2-ACYLAMINOTHIAZOLE DERIVATIVE OR SALT THEREOF
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 - 17 . (canceled)
18 . A 2-acylaminothiazole derivative represented by the following Formula (V) or a pharmaceutically acceptable salt thereof:
wherein the symbols have the following meanings:
Ar 2 : phenyl or pyridyl, each of which may be substituted,
R 3 : aryl or monocyclic aromatic heterocycle, each of which may be substituted,
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.
19 . The compound according to claim 18 , wherein R 3 is phenyl or thienyl, each of which can be substituted.
20 . The compound according to claim 19 , wherein R 3 is phenyl or thienyl, each of which can be substituted with 1 to 3 halogen atoms; when substituted with 2 or 3 halogen atoms, the halogen atoms can be identical or different.
21 . The compound according to claim 20 , wherein R 4 is 4-(piperidin-1-yl)piperidin-1-yl, 4-propylpiperidin-1-yl, 4-cyclohexylpiperazin-1-yl, or 4-propylpiperazin-1-yl.
22 . The compound according to claim 21 , 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.
23 . The compound according to claim 22 , 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.
24 . A compound selected from the group consisting of
N-[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]-3-fluoro-4-hydroxybenzamide,
3-chloro-N-[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]-4-(2-hydroxyethoxy)benzamide,
N-[4-(4-chlorothiophen-2-yl)-5-(4-propylpiperidino)thiazol-2-yl]-2-methoxyisonicotinamide,
3-chloro-N-[4-(4-chlorothiophen-2-yl)-5-(4-propylpiperazin-1-yl)thiazol-2-yl]-4-(2-hydroxyethoxy)benzamide,
5-chloro-N-[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]-6-(3-hydroxypropoxy)nicotinamide,
5-chloro-N-[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]-6-[(3-hydroxypropyl)amino)]nicotinamide,
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylic acid,
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-propylpiperazin-1-yl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylic acid,
N-[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]-4-(4-cyanopiperidino)-3,5,-difluorobenzamide,
1-(2-chloro-4-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl}phenyl)-piperidine-4-carboxylic acid,
1-(2-chloro-4-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl}-6-fluorophenyl)piperidine-4-carboxylic acid,
1-(2-chloro-4-{[4-(4-chlorothiophen-2-yl)-5-(4-propylpiperazin-1-yl)thiazol-2-yl]carbamoyl}phenyl)piperidine-4-carboxamide,
5-chloro-N-[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]-6-(4-hydroxymethylpiperidino)nicotinamide,
1-(3-chloro-5-{[5-(4-cyclohexylpiperazin-1-yl)-4-(4-fluorophenyl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylic acid,
1-(3-chloro-5-{[5-(4-cyclohexylpiperazin-1-yl)-4-(3-trifluoromethylphenyl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylic acid,
5-chloro-N-[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]-6-{4-[(2-methoxyethyl)carbamoyl]piperidino}nicotinamide,
5-chloro-N-[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]-6-{4-[(3-methoxypropyl)carbamoyl]piperidino}nicotinamide,
5-chloro-N-[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]-6-[4-(morpholinocarbonyl)piperidino]nicotinamide,
and pharmaceutically acceptable salts thereof.
25 . A pharmaceutical composition comprising a therapeutically effective amount of any one of the pharmaceutical compounds of claim 18 .
26 . The pharmaceutical composition according to claim 25 , wherein the pharmaceutical composition is adapted for oral administration.
27 . The pharmaceutical composition according to claim 26 , wherein the effective amount of the compound is a daily dosage of between about 0.01 and about 1 mg/kg.
28 . The pharmaceutical composition according to claim 27 , wherein the pharmaceutical composition in the form of one or more tablets.
29 . A method for the treatment of thrombocytopenia in a subject in need thereof, the method comprising: administering a therapeutically effective amount of the compound according to claim 18 to a subject in need thereof, such that thrombocytopenia is treated in the subject.
30 . The method according to claim 29 , wherein the subject has idiopathic thrombocytopenic purpura.
31 . The method according to claim 30 , wherein the method comprises: administering the effective amount of the compound in an oral dosage form comprising the compound and a pharmaceutically acceptable carrier.
32 . The method according to claim 31 , wherein the effective amount of the compound is a daily dosage of between about 0.01 and about 1 mg/kg.
33 . The method according to claim 32 , wherein the method comprises: administering the effective amount of the compound in the form of one or more tablets once daily.
34 . The method according to claim 31 , wherein the method comprises: administering the therapeutically effective amount of the compound to the subject having a depressed platelet level, wherein the platelet level in the subject is increased or recovered.
35 . The method according to claim 29 , wherein the thrombocytopenia is due to chemotherapy or radiotherapy for malignant tumors, aplastic anemia, myelodysplastic syndrome, liver disease, or HIV.
36 . The method according to claim 35 , wherein the thrombocytopenia is due to chemotherapy or radiotherapy for malignant tumors, or liver disease.
37 . The method according to claim 36 , wherein the method comprises: administering the effective amount of the compound in an oral dosage form comprising the compound and a pharmaceutically acceptable carrier.
38 . The method according to claim 37 , wherein the effective amount of the compound is a daily dosage of between about 0.01 and about 1 mg/kg.
39 . The method according to claim 38 , wherein the method comprises: administering the effective amount of the compound in the form of one or more tablets once daily.
40 . The method according to claim 35 , wherein the method comprises: administering the therapeutically effective amount of the compound to the subject having a depressed platelet level, wherein the platelet level in the subject is increased or recovered.
41 . The method according to claim 35 , wherein the method comprises: administering a therapeutically effective amount of the compound to the subject prior to the chemotherapy or radiotherapy when thrombocytopenia is likely to be caused by the chemotherapy or radiotherapy.
42 . The method according to claim 29 , wherein the method comprises: administering the therapeutically effective amount of the compound to the subject such that administration results in cell proliferation and production of mature megakaryocytes and platelets.