WO1988008417A1 - Iodized benzene diamino compounds, process for their preparation and contrast products containing them - Google Patents

Abstract

Compounds of formula (I), in which R1? and R2? are chosen independently of each other from the groups of formula -CH2?-CH2?OH and -CH2?-CHOH-CH2?OH are usable as contrast products.

Description

 Iodinated benzene diamino compounds, their preparation process and contrast media containing them.

The present invention relates to compounds which can be used in contrast agents for radiography.

For a long time, iodobenzene compounds having on the benzene nucleus several iodine atoms have been used as contrast agents, generally 3 iodine atoms per benzene nucleus, and various other substituents. These other substituents are pharmacologically acceptable groups which allow administration of the compounds in humans and animals. These substituents are generally chosen, on the one hand, to give the compounds sufficient water solubility for the administration of these compounds in aqueous solution and, on the other hand, to give these compounds sufficient tolerance by the human organism.

For this purpose, nonionic structures have been proposed, that is to say iodobenzene derivatives having nonionic substituents.

Thus, in patent FR-A-2 053 037, carbamoyl iodobenzene compounds have been proposed containing in total at least one N-hydroxy alkyl group and at least two hydroxy groups.

A compound illustrating this class is metrizamide which, however, turns out to be of limited stability.

The present invention aims to provide new nonionic compounds which are well tolerated by the human body, very stable in aqueous solution, which have a high solubility in water and which in aqueous solution have a low viscosity.

dans laquelle R₁ et R₂ sont choisis indépendamment l'un de l'autre parmi les groupes de formule -CH₂-CH₂OH et -CH2-CHOH-CH₂OH.To this end, the subject of the present invention is compounds of formula:

in which R ₁ and R ₂ are chosen independently of one another from the groups of formula -CH ₂ -CH ₂ OH and -CH2-CHOH-CH ₂ OH.

The compounds of formula I can be prepared by alkylation of a compound of formula:

dans laquelle R₁ a la définition donnée précédemment avec un réactif d' alkylation de formule :

in which R ₁ has the definition given above with an alkylating reagent of formula:

dans laquelle R' est un groupe alkyle inférieur tel qu'un groupe méthyle, par : a) réaction avec une aminé de formule : NH₂-R₁ (V) de façon à obtenir un composé de formule :R ₂ -Z (III) in which R ₂ has the meaning given above and Z represents a labile group. As alkylating agent R ₂ Z, it is possible in particular to use chlorine, bromine and iodine derivatives. The alkylation reaction can be carried out in an aqueous or organic solvent, in the presence of a base, in particular NaOH, KOH, K ₂ CO ₃ , NaH, MeONa. The compounds of formula II can be obtained in a conventional manner. In particular, these compounds of formula II can be obtained from a compound of formula

in which R ′ is a lower alkyl group such as a methyl group, by: a) reaction with an amine of formula: NH ₂ -R ₁ (V) so as to obtain a compound of formula:

b) réduction par H₂ en présence de Pd/C de façon à obtenir un composé diamino de formule :

b) reduction with H ₂ in the presence of Pd / C so as to obtain a diamino compound of formula:

c) iodination of this compound so as to obtain an iodine compound of formula:

d) acylation par le chlorure de l'acide glycolique O-acétylé de façon à obtenir un composé de formule

d) acylation with O-acetylated glycolic acid chloride so as to obtain a compound of formula

in which R ′ ₁ is a group R _{1 in} which the hydroxy groups are acetoxyacetylated and e) deprotection.

A subject of the present invention is also contrast products which comprise at least one compound of formula I.

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

The preferred pharmaceutical form of the contrast agents according to the invention consists of aqueous solutions of the compounds.

The aqueous solutions generally contain a total of 5 to 100 g of aomposes per 100 ml and the injectable quantity of such solutions can generally vary from 1 to 1000 ml.

These compositions can be administered by all the routes conventionally used for iodinated nonionic contrast media and in particular in the subarachnoid space and by the parenteral route (intravenous, intraarterial route, etc.).

An example of a composition according to the present invention will be given below.

Composition

Compound of Example 1 65 g Water for injection QSP 100 ml

The following examples illustrate the preparation of the compounds according to the invention. EXAMPLE 1

Preparation of 2,4,6-triiodo 3,5-bis N (2-hydroxy ethyl) glycolamido -N- (2,3-dihy3roxy propyl) benzamide. a) Preparation of 3.5-dinitro-N- (2,3-dihydroxy propyl) benzamide.

