Benzophenone thiazole derivatives useful for inhibiting formation of microtubule and method for producing the same
Disclosed are a novel thiazole-containing benzophenone derivative represented by formula 1, and an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof, a pharmaceutical composition comprising the derivative, a use of the derivative as therapeutic agent and a method for preparing the derivative. The benzophenone thiazole derivatives inhibit formation of microtubules and eliminate actively proliferating cells of malignant tumors to control general cell proliferation. In formula 1, R, R 1 and R 2 are defined as above.
1. A compound represented by formula (1) below or a stereoisomer thereof, and a pharmaceutically acceptable salt thereof:
wherein
R 1 and R 2 are each independently hydrogen or methyl; and
R is joined with R 1 or R 2 to form a 5-membered ring or R is selected from the group consisting of hydrogen, methyl, ethyl,
2. The compound according to claim 1 selected from the group consisting of:
N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-aminoacetamide;
(S)—N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide;
(S)—N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-phenylpropanamide;
N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-(dimethylamino)acetamide;
(S)—N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)pyrolidine-2-carboxamide;
(S)—N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-4-methylpentanamide;
(S)—N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-cyclohexylpropanamide;
N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide; and
(R)—N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide.
3. The compound according to claim 1 , wherein the compound is (S)—N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide.
4. The compound according to claim 1 , wherein the compound is (S)—N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-phenylpropanamide.
5. A pharmaceutical composition, comprising the compound according to claim 1 as an active ingredient, and a pharmaceutically acceptable excipient or carrier.
6. A method for preparing a compound represented by formula (6), comprising reacting a (Compound 516), [{4-(2-aminothiazol-4-yl)-2-(1H-1,2,4-triazol-1-yl)phenyl}(3,4,5-trimethoxyphenyl)methanone], with a compound represented by formula (3) or formula (5):
wherein R 1 ′ is Fmoc(9-fluorenylmethoxycarbonyl) group or CH 3 ; R 2 is H or CH 3 ; and R is joined with R 2 to form a 5-membered ring or R is selected from the group consisting of hydrogen, methyl, ethyl,