Analgesic 1,2,4,5-tetra-alkyl-4-arylpiperidines

#4-Arylpiperidines have long been recognized as a valuable class of compounds capable of effecting the central nervous system in animals. Several 4-phenylpiperidines having various substituents attached to the piperidine ring are known. McElvain et al., for example, disclose a number of 1-methyl-4-alkyl-4-arylpiperidines in U.S. Pat. No. 2,892,842. In J. Am. Chem. Soc., 80, 3915-3923 (1958), McElvain et al. reported the preparation of 1,3,4-trimethyl-4-(2-methoxyphenyl)piperidine as a bi-product in the synthesis of a 1,4-dialkyl-4-arylpiperidine. A number of 1,2,3-trialkyl-3-arylpiperidines have been reported as analgesic drugs, see U.S. Pat. Nos. 3,043,845 and 2,892,842. Similarly, various 1-aroyl-3,4-dialkyl-4-arylpiperidines have been reported to be useful as central nervous system depressants, U.S. Pat. No. 3,080,372. It recently has been discovered that not only is an alkyl group located in the piperidine 3-position important for unique biological activity, but also that separation of optical isomers provides compounds displaying narcotic agonist activity and mixed agonist-antagonist activity, see U.S. Pat. No. 4,081,450.

#An object of this invention is to provide 4-arylpiperidines which are more highly substituted in the piperidine ring than any of the prior art compounds.

#This invention provides 1,2,4,5-tetra-alkyl-4-arylpiperidines which are useful as analgesics. The invention is more particularly directed to 4-phenylpiperidines having the formula: ##STR1## wherein: R.sup.1 is hydrogen, hydroxy or methoxy;

#In an effort to more fully illustrate the operation of this invention, the following detailed examples are provided. The examples are illustrative only and are not intended to limit the scope of the invention.

#A solution of 5.2 g. of 1,4,5-trimethyl-4-(3-methoxyphenyl)piperidine in 100 ml. of five percent aqueous acetic acid containing 34.2 g. of mercuric acetate was heated to 85.degree. C. and stirred for eight hours. The reaction mixture next was cooled to room temperature and filtered. The filtrate was stirred and saturated with excess hydrogen sulfide for twenty-five minutes, and then stirring was continued for an additional thirty minutes. After filtering the reaction mixture twice through super flow filter aid, the filtrate was made alkaline with fifty percent sodium hydroxide. The alkaline solution was extracted several times with diethyl ether, and the ethereal extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure afforded 4.11 g. of the product as an oil. The oil was distilled to provide 2.0 g. of 1,4,5-trimethyl-4-(3-methoxyphenyl)-1,4,5,6-tetrahydropyridine. B.P. 114.degree.-118.degree. C. at 0.1 torr.

#To a stirred solution of 19.6 g. of 1,4,5-trimethyl-4-(3-methoxyphenyl)-1,4,5,6-tetrahydropyridine in 200 ml. of ethyl acetate containing 5 ml. of ethanol was added in one portion 10 g. of tetrafluoroboric acid-diethyl ether complex. The precipitate which formed was collected by filtration and recrystallized from 200 ml. of ethyl acetate and 5 ml. of ethanol to provide 9.43 g. of 1,4,5-trimethyl-4-(3-methoxyphenyl)-3,4,5,6-tetrahydropyridinium tetrafluoroborate. M.P. 126.5.degree.-129.degree. C.