Patent GB-767788-A (GB)
Title: Polyiodinated phenyl fatty acid compounds and process for their manufacture
IPC: A61K49/04
Filed: 1954-12-08
Abstract: The invention comprises compounds of formula <FORM:0767788/IV(b)/1> and alkali and alkaline earth metal and amine salts thereof, where X is H, OH, I, NH2, alkoxy, acyloxy, or carboxylic acylamino, R is an alkyl group containing up to 6 carbon atoms, and n is an integer from 0 to 4, the group -(CH2)nOR containing from 1 to 7 carbon atoms.  The compounds, where X is -OH or -NH2 may be prepared by condensing m-hydroxy- or m-nitrobenzaldehyde with a metal salt of an acid of formula <FORM:0767788/IV(b)/2> in the presence of the corresponding acid anhydride, hydrogenating and hydrolysing the resulting a -substituted cinnamic acid to the corresponding propionic acid, and then iodinating with iodine and potassium iodide in alkali, or with iodine monochloride in acetic acid.  Alternatively, the m-hydroxy- or m-nitro-benzaldehyde may be first iodinated and the preparation continued as above.  The compounds, where X is -NH2 may be acylated to form the acylamino derivatives, or they may be diazotized and the diazonium salt treated (a) with ethanol and cuprous ion to obtain compounds where X is H, (b) with sulphuric acid to obtain compounds where X is -OH, or (c) with potassium iodide to obtain compounds where X is iodine. Compounds where X is -NH2, but which have not been iodinated, may be diazotized and treated with sulphonic acid, and then iodinated to obtain compounds where X is -OH.  The compounds of the invention may also be prepared by condensing m-nitro benzaldehyde with a metal acetate in the presence of acetic anhydride, reducing the cinnamic acid so formed to 3-aminophenyl propionic acid which is then iodinated, introducing bromine at the a -carbon atom, and reacting the brominated compound with a metal alkoxide to replace the bromine atom with an alkoxy group.  A further preparation comprises reacting a compound such as <FORM:0767788/IV(b)/3> with a compound such as CH3OCH2Cl, replacing the benzyl radical with hydrogen, iodinating, and then hydrolysing the nitrile group to a carboxyl group to obtain a compound where X is -OH.  In examples the following compounds are prepared :-a  - ethoxy - b  - (2,4,6 - triiodo - 3 - aminophenyl) propionic acid; a  - methoxy - b  - (2,4,6 - triiodo - 3 - aminophenyl) propionic acid; a  - n - amyloxy - b  - (2,4,6 - triiodo - 3 - aminophenyl) propionic acid; a  - methoxy - b  - (2,4,6 - triiodo - 3 - hydroxyphenyl) propionic acid; a  - ethoxy - b  - (2,4,6 - triiodo - 3 - hydroxyphenyl) propionic acid; a -propoxy-b -(2,4,6 - triiodo - 3 - hydroxyphenyl) propionic acid; a  - n - amyloxy - b  - (2,4,6 - triiodo - 3 - hydroxyphenyl) propionic acid; a -(2,4,6-triiodo - 3 - aminobenzyl) - b  - methoxy - propionic acid; a  - (2,4,6 - triiodo - 3 - hydroxybenzyl) - b  - methoxy - propionic acid; a  - (2,4,6 - triiodo - 3 - aminobenzyl) - b  - ethoxypropionic acid; a  - (2,4,6 - triiodo - 3 - hydroxybenzyl) - b  - ethoxypropionic acid; a  - (2,4,6 - triiodo - 3 - aminobenzyl) - b  - n - butoxypropionic acid; a  - (2,4,6 - triiodo - 3 - hydroxybenzyl) - b  - isoamyloxypropionic acid; a  - (2,4,6 - triiodo - 3 - aminobenzyl) - g  - methoxybutyric acid; a  - (2,4,6 - triiodo - 3 - hydroxybenzyl) - g  - methoxybutyric acid; a  - (2,4,6 - triiodo - 3 - aminobenzyl) g  - ethoxybutyric acid; a  - (2,4,6 - triiodo - 3 - hydroxybenzyl) - g  - ethoxybutyric acid; a  - (2,4,6 - triiodo - 3 - aminobenzyl) - g  - butoxybutyric acid; a  - (2,4,6 - triiodo - 3 - hydroxybenzyl) - g  - propoxybutyric acid; a  - (2,4,6 - triiodo - 3 - aminobenzyl) - d  - methoxy valeric acid; a -(2,4,6-triiodo-3-hydroxybenzyl)-d  - ethoxy valeric acid; a  - (2,4,6 - triiodo - 3 - aminobenzyl) - d  - butoxy - valeric acid; a - (2,4,6 - triiodo - 3 - aminobenzyl) - e  - methoxycaproic acid; a - (2,4,6 - triiodo - 3 - hydroxybenzyl) - e  - ethoxycaproic acid; a - methoxy - b  - (2,4,6 - triiodophenyl) propionic acid; a  - methoxy - b  - (2,3,4,6 - tetraiodophenyl) propionic acid; a -methoxy-b -(2,4,6-triiodo-3-methoxyphenyl) propionic acid; a  - ethoxy - b  - (2,4,6 - triiodo - 3 - acetyloxyphenyl) propionic acid; and a  - ethoxy - b  - (2,4,6 - triiodo - 3 - acetylaminophenyl) propionic acid.ALSO:An X-ray contrast agent comprises a non-toxic pharmaceutical carrier mixed with a polyiodinated phenyl fatty acid of formula:-  <FORM:0767788/VI/1> or an alkali or alkaline earth metal or amine salt thereof, where X is H, OH, I, NH2, alkoxy, acyloxy, or carboxylic acylamino, R is an alkyl group having up to 6 carbon atoms, and n is 0 to 4, the group -(CH2)nOR containing from 1 to 7 carbon atoms.  The acid or salt may be incorporated in tablets containing starch, gums or sugar, or dissolved or suspended in milk, water, orange juice or other potable liquid, or in water containing methylcellulose or kaolin.  The compound may be used as the sodium or calcium salt, or as a salt of mono, di- or triethanolamine or the corresponding propanolamines, diethyl and dipropyl amines.  Examples of compounds are given such as a  - ethoxy - b  - (2, 4, 6 - triiodo - 3 - aminophenyl) propionic acid, a  - methoxy - b  - (2, 4, 6 - triiodo - 3 - hydroxyphenyl) propionic acid, and a  - (2, 4, 6 - triiodo - 3 - aminobenzyl) - b  - methoxy - propionic acid.