【作者】 兰玉坤；

【导师】 李志良；

【作者基本信息】 重庆大学 ， 分析化学， 2004， 硕士

【摘要】 糖尿病是一种常见的慢性病,也是当今世界发病率和死亡率都很高的一种疾病。糖尿病主要的危害是慢性并发症,致使一些器官发生病变,其主要原因是由于体内胰岛素抵抗引起的高血糖、代谢紊乱所导致的,这种代谢异常疾病的特征是高血糖,并会引起精神病、肾病、视网膜病、高甘油三酯血症、肥胖和其他心血管病等代谢综合症。现在治疗糖尿病的药物大都具有明显的毒副作用,因此寻找安全、高效的新型治疗糖尿病的药物成为一项艰巨的任务。在现有治疗糖尿病的药物中,噻唑烷二酮类药物(TZD)是以过氧化物酶体增殖因子活化受体-γ(PPARγ)为靶点的新型胰岛素增敏剂,通过激活PPARγ核受体来改善胰岛素抵抗,进而有效地降低血糖。本文所合成的具有抗糖尿病药效的新化合物中,都分别具有PPARδ、PPARα和PPARγ活性中的一种或几种活性,并且在相同浓度下有的化合物活性比罗格列酮要高,此类胰岛素增敏剂既能提高机体对胰岛素的敏感性,又可以通过调节自由脂肪酸和甘油三酯的含量来降低白色脂肪的沉积,可望有减少心血管并发症及不诱导肥胖等作用。本文的主要内容和研究结果如下:1、完成了化合物 2-[(1-甲基,2-苯甲酰)-乙烯胺]-3- {[4-(2-咔唑-9-基)-乙氧基]苯基}丙酸和2-[(2-苯甲酰基)苯胺]-3-{[4- (2-咔唑-9-基)-乙氧基]苯基}丙酸的合成及分析。2-[(1-甲基,2-苯甲酰)-乙烯胺]-3- {[4-(2-咔唑-9-基)-乙氧基]苯基}丙酸在弱酸性条件下不稳定,2-[(2-苯甲酰基)苯胺]-3-{[4- (2-咔唑-9-基)-乙氧基]苯基}丙酸因为在专利保护范围内,又对其结构进行了修饰,合成下面几类化合物。2、进行了化合物2-[2-(4-氟苯甲酰基)苯胺]-3- {[4-(2-咔唑-9-基)-乙氧基]苯基}丙酸和2-{1–[2-(4-氯(氢)苯甲酰)]-环己胺}-3-{[4- (2-咔唑-9-基)-乙氧基]苯基}丙酸的合成及分析。因为在化合物合成过程中进行催化脱氢反应时,同时会发生氢解反应,所以合成了这两类化合物,2-[2-(4-氟苯甲酰基)苯胺]-3- {[4-(2-咔唑-9-基)-乙氧基]苯基}丙酸较稳定,对其结构进行了图谱解析;因为2-{1–[2-(4-氯(氢)苯甲酰)]-环己胺}-3-{[4- (2-咔唑-9-基)-乙氧基]苯基}丙酸稳定性较差,不能分离得到纯度较高的产品。3、完成了化合物2-[2-(4-取代苯甲酰基)苯胺]-3- {[4-(2-咔唑-9-基)-乙氧基]苯基}丙酸的合成及分析。此系列共合成了八个化合物,并对其进行光谱分析及结构解析。活性测试发现其中有的化合物活性较高,有进一步研究的价值。更多还原

【Abstract】 Diabetes is a chronic disease that is associated with a high degree of morbidity and mortality. Its primary endangerment is chronic syndrome which leads to pathological changes of some apparatus due to hypertension and metabolizability turbulence which are induced by insulin resistance. This disease can also lead to lunacy, nephropathy, retinopathy, high plasma triglycerides and other disease. Some new antidiabetic drugs were invented with high efficiency and obvious toxicity.The molecular mechanism of thiazolidinedione (TZD) is activation of peroxisome proliferator-activator receptor gamma (PPARγ). The PPARγ agonist TZD class of antidiabetics has been shown to improve insulin resistance and reduces hypertension. In this theses, it’s reported that some novel antidiabetics compounds with higher activity of both PPARαand PPARγreceptors than rosiglitazone at the same concentration . These compounds can improve insulin sensitivity and effectively decreases free fatty acids and triglycerides. The main content is followed: 1. Synthesis and analysis of 2-[(1-methyl-2-benzoyl)-vinylamino]-3-{[4-(2-carbazol-9-yl)-ethoxyl] phenyl} propionic acid and 2-[(2-benzoyl)-phenylamino]-3-{[4-(2-carbazol-9-yl)-ethoxyl] phenyl}propionic acid. The former is unstable in weak acidic medium, the latter which has been protected in patent requires to be modified and synthesis the followed compounds.2. Synthesis and analysis of 2-[2-(4-fluorobenzoyl) phenylamino]-3-[4-(2-carbazol-9-yl-ethoxy)-phenyl]-propionic acid and 2-{1-[2-(4-chloro (hydrogen) benzoyl)]-cyclohexanamino}-3-[4-(2-carbazol-9-yl-ethoxy)-phenyl]-propionic acid. Two series of were synthesized due to hydrogenolysis during dehydrogenation in the reaction of raw material. The former is very stable while the latter is quite unstable and to get highly in pure.3. Synthesis and analysis of 2-[2-(4-substituted benzoyl) phenylamino]-3-{[4-(2-carbazol-9-yl)-ethoxy]-phenyl}-propionic acid. Structures of synthesized products were affirmed by ultraviolet, infrared, nuclear magnetic resonance spectroscopies and mass spectrometry. Some target compounds possess high PPARγactivity and are worthy to research and develop further.更多还原