2-Acylaminothiazole derivative or salt thereof
View Patent ↗A 2-acylaminothiazole derivative or a pharmaceutically acceptable salt thereof having an excellent effect of proliferating human c-mpl-Ba/F3 cells and an activity of increasing platelets based on the effect of promoting the formation of megakaryocytic colonies. A compound or a pharmaceutically acceptable salt thereof useful in treating thrombocytopenia.
1. A 2-acylaminothiazole derivative compound represented by the following Formula (V), or a pharmaceutically acceptable salt thereof:
wherein the symbols have the following meanings:
Ar 2 : substituted or unsubstituted phenyl or monocyclic aromatic heterocycle;
R 3 : a substituted or unsubstituted thienyl;
R 4 : a group represented by Formula II:
wherein X is C(R 27 )R 28 or NR 26 and m=n=2;
wherein CR 20 R 21 and CR 22 R 23 can be identical or different; and
wherein each of R 20 , R 21 , R 22 , R 23 , R 26 , R 27 , and R 28 can be the same or different and can be selected from the group consisting of H; —OH; —O-lower alkyl; a substituted or unsubstituted lower alkyl; a substituted or unsubstituted cycloalkyl; a substituted or unsubstituted aryl; a substituted or unsubstituted arylalkyl; a substituted or unsubstituted aromatic heterocycle; a substituted or unsubstituted aromatic heterocyclic alkyl; a substituted or unsubstituted nonaromatic heterocycle; lower alkenyl; lower alkylidene; —COOH; —COO-lower alkyl; —COO-lower alkenyl; —COO-lower alkylene-aryl; —COO-lower alkylene-aromatic heterocycle; carbamoyl or amino, each of which can be substituted with one or more groups selected from the group consisting of lower alkyl which can be substituted with halogen, —OH, —O-lower alkyl, or —O-aryl; —NHCO-lower alkyl; and oxo.
2. The compound according to claim 1 , wherein Ar 2 is phenyl or pyridyl, each of which can be substituted.
3. The compound according to claim 1 , wherein R 3 is a thienyl which is substituted with 1 to 3 halogen atoms, which can be identical or different.
4. The compound according to claim 3 , wherein R 4 is 4-(piperidin-1-yl)piperidin-1-yl, 4-propylpiperidin-1-yl, 4-cyclohexylpiperazin-1-yl, or 4-propylpiperazin-1-yl.
5. The compound according to claim 4 , wherein Ar 2 is phenyl which is unsubstituted at 2- and 6-positions, substituted with —H, —F, —Cl, or —Br at 3-position, substituted with —F, —Cl, or —Br at 5-position, and substituted at 4-position; or pyridin-3-yl which is unsubstituted at 2- and 4-positions, substituted with —F, —Cl, or —Br at 5-position, and substituted at 6-position.
6. The compound according to claim 5 , wherein Ar 2 is phenyl which is substituted at 4-position with a group selected from the group consisting of —O—R Y , —NH—R Y , a substituted or unsubstituted piperidin-1-yl and a substituted or unsubstituted piperazin-1-yl; or pyridin-3-yl which is substituted at 6-position with a group selected from the group consisting of —O—R Y , —NH—R Y , a substituted or unsubstituted piperidin-1-yl and a substituted or unsubstituted piperazin-1-yl, wherein R Y is lower alkyl which can be substituted with one or more groups selected from the group consisting of —OH, —O-lower alkyl, amino which can be substituted with one or two lower alkyl, —CO 2 H, —CO-lower alkyl, carbamoyl which can be substituted with one or two lower alkyl, cyano, aryl, aromatic heterocycle, nonaromatic heterocycle and halogen.
7. The compound according to any one of claims 1 - 6 wherein the pharmaceutically acceptable salt is a maleate salt.
8. A compound selected from the group consisting of: 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylic acid, and pharmaceutically acceptable salts thereof.
9. The compound of claim 8 , wherein the pharmaceutically acceptable salt is the maleic acid salt.
10. A pharmaceutical composition comprising a therapeutically effective amount of any one of the pharmaceutical compounds of claims 1 - 6 and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 7 and a pharmaceutically acceptable carrier.
12. The pharmaceutical composition according to claim 10 , wherein the pharmaceutical composition is formulated for oral administration.
13. The pharmaceutical composition according to claim 11 , wherein the pharmaceutical composition is formulated for oral administration.
14. A pharmaceutical composition for treating thrombocytopenia, the composition comprising: a therapeutically effective amount of a compound selected from the group consisting of
and pharmaceutically acceptable salts thereof; and
a pharmaceutically acceptable carrier.
15. The pharmaceutical composition of claim 14 , wherein the compound is: