CS214835B2 - Method of making the bis-amides of the 5-amino-2,4,6-triiodizophtale acid - Google Patents

Description

The present invention relates to the preparation of novel 5-amino-2,4,6-triiodoisophthalic acid bis-amides.

For perfect X-ray imaging, for example of essential parts of the vascular system, such as the aorta, or for perfect imaging of the urinary tract, solutions of constituents must be applied at high concentrations in order to obtain good contrast of the system of interest. High concentrations of contrast agents require very good solubility of the contrast agents while at the same time low toxicity and good tolerability.

It is known that the general compatibility of contrast agents depends on their hydrophilic character (PK Knoefel, Radiocontrast Agents, Vol. Pergamon Press 1971, p. 133 et seq.) And that the electrical charge of the cation and anion contributes substantially to mitigating lipophilic-toxic effects, particularly triiodinated aromatics.

In currently used x-ray contrast media salt solutions, the iodine-containing anion is a contrast-providing component, while the cation does not fulfill any of the roles required to cause a number of adverse effects:

Thus, all ions contribute to the osmotic pressure of the salt solutions of X-ray contrast agents at a ratio of their molar concentration, i.e., for example, that in salts of substituted triiodobenzoic acids half of the osmotic pressure is due to the iodine-free and thus 1 cation-free contrast effect. The high osmotic pressure of concentrated X-ray contrast agent solutions is responsible for a number of undesirable pharmacological effects, such as vasodilation, pain, as well as diuretic effect and thus dilution of the excreted contrast agent in urography. Further, conventional high molecular weight iodine-base cations such as meglumine, glucamine, lysine, arginine and others increase the viscosity of contrast agent solutions considerably.

Lower molecular weight cations increase the viscosity of contrast agent solutions only slightly, but they have a toxic effect. Thus, brain brain damage and vascular pain induced by sodium ions and higher ethanolamine toxicity are described [EVILL, CA and GT Benne: Metrizamide as a non-ionic urographic agent, and comparison with sodium iothalamate and its dimer, Invest Radiol 9: 434] 437 (1974), HILAL, SK: Trands in Preparation of New Angiographic Contrast Media with Special Emphasis on Polymeric Derivatives, Invest Radiol 5: 458-468 (1970).

On the one hand, suitable compounds of the invention have the advantages of comparing 214835 for the formation of cations

However, they do not have their disadvantages.

They are characterized by the following properties:

Electric charge is maintained as a carrier of hydrophilic properties and as a cause of the extremely good solubility of the triiodaromates.

The osmotic pressure of the contrast agent solutions decreases significantly as the proportion of the non-contrasting cationic osmotic pressure is eliminated.

The viscosity is significantly reduced because the salt concentration is significantly reduced at the same iodine concentration. This allows the production of highly concentrated and yet very low viscous solutions. The lower viscosity of the solutions facilitates their application, and it has proved to be favorable in selective angiography that the microcirculation is influenced by less than the viscous solutions.

According to the invention, 2,4,6-triiodoisophthalic acid derivatives are suitable as bases, which have the necessary low toxicity and are suitable to form readily water-soluble salts with acid contrast agents.

These novel compounds of the invention have the general formula I

CO-N " i X, i.

r) in which denotes

X C 1 -C 8 alkylene residue,

R ¹ is hydrogen,

R ² is hydrogen, methyl, ethyl or 2-hydroxyethyl,

R ³ is hydrogen or methyl,

R ⁴ is hydrogen, methyl, ethyl or 2-hydroxyethyl,

R ^{5 a} hydroxylated C 2 -C 3 -alkyl radical having 1 to 2 hydroxy groups,

R ⁶ is hydrogen, methyl, ethyl, or 2-hydroxyethyl,

R ^{7 is a} hydroxylated C 2 -C 3 -alkyl radical having 1-2 hydroxy groups, as well as their salts with acids suitable for contrast agents.

