SK279646B6 - Iodinated benzene derivatives, method of their preparation and contrast products them containing - Google Patents

Abstract

Disclosed are iodinated derivatives having the general formula (I), wherein R is selected among 2,3-dihydroxypropyl and 1,3-dihydroxy-2- propyl groups. These compounds can be used as contrasting products for X-ray image formation. There is further disclosed a method of iodinated benzene derivatives preparation having the general formula (I) and the contrast products containing said derivatives.

Description

Technical field

The invention relates to iodinated benzene derivatives which are useful as contrast agents in radiological examination. The invention also relates to a process for the preparation of these substances.

BACKGROUND OF THE INVENTION

Iodinated benzene derivatives have been used for a long time as contrast agents, which contain several iodine atoms on the benzene ring, usually 3 iodine atoms and, in addition, various other substituents. These additional substituents are pharmaceutically acceptable groups that allow administration of the compounds to humans and animals. These substituents are generally chosen to increase, on the one hand, the solubility in water, thereby permitting the use of these substances in aqueous solution and, on the other hand, to increase the compatibility of the substances with the human organism.

For this purpose, a nonionic structure has been proposed, i.e. the substituents were nonionic in nature.

In French patent no. No. 2,053,037 it is proposed to use carbamoyl iodobenzene derivatives containing at least one N-hydroxyalkyl group and at least two hydroxy groups.

A compound of this group is, for example, metzamide, but it has poor stability.

In European patent no. 357 467 proposes the use of some non-ionic substances which are well tolerated and still in aqueous solution.

These substances can be expressed by the general formula where

R 1 represents a group of the general formula

- N - CO - R ₅

I

R6 where

R 5 represents a C 1 -C 4 alkyl radical, a hydroxyalkyl or a polyhydroxyalkyl radical each having 1 to 4 carbon atoms, and

R 8 represents a hydrogen atom or an alkyl, hydroxyalkyl or polyhydroxyalkyl radical having from 1 to 4 carbon atoms or a group of the formula ^r 8

I

- CO - N - R ₇ where

R 7 represents a hydroxyalkyl or polyhydroxyalkyl radical having from 1 to 4 carbon atoms and each

R 8 represents a hydrogen atom or an alkyl radical of 1 to 4 carbon atoms,

R2 represents a hydrogen atom or a hydroxyalkyl or polyhydroxyalkyl radical having from 1 to 4 carbon atoms,

R3 represents a hydrogen atom or an alkyl radical of 1 to 4 carbon atoms;

R4 represents a hydrogen atom or an alkyl, hydroxyalkyl or polyhydroxyalkyl radical having from 1 to 4 carbon atoms.

SUMMARY OF THE INVENTION

The present invention provides novel compounds which belong to the group of iodinated benzene derivatives and have good stability and at the same time good aqueous solubility. These substances can be expressed by the general formula (I)

wherein R is 2,3-dihydroxypropyl or 1,3-dihydroxy-2-propyl.

One of the compounds of the invention is 5- (3-hydroxy-2- (hydroxymethyl) propionamido) -N, N'-dimethyl-Ν, Ν'-bis- (2,3-dihydroxypropyl) 2,4,6-triiodoisophthalamide with formula (A).

Another compound of the invention is 5- (3-hydroxy-2- (hydroxymethyl) propionamido) -N, N'-dimethyl-N, N'-bis (1,3-dihydroxy-2-propyl) 2,4,6- triiodoisophthalamide of formula.

These formulas include both racemic substances and stereoisomers that arise from the presence of an asymmetric carbon atom, while at the same time preventing the rotation of some bonds due to steric hindrance by iodine atoms.

It has been unexpectedly found that the compound of formula (A) has better aqueous solubility than the compound of Example I of said European patent application, i. j. 5- (3-hydroxy-2- (hydroxymethyl) -N- (2,3-dihydroxypropyl) -propionamido) -N ', N-bis- (2-hydroxyethyl) -2,4,6-triiodoisophthalamide.

In addition, the compounds according to the invention have the advantage over the substance in question that they are more readily available, since it is not necessary to carry out the final N-alkylation in their case, which results in purification problems on an industrial scale.

Said substances can be obtained by:

a) reacting the acid dichloride of formula (II)

COCI

wherein R 'represents a hydroxyl-protected-CH- (CH 2 OH) 2 group with an amine of 1- (N-methylamino) propane-2,3-diol and 2- (N-methylamino) propane-1,3-diol to form a compound of formula (III)

(Hl)

b) deprotecting R '.

The compounds of the general formula (II) have been described in French Pat. 2,632,304.

The present invention also provides contrast media which contain at least one compound of the invention as an active ingredient.

These compositions are used in humans and animals for radiological examination.

Preferred dosage forms for use herein are suitable solutions of the compounds of the invention.

