DE1129260B - X-ray contrast media - Google Patents

Description

X-ray contrast media Numerous N-acyl derivatives of 3,5-diamino-2,4,6-triiodobenzoic acid have been produced, of which the hitherto most non-toxic, 3,5-di- (acetamino) -2,4,6-triiodobenzoic acid, has gained importance as an X-ray contrast medium. But this connection still shows the disadvantage that the solubility of their sodium salt is usually required for the high concentrations are not sufficient, so that mixed salts such. B. with methylglucamine, must be used, but the solutions are undesirable for many injection purposes give high viscosity. Attempts have been made to circumvent this disadvantage by a mixture of the sodium salts of 3,5-diacetamino and 3,5-dipropionylamino-2,4,6-triiodobenzoic acid related, but then the higher toxicity of the 3,5-dipropionyl compound had to accept.

To increase the degree of hydrophilicity, N- (hydroxyalkanoyl) - or N- (alkanoyloxyalkanoyl) derivatives of 3,5-diamino-2,4,6-trijodbenzoic acid which, however, were too toxic and thus not lead to usable preparations to have.

It has been found that, surprisingly, compounds of the general formula where R1 is hydrogen, an alkanoyl radical with 1 to 3 carbon atoms, which in the case of the acetyl radical can also be alkoxylated with an alkyl radical containing 1 to 3 carbon atoms, R2 is an alkyl radical with 1 to 3 carbon atoms and Y is hydrogen or the radical of a physiologically acceptable inorganic and / or represents organic base, which do not have the disadvantages described.

First of all, it is shown that this introduction of an alkoxy group into at least one acetyl group of the comparatively known N-acetylated 3,5-diamino-2,4,6-tri-odbenzoic acids reduces the toxicity, as is shown in the following table, in which the LD50 values intravenous injection on small rodents of substances 1 to III are compared with those of the comparatively known compounds IV to VIII (cf. AA Lars en, J. Am. Soc., 78, p. 3210 [1956], table III) explained: Substituent in | LD60 3-position To 5-position | g / kg iv I amino methoxyacet- 13.5 (R) amino II acetamino methoxyacet- 16 (R) amino III methoxyacet- methoxyacet- 16 (R) amino-amino IV acetamino- acetamino- 12.5 to 14.3 (M) 14.7 (R) V amino acetamino 6.5 to 7.9 (M) VI amino hydroxyacet- 4.32 (M) amino VII acetamino hydroxyacet- 7.8 to 9.2 (M) amino VIII acetamino acetoxyacet- 7.8 to 9.2 (M) amino (R = rat, M = mouse) In addition, the salts of the substances are distinguished by unexpectedly better solubilities. The mixed salts with physiologically acceptable inorganic and organic bases are consistently more soluble in water than the comparatively known N-acylated 3,5-diamino-2,4,6-triiodobenzoic acids.

Sodium salts, much more easily soluble.

After i. v. application in the form of their salts mainly to almost exclusively via the kidney tract retired, some even particularly quickly, so that they, possibly in Combination with additives customary in galenic pharmacy as special kidney contrast media indicate, with the outstanding non-toxicity and the high solubility of the salts make it possible to produce highly concentrated and not very viscous solutions.

However, the use of the substances according to the invention is not alone limited to the kidney display. The advantages outlined make them ideal X-ray contrast media z. B. for angiography, angiocardigraphy and vasography, in which large amounts of contrast medium solution enter the veins or Arteries must be injected, with mixtures of the acylated 3,5-diamino-2,4,6-triiodobenzoic acids for the purpose of further increasing the solubility in the form of appropriately suitable salt solutions can be used as an X-ray contrast medium.

The substances are also suitable for representing other body cavities, such as B. in hysterosalpingography, bronchography and peroral gastrography. The then necessary, higher viscosity of the X-ray contrast agent can be achieved once are achieved by choosing a higher salt concentration, in particular by using a viscosity promoting cations, e.g. B. methylglucamine, or by adding a small amount Amount of a thickener, e.g. B. carboxymethyl cellulose.