Lower alkyl groups may be straight or branched and contain 1 to 4 carbon atoms. Methyl is preferred. However, alkyl groups such as ethyl, n-propyl or isopropyl are also suitable.

When these groups are hydroxy-substituted, they may be straight or branched.

They contain 2 to 4, preferably 2 to 3, carbon atoms and 1 to 3, preferably 2, hydroxyl groups in the alkyl radical. Suitable hydroxyalkyl radicals include, for example:

2-hydroxypropyl,

3-hydroxypropyl,

1- (hydroxymethyl) ethyl,

2.3- dihydroxybutyl,

2.4- dihydroxybutyl,

3.4- dihydroxybutyl,

2.3-dihydroxymethylpropyl, (tris-hydroxymethyl) methyl,

2.3.4- trihydroxyhutyl,

1.3.4-trihydroxybutyl and preferably

2-hydroxyethyl,

1.3- dihydroxyisopropyl,

2.3- dihydroxypropyl residue.

The aminoacyl radicals R ¹ , R ^2, N-X-CO- (R ¹ and R ² are as defined above) are derived from the known synthetic and natural amino acids. Thus, X represents a straight or branched alkylene radical which may be optionally substituted by a hydroxyl, methoxy or amino group. Preferred radicals X are straight or branched, lower alkylene radicals having 1 to 3, in particular 1 to 2 carbon atoms, such as methylene, ethylene, propylene, butylene, methylmethylene, methylethylene, methylpropylene, methylbutylene and ethylpropylene, hydroxyethylene, hydroxymethylmethylene, methoxymethylmethylene .

The compounds of the formula I according to the invention are used in particular in order to convert the acids of the contrast agents into their salts.

Basically all known intravenous acids of the contrast agents are suitable for salt formation, as is currently preferred in urography and angiography and for the visualization of body cavities of conventional iodinated contrast agents, such as mononuclear triiodinated benzoic acids such as amidotriazoic acid, iodamide, Jothalamic acid, Joxithalamic acid, Yoglycic acid and the like.

Dinuclear hexaiodoated monocarboxylic acids such as ioxaglycinic acid and others and dinuclear hexaiodoic dicarboxylic acids such as iocarminic acid and others.

The salts according to the invention, which consist of one triiodinated cation and one known iodinated acid anion of the contrast agent, are known for their stable salt solution stability and excellent compatibility, as shown in the following table by way of example of the compounds of the invention bis- (2-hydroxyethyl) amide iothalate -aminoacetamido-2,4,6-triiodoisophthalic acid (A-Jothalamate) and bis- (n-methyl-2,3-dihydroxypropyl) amide-amidotriazoate 5-amidoacetamido-2,4,6-isophthalic acid (B-amidotrizoate) ).

TABLE I

A-Jotha- Na-Jothala- Megljotha- B-Amido- Megl.Amldolamate to have a laminate trizoate trizoate iodine in salt 58% solution viscosity with 300 mg iodine in ml, 37 ° CvcP 2,4 molarity solution with 300 mg iodine in mol / lire 0.394

111, with mice (20 g) g iodine / kg 5 10.5 DL 50 rats (100 g) g iodine / kg? 10

DL 50 was determined in mice and rats of 30 mg of iodine in 1 ml at a rate of 2 ml per minute

Thus, the above table shows, by way of example, the iothalamate salt of the invention that the novel compounds are characterized by a particularly high iodine content, which is only achieved with less well tolerated sodium salts. Furthermore, it can be seen that the viscosity of the salt solution according to the invention is particularly low and that the molarity and thus the osmotic pressure of the salt solution is substantially lower than the molarity and osmotic pressure of the sodium and meglumine salt solutions. Also, the tolerability of the compounds of the invention in mice and rats is clearly superior to that of the known sodium and meglumine salts.

