CS207563B2 - Process for the preparation of 2,4,6-triiodo-5-ibis [(2,4,6-triiodophenyl) carbamoylmethyl] -aminoacetanes-benzoic acid derivatives useful as radiographic contrast agents - Google Patents

Abstract

It is an object of the present invention to provide a novel process for the preparation of novel polyiodic ionic benzene derivatives useful as x-ray contrast agents. In particular, the invention relates to a process for the preparation of novel compounds comprising at least two triiodo benzene residues and one carboxyl group, which are characterized by low toxicity and provide good contrast, and can be prepared by methods which are commercially available, so that the cost of their production is relatively high. low. U.S. Patent No. 2,708,678 discloses a compound containing two triiodo benzene residues and a single carboxyl group, formulas

Description

(54) Process for the production of 2,4,6-triiodo-5-bis[(2,4,6-triiodophenyl)carbamoylmethyl]-aminoethane-benzoic acid derivatives, usable as contrast agents in radiography

2

The subject of the invention is a method for producing new polyiodide ionic benzene derivatives, usable as contrast agents in radiography.

The invention particularly relates to a process for the production of new compounds containing at least two triiodinated benzene residues and one carboxyl group, which are characterized by low toxicity and provide good contrast, and which can be prepared by processes applicable on an industrial scale, so that the costs of their production are relatively low.

In US patent 2,708,678, a compound containing two triiodinated benzene radicals and a single carboxyl group is already described, with the formula

COOH

However, all attempts to prepare this compound by the process described in the aforementioned patent specification failed, whatever the reaction conditions used.

The invention relates to a method for producing compounds of general formula III

COOH

where

Ri means a residue of the general formula —CONHRs, where

R 5 represents an alkyl radical with 1 to 4 carbon atoms, or a radical of the formula

R7

Z —N \

Where is it?

R7 represents an alkanoyl radical having 2 to 6 carbon atoms and

R 5 represents an alkyl radical with 1 to 4 carbon atoms, each of the symbols R 2 and R 3 represents a radical of the general formula '—CONHR 6 , where

R9 represents a hydroxyalkyl radical with 1 to 4 carbon atoms, and

R4 represents a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, as well as their salts with pharmaceutically acceptable bases.

Salts of the acids of the general formula III include, in particular, alkali metal salts such as sodium and potassium, ammonium salts, alkaline earth metal salts such as calcium, and salts of organic bases such as ethanolamine or methylglucamine.

Compounds of general formula III are prepared according to the invention by reacting an amine of general formula IV

R1 and R1 have the meanings given above, with a chloromethylated compound of general formula Vb

where

R2 and R3 have the meanings given above.

This reaction can optionally be followed by N-alkylation, N-hydroxyalkylation, N-acylation or N-polyhydroxyacylation, deacylation as well as esterification or conversion into a salt according to known methods.

Amines of general formula IV, where R1 is hydrogen, can be prepared by condensation of an amine of general formula VI

COOH

where

R 1 is as defined above, with the acid chloride of formula VII

with subsequent hydrazinolysis of the obtained condensation product of general formula VIII

COOH

where

Ri has the same meaning as Ri or, in the case where Ri contains a hydroxyl group, Ri' means the corresponding acid chloride acylation product of formula VII.

The condensation reaction of the amine of general formula IV with the acid chloride of formula VII is preferably carried out in a polar solvent, such as dimethylacetamide or dimethylformamide, at a temperature in the range of 20 to 100 °C, using an excess of acid chloride. The reaction time can vary from 2 hours to 4 days.

Hydrazinolysis of the product of general formula VIII is carried out by a known procedure by the action of hydrazine in an aqueous medium (see, for example, J. Am. Chem. Soc. 71, p. 1856 [1949]; H. R. Ing. and R. G. Manské, J. Chem. Soc., p. 2348 [1926]; Chem. Ver, 83, p. 244 [1950]). Preferably, a large excess of hydrazine is used (4 to 8 moles per 1 mole of compound of general formula VIII).

Amines of general formula IV, where R 1 represents a lower alkyl group, can also be prepared by reacting a compound of general formula IX

COOH

where

R1 has the above meaning, with an alkylating agent, to give a compound of general formula X

where

Ri and Ra have the above-mentioned meaning, which is then treated with ammonia.

