NO840688L - ROENTGENKONTRASTMIDLER - Google Patents

Description

The present invention relates to non-ionic iodine or bromo-benzene compounds suitable for use as X-ray contrast agents, characterized in that they have the formula:

in which:

X is an iodine or bromine atom,

R is a hydrogen atom or acetyl, ethoxyacetyl or trifluoroacetyl,

m is an integer from 0 to 2,

n is an integer from 0 to 4,

as the sum of m + n is at least equal to 2.

and A independently represent an amino-alcohol residue of formula:

in which:

represents a hydrogen atom, a C 1-6 alkyl group, or a mono- or polyhydroxy alkyl group, and

R A „ represents a mono- or polyhydroxy C1 . — b, alkyl group.

These and other features of the invention appear in patent

the requirements.

The compounds are suitable for use as X-ray contrast

agents either alone or in admixture with suitable carriers.

Iodobenzene compounds with a majority of iodine atoms on the benzene

nucleus, generally three iodine atoms for each benzene nucleus, and a variety of other substituents, have been used for a long time as X-ray contrast agents. The other substituents

important information

For archival reasons, the Norwegian Patent Office only has access to documents for this generally available patent application that contain handwritten notes, comments or crossing outs, or that may be stamped "Expired" or the like. We have therefore had to use these documents for scanning to create an electronic edition.

Handwritten remarks or comments have been part of the proceedings, and must not be used to interpret the content of the document.

Cross-outs and stampings with "Expired" etc. indicates that newer documents have been received during the proceedings to replace the earlier document. Such crossing out or stamping must not be understood as meaning that the relevant part of the document does not apply.

Please ignore handwritten remarks, comments or crossing outs, as well as any stamps with "Expired" etc. which have the same meaning.

Poor original figures or text, copied as best as possible.

are pharmacologically tolerable groups that allow administration of the compounds to humans and animals. The said substituents are generally chosen on the one hand to give the compounds a sufficient water solubility for supplying the compounds in aqueous solution and on the other hand to give the compounds a suitable tolerability in humans.

For this purpose, non-ionic structures have been proposed, i.e. iodobenzene derivatives with non-ionic substituents.

In French patent document 2,053,037, carbamoyl-iodobenzene compounds are proposed which include a total of at least one N-hydroxyalkyl group and at least two hydroxy groups.

Metripzamides a compound that illustrates this class but this compound has been found to have a limited stability.

More recently, other nonionic iodobenzene compounds with a hydroxyalkyl group have been proposed (see French Patents 2,293,919 and 2,354,316).

The purpose of the present invention is to provide new compounds with a hydroxyalkyl group where these compounds are well tolerated by humans, are very stable in aqueous solution and can be easily produced at low cost.

An advantageous group of compounds of formula (I) consists of compounds of formula (Ia):

wherein X, R, A^ and have their previously indicated meanings.

Another advantageous group of compounds of formula (I) consists of the compounds of formula (Ib):

wherein X, and A^ have the previously indicated meanings.

Among the compounds of formula (I), (Ia) or (Ib), those in which the amino alcohol residues A^ and A^ include at least two hydroxy groups are preferred.

The compounds (I) can be easily prepared from compounds (II):

in which X has the above meaning, by a process which comprises condensing a compound of the above formula (II) an amine of formula (III): in which A'^ denotes a group A^ with protected hydroxy groups, to give an amine of formula (IV): and optionally amines (IV) are acylated with an acid fluoride of formula R' Cl (V) in which R' represents a group R of the acyl type, to give a compound of formula (VI):

in which A'^ is a group A^ in which the hydroxy groups are protected and n > 0,

or with a compound of formula (VIII):

wherein A'^ is a group A2 with protected hydroxy groups,

to give a compound of formula (IX):

and the protective groups are removed.

As a modification, the reaction sequence can also be reversed, and in this case the process first comprises acylating the amine (II) with an acid chloride of formula (V) to give an acid dichloride of formula (X):

and then this acid chloride (X) is condensed with amine of formula (III) to give a compound of formula (VI).

In a further modification, instead of an amine of formula (III), an unprotected amine of formula A^H (XI) can be used and then only the hydroxy groups are protected.

