SI8911042A - Process for obtaining triiodine benzene compounds with non-ionic iodine and contrast products containing them - Google Patents

Abstract

The invention relates to new nonionic compounds of formula <IMAGE> These compounds can be employed as contrast agents.

Description

PROCEDURE FOR THE PRODUCTION OF THREE JODOBENSEN COMPOUNDS WITH NON-ION IODINE AND CONTRASTIC PRODUCTS CONTAINING THEM

TECHNICAL FIELD OF THE INVENTION

The invention is in the field of synthetic organic chemistry.

TECHNICAL PROBLEM

A technical problem which the present invention solves is a solution for the production of new iodinated organic compounds, which can be used as contrast products in radiography.

BACKGROUND OF THE INVENTION

For a long time, iodobenzene compounds have been used as contrast products which have more iodine atoms in the benzene nucleus, up to 3 iodine atoms per each benzene nucleus and various other substituents. These other substituents are pharmacologically acceptable groups that allow the administration of compounds to humans and animals, and are selected in the usual way, partly because of the satisfactory solubility of the compounds in water so that they can be administered in aqueous solution, and partly because of the satisfactory tolerance of the compounds by human organism.

Non-ionic structures, that is, iodobenzene derivatives having non-ionic substituents, are provided for this purpose.

Patent FR-A-2 053 037 discloses carbamoylodobenzene compounds which together contain at least one Nhydroxy-alkyl group and at least two hydroxy groups.

A compound illustrating this class is metrizamide, which has already been shown to have limited stability.

DESCRIPTION OF THE TECHNICAL PROBLEM SOLUTION

The object of the present invention is to provide novel non-ionic compounds which the human body can tolerate, which are very stable in aqueous solution, have a high degree of solubility in water and which have poor viscosity in water.

In this context, the compounds of the formula of the present invention are intended to:

R ₃

where:

R 1 represents a compound of the formula:

-N-CO-Rs

Re

Rg represents a C1-C4 alkyl group, a C1-C4 hydroxyalkine group, or a C1-C4 polyhydroxyalkyl group,

R ₆ represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 hydroxyalkine group, or a C 1 -C 4 polyhydroxyalkyl group, or a group of the formula:

R ₈

-CO-N-R7

R ₇ represents a C1-C4 hydroxyalkyl group or a C1-C4 polyhydroxyalkyl group,

Ra represents a hydrogen atom or a C1-C4 alkyl group,

R ₂ represents a hydrogen atom, a C 1 -C 4 hydroxyalkine group or a C 1 -C ₄ polyhydroxyalkyl group

R ₃ represents a hydrogen atom or a C 1 -C 4 alkyl group,

R4 represents a hydrogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkine group or a C1-C4 polyhydroxyalkyl group.

In the present invention, the polyhydroxyalkyl group is a straight or branched polyhydroxyalkyl group.

A preferred compound of formula I is a compound of formula I wherein R 1 = -CO-NH-CH ₂ -CH 2 OH, R ₂ = -CH ₂ -CH ₂ OH, R ₃ = -CH ₂ CHOH-CH ₂ OH.

Among others, the preferred group of compounds of formula I are those which form compounds of diamino-symmetric type, that is, compounds of formula:

R ₃

CH ₂ OH

II ch ₂ oh

The compounds of formula I can be prepared in a conventional manner, with certain acylation and / or alkylation reactions, and the starting compounds are known.

Thus, compounds of diamino-symmetric type (compounds of formula II) can be further enhanced:

a) by acylation of a diamino compound of the formula:

R ₃

wherein R * 2 represents a group R2 whose hydroxy groups are protected by acid chloride of the formula:

RCOC1 IV where R represents a group

CH

CH 2 -OH

CH ₂ -OH which hydroxy groups are protected,

b) optionally alkylating the resulting compound with an alkylating reagent of formula

R ' ₄ Z wherein R' ₄ is as described above except that it cannot be hydrogen and Z represents a labile group such as a chlorine, bromine or iodine atom in the presence of a base such as sodium methyl phthalate, sodium hydride, or sodium hydroxide,

c) by removing the protection.

The compounds of formula III are described in French Patent FR-A-2 614 299.

