Patent GB-849282-A (GB)
Title: Pharmaceutical compositions comprising substituted 1,2,3,6-tetrahydropyridines
Inventor: WRAGG WILLIAM ROBERT
IPC: C07D211/48
Filed: 1957-08-27
Abstract: Compounds of general formula: <FORM:0849282/IV(b)/1> wherein R1 is hydrogen or a lower alkyl group (1 to 4 carbon atoms), R2, R21, R6 and R61 each represents a lower alkyl group and R3, R4 and R5 which may be the same or different each represents a hydrogen atom or a lower alkyl group are prepared by known methods for the conversion of 4-piperidinols into the corresponding 1 : 2 : 3 : 6-tetrahydropyridines, e.g. by heating with 50% sulphuric acid from compounds of general formula:  <FORM:0849282/IV(b)/2> Compounds of general formula II may themselves be prepared from compounds of general formula: <FORM:0849282/IV(b)/3> by known methods of alkylation, e.g. by heating with aqueous formaldehyde when R1=methyl, compounds of general formula III being obtainable by conversion, by known methods, of the carbonyl group in compounds of general formula: <FORM:0849282/IV(b)/4> into a carbinol group, e.g. by reaction with a Grignard reagent. Compounds of formula II wherein R4=ethyl may also be prepared from compounds of general formula: <FORM:0849282/IV(b)/5> by known methods for the reduction of an ethynyl group to an ethyl group, e.g. by catalytic hydrogenation, compounds of formula V wherein R1 is an alkyl group other than methyl being obtainable by alkylation by known methods of compounds of general formula:  <FORM:0849282/IV(b)/6> Compounds of formula I which are tertiary amines (R1=alkyl may be prepared from the corresponding secondary amine (R1=H) by known methods whereby alkylation is achieved without concomitant reaction with the 4 : 5 double bond, e.g., by using an alkylating agent in the form of a reactive ester, e.g. methyl iodide or methyl-p-toluenesulphonate in the presence of an acid binding agent.  Specific examples relate to the preparation of 4-ethyl-1 : 2 : 2 : 6 : 6-pentamethylpiperidin-4-ol and its conversion to 4-ethyl-1 : 2 : 2 : 6 : 6:-pentamethyl-1 : 2 : 3 : 6 - tetrahydropyridine; the preparation of 1 : 2 : 2 : 6 : 6 - pentamethyl-1 : 2 : 3 : 6-tetrahydropyridine; 2 : 2 : 6 : 6-tetramethyl-1 : 2 : 3 : 6-tetrahydropyridine, 2 : 6-diethyl-2 : 3 : 6-trimethyl-1 : 2 : 3 : 6-tetrahydropyridine and 1 : 2 : 2 : 4 : 6 : 6-hexamethyl-1 : 2 : 3 : 6-tetrahydropyridine by the same method; the preparation of 2 : 2 : 4 : 6 : 6-pentamethylpiperidin-4-ol from 2 : 2 : 6 : 6-tetramethylpipirid-4-one and conversion of its hydroiodide to 2 : 2 : 4 : 6 : 6-pentamethyl-1 : 2 : 3 : 6 -tetrahydropyridine (hydriodide); the preparation of 4-ethyl-2 : 2 : 6 : 6-tetramethyl-1 : 2 : 3 : 6-tetrahydropyridine (hydroiodide) by the same method; the preparation of 1-ethyl-2 : 2 : 6 : 6-tetramethylpiperidin-4-ol and its converstion to 1-ethyl2 : 2 : 6 : 6-tetramethyl-1 : 2 : 3 : 6-tetrahydropyridine.ALSO:A hypotensive composition for oral and parenteral use comprises a pharmaceutical carrier and at least one tetrahydropyridine of the planar formula:-  <FORM:0849282/VI/1> wherein R1, R3, R4 and R5 are hydrogen atoms or lower alkyl groups (having from 1 to 4 carbon atoms) and R2, R21, R6 and R61 are lower alkyl groups, and salts thereof, for example phosphates, nitrates, sulphates, 8-chlorotheophyllinates, maleates, fumarates, citrates, tartrates, methane sulphonates, ethane disulphonates and hydrohalides, e.g. hydrochlorides.  Specified compounds of the above general formula are the 1,2,2,6, 6-pentamethyl; 2,2,6,6-tetramethyl; 1,2,2,4,6,6-hexamethyl; 2,2,4,6,6-pentamethyl; 4-ethyl-1,2, 2,6,6-pentamethyl and 4-ethyl-2,2,6,6-tetramethyl -1,2,3,6-tetrahydro-pyridines and their salts.  The compositions may be in solid unit dosage form, e.g. tablets, capsules and powders containing conventional excipients and/or diluents, and generally containing at least 0,1% by weight of the active substance, or in liquid form, e.g. sterile solutions and suspensions, elixirs, syrups and emulsions which may contain soluble or insoluble diluents and/or liquid excipients and at least 0,025% by weight of the active substance in parenteral preparations or 0,1% in oral preparations. The preparation is described of tablets containing each of the specified active substances and of injectable aqueous solutions comprising the hydrochlorides of the 1,2,2,6,6-pentamethyl and 2,2,6,6-tetramethyl derivatives.  A general method of preparation of the active compounds is described (see Group IV(b)].