【作者】 刘红萍；

【导师】 杨大成；

【作者基本信息】 西南大学 ， 有机化学， 2008， 硕士

【摘要】 糖尿病（Diabetes Mellitus,DM）是由多种原因引起的内分泌代谢疾病,是世界上第三大非传染性慢性疾病。糖尿病的治疗药物很多,但大部分药物都具有明显的毒副作用。寻找高效低毒的新型药物,仍然是化学与药学工作者的艰巨任务。β-氨基酮类化合物是合成许多药物及天然产物的关键中间体,同时也是重要的生物活性物质,具有止咳、抗菌、抗炎、抗癌、抗病毒、镇静、止痛、降压、抑制水肿和抗凝血等多种生物功能。研究该类化合物的合成方法和应用很有意义。本课题组合成了大量β-氨基酮类化合物,进行了广泛的生物活性研究,发现了多种生物活性,其中部分化合物具有抗糖尿病活性。β-氨基酮类化合物作为抗糖尿病药物先导化合物的研究未见报道。本文在以上研究工作的基础上,根据药物设计原理,结合生物活性实验结果,重新设计并合成了多个系列的β-氨基酮类化合物及其衍生物,并进行了生物活性和构效关系的初步研究。（1）1-芳（芳烷）基-3-芳基-3-芳胺基-1-丙酮的设计、合成和生物活性初步研究结合文献报道的类似物合成方法,对该类化合物的合成进行了方法学研究,探索出了该类化合物的最佳合成条件和合成通法。在乙醇、正丙醇或乙醇/氯仿溶剂中,以浓盐酸为催化剂,反应组分在室温反应10h-90h,可以直接生成1-芳（芳烷）基-3-芳基-3-芳胺基-1-丙酮（T-1～T-3）,收率30.9%～98.6%。合成的49个该类化合物中,48个为未见报道的新物质。所有化合物的结构经IR和¹H NMR确证,部分产物还经过¹³C NMR和MS确证。初步筛选结果显示,大多数目标化合物具有强度不等的α-葡萄糖苷酶的抑制活性以及过氧化物酶体增殖物激活受体（PPAR）反应元件激活活性,其中有12个化合物对α-葡萄糖苷酶的抑制活性达到或超过了同浓度的阿卡波糖,有4个化合物显示出很好的过氧化物酶体增殖物激活受体反应元件（PPRE）激活活性。尤为可喜的是,4-（1-（3-氯苯胺基）-3-氧代-5-（6-甲氧基萘-2-基）戊氨基）-N-（5-甲基异噁唑-3-基）苯磺酰胺（5c）显示了良好的α-葡萄糖苷酶的抑制活性和PPRE激活活性,有望成为新型的具有双重作用靶点的抗糖尿病药物的候选先导化合物!（2）1-芳（芳烷）基-3-芳基-3-芳胺基-1-丙醇的设计、合成和生物活性初步研究为了增加样品的溶解性,进而增强其抗糖尿病活性,我们选择了KBH₄还原Mannich碱的羰基以制备醇的研究思路。在还原1-芳（芳烷）基-3-芳基-3-芳胺基-1-丙酮类化合物的反应中,研究了不同活化剂对KBH₄的还原能力、反应速度和产物收率的影响,最后通过溶剂、反应温度、原料配比等的改变,对此反应进行了优化。实验发现,以甲醇做溶剂,按1.5倍KBH₄投料,室温反应5h～18h均可以得到很好的实验结果,收率大多在90%以上;LiCl有助于KBH₄在常温下将酯还原。该反应具有条件温和、操作简便、收率高等优点。利用这种方法,我们将合成的Mannich碱（T-1～T-3）在上述优化条件下还原,经薄层层析,分离得到37个新化合物。还原产物的结构经IR、¹H NMR确证,部分化合物还经过¹³C NMR和MS确证。绝大多数目标化合物比对应Mannich碱的α-葡萄糖苷酶抑制活性增强几倍到十几倍。特别是产物的3-芳基上有2个取代基和3-芳胺基上有-COOH时其α-葡萄糖苷酶的抑制活性超过了浓度是其10倍的阿卡波糖。还原后的得到的两组非对映异构体对α-葡萄糖苷酶的抑制活性差别很大。（3）1-（4-羟基）芳基-3-芳基-3-芳胺基-1-丙酮的设计、合成和生物活性初步研究根据上述两个系列化合物构效关系结论,设计了六个系列1-（4-羟基）芳基-3-芳基-3-芳胺基-1-丙酮类化合物。进行了该类化合物合成方法的研究,探索了该类化合物的最佳合成条件和合成通法。IR、1H NMR、¹³C NMR和MS检测显示,在乙醇或正丙醇溶剂中,适量浓盐酸或I₂为催化剂,在室温条件下,通过直接Mannich反应,成功地实现了对羟基苯乙酮和3-硝基-4-羟基苯乙酮羰基的α-C上的Mannich反应,而非文献报道的苯环羟基邻位的Mannich反应。反应的产物单一而没有后续成环反应,收率达到50.0%～98.6%。所合成56个化合物均为未见报道的新化合物。其中,4-（1-（3,4～二氯苯基）-3-（4-羟基苯基）-3-氧代丙氨基）苯甲酸（Q-1-14）对α-葡萄糖苷酶的抑制活性超过了浓度是其10倍的阿卡波糖。多数化合物显示出中等的PPAR反应元件的抑制活性。（4）噻唑烷二酮类化合物的设计、合成和生物活性初步研究对文献报道的3条合成噻唑烷-2,4-二酮的路线进行了比较和改进,高纯度地合成了噻唑烷-2,4-二酮。再利用克脑文格反应和改进的固相缩合反应制得了6个5-芳亚甲基噻唑烷-2,4-二酮中间体。通过N-Mannich反应和与BrCH₂COOCH₃的缩合对5-芳亚甲基噻唑烷-2,4-二酮的3-N进行了修饰,得到7个目标产物。所有中间体和目标产物都经过了IR、¹H NMR确证,部分样品进行了¹³C NMR和MS确证。α-葡萄糖苷酶抑制活性实验显示,中间体5-（4-羟基苯亚甲基）噻唑烷-2,4-二酮（Si）和目标化合物5-（4-羟基苯亚甲基）-3-（（4-硝基苯胺）甲基）噻唑烷-2,4-二酮（SM-1）的α-葡萄糖苷酶抑制活性超过了10倍浓度的阿卡波糖。部分化合物显示中等的PPAR反应元件的激活活性。本研究共合成了8个原料和中间体、149个目标化合物,其中148个目标化合物为新物质。本研究发现了β-氨基酮类化合物新的生物活性,为研发高效、低毒的抗糖尿病药物先导化合物提供了新的思路。更多还原

【Abstract】 Diabetes is a kind of the endocrine and metabolic diseases caused by many factors,and is the third largest non-communicable chronic disease in the world.There are a lot of drugs used for the treatment of diabetes,but most of them have serious side effects.For chemists and pharmacy researchers it should be a fascinating task to find other high efficiency and safety antidiabetic drugs.