Other compounds of formula III can be obtained in an analogous manner by starting with alkyl-3,5-dinitrobenzoate of formula:

wherein R 'represents a C 1 -C 4 alkyl group such as a methyl group.

Diamino-symmetric compounds may be prepared in the same way as compounds of formula VI:

a) by reaction with an amino of the formula:

NH-R ₂ VII

I

R ₃ in such a way as to obtain a compound of the formula:

R3

I

VIII

b) by reduction with ammonium sulfide to give a compound of the formula:

R3

I

c) by acylating a compound of formula IX with an acid chloride of formula RCOC1 (IV) in such a way as to obtain a compound of formula:

Ra

I

d) by reducing and iodizing a compound of formula X in such a way as to obtain a compound of formula:

Ra

R

XI

Ί

e) optionally alkylating a compound of formula XI with an alkylating reagent of formula V in such a way as to obtain a compound of formula:

f) deprotecting a compound of formula XII,

g) by acylating the obtained deprotected compound with an acid chloride of the formula:

ci-co-r ' ₅ XIII where R' ₅ represents a group R ₅ whose hydroxy groups are protected so that after the deprotection is obtained a compound of the formula:

R3

ci ^ -oh

Cl ^ -OH

XIV whereby steps f and g can also be interchanged, and possibly

h) by alkylation to obtain a compound of formula I wherein R8 is not hydrogen.

Compounds of symmetric isophthalic type (compounds of formula I wherein R 1 = -CO-NR ₂ ) can be obtained

I

R ₃

a) By acylation of an amine of the formula:

with an acid chloride of the formula RCOC1 (IV), a compound of the formula is obtained:

in such a way that

b) by reacting an amine of formula H-N-R2 (VII) with a compound of formula

R ₃

XVI in such a way as to obtain a compound of the formula:

R ₃

and then eventually

c) alkylate a compound of formula XVII with an alkylation reagent of formula R ' ₄ Z as defined above at the end

d) protecting groups, groups -CH (CH2OH) 2 or

e) eliminating protecting groups, groups -CH (CH2OH) 2 and optionally

f) alkylate a compound having a deprotected alkylating reagent of formula R ' ₄ Z.

Compounds disimetričnega isophthalic type (the compound of formula I, wherein R-CO-N-R7, with the provision that R 7 is not equal to R 2; R is not equal to R ₃₎

Rs can be obtained by:

a) by acylation of an amine of the formula:

XVIII with chloride of formula RCOC1.

b) possibly alkylating with an alkylating reagent of the formula R ' ₄ Z and

c) by eliminating the -CH (CH2OH) ₂ protecting groups.

The compounds of formula XVIII can be obtained as described in EP-0 015 867.

In one embodiment, the compounds of the disymmetric isophthalic type may be obtained:

a) by acylation of an amine of the formula:

wherein R ' ₇ represents a group R ₇ whose hydroxy groups are protected by acid chloride of formula RCOC1 (IV) in such a way as to obtain a compound of formula:

b) by reaction of an amine of the formula:

HN-R ₂

I

R ₃ (VII) with a compound of formula XX in such a way as to obtain a compound of formula:

Ra

and then possibly:

c) alkylating a compound of formula XXI with an alkylating reagent of formula R ' ₄ Z as defined above and lastly,

d) eliminating protecting groups, groups -CH (CH ₂ OH) ₂ and optionally,

f) alkylate a compound having a deprotected alkylating reagent of formula R ' ₄ Z.

These contrast products are used in humans and animals for radiological purposes.

The preferred pharmaceutical form of the contrast products of the present invention consists of aqueous solutions of the compounds.

Aqueous solutions generally contain a total of 5 to 100 g of a compound of Formula I per 100 ml of injectable amount, such as solutions that can vary substantially from 1 to 1000 ml.

Aqueous solutions of the compounds of formula I may also contain certain additives, such as:

- sodium chloride at a concentration between 0,1 and 2 mM / l

- sodium citrate at a concentration between 0,1 and 10 mM / l

- heparin in doses ranging from 10 to 100 units per 100 ml solution.

These preparations can be administered in all the classical ways used for contrast products with non-ionic iodine. They can be administered enterally or paranterally (intravenously, intraarterially, opacification of the cavities) and especially in the subarachnoid space.

Below is an example of a preparation of the present invention.