This reaction between compounds of formula IV and formula Vb is preferably carried out in a basic aqueous medium, for example in an excess of normal sodium hydroxide solution at a temperature in the range of 60 to 90° C. The reaction time may vary between 6 and 48 hours.

Chlorinated compounds of the general formula Vb can be prepared by reacting chloroacetyl chloride with the corresponding aniline under conventional conditions, optionally followed by saponification.

The following examples illustrate the invention in more detail. Sections A, B and C describe the preparation of amines of formula IV, compounds of formula Vb and compounds of formula III.

In these examples, product purity was monitored:

1. chromatographically on a thin fluorescent layer of silica gel [Merck, F. 254), using washing systems

1] benzene/methyl ethyl ketone/formic acid (60/25/20) — washing system 1,

2) ethyl acetate/isopropanol/ammonia (55/35/ /40) — washing system 2, . 3 j ethyl acetate/isopropanol/ammonia (35/35/ /40) — washing system 3,

4) n-butanol/acetic acid/water (50/11/ /25] — washing system 4.

Note:

Some washing systems in thin layer chromatography, especially washing system 4, allow the separation of individual isomers of acids containing the N-methyl-N-acylaminobenzoic acid functional group.

For example, the pure mono-N-methylated compound of general formula III gives two spots (poorly resolved, but nevertheless quite distinct and in varying proportions depending on the amount of the individual acids), and the di-N-methylated compound gives three spots.

2. The purity of the compounds was further determined according to:

1) amount of halogens

2) the amount of carboxylic acid by back titration with sodium hydroxide solution,

3) the amount of active hydrogen and carboxyl functional group by sodium methoxide in a non-aqueous medium in the presence of azo violet,

4) the amount of carboxyl group in a dimethylformamide solution of tetrabutylammonium hydroxide dissolved in isopropanol,

5) the amount of aliphatic amines by perchloric acid in an acetic acid environment.

A. Preparation of amines of general formula IV

I. Preparation of 2,4,6-triiodo-3-N-hydroxyethylcarbamoyl-5-aminoacetylaminobenzoic acid (compound I)

a] Preparation of 2,4,6-triiodo-3-N-phthalimidoacetoxyethylcarbamoyl-5-phthalimidoacetylaminobenzoic acid

O / ^co 'NHCOC&N 2 \

rn

Dissolve in 300 ml of dimethylacetamide

180 g (0.3 mol) of 2,4,6-triiodo-3-N-hydroxyethylcarbamoyl-5-aminobenzoic acid and 170 g (0.76 mol) of phthaloylglycine chloride are added in portions while cooling in an ice bath. The reaction mixture is stirred overnight at room temperature and then diluted by adding 1000 ml of water. The precipitate that forms is filtered off with suction, washed with water, filtered off with suction again and dried in an oven. This gives 275 g of a white product, which corresponds to a yield of 95% of theory. Purity check:

Thin layer chromatography using washing system 1:

Rf of the starting triiodide acid 0.4

Rf of starting phthaloylcin 0.77

Rf of the condensation product 0.68

b) Preparation of 2,4,6-triiodo-3N-hydroxyethylcarbamoyl-5-aminoacetamidobenzoic acid

COOH

HOCH* CHjNHC O4^NHCOCH ₂ NH ₂

197 g (0.20 mol) of the previous product is suspended in 600 ml of water and 60 g (1.2 mol) of hydrazine hydrate and the resulting suspension is heated for 2 hours with stirring at a temperature of 80 degrees Celsius. During heating, the suspended substance dissolves and towards the end of the reaction a crystalline substance is precipitated. After cooling, the precipitate is filtered off with suction, washed and dried in a drying oven, thereby obtaining 125 g of product, which corresponds to a yield of 95% of theory. Purity control:

1. thin layer chromatography using washing system 1:

Rf of starting material 0.68

Rf of the obtained product 0.05

When detected with ninhydrin, a yellow-orange spot is formed.

2. Product purity according to the amount of iodine contained: 97.7%

3. Product purity according to the amount of caustic soda consumed: 100%

III. Preparation of 2,4,6-triiodo-3-N-methylcarbamoyl-5-aminoacetylaminobenzoic acid (compound III)

Proceed as in the preparation of the compound

I, only acids are used as starting materials

2,4,6-triiodo-3-N-methylcarbamoyl-5-aminobenzoate.

