Patent GB-840446-A (GB)
Title: Improvements in or relating to amines of therapeutic utility
Inventor: COLLINS RAYMOND FREDERICK
Filed: 1957-09-03
Abstract: The invention comprises compounds of the formula <FORM:0840446/IV(b)/1> and acid addition salts thereof, wherein R is an alkyl, aryl, substituted aryl or aralkyl group, R1 and R2 are hydrogen or alkyl or hydroxyalkyl groups of 1-3 carbon atoms, R3 is hydrogen, methyl or methoxy, X represents -S-, -SO- or -SO2- and n is an integer from 3-9.  The compounds are made by: (a) reacting a compound of the formula <FORM:0840446/IV(b)/2> with a compound of the formula Q-(CH2)n-X-R where Z is a tertiary amino group R1R2N or a group convertible to a primary, secondary or tertiary amino group, Q is a reactive ester group, e.g. halogen, methanesulphonate or tosylate and M is an alkali-metal, followed by conversion of Z if required; (b) reacting a compound of the formula <FORM:0840446/IV(b)/3> with a compound of the formula M-X-R followed by conversion of Z if required; (c) when R is alkyl or aralkyl, reacting <FORM:0840446/IV(b)/4> with Q-R followed by conversion of Z if required; (d) by nitrating a compound of the formula <FORM:0840446/IV(b)/5> followed by reduction of the resulting p-nitrocompound to the amine compound and subsequent alkylation or hydroxyalkylation of the amino group if desired; and (e) oxidizing products wherein X is -S- or -SO- to the more highly oxidized form. Suitably Z may be : as a group convertible to primary amino, acylamino, nitro, carbonamido, alkoxycarbonylamido or arylazo; as a group convertible to secondary amino, acylalkylamino (by hydrolysis) or acrylamino by reduction; and as a group convertible to tertiary amino, quaternary ammonium (by pyrolysis) and acylalkylamino (by reduction).  Products wherein R1R2N is a primary amino group may be converted into secondary and tertiary amines by known methods.  The products are used in the treatment of bilharziasis, suitably in the form of acid addition salts such as the hydrohalides, phosphates, sulphates, methanesulphonates and isethionates.  Examples describe the preparation of 5-phenylthio-, 5-benzylthio- and 5-p-aminophenylthio-, p-aminophenoxypentane; 5-phenylthio -, 5 - p - chlorophenylthio and 5-methylthio -, o - methoxy - p - amino - phenoxypentane; 5 - phenylthio - 1 - (o - methoxy-p - dimethylamino (and p - hydroxyethylamino) - phenoxy) - pentane; 1 - (p - amino-o - methoxyphenoxy) - 3 - phenylthio - propane and analogous sulphones and sulphoxides such as 5-p-aminophenoxy-pentyl-p-acetamido-phenyl sulphone.  p - Nitrophenoxyalkyl thio-ethers corresponding to the aminophenoxy thio-ethers of the examples are obtained as intermediates and also p-nitrophenoxyalkyl sulphones and sulphoxides such as p-nitrophenoxy-pentyl phenyl sulphone and sulphoxide, p - nitrophenoxypentyl p - acetylaminophenyl sulphone and p-nitro - o - methoxyphenoxypentyl phenyl sulphone.  1 - (p - b  - Chloroethoxycarbonylamino - o-methoxyphenoxy) - 5 - phenylthiopentane is made by the action of chloroethyl chloroformate on 1 - (o - methoxy - p - amino - phenoxy) - 5-phenylthio-pentane.  1 - (p - Dimethylamino - o - methoxyphenoxy)-5 - phenylthio - pentane methiodide is made by the action of methyl iodide on the primary base.  3 - Phenylthiopropyl bromide is made by the action of 1 : 3-dibromopropane on thiophenol.  5 - o - Methoxy - p - nitrophenoxy - pentyl - thiol is made by treating 5-o-methoxy-p-nitrophenoxy-pentyl bromide with thiourea and hydrolysing the resulting 5-o-methoxy-p-nitrophenoxy-pentyl thiouronium bromide.ALSO:Therapeutic preparations for the treatment of bilharziasis comprise compounds of the formula <FORM:0840446/VI/1> or acid addition salts thereof, wherein R is an alkyl, aryl, substituted aryl or aralkyl group, R1 and R2 are hydrogen or alkyl or hydroxyalkyl groups of 1-3 carbon atoms, R3 is hydrogen, methyl or methoxy, X represents -S-, -SO- or -SO2- and n is an integer from 3 to 9 (see Group IV (b)), in association with a pharmaceutical carrier.  The preparations may take the form of liquids or solids for oral administration as solutions, suspensions, syrups, elixirs, emulsions, powders or tablets, or may take the form of sterile solutions for parenteral administration.