NZ240566A

NZ240566A - Symmetrical and asymmetrical 1,3-bis-[3-(mono- or

Info

Publication number: NZ240566A
Application number: NZ240566A
Authority: NZ
Inventors: Fulvio Uggeri; Marino Brocchetta
Original assignee: Bracco Ind Chimica Spa
Priority date: 1990-11-16
Filing date: 1991-11-12
Publication date: 1994-02-25
Also published as: EP0557345B1; MX9102103A; IL100054A0; JPH06504268A; ES2060415T3; DK0557345T3; KR930702281A; ZA919065B; DE557345T1; IE913986A1; DE69104059D1; HUT65652A; DE69104059T2; ATE111441T1; IT9022088A1; IT9022088A0; HU9301375D0; JP2977613B2; GR930300134T1; WO1992008691A1

Abstract

Symmetrical or asymmetrical 1,3-bis-[3-(mono- or poly-hydroxy)acylamino-5-(mono- or polyhydroxyalkyl)-aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-hydroxy- or hydroxyalkyl-propanes, useful to constitute the opacifying component of X-ray contrast media, are described.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £40566 566 Priority Date(s): Complete Specification Filed: .f«V Class: AQ7t<^r51 J .ftki &W3.W. Publication Date: ... .?3.FEP. P.O. Journal, No: •W p. i 4 12 NOV 199!,i:, / Patents Form No. 5 Number PATENTS ACT 1953 Dated 2*1^3 -UJW/vv COMPLETE SPECIFICATION %\ 1,3-BIS-[3-(MONO- OR P6ir¥-HYDR0XY) ACYLAMINO-5-(MONO- OR POLY-HYDROXYALKYL)AMINOCARBONYL-2,4 , 6-TRIIODO-BENZOYL-AMINO]-HYDROXY- OR HYDROXYALKYL PROPANES, THEIR METHODS OF PREPARATION AND X-RAY CONTRAST MEDIA CONTAINING THEM We, BRACCO INDUSTRIA CBIMICA S.p.A. and Italian company of Via E. Folli, 50 Milano, Italy do hereby declare the invention for which I/we pray that a Patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 - (... followed by la) 1 a 10 15- 20 25 This invention relates to symmetrical or asymmetrical l,3-bis-[3-(mono- or ..di -hydroxy)acylamino-5-(mono- or polyhydroxyalkyl)aminocarbony1-2,4,6-triiodo-benzoyl-amino]-hydroxy- or hydroxyalky1-propanes, useful to constitute the opacifying component of X-ray contrast media, of general formula (X) ro L A B wherein: R, R', which are the same or different, are a straight or branched mono- or di-hydroxyaIky 1 -C^ residue containing lor 2 OH groups, R'2, R2> R3» which are the same or different, are H or CH. 3' 2' or ch R-p , R2,, R3, , which are the same or different, are H 3, groups of formula -CH(CH2OhT)CH(OH)CH2OH, -CH(CH20H)2, H(0H)-o Alkyl(OH)is one of the -CH(CH2 OH)CH(OH)CH2 OH ch2oh, -ch2(choh)4ch2oh, or -ch2ch2oh, 5 OCT 1993 Z 2 2 4 0 5 6 6 X is one of the groups -CH(OH)-, -CH(CH2OH)-, -C(OH)(CH2OH)- or -C(CH2OH)2-, A and B, may be the same or different. The invention also comprises the possible enantio-5 mers, diastereoisomers and/or rotamers of compounds (i). The invention also relates to a process for the preparation of these non-ionic compounds, as well as to the X-ray contrast media which contain them as opa-10 cifying components. Preferred compounds of formula (I) are the ones in which R2, R2'/ R3S are H. Particularly preferred are the ones in which X represents the -CH(OH)- group. From the structural point of view, the non-ionic X-ray 15 contrast agents which are more similar to the ones of this invention are the a,cO-bis-[3-hydroxyacylamino-5-(dihydroxyalkyl) axninocarbonyl-2,4,6-triiodo-benzoyl-aminoj-oxaalkanes described in patents DE 2805928 and US 4,139,605. In these compounds the two triiodo-ben-20 zoyl-amino residues are joined via an oxaalkylenic residue of formula -C H. -(O-C H~ )n .