60% 47% 54% 47% 2.7 5.2 3.5 5.0 0,787 0,787 0.394 0,787 8.0 4,5 (4,1-4,9) - - 7.0 7.4 Ϊ 10 7.5

(6.8-7.9) intravenous injection of solutions containing

The excellent compatibility of the new salts in conjunction with their low viscosity allows the production of highly concentrated, yet easy to inject, contrast media solutions. According to the invention, contrast agents can be used in the form of solutions of their salts in concentrations of 20 to 500 mg of iodine per ml of solution.

The process for the preparation of the compounds of the formula (I) according to the invention consists essentially in that the compound of the formula (IV) is known per se

where

X and R ³ to R ⁷ have the meanings given above, undergo hydrazinolysis in a manner known per se, and the base thus obtained, if desired, is optionally N-alkylated and / or converted into an acid salt with the intermediary protection of the free hydroxyl groups suitable for X-ray contrast agents.

Compounds of formula I in which R ¹ and R ² simultaneously represents a hydrogen atom, are obtained preferably from the compounds of formula IV using hydrazinolysis. The hydrazinolysis is carried out in a manner known per se, as is generally known [cf., for example, DOS 2,253,567, J. Am. Chem. Soc. 71, 1856 (1949), J. Chem. Soc. 2343, 1926, Chem. Ber. 83, 244 (1950)]. To this end, the starting product of the formula IV is dissolved, for example, in an organic, preferably water-miscible solvent (such as methanol or ethanol) and reacted with hydrazine, preferably in an alcoholic solution, the hydrazine being expediently used in excess.

The subsequent introduction of the alkyl or hydroxy substituted alkyl group R ³ is also carried out according to the N-alkylation methods known to the person skilled in the art, such as by reacting in an alkaline solution with the corresponding alkyl sulfate or alkyl halide, preferably bromide, at room temperature.

If it is advantageous for the reaction to protect the intermediately free hydroxyl groups present in the molecule from N-alkylation, these are carried out in a conventional manner by means of readily reversible groups. The introduction of such protecting groups may be carried out by esterification (for example by introducing a preferred acetyl or benzyl residue) or by etherification (for example by introducing a triphenylmethyl radical).

The protection of the hydroxyl group can also be carried out by ketalization or acetalization, for example with acetaldehyde, acetone or dihydropyran.

Later cleavage of the intermediate protecting groups to liberate the final desired hydroxyl groups is also carried out by methods generally known to those skilled in the art. Thus, for example, the deprotection can be carried out without a separate reaction step with the treatment and isolation of the reaction products. However, it can be carried out in a conventional manner in a separate reaction step. Acyl protecting groups can be removed, for example, by alkaline hydrolysis, and acetal, ketal or ether protecting groups can be removed by acid hydrolysis.

The production of the described salts according to the invention is carried out in a manner known per se by reacting, for example, an iodinated organic acid with a base in water in equivalent weight ratios. The salts of the invention may be isolated from the aqueous solution by conventional means such as, for example, evaporation of the solvent or precipitation with organic solvents.

The novel starting materials of the formulas II or IV are conveniently prepared from the known 5-amino-acid dichloride, optionally

5-alkylamino-2,4,6-triiodoisophthal (alkyl = = CH 3) by known methods.

In the first reaction step, the N-acylated 5- (R ³ -amino) -2,4,6-triiodoisophthalic acid dihalide is conventionally reacted with the corresponding halobutyric acid Hal.X.COCl (where Hal and X are as defined above).

In the second reaction step, the amidation of the two carbonyl groups is then carried out by reaction of the acid chloride with HN.R @ ⁴ R @ ⁵ or HN.R @ ⁶ R @ ⁷ in a manner known per se. Both amidation reactions are carried out, for example, in a suitable solvent at a temperature of 0 to 100 ° C, preferably at a temperature of 20 to 80 ° C. Suitable solvents include, but are not limited to, polar solvents such as water, dioxane, tetrahydrofuran, dimethylformamide, dimethylacetamide, hexametapol and the like, and mixtures thereof. Since the amidation reaction proceeds exothermically, it is optionally expedient to cool the reaction mixture slightly so that the reaction temperature can be maintained at about 50 to 60 ° C. Hydrogen chloride released during the amidation reaction is bound either by an appropriate excess of HN.R ⁴ R ⁵ or HN.R ⁶ R ⁷ , respectively, or by addition of a conventional proton acceptor. As proton acceptors, preferably tertiary amines such as triethylamine, tributylamine or pyridine are used.

