Patent GB-761888-A (GB)
Title: Improvements in or relating to therapeutically useful diamines
Inventor: BERG SAMUEL SIDNEY
Filed: 1954-01-21
Abstract: The invention comprises di-(p-aminophenoxy) compounds of the general formula <FORM:0761888/IV(b)/1> wherein R1 to R4 are the same or different and each is a hydrogen atom or an alkyl or hydroxyalkyl group containing not more than 3 carbon atoms and A is an unbranched hydrocarbon chain containing 3-9 carbon atoms which may be saturated or may contain one or more ethylene linkages and which may be substituted by one or more alkyl groups containing 1-4 carbon atoms, such that when A is an unsubstituted saturated unbranched hydrocarbon chain either the grouping R1R2 is different from the grouping R3R4 or at least one of R1, R2\t R3 and R1 is a hydroxyalkyl group, their acid addition salts and, when they contain at least one primary amino group, their sodium formaldehyde bisulphite derivatives.  They may be prepared by reaction of a compound <FORM:0761888/IV(b)/2> with a compound <FORM:0761888/IV(b)/3> wherein X and Y are the same or different tertiary amino groups or groups convertible to primary, secondary or tertiary amino groups such as acylamido, nitro, carbonamido, carboxy, alkoxycarbonyl, arylazo or quaternary ammonium groups, M is an alkali metal, A1 is the group A or a corresponding less-saturated hydrocarbon chain and Q is a halogen atom or a methane sulphonate group, followed, if necessary, by conversion of the groups X and Y to the desired amino groups and, if necessary, by reduction of A1 to form A.  When products in which the groups -NR1R2 and -NR3R4 are identical are required 2 mols. of the compound <FORM:0761888/IV(b)/4> wherein X = Y may be condensed with one mol. of the diester Q-A1-Q.  The compounds of the invention may also be prepared (a) by nitration of the appropriate unsubstituted diphenoxy compound followed by reduction of the nitro groups to amino groups which may then be alkylated or hydroxyalkylated, or (b) by condensation of <FORM:0761888/IV(b)/5> with <FORM:0761888/IV(b)/6> with elimination of halogen, the groups A1 and A2 being together equal to A.  In the examples: (1) and (3) potassium p-nitrophenoxide is refluxed with 1 : 5-dibromo-3-methylpentane in ethylene glycol to give 1 : 5-di-(p-nitrophenoxy)-3-methyl pentane which is catalytically reduced to the corresponding diamino compound, the dihydrochloride and bis-sodium formaldehyde bisulphite derivative of which are also described; cis - and trans - 1 : 4 - di - (p - nitrophenoxy)-but-2-ene are prepared similarly and the corresponding di-amino compounds are prepared from them by reduction with iron and acetic acid; (2) ethylene chlorohydrin is boiled with 1 : 5 di-(p-aminophenoxy) pentane and calcium carbonate in water to give 1 : 5-di-[p-di-(2 - hydroxyethyl)aminophenoxy] pentane; the corresponding octane compound is prepared similarly; (4) the pentane derivative of Example (3) is prepared by refluxing 1 : 5-dibromopentane with p - di - (2 - hydroxyethyl) aminophenol and potassium hydroxide in ethanol; (5) chloro acetyl chloride with 1 : 5-di-(p-aminophenoxy) pentane in acetic acid with sodium acetate gives 1 : 5-di-(p-chloracetamidophenoxy) pentane which on refluxing with potassium acetate in acetic acid gives 1 : 5-di-(p-acetoxyacetamidophenoxy) pentane and this on reduction with lithium aluminium hydride in tetrahydrofuran followed by decomposition with ethyl acetate and NaOH gives 1 : 5-di-(p-2-hydroxyethylaminophenoxy) pentane; (6) ethyl chloroacetate is boiled with 1 : 5-di-(p-aminophenoxy) pentane and sodium carbonate in ethanol to give 1 : 5-di-(p-ethoxycarbonylmethylaminophenoxy) pentane which on reduction and decomposition as in Example (5) gives the product of that example; (7) N-acetyl-p-methylaminophenol is refluxed with 1 : 5-dibromopentane and sodium in ethanol and the product is hydrolysed with hydrochloric acid to give 1 : 5-di-(p-methylaminophenoxy) pentane, which on refluxing with ethylene chlorohydrin and calcium carbonate in water gives 1 : 5-di-[p - (2 - hydroxyethyl)-methylaminophenoxy] pentane; (8) p-methylaminophenol sulphate, potassium acetate and formamide are refluxed in acetic acid to give N-formyl-p-methylaminophenol, this is refluxed with 5-p-nitro phenoxy pentyl bromide and sodium in ethanol to give 1 - p - nitrophenoxy - 5 - p - (N - formylmethylamino) phenoxy pentane, this on catalytic reduction gives 1-p-aminophenoxy-5-p-(N-formylmethylamino) phenoxy pentane which is reacted with acetic anhydride in pyridine at 60 DEG  C. to give 1 - p - acetamidophenoxy - 5 - p - (N-formylmethylamino) phenoxy-pentane and the latter is reduced as in Example (5) giving 1-p-ethylaminophenoxy - 5 - p - dimethylaminophenoxy - pentane; treatment of this product with acetic anhydride in pyridine yields 1-p-N-ethylacetamidophenoxy - 5 - p - dimethylaminophenoxy - pentane which on reduction yields 1 - p - diethylaminophenoxy - 5 - p - dimethylaminophenoxy-pentane; (9) p-di-(2-hydroxyethyl)aminophenol is refluxed with potassium hydroxide and 5-p-nitrophenoxypentyl bromide in ethanol, the resulting nitro compound is catalytically reduced without being isolated and the resulting amine is condensed with benzaldehyde to give 1-p-benzylideneaminophenoxy-5 - p - di - (2 - hydroxyethyl) - aminophenoxypentane which on steam distillation with hydrochloric acid yields 1-p-aminophenoxy-5-p-di-(2-hydroxyethyl) aminophenoxy-pentane.  