β-amino ketones are not only the key intermediates for many drugs and natural products,but also important bioactive substances.Someβ-amino ketones possess anticough,antibacterial,antiinflammatory, anticancer,antivirus,sedation,analgesia,antihypertension,anticoagulation,and so on. It is of great significance to explore the effective synthetic methodology and medicinal applications for these compounds.Our research group synthesized differentβ-amino ketones and extensively evaluated bioactivity previously,and found various biological activities,such as anticancer, antibacterial,antiestrogen.Surprisingly,some of these compounds have obvious antidiabetic activity. As our knowledgement,it hasn’t been reported thatβ-amino ketones have antidiabetic activity before our discovery.In this study,based on above experimental results and the principles of drug design,we redesigned and synthesized a number of series ofβ-amino ketones and their derivatives for carrying out the preliminary study on antidiabetic activities and structure-activity relationships.[1]Design,synthesis and bioactivities research of 3-aryl-1-aryl（arylalkyl）-3-aryamino-1-acetone Based on the synthetic methods ofβ-amino ketones and its analogues reported in the literature, the synthetic methodology of the title compounds were studied comprehensively,and the optimum synthetic conditions and synthetic rules of such compounds were also explored deeply.The components stirred at the room temperature in ethanol,1-propanol,or ethanol/chloroform,catalyzed with concentrated hydrochloric acid,directly to give 3-aryl-1-aryl（arylalkyl）-3-arylamino-1-acetone with the yields of 30.9%to 98.6%.The structures of the forty eight new compounds were confirmed by IR and ¹H NMR,some also confirmed by ¹³C NMR and MS.The preliminary bioassay showed that most target molecules had a certainα-glucosidase inhibitory activity and peroxisome proliferator-activated receptor（PPAR） responce element activated activity.There were tweelve compounds whose a glucosidase inhibitory activity reached or exceeded acarbose in the same range of concentration and four compounds which possess good PPAR responce element activated activity. It was particularly gratified that 4-（1-（3-chlorophenyl）-3-hydroxy-5-（6-meth-oxynaphthalen-2-yl） -pentylamino）-N-（5- methylisoxazol-3-yl） benzenesulfonamide（5c） posses goodα-glucosidase inhibitory activity and PPAR response element（PPRE） activated activity,which is deserved further researched as double targeted antidiabetic leading compound.[2]Design,synthesis and bioactivities assay of 3-aryl-1-aryl（arylalkyl）-3-arylamino-1-propanolIn order to increase the solubility of samples and to enhance their antidiabetic activity,we selected KBH₄ to reduce the carbonyl of Mannich bases to prepareβ-aminoalcohol.In the reduction of 3-aryl-1-aryl（arylalkyl）-3-arylamino-1-acetones,different activating agents affected on reducting capacity of KBH₄,reacting rate and the yield.The reaction conditions were optimized via the change of solvents,reacting temperatures,the ratios of starting materials,and so on.It was found that in methanol and 1.5 equivalent KBH₄ used,the reduction reaction could be carried out at room temperature for 5～18 h,the reduction yields of mostβ-amino ketones were more than 90%.It was also found that LiCl could help KBH₄ reduce esters at room temperature.The reaction was mild, handy and with high yields.In this optimized condition,the selected Mannich bases（T-1～T-3） was reduced and thirty seven new compoudi were pured by TLC,All of them were confirmed by IR, ¹H NMR,some also were confirmed further by ¹³C NMR and MS.The vast majority of target compounds ofα-glucosidase inhibitory activity was enhanced several times to over 10 times more than the corresponding Mannich bases.Theα-glucosidase inhibitory activity of the compounds,which had two substituted groups on the 3- site of aryl ring and withα-COOH on the 3-arylamino surpassed the positive control drug acarbose with 10 times concentration. Two groups of non-enantiomers exhibited great difference inα-glucosidase inhibitory activity.