DE1493979C3 - Bis- (5-amino-2,4,6-triiodo-N-alkylisophthalic acid amide) derivatives of dicarboxylic acids, their salts with pharmaceutically acceptable cations, processes for the preparation of these compounds and X-ray contrast media containing them - Google Patents

Description

NH

CONHR

where R denotes a corresponding lower alkyl radical with a corresponding dicarboxylic acid dihalide condensed in a manner known per se and, if appropriate, the product thus obtained in a salt with pharmaceutically usable Converts cations.

3. X-ray contrast medium, characterized in that it is one of the im Claim 1 contain compounds mentioned.

The invention relates to bis (5-amino-2,4,6-triiodo-N-alkyl-isophthalic acid amide) derivatives of dicarboxylic acids, their salts with pharmaceutically acceptable cations, processes for the preparation of these compounds and X-ray contrast media containing them according to the preceding claims.

The compounds according to the invention can be used as an active component of X-ray contrast media, in particular of means for intravenous cholangiography (x-ray of the bile ducts), use.

The salts of the compounds according to the invention with, in intravenous X-ray contrast media, known pharmaceutically acceptable cations, such as. B. the sodium, N-methylglucamine and diethanolamine salts, are soluble in water. Solutions of these salts can be administered intravenously, with side effects occurring only to a small extent. The salts are upon such administration quickly eliminated from the system. The higher members of the series are preferred excreted by the liver via the biliary system and serve in this way - due to their proportion-

Table I.

COOH

moderately high iodine content - to make the structures of the biliary system visible, such as B. the gallbladder and the bile ducts when irradiated with X-rays in a manner known for this purpose. The lower members of the series are to a considerable extent excreted by the kidney and can can be used to visualize the urinary system. The low toxicity and high salt solubility several of these compounds also make them useful as vasographic agents (i.e. as a means of x-raying the vessels).

40 On progress in application technology

Using aqueous solutions of the di-N-methylglucamine salts of those described in the examples Acid amides were determined for acute intravenous toxicity in mice. The results of these determinations and the solubility data for the disodium salts of the invention Acid amides are given in Table I.

COOH

-Jv J- _NH _ _R 2_ _NH _J L _CO NHR ³

example

R ¹ . R ³

LD ₅₀ value. mouse
(g / kg)

Solubility of
Disodium salt

(e / lOOccm
Solution; 25 ^: C)

CH ₃ -CH ₃ -

CO (CH ₂ J ₄ CO -
CO (CH ₂ J ₆ CO-

14-16.5
! 9.5

y / y

continuation

example R ¹ . R- ' - CO (CH ₂ ) ₈ CO - LD ₅₀ -Werl, mouse Solubility of
Disodium salt - CO (CH ₂ ), ₀ CO - (g / kg) (g / l OO ecm
Solution; 25 C) 3 CH ₃ - -CH (CH ₂ J ₆ CO- 13.1 47 4th CH ₃ - -CO (CH ₂ J ₈ CO- 4.8 50 5 CH ₃ CH ₂ CH ₂ - -CO (CH ₂ J ₈ CO- 8.4 > 93 6th CH ₃ CH ₂ CH ₂ - 3.5 7th CH ₃ (CH,), - 2.3

CH ₃ -

- COCO-

10.3

Salts of the acid amides according to the invention with cations, as are normally found in X-ray contrast media !! are used, are much more water-soluble than known, comparable compounds Structure that have acquired major economic importance. For example, commercial preparations of the compound 3,3 '- {adipoyldiimino) -bis- (2,4,6-triiodobenzoic acid), also known under the name "iodipamide", the structure of which is shown as follows will:

COOH

W-NHCO (CH ₂ J ₄ CONH

regarded as the media of choice for intravenous visualization of the gallbladder and bile ducts. The disodium and di-N-methylglucamine salts of "iodipamide" are about 17% and about 45% (weight / volume) soluble in water at 25 ° C (Dorn, H., Pharmazie, 12, 321 [1957]).

From the last column of Table I it can be seen how much higher the solubility of the disodium salts is

Tables

Acid amides according to the invention compared to the above specified solubility of the salts of the known compound mentioned. The di-N-dimethylglucamine salts these acid amides are even more soluble than the sodium salts. The methylglucamine salt the acid of Example 3 is e.g. B. soluble to more than 100 g / 100 ecm. The greater water solubility the salts of the acid amides according to the invention make the administration of appropriate doses of the radio-opaque Substance in very small solution volumes

possible.