The crude product obtained is purified by taking up with 95% ethanol (approximately 3000 g per 5 liters), heating under reflux and then filtering while hot. The total yield after condensation and purification corresponds to

62.5% of theory.

VI. Preparation of 2,4,6-triiodo-3-amino-acetamidobenzoic acid (compound VI)

The procedure is the same as for the preparation of compound I, except that 2,4,6-triiodo-3-aminobenzoic acid is used as the starting iodinated compound.

VII. Preparation of 2,4,6-triiodo-3-acetamido-5-aminoacetamidobenzoic acid compound VII)

The procedure is the same as for the preparation of compound I, except that 2,4,6-triiodo-3-acetamido-5-aminobenzoic acid is used as the starting iodinated compound.

VIII. Preparation of 2,4,6-triiodo-3-N-methylcarbamoyl-5-N-methyl-N-aminoacetylaminobenzoic acid (compound VIII) aj 2,4,6-triiodo-3-N-methylcarbamoyl-5-N-methylchloroacetamidobenzoic acid

380 ml (4 moles) of dimethyl sulfate are added dropwise at a temperature of 5 to 10 °C to a solution of 1300 g (2 moles) of 2,4,6-triiodo-3-N-methylcarbamoyl-5-chloroacetamidobenzoic acid (US patent 3,210,412) in three liters of 2 N sodium hydroxide solution. After the addition is complete, the temperature of the reaction mixture is allowed to rise to ambient temperature and the reaction mixture is stirred for a further 20 hours. Insoluble components are removed by filtration, after which a precipitate is separated by acidification with concentrated hydrochloric acid to pH 1, which is filtered off with suction, washed several times with water and dried at a temperature of 60 °C. Purification is carried out by dissolving the crude product in 900 ml of 2 N sodium hydroxide solution and salting out by adding 1000 g of sodium chloride. After stirring for 24 hours at room temperature, the precipitate formed is filtered off with suction and redissolved in 2500 ml of water. The solution is filtered and acidified with concentrated hydrochloric acid to pH 1. The precipitated product is washed with water, filtered off with suction and dried at 60 °C, yielding 672 g (51% of theory) of the desired product. Purity check:

1. Thin layer chromatography using washing system 2

Rf of starting material 0.1

Rf of the obtained methyl derivative (2 isomers) 0.2 and 0.25

2. Purity: according to the amount of iodine 97% according to the amount of chlorine 104%

b) 2,4,6-Triiodo-3-N-methylcarbamoyl-5-N-methyl-N-aminoacetylaminobenzoic acid

314 g (0.49 mol) of the above acid are dissolved in 3500 ml of concentrated ammonia and the resulting solution is heated for 20 hours at 60 °C. After evaporation to dryness under reduced pressure, the residue is taken up in 300 ml of water and the solution is acidified with sulfur dioxide. The reaction mixture is left to crystallize in a refrigerator for 48 hours, after which the formed crystals are filtered off with suction, washed several times with water and dried in an oven at 80 °C. 160 g (yield 51% of theory) of product are obtained. Purity check:

1. Thin layer chromatography using washing system 3

Rf of the obtained product 0.75

2. Purity:

as determined with caustic soda 102% as determined with sodium methoxide 98%

X. Preparation of 2,4,6-triiodo-3N-methyl-N-aminoacetylaminobenzoic acid (compound X)

a) Preparation of 2,4,6-triiodo-3-chloroacetamidobenzoic acid (according to US patent number 3,210,412).

Cleanliness check:

1. Thin layer chromatography using washing system 2:

Rf of starting material 0.3

Rf of the obtained product 0.25

2. Purity as determined by caustic soda:

99.8%

b) Preparation of 2,4,6-triiodo-3-N-methyl-N-chloroacetylaminobenzoic acid

591.5 g (1 mol) of the product obtained above are dissolved in 2.3 mol of 5 N sodium hydroxide solution and 100 ml of acetone.

1.3 mol of methyl iodide are added dropwise to the resulting solution, the temperature being maintained at 10 °C with an ice bath. After 16 hours of stirring at ambient temperature, the reaction mixture is poured into 2 liters of hydrochloric acid diluted in a ratio of 1:10, the reaction mixture being cooled in an ice bath. The product is separated, which is filtered off with suction and washed several times with water. After drying in an oven at a temperature of 50 °C, 591 g are obtained, which corresponds to a yield of 85% of theory.