In the Provisional Specification compounds in which the group A is a saturated unbranched hydrocarbon chain and -NR1R2 is identical with -NR3R4 (R1 and R2 both being alkyl groups and also described and the following additional examples are given: (1) potassium p-nitrophenoxide and 1 : 7-dibromoheptane give 1 : 7-di - (p - nitrophenoxy) - heptane from which the diamine, the dihydrochloride and dimethanesulphonate of which are described, is prepared by catalytic reduction; the corresponding butane and octane derivatives, their dihydrochlorides and the methane sulphonate of the latter are prepared similarly; (2) p-dimethylaminophenol, potassium hydroxide and 1 : 5-dibromopentane give 1 : 5-di-(p-dimethylaminophenoxy) pentane, the dihydrochloride of which is described; (3) N-acetyl p-methylaminophenol and 1 : 3-dibromopropane with sodium in alcohol give 1 : 3-di-(N-acetyl p-methylaminophenoxy) propane, which on acid hydrolysis gives 1 : 3-di-(p-methylaminophenoxy) propane hydrochloride and thence the free base; (4) cis-and trans-1 : 4-di-(p-aminophenoxy) but-2-ene are separately reduced over Pto, each yielding 1 : 4-di-(p-aminophenoxy) butane; (5) 1 : 5-di-(p-aminophenoxy) pentane with acetic anhydride in pyridine gives 1 : 5-di-(p-acetamidophenoxy) pentane (also prepared by condensation of p-acetamidophenol with 1 : 5-dibromopentane) which on reduction with lithium aluminium hydride gives 1 : 5-di-(p-ethyl-aminophenoxy) pentane; 1 : 5-di-(p-n-propionamidophenoxy) pentane and 1 : 5-di-(p-n-propylaminophenoxy) pentane are similarly prepared; (6) 1 : 5 - di - (p - n - propyl - n - propionamidophenoxy) pentane, prepared from 1 : 5-di-(p-n-propylaminophenoxy) pentane and propionic anhydride, is reduced to 1 : 5-di-(p-di-n-propyl aminophenoxy) pentane, the disulphate of which is described; (7) 1 : 3-di-(p-aminophenoxy) propane, sodium carbonate and methyl iodide are refluxed in alcohol to give the corresponding trimethyl ammonium iodide which on heating under reduced pressure gives 1 : 3-di-(p-dimethylaminophenoxy) propane; (8) 1 : 5-di-(p-aminophenoxy) pentane is refluxed in acetone and the solution then catalytically reduced to give, after chromatographic absorbtion over alumina and elution with light petroleum, 1 : 5-di - (p - isopropylaminophenoxy) pentane; (9) 1 : 5-di-(p-aminophenoxy)-pentane and ethyl iodide are refluxed with sodium in alcohol, the residue remaining after evaporation is treated with NaOH solution, and the separating oil is distilled to give 1 : 5-di-(p-diethylaminophenoxy) pentane; and (10) 1 : 5-di-(p-aminophenoxy) pentane is converted into its bis-sodium formaldehyde bisulphite addition compound.ALSO:A therapeutic composition for the treatment of bilharziasis contains a compound of the formula <FORM:0761888/VI/1> wherein R1-R4 are the same or different and each is a hydrogen atom or an alkyl or hydroxyalkyl group containing not more than three carbon atoms and A is an unbranched hydrocarbon chain containing 3-9 carbon atoms which may be saturated or may contain one or more ethylene linkages and which may be substituted by one or more alkyl groups containing 1-4 carbon atoms, such that when A is an unsubstituted saturated unbranched hdrocarbon chain either the grouping R1R2 is different from the grouping R3R4 or at least one of R1, R2, R3 and R4 is a hydroxyalkyl group, or its acid addition salt or, if it contains at least one primary amino group, its sodium formaldehyde bisulphate derivative, together with a pharmaceutical carrier.  The latter may be either solid or liquid and the composition may be in the form of tablets, powders, capsules or other forms suitable for oral ingestion. Liquid diluents such as water may be employed in sterile conditions for parenteral use.  Diluents and excipients referred to are starch, lactose, talc, stearic acid, magnesium stearate and gums and any tabletting material may be used.  In the Provisional Specification compositions containing compounds of the above general formula in which A is a saturated unbranched hydrocarbon chain and - NR1R2 is identical with - NR3R4 (R1 and R2 both being alkyl groups) are also described.