COOH Even more important is the fact

that the compounds according to the invention have a lower toxicity compared to the known similar compounds, beyond the LD ₅₀ data given in Table I, additional pharmacological data with respect to the compounds of Examples 1, 2, 3, 4 and 8 also show the superior properties of the compounds according to the invention compared to the known comparable compounds.

Comparative toxicity studies of the compounds of Examples 1,2,3 (di-N-methylglucamine salt), 4 and 8 and the di-N-methylglucamine salt of 3,3 '- (adipoyldiimino) - bis - (2,4,6 - triiodobenzoic acid) supplied the tables compiled in the following tables Results.

Connection of example no.

LD ₅₀ (mg / kg) rat dog mouse 18 700 25,000 16 500 - '· - 19 500 6600 10,000 13100 2400 6310 4 790 - - 10300 (3400) *) - 4100

Intercerebral Intracisternal LDjo value, LDjo value, Mouse rat

(mg / kg)

(mg / kg)

2. ■

3 (Di-N-methylglucamine salt) (75%)
4th

Di-N-methylglucamine salt of
3.3 '- (Adipoyldiimino) -bis- (2,4,6-triiodobenzoic acid) (52%) (comparison)

945

1120

62.1

Pharmazie, 12, 321 (1957). 7th

173

0/7 a 66 **)

about 5

} 2 ^tn · Pharmazie, 12, 321 (1957).

) Of the 7 rats tested, none died at the dose of 66 mg / kg. This means that the intracistemal LD ₃₀ -VVMt is above ⁶⁶ mg / kg.

Blood-brain barrier damage in laboratory animals has been reported to be more reliable Reference to the local tissue toxicity. When checking for an amendment the method of Whiteleather and De Saussure, Radiology, 67, 537-543, 1956, was the damage to the dog's blood-brain barrier when a solution of the di-N-methylglucamine salt was administered the compound of Example 3 is noticeably less than when a comparable solution of "iodipamide" -di-N-methylglucamine is administered.

Other pharmacological effects of the compound of Example 3 are compared to those of "iodipamide" also cheap.

Using aqueous solutions of the di-N-methylglucamine salts of the acids described in the above examples, intravenous cholangiographic studies were carried out on cats. Gallbladder visualization was achieved in all cases, and in most cases were achieved favorable results in comparison to »iodipamide«.

A 75% solution of the di-N-methylglucamine-N-alkylisophthalic acid amide to build. The nitro group is reduced to the corresponding 5-amino-N-isophthalic acid amide by catalytic hydrogenation, then by iodination using iodine monochloride or potassium iodine dichloride as Iodizing agent is converted into the corresponding triiodine compound. The 5-amino-N-alkyl-2,4,6-triiodisophthalic acid amide obtained is - preferably after purification - as a starting material for the preparation of the compounds according to the invention suitable.

The following examples serve to illustrate the invention.

example 1

5,5 '- (AdipoyIdiimino) -bis- (2,4,6-triiodo-N-methylisophthalic acid amide)

228 g (0.4 mol) of 5-amino-2,4,6-triiodo-N-methylisophthalic acid amide were added to 400 ecm of dimethylacetamide with stirring and heating. Than the temperature Had reached 95 ° C, 27.5 g (0.15 mol) of adipoyl chloride was added all at once, followed by one same amount added slowly over 15 minutes. So a total of 55 g

Salt of the compound from Example 3 was added in clinical 25 adipoyl chloride. After adding the adi

used for intravenous visualization of the gallbladder. there has been a good visualization of the gallbladder and bile ducts is achieved. In many cases it will be progressive Radiation opacity first visible the wall of the gallbladder, followed by the Rest of the organ. No side effects were found.