-O-C H» - contai- n 2n n 2n 0-4 n dn ning from 4 to 12 atoms of C and from 1 to 5 atoms of 0. They can produce oversaturated solutions and after some time, these ones may spontaneously crystallize, 2 5 therefore causing a limitation to the use of such compounds. Patent US 4,062,934 describes N,N'-bis-(3-N-methyl-N-acetylamino-5-N-gluconylamino-2,4,6-triiodo-benzoyl )-diaminoalkanes. Due to an iodine content comparatively low, they show a reduced opacifying capa-30 city. In addition, their solutions are quite viscous. These features cause some problems when the product is 240 566 used in procedures which require administration via catheter. N ,N1-bis-(3-acylamino-5-N-methyl-carbamoyl-2,4, 6-triiodo-benzoyl-amino)-carboxyalkanes are described in 5 patent application GB 1,488,904. The preparation of solutions acceptable from the pharmacological point of view requires that free carboxylic groups, where present, are neutralized. Therefore, if compared to the non-ionic contrast agents, the solutions of the com-10 pounds described in the above mentioned patent application have a high osmolality. Similarly, their neurotoxicity is higher than the one of the non-ionic contrast media. Sovak et Al. described in application WO 8501727, 15 among other compounds, also N,N'-bis-[3,5-bis-(N-2,3-dihydroxy-propyl-N-acetylamino)-2,4;6-triiodo-benzoyl]-ethylendiamines and the corresponding N'-hydroxyalkyl-derivatives. The synthesis of these compounds is quite difficult. The four 2,3-dihydroxy-propyl groups are ob-20 tained by treating the corresponding tetraalkenylderi-vatives with 1-butyl-hydroperoxide in the presence of osmium tetroxide. The reaction occurs in a fragmented and unaccomplished way. None of the compounds described, mentioned or claimed by Sovak has as conjunction 25 bridge of the two 2,4,6-triiodo-benzoyl-amino residues the hydroxyalkylenic chain of formula -CI^-X-CI^-, with X equivalent to -CH(OH)-, -CH(CH2OH)-, -C(OH)(CH2OH)-or -CfCHjOH^-, which is characteristic of this invention. 30 A last reference concerns the European patent ap plications EP 74307 and EP 74309 abandoned in 1985. 240566 The first one only describes aromatic bi- or tricyclic compounds where the aromatic moiety contains iodine and bromine atoms at the same time and in the same molecule. 5 The second one does not describe new compounds, but a process which increases the tolerability of opacifying compositions by using a mixture of iodobenzenic and bromobenzenic compounds. The general formulas describing these compounds are extremely wide, unclear 10 and indefinite and include billions of compounds basically different among them. The compounds of formula (I) belong to the class of non-ionic contrast agents for X-ray diagnosis, which are more and more replacing the salts up to now used of 15 the derivatives of 2,4,6-triiodo-benzoic acid, due to their better tolerability and the reduced side-effects. Thanks to the elimination of the ionic species, their solutions, if compared to the ones of the ionic agents, have the same content of iodine, but a lower osmotic 20 pressure, that's to say a lower osmolality. Therefore, for instance, in angiography, they cause less pain and endothelial damage. In subarachnoidal administration for myelography and cisternography, unlike the previously used contrast media, they rarely cause arachnoidi-25 tis or epileptic disorders. Unfortunately non-ionic contrast agents, consisting of iodinated monocyclic aromatic nuclei, are still too hypertonic, despite their excellent physical and pharmacological properties, if compared with blood, at the high dosages and 3 0 high concentrations which many diagnoses require. This fact led to the development of bicyclic hexaiodinated 24 0 5 6 6 compounds, whose osmolality is reduced in comparison with the total amount of iodine in the molecule. However, concentrated solutions of these compounds are frequently too much viscous. In addition, a large 5 number of products, even if they are expected to be promising from the theoretical point of view, are not enough soluble. For this reason, researchers investigated on new hexaiodinated bicyclic derivatives characterized by: 10 high solubility, low viscosity and osmolality as well as high intravenous, intracisternal and intracerebral tolerability and minimum tendency to give side effects (pain, temperature increase, nausea, decrease of pressure and vessel damages). 