The inorganic or organic salts leaving during the reaction are separated in a manner known per se, preferably, for example, by means of conventional ion exchange columns or by filtration over known adsorbents, such as diaion or Amberlite XAD-2 and 4.

Preparation of starting compounds of formula IV is carried out dichloride 5- (R ⁵ -amino) -2,4,6-triiodoisophthalic acylation of an aromatic amino group in position 5 of the corresponding N-phthaloyl-X-COCl (X is defined above) itself by known methods and subsequent amidation of the acid chloride groups at the 1 and 3 positions as described above. The preparation of the starting product (IV) is described in detail in the example of 2,4,6-triiodo-5-phthalimido-acetamidoisophthalic acid bis- (N-methyl-2,3-dithyloxypropyl) -lamide:

To an ice-cooled solution of 119.1 g (0.2 mol) of 5-aminoisophthalic acid dichloride in 0.5 liter of dimethylacetamide was added portionwise with stirring, 178.9 g of N-phthaloylglycine chloride, stirred for several hours under ice-cooling, and then overnight at room temperature. The solution is then stirred slowly into about 10 liters of water, stirred for 45 minutes, the precipitate is filtered off with suction, washed with water and then taken up in 3 liters of ethyl acetate.

The filtered ethyl acetate phase is washed with half-saturated sodium bicarbonate solution and twice with water, dried over sodium sulphate and concentrated in vacuo. The residue was then treated with ether and dried under vacuum at 50 ° C. There was thus obtained 2,4,6-triiodo-5-phthalimidoacetamidoisophthalic acid dichloride (127.3 g, 81%), m.p. ~ 255 ^° C (dec.).

To a solution of 78.3 g (0.1 mol) 2,4,6-triiodo-5-phthalimidoacetamidoisophthalic acid dichloride in 0.25 liter dimethylacetamide heated to 50 ° C was slowly added dropwise a solution of 31.5 g of N-methylaminopropane- 2,2-diol in 0.15 liters of dimethylacetamide. After the warming has subsided, it is then added

71.3 ml of tributylamine and stirred at 50 ° C for an additional hour. After cooling to room temperature, the solvent is evaporated off under vacuum, the residue is treated with 2 liters of methylene chloride for 1 hour, the precipitate is filtered off with suction, washed again with methylene chloride, once again with 2 liters of methylene chloride, sucked off and dried under vacuum at 50 ° C. The crude product is then heated with stirring with water, followed by crystallization. After cooling with stirring, the precipitate is filtered off with suction and dried at 50 DEG C. in vacuo. 66.0 g (72%) of 2,4,6-triiodo-5-phthalimidoacetamidoisophthalic acid bis (N-methyl-2,3-hydroxypropyl) diamide, m.p. 303 DEG C. (decomposition).

By definition, -CONR ⁴ R ⁵ and -CONR ⁶ R ⁷ may also be different in the compounds of the invention. In this case, the amidation of the —COCl groups at positions 1 and 3 is also carried out according to the above embodiments, but successively, i.e. first with the base HN — R ⁴ R ⁵ and then with another base HN — R ⁶ R ⁷ as in details given in the preparation of 2,4,6-triiodo-5-phthalimidoacetamidoisophthalic acid (2,3-dihydroxypropyl) - (N-methyl-2,3-dihydroxypropyl) diamide:

To a solution heated to 60 ° C containing 42.1 g (0.4 mol) of N-methylaminopropane 214835

Of -2,3-diol in 1 liter of dioxane, 156.6 g (0.2 mol) of acid dichloride are added with stirring