As starting material, it is also possible to use an isophthalic acid diester with fomel (XII):

wherein R'' is an alkyl group, this process thus comprising condensing said diester with an amine of formula (XI) to give a compound of formula

(XIII):

and then successively the nitro group in connection with (XIII) is reduced and the benzene nucleus is halogenated to give a compound of formula (XIV):

which can then be deprotected to give a compound of formula (VI).

The iodobenzene compounds (I) are useful for conventional X-ray objectives, typically for angiography and myelography.

The bromobenzene compound of formula (I) is typically used for digitized radiography and especially for digitized angiography.

In addition, the bromobenzene compounds of formula (I) can be used in admixture with iodobenzene compounds which can either be iodobenzene compounds of formula (I) or other iodobenzene compounds. The mentioned other compounds can typically be non-ionic compounds such as 5-(N-2,3-dihydroxypropyl-N-acetyl-amino)-2,4,6-triiodo-N,N'-bis-(2,3 -dihydroxypropyl)isophthalamide and 5-(N-2-hydroxy-propionyl-amino)-2,4,6-triiodo-N,N'-bis(1,3-dihydroxy-2-propyl)' isophthalamide, or ionic compounds such as diatrizoic acid, iothalamic acid, metrizionic acid, acetrizoic acid, iodamide, ioxythalamic acid, ioglunide, ioxaglinic acid, iocamic acid, adipiodone and ioglucanic acid.

It has been found that the use of mixtures of such compounds gives a greater tolerability than the iodobenzene compound used alone, while the opacity is of the same order of magnitude.

This is of great interest as bromine is usually cheaper than iodine.

In such mixtures, the bromobenzene compound of formula (I) advantageously represents from 1/2 to 2/1 (molar basis) of the iodobenzene compounds.

The invention thus leads to X-ray contrast agents which include iodobenzene compounds of formula (I), bromobenzene compounds of formula (I), mixtures of bromobenzene compounds of formula (I) with iodobenzene compounds of formula (I) or, mixtures of bromobenzene - compound of formula (I) with other iodobenzene compounds.

The preferred pharmaceutical forms of the X-ray contrast agents consist of aqueous solutions of the aforementioned compounds.

The aqueous solutions generally contain a total of 5-100 g of iodobenzene and/or bromobenzene compounds per 100 ml and the injectable amount of these solutions can generally vary from 5 ml to 1000 ml.

Examples of such contrast agent mixtures are given in the following for illustrative purposes.

Mixture A

Mixture B Mixture C Mixture D Mixture E Mixture F

The following examples shall illustrate the invention.

In the examples, the compounds were characterized by thin layer chromatography (TLC) determined with a Merck silica gel F254 plate with the following eluents:

EXAMPLE 1

Preparation of 5-[N-bis(p-hydroxyethyl)carbamoylmethyl-N-acety] amino/-2 , 4, 6-tri iodo -N, N' -bis^bis ((i -hydroxyethyl j^isophthalamide.

a) Preparation of 5-amino-1,4,6-tri. iodo-isophthalic acid chloride 1.5 kg of 5-amino-2,4,6-triiodo-isophthanoic acid is suspended with 4.025

liter of thionyl chloride and 5 ml of dimentylformamide. The reaction mixture is heated for 5 hours at 60°C. After evaporation of excess thionyl chloride under vacuum, the material is washed with 4 liters of water and then filtered and washed thoroughly with diisopropyl ether. The resulting product is then dried in air and then under vacuum. Yield 87.3%

TLC (eluent 1): Rf : 1 (2% acetone solution)

IR and ^HNMR spectra correspond to the shown structure-new

b) Preparation of 5-amino-2,4,6-triiodo-N,N',-bis-Zbis-(fr-hydroxyethyl L/isophthalamide

1.6 kg (2.68 mol) of the 5-amino-2,4,6-triiodo-isophthalic acid chloride are dissolved in 4 liters of dimethylacetamide in the presence of 1.13 liters of triethylamine (8.04 mol).

Diethanolamines (775 ml, 8.04 mol) are added gradually while the temperature of the reaction mixture is kept between 15 and 20°C. The reaction mixture is further stirred overnight at room temperature. The triethylamine hydrochloride is suctioned off on a filter and the dimethylacetamide is evaporated to dryness.

The resulting oil is dissolved in water and crystallized

overnight at room temperature.

