本文選題：正性肌力作用 + 強(qiáng)心藥　； 參考：《延邊大學(xué)》2014年博士論文

【摘要】：本論文根據(jù)生物電子等排和拼合原理,以維司力農(nóng)為先導(dǎo)化合物,設(shè)計(jì)合成了7個(gè)系列117個(gè)全新的維司力農(nóng)衍生物及其類(lèi)似物。對(duì)所合成的目標(biāo)物通過(guò)測(cè)定其對(duì)家兔離體左心房搏出量的影響,對(duì)化合物的正性肌力活性進(jìn)行了初步評(píng)價(jià),同時(shí)對(duì)那些具有正性肌力活性的化合物進(jìn)行了變時(shí)性實(shí)驗(yàn)研究。結(jié)果顯示,一些衍生物在測(cè)試濃度下顯示出比上市藥物米力農(nóng)更好的正性肌力活性。目標(biāo)化合物結(jié)構(gòu)均經(jīng)1HNMR和MS確證了結(jié)構(gòu),部分化合物測(cè)試了13C NMR和IR。 本論文的研究工作可分為三個(gè)部分： 1、設(shè)計(jì)合成了4個(gè)系列三唑乙酰胺類(lèi)化合物(共75個(gè)),測(cè)定其對(duì)家兔離體左心房搏出量的影響,對(duì)化合物的正性肌力活性進(jìn)行了初步評(píng)價(jià)。結(jié)果顯示,發(fā)現(xiàn)有2個(gè)系列的目標(biāo)化合物(1和2)在測(cè)試濃度下顯示出比對(duì)照藥物米力農(nóng)更好的正性肌力活性,其中活性最好的化合物是8a,在濃度為3×10-5M時(shí),增強(qiáng)左心房搏出量的強(qiáng)度達(dá)20.29±0.18%(米力農(nóng)：2.46±0.07%),是米力農(nóng)的8倍。 2、設(shè)計(jì)合成了1個(gè)系列喹喔啉類(lèi)化合物(共16個(gè)),并初步評(píng)價(jià)了它們的體外正性肌力活性。結(jié)果顯示,只有少部分目標(biāo)化合物的活性強(qiáng)于對(duì)照藥米力農(nóng),其中化合物14k的活性最好,在濃度為3×10-5M時(shí),增強(qiáng)左心房搏出量的強(qiáng)度達(dá)5.34±0.05%(米力農(nóng)：2.46±0.07%),是米力農(nóng)的2倍。 3、設(shè)計(jì)合成了2個(gè)系列呔嗪類(lèi)化合物(共26個(gè)),并初步評(píng)價(jià)了它們的體外正性肌力活性。發(fā)現(xiàn)大部分目標(biāo)化合物都表現(xiàn)出了很好的活性,其中化合物25m的活性最好,在濃度為3×10-5M時(shí),增強(qiáng)左心房搏出量的強(qiáng)度達(dá)12.02±0.20%(米力農(nóng)：2.46±0.07%),是米力農(nóng)的5倍。 本論文對(duì)維司力農(nóng)進(jìn)行了結(jié)構(gòu)修飾,并對(duì)目標(biāo)化合物進(jìn)行了正性肌力活性的初期篩選。活性篩選結(jié)果顯示大部分化合物達(dá)到了預(yù)期的活性增強(qiáng)的設(shè)計(jì)目的,且獲得了正性肌力活性?xún)?yōu)于對(duì)照藥物米力農(nóng)的幾個(gè)優(yōu)選化合物。這一點(diǎn)與我們當(dāng)初的設(shè)計(jì)思想不謀而合,也與實(shí)驗(yàn)數(shù)據(jù)基本相互符合。
[Abstract]:In this paper, according to the principle of equal arrangement and splicing of biological electrons, seven series of 117 new derivatives of Visrinon and their analogues were designed and synthesized with Visrinon as the leading compound. The positive inotropic activity of the compound was preliminarily evaluated by measuring the effect of the target compound on the left atrial beat volume of rabbits in vitro. Meanwhile, the chronotropic experiments of those compounds with positive myotropic activity were carried out. The results showed that some derivatives showed more positive inotropic activity than milrinone at the test concentration. The structures of the target compounds were confirmed by 1HNMR and MS, and some of the compounds were identified by 13C NMR and IR. The research work of this thesis can be divided into three parts: 1. Four series of triazolacetamide compounds (75) were designed and synthesized. The effects of these compounds on isolated left atrial beats were determined and the positive inotropic activity of the compounds was evaluated. The results showed that two series of target compounds (1 and 2) showed positive inotropic activity at the test concentration, which was better than that of the control drug milrinone. The most active compound was 8 a, and at the concentration of 3 脳 10 ~ (-5) M, the positive inotropic activity was better than that of the control drug milrinone at the concentration of 3 脳 10 ~ (-5) M. The intensity of enhancement of left atrial output was 20.29 鹵0.18. (Milinon: 2.46 鹵0.07) was 8 times higher than that of milrinone. 2. A series of quinoxaline compounds (16 of them) were designed and synthesized, and their positive inotropic activities in vitro were preliminarily evaluated. The results showed that only a few of the target compounds were more active than those of the control drug milrinone, and the activity of compound 14k was the best. When the concentration was 3 脳 10 ~ (-5) M, the intensity of enhancing the left atrial beat was 5.34 鹵0.05 (milrinon: 2.46 鹵0.07), twice as much as that of milrinone. 3. Two series of pyrazines were designed and synthesized, and their positive inotropic activities in vitro were preliminarily evaluated. It was found that most of the target compounds showed good activity, of which 25 m had the best activity, and the intensity of enhancement of left atrial beat was 12.02 鹵0.20 when the concentration was 3 脳 10 ~ (-5) M (Milinon: 2.46 鹵0.07), which was 5 times of that of milrinone. In this paper, the structure of Visrinon was modified, and the initial screening of positive myotropic activity of the target compound was carried out. The results of activity screening showed that most of the compounds had achieved the design purpose of expected activity enhancement, and the positive inotropic activity was better than that of the control drug milrinone. This is consistent with our original design idea, but also with the experimental data is basically in line with each other.
【學(xué)位授予單位】：延邊大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R914.5;R96

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本文編號(hào)：1990941