IE891800L - Novel iodinated non-ionic triiodobenzene compounds and¹contrast media containing them - Google Patents

Description

63861 The present invention relates to compounds which can be used in contrast agents for radiography.

Iodobenzene compounds which have, on the benzene ring, several iodine atoms, generally 3 iodine 5 atoms per benzene ring, and various other substituents have been used as contrast agents for a long time.

These other substituents are pharmacologically acceptable groups which make it possible to administer the compounds to man and animals. These substituents 10 are generally chosen, on the one hand, in order to confer sufficient water-solubility on the compounds for the purpose of administering these compounds in aqueous solution and, on the other hand, in order to confer on these compounds a sufficient tolerance by the human 15 body.

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

Thus, in Patent FR-A-2,053, 037, 20 iodobenzenic carbamoyl compounds containing, in total, at least one N-hydroxyalkyl and at least two hydroxyl groups were proposed.

A compound illustrating this class is metrizamide, which has, however, proved to be of 25 limited stability.

The present invention is aimed at providing novel nonionic compounds which are well tolerated by the human body, very stable in aqueous solution, which 2 have a high solubility in water and which, in aqueous solution, have a low viscosity.

To this end, the subject of the present invention is compounds of formula: r. in which represents a group of formula j. - CO - ,, "6 Rs representing a C^-C* alkyl group, a Cj-C4 hydroxyalkyl group or a cx-c« poly hydroxy alkyl group, R6 representing a hydrogen atom, a Cx-C4 alkyl group, a 10 Cj-C, hydroxyalkyl group or a Cj-C4 polyhydroxyalkyl group, or a group of formula R. 18 - co - n - r R, representing a hydroxyalkyl group or a Cj-C* polyhydroxyalkyl group R8 representing a hydrogen atom or a Cj-C4 alkyl group 3 R2 represents a hydrogen atom, a Cx-C4 hydroxyalkyl group or a C^-C, polyhydroxyalkyl group, R3 represents a hydrogen atom or a Ci-C4 alkyl group, and R4 represents a hydrogen atom, a Ci-C4 alkyl group, a Ca-C4 hydroxyalkyl group or a cx-c4 polyhydroxyalkyl group.

In the present invention, polyhydroxyalkyl denotes a linear or branched polyhydroxyalkyl group. 10 A preferred compound of formula I is the compound of formula I in which Rx = -CO-NH-CH2-CH2OH, R2 - -CH2-CH2OH, R3 = H R4 - -CH2-CHOH-CH2OH.

Moreover, a preferred group of compounds of 15 formula I is that consisting of the compounds of symmetrical diamino type, that is to say the compounds of formula f> co-n —r2 IX , , «-4 "'CK20H sc«2oh ^ch2oh The compounds of formula I can be prepared conventionally, especially by acylation and/or alkylation reactions, starting from known compounds.

Thus, the compounds of symmetrical diamino type (compounds of formula II) can be prepared by a) acylation of a diamino compound of formula CON—R' „ ■M'- 2 I 2 XXX R2' representing a R2 group in which the hydroxyl groups have been protected, with an acid chloride of formula RC0C1 IV in which R represents CH -OH / 2 group in which the hydroxyl groups a c h ^CH -OH are protected, b) optionally alkylation of the compound obtained with an alkylating agent of formula R'4Z in which R'4 has the meaning given above, except for hydrogen, and Z represents a labile group such as a chlorine, bromine or iodine atom, in the presence of a base such as sodium methoxide, sodium ethoxide, sodium hydride or sodium hydroxide, c) deprotection.

Compounds of formula III are described in french Application FR-A-2,614,299.

The other compounds of formula III can be prepared analogously from, especially, an alkyl 3,5-dinitrobenzoate of formula in which R' is a Cj-C4 alkyl group such as a methyl group.

Asymmetric diamino compound can also be prepared from a compound of formula VI by: a) reaction with an amine of formula coor* vi nh-r 2 VII r 3 so as to obtain a compound of formula VIII 2" "w2 b) reduction with ammonium sulphide so as to obtain a compound of formula r con —r. o ho, ix r - w2 c) acylation of the compound of formula IX with an acid chloride of formula RC0C1 (IV) so as to obtain a compound of formula d) reduction and iodination of the compound of formula X so as to obtain a compound of formula 7 Tj =0-h hn I co I I Z N H.

