MXPA97002088A - X-ray contrast media, yoda - Google Patents

Abstract

The invention provides the iodinated bis-phenyl compounds, useful as X-ray contrast agents, of the formula y (wherein each C6R5 portion may be the same or different, each R denotes a hydrogen or iodine atom, or a group M, two or three non-adjacent groups R on each portion C6R5 denotanatoms of iodine and 1, 2o3, groups R on each portion C6R5 denote groups M; X denotes a group that provides a chain of 1, 2 or 3 atoms linking the two groups C6R5, preferably where X is or contains the chain forming the bridge, a carbonyloxy group, each C6R5 group being a triiodophenyl group or a group in which each R is different from hydrogen, and each M is independently a nonionic hydrophilic moiety, M is preferably a non-ionic hydrophilic portion comprising a monohydroxy- or polyhydroxy-alkyl group) and isomers, especially stereoisomers and rotamers thereof

Description

X-RAY CONTRAST MEDIA, YODATES i_? O L. d. il 1 / C U V I L C L C l l S l C d Ü S m orations in and related to contrast media, and in particular to iodinated X-ray contrast media. The contrast media can be administered in medical imaging procedures, for example x-rays, magnetic resonance and ultrasound imaging, to improve the image contrast in images of a subject, in general a human or an animal body not human. The resulting enhanced contrast makes it possible for different organs, tissue types or body compartments to be clearly observed or identified. In the formation of X-ray images, contrast media work by modifying the X-ray absorption characteristics at the body sites within which they are distributed. Clearly, however, the usefulness of a material as a contrast medium is greatly governed by its toxicity, by its diagnostic efficacy, by other adverse effects it may have on the REF: 24321 subject to which it is administered, and by its ease storage and ease of administration. Since such means are conventionally used for diagnostic purposes instead of achieving a direct therapeutic aspect, when new contrast media are developed there is a general desire to develop means that have as little effect as possible on the various biological mechanisms of the cells or of the body, since this will lead in general to less toxicity of the animal and less adverse clinical effects. The adverse biological effects and the toxicity of a contrast medium are contributed by the components of the medium, for example the solvent or the carrier as well as the contrast agent and its components (for example ions where it is ionic) and etabolites. The following main contributing factors to the toxicity to the contrast media and to the adverse effects have been identified: the chemotoxicity of the contrast agent, the osmolality of the contrast medium, and the ionic composition (or the lack of it) of the medium of contrast.

In coronary angiography, for example, injection into the circulatory system of contrast media has been associated with several serious effects on cardiac function. These effects are severe enough to place limitations on the use in angiography of certain contrast media. In this procedure, for a short periads * of time a bolus of contrast medium instead of blood flows through the circulatory system and differences in the chemical and physicochemical nature of the contrast medium and the blood that it temporarily imposes, it can give rise to undesirable effects, for example arrhythmias, QT prolongation, and, especially, reduction in cardiac contractile force and the appearance of ventricular fibrillation. There have been many investigations regarding these negative effects on the cardiac function of the infusion of the contrast media of the circulatory system, for example, during angiography and the means for the reduction or elimination of these effects have been widely sought. The first injectable ionic X-ray contrast agents, based on triiodophenylcarboxylate salts, were particularly associated with osmotoxic effects deriving from hypertonicity of the injected contrast media. This hypertonicity produces osmotic effects such as draining water from red blood cells, endothelial cells, and muscle cells of the heart and blood vessels. The loss of water makes the red blood cells rigid, and the constitution of hypertonicity, of chemotoxicity and non-optimal ionic strength, separated or jointly reduce the contractile force of muscle cells and cause dilation of small blood vessels and a decrease resulting in blood pressure. The problem of osmotoxicity was driven by the development of nonionic triiodophenyl monomers, such as iodohexol, which allowed to achieve the same iodine concentrations effective for contrast, with the resulting osmotoxicity effects, very reduced. The interest towards reduced osmotoxicity led in the due course to the development of non-ionic dimeros of bis- (triiodophenyl) such as iodixanol, which reduce the problems associated with osmotoxicity even allowing effective concentrations of iodine to be achieved for the contrast, with hypotonic solutions. This ability to achieve effective iodine concentrations for the contrast, without taking the osmolality of the solution to isotonic levels (approximately 300 mOsm / Kg of H, 0) also made possible the contribution to the toxicity of the ionic imbalance to be directed by the inclusion of various plasma cations, as discussed for example in WO-90/01194 and WO-91/13636 of Nycomed Imaging AS. However, the X-ray contrast media, at high, commercial iodine concentrations of about 300 mg / ml, have relatively high viscosities in the range of about 15 to about 60 mPas at room temperature, with the dimeric media being generally more viscous than monomeric media. Such viscosities impose problems on the manager of the contrast medium, requiring gradually large orifice needles or high applied pressure, and are particularly pronounced in pediatric radiography and in radiographic techniques that require rapid bolus administration, for example, in angiography.

This problem of viscosity is recognized as having a serious barrier to the development of X-ray contrast agents and high opacity, especially in the case of compounds of high iodine value, and their solution offers the opportunity to either produce contrast agent solutions with higher iodine concentrations than conventional ones or solutions with conventional iodine concentrations but with lower viscosities, which can be more easily injected and which are usable in a wider range of diagnostic investigations. The present invention is directed to the problem of viscosity encountered with the materials of the prior art and thus observed from one aspect, the invention provides bis-phenyl-iodinated compounds useful as contrast agents, X-rays of the formula I I) (wherein each OR 5 portion may be the same or different, each R denoting a hydrogen or iodine atom or an M group, two or three non-adjacent R groups on each CbRb portion denote iodine atoms and one, two or three groups R on each portion C6Rs denote groups M, X denotes a group that provides a chain of 1, 2 or 3 atoms that are linked to the two groups CDRs, preferably where X is or contains in the chain forming the bridge a carbonyloxy group, being each CR group a triiodophenyl group or a group in which each R is different from hydrogen, and each M is independently a nonionic hydrophilic portion, M being preferably a nonionic hydrophilic moiety comprising a monohydroxy- or polyhydroxy-alkyl group) and the isomers, especially the stereoisomers and rotamers, thereof. It was found that the short chain di compounds according to the invention possess desirably low viscosities in aqueous solution. The compounds of the formula I are preferably asymmetric. This can be achieved by the use of a chain-forming X group of 2 or 3 atoms, asymmetric and / or by the selection of non-identical CRb groups, for example by the non-identical substitution of the iodophenyl end groups. Asymmetric molecules are preferred since they have been found to have better water solubility. Such non-identical substitution of the phenyl end groups, the C ^ R- portions, can be achieved by having different numbers or positions of the substitution with iodine and / or by different numbers, positions or identities of the substitution of M. To make maximum the iodine charge, the triiodophenyl end groups are preferred, for example the groups of the formula in these the two R groups can be the same or different, although preferably both represent the groups M. Where a phenyl end group is disubstituted with iodine, it is preferably of the formula (where M again can be the same or different). In general, diiodophenyl-diiodophenyl dimers will be less preferred than diiodophenyl-triiodophenyl or triiodophenyl-triiodophenyl dimers, primarily due to their reduced iodine charge, for example, 4 instead of 5 or 6 iodine atoms per dimeric molecule. Of course the triiodophenyl-triiodophenyl dimers are generally preferred due to their higher iodine charge. The solubilization groups M can be any of the non-ionizing groups conventionally used to improve the solubility in water. Suitable groups include, for example, alkyl groups of 1 to 10 carbon atoms straight or branched chain, preferably groups of 1 to 5 carbon atoms, optionally with one or more CH, -. or CH replaced by oxygen or nitrogen atoms and optionally substituted with one or more groups selected from oxo, hydroxyl, amino, carboxyl derivative, and oxo-substituted sulfur and phosphorus atoms. Particular examples include polyhydroxyalkyl, hydroxyalkoxyalkyl and hydroxypolyalkoxyalkyl and such groups attached to the phenyl group via an amide bond such as hydroxyalkylaminocarbonyl, N-alkyl-hydroxyalkylaminocarbonyl, and bis-hydroxyalkylaminocarbonyl. Preferred among such groups are those containing 1, 2, 3, 4, 5 or 6, especially 1, 2 or hydroxyl groups, for example -CONH-CHrCH2OH -CONH-CH? CH0HCH20H -CONH-CH (CH2OH) 2 -CON (CH2CH2OH): as well as other groups such as -CONH- -CONHCH, -OCOCH, -N (C0CH3) H - (COCH3) - (alkyl of 1 to 3 carbon atoms) -N (COCH3) -mono, bis or tris-hydroxy- (alkyl of 1 to 4 carbon atoms) -N (COCH2OH) -mono, bis or tris-hydroxy- (alkyl of 1 to 4 carbon atoms) -C (COCH.) (mono, bis or tris) -hydroxy (alkyl of 1 to 4 carbon atoms)) -N- (COCH OH) 2 -CON (CHCHOHCH2OH) (CH2CH; OH) -CONH-C (CH ^ OH), and -CONH-CH (CH; OH) (CHOHCH? OH).

In general, the M groups will each preferably comprise a polyhydroxy group (alkyl of 1 to 4 carbon atoms), such as 1,3-dihydroxyprop-2-yl or 2,3-dihydroxypropyl. Other M groups of this type, such as are conventional in the field of x-ray contrast agents, of triiodophenyl, can also be used in the introduction of the M groups onto the iodophenyl structures and can be achieved by conventional techniques. In the compounds of the invention, the linker group X is conveniently a 1, 2 or 3 membered chain comprising carbon, nitrogen, oxygen or sulfur atoms, for example a chain of an O, S, N or C atom, a chain of two atoms of NN, NC, NS, CC or CO, or a chain of three atoms of NCN, OCN, CNC, OCO, NSN. CSN COC, OCC or CCC, for example: an oxygen atom or a group NR1, CO, S02 or CR •; a group COCO, CONR1, COCRi1, SOCR2 ~, SO ^ NR1, CRR; 1, CR ^ NR1 OR CR ^ O; a group NR ONR1, OCONR1, CONREO, CONR ^ RS, 0C00, CR: 2OCRL, OCRNCO, CR1 CONR1, CRSCR ^ CR ^, COCR ^ CO, CR ^ R '^ CR1 ^ CR ^ SO ^ NR1, CR ^ OCO, O NR-SO, NRX; where R1 is hydrogen or an alkyl group of 1 to 6 carbon atoms or an alkoxy group optionally substituted by hydroxyl, alkoxy, oxa or oxo (for example, a polyhydroxyalkyl, formyl, acetyl, hydroxyl, alkoxy or hydroxyalkoxy group), or where Annex to the carbon Rx can also be a hydroxyl group. Advantageously, group X is not symmetric. This can be achieved for example by the asymmetric substitution of a symmetric chain (for example N-C-N substituted as NHCONR1) or by selection of an asymmetric chain (for example OCN substituted as OCONR1). In particular, it is preferred that linker group X must be polar and also that it must be hydrophilic. Thus, examples of preferred structures according to the invention include: where M and R1 are as defined hereinabove. The preferred particular compounds are those of the formula The compounds of the invention can generally be prepared in three steps: (a) dimer formation, (b) iodination of the phenyl groups and (c) substitution of the phenyl groups and / or optionally the linking portions by solubilization portions. In theory, while steps (a), (b) and (c) can be performed in any order, it will be preferred in general to perform the dimer formation step before the iodization step and, for reasons of economy, will be preferred performing the iodization step as late as a stage in the synthesis is feasible to reduce iodine waste. The dimer formation step itself can be a multi-step process, with a suitable, activated first linker binding to a monomer before the resulting linker-monomer conjugate is reacted with a second monomer. Alternatively, the formation of the dimer may be in the form of monomer reaction similarly or cooperatively substituted with the conjugation of the monomers leading to the formation of the dimer. Where the linking group X is desired, it can be produced by modification, for example substitution, oxidation or reduction, of a precursor linker, for example in a precursor monomer. In all cases conventional synthetic methods well known in the literature can be used (for example, methods analogous to those used and described for the production of the dimers referred to in WO-94/14478). The dimeric compounds of the invention can be used as X-ray contrast agents and for this purpose they can be formulated with conventional carriers and excipients to produce diagnostic contrast media. Thus, viewed from a further aspect, the invention provides a diagnostic composition comprising a compound of formula I (as defined above) together with at least one physiologically tolerable carrier or excipient., for example an aqueous solution in water for injections, optionally together with aggregated plasma ions or dissolved oxygen. The compositions of the contrast agent of the invention may be in ready-to-use concentrations or may be formulated in concentrated form for dilution prior to administration. In general, ready-to-use compositions will have iodine concentrations of at least 100 mg / ml, preferably at least 150 mg / ml, with concentrations of at least 300 mg / ml, for example 320 to 400 mg / ml which are in general preferred. The higher the iodine concentration, the higher the diagnostic value, but the higher the viscosity and the osmolality of the solution. Normally the maximum concentration of iodine for a given compound will be determined by its solubility, and by the upper tolerable limits for viscosity and osmolality. For the means of. In contrast to those administered by injection, the desirable upper limit for the viscosity of the solution at room temperature (20 ° C) is 30 Pas; however, viscosities of up to 50 or even up to 60 mPas can be tolerated, although their use in pediatric radiography will then be generally contraindicated. For the contrast media that are going to be given by bolus injection, for example, in angiographic procedures, the osmotoxic effects must be considered and preferably the osmolality must be less than 1 Osm / kg of H0, especially less than 850 mOsm / Kg of H20, in particular between 50 or less, preferably between 10, Osm of isotonicity (approximately 300 mOsm / Kg of H, 0). With the dimers of the invention, such targets of viscosity, osmolality and iodine concentration can easily be met. Of course, effective concentrations of iodine can be achieved with hypotonic solutions. It may be desirable in this way to constitute the tonicity of the solution by the addition of plasma cations to reduce the contribution of the toxicity that results from the effects of ionic imbalance after bolus injection. Such cations will desirably be included in the ranges suggested in WO-90/01194 and WO-91/13636. The preferred plasma cation contents for the contrast media of the invention, especially contrast media for angiography, are as follows: sodium: 2 to 100, especially 15 to 75, particularly 20 to 70, more particularly 25 to 35 mM calcium: up to 3.0, preferably 0.05 to 1.6, especially 0.1 to 1.2, particularly 0.15 to 0.7 mM potassium: up to 2, preferably 0.2 to 1.5, especially 0.3 to 1.2, particularly 0.4 to 0.9 mM magnesium: up to 0.8, preferably 0.05 to 0.6, especially 0.1 to 0.5, particularly 0.1 to 0.25 mM The plasmatic cations may be present, totally or partially, as counter ions in ironic contrast agents. Otherwise, these will generally be provided in the form of salts with physiologically tolerable counter-anions, for example, chloride, sulfate, phosphate, acid carbonate, etc., with especially preferred plasma anions, which are preferably used. In addition to the plasma cations, the contrast media may contain other counterions where the dimer is ionic and such counterions will of course be preferably physiologically tolerable. Examples of such ions include alkali metal and alkaline earth metal ions, ammonium, meglumine, ethanolamine, diethanolamine, chloride, phosphate, and acid carbonate. Other conventional counterions in the pharmaceutical formulation can also be used. The compositions may additionally contain additional conventional components in the X-ray contrast media, for example, dampers, etc. The invention will now be further described with reference to the following non-limiting examples.