[3]Design,synthesis and bioactivities research of 3-aryl-1-（4-hydroxyl）aryl-3-arylamino-1-acetoneBased on the structure-activity relationship of the above two series of compounds,six series of 1-（4-hydroxyl）-3-aryl-3-arylamino-1-acetones were designed.We studied the synthetic method of such kind of compouds,and explored the optimum synthetic conditions and synthetic law of these kind ofβ-amino acetones beating hydroxy group on the aromatic ring.The chemical structure detection of IR,¹H NMR,¹³C NMR and MS showed that the Mannich reaction could realize successfully through direct Mannich reaction and take placed atα-carbon atom of the carbonyl of p-hydroxyl acetophenone and 3-nitro-4-hydroxylacetophenone rather than on the neighboring carbon atom of-OH reported in ethanol or 1-propanol catalysed by suitable concentrated hydrochloric acid or I₂ at room temperature.The products were classicalβ-amino acetones and without further cyclization.The fifty six new compounds were obtained in the yields of 50.0%～98.6%.Theα-glucosidase inhibitory activity of 4-（1-（3,4-dichlorophenyl）-3-（4-hydroxyl phenyl）-3-oxo-propyl amino）benzoic acid（H-1-14） surpassed the positive controlled drug acarbose with 10 times concentration.Most compounds showed moderate PPRE inhibitory activity.[4]Design,synthesis and bioactivities research of thiazolidine-2,4- dionesTo get our designed target compounds,the three synthetic routes reported in the literature were adopted in our research and some were improved,and then the thiazolidine-2,4-dione was synthesized with high yield and purity successfully.Moreover,six thiazole-2,4-dione at 5-site substituted on benzene ring intermediates were produced through Knoevenagel condensation and improved solid phase condensation.The modification stucturally was carried out on 3- N atom of thiazole-2,4- dione at 5-site substituted on benzene ring by N-Mannich reaction and condensation with BrCH₂COOCH₃.Sevne target products were gained with satisfied yield.All the intermediates and target products were verified by IR,¹H NMR,some confirmed further by ¹³C NMR and MS. The results ofα-glucosidase inhibitiory activity showed that theα-glucosidase inhibitory activity of the intermediate 5-（4-hydroxylbenzylidene）thiazolidine-2,4-dione（Si） and the target compound 5-（4-hydroxylbenzylidene）-3-（（4-nitrophenylamino）-methyl）thiazolidine-2,4-dione（SM-1） exceeded the positive control Acarbose although the concentration of Acarbose is 10 times of Si and SM-1. Moreover,some compounds performed PPRE activated activity moderately.In this paper,eight intermediates,one hundred and forty nine target compounds were synthesized totally,among of them,one hundred and forty-eight target compounds were new compounds.This study found out the new pharmacological effects ofβ-amino ketones,and thus it provided a new approach for the R&D of pharmaceuticals for treatment of diabetes with high efficiency,low toxicity.更多还原