Patent GB-1019775-A (GB)
Title: [ª‡-(alkylideneacyl)naphthyloxy]alkanoic acids
IPC: A61K31/19
Filed: 1962-11-12
Abstract: The invention comprises compounds of the general formula <FORM:1019775/C2/1> in which each R1 and R2 is a hydrogen or halogen atom or a C1-5 alkyl radical; each of R4, R5 and R6 is a hydrogen or a halogen atom or a hydroxyl, C1-5-aliphatic, alicyclic mononuclear aryl, hydroxyaryl, haloaryl, mononuclear aryl-substituted C1-5 aliphatic mononuclear aryloxy, morpholinyl-C1-5 aliphatic, carboxy-substituted C1-5 alkyl, mononuclear arylthio-substituted C1-5 alkyl, mononuclear arylthio, dialkylamino-C1-5 or trihalo methyl-substituted C1-5 alkyl radical or R4 and R6 are joined together to form with the carbon atoms to which they are attached a 3 to 6 carbon ring, with the proviso that R4, R5, R6 do not all represent hydrogen atoms; B is a divalent C1-5 aliphatic, divalent mononuclear arylene or divalent C1-5 aliphatic-substituted mononuclear arylene radical; X is a hydroxyl group or a salt of a hydroxyl group or an alkoxyl, amino, alkylamino or piperidino group and the preparation thereof by converting a (saturated aliphatic) acylnaphthyloxy organic monocarboxylic acid of the formula <FORM:1019775/C2/2> to a salt of a Mannich base of the formula <FORM:1019775/C2/3> and treating the latter with a weak base, R7 and R8 being defined such that NHR7R8 is ammonia or a primary or secondary amine, the (saturated aliphatic) acylnaphthyloxy organic mono-carboxylic acid being prepared either by reacting an a -halo-organic monocarboxylic acid ester with a (saturated-aliphatic) acylnaphthol, and hydrolysing the ester formed to the acid, or reacting a naphthyloxy-organic monocarboxylic acid with a (saturated-aliphatic)-acyl halide according to the Friedel-Crafts reaction.  Compounds of the invention wherein the unsaturated acyl group is Ar-CH = CR6CO-where Ar is an unsubstituted or substituted aryl group (as defined) may be prepared by reacting an aryl or substituted aryl aldehyde with a saturated acylnaphthyl oxy derivative of a monocarboxylic acid.  When the saturated acylnaphthyloxy derivatives of a monocarboxylic acid has two methyl groups and a hydrogen attached to the carbonyl group of the acyl function the unsaturated acyl group may be formed by brominating the saturated acyl group and dehydrohalogenating the bromo derivative. Where one methyl group is replaced by ethyl or a higher alkyl group the double bond will generally occur between the carbon in the alpha-position to carbonyl group and the higher alkyl group and when both methyl groups are replaced, unsaturation occurs between the alpha carbon and the alkyl group containing the larger number of carbon atoms.  Saturated acyl naphthols are prepared from an alkoxynaphthol and the desired saturated aliphatic acid in the presence of boron trifluoride and removing the alkoxy group, or by first forming a carboxylic acid ester from an appropriate R1, R2-substituted-naphthol then subjecting the ester to a Fries rearrangement, or by subjecting an alkoxynaphthol to a Friedel-Crafts reaction with an acyl halide, or by alkylating a cyanonaphthol to the alkoxy cyanonaphthalene, reacting this with a Grignard reagent and hydrolysing the product to give an alkoxy saturated acylnaphthalene and removing the alkyl groups, or submitting an acetamido naphthylamine to a Friedel-Crafts reaction, removing the acetyl group to give a saturated acyl-naphthylamine and diazotizing this to replace the amino group by hydroxyl, or by reacting an iodo-alkoxy-naphthalene with magnesium to form a Grignard reagent then with an alkylnitrile followed by hydrolysis and removal of the alkoxy group.  4 - Chloro - 1 - hydroxy - 2 - butyronaphthone is prepared from 1-hydroxy-2-butyronaphthone and tert.-butylhypochlorite.  Ethyl 4-chloromethylbenzoate is prepared by chlorinating p-tolunitrile to form 4-chloromethylbenzonitrile, hydrolysing this to 4-chloromethylbenzoic acid and esterifying the acid.  Methyl 3-bromomethylbenzoate is prepared by brominating 3-methylbenzoyl chloride and reacting the product with methanol.  4 - (1 - Naphthyloxy)benzoic acid is prepared from 1-naphthol and 4-iodo benzoic acid.ALSO:Pharmaceutical compositions comprise compounds of the general formula <FORM:1019775/A5-A6/1> in which each of R1 and R2 is a hydrogen or a halogen atom or a C1-5 alkyl radical, each of R4, R5 and R6 is a hydrogen or a halogen atom or a hydroxyl, C1-5-aliphatic, alicyclic, mononuclear aryl, hydroxyaryl, haloaryl, mononuclear aryl substituted C1-5-aliphatic, mononuclear aryloxy, morpholino substituted C1-5 aliphatic, carboxy-substituted C1-5 alkyl, mononuclear arylthio-substituted C1-5 alkyl, mononuclear arylthio dialkylamino-substituted C1-5 a halomethyl-substituted C1-5 alkyl radical or R4 and R6 are joined together to form with the carbon atom to which they are attached a 3 to 6 carbon ring, with the proviso that R4, R5, R6 do not all represent hydrogen atoms.  B is a divalent C1-5 aliphatic, divalent C1-5 aliphatic, divalent mononuclear arylene, or divalent C1-5-aliphatic-substituted mononuclear arylene radical, X is an hydroxyl group or a salt of a hydroxyl group or an alkoxyl, amino, alkylamino a piperidino group, together with an inert pharmaceutical diluent.  The compositions which have diuretic, natriuretic and chloruretic properties, may contain other known hypotensive or diuretic agents, and may be in the form of tablets pills, capsules elixirs or solution for injections.