XI e) optionally alkylation of a compound of formula XI with an alkylating agent of formula V so as to obtain a compound of formula xir con x f) deprotection of the compound of formula XII g) acylation of the deprotected compound obtained with an acid chloride of formula Cl-CO-R'j XIII R's denoting a Rs group in which the hydroxyl groups are 10 protected, so as to obtain, after deprotection, a compound of formula 8 co i I ^CH_OH ch 2 ^CIjOl it being possible for Stages f and g to be carried out in reverse order, and optionally h) alkylation in order to obtain a compound of formula I, in which R6 is other than hydrogen.

Compounds of symmetric isophthalic type (compounds of formula I in which r * -co-n- 1 i can be prepared by a) acylation of an amine of formula xv ~ c0c1 z with an acid chloride of formula RCOCl (IV), so as to obtain a compound of formula _ - XVI r -co-hn- b) reaction of an amine of formula H-n-r„ I 2 RJ with a compound of formula XVI so as to obtain a compound of formula R3 I 2 co-w —r2 c xvii r-co-nh' ^ ^co-k-r 1 I 2 I r3 then optionally either c) alkylation of the compound of formula XVII with an alkylating agent of formula R'4Z as defined above and finally d) removal of the protective groups of the -CH(CH2OH)2 group, or e) removal of the protective groups of the -CH(CH2OH)2 group and optionally f) alkylation of a deprotected compound with an alkylating agent R'4Z.

The compounds of asymmetric isophthalic type (compounds of formula I in which Rx = -CO-n-r i 7 R6 with R7 # R2 and/or R„ * R3) can be prepared by a) acylation of an amine of formula r 3 co-n r xviii H 2 e z with an acid chloride of formula RCOCl, b) optionally alkylation with an alkylating agent of formula R'4Z and c) removal of the protective groups of the -CH-(CH2OH)2 group.

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

As an alternative, the compounds of asymmetric isophthalic type can be prepared by a) acylation of an amine of formula C0C1 in which R'7 represents a R7 group in which the hydroxyl groups are protected, with an acid chloride of formula RCOCl (IV) so as to obtain a compound of formula xix I R 8 11 b) reaction of an amine of formula h*"r2 (vii) R3 with the compound of formula XX so as to obtain a compound of formula co-n-r. 2 xxi then optionally either c) alkylation of the compound of formula XXI with an alkylating agent of formula R'4Z as defined above and finally d) removal of the protective groups of the -CH(CH2OH)2 group or e) removal of the protective groups of the -CH(CH2OH)2 group and optionally f) alkylation of a deprotected compound with an alkylating agent R'4Z. 12 Another subject of the present invention is contrast agents which comprise at least one compound of formula I.

These contrast agents are used in man 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 compounds of formula I per 100 ml and the injectable amount of such solutions can generally vary from 1 to 1000 ml.

The aqueous solutions of the compounds of formula I can also contain certain additives such as: - sodium chloride at concentrations between 0.1 and 10 mM - disodium EDTA at concentrations between 0.1 and 2 mM - sodium citrate at concentrations between 0.1 and 10 mM - heparin at doses between 10 and 100 units per 100ml of solution.

These compositions can be administered by any route conventionally used for iodinated nonionic contrast agents. Thus, they can be administered enterally or parenterally (intravenous route, intraarterial route, opacification of the cavities) and in particular into the subarachnoid space. 13 An example of a composition according to the present invention will be given below.

Composition Compound of Example 1 65 g Water for injectable preparation g.s. for 100 ml The following examples illustrate the preparation of the compounds of formula I.

