Patent GB-1125619-A (GB)
Title: Derivatives of bis-isoquinolines
Inventor: COPP FREDERICK CHARLES
IPC: C07D221/20
Filed: 1965-11-15
Abstract: 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 R<SP>1</SP> and R<SP>2</SP> are H and R<SP>4</SP> and R<SP>5</SP> are alkyl groups or R<SP>4</SP> and R<SP>5</SP> are H and R<SP>1</SP> and R<SP>2</SP> are alkyl groups, or R<SP>1</SP> and R<SP>2</SP> together with the carbon atom to which they are attached form a 1,1-divalent cycloalkane group, R<SP>6</SP> 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 R<SP>6</SP>Q, 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 R<SP>4</SP> and R<SP>5</SP> 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 - 6<SP>1</SP> - 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 - 6<SP>1</SP>- 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,N<SP>1</SP> - bis - (2,3<SP>1</SP>,4<SP>1 </SP>- 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,N<SP>1</SP>  -  bis - (2,3<SP>1</SP>,4<SP>1 </SP> -  methylenedioxyphenyl - 2 - methylpropyl) - sebacamide and N,N<SP>1</SP> - 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.