新型四氢异喹啉类化合物的合成及其抗真菌和抗生育活性研究

Synthesis of novel tetrahydroisoquinolines and study of their anti-fungal and contraceptive activities

目的1设计合成新型四氢异喹啉类化合物，寻找具有抗真菌和抗生育双重作用的化合物，为研究具有抗真菌作用的避孕药物提供先导结构。方法：以3，4-二甲氧基苯乙胺为原料，经Pictet—Spengler反应、碱中和、取代反应、HBr裂解反应制得目标化合物并进行体外抑菌实验和杀精实验。结果：共合成14个目标化合物，它们是2-正辛烷基-6，7-二甲氧基-1，2，3，4-四氢异喹啉盐酸盐（1）、2-正壬烷基-6，7-二甲氧基-1，2，3，4-四氢异喹啉盐酸盐（2）、2-正癸烷基-6，7-二甲氧基-1，2，3，4-四氢异喹啉盐酸盐（3）、2-正十二烷基-6，7-二甲氧基-1，2，3，4-四氢异喹啉盐酸盐（4）、2-正十二烷基-6，7-二乙酰氧基-1，2，3，4-四氢异喹啉盐酸盐（5）、2-正戊烷基-6，7-二甲氧基-1，2，3，4-四氢异喹啉氢溴酸盐（6）、2-正己烷基-6，7-二甲氧基-1，2，3，4-四氢异喹啉氢溴酸盐（7）、2-正庚烷基-6，7-二甲氧基-1，2，3，4-四氢异喹啉氢溴酸盐（8）、2-正辛烷基-6，7-二甲氧基-1，2，3，4-四氢异喹啉氢溴酸盐（9）、2-正壬烷基-6，7-二甲氧基-1，2，3，4-四氢异喹啉氢溴酸盐（10）、2-正癸烷基-6，7-二甲氧基-1，2，3，4-四氢异喹啉氢溴酸盐（11）、2-正十二烷基-6，7-二羟基-1，2，3，4-四氢异喹啉氢溴酸盐（12）、2-正十四烷基-6，7-二羟基-1，2，3，4-四氢异喹啉氢溴酸盐（13）、2-十六烷基-6，7-二羟基-1，2，3，4-四氢异喹啉氢溴酸盐（14），其中化合物5～14均未见文献报道。实验结果显示，所有目标化合物均有抗真菌活性，6个目标化合物具有抗真菌和抗生育双重作用，其中化合物11、12的活性最强。结论：发现一类具有抗真菌和抗生育双重作用的新型四氢异喹啉类化合物，为研究开发具有抗真菌活性的避孕药提供了先导结构。

Objective：To synthesize novel tetrahydroisoquinolines with both anti-fungal and contraceptive activities, so as to provide precursor structures for contraceptives with anit-fungal activities. Methods： 3,4-dimethoxyphenylethylamine was taken as the template and the title compounds were synthesized through Pictet-Spengler reaction, neutralization reaction, substitution, hydrolysis, and acylation. The anti-fungal activity and sperm-killing activity of the target compounds were tested in vitro. Results： Fourteen title compounds were obtained and they were： 2-octyl-6, 7-dimethyl-1, 2, 3, 4-tetrahydro-isoquinoline hydrochloride（1）, 2-nonyl-6,7-dimethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride （2）, 2-decyl-6,7-dimethy- 1,2,3,4-tetrahydroisoquinoline hydrochloride（3）, 2-dodecyl-6,7-dimethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride（4）, 2-dodecyl-6,7-diacetoxy-1, 2,3,4-tetrahydro-isoquinoline hydrochloride（5 ）, 2-pentyl-6,7-diacetoxy-1,2,3,4-tetrahydro-isoquinoline hydrobromide（6）, 2-hexyl-6, 7-diacetoxy-1,2,3,4-tetrahydro-isoquinoline hydrobromide （7）, 2-heptyl-6,7-diacetoxy-1,2,3,4-tetrahydro-isoquinoline hydrobromide （8）, 2-octyl-6,7-dimethyl-1,2,3,4-tetrahydro-isoquinoline hydrobromide（9）, 2-nonyl-6,7-dimethyl-1,2,3,4-tetrahydro-isoquinoline hydrobromide（10）, 2-decyl-6, 7-dimethy-1,2, 3, 4-tetrahydro-isoquinoline hydrobromide （ 11 ）, 2-dodecyl-6, 7-dihydroxyl-1,2, 3, 4- tetrahydro-isoquinoline hydrobromide （12）, 2-tetradecyl-6, 7-dihydroxyl-1,2, 3,4-tetrahydro-isoquinoline hydrobromide （13）, and 2- cetyl-6,7-dihydroxyl-1,2,3,4-tetrahydro-isoquinoline hydrobromide（14）. Compounds 5-14 were firstly reported. It was found that all the 14 compounds had anti-fungal activity and 6 compounds also showed sperm-killing activities, with compounds 11,12 having the strongest activities. Conclusion： A group of novel compounds with both anti-fungal and contraceptive activities have been synthesized, which provide a precursor structure for developing new contraceptives with anti-fungal activities.