SI8610621A8 - New bis-(hydroxyalkyl-amides) 5-(n-alkyl-alpha-hydroxyacylamino) -2,4,6-threeiodine-isophthalic acid and process for their preparation - Google Patents

Description

P P 621/86

BRACCO INDUSTRIA CHIMICA S.p.A.

New bis- (hydroxyalkyl-amides) 5- (N-alkyl-o ' -hydroxyacylamino) -2,4,6-triodo-isophthalic acid and process for their preparation

C 07 C 103/24

A 61 K 29/02

The present invention relates to the technical field of organic chemistry, specifically to new 2,4,6-tridio-isophthalic acid derivatives useful as a shadow component in X-ray contrast media, and to a process for their preparation.

5-acylamino-2,4,6-triio-isophthalic acid diamides and their use in X-ray contraceptives by agents is known from CH-PS 544.551 · Contains only simple, unsubstituted aliphatic acyl groups, generally acetyl groups. Some representatives of this group that have carbohydrate residues are sufficiently water-soluble, e.g. 3-Aoethylamino5-N-methyl-acetylamino-2 $ 4,6-tri-iodo-benzoylglucosamine, which became known under the common name METRI2AMIDE. Also compare compound no. 11 US-PS 3 701 771, GB-PS 1 321 591,

CH-PS 554 551, AT-PS 318 134 oz. DE-OS 2 031 724; publications T. Almen, S. Salvesen, K. Goalkeeper; Acta Radiologia Suppl. 335 (1973), 1-13, 233-75, 312-38. However, its difficult accessibility, its appearance in the form of a virtually inseparable isomer mixture, and in particular the relatively insignificant stability in the aqueous solution, which significantly limits its usefulness and makes it difficult to handle.

The advancement was bis- (1,3-dihydroxyisopropyl 1 mj d) L-5- <x -hydroxypropionylamino-2,4,6-tri iodo-isophthalic acid, which became known as IOPAMIDOL. Cf. See also DE-PS 2 547 789, GB-PS 1 472 050,

US-PS 4 001 323, Felder et al. II FARMACO, Ed. Sc. j52,

835-844 (1977). It has a much simpler structure, greater stability, easier insulation and a lower viscosity of its concentrated aqueous solutions. The toxicity of this compound is very low.

Recently, two further derivatives of 5-acylamino-2,4,6-triodo-isophthalic acid, namely bis- (2,3-dihydroxypropylamide) 5- (N-2-hydroxyethyl-acetyl-), have become known from BE-PS 855 580. amino) -2,4,6-triodo-isophthalic acid and bis (2,3-dihydroxypropylamide) 5- (N-2,3-dihydroxypropyl-acetylamino) -2,4,6-triodo-isophthalic acid having similar properties. They are derived from the barely soluble bis- (2,3dihydroxypropylamide) 5-acetylamino-2,4,6-tri iodine of ophthalic acid; water solubility is Ί% (g / v) at 20 to 40 ° C. It is therefore no wonder that some isomers in water are insoluble and therefore practically useless. Cf. BE-PS 855 580, p. 21 to 22.

Phasevo has clearly demonstrated in recent years that it is extremely difficult and rarely successful to find compounds that would have the properties that are needed today for non-ionic X-ray contrast media for widespread use. These properties are true water solubility sufficient to produce stable, i.e. non-unsaturated concentrated solutions, maximum general and neurotropic transferability, minimal osmolality, low viscosity, maximal stability against hydrolytic influences, and a simple enough structure to allow economical synthesis as well as facilitate isolation and cleaning.