EXAMPLE l N, N'-bis [2,4,6-triyod] -3,5-bis (2,3-dihydroxypropylaminocarbonyl) phenyl] -urea to_. 5-Amino-2, 4, 6-triiodo-N ^ N '-bis (2,3-diacetoxy-propyl) -isophthalamide The 5-amino-2,4,6-triiodo-N, N'-bis (2,3-dihydroxy-propyl) -isophthalamide (14.08 g, 0.02 mol), which had been prepared according to British Patent GB -A-1548594, was suspended in pyridine (200 ml) and acetic anhydride (57.1 g, 0.56 mol) was added dropwise with stirring and cooling. After stirring overnight, the mixture was poured into ethyl acetate (300 ml) and 20% aqueous HCl (200 ml). After extraction, the organic phase was washed with 2 M aqueous HCl (20 mL), brine (70 mL), dried (sodium sulfate) and evaporated. Yield 17.4 g (100%). The crude material was used without further purification, since analysis by HPLC and 1E NMR indicated that the product had a purity greater than 97%.

NMR ^ H (acetone-d: 8.76-8.83 (m, 2H, NH), 5.50 (broad s, 2H, NH2), 5.20-5.32 (, 2H), 4.43 (dd, J: = 11.8 Hz, J = 3.4 Hz, 2H), 4.29 (dd, Jt = 11.8 Hz, J2 = 6.0 Hz), 3.69-3.86 (m, 2H), 3.49-3.63 (m, 2H), 1.95-2.07 (m, 12H) MS (ESP ): 706 (M + l). b. N, Nf-bis [2,4,6-triiodo-3,5-bis (2,3-diacetoxypropyl-aminocarbonyl) phenyl] -urea The 5-amino-2,4,6-triiodo-N, N'-bis (2,3-diacetoxypropyl) -isophthalamide (10.4 g, 0.012 mol) was dissolved in anhydrous dioxane (20 ml) and a solution was added to the solution. 20% phosgene in toluene (3.1 ml). The mixture was stirred for one week in a closed vessel with thick walls, at room temperature. After evaporation, the residue was purified by preparative high-performance liquid chromatography (HPLC). Yield 10.0 g (94%).

NMR -H: 8.24-8.98 (m, 6H, NH), 5.07 (broad s, 4H), 4.12-4.35 (m, 8H), 3.31-3.60 (m, 8H), 2.00 (s, 24H, CH.CO. ). MS (ESP): 1771 (pf). c_. N, N '-bis [2,4,6-triiodo-3,5-bis (2,3-dihydroxy-propylaminocarbonyl) phenyl] urea N, N'-bis [2,4,6-triiodo-3,5-bis (2,3-diacetoxypropyl aminocarbonyl) phenyljurea (4.0 g, 2.26 mmol) was dissolved in a 1: 1 mixture of water and methanol (25 ml). ) containing sodium hydroxide (1.44 g, 36 mmol).

After stirring for 6 h at 40 ° C, the solution was treated with a strongly acidic ion exchange resin (Amberlyst 15), the solvent was removed and evaporated to give the pure product. Performance 3.24 g (100%) NMR ^ (DMSO-ds): 7.98-8.60 (m, 6H, NH), 4.65-4.80 (m, 4H), 4.44-4.57 (m, 4H), 3.62-3.75 (m, 4H), 3.02-3.55 (m, 16 H). 13 C NMR (DMSO-dβ): 170.7, 170.4, 170.3, 151.8, 151.7, 150. 1, 143.5, 100.9, 100.8, 100.7, 100.5, 100.3, 89.8, 89. 6, 70.1, 70.0, 64.1, 42.7, 42.6. MS (ESP): 1458 (M + + Na +).

Example 2 \ N, N '-bis [2,4,6-triiodo-3,5-bis (2,3-dihydroxypropylaminocarbonyl) phenyl] -N-methyl-urea N, N'-bis [2,4,6-triiodo-3,5-bis (2,3-dihydroxypropylaminocarbonyl) phenyl] urea (7.32 g, 5.1 mmol) was dissolved in 2 M aqueous sodium hydroxide (10 ml) and methyl iodide (0.95 ml) was added. The mixture was stirred at room temperature for 60 hours, treated with a strongly acidic ion exchange resin (Amberlyst 15) evaporated and purified by preparative HPLC. Yield 4.7 g (63%) of the product as a white solid. 1 H-NMR (DMSO-de): 8.80 (broad d, 1H, NH), 8.42 (broad d, 3H, NH), 8.05 (broad d, 1H, NH), 4.42-4.85 (m, 8H), 3.01-3.78 (m, 23 H). NMR: 3C (DMSO-d6): 170.2, 170.1, 170.0, 152.6, 152.5, 150.7, 150.3, 150.2, 149.2, 149.5, 144.2, 101.3, 101.2, 100.0, 99.5, 90.5, 90.1, 70.5, 70.3, 64.4, 64.3, 43.1 , 42.9, 36.0. MS (ESP): 1470 (M + + Na *).

Example 3 N, N'-bis [2,4,6-triiodo-3,5-bis (2,3-dihydroxypropylaminocarbonyl) phenyl] -n-hydroxyethyl-urea N, N'-bis [2,4,6-triiodo-3,5-bis (2,3-dihydroxypropylaminocarbonyl) phenyl] -urea (2.0 g, 1.4 mmol) was dissolved in water (13 ml) containing sodium hydroxide 2M (7 mi). 2-Bromoethanol (1 g, 8.4 mmol) was added and the mixture was stirred at room temperature for 60 hours, treated with a strongly acidic ion exchange resin (Amberlyst 15) evaporated and purified by preparative HPLC. Yield 1.45 g (70%) of the product as a white solid.

X H NMR (DMSO-d 6): 9.10-9.38 (, 1H, NH), 7.90-8.65 (m, 4H, NH), 3.02-3.91 (m, 24H). C NMR (DMSO-d6): 170.2, 153.2, 150.9, 150.3, 149.1, 144.1, 101.3, 100.9, 100.7, 100.3, 90.6, 89.8, 70.5, 70.4, 70.1, 64.4, 63.2, 60.6, 53.2, 43.1, MS ( ESP): 1502 (M + + Na +).

Example 4: N, N'-bis [2,4,6-triiodo-3- (2-hydroxyethyl-a-inocarbonyl) -5- (1,3-dihydroxyprop-2-ylamino-carbonyl) -phenyl] -urea to. L-Amino-2,4,6,6-triiodo-3,5-isophthalic acid dichloride.

L-amino-2,4,6-triiodo-3,5-isophthalic acid (200 g, 0.358 mol) was added to thionyl chloride (150 mol). The mixture was stirred at reflux temperature for 6 h and then allowed to cool to room temperature. After evaporation, the solid residue was dissolved in ethyl acetate (300 ml) which was again evaporated to dryness. The residue was dissolved in ethyl acetate (2000 mL) and the resulting solution was washed with a solution of sodium chloride (250 g) and sodium acid carbonate (120 g) in water (2000 mL) which had been cooled to 0 ° C. The organic phase was separated, washed with brine and dried (sodium sulfate). Evaporation gave 202 g (94%) of the product as a white solid.

XH NMR (DMSO-de): 10.79 (broad s, 2H). 13 C NMR (DMSO-d 6): 170.1, 149.7, 149.4, 78.94, 78.90. MS (ESP, m / e): 595, 593 (M +). b. l-Amino-2,, 6-triiodo-3- (2-acetoxyethylamino-carbonyl) -5- (1, 3-diacetoxiprop-2-ylaminocarbonyl) -benzene. 1-Amino-2,4,6-triiodo-3,5-isophthalic acid dichloride (10.0 g, 16.8 mmol) was dissolved in N, N-dimethylacetamide (DMAC, 80 mL) and triethylamine (14 mL) was added. After the addition of 2-amino-1,3-propanediol (2.14 g, 23.55 mmol), the mixture was stirred for 60 hours. Ethanolamine (5.0 ml) was added and the mixture was stirred for another 24 hours. After evaporation of the solvents, the solid residue was dissolved in pyridine (250 ml) and acetic anhydride (200 ml). After stirring for 20 hours, the solvents were evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water, with dilute aqueous HCl, with aqueous NaHC03, dried (magnesium sulfate) and evaporated. Chromatography on silica using ethyl acetate / heptane (6: 1) followed by preparative HPLC (RP-18, acetonitrile: water 35:65) gave 4.74 g (35%) of the product.

NMR! H (CDC13): 6.01-6.17 (2s broad, 2H, NH), 5.11 (broad s, 2H, NH2), 4.59-4.67 (m, 1H, CH), 4.22-4.40 (m, 6H, CH20 ), 3.69-3.78 (m, 2H, NCH), 2.12 (s, 3H), 2.08 (s, 6H). MS (ESP m / e) ': 823 ([M + Na] +), 801 ([m + 1] +). c. N, N '-bis [2,4,6-triiodo-3-yl-hydroxyethylamino-carbonyl) -5- (1,3-dihydroxyprop-2-ylaminocarbonyl) -phenyl] urea.

L-amino-2,4,6-triiodo-3- (2-acetoxyethylaminocarbonyl) -5- (1,3-diacetoxyprop-2-ylaminocarbonyl) benzene (0.957 g, 1.20 mmol) was mixed with phosgene (8.86 ml of 20% solution, toluene) and dioxane (3 ml) in a thick-walled stoppered flask, which was then kept at 60 ° C for 18 hours. The mixture was allowed to cool to room temperature and the solvents were evaporated. Dioxane (5 ml) was added and distilled at atmospheric pressure. This procedure was repeated twice. Dioxane (10 ml) 1-amino-2,4,6-triiodo-3- (2-acetoxyethylaminocarbonyl) -5- (1,3-diacetoxyprop-2-ylaminocarbonyl) benzene (0.926 g) was added. , 1.16 mmol) and mercury trifluoroacetate (26 mg, 0.23 mmol) and the solvent was distilled again at atmospheric pressure for 1 hour. Dioxane (10 mL) was added and the mixture was stirred at room temperature for 16 hours. The solvent was distilled once more, and after evaporation, the residue was dissolved in a mixture of methanol (35 ml) and 0.4 M aqueous sodium hydroxide (50 ml). After stirring for 2 hours, the solution was neutralized using a strongly acidic cation exchange resin, filtered and lyophilized. The residue was purified by preparative HPLC. Yield: 0.43 g (27%).