Preparation:

The compound of Example 1 85 g

Water for injection, QSP 100 ml

The following examples illustrate the preparation of a compound of formula I.

EXAMPLE 1

5- (3-hydroxy-2- (hydroxymethyl) -N- (2,3-dihydroxypropyl) propionamido) -N ', N-bis- (2-hydroxy-ethyl) -2,4,6-triodoisophthalamide

a) 5- (2-Isopropyl-1,3-dioxane-5-carboxyamido) -2,4,6 triodoisophthaloyl dichloride

137 g of 5-amino-2,4,6-triodoisophthaloyl hydride (0.23 mol) were dissolved in 460 ml of DMAC, to which 110 g (0.57 mol) of chloride were added.

2-Isopropyl-1,3-dioxane-5-carboxylic acid. The reaction mixture was stirred at room temperature for 4 days with stirring. The DMAC was removed in vacuo. The resulting oil was extracted with three liters of ethyl acetate and washed twice with 1 liter of ice water. The organic phase was dried and concentrated to dryness. The product crystallizes in 200 ml of CH ₂ Cl ₂ . Filtration gave 110 g of a solid.

Yield 64%. TLC (Thin Liquid Cromatography): SiO ₂ CH ₂ C1 ₂ Rf: 0.13 (60 F 254) SiO ₂ ether / petroleum ether 50/50 Rf: 0,52

b) 5- (2-Isopropyl-1,3-dioxane-5-carboxyamido) -N ', N-bis- (2-hydroxy-ethyl) -2,4,6-tridio-isophthalamide

130 g of the product from step a of this example (0.173 mol) were dissolved in 750 ml of DMAC solvent and 75 ml (0.534 mol) of triethylamine. 33.7 g of ethanolamine (0.552 mol) were added dropwise to the reaction mixture. The reaction was then left at room temperature for 3 hours and stirred constantly. Filtration separated the triethylaminchlorohydrate and the DMCA was removed in vacuo. The resulting oil crystallizes in a liter of water. The product was filtered and dried in vacuo. Yield: 95%

TLC: SiO ₂ Rf: 0.25 CH ₂ C1 ₂ / methanol 9/1 (60F254) SiO2 Rf: 0.67 CH ₂ Cl ₂ / methanol ₈ / ₂ % J: 45.6 (found) - 47.6 ( calculated)

HPLC - Hypersyl trademark column; Op.) C8 5µ 15cm

HPLC purity: 97% NaH ₂ PO4 0.01 M = 50

Methanol = 50 (HPLC-High Pressure Liquid Cromatography);

c) 5- (3-Hydroxy-2- (hydroxymethyl) -N- (2,3dihydroxypropyl) propionamido) -N ', N-bis- (2-hydroxy-ethyl) 2,4,6-triodoisophthalimide

To a suspension of 100 g of the product from step b of this example (0.0125 mol) in 350 ml of ethylene glycol, 125 ml of 4N methylate (0.5 mol) at 60 ° C was added dropwise, followed by 65 g of l-chloro-2. 3propandiol (0.625 mol). After 1 hour at 60 [deg.] C., the reaction mixture was converted to mass. 100 ml of 4M methylate (0.4 mol and 55.2 g of 1chloro-2,3-propane diol (0.5 mol) were added and maintained overnight at 60 ° C. 31 ml of 4N methylate (0.125 mol) was added again. ) and 20.7 g of l-chloro-2,3-propanediol and stirred for 4 hours at 60 [deg.] C. The mineral salts are removed by filtration. The reaction medium was concentrated to dryness and redissolved in 300 ml of ethanol.

The ethylene glycol was evaporated in vacuo and the residue was crystallized from one liter of isopropyl alcohol. The precipitate was filtered and purified by HPLC (RP 18) eluted with water.

Total yield (alkylation-deprotection): 52%

1) TLC (silicon dioxide 60F254): CH2Cl2 / methanol 7/3 Rf: 0.4

2) HPLC Hypersyl C8 5 μ 15 cm

Buffer NaH ₂ PO ₄ 0.01 M - 97 methanol - 3

97% purity

3)% J: 45.8 (found) - 48.4 (calculated)

4) NMR (DMSO)

Massive, poorly resolved, centered at 3.5 ppm (ppm per million; 18 H); massive, centered at 4.5 ppm (OH) alternated with D2O (6 H); large peak at 8.4 ppm (NH) alternated with D ₂ O (2 H).

