2-iminopyrrolidine derivatives
A 2-iminopyrrolidine derivative represented by the formula: {wherein ring B represents a benzene ring, pyridine ring, etc.; R 101 –R 103 represent hydrogen, halogen, C 1-6 alkyl, etc.; R 5 represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, etc.; R 6 represents hydrogen, C 1-6 alkyl, C 1-6 alkyloxycarbonyl, etc.; Y 1 represents a single bond, —CH 2 —, etc.; Y 2 represents a single bond, —CO—, etc.; and Ar represents hydrogen, a group represented by the formula: [wherein R 10 —R 14 represent hydrogen, C 1-6 alkyl, hydroxyl, C 1-6 alkoxy, etc.; and R 11 and R 12 or R 12 and R 13 may bond together to form a 5- to 8-membered heterocyclic ring], etc.}, or a salt thereof.
1. 1-(3-tert-Butyl-4-methoxy-5-morpholino-phenyl)-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)-ethanone hydrobromide.
2. 1-{3-tert-Butyl-5-[4-(2-hydroxy-acetyl)piperazin-1-yl]-4-methoxy-phenyl}-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)-ethanone hydrobromide.
3. Ethyl (4-{3-tert-butyl-5-[2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)-acetyl]-2-methoxy-phenyl}piperazin-1-yl)-acetate dihydrochloride.
4. 1-(3-tert-Butyl-4-methoxy-5-piperazin-1-yl-phenyl)-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)-ethanone dihydrochloride.
5. (4-{3-tert-Butyl-5-[2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)-acetyl]-2-methoxy-phenyl}-piperazin-1-yl)-acetic acid dihydrochloride.
6. A compound represented by the formula:
[wherein R 101 represents C 1-6 alkoxy or C 1-6 alkylaminocarbonyl;
R 102 represents C 1-6 alkoxy;
R 104 represents hydrogen or halogen;
R 105 represents hydrogen;
R 5 hydrogen;
R 6 represents hydrogen;
Y 1 represents —CH 2 —;
Y 2 represents —CO—; and
Ar represents a group represented by the formula:
(wherein R 10 represents hydrogen;
R 11 represents C 1-6 alkyl;
R 12 represents hydroxyl, C 1-6 alkoxy or C 1-6 alkylaminocarbonyloxy;
R 13 represents C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkoxy or 5- to 14-membered non-aromatic heterocyclic group, each of the foregoing members being optionally substituted with at least one group selected from hydroxyl, cyano, C 1-6 alkoxy, C 2-7 acyl, C 1-6 alkoxyalkylcarbonyl, C 1-6 alkylamino, oxo, C 1-6 carboxyalkyl and hydroxymethylcarbonyl;
R 14 represents hydrogen; and
R 12 and R 13 may bond together to form a 5- to 8-membered heterocycle optionally having 1 to 4 hetero atoms selected from N, S and O and also optionally substituted by cyano-C 1-6 alkyl)]
or a salt thereof.
7. A compound selected from any one of the group consisting of:
1-(3-tert-Butyl-4-methoxy-5-morpholino-phenyl)-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)-ethanone;
1-{3-tert-Butyl-5-[4-(2-hydroxy-acetyl)piperazin-1-yl]-4-methoxy-phenyl}-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)-ethanone;
Ethyl (4-{3-tert-butyl-5-[2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)-acetyl]-2-methoxy-phenyl}piperazin-1-yl)-acetate;
1-(3-tert-Butyl-4-methoxy-5-piperazin-1-yl-phenyl)-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)-ethanone; and
(4-{3-tert-Butyl-5-[2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)-acetyl]-2-methoxy-phenyl}-piperazin-1-yl)-acetic acid;
or a salt thereof.
8. 1-(3-tert-Butyl-4-methoxy-5-morpholino-phenyl)-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)-ethanone, or a salt thereof.
9. 1-{3-tert-Butyl-5-[4-(2-hydroxy-acetyl)piperazin-1-yl]-4-methoxy-phenyl}-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)-ethanone, or a salt thereof.
10. Ethyl (4-{3-tert-butyl-5-[2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)-acetyl]-2-methoxy-phenyl}piperazin-1-yl)-acetate, or a salt thereof.
11. 1-(3-tert-Butyl-4-methoxy-5-piperazin-1-yl-phenyl)-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)-ethanone, or a salt thereof.
12. (4-{3-tert-Butyl-5-[2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)-acetyl]-2-methoxy-phenyl}-piperazin-1-yl)-acetic acid, or a salt thereof.
13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or 7 to 12 .
14. A pharmaceutical composition comprising a compound according to claim 6 .
15. A method for treating thrombosis, vascular restenosis, deep venous thrombosis, and inflammatory disease, comprising administering to a patient a compound according to claim 6 , or a pharmaceutical composition comprising a compound according to claim 6 , in an amount effective to antagonize a thrombin receptor.
16. The method according to claim 15 , wherein the thrombin receptor is a PAR-1 thrombin receptor.