Patent GB-765902-A (GB)
Title: Substituted cyclohexylamines and process for preparing same
Filed: 1954-12-16
Abstract: The invention comprises compounds of the formula <FORM:0765902/IV(b)/1> wherein R1 and R2 are the same or different lower aliphatic (i.e. up to 6 carbon atoms) or aralkyl hydrocarbon radicals, R3 and R4 are the same or different aliphatic hydrocarbon radicals, each having up to 6 carbon atoms, saturated or unsaturated carbocyclic radicals having 5 or 6 carbon atoms in the ring, saturated or unsaturated heterocyclic radicals or aryl aliphatic radicals and wherein R3 and R4 when cyclic may be substituted by chlorine or bromine atoms or by alkyl or alkoxy groups having up to 6 carbon atoms, X is alkyl having up to 6 carbon atoms and n is 0-3, and their non-toxic acid addition and quaternary salts; and their preparation by two methods: (1) when R3=R4, by reacting a Grignard reagent R3MgZ (Z=Cl or Br) or a compound R3Li with the appropriate ester and hydrolysing the product, or (2) by reacting said ester with ammonia at elevated temperature and pressure to form the corresponding amide, dehydrating this to the nitrile, reacting this with one equivalent of a compound R3MgZ or R3Li, hydrolysing the product to give a ketone Xn.NR1R2.C6H8.COR3, reacting this with one equivalent of a compound R4Li or R4MgZ and hydrolysing the product. Acid addition and quaternary salts may be prepared by the usual methods, quaternary alkyl sulphates being conviniently prepared from the alkyl esters of sulphuric acid, e.g. (CH3)2SO4.  Quaternary ammonium iodides may be transformed into the corresponding bromides or iodides by heating in methanol solution with a slight excess of the appropriate silver halide.  In the examples the following compounds and their salts are prepared by the first of the above general methods, using the appropriate Grignard reagent: diphenyl- and a ,a 1-dithienyl-4-dimethylaminocyclohexyl carbinols, the corresponding 3- and 2-dimethylaminocyclohexyl carbinols, diphenyl-(2 - dimethylamino - 3 - methyl) -, diphenyl-3 - methyl - 4 - dimethylamino - and diphenyl-(4 - methyl - 3 - dimethylamino) - cyclohexyl carbinols, and the corresponding a ,a 1-dithienyl compounds and various salts and quaternary compounds thereof, dicyclohexyl- and m,m1-dimethoxydiphenyl - 3 - dimethylaminocyclohexyl carbinols and diethyl-, p,p1-dichlorphenyl-, and p,p1-ditolyl-4-dimethylaminocyclohexyl carbinols. a ,a 1-Dipyridyl-4-dimethylaminocyclohexyl carbinol is prepared from 4-dimethylaminocyclohexylcarboxylate and 2-pyridyl lithium, and with methyl iodide it gives a methiodide. Phenyl-21-pyridyl-4-dimethylaminocyclohexyl carbinol is prepared as follows:-ethyl p-dimethylamino cyclohexyl-carboxylate and ammonia give p-dimethylaminocyclohexylcarboxylic acid amide which with P2O5 gives p-dimethylaminocyclohexyl nitrile and this with phenyl magnesium bromide gives phenyl-p-dimethylaminocyclohexyl ketone; the latter with 2-pyridyl lithium gives the required carbinol: with cyclopenyl- or cyclohexyl-magnesium bromide it gives phenyl-cyclopentyl- or phenylcyclohexyl - 4 - dimethylaminocyclohexyl carbinol. Acetates, propionates, succinates, maleates, tartrate, citrates, benzoates and salicylates of the above bases can be prepared by treating the appropriate quaternary halide with an alkali metal hydroxide and then neutralizing the so-formed quaternary ammonium hydroxide with the appropriate organic acid.  The following compounds are also referred to: propyl-cyclopentyl-2,6-diethyl-, a ,a 1-dipyrrolyl and 2,21-dithiazolidinyl-4-dimethylaminocyclohexyl - carbinols, phenyl - 5 - metathiazolyl- and 2,21-dipyrimidinyl-4-diethylamino-cyclohexyl carbinols, and di-(41-methyl-cyclohexyl) - 3 - (N - ethyl - N - benzyl - amino) - carbinol.  The preparation of dialkylaminocyclohexyl carboxylic acid esters is illustrated by the preparation of ethyl-4-dimethylaminocyclohexyl carboxylate by hydrogenating ethyl p-aminobenzoate and reacting the so-formed ethyl 4-aminocyclohexyl carboxylate with formic acid and formalin. Alternatively ethyl p-dimethylaminobenzoate may be reduced.  In another process diethylaniline gives, with phosgene in the presence of AICl3, p-diethylaminobenzoyl chloride which on hydrolysis, esterification and reduction gives ethyl 4-diethylaminocyclohexyl carboxylate.ALSO:A pharmaceutical composition comprises a cyclohexylamine compound of the formula:-  <FORM:0765902/VI/1> wherein R1 and R2 are the same or different lower aliphatic (i.e. up to 6 carbon atoms) or aralkyl hydrocarbon radicals, R3 and R4 are the same or different aliphatic hydrocarbon radicals each having up to 6 carbon atoms, saturated or unsaturated carbocyclic radicals having 5 or 6 carbon atoms in the ring, saturated or unsaturated heterocyclic radicals or aryl aliphatic radicals, and where in R3 and R4 when cyclic may be substituted by chlorine or bromine atoms or by alkyl or alkoxy groups having up to 6 carbon atoms, X is alkyl having up to 6 carbon atoms and n is 0-3, or a non-toxin acid addition or quaternary salt of such a compound, together with an inert carrier or diluent.  The compositions may be in the form of tablets with or without binders such as gums, sugars or starches, as elixirs containing synthetic flavouring material, as capsules, as injectable solutions with carriers such as water, ethyl alcohol or polyethylene glycol, or as topical ointments or creams.  They are stated to possess antispasmodic and parasympathetic blocking activity.