Patent GB-748786-A (GB)
Title: Manufacture of new compounds and of x-ray contrast media containing the same
IPC: C07D295/15
Filed: 1953-07-13
Abstract: The invention comprises compounds of the formula <FORM:0748786/IV(a)/1> where X is -CO-, -CO-CO- or -CO-Z -CO (having 1-20 carbon atoms), R and R1 are hydroxy, alkoxy, amino or substituted amino, and Z is an aliphatic or cyclic residue which may be substituted or interrupted by hetero-atoms; also salts of the above with inorganic and organic bases.  Preferred are the symmetrical compounds in which R represents <FORM:0748786/IV(a)/2> The compounds are made by condensing 2:4:6-tri-iodo-3-aminobenzoic acid or an ester or amide thereof with a dihalide, mono-ester monohalide or mono-amide monohalide of a dibasic or polybasic carboxylic acid (or of carbonic acid).  If the group -COR1 is carboxylic acid this may be converted into an ester or amide group in the product, preferably via the acid halide. Substituents in Z can be protected and afterwards regenerated, e.g. carboxylic acid from a functional derivative, or hydroxy from acyloxy.  In the examples: (1) the following are prepared by condensing 2:4:6 - tri - iodo - 3 - aminobenzoic acid (or the appropriate derivative thereof) with acid halides:-malonic acid di-(3-carboxy-2:4:6-tri-iodo-anilide), succinic acid di-(3-carboxy-2:4:6 - tri - iodo - anilide), oxalic acid monoethyl ester mono-(3-carboxy-2:4:6-tri-iodo-anilide), oxalic acid di-(3-carboxy-2:4:6-tri-iodo-anilide), adipic acid di-(3-carboxy-2:4:6-tri - iodo - anilide), suberic acid di - (3 - carboxy-2:4:6-tri-iodo-anilide), azelaic acid di-(3-carboxy - 2:4:6 - tri - iodo - anilide), adipic acid monoethyl ester mono-(3-carboxy-2:4:6-tri - iodo - anilide), N:N1 - di - (3 - carboxy - 2:4:6 - tri - iodophenyl) - urea, tricarballylic acid di - (3 - carboxy - 2:4:6 - tri - iodo - anilide)-the trihalide being used and the third carboxylic halide group hydrolysed to the free acid-adipic acid mono-(3-carboxy-2:4:6-triiodo - anilide), a :g  - dibromadipic acid di - (3 - carboxy - 2:4:6 - tri - iodo - anilide), anhydromethylenecitric acid di - (3 - carboxy - 2:4:6 - tri - iodo - anilide), diglycollic acid di - (3 carboxy - 2:4:6 - tri - iodo - anilide), thiodiglycollic acid di - (3 - carboxy - 2:4:6 - tri - iodo-anilide), adipic acid monoethyl ester mono(3 - carbamido - 2:4:6 - tri - iodo - anilide), adipic acid di - [3 - (N - carboxymethyl - carbamido) - 2:4:6 - tri - iodo - anilide], terephthalic acid di-(3-carboxy-2:4:6-tri-iodo-anilide) and fumaric acid di-(3-carboxy-2:4:6-triiodo - anilide); (2) N - phenyl - N1 - (3 - carboxy - 2:4:6 - tri - iodophenyl) - urea is obtained from 2:4:6 - tri - iodo - 3 - aminobenzoic acid and phenyl isocyanate; (3) 3-chloracetylamino - 2:4:6 - tri - iodobenzoic acid is condensed with piperazine to give piperazineN:N1 - diacetic acid di - (3 - carboxy - 2:4:6 - tri-iodo-anilide); (4) the ethyl esters mentioned under (1) are hydrolysed to the free acids; (5) adipic acid di-(3-carboxy-2:4:6-tri-iodo-anilide) is converted into the di-carboxylic chloride and thence into the dimethyl ester; (6) oxalyl chloride is condensed with one mol. of 2:4:6-tri-iodo-3-aminobenzoic acid and one mol. of ammonia or diethylamine to give the substituted oxamide; (7) adipic acid di-(3-carboxy-2:4:6-tri-iodo-anilide) is converted into its sodium, lithium, ethanolamine, diethanolamine, triethanolamine, glucosamine, lysidine and piperazine salts.  It is also stated that R1 may represent an aminoethyl ester, dimethylaminoethyl ester, hydroxyethylamide, acetoxyethylamide or carbomethoxymethylamide residue.  Z may be substituted by hydroxy, oxo or amino groups or functional derivatives of these, or by halogen, especially iodine, or Z may be interrupted by -O-, -S-, -S-S-, -NH- or substituted -NH-.ALSO:X-ray contrast media contain as essential constituent a compound of the formula <FORM:0748786/VI/1> where X is -CO-, -CO-CO- or -CO-Z-CO- (having 1-20 carbon atoms), R and R1 are hydroxy, alkoxy, amino or substituted amino, and Z is an aliphatic or cyclic residue which may be substituted or interrupted by hetero-atoms; also salts of the above with inorganic and organic bases.  Preferred are the symmetrical compounds in which R represents <FORM:0748786/VI/2> Some of the compounds are particularly useful as contrast media for the kidneys, others being suitable for cholecystography, vasography, bronchography and salpingography.  Many compounds are specified as suitable, being of two types according as the tri-iodophenyl group is present once or twice in the molecule. Those of the first type mentioned have X the residue of oxalic acid, adipic acid and carbonic acid, R being hydroxy, ethoxy, amino, diethylamino and anilino and R1 being hydroxyl. Compounds of the second type mentioned have the group X derived from carbonic acid, oxalic acid, malonic acid, succinic acid, adipic acid, suberic acid; azelaic acid, tricarballylic acid, dibromadipic acid, anhydromethylenecitric acid, diglycollic acid, thiodiglycollic acid, terephthalic acid, fumaric acid and piperazine-N:N1-diacetic acid, R1 being hydroxyl, amino and carboxymethyl-amino.  R1 may also be aminoethoxy, dimethylaminoethoxy, hydroxyethylamino acetoxyethylamino or carbomethoxymethylamino.  Sodium, lithium, ethanolamine, diethanolamine, triethanolamine, glucosamine, lysidine and piperazine salts of adipic acid di-(3-carboxy-2 : 4 : 6-tri-iodo-anilide) are mentioned.  The compounds are used in aqueous solution or colloidal suspension, with or without protective colloids or wetting agents. An example is given of a solution prepared from the sodium salt of adipic acid di-(3-carboxy-2 : 4 : 6-tri-iodo-anilide), piperazine and citric acid, with or without the material known under the Registered Trade Mark "Tylose."