The product is filtered and dried under vacuum. Yield 73.8%

TLC: Eluent 2. Rf: 0.67, 0.63 (presence of 2 atropisomers)

c) Preparation of 5-acetamido-2,4,6-triiodo-N,N'-bis-Zbis-(ft-acetoxyethyl7isophthalamide

5-amino-2,4,6-triiodo-N,N'-bis/bis(-hydroxyethyl/-isophthalamide)-(1.45 kg, 1.98 mol) is dissolved in ethylene glycol dimethyl ether (2.2 liters) . After adding acetyl chloride (1.06 liters,

14.85 mol) the solution is heated at 8<D°C. Crystallization takes place spontaneously when the mixture is left overnight at room temperature.

This material is then filtered and dried to yield 1.58 kg of product. Yield 85%.

TLC: Eluent 3 : Rf : 0.25.

d) Preparation of N-bis-(fc-acetoxyethyl)-ct-bromoacetamide-wlbj.s- i(^ace t °]S^Xe - )■ .a.m-i-n' ^ydr g^.iQr id 15 g diethanolamine was gradually added to a solution of 0.6 liters of acetic acid saturated at 20°C with gaseous hydrochloric acid. The solution is set aside overnight, after which it is evaporated to dryness and taken up in diisopropyl ether. The resulting product is filtered off and then dried under vacuum. Yield 96%.

N-bis-(ft-acetoxyethyl)-<X^-bromo-acetamide

16.9 g (0.070 mol) of N-bis-((i-acetoxyethyl)amine are dissolved in 65 ml of a solution of dichloroethane containing 6.85 g of sodium bicarbonate. This solution is dried at 50°C

for 1 hour. After filtering off the formed sodium chloride, drying over sodium sulfate and filtering, 13.7 g (0.068 mol) of bromoacetyl bromide are added to the resulting material at 10 to 15°C followed by 6.9 g (0.068 mol) of triethylamine. The reaction mixture is set aside overnight at room temperature and the triethylamine hydrochloride bromide is filtered off with suction. The ModeriLutes recovered in this way are waxed with water, dried over sodium sulfate and then evaporated to dryness to give 16.3 g of an oil. Yield 77%.

TLC: ethyl acetate/methylene chloride (25/25): Rf: 0.63.

IR and ^HNMR spectra correspond to the structural formula.

e) Preparation of 5- ZN- bis- {( i - hydroxyethyl) carbamoyl-methyl- N- acetyl- amino/- 2, 4, 6- triiodo- N, N'- bis- Zbis-( ft- hydroxyethylL/ isophthalamide

200 g of 5-acetamido-2,4,6-triiodo-N,N'-bis-/bis-(^-acetoxyethyl_)_/isophthalamide is added to a suspension of 5.6 g (0.234 mol) sodium hydride 340 ml anhydrous dimethylformamide . After reaction for 1 hour, 72.3 g (0.233 mol) of N-bis-(acetoxyethyl)-cC-bromoacetamide are added at room temperature. The reaction mixture is set aside overnight and then evaporated to dryness.

The resulting oil is saponified by dissolving in 638 ml of 2N sodium hydroxide (1.366 mol) and 300 ml of ethanol.

After stirring for 1 hour, water (3.4 liters) is added followed by "Amberlite" IRN77 cationic resin (1.08 liters). After filtration, the mother liquors are treated with 1.46 liters of IRN78 anionic resin. The suspension is filtered and the liquids evaporated to dryness to give a white crystalline material recrystallized from 700 ml of butanol. Dividend 7 3%.

TLC: Eluent 4 - Rf : 0.2 and 0.25 (atropisomers).