15 In particular, physicians need new contrast media characterized by a wide range of possible uses, i.e. in urography, angiography, cardioangiography, flebography, myelography, cisternography, lymphography, isterosal-pingography, bronchography and gastrography or the vi-20 sualization of articular cavities. The products of this invention are generally characterized by a good water solubility, which can exceed 100 g per 100 ml of solution at 20°C, and a low toxicity. 25 If compared to the known hexaiodinated dimers, they show low osmolality without causing a foreseeable corresponding rise in the viscosity. One of the preferred compounds of the invention is for example l,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-30 (1,3-dihy droxy-i sopropy 1) aminocarbonyl-2,4,6-tr iiodo- benzoyl-amino]-2-hydroxy-propane (compound A of Table 24 0 566 6 2). It gives stable aqueous solutions which contain, at 20°C, more than 100 g of product in 100 ml of solution. As far as the physiological characteristics are concerned, the study of plasma kinetics revealed half life for the distribution and elimination phases of 2.9 and 22.9 min, after intravenous administration in rats (200 mgl/kg). The apparent volume of distribution is 123.5 ml/kg showing that the product is distributed in plasma and the extracellular spaces. The total clearance is 7.9 ml . min-"*"* . kg~\ Elimination occurs mainly through urinary pathway and in less extent through the bile. After 7 hours from the administration, 76.7% of the administered dose was found in the urine and 3.5% in the bile. Its tolerability is very good as reported in Table 1. In Table 2, there are reported the values of some characteristic properties of preferred products of this invention in comparison with IODIXANOL (Nycomed), which is an hexaiodinated non-ionic dimer in advanced phase of development (EP 108638; CLINICA 413, p 7, 08.08.90). The process for the preparation of the l,3-bis-[3-(mono- or di -hydroxy)acylamino-5-(mono- or poly-hy-droxyalky1)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-Joj^droxy- or hydroxyalkyl-propanes of general formula (I) is characterized in that a 1,3-diamino-hydroxy- or hydroxyalkyl-propane of general formula (II) I R3-HN-CH2-X-CH2-NH-R3» (II) wherein R3 and R31 are H or CH3, X represents the grcjups -CH(OH)-, -CH(CH2OH)-, -C(OH) (CH20H)- or 24 0 5 7 -C(CH2OH)2- and one of the amino groups may be protected by a suitable protective group, is reacted, directly or by a multi-step process, with a reactive derivative of a 3-(mono- or di-acyloxy)acylamino-5-(mono-or poly-hydroxyalkyl)aminocarbonyl-2,4,6-triiodo-ben-zoic acid of general formula (III) I2 10 9 V cm). wherein: 15 R.^ R2, are H or CH3, RA, is a straight or branched mono- or di-acy- loxyalkyl C]_-C]_3 residue containing from 3 to 13 atoms of C and from 1 to 2 lower acyloxy groups C2~C5' 20 Alkyl(oh) , is one of the groups of formula -ch2ch(oh)ch2oh, -ch2ch2oh, ~ch(ch2oh)2, -CH(CH2OH)CH(OH)CH2OH or -CH2(CHOH)4CH2OH, where the hydroxy groups may be preferably protected by acetalic or Ketalic groups, 25 CO-Y, is the residue of a mixed anhydride or, preferably, a halocarbonyl group, to give a compound of general formular-flV.).^ frtsy. 