Synthesis and stereochemistry of spirobenzylisoquinoline analogues

• Main Authors: Huang Meng-ting, 黃孟婷
• Other Authors: Chen Chi-Ming
• Format: Others
• Language: zh-TW
• Published: 1998
• Online Access: http://ndltd.ncl.edu.tw/handle/21311421056997532109

碩士 === 台北醫學院 === 藥學研究所 === 86 === Synthesis and Stereochemistry of Spirobenzylisoquinoline Analogues JKL 1067 ( 2,3-methylenedioxy-9,10-dimethoxyspirobenzylisoquinoline ) (4), a synthetic antiarrhythmic drug can slow down the heart rate and enhance the cardiac contractility. In the previous study, three spirobenzylisoquinoline analogues, show the equal or somewhat even more potent effect compared with JKL 1067 (4) in cardiac tissues. In the present study, spirobenzylisoquinoline 26 were prepared based on the structure modification of these three analogues. Protoberberine42 was synthesized from the Mannich condensation of the benzyl- isoquinoline 41 with formalin and followed reaction with methiodide to yield the N-methyltetrahydroprotoberberinium iodide 43. Finally, Stevens rearrange- ment of 43 catalyzed by dimsyl sodium in DMSO gave the target compound 26. In order to study the enantioselectivity of JKL 1067 (4) on cardiac tissue, JKL 1067 (4) was prepared and then resoluted by S-(+)-binaphthylphosphoric acid (53a) and R-(-)-binaphthylphosphoric acid (53b) to gave two enantiomers, (-)-JKL 1067 (4a) and (+)-JKL 1067 (4b). Optical purity of the enatiomer was conformed by specific rotation, chiral HPLC, and CD spectra. Analog 4, 4a, 4b and 26 will be tested on the isolated cardiac tissue. Several spirobenzyliso- quinoline 19, 20, 21, 22 and 25 were also well-resolved in a cellulose-base chiral column by HPLC ( separation factor a = 1.3~2.8 ). A computer program of Catalyst, was utilized to perform conformational analysis of the fifteen analogues. Two three-dimensional pharmacophore models of hypo-R.V. and hypo-L.A. were generated. These composed of two hydrogen bond acceptors and three hydrophobic groups. Then we could use these models to search the biosteric compounds from the several databases such as NCI, Minibiobyte and Sample. The three-dimensional pharmacophore could be further utilized as one of the tools to design more active antiarrythemic drug.