BENZYLAMINE ANALGESICS

摘要

1417450α- Cycloalkylbenzylamines and their pharmaceutical compositions AMERICAN HOME PRODUCTS CORP 6 April 1973 [6 April 1972] 16565/73 Heading C2C The invention comprisesα-cycloalkyl benzylamines having the general Formula A wherein R1 is hydrogen, lower alkyl, or lower alkyl carbonyl; R2 is lower alkylamino, N- lower alkyl - N - methylamino, N - phenloweralkyl - N - methylamino, 1 - pyrrolidinyl, 4 - morpholino, N - lower alkenyl - N - methylamino, N - cycloalkylmethyl - N - methylamino, or N - oxo - N - lower alkyl - N- methylamino; R3 is hydrogen or methyl; X is hydrogen, hydroxy, lower alkoxy, lower alkoxy-methoxy, lower alkylcarbonyloxy, or halo; and n is an integer of from 3 to 6; and wherein the cycloalkane ring may be substituted or unsubstituted, or a pharmacologically acceptable acid addition salt thereof or a compound of Formula B wherein R1, X and n are as defined above, R2 is lower alkylamino, N-lower alkyl-N-methylamino, N - phenloweralkyl - N - methylamino, N - lower alkenyl - N - methylamino, N- cycloalkylmethyl - N - methylamino or N- oxo - N - lower alkyl - N - methylamino, and wherein the cylcoalkyl ring may be substituted or unsubstituted or a pharmacologically acceptable acid addition salt thereof. Compounds of Formula A wherein R3 is hydrogen and which are substantially free of trans epimers may be prepared by reducing a compound of Formula C e.g. with a complex metal hydride or diborane, to give a compound of Formula A in which R1 is H, optionally etherifying or esterifying to obtain a compound of Formula A in which R1 is lower alkyl or alkyl carbonyl and optionally forming an acid addition salt therefrom, separation of the cis compound from the trans epimer being carried out, if necessary, at any time after the reduction reaction. Compounds of Formula A wherein R3 is methyl and which are substantially free from trans epimers, and their acid addition salts, may be prepared by methylating, e.g. with CH 3 MgBr a compound of Formula C to give a compound of Formula A in which R3 is methyl and R1 is H optionally followed by subsequent steps as described immediately above. Compounds of Formula B and acid addition salts thereof may be prepared by hydrogenolysis of a compound of Formula D wherein R4 is methyl or benzyl, R5 is lower alkyl, phen-loweralkyl, lower alkenyl or cycloalkylmethyl and Z is an ion, e.g. a halide ion, to give a compound of Formula B wherein R1 is hydrogen optionally followed by etherification or esterification and/or salt formation as described above or by reaction with a peracid to obtain a compound of Formula B wherein R2 is N-oxo- N-lower alkyl-N-methylamino. Compounds of Formula B in which R2 is lower alkylamino may be prepared by reducing a compound of Formula F wherein R5 is lower alkyl and X and n are as defined above. Compounds of Formula A or B may be converted to other compounds of Formula A or B respectively by applying known reactions, e.g. etherification, esterification, hydrolysis, hydrogenolysis of N-benzyl compounds, peracid N- oxidation or N-alkylation to modify one or more of the groups R1, R2, R3 and X. 2 - (m - Methoxybenzylidene) - cyclohexanone, 2 - (m - methoxymethoxybenzylidene)- cycloheptanoe and 2 - benzylidenecycloheptanone are prepared by reacting the corresponding benzaldehydes with the appropriate cycloalkanone. Octahydro - 3 - (m - methoxyphenyl) - 2 - methyl- 1,2 - benzisoxazole, octahydro - 2 - (m - methoxymethoxyphenyl) - 2 - methyl - 1,2 - benzisoxazole, octahydro - 2 - methyl - 3 - phenyl - 1,2 - benzisoxazole, hexahydro - 3 - (m - methoxymethoxyphenyl)- 2 - methyl - 2H - cyclopent[d]isoxazole, octahydro - 3 - (m - methoxymethoxyphenyl) - 2- methyl - 2H - cyclohept[d]isoxazole and decahydro - 3 - (m - methoxymethoxyphenyl) - 2- methylcyclooct[d]isoxazole are prepared by reacting the appropriate cycloalkene with the appropriate C-phenyl-N-methylnitrone and are converted to the corresponding 2,2-benzisoxazolium iodides by reaction with methyl iodide. Cis - 2 - [m - methoxymethoxy -α(methylamino) benzyl]cyclohexanol is reacted with cyclopropane carboxylic acid chloride to obtain cis - 2 - [α- (oyclopropylacetyl)methylamino - mmethoxymethoxybenzyl] - cyclohexanol. 2 - [α- (Dimethylamino) - methoxymethoxybensyl]cyclohexanone is prepared by reacting 2- m-methoxymethoxybenzylidine cyclohexanone with dimethylamine. Pharmaceutical compositions having analgesic activity for oral or parenteral administration comprise a compound of Formula A or B or a pharmacologically acceptable acid addition salt thereof together with a pharmaceutically acceptable carrier.