Immuno inhibitory pyrazolone compounds
Compounds of formula (IA) or (IB) are inhibitors of CD80 and useful in immunomodulation therapy: wherein Ar represents an optionally substituted monocyclic or bicyclic aromatic or heteroaromatic group having from 5 to 10 ring atoms; R 1 and R 2 independently represent H, or C 1 -C 6 alkyl; R 3 represents H; F; CI; Br, —NO 2 ; —CN; C 1 -C 6 alkyl optionally substituted by F or CI; or C 1 -C 6 alkoxy optionally substituted by F; R 4 represents a carboxylic acid group (—COOH) or an ester thereof, or —C(═O)NR 6 R 7 , —NR 7 C(═O)R 6 , —NR 7 C(═O)OR 6 , —NHC(═O)NR 7 R 6 or —NHC(═S)NR 7 R 6 wherein R 6 represents H, or a radical of formula -(Alk) m -Q wherein m is 0 or 1, Alk is an optionally substituted divalent straight or branched C 1 -C 12 alkylene, or C 2 -C 12 alkenylene, or C 2 -C 12 alkynylene radical or a divalent C 3 -C 12 carbocyclic radical, any of which radicals may be interrupted by one or more —O—, —S— or —N(R 8 )— radicals wherein R 8 represents H or C 1 -C 4 alkyl, C 3 -C 4 alkenyl, C 3 -C 4 alkynyl, or C 3 -C 6 cycloalkyl, and Q represents H; —CF 3 ; —OH; —SH; —NR 8 R 8 wherein each R 8 may be the same or different, or form a ring when taken together with the nitrogen to which they are attached; an ester group; or an optionally substituted aryl, aryloxy, cycloalkyl, cycloalkenyl or heterocyclic group; and R 7 represents H or C 1 -C 6 alkyl; or when taken together with the atom or atoms to which they are attached R 6 and R 7 form a monocyclic heterocyclic ring having 5, 6 or 7 ring atoms; and X represents a bond or a divalent radical of formula -(Z) n -(Alk)- or -(Alk)-(Z) n - wherein Z represents —O—, —S— or —NH—, Alk is as defined in relation to R 6 and n is 0 or 1.
1. A compound of formula (IA) or (1B) or a pharmaceutically or veterinarily acceptable salt thereof:
wherein
Ar represents an optionally substituted monocyclic or bicyclic aromatic or heteroaromatic group having from 5 to 10 ring atoms,
R 1 and R 2 independently represent H, or C 1 -C 6 alkyl;
R 3 represents H; F; Cl; Br; —NO 2 ; —CN; C 1 -C 6 alkyl optionally substituted by F or Cl; or C 1 -C 6 alkoxy optionally substituted by F;
R 4 represents a carboxylic acid group (—COOH) or an ester thereof, or —C(═O)NR 6 R 7 , —NR 7 C(═O)R 6 , —NR 7 C(═O)OR 6 , —NHC(═S)NR 7 R 6 or —NHC(═S)NR 7 R 6 wherein
R 6 represents H, or a radical of formula —(Alk) m -Q wherein
m is 0 or 1
Alk is an optionally substituted divalent straight or branched C 1 -C 12 alkylene, or C 2 -C 12 alkenylene, or C 2 -C 12 alkynylene radical or a divalent C 3 -C 12 carbocyclic radical, any of which radicals may be interrupted by one or more —O—, —S—or —N(R 8 )— radicals
wherein R 8 represents H or C 1 -C 4 alkyl, C 3 -C 4 alkenyl, C 3 -C 4 alkynyl, or C 3 -C 6 cycloalkyl, and
Q represents H; —CF 3 ; —OH; —SH; —NR 8 R 8 wherein R 8 is defined as above, and each R 8 may be the same or different; an ester group; or an optionally substituted aryl, aryloxy, cycloalkyl, or cycloalkenyl; and
R 7 represents H or C 1 -C 6 alkyl; and
X represents a bond or a divalent radical of formula —(Z) n -(Alk)- or -(Alk)-(Z) n - wherein Z represents —O—, —S— or —NH—, Alk is as defined in relation to R 6 and n is 0 or 1.
2. A compound as claimed in claim 1 wherein R 1 in compounds (IA) and each of R 1 and R 2 in compounds (IB) is other than hydrogen.
3. A compound as claimed in claim 1 wherein R 4 represents a carboxylic acid group (—COOH) or an ester group of formula —COOR wherein R is methyl, ethyl n- or iso-propyl, n-, sec- or tert-butyl, or benzyl.
4. A compound as claimed in claim 1 wherein R 6 represents a radical of formula -(Alk) m -Q wherein m is 1, Alk is —CH 2 —, CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, or —CH 2 CH(CH 3 )CH 2 —, or a divalent cyclopropylene, cyclopentylene or cyclohexylene radical, optionally substituted by OH, oxo, CF 3 , methoxy or ethoxy, and Q represents hydrogen; —NR 8 R 8 wherein each R 8 may be the same or different and selected from hydrogen, methyl, ethyl, n- or isopropyl or tert-butyl; a methyl, ethyl or benzyl ester; or an optionally substituted phenyl, phenoxy, cyclopentyl, or cyclohexyl group.
5. A compound as claimed in claim 1 wherein R 7 represents hydrogen, methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl.
6. A compound as claimed in claim 1 wherein Ar is optionally substituted phenyl, 2-, 3-, or 4-pyridyl, 2-, or 3-furyl, 2-, or 3-thienyl, benzfur-2-yl, or benzthien-2-yl.
7. A compound as claimed in claim 1 wherein Ar is substituted by F, Cl, methyl, methoxy, or methylenedioxy.
8. A compound as claimed in claim 1 wherein Ar is 3-fluorophenyl, or 2- or 3-furyl.
9. A compound as claimed in claim 1 wherein R 3 is H, F, Cl, methyl, methoxy, or methylenedioxy.
10. A compound as claimed in claim 1 wherein X is a bond, or a —CH 2 or —CH 2 CH 2 — radical.
11. A compound as claimed in claim 1 which is of formula (IC) or a pharmaceutically or veterinarily acceptable salt thereof:
12. A compound as claimed in claim 11 wherein the radical —C(═O)NR 6 R 7 is in the 4-position of the phenyl ring.
13. A compound as claimed in claim 11 wherein R 7 is hydrogen and R 6 is -AlkNR 8 R 8 wherein the R 8 represents H or C 1 -C 4 alkyl, C 3 -C 4 alkenyl, C 3 -C 4 alkynyl, or C 3 -C6 cycloalkyl.
14. A pharmaceutical or veterinary composition comprising a compound as claimed in claim 1 together with a pharmaceutically or veterinarily acceptable excipient or carrier.
15. A composition according to claim 14 wherein the compound is in an amount effective for treatment of conditions which benefit from immunomodulation.
16. A medicament for the treatment of conditions which benefit from immunomodulation comprising an effective amount of the compound according to claim 1 together with a pharmaceutically or veterinarily acceptable excipient or carrier; wherein the conditions are selected from rheumatoid arthritis, psoriasis, multiple sclerosis, and diabetes.