Patent GB-791997-A (GB)
Title: Acylated 3, 5-diamino-polyhalobenzoic acids and their preparation
IPC: A61K49/04
Filed: 1954-03-23
Abstract: The invention comprises (a) compounds of the general formula: <FORM:0791997/IV (b)/1> (wherein X, Y and Z represent hydrogen, bromine or iodine, at least two of them being halogen, and R and R1 represent identical or different alkanoyl, hydroxyalkanoyl or alkanoyloxyalkanoyl radicals, together containing not more than 10 carbon atoms, provided that when X, Y and Z are all iodine and R and R1 are alkanoyl radicals other than butyryl, then R and R1 must be different); and (b) their water-soluble salts; (c) the preparation of the compounds of (a), and of the compounds excluded from (a) by the proviso thereto, by treating the corresponding compounds in which R1 is hydrogen with an alkanoic or alkanoyloxyalkanoic acid, acid anhydride or acid halide or a hydroxyalkanoic acid, producing the desired total number of carbon atoms in R+R1, followed, if desired, by hydrolysis of an alkanoyloxy group if present to a hydroxy group; (d) the combination of (c) with the preparation of the starting materials therefore by halogenating a compound of the general formula: <FORM:0791997/IV (b)/2> by treatment with one or more halogenating agents affording available bromine or iodine; and (e) radiopaque compositions for intravenous administration containing water-soluble salts of the compounds of (a) (without the proviso) (see Group VI).  In examples: (1) 5-acetamido-3-aminobenzoic acid is diiodinated with iodine monochloride in hydrochloric acid and the product is acylated with acetic anhydride in the presence of aqueous perchloric acid; the sodium salt of the resulting 3 : 5-diacetamido-diiodobenzoic acid is described; the acylating agent may be replaced by (2) propionic anhydride, or (3) butyric anhydride, both in the presence of conc. H2SO4; (4) 5-acetamido-3-amino-2 : 4 : 6-triiodobenzoic acid is prepared by iodinating 5-acetamido-3-aminobenzoic acid or its diiodo derivative with potassium iododichloride in dilute caustic soda and is acylated with formic acid in the presence of acetic anhydride, the product being converted to its sodium salt; the acylating agent may be replaced by (5) propionic anhydride and conc. H2SO4; (6) butyric anhydride and conc. H2SO4; and (7) isocaproyl chloride; (8) 3-amino-5-butyramidobenzoic acid is iodinated as in (1) and the diiodo compound is acylated with acetic anhydride and conc. H2SO4; (9) 3-amino-5-hydroxyacetamidobenzoic acid is diiodinated as in (1) and the product (the diethanolamine salt of which is described) is acetylated as in (8) to produce 3-acetamido-5-acetoxyacetamido-diiodobenzoic acid; (10) the product of (9) is hydrolysed with dilute caustic soda to 3-acetamido - 5 - hydroxyacetamidodiiodobenzoic acid; (11) 3-amino-5-hydroxyacetamidodiiodobenzoic acid is further iodinated in dilute caustic soda with an iodine monochloride-potassium chloride solution and the product is acetylated as in (9); (12) the product of (11) is hydrolysed as in (10); the product may be reacted with valeryl chloride to give 3-acetamido - 5 - valeryloxyacetamido - 2 : 4 : 6 - triiodobenzoic acid; (13) 3-amino-5-acetamidobenzoic acid is tribrominated with bromine in aqueous solution and the product is acetylated with acetic anhydride and conc. H2SO4; the sodium salt of the product is described; (14) 3 : 5-diaminobenzoic acid is triiodinated with iodine monochloride in hydrochloric acid and the product is diacylated with butyric anhydride in the presence of conc. H2SO4.  Additional salts specified are ammonium salts and salts with alkylamines (e.g. diethylamine) and alkanolamines (e.g. diethanolamine or methylglucamine).  Starting materials.  The compounds of the second general formula above are prepared by selectively reducing 3 : 5-dinitrobenzoic acid (e.g. with ammonium sulphide) to 3-nitro-5-aminobenzoic acid, acylating the amino group and then reducing the second nitro group either chemically or catalytically (e.g. with hydrogen in the presence of Raney nickel catalyst or with hydrazine in the presence of Raney nickel).  The preparation of the starting materials of Examples (1)-(13) above is described in detail.  3 : 5-Diaminobenzoic acid is prepared by reducing both nitro groups of 3 : 5-dinitrobenzoic acid, dissolved in aqueous caustic soda, by means of hydrogen in the presence of platinum oxide catalyst.ALSO:Radiopagne compositions for intravenous administration comprise a non-toxic water-soluble salt of a compound of the formula <FORM:0791997/VI/1> (wherein X, Y and Z represent hydrogen, bromine or iodine, at least two of them being halogen, and R and R1 represent identical or different alkanoyl, hydroxyalkanoyl or alkanoyloxyalkanoyl radicals, together containing not more than 10 carbon atoms), and a solvent or diluent.  The compounds in which R and R1 contain one or two carbon atoms are particularly suitable as intravenous urographic agents for excretory urography or retrograde pyelography, and those of higher molecular weight as intravenous cholecrystographic agents. Salts specified are those of the alkali metals (especially sodium), ammonium, alkylamines (e.g. diethylamine) and alkanolamines (e.g. diethanolamine or methylglycamine).  The properties of the sodium salt of 3 : 5-diacetamidodiiodobenzoic acid are described.