2,4,6-triiodo-5-phthalimidoacetamidoisophthalic acid, the reaction mixture was further stirred at 60 ° C for three hours, filtered and the filtrate concentrated in vacuo. The residue is then stirred for 20 minutes with 2.5 liters of water, the separated precipitate in 3 liters of ethyl acetate is shaken with 1 liter of aqueous sodium bicarbonate solution and 1 liter of water, dried over sodium sulfate and concentrated in vacuo. The residue was treated with ether. After drying in vacuo at 50 ° C, 2,4,6-triiodo-5-phthalimidoacetamidoisophthalic acid (N-methyl-2,3-dihydroxypropyl) amide chloride is thus obtained (108.4 g [64%).

Mp 268-272 ° C (dec.).

To a solution of 68.0 g of 2,4,6-triiodo-5-phthalimidoacetamidoisophthalic acid N-methyl-2,3-dihydroxypropyl iamide chloride in 1.5 liters of dimethylacetamide heated to 60 ° C was added dropwise 18.2 g of 1- of amino-2,3-propanediol in 100 ml of dimethylacetamide, stirred at 50 ° C for two hours and the dimethylacetamide was removed in vacuo. The residue was treated twice with methylene chloride, filtered off with suction and dried in vacuo at 50 ° C. There was thus obtained 2,4,6-triiodo-5-phthalimidoacetamidoisophthalic acid (2,3-dihydroxypropyl) - (N-methyl-2,3-dihydroxypropyl) diamide.

Yield: 38.3 g (56%).

Melting point 286-289 ° C (dec.). Examples

Example 1

5-Aminoacetamido-2,4,6-triiodoisophthalic acid bis (N-methyl-2,3-dihydroxypropyl) -diamide

To a suspension of 92.6 g of 2,4,6-triiodo-5-phthalimidoacetamidoisophthalic acid bis (n-methyl-2,3-dihydroxypropyl) -diamide (m.p. ~ 303 ° C, decomposition) in 600 ml of ethanol is stirred at room temperature. 18.2 ml of 80% hydrazine hydrate are added dropwise with stirring, and then the reaction mixture is refluxed for two hours. After cooling, 300 ml of 1 N hydrochloric acid are added to the reaction mixture. The reaction mixture was stirred for 1 hour at room temperature, the precipitate was filtered off with suction, the filtrate was freed from ethanol in vacuo and the remaining aqueous solution was filtered through a basic ion exchanger. The filtrate is then evaporated in vacuo, the residue is stirred with 300 ml of n-butanol under reflux and stirred at room temperature. The precipitate is filtered off with suction, washed with cold n-butanol and dried under vacuum at 50 ° C.

Yield: 62.4 g (79% _of theory), m.p. ~ 263 DEG C. (decomposition).

Analogously were prepared: a) 5-Aminoacetamide-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl) - (N-methyl-2,3-dihydroxypropyl) -diamide, melting point 251 ° C (decomposition) from ( 2,4,6-triiodo-5-phthalimidoacetamidoisophthalic acid 2,3-dihydroxypropyl) - (N-methyl-2,3-dihydroxypropyl) diamide, m.p. 286 DEG-289 DEG C. (decomposition).

b) 5- (2-Aminopropionamido) -2,4,6-diiodoisophthalic acid bis (2,3-dihydroxypropyl) -diamide, yield 49% of theory, m.p. 248 DEG C. (decomposition) from bis (2,3-dihydroxypropyl) 2,4,6-triiodo-5-phthalimidopropionamidoisophthalic acid diamide, m.p. ~ 298 ° C (dec.).

c) 5- (3-Aminopropionamido) -2,4,6-triiodoisophthalic acid bis- (2,3-dihydroxypropyl) -diamide, yield 26% of theory, m.p. 278-281 ° C (decomposition) from bis- 2,4,6-triiodo-5-phthalimidopropionamidoisophthalic acid, 3-dihydroxypropyl) diamide, m.p. 298-300 ° C (dec.).

d) 5-Aminoacetamido-2,4,6-triiodoisophthalic acid tetrakis- (2-hydroxyethyl) -diamide, 44% yield, m.p. 262-263 ° C (decomposition) from tetrakis (2-hydroxyethyl) -diamide 283 ^DEG- 285 ^DEG C. (decomposition), 2,4,6-triiodo-5-phthalimidoacetamidoisophthalic acid.

