本文選題：4芳香基-1　切入點(diǎn)：4-二氫吡啶衍生物　出處：《南方醫(yī)科大學(xué)》2017年博士論文　論文類(lèi)型：學(xué)位論文

【摘要】：本研究先合成得到四種4芳香基-1,4-二氫吡啶(4-Aryl-1,4-dihydropyridines)化合物,并通過(guò)與臨床常用局麻藥比較,進(jìn)一步分析其局麻作用和毒性反應(yīng),為尋找更好的局麻藥提供理論依據(jù)和實(shí)驗(yàn)基礎(chǔ)。方法將100ml乙醇中分次加入1Ommol醋酸銨、1Ommol芳香醛、1Ommol乙酰乙酸乙酯,回流2-3h,然后冷卻至室溫,合成四種4芳香基-1,4-二氫吡啶化合物,并分析晶體結(jié)構(gòu)。通過(guò)建立多種動(dòng)物模型來(lái)分析比較4芳香基-1,4-二氫吡啶與常用局麻藥利多卡因、丁卡因、羅哌卡因、布比卡因在表面麻醉、局部浸潤(rùn)麻醉、外周神經(jīng)阻滯和腰麻的效果。建立大鼠局麻藥神經(jīng)毒性和心臟毒性的模型,分析比較4芳香基-1,4-二氫吡啶化合物與常用局麻藥的毒性反應(yīng)和脂肪乳劑對(duì)局麻藥毒性反應(yīng)的逆轉(zhuǎn)作用。結(jié)果1.得到四種4芳香基-1,4-二氫吡啶化合物,分別命名為4芳香基-1,4-二氫吡啶化合物1、4芳香基-1,4-二氫吡啶化合物2、4芳香基-1,4-二氫吡啶化合物3、4芳香基-1,4-二氫吡啶化合物4。2.通過(guò)動(dòng)物表面麻醉和局部浸潤(rùn)麻醉模型研究,發(fā)現(xiàn)只有4芳香基-1,4-二氫吡啶4具有麻醉作用,表面麻醉效果優(yōu)于丁卡因、布比卡因和利多卡因(P0.05),通過(guò)對(duì)角膜的六邊形細(xì)胞比率(6A)、角膜細(xì)胞變異系數(shù)(CV)、中央角膜厚度的研究發(fā)現(xiàn)4芳香基-1,4-二氫吡啶4對(duì)角膜無(wú)明顯的損傷;局部浸潤(rùn)麻醉效果也優(yōu)于利多卡因、羅哌卡因、布比卡因(P0.05)。3.分別將4芳香基-1,4-二氫吡啶化合物4和羅哌卡因、布比卡因?qū)Υ笫笪簿植啃猩窠?jīng)阻滯,顯示4芳香基-1,4-二氫吡啶化合物4的麻醉作用持續(xù)時(shí)間長(zhǎng),與羅哌卡因、布比卡因神經(jīng)阻滯組比較,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)。4.通過(guò)建立大鼠腰麻模型,比較4芳香基-1,4-二氫吡啶化合物4、羅哌卡因、布比卡因腰麻的效果,顯示4芳香基-1,4-二氫吡啶化合物4鎮(zhèn)痛作用和作用時(shí)效優(yōu)于羅哌卡因和布比卡因。與其他兩藥相較,4芳香基-1,4-二氫吡啶化合物4還能降低腰麻大鼠腦脊液中TNF-α和IL-2的分泌和抑制Caspase3活性,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)。5.4芳香基-1,4-二氫吡啶化合物4也具有局麻藥共同的毒性反應(yīng),中毒劑量可致不同程度的心臟毒性或中樞神經(jīng)毒性。脂肪乳劑能逆轉(zhuǎn)大鼠4芳香基-1,4-二氫吡啶化合物4中毒時(shí)的不良心臟反應(yīng)和驚厥、抽搐等神經(jīng)毒性反應(yīng)(P0.05)。結(jié)論本研究成功制備的四種4芳香基-1,4-二氫吡啶化合物1～4中,只有4芳香基-1,4-二氫吡啶化合物4具有麻醉活性。其表面麻醉、局部浸潤(rùn)麻醉、神經(jīng)阻滯麻醉、腰麻效果都好,但是過(guò)量使用也同樣具有神經(jīng)和心臟毒性,用脂肪乳劑可逆轉(zhuǎn)4芳香基-1,4-二氫吡啶的心臟和中樞神經(jīng)毒性。
[Abstract]:This study first synthesized four kinds of 4 aromatic -1,4- two hydrogen pyridine (4-Aryl-1,4-dihydropyridines) compounds, and through comparison and analysis of the clinical commonly used local anesthetics, local anesthetic toxicity and further provide theoretical and experimental basis for finding better local anesthetics. Methods 100ml ethanol fractionated into 1Ommol ammonium acetate, aromatic 1Ommol 1Ommol aldehyde, ethyl acetoacetate, 2-3H reflux, and then cooled to room temperature, synthesis of four kinds of 4 aromatic -1,4- two hydrogen pyridine compounds, and crystal structure analysis. Through the establishment of a variety of animal models to analyze and compare 4 -1,4- two aromatic hydrogen pyridine and commonly used local anesthetic lidocaine, tetracaine, ropivacaine, bupivacaine in surface anesthesia, local infiltration anesthesia, peripheral nerve block and spinal anesthesia effect. To establish the rat neurotoxicity of local anesthetics and heart toxicity model, analysis and comparison of 4 aromatic hydrogen pyridine of two -1,4- Reversal effect of fat emulsion on