X H NMR (DMSO-D 6): 8.03-8.59 (, 6H), 4.42-4.77 (m, 6H), 3-10-3.83 (m, 18H).

Example 5 N, N -bi s [2, 4, 6-triiodo-3- (2-hydroxy-ethylaminocarbonyl) -5- (1,3-dihydroxyprop-2-ylamino-carbonyl) - f eni l] -n-hydroxieti lurea N, N'-bis [2,4,6-triiodo-3- (2-hydroxyethyl-aminocarbonyl) -5- (1,3-dihydroxyprop-2-ylamino-carbonyl) -phenyljurea (0.27 g, 0.2 mmol) of Example 4 was dissolved in water (7 ml) containing 2 M aqueous NaOH (1.0 ml) and 2-bromoethanol (0.084 ml, 1.2 mmol). After stirring for 20 hours, the solution was neutralized with a strongly acidic cation exchange resin and evaporated to dryness. The residue was purified by preparative HPLC. Yield 138 mg (50%).

NMR -H (DMSO-d.): 9.06-9.22 (, 1H), 8.03-8.46 (, 4H), 4.22-4.69 (m, 7H), 3.43-3.87 (m, 22H).

Example 6. N, N'-bis [2,4,6-triiodo-3- (2-hydroxyethyl-a-inocarbonyl) -5- (1,3-dihydroxyprop-2-ylamino-carbonyl) -phenyl] -N - (2,3-dihydroxypropyl) urea N, N'-bis [2,4,6-triiodo-3- (2-hydroxyethylaminocarbonyl) -5- (1,3-dihydroxyprop-2-ylaminocarbonyl) -phenyljurea (0.25 g, 0.18 mmol) was dissolved in water ( 5 ml) followed by 2 M aqueous NaOH (2.1 ml) and, after 5 min. Bromopropan-2, 3-diol (0.196 ml) was added. The solution was stirred for 4 days, neutralized with a strongly acidic cation exchange resin and evaporated to dryness. Purification by preparative HPLC gave 38 mg (14%) of the product as a white solid. MS (ESP, m / e: 1450 (M +).

Example 7_. N, N'-bis [2,4,6-triiodo-3- (2-hydroxy-ethylaminocarbonyl) -5- (2,3-dihydroxypropyl-amino-carbonyl) -phenyl] urea to. l-amino-2,4,6-triiodo-3- (2-acetoxyethylaminocarbonyl) -5- (2,3-diacetoxypropylaminocarbonyl) benzene.

The l-amino-2,6,6-triiodo-3,5-isophthalic acid dichloride (3.03 g, 5.1 mmol), prepared according to Example 4a, was added to a solution of triethylamine (4.26 ml) in DMAC (20 mL). my) . A solution of l-amino-2,3-propanediol (0.51 g, 5.6 mmol) in DMAC (3 mL) was added and, after stirring for 16 hours at room temperature, ethanolamine (1.55 g, 25.5 mmol) was added. . After stirring for another 16 hours, the solvents were evaporated, the residue was dissolved in pyridine (75 ml), acetic anhydride (60 ml) was added and the solution was stirred for 17 hours. The solvents were evaporated, the residue was dissolved in ethyl acetate and the solution was washed with water, with 0.2 M aqueous HCl solution, and aqueous NaHCOj, dried (magnesium sulfate) and evaporated. Purification by preparative HPLC gave 1.28 g (31%) of the product as a white solid.

NMR: H (DMSO-d6): 8.60-8.71 (m, 2H), 5.42-5.51 (m, 1H), 5.02-5.13 (m, 1H), 4.24-4.33 (m, 1H), 4.08-4.21 (m, 3H), 3.32-3.49 (m, 5H), 2.00 (2s, 9H). MS (ESP, m / e): 823 ([M + Na] +), 801 (M + 1). b. N, N'-bis [2,4,6-triiodo-3- (2-hydroxyethylamino-carbonyl) -5- (2,3-dihydroxypropylaminocarbonyl) -phenyl] -urea.

L-amino-2, 6-triiodo-3- (2-acetoxyethylaminocarbonyl) -5- (2,3-diacetoxypropyl aminocarbonyl) benzene (1.99 g, 2.48 mmol) was dissolved in dioxane (7 ml) together with a solution of phosgene in toluene (20%, 18 ml) in a thick-walled flask. The mixture was heated at 60 ° C for 16 hours, and after cooling to room temperature the solvents were evaporated. Dioxane (10 ml) was added and distilled at atmospheric pressure. This procedure was repeated 3 times. The residue was dissolved in dioxane (10 ml) containing mercury trifluoroacetate (35 mg) and l-amino-2, 6-triiodo-3- (2-acetoxyethylaminocarbonyl) -5- (2,3-diacetoxypropyl aminocarbonyl) benzene (2.0 g, 2.50 mol). The flask was heated and the solvent slowly distilled. Another portion of dioxane (10 ml) was added and then distilled again. The residue was dissolved in a mixture of methanol (60 ml) and 0.22 M aqueous NaOH (90 ml) and, after stirring for 6 hours, the solution was neutralized with a strongly acidic cation exchange resin. After evaporation of the solvents, the residue was purified by preparative HPLC to give 1.26 g (37%) of the product as a white solid.

XR-NMR (DMSO-de): 8.02-8.67 (M, 6H), 4.60-4.84 (m, 4h), 4.43-4.57 (m, 2H), 3.02-3.75 (m, 18H). I3C NMR (DMSO-de): 169.7, 169.5, 151.4, 150.0, 142.9, 99.9, 86.9, 70.1, 70.0, 69.9, 64.0, 59.2, 42.6, 41.7.

Example 8. N, N'-bis [2,4,6-triiodo-3- (2-hydroxyethyl-aminocarbonyl) -5- (2,3-dihydroxypropylaminocarbonyl) -phenyl] -N-hydroxyethylurea N, N'-bis [2,4,6-triiodo-3- (2-hydroxyethylaminocarbonyl) -5- (2,3-dihydroxypropylamino-carbonyl) -phenyljurea (0.216 g, 0.157 mmol) was dissolved in a mixture of water (6 ml) and 2 M aqueous NaOH (0.9 ml) together with 2-bromoethanol (0.067 ml). The mixture was stirred for 20 hours, neutralized with a strongly acidic cation exchange resin and evaporated to dryness. Purification using preparative HPLC gave 105 mg (47%) of the product as a white solid.

NMR: H (DMSO-d: 9.11-9.22 (m, 1H), 7.84-8.61 (m, 4H), 4.41-4.80 (m, 7H), 3.02-3.87 (m, 22H). 13 C NMR (DMSO-dc): 170.2, 169.9, 153.2, 151.0, 150.9, 150. 4, 144.2, 144.1, 100.2, 70.5, 64.4, 60.6, 59.6, 43. 1, 42.1. MS (ESP, m / e): 1420 (M *).

Example 9. N, N'-bis [2,4,6-triiodo-3- (2-hydroxyethyl-aminocarbonyl) -5- (2,3-dihydroxypropylaminocarbonyl) -phenyl] -n- (2,3-dihydroxypropyl) urea N, N'-bis [2,4,6-triiodo-3- (2-hydroxyethylaminocarbonyl) -5- (2,3-dihydroxypropylamino-carbonyl) phenyl] urea (0.353 g, 0.257 mmol) was dissolved in a mixture of water (8 ml) and 2 M aqueous NaOH (0.9 ml) together with l-bromo-2,3-dihydroxypropane (0.136 ml, 1.55 mmol). After stirring at room temperature for 160 hours, the solution was neutralized using a strongly acidic cation exchange resin. After evaporation, the residue was purified using preparative HPLC. Yield: 100 mg (27%) of the product as a white solid.

NMR: H (DMSO-dí): 9.45-9.63 (m, 1H), 7.94-8.68 (m, 4H), 5.82-6.07 (m, 1H); 5.12 (broad s, 1H); 4.43-4.80 (m, 6H), 4.13 (m, 1H), 3.04-3.97 (m, 14H). 13 C NMR (DMSO-D): 169.8, 169.5, 153.5, 150.8, 150.5, 150.0, 149.9, 143.7, 99.8, 90.3, 70.0, 64.0, 59.2, 42.7, 41.7.

Example 10. N, Nf -bis [2,4,6-triiodo-3-acetamido-5- (2,3-dihydroxypropylaminocarbonyl) phenyl] urea N, N'-bis (3-nitro-5-carboxyphenyl) urea L-Nitro-3-aminobenzoic acid (9.11 g, 50 mmol) was mixed with phosgene (13 ml of a 20% solution in toluene) and Na C03 (7.4 g, 70 mmol) in toluene (20 ml). The mixture was stirred at 60 ° C for 2 hours and then at room temperature for 16 hours. After the addition of the additional toluene (4 ml), the stirring was continued at 100 ° C for 9 hours. Toluene (4 mL) was added, and stirring was continued for 20 hours at 40 ° C. After cooling to room temperature, the solution was poured into 1 M aqueous HCl (200 ml). The off-white precipitate was filtered, washed with a mixture of ethanol and 2 M aqueous HCl (4 mL), filtered and dried. Yield 8.2 g (84%).

NMR: H (DMSO-do): 9.63 (s, NH, 2H), 8.65 (dd, J: = J2 = 22 Hz, 2H), 8.34 (dd, J? = 1.6 Hz, J? = 1.5 Hz, 2H ), 8.18 (dd, J: = 1.5 Hz, J = 1.3 Hz, 2H), 3.3-3.8 (broad s, 2H, OH). 13 C NMR (DMSO-do): 165.8, 152.7, 148.5, 141.4, 133.1, 125.3, 117.3, 116.6. MS (ESP, m / e): 389 (M +, 100%), 411 ([M + Na] 55%) b. N, N'-bis (3-nitro-5-methoxycarbonylphenyl) urea.

N, N'-bis (3-nitro-5-carboxyphenyl) urea (0.5 g, 1.3 mmol) was dissolved in methanol (15 mL) containing concentrated sulfuric acid (0.5 mL) and the solution was stirred at 60 ° C for 20 minutes. hours. After cooling to room temperature, the solution was poured into water (40 ml). The yellowish precipitate was filtered, washed with a saturated aqueous solution of NaHCO 3, with water and dried. Yield 0.53 g (98%). NMR; H (DMSO-de): 9.78 (broad s, NH, 1H), 8.68 (dd, J? = 2.1 Hz, J2 = 2.0 Hz, 2H), 8.46 (dd, J? = 2.2 Hz, J = 2.0 Hz, 2H), 8.23 (dd, J: = 2.2 Hz, J; = 2. O Hz, 2H), 3.92 (s, OCH., 6H). NMR: C (D SO-df): 164.9, 153.1, 148.5, 142.0, 131.6, 124.9, 117.0, 116.9. c. N, N'-bis [3-nitro-5- (2,3-dihydroxypropyl-1-aminocarbonyl) phenyl] urea.

N, N'-bis) 3-nitro-5-methoxycarbonylphenyl) urea (0.209 g, 0.5 mmol) was heated with 1-amino-2,3-propanediol (0.114 g, 1.2 mmol) at 95 ° C. After 30 min., The pressure was reduced to 200 mm Hg and heating was continued for 3 hours. The crude reaction mixture was purified by preparative HPLC to give 164 mg (61%) of the product as a white solid.

NMR LH (DMSO-de): 9.61 (s, 2H), 8.79 (t, J = 6.4 Hz, 2H), 8.67 (dd, Hz, J2 = 2.0 Hz, 2H), 8.25 (dd, J: = J2 = 2.0 Hz, 2H), 4.84 (d, J = 4.5 Hz, OH, 2H), 4.58 (t, J = 5.6 Hz, OH, 2H), 3.65 (m, 2H), 3.30-3.50 (m, 6H), 3.21 (m, 2H). NMR: jC (DMSO-dg): 164.8, 152.6, 148.5, 141.1, 136.8, 124.2, 115.9, 115.4. MS (ESP, m / e): 537 (m \ 100%), 519 ([M-H20] +, 56%). d. N, N '-bis [3-amino-5- (2,3-dihydroxypropylaminocarbonyl) phenyljurea.