But now we have found new 2,4,6-triiodisophthalic acid derivatives of the general formula (H0) ₂ -allcyl-NH-CO (HO) ₂ -alkyl.-NH-CO co-ch (oh) -rv which mean (H0 ) _2- alkyl-dihydroxypropyl,

R is hydrogen or methyl and

R _{1 is an} alkyl residue having 1 to 4 carbon atoms and a process for their preparation, which is carried out in such a way that the reactive functional derivative of 5- (N-alkyl-oC ~ hydroxyacyl-amino) -2,4,6-tridio-isophthalic acid formula

J

CO-CH-R i

A (II) where R and R _{1 have} the above meaning, A means a lower acyloxy residue of about 1 to 5 carbon atoms or a halogen atom and a Y-CO-reactive residue of an acid halide or anhydride, reacted with di- or trihydroxyalkylamine, of which the hydroxyl functions may be masked by acetalization or ketalization and in the resulting bis- (hydroxyalkylamide) derivative of 5- (N-alkyl-N-hydroxyacyl-amino) -2,4,6-tri-iodo-isophthalic acid. hydrolytically cleave masking function A and, if appropriate, the acetal or ketal function present to the hydroxy function.

- 5 Alternatively, a reactive derivative of 5- (Nalkyl-1-hydroxyacyl-amino) -2,4,6-tri iodine floor saliva of the general formula (V) can be prepared and reacted with dihydroxypropylamine, or functional derivatives and hydrolytically cleaved in the obtained product of the masking group and all hydroxyl functions are released.

Preferably, the reactive acid derivatives are suitable for their metabolism: their acid halides, in particular acid chlorides, i.e. 5- ( ^N -alkyl- "- acyloxyacyl-amino) -2,4,6-tri-isophthalic acid dichloride or the corresponding acid anhydride with organic or inorganic acid. Examples of suitable organic acids are: lower fatty acids, such as e.g. propionic, butyric, valeric, or carbon dioxide esters, such as e.g. monomethylester, monoethylester or carbonic acid monobenzylester. Suitable inorganic acids include: hydrochloric acid, sulfuric acid polyester, phosphoric acid, phosphoric acid, phosphorous acid dialkyl ester, e.g. phosphoric acid diethyl ester.

The reaction with dihydroxypropylamine or a derivative thereof is usually carried out in a solvent inert to the reaction of e.g. in an aprotic solvent, such as dimethylf omami du, dimethylacetamide, etc., at a temperature range of about -0 to about +150 ° 0.

Preferably, the following compounds for metabolism are used as the hydroxyalkines or their derivatives:

1,5-dihydroxyisopropylamine (Serinol), 2,3-dihydroxypropylamine, tris- (hydroxymethyl) -aminomethane [2-amino-2-hydroxymethyl-1,3-propanediol, as well as their ketals or acetals, e.g. 5-affino-2,2-dimethyl-1,3-dioxane, 4-aminomethyl-2,2-dimethyl-1,3-dioxolane, 5-amino-2-methyl-1,5-dioxane, 5 amino-2-phenyl- 1,5-dioxane or 5-amino-1,3-dioxane.

The hydroxyl function must be masked to introduce hydroxyacyl residues and for some metabolism of the compounds containing them. Typically, an acyloxyl function A consisting of a lower acyloxyl moiety, preferably an acetoxyl moiety, can be used for this purpose, which, at the final stage, can be easily converted by alkaline saponification to a hydroxyl function.

Particularly for the preparation of hydroxyacetyl derivatives, suitable halogenacetyl compounds of formula (V), wherein R is hydrogen and A halogen, preferably chlorine, can also be derived. By alkaline saponification, the halogenacetyl group is converted into the hydroxyacetyl group that is desired in the simplest way.

- 7 Overall, the new compounds of Formula (I) are characterized by high water solubility that achieves absolute peak values for individual representatives, optimum portability and relatively low osmolality, as well as their high stability against hydrolytic influences, with only a clear surpass inherently good stability on the aromatic N atom of the non-alkylated starting materials from which they originate. This enhanced stability against hydrolytic influences is important for the prevention of trace amounts of free aromatic amines only in the light of their possible but unacceptable cytotoxic effects in relation to X-rays. Cf. to this: A. Norman et al, Radiology 129. 199-205 (Oct. 1978).