■*"HNMR and IR analysis correspond to the structure.; EXAMPLE 2; Preparation of 5-/ bis-(fl- hydroxyethyl) carbamoylmethyl- N-acetyl- amineb/- 2, 4,6-tribromo-N, N'- bis -/ bis-(Q-hydroxyethyl)/ isophthalamide ; ; a) Preparation of 5-amino-2,4,6-tribromo-isophthalic acid chloride 5-amino-2,4,6-tribromo-isophthalic acid chloride (500 g, 1.2 mol); suspend with thionyl chloride (3 litres) and dimethylformamide (1 ml). The blading is boiled under reflux for 4 hours. After evaporation of excess thionyl chloride, the material is waxed with diisopropyl ether (2 litres). The entire product is precipitated by the addition of petroleum ether. The dichloride is filtered off, washed thoroughly with petroleum ether and dried under vacuum. Yield 90%. ;TLC: Eluent 7. Rf = 0.9.;b) Preparation of 5-amino- 2, 4, 6- tribromo- N, N'- bis-/ bis-( ph- hydroxyethyl)/ isophthalamine ; 5-amino -2,4,6-tribromo-isophthalic acid chloride (363 g) is dissolved in acetone (380 ml). Diethanolamine (236 ml) dissolved in water (200 ml) and potassium bicarbonate (236 g) are slowly added thereto while the temperature of the reaction mixture is maintained at about 20°C. The product crystallizes after stirring for several days at room temperature. After filtration and drying under vacuum, the product is recrystallized from 1500 ml of absolute ethanol. Yield 70%.. ;TLC: Eluent 7 : Rf = 0.55 and 0.65.;Eluent 6 : Rf = 0.48 and 0.52.;c) Preparation of 5-acetamido-2, 4, 6- tribromo-N,N'-bis-/bis-((3-acetoxyethyl)/isophthalamide; 10 g (0.016 mol) of 5-amino-2,4,6-tribromo-N,N'-bis-/bis- The -hydroxyethyl^/isophthalamide is dissolved in 20 ml of ethylene glycol dimethyl ether. After adding 9.52 ml of acetyl chloride, the solution is heated at 80°C for 45 minutes, after which it is cooled to room temperature and stirred overnight. The white crystalline material is filtered off, washed with diethyl ether, ;and then dried in an oven. Yield 74%.;TLC:.Eluent 7 Rf : 0.72;Eluent 6 Rf : 0.88;d) Preparation<g>of 5-/ N- bis- ( 6- hydroxyethyl) carbamoyl- methyl-N- acetyl- amino/- 2. 4, 6- tribromo- N, N',- bis-/ bis-( 3- hydroxyethyl)-/ isophthalamide; 5-acetamido-2 , 4,6-tribromo-N,N'-bis-/bis- (@-acetoxyethyl_)_/isophthalamide (5 g, 6.2 mol) is added to a suspension of NaH (0.299 g, 7.5 mmol) in anhydrous Dimethylacetamide (10 ml). ;After reaction for 1 hour (hydrogen is evolved), 2.32 g of N-bis-({6-acetoxyethyl)-oC-bromoacetamide diluted in 2 ml of DMAC are added thereto. The reaction mixture is set aside overnight at room temperature and then evaporated to dryness. The resulting oil is saponified by dissolving in 8 ml of ethanol and 20 ml of 2N sodium hydroxide. The solution is then treated sequentially with a cationic resin ("Amberlite" IRN77), and then with an anionic resin ("Amberlite" IRN78). After filtration, the liquids are evaporated to dryness. ;The resulting material recrystallized from butanol. Dividend 7 0%. ;TLC: Eluent 7 Rf : 0.35 and 0.40. ;Eluent 5 (60/40) Rf : 0.22 and 0.28. ;Bromotritration : 98%.;EXAMPLE 3■ ;Preparation of 5-ZN-tris- ( hydroxymethyl )■- methyl- carbamoyl-methyl- N- acetyl- amino/- 2, 4, 6- tri in od- N, N '-bis-Zbis-(9-hydroxyethyl/isophthalamide; a) Preparation of tris(acetoxymethyl)aminomethane hydrochloride; 100 g of tris(hydrochloridemethyl)aminomethane hydrochloride are dissolved at 100°C in 240 g of acetic anhydride and 320 ml of acetic acid. The reaction mixture is heated at 100°C for 10 hours and then evaporated to dryness. The remaining oil is repeatedly waxed with ether after which it is evaporated to dryness to give 1.44 g of a colorless oil (yield: 73%). ;^HNMR and IR spectral analyzes correspond to the structure.;b) Preparation of N-(tris-acetoxymethyl)methyl-rf-bromo-acetamide ;The compound obtained under a) is treated as described in example 1 (.