Patent GB-812360-A (GB)
Title: New aromatic esters and pharmaceutical preparations containing them
Filed: 1955-07-13
Abstract: The invention comprises esters of benzoic acid or ortho-hydroxy-benzoic acid substituted in the para position by a group Y-NH, wherein Y is an alkyl, oxa-alkyl, cycloalkyl or cycloalkyl-alkyl radical of 4 to 7 carbon atoms with poly-(1 : 2) glycols of the formula <FORM:0812360/IV (b)/1> in which n is a whole number greater than 7, R is hydrogen or a C1-4 alkyl radical, and the symbols R1 are hydrogen or a C1-4 alkyl or alkoxyalkyl radical, provided that, in at least n/2 and at most n-1 groups -C2H3(R1)-O-, R1 is hydrogen.  The esters may be prepared by reaction of a lower alkyl ester of the appropriately substituted benzoic acid with a polyglycol of the above formula, preferably in the presence of a transesterification catalyst such as an alkoxide.  The invention also includes poly-(1 : 2)-glycol ester mixtures in which n has an average value, and these may be purified and separated into their components by methods such as counter current extraction or high vacuum or molecular distillation.  Examples describe the preparation of the following compounds: the esters of para-(n-butylamino)-benzoic acid with heptaethylene glycol-o -methyl ether - o 1 - [2 - hydroxy - n - propyl ether-(1)], the corresponding nona-ethylene glycol, octa-ethylene glycol-o -methyl ether-o 1-[2 - hydroxy - 3 - ethoxy - propyl ethyl - (1)], hepta - ethylene glycol - o :o 1 - di - [2 - hydroxy - n - propyl - ether - (1)] and a polyether alcohol of the formula <FORM:0812360/IV (b)/2> wherein n has an average value of 12 and (n+y) one of 16; the mono-ester of p-(n-hexyl-amino) benzoic acid with heptaethylene-glycol-o :o 1-di - 2 - hydroxy - n - propyl ether - (1); the ester of p-(n-butylamino) salicylic acid with an ether of the formula <FORM:0812360/IV (b)/3> where n has an average value of 12; the ester mixture of the formula <FORM:0812360/IV (b)/4> of average molecular weight 880, and the corresponding N-cyclohexyl ester mixture of average molecule weight 866; and an ester of the formula <FORM:0812360/IV (b)/5> of average molecular weight 1009. Starting materials.  Polyether-alcohols <FORM:0812360/IV (b)/6> may be prepared by condensing a polyethylene glycol <FORM:0812360/IV (b)/7> with y mols. of an ethylene oxide <FORM:0812360/IV (b)/8> and the product may be further condensed with ethylene oxide to give a polyethylene glycol <FORM:0812360/IV (b)/9> By the use of differently substituted ethylene oxides in several successive reaction stages the several substituents R1 can be distributed in any desired manner in the polyethylene glycol chain.  Alternatively a substituted polyethylene glycol monoalkyl ether <FORM:0812360/IV (b)/100> may be condensed with ethylene oxide.  In the examples the following compounds are formed by the above methods: an ether of the formula <FORM:0812360/IV (b)/111> wherein n has an average value of 12 and (n + y) one of 16 and a similarly constituted compound having an average molecular weight of 674, an ether of the formula <FORM:0812360/IV (b)/122> in which n has an average value of 12 and an ether of the formula <FORM:0812360/IV (b)/133> of average molecular weight 760. Polyetheralcohols may also be synthesized by reacting a reactive ester, such as a benzene sulphonate, of an ether alcohol with an alkali metal salt of an ether alcohol.  