The viscosity of aqueous solutions of these compounds is highly dependent on their specific structure. Within the framework of the proposed compounds, it can vary greatly and thus optimally adapt to the different requirements of each application.

It is particularly surprising and valuable that by introducing lower unsubstituted, i.e. hydrophobic, alkyl residues, onto the aromatic N atom in position 5 of the parent compound: e.g. bis-(1,5-dihydroxyisopropylamide) L-5-a-hydroxypropionylamino-2,4,6-triiod isophthalic acid IOPAKEDOL or bis (2,5-dihydroxypropylamide) 5-hydroxyacetylamino2,4,6-trid-isophthalic acid : Not only water retention remains, but even with N-methyl compounds, it is even significantly strengthened and furthermore increases stability against hydrolytic events.

At 20 ° C, IOPAMIDOL has a water solubility of 440 mg / ml <i.e. 89.7% (g / v)), the hydrate correspondingly 507 mg J / ml (i.e. 62.7% (g / v)). 5-N-alkyl derivatives belonging to (g / v). In addition, their hydrolysis stability is higher than that of the corresponding, non-alkylated compounds.

The new X-ray contrast agents of the formula (I) have, on the basis of their excellent properties, in particular good water solubility, non-ionic character, high stability, very good portability and relatively simple structures, a very wide range of applications. To prepare them economically and therefore to be used for purposes where the cost of contrast media is limited.

The focus of their use is vascular imaging, ie angiography, such as. arteriography, cardiac imaging (cardiography) and cardiac coronary angiography (coronary angiography), abdominal selective abdominal and thoracic aortography, further renal and cerebral angiography, phlebography as well as urography and contrast enhancement in computed tomography. The last use mentioned requires very large amounts of contrast medium, e.g. 250 ml of contrast medium solution with 500 mg of iodine / ml containing 75 g of total iodine. It is understandable that for such high doses for purely diagnostic purposes, portability and safety requirements are unusually high. Further areas of application are e.g. bronchography, imaging of body cavities and fluid spaces, as well as lymphangiography.

- 9 The invention is illustrated by the following embodiments.

EXAMPLE 1

Bis- (1,3-Dihydroxyisopropylamide) L-5- (N-methyl-Ck-hydroxypropionylamino) -2,4,6-trid-isophthalic acid

A solution of 14.5 g of L-5- (N-methyl-a-acetoxypropionylamino) -2,4,6-tri-iodo-isophthalic acid (0.02 mol) dichloride in 35 ml DMF was added with stirring at 0 to 2 ° C. (dropwise 9.1 g of Serinol C 1 = 1,3-dihydroxyisopropylamine) (0.1 mol) in 30 ml of DMP. Stirred for another 3 hours at 20 ° C and finally evaporated the reaction solution to the syrup. The residue was crystallized by trituration with The crude product is taken up in 100 ml of water, the evacuated solvent is removed by evacuation and kept at 40 to 50 ° C with aqueous 2 n sodium hydroxide solution at pH 11.6, and the acetoxy function is now hydrolyzed. maintaining the pH constant with the addition of sodium hydroxide, completely consuming 29 ml of 2 n sodium hydroxide.

- 40 Dilute the resulting alkaline solution with 200 ml of water and percolate through a column filled with cationic (n \ exchange resin (e.g. Amberlite ^ ^J IR 120) and anion exchange resin (e.g. Amberlite ^ IR-45) <

Evaporate the column eluate to dryness.

Yield: 11.08 gbis- (1.5 "dihydroxyisopropylamino) L-5- (Nmethyl-α-hydroxypropionyl-amino) -2,4,6-trid-isophthalic acid,

i.e. 7θ% theory.

M.p .: (after recrystallization from abs. Ethanol)

280 ° C (sinter at 210 ° 0).

Quartz Gel DC: Running. vehicle ethyl acetate / glacial acetic acid / water = 10: 5: 5 · Lisa at Rf 0.29.