N, N'-bis [3-nitro-5- (2,3-dihydroxypropylaminocarbonyl) phenyljurea (0.103 g, 0.19 mmol) was dissolved in a mixture of methanol (14 ml) and water (6 ml) containing aqueous HCl 2. M (0.2 ml) and a Pd / C catalyst (10%, 0.1 g). The hydrogenation was carried out at 4.22 kg / cm2 (60 psi). The catalyst was filtered and the solvents were evaporated. The residue was redissolved in water and lyophilized giving 0.102 g (97%) of the product. 1H-NMR (D20): 7.60 (s, 4H), 7.29 (s, 2H), 3.74-3.82 (m, 2H), 3.38-3.54 (m, 4H), 3.22-3.37 (m, 4H). 13 C NMR (D20): 168.6, 154.0, 139.9, 136.1, 131.1, 118.6, 118.5, 117.0, 116.9, 116.2, 70.1, 63.2, 42.4. ms (ESP, m / e): 477 (* T, 100%). and. N, N '-bis [3-amino-2,4,6-triiodo-5- (2,3-dihydroxy-propylaminocarbonyl) phenyl] urea N, N'-bis [3-amino-5- (2,3-dihydroxypropylaminocarbonyl) phenyl] urea (0.50 g, 0.91 mmol) was dissolved in a methanol mixture. { 4 ml) and water (46 ml) and an aqueous solution of KIC12 (6 mmol) was added. After adjusting the pH to 2 with aqueous HCl, the solution was filtered for 12 hours at 40 ° C. After the addition of an aqueous solution of NaHS03, the solvents were evaporated and the residue was triturated three times with a methanol-water mixture (3: 7) giving 1.02 g (89%) of the product.

NMR: H (DMSO-dβ): 8.41 (broad s, 1H), 8.20-8.33 (m, 2H), 8.11-8.17 (d, J = 7.0 Hz, 1H), 5.40 (broad s, NH2, 4H), 3.62-3.74 (m, 2H), 3.44-3.52 (m, 2H), 3.34-3.43 (m, 2H), 3.21-3.32 (m, 2H), 3.07-3.21 (m, 2H). 13 C NMR (DMSO-de): 170.7, 170.6, 151.9, 149.3, 148.9, 143.1, 143.0, 142.8, 70.6, 70.4, 64.4, 43.1, 43.0. MS (ESP, m / e: 1232 (m \ 20%), 1254 ([M + Na] \ 100%), 1270 ([M + Kf, 50%). f. N, N'-bis [3-acetamido-2,4,6-triiodo-5- (2,3, -dihydroxypropylaminocarbonyl) phenyl] urea.

N, N'-bis [3-amino-2,4,6-triiodo-5- (2,3-dihydroxypropylaminocarbonyl) phenyljurea (0.155 g, 0.126 mmol) was mixed with acetic anhydride (2 mL) and sulfuric acid was added. concentrated (3 drops). The mixture was filtered at 70 ° C for 5 hours and then at room temperature for 17 hours. After evaporation of the solvent, the residue was dissolved in a mixture of methanol (2.5 ml) and water (0.4 ml), the pH was adjusted to 10 with 10 M aqueous NaOH and stirred at 50 ° C for 5 hours. After evaporation of the solvent, the residue was triturated with water and the solid filtered and dried. Yield 0.15 g (90%).

X H NMR (DMSO-dβ): 9.80-10.10 (2 s broad, 2H), 8.20-8.75 (, 4H), 4.70 (s, OH, 2H), 4.48 (s, OH, 2H), 3. 64-3.98 (m, 2H), 3.41-3.56 (, 4H), 3.03-3.26 (m, 4H), 2.04 (s, 6H). 13 C NMR (DMS0-d6): 170.3, 170.2, 168.3, 168.2, 168.1, 151. 9, 151.7, 150.3, 144.4, 144.3, 108.2, 108.1, 99.5, 99.4, 99.3, 99.2, 98.1, 98.0, 97.9, 70.6, 70.4, 64.4, 43. 1, 23.5. MS (ESP, m / e): 1339 ([M + Na] +, 100%).

Example 1_1_. N, N'-bis [2,4,6-triiodo-3- (2-hydroxy-acetamido) -5- (2,3-dihydroxypropylamino-carbonyl) -phenyljurea to . N, N'-bis [3-amino-2,4,6-triiodo-5- (2,3-diacetoxy-propylaminocarbonyl) phenyl] urea.

N, N'-bis [3-amino, 2,4,6-triiodo-5- (2,3-dihydroxypropylaminocarbonyl) phenyl] urea (1.23 g, 1.0 mmol) was dissolved in a mixture of acetic anhydride (5 ml). ), pyridine (5.5 ml) and dimethyl formamide (5 ml). The solution was stirred at room temperature for 65 hours, and the solvents were evaporated. The residue was dissolved in methylene chloride (250 ml), and the solution was washed with water (2 x 50 ml), with 0.1 M aqueous HCl (50 ml), with water (100 ml) and a saturated aqueous solution of NaHCO 3. . After drying (Na2SO4) and evaporation, the NMR and HPLC analyzes of the residue showed an essentially pure product. Yield: 1.0 g (71%).

NMR -H (DMSO-de): 8.73 (broad s, 1H), 8.44-8.63 (m, 2H), 8.32-8.45 (m, 1H), 5.30-5.45 (s, NH2, 4H), 5.02-5.16 ( m, 2H), 4.10-4.37 (m, 4H), 1.80-2.05 (m, 12H). 13 C NMR (DMSO-d 6): 170.8, 170.6, 170.3, 149.1, 148.9, 148.3, 147.8, 143.3, 143.2, 136.6, 124.4, 92.6, 92.0, 70.1, 70.0, 63.5, 21.5, 21.0. MS (ESP, m / e): 1400 (m +, 100%). b. N, N'-bis [2,4,6-triiodo-3- (2-acetoxyacetamido) -5- (2, 3-diacetoxipropylaminocarbonyl) phenyljurea.

N, N'-bis [3-amino-2,4,6-triiodo-5- (2,3-diacetoxypropyl aminocarbonyl) phenyljurea (1.0 g, 0.71 mmol) was dissolved in acetoxyacetoxychloride (5 ml) and the solution stirred at room temperature for 24 hours. After heating to 60% C for 2.5 hours, the solution was evaporated to dryness and the residue was triturated with water (40 ml). The burnt color precipitate was filtered, washed again with water (20 ml) and dried. Yield: 0.92 g (81%).

XH NMR (DMSO-D6): 10.05-10.30 (m, 2h), 8.62-9.06 (m, 2H), 8.22-8.58 (m, 2H), 5.02-5.15 (m, 2H), 4.66 (s broad, 4H ), 4.23-4.39 (m, 2H), 4.12-4.23 (m, 2H), 3.35-3.62 (, 4H), 2.11 (s, 6H), 2.00 (s, 12H). NMR 13c (DMSO-d6): 170.7, 170.4, 170.1, 165.7, 150.1, 150.0, 144.5, 144.4, 143.3, 143.2, 108.5, 108.3, 108.1, 97.6, 97.3, 70.0, 63.5, 62.6, 61.0, 21.5, 21.0. MS (ESP, m / e): 1599 (M +, 100%), 1621 ([M + Na] ", 23%). c. N, N'-bis [2,4,6-triiodo-3- (2-hydroxyacetamido) -5- (2,3-dihydroxypropylaminocarbonyl) phenyljurea.

N, N'-bis [2,4,6-triiodo-3- (2-acetoxyaceta ido) -5- (2,3-diacetoxypropyl aminocarbonyl) phenyljurea (0.88 g, 0.55 mmol) was dissolved in a methanol mixture (10 mL) and 2 M aqueous NaOH (2.5 mL). After stirring for 15 min. at room temperature, the pH was adjusted to 4 with a strongly acidic ion exchange resin, and after filtration, evaporated to dryness. The residue was purified by preparative HPLC. Yield: 0.58 g (78%).

XH NMR (DMSO-d6): 9.68-9.93 (m 2H), 8.42-8.64 (m, 2H), 8.24-8.48 (m, 2H), 4.00 (s, OH, 6H), 3.60-3.73 (, 6H) , 3.36-3.54 (m, 6H), 3.04-3.38 (m, 4H). 13 C NMR (DMSO-d 6): 171.0, 170.8, 170.6, 170.3, 170.2, 151.8, 151.7, 150.3, 150.2, 144.3, 144.1, 143.9, 143.8, 108.1, 108.0, 107.9, 99.5, 99.3, 97.9, 97.8, 97.7, 70.4, 64.6, 62.3, 43.1 MS (ESP, m / e): 1349 (m \ 36%), 1379 ([m + Na] +, 100%).

Example 12. N, N'-bis [2,4,6-triiodo-3- (2-hydroxy-propionamido) -5- (2,3-dihydroxypropylaminocarbonyl) -phenyljurea to. N, N '-bis [2,4,6-triiodo-3- (2-acetoxypropionamido) -5- (2, 3-acetoxypropylaminocarbonyl) phenyljurea, N, N'-bis [3-amino-2,4,6-triiodo-5- (2-acetoxy-propionamido) -5- (2, 3-acetoxypropylaminocarbonyl) -phenyl] urea prepared as described above and chloride of 2-acetoxypropionic acid (4.0 ml) were mixed and stirred at 60 ° C for 2 hours and 14 hours at 85 ° C. The solvents were evaporated and the residue was triturated with water (50 ml). The greenish solid was filtered and used without purification in the next step. Yield: 0.92 g (79%) XH NMR (DMSO-ds): 10.08-10.25 (m, 2H), 8.70-9.30 (m, 2H), 8.08-8.75 (m, 2H), 5.15-5.27 (m, 2H), 5.03-5.16 (, 2H), 4.23-4.36 (m, 2H), 4.11-4.25 (m, 2H), 3.23- 3.54 (m, 4H), 2.10 (s, 3H), 2.06 (2s, 15H), 1.47-1.55 (m, 6H). NMR: C (DMSO-d6): 170.7, 170.4, 170.0, 151.8, 150.1, 149.0, 144.5, 143.5, 143.3, 143.2, 108.3, 107.9, 106.4, 97.7, 97.6, 70.5, 70.0, 69.9, 63.6, 63.5, 63.4 , 21.5, 21.3, 21.0, 18.0 b. N, N '-bis [2,4,6-triiodo-3- (2-hydroxypropionamido) -5- (2,3-dihydroxypropylaminocarbonyl) phenyl] urea.

N, N'-bis [2,4,6-triiodo-3- (2-acetoxypropionamido-5- (2,3-acetoxypropylamino-carbonyl) phenyl] urea (0.85 g, 0.52 mmol) was dissolved in a methanol mixture (10 ml) and 2 M aqueous NaOH (2.5 ml) and the solution was stirred at room temperature for 2 hours.The pH was then adjusted to 4 using a strongly acidic ion exchange resin, and after filtration it was evaporated to dryness The residue was purified by preparative HPLC Yield: 370 mg (51%).

NMR I (DMSO-d6): 9.58-9.84 (m, 2H), 8.22-8.64 (m, 4H), 5.50-5.70 (m, 2H), 4.67 (broad s, OH, 2H), 4.48 (broad s, OH, 2H), 4.13-4.17 (m, 2H), 3.64-3.75 (m, 2H), 3.40-3.61 (m, 2H), 3.26-3.35 (m, 2H), 3.07-3.25 (m, 4H), 1.35-1.42 (m, 6H). NMR ljC (DMSO-d6): 173.0, 172.8, 170.3, 170.2, 151.8, 150.2, 144.2, 143.9, 108.0, 99.5, 99.2, 97.8, 97.6, 97.5, 70.4, 70.3, 68.0, 64.4, 43.1, 21.5, 21.0.

MS (? SP, m / e): 1374 (M *, 20%,!, 1397 ([M + Na] \ 100%).

Example 13_, N, N'-bis [2,4,6-triiodo-3- (2,3-dihydroxypropionylamido) -5- (2, 3-d hydroxypropylamino-carbonyl) phenyljurea to. N, N'-bis [2,4,6-triiodo-3- (2,2-dimethyl-l, -dioxalan-4-carboxamido-5- (2,3-diacetyropylaminocarbonyl) phenyl] urea.

The potassium salt of 2,2-dimethyl-1,3-dioxalan-4-carboxylic acid (1.50 g, 8.1 mmol) was suspended in anhydrous ether (35 mL) and cooled to 0 ° C. Oxalyl chloride (1.03 g, 8.1 mmol) was added and the solution was stirred for 2 hours at 0 ° C and then for 24 hours at room temperature. The mixture was filtered and the filtrate was evaporated. A solution of N, N '-bis [3-amino-2,4,6-triiodo-5- (2,3-acetoxy-propylaminocarbonyl) phenyljurea (1.9 g, 1.36 mmol) prepared as described above was then added dimethylacetamide (10 ml) and the resulting solution was stirred for 60 hours at room temperature. The addition of ether (60 ml) resulted in the formation of a precipitate which was further triturated with ether (50 ml) to give 1.88 g (84%) of the product.