EXAMPLE 1 Preparation of 5-T 3-hvdroxv- 2-hvdroxvmethvl-N-12.3-dihvdroxypropvl) prooionamido 1 -N' ,N"-bis (2-hvdroxyethyl \ -2.4.6-triiodoisophthalamide a) Preparation of 5-r2-isopropvl-'l#3-dioxane-5-carboxamidol-2,4.6-triiodoisophthalovl dichloride 15 137 g of 5-amino-2,4,6-triiodoisophthaloyl chloride (0.23 mol) are dissolved in 460 ml of DMAC, to which are added 110 g (0.57 mol) of 2-isopropyl-1,3-dioxane-5-carboxylic acid chloride. The reaction mixture is maintained for 4 days under argon at room 20 temperature with stirring. The DMAC is removed under vacuum. The oil obtained is extracted with 3 1 of ethyl acetate and washed twice with 1 1 of ice-cold water. The organic phase is dried and concentrated to dryness. The product is crystallized from 200 ml of CH2C12. After 25 filtration, 110 g of solid are obtained: Yld.: 64% TLC: Si02 CH2C12 Rf: 0.13 (60 F 254) Si02 ether /petroleum ether 50/50 14 Rf: 0.52 b) Preparation of 5-r2-isopropvl-1.3-dioxane-5-carboxamidol-N' .N"-bisf 2-hvdroxvethvl) - 2,46-triiodoisophthalamide 5 130 g of product obtained in a (0.173 mol) are dissolved in a solution of 750 ml of DMAC and 75 ml (0.534 mol) of triethylamine. 33.7 g of ethanolamine (0.552 mol) are added dropwise to the reaction mixture. The reaction mixture is then left for 3 hours at room 10 temperature with stirring. Triethylamine hydrochloride is separated by filtration and the DMAC is removed under vacuum. The oil obtained is crystallized from 1 litre of water. The product is filtered and dried under vacuum.

Yld.: 95% TLC: Si02 Rf: 0.25 CH2C12/methanol 9/1 (60F254) Si02 R£: 0.67 CH2C12/methanol 8/2 % I: 45.6 (found) - 47.6 (theory) Hypersil C8 5|i 15 cm 20 HPLC Purity: 97% 0.01M NaH2PO« = 50 Methanol = 50 c) Preparation of 5-r3-hvdroxv-2-hvdroxymethvl-N- < 2.3-dihvdroxvpropvl 1 propionamido1-N' .N"-bis(2-hvdroxvethvl>-2.4.6-triiodoisophthalamide A suspension of 100 g of the product obtained in b (0.125 mol) in 350 ml of ethylene glycol is treated dropwise with 125 ml of 4N mol) sodium methoxide (0.5 mol) at 60°C and then with 65 g of l-chloro-2,3-propanediol (0.625 mol). After 1 hour at 60°C, the reaction mixture solidifies. 100 ml of 4N sodium methoxide (0.4 mol) and 55.2 g of 1-chloro-2,3-propanediol are added. The mixture is held 5 overnight at 60°C. 31 ml of 4N [lacuna] methoxide (0.125 mol) and 20.7 g of l-chloro-2,3-propanediol are again added. Stirring is maintained for 4 hours at 60°C. The inorganic salts are removed by filtration. The ethylene glycol is evaporated under vacuum. 10 The distillation residue is taken up in 800 ml of 10N HC1 and is left stirring overnight at room temperature. The reaction mixture is concentrated to dryness and redissolved in 300 ml of ethanol. The inorganic salts are removed by filtration. The ethanol 15 is evaporated under vacuum and the residue is crystallized from 1 litre of isopropyl alcohol. The precipitate is filtered and purified by HPLC (RP 18) (elution water).

Overall yld. (alkylation/deprotection/purification): 20 52% 1) TLC (silica 60F254): Cfl2Cl2/methanol 7/3 Rf: 0.4 2) HPLC Bypersil C8 5|i 15 cm Buffer 0.01 M MaH2P04 — 97 methanol — 3 97% pure 3) % I: 45.8 (found): 46.4 (theory) 4) NMR (DMSO) Large, poorly resolved peak, centred at 16 3.5 ppm (18 B); large peak, centred at 4.5 ppm (OB), exchangeable with D20 (6 B); broad peak at 8.4 ppm (NB), exchangeable with D20 (2 B).

EXAMPLE 2 - Preparation of 5-alvcolamido-3-T 3-hvdroxv-2-hvdroxvmethvl- N- (2.3-dihydroxvpropvl) propionamido 1 -2.4.6-triiodo-N-(hvdroxvethvl)benzamide a) Preparation of 3,5-dinitro-N-f2-hvdroxv-ethvl)bpn?amiHp 750 g (3.32 mol) of methyl 3,5-dinitrobenzoate are suspended in 2 litres of methanol in the presence of 222.7 g (3.65 mol) of ethanolamine. The reaction mixture is left for 48 hours at reflux until the ester has disappeared. After 4 hours at room temperature, the crystallized product is filtered, washed with 500 cm3 of methylene chloride and then oven-dried at 60°C under vacuum for 4 hours. This process makes it possible to recover 718 g of product with a yield of 85%.

