Patent GB-851373-A (GB)
Title: Improvements in or relating to amines
Inventor: COLLINS RAYMOND FREDERICK
Filed: 1957-09-26
Abstract: The invention comprises therapeutic compounds of the formula : <FORM:0851373/IV(b)/1> and acid addition salts thereof, wherein R1 and R2 are hydrogen or alkyl or hydroxyalkyl groups of up to four carbon atoms, e.g. methyl or hydroxyethyl, R is alkyl, aryl, substituted aryl or aralkyl, R3 is hydrogen, methyl or methoxyl, Y is a -CO-, -CHOH- or -CH(O Acyl)-group and n is an integer from 1-9, preferably 4, 5 or 6.  The compounds are made by, (a) reacting a compound <FORM:0851373/IV(b)/2> with a compound Q-(CH2)n-Y-R wherein Z is a p  tertiary amino group or a group convertible to a primary, secondary or tertiary amino group R1R2N-, Q is a reactive ester group, e.g. a halogen atom or a methane sulphonate group and M is an alkali metal, followed by conversion of Z if required, or (b) except when n = 1, reacting a compound of the formula <FORM:0851373/IV(b)/3> with a compound of the formula M-Y1 wherein Y1 is a group convertible into (CH2)m,CO,\R, (CH2)m,CHOH,R or (CH2)m,CHO Acyl,R and the sum of m and p is equal to n, followed by conversion of Y1 and of Z if required.  Suitably Z may be: as a group convertible to primary amino; acylamino, nitro, carbonamido, alkoxycarbonylamino or arylazo; as a group convertible to secondary amino; acyalkylamino (by hydrolysis) or acylamino (by reduction); and as a group convertible to tertiary amino; quaternary ammonium (by pyrolysis) and acylalkylamino (by reduction).  Suitably Y1 may be the group -CH(CO,C6H5),COOC2H5, convertible to CH2COC6H5 by ketonic hydrolysis. Products containing primary or secondary amino groups may be converted to secondary or tertiary amines by the known methods.  The products are used in the treatment of bitharziasis, suitably in the form of their acid addition salts such as the hydrohalides, phosphates, sulphates, methanesulphonates and isethionates.  Examples describe the preparation of a -p-aminophenoxy o -benzoylalkanes; a -(p - amino - o - methoxy - phenoxy) o -benzoyl-alkanes; corresponding alcohols formed by reduction and acetyl derivatives thereof; b  - (p - amino - o - methoxy - phenoxy) a -methyl (and a -phenyl)-ethanol; and 1-(pdimethylamino- and p-hydroxyethylamino omethoxyphenoxy)-4-benzoyl-butane.  a -p-Nitrophenoxy-o -acyl (e.g. benzoyl or acetyl) alkanes and the corresponding alcohols obtainable by reduction and acetyl derivatives thereof, used as intermediates are prepared by methods (a) and (b) above (Z = NO2).  1 - (p - Acetamido - o - methoxy - phenoxy) - 4 - benzoyl-butane is made by the action of 4-benzoylbutyl bromide on o-methoxy-p-acetamidophenol and also by acetylating the corresponding amine.  1 - (4 - Dimethylamino - 2 - methoxy - phenoxy) - 4-benzoyl-butane methiodide is made by the action of methyl iodide on 1-(4-amino-2-methoxyphenoxy)-4-benzoyl butane.  1 - (4 - b  - Chloroethoxycarbonylamino - 2 - methoxyphenoxy)-4-benzoylbutane is made by the action of chloroethyl chloroformate on 1-(4-amino-2-methoxyphenoxy)-4-benzoyl butane. 4-Benzoyl-1-methanesulphonyloxy butane is made by the action of methane sulphonyl chloride on 4-benzoyl butanol.  6-Benzoylhexyl bromide is made by reaction of 1 : 5-dibromopentane with ethyl benzoylacetate followed by cleavage with 50% hydrobromic acid. 5-Benzoylpentyl bromide is made by cleavage of 1-p-methoxyphenoxy-5-benzoyl pentane with hydrobromic acid. p-Methoxyphenoxy-5-benzoylpentane is made by treating ethyl benzoyl acetate with 4-p-methoxyphenoxy-butyl bromide and decomposing the resulting ethyl a -4-p-methoxyphenoxy-butyl-a -benzoyl acetate. Ethyl 2-(4-p-nitrophenoxybutyl-2-benzoyl acetate is made by treating 4-p-nitrophenoxybutyl bromide with ethyl benzoyl acetate.ALSO:Preparations for the treatment of bilharziasis comprise compounds of the formula:  <FORM:0851373/VI/1> and acid addition salts thereof, wherein R1 and R2 are hydrogen or alkyl or hydroalkyl groups of 1-4 carbon atoms, e.g. methyl or hydroxyethyl, R is alkyl, aryl, substituted aryl or aralkyl, R3 is hydrogen, methyl or methoxyl, Y is a -CO-, -CHOH- or -CH(Oacyl)-group and n is an integer from 1-9, preferably 4, 5 or 6 (see Group IV(b)) and a pharmaceutical carrier.  The preparations may suitably be in the form of solutions, suspensions, elixirs, emulsions, capsules, powders or tablets for oral administration, for example compressed powders or tablets may contain the active compound admixed with diluents such as starch, lactose, stearic acid, magnesium stearate or dextrin. Preparations for parenteral administration may suitably take the form of solutions or suspensions in water or other liquids.