Study On Synthesis And Antiarrhythmic Activity Of Derivatives Of 1,2,3,4-tetrahydroisoquinolines And 1-benzyl-1,2,3,4-tetrahydroisoquinolines

It is current tendency to develop class Ⅲ antiarrhythmic drugs with blocking activity of potassium channel and additional blocking activities of sodium channel, calcium channel or β-receptor . The results of large scale clinic triaF of class Ⅲ antiarrh)'thrnic drug showed that Sotalol , a marketing class Ⅲ drug with blocking activity of potassium channel and β-blocking activity, was much more favorable to decrease the mortality rate. These results promoted us to design compounds which would possess class Ⅲ a action associated with P - blocking activity. Compound SIPI-926 , a tetrahydroiso- quinolines derivative , has excellent class Ⅲ activity . In this paper , SIPI-926 was taken as lead compound and four series of derivatives were designed. 75 target compounds were synthesized and their structures were determined by Elemental Analysis, NMR and Mass Spectrum. The SAR and 3D QSAR were also discussed. 9 Compounds of 2-(1-hydroxyl-4'methylsulfonamidophenylethyl)-1,2,3,4-tetra- hydroisoquinolines (Ⅰ) were synthesized by introducing the fragment of sotalol into 1,2,3,4-tetrahydroisoquinolines. To observe the influence of l-benzyl on the antiarrhythmic activity of compounds (Ⅰ), 18 compounds of 1-benzyl-2-(1-hydroxyl-4-rnethylsulfonamidophenylethyl)-1,2,3,4- tetrahydroisoquinol ines (Ⅱ) were synthesized To increase the selective action β 1-receptor , 15 compounds of 2-(1-phenoxyl-2-hydroxyl-propyl)-1,2,3,4-tetrahydroisoquinol ines (Ⅲ) were synthesized by combining the pharmacophore of β1 blockers with 1,2,3,4-tetrahydroisoquitiohities. Also, 33 compounds of 1 -benzyl-2-( 1 -phenoxyl-2-hydroxyl-propyl)- 1,2,3,4- tetrahydro-isoquinolines (Ⅳ) were3esi5d to observe the influence of 1- benzyl on the antiarrhythmic activity of compounds (Ⅲ). Based on the result of pharmacological screening in vitro, 15 effective compounds (Ⅰ-3, Ⅰ-7, Ⅱ-4, Ⅱ-5, Ⅱ-9, Ⅲ-2, Ⅲ-3 Ⅲ-8, Ⅲ-12 Ⅲ-13, Ⅲ-15, Ⅳ-2, Ⅳ-11, IV-26, IV-28 )displayed prolonging effective refractory period, among of them, 8 compounds (Ⅰ-7, Ⅱ-4, Ⅲ-2, Ⅲ-3 Ⅲ-8 , Ⅲ-12, Ⅳ-2, Ⅳ-11) showed similar to Sotalol or SIPI-926. The results of structure activity relationship (SAR) of the target compounds showed that the activity of tetrahydroisoquinolines derivatives (Ⅰ) and (Ⅲ) were superior to that of the corresponding 1-benzy-tetrahydroisoquinohines derivatives (Ⅱ) and (Ⅳ); Compounds with 3,4-dimethoxyl or 6-methylsulfonarnido on the ring A, the amino group on the ring C and amino or methylsulfonamido group on the ring D showed more potential activity. Additionally, 3 D QSAR of series compounds (Ⅱ) , (Ⅲ) and (Ⅳ) were studied with CoMFA ,three CoMFA models were established. Target compounds (Ⅰ) were obtained by reduction of ketones (5), which were obtained from the reaction of 1,2,3,4-tetrahydroisoquinolines (2) with 2-bromo-4' rnethylsulfonarnido-acetophenone (4). Through the reduction of (11) , which were prepared from the reaction of 1-benzyl-I,2,3,4-tetrahydroisoquinolines (10) with (4), target compounds (Ⅱ) were obtained. The nitro compounds of (Ⅲ) were prepared by the reaction of(2) with 1-phenoxyl-3-chloro-2-propanol (13), the amines compounds of (Ⅲ) were obtained from nitro compounds. After trying five approaches, the corresponding...