Patent GB-1119886-A (GB)
Title: Analgesic compositions
IPC: A61K31/34
Filed: 1966-07-08
Abstract: 4 - (Di - lower alkyl) - aminomethyl - 2 - (lower alkyl) - 1,3 - dioxolanes, 4 - piperidinomethyl - 2,2-diphenyl-1,3 -dioxolane and 4-morpholino-methyl-2,2-dimethyl-1,3-dioxolane are prepared by the method of Specification 601,612 which teaches treatment of the corresponding 4-halomethyl derivative with a secondary amine. Substituted dioxolanes of Formula I <FORM:1119886/C2/1> where R1 and R2 are lower alkyl, or -NR1R2 is a heterocyclic radical, R3 is hydrogen, lower alkyl or phenyl, and R4 is lower alkyl or phenyl, and wherein the phenyl groups may be substituted by one or more halogen atoms, lower alkyl or lower alkoxy groups, are obtained by reacting a 4-chloromethyl compound with a secondary amine.  Compounds of Formula I above wherein the 2-position bears a single substituent or two different substituents may be resolved into their pure isomeric forms, or these isomeric forms may be synthesized, e.g. D-, L- or DL-mannitol is treated with acetone and zinc chloride, the corresponding D-, L- or DL-isomer of 1,2,5,6-di-isopropylidene mannitol thus obtained is treated with lead tetra-acetate in the presence of sodium borohydride, the L-, D- or LD-isomer of isopropylidene glycerol thus formed is treated with p-toluene sulphonyl chloride and the tosylate obtained treated with acetaldehyde to form L-, D- or LD-4-hydroxymethyl-2-methyl-1,3 -dioxolane as a mixture of the cis- and trans-stereoisomers. Treatment with dimethylamine yields the cis-trans-D-, cis-trans-L-, or cis-trans-D,L-4-dimethylaminomethyl - 2 - methyl - 1,3 - dioxolane, the cis- and trans-isomers being separated by distillation, the low-boiling fraction being designated the cis-isomer.ALSO:An analgesic composition comprises a substituted 1, 3-dioxalane having the formula <FORM:1119886/A5-A6/1> wherein R1 and R2 are lower alkyl groups or when linked together with the amino nitrogen atom form a heterocyclic radical such as the pyrrolidino, piperidino, morpholino, piperazino, or thiomorpholino radical, wherein R3 is hydrogen, a lower alkyl group or a phenyl group; R4 is a lower alkyl group or a phenyl group; said phenyl groups when present optionally bearing one or more lower alkyl, lower alkoxy or halo groups ("lower" indicating both straight and branched chain radicals containing from 1 to 6 carbon atoms); together with one or more pharmacologically active analgesic components (e.g. phenacetin), or an N-lower alkyl-4-phenyl-4-carbo lower alkoxy piperidine, wherein the phenyl group may bear one or more lower alkyl, lower alkoxy or halo substituents (e.g. N-methyl-4-phenyl-4-carbethoxy piperidine). The composition may also include caffeine or aspirin or a mixture thereof.  The substituted 1, 3-dioxolane may be present as a salt of hydrochloric, phosphoric, sulphuric, citric or maleic acids; and the N-lower alkyl-4-phenyl-4-carbo lower alkoxy-piperidine may be present as a non-toxic pharmaceutically acceptable salt e.g. the hydrochloride.  The compositions may be in unit dosage forms such as tablets, suspensions, solutions and suppositories and may be p administered orally, parentally or rectally.  Preferred substituted 1, 3-dioxolanes are 4-dimethylaminomethyl-2-methyl-1, 3-dioxolane and various isomers thereof, 4-piperidinomethyl-2, 2-diphenyl-1, 3-dioxolane and 4-morpholinomethyl-2, 2-dimethyl-1, 3-dioxolane.