Patent GB-810853-A (GB)
Title: 4-aryl-1-(substituted)-piperidine-4-carboxylates
Filed: 1956-08-28
Abstract: The invention comprises compounds of the general formula: <FORM:0810853/IV (b)/1> and acid addition salts thereof, wherein X is an alkylene radical having 2 to 6 carbon atoms and having its free valency bonds on different carbon atoms, Z is O, S, SO, SO2, NH or N-(lower alkyl), Ar is an aryl radical of the benzene series including phenyl and phenyl substituted by nitro, amino, (lower alkyl) amino, di-(lower alkyl) amino, (lower alkanoyl) amino, lower alkoxy, lower alkylmercapto, lower alkylsulphonyl, lower alkyl, hydroxy or halo, and "lower" indicates groups containing 1 to 6 carbon atoms; and the manufacture thereof by reacting a lower alkyl 4-phenylpiperidine-4-carboxylate with an alkylating agent containing the group X-Z-Ar, or, when Z is NH, or N-(lower alkyl), heating a lower alkyl 4-phenyl-1 - (haloalkyl) piperidine-4-carboxylate, with an amine having the formula ArNH2 or ArNH (lower alkyl) and, if desired, reacting the free base product with an organic or inorganic acid to form an acid addition salt.  In the process of the invention the alkylating agent is preferably an aryl-Z-alkyl ester of a strong inorganic or organic sulphonic acid, and, in the process in which the compound wherein Z is NH or N-(lower alkyl) is prepared from the lower alkyl 4-phenyl-1-(haloalkyl) piperidine-4-carboxylate, said 1-(haloalkyl) piperidine derivative is prepared by reacting the corresponding lower alkyl 4-phenyl-1-(hydroxyalkyl) piperidine-4-carboxylate with a halogenating agent, preferably thionyl chloride, phosphorus oxychloride or tribromide.  The compounds of the invention may also be prepared by reaction of a lower alkyl-4-phenyl-piperidine-4-carboxylate with the appropriate aryl-Z-alkanal under catalytic hydrogenation conditions.  In an example, ethyl - 4 - phenylpiperidine - 4 -carboxylate hydrochloride is refluxed with 3-phenoxypropyl bromide in n-butanol in the presence of sodium carbonate to form ethyl 4-phenyl - 1 - (3 - phenoxypropyl) piperidine 0 4-carboxylate, the free base being converted into the hydrochloride salt, and the free base again recovered from the said salt by the addition of sodium hydroxide.  The preparation may also be carried out using ethyl 4-phenylpiperidine-4-carboxylate in free base from, or alternatively with other esters such as 3-phenoxypropyl para-toluene sulphonate or iodide.  Similarly is prepared ethyl 4-phenyl-1-(2-phenoxyethyl)-, and ethyl 4-phenyl-1-(4-phenoxybutyl)-piperidine-4-carboxylates and their hydrochlorides, methyl 4 - phenyl - 1 - (4 - phenoxybutyl)-, ethyl 4 - phenyl - 1 - [2 - (4 - n - butylphenoxy) ethyl]-, n - propyl 4 - phenyl - 1 - (3 - phenoxypropyl)-, ethyl 4-phenyl-1-[3-(3,4-dimethoxyphenoxy)propyl], iso - butyl 4 - phenyl - 1 - (2-phenoxypropyl)-, ethyl 4-phenyl-1-[2-(4-ethylmercaptophenoxy) ethyl]-, n-hexyl 4-phenyl-1-(3-phenoxypropyl)-, ethyl 4-phenyl-1-[2-4-ethylsulphonylphenoxy) ethyl] -, - [2 - (4 - dimethylaminophenoxy) ethyl] -, - [2 - (4 - n - butylaminophenoxy)ethyl]-, -[2-(2,4-dichlorophenoxy) ethyl] -, - [2 - (3 - hydroxyphenoxy) ethyl]-, -[2-(4-nitrophenoxy) ethyl]-, and -[3-(4-nitrophenoxy) propyl] - piperidine - 4 - carboxylates (and the hydrochloride of the last-named compound).  Ethyl 4-phenyl-1-[3-(4-aminophenoxy) propyl] - piperidine - 4 - carboxylate and its dihydrochloride are prepared by reduction of the corresponding nitro-compound by hydrogen in the presence of a platinum oxide catalyst, whilst ethyl 4-phenyl-1-[2-(4-aminophenoxy) ethyl] - piperidine - 4 - carboxylate is similarly prepared and furthermore is converted into the (4-acetylaminophenoxy) compound by acetyl chloride or acetic anhydride.  