本文選題：雙環(huán)噠嗪酮類化合物　切入點(diǎn)：合成　出處：《遼寧大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：雙環(huán)噠嗪酮類化合物是一類重要的有機(jī)雜環(huán)化合物,經(jīng)研究表明具有廣泛的生物活性。本文在研究雙環(huán)噠嗪酮類化合物的結(jié)構(gòu)特點(diǎn)和生理活性的基礎(chǔ)上,通過計算機(jī)輔助藥物設(shè)計軟件Sybyl虛擬篩選設(shè)計了17個雙環(huán)噠嗪酮類化合物,并合成了排名靠前的10個雙環(huán)噠嗪酮類似物。具體合成方法如下:(1)以乙氧基亞甲基丙二睛為原料,經(jīng)水合肼環(huán)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,以之作為重要中間體,經(jīng)吡唑N烷基化,氰基水解,扣六元環(huán),得到5-溴-7-環(huán)丙基甲基-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮和5-溴-7-異丙基-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮兩個重要中間體;溴原子再分別被哌啶和嗎啡啉分別取代得到7-環(huán)丙基甲基-5-哌啶-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮、7-環(huán)丙基甲基-5-嗎啡啉-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-嗎啡啉-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮4個重要中間體,和溴代葡萄糖反應(yīng),再脫保護(hù)得到3個終產(chǎn)物;(2)以上一步的4個中間體為原料,和碳酸乙烯酯反應(yīng)得到4個終產(chǎn)物;(3)以7-環(huán)丙基甲基-5-哌啶-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮為原料和環(huán)氧氯丙烷反應(yīng),再開環(huán)得到1個終產(chǎn)物。(4)以化合物7-環(huán)丙基甲基-5-嗎啡啉-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮和7-丙叉基-5-嗎啡啉-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮為原料,和氯乙酸乙酯反應(yīng)得到2個終產(chǎn)物。通過紅外光譜以及核磁共振氫譜等方法對10個化合物的結(jié)構(gòu)進(jìn)行了確證,均未見文獻(xiàn)報道。同時,對化合物(14)(15)(17)(18)(19)進(jìn)行體內(nèi)抗腫瘤活性測定,發(fā)現(xiàn)由路線一得到的化合物(14)7-環(huán)丙基甲基-5-哌啶-3-(3,4,5-三羥基-6-(羥甲基)四氫-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-(3,4,5-三羥基-6-(羥甲基)四氫-2H-吡喃-2-基)-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮及由路線二得到的化合物(18)7-環(huán)丙基甲基-3-(2-羥乙基)-5-嗎啡啉-3H-吡唑并[3,4-d][1,2,3]三嗪-4(7H)-酮均表現(xiàn)出明顯的抗腫瘤活性,其中化合物(14)活性最好,抑瘤率為43.28%�；衔�(14)的急性毒性實(shí)驗(yàn)結(jié)果表明灌胃給藥組LD504000 mg/kg,靜脈注射給藥組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.
【學(xué)位授予單位】：遼寧大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R914;R96

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