The preparation of the compounds to be used according to the invention can be done in different ways. The 3-amino-5-alkoxyacetamino-2,4,6-triiodobenzoic acids can be obtained by direct partial acylation of 3,5-diamino-2,4,6-triiodobenzoic acid obtained with the corresponding alkoxyacetic anhydride, expediently by several days Reaction at room temperature and in the presence of an acidic catalyst such as p-toluenesulfonic acid. They can also be obtained by iodizing the z. B. from 3-nitro-5-aminobenzoic acid 3-amino-5-alkoxyacetaminobenzoic acids easily accessible by acylation and subsequent hydrogenation, expediently in a dilute aqueous solution with potassium iodine dichloride.

The 3, 5-di- (alkoxyacetylamino) -2,4,6-trijodbenzoic acids can are obtained e.g. B. by treating the 3-amino-5-alkoxyacetamino-2,4,6-triiodobenzoic acids with excess alkoxyacetic anhydride at elevated temperature, expediently between 130 and 180 "C and subsequent alkaline saponification of the resulting polyacyl products.

The 3-alkanoylamino-5-alkoxyacetylamino-2,4,6-triiodobenzoic acids can be prepared either by 3-acylation of 3-amino-5-alkoxyacetamino-2,4, 6-triiodobenzoic acids by means of anhydrides or halides of lower fatty acids or but by 3-acylation of a 3-amino-5-alkanoylamino-2,4,6-triiodobenzoic acid medium the anhydride of an alkyloxyacetic acid.

If 3-amino-5-alkanoylamino- or 3,5-di- (alkanoylamino) -2,4,6-triiodobenzoic acids are used or the crude polyacyl products of the latter obtained in the acylation with excess alkoxyacetic anhydride, suitably at a temperature between 140 and 200 "C with subsequent distilling off of acid and anhydride in vacuo as well Saponification of the resulting polyacyl products is formed under Displacement of alkanoyl residues 3,5-Di- (alkoxyacetamino) - in addition to more or less 3-alkoxyacetamino-5-alkanoylamino-2,4,6-triiodobenzoic acid.

The N-substituted 3,5-diamino-2,4,6-triiodobenzoic acids which can be prepared in this way are strong acids, their neutral salts with physiologically acceptable inorganic ones and / or organic bases, such as. B. those of sodium, lithium, methylglucamine, Morpholines, the ethanolamines, etc., which can be sterilized hot without decomposition in an aqueous solution Solutions with high levels of bound iodine result, such as those in particular for injectables X-ray contrast media are required.

Process for the preparation of the compounds to be used according to the invention The reaction mixture of 50 g of 3,5-diamino-2,4,6-triiodobenzoic acid monohydrate, 1 gp-toluenesulfonic acid and 40 ml of methoxyacetic anhydride is extracted with the exclusion of moisture Stirred for 10 days at room temperature, a dark-colored precipitate forming separates, which is sharply sucked off and then with absolute alcohol and ether is washed. For cleaning, the gray-green crude product is dissolved in 2N sodium hydroxide solution, the alkaline solution is adjusted to pH 3 with hydrochloric acid and after the addition of activated charcoal stirred for a short time. It is then filtered and precipitated with strong hydrochloric acid. To suctioning off the precipitate, washing and drying in air gives 30.6 g (55% of theory) of almost pure 3-amino-5-methoxyacetamino-2,4,6-trijodbenzoic acid from the decomposition point 250 to 252 "C. The last impurities are removed by briefly Boil with methanol or by recrystallizing the ammonium salt from ammonium chloride Water.

The reagent grade acid has a decomposition point of 267 to 270 "C.

728 g of 3-amino-5-nitrobenzoic acid, dissolved in 3.6 l of tetrahydrofuran, are slowly mixed with 728 g of methoxyacetic anhydride and 2 hours on the Steam bath heated with stirring and reflux, a precipitate being formed. Afterward the solvent is largely distilled off, the last portion with addition of 21 water in a vacuum. The precipitate obtained is filtered off with suction and washed with water and dried. The yield of 5-nitro-3-methoxyacetylaminobenzoic acid is 1007 g (99% of theory), melting point 230 to 2320 ° C. with decomposition.

330 g of this nitro compound are dissolved in 3 l of water as the ammonium salt and after previous filtration through activated charcoal in the presence of 30 g of Raney nickel at 25 to 400 C and a hydrogen pressure of 100 atmospheres catalytically to the end hydrogen uptake of hydrogen. The filtered solution is mixed with 230 ml of glacial acetic acid acidified, the precipitate which has separated out is filtered off with suction, washed and dried. Man 290 g (92% of theory) of 3-amino-5-methoxyacetylaminobenzoic acid monohydrate are obtained in this way with a melting point of 200 "C.