EXAMPLE 2

5-glycolamido-3- (3-hydroxy-2- (hydroxymethyl) -N- (2,3dihydroxypropyl) propionamido) -2,4,6-tridio-N-hydroxyethylbenzamide

a) 3,5-dinitro-N- (2-hydroxyethyl) benzamide

750 g (3.32 mol) of methyl-3,5-dinitrobenzoate are suspended in 2 liters of methanol in the presence of 222.7 g (3.65 mol) of ethanolamine.

The reaction mixture was refluxed for 48 hours until ether was run out. After 4 hours at room temperature, the product crystallizes and is filtered. Was washed with 500 cm ³ of methylene chloride, and the course of 4 hours was dried in a drying chamber in vacuo. This process allows us to isolate 718 g of product at 85% yield. Melting point: 140 ° C

TLC (toluene / methylene ketone / formic acid 60/25/25) Rf: 0.5

b) 3-Nitro-5-amino-N- (2-hydroxyethyl) benzamide

To a suspension of 25.5 g (0.1 mol) of 3,5-dinitro-N- (2hydroxyethyl) benzamide in 135 cm ^{3 of} water, 12.25 g (0.18 mol) of ammonium sulfide was added at 70 ° C. First, the homogeneous mixture forms a sediment after 0.5 hours, and then the reaction mixture is allowed to cool to room temperature and stirring is continued for two hours. The precipitate was filtered off, washed with methanol (70 cm ³ ) and then dried in a drying chamber at 60 ° C.

Obtained mass 15.1 g - Yield 67%

TLC (toluene / methylene ketone / formic acid 60/25/25) Rf: 0.3 ¹ H NMR (DMSO): 3.4 ppm (massive; 4H, CH 2 aliphatic); 4.65 ppm (massive, H, which can be replaced by D2O, NH2); 5.9 ppm (s, H exchangeable with D ₂ O, OH); 7.4-7.7 ppm (2m; 3H, aromatic protons), 8.6 ppm (massive, 1H, NH).

c) 3-nitro-5- (2-isopropyl-1,3-dioxane-5-carboxyamido) -Nhydroxy or thi-benzamide g (0.177 mol) of 3-nitro-5-amino-N- (2-hydroxyethyl) benzamide was dissolved in 400 cm ³ DMAC. By adding 74.9 g (0.389 mol) of 2-isopropyl-1,3-dioxane-5-carboxylic acid chloride in the presence of triethyl amine (54.6 cm ³ ), a net thermal effect was obtained. The reaction mixture was maintained at room temperature for 18 hours under an argon atmosphere. The mixture was filtered and the filtrate was diluted with water and extracted with ethyl acetate. The residue obtained after evaporation of the solvent was treated with potassium carbonate (12 g) in 300 cm ^{3 of} methanol. After 48 hours of hours of stirring at room temperature, the mixture was concentrated, and then ¹⁶ extracted with ethyl acetate. The crude product obtained was recrystallized from ether / ethyl acetate 80/20 after treatment.

37.8 g of product were isolated in 56% yield. TLC (ethyl acetate Rf : 0.48). HPLC Hyersyl C8 5µ 15 cm. NaHPO ₄ buffer 0.01 M 50% MeOH 50%

Purity: 94%

d) 5-amino-3 (2-isopropyl-1,3-dioxane-5-carboxyamido) -2,4,6 trido-N-hydroxyethyl-benzamide

The methanyl solution of (1,4 1) 3-nitro-5- (2-isopropyl-1,2-dioxane-5-carboxyamido) -N-hydroxyethyl-benzamide was stirred under a hydrogen atmosphere (5.10 ⁵ Pa) for 5 hours at 50 ° C in the presence of 4 g of palladium charcoal. The catalyst was then removed by filtration and the filtrate evaporated under reduced pressure. The resulting compound was suspended in 950 cm &lt; ^{3 &gt; of} water. The mixture was homogenized by the addition of 20 cm ^{3 of} 2N hydrochloric acid. Then 63 cm3 of iodine chloride (70% iodine) was added dropwise and the mixture was stirred vigorously. After 24 hours at room temperature, the precipitate was filtered off, clarified with water and collected in ether. After drying, 32 g of product were obtained, which represented a 42% yield. TLC (dichloromethane / methanol 90/10) Rf: 0.8.

