ANTITUMOR QUINOXALINE DERIVATIVES HAVING INHIBITORY ACTIVITY AGAINST HISTONE DEACETYLASE AND PREPARATION METHOD THEREOF

摘要

PURPOSE: Quinoxaline derivatives and a preparation method thereof are provided, which derivatives have inhibitory activity against histone deacetylase, which removes an acetyl group from the lysine tail in the N-terminal of histone, by selectively inducing the terminal differentiation of the tumor cells, and thus by inhibiting the growth of tumor cells. CONSTITUTION: The quinoxaline derivatives represented by formula (1) are provided, wherein R1 is aryl, heteroaryl or C3-C8 cycloalkyl which is optionally substituted by one or more substituents selected from hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro, amide and sulfone in which the heteroaryl contains one or more elements selected from nitrogen, sulfur and oxygen in a ring; R2 is hydrogen or arylalkyl; A is O, S, CH2, sulfone(SO2), sulfoxide(SO), CONH, NHCO, NX or NXSO2 in which X is hydrogen, C1-5 alkyl or independently the same as R1; and n is 0, 1, 2 or 3. The method for preparing a compound of formula (2) comprises the steps of: (a) acylation of 2-bromo arylalkyl carboxylic acid of formula (6) with 3,4-diamino benzoic ester of formula (7) in an aprotic solvent to prepare a compound of formula (8); (b) cyclization of the compounds of formula (8) in the presence of inorganic salts to prepare quinoxaline ester of formula (9); (c) treating the quinoxaline ester of formula (9) with hydroxide salts to prepare an organic acid of formula (10); and (d) acylation of the organic acid of formula (10) with the protected hydroxyl amine and hydrogenating the reaction product in the presence of palladium, wherein Y is O, S, CH2, SO2, SO or NX.