雷诺嗪和类似物的合成及其抗心绞痛活性研究
摘要
近年来由于社会环境所带来的精神应激日益增加，导致冠心病心绞痛病发病率越来越多。抗心绞痛类药物主要有硝酸酯及亚硝酸酯类、钙拮抗剂、β-阻滞剂等。目前已有药物的疗效各有优缺点，因此，国内外医药工作者不断研究，寻求治疗心绞痛的更有效，副作用更少的药物。
雷诺嗪是一类钙拮抗剂药物，同时又有β-阻滞剂作用的一类西药，临床前研究表明对心绞痛有显著疗效，副作用少，并能克服现有药物的一些缺点。因此对文献报道的雷诺嗪的合成工艺进行改进是有必要的。
本论文以雷诺嗪为先导物，根据剖裂拼合等经验规则对其进行结构改变，设计并合成了五种未见文献报道的哌嗪类化合物，并经质谱、元素分析、红外及核磁共振氢谱确证其结构。通过药理实验结果证明它们在抗心绞痛方面都有显著活性。其中TM4活性最好，优于阳性对照药普奈洛尔。
The incidence of angina pectoris tends to highten these years, along with the increase of the social pressure. At present, There are several main types medicines for angina pectoris, namely, nitric acid ester> calcium antagonist -blocking agent and so on. They have their respective advantages and disadvantages. And The workers of medicine are always trying their best to find more efficient medicine in these field.
Ranolazine, a kind of anti-angina medicine not only can affect calcium entry but also P -blockade, in the preclinical research, it manifests distinguish curative effects, and few side-effects. It also can compensate the defects of some other medicines for angina. So it is necessary to find a new feasible process of synthesizing Ranolazine.
At the same time, according with the rules of dissection and association ,we design and synthesize five compounds which are not reported in the document, using Ranolazine as lead compound. Their structure have been identified by MS IR 'H-NMR and Elemental analysis. In addition, the pharmacological experiment has shown that their anti-angina curative effects are distinguished. Among them, TM4 should be the best one, which excels the contrast medicine-propranolol.
雷诺嗪是一类钙拮抗剂药物，同时又有β-阻滞剂作用的一类西药，临床前研究表明对心绞痛有显著疗效，副作用少，并能克服现有药物的一些缺点。因此对文献报道的雷诺嗪的合成工艺进行改进是有必要的。
本论文以雷诺嗪为先导物，根据剖裂拼合等经验规则对其进行结构改变，设计并合成了五种未见文献报道的哌嗪类化合物，并经质谱、元素分析、红外及核磁共振氢谱确证其结构。通过药理实验结果证明它们在抗心绞痛方面都有显著活性。其中TM4活性最好，优于阳性对照药普奈洛尔。
The incidence of angina pectoris tends to highten these years, along with the increase of the social pressure. At present, There are several main types medicines for angina pectoris, namely, nitric acid ester> calcium antagonist -blocking agent and so on. They have their respective advantages and disadvantages. And The workers of medicine are always trying their best to find more efficient medicine in these field.
Ranolazine, a kind of anti-angina medicine not only can affect calcium entry but also P -blockade, in the preclinical research, it manifests distinguish curative effects, and few side-effects. It also can compensate the defects of some other medicines for angina. So it is necessary to find a new feasible process of synthesizing Ranolazine.
At the same time, according with the rules of dissection and association ,we design and synthesize five compounds which are not reported in the document, using Ranolazine as lead compound. Their structure have been identified by MS IR 'H-NMR and Elemental analysis. In addition, the pharmacological experiment has shown that their anti-angina curative effects are distinguished. Among them, TM4 should be the best one, which excels the contrast medicine-propranolol.
引文
1、李兵译．日本医学介绍，1994，15(4)：169-172
2、几文升 等．药物化学．高等教育出版社，2001．7：290-296
3、苏耀勋．新医学．1994，25(4)：458-459
4、汪送来等．药学进展．2001，25(6)：349-350
5、Kantor PF, Lucien A,kozak R,et al. The antianginal drug trimitazedine shifts cardiac energy metablism form fatty acid oxidation to glucose oxidation by inhibiting mitochondrial Iongchain 3-ketoacyl coenzyme Athiolase[J].Circ Res, 2000,86(5) 580-588
6、Detry JM. Clinical features of an anti-anginal drug in angina pectorist[J]. Eur Heart j,1993, 14 (Suppl G): 18-24
7、秦伯益．新药评价概论．人民卫生出版社，1998．8：8-11
8、郭宗儒 编著．药物化学总论．中国医药科技出版社，1996．6，260-269
9、Mager PP, Pharmazie in unser Zeit, 17,1988,(4) 106P, (5) 129P, (6) 177P
10、EndoA et al, J Antibiot, 29, 1976, 1346P
11、Lee T J, TIPS, 8, 1987, 442P
12、ShenTY and Winter CA, Adv Drug Res, 12,1977, 89P
13、Wermuth CG, in"Drug metabolism and Drug Design: Quo Vardis?" Briot M et al eds, Montpellier, Sanofi-Clin-Midy.
