Patent GB-776690-A (GB)
Title: New quaternary tropeine compounds and processes for their preparation
Filed: 1955-03-03
Abstract: The invention comprises compounds of the formula <FORM:0776690/IV(b)/1> where R is straight or branched chain alkyl or alkenyl of 7-11 carbon atoms, or cycloalkylalkyl or cycloalkenyl-alkyl, R1 is an acyl radical containing an aromatic ring and X is a non-toxic anion.  These are made by reacting tropine or an R-substituted nortropine with an acid R1OH (or reactive derivative thereof) and a quaternating agent RX or CH3X in either order.  The quaternization is preferably carried out in a strongly polar solvent such as acetonitrile or formamide or an excess of the quaternating agent.  It may be effected at room temperature (several days to several months) or with gentle warming up to 60 DEG  C. (several hours to two weeks).  Stereoisomers around the N atom are obtained according to the order in which the R and CH3 radicals are introduced.  Examples show the preparation of compounds where R is heptyl, octyl, 2-ethylhexyl, nonyl, decyl, undecyl, undecenyl and b -cyclohexylethyl and R1 is benzoyl, salicyloyl, mandelyl, tropyl, benziloyl, diphenylacetyl, a -phenylcinnamoyl, N-phenylglycinyl, xanthene-9-carboxyl, 2-furoyl, nicotinoyl, isonicotinoyl and 2:6-dichloro-isonicotinoyl.  In a further example the benzilic ester of tropine (or hydrochloride salt thereof) is converted by thionyl chloride to the diphenylchloroacetyl ester and thence by ethanol to the diphenyl-ethoxyacetyl ester, which is finally quaternated with octyl bromide.  In all the above X is bromide except for the N-octyl tropyl derivative where the chloride and iodide are also mentioned. Hydrochloride salts of the intermediate tertiary bases are described. Other suitable groups for R are 2-methyl-3-methylpentyl, 2:2-dimethylpentyl, 2:2:4-trimethyl-pentyl, 2:6-dimethyloctyl, 3-heptenyl, 4-ethyl-2 - hexenyl, 4 - ethenyl - heptyl and b  - 2 - cyclohexenyl-ethyl. Other acyl residues R1 are those of a -phenoxy-phenylacetic, a -thienyl-phenylacetic, a  - thienyl - phenyl - glycollic, o-benzoylbenzoic, fluorene - 9 - carboxylic, cyclohexyl - phenylacetic, cyclohexyl - phenylgly - collic and a -naphthylacetic acids.  The anion X may be halide, sulphate or toluene-p-sulphonate. The starting materials are made by reacting succindialdehyde, acetone-dicarboxylic acid and ammonia or an alkylamine of 7-11 carbon atoms and reducing the resulting nortropinone or N-alkyl-nortropinone to the nortropine or N-alkyl-nortropine.ALSO:Tropine derivatives of the formula <FORM:0776690/VI/1> where R is straight or branched chain alkyl or alkenyl of 7-11 carbon atoms, or cycloalkyl-alkyl or cycloalkenyl-alkyl, R1 is an acyl radical containing an aromatic ring (which may be part of a heterocyclic system) and X is a non-toxic anion, are made into tablets, pills, dragees, powders, capsules, solutions, suspensions or dispensions for oral, subcutaneous, intramuscular or tpical administration with the usual diluents, binders and lubricants, e.g. sugar, lactose, talcum, starch, pectin, gelatin, gum arabic, methyl cellulose, yeast extract, agar and tragacanth, or dissolved in water or physiological salt solution.