Patented June 1, 1954 2,680,133 UNITED STATES PATENT OFFICE 2,680,133 ODNE-CONTAINING AMNO-BENZOY, DERVATIVES OF AMNO ACDS Vernon H. Wallingford, Ferguson, Mo., assignor to Mallinckrodt Chemical Works, St. Louis, Mo, a corporation of Missouri No Drawing. Application August 24, 1951, Serial No. 243,577 8 Claims. (C. 260-518) 2 This invention relates to iodine-containing proposed as X-ray contrast agents; but only a few amino-benzoyl derivatives of amino acids and of these are now recognized as being of any prac more particularly to 3-amino-2,4,6-triiodo deriva tical value. The problem remains of providing tives of benzoyl amino acid compounds and to a high degree of contrast for X-ray diagnosis with methods for their preparation. greater safety and comfort to the patient. This This application is a continuation-in-part of can be achieved, for example, by providing con my copending application Serial No. 94,253, filed trast agents that are (1) less toxic, so that larger May 19, 1949, now abandoned. amounts can be given to the patient; (2) more Briefly the invention comprises methods of soluble, so that greater concentrations of the con making certain compounds of a group having the O trast agent are possible; or (3) more opaque to formula: X-rays because of a greater proportion of iodine CO-N-R-COOH but without a corresponding increase in toxicity. ly Iodinated derivatives of benzoic acid are among I- I those compounds that have been proposed as 15 X-ray contrast agents. Although they appear to NE be promising X-ray contrast agents because of the large amount of iodine that they contain, the toxicity or the in Solubility of the known deriva tives of these compounds have generally been where R is selected from the group consisting of 20 found to be too great for this purpose. methylene, and polymethylene radicals, and R' is It has been found in accordance with the pres selected from the group consisting of alkyl and ent invention that the properties required in a phenyl radicals and hydrogen, by reducing a good X-ray contrast agent are obtained in certain m-nitro-benzoyl derivative of an amino acid with compounds of the type: zinc and hydrochloric acid and thereafter io 25 dinating the benzoyl nucleus with iodine mono CO-N-R-COOH chloride. The present invention also includes new compounds of the type described above, as I- -I well as methods for reducing the nitro group of a nitro-benzoyl derivative of an amino acid with -NE zinc and hydrochloric acid. 30 Among the objects of this invention are the provision of new compounds which are 3-amino 2,4,6-triiodobenzoyl derivatives of amino acids; where R represents a methylene, substituted the provision of Compounds of the type indicated 3. 5 methylene, polymethylene, or substituted poly which are useful intermediates for the prepara methylene residue, the substituents being alkyl tion of other compounds of related structure; the and phenyl radicals and hydrogen, and the non provision of compounds of the type referred to toxic salts thereof. which possess relatively low toxicity toward hu An outstanding property of these new com man bodies; the provision of compounds of the 40 pounds is the remarkably greater solubility of type referred to which possess substantial solu certain of their salts compared with the solubil bility in water; the provision of improved con ity of the corresponding salts of the simple poly trast media for X-ray diagnosis; the provision iodinated aminobenzoic acids. This is particu of compounds which are relatively stable under larly true of the Salts of the alkali metals, am normal conditions of storage and use and in the 45 monia, and amines. Another equally valuable presence of body fluids, and the provision of property of many of these compounds is their methods for preparing compounds of the type re Substantially lower toxicity as compared with the ferred to. Other features will be in part ap corresponding polyiodinated aminobenzoic acids. parent and in part pointed out hereinafter. These compounds can be prepared by convert The invention accordingly comprises the prod 50 ing a polyiodinated m-aminobenzoic acid to the lucts and methods hereinafter described, the scope acid chloride and coupling the product with an of the invention being indicated in the following amino acid. Alternatively, to prepare m-amino claims. hippuric acid, for example, m-nitro-benzoic acid may be coupled with aminoacetic acid and the Because of the opacity of iodine to X-rays, resulting nitro compound reduced with ammo many iodinated organic compounds have been 55 nium sulfide and finally iodinated. 2,680,188 3. 