Aqueous solutions usually contain 5 to 100 g of the compound of the invention per 100 ml, the injection amount of these solutions may be in the range of 1 to 100 ml.

Aqueous solutions containing the compounds of the invention may contain still further additives, for example

- sodium chloride in the range 0,1 to 10 mM,

- disodium EDTA in the range 0,1 to 2 mM,

- sodium citrate in the range 0,1 to 10 mM,

- heparin at a dose ranging from 10 to 100 units per 100 ml of solution.

Said compositions may be administered by any conventional route of administration to contrasting nonionic iodinated compounds. This may be by enteral or parenteral administration, such as intravenous, intrarterial, intravascular, and especially subarachnoid administration.

The composition of the contrast agent according to the invention will be described below.

Component Amount of Compound A of the invention 65 g water for injection up to 100 ml

The invention is illustrated by the following examples, which are not to be construed as limiting the scope thereof.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of 5- (3-hydroxy-2 (hydroxymethyl) propionamido) -N, N'-dimethyl-N, N'-bis- (2,3-dihydroxypropyl) -2,4,6-triiodoisophthalamide

a) Preparation of (2-isopropyl-1,3-dioxane-5-carboxamido) N, N'-dimethyl-N, N'-bis- (2,3-dihydroxypropyl) -2,4,6-triiodoisophthalamide g, 98 5- (2-Isopropyl-1,3-dioxane-5-carboxamido) -2,4,6-triiodoisophthaloyl dichloride (mmol) was suspended in isopropanol (300 mL) containing triethylamine (41 mL, 249 mmol). 31 g (295 mmol) of N-methylaminopropane-2,3-diol are then added dropwise. After stirring at room temperature for 12 hours, the triethylamine hydrochloride was filtered off.

The filtrate was evaporated to dryness, dissolved in water and chromatographed on a OH-IRA 67 resin column.

After evaporation, the product is purified on a column of silanized silica gel Kieselgel 60 (Merck), eluting with water.

After evaporation of the appropriate fractions to dryness, 60 g of product are obtained in the form of a white powder in a yield of 68.5%. Amount of iodine: 96,4%

HPLC purity: 97% Hypersil CB 25 cm 5 / µm

NaH 2 PO 4 0.01 M 60 methanol 40

Silica thin layer chromatography: Rf 0.12

0.25

0.30

0.36

Elution: 55: 30: 10 chloroform / methanol / ammonia

NMR Spectrum: (DMSO): 1 H 200 MHz, 0.9 ppm (doublet) CH ₃ (6H), 2.8 (singlet) B-CH ₃ (3H), 3 (singlet) N-CH ₃ (3H) ), 3.3 (m) N-CH ₂ and CH (5H), 3.5-3.9 (multiplet) CH _2, and CH (8H), 4.3 (q), CH (3H), 4, Δ (triplet) OH (2H), 4.7 (doublet) OH (2H), 10.2 (broad multiplet) NH (1H).

b) Preparation of 5- (3-hydroxy-2- (hydroxymethyl) propionamido) -N, N'-dimethyl-N, N'-bis- (2,3-dihydroxypropyl) -2,4,6-triiodoisophthalamide g, 50 6 mmol of the compound from step a) are dissolved in 101 ml of 10 equivalents of 5 N hydrochloric acid. The mixture was stirred at room temperature for 12 hours. The solution was filtered and evaporated to dryness. The solid obtained is dissolved in 100 ml of diethyl ether, then filtered and chromatographed on Kieselgel 60 (Merck), eluting the column with water. After evaporation of the appropriate fractions to dryness, 38 g of a white powder are obtained.

Yield = 90% Iodine content = 98.3% Purity by HPLC is at least 98% Hypersil C8 25 cm 5 / pm

NaH ₂ PO 4 0.01 M 95 methanol 5

Silica thin-layer chromatography:

Rf 0.56

0.63

0.67

The eluent used was a mixture of chloroform, methanol and aqueous ammonia in a ratio of 55: 30: 10 NMR (DMSO) 1 H 200 MHz, 2.7 (massive) CH (IH), 2.85 (broad singlet) N-CH ₃ ( 3H), 3.08 (poorly differentiated d) _N-CH3 (3H), 3.10-3.35 (m) N-CH2, 3.45 (q) N-CH 2 and CH (5H), 3, 5-3.9 CH2 and CH (8H), 4.3 (quadruplet), CH2 (4H), 3.6-4 (massive) OH (6H), 9.9 ppm (massive) NH (IH).

