Chemical compounds

Details Chemical compounds Chemical compounds

2000-07-26

2001-09-18

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...

C548S243000, C548S253000, C548S512000, C548S514000, C548S516000

Reexamination Certificate

active

06291507

ABSTRACT:

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 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 nephritis, 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). A CCR2 antagonist 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 other cytokine mediated effects including MCP-2 and/or MCP-3 mediated effects when those cytokines are acting through the MCP-1 receptor.
J. Chem. Soc. Perkin Trans I (1995) 1131-1136 discloses a number of bicyclic compounds which are intermediates in the production of biologically active indole compounds.
EP-A-189690 discloses that inter alia certain cycloalkanopyrrole derivatives can be useful in treating elevated intra-ocular pressure, whilst WO 9730704 suggests that related compounds may be used in treating or preventing macular oedema.
The applicants have found that a class of compounds containing a bicyclic moiety are CCR
1
receptor antagonists. 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.
Accordingly the present invention provides a pharmaceutical composition which comprises a compound of formula (I)
or a pharmaceutically acceptable salt, an ester or amide thereof, which are inhibitors of monocyte chemoattractant protein-l; and wherein
A and B form an optionally substituted alkylene chain so as to form a ring with the carbon atoms to which they are attached;
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
1
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.
Suitably the compositions comprise a compound of formula (I) or a salt or in vivo hydrolysable ester thereof.
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 that R
4
is selected from 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 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
1
are independently selected from hydrogen or alkyl, particularly C
1-4
alkyl.
Compounds of formula (I) are inhibitors of monocyte chemoattractant protein-1 and therefore can be used to treat inflammatory disease. Thus the invention further provides a compound of formula (I) for use in the treatment of inflammatory disease.
In yet a further embodiment, the invention provides the use of a compound of formula (I) in the preparation of a medicament for the treatment of inflammatory disease.
In this specification the term ‘alkyl’ when used either alone or as a suffix includes straight chained, 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” comprise alkyl groups as is understood in the art.
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 8 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, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl or benzofiuryl.
“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, oxo, ═CR
11
R
12
, C(O)
n
R
11
, OR
11
, S(O)
m
R
11
, NR
12
R
3
, C(O)NR
12
R
13
, OC(O)NR
12
R
13
, ═NOR
11
, —CHNOR
11
, —NR
12
C(O)
n
R
11
, —NR
11
CONR
12
R
13
, —N═CR
12
R
13
, S(O)
m
NR
12
R
13
or —NR
12
S(O)
m
R
11
where R
11
, R
12
and R
13
are independently selected from hydrogen or optionally substituted hydrocarbyl, or R
12
and R
13
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. It should be understood that functional group

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