(.d)(£ ) to give N-(tris-acetoxymethyl)methyl-«C-bromoacetamide with a yield of 75%. ;''"HNMR and IR analysis correspond to the structure.;c) Preparation of 5-/ N- tris( hydroxymethyl) methyl- carbamoyl-methyl- N- acetyl- amino/- 2 , 4 , 6- triiodo- N, N' - bis-/ bis-(^- hydroxyethyl L/ isophthalamide; The method described in example l( e) is used during application; of the compound obtained under (b) instead of N^bic(acetoxyethyl)-c<-bromo-acetamide. ;EXAMPLE 4;Preparation of 5-/N-tris(hydroxymethyl) methyl- carbamoyl- methyl- N-acetyl-amino/ isophthalamide. ; The compound is obtained as described under example 2(d) using the compound obtained in example 3(b) instead; for N-bis-(acetoxyethyl)-«K,-bromoacetamide.; EXAMPLE 5; Preparation of 5-/ N- bis - ({ 3 - hydroxyethyl) carbamoyl- methyl- N-trifluoroacetyl- amino/- 2 , 4, 6- tribromo- N, N' - bis-/ bis- ((^- hydroxyethyl) / isophthalamide; a) Preparation of 5-trifluoroacetylamido-2,4,6-tribromo-N,N'-bis-/bis(fi-trifluoro-acetoxyethyl)/isophthalamide. ;5-amino-2, 4, 6-tribromo-N, N' -bis-/bis-(f-hydroxyethyl) isophtala-.,mid (10 g, 0.16 mol) dissolved in ethylene glycol dimethyl ether (20 ml) is trifluoroacetylated in the presence of trifluoroacetic anhydride (33.6 g, 0.16 mol) at 80°C for 4 hours. The material is set aside overnight at -10°C to give a white precipitate which is waxed with isopropyl ether and then dried in an oven. ;b) Preparation of 5-/ N- bis-( G- hydroxyethyl) carbamoyl- methyl-N- trifluoroacetyl- amino/- 2, 4, 6- tribromo- N, N'- bis-/ bis-( fi- hydroxyethyl )/ isophthalamide; The compound is obtained by the compound obtained under (a); as described in example 1(e).; EXAMPLE 6; Preparation of 5-/ N- bis-(- hydroxyethyl) carbamoyl- metvl-N- trifluoro-acetyl - amino/- 2, 4, 6- triiodo- N, N'- bis-/ bis-( O-hydroxyethyl/ iophthalamide ; The compound is obtained as described under example 5 from 5-amino-2,4,6-triiod-N,N'-bis-/bis- ((5-hydroxyethyl J_/isophthalamide. ; EXAMPLE 7; Preparation of 5-/ N- (2, 3- dihydroxypropyl- carbamoyl- methyl)-N- acetyl- amino/- 2 , 4 , 6- tri iod- N, N'— bis-( 2 , 3- dihydroxypropyl)- isophthalamide ; ; The compound is obtained as described in example 1.; EXAMPLE 8; Preparation of 5-/N-(2,3-dihydroxypropyl-carbamoyl-methyl)-N-acetylamino/- 2,4,6-tribromo-N,N'-bis -(2,3-dihydroxypropyl)isophthalamide; ; The compound is obtained as described in example 2. ;EXAMPLE 9;Preparation of 5-/N-bis-(tf-hydroxyethyl)-carbamoyl-carbonyl-amino/- 2:/ 4 , 6- tri in od- N, N' - bis-/ bis- ($- hydroxyethyl/ isophthalamide ; ; a) Preparation of N-bis-(fl-hydroxyethyl) oxamic acid, potassium salt; Potassium methoxalate (156 g, 1 mol) is dissolved in water (300 ml); and diethanolamine (150 g, 1.4 mol) is added thereto. The mixture is stirred overnight at room temperature and then for 6 hours at 50°C, after which it is crusted for 24 hours. After suction on the filter and washing with absolute ethanol, a first portion (35 g) is obtained. After evaporation of the reaction liquids, the residue is taken up in 250 ml of absolute ethanol. The resulting precipitate is filtered off and washed with absolute ethanol to give another portion (32 g) of product, i.e. a total yield of 32%. The IR spectrum corresponds to the structure. b) Preparation of N-bis-(fi-acetoxyethyl) oxamic acid The compound obtained under (a) (90 g, 0.42 mol) is added to 1800 ml of acetic acid saturated gaseous hydrochloric acid. The mixture is stirred at room temperature for 48 hours and then insoluble material (potassium chloride) is filtered off and the filtrate is evaporated to give an oil which crystallizes. It is taken up in 400 ml of isopropyl ether and then crystallized overnight with stirring. The resulting material is filtered off, washed with isopropyl ether and dried to give 75 g of product, i.e. a yield of 69%. The IR spectrum matches the structure. c) Preparation of N-bis-(fla-acetoxyethyl) oxamic acid chloride The compound obtained under (b) (95 g, 0.28 mol) is dissolved in thionyl chloride (250 ml), and the solution is heated at 80°C; for 2 hours. The thionyl chloride is evaporated and the material taken up twice in 100 ml of benzene which is removed under vacuum to give an oil-active concentrate which is used without further purification. ;d) Preparation of 2, 4, 6^- tri in od- 3, 5- bis-/ bis-acetoxyethyl) carbamoyl/ aniline ; To 0.1 mol of 5-amino-2,4,6-triiodo-isophthalic acid chloride dissolved In 10 ml of DMAC are added at 20-25°C N-bis-(Q-acetoxyethyl)amine hydrochloride (6.8 g, obtained under example 1 (d)) and triethylamine (7.7 ml). After stirring for 16 hours at room temperature, the triethylamine hydrochloride is sucked off the filter and the reaction solution is poured into water. The resulting gummy substance is dissolved in dichloroethane, after which the solution is washed three times with water, dried and evaporated to dryness. Yield 7 0%. ;TLC: Eluent 3 Rf : 0.8 and 0.9 (2 isomers);e) Preparation of 5-/ N- bis-( @>- acetoxyethyl) carbamoyl-carbonyl-amino/^ 