Example 2

Preparation of 5- (3-hydroxy-2 (hydroxymethyl) propionamido) -N, N'-dimethyl-N, N'-bis- [1,3-dihydroxy-2, propyl] -2,4,6-triiodoisophthalamide

(a) Preparation of (isopropyl-1,3-dioxane-6-carboxamido) -N, N'-dimethyl-Ν, Ν-bis- (1,3-dihydroxy-2-propyl) -2,4,6-triiodoisophthalamide

1.46 g, 13.9 mmol of N-methylaminopropane-1,3-diol, obtained according to European patent specification no. 25 083, EPROVA AG, is dissolved in a mixture of 20 ml of N, N-dimethylacetamide and 2 ml, 14.4 mmol of triethylamine. Then, 5- (2-isopropyl-1,3-dioxane-5-carboxamido) -2,4,6-triiodoisophthaloyl dichloride (3.5 g, 4.65 mmol) was added portionwise. The mixture was stirred for 3 hours at 30 ° C and then for 12 hours at room temperature. The triethylamine hydrochloride is then filtered off.

The filtrate is evaporated to dryness and the residue is crystallized in a mixture of 20 ml of isopropanol and 200 ml of ethyl ether.

After filtration and drying, 3.6 g of a white powder are obtained in a yield of 87%. SiO ₂ thin layer chromatography: Rf 0.16

0.28.

The eluting agent is a 60: 35: 25 mixture of toluene, methyl ethyl ketone and formic acid.

NMR (DMSO) 1 H 200 MHz, 0.9 (doublet) CH 3 (6H), 1.7 (massive) CH (1 H), 2.79 (singlet) N-CH 3 (3H) isomer Z, 2.99 (singlet) ) N-CH3 (3H) isomer E, 3.4 - 4 (multiplet) CH, CH ₂ (15H), 4.8 (multiplet) CH ₂ OH (4 H), 10.2 ppm (multiplet) NH (H) .

b) Preparation of 5- (3-hydroxy-2- (hydroxymethyl) propionamido) -N, N'-dimethyl-N, N'-bis (1,3-dihydroxy-2-propyl) -2,4,6-triii of iodoisophthalamide g, 3.4 mmol of the compound from step a) was dissolved in 10 mL, 15 equivalents of 5 N hydrochloric acid. The mixture was stirred at 45 ° C for 3 hours and then at room temperature for 12 hours. Then the solution is evaporated to dryness. The residue obtained is dissolved in 50 ml of ethyl ether, the solution is filtered and the material is dissolved in 50 ml of water and then chromatographed on M ⁺ IRN 77 resin and OH IRA 68.

Fractions were collected and evaporated to give a white powder (1.7 g, 60.7%).

Iodine content: 98.4% SiO2 thin layer chromatography: Rf 0.26

0.33

0.45.

A 50: 25: 11 mixture of butanol, water and acetic acid was used as eluent.

NMR (DMSO) > H 200 MHz, 2.7 (broad singlet) N-CH 3 (3H), isomer Z, 3 (broad singlet) N-CH 3 (3 H), isomer E, 3, 3 - 4.05 ( massive, poorly separated) CH, CH ₂ OH (15H), 4.45 (massive, poorly separated) CH ₂ OH (6H), 9.8 ppm (massive) NH (IH).

NMR (DMSO) C 200 MHz, 170.6 ppm (2C), 172 ppm (1C),

I I o o

149 ppm (C * - C), 145 ppm (C * - NH), 100 - 98 - 90 ppm (C _fc -1),

ABOUT

- 57 - 52 ppm (C - H), 59.1 - 59.9 ppm (CH ₂ --OH), 32.8 - 30.1 ppm (CH 3 - N).

Claims (9)

PATENT CLAIMS 1. Iodinated benzene derivatives of general formula (I) CH; CON-R where R is 2,3-dihydroxypropyl or 1,3-dihydroxy-2-propyl. 2. 5- (3-Hydroxy-2- (hydroxymethyl) propionamido) -N, N'-dimethyl-N, N'-bis- (2,3-dihydroxypropyl) -2,4,6-triiodoisophthalamide. 3. 5- (3-Hydroxy-2- (hydroxymethyl) propionamido) -N, N'-bis- (1,3-dihydroxy-2-propyl) -2,4,6-triiodoisophthalamide. A process for the preparation of iodinated benzene derivatives of the general formula (I) according to claim 1, characterized in that (a) reacting the acid dichloride with the general formula R 1 represents a hydroxyl-protected -CH- (CH ₂ OH) ₂ group with an amine of 1- (N-methylamino) propane-2,3-diol and 2- (N-methylamino) propane-1,3- diol to give a compound of formula (III) ₃ CO-N-R (II) b) deprotecting R '. A contrast agent comprising at least one iodinated benzene derivative of the general formula (I) according to claim 1, in a form suitable for administration. A contrast agent according to claim 5, characterized in that it comprises an iodinated derivative according to claim 2. 7. A contrast agent as claimed in claim 5 comprising an iodinated derivative according to claim 3. 8. A contrast agent as claimed in claim 6, which is formulated as an aqueous solution. A contrast agent as claimed in claim 7, characterized in that it is formulated as an aqueous solution.