The other compounds of the invention are also useful X-ray contrast media In animal experiments, these compounds make one or more structures of the excretory organs visible. -. ·. ■

In the work of Hayes et al., »Experimental Evaluation of Concentrated Solutions of Iothalamic Acid Derivatives as Angiographic Contrast Media " in American Journal of Roentgenology, Radium Therapy and Nuclear Medicine, 97, pp. 755-761 (1966), the suitability of 5,5 '- (adipoyldümino) -bis- [2,4,6-triiodo-N-methylisophthalic acid amide] explained as an angiographic contrast agent. Also the work of S. K. H i 1 a 1, "Hemodynamic Responses in the Cerebral Vessels to Angiographic Contrast Media "Acta Radiologica, 5, (pp. 211 to 230, in particular P. 226 [1966]), it can be seen that the above-mentioned compound is a suitable angiographic Contrast medium is.

Poylchlorids was stirred for a further 15 minutes at about 95 ° C and then poured into 21 hot water.

When this mixture was cooled to room temperature, a gummy mass separated out. The mother liquor was discarded and the gummy mass was dissolved in water with sufficient sodium hydroxide added to achieve complete dissolution. The solution was acidified with hydrochloric acid and acetic acid, treated with decolorizing activated charcoal and filtered. The filtrate was then strongly acidified with hydrochloric acid, an amorphous, granular solid substance separating out. This was filtered off, digested ¹ J ₂ hours with 500 cc of hot ethanol, collected on a filter, washed with ethanol and dried at 110 ⁰ C. The yield of crude 5,5 '- (adipoyldiimino) -bis- (2,4,6-triiodo-N-methylisophthalic acid amide) was 183 gi ·· "The neutralization equivalent weight was determined to be 618; calculated = 627. ·

The acid amide obtained as above became his second and third times from the solution Sodium salt precipitated. The product obtained in the third precipitation was then heated to 400 ecm Dissolved dimethylformamide, and 1.5 liters of water were slowly added. The mixture became digested and filtered while hot to give a crystalline product which after the Drying at 110 ° C weighed 126 g. The neutralization

Preparation of the compounds according to the invention

Process for the preparation of the starting materials 55 equivalent weight of this product was 724. This

5-amino product used in the process of the invention was dissolved in 11% dilute sodium hydroxide solution N-alkyl-2,4,6-triiodisophthalic acid amides are in the. and the solution acidified to pH 5, whereupon below

U.S. Patent 3105,197. Then concentrate in a hot solution of 25 ecm

Such a procedure is briefly specified. ter hydrochloric acid was filtered in 75 ecm of water. The

5-nitroisophthalic acid is produced according to known methods 60. The mixture was cooled and the solid substance

converted into its dimethyl ester, and one of the filtered, washed with water and gel at 110 ⁰ C

Ester groups are then carefully hand-dried. Yield 114g (45%). Melting point 302 ⁰ C

Development of a solution of the diester with one equivalent (corr.) with decomposition. Calculated for C ₂₄ H ₂₀ N ₄ O ₈ J ₆ :

Sodium or potassium hydroxide in a reaction neutralization equivalent weight of 627, iodine content

medium consisting of a mixture of methanol and 65 60.7%. Found (after correction for a water

Acetone is made, selectively hydrolyzed. The obtained content of 1.18%): neutralization equivalent weight

Monoester is with a lower primary alkyl 619, iodine content 60.2%. The infrared spectrum was

_am ; “treated to make the corresponding 5-nitro- itself consistent with the postulated structure

Example 2

5,5 '- (Suberoyldiimino) -bis- (2,4,6-triiodo-N-methylisophthalic acid amide)

The preparation was carried out in a similar manner as in Example 1 using 300 ecm of dimethylacetamide, 180 g (0.314MoI) 5-amino-2,4,6-triiodine-N - methylisophthalic acid amide and 0.23 mol of crude suberoyl chloride carried out. It was at one Reaction temperature of 90 to 105 ° C worked.

The product was isolated and purified in a similar manner to Example 1. The yield of 5,5 '- (suberoyldiimino) - bis - (2,4,6 - triiodo - N - methylisophthalic acid amide) was 69.5 g (34%). Melting point 278 to 280.5 ° C (corr.) With decomposition. Calculated for C ₂₆ H ₂₄ N ₄ O ₈ J ₆ : neutralization equivalent weight 641; Iodine content 59.4%. Found: neutralization equivalent weight 638; Iodine content 57.9%. The infrared spectrum was in agreement with the postulated structure.