e) 5-amino-3- (N- (2,3-dihydroxypropyl) -2-isopropyl-1, 3dioxane-5-carboxyamido) -2,4,6-trido-N-hydroxyethyl-benzamide

To a solution of the compound of step d of this example (20 g, 0.027 mol) in a mixture of ethylene glycol dimethylformamide (volume / weight) (160 ml) was added dropwise 84 cm3 of sodium methylate (4N) (0.337 mol). The temperature of the mixture increased to 60 ° C for 0.5 hours, and 36.1 cm3 of l-chloro-2,3propanediol (0.432 mol) was added at this temperature. The reaction mixture was maintained at 60 ° C for 60 hours under a nitrogen atmosphere. The mineral substances were removed by filtration and ethylene glycol and DMF (dimethylformamide) were evaporated in vacuo. The crude product obtained was purified on silica gel (eluted with water and then with water / methanol 50/50). 16.5 g of product was isolated, which represented a 76% yield.

TLC (dichloromethane / methanol 80/20). Rf: 0.8.

f) 5-amino-3- (3-hydroxy-2- (hydroxymethyl) -N- (2,3dihydroxypropyl) propionamido) -2,4,6-trido-N-hydroxyethylbenzamide g (0.02 mol) of the product from step In this case, protection was also removed for 48 hours in the presence of 80 cm ^{3 of} 10N hydrochloric acid at room temperature. After neutralization and evaporation under reduced pressure, the residue was collected as a precipitate in a mixture of methanol-ether (9/1), filtered and then purified by HPLC (RP 18 - eluted with water and then with water / methanol 90/10) . We isolated 4 g of product at a total yield (deprotection, purification) of 30%.

TLC (dichloromethane / methanol 80/20). Rf: 0.25.

HPLC Hypersyl C8 5µ 15 cm.

NaHPOi Buffer 0.01 M 90%

MeOH 10%

Purity: 97%

g) 5-N-glycolamido-3- (3-hydroxy-2- (hydroxymethyl) -N- (2,3-dihydroxypropyl) propionamido) -2,4,6-triiodo-N-hydroxyethylbenzamide

5.5 g of O-acetyl-glycolic acid chloride (0.04 mol) were added dropwise to a solution of 3 g of the compound of step f of this example (0.004 mol) in 30 cm3 of anhydrous DMAC at room temperature. The temperature of the reaction mixture was raised to 40 ° C for 12 hours and then poured into 250 cm ^{3 of} ice water. The resulting precipitate was filtered and then extracted with ethyl acetate. After treatment and evaporation, the resulting product was dissolved in 50 cm3 of methanol, after which a deprotection reaction was carried out in the presence of 10 cm3 of IN soda (Na2CO3).

The solution was stirred for 24 hours at room temperature and then demineralized by successive passage through H ⁺ resin (IRN77) and OH ”(IRN78). After evaporation to dryness, the residue was collected with ethyl ether, filtered and then dried. The resulting mass is 1.5 g in 47% yield.

TLC (ethyl acetate / methanol / ammonia 60/40/1). Rf: 0.25.

HPLC Hypersyl C8 5µ 15 cm.

NaHPO ₄ Buffer 0.01 M 90%

MeOH 10%

Purity: 98%

EXAMPLE 3

3,5-bis (3-hydroxy-2-hydroxymethyl-propionamido) -2,4,6trido-N- (2,3-dihydroxypropyl) benzamide

a) 3,5-Diamino-2,4,6-triodo-N- (2,3-diacetoxypropyl) benzamide

301.5 g (0.5 mol) of 3,5-diamino-2,4,6 ~ tridio-N- (2,3diacetoxypropyl) benzamide were suspended in 1 liter of anhydrous pyridine cooled to 15 ° C. Then 2450 ml of anhydrous acetic acid was added, the solution was stirred at room temperature for 18 hours and poured into acidified water. Extraction with ethyl acetate, drying of the organic phase and evaporation gave 270 g of the product in 78.5% yield.