Cleanliness check:

1. Thin layer chromatography using washing system 2

Rf of the starting compound 0.25

Rf of the methylated product (after decomposition into 2 isomers) 0.35 and 0.45

2. Purity by chlorine determination: 92% by iodine determination: 100% by sodium methoxide determination 92%

c) 2,4,6-triiodo-3-N-methyl-N-aminoacetylaminobenzoic acid

590 g (0.90 mol) of the above acid are dissolved in 9 liters of concentrated ammonia. After almost complete dissolution, 3 g of insoluble components, which are the methyl ester of the starting acid, are separated by filtration.

The resulting pale yellow solution is heated for 20 hours at 60 °C, after which it is concentrated under reduced pressure to a volume of 2 l. This crystallizes the ammonium salt, which is filtered off with suction, redissolved in 500 ml of water with the addition of the smallest possible volume of sodium hydroxide, and then redissolved by adding acetic acid to pH 4. After filtration with suction, washing with water and drying, 316 g of white product are obtained, which corresponds to a yield of 52% of theory.

Cleanliness check:

1. Thin layer chromatography using washing system 1

Rf of the starting compound 0.9

Rf of the obtained product (detection with ninhydrin with the formation of a yellow spot) 0.25

2. Purity as determined by caustic soda:

98.5% as determined by sodium methoxide

100%

XIII. Preparation of 2,4,6-triiodo-3-N-methyl-N-acetylamino-5-aminoacetamidobenzoic acid (compound XIII)

The procedure is, with a few exceptions noted below, as in the preparation of compound I, except that 2,4,6-triiodo-3-N-methyl-N-acetylamino-5-aminobenzoic acid (U.S. Patent No. 3,178,473) is used as the starting iodinated compound.

1) Washing of the condensation product with phthaloylglycine is carried out by introducing 1554 g of the product into 2 l of ethyl alcohol with a concentration of 95%, and 1200 g of purified product is obtained.

2) The crude product from hydrazinolysis is purified by dissolving 267 g in 550 ml of sulfuric acid, diluted in a ratio of 1:10, at a temperature of 80 °C.

By hot filtration, 25 g of phthalhydrazide of the formula are separated.

The acidic filtrate is then filtered through activated carbon and neutralized with ammonia to pH 4 to 5. This separates out a crystalline precipitate, which is washed with water, filtered off with suction and dried in an oven at a temperature of first 70°C, then 105°C, yielding 211 g of white product.

3) Adding hot sulfuric acid to the liquid portion from hydrazinolysis yields 390 grams of a white product with the same properties as 211 g of the previous product.

Table I provides data on the preparation of amines of the general formula IV by condensation and hydrazinolysis, as well as data on the amines thus obtained. Table II summarizes data on the preparation of amines of the general formula IV from chlorinated derivatives of the general formula IX, as well as data on the amines thus obtained.

Amin

Table I

Starting Condensation product triiodinated Rf in washing system yield %

Rf in the washing system

Amines obtained by hydrazinolysis Rf in washing system Rf in washing system yield %

2

I Ul 0.4 0.65 0.68 0.4 95 100 0.05 0.05 0.1 0.5 0.45 95 62 VI 0.7 0.55 (1) not insulated 0.5 0.1 in base 3 71 total virus 0.5 0.4 85 0.05 0.44 73 XIII 0.65 0.4 90 0.05 0.45 66

0.53

Note:

(1) in the washing system benzene/methyl ethyl ketone/formic acid (80/20/10)

Table II Amen Default Chlorinated condensation Amen triiodinated product Rf in pro- Rf in pro- yield substance Rf in pro- Rf in pro- yield washing machine washing machine % Rf in the wash- washing washing % system 1 system 2

va system 2 system 2 system 1

VIII 0.1 0.2 and 0.25 0.5 51 0.3 0.75 51 X 0.25 0.3 and 0.45 0.9 97 0.25 0.15 and 0.25 54

Table III shows the formulas of the amines of general formula IV thus prepared.