2, 4, 6- tri iodo- N, N' bis-/ bis- (( 3- acetoxyethyl) / ; isophthalamide ; 2,4, 6-tri iodo-3, 5-bis-/bis (acetoxyethyl) carbamoyl_l/-aniline (91.1 g , 0.1 mol) is dissolved in dimethylacetamide and the acid chloride obtained under (c) (84 g, 0.3 mol) is added thereto. ;The reaction mixture is kept under constant stirring for 24 hours at room temperature and then poured into 750 ml of water + ice, and a gummy precipitate forms. The supernatant liquids are poured off and the gummy residue is taken up in 250 ml of ethylene glycol dimethyl ether. The material is allowed to crystallize for 24 and is then filtered off with suction and dried to give 85.g of product, i.e. a yield of 73, 5%.; TLC: Eluent 9 Rf : 0.7.; f) Saponification; The product obtained under (e) above (85 g) is dissolved in 2N sodium hydroxide (260 ml). After stirring at room temperature for 4 hours, water (1 liter) is added and "Amberlite" IRN77 cationic resin (400 ml) is added. After filtration, the mother liquors are treated twice with 3SA activated carbon (2%) for 2 hours at room temperature. After filtration, the filtrate is treated with "Amberlite" IRN78 anionic resin (600 ml). The suspension is filtered and the liquids are evaporated. The resulting amorphous material is washed with ethanol. After extraction on a filter and drying, a white product is obtained with a yield of 47%. ;TLC: Eluent 7 Rf : 0.28 and 0.32.;Iodine titration : 98.5%.;EXAMPLES 10-12;Using the method of Example 9, the compounds listed in Table I were obtained. ; EXAMPLE 15; Preparation of 5-/N-bis-(if-hydroxyethyl)carbamoylmethyl-N-methoxyacetyl-amino/- 2,4,6-tribromo-N,N'-bis-/bis-(ft-hydroxyethyl) / isophthalamide; ; a) Preparation of 53>?5-(N-Methoxyacetyl-amino)-2,4,6-tribromo-isophthalic acid chloride; 22.7 gv (0.05 mol) 5-amino-2,4,6-tribromo-isophthalic acid chloride suspended in 75 ml of CHCl 3 in the presence of 8 ml (0.055 mol) of triethylamine is added dropwise with stirring at a temperature below 10°C to a chloroform solution containing 0.25 mol of methoxyacetic acid chloride. The latter is prepared in situ in CHCl3 from 18.7 ml (0.25 mol) methoxyacetic acid and 18. ml (0.25 mol) thionyl chloride by stirring for one hour at a temperature below 10°C. The reaction mixture is heated at the reflux temperature for chloroform for 24 hours until the starting material completely disappears. The resulting material is waxed with the dilute aqueous bicarbonate solution, dried and the chloroform phase is evaporated to give 19.6 g of a white solid (74.5% yield) with an apparent melting point of 145°C. ;TLC: Eluent Rf = 0.87;b) Preparation of 5- methoxyacetyl-amine-2, 4, 6- tribromo-N, N' - bis-/ bis~(&- hydroxyethyl) / isophthalamide ; 42 g ( o.08 mol) of the acid chloride obtained under (a) is dissolved in 40 ml of acetone. An aqueous diethanolamine solution and 0.24 mol of potassium bicarbonate are gradually added while the temperature of the reaction mixture is maintained at approximately 20°C. After several days at room temperature, the crystalline material is filtered off and waxed repeatedly with diethyl ether and dried in an oven. ;c) Preparation of 5-(methoxyacetylamine)-2,4,6-tribromo-N,N'-bis-/ bis-(ft-acetoxyethyl)/ isophthalamide ;The compound obtained under (b) is dissolved in ethylene glycol dimethyl ether . After adding acetyl chloride, the solution is heated at 80°C for one hour. The solution is then cooled to room temperature. After stirring for several days, the crystalline material is filtered off, washed with diethyl ether and dried under vacuum.;d) Preparation of 5-/N-bis-(@-hydroxyethyl) carbamoyl-methyl-N-methoxyacetyl/- 2, 4 , 6- tribromo- N, N' - bis-/ bis-(( i - hydroxyethyl) / isophthalamide; The compound obtained under (c) is added to a suspension; of NaH in anhydrous dimethylacetamide. After reaction for one hour (hydrogen is evolved ) N-di(acetoxyethyl) - d-bromoacetamide diluted in DMAC is added thereto. ;The reaction mixture is set aside overnight at room temperature and then evaporated to dryness. ;The resulting oil is saponified by dissolving in ethanol with added 2N sodium hydroxide. The solution is then treated ;i sequence with a cationic resin ("Amberlite" IRN77); and with an anionic resin ("Amberlite" IRN78). After filtering off the resin, the liquids are evaporated to dryness. ;IR and "*"HNMR spectra are consistent with the structure.