Iodine Purity: 98.3%

TLC toluene / methylethylketone / HCOOH 60/25/35. Rf: 0.70.

b) 3,5-bis (2-isopropyl-1,3-dioxane-5-carboxyamido) -2,4,6trido-N- (2,3-diacetoxy-propyl) benzamide

114.5 g (0.166 mol) of the compound obtained in step a of this example was dissolved in 350 ml of anhydrous DMAC. At 0 ° C, 128 g (0.86 mol) of 2-isopropyl-1,3-dioxane-5-carboxylic acid chloride were added. The mixture was stirred overnight and then poured over an ice-water mixture. The precipitate was filtered off, clarified with water and dried in vacuo at 50 ° C.

c) 3,5-bis (2-isopropyl-1,3-dioxane-5-carboxyamido) -2,4,6trido-N- (2,3-dihydroxypropyl) benzamide

175 g of the compound obtained in step b of this example was suspended overnight in 2.5 liters of methanol at room temperature in the presence of 45 g of potassium carbonate. After evaporation of the reaction mixture, the product crystallizes from water. After filtration and drying, crystals obtained in 85% yield are used directly in the next step.

d) 3,5-bis (3-hydroxy-2-hydroxymethyl-propionamido) -2,4,6trido-N- (2,3-dihydroxypropyl) benzamide

The compound obtained in step c of this example was dissolved in 2 liters of 5N HCL at 50 ° C. After stirring for 18 hours, the resulting suspension was filtered, the filtrate was concentrated in vacuo and the residue was collected in isopropranol. In two experiments, 108 g of crystallized product were obtained, in a yield of 94%.

TLC (SiO ₂ butanol 60, water 25, CH3COOH 1 liter). Rf: 0.2. The product was purified by HPLC over SiO ₂ RP18 15.25µ, eluent: pure water in 47% yield. Purity per iodine 99.6%. HPLC purity 89.1% (Hypersyl C85µ 15cm NaH ₂ PO ₄ 0.0lM 95, MeOH 5).

1 H NMR 200 MHz (DMSO)

8.5 ppm (m, IH interchangeable with D ₂ 0 9.9 ppm (t, 2H interchangeable with D ₂ O 4.6 ppm (m, 6H interchangeable, OH) 3.4 ppm (m, 13H, CH) 2.7 ppm (m, 2H, NH-CH ₂ ).

O-CONH)

O-NH-CO)

EXAMPLE 4

5- (3-hydroxy-2- (hydroxymethyl) -N- (2-hydroxyethyl) propionamido) -N- (2-hydroxyethyl) -N '- (2,3-dihydroxypropyl) 2, 4,6-tridio- isophthalimide

a) 5- (2-Isopropyl-1,3-dioxane-5-carboxyamido) -2,4,6-tridio3-N '- (2-acetoxyethyl) carbamoyl-benzoyl chloride

5.36 g of 2-isopropyl-1,3-dioxane-5-carboxylic acid (0.0308 mol) were dissolved in 18 ml of DMAC. The reaction mixture was cooled to 5 ° C and 2.55 ml of SOCl 2 (0.0350 mol) was added dropwise so that the temperature remained below 15 ° C. After complete addition, the reaction mixture was allowed to stand at room temperature for 3 hours, then 6.0 g (0.00906 mol) of 5-amino-2,4,6-triiodo-3- (Nacetoxyethyl) carbamoyl-benzoyl chloride were added. The reaction mixture was left under argon atmosphere for 4 hours at room temperature. The DMAC was removed in vacuo, the resulting oil was collected in ethyl acetate, the organic phase was washed with water, dried and concentrated to dryness. The product crystallizes from 100 ml of ether. After filtration and drying, 1.8 g of product are obtained in 24% yield.