MN H DMSO-d): 9.57-10.10? M, ZH), 8.26-8.55 (m, 1H), 3.08-4.37 (m, 16H), 1.87-2.04 (m, 12Hj., RM DMSO-d): I " 72.4, 170.9, 170.1, 150.1, 147.0, 144.4, 143.8, 141.9, 127.9, 100.1, 99.8, 99.6, 99.1, 97.7, 97.6, 97.4, 74.2, 70.4, 66.9, 66.8, 64.8, 64.4, 64.1, 43.1, 43.0, 37.9, 35.0, 21.8, 21.5 ms (ESP, m / e): 1656 (M ", 100%), 1679 ([M + Na] *, 80%). b. N, N '-b' s [2,4,6-triiodo-3- (2,3-dihydroxypropionyl-amido) -5- (2,3-dihydroxypropylaminocarbonyl) phenyljurea.

N, N'-bis [2,4,6-triiodo-3- (2, 2-d? Meth? -1,3-dioxalan-4-carboxamido) -5- (2,3-diacetoxy) was mixed. propylaminocarbonyl) phenyljurea (0.60 g, 0.36 mmol) with K CO (0.40 g, 2.8 mmol) in methanol (40 mL). The solution was stirred for 88 hours, the solution was filtered and the filtrate was evaporated to dryness. The residue was dissolved in water (20 ml) and the pH was adjusted to 2 using aqueous 2M HCl. After stirring for 3 hours, the solution was evaporated to dryness and the residue was purified by HPLC. Two isomeric fractions were separated and collected. Yield: 240 mg (fraction 1) + 45 mg (fraction 2); 56% l is physical, Fraction ?? -? ¿: Mso-d 9.67-9.90 (m, 2H! 8.23-8.60 > m, 4H), 3.06-3.34 (m, 16H), 4.02-4.20 (m, 8H). CMS-D-NMR): 171.0, 170.8, 1"? 0.3, 170.2, 151.8, 151. "?, 150.2, 144.3, 144.1, 143.9, 143.8, 108.1, 103. 0, 107.8, 99.5, 99.3, 99.2, 97.8, 97.6, 74.2, 70. 4, 64.7, 64.4, 43.2, 43.1. MS (ESP, m / e): 1408 (M \ 100%), 1431. { [M + Na] *, 10%).

Fraction 2: 9.62-10.05 (m, 2H), 8.25-8.60 (m, 4H), 5.65-5.90 (m, 2H), 4.62-4.90 (, 4H), 4.42-4.53 (m, 2H), 4.02-4.10 (m, 2H), 3.40-3.82 (m, 10H), 3.05-3.32 (m, 4H).

Example 14. N, N'-bis [2,4,6-triiodo-3-amino-5- (1,3-d? Acetoxy? Prop-2-ylamidocarbon? L) phen? L] urea to. N, N'-bis [3-n? Tro-5- (1, 3-dihydroxyprop-2-ylamino-carbonyl) phenyl] urea.

The reaction was performed analogous to the synthesis described above for Example 10c, starting from N, N'-bis (3-nitro-5-methoxycarbonyl-phenol) urea (12.0 g, 28.7 mmol) and serinol (6.83). g, 75 rr.ol). The crude reaction product was purified by trituration with acetonitrile (2 x 50 mL), with water 200 mL, and with acetonitrile (3 x 50 mL) to give the product 95% pure. Yield: 12.0 g (78%). 1 H NMR (DMSO-d.): 10.06, 9.72 (2, ArNH, 2H), 8.68-8.73 (m, 2H), 8.44-8.51 (m, 2H), 8.38-8.43 (m, 2H), 8.23-8.27. (m, 2H), 4.66-4.73 (m, 4H), 3.92-4.13 (, 2H), 3.44-3.60 (m, 8H). NMR - "C: 164.9, 164.6, 152.9, 148.6, 148.4, 141.9, 141.1, 137.0, 131.8, 124.9, 124.4, 117.1, 115.7, 115.3, 60.7, 54.8, 53.3.

N, N'-bis [2,4,6-triiodo-3-amino-5- (1, 3-hydroxyprop-2-ylaminocarbonyl) phenyl] urea.

N, N'-bis [3-nitro-5- (1,3-dihydroxyprop-2-ylaminocarbonyl) phenyljurea (5.6 g, 10.4 mmol) was dissolved in a mixture of methanol (100 ml) and water (14 ml) containing 2M aqueous HCl (10.4 ml) and a Pd / C catalyst (10%, 0.5 g). Hydrogenation was carried out at 4.22 kg / cirr (50 psi). The catalyst was filtered, the methanol was evaporated and the aqueous solution was lyophilized. The residue was dissolved in a mixture of methanol (36 ml) and water (775 ml) and then KIC1 (32.9 g, 97 mmol) was added. After the agitation by ~ 2 hours, a 2M aqueous solution of NaHSO was added. and the solide was "filtered." After washing the precipitate with methanol (3 x 50 mL), the residue was dried.

Yield: 13.9 g (75%). NMR i (DMSO-d.): 7.90-8.36 (m, 4H), 5.32-5.40 (m, 4K), 3.30-4.25 (m, 14H). NMR: 'C (DMSO-d.): 170.1, 151.9, 149.1, 148.9, 148.8, 146. 6, 143.1, 143.0, 88.8, 88.6, 83.0, 82.8, 81.5, 78. 7, 78.6, 78.5, 76.9, 59.8, 53.6, 53.5. MS (ESP, m / e): 1254 ([M + Na] 100%). c. N, N '-bis [2,4,6-triiodo-3-amino-5- (1,3-diacetoxy-prop-2-ylaminocarbonyl) phenyl] urea.

N, N'-bis [2,4,6-triiodo-3-amino-5- (1, 3-hydroxyprop-2-ylaminocarbonyl) phenyl] urea (4.0 g, 3.26 mmol) was suspended in a mixture of acetic anhydride (10 mL) and pyridine (10.5 mL) and the mixture was stirred for 16 h at room temperature. The solvents were evaporated and the residue was suspended in water (150 ml). The solid was filtered, washed with aqueous 0.1 M HCl (2 x 50 mL), water (2 x 50 mL) and dried. Yield: 3.8 g (84%).

? MM H, DMSO-d): 8.55-8.95 (m, 2H), 3.10-8.35 (m, 2 '? ", 5.36-5.63 (, 4H), 4.10-4.20 (m, 8H), 3.83-3.95 ( m, 2H), 1.99-2.07 (m, 12H), C NMR-DMSO-d.): 170.7, 170.2, 149.0, 148.9, 148.7, 143.3, 143.2, 143.1, 89.2, 82.8, 78.5, 73.3, 78.2, 62.6, 47.4, 21.3 MS (ESP, m / e): 1422 ([M + Na] *, 70%), 1478 ([M + C = H; N] *, 100%).

Example 15. N- [3-hydroxymethyl-5- (2,3-dihydroxy-propyl-aminocarbonyl) -2,4,6-triiodophenyl] -N '[3,5-bis (2,3-dihydroxypropylaminocarbonyl) -2 , 4, 6-triyodofeniljurea to. l-hydroxymethyl-3-nitro-5-benzoic acid methyl ester.

The monomethyl ester of 1-nitroisophthalic acid (22.5 g, 100 mmol) was dissolved in anhydrous THF (675 ml) and BF. Et 0 (25.2 ml, 200 mmol) was added. NaBH (5.1 g, 135 mmol) was then added in portions over 1 h. After stirring for an additional 2 h, ethanol (20 ml) was added slowly followed by water (200 ml) and diethyl ether (400 ml). The phases were separated and the aqueous phase was extracted once with diethyl ether (100 ml). The organic phases 32 The samples were washed with saturated aqueous NaHCC solution, dried (NaSO,) and evaporated. Yield 20 g (96%). HPLC analysis indicated a purity > 95% of the product.

NMR -H (CDC1): 8.72 (s, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 4.86 (s, 2H), 3.97 (s, 3H), 2.37 (broad s, 1H). b. l-hydroxymethyl-3-nitro-5- (2,3-dihydroxypropyl-aminocarbonyl) benzene.

The methyl ester of Example 3a (20.5 g, 97 mmol) was mixed with 2,3-dihydroxypropylamine (9.6 g, 106 mmol) and the mixture was heated to 90 ° C. After 45 m., The pressure was reduced to 200 mm Hg and the heating was continued for 2 h. The crude product, which had a purity > 95% according to the HPLC analysis was used without further purification in the next step. Yield 22.8 g (87%).

NMR: H (CD3OD): 8.57 (s, 1H), 8.38 (s, 1H), 8.19 (s, 8H), 4.77 (s, 2H), 3.81-3.88 (m, 1H), 3.39-3.63 (, 4H).

? J c. 3-hydroxymethyl-5- (2,3-dihydroxypropylamino) carbonyl; aniline.

L-hydroxymethyl-3-nitro-5- (2,3-dihydroxypropylaminocarbonyl) benzene (12.0 g, 44.4 mmoi) was hydrogenated in methanol (150 ral) at 4.22 Kg / crrr (60 psi) of H, using Pd / C ( 10%, 100 mg) as the catalyst. The catalyst was removed by filtration and the residue was evaporated. The addition of methane! (10 ml) precipitated the product as a white solid, which was filtered and dried. Yield: 6.6 g (62%).

NMR -H (CD-.OD): 7.05-7.09 (m, 1H), 6.98-7.03 (m, 1H), 6.83-6.87 (m, 1H), 4.53 (s, 2H), 3.77-3.85 (m, 1H), 3.8-3.59 (m, 4H), 3.32-3.42 (m, 1H) MS (ESP, m / e): 241 ([M + l] \ 100%). d. 3-hydroxymethyl-5- (2,3-dihydroxypropylamino-carbonyl) -2,4,6-triiodoaniline. 3-Hydroxymethyl-5- (2,3-dihydroxypropylaminocarbonyl) aniline (500 mg, 2.1 mmol) was dissolved in water (175 ml) and an aqueous solution of KIC1 was added; (70%, w / w) in 0.1 ml portions for 8 h. A total amount of 1.0 ml of KIC1 solution was added. After a total reaction time of 6 hours, the solution was extracted with ethyl acetate. { i: J ^ 1 'which was separated and washed with a Na S0 solution (0.2 M, 100 ml). Evaporation followed by purification by preparative HPLC gave 432 mg (33%) of the pure product.

NMR -H (CD ^ OD): 5.10 (s, 2H), 3.90-3.98 (m, 1H), 3.72 (ddd, J; = 0.7 Hz, J- = 4.2 Hz, J, = 11.4 Hz), 1H) , 3.60 (dd, J- = 6.0 Hz, J_ = 11.4, 1H), 3.49 (ddd, J; = 1.2 Hz, J2 = 6.0 Hz, J, = 13.5 Hz, 1H), 3.37 (ddd, J: = 1.2 Hz, Jt = 6.1 Hz, J = 13.2 Hz, 1H), 2.62 (s, 1H), 2.28 and 2.34 (2s, 2H). MS (ESP, m / e): 618 (M ', 100%), 640 ([M + Na] 55%). and. 3-acetoxymethyl-5- (2,3-diacetoxypropyl aminocarbonyl) -2,4,6-triiodoaniline. 3-Hydroxymethyl-5- (2,3-dihydroxy-propylaminocarbonyl) -2,4,6-triiodoaniline (1.32 g, 2.1 mmol) was dissolved in pyridine (10 mL) containing acetic anhydride (10 mL). The mixture was stirred at room temperature for 2 h and methylene chloride (100 ml) was added and the solution was washed with water (3 x 25 ml). The organic phase was washed with water (3 x 50 ml) and a saturated aqueous solution of NaHCO. (2 x 50 mi).

After drying (NaSO;) and evaporation, the residue was purified by flash chromatography on a silica column using a mixture of methylene chloride and methanol (95: 5) as the eluent. Yield: 1.30 g (82%).

H NMR (CDC1.): 5.99 (broad s, 1H), 5.52 (s, 2H), 5.25 (broad s, 1H), 5.11 (s, 2H), 4.23-4.45 (m, 2H), 3.56-3.87 ( m, 3H), 2.08 (s, 9H). f. N- [3-acetoxymethyl-5- (2,3-diacetoxypropylaminocarbonyl) -2,4,6-triiodophenyl] -N '- [3,5-bis (2,3-diacetO? Ipropylaminocarbonyl) -2,4 , 6-triiodophenyl] urea. 3,5-bis (2,3-diacetoxypropyl-aminocarbonyl) -2,4,6-triiodoaniline (260 mg, 0.30 mmol) was dissolved in dioxane (1.0 ml) and a solution of phosgene in toluene (1.93 M, 1.8 mi). The flask was hermetically sealed and then heated to 60 ° C for 17 h. After cooling to room temperature, the solvent was distilled under reduced pressure. Dioxane (3 mL) was added and distilled again. This procedure was repeated twice. Dioxane added (1 ml) followed by 3-acetoxymethyl-5- (2,3-diacetoxypropyl aminocarbonyl) -2,4,6-triiodoaniline '"1,245 g, 0.31 mmol! And Hg (OCOCF.) (20 mg). The mixture was stirred for 16 h at room temperature, the solvent was evaporated and the residue was purified by preparative HPLC Yield: 0.192 g (39%) MS (ESP, m / e): 1643 (m ", 100%), 1665 ([ M + Na] ", 34%). g. N- [3-hydroxymethyl-5- (2,3-dihydroxypropyl lamino-carbonyl) -2,4,6-triiodophenyl] -N '- [3,5-bis (2,3-dihydroxypropylaminocarbonyl) -2,4, 6-triiodophenyljurea.

