Patent GB-778919-A (GB)
Title: Improvements in or relating to substituted p-aminophenyl ethers
Inventor: ASHLEY JULIUS NICHOLSON
IPC: C07C335/18
Filed: 1954-09-25
Abstract: The invention comprises compounds of the formula: <FORM:0778919/IV(b)/1> and salts thereof, where R1 and R2 represent hydrogen or an alkyl, hydroxyalkyl or alkoxyalkyl group of not more than 6 carbon atoms, A represents a saturated or unsaturated hydrocarbon chain of not less than 3 and not more than 9 carbon atoms, which may be unbranched or may be substituted by one or more alkyl groups, and either R3 represents the group OR4 and Z represents an oxygen atom, or R3 represents the group NR5R6 and Z is oxygen or sulphur, R4 being an alkyl group of up to 6 carbon atoms and R6 and R5 being either hydrogen atoms or alkyl groups of up to 6 carbon atoms or aryl or substituted aryl groups.  The compounds are prepared either by reaction of a compound of the general formula: <FORM:0778919/IV(b)/2> with a compound of the general formula Q-A1-NH-CZR3, wherein X is the group -NR1R2 or a group convertible thereto, M represents an atom of hydrogen or an alkali metal, Q represents the radical of a reactive ester, such as a halogen atom, A1 is the group A or a corresponding less saturated chain, followed if necessary by treatment of the product to convert X to -NR1R2 and A1 to A or by treating a compound of the formula: <FORM:0778919/IV(b)/3> where X and A1 are as defined above and Y is a group convertible to the group NH.CZR3 to effect the said conversion and if necessary converting the groups X and A1 to -NR1R2 and A respectively.  Convertible groups represented by X comprise (a) groups convertible to primary amino groups: acylamido, carbonamido, alkoxycarbonylamido and anil (by hydrolysis), nitro, nitroso and arylazo (by reduction; (b) groups convertible to secondary amino groups: anil, alkoxycarbonylamido and acylamido (by reduction) and acylalkylamido by hydrolysis. Convertible groups represented by g are: (a) for the preparation of ureas and thioureas: primary and secondary amino groups (by treatment with cyanic or thiocyanic acids or their alkali metal salts or isocyanic or isothiocyanic esters); isocyanato and isothiocyanato groups (by treatment with ammonia or primary or secondary amines) and unsubstituted urea or thiourea groups, which may be alkylated; (b) for the preparation of urethanes: primary and secondary amino groups (by treatment with haloformic esters) and isocyanato groups (by treatment with aliphatic alcohols. The compounds are used in the treatment of bilharziasis.  In examples: (1) 1-p-nitrophenoxy-5-aminopentane is treated with potassium cyanate in dilute hydrochloric acid and the resulting 1 - p - nitrophenoxy - 5 - ureidopentane is reduced by catalytic hydrogenation; 1-p-dimethylamino - and 1 - p - (2 - hydroxyethyl)-aminophenoxy - 5 - ureidopentane may be similarly prepared by hydrolysis of the corresponding 5-phthalimidopentanes and treatment with potassium cyanate; 1-p-aminophenoxy - 6 - ureidohex - 3 - ene may be similarly prepared by hydrolysis of 1-p-acetamidophenoxy - 6 - phthalimidohex - 3 - ene and treatment with potassium cyanate, followed by hydrolysis of the acetyl group; (2) 1-p-nitrophenoxy - 5 - aminopentane is treated with ethyl chloroformate in the presence of diethylaniline and the resulting 1-p-nitrophenoxy-5-ethoxycarbonylaminopentane is reduced catalytically to 1 - p - aminophenoxy - 5 - ethoxy-carbonylaminopentane which is converted to its methane sulphonate; and (3) p-ethoxyphenylisothiocyanate is reacted with 1-p-nitrophenoxy-5-aminopentane to give 1-p-nitrophenoxy - 5 - (3 - p - ethoxyphenylthioureido) pentane which is reduced by sodium sulphide to give 1 - p - aminophenoxy - 5 - (3 - p - ethoxyphenylthioureido) pentane.  Specification 769,706 is referred to.ALSO:Therapeutic compositions for the treatment of bilharziasis comprises compounds of the formula <FORM:0778919/VI/1> and salts thereof, where R1 and R2 each represent hydrogen or an alkyl, hydroxyalkyl or alkoxyalkyl group of not more than 6 carbon atoms, A represents a saturated or unsaturated hydrocarbon chain of not less than 3 and not more than 9 carbon atoms, which may be unbranched, or may be substituted by one or more alkyl groups, and either R3 represents the group OR4 and Z represents an oxygen atom, or R3 represents the group NR5R6 and Z is oxygen or sulphur, R4 being an alkyl group of up to 6 carbon atoms and R5 and R6 being hydrogen atoms, alkyl groups of up to 6 carbon atoms or aryl or substituted aryl groups; in association with a pharmaceutical carrier.  The carrier may suitably be a solid material or a sterile liquid for parenteral injection.  For example the compounds may be admixed with solid diluents such as starch, lactose, talc, stearic acid, magnesium stearate and gums to form tablets or powders or may employed, with or without other adjuvants in capsules, e.g. gelatin capsules.  A suitable liquid diluent for parenteral injection is sterile water.  Specified active compounds include 1 - p - aminophenoxy - 5 - ureido - pentane, 1 - p - dimethylaminophenoxy - 5 - ureido - pentane, 1 - p - di (2 - hydroxyethyl) aminophenoxy - 5 - ureido-pentane, 1 - p - aminophenoxy - 5 - ethoxycarbonyl-aminopentane methane sulphonate and 1 - p - aminophenoxy - 5 - (3 - p - ethoxyphenylthioureido) pentane.