Melting point 140°C.

TLC (toluene/methyl ethyl ketone/formic acid (60/25/25) Rf s 0.5. b) Preparation of 3-nitro-5-amino-N-(2-hvdroxvethvl)benzamide 12.25 g (0.18 mol) of ammonium sulphide are added, at 70°C, to a suspension of 25.5 g (0.1 mol) of 3,5-dinitro-N-(2-hydroxyethyl)benzamide in 135 cm3 of water. At the end of the addition, the initially 17 homogeneous mixture reprecipitates after 1/2 hour at 70°C. The reaction mixture is left to return to room temperature and stirring is continued for 2 hours. The precipitate is filtered, washed with methanol (70 cm3) 5 and then oven-dried (60°C).

Mass obtained 15.1 g - Yield 67%.

TLC (toluene/methyl ethyl ketone/formic acid 60/25/25). R£: 0.3. 1H NMR (DMSO): 3.4 ppm (large peak: 4H, aliphatic CHj); 10 4.65 ppm (large peak, H exchangeable with D20, NHj); 5.9 ppm (singlet, H exchangeable with D20, OH); 7.4 - 7.7 ppm (2 multiplets, 3H, aromatic protons); 8.6 ppm (large peak, 1H, NH). c) Preparation of 3-nitro-5-r2-isopropvl-15 1,3-dioxane-5-carboxamido 1 -N- (hvdroxvethyl \ ben z amide 40 g (0.177 mol) of 3-nitro-5-amino-N-(2-hydroxyethyl)benzamide are dissolved in 400 cm3 of DMAC. The addition, in the presence of triethylamine (54.6 cm3), of 74.9 g (0.389 mol) of the chloride of 20 2-isopropyl-l,3-dioxane-5-carboxylic acid produces a marked heat effect.

The reaction mixture is maintained for 18 hours under argon at room temperature. The mixture is filtered and the filtrate, diluted with water, is 25 extracted with ethyl acetate. The residue obtained after evaporation of solvent is treated with potassium carbonate (12 g) in 300 cm3 of methanol. After stirring for 48 hours at room temperature, the mixture is 18 concentrated and is then extracted with ethyl acetate. The crude product obtained after treatment is recrystallized from an 80/20 ether/ethyl acetate mixture. 37.8 g of product are isolated with a yield of 56%.

TLC (ethyl acetate R{: 0.48).

HPLC Hypersil C8 5ji 15 cm.

Buffer for 0.01M NaH2P04 50% MeOH 50% Purity: 94%. d) Preparation of 5-amino-3-r2-isopropvl-1.3-dioxane-5-carboxamido1-2,4.6-triiodo-N- ( hvdroxvethvl) hftnganii rff 15 A methanolic solution (1.4 1) of 40 g of 3-nitro-5- [ 2-isopropyl-l, 3-dioxane-5-carboxamido] -N-(hydroxyethyl)benzamide is stirred under a hydrogen atmosphere (5.105 Pa) for 5 hours at 50°C and in the presence of 4 g of palladium-on-charcoal. The catalyst 20 is then removed by filtration and the filtrate evaporated under reduced pressure. The resulting compound is suspended in 950 cm3 of water. The mixture is homogenized by addition of 20 cm3 of 2N hydrochloric acid. 63 cm3 of iodine chloride (containing 70% iodine) 25 are then introduced dropwise with vigorous stirring.

After 24 hours at room temperature, the precipitate is filtered, washed with water and taken up in ether. After drying, 32 g of product are obtained, i.e. a 19 yield of 42%.

TLC (90/10 dichloromethane/methanol) Rf: 0.8. e) Preparation of 5-amino-3-fN- {2.3-dihydroxvpropvll -2-isopropvl-l. 3-dioxane-5 5-carboxamidol -2.4.6-triiodo-N-1 hvdroxvethvl \ benzamide 84 cm3 of 4N sodium methoxide (0.337 mol) are added dropwise to a solution of the compound obtained in d) (20 g, 0.027 mol) in a v/v ethylene glycol/dimethylformamide mixture (160 ml). The mixture 10 is brought to 60°C over 1/2 hour and 36.1 cm3 of 1-chloro-2,3-propanediol (0.432 mol) are added at this same temperature. The reaction mixture is maintained for 60 hours at 60°C under nitrogen. The inorganic salts are removed by filtration. The ethylene glycol and the DMF are evaporated under vacuum. The resulting crude product is purified on silanated silica (elution water then 50/50 water/methanol). 16.5 g of product are isolated. Yield: 76%.