3 0 * *n\l I -«ocr»ajS) t 8 A!kyl(OH)].5 (IV). wherein R, r->» R. 10 15 20 25 30 "1' ^2' ~3' "1 ' R2'' ^3 ' ^4' ^-L^J'x^il'l-5' and X have the meaning as previously defined and R,. may be R or R^, preferably according to one of the two following procedures: a) a compound of formula (II) is reacted with a compound of formula (III) in a molar ratio of 1:2 in a solvent and in the presence of a basic condensation agent in order to obtain the corresponding compound of formula (IV) where R,. corresponds to R^, b) a compound of formula (II), where one of the two amino groups is protected by a suitable protective group, is reacted with a compound of formula (III) in a molar ratio of 1:1 in a solvent and in the presence of a basic condensation agent in order to obtain, after hydrolysis of the protective groups, the corresponding l-[3-(mono- or di-hydroxy)-acylamino-5-(mono- or poly-hydroxyalkyl)aminocarbonyl-2 ,4 , 6-triiodo-benzoyl-amino]-3-aminohydroxy-alkyl derivative of general formula (tT)'"--~ i2 O. .N. AlkyKOH^.s r3-, Alky1(OH) s°cri993gj 2 4 0 5 6 6 9 10 15 20 wherein R, R2, R3, R3', Alkyl(OH)1_5 and X have the meaning as previously defined, and this compound (V) is subsequently reacted with a derivative of formula (III) in the presence of a basic condensation agent to obtain compound (IV) where R^ is R, then, the compound of formula (IV), obtained by synthetic methods a) or b), is transformed by hydrolysis of the protective groups, into the corresponding compound of formula (I). Finally, in case that R^, R^' are H, this last one may, if desidered, be methylated in alkaline medium. Methylation occurs through reaction with suitable methylating agents, for instance methyl halides, dimethyl sulphate, methylsulphonate, dime thy lcarbonate. For instance, the di-sodium derivative of general formula (VI) R-> ?2* O. .N. ^=5^ Alkyl(OH)i.5 (VI). 25 30 is prepared in a basic environment, preferably in the presence of alcoholate or alkaline hydroxide, and is then transformed into the corresponding dimethyl derivative of general formula (VII) I2 NL COO- MkylCOH^.g O * R' (VII). CH; 240 56 10 by treatment with methyl halides, dimethylsulphate, dimethyl carbonate, methyl methanesulphonate, methyl benzenesulphonate, methyl toluenesulphonate. In case of direct reaction of the product of gene-5 ral formula (II) with a compound of general formula (III), according to synthesis a), symmetrical products are obtained, where both residues A and B of general formula (I) are identical. Following the multistep reaction according to 10 synthesis b), asymmetrical products may be obtained, in which the residues A and B of general formula (I) are different. In fact, during the second step of the reaction, a compound of formula (III), which is different from the one used during the first step of the reac-15 tion, may be used. Anhydrous tertiary amines, potassium hydroxide, sodium hydroxide, sodium bicarbonate, calcium carbonate, magnesium carbonate may be used as basic condensation agents. 20 In both a) and b) synthesis, anhydrides with orga nic or inorganic acids, azides, derivatives of phosphoric acids, alkylcarbonic acids may be used as compounds of formula (III). Therefore, the reactive residue Y in compounds of 25 formula (III) represents the residue of an inorganic or organic acid such as: chlorine, bromine, iodine, phosphite, azide, acyloxy or alkoxycarbonyloxy. The preferred group CO-Y is the residue CO-Cl. The hydroxy functions in the Alkyl(OH)1_5 group of 30 formula (III) may be preferably protected by transformation into the corresponding acetales or ketals. 240566 n Examples of such protective groups may be for instance methylidene, ethylidene, 1-methyl-ethylidene, 1-ethyl-ethylidene, 1-t-butyl-ethylidene, 1-phenyl-ethylidene, 2,2,2-trichloro-ethylidene, 1-ethyl-propylidene. These 5 groups may be easily and fully submitted to hydrolysis through a short treatment with a strong acid, for instance diluted hydrochloric acid, aqueous trifluoroacetic acid or through a strongly acidic ion exchange resin, realeasing the corresponding ketonic 10 compounds, usually acetone, methylethylketone or diethylketone. The lower acyloxy protective C2-Cg groups, included in the residue of formula (III), may be for instance acetoxy, propionyloxy, butiroyloxy and may be 15 easily submitted to hydrolysis by treatment with alkaline aqueous solutions, in order to obtain the desired mono- or poly-hydroxyalkyl