Example 3

5,5 '- (Sebacoyldiimino) -bis- (2,4,6-triiodo-N-methylisophthalic acid amide)

580 g (1 mol) of S-amino ^ ao-triiodo-N-methylisophthalic acid amide were added in proportions to 750 ecm of dimethylformamide at 70 to 90 ° C. with stirring. When the temperature reached 90 ° C, 120 g (0.5 mole) of sebacoyl chloride was added and heating continued until the temperature reached 120 ° C. There was then practically complete dissolution. The temperature was held at 120 ° C. for _{V for 2 hours.} Then 750ccm of water was added. The clear solution was digested at 70 to 90 ° C. for 2 hours; during this time the product crystallized out. The product was filtered off and washed with 200 ecm 50% dimethylformamide and then with 200 ecm water.

The moist product was dissolved in dilute sodium hydroxide solution and the solution with a few ecm ammonium hydroxide is added and the mixture is heated to 70 ° C. The solution was made weakly acidic (pH 5), treated with decolorizing activated charcoal and the mixture in hot (70 to 90 ° C) dilute hydrochloric acid (80 ecm concentrated acid in 21 water) filtered. The mixture was digested at 70 to 90 ° C. for 1 hour and the product was filtered off and washed with water and dried at 110 ° C. Yield 453 g (neutralization equivalent weight 640, calculated 655).

This product was dissolved in 500 ecm hot dimethylformamide, 500 ecm hot water was added to the solution and the mixture was digested at 70 to 80 ° C. for 1 hour. During this time crystallization occurred. The product was filtered off and washed, first with 200 ecm of 50% dimethylformamide and then with 500 ecm of water. The product was then dissolved in dilute sodium hydroxide solution and the solution was acidified to pH 5 with dilute hydrochloric acid. The solution was treated twice with decolorizing activated charcoal and then poured into a 70 to 90 ° C. mixture of 80 ecm of concentrated hydrochloric acid and 1 liter of water with stirring. The precipitation _{mixture was digested for 2} hours, after which the product was filtered off, washed well with water and dried at 110.degree. The yield of 5,5 '- (sebacoyldiimino) -bis- (2,4,6-triiodo-N-methylisophthalic acid amide was 353 g (54%). Melting point 279 to 279.5 ° C. (corr.) With decomposition. Calculated for C ₂₈ H ₂₈ N ₄ O ₈ I ₆ : neutralization equivalent weight 655; iodine content 58.2%. Found: neutralization equivalent weight 652, iodine content 57.9%.

Example 4

y
N-methylisophthalic acid amide)

ίο Dodecanedicarboxylic acid dichloride was added by adding of 62 g (0.3 mol) of phosphorus pentachloride in 3 portions to a solution of 25 g (0.11 mol) 1,10-bodecanedicarboxylic acid in 50 ecm toluene. The reaction mixture was allowed to stand overnight, after which the excess phosphorus pentachloride removed under reduced pressure and the residue distilled in vacuo to give 8.7 g (30%) dodecanedicarboxylic acid dichloride with a boiling point of 169 to 172 ° C / 3 mm Hg were obtained.

9.7 g (0.033 mol) of the dodecanedicarboxylic acid dichloride obtained in this way were added at 121 ° C. to a solution of 37.3 g (0.065 mol) of 5-amino-2,4,6-triiodo-N-methylisophthalic acid amide in 60 ecm of dimethylformamide given. The temperature rose rapidly to 135 ° C. The mixture was stirred and kept for ₂ hours at 120 to 123 ° C., after which it was diluted with 60 ecm of water. The mixture was digested for ₂ hours at 70 to 80 ° C., after which the solid was filtered off, dissolved in sodium hydroxide solution and reprecipitated by adding hydrochloric acid, 31.6 g of product with a neutralization equivalent weight of 616.5 (calculated 669) being obtained. This product was purified by recrystallization four times from dimethylformamide / water = 50:50, each recrystallization being followed by precipitation of the acid from a solution of its sodium salt. The yield of 5,5 '- (dodecanedioyldiimino) - bis - (2,4,6 - triiodo-N-methylisophthalic acid amide) was 14.3 g (33%). Calculated for C ₃₀ H ₃₂ J ₆ N ₄ O ₈ : neutralization equivalent weight 669; Iodine content 56.95%. Found: neutralization equivalent weight 666; Iodine content 55.8%. Melting point 288 ° C (with decomposition). The infrared spectrum was in agreement with the postulated structure.