TLC (80/20 dichloromethane/methanol). Rf: 0.8. 20 f) Preparation of 5-amino-3-r 3-hvdroxv- 2-hvdroxvmethvl-N- (2.3-dihydroxypropvl \ propionamido 1 -2.4.6-triiodo-N- {hydroxyethvl) hftngami 16 g (0.02 mol) of the product obtained in e) are deprotected in the presence of 80 cm3 of 10N 25 hydrochloric acid for 48 hours at room temperature. After neutralization and evaporation under reduced pressure, the residue is precipitated from a (9/1) methanol/ether mixture, filtered and then purified by HPLC (RP 18 (elution water then 90/10 water/methanol)). 4 g of product are isolated with an overall yield (deprotection, purification) of 30%.

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

HPLC Hypersil C8 5|i 15 cm.

Buffer for 0.01M NaH2P04 9 0% MeOH 10% Purity: 97%. g) Preparation of 5-N-qlvcolamido-10 3-T3-hydroxv-2-hvdroxymethvl- N-(2.3-dihvdroxvpropvl)propi onamido1-2.4.6-triiodo-N-(hydroxvethvl)benzamide .5 g of O-acetylated glycolic acid chloride (0.04 mol) are added dropwise at room temperature to a 15 solution of 3 g of the compound obtained in Stage f (0.004 mol) in 30 cm3 of anhydrous DMAC. The reaction mixture is brought to 40°C for 12 hours and is then poured onto 250 cm3 of ice-cold water. The precipitate obtained is filtered and then extracted with ethyl 20 acetate. After treatment and then evaporation, the product obtained, dissolved in 50 cm3 of methanol, is deprotected in the presence of 10 cm3 of IN sodium hydroxide solution. The solution is kept stirring for 24 hours at room temperature and is then demineralized 25 by passing successively through H+ (IRN77) and OH" (IRN78) resins. After evaporation to dryness, the residue is taken up in ethyl ether, filtered and then dried. 21 Mass obtained 1.5 g. Overall yield: 47%.

Iodine purity: 99%.

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

HPLC Hypersil C8 5p 15 cm.

Buffer for 0.01M NaH2P04 90% MeOH 10% Purity: 98% EXAMPLE 3 - Preparation of 3.5-bis(3-hvdroxv-2-1 hvdroxymethvl) propionamido) -2.4.6-triiodo-N-{2.3-dihYdroxvpropvl\benzamide a) Preparation of 3-5-diamino-2«4.6-triiodo-N- (2 .3-diacetoxvpropvl \ bepyani^ 301.5 g (0.5 mol) of 3,5-diamino-2,4,6-triiodo-N- (2,3-dihydroxypropyl) benzamide are suspended in 1 1 of anhydrous pyridine cooled to around 15°C. After addition of 2450 ml of acetic anhydride, the solution is stirred for 18 h at room temperature and then poured into acidified water. After extraction with ethyl acetate, drying of the organic phase and evaporation, there are obtained 270 g of product with a yield of 78.5%.