207583

Table III

COOH jk·* lil

VI

COOH

NHCOCH^NH^

VII

COOH

And σ

CHXONhY'' ΉΗ0001γ1Η _ζ

XCOOH

J

NHCOCH _Í NH _Z

B. Preparation of derivatives of general formula Vb

XXVII. Preparation of 2,4,6-triiodo-3,5-bis-(N-hydroxyethylcarbamoyl)-chloroacetanilide

In 2 l of dimethylacetamide, 645 g (1 mol) of 2,4,6-triiodo-3,5-bis-(N-hydroxyethylcarbamoyl)-aniline, described in French patent no.

172 953. 430 ml (6 mol) of chloroacetyl chloride are then slowly added to the resulting solution while cooling with an ice bath. The reaction mixture is then stirred for 3 hours at ambient temperature.

The completion of the reaction is determined by thin layer chromatography on silica gel using the eluent ethyl acetate/isopropanol/ammonia (50/35/20). Rf = 0.5. The reaction mixture is then poured into 6 liters of water, whereby a very fine, difficult to centrifuge white precipitate is obtained. After washing with water, the resulting 2,4,6-triiodo-3,5-bis-(N-chloroacetoxyethylcarbamoyl)-chloroacetanilide is saponified with stirring in liters of 2 N sodium hydroxide at ambient temperature, first for 2 hours, then for 2 hours at 40 °C.

Purity is checked by chromatography on a silica gel layer using the same washing system. Rf = 0.35.

The reaction mixture is then cooled, neutralized by adding 100 ml of concentrated hydrochloric acid and left to stand with stirring overnight at ambient temperature. The resulting product is filtered off with suction, washed with water and dried at 60 °C overnight, yielding 672 g of product, corresponding to a yield of 93% of theory. Purity check:

Using sodium methoxide 105% by iodine determination 99% by chlorine determination 102.8%

C. Preparation of compounds of general formula III

31. Preparation of 2,4,6-triiodo-3-N-methylcarbamoyl-5-bis-{[2,4,6-triiodo-3,5-bis-(N-hydroxyethylcarbamoyl)phenyl]carbamoylmethyl}aminoacetamidobenzoic acid (compound 31)

A solution of 126 g (0.2 mol) of 2,4,6-triiodo-3-N-methylcarbamoyl-5-aminoacetamidobenzoic acid (compound III) in 220 ml of N sodium hydroxide solution is mixed with a solution of 288 g of 2,4,6-triiodo-3,5-bis-(N-hydroxyethylcarbamoyl)-chloroacetanilide (XXVII) in 400 ml of N sodium hydroxide solution. The reaction mixture is heated with stirring at 85 °C for 20 hours, then cooled to 20 °C and acidified to pH 1. A gummy product is formed which crystallizes overnight at ambient temperature. This product is filtered off with suction, washed with water and dried in an oven to give 280 g of crude acid. This is dissolved in water, the pH of the solution is adjusted to 7 by adding ammonia, a small amount of insoluble components is filtered off and the filtrate is acidified to pH 1 with hydrochloric acid, diluted in a ratio of 1:10. The precipitate formed is filtered off with suction, washed with water and dried, thereby obtaining 224 g of crude acid.

Purity determination using sodium hydroxide: 112%

Cleaning:

1. via ammonium salt:

224 g of the acid are dissolved in 150 ml of water and the resulting solution is neutralized by adding ammonia. A crystalline precipitate is precipitated. The reaction mixture is stirred for 24 hours at ambient temperature, after which the precipitate is filtered off with suction, washed with water and a sufficient amount of 10 N sodium hydroxide solution is added to it until it dissolves. It is precipitated from the solution again by adding hydrochloric acid. After filtration with suction, washing with water and drying, 155 g of the acid is obtained.

Purity determination using sodium hydroxide: 107%

2. via methylglucamine salt:

From 155 g of the acid thus obtained, a solution of methylglucamine salt containing 28% iodine is prepared. The insoluble fraction is separated by centrifugation and filtration through a millipore filter. The filtrate is acidified with hydrochloric acid to pH 1. The precipitate formed is filtered off with suction. This procedure is repeated once more, whereby 74 g of acid is obtained, which corresponds to a total yield of 18.5 %.