R groups of formula (I). The reaction of a compound of general formula (II) with one of formula (III) to give a compound (IV) takes 20 place preferably in an aprotic solvent, such as, for instance, dimethylacetamide (DMAC), dimethylformamide (DMF), hexamethylphosphoramide (HMPT) or dioxane, but also in acetone, ethyl alcohol and isopropyl alcohol. The temperature is not critical. The reaction takes 25 place when temperature ranges from -108C to + 150CC, preferably within 0°C and 100°C. 1,3-Diamino-hydroxy- or hydroxyalkyl-propanes of general formula (II) are described in literature, for instance in "Beilsteins Handbuch der Organischen Che-30 mie": 1,3-diamino-2-hydroxy-propane, Beil.4 H 290, E II 24 0 5 66 12 739, E III 766, E IV 1694; l,3-bis-(methylamino)-2-hydroxy-propane, Beil. 4 E IV 1695; l,3-diamino-2,2-bis-hydroxymethyl-propane, Beil. 4 5 E III 850; 1,3-bis-(methylamino)-2,2-bis-hydroxymethyl-pro- pane, Beil. 4 E III 851. When a compound of formula (II) is reacted with one of formula (III) in a molar ratio of 1:1 according 10 to synthesis b), then the 1,3-diaminoderivative of formula (II) is monoprotected on one of the two amino groups in order to avoid side-reactions. Protective groups which meet this purpose may be for instance acetyl, dichloroacetyl, trifluoroacetyl groups. Tri-15 fluoroacetyl is particularly preferred. Afterwards, these groups may be easily and completely hydrolysed through treatment with alkaline aqueous solutions. The reactive derivatives of the 3-(mono- or di -acyloxy)acylamino-5-(mono- or poly-hydroxyalkyl)amino-20 2,4,6-triiodo-benzoic acids of general formula (III) are obtained by reaction of a reactive derivative of a 3-(mono- or poly-acyloxy)acylamino-2,4,6-triiodo-iso-phthalic acid of general formula (VIII) 25 (viii). | ~5OCTl993gl 30 wherein R^, R^, and Y are as previously defined, or by reaction of a derivative belonging to the ones already 240566 13 described in patents CJS 4,001,323 and EP 26281 with the hydroxyalkyamines 2-hydroxy-ethylamine, 1,3-dihydroxy-isopropylamine (serinol), 2,3-dihydroxy-propylamine (isoserinol), 3-amino-l,2,4-butantriol, or with the 5 corresponding N-methylamines, or with N-methyl-glucamine or with a corresponding derivative thereof wherein the hydroxy groups are preferably protected by chelatization, for instance with 5-amino-2,2-dimethyl-1,3-dioxane, 5-amino-2-methyl-2-ethy1-1,3-dioxane, 5-10 amino-1,3-dioxane, 5-amino-2,2-diethyl-l,3-dioxane, 4-aminomethyl-2,2-dimethy1-1,3-dioxolane, 4-aminomethyl-2,2-diethy1-1,3-dioxolane, 5-amino~6-hydroxy-2,2-di-methyl-1,3-dioxepane or 5~amino-6-hydroxy-2-ethyl-2-methyl-l,3-dioxepane. 15 The reactive derivatives of 3-(mono- or poly-acy loxy ) acylamino-2 , 4 , 6-triiodo-isophthalic acid (VIII) are generally reacted with one of the above mentioned amines in a molar ratio of about 1:2 without using a basic condensation agent, or in a ratio of 1:1 by using 20 a basic condensation agent in an inert organic solvent. For instance, dioxane or tetrahydrofuran (THP) are preferred solvents. The HY acid, released during the reaction of (VIII) with the amine, is neutralized by the second mole of the amine, giving the corresponding am-25 monium salt, or by the basic condensation agent used. Some of the preferred reactive derivatives of the 3-(mono- or poly-acyloxy)acylamino-5-(mono- or poly-hydroxyalkyl ) aminocarbonyl-2 , 4 , 6-triiodo-benzoic acids of general formula (III) have already been described in 30 patents DE 2805928 or US 4,139,605. The compounds of this invention may be used as 240 566 14 opacifying agents in non-ionic contrast media for X-ray diagnosis. They may be formulated in a suitable carrier agent which is acceptable from the pharmacological point of 5 view. Suitable carrier agents include, for instance, the ones which can be used for enteral or parenteral administration, such as