toxicity and toxic reaction of complexes with commonly used local anesthetics. Results of 1. four 4 -1,4- two aromatic hydrogen pyridine compounds, named 4 aromatic hydrogen pyridine compounds 1,4 -1,4- two -1,4- two aromatic hydrogen pyridine compounds 2,4 -1,4- two aromatic hydrogen pyridine aromatic compounds 3,4 -1,4- two 4.2. hydrogen pyridine compounds through the animal model of surface anesthesia and local infiltration anesthesia, found that only 4 of the aromatic -1,4- two hydrogen pyridine 4 has anesthetic effect, better than tetracaine anesthesia, bupivacaine and lidocaine (P0.05), the percentage of hexagonal cells of the corneal keratocytes (6A), the coefficient of variation (CV). Study on central corneal thickness found no obvious injury in 4 -1,4- two aromatic hydrogen pyridine 4 on the cornea; local anesthesia is better than lidocaine, ropivacaine, bupivacaine (P0.05).3. cloth The 4 aromatic hydrogen pyridine compounds and 4 -1,4- two ropivacaine, bupivacaine on local nerve block of rat tail, 4 -1,4- two aromatic hydrogen pyridine compound anesthetic effect 4 lasted for a long time, and the comparison of ropivacaine, bupivacaine nerve block group, the difference was statistically significant (P0.05.4.) through the establishment of rat spinal anesthesia comparison of 4 models, -1,4- two aromatic hydrogen pyridine compounds 4, ropivacaine, bupivacaine, 4 -1,4- two aromatic hydrogen pyridine compounds showed 4 analgesic effect and time effect is better than that of ropivacaine and bupivacaine. Compared with other two drugs, 4 aromatic -1,4- two hydrogen pyridine compound 4 can reduce the secretion and inhibit the activity of Caspase3 TNF- alpha and IL-2 spinal anesthesia in cerebrospinal fluid of rats, the difference was statistically significant (P0.05).5.4 -1,4- two aromatic hydrogen pyridine compound 4 has the toxicity reaction of local anesthetics in common. Exposure to different degrees can cause cardiac toxicity or neurotoxicity. Fat emulsion can reverse the rat 4 -1,4- two aromatic hydrogen pyridine compounds 4 poisoning adverse cardiac response and convulsions, seizures and other neurotoxic reactions (P0.05). Conclusion: we have successfully prepared four kinds of 4 aromatic -1,4- two hydrogen pyridine compound 1~4. Only 4 -1,4- two aromatic hydrogen pyridine compound 4 has activity. The surface anesthesia anesthesia, local anesthesia, nerve block anesthesia, spinal anesthesia has a good effect, but excessive use also has the nerve and cardiac toxicity, with fat emulsion can be reversed by 4 -1,4- two aromatic hydrogen pyridine heart and neurotoxicity.

【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R914;R965

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本文編號(hào)：1634347