The L-5- (Nmethyl-oc-aceto-6-propionyl-amino) -2,4,6-tri-iodo-isophthalic acid dichloride used as an intermediate is obtained as follows:

A) 5-Amino-2,4,6-triodo-isophthalic acid is treated according to the method described in DE-OS 2 050 217 in sulfuric acid with formaldehyde to give 6-methylamino-2,4,6-trid-isophthalic acid from the ground . 198 MS 200 ° C.

DC on silica gel with ethylmethylketone / ethanol / water / ice = 20: 8: 5: 1 »5 · Rf 0,55 ·

8) 25 g ff-metj. 1 "for nn-2,4,6-tert-butyl naphthalic acid in 120 ml of thionyl chloride in the presence of 0,1 ml

- 11 quinolines cook 7 in? at reflux. After complete distillation of thionyl chloride, the residue is stirred in 120 g of ice water containing table salt (125 g) and sodium bicarbonate (12 g).

The product was extracted with ethyl acetate (200 ml). From the extract, 5-methylamino2,4,6-trihydro-isophthalic acid dichloride was obtained by evaporation. Tal. is 167 ° 0 · Thin layer chromatography on silica gel with benzene / hexane »1: 1; Rf 0.50.

O ^ ClgJjNOg CI Calc .: 11.62% 01 Found: 11.74%

J calc .: 62.44% J calc .: 62.74%.

C) 12 g of 5-n-ethylamino-2,4,6-triodo-isophthalic acid dichloride (0.02 mol) was added dropwise at 0 to 2 ° C of La-acetoxy-propionic acid chloride (0-2 mol) ( 0.03 mol) »Then stir for 1 to 2 hours at 20 ° C. The reaction solution was stirred in ice water. The recovered product is filtered off, dried and recrystallized from a little benzene.

Thus, 14 g of L-5- (N-methyl-a-acetoxypropionyl-amino) -2,4,6-triiod isophthalic acid dichloride are obtained from m.p. 187 to 190 ° C.

- 12 DO on silica gel with hexane / chloroform / ethyl acetate = J: 1: 1; 2 spots at Ef 0.22 and 0.5.

C ^ H ^ OlgJjCTO ^ 01 Calcd: 9.79% 01 Found: $ 9.80

J Calc .: 52.59% J Found ::52.46 $

EXAMPLE 2

Bis- (2,5-dihydroxypropylamide) L-5- (N-methyl- <RTI ID = 0.0> hydroxypropionyl-amino) -2,4,6-trifluoro </RTI> isophthalic acid

14.5 g of I * -5- (N-methyl-a-acetoxypropionyl · * amino) -2,4,6-triiod isophthalic acid dichloride (0.02 mol) in 30 ml

The DMF was dissolved dropwise with 9.4 g of 2,3-dihydroxypropylamine (1 = 1-amino-2,3-propanediol), 50 ml of DMF was added and digested and processed in the manner described in Example 1.

10.8 g of bis- (2,3-dihydroxypropylamide) L-5- (N-methylα-hydroxypropyl 1-amino) -2,4,6-trifluoro-isophthalic acid are obtained, i.e. 68% of theory.

Tal. (after recrystallization from ethanol) 195 ° 0 (sinter at 187 ° C).

DO on quartz gel: run. agent ethyl acetate / glacial acetic acid / water = 10: 5: 3. One spot at Rf 0.45. θ18 ^Η 24 ^ 3 ^ 3θ8 ^, ^ 2θ ^J Calc .: 47.05% Found: 47.00%

H ^ O calcd: 2.23% found: 2.8%.

