Patent GB-788585-A (GB)
Title: Monoalkylaminoalkyl esters of substituted benzoic acids
Filed: 1956-03-21
Abstract: The invention comprises esters of the formula (1) <FORM:0788585/IV (b)/1> wherein X is -OR or -NH2, Y is -NH2 when X is OR, or OR when X is NH2, R being an alkyl radical containing up to 8 carbon atoms, R1 is a straight or branched alkylene radical of from 2 to 8 carbon atoms and R11 is a cycloalkyl radical containing up to 8 carbon atoms; and the acid-addition salts thereof.  The esters may be prepared by reacting an alkanol of the formula <FORM:0788585/IV (b)/2> (wherein A is a benzyl or substituted benzyl, benzhydryl, a - or b -menaphthyl, carbobenzoxy or substituted carbobenzoxy, carbo-allyloxy or halocarbobenzoxy group) with a compound of the formula <FORM:0788585/IV (b)/3> (wherein D and E are as X and Y above and additionally may be NO2 in place of NH2 and X is a halogen or an alkoxy group containing up to 8 carbon atoms) and then subjecting the ester so formed to a hydrogen reducing atmosphere to remove A and reduce -NO2 if present to -NH2.  The esters may also be prepared without the intervention of the hydrogenolysable group A.  In examples: (1) 3-nitro-4-n-butoxybenzoyl chloride and 2-(benzyl-n-propylamino) ethanol on refluxing in benzol give 2 - (benzyl - n - propylamino) ethyl 3 - nitro - 4 n-butoxybenzoate hydrochloride which on hydrogenation in presence of palladium on charcoal gives 2 - (n - propylamino) ethyl 3 - amino - 4 - n-butoxybenzoate; (2)-(16) excluding (3) and (8) the following intermediates are prepared similarly: 2-(benzylethylamino) ethyl 2-(benzyl-isopropylamino) ethyl, 2-(benzyl-n-butylamino) ethyl, 2-(benzylcyclohexylamino) ethyl, 3-(benzyl-methylamino)-1-propyl, 1-(benzylmethylamino)-2-propyl, 1 - (benzyl - n - propylamino) - 2 - propyl, and 2-(benzyl-n-propylamino)-1-butyl 3-nitro-4-n-butoxybenzoate hydrochlorides, 2-(benzyl-n-propylamkno)ethyl, 2-(benzyl-n-butylamino) ethyl, and 2-(benzyl-tertiary-octylamino) ethyl 3-nitro-4-ethoxybenzoate hydrochlorides and 2-(benzyl-ethylamino) ethyl and 2-(benzyl-n-propylamino)-ethyl 3- nitro-4-n-propoxybenzoate hydrochlorides, and the corresponding non-benzylated 3-amino compounds then prepared from these as in (1) and isolated as their mono- or di-hydrochlorides; (3) 3-nitro-4-n-butoxybenzoyl chloride and 2-(methylamino) ethanol are heated at 50-55 DEG  C. in chloroform saturated with HCl gas to give 2-(methylamino) ethyl 3-nitro-4-n-butoxybenzoate hydrochloride which on hydrogenation gives 2 - (methylamino) ethyl 3 - amino - 4 - n - butoxybenzoate dihydrochloride; (8) 3-(carbobenzoxycyclohexylamino) - 1 - propanol and 3-nitro-4-n-butoxybenzoyl chloride react as in (1) to give 3-(cyclohexylcarbobenzoxyamino)-1-propyl 3-nitro-4-n-butoxybenzoate hydrochloride which on hydrogenation as in (1) gives 3-(cyclohexylamino) - 1 - propyl 3 - amino - 4 - n - butoxybenzoate dihydrochloride.  It is stated that the isomeric alkylamino alkyl 3-alkoxy-4-aminobenzoates have also been prepared and that these, in addition to the 3-amino-4-alkoxy compounds, possess an sthetic properties.  Starting materials.  Alkylamino - alkanols R11-NH-R1-OH may be prepared by alkylation of aminoalkanols and then converted to compounds of formula (2) wherein A is a benzyl or substituted benzyl radical by catalytic reductive condensation with benzaldehyde or a substituted benzaldehyde.  2 - (Benzylethylamino)- and 2-(benzylisopropyl amino)-ethanols are prepared by this condensation method.  Such compounds (2) may also be prepared by reacting an aminoalkanol with benzaldehyde or a substituted benzaldehyde to form an N-benzylaminoalkanol and thereafter alkylating this, e.g. by reductive condensation with an aldehyde. 2-(Benzyl-n-propylamino)-and 2 - (cyclohexylbenzylamino) - ethanols, 3 - (benzylmethylamino) - 1 - propanol, 1 - (benzylmethylamino) - 2 - propanol, 1 - (benzyl - n - propylamino) - 2 - propanol and 2 - (benzyl - n - propylamino)-1-butanol are prepared by this condensation method. Such compounds (2) may also be prepared by reacting benzylalkylamines with alkylene oxides.  Ethylene oxide and N-benzyl-tertiary-octylamine (prepared by reductive condensation of tertiary-octylamine with benzaldehyde) give 2-(benzyl-tertiary-octylamino) ethanol by this method.  Compounds (2) in which A has the other values referred to above are prepared by reacting the N-alkylaminoalkanol with, for example, carbobenzoxychloride.  3 - (Cyclohexylcarbobenzoxyamino)-1-propanol is prepared by this method.ALSO:Pharmaceutical preparations contain a compound of the general formula  <FORM:0788585/VI/1> (wherein X is -OR or NH2, Y is - NH2 when X is -OR, or -OR when X is -NH2, R being an alkyl radical of up to 8 carbon atoms, R1 is a straight or branched alkylene radical of from 2 to 8 carbon atoms and R11 is a cycloalkyl radical or an alkyl radical of up to 8 carbon atoms) or a water-soluble non-toxic acid-addition salt thereof.  The preparations include sterile solutions, dispersions in an oil, emulsion, jelly, or cream base, either alone or with other therapeutic agents such as antihistamines, sulfa drugs or antibiotics, troches, lozenges and mixtures with suitable pharmaceutical carriers.  Examples describe preparations containing: (1) 2 -(ethylamino)ethyl 3 - amino - 4 - n - butoxy-benzoate hydrochloride, benzyl alcohol and water; (2) 2-(ethylamino)ethyl 3-amino-4-n-propoxybenzoate hydrochloride, methocel, propylene glycol and water; (3) 2-(n-propylamino) ethyl 3 - amino - 4 - n - propoxybenzoate hydrochloride, propylene glycol and carbowax; and (4) an isotonic solution containing the active ingredient of (1).