Iodine purity: 98.3% TLC toluene/methyl ethyl ketone/HCOOH 60/25/35 Rf: 0.70. 22 b) Preparation of 3.5-bis(2-isopropvl-1.3-dioxane-5-carboxamido)-2,4.6-triiodo-N- (2.3-diacetoxvpropvl)benzamide 114.5 g (0.166 mol) of the compound obtained 5 in a) are dissolved in 350 ml of anhydrous DMAC. Addition of 128 g (0.66 m) of the chloride of 2-isopropyl-l, 3-dioxane-5-carboxylic acid takes place at 0°C. After stirring overnight, the reaction mass is poured into an ice/water mixture. The precipitate is 10 filtered, washed with water and then dried under vacuum at 50°C. c) Preparation of 3.5-bisf2-isopropvl-1.3-dioxane-5-carboxamidol -2.4.6-triiodo-N- (2.3-dihvdroxypropvl) 175 g of the compound obtained in b), in suspension with 2.5 1 of methanol, are stirred at room temperature in the presence of 45 g of potassium carbonate overnight. After evaporation of the reaction mass, the product crystallizes from water. After 20 filtration and drying, the crystals, obtained with a yield of 85%, are used directly in the following stage. d) Preparation of 3.5-bisf3-hvdroxy-2- (hvdroxvmethvl) propionamido) -2.4.6-triiodo-N-12.3-dihvdroxvpropvl) benzamide The compound obtained in c) is dissolved in 2 1 of 5N HC1 at 50°C. After stirring for 18 h, the suspension obtained is filtered. The filtrate is concentrated under vacuum and the residue taken up in 23 isopropanol. 108 g of crystalline product are obtained in 2 crops with a yield of 94%.

TLC Si02 Butanol 60, water 25, CH3COOH 1 Is Rf: 0.2. The product is purified by preparative HPLC on Si02 RP 18 15.25 |i, eluent pure water with a yield of 47%. Iodine purity 99.6%.

HPLC purity 99.1% (Hypersil C8 5ji 15 cm, 0.01M NaH2P04 95, MeOH 5). 200 MHz *H NMR (DMSO) 8.5 ppm (m, 1H exchangeable with D20, O-CONH) 9.9 ppm (t, 2H exchangeable with D20, O-NH-CO) 4.6 ppm (m, 6H exchangeable, OH) 3-4 ppm (m, 13H, CH) 2.7 ppm (m, 2H, NH-CHj).

EXAMPLE 4 - Preparation of 5-T3-hvdroxv- 2-hvdroxvmethvl-N- f 2-hvdroxvethvl Ipropionami doi-N-(2-hvdroxvethvl)-N'-12.3-dihvdroxvpropvl)-2.4.6-triiodoisophthalamide a) Preparation of 5-f2-isopropvl-1.3-dioxane 5-carboxamido)-2.4.6-triiodo- 3-rN/-r2-acetoxvethy1 ^garbamr>Y3 ibenzovl chloride 5.36 g of 2-isopropyl-l,3-dioxane- -carboxylic acid (0.0308 mol) are dissolved in 18 ml of DMAC. The reaction mixture is cooled to 5°C and 2.55 ml of S0C12 (0.0350 mol) are poured dropwise so that the temperature remains below 15°C. After the end of the addition, the reaction mixture is left for 3 hours at room temperature. 24 6.0 g of 5-amino-2,4,6-triiodo-3-[ (N-2-acetoxyethyl)carbamoyl]benzoyl chloride (0.00906 mol) are then added. The reaction mixture is maintained under argon for 4 days at room temperature.

The DMAC is removed under vacuum. The oil obtained is taken up in ethyl acetate; the organic phase is washed with water, dried and concentrated to dryness. The product is crystallized from 100 ml of ether.

After filtration and drying, 1.8 g of product are obtained, i.e. a yield of 24%.

TLC (silica 60F 254): 80/20 ethyl acetate/petroleum ether - Rf = 0.83. b) Preparation of 5-(2-isopropvl-1.3-dioxane-15 5-carboxamido1-2.4.6-triiodo-N- (2-acetoxvethyl 1 -N7 - (2.3-dihvdroxypropYl) isophthalamide 1 g of the product obtained in a (0.00122 mol) is dissolved in 100 ml of DMAC and then 0.26 ml of triethylamine (0.00189 mol) are added. 20 0.18 g of 3-amino-1,2-propanediol (0.00196 mol) is added dropwise to the reaction mixture. After the addition, the reaction mixture is left stirring under argon at room temperature for 24 hours.

Triethylamine hydrochloride is filtered off 25 and then the DMAC is evaporated. The oil thus obtained is crystallized from 20 ml of ether.

After filtration and drying, 0.8 g of product is obtained with a yield of 75.5%.