14、Kim SW et al, Polumeric drug systems, in "Drug Design",Vol X,Ariens EJ ed, New York, Academic Press, 1981,193P.
15、王立升．广西大学学报(自然科学版)，2001，6 26(2)：105-107
16、王立升．博士学位论文．沈阳药科大学，1994．11：11-13
17、姜红宇．硕士学位论文．广西大学，2001．5：22P
18、王立升等．中国医药工业杂志．1997，28(10)：438-440
19、罗代暄主编．化学试剂与精细化学品合成基础．高等教育出版社，1991，5：104-106 谢晶曦等，药学学报，16，1981，306页。
20、European Patent Office 0126449
21、H 盖尔曼 等．有机合成第一册．科学出版社，1957：75-76
22、韩长日 等主编．药物制造．科学技术文献出版社，2000．3：224-227
23、日本特许，106983 (1975)
24、日本特许，6979 (1976)
25、陈夏英．医药工．(10) 4 (1982)
26、广东利民制药厂．脑益嗪鉴定会资料(1976)
27、孙福成冲国医刊．1999，34(3)：10-11
28、李奎仪主编．中药药理实验方法学．上海科学技术出版社，P11O-111
2、几文升 等．药物化学．高等教育出版社，2001．7：290-296
3、苏耀勋．新医学．1994，25(4)：458-459
4、汪送来等．药学进展．2001，25(6)：349-350
5、Kantor PF, Lucien A,kozak R,et al. The antianginal drug trimitazedine shifts cardiac energy metablism form fatty acid oxidation to glucose oxidation by inhibiting mitochondrial Iongchain 3-ketoacyl coenzyme Athiolase[J].Circ Res, 2000,86(5) 580-588
6、Detry JM. Clinical features of an anti-anginal drug in angina pectorist[J]. Eur Heart j,1993, 14 (Suppl G): 18-24
7、秦伯益．新药评价概论．人民卫生出版社，1998．8：8-11
8、郭宗儒 编著．药物化学总论．中国医药科技出版社，1996．6，260-269
9、Mager PP, Pharmazie in unser Zeit, 17,1988,(4) 106P, (5) 129P, (6) 177P
10、EndoA et al, J Antibiot, 29, 1976, 1346P
11、Lee T J, TIPS, 8, 1987, 442P
12、ShenTY and Winter CA, Adv Drug Res, 12,1977, 89P
13、Wermuth CG, in"Drug metabolism and Drug Design: Quo Vardis?" Briot M et al eds, Montpellier, Sanofi-Clin-Midy.
14、Kim SW et al, Polumeric drug systems, in "Drug Design",Vol X,Ariens EJ ed, New York, Academic Press, 1981,193P.
15、王立升．广西大学学报(自然科学版)，2001，6 26(2)：105-107
16、王立升．博士学位论文．沈阳药科大学，1994．11：11-13
17、姜红宇．硕士学位论文．广西大学，2001．5：22P
18、王立升等．中国医药工业杂志．1997，28(10)：438-440
19、罗代暄主编．化学试剂与精细化学品合成基础．高等教育出版社，1991，5：104-106 谢晶曦等，药学学报，16，1981，306页。
20、European Patent Office 0126449
21、H 盖尔曼 等．有机合成第一册．科学出版社，1957：75-76
22、韩长日 等主编．药物制造．科学技术文献出版社，2000．3：224-227
23、日本特许，106983 (1975)
24、日本特许，6979 (1976)
25、陈夏英．医药工．(10) 4 (1982)
26、广东利民制药厂．脑益嗪鉴定会资料(1976)
27、孙福成冲国医刊．1999，34(3)：10-11
28、李奎仪主编．中药药理实验方法学．上海科学技术出版社，P11O-111