158 g (0.7 moles) of methyl 3,5-dinitro benzoate are dissolved in 450 cm ³ of methanol, in the presence of 57 grams (0.63 mole) of 2,3-1-amino-propanediol. The reaction mixture is left for 48 hours at reflux until the ester disappears. After 4 hours at 0 ° C., the crystallized product is filtered, washed, with successively 800 cm ³ and 500 cm ³ of methylene chloride, then dried in an oven at 60 ° C. under vacuum for 4 hours. This process makes it possible to recover 130 grams of product with a yield of 72.8%. Melting point: 124º C.

TLC (toluene / methyl ethyl ketone / formic acid 60/25/25) Rf = 0.45

¹ H NMR (DMSO): 9H (CH ₂ , CH) multiplet (3.2-3.9); 2H (OH, NH) multiplet (4.5-5): 3H (CH) multiplet (8.9-9.4). b) Preparation of 3,5 diamino-N- (2,3-dihydroxy propyl) benzamide

40 grams of 3,5-dinitro-N- (2,3-dihydroxypropyl) benzamide and 5 grams of palladium carbon at 10% are placed in solution in an autoclave with 1000 cm ³ of water. the suspension, subjected to strong stirring, is hydrogenated under a pressure of 6.10 ⁵ Pa at room temperature for 5 hours. After wire tration of the catalyst, the solution is iodized immediately, without purification. TLC (butanol / water / acetic acid 50/25/11) Rf = 0.28. c) Preparation of 2,4,6-triiodo-3,5-diamino-N- (2,3-dihydroxy propyl) benzamide

The solution resulting from the hydrogenation is acidified by adding 20 cm of a 10N solution of hydrochloric acid.

75 cm of iodine chloride (70% iodine) are then introduced dropwise over 30 minutes, with vigorous stirring, at room temperature. After half an hour at room temperature, the precipitate is filtered, washed with water and then dried in an oven at 60 ° C for 18 hours. Yield: 90% Iodine purity: 98.3%

Melting point: 214º C with decomposition. TLC (toluene / methyl ethyl ketone / formic acid 60/25/25) Rf: 0.5. ^T H NMR (DMS0): 5H (CH _2, CH) multiplet (3.1-3.9); 1 H (NH) triplet (8.2); (NH ₂ , OH) singlet (4.9). d) Preparation of 2,4,6-triiodo-3,5-bis [acetoxy acetamido] -N- [2,3- (acetooxy acetoxy) propyl] benzamide

80 g of O-acetylated glycolic acid chloride (0.586 mole) are added dropwise, at 0º C, to a solution consisting of 60.3 grams of 2,4,6-triiodo-3,5-diamino- N- (2,3-dihydroxy propyl) benzamide, dissolved in 300 cm ³ of anhydrous DMAC.

The reaction medium is left overnight at room temperature and then poured onto a mixture of 600 cm ³ of ethyl acetate. After recovery of the organic phase, the aqueous phase is again extracted with twice 200 cm ³ of ethyl acetate. The organic phases are then combined, dried over

Na ₂ SO ₄ then evaporated to dryness. 57 grams of product are thus recovered with a yield of 57%.

TLC (toluene / methyl ethyl ketone / formic acid

60/25/25) Rf: 0.30.

Iodine purity: 99.1%. e) Preparation of 2,4,6-triiodo-3,5-bis

(glycolamido) -N- (2,3 dihydroxy propyl) benzamide

57 g of the product described in the previous step (d) are deprotected in the presence of 500 cm ³ of methanol and 20 g of potassium carbonate. The suspension is kept at room temperature for 18 hours with stirring. After filtration of the potassium salts, the solution is evaporated to dryness.

The residue is dissolved in 1 liter of water and then purified by passage through a 200 cm ³ resin column

H ⁺ (IRN 77) previously regenerated with a 2N hydrochloric acid solution.

The resulting solution is discolored in black and then evaporated to dryness. The water is removed by azeotropic distillation with twice 100 cm ³ of ethanol. The residue is suspended in 200 cm ³ of ethanol and then filtered after stirring overnight at room temperature. 40 grams of product are recovered with a yield of 80%.

TLC (butanol / water / acetic acid 50/25/11) Rf: 0.35.

Iodine purity: 100.75%.

