Benzoxazole carboxamides for treating CINV and IBS-D
View Patent ↗Compounds of formulae I and II: are disclosed as 5-HT 3 inhibitors. Those compounds that exhibit central activity are useful in treating CINV; those that inhibit peripheral receptors are useful to treat IBS-D.
1. A compound of formula
wherein
R 1 , R 2 and R 3 are independently selected from hydrogen, halogen, amino, alkylamino, dialkylamino, acylamino, morpholinyl, —O-loweralkyl, hydroxy, loweralkyl, fluoroloweralkyl, —O-lowerfluoroalkyl, methylenedioxy, ethylenedioxy, alkoxy-loweralkyl and hydroxyloweralkyl;
R 4 is an imidazolylalkyl residue wherein the imidazole of said imidazolylalkyl is optionally substituted with up to three groups chosen from halogen, (C 1 -C 4 )alkyl, substituted (C 1 -C 4 )alkyl and NH 2 ; and
Ar is chosen from the group consisting of
(i) aryl;
(ii) heteroaryl;
(iii) substituted aryl;
(iv) substituted heteroaryl; and
(v) dihydroheteroaryl.
2. A compound according to claim 1 wherein R 1 , R 2 and R 3 are hydrogen.
3. A compound according to claim 1 wherein one of R 1 , R 2 and R 3 is halogen.
4. A compound according to claim 1 wherein R 1 and R 3 are hydrogen and R 2 is chosen from amino, halogen, methoxy, hydroxy, acetylamino, and 4-morpholinyl.
5. A compound according to claim 1 wherein Ar is chosen from the group consisting of phenyl and phenyl substituted with from 1 to 4 groups independently selected from (C 1 to C 4 )alkyl, phenyl, phenoxy, halogen, (C 1 to C 4 )alkoxy, amino, (C 1 to C 4 )alkylamino, di(C 1 to C 4 )alkylamino, anilino, heterocyclyl, methylheterocyclyl, methylenedioxy, (C 1 to C 4 )acylamino, (C 1 to C 4 )alkynyl and nitro.
6. A compound according to claim 5 wherein Ar is chosen from the group consisting of phenyl and phenyl substituted with one or two residues chosen independently from (C 1 to C 4 )alkyl, 4-methylpiperazin 1-yl, morpholin-4-yl, pyridin-4-yl, phenyl, phenoxy, amino, anilino, halogen, methoxy, dimethylamino, methylenedioxy, acetylamino, propyn-1-yl and nitro.
7. A compound according to claim 1 wherein Ar is chosen from the group consisting of heteroaryl, dihydroheteroaryl and substituted heteroaryl.
8. A compound according to claim 7 wherein Ar is chosen from thiophene, cyclopenta[b]thiophene, furan, thiazole, isoxazole dihydrobenzofuran, benzofuran, pyridine, benzothiophene, 3-pyridine-2-one, and their methylated and halogenated congeners.
9. A compound according to claim 1 chosen from:
N-[3-(2-Methylimidazol-1-yl)propyl]-2-phenylbenzoxazole-4-carboxamide and
N-[2-(2-Methylimidazol-1-yl)ethyl]-2-phenylbenzoxazole-4-carboxamide.
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 .
11. A pharmaceutical composition according to claim 10 additionally comprising a second antiemetic agent.
12. A pharmaceutical composition according to claim 11 wherein said second antiemetic agent is a neurokinin antagonist.
13. A method of treating irritable bowel syndrome or emesis which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 .
14. A method according to claim 13 wherein said disorder is irritable bowel syndrome.
15. A method according to claim 13 for treating emesis.
16. A method for treating post-operative nausea or vomiting which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 .