The purity of the product is determined by:

— thin layer chromatography on silica gel using an eluent of n-butanol/water/acetic acid (50/25/11):

Rf of the starting chlorinated product 0.75

Rf of the starting amine 0.25

Rf of the condensation product 0.25 — using 0.1 N sodium hydroxide solution 103% — using sodium methoxide 100% — according to iodine content 97%.

32. Preparation of 2,4,6-triiodo-3-N-methylacetamido-5-bis-{[2,4,6-triiodo-3,5-bis-(N-hydroxyethylcarbamoyl)phenyl]carbamoylmethyl}aminoacetamidobenzoic acid (compound 32]

Proceed as in the preparation of the compound

31, except that amine XIII is used instead of amine III.

33. Preparation of 2,4,6-triiodo-3-N-methylcarbamoyl-5-bis-{[2,4,6-triiodo-3,5-bis(N207563]

-hydroxyethylcarbamoyl)-phenyl]-carbamoylmethylJ-amino-N-methyl-acetamidobenzoic acid (compound 33)

Proceed as in the preparation of the compound

31, except that amine VIII is used instead of amine III.

Table V shows data relating to the preparation of compounds of general formula III as well as the compounds obtained, the formulas of these compounds being shown in Table VI.

Compound- Initial Initial Yield Rf in the pro- Yield Rf in the pro- Purification Determination by Rf in the washing system amine chloride crude washing acetylation washing method yield NaOH CHsONa J acid system product system 1 + saponification- system 1 % °/o % % 1 4 % none % after saponification

in what C3 CM 1 ” that ID m o

what about +?

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what about

what what what rH □3

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CM

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4 o'clock

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cd ft >o f—I o

and ca &.

about the function

P.

o (Λ what in what oo oo

CM

CO oo co co řx rW r—1 rQ

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No

CLi

CH^NHCO

NHCOCHjN , “From conhch^qh ₂ oh

CH,C ONH^X^CONHCH^H^H conhch ₂ ch ₂ qh

CH _from C0NH

CONHCH^H^OH

Cfi^COty CH.

COOH

J nhcockn

COOH

D. Preparation of the solution for injection

CH^CONH

CH _Z CONH'

CONHCHM>OH

I X *Ό' 'CONHCH^CH^OH J

CONHCH^CH^OH :oZ 'CQNHCHXHOH 2,

CONHCH ₀ CH ₀ OH i AA CH^CGNH^ Y^C0NHCH ₂ CH ₂ 0H J You CONHCH^H^OH qh ₂ conh rot X^CONHChL CH ₂ OH J Table VII

Solutions for injection, of medical quality, are prepared using methylglucamine salt or sodium salt; these solutions contain 28, 38 or 48 g of iodine per 100 ml of solution (hereinafter referred to as solutions containing 28%, 38% and 48% iodine).

After filling the ampoule in a nitrogen atmosphere, the product is sterilized by heating at 120°C for 20 minutes.

Table VII shows the results of viscosity measurements of 28% solutions of methylglucamine salts at 37° C. The results show that, contrary to what could be expected, solutions of the compound of general formula III are characterized by relatively low viscosities.

Compound Viscosity vcB [in Pa. s] at 37 °C

10.2 [0.0102]

Table VIII shows the results of osmolality measurements.

The osmolality rate is obtained by extrapolating the values obtained by successive dilutions of solutions containing 28% or 38% iodine.

Osmolality is measured with a FISKE osmometer, model 230/D/330 — D. This instrument indicates the osmolality value in milliosmoles per 1 kg of solution. The instrument works on the principle of cryoscopy. Measurements were made with solutions containing 28% iodine.

Table VIII

Compound Osmolality mosm/kg

31 350 32 270 33 370 and ⁺ 1410 b+ 1390 c ⁺ 950

The compounds a ⁺ , b+, c ⁺ are the following reference compounds:

a: 2,4,6-triiodo-3-N-methylcarbamoyl-5-acetamidobenzoic acid, b: 2,4,6-triiodo-3-N-hydroxyethylcarbamoyl-5-acetamidobenzoic acid, c: 5,5’-adipoyldiimido-bis-(2,4,6-triiodo-N-methylisophthalamic acid j.

It is clear that the compounds of general formula III in the form of the methylglucamine salt are characterized by a significantly lower osmolality compared to the reference compounds.

The results of toxicological and pharmacological tests are presented below.

