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US 6,441,004 B1Granted
Monocyte chemoattractant protein-1 inhibitor compounds
AssigneeZeneca Limited
InventorsAlan Wellington Faull, Andrew John Barker, Jason Grant Kettle
Life of this patent
Estimating the term…
Abstract
The invention concerns the use of a compound of the formula (I) in which Z, X, T, A, R1, R2, p and q have any of the meanings defined herein, and their pharmaceutically acceptable salts or in vivo hydrolysable esters, in the treatment of a disease or condition mediated by monocyte chemoattractant protein-1 (MCP-1). Certain of the components of formula (I) are novel and are provided, together with pharmaceutical compositions thereof, as further features of the invention.
Claims15
A method for antagonising an MCP-1 mediated effect in a warm-blooded animal in need thereof comprising administering to said animal an antagonising-effective amount of a compound of the formula (I):
- wherein
- R1 is independently selected from trifluoromethyl, C1-4alkyl, halo, hydroxy, C1-4alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, amino, cyano, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkanoylamino, nitro, carbamoyl, C1-4alkoxycarbonyl, thiol, C1-4alkylsulphanyl, C1-4alkylsulphinyl, C1-4alkylsulphonyl, sulphonamido, carbamoyl C1-4alkyl, N—(C1-4alkyl)carbamoylC1-4alkyl, N—(C1-4alkyl)2carbamoyl-C1-4alkyl, hydroxy C1-4alkyl, C1-4alkoxy C1-4alkyl, morpholino, pyrrolidinyl, carboxy C1-4alkylamino, R3 and —OR3, where R3 is optionally substituted aryl or an optionally substituted 5- or 6-membered heteroaryl ring;
- p is 0-4 and R1 can have the same or different values when p is 2-4 with the proviso that no more than one R1 can be chosen from the group amino, C1-4alkylamino, di(C1-4alkyl)amino, morpholino and pyrrolidinyl;
- T is of the formula
- —(CHR4)m—,
- where R4 is independently selected from hydrogen or C1-4alkyl and m=1-3 and R4 can have different values when m is 2 or 3;
- X is CO2R4, SO3H, cyano, —SO2NHR4, —SO2NHAr, or —CONHR5 wherein:
- R4 is as defined above;
- Ar is an optionally substituted phenyl or optionally substituted 5 or 6 membered heteroaryl ring;
- and
- R5 is H, cyano, C1-4alkyl, OH, —SO2—C1-4alkyl, —SO2CF3, or —SO2-phenyl, or R5 is —(CHR4)r—COOH where r is 1-3 and each R4 can take a different value, as defined above, when r is 2-3;
- A is selected from phenyl, naphthyl, furyl, pyridyl and thienyl;
- R2 is independently selected from trifluoromethyl, C1-4alkyl, halo, hydroxy, CF3O—, C1-4alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, amino, cyano, C1-4alkylamino, (C1-4alkyl)2amino, C1-4alkanoylamino, nitro, carboxy, carbamoyl, C1-4alkoxycarbonyl, thiol, C1-4alkylsulphanyl, C1-4alkylsulphinyl, C1-4alkylsulphonyl, sulphonamido, carbamoylC1-4alkyl, N—(C1-4alkyl)carbamoylC1-4alkyl, N—(C1-4alkyl)2carbamoyl-C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl or two R2 values together may form a divalent radical of the formula —O(CH2)1-4O— attached to adjacent carbon atoms on ring A;
- q is 0-4 and R2 can have the same or different values when q is 2-4;
- Z is hydrogen, fluoro, chloro, bromo, iodo, methyl, trifluoromethyl, hydroxymethyl, carboxyC3-6cycloalkyl or;
- Z is —(CHR4)r—NR6R7, where r is 0-2, R6 and R7 are independently selected from H and C1-4alkyl, or R6 and R7 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.
14 more elements
A method for the treatment of a disease or medical condition mediated by MCP-1 comprising administering to a warm-blooded animal in need thereof a treatment-effective amount of a compound of the formula (I):
- wherein
- R1 is independently selected from trifluoromethyl, C1-4alkyl, halo, hydroxy, C1-4alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, amino, cyano, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkanoylamino, nitro, carbamoyl, C1-4alkoxycarbonyl, thiol, C1-4alkylsulphanyl, C1-4alkylsulphinyl, C1-4alkylsulphonyl, sulphonamido, carbamoyl C1-4alkyl, N—(C1-4alkyl)carbamoylC1-4alkyl, N—(C1-4alkyl)2carbamoyl-C1-4alkyl, hydroxy C1-4alkyl, C1-4alkoxy C1-4alkyl, morpholino, pyrrolidinyl, carboxy C1-4alkylamino, R3 and —OR3, where R3 is optionally substituted aryl or an optionally substituted 5- or 6-membered heteroaryl ring;
- p is 0-4 and R1 can have the same or different values when p is 2-4 with the proviso that no more than one R1 can be chosen from the group amino, C1-4alkylamino, di(C1-4alkyl)amino, morpholino and pyrrolidinyl;
- T is of the formula
- —(CHR4)m—,
- where
- R4 is independently selected from hydrogen or C1-4alkyl and m=1-3 and R4 can have different values when m is 2 or 3;
- X is CO2R4, SO3H, cyano, —SO2NHR4, —SO2NHAr, or —CONHR5;
- wherein
- R4 is as defined above;
- Ar is an optionally substituted phenyl or optionally substituted 5 or 6 membered heteroaryl ring;
- R5 is H, cyano, C1-4alkyl, OH, —SO2—C1-4alkyl, —SO2CF3, —SO2-phenyl, or R5 is —(CHR4)r—COOH where r is 1-3 and each R4 can take a different value, as defined above, when r is 2-3;
- A is selected from phenyl, naphthyl, furyl, pyridyl and thienyl;
- R2 is independently selected from trifluoromethyl, C1-4alkyl, halo, hydroxy, CF3O—, C1-4alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, amino, cyano, C1-4alkylamino, (C1-4alkyl)2amino, C1-4alkanoylamino, nitro, carboxy, carbamoyl, C1-4alkoxycarbonyl, thiol, C1-4alkylsulphanyl, C1-4alkylsulphinyl, C1-4alkylsulphonyl, sulphonamido, carbamoylC1-4alkyl, N—(C1-4alkyl)carbamoylC1-4alkyl, N—(C1-4alkyl)2carbamoyl-C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl or two R2 values together may form a divalent radical of the formula —O(CH2)1-4O— attached to adjacent carbon atoms on ring A;
- q is 0-4 and R2 can have the same or different values when q is 2-4;
- Z is hydrogen, fluoro, chloro, bromo, iodo, methyl, trifluoromethyl, hydroxymethyl, carboxyC3-6cycloalkyl, or
- Z is —(CHR4)r—NR6R7, where r is 0-2, R6 and R7 are independently selected from H and C1-4alkyl or R6 and R7 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.