EXAMPLE 16

Preparation of 5-/ N- bis-(^- hydroxyethyl) carbamoyl- methyl-N- methoxyacetyl- amino/- 2, 4, 6- tri in od- N, N'- bis-/ bi s-( fi -hydroxyethyl ) / isophthalamide

The connection is achieved as described in example 15.

EXAMPLE 17

Preparation of 5-/ N- tris-( hydroxymethyl) methyl- carbamoyl- methyl- N- acetyl- amino/- 2, 4, 6- tribromo- N, N'- bis-( 2, 3- dihydroxypropyl) isophthalamide

a) Preparation of 5-acetamide-2,4,6-tribromo-isophthalic acid chloride

25.6 ml (0.36 mol) of acetyl chloride are added dropwise to a solution containing 110 g (0.24 mol) of 5-amino-2,4,6-tribromo-isophthalic acid chloride in 120 ml of dimethylacetamide at 0°C.

The solution is heated for 2 hours at 40°C and then stirred

at a room temperature. The white product which gradually crystallizes is filtered off after 16 hours, washed with water to which a few drops of sodium hydroxide solution have been added to pH 7, then washed with isopropyl ether. Dividend 39.5%.

A further portion is obtained by precipitating the mother liquors with ice-mixed water, which gives a total yield of 83%.

TLC: upon condensation with propylamine, the product migrates

to Rf 0.6 in the eluent benzene/methyl ethyl ketone/formic acid (50/25/20).

IR and RMN spectra are consistent with the structure.

b) Preparation of 5-acetamido, 2,4,6-tribromo-N,N'-bis-(2,3-dihydroxypropyl)isophthalamide 40 g (0.080 mol) 5-acetamide-2,4,6-tribromo-isophthalic acid chloride dissolved in 40 ml of acetone is added dropwise to a solution of 3-aminopropane-1,2-diol (0.24 mol) in 40 ml of water in the presence of 0.24 mol of potassium bicarbonate. The reaction mixture is stirred for 16 hours at room temperature. The product that crystallizes out is suctioned off on a filter and waxed 3 times with ethanol to remove the excess of aminopropanediol.