Acute toxicity assessment

Intravenous toxicity in mice

The test uses IOPS mice of Swiss origin, OFI strain. Each dose is administered to a group of 10 mice, comprising 5 males and 5 females. Injections are administered manually into the tail vein at a rate of 2 ml/minute.

Death is determined 24 hours after application.

Excretion of the studied compounds via bile in cats:

These tests are performed on adult cats, male or female, weighing 3 to 4 kg.

The test substance is administered by intravenous injection at a dose of 0.10 g/kg iodine into the subcutaneous vein of the inner side of the lower limb. The excretion of the compound is monitored radiographically.

Images of the gallbladder and urinary bladder are taken 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours after administration of the test compound.

Effect on femoral loss:

This test is performed on mongrel dogs or bitches weighing 7 to 12 kg, anesthetized with Nembutal.

The dose of Nembutal used is 30 mg/kg with premedication with ventranqvil, total intravenous injection 2.5 mg, breathing is spontaneous.

Changes in loss are detected at the level of the femoral artery, right or left, using electromagnetic recording.

Injections are made into the collateral femoral artery in front of the sensor using a catheter adjusted downstream to avoid disrupting blood flow.

The injections always have a volume of 1.5 ml, which is injected within 3 to 5 seconds.

An equal volume of isotonic sodium chloride solution is also injected.

The results of these tests are shown in Table IX.

Table IX

Compound Content of compound III, in % methyl-sodium salt of glucamine Acute toxicity, mouse, g, iodine/kg, intravenous administration Peripheral vasodilation femoral wasting Bile excretion in cats, intravenous administration of 0.10 g iodine/kg 31 28 15 + 0 32 28 15 + 0 33 38 17 + + and 28 5.4 + + + 0 b 30 5.6 + + + 0 c 28 6.2 + + 0 d 38 5.7 + + + 0

mixture of both salts e 28 2 + + + + + + + +

Note:

a: 2,4,6-triiodo-3-methylcarbamoyl-5-acetamidobenzoic acid, b: 2,4,6-triiodo-3-N-hydroxyethylcarbamoyl-5-acetamidobenzoic acid, c: 5,5’-adipoyldiimino-bis-(2,4,6-triiodo-N-methylisophthalamic acid), d: 2,4,6-triiodo-bis-3,5-(acetamido-benzoic acid, e: 3,3’-adipoyldiimino-bis-(2,4,6-triiodo-benzoic acid].

Note:

The number of crosses is proportional to the observed effect.

Below are also the results of a toxicological test performed on rats by intracisternal injection using the method of E. Melartin (see Investigative Radiology, 1970, 5, 1, 13—21).

Table

Compound Dose for 1 rat Death 31 56 mg J 1/10 32 50 mg J 0/10 33 56 mg J 0/10 c 17 mgj 9/10

As is apparent from the above description, the compounds of general formula III are useful as contrast agents in radiography. Their main uses are in urography, angiography, cholangiography and myelography.

A preferred pharmaceutical form for the use of contrast agents according to the invention are aqueous solutions of salts of compounds of general formula III.

These aqueous solutions preferably contain 5 to 100 g of salt in 100 ml of solution, and the injectable amount of these solutions is in the range of 5 to 1000 ml.

Claims (1)

I will invent the object Process for the preparation of 2,4,6-triiodo-5- (bis- ((2,4,6-triiodophenyl) -carbamoylmethyl) -aminoacetamido) benzoic acid derivatives useful as radiographic contrast agents of formula III n-co-ch- n CHfONH where R1 is a radical of the formula —CONHR8 wherein R5 is a C1 -C4 alkyl radical or a radical of the formula R7 Z —N \ Re in which R 7 represents an alkanoyl radical having 2 to Θ carbon atoms and R 5 represents a C 1 -C 4 alkyl radical, each of R 2 and R 3 being a radical of the formula -CONHR 8 in which: R 9 represents a hydroxyalkyl radical having 1 to 4 carbon atoms, and R 1 represents a hydrogen atom or a C 1 -C 4 alkyl radical, and salts thereof with pharmaceutically acceptable bases, characterized in that the amine of the formula IV COOH where R 1 and R 1 are as defined above, reacted with a compound of formula Vb (Vb) wherein R a and R 3 are as defined above, in an aqueous basic medium at a temperature in the range of 60 to 90 ° C.