4 It has been found in accordance with the pres monium chloride Solution (20 g. in 100 ml, of ent invention, however, that these compounds are Water) and dissolved in hot water (500 ml.) coil most advantageously prepared by first reducing taining a few drops of ammonium hydroxide. the m-nitro-benzoyl derivative of an amino acid This solution was heated With activated carbon, with zinc and hydrochloric acid, and then io filtered and then 3-amino-2,4,6-triiodohippuric dinating the benzoyl nucleus with iodine nono acid was precipitated from the hot Solution With chloride without first isolating the amine deriva acetic acid (10 ml.). After it was Washed and tive. The action of zinc and hydrochloric acid dried the acid weighed 46.7 g. It melted at 230° is a surprising feature of this process because C. with decomposition when it was placed in the they have not heretofore been regarded by the art O neiting point apparatus at 25° C. and the as general reactants for the reduction of nitro temperature was increased at the rate of 3 per aromatic compounds. minute. There are many amino acids that can be used The nother liquor, from which the original in preparing the compounds of this invention. crude iodinated product was obtained, was treated In addition to the common amino aliphatic acids, With additional iodine monochloride (30 g.) in phenyi-substituted amino carboxylic acids may Concentrated hydrochloric acid (30 ml.) for two be employed, provided the amino group itself is hours at 60° C. From this an additional 20 g. attached to an aliphatic carbon atom. In gen of Crude iodinated product was obtained. After eral, this reaction has not been found suitable for it had been purified through the annonium salt, amino acids that contain more than one nitrogen 20 it weighed 15.5 g. and melted at 225 C. With de atom. composition. The following examples illustrate the inven The combined yield of purified product was tion: 62.2 g. (74.4% of theory based on Ineta-nitroben EXAMPLE 1. zoyl chloride). The 3-amino-2,4,6-triiodohip 25 puric acid Was not completely colorless but re 3-amino-2,4,6-triiodohippatric acid tained a slight tan cast. Analysis showed 65.9 Meta-nitrobenzoyl chloride (28.3 g.) was added and 66.1% iodine, compared with 66.5% which slowly with stirring to aminoacetic acid (15 g.) is theory for C9H7O3N23, ihe neutralization and water (50 ml.), while the mixture was kept equivalent was found to be 569.3. Theory is 571.7. slightly alkaline to phenolphthalein with sodium 30 EXAMPLE 2 hydroxide solution (35 Bé.) and the tempera ture was maintained at about 30° C. Addition of Sodium Salt of 3-amino-2,4,6-triiodohippuric the chloride required about 35 minutes and a acid total of 27 ml. of the sodium hydroxide solution A suspension of purified 3-amino-2,4,6-triiodo Was used. Stirring was continued for about one hippuric acid (10 g.) in water (30 ml.) was made hour after all of the chloride was added. Slightly alkaline to litmus with sodium hydroxide The resulting clear and slightly yellowish solu and the resulting reddish solution was evaporated tion was transferred to a separatory funnel and under reduced pressure. Light tain crystals re gradually added over a period of 30 minutes to Sulted. The Solubility of the Sodium Salt of 3 a stirred mixture of zinc dust (10 g.) and water amino-2,4,6-triiodohippuric acid was 10 g. in 23.5 (75 ml.) while the mixture was kept acid to ml. Of Water at 28° C. Congo red with concentrated hydrochloric acid. Two additional 10 g. portions of zinc dust Were EXAMPTE 3 added. After the reduction Was apparently Con Diethanolamine Salt of 3-amino-2,4,6-triiodo plete, fresh zinc dust (5 g.) was added and the hippuric acid mixture was heated and Stirred to insure Com plete reduction. Altogether, 105 ml. of concen A Suspension of free 3-amino-2,4,6-triiodohip trated hydrochloric acid and 35 g. of zinc dust puric acid (10 g.) in water (25 ml.) was neutral Were used. The excess zinc was filtered off and ized With diethanolamine (2.5 ml.) and then the resulting clear and colorless Solution was evaporated under reduced pressure. The result diluted to about 2000 ml. To it was added a ing diethanolamine salt of 3-amino-2,4,6-triiodo mixture of iodine monochloride (60 g.) and con hippuric acid could not be crystallized but was ob centrated hydrochloric acid (60 mi.). Since the tained as a clear, reddish, glassy Solid. It was reaction was not rapid, the Solution Was heated extremely soluble in water. on a steam bath for about one hour at 55-60° C. A tan product separated which, after filtering EXAMPLE 4 and drying, Weighed 50 g. It was evidently a N-(3-amino-2,4,6-triiodoben2Oyl)-e-amino-n- mixture of di- and triiodo compounds because at Caproic dicid tempts to purify it by crystallization as the am monium Salt gave fractions neiting from 50° C.