240 g of this amino compound in 66 l of water are added with stirring 83 ml of concentrated hydrochloric acid and 1.641 2N potassium iodine dichloride solution were added. To Stirring for 20 hours at room temperature, the precipitate formed is suctioned off, washed and dried, 568 g (95% of theory) of crude 3-amino-5-methoxyacetamino-2,4,6-trodbenzoic acid with a decomposition point of 239 to 255 "C. For further purification will that Crude product with 568 ml of concentrated ammonia solution in the crystalline ammonium salt transferred.

After suctioning off, 494 g (80% of theory) of ammonium salt dihydrate are obtained, which is treated with activated charcoal in aqueous solution. The filtered solution will acidified again with hydrochloric acid, and after suctioning off, washing and drying the precipitate 409 g (90 ovo of theory) 3-amino-5-methoxyacetamino-2,4,6-triiodobenzoic acid with a decomposition point of 267 to 270 "C can be obtained.

54.6 g of 3,5-nitraminobenzoic acid are dissolved in 300 ml of dioxane with 40 g Ethoxyacetic anhydride reacted and after removal of the dioxane and the resulting Ethoxyacetic acid 65 g (81,010 of theory) 3-ethoxyacetamino-5-nitrobenzoic acid obtained from melting point 159 to 162 "C.

53,6g3-ethoxyacetamino-5-nitrobenzoic acid become in ammoniacal Solution by hydrogenation in a roller autoclave in the presence of Raney nickel to the corresponding Amino compound reduced. The solution obtained in this way is after the catalyst has been separated off diluted with water to a volume of 6000 ml and after adding 1500 ml of glacial acetic acid iodized with 300 ml of a 2N potassium iodine dichloride solution with stirring at room temperature. The reaction mixture is then left for a further 48 hours at room temperature touched. The resulting precipitate is filtered off and washed with dilute aqueous sulphurous acid, washed with water, then with methanol ether and dried. For the purpose of further purification, aqueous ammonium salt solution prepared therefrom is over neutral A1203 filtered, after which the filtrate is acidified, filtered off with suction, washed and drying the precipitate 94 g (76.5% of theory) of pure 3-amino-5-ethoxyacetamino-2,4,6-triiodobenzoic acid with a decomposition point of 250 to 254 "C.

A mixture of 120 g of 3-amino-5-methoxyacetylamino-2,4,6-triiodobenzoic acid and 200 ml of methoxyacetic anhydride are heated to 160 ° C. for 20 minutes while stirring. 140 ml of excess anhydride are then distilled off in vacuo. Of the The residue is dissolved in 200 ml of water and about 100 ml of concentrated sodium hydroxide solution at pH 10 heated on a water bath for 1 hour, neutralized, treated with charcoal, filtered and precipitated with hydrochloric acid. The suspension of 134 g of isolated crude product in 1.341 Ethanol is mixed with 18 ml of concentrated ammonia solution, whereupon after the ammonium salt separates out in a short time. After a few hours, the salt is sucked off, dissolved in 700 ml of water, decolorized with activated charcoal and precipitated with hydrochloric acid. To the Removal of the last traces of dye, the cleaning is repeated with the ammonium salt or the aqueous ammonium salt solution is filtered through 700 g of aluminum oxide.

102 g (76% of theory) of di- (methoxyacetylamino) -2,4,6-trij are obtained in this way odbenzoic acid with a decomposition point of 270 to 272 "C.

SOg 3-Amino-5-ethoxyacetamino-2,4,6-triiodobenzoic acid are used in 85 ml of ethoxyacetic anhydride and heated after complete dissolution at 160 "C for 15 minutes long stirred. After cooling, the reaction mixture is stirred into 900 ml of petroleum ether the petroleum ether decanted after 30 minutes and the remaining oil with 120 ml of approx. 100% sodium hydroxide solution heated on the steam bath for 1 hour.

The mixture is then allowed to cool and the crude acid is precipitated by addition dilute hydrochloric acid (1: 1).

