替莫唑胺衍生物的合成及生物活性研究

【作者】 汪春梅；

【导师】 欧阳贵平；

【作者基本信息】 贵州大学 ， 有机化学， 2008， 硕士

【摘要】 替莫唑胺是一种新型的咪唑四嗪类化合物,具有较好的脑胶质瘤抑制作用,同时对白血病、黑色素瘤、淋巴瘤和实体瘤也有较好的疗效。大量的研究工作在3-位、4-位、6-位、8-位进行取代,合成了各种类型的替莫唑胺衍生物,构效实验表明,8-位酰胺类衍生物有较好的肿瘤抑制作用。本文以5-氨基咪唑-4-甲酰胺与甲氨基甲酰氯为起始原料,分别经过重氮化和消去反应得5-重氮基咪唑-4-甲酰胺与异氰酸甲酯,再将两种中间体常温下反应得先导化合物替莫唑胺,并进行了条件优化,总产率由65.66%提高到69.69%。针对替莫唑胺及其衍生物的作用特点,为增加替莫唑胺的脂溶性,通过羧酸化、酰氯化,再与芳香胺类直接反应,在8-位引入了芳基,共合成14个N-取代-3-甲基-4-氧代咪唑[5,1-d][1,2,3,5]四嗪-8-甲酰胺类衍生物;用酰氯与二胺反应合成了3个芳香类双替莫唑胺衍生物和三个3个脂肪类双替莫唑胺衍生物,20个目标化合物均未见文献报道。通过元素分析、IR、¹H-NMR、及¹³C-NMR对目标化合物的结构进行了表征,并以化合物TD-2为例进行了结构解析。初步体外抗前列腺肿瘤（PC3）细胞实验表明:TD-5、TD-6、TD-9、TD-10在浓度为1μM时有一定的抗前列腺肿瘤活性;TD-7、TD-8、TD-13、TD一19在浓度为10μM时有一定的抗前列腺肿瘤活性。更多还原

【Abstract】 Temozolomide is one of the new imidazoletetrazine compounds,which has good antitumour active to brain glioma,leukemia,melanoma,lymphoma and solid tumor. Many research workers have synthesized many temozolomide derivatives which were substituted in 3-,4-,6- and 8-,and the testing of biological activity indicated that 8-substituted amide derivatives of temozolomide had better antitumour active.On the base of the characteristics of temozolomide and its derivatives, 5-diazoimidazole-4-carboxamide was prepared from 5-aminoimidazole-4-carboxa mide through diazotization reaction,methyl isocyanate was prepared from methyl carbamyl chloride by elimination reaction,the two intermediates was stirred at room temperature and temozolomide was gotten.General yield was increased to 69.69% from 65.66%under the optimum reaction condition.In order to inhencing the fat-soluble we could introduce aryl in 8- of temozolomide.Temozolomide was carboxylated and acyl chloridized,then reacted with aryl amines and obtained fourteen N-substituted-3-methyl-imidazol[5,1 -d][1,2,3,5]tetrazine-8-carboxamide derivatives,three bis-temozolomide aryl derivatives and three bis-temozolomide acyclic derivatives were synthsized as control study,all of them have never been reported in literature.The structure of final products were characterized correcttly by elemental analysis,IR,¹H-NMR,and ¹³C-NMR,the structure and spectral data of TD-2 were elucidated in details in the paper.Preliminary studies on inhibitory activity of temozolomide derivatives against prostatic neoplasms（PC3） showed that TD-5, TD-6,TD-9,TD-10 and TD-20 had certain antitumor actives to PC3 at 1μM and TD-7,TD-8,TD-11,TD-13,TD-19 had certain antitumor actives to PC3 at 10μM.更多还原