EXAMPLE 3

Bis- (2,5-dihidroksipropilamid) 5- ^{J CHR,} N-ethyl-iiidroksiacetilamino) -2,4,6-tri iodine-isophthalic acid

To a solution of 18.2 g of 1-amino-2,5-propanediol in 7θ or DMAC, 28.4 g of 5- (N-methyl-acetoxyacetyl-amino) -2,4 dichloride were added dropwise at 5 ° θ for 45 minutes. , 6-tridio-isophthalic acid in 90 ml of DMAC. The reaction mixture was stirred for several hours and then evaporated in vacuo to a syrup. The residue was triturated with methylene chloride and acetone, the solvent was decanted, the residue was removed by evacuation, the solvent still held, taken up in 200 ml of water and carefully maintained at 45 ° C by addition of 5 ° ml of 2 n sodium hydroxide solution at pH 11 to 11.5 µg, thereby hydrolyzing the acetoxy group.

The resulting solution is desalted with a percolation / column (R) filled with cation exchange resin (eg 200 ml Amberlite ^k 'IR-120) and another column filled with anion exchange resin (eg 250 ml Amberlite ^ IR-45).

The eluate was evaporated, the residue was dissolved in methanol, methylene chloride was added to the solution, precipitating the desired product. Yield: 22 g of the title compound, i.e. 71% of theory.

Melting point: about 190 ° C (sintered at about 165 ° C).

Silica gel DC: 2-butanone / glacial acetic acid / water = 15 ^: 5 ^: 5 · Stains at Rf 0.48 and 0.40.

θή ^ 22 ^ 5 ^ 5θδ • '- ^{Air ^:} ^ 8.99% and Found .: 48.69%.

The playable compound is soluble in water (5 S in 1 ml of water) and in methanol. (100% g / v).

The dichloride used for 5- (N-methylacetoxyacetyl-amino) -2,4,6-trihydro-isophthalic acid is obtained as an intermediate, as follows:

g of 5-methylamino-2,4,6-trid-isophthalic acid dichloride (0.0525 mol) in 80 ml of DMAC was added dropwise with 10.7 g of acetoxyacetyl chloride while stirring at 0 to 5 ° θ.

The mixture was then stirred overnight at room temperature. The reaction solution was stirred in ice water. 56.7 6 Dichloride of 5- (N-methyl-acetoxyacetyl-amino) -2,4,6-triiodisophthalic acid was obtained from m.p. 198 to 200 ° 0. Yield: 98.8% DC theory on silica gel with benzene / methanol = 10: 5 »Rf = 0.64. O ₁₅ H ₈ C1 ₂ J ₅ NO ₅ Calc: 01 9.9% J 55.5% Found: C1 10.05%, J 55.41%.

EXAMPLE 4

Bis- (R (+) 2,5-dihydroxypropylamide) 5- (N-methyl-hydroxyacetyl-amino) -2,4,6-trifluoro-isophthalic acid

This compound is obtained as a suitable racemic compound by the fact that, similar to that described in Example 3, in solution

7 6 B (+) 1-amino-2,3-propanediol (0.077 mol) in 40 ml of DMAO in which 10.8 g of potassium carbonate (0.077 mol) is suspended, dropwise add 20.2 g of 5- (N-) dichloride. methylacetoxyacetyl-amino) -2,4,6-tri-iodo-isophthalic acid dissolved in 40 ml of DMAO, the reaction mixture was stirred for several hours and then processed.

15 »2 g of the title compound are obtained, i.e. 69.5% of theory.

Melting points: 283 to 284 ° 0.

DO: Rf e 0.24. Tek. isopropanol / isobutanol / ammonia 25% is 7 ^: 7j6.

θ17 ^ 22 ^ 3 ^ 3θ8 ^: i ^zra o * ^: 43.99% »found: 48.74 ·%.

Ca] p ° = + 4.85 °, Ca] ^ ° ₆ = ⁰ (c = 10% in water).