To purify the isolated crude product in 800 ml of water as Dissolved sodium salt at a pH = 4.9 and this solution over an aluminum oxide column filtered. After acidifying the filtrate with dilute hydrochloric acid, filtering off with suction and drying of the precipitate, 42 g (74% of theory) of pure 3,5-di- (ethoxyacetamino) -2,4,6-triiodobenzoic acid are obtained with a decomposition point of 252 to 255 "C. a) 100 g of pure 3-amino-5-methoxyacetylamino-2,4,6-triiodobenzoic acid and 150 ml of acetic anhydride are in the presence of 2 g of p-toluenesulfonic acid for 3 hours heated on the steam bath while stirring. After cooling, the reaction mixture becomes diluted with ether and sucked off the precipitate. It is suspended in 400 ml of water and brought into solution in the heat with the addition of lye at pH 10. The alkaline Solution is then neutralized, filtered through charcoal and then with concentrated Acidified hydrochloric acid, 91 g (85% of theory) of 3 - acetylamino - 5 - methoxyacetylamino-2,4,6-triiodobenzoic acid with a decomposition point of 270 to 276 ° C. b) 30 g of 3-amino-5-acetylamino-2,4,6-triiodobenzoic acid and 50 ml of methoxyacetic anhydride are heated to about 1400 C. for 25 minutes. At 130 "C are then in a vacuum 30ml of liquid distilled off. The residue is suspended in 150 mol of water and, as described under a), cleaned. 23.4 g (70% of theory) are obtained 3-Acetylamino-5-methoxyacetylamino-2,4,6-triiodobenzoic acid having a decomposition point from 268 to 274 "C.

100 g of pure 3-amino-5-methoxyacetylamino-2,4,6-triiodobenzoic acid are reacted with 200 ml of propionic anhydride and 2 g of p-toluenesulfonic acid analogously to a) and worked up. 86.3 g (79% of theory) of 3-propionylamino-5-methoxyacetylamino-2,4,6-triiodobenzoic acid are obtained with a decomposition point of -271 to 275 "C.

A mixture of 50 g of 3-amino-5-ethoxyacetamino-2,4,6-triiodobenzoic acid and 80 ml of acetic anhydride is heated to about 130 ° C. for about 30 minutes with stirring. Then the cooled reaction mixture is stirred with 800 ml of petroleum ether diluted. After about 1 hour, the petroleum ether layer is decanted off and the residue 1 hour with 120 ml of an approx. 100% own sodium hydroxide solution heated to 100 "C. From the alkaline solution, the crude acid is mixed with dilute hydrochloric acid after cooling (1: 1) precipitated again in 600 ml of water by adding dilute sodium hydroxide solution is solved up to a PH 5. This sodium salt solution is passed over an aluminum oxide column filtered. The precipitate separated after acidification of the filtrate is removed by stirring washed in 500 ml of methanol, filtered off with suction and dried. 44 g (82.6 0 / o of theory) 3-acetamino-5-ethoxyacetamino-2,4,6-triiodobenzoic acid with a Decomposition point from 268 to 272 "C.

400 ml of acetic anhydride are mixed with 600 ml of 980/0 but formic acid at -15 "C added, the reaction temperature should not exceed +11 "C, and without further The reaction mixture is then cooled with 100 g of 3-amino-5-methoxyacetamino-2,4,6-triiodobenzoic acid added with stirring. After 11/2 hours of stirring at 55C after the Cool down the deposited precipitate is filtered off with suction and washed with ether. That already pure white The crude microcrystalline product is purified using the sodium salt. This gives 84.3 g (80.70 / 0 of theory) 3 -formamino-5-methoxyacetamino-2,4,6-triiodobenzoic acid with a decomposition point of 277 "C.

A mixture of 12 g of 3,5 - di - (acetylamino) -2,4,6-triiodobenzoic acid, 3 g of the sodium salt of this acid and 30 ml of methoxyacetic anhydride are under Stir heated to 190 "C for about 15 minutes.

Then 20 ml of methoxyacetic acid or methoxy anhydride are added at 130 "C in a vacuum distilled off. The residue suspended in 40 ml of water is concentrated with Sodium hydroxide solution heated on a water bath at pe 10 for 1 hour. Then the solution is neutralized, filtered through charcoal and precipitated with concentrated hydrochloric acid. The secluded The crude product is purified using the ammonium salt, 11.5 g (68 0 / o of theory) a - mixture obtained with a decomposition point of 266 to 268 "C. From the analysis of the sharply dried, anhydrous product results for the mixture as follows Composition: about 85 mole percent 3,5-di- (methoxyacetylamino) -2,4,6-triiodobenzoic acid and about 15 mole percent 3-acetylamino -5-methoxyacetylamino-2,4,6-triiodobenzoic acid.

