双环哒嗪酮类化合物的合成及抗肿瘤活性研究

发布时间：2018-03-18 06:26

本文选题：双环哒嗪酮类化合物　切入点：合成　出处：《辽宁大学》2017年硕士论文　论文类型：学位论文

【摘要】：双环哒嗪酮类化合物是一类重要的有机杂环化合物,经研究表明具有广泛的生物活性。本文在研究双环哒嗪酮类化合物的结构特点和生理活性的基础上,通过计算机辅助药物设计软件Sybyl虚拟筛选设计了17个双环哒嗪酮类化合物,并合成了排名靠前的10个双环哒嗪酮类似物。具体合成方法如下:(1)以乙氧基亚甲基丙二睛为原料,经水合肼环合,得到5-氨基-4-氰基-1H-吡唑,再用NBS溴化得到3-溴-5-氨基-4-氰基-1H吡唑,以之作为重要中间体,经吡唑N烷基化,氰基水解,扣六元环,得到5-溴-7-环丙基甲基-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮和5-溴-7-异丙基-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮两个重要中间体;溴原子再分别被哌啶和吗啡啉分别取代得到7-环丙基甲基-5-哌啶-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮、7-环丙基甲基-5-吗啡啉-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮、7-丙叉基-5-哌啶-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮和7-丙叉基-5-吗啡啉-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮4个重要中间体,和溴代葡萄糖反应,再脱保护得到3个终产物;(2)以上一步的4个中间体为原料,和碳酸乙烯酯反应得到4个终产物;(3)以7-环丙基甲基-5-哌啶-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮为原料和环氧氯丙烷反应,再开环得到1个终产物。(4)以化合物7-环丙基甲基-5-吗啡啉-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮和7-丙叉基-5-吗啡啉-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮为原料,和氯乙酸乙酯反应得到2个终产物。通过红外光谱以及核磁共振氢谱等方法对10个化合物的结构进行了确证,均未见文献报道。同时,对化合物(14)(15)(17)(18)(19)进行体内抗肿瘤活性测定,发现由路线一得到的化合物(14)7-环丙基甲基-5-哌啶-3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮和化合物(15)7-丙叉基-5-哌啶-3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮及由路线二得到的化合物(18)7-环丙基甲基-3-(2-羟乙基)-5-吗啡啉-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮均表现出明显的抗肿瘤活性,其中化合物(14)活性最好,抑瘤率为43.28%。化合物(14)的急性毒性实验结果表明灌胃给药组LD504000 mg/kg,静脉注射给药组LD50100 mg/kg。
[Abstract]:Bicyclic pyridazinones are an important class of organic heterocyclic compounds, which have been shown to have a wide range of biological activities. In this paper, the structure and physiological activities of bicyclic pyridazinones are studied. A total of 17 bicyclic pyridazinones were designed by computer aided drug design software (Sybyl), and 10 bicyclic pyridazinone analogues were synthesized. The synthesis method is as follows: 1) ethoxy methylene propanedionitrile is used as the raw material. 5-amino-4-cyano-1H-pyrazole was synthesized by cyclization of hydrazine hydrate, and 3-bromo-5-amino-4-cyano-1-H-pyrazole was obtained by NBS bromination. Two important intermediates of 5-bromo-7-cyclopropyl-methyl-3H-pyrazolo-[ 3o4-d] triazine-4- (7H) -triazinone and 5-bromo-7-isopropyl -3H-pyrazolo [34-d] [1O2O3] triazine-47H- one were obtained. The bromine atoms were then replaced by piperidine and morphine to obtain 7- cyclopropylmethyl-5- piperido-3H-pyrazolo [34-d] [1o _ 2o _ 3] triazine-7H _ (7H) -pyrazolone _ 7-cyclopropylmethyl-5H-pyrazoline-3H-pyrazole [34-d] [1o _ 2o _ 3] _ triazine _ _ _ ~ _ _ _. Four important intermediates, namely -4H _ 4H _ 4-one and 7-propyl-5-morpholine -3H _ pyrazolo [3H _ 4-d] ~ (3) triazine-4H _ (7) H _ (1) -ketone, Four intermediates with more than one step were obtained by reaction with brominated glucose and then deprotected. In the reaction with ethylene carbonate, four final products, Con 3), were reacted with epichlorohydrin using 7-cyclopropylmethyl -5- piperidine [3H-pyrazolido [3zolapylazo] [1 (2 +) 3] triazine-4- (7H) -dodecanone as raw material and epichlorohydrin as the starting material. A final product, I. e., 4, was obtained by ring opening.) the compound 7- cyclopropyl methyl-5- morpholine -3H-pyrazolopyrazo [34-d] [1h2n3] triazine-4- 7Hazolone and 7- propyl -5morphine-3H-pyrazolyl [34-d] [1h2n3] triazine-4Hzapyranone were used as raw materials, Two final products were obtained from the reaction with ethyl chloroacetate. The structures of 10 compounds were confirmed by IR and NMR, and none of them were reported in the literature. Meanwhile, the antitumor activity of the compound was determined in vivo. It has been found that the compound of 147- cyclopropyl methyl-5- piperidine-3-trihydroxy-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-pyrazolyl [34-d] [1 + 2d] triazine-47H-butanone and its compound 157- propyl-5- piperidine-3-trihydroxyl-trihydroxy-6-( methyl) tetrahydro-2H- pyridyl-pyrazolone and its compound 157- propyl-5- piperidine-3-trihydroxyl-trihydroxy-6-( methyl) tetrahydro-2H- pyridine. The antitumor activity of triazine-4-d and its compound 18 ~ (18) -cyclopropyl methyl -3-oxy _ 2-hydroxyethyl -5-morpholine [34-d] [1 ~ (2 +)] ~ (2) triazine-4H _ (7) H ~ (-1) showed obvious antitumor activity, and the compounds obtained from route two showed obvious antitumor activity. The results of acute toxicity test showed that the LD504000 mg / kg in the oral administration group and LD50100 mg / kg in the intravenous administration group.
【学位授予单位】：辽宁大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

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