Patent GB-775811-A (GB)
Title: Polyiodinated phenoxy-fatty acids and process for their manufacture
IPC: A61K49/04
Filed: 1955-01-07
Abstract: The invention comprises compounds of the formula: <FORM:0775811/IV(b)/1> wherein R is an alkoxyalkyl group, R1 is hydrogen or an alkyl group, R and R1 together containing from 2 to 4 carbon atoms, and Y is H, OH or I, and their non-toxic alkali metal, alkaline earth metal and amine salts.  The invention also includes preparation of compounds of the above formula when Y is H by reacting 2,4,6-tri-iodophenol with a nitrile X.C.R.R1.CN or an ester X.C.R.R.1.COOR11, wherein X is a halogen atom and COOR11 is a carboxylic ester group, in the presence of an alkali metal alcoholate, and hydrolysing the product; and preparation of compounds of the above formula when Y is H, OH or I by diazotizing the corresponding 3-amino-2,4,6-triodophenoxy-aliphatic acid and replacing the diazonium group by hydrogen (e.g. by refluxing with ethanol in the presence of cuprous ion or by treatment with hypophosphorous acid), by hydroxyl (e.g. by heating with aqueous sulphuric acid), or by iodine (e.g. by reaction with a soluble metal iodide). (Reference is also made to the replacement of the nitrile or ester in the first method by a neutral salt of the corresponding carboxylic acid.)  The products are useful as radiopaque agents in cholecystography.  In examples: (1) 2:4:6-tri-iodophenol and methyl a -bromo-b -methoxypropionate are heated in butanol under reflux in the presence of sodium butoxide, and the resulting methyl a -(2:4:6-tri-iodophenoxy) -b -methoxypropionate is hydrolysed to the free acid; a -(2:4:6-tri-iodophenoxy)-a -methyl -b -methoxypropionic acid is similarly prepared; (2) ethyl a -bromo-b -ethoxypropionate similarly yields a -(2:4:6-tri-iodophenoxy) -b -ethoxypropionic acid; (3) a -(3-amino-2:4:6-tri-iodophenoxy) -b -methoxypropionic acid is diazotized and the product treated with aqueous potassium iodide solution to produce a -(2:3:4:6 - tetraiodophenoxy) - b  - methoxypropionic acid the corresponding b -ethoxyacid is similarly obtainable; (4) diazotized a -(3-amino -2:4:6 - tri - iodophenoxy) - b  - methoxypropionic acid is added dropwise to boiling dilute sulphuric acid, yielding, after further heating, a -(3-hydroxy-2:4:6-tri-iodophenoxy) -b -methoxypropionic acid. Salts may be prepared by reacting the acids with, for example, sodium, potassium, calcium or magnesium hydroxide, diethylamine, mono-, di- or triethanolamine or dipropanolamine.  Starting materials. 3-Amino-2:4:6-tri-iodophenoxy-acids are prepared by condensing m-acetylaminophenol with an ester BrC(R)(R1) COOEt in the presence of sodium ethoxide to produce a compound of the formula: <FORM:0775811/IV(b)/2> hydrolysing the ester and acetylamino groups and iodinating the resulting aminophenoxy-acid.  The preparation of the starting material of Example (3) is described in detail.ALSO:A pharmaceutical composition for use in cholecystography contains as a radiopaque agent a compound of the formula <FORM:0775811/VI/1> (wherein R is an alkoxyalkyl group R1 is hydrogen or an alkyl group, R and R1 together containing from 2 to 4 carbon atoms, and Y is H, OH or I) or an alkali metal, alkaline earth metal or amine salt thereof-The compounds may be dispensed in tablets containing inert carrier or binders such as starch, gums and sugar, or in powdered form in capsules or dissolved or suspended in milk, water, orange juice or other portable liquid, or combined with edible emulsifiers, or may be in the form of elixirs with flavoured aqueous alcohol mixtures.  The free acids may also be put up in ampoules, suspended in water contaning pectin, methyl cellulose, kaolin or other suspending and antacid preparations.