The product of Example 15f was dissolved in a mixture of methanol (5 ml) and water (5 ml) and the pH was adjusted to 12 using a 2M aqueous solution of NaOH. After stirring for 2 hours, the pH was adjusted to 6.5 using aqueous HCl and the solvents were evaporated. Yield: 68 mg (44%). MS (ESP, m / e): 1349 (M ', 15%), 1372 ([M + Na], 100%).

Example 16 • 2,4,6-triiodo-3-acetylamino-5- • a, 3-dihydroxy-prop-2-ylaminocarbonyl) phenylaminocarboni-2 ', 4', 6'-triiode -3 '-aceti lamino-5' - (1,3-dihydroxyprop p-2-ylaminocarbonyl) encene to. 1-nitro-3-amino-5-benzoic acid methyl ester hydrochloride.

L-Nitro-3-aminobenzoic acid (II g, 82.5 mmol) was dissolved in methanol (100 mL) and HCl gas was bubbled into the solution for 30 min. After stirring for 17 h at room temperature, the solvent was evaporated and the residue was washed with ether (3 x 50 mL) to give the product as a white solid. Yield: 15.3 g (82%).

NMR "'H (DMSO-d,): 7.73-7.81 (m, 1H), 7.68-7.71 (m, 1H), 7.65-7.67 (m, 1H), 5.00 (s, NH3, 3H) 3.83 ( s, OCH, 3H). b. 3-Nitro-5-methoxycarbonylphenylaminocarbonyl- (3'-nitro-5'-methoxycarbonylbenzene).

The hydrochloride of l-nitro-3-amino-5-benzoic acid methyl ester (0.92 g, 4.72 mmol) and the monomethyl ester of 5-nitroisocalic acid (1.06 g, 4.27 mmol) were suspended in a POCl3 mixture ( 4 ml) and toluene (15 ml). The mixture was heated until the solution was homogeneous and then, the solution was stirred for 16 h at room temperature. The solvents were evaporated and the oily residue was dissolved in methylene chloride. The solution was washed: cn 0.1 M aqueous HCi (3 x 50 ml) and with a saturated aqueous solution of NaHCO. (50 ml), treated with mineral carbon, dried (magnesium sulfate) and evaporated. The product was essentially pure by HPLC analysis. Yield: 1.25 g (66%). NMR 'H (DMSO-d.): 11.28 (s, 1H), 9.09 (t, J = 1.8 Hz, 1H), 9.03 (t, J = 1.8 Hz, 1H), 8.95 (t, J = 1.7 Hz, 1H), 3. 81 (t, J = 1.6 Hz, '1H), 8.78 (t, J = 1.7 Hz, 1H), 8.38 (2t, J; = 1.6 Hz, J = 1.5 Hz, 1H), 3.96 (s, OCH, 3H), 3.93 (s, OCH, 3H). MS (ESP, m / e): 426 ([M + Na] 100%, 442 ([M + K] t, 14%). c. 3-Nitro-5- (1, 3-dihydroxyprop-2-ylaminocarbonyl) -phenylaminoca bonyl- [3'-nitro-5 '- (1,3-dihydroxoprop-2-ylaminocarbonyl) benzene]. 3-Nitro-5-methoxycarbonyl-phenyl-aminocarbonyl- (3'-nitro-5 '- (1,3-methoxycarbonyl-benzene) (0.40 g, 1.0 mmol) and serinol (0.23 g, 2.5 mmol) were mixed and heated at 95 ° C. After 30 min, the pressure was reduced to 200 mm Hg and the heating was continued for 3 h.The reaction mixture was purified by preparative HPLC Yield: 0.27 g (52%).

NMR H-DMSO-d): 11.2 (broad s, 1H), 8.94-8.98 (m, Z '?), 3.39-3.92 (m, 2H), 8.61-8.65 (m, 1H), 8.61 (d, J = ".2 Hz, 1H *, 3.52-3.55 (, 1H), 8.46 (d, J = 7.8 Hz, IH1, 4.60-4.31 (m, 4H), 3.96-4.08 (m, 2H), 3.51-3.59; m, 3H) MS (ESP, m / e): 522 (M \ 100%), 504 ([MH.O] *, 65%). d. 3-amino-5- (1,3-dihydroxyprop-2-ylaminocarbonyl) phenylammocarbonyl- [3 '-amino-5' - (1,3-dihydroxyprop-2-ylaminocarbonyl) benzene] dihydrochloride]. 3-Nitro-5- (1,3-dihydroxyprop-2-ylaminocarbonyl) phenylaminocarbonyl- [3'-nitro-5 '(1,3-dihydroxyprop-2-ylaminocarbonyl) benzene] (1.03 g, 1.98 mmol) was hydrogenated in a solution containing methanol (40 ml), concentrated HCl (2 ml), water (2 ml) and a Pd / C catalyst (10%, 0.2 g) at 4.22 kg / cm- (60 psi). The catalyst was filtered and the solvent was evaporated. Water (150 ml) was then added and the solution lyophilized. Yield: 0.98 g (93%).

NMR -H (DMSO-d containing 1% TFA): 10.83 (s, 1H), 8. 25 (d, J = 8.0 Hz, 1H), 8.23 (t, J = 2.0 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.07 (t, J = 2.0 Hz, 1H), 8.03 (t, J = 2.0 Hz, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.70 (t , J = 2 Hz, 1H), ^ .46 (t, J = 2.0 Hz, 1H), 4.30 (s broad, 6H), 3.95-4.01 (, 2H), 3.54 (t, J = 5.5 Hz, 3H) . M3? SP, m / e) *: 461 (M ", 100%). and. 3-amino-2,4,6-triiodo-5- (1,3-dihydroxyprop-2-aminocarbonyl) phenylaminoca bonyl- (3'-amino-2'-4'-6'-triiodo-5 '- (1 , 3-dihydrox? Prop-2-yl aminocarbonyl) -benzene].

The 3-amino-5- (1,3-dihydroxyprop-2-ylaminocarbonyl) phenyl ami or -carbonyl- [3'-amino-5 '- (1,3-dihydroxyprop-2-ylaminocarbonyl) benzene dihydrochloride was dissolved] (0.50 g, 0.94 mmol) in a mixture of methanol (225 ml) and water (675 ml) and the pH was adjusted to 2.0 with aqueous HCl. KIC1 added (1.91 g, 5.64 mmol) and the solution was stirred at 40 ° C. Added a portion of KIC1; (0.1 g) after 24 h, and then 48 h, the reaction was terminated by the addition of an aqueous solution of NaHSO. After evaporation of the solvents, the residue was purified by preparative HPLC. Yield: 0.05 g (8.3%). H-NMR (DMSO-dβ): 9.85-10.05 (m, .H), 8.87-9.00 (m, 1H), 7.80-8.15 (m, 1H), 5.52 (s, H ^, 2H), 5.47 (s, NH, 2H), 4.40 (t, J = .0 Hz, 2H), 4.15-4.24 (m, 2H), 4.06, d, = 7.0 Hz, 1H), 4.04 (d, J = 7.0 Hz, 1H), 3.78-3.35 'm, 3H), 3.57-3.64 (m, 3H), 3.40-3.56 (m, 2H). PMN C 'DMSO-d.): 170.3, 170.2, 165.7, 150.0, 149.9, 149.6, 148.9, 148.1, 143.0, 147.5, 141.7, 64.2, 59.7, 53.4. MS (ESP, m / e): 1215 (M, 100%).

F. 3-acetylamino-2,4,6-triiodo-5- (1,3-dihydroxyprop-2-laminocarbonyl) phenylaminocarbonyl- [3'-acetylamino-2 ', 4', 6'-triiodo-5 '(1, 3-dihydroxyprop-2-ylammo-carbonyl) benzene]. 3-Amino-2,4,6-triiodo-5- (1,3-dihydroxyprop-2-ylaminocarbonyl) phenylaminocarbonyl- [3'-amino-2 ', 4', 6'-triiodo-5 '- ( 1,3-dihydroxyprop-2-ylaminocarbonyl) benzene] (75 mg, 0.062 mmol) in acetic anhydride (0.6 ml) containing concentrated sulfuric acid (0.04 ml). The mixture was heated at 60 ° C for 75 min. and, after cooling, the solvent was evaporated. The dark residue was dissolved in a mixture of methanol (0.35 ml) and water (0.15 ml), the pH was adjusted to 10-11 using 2 M NaOH and the solution was stirred at 50 ° C for 5 h. After cooling to room temperature, the pH was adjusted to 7 with aqueous 2M HCl, and the solvent was evaporated. The residue was purified by preparative HPLC. Yield: 0.076 g (94%).

PMN -H (DMSO-d.): 10.27-10.48 (m, 1H), 9.97 (broad s, 1H), 9.94 (broad s, 1H), 8.21 (d, J = 7.0 Hz, 1H), 8.11 'd , J = 7.0 Hz, 1H), 4.43-4.56 (m, 4H), 3.72-3.88 (m, 2H), 3.60-3.70 (m, 4H), 3.40-3.60 (m, 4H), 2.07-2.08 (m , 6H). 3 C-NMR (DMSO-d.): 169.9, 169.7, 168.2, 165.2, 151.0, 148.4, 144.7, 144.6, 144.3, 144.2, 142.8, 142.7, 59.6, 59.5, 53.6, 31.1. MS (ESP, m / e): 1399 (M ~, 100%).

Example 17. 2, 4,6-triiodo-3-hydroxyacetylamino-5- (1,3-dihydroxyprop-2-ylaminocarbonyl) phenylaminocarbonyl-2 ', A', 6 '-triyodo-3'-hydroxyacetylamino-5' - ( 1,3-dihydroxyprop-2-ylaminocarbonyl)] benzene to. 2,4,6-triiodo-3-amino-5- (1,3-diacetoxyprop-2-ylaminocarbonyl) phenylaminocarbonyl-2 ', 4', 6'-triiodo-3'-amino-5 '- (1, 3 -diacetoxiprop-2-ylaminocarbonyl)] -benzene. 3-Amino-2,4,6-triiodo-5- (1,3-i? -hydroxyprop-2-ylaminocarbonyl) phenyl aminocarbonyl- [3'-amr.c-2 ', 4', 6 '-tri-cydo was prepared -5 '- (1, 3-dihydroxyprcp-2-mocarbonyl) benzene] (0.10 g, 0.082 mmol) as described in Example 15, was dissolved in a mixture of acetic anhydride (5 ml) and pyridine (5.5 ml). ). The mixture was stirred at 40-45 ° C for 6 h, the solvents were evaporated and the residue was dissolved in ethyl acetate (25 ml). After washing with water (25 ml), 0.5 M aqueous HCl, water and saturated aqueous NaHCO- solution, the solution was dried (magnesium sulphide) and the solvent was evaporated. Yield: 0.11 g (100%).

RMN -H! DMSO-d.-): 9.94-10.04 (m, 1H), 8.67 (d, J = 7.0 Hz, 1H), 8.65 (d, J = 7.0 Hz, 1H), 5.54 (s, NH2, 2H), . 50 (s, NH, 2H), 4.27-4.40 (m, 2H), 4.11.4.16 (m, 3H), 2.01-2.03 (m, 12H). NMR: C (DMSO-cU): 170.7, 170.4, 170.3, 165.7, 149.6, 149. 5, 149.0, 148.2, 147.6, 141.8, 62.6, 47.4, 21.3. MS (ESP, m / e): 1385 (M *, 100%). * b. 2,4,6-triiodo-3-hydroxyacetylamino-5- (1,3-dihydroxypropyl-2-ylaminocarbonyl) phenylaminocarbonyl-2 ', 4', 6'-tri- iodo-3 '-hydroxyacet i lamino-5' - (1,3-dihydroxyprop-2-ylaminocarbonyl) benzene. 2, 4, 6-tr? And cdo-3-aminc-5- (1,3-d-acetoxy-op-2-ylaminocarbonyl) phenylaminocarbonyl-2 ',', 6'-tri-iodo-3 '-amino-5 was suspended '- (1, 3-diacetoxoprop-2-ylcarbonyl)] benzene (94 mg, 0.068 mmol) in acetoxyacetyl chloride (3 ml) and the mixture was stirred at 65 ° C for 4 h, allowed to cool and then It vanished. The residue was dissolved in a mixture of methanol (3 mL), water (3 mL) and 1M aqueous NaOH (0.50 mL) and the solution was stirred for 3 h. The solution was neutralized using a strongly acidic cation exchange resin and the solvents were evaporated. The residue was purified by preparative HPLC. Yield: 90 mg (100%). MS (ESP, m / e): 1582 (M \ 100%).