Example 5

5,5 '- (Suberoyldiimino) -bis- (2,4,6-triiodo-N-propylisophthalic acid amide)

The required starting materials were prepared by processes similar to those in the USA patent 31 05 197 have been described.

A. 5-Nitro-N-propylisophthalic acid amide

100 g (1.70 mol) of n-propylamine were added to a solution of 153 g (0.68 mol) of 5-nitroisophthalic acid monomethyl ester given in 700 ecm of methanol. The container was tightly closed and the reaction mixture was allowed to stand for 4 days.

After this time, the solvent was evaporated and the remaining oil in 1.51 diluted sodium hydroxide solution. The solution would be made weakly acidic (pH 5 to 6) and the obtained Solution slowly with stirring to an excess of dilute hydrochloric acid (80 ecm concentrated acid in 400 ecm of water). The product was filtered off and acidified a solution twice of the sodium salt reprecipitated. The product was

509582/427

1 "* C

then recrystallized from 500 ecm of 50% ethanol, washed and dried at 110 ° C. The yield of 5-nitro-N-propylisophthalic acid amide was 98 g (57.5%). Neutralization equivalent weight 247 (calculated 252). The infrared spectrum was in agreement with the postulated structure.

B. 5-Amino-N-propylisophthalic acid amide

An alcoholic solution of 80 g (0.32 mol) of 5-nitro-N-propylisophthalic acid amide was in the presence hydrogenated of a Pd / C catalyst. The catalyst was filtered off and the solvent evaporated. The residue was dissolved in dilute sodium hydroxide solution and the product by adding a Excess acid precipitated. The product was filtered off, washed with water and dried at 70.degree. The yield of 5-amino-N-propylisophthalic acid amide was 42 g (59%). Melting point 194.7 to 195.7 ° C (grain). The infrared spectrum was conforms to the postulated structure.

C. 5-Amino-2,4,6-triiodo-N-propylene isophthalic acid amide

160.5 g of 95% strength JCl in 160 ecm of concentrated hydrochloric acid were slowly transformed into one with stirring Mixture of 42 g (0.19 mol) of 5-amino-N-propylisophthalic acid amide and dilute hydrochloric acid (45 ecm concentrated hydrochloric acid in 400 ecm water). Enough water was added to bring the volume to about 1350 ecm and the mixture became Stirred and heated on a steam bath for 20 hours.

The reaction mixture was cooled and the product was filtered off and dissolved in sodium hydroxide solution (40 g of 50% NaOH dissolved in 500 ecm of water). The solution was made weakly acidic with acetic acid (pH 5), with decolorizing Treated activated carbon and poured into hot hydrochloric acid (50 ecm concentrated acid in 150 ecm Water) filtered. The mixture was cooled and the crystals were filtered off, washed with water and dried at 70 ° C. The yield of 5-amino-2,4,6-triiodo-N-propylisophthalic acid amide was 109 g (96%). Melting point 242 to 243 ° C (corr.) With decomposition. Neutralization equivalent weight 594 (calculated 600). The infrared spectrum was in agreement with the postulated structure.

D. 5,5 '- (Suberoyldiimino) -bis- (2,4,6-triiodo-' N-propylisophthalic acid amide)

18.8 g (0.09 mol) of suberoyl chloride were added to 122 ° C to a solution of 107.5 g (0.18 mol) of 5-amino-2,4,6-triiodine-N-propylisophthalic acid amide in 160 ecm of dimethylformamide given. The temperature rose instantly to 136.5 ° C, during a violent one HCl evolution proceeded. The mixture was heated to 128 ° C for 2 hours, after which 160 ecm of water were admitted. A rubbery material deposited which was removed when the product was cooled and scratching the piston wall may be transformed into a semi-solid mass. The liquid was decanted off and the residue was dissolved in sodium hydroxide solution and by adding an excess precipitated again in hydrochloric acid. This product has been purified by separating three times from dimethylformamide / Water = 1: 1 was recrystallized, followed by precipitation by acidification of an aqueous solution of the sodium salt. The yield of 5,5 '- (suberoyldiimino) - to - (2,4,6 - triiodine - N - propylisophthalic acid-

amide) was 71 g (60%). Melting point 286.5 ° C with decomposition. Calculated for C ₃₀ H ₃₂ N ₄ O ₈ I ₆ : neutralization equivalent weight 669, iodine content 56.9%. Found: neutralization equivalent weight 671, iodine content 55.7%. The infrared spectrum was in agreement with the postulated structure.