TLC (silica 60F254): CHCl3/MeOH/NH«OH 53/30/10 Rf « 0.77. c) Preparation of 5-f3-hvdroxv-2-hvdroxvmethvl-N- (2-hvdroxvethvl \ propionamido1-N-12-hvdroxvethvl-N' - f 2.3-dihvdroxvpropvl)-2.4.6-triiodoisophthalamide 0.4 g of the product obtained in b (0.000458 mol) is dissolved in 0.7 ml of ethylene glycol and 0.69 ml of a 4N sodium methoxide solution (0.00275 mol). 0.18 ml of chloroethanol (0.00275 mol) is added to this solution. The reaction mixture is heated at 40°C for 5 hours. 0.34 ml of 4N sodium methoxide and 0.1 ml of chloroethanol are added.

The mixture is maintained overnight at 40°C. The pH of the reaction mixture is brought to 7.00 by addition of dilute hydrochloric acid.

The ethylene glycol is evaporated under vacuum.

The distillation residue is taken up in 6 ml of water and 5 ml of concentrated hydrochloric acid and is then left stirring overnight at room temperature.

The reaction mixture is concentrated and then purified by preparative HPLC (RP 18, elution with water). After evaporation and drying, 0.1 g of product is obtained, i.e. an overall yield (alkylation/ purification) of 27%.

TLC (silica 60F254): 7/3 CH2Cla/methanol - Rf = 0.33. HPLC: Hypersil column C8 5 |i 25 cm 26 0.01M NaH2P04/Me0H: 95/S purity 95% *H NMR (Bruker - 200 MHz) in DMSO: conforms to the expected structure.

Claims (12)

CLAIMS 27

1. Compounds of formula CO z I CH,OH CH *;nch2OH;in which;Rj represents a group of formula;- N - CO- Rs;!;Rs representing a Cj-C4 alkyl group, a C1-C4 hydroxyalkyl group or a C1-Ci polyhydroxyalkyl group,;Rc representing a hydrogen atom, a C1-C4 alkyl group, a Cj-C4 hydroxyalkyl group or a Ci-C4 polyhydroxyalkyl group, or a group of formula;T';- CO - N - R,;R7 representing a C1-C4 hydroxyalkyl group or a Cj-C^ polyhydroxyalkyl group;R8 representing a hydrogen atom or a C1-C4 alkyl group R2 represents a hydrogen atom, a C1-C4 hydroxyalkyl group or a Ci-C4 polyhydroxyalkyl group,;R3 represents a hydrogen atom or a C1-C4 alkyl group,;and;R4 represents a hydrogen atom, a Cj-C4 alkyl group, a Cj-C4 hydroxyalkyl group or a Cj-C4 polyhydroxyalkyl group.;28;

2. Compounds according to Claim 1 of formula;CO-N— R.;f° CH.OH ?°;CH;CHjOH;II;l -CH.OH CH. * \ CH2OH in which R2, R3 and R4 have the meanings given in Claim 1.

3. Compound according to Claim 1 which is 5-[3-hydroxy-2-hydroxymethyl-N- (2,3-dihydroxy- propyl)propionamido]-N' ,N"-bis (2-hydroxyethyl) -2,4,6-triiodoisophthalamide.

4. Compound according to Claim 1 which is 5-glycolamido-3- [ 3-hydroxy-2-hydroxymethyl-N- (2,3-di-hydroxypropyl) propionamido ] -2,4,6-triiodo-N- (hydroxy-ethyl)benzamide.

5. Compound according to Claim 1 which is 3,5-bis (3-hydroxy-2- (hydroxymethyl) propionamido-2,4,6-triiodo-N- (2,3-dihydroxypropyl) benzamide.

6. Compound according to Claim 1 which is 5-[3-hydroxy-2-hydroxymethyl-N- (2-hydroxy ethyl) propionamido ] -N- (2-hydroxyethyl) -N' - (2,3-dihydroxypropyl) -2,4,6-triiodoisophthalamide.

7. Contrast agent, characterized in that it contains at least one compound according to any one of Claims 1 to 6.

8. Contrast agent according to Claim 7, characterized in that it consists of an aqueous solution of the compound (s). - 29 -

9. A compound of the formula I given and defined in Claim 1, substantially as hereinbefore described and exemplified.

10. A contrast agent according to Claim 7, substantially as hereinbefore described.

11. A process for the preparation of a compound of the formula I given and defined in Claim 1, substantially as hereinbefore described and exemplified.

12. A compound of the formula I given and defined in Claim l, whenever prepared by a process claimed in Claim 11. F. R. KELLY & CO. AGENTS FOR THE APPLICANTS.