Example 18_, 2,4,6-triiodo-3-acetylamino-5- (2,3-dihydroxypropylaminocarbonyl) phenylaminocarbonyl-2 ', 4', 6'-triiodo-3'-acetylamino-5 '- (2,3- dihydroxypropylaminocarbonyl)] benzene to. 3-Nitro-5- (2,3-dihydroxypropylaminocarbonyl) -phenylaminocarbonyl- [3'-nitro-5 '- (2,3-dihydroxypropyl-1-aminocarbonyl) benzene] 3-nitro-5-r > ethanol rbonyl feni lami nocarbonyl- (3'-nitro-5'-methoxycarbonylbenzene) (1.21 g, 3.0 mmol) in ammonopropane-2,3-diol (0.55 g, 6.0 mmol) and the mixture was heated to 90 ° C . After 30 min., The pressure was reduced to 200 mm Hg and heating was continued for 90 min. The product was purified by preparative HPLC. Yield: 0.73 g (47%).

NMR -H (DMSO-d.): 11.32 (s, 1H), 9.02 (t, J = 6.0 Hz, 1H). 8.93-8.97 (m, 3H), 8.88 (t, J = 1.7 Hz, 1H), 8.86 (t, J = 6.0 Hz, 1H), 8.68 (t J = 1. 5 Hz, 1H), 8.51 (t, J = 1.8 Hz, 1H), 3.62-3.72 (m, 2H), 3.36-3.48 (m, 2H), 3.33-3.36 (m, 4H), 3.18-3.29 (m, 2H), 3.09 (s, 4H) . MS (ESP, m / e): 545 ([M + Na] ', 65%), 522 (M \ 100%), 504 ([M-18] \ 19%). b. 3-amino-2,, 6-triiodo-5- (2,3-dihydroxypropylamino-carbonyl) phenylaminocarbonyl- [3'-amino-2'-4'-6'-triiodo-5 '- (2,3-dihydroxypropyl) ilaminocarbonyl) benzene]. 3-Nitro-5- (2,3-dihydroxy-prcpylaminocarbonyl) phenylaminocarbonyl- [3'-nitro-5 '- (2,3-dihydroxypropyl-aminocarbonyl) benzene] (2.0 g, 2.0 mmol) was hydrogenated in a solution which it contained methanol (70 ml), concentrated HCl (4 ml), water (4 ml) and a catalyst Pd / C (10%, 0.6 g) at 4.22 kg / crtr (60 psi). The catalyst was filtered and the solvent evaporated. Water (150 ml) was then added and the solution lyophilized. Yield: 2.0 g (98%). The crude product was used immediately without purification in the next step: The product was dissolved in a mixture of methanol and water (1: 3, 1200 ml) and an aqueous solution of KICl was added. (5.34 g, 22.6 mmol). The reaction mixture was stirred at 40 ° C for 30 h and then a 0.5 M aqueous solution of NaHSO: (1 mL) was added. After evaporation of the solvents, the residue was purified by preparative HPLC. Yield: 0.63 g (13).

NMR -H (DMSO-d,): 9.86-10.00 (m, 1H), 8.18-8.45 (m, 2H), 5.44-5.47 (, 4H), 4.66.4.78 (m, 2H). , 4.45-4.55 a, 2H), 3.59-3.78 (m, 2H), 3.41-3.56 (m, 2H), 3.30-3.43 (, 2H), 3.10-3.36 (m, 2H). NMR: 3C (DMSO-d .;): 170.7, 165.6, 149.9, 148.5, 147.8, 147.1, 140.8, 108.0, 85.2, 84.4, 80.9, 79.2, 78.3, 70.0, 64.0, 42.6. MS (ESP, m / e): 1216 (M \ 100%), 1238 ([M + Na] \ 20%. < > 7 c. 2, 4,6-riodo-3-acetylamino-5- (2,3-d? -hydroxypropyl-ammocarbonyl) phenylaminocarbonyl-2 ', 4', 6'-triiodo-3'-acet? Amiam-5 '- ( 2, 3-dihi roxipropi laminocarbcnil)] -benzene. 3-Amino-2,4,6-triiodo-5- (2,3-dihydroxypropyl-laminocarbonyl) phenylaminocarbonyl- [3'-amino-2 ',', 6'-triiodo-5 '- (2, 3) was dissolved dihydroxypropyl laminocarbonyl) benzene] (100 mg, 0.082 mmol) in acetic anhydride (7 mL), a drop of concentrated sulfuric acid was added and the mixture was stirred at 60 ° C for 1.5 h. The solvent was evaporated and the residue was dissolved in a mixture of methanol and water (3: 1, 10 ml) and the pH was adjusted to 13 with a 2M aqueous NaOH solution. The mixture was stirred for 16 h at 50 ° C, diluted with water. { 20 ml) and the pH was adjusted to neutral using a strongly acidic ion exchange resin. The solvents were removed by evaporation and the residue was purified by preparative HPLC. Yield: 75 mg (71%). MS (ESP, m / e): 1301 (M *, 81%), 1324 ([M + Na] ~ m 100%.

Example 19, 2, 4, 6-triiodo-3-hydroxyacetylamino-5- (2, 3-1 ihi drox ip rcp 11 ami nocar bon i 1) fen i 1a inocarboni 1 -2 ',', 6- t iyodo- 3 '-hydroxyacetylamino-5' - (2,3-dihydroxypropyl aminocarbonyl) benzene to. 2,4,6-triiodo-3-amino-5- (2,3-di-acetoxypropylaminocarbonyl) phenylaminocarbonyl-2 ', 4', 6'-triiodo-3'-amino-5 '- (2,3-diacetoxypropyl) aminocarbonyl)] benzene. 3-Amino-2,4,6-triiodo-5- (2,3-dihydroxypropylaminocarbonyl) phenylaminocarbonyl- [3'-amino-2 ', 4', 6 ', tri iodo-5'- (2, 3-dihydroxypropylamino-carbonyl) benzene] (100 mg, 0.82 mmol) according to Example 17, was dissolved in a mixture of acetic anhydride (2 ml) and pyridine (2 ml). The mixture was stirred at room temperature for 17 h, the solvents were evaporated and the residue was dissolved in ethyl acetate (50 ml). After washing with an aqueous solution of HCl (0.1 M, 25 ml), a saturated aqueous solution of NaHCO 5, drying with sodium sulphate and evaporation, the residue was purified by preparative HPLC. Yield: 100 mg (88%).

NMR: H (DMSO-d,): 9.89-10.27 (m, 1H), 8.56-8.70 (m, 2H), 5.54 (s, 2H), 5.51 (s, 2H), 5.06-5.13 (m, 2H) , 5-4 im, 2H) 4.16-4 (m,: H) 3.30-3.5í .m,4H-, 2.02 s, 12H). MS: ES ?, / e): 1335 (m \ 100; 1464 ([m + pyridine] t, 19,. b. 2,4,6-triiodo-3-hydroxyacetylamino-5- (2,3-dihydroxypropylaminocarbonyl) phenylaminocarbonyl-2 ', 4', 6'-triiodo-3 '-hydroxyacetylaminc-5' - (2,3, -dihydroxypropylaminocarbonyl) ]benzene. 2,4,6-Triiodo-3-amino-5- (2,3-diacetoxypropylaminocarbonyl) phenylaminocarbonyl-2 ', 4', 6'-triiodo-3'-hydroxyacetylamino-5 '- (2,3-dihydroxypropylaminocarbonyl) was dissolved. )] benzene (35 mg, 0.025 mmol) in acetyl: xiacetyl chloride (1 ml) and the mixture was heated at 70 ° C for 1.5 h. After cooling to room temperature, the solvent was evaporated and the residue was dissolved in a mixture of methanol and water (3: 1, 1 ml). A 1M aqueous solution of NaOH (0.23 ml) was added, and after stirring for 15 min. Water (20 ml) was added and the solution was neutralized with a strongly acidic ion exchange resin. The solvents were evaporated and the residue was purified by preparative HPLC. Yield: 14 mg (61%). MS (ESP, m / e): 1332 (pT, 100%). _ ~ ^ rr.plo 20. 2, 4, 6-triiodo-3- (2-hydroxypropicni lamino) - ~ - 2, 3-dihydroxypropylaminocarboni 1) phenylaminocarbonyl-2 ', 4', 6 '-tri odo-3' - (2-hydroxypropionylamino) -5 '- ?, 2,3-dihydroxypropylaminocarbonyl) benzene 2,4,6-triiodo-3-amino-5- (2,3-diacetoxypropylaminocarbonyl) phenylaminocarbonyl-2 ', 4', 6'-tri- iodo-3'-amino-5 '- (2,3) was dissolved. diacetoxip-phenylaminocarbonyl) J-benzene (100 mg, 0.072 mmol) in α-acetoxypropionyl chloride (1 mL) and the mixture was stirred at 40 ° C for 17 h. The solvent was evaporated and the residue was suspended in a mixture of methanol and water (1: 1, 4 ml). An aqueous solution of NaOH (1M, 0.5 ml) was added and the solution was stirred for 5 h. Water (20 ml) was added and the pH adjusted to neutral using a strongly acidic cation exchange resin. The solvent was evaporated and the residue was purified by preparative HPLC. Yield: 33 mg (43%).

NMR 'H (DMSO-d.-): 10.16-10.55 (m, 1H), 9.54-9.86 (, 2H), 8.40-8.65 (m, 2H), 5.60 (broad s, 2H), 4.70 (broad s, 2H), 4.46 (broad s, 2H), 4.08-4.22 (m, 2H), 3.60-3.71 (m, 2H), 3.32-3.58 (m, 2), 3.15-3.32 (m, 2H), 3.04-3.22 (m, 4H), 1.39 (d, J = 7.0 Hz, 6H).

? MN "" c (DMSO-d.): 172.4, 170.0, 169.8, 169.7, 150.7, 1 8.0, 143.3, 143.2, 143.1, 142.3, 104.6, 100.8, 100.2, 100.0, 99.8, 97.2, 96.9, 95.0, 90.7 , 90.5, 69.3, 67.6, 64.0, 42.7, 21.0. MS (ESP, m / e): 1361 (M ~, 100%), 1383 ([M + Na] *, 25%.

Example 21. Di [2, 4, 6-triiodo-N, '- (2, 3-dihydroxy-propyl) -3,5-acetylamino-phenyl ether to. 3, 5-dinitroanisol.

Sodium (575 mg, 25 mmol) was dissolved in absolute methanol (100 mL). Then 1,3,5-trinitrobenzene (4.26 g, 20 mmol) was added and the solution was stirred overnight. After evaporation of the solvent, water was added and the precipitate was filtered, washed with water and dried. The material was used without further purification in the next step. Yield: 3.4 g (86%).

NMR: H (CDC1: 8.65 (t, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 2H), 4.01 (s, 1H). b. 3, c-di itrofe oi They were heated at reflux temperature for 16 h 3, 5-dinitroanisole (1.36 g, 6.9 mmol) and concentrated aqueous HBr (50 mL). After cooling to room temperature, the solid precipitate was filtered, washed with water and dried. Yield: 325 mg (25%).

NMR '-H (CDC1.): 8.64 (t, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 2H), 2.0 (broad s, 1H). c. 3, 5-diacetylaminophenol. 3,5-Dinitrophenol (325 mg, 1.77 mmcl) was dissolved in glacial acetic acid (20 ml) and hydrogenated at 4.22 kg / cm- (60 psi) using a Pd-C catalyst (10%, 50 mg). The reaction mixture was filtered and acetic anhydride (2 mL) was added. The solution was heated to 100 ° C and then allowed to cool again. The solvents were removed by evaporation and the residue was purified by chromatography on silica gel using a mixture of methanol and ethyl acetate (10:90) as the eluent. Yield: 90 mg (24%).