¹ H NMR (DMSO): 5H (CH ₂ , CH) multiplet (3.1-3.8);

4H (CH ₂ ) singlet (4.1); 5H (OH) singlet (4,5); 1H (NH) 8.6: 2H (NH) singlet (9.9). f) Preparation of 2,4,6-triiodo-3,5-bis [N (2-hydroxy ethyl) glycolamido] -N- (2,3-dihydroxy propyl) benzamide 50 grams of 2,4,6-triiodo-3,5-bis (glycol amido) -N- (2,3-dihydroxy propyl) benzamide (0.069 mole) are dissolved in a solution consisting of 8.8 grams of LiOH, H ₂ O in 75 ml of water. After heating at 50º C for three hours, 22.5 grams of distilled 2-chloro ethanol are added dropwise. The reaction medium is maintained at 45 ° C overnight, then evaporated to dryness. The residue is taken up in isopropanol, filtered and then dried in an oven at 50 ° C for 4 hours.

The solid recovered is then purified after dissolution in 500 cm of water, by successive passages over 75 cm ³ of H + resins (IRN 77) and 110 cm ³ of OH- resin (IRN 78). The resulting solution is discolored in black and then evaporated to dryness. After recovery with ether, the white crystals are filtered and then dried in an oven (yield 50%).

Melting point: 200º C without decomposition. Iodine purity: 97%.

TLC (butanol / water / acetic acid 50/25/11) = 2 spots at Rf 0.2 and 0.3.

¹ H NMR (DMSO): ¹⁷ H (CH ₂ CH) multiplet (3.1-4.1); 6H (OH); poorly resolved singlet (4.1-4.9); 1H (NH) singlet (8.6). EXAMPLE 2

Preparation of 2,4,6-triiodo-3,5-bis [N (2-hvdroxy ethyl) glycolamido] -N- (2-hydroχy ethyl) benzamide a) Preparation of 3,5-dinitro-N- (2- hydroχy ethyl) benzamide

113 grams of methyl 3,5-dinitro benzoate are dissolved in 250 cm ³ of methanol in the presence of 31 cm ³ of 2-amino ethanol. The reaction mixture is left under reflux for 24 hours, until the ester disappears.

The amide obtained is then precipitated by adding 500 cm ³ of methylene chloride. After filtration and drying, 98 grams of product are recovered with a yield of 76%.

Melting point: 145ºC.

TLC (toluene / methyl ethyl ketone / formic acid

60/25/25) Rf: 0.55.

¹ H NMR (DMSO + D ₂ O): 4 H (CH ₂ ) quadruplet (3.6); 3H

(Aromatic CH) singlet (9.1). b) Preparation of 2,4,6-triiodo-3,5-diamino-N- (2-hvdroxy ethyl) benzamide

51 grams of 3,5-dinitro-N- (2-hydroxy ethyl) benzamide, suspended in 1.5 liters of water and 250 cm of dioxane are hydrogenated in the presence of 7 grams of 10% palladium carbon, under a pressure of 6.10 ⁵ Pa. After 5 hours of reaction, the catalyst is filtered, the solution is acidified with 30 cm ³ of 10 N HCl and then iodized by the dropwise addition of 115 cm ³ of 70% iodine chloride. under strong agitation. 30 minutes after the end of the addition, the precipitate is filtered, cleared with water and then dried in an oven overnight at 50 ° C. Yield: 83% TLC (toluene methyl ethyl ketone / formic acid 60/25 / 25) Rf: 0.67 Purity in iodine: 97.9%

¹ H NMR (DMSO): 4H (CH ₂ ) multiplet (3.2-3.8); 5H (NH ₂ , OH) singlet (4.8); 1H (NH) triplet (8.4). c) Preparation of 2,4,6-triiodo-3,5 bis [N-acetoxy acetamido] -N- [2 (acetooxy acetoxy) ethyl] benzamide

62 grams of 0-acetylated glycolic acid chloride (0.45 mole) are added dropwise. drop, at -5º C, to a solution containing 57.3 grams of 2,4.6 triiodo-3,5-diamino-N- (2-hydroxy ethyl) benzamide, in 250 cm ³ of anhydrous DMAC. After returning to room temperature, the reaction medium is left under stirring for 18 hours then poured onto 1 liter of ice water. The precipitate obtained is filtered, then washed with ether and dried in an oven. Yield: 95%

TLC (toluene / methyl ethyl ketone / formic acid 60/25/25) Rf: 0.37. Iodine purity: 98%.