Example 6

5,5 '- (Sebacoyldiimino) -bis- (2,4,6-triiodo-N-propylisophthalic acid amide)

The preparation was carried out in a similar manner as in Example 1 using 100 ecm of dimethylacetamide, 65 g (0.108MoI) 5 - amino - 2,4,6 - triiodo-N-propylisophthalic acid amide, 13 g (0.054 mol) sebacoyl chloride and a reaction temperature of 90 carried out up to 105 ° C.

The product was isolated and purified in a manner similar to that in Example 1, but precipitation of the ammonium salt was also carried out. The yield of 5,5 '- (sebacoyldiimino) -bis- (2,4,6-triiodo-N-propylisophthalic acid amide) was 26.2 g (35%). Melting point 286 to 286.5 ° C (corr.) With decomposition. Calculated for C ₃₂ H ₃₆ N ₄ O ₈ I ₆ : neutralization equivalent weight 683, iodine content 55.7%. Found: neutralization equivalent weight 682, iodine content 54.6%. The infrared spectrum was in agreement with the postulated structure.

B e i s ρ i e 1 7

5,5 '- (Sebacoyldiimino) -bis- (N-butyl-2,4,6-triiodoisophthalic acid amide)

The required starting materials were prepared by processes similar to those in the USA patent 31 05 197 have been described.

A. N-Butyl-5-nitroisophthalic acid amide

A solution of 225 g (1 mol) of 5-nitroisophthalic acid monomethyl ester and 250 ecm of n-butylamine in 11% of absolute methanol was refluxed for 16 hours. The solvent was evaporated and the remaining oil was dissolved in dilute aqueous sodium hydroxide solution. The product was precipitated by adding an excess of hydrochloric acid and this treatment was repeated twice, with a slight improvement in the purity occurring. Neutralization equivalent weight 187 (calculated 266). Finally the product was dissolved in 1 liter of hot acetone. The solution was filtered and an equal volume of water was added. The solvents were slowly evaporated and on cooling the concentrated solution the product separated out. The crystals were filtered off, washed with water and dried at 110 ° C. The yield of N- (n-butyl) -5-nitroisophthalic acid amide was 103 g (39%). Calculated for C ₁₂ H ₁₄ N ₂ O ₆ : neutralization equivalent weight 266. Found: neutralization equivalent weight 268.

A second run, carried out in a similar manner, gave a neutralization equivalent weight product 263 and from melting point 174.2 to 175.2 ° C (corr.).

B. 5-Amino-N-butylisophthalic acid amide

A solution of 103 g (0.39 mol) of N- (n-butyl) -5-nitroisophthalic acid amide in 400 ecm of ethanol was hydrogenated in the presence of a Pd / C catalyst. the

14 υ y / y

The catalyst was filtered off and the solvent evaporated. The yield of 5-amino-N-butylisophthalic acid amide was 86 g (94%). Melting point 199.2 to 199.7 ° C (corr.). The infrared spectrum was located conforms to the postulated structure.

C. 5-Amino-N-butyI-2,4,6-triiodisophthalic acid amide A solution of iodine monochloride (205 g of 95% JCl in 205 ecm concentrated hydrochloric acid) slowly became a slurry of 86 g with stirring (0.36 mol) 5 - amino -N-butylisophthalic acid amide, 800 ecm water and 89 ecm concentrated hydrochloric acid given. The mixture was diluted to a volume of approximately 2650 ecm and placed on a steam bath heated and stirred for about 20 hours.

The reaction mixture was cooled and the deposited solid was filtered off and washed with water. It was then dissolved in sodium hydroxide solution diluted with 1,300 ecm. The solution was then made weakly acidic (pH 5) with the aid of acetic acid. The solution was treated with sodium bisulfite then with decolorizing activated charcoal and filtered into hot hydrochloric acid (40 ecm concentrated acid in 200 ecm water) with stirring. The mixture was cooled and the deposited solid was filtered off. This treatment was repeated to obtain 192 g (86%) of 5-amino-N-butyl-2,4,6-triiodoisophthalic acid amide. Melting point 247 to 249 ° C (grain) with decomposition. Calculated for C ₁₂ H ₁₃ N ₂ O ₃ J ₃ : neutralization equivalent weight 614. Found: neutralization equivalent weight 606. The infrared spectrum was in agreement with the postulated structure.

