GB971752A - Phenyl-alkylamines,their manufacture and use - Google Patents

Abstract

The invention comprises phenylalkylamines of the formula <FORM:0971752/C1/1> and physiologically tolerable acid addition salts thereof, wherein OR1 is a hydroxy, methoxy, ethoxy or benzyloxy group, R2 is an alkyl group of 1-4 carbon atoms and R3 and R4 are alkyl groups of 1-4 carbon atoms or, together with the adjacent central carbon atom, represent a saturated acyclic ring system of 5 or 6 carbon atoms. The compounds are prepared by (a) reducing a corresponding primary b -phenylalkylamine in the presence of a ketone of the formula R3-CO-R5 wherein R5 may be an alkyl or an alkenyl group of 1-4 carbon atoms; (b) reacting the appropriate primary b -phenylalkylamine with an ester R3(R4)-CH-X, wherein X is an inorganic or organic acid radical, if desired in the presence of an acid-binding agent; (c) heating the appropriate primary b -phenyl-alkylamine with an alcohol of the formula R3(R4)-CHOH in the presence of Raney nickel; (d) reacting an appropriate b -phenylalkanol with an amine R3(R4)CHNH2; (e) reacting an appropriate b -phenylalkyl halide with an amine R3(R4)-CH-NHR6 wherein R6 is hydrogen or a benzyl group which is subsequently split off by hydrogenation; (f) reducing an appropriate a -phenylaldehyde in the presence of an amine R3(R4)CH-NH2 or (g) reducing the appropriate a -phenylalkanoyl-N-alkylamide with LiAlH4. If the group OR1 in the products is a methoxy, ethoxy or benzyloxy group, it may be treated by known methods for the cleavage of such ethers to give the corresponding hydroxy compound or conversely a hydroxyl group may be etherified to give the methoxy or ethoxy compounds. Primary 2-phenyl-2-alkyl-butylamines used as starting materials are prepared by reducing the corresponding (hydroxy-methoxy-, ethoxy- or benzyloxy-) phenyl-a -ethyl-a -alkyl-acetonitriles, obtainable by heating the corresponding benzyl cyanide with the appropriate alkyl halides in the presence of sodamide. Starting materials bearing a p-hydroxy-substituent may be made via the unsubstituted benzyl cyanide, e.g. 2-(41-hydroxy-phenyl)-2-ethyl-butylamine is made by treating benzyl cyanide with ethyl bromide in the presence of sodamide, nitrating the resulting phenyldiethyl-acetonitrile to 4-nitrophenyl-diethyl-acetonitrile, reducing to 4-aminophenyl-diethyl-acetonitrile, diazotizing and boiling to 4-hydroxyphenyl-diethyl-acetonitrile and hydrogenating. Phenylalkyl halides of the formula R1O-C6H4C(R2)(C2H5) -CH2-Hal are made by reducing phenyl-dialkyl-acetic acids to the carbinols with LiAlH4 and halogenating e.g. with HBr. 3-Ethoxy-benzyl-cyanide is made by etherifying 3-hydroxybenzyl alcohol with diethyl sulphate, reacting the resulting 3-ethoxybenzyl alcohol with HBr to give the bromide and treating with potassium cyanide. 3-Benzyloxy-benzyl-cyanide is made by reacting 3-hydroxybenzyl alcohol with benzyl bromide, reacting the resulting 3-benzyloxybenzyl alcohol with HBr to give 3-benzyloxybenzyl bromide and treating with potassium cyanide. Pharmaceutical preparations having analgesic activity comprise the above compounds of the invention in admixture or conjunction with a pharmaceutical carrier. The preparations preferably take the form of tablets or dragees for oral administration. The active compounds may be used in the form of their addition salts with organic and inorganic acids such as hydrohalic, phosphoric, sulphamic, mono- and di-carboxylic acids and citric, aceturic, aspartic, p-aminobenzoic, salicylic and ethylenediamine-tetracetic acids.