Patent GB-777758-A (GB)
Title: Improvements in or relating to aryl carbamate esters of arylamino alcohols and acid addition salts thereof, and process for preparing the same
IPC: C07C271/06
Filed: 1955-02-25
Abstract: The invention comprises compounds of the formula <FORM:0777758/IV(b)/1> where Ar is a phenyl, alkylphenyl, alkoxyphenyl or halophenyl radical, one of the radicals R1 and R2 is hydrogen or a straight chain saturated hydrocarbon radical having from 1 to 4 carbon atoms and the other is an aryl carbamyloxy group ArNHCOO- in which Ar is a phenyl, alkylphenyl, alkoxyphenyl or halophenyl radical and Am is a di-lower-alkylamino radical having 2-8 carbon atoms, or a saturated monocyclic heterocyclic radical attached through the nitrogen atom; and their acid addition salts.  The compounds are made by treating the corresponding carbinols <FORM:0777758/IV(b)/2> <FORM:0777758/IV(b)/3> (wherein R is hydrogen or a straight chain saturated hydrocarbon radical) with an aromatic isocyanate and if desired converting the resulting base into an acid addition salt.  Suitably, the radical Ar may be phenyl, tolyl, ethylphenyl, chlorophenyl or anisyl radical, Am may be an amino group substituted by methyl, ethyl or n-propyl radicals or may be a piperidino, pipecolino, pyrrolidino, methylpyrrolidino, lupetidino or ethylpiperidino group.  The compounds may be used as local anaesthetics, suitably in the form of their acid addition salts with non-toxic acids such as hydrochloric, hydrobromic, sulphuric, maleic, citric, tartaric, formic and phosphoric acid.  In examples, phenyl isocyanate is reacted with the appropriate arylalkanolamine to give (1) 1-phenylcarbamyloxy - 3 - dimethylamino - 1 - phenylpro - pane; (2) 1 - phenylcarbamyloxy - 3 - piperi - dino - 1 - phenylpropane; (3) 1 - phenylcarbamyloxy - 2 - methyl - 1 - phenyl - 3 - piperi - dinopropane (obtained as two diastereoisomeric pairs m.pt. 223-224 DEG  C. and 229-230 DEG  C. respectively); (4) 1-phenylcarbamyloxy-3-diethylamino - 2 - methyl - 1 - phenylpropane; (5) 2 - phenylcarbamyloxy - 3 - diethylamino - 1 - phenylpropane, and (6) 2-phenylcarbamyloxy-1-phenyl - 3 - (2 - pipecolino) - propane; the above products being isolated as their hydrochlorides.  Many other carbamates which may be prepared according to the invention are specified.  Starting materials.  1-Aryl-3-amino-propan-1-ols of the formula I above are made by reducing the corresponding ketone Ar.Co.CH(R).CH2.Am (obtainable by treating a ketone Ar.CO.CH2.R with formaldehyde and an amine H-Am.), suitably by reaction with lithium aluminium hydride, platinum and hydrogen or sodium and butanol.  This process is used for the preparation of 3-dimethylamino-1-phenylpropan - 1 - ol; 1 - phenyl - 3 - piperidinopropan-1 - ol; 1 - phenyl - 2 - methyl - 3 - piperidinopropropan-1-ol (two diastereoisomeric pairs) and 1-phenyl-2-methyl-3-diethylamino-propan-1-ol. 1-Aryl-3-amino-propan-2-ols of the formula II above are made by treating a 2:3-epoxy-1-aminopropane with an aryl Grignard reagent. For example 3-diethylamino-1-phenyl-propan-2-ol and 1-phenyl-3-(2-pipecolino)-propan-2-ol are made by treating the corresponding epoxyaminopropanes with phenyl magnesium bromide and hydrolysing the product.ALSO:Local anaesthetics comprise compounds of the formula <FORM:0777758/VI/1> (see Group IV(b)) wherein Ar is a phenyl alkylphenyl, alkoxyphenyl or halophenyl radical, one of the radicals R1 and R2 is hydrogen or a straight chain saturated hydrocarbon radical of 1 to 4 carbon atoms and the other is an aryl carbamyloxy group Ar - NH - CO - O - in which Ar is a phenyl, alkylphenyl, alkoxyphenyl or halophenyl radical, and Am is a di-lower-alkylamino radical of 2 to 8 carbon atoms or a saturated monocyclic heterocyclic amino radical attached through the nitrogen atom, and their acid addition salts, preferably suspended in an ointment or cream base, for topical administration.  An example describes a cream comprising stearic acid, glycerin, cetyl alcohol, sorbitan monostearate, ethyl, p - hydroxybenzoate, sodium lauryl sulphate, polyoxyethylene sorbitan monostearate, sodium phosphate, 1 - phenylcarbamyloxy - 3 - dimethylamino - 1 - phenylpropane hydrochloride and distilled water.  Many other aminoalkyl carbamates of the above general formula are specified.