EXAMPLE 5

Bis- (2,3-dihydroxypropylamide) 5- (N-methyl-hydroxyacetylamino) -2,4-6-tri-isophthalic acid

A. Bis- (2,3-isopropylidenedioxypropylamide) = 5- (N-methyl-hydroxyacetyl 1-amino) -2,4,6-trifluoro-butyric acid bis- (2,2-dimethyl- 1,3-dioxolane- (4) -ylmethyl-amide) 5- (Isomethyl 1-chloroxyacetyl-amino) -2,4,6-trifluorophthalic acid

17 g of 5- (N-methyl-acetoxyacetyl-amino) -2,4,6-trifluoro-isophthalic acid dichloride (0.025 mol) in 50 ml of DMAO are added dropwise at 5 to 8 ° C with stirring, a solution of 16 g of 4-amino16 methyl-2, 2-dimethyl-1,3-dioxolane (0.122 mol). The mixture was stirred at room temperature for 18 hours, the filtered hydrochloride was filtered off and the filtrate was completely evaporated in vacuo. The evaporation residue was suspended in water, filtered off, dissolved in aqueous methanol and treated at 2θ to 55 ° C with 2 n sodium hydroxide solution at pH

10.5 to 11.0, wherein the acetoxy group is completely hydrolyzed. The resulting solution was neutralized exactly by the careful addition of hydrochloric acid, the filter filtered and evaporated to dryness. The residue is taken up in water, crystallizing the resulting bis- (2,5-isopropylidenedioxypropylamide) 5- (N-methylhydroxyacetyl-amino) -2,4,6-tridio-isophthalic acid. Yield: 15.2 g, i.e. 71% of theory.

M.p .: (after recrystallization from diluted methanol) 180 to 181 ° C.

DO: Rf = 0.295, flow. chloroform / hexane / methanol 5: 5: 1.

θ25 ^ 3Ο ^ 5 ^ 5θ8 ^: calc. 44.41%; found: 44.08%.

This compound is very easily soluble in methanol, ethanol, and chloroform, but in contrast very little soluble in water.

B. Bis- (2,3-Dihydroxypropylamide) 5- (N-methyl-hydroxyacetyl-amino) -2,4,6-trid-isophthalic acid g bis- (2,3-isopropylidenedioxypropylamide) 5- (N-methyl- of hydroxyacetyl-amino) -2,4,6-triio-isophthalic acid was dissolved in a solution of 185 ml of 0.1 n aqueous hydrochloric acid and 185 ml of methanol and maintained under stirring for 5 hours at 50 ° C. Hydrochloric acid is removed from the reaction solution by percolation through a column filled with 75 ml of weakly basic ion exchange resin, e.g. Amberlite ^) IR-45 and evaporated to dryness.

Yield: 12.2 g of bis- (2,3-dihydroxypropyl-amide) 5 (N-methyl-hydroxyacetyl-amino) -2,4,6-tri-iodo-isophthalic acid, i.e. 90% of the theory.

M.p .: 190 ° C (amorphous product).

After recrystallization from 95% ethanol; mp: 300 ° 0 on decay.

An indication of the best known embodiment to the applicant for the economic exploitation of the claimed invention

Bis- (2,3-dAlihydroxypropylamide) 5-XHnethyl-; idixoxyacetylamino) -2,4,6-triiod isophthalic acid έ _---------------—-

To a solution of 18.2 g of 1-amino-2,3-propanediol in 70 ml of DMAC was added dropwise at 5 ° 0 with stirring for 45 minutes 28.4 g of 5- (N-methyl-acetoxyacetyl-amino) -2,4 dichloride , 6-tridio-isophthalic acid in 90 ml of DMAC. The reaction mixture was stirred for several hours and then evaporated in vacuo to a syrup. The residue was triturated with methylene chloride and acetone, the solvent was decanted, the residue was removed by evacuation, the remaining solvent was taken up in 200 ml of water and carefully maintained at 45 ° C with the addition of 50 ml of 2 n sodium hydroxide solution at pH 11 to 11.5, whereby the acetoxyl group is hydrolyzed.

The resulting solution is desalted with a percolation / column (R) filled with cation exchange resin (eg 200 ml Amberlite 'IR ^J -120) and another column filled with anion exchange resin (eg 250 ml Amberlite ^ IR-45).