J OCH, Found ....... 56.9 0 / o 8.55 01o, equivalent weight through potentiometric titration 669 mol-Calculated for the J OCH3 weight dimethoxy compound ... -56.5 0 / o 9.2 0 / o 674 monomethoxy compound 59.1 0 / o 4.8 0 / o 644 55 g of 3,5-diamino-2,4,6-triiodobenzoic acid monohydrate are poured into a solution of 1 g of p-toluenesulfonic acid in 76 mol with vigorous stirring Acetic anhydride entered. After a few minutes the reaction sets in, whereby the Reaction temperature should not exceed 90 "C. The excess acetic anhydride is then distilled off to dryness in a water jet vacuum. The one with 105 ml of methoxyacetic anhydride added residue is then heated to 135 to 140 ° C. with stirring heated, with dissolution taking place after about 30 minutes. After that, the anhydride distilled off in a water jet vacuum and the dry residue in 2N sodium hydroxide solution warm dissolved, the solution for saponification of the polyacyl products boiled for 10 minutes, wherein Formaldehyde escapes. The brown, alkaline solution is made up to pH 3 with hydrochloric acid added, the acidic solution stirred with decolorizing charcoal, filtered and then the The filtrate was strongly acidified with hydrochloric acid. The resulting weakly colored precipitate is suctioned off and washed with water. After drying the precipitate in the air 56.8 g of crude product with a decomposition point of 247 to 248 "C. For purification it is triturated with 60 ml of dioxane, the colorless product is suctioned off and so long washed with dioxane until the filtrate runs colorless. Then the The residue is washed thoroughly with ether and obtained after drying in the air 45.3 g of colorless microcrystalline powder with a decomposition point of 266 "C, a mixture of about 800 / o 3-acetamino-5-methoxyacetamino-2,4,6-tri- iodobenzoic acid (I) with about 20% is 3,5-di- (methoxyacetamino) -2,4,6-triiodobenzoic acid (II).

Found Calculated I II methoxyl content 5v6% 4.8% 9.20 / 0 54.8 g of 3,5-diamino-2,4,6-triiodobenzoic acid monohydrate are dissolved in 285 ml of acetic anhydride at 75C dissolved with stirring, the solution cooled to 50 ° C. and 4 drops of concentrated sulfuric acid added, with an intensifying precipitate with a slight warming fails. After subsequent warming on the steam bath for 20 minutes and then Ice cooling, the crude 3,5-di- (acetamino) -2,4,6-triiodobenzoic acid is suctioned off and washed with cold acetic anhydride and then with ether.

The air-dry 59.9 g of crude product are mixed directly with stirring 105 ml of methoxyacetic anhydride reacted at 150 "C in 5 to 10 minutes to dissolve, whereupon the solution is concentrated to dryness in a water jet vacuum. The dry residue is dissolved in 2N sodium hydroxide solution and the solution is boiled for 10 minutes, with formaldehyde escapes. After cooling and diluting, the alkaline solution is diluted with Hydrochloric acid acidified to pH 3.2, stirred with decolorizing charcoal and filtered. The pure filtrate is strongly acidified with concentrated hydrochloric acid, the precipitate Aspirated, washed with water and air dried. The obtained 55 g Pale colored crude product with a decomposition point of 263 ° C will be as before cleaned with dioxane. The pure product obtained in this way is treated twice with 200 ml of water each time stirred, filtered off with suction, washed with water and dried in the air.

50.3 g of trihydrate are thus obtained as a white, microcrystalline powder a mixture of about 330 / o (I) 3-acetamino-5-methoxyacetamino-2,4,6-triiodobenzoic acid and about 67% (II) 3,5-di (methoxyacetamino) -2,4,6-triiodobenzoic acid.

Analysis: Found Calculated Water - 7.48% 7.42% methoxyl (based on anhydrous substance) ...... 7.74 0 / o I: 4.8 0 / o II: 9.20 / o For the No protection is claimed for the method of making the compounds.

Example 1 58.56 g of 3-amino-5-methoxyacetamino-2,4,6-triiodobenzoic acid are with the addition of 3.892 g sodium hydroxide 100% in double distilled Dissolved in water. As stabilizers, 0.32 g of the solution are tert. Sodium citrate 2 H2O and 0.07 g of the sodium salt of ethylenediaminetetraacetic acid were added. It will be with double distilled water made up to 100 ml.

