted aryl or heteroaryl ring;
R
2
is carboxy, cyano, —C(O)CH
2
OH, —CONHR
4
, —SO
2
NHR
5
, tetrazol-5-yl, SO
3
H, or a group of formula (VI):
 where R
4
is selected from hydrogen, alkyl, aryl, cyano, hydroxy, —SO
2
R
9
where R
9
is alkyl, aryl, heteroaryl, or haloalkyl, or R
4
is a group-(CHR
10
)
r
—COOH where r is an integer of 1-3 and each R
10
group is independently selected from hydrogen or alkyl; R
5
is alkyl, optionally substituted aryl such as optionally substituted phenyl or optionally substituted heteroaryl such as 5 or 6 membered heteroaryl groups, or a group COR
6
where R
6
is hydrogen, alkyl, aryl, heteroaryl or haloalkyl; R
7
and R
8
are independently selected from hydrogen or alkyl, particularly C
1-4
alkyl; and
R
3
is hydrogen, a functional group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aralkyl, optionally substituted aralkyloxy, optionally substituted cycloalkyl; in combination with a pharmaceutically acceptable carrier or diluent.
Suitably the composition comprises a compound of formula (I) or a salt or in vivo hydrolysable ester thereof.
Compounds of formula (I) are inhibitors of monocyte chemoattractant protein-1. In addition, they appear to inhibit RANTES induced chemotaxis. RANTES (Regulated upon Activation, Normal T-cell Expressed and Secreted) is another chemokine from the same family as MCP-1, with a similar biological profile, but acting though the CCR1 receptor. As a result, these compounds can be used to treat disease mediated by these agents, in particular inflammatory disease.
Example of such compounds are compounds where A, B, X, R
1
and R
3
are as defined above, and where R
2
is as defined above but R
4
is selected from cyano, hydroxy, —SO
2
R
9
where R
9
is alkyl, aryl, hcteroaryl, or haloalkyl, or R
4
is a group-(CHR
10
)
r
—COOH where r is an integer of 1-3 and each R
10
group is independently selected from hydrogen or alkyl; R
5
is optionally substituted phenyl or optionally heteroaryl groups, or a group COR
6
where R
6
is alkyl, aryl, heteroaryl or haloalkyl; R
7
and R
8
are independently selected from hydrogen or alkyl, particularly C
1-4
alkyl.
In this specification the term “heteroatom” refers to non-carbon atoms such as oxygen, nitrogen or sulphur atoms. The term ‘alkyl’ when used either alone or as a suffix includes straight chain and branched structures. These groups may contain up to 10, preferably up to 6 and more preferably up to 4 carbon atoms. Similarly the terms “alkenyl” and “alkynyl” refer to unsaturated straight or branched structures containing for example from 2 to 10, preferably from 2 to 6 carbon atoms. Cyclic moieties such as cycloalkyl, cycloalkenyl and cycloalkynyl are similar in nature but have at least 3 carbon atoms. Terms such as “alkoxy” and “alkanoyl” comprise alkyl moieties as defined above, attached to the appropriate functionality.
The term “halo” includes fluoro, chloro, bromo and iodo. References to aryl groups include aromatic carbocylic groups such as phenyl and naphthyl. The term “heterocyclyl” includes aromatic or non-aromatic rings, for example containing from 4 to 20, suitably from 5 to 10 ring atoms, at least one of which is a heteroatom such as oxygen, sulphur or nitrogen. Examples of such groups include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, iosquinolinyl, quinoxalinyl, benzthiazolyl, benzoxazolyl, benzothienyl or benzofuryl.
“Heteroaryl” refers to those groups described above which have an aromatic character. The term “aralkyl” refers to aryl substituted alkyl groups such as benzyl.
Other expressions used in the specification include “hydrocarbyl” which refers to any structure comprising carbon and hydrogen atoms. For example, these may be alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl.
The term “functional group” refers to reactive substituents. They may comprise electron-donating or electron-withdrawing. Examples of such groups include halo, cyano, nitro, C(O)
n
R
11
, OR
11
, S(O)
m
R
11
, NR
12
R
12′
, C(O)NR
12
R
12′
, OC(O)NR
12
R
12′
, —CH═NOR
11
, —NR
12
C(O)
n
R
11
, —NR
11
CONR
12
R
12′
, —N═CR
12
R
12′
, S(O)
m
NR
12
R
12′
or —NR
12
S(O)
m
R
11
where R
11
, R
12
and R
12′
are independently selected from hydrogen or optionally substituted hydrocarbyl, or R
12
and R
12′
together form an optionally substituted ring which optionally contains further heteroatoms such as S(O)
m
, oxygen and nitrogen, n is an integer of 1 or 2, m is 0 or an integer of 1-3. Where functional groups comprise S(O)
m
NR
12
R
12′
or —NR
12
S(O)
m
R
11
, m is generally an integer f

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