The eluate was evaporated, the residue was dissolved in methanol, methylene chloride was added to the solution, precipitating the desired product. Yield: 22 g of the title compound, i.e. 71% of theory.

Melting point: about 190 ° C (sintered at about 165 ° θ).

DC on the gelatin gel: 2-butanone / glacial acetic acid / water liquid = 15: 3: 5 · Stains at Rf 0.48 and 0.40.

- / 2θτ422 ^ 3 ^ 3θθ ΐ ^{ΖΓ &} θ · ^: 48.99%; found: 48.69%.

The soluble compound can be soluble in water (J g in 1 ml of water) and in methanol (100% g / v).

5- (N-Niethylacetoxyacetyl-amino) -2,4,6-trihydro-isophthalic acid dichloride used as an intermediate is obtained as follows:

> 2 g of 5-Niethylamino-2,4,6-triiodo-isophthalic acid dichloride (0.0525 mol) in 80 ml of DMAC was added dropwise with 10.7 6 acetoxyacetyl chloride while stirring at 0 to 5 ° θ.

The mixture was then stirred overnight at room temperature. The reaction solution was stirred in ice water. 36.7 S of 5- (N-methyl-acetoxyacetyl-amino) -2,4,6-tri iodophthalic acid dichloride is obtained from m.p. 198 to 200 ° 0. Yield: 98.8% DO theory on silica gel with benzene / methanol = 10: 3; Rf = 0.64.

° 13 ^H 8 ^C1 2 ^J 3 ^NO 5 ^{Calc: 01} 9.9% S 53.5% Found: CI 10.05%, S 53.41%.

Claims (4)

1. Process for the preparation of bis (hydroxyalkylamides) 5- (N-alkyl-O-hydroxyacyl-aryano) -2,4,6-tri-iodo-isophthalic acid of the general formula (H0) _2- allyl-NH-co (HO) _2- alkyl-NH- CO (I), CO-CH (OH) -R in which (H0) ₂ ~ alkyl is dihydroxypropyl, R is hydrogen or methyl and R, an alkyl residue having 1 to 4 carbon atoms, characterized in that the reactive functional derivative is 5- (N-alkyl-cx-hydroxy-acylamino) A process according to claim 1, characterized in that dimethylformamide, dimethylacetamide, is used as an inert organic solvent. 2,4,6-Triodo-isophthalic acid of general formula J N / ^R 1 (II), CO-CH-R i A P 621/86 -M where R.in have the above meaning, Y is an acid halide residue such as chlorine, A is an acyloxy residue of 1 to 5 carbon atoms, reacted with dihydroxyalkylamine of formula (HO) _2- alkyl-NH ₂ as 1,3 -dihydroxy-isopropylamine or 2,3-dihydroxypropylamine or its ketal, in the presence of an inert organic solvent, at a temperature of -10 ° C to +150 ° C, and in the case of the product obtained, hydrolytically cleaves masking function A and, optionally, acetal or ketal function into the hydroxy function. Process according to claim 1, characterized in that alkaline saponification with NaOH is carried out. 4. New bis (hydroxyalkylamides of 5- (N-alkyl-10-hydroxyacyl-amino) -2,4,6-triiod isophthalic acid of the general formula wherein (HO) _2- alkyl dihydroxypropyl, R is hydrogen or methyl and an alkyl residue having 1 to 4 carbon atoms. For BRACCO INDUSTRIA CHIMICA S.p.A.: 19552-V-91-KA SUMMARY We propose a process for the preparation of new bis- (hydroxyalkyl-amides) 5- (N-alkyl-OC-hydroxy-acylamino) -2,4,6-triiodisophthalic acid (H0) _2- alld. 1 -NH-CO (HO) ₂ - alkyl 11 -NH-CO ^X CO-CH (OH) -R J / Ri (ID N 'CO-CH-R i But with metabolism Y-CO γ-co j and dihydroxypropylamine or a ketal thereof, and, if necessary, by hydrolysis of the product obtained. Compounds (I) are useful as hay components in X-ray contrast media.