Chemische Verbindungen mit pharmakologischer Wirksamkeit

摘要

1,125,619. Derivatives of bis-isoquinolines. WELLCOME FOUNDATION Ltd. 11 Nov., 1966 [15 Nov., 1965], No. 48507/65. Heading C2C. Novel compounds of the general formula wherein R1 and R2 are H and R4 and R5 are alkyl groups or R4 and R5 are H and R1 and R2 are alkyl groups, or R1 and R2 together with the carbon atom to which they are attached form a 1,1-divalent cycloalkane group, R6 is a C 1- C 4 saturated or unsaturated hydrocarbyl group, n is 3-9, X is H or alkyl, Y is alkyl, or an additional chemical bond may be formed between C (1) and N (2) in the absence of X and Y, each fused benzene ring may be optionally substituted with one or more alkoxy groups, Z, which may be the same or different or Z may be a fused heterocyclic ring, the above alkyl and alkoxy groups having from 1-4 carbon atoms and A- is a pharmaceutically acceptable anion, are prepared by quaternizing a tertiary base of the general formula with a reactive derivative R6Q, where Q provides the anion A, e.g. halide, p-toluenesulphonate or sulphate. If the anion formed is not pharmaceutically acceptable, it may be changed by known metathesis methods. Compounds of the second general formula above, wherein R4 and R5 are both hydrogen, one of the Z groups is a 6-alkoxy group and an additional double bond is formed between C (1) and N (2) in the absence of X and Y, may be prepared by the Ritter reaction, i.e. 2 moles of the appropriate substituted benzyl dialkyl carbinol or the corresponding 1,1 .dialkyl.2. benzyl ethylene are reacted with the appropriate alpha-omega-dioyanoalkane. Compounds of the second general formula above, wherein an additional bond is formed between C (1) and N (2) in the absence of X and Y, may be prepared by reacting a compound of the general formula with POOl 3 . Compounds of the second general formula above, wherein X is hydrogen and Y is alkyl, are prepared by reacting a compound of the general formula with hydrogen in the presents of a catalyst, e.g. Adam's catalyst. Compounds of the second general formula above, wherein X and Y are both alkyl, are prepared by reacting a compound of the previous general formula with an appropriate alkyl magnesium halide. m-Ethoxyphenylacetone is prepared by reacting m-ethoxybenzaldehyde, nitroethane and nbutylamine and oxidizing the resulting 1-methoxyphenyl - 2 - nitro - prop - 1 - ene with iron powder, ferric chloride and water. By a similar method 2,3 - dimethoxyphenylacetone, 1 - mmethoxyphenyl - butan - 2 - one, 1 - 61 - benzdioxinyl acetone, 1 - (3,4 - dimethoxyphenyl)- butan-2-one and 1 - (3,4 - methylenedioxyphenyl) - butane - 2 - one and the intermediates l-(2 dimethoxyphenyl) - 2 - nitro - prop - 1 - ene, 1-mmethoxyphenyl - 2 - nitrobut - 1 - ene, 1 - 61- benzdioxinyl - 2 - nitroprop - 1 - ene, 1 - (3,4- dimethoxyphenyl) - 2 - nitro - but - 1 - ene and 1 - (3,4- methylenedioxyphenyl) - 2 - nitro - but - 1 - ene are prepared. 2 - m - Ethoxybenzylpropan - 2 - ol is prepared by reacting m-ethoxyphenylacetone with methyl magnesium iodide. By a similar method 2-(2-3- dimethoxybenzyl-, 2,6 - benzdioxinylmethyl-, 2-m, methoxybenzyl-, 2 - (3,4 - dimethoxybenzyl)., 2- (3,4 - methylenedioxybenzyl). and 2 - (4 - ethoxy- 3 - methoxybenzyl) - propan - 2 - ol, 2 - (3,4- methylenedioxyphenyl. and 2 - (3,4 - dimethoxybenzyl) - butan - 2 - ol, 3 - (3,4 - dimethoxybenzyl) - pentan - 3 - ol and 1 - m - methoxybenzylcyclopentan-1 -ol are prepared. N,N1 - bis - (2,31,41 - dimethoxyphenyl - 2 - methyl - propyl) - sebacamide is prepared by warming a suspension of sodium hydride in dry dimethyl sulphoxide and adding 3,4-dimethoxyphenylacetonitrile whilst cooling, the mixture is warmed and methyl iodide added and the whole process repeated to yield 2-(3,4-dimethoxyphenyl) - 2 - methylpropionitrile which is reduced with LiAlB 4 to yield 2-(3,4-dimethoxyphenyl) - 2 - methylpropylamine which on treating with anhydrous sodium carbonate and sebacoyl chloride in chloroform yields the required product. N,N1 - bis - (2,31,41 - methylenedioxyphenyl - 2 - methylpropyl) - sebacamide and N,N1 - bis - (2,21,51 - dimethoxyphenyl - 2 - methylpropyl)-sebacamide are prepared similarly. The by-product sebacamide is produced when 2-(3,4- methylenedioxybenzyl)-propan-2-ol is reacted with sebaconitrile. Pharmaceutical compositions having neuromuscular blocking action comprise as active ingredient compounds of the first general formula above in admixture with a pharmaceutically acceptable carrier. The formulation may be an aqueous or non-aqueous solution and may contain bacteriostatic agents, antioxidants, buffers, thickening agents, suspending agents or other acceptable additives.