¹ H NMR (DMSO): 9H (CH ₃ ) doublet (2.1); 2H (CH ₂ -N) poorly resolved triplet (4.2); 6H (CH ₂ -O) singlet (4.6); 1H (NH) (8.7); 1H (NH) triplet (11). d) Preparation of 2.4.6-triiodo-3,5-bis¬

(glycolamido) -N- (2-hydroxy ethyl) benzamide

4.36 grams of the product obtained in the previous step are deprotected in the presence of 25 cm ³ of methanol and 2 grams of potassium carbonate. The suspension is stirred for 18 hours, then filtered and concentrated to dryness. The residue is dissolved in 100 cm of water and demineralized by passage over resin H (IRN 77). The resulting solution is evaporated to dryness in the presence of ethanol. After washing the solid with ethanol, the product is filtered and then dried in an oven at 50º C.

Yield: 75%.

Iodine purity: 102%.

TLC (butanol / water / acetic acid 50/25/11) Rf: 0.62. ¹ H NMR (DMSO + D ₂ O, CF ₃ - COOD) 4 H (-CH ₂ -CH ₂ ) quadruplet (3.5); 4H (CH ₂ -O) singlet (4.1). e) Preparation of 2,4,6-triiodo-3,5 bis [N (2-hydroxy ethyl) glycolamido] -N- (2-hydroxy ethyl) benzamide 2.1 grams of 2,4,6-triiodo-3,5-bis

(glycolamido) -N- (2-hydroxy ethyl) benzamide are dissolved in a solution consisting of 0.38 grams of

LiOH in 6 cm of water.

After two hours of heating at 50 ° C, 0.6 cm ³ of distilled 2-chloro ethanol are added dropwise. The resulting solution is heated at 50º C for two hours and then left overnight at room temperature. After evaporation to dryness in the presence of ethanol, the residue is taken up in isopropanol and then demineralized in aqueous solution by successive passages over H + resin (IRN 77 6 cm ³ ) and OH- (IRN 78; 10 cm ³ ). Evaporation to dryness of the aqueous solution makes it possible to obtain 1 gram of white crystals.

Yield: 43%.

TLC (butanol / water / acetic acid 50/25/11): 3 stains

Rf 0.35, 0.40 and 0.45.

Purity in iude: 98.5%.

EXAMPLE 3:

Preparation of 2,4,6-triiodo-3,5 bis [N- (2,3-dihydroχy propyl) glycolamido] -N- (2-hydroxy ethyl) benzamide

41.3 g of 2,4,6-triido-3,5-bis (glycolamido) -N- (2-hydroxy ethyl) benzamide are dissolved in a solution consisting of 7.6 g of LiOH in 50 cm ³ of water.

After two hours of heating at 50ºC, 15.0 ml of 1-chloro, 2,3-dihydroxypropane are added dropwise.

The resulting solution is heated at 50º C for 4 hours and then left at room temperature overnight. After evaporation to dryness in the presence of ethanol, the residue is taken up in '' isopropanol then demineralized in aqueous solution by passages successive on H ⁺ resin (IRN 77; 100 cm ³ ) and OH- (IRN 78; 125 cm ³ ). Dry evaporation of the aqueous solution gives 43.3 g of white crystals. Yield: 86.5%.

CCCM (dichloromethane / methanol: 6/4): two spots. Rf: 0.3 - 0.45. Iodine purity: 101%.

Claims

CLAIMS 1. Compounds of formula:

in which R ₁ and R ₂ are chosen independently of one another from the groups of formula -CH ₂ -CH ₂ OH and -CH ₂ -CHOH-CH ₂ OH. 2. Compound according to claim 1 which is 2,4-6-triiodo 3,5-bis [N (2-hydroxy ethyl) glycolamido] -N- (2,3-dihydroxy propyl) benzamide. 3. A compound according to claim 1 which is 2,4,6-triiodo-3,5-bis [N (2-hydroxy ethyl) glycolamido] -N- (2-hydroxy ethyl) benzamide. 4. Compound according to claim 1 which is 2,4,6-triiodo-3,5-bis [N (2,3-dihydroxy propyl) glycolamido] -N- (2-hydroxy ethyl) benzamide. 5. Contrast product, characterized in that it contains at least one compound according to any one of claims 1 to 4. 6. Contrast product according to claim 5, characterized in that it consists of an aqueous solution of the compound (s). 7. Process for the preparation of a compound according to claim 1, characterized in that an alkylation of a compound of formula is carried out:

in which R ₁ has the meaning given above with an alkylating reagent of formula R ₂ -Z (III) in which R ₂ has the meaning given above and Z represents a labile group.