This solution, which has a pH of 7.5, is filtered, in ampoules filled and sterilized at 120 ° C for 20 minutes. The remedy is for urography certainly.

Specific weight at 20 "C 1.408. Viscosity at 20 ° C 5.52 cP, at 37 ° C 3.46 cps. Iodine content 370 mg / ml.

Example 2 65.5 g of 3,5-di (methoxyacetamino) -2,4,6-triiodobenzoic acid are with 4.96 g of methylglucamine, 2.87 g of sodium hydroxide in double distilled water dissolved, with 0.32 g of tert as stabilizers. Sodium citrate 2H2O and 0.04 g of the sodium salt of ethylenediaminetetraacetic acid are added. The solution is made up to 100 ml with double distilled water, filtered, filled in ampoules and sterilized for 20 minutes at 120 "C. PH = 7.3. Specifics Weight at 20 "C 1.424. Viscosity at 20" C 11 cP, at 37 "C 5.8 cP. Iodine content 370 mg / ml.

Example 3 62.66 g of 3-acetylamino -5-methoxyacetylamino-2,4,6-triiodobenzoic acid are tert with 3.89 g of sodium hydroxide (1000 /, in) with the addition of 0.32 g.

Sodium citrate - 2 H2 0 and 0.04 g of the sodium salt of ethylenediaminetetraacetic acid 100 ml dissolved in double distilled water as stabilizers. PH 7.3; specific Weight at 20 "C. 1.406. The solution is filtered, filled into ampoules and at Sterilized at 120 "C. Iodine content 370 mg / ml. Viscosity at 20 ° C 7.34 cP, at 37" C 5.1 cP. The remedy is particularly useful for angiography, angiocardiography and vasography suitable.

Example 4 59.96 g of 3-amino-5-ethoxyacetamino-2,4,6-triiodobenzoic acid are added with the addition of 3.89 g of sodium hydroxide 100% in double distilled water solved. As stabilizers, 0.32 g of the solution are tert. Sodium citrate -2 2 H2 0 and 0.04 g of the sodium salt of ethylenediaminetetraacetic acid were added. It will be with double distilled water made up to 100 ml.

This solution, which has a pH of 7.3, is filtered, in ampoules filled and sterilized at 1200C for 20 minutes. Specific gravity at 20 "C 1.417.

Viscosity at 20 ° C 6.38 cP, at 37 ° C 3.59 cP. The agent is for the kidney and vascular presentation is determined.

Example 5 63.06 g of 3-formylamino - 5 - methoxyacetamino-2,4,6-trodbenzoic acid monohydrate are with 3.89 g of sodium hydroxide 1000 / o, 0.32 g of tert. Sodium citrate 2 H2 0 as well 0.04 g sodium salt, the ethylenediamine tetraacetic acid with double distilled Water on 100 ml dissolved. PH = 7.2; specific gravity at 200 C 1.432. viscosity at 20 "C 6.7cP, at 37C 4.0cP, 1 ml contains 370 mg of bound iodine. The solution becomes filled into ampoules and sterilized at 120 ° C for 20 minutes.

Claims (3)

PATENT CLAIMS: 1. X-ray contrast media containing compounds of the general formula as shading substance where R1 is hydrogen or an alkanoyl radical with 1 to 3 carbon atoms, which in the case of the acetyl radical can also be alkoxylated with an alkyl radical containing 1 to 3 carbon atoms, R2 is an alkyl radical with 1 to 3 carbon atoms and Y is hydrogen or the radical of a physiologically acceptable inorganic and / or represents organic base. 2. X-ray contrast medium according to claim 1, containing as a shadow Substance is a mixture of 3,5-di- (alkoxyacetamino) -2,4,6-triiodobenzoic acid and 3 -Alkanoylamino-5-alkoxyacetamino-2,4,6-triiodobenzoic acid and / or its salts with physiologically acceptable inorganic and / or organic bases. 3. X-ray contrast medium according to claim 1 and 2, containing as a shadow Substance is a mixture of 3,5-di- (methoxyacetamino) -2,4,6-triiodobenzoic acid and 3-acetamino-5-methoxyacetamino -2,4,6-triiodobenzoic acid and / or its salts with physiologically acceptable inorganic ones and / or organic bases.