Indole derivatives as MCP-1 receptor antagonists

Details Indole derivatives as MCP-1 receptor antagonists Indole derivatives as MCP-1 receptor antagonists

2000-02-03

2001-09-11

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...

C548S465000, C548S492000

Reexamination Certificate

active

06288103

ABSTRACT:

The present invention relates to anti-inflammatory compounds that act via inhibition of Monocyte Chemoattractant Protein-1 (MCP-1) and in particular 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 (Grinun 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. Japanese patent application no. JP 04273857-A discloses indole compounds for treating hypertension with a phenyl sulphonyl moiety attached to the nitrogen of the indole ring. International patent application WO96/33171 discloses similar compounds for therapy of HIV-1 infections.
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 the present invention provides a compound of the formula (I)
which is an inhibitor of monocyte chemoattractant protein-1 and wherein:
R
1
is independently selected from trifluoromethyl, C
1-4
alkyl, halo, hydroxy, C
1-4
alkoxy, 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 1-4 and R
1
can have the same or different values when p is 2-4;
T is of the formula
—(CHR
4
)
m
—(SO
2
)—(CHR
4
)
s
—,
(where R
4
is hydrogen or C
1-4
alkyl, m=0-2, s=0-2, m+s=0-2, and R
4
can take different values when m+s=2);
X is carboxy, tetrazol-5-yl, cyano, SO
3
H, —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 cyano, 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
here 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, trifluoromethoxy, cyano, C
1-4
alkoxy, C
1-4
alkanoyl, C
1-4
alkanoyloxy, amino, C
1-4
alkylamino, di(C
1-4
alkyl)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
14
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, methoxy, methylsulphanyl, methylsulphinyl, methylsulphonyl or carboxyC
3-6
cycloalkyl, —(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 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, t-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 example “hydroxyC
1-4
alkyl” includes 1-hydroxyethyl and 2-hydroxyethyl. The term “halo” refers to fluoro, chloro, bromo and iodo.
Suitable optional substituents for aryl and heteroaryl are any of the values defined for R
1
and R
2
above. “Aryl” means phenyl or naphthyl. “Heteroaryl” means an aromatic mono- or bicyclic-5-10 membered ring with up to three or five ring heteroatoms (in mono or bicyclic rings respectively) selected from nitrogen, oxygen and sulphur. Examples of “heteroaryl” include thienyl, pyrrolyl, furanyl, imidazolyl, thiazolyl, pyrimidinyl, pyridinyl, indolyl, benzimidazolyl, benzthiazolyl, quinolyl and isoquinolinyl.
An example of “C
1-4
alkanoyloxy” is acetoxy. Examples of “C
1-4
alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of “C
1-4
alkoxy” include methoxy, ethoxy and propoxy. Examples of “C
1-4
alkanoylamino” include formamido, acetamido and propionylamino. Examples of “C
1-4
alkylsulphanyl” include methylthio and ethylthio. Examples of “C
1-4
alkylsulphinyl” include methylsulphinyl and ethylsulphinyl. Examples of “C
1-4
alkylsulphonyl” include methylsulphonyl and ethylsulphonyl. Examples of “C
1-4
alkanoyl” include propanoyl and ethanoyl. Examples of “C
1-4
alkylamino” include methylamino and ethylamino. Examples of “di(C
1-4
alkyl)amino” include di-N-methylaamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of “C
1-4
alkoxyC
1-4
alkyl” methoxymethyl and propoxyethyl. Examples of “carbamoylC
1-4
alkyl” are methylcarboxamide and ethylcarboxarnide. Examples of “carboxyC
3-6
cycloalkyl” are 2-carboxycyclopropyl and 3-carboxycyclopentyl. Examples of “N—(C
1-4
alkyl)carbamoylC
1-4
alkyl” are methylaminocarbonylethyl and ethylaminocarbonylpropyl. Examples of “N—(C
1-4
alkyl)
2
carbamoyl-C
1-4
alkyl” are dimethylaminocarbonylethyl and methylethylaminocarbonylpropyl. Examples of “carboxyC
1-4
alkylamino” are carboxymethylamino and carboxypropylamino.
Preferred values for R
1
, p, Z, X, T, A, R
2
and q are as follows.
Preferred values for R
1
are C
1-4
alkoxy, halo, nitro, amino, trifluoromethyl and carboxyC
1-4
alkylamino, more preferably chloro and/or C
1-4
alkoxy. Where R
1
is halo, fluoro, chloro or bromo ar

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