Example 2

5-Aminoacetamido-2,4,6-triiodoisophthalic acid bis (N-methyl-2,3-dihydroxypropyl) -diamide

5-aminoacetamido-2,4,6-triiodoisophthalic acid 394.3 g monomethylamide acid

5-acetamido-2,4,6-triiodoisophthalic (jothalamic acid) 306,4 g disodium calcium acetate 0,1 g redistilled water to 1000 ml

Prior to filling, the solution is optionally adjusted to a pH of 6.5 to 7.5 by addition of a small amount of the appropriate acid or base, filtered through a bacterial filter, filled and sterilized. It contains 380 mg of iodine per ml.

Example 3

Bis (N-methyl-2,3-dihydroxypropyl) -diamide salt of 5-aminoacetamido-2,4,6-triiodoisophthalic acid and 5,5 '- (3,6-dioxooctanedioldiimino) -bis [2,4,6- 3- (2-methoxy-1-methylcarbamoylethyl)] isophthalamide

Acid bis (N-methyl-2,3-dihydroxypropyl) diamide 5214838

-Aminoacetamido-2,4,6-triiodoisophthalic acid 29.4 g

5,5 (3,6-dioxaoctanedioyldiimino) -bis [2,4,6-triiodo-3- (2-methoxy-1-methylcarboylethyl) iisophthalamide 37,1 g adetate disodium salt 0,01 g redistilled water to 100 ml

The solution is optionally adjusted to a pH of 6.5 to 7.5 by adding a small amount of the appropriate acid or base in the solution. The solution is filtered through a bacterial filter, filled and sterilized. Contains 380 ml of iodine in 1 ml.

Example 4

Iothalamic acid salt with 5-aminoacetamido-2,4,6-triiodoisophthalic acid bis (2-hydroxyethyl) diamide

5-Aminoacetamido-2,4,6-triiodoisophthalic acid bis- (2-hydroxyethyl) -diamide 27.2 g 5-acetamido-2,4,6-triiodoisophthalic acid monomethylamide (jothalamic acid) 24.2 g disodium calcium edetate 10 mg redistilled water to 100 ml

Before filling, the pH of the solution is optionally adjusted to 6.5 to 7.5 by adding a small amount of the appropriate acid or base. The solution is then filtered through a bacterial filter, filled and sterilized. It contains 300 mg of iodine in 1 ml of solution.

Example 5

Amidotriazoic acid salt and bis- (N-methyl-2,3-dihydroxypropyl) -diamide

5-aminoacetamido-2,4,6-triiodoisophthalic acid

As described in Example 2, 5-aminoacetamido-2,4,6-triiodoisophthalic acid bis- (N-methyl-2,3,3-dihydroxypropyl) -diamine is obtained and a solution of the corresponding iodine-containing contrast agent is obtained from amidotriazoic acid and amidotriazoic acid. mg j / ml.

Example 6

5- (4-Aminobutyrylamino) -2,4,6-triiodoisophthalic acid bis- (N-methyl-2,3,3-dihydroxypropyl) -diamide

To a suspension of 94.7 g (0.1 mol) of bis- (N-methyl-2,3-dihydroxypropyl) -diamide

2,4,6-tri-5- (4-phthalimido-butyrylamino) isophthalic acid (m.p. 285 DEG C. with decomposition) in 600 ml of ethanol is added dropwise at room temperature while stirring with 18.2 ml of 80% hydrazine hydrate and then heated at reflux for 2 hours. After cooling, 300 ml of 1 N hydrochloric acid are added to the reaction mixture. Subsequently, the reaction mixture was stirred at room temperature for 1 hour, the precipitate was filtered off with suction, the filtrate was freed from ethanol in vacuo and the remaining aqueous solution was filtered through a basic ion exchanger. The filtrate is then concentrated in vacuo, the residue is stirred under reflux with 300 ml of n-butanol and stirred at room temperature. The precipitate is filtered off with suction, re-treated with cold n-butanol and dried under vacuum at 50 ° C. Yield: 34 g (42% _of theory), m.p. 270 DEG C. (dec.).

