Patent GB-948874-A (GB)
Title: 4-aryl-4-propionyl-piperidine derivatives
Filed: 1962-02-26
Abstract: The invention comprises (1) compounds of the general formula: <FORM:0948874/C2/1> wherein R represents an alkyl or alkenyl group of 3 to 4 carbon atoms which is substituted in the 3 or 4 position by a monocyclic aromatic group (e.g phenyl, alkyl-substituted phenyl, 2-furyl or 4-pyridyl), and their acid addition salts, and pharmaceutical compositions containing them (see Division A5); (2) the preparation of compounds (1) (a) reacting 4-(3-hydroxyphenyl)-4-propionyl-peridine with an R halide, or (b) (when R represents a phenyl-or alkyl-substituted-phenyl-alkyl or -alkenyl group) hydrolysing with an acid a ketimine of the general formula: <FORM:0948874/C2/2> (wherein R1 has the meaning given immediately above for R, and Alk represents an alkyl group) or (c) reacting a 3-(3-hydroxyphenyl)-3-propionyl-1, 5-dihalopentane with an amine R-NH2 or (d)(when R represents a phenyl- or alkyl-substituted-phenyl-alkyl group) by hydrolysing with an ethersplitting agent a compound of the general formula <FORM:0948874/C2/3> (wherein R111 has the meaning given immediately above for R and Alk represents an alkyl group), and in cases (a), (b) and (c) if desired, converting the product into an acid addition salt; (3) the combination of process (a) with the preparation of the starting material by reacting a m-alkoxylbenzyl cyanide with a di-(b -haloethyl)-tosylamine in the presence of a basic condensation agent to form a 1-tosyl - 4 - (3 - alkoxyphenyl) - 4 - cyanopiperidine, reacting this with an ethyl Grignard reagent and decomposing the magnesium complex to form a 1-tosyl- 4 -(3-alkoxyphenyl-piperidyl-(4) ethyl ketimine and hydrolysing the latter; (4) the combination of process (b) with the preparation of the starting material by reacting a m-alkoxybenzyl cyanide with a tertiary amine of the formula (Hal-CH2CH2)2NR1 (wherein Hal represents a halogen atom) in the presence of a basic condensation agent to form a 4-cyanopiperidine derivative, reacting this with an ethyl Grignard reagent and decomposing the magnesium complex; (5) the combination of process (d) with the preparation of the starting material by reacting an m-alkoxybenzyl cyanide with a compound of the formula Hal-CH2CH2-NR11R111(where R11 represents a benzyl group), reacting the product with a compound of the formula X-CH2CH2-X (wherein X represents a halogen atom or a sulphonic ester group) to form a 4-(3-alkoxyphenyl)-4-cyanopiperidinium compound, reacting this with an ethyl Grignard reagent and decomposing the magnesium complex to form a ketimide, which is then hydrolysed to a 4-(3-alkoxyphenyl)-4-propionyl-piperidinium compound and the latter reduced.ALSO:Pharmaceutical compositions comprise a compound (having analgesic and morphineantagonistic properties) of the general formula <FORM:0948874/A5-A6/1> (wherein R represents an alkyl or alkenyl group or 3 or 4 carbon atoms which is substituted in the 3 or 4 position by a monocyclic aromatic group, e.g. phenyl, alkyl-substituted phenyl, 2-furyl or 4-pyridyl), or an acid addition salt thereof, together with a pharmaceutical carrier or excipient and, if desired, a morphinic analgesic.  In examples, 1-cinnamyl-4-(3-hydroxyphenyl) - 4 - propionylpiperidine methanesulphonate or 1 - (3 - phenylpropyl) - 4 - (3 - hydroxyphenyl) - 4 - propionylpiperidine hydrochloride is made up into ampoules of injectable solution also containing hydroxyethyltheophylline, suppositories and tablets.  Reference is also made to pills, capsules, dragees, suspensions, emulsions, syrups, linctuses and elixirs.