In examples illustrating this method of procedure: (1) the benzene sulphonic acid ester of diethylene glycol monomethyl ether with triethylene glycol and sodium gives penta ethylene glycol monomethyl ether, this with benzene sulphochloride gives a benzene sulphonic acid ester, the latter with diethylene glycol gives heptaethylene glycol monomethyl ether, this is then converted to its benzene sulphonic acid ester and the latter with 1 : 2-propylene glycol gives heptaethylene glycol-o -methyl ether - o 1 - [2 - hydroxy - n - propylether - (1); nonaethylene glycol - o  - methyl ether - o 1 - [2 - hydroxy - n - propyl ether - (1)] is similarly prepared from nona-ethylene glycol methyl ether, itself prepared from the benzene sulphonic acid ester of heptaethylene glycol monomethyl ether and diethylene glycol; (2) octa - ethylene glycol - o  - methyl ether - o 1 - [2-hydroxy - 3 - ethoxy - propyl ether - (1)] is prepared by reacting the benzene sulphonic acid ester of octa ethylene glycol monomethyl ether (itself prepared by reacting pentaethylene glycol monomethyl ether benzene sulphonate with triethylene glycol and reacting the resulting octaethylene glycol monomethyl ether with benzene sulphochloride) with glycerine-o -ethyl ether; (3) triethylene glycol with benzene sulphochloride gives a dibenzene sulphonic acid ester of triethylene glycol which with diethylene glycol gives heptaethylene glycol and some dodecaethylene glycol; the former is converted to its dibenzene sulphonic acid ester and this with 1 : 2-propylene glycols gives hepta-ethylene glycolo :o 1 - di - [2 - hydroxy - n - propyl ether - (1)]; (4) 2 - (a  : a 1 - dimethoxy - iso - propoxy) - ethanol is prepared from a  : a 1-dimethoxybenzene sulphonate and ethylene glycol.  Further starting materials.  Para-hexyl-amino benzoic acid ethyl ester is prepared from n-hexyl bromide and ethyl p-aminobenzoate in the presence of copper powder; para-hexahydrobenzylamino benzoic acid ethyl ester is prepared from ethyl-p-aminobenzoate and hexahydrobenzaldehyde with zinc dust in acetic acid; para-cyclohexylamino benzoic acid ethyl ester is prepared from bromocyclohexane and ethyl-p-amino benzoate; para-(2-butoxyethylamino) benzoic acid ethyl ester is prepared from ethyl-p-aminobenzoate and 2-butoxyethyl benzene sulphonate, the latter being prepared from ethylene glycol monobutyl ether and benzenesulphochloride.ALSO:A pharmaceutical preparation suitable for enteral, parenteral or oral administration contains an ester of benzoic acid or parahydroxybenzoic acid substituted in the para-position by the group Y-NH, in which Y is an alkyl, oxaalkyl, cycloalkyl or cycloalkylalkyl radical containing 4 to 7 carbon atoms with a poly-(1 : 2 glycol of the formula <FORM:0812360/VI/1> in which n is a whole number greater than 7, R is hydrogen or a C1-4 alkyl radical, and the symbols R1 represent hydrogen or a C1-4 alkyl or alkoxyalkyl radical, provided that, in at least n/2 and at most n - 1 groups -C2H3(R1) -0-, R1 is hydrogen, in admixture with a pharmaceutical carrier.  Suitable carriers include water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum and cholesterol.  The pharmaceutical preparations may be made up as tablets, dragees, solutions, suspensions or emulsions and they may be sterilized and/or contain auxiliary substances, such as preserving agents, stabilizing agents, wetting or emulsifying agents, salts for regulating the osnotic pressure or buffers, and also other therapeutically valuable substances.  In the examples a syrup is prepared from the ester of para-n-butyl-amino-benzoic acid with hepta-ethylene-glycol - o  - methyl ether - o 1 - [2 - hydroxy - n-propyl ether-(1)], sugar, parahydroxy benzoic acid ethyl ester, sodium carboxymethyl cellulose, citric acid, oil of lemon, vanillin, artificial banana essence, "Tween 20" (Registered Trade Mark) and de-ionized water and ampules are made up from the ester of para-n-butyl-amino-benzoic acid with octa-ethylene-glycol-o -methyl ether - o 1 - [2 - hydroxy - 3 - ethoxy-propyl ether-(1)], sodium chloride and distilled water.