15 more elements
A compound of the formula (A):
- wherein
- Ra is 4-methoxy, 4-phenyl, 4-amino, 4-thien-2-yl, 5-chloro, 5-methoxy, 5-nitro, 5-bromo, 5-phenoxy, 5-fluoro, 5-carboxymethylamino, 5-amino, 6-fluoro, 6-trifluoromethyl, 6-nitro or 6-chloro;
- c is 0, 1 or 2 provided that there is no more than one methoxy group;
- W is hydrogen, bromo, methyl or transcyclopropyl-2-carboxylic acid;
- G is phenyl or thien-2-yl;
- when G is phenyl Rb is 3-chloro, 3-trifluoromethyl, 3-nitro, 3-methoxy, 4-trifluoromethyl, 4-trifluoromethoxy or 4-chloro;
- when G is thien-2-yl Rb is 5-chloro;
- d is 1 or 2;
- or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
6 more elements
A compound selected from:
- N-(3,4-Dichlorobenzyl)-5-nitroindole-2-carboxylic acid;
- N-(3-Methylbenzyl)-5-nitroindole-2-carboxylic acid;
- N-(3-Chlorobenzyl)-5-nitroindole-2-carboxylic acid;
- 5-Nitro-N-(3-trifluoromethylbenzyl)-indole-2-carboxylic acid;
- 5-Fluoro-N-(3-trifluoromethylbenzyl)indole-2-carboxylic acid;
- 6-Fluoro-N-(3-trifluoromethylbenzyl)indole-2-carboxylic acid;
- 3-Bromo-N-(3-trifluoromethylbenzyl)indole-2-carboxylic acid;
- N-(3,4-Dichlorobenzyl)-4-(thien-2-yl)indole-2-carboxylic acid;
- N-(3,4-Dichlorobenzyl)-3-(trans-2-carboxy-cyclopropyl)indole-2-carboxylic acid;
- 5-Chloro-N-(3,4-dichlorobenzyl)indole-2-carboxylic acid;
- 6-Chloro-N-(3,4-dichlorobenzyl)indole-2-carboxylic acid;
- and
- N-(3,4-Dichlorobenzyl)-4-methoxyindole-2-carboxylic acid;
- and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof.
11 more elements
A compound of the formula (I′):
- wherein
- Re is methoxy, fluoro, chloro, bromo, nitro, amino, phenoxy or trifluoromethyl;
- x is 1 or 2 with the proviso that there is at most one methoxy group;
- X′ is carboxy;
- A′ is phenyl;
- Rf is chloro, bromo, methyl, methoxy, trifluoromethyl or trifluoromethoxy;
- y is 1 or 2;
- and
- Z′ is hydrogen;
- or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
7 more elements
A compound of the formula (I′):
- wherein
- Re is methoxy, fluoro, chloro, bromo, nitro, amino, phenoxy or trifluoromethyl;
- x is 1 or 2 with the proviso that there is at most one methoxy group;
- X′ is carboxy;
- A′ is phenyl;
- Rf is chloro, bromo, methyl, methoxy, nitro, trifluoro methyl or trifluoromethoxy;
- y is 2;
- and
- Z′ is hydrogen;
- or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
7 more elements
A compound of the formula (I):
- wherein
- R1 is independently selected from trifluoromethyl, C1-4alkyl, halo, hydroxy, C1-4alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, amino, cyano, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkanoylamino, nitro, carbamoyl, C1-4alkoxycarbonyl, thiol, C1-4alkylsulphanyl, C1-4alkylsulphinyl, C1-4alkylsulphonyl, sulphonamido, carbamoylC1-4alkyl, N—(C1-4alkyl)carbamoylC1-4alkyl, N—(C1-4alkyl)2carbamoyl-C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, morpholino, pyrrolidinyl, carboxyC1-4alkylamino, R3 and —OR3, where R3 is optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl ring;
- p is 1 or 2, and R1 can have the same or different values when p is 2 with the proviso that no more than one can be chosen from the group amino, C1-4alkylamino, di(C1-4alkyl)amino, morpholino and pyrrolidinyl;
- Z is hydrogen;
- X is carboxy;
- T is —CH2—;
- A is phenyl;
- R2 is independently selected from chloro, bromo, methyl, methoxy, nitro, trifluoromethyl and trifluoromethoxy;
- q is 2;
- the positions ortho to T on the phenyl ring A are unsubstituted;
- and
- position 7 of the indole ring is unsubstituted;
- or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
10 more elements
Dependencies are inferred from the claim text.