In further examples, replacing the alkylating agent containing an X-O-Ar group by one containing an X-S-Ar group, an X-SO2-Ar, an X-SO-Ar group, or an X-NH-Ar group, similarly are prepared ethyl 4 - phenyl - 1 - (2 - phenylmercaptoethyl) piperidine-4-carboxylate and its hydrochloride, ethyl 4 - phenyl - 1 - (3-phenylmercaptopropyl) piperidine-4-carboxylate and its hydrochloride, and methyl 4 - phenyl - 1 - (4 - phenylmercaptobutyl)-, isopropyl 4-phenyl-1-(2-phenylmercaptopropyl) -, n - butyl 4 - phenyl - 1 - (2-phenylmercaptopropyl)-, and n-hexyl 4-phenyl-1 - (3 - phenylmercaptopropyl)piperidine - 4-carboxylates, ethyl 4 - phenyl - 1 - (3 - phenylsulphonylpropyl) - piperidine-4-carboxylate and its hydrochloride, ethyl 4-phenyl-1-(2-phenyl-sulphonylethyl) -, - [2 - (4 - n - butoxyphenylsulphonyl) ethyl]-, and -[3-(4-nitrophenylsulphonyl) propyl] - piperidine - 4 - carboxylates, methyl 4 - phenyl - 1 - (4 - phenylsulphonylbutyl) - piperidine - 4 - carboxylate, ethyl 4-phenyl - 1 - (3 - phenylsulphinylpropyl) - piperidine-4-carboxylate and ethyl 4-phenyl-1-[2-(2 - nitrophenylamino) - ethyl] - piperidine - 4-carboxylate. Examples of the manufacture of compounds of the general formula wherein Z is NH or N-(lower alkyl), by the alternative method, describe the preparation of ethyl 4-phenyl - 1 - (2 - phenylaminoethyl) - and - [2-(N - methyl - N - phenylamino) ethyl] - piperidine-4-carboxylates and their dihydrochlorides by reacting ethyl 4-phenyl-1-(2-hydroxyethyl) piperidine-4-carboxylate with thionyl chloride to form ethyl 4-phenyl-1-(2-chloroethyl)-piperidine-4-carboxylate and reacting this as its hydrochloride with either aniline or N-methylaniline and preparing the dihydrochlorides of the bases so formed.  In similar manner are prepared ethyl 4 - phenyl - 1 - (3 - chloropropyl) piperidine - 4 - carboxylate and its hydrochloride, methyl 4 - phenyl - 1 - (4 - chlorobutyl) -, ethyl 4 - phenyl - 1 - (2 - bromoethyl)-, isobutyl 4 - phenyl - 1 - (2 - chloropropyl)-, and n - hexyl 4 - phenyl - 1 - (3 - chloropropyl) piperidine-4-carboxylates from which are prepared ethyl 4-phenyl-1-(3-phenylaminopropyl)-and - [3 - (N - ethyl - N - phenylamino) propyl]-, methyl 4 - phenyl - 1 - [4 - (3,4 - diethoxyphenylamino) butyl]-, ethyl 4-phenyl-1-[2-(4-n - butylaminophenylamino) - ethyl]-, isobutyl 4 - phenyl - 1 - [2 - (4 - nitrophenylamino) propyl]-, ethyl 4-phenyl-1-[2-(2,4-dibromophenylamino) - ethyl]-, and n-hexyl 4-phenyl-1-[3-(4-isopropylphenylamino) propyl] - piperidine - 4-carboxylates.  Ethyl 4-phenyl-1-[3-(3,4-dimethoxyphenylamino) propyl] - piperidine - 4 - carboxylate may be similarly prepared from the corresponding chloro compound and 3,4-dimethoxyaniline. A list of organic and inorganic salt-forming acids is also given.  Lower alkyl 4-phenyl-1-(hydroxyalkyl) piperidine-4-carboxylates are prepared by reacting a lower alkyl 4-phenylpiperidine-4-carboxylate with a hydroxyalkyl halide, HO-X-halogen, in particular, ethyl 4-phenyl-1-(3-hydroxypropyl) piperidine-4-carboxylate, as its hydrochloride, is prepared by reacting ethyl 4-phenylpiperidine carboxylate hydrochloride with trimethylene chlorohydrin. Specification 501,135 is referred to.ALSO:Pharmaceutical compositions, in liquid form, e.g. in aqueous or aqueous-ethanol media, or in solid form, e.g. tablet or powder, contain compounds of the general formula <FORM:0810853/VI/1> and their acid addition salts, where "lower" indicates 1-6 carbon atoms in the group, X is a divalent alkylene group containing 2-6 carbon atoms and whose valency bonds are on different carbon atoms, Z is O, S, SO, SO2, NH or N (lower alkyl) and Ar is a mono cyclic aryl radical containing six ring atoms and includes a phenyl radical substituted by nitro, amino (lower alkyl) amino di- (lower alkyl) amilno, (lower alkanoyl amino, lower alkoxy, ower alkylmercapto,) lower alkylsulphonyl, lower alkyl, hydroxy or halo.  Tablets may be prepared using conventional excipients, and powders may be compounded in capsule form. Specification 501,135, [Group IV], is referred to.