The following compounds were prepared analogously:

(a) 5- (4-Amino-butyrylamino) -2,4,6-triiodoisophthalic acid bis- (2,3-dihydroxy-propyl-diamide), yield 34% of theory, m.p. 2,4,6-triiodo-5- (4-phthalimido-butyrylamino) -isophthalic acid 3-dihydroxypropyl) -diamide, m.p. 285 DEG-287 DEG C. (decomposition).

b) 5- (4-Aminobutyrylamino) -2,4,6-triiodoisophthalic acid bis- (2-hydroxy-1-hydroxymethyl-ethyl) -diamide, yield 41% of theory, melting point 265 DEG C. (decomposition) from bis- 2,4,6-triiodo-5- (4-phthalimido-butyrylamino) -isophthalic acid (2-hydroxy-1-hydroxymethylethyl) -diamide, m.p. 276 DEG C. (decomposition).

c) 5- (3-Amino-propionamido) -1,4,6-triiodoisophthalic acid bis- (2-hydroxy-1-hydroxymethylmethylethyl) -diamide, yield 51% of theory, melting point 287 ° C (decomposition) from bis- 2,4,6-triiodo-5- (3-phthalimidopropionamido) isophthalic acid (2-hydroxy-1-hydroxymethyl-ethyl) -diamide, m.p. 300 DEG C. (decomposition).

d) 5- (2-Amino-propionamido) -2,4,6-tri-iodo-isophthalic acid tetrakis- (2-hydroxyethyl) -diamide, yield 68% of theory, melting point 270 DEG C. (decomposition) from tetrakis- ( 2,4,6-triiodo-5- (2-phthalimidopropionamido) -isophthalic acid 2-hydroxyethyl) diamide, m.p. 293 DEG C. (decomposition).

e) 5- (3-Amino-propionamido) -2,4,6-triiodoisophthalic acid tetrakis- (2-hydroxyethyl) -diamide, yield 44 o / o theory, melting point 290 ° C (decomposition) from tetrakis- (2) 2,4,6-Trio-5- (3-phthalimidopropionamido) -isophthalic acid, hydroxyethyl) diamide, m.p. 295 DEG C. (decomposition).

Claims (1)

Process for the preparation of 5-amino-2,4,6-triiodoisophthalic acid bis-amides of the formula CO ~ N ^ «·. i \ n Λ J. J o ^χ N -Λ - c CHV ^X V ^X CO N ^of ft "in which it denotes X C 1 -C 8 -alkylene radical, R ¹ is hydrogen, R ² is hydrogen, methyl, ethyl or 2-hydroxyethyl, R ³ is hydrogen or methyl, R ⁴ is hydrogen, methyl, ethyl or 2-hydroxyethyl, R ^{5 a} hydroxylated C 2 -C 3 -alkyl radical having 1-2 hydroxy groups, R ⁶ is hydrogen, methyl, ethyl or 2-hydroxyethyl, R ^{7 a} hydroxylated C 2 -C 3 -alkyl radical having 1-2 hydroxy groups, as well as their salts with acids suitable for contrast agents, characterized in that the compound of the formula IV CQ - N O f! Ά. lj N o X-CO. In what X and R ³ to R ⁷ are as defined above, undergo hydrazinolysis known per se, and the base thus obtained is optionally Intermediate protection of free hydroxyl groups is N-alkylated and / or converted to a salt with an acid suitable for contrast agents.