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    • 9. 发明公开
    • 히스톤 디아세틸라제 저해활성을 갖는 퀴녹살린 유도체 및그의 제조방법
    • 具有抗组氨酸脱乙酰酶的抑制活性的抗肿瘤剂喹啉衍生物及其制备方法
    • KR1020050023107A
    • 2005-03-09
    • KR1020030060178
    • 2003-08-29
    • 한국화학연구원크리스탈지노믹스(주)
    • 이철해김봉진정희정김재학전미애성태현조중명노성구이태규현영란김진환
    • C07D241/44
    • 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.
    • 目的:提供喹喔啉衍生物及其制备方法,该衍生物通过选择性诱导肿瘤细胞的末端分化而对组蛋白脱乙酰酶具有抑制活性,其通过选择性诱导肿瘤细胞的末端分化而从组蛋白的N末端的赖氨酸尾部除去乙酰基, 从而通过抑制肿瘤细胞的生长。 组成:提供由式(1)表示的喹喔啉衍生物,其中R 1是芳基,杂芳基或任选被一个或多个选自羟基,卤素,烷氧基,烷基,氨基,烷基氨基,羧基, 硝基,酰胺和砜,其中杂芳基在环中含有一个或多个选自氮,硫和氧的元素; R2是氢或芳基烷基; A是O,S,CH2,砜(SO2),亚砜(SO),CONH,NHCO,NX或NXSO2,其中X是氢,C1-5烷基或与R1独立地相同; 制备式(2)化合物的方法包括以下步骤:(a)将式(6)的2-溴芳基烷基羧酸与3,4-二氨基苯甲酸 (7)的酯在非质子溶剂中制备式(8)的化合物; (b)在无机盐存在下环化式(8)化合物以制备式(9)的喹喔啉酯; (c)用氢氧化物盐处理式(9)的喹喔啉酯以制备式(10)的有机酸; 和(d)用保护的羟基胺酰化式(10)的有机酸,并在钯存在下氢化反应产物,其中Y是O,S,CH 2,SO 2,SO或NX。