TLC (silica 60F 254) ethyl acetate / petroleum ether 80/20 - Rf = 0.83

b) 5- (2-Isopropyl-1,3-dioxane-5-carboxyamido) -2,4,6-triiodo- (2-acetoxyethyl) -N '- (2,3-dihydroxypropyl) isophthalamide g of the product obtained in step but of this example (0.00122 mol) was dissolved in 100 ml of DMAC and then triethylamine (0.26 ml, 0.00189 mol) was added. 0.18 g of 3-amino-1,2-propanediol (0.00196 mol) was added dropwise to the reaction mixture. After addition, the reaction mixture was allowed to stir at room temperature for 24 hours. The triethylaminochlorohydrate was filtered and then the DMAC was evaporated. The oil thus obtained crystallizes from 20 ml of ether. After filtration and drying, 0.8 g of product was obtained in 75.5% yield. TLC (silicon dioxide 60F254):

CHCl ₃ / MeOH / NH ₄ OH 53/30/10 Rf = 0.77.

c) 5- (3-hydroxy-2- (hydroxymethyl) -N- (2hydroxyethyl) propionamido) -N- (2-hydroxyethyl-N '- (2,3-dihydroxy-propyl) -2,4,6-triodoisophthalimide

0.4 g of the product obtained in step b of this example (0.000458 mol) was dissolved in 0.7 ml ethylene glycol and 0.69 ml 4N sodium methylate solution (0.00275 mol). 0.18 ml of chlorine ethanol (0.00275 mol) was added to this solution. The reaction mixture was heated to 40 ° C for 5 hours. 0.34 ml of 4N sodium methylate and 0.1 ml of chloroethanol were added. The whole was maintained at 40 ° C for one night and then, by adding dilute hydrochloric acid, the pH was adjusted to 7.00. The ethylene glycol was evaporated to dryness and the distillation residue was collected with 6 ml of water and 5 ml of concentrated hydrochloric acid and left stirring at room temperature overnight. The reaction mixture was concentrated, purified by preparative HPLC (RP 18, eluted with water). After evaporation and drying, 0.1 g of product was obtained, giving an overall yield (alkylation-purification) of 27%.

TLC (silica 60F254): CH2Cl2 / methanol 1/7/3 Rf = 0.33.

HPLC: Hypersyl C8 5μ 25cm column

NaH ₂ PO4 0.01 M / MeOH: 95 / S Purity 95%

1 H NMR (Bruker - 200 MHZ) in DMSO: corresponds to the submitted structure.

for

GUERBET S.A.

THE BEST WAY TO APPLY INVENTION IN THE ECONOMY,

WHO ARE KNOWN TO THE APPLICANT

EXAMPLE 1

5- (3-hydroxy-2- (hydroxymethyl) -N- (2,3-dihydroxypropyl) propionamido) -N ', N-bis- (2-hydroxy-ethyl) -2,4,6-triiodothiol thalamide

a) 5- (2-Isopropyl-1,3-dioxane-5-carboxyamido) -2,4,6 triodoisophthaloyl dichloride

137 g of 5-amino-2,4,6-triodoisophthaloyl hydride (0.23 mol) were dissolved in 460 ml of DMAC to which 110 g (0.57 mol) of 2-isopropyl-1,3-dioxane-5-carboxylic acid chloride were added. . The reaction mixture was stirred at room temperature for 4 days with stirring. The DMAC was removed in vacuo. The resulting oil was extracted with three liters of ethyl acetate and washed twice with 1 liter of ice water. The organic phase was dried and concentrated to dryness. The product was crystallized in 200 ml of CH2Cl2. Filtration gave 110 g of a solid.

Yield 64%. TLC (Thin Liquid Cromatography): SiO2 CH2CI2 Rf: 0.13 (60 F 254) SiO2 ether / petroleum ether 50/50 Rf: 0.52

b) 5- (2-Isopropyl-1,3-dioxane-5-carboxyamido) -N ', N-bis- (2-hydroxy-ethyl) -2,4,6-tridio-isophthalamide

130 g of the product from step a of this example (0.173 mol) were dissolved in 750 ml of DMAC solvent and 75 ml (0.534 mol) of triethylamine. 33.7 g of ethanolamine (0.552 mol) were added dropwise to the reaction mixture. The reaction was then left at room temperature for 3 hours and stirred constantly. Filtration separated the triethylaminchlorohydrate and the DMCA was removed in vacuo. The resulting oil crystallizes in a liter of water. The product was filtered and dried in vacuo. Yield: 95%

TLC: SiO ₂ Rf: 0.25 CH ₂ Cl ₂ / methanol 9/1 (60F254) SiO 2 Rf: 0.67 CH ₂ Cl ₂ / methanol ₈ / ₂ % J: 45.6 (found) - 47.6 ( calculated)