The product is then dissolved in methanol under reflux conditions, the inorganic salts are filtered off while hot and the purified product is crystallized from methanol.

c) Preparation of 5-/N-tris-(hydroxymethyl)methyl-carbamoyl-methyl-N-acetyl-amine/- 2,4,6-tribromo-N,N'-bis-(2,3-dihydroxys-propyl ) isophthalamide

The compound obtained as described in Example 4 using the compound obtained under (b) instead of 5-acetamide-2,4,6-tribromo-N,N'-bis-(bis-(-acetoxyethyl)-isophthalamide.

EXAMPLE 18

Preparation of 5-/N-bis-(if-hydroxyethyl)-carbamoyl-methyl-N-acetyl-amino/- 2,4,6-tribromo-N,N'-bis-(2,3-dihydroxypropyl)isophthalamide

The compound is obtained as described in Example 2, using 5-acetamido-2,4,6-tribromo-N,N'-bis-(2,3-dihydroxypropyl)isophthalamide (Example 17b) instead of 5-acetamide-2 ,4, 6-tribromo-N, N' -bis-/bis- ($-acetoxyethyl_)_/isophthalamide.

EXAMPLE 19

Preparation of 5-/ N- bis-- hydroxyethyl) carbamoyl- methyl-N- methylacetyl- amino/- 2, 4, 6- tribromo- N, N'- bis-( 2, 3- dihydroxypropyl) isophthalamide

a) Preparation of 5-(N-methoxyacetylamino)-2,4,6-tribromo-N,N'-bis-(2,3-dihydroxypropyl)-isophthalamide 42 g (0.08 mol) 5-methoxy- acetylamine-2,4,6-tribromo-isophthalic acid chloride dissolved in 40 ml of acetone is added dropwise to a solution of 0.24 mol of 3-amino-propane-1,2-diol in 40 ml of water in the presence of 0.24 mol of potassium bicarbonate. The reaction mixture is stirred for 16 hours at room temperature. The crystalline material is sucked off on a filter and then washed three times with ethanol.

After dissolving the product in methanol under reflux with subsequent filtration in a hot state to remove the inorganic salts, the product is purified by recrystallization from methanol.

IR and HNMR spectra are consistent with the structure.

b) Preparation of 5-/ bis-(6-hydroxyethyl)- carbamoyl-methyl- N- methoxyacetyl- amino/- 2, 4, 6- tribromo- N, N'- bis-( 2, 3- dihydroxy- propyl) isophthalamide

The compound is obtained as described in Example 15 using the preparation obtained in (b).

Claims (10)

1. Non-ionic iodine or bromo-benzene compounds for use as X-ray contrast agents, characterized in that they have the formula: in which: X is an iodine or bromine atom R is a hydrogen atom, or acetyl, methoxyacetyl or trifluoroacetyl, m is an integer from 0 to 2, n is an integer from 0 to 4, the sum of m + n is at least equal to 2, and A^ independently represent an amino-alcohol residue of formula: in which: R-1 represents a hydrogen atom, a C1. —D alkyl group, or a mono- or polyhydroxy C1 . — D, alkyl group, and R Z „ represents a mono- or polyhydroxy C l . — b, alkyl group. 2. Compounds as stated in claim 1, characterized in that they have the formula: wherein X, R, and A^ have the above meaning. 3. Compounds as stated in claim 1, characterized in that they have the formula wherein X, A^ and A^ have the above meaning. 4. Compound as stated in claims 1-3, characterized in that the amino alcohol residues A^ and A^ include at least two hydroxy groups. 5. 5-[N-bis-(S-hydroxyethyl)carbamoylmethyl-N-acetyl-amino]-2,4,6-tribromo-N,N'-bis-(P-hydroxyethyl)-isophthalamide. 6. 5-[bis-(!(i-hydroxyethyl)carbamoylmethyl-N-acetyl-amino]-2,4,6-tribromo-N,N'-bis-([i]-hydroxyethyl)-isophthalamide. 7. X-ray contrast agents, characterized in that they comprise a compound as specified in claims 1--6. 8 X-ray contrast agents as stated in claim 7, characterized in that they comprise a mixture of a bromobenzene compound with (I) and of an iodobenzene compound. — p 9. X-ray contrast agents as stated in claim 8, characterized in that they comprise a mixture of a bromobenzene compound of formula (I) and of an iodobenzene compound of formula (I). 10. Use of X-ray contrast agents as stated in requirement k IT. AI 4sr JLr 1 - 9 1 ^—£o-r-m_av-/ aqueous!^ solution^.