NMR -H 'CD OD): 7.24 (t, J = 2.0 Hz, 1H), 6.92 (d, J = 2.0 Hz, 2H), 2.12 (S, 6H). d. 3, 5-dinitrophen-l-3 ', 5'-diacetylaminophenyl ether. 3, 5-Diacetylaminophenol (90 mg, 0.43 mmol) and t-in trobenzene (0.111 g, 0.52 mmol) were dissolved in anhydrous DMF (10 mL) and K C03 (0.124 g, 0.90 mmol) was added. After stirring for 17 h, water (20 mL) was added and the solution was extracted with ethyl acetate. After washing with water (2 x 10 ml), drying (sodium sulfate), and evaporation of the solvent, the residue was purified by chromatography on silica gel using ethyl acetate as the eluent. Yield: 0.121 g (75%). MS (ESP, m / e): 375 ([m + 1] *, 100%), 397 ([M + Na], 39%), 413 ([M + K] 35%). e. Di (3,5-diacetylaminophenyl) ether 3,5-Dinitrophenyl-3 ', 5'-diacetylaminophenylether (0.12 g, 0.32 mmol) was dissolved in glacial acetic acid (5 mL) and heated to reflux temperature. Iron powder (0.3 g) was added in portions for 5 min. After heating at reflux for 2 h, the solution was allowed to cool to room temperature, acetic anhydride (1.5 ml) was added, and the heating was continued for another 2 h The solvents were then removed by evaporation, the residue was treated with acetate The ethyl acetate was filtered and evaporated, the residue was dissolved in acetone and the solution was filtered through a pad of silica gel.The evaporation of the solvent gave 84 mg (56%) of the product.

NMR -H (CD.OD): 7.62 (s, 2H), 7.08 (s, 4H), 2.12 (s, 12H). MS (ESP, m / e): 399 ([M + 1 J ~, 62%), 421 ([M + Na] +, 41%), 437 ([M + K] *, 100%).

Di (3,5-diacetylamino-2,4,6-triiodophenyl) ether The iodination of di (3,5-diacetyl inophenyl) ether was carried out using standard procedures for the iodination of the activated aromatic compounds, for example, using KIC1¿ in an aqueous solution or in a mixture of water and an alcohol as it is described in the literature (see for example EP-AS-501875 and DE-A-2629228). The purification of the product is carried out by chromatography or recrystallization. g. Di [2,4,6-triiodo-N, N '- (2,3, -dihydroxypropyl) -3,5-acetylaminophenyl] ether.

The alkylation of di (3,5-diacetylamino-2,4,6-triiodophenyl) ether is carried out analogously to similar reactions described in the literature, for example using sodium methoxide as the base, in a suitable solvent such as propylene glycol, and 3-chloropropane-1,2-diol (see, for example: US 4250113). The product is purified by preparative HPLC.

Example 22, Di [3-hydroxyacetylamino-5- (2,3-dihydroxypropylaminocarbonyl) -2,4,6-triiodophenyl] -methanol to. Di (3-acetylphenyl) ketone.

Acetophenone (57.6 g, 0.48 mmol) and A1C1, (160 g, 1.2 mol) were mixed and heated to 100 ° C under an argon atmosphere for 30 min. After cooling to room temperature, carbon tetrachloride (300 ml) was added and the mixture was heated at reflux temperature for 4 h After cooling to room temperature, a mixture of water and concentrated HCl (300 ml, 1 ml) was added. 1) The aqueous phase was extracted with chloroform (3 x 200 ml) and the combined organic phases were evaporated The residue was dissolved in 70% ethanol (400 ml) and the solution briefly heated to reflux temperature. Evaporation of the solvents followed by recrystallization from aqueous acetone gave the pure product Yield: 49.9 g (77%) - NMR -H (CDC1.): 8.36 (t, J = 1.5 Hz, 2H), 8.20 (dt, J; = 7.8 Hz, J- = 1.5 Hz, 2H), 7.98 (dt, J3 = 7.7 Hz, J- = 1.5 Hz, 2H), 7.62 (t, J = 7.7 Hz, 2H), 2.65 (s, 6H). MS (ESP, m / e): 268 (M +, 100%). b. Di (3-nitro-5-carboxyphenyl) ketone.

The Di (3-acetylphenyl) ketone (60.0 g, 0.224 mol) was dissolved in concentrated sulfuric acid (400 ml) and the solution was cooled to 0 ° C. A mixture of concentrated sulfuric acid was then added dropwise (120 ml) and concentrated nitric acid (120 ml) and the solution was then stirred at room temperature for 17 h. After stirring for another 24 h at 40 ° C per h h at 0 ° C, the reaction mixture was emptied on ice and the precipitate was collected, washed with water and dried. Yield: 77.6 g (96%).

NMR -H 'DMSO-d.): 8.83 (t, J = 1. 8 Hz, 2H), 8.67 (t, = 1.8 Hz, 2H), 8.57 (t, J = 1.8 Hz, 2H), 3.9 (s) broad, 2H). MS (ESP, m / e): 359 ([M-l] ~, 100%). c. Dimethyl ketal of the dimethyl ester of di (3-nit ro-5-carboxyphenyl) ketone Di (3-nitro-5-carboxyphenyl) ketone (10.0 g, 28 mmol) was dissolved in methanol (250 ml) containing concentrated sulfuric acid (20 ml) and the solution was heated at reflux temperature for 17 h. The solvent was evaporated, water (70 ml) and ethyl acetate (300 ml) were added and the organic phase was separated and dried. After evaporation of the solvent, the residue was dissolved in tetrahydrofuran containing potassium carbonate (3.87 g, 28 mmol) and iodoform (5.0 ml) and the solution was stirred at room temperature for 70 h. The reaction mixture was filtered and evaporated to dryness and the residue was purified by preparative HPLC. Yield: 2.6 g (25%).

NMR "H (CDC1): 8.76-8.78 (m, 2H), 8.58 (t, J = 1.7 Hz, 2H), 8.41 (t, J = 1.6 Hz, 2H), 3.98 (s, 6H), 3.19 (s) , H) MS (El, m / e): 403 ([M-OCH.] 100%). d. Di [3-nitro-5- (2,3-dihydroxypropylaminocarbonyl) -phen?] Ketone.

The dimethyl ketal of the dimethyl ester of di (3-n-tro-5-carboxyphenyl) ketone (1.0 g, 2.3 mmol) in methanol (3.0 ml) containing aminopropane-2,3-diol (0.34 g, 9.2 mmol ) and the mixture was heated to 95 ° C for 2.5 h at 200 mm Hg. After cooling to room temperature the solvent was removed by evaporation and the residue was purified by HPLC. Yield: 0.78 g (67%).

NMR; H (DMSO-d6): 9.03-9.15 (m, 2H), 8.90-9.03 (m, 2H), 8.58-8.73 (m, 4H), 4.38 (broad s, 2H), 4.12 (broad s, 2H) ), 3.61-3.70 (m, 2H), 3.39-3.48 (m, 2H), 3.35 (broad s, 2H), 3.33 (broad s, 2H), 3.15-3.26 (m, 2H).

? MN C (DMSO-d.): 163.9, 143.3, 138.1, 137.9, 136.9, 134.1, 126.9, 126.4, 70.5, 64.3, 43.8. M? ES? ", M / e" /: 504 (M ~, 100%). and. D? [3-amino-5- (2,3-dihydroxypropyl) laminocarboni 1) -phenyl-1-methanol.

Di [3-nitro-5- (2,3-dihydroxypropylammocarbonyl) phenyljketone (0.70 g, 1.4 mmol) was dissolved in methanol (40 mL) and hydrogenated at 4.22 kg / cm 2 (60 psi) using a Pd / catalyst. C (10%, 0.20 g). The catalyst was filtered and the solvent was evaporated. Analysis by H-NMR indicated complete conversion to the product Yield: 0.62 g (100%).

NMR -H (DMSO-dí): 8.36-8.57 (m, 1H), 7.77-8.35 (m, 3H), 7.04-7.72 (m, 4H), 5.62-5.75 (m, 1H), 5.10 (s broad, 1H), 4.23 (broad s, 1H), 4.06 (broad s, 2H), 3.60-3.85 (m, 4H), 2.91-3.40 (m, 10H). MS (ESP, m / e): 449 (M ", 100%).

F. Di [3-amino-5- (2,3-dihydroxypropylaminocarbonyl) -2,4,6-triiodophenolylmethanol.

The iodination of d [3-amino-5- (2,3-dihydroxy) propylaminocarbonyl) phenyl] methanol is carried out using the standard procedures for the iodination of the active aromatic compounds, for example using KIC1 in an aqueous solution or in a mixture of water and an alcohol, as described in the literature (see for example EP-A-501875 and DE-A-2629223). The purification of the product is carried out by chromatography or recrystallization. g. Di [3-hydroxyacetylamino-5- (2,3-dihydroxypropyl-aminoca bonyl-2,4,6-triiodophenyl) methanol.

Acylation of d [3-amino-5- (2,3-dihydroxypropylaminocarbonyl) -2,4,6-triiodophenyl] methanol using acetoxyacetyl chloride is carried out analogously to Example 19b. The crude product is then hydrolyzed with aqueous NaOH. The product is purified by HPLC.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (14)

1. A compound of the formula I (characted in that each C.R5 portion may be the same or different, each R denoting a hydrogen or iodine atom or an M group, two or three non-adjacent R groups on each CR portion denote iodine atoms, and one or two R groups on each C0 5 portion denote M groups; X denotes a group that provides a chain of 1, 2 or 3 atoms that is linked to the two groups CORR ^; and each M is independently a nonionic hydrophilic portion) and the isomers thereof.
2. 2. A compound according to claim 1 characted in that X is or contains in the chain forming the bridge, a carbonyloxy group and each R group is a triiodhophene group or a group each R is different from hydrogen
3. 3. A compound according to claim 1, characted in that each M is a monohydroxy- or polyhydroxy-alkyl group.
4. 4. A compound according to claim 1, characted in that X is an asymmetric group that provides a chain of 2 or 3 carbon atoms that binds to the two CeR5 groups.
5. 5. A compound according to claim 1, characted in that the two groups C R = are not identically substituted.
6. 6. A compound according to claim 1, characted in that at least one C0Rf group is of the formula R I ~ -where the two R groups are the same or different
7. . A compound according to claim 1, characted in that at least one C group R of the formula where the M groups are the same or different
8. 8. A compound according to claim 1, characted in that the groups M are alkyl groups of 1 to 10 carbon atoms straight chain or branched chain, which have one or more CH or CH portions replaced with oxygen or nitrogen atoms or which are substituted with one or more selected groups of oxo, hydroxyl, amino, a carboxyl derivative, and sulfur and phosphorus atoms substituted with oxo.
9. 9. A compound according to claim 1, characted in that the M groups are the polidohydroxyalkyl groups, optionally hydroxyacid or hydroxypolyalkoxyalkyl groups attached to the phenyl group via an amide bond.
10. 10. A compound according to claim 1, characted in that the M groups are selected from -CONH-CH.CH-OH -CONH-CH.CHOHCH.OH -CONH-CH (CH: OH) .- -C0N (CH : CH, 0H). -CONH -CONHCH. -0C0CH-. -N (C0CH.) H -N (COCH- - (alkyl of 1 to 3 carbon atoms) -N (COCH) -mono, bis or tris-hydroxy- (alkyl of 1 to 4 carbon atoms) -N ( C0CH20H) -mono, bis or tris-hydroxy- (alkyl of 1 to 4 carbon atoms) -C (C0CH_.) (Mono, bis or tris-hydroxy (alkyl of 1 to 4 carbon atoms)) -N- ( COCH-OH): -COCH CHOHCH CH (CH CH CH) -7TNH-C OHCH) and -3NH-CH (CH CH) CHOHCH).
11. 11. A compound according to claim 1, characted in that the M groups are polyhydroxy- (alkyl of 1 to 4 carbon atoms) groups.
12. 12. A compound according to claim 1, characted in that X is an oxygen atom or a group NR :, CO, SO /, CR2 :, COCO, CONR ", COCR.", SOCR / -, SO.NR1, CR; / CR?:, CR. NR1, CR:; 0, NR: CONR :, OCONR-, CONR: CO, CONR'CR1;, OCOO, CR'OCR1;, OCR: -CO, CR-CONR1, CR ^ CR ^ CR;, COCR; R : CO, CR ^ NR ^ R1, CR: SONR :, CR \ OCO, NR ^ O ^ NR1, where R1 is hydrogen or an alkyl of 1 to 6 carbon atoms or an alkoxy group, optionally substituted with hydroxyl, alkoxy, oxa or oxo, or where R 1 bonded to a carbon can also be a hydroxyl group.
13. 13. A compound according to claim 1, of one of the following formulas: (characted in that M is as defined in claim 1 and R1 is as defined in accordance with claim 12).
14. 14. A diagnostic composition, characted in that it comprises a compound of formula I as defined according to any of the preceding claims, together with at least one physiologically tolerable carrier or excipient.