HPLC - Hypersyl c8 5μ 15cm column

HPLC purity: 97% NaH ₂ PO4 0.01 M = 50; Methanol = 50

c) 5- (3-Hydroxy-2- (hydroxymethyl) -N- (2,3dihydroxypropyl) propionamido) -N ', N-bis- (2-hydroxy-ethyl) 2,4,6-triodoisophthalimide

To a suspension of 100 g of the product from step b of this example (0.0125 mol) in 350 ml of ethylene glycol, 125 ml of 4N methylate (0.5 mol) at 60 ° C was added dropwise, followed by 65 g of l-chloro-2. 3propandiol (0.625 mol). After 1 hour at 60 [deg.] C., the reaction mixture was converted to mass. 100 ml of 4M methylate (0.4 mol and 55.2 g of 1chloro-2,3-propane diol (0.5 mol) were added and maintained overnight at 60 ° C. 31 ml of 4N methylate (0.125 mol) was added again. ) and 20.7 g of l-chloro-2,3-propanediol and stirred for 4 hours at 60 [deg.] C. The mineral salts are removed by filtration. The reaction medium was concentrated to dryness and redissolved in 300 ml of ethanol.

The ethylene glycol was evaporated in vacuo and the residue was crystallized from one liter of isopropyl alcohol. The precipitate was filtered and purified by HPLC (RP 18) eluted with water.

Total yield (alkylation-deprotection): 52%

1) TLC (silicon dioxide 60F254): CH2Cl2 / methanol 7/3 Rf: 0.4

2) HPLC Hypersyl C8 5 μ 15 cm

Buffer NaH ₂ PO4 0.01 M = 97; methanol = 3; 97% purity

3)% J: 45.8 (found) - 48.4 (calculated)

4) NMR (DMSO)

Massive, poorly resolved, centered at 3.5 ppm (ppm per million; 18 H); massive, centered at 4.5 ppm COBK, alternated with D ₂ O (6 H); large peak at 8.4 ppm (NH) alternated / ^ ^ D ₂ O (2 H). \>

Representative: Jan

Claims (8)

PATENT APPLICATIONS 1. Compounds characterized in that they have the formula: Ra And where R 1 represents a compound of the formula: -N-CO-Rs Rs represents a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, or a C1-C4 polyhydroxyalkyl group, R6 represents a hydrogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkine group or a C1-C4 polyhydroxyalkyl group, or a group of the formula: Rs -CO-N-R7 R7 represents a C1-C4 hydroxyalkyl group or a C1-C4 polyhydroxyalkyl group, Rg represents a hydrogen atom or a C1-C4 alkyl group, R ₂ represents a hydrogen atom, a C1-C4 hydroxyalkyl group or a C1-C4 polyhydroxyalkyl group R ₃ represents a hydrogen atom or a C 1 -C 4 alkyl group, R ₄ represents a hydrogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkine group or a C1-C4 polyhydroxyalkyl group Compounds according to claim 1, characterized in that they have the formula: R ₃ I N - R CO ch; ch ₂ oh CH ₂ OH II wherein R ₂ , R 3 and R ₄ are as defined in claim 1. Compound according to claim 1, characterized in that it is 5- (3-hydroxy-2- (hydroxymethyl) -N- (2,3-dihydroxypropyl) propionamido) -N ', N-bis- (2-hydroxyethyl) ) -2,4,6-triiodoisophthalamide. Compound according to claim 1, characterized in that it is 5-glycolamido-3- (3-hydroxy-2- (hydroxymethyl) -N- (2,3-dihydroxypropyl) propionamido) -2,4,6-tridio-Nhydroxyethyl-benzamide. Compound according to claim 1, characterized in that it is 3,5-bis (3hydroxy-2-hydroxymethyl-propionamido) -2, 4,6-triiodo-N- (2,3dihydroxypropyl) benzamide. A compound according to claim 1, characterized in that it is 5- (3-hydroxy-2- (hydroxymethyl) -N- (2-hydroxyethyl) propionamido) -N- (2-hydroxyethyl) -N '- (2 , 3-dihydroxypropyl) 2,, 4,6-tridio-isophthalimide Contrast product, characterized in that it contains at least one compound according to claims 1 to 6. Contrast product according to claim 7, characterized in that it is made from an aqueous solution of the compound.