D. 5,5 '- (Sebacoyldiimino) -bis- (N-butyl-2,4,6-triiodoisophthalic acid amide)

19.5 g (0.0815 mol) of sebacoyl chloride were added dropwise at 90 ° C. to a solution of 100 g (0.163 mol) of 5-amino-N-butyl-2,4,6-triiodisophthalic acid amide in 200 ecm of dimethylformamide. When the temperature of the solution reached 100 ° C, the heating was stopped and the reaction mixture was allowed to slowly cool to room temperature. 550 ecm of water were added and the product separated out as a gummy mass. The product was isolated and purified in a similar manner to Example 1. The yield of 5,5 '- (sebacoyldiimino) - bis - (N - butyl - 2,4,6 - triiodoisophthalic acid amide was 29.7 g (26%). Melting point 269.5 to 271 "C (corr.) With decomposition Calculated ίο for C ₃₄ H ₄₀ N ₄ O _{8 I 6} : neutralization equivalent weight 697, iodine content 54.7%. Found: neutralization equivalent weight 708, iodine content 53.7%. The infrared spectrum was in agreement with the postulated structure.

Example 8

5,5 '- (TerephthaloyIdiirnino) -bis- (2,4,6-triiodo-N-methylisophthalic acid amide)

10.15 g (0.05 MoI) of terephthaloyl chloride were added at a temperature of 102 ⁰ C to a solution of 57.2 g (0.1 mole) of 5-amino-2,4,6-triiodo-N-methylisophthalsäureamid in 150 ecm dimethylacetamide given. The temperature immediately increased to 106 ° C.

The solution was then heated for 2 hours at 115 to 118 ⁰ C, after which 150 cc of water was added. The mixture was cooled in an ice water bath, and the deposited crystals were filtered off. The product was washed with acetone and purified by recrystallization from 50% aqueous dimethylacetamide. The product was dissolved in dilute sodium hydroxide solution and reprecipitated by adding excess hydrochloric acid. The yield of 5,5 '- (terephthaloyldiimino) - bis - (2,4,6 - triiodo-N-methylisophthalic acid amide) was 10.9 g (17.1%). Melting point 316 to 320 ° C (corr.) With decomposition. Calculated for C ₂₆ H ₁₆ N ₄ O ₈ I ₆ : neutralization equivalent weight 637, iodine content 59.8%. Found: neutralization equivalent weight 649 (after correction for a water content of 3.54%), iodine content 58.6% (corr.). The infrared spectrum was in agreement with the postulated structure.

Claims (2)

Patent claims: 1. Bis (5-amino-2,4,6-triiodo-N-alkyl-isophthalic acid amide) derivatives of dicarboxylic acids, comprising the connections a) 5,5 '- (Adipoyldiimino) -bis [2,4,6-triiodo-N-methyl-isophthalic acid amide], b) 5,5 '- (suberoyldiimino) - bis [2,4,6 - triiodo-N-methyl-isophthalic acid amide], c) 5,5 '- (Sebacoyldiimino) - bis [2,4,6 - triiodo-N-methyl-isophthalic acid amide], d) S.S'-iDodecändioyldiiminoi-bis ^ AOTtrijod-N-methyl-isophthalic acid amide], e) 5,5 '- (Suberoyldiimino) - bis [2,4,6 - triiodo-N-propyl-isophthalic acid amide], 0 5,5 '- (sebacoyldiimino) - bis [2,4,6 - triiodo-N-propyl - isophthalic acid amide], g) 5,5 '- (Sebacoyldiimino) - bis [2,4,6 - triiodo-N-butyl-isophthalic acid amide] or h) 5,5 '- (Terephthaloyldiimino) - bis [2,4,6 - triiodo-N-methyl-isophthalic acid amide]
and their salts with pharmaceutically acceptable cations. 2. Process for the preparation of compounds according to claim 1, characterized in that one fJ-Amino-N-alkyl ^ Ao-triiodisophthalic acid monoamide the formula