buffered sterile aqueous solutions containing tromethamine, phosphate, citrate and/or bicarbonate ions, ionically balanced solutions 10 containing physiologically acceptable anions and cations such as: Cl^~\ Ca^+^ , Na^ + ^, + ^ (2+) and Mgv . Solutions of the contrast agents of this invention may also contain a small amount of a physiologically tolerable chelating agent, such as the 15 sodium and calcium salts of EDTA, in concentrations from 0,05 to 2 mM/1, or even heparin, at a dosage ranging from 5 to 500 units per 100 ml of solution, or another suitable anticoagulant agent. Hypotonic solutions of the contrast media of this 20 invention may be isotonically balanced by adding the correct amount of Merlis liquid (The Am. J. of Phys. Vol. 131, 1940 p. 67-72). Useful concentrations of iodine for such contrast media vary from 14 0 to 500 mgl/ml at a dosage of 10-300 ml, according to the desi-25 red diagnostic use. The following experimental examples show the basic principles of this invention. EXAMPLE 1 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(l,3-dihydro-30 xy-isopropyl)-aminocarbonyl-2,4,6-triiodo-benzoyl-amino ]-2-hydroxy-propane. 240566 15 a) 124 g of 3-(L-2-acetoxy-propionyl)amino-5-(l,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.162 mol), obtained according to the procedure described in DE 2805928/Example 5 1, are solubilized in 490 ml of dimethylformamide (DMF). The resulting solution is cooled to 0-5°C, added of 32.4 g of anhydrous tributylamine (0.175 mol) and then dropwise mixed under stirring with a solution of 7.66 g of 1,3-diamino-2-hydroxy-10 propane (0.085 mol) in 200 ml of DMF. The reaction mixture is kept under stirring at 0-5°C for 1 h, then is left at room temperature for about 20 h. Hence the solvent is evaporated under vacuum. The residue is crystallized with ethyl acetate. The 15 crystalline precipitate is filtered and dried, then suspendend in 600 ml of water at 50°C. pH is adjusted at 10.3 with NaOH 2N and the mixture is stirred until the acetoxy groups of the propionyl residues are totally hydrolysed. The resulting 20 solution is made free from salts by passage p through ion exchange resins (360 ml of Amberlite IR 120 and 400 ml of DuoliteR A 30B). The eluate is evaporated to dryness and crystallized from 600 ml of ethyl alcohol. After filtration and drying 25 75.8 g of 1,3-bis-[3-(L-2-hydroxy-propionyl)amino- 5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane are obtained. Yield: 64% m.p.: 280°C (dec.) 30 Elemental Analysis (%) 4 0 5 6 6 16 CHIN Calculated: 25.47 2.48 52.08 5.76 Found: 25.47 2.35 52.12 5.53 [o02°436 = -6.03° (c = 9.6% H20) 5 Solubility in ^0 at 20°C : > 100% w/v. TLC: (Silica Gel 60 ^254' Merck) Eluent: CHC13/CH3OH/NH4OH 25% = 6/3/1 v/v/v. Rf = 0.14. HPLC: Rt = 12.4 min. Titre = 98.5% (on the area) Chromatographic conditions: 10 Column: LICHROSORBRRP 18 (Merck), 5 p (250 x 4 mm) Eluent: A) H20 B) CH3CN Gradient (flow 1 ml/min; Detector UV 254 nm): time (min) = 0-3; 3-25; 25-30 %B = 0; 0-40; 40 15 b) the above disclosed compound can be obtained also by reacting, according to the procedure of the previous Example la), 65.2 g of 3-(L-2-acetoxy-propionyl)amino-5-(4,4-dimethyl-3,5-dioxa-cyclo-hexyl)aminocarbonyl-2,4,6-triiodo-benzoylchloride 20 (0.081 mol), described in DE 2805928/Example lB(b), with 3.83 g of l,3-diamino-2-hydroxy-propane (0.042 mol) in 350 ml of DMF in the presence of 16.2 g of tributylamine (0.087 mol). The obtained product is transformed into 1,3-bis-25 [3-(L-2-acetoxy-propionyl)amino-5-(1,3-dihydroxy- isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino ]-2-hydroxy -propane by treatment with HCl 2N and corresponding elimination of acetone. This product is suspended in water at 50°C, the pH is adjusted 30 to 10.3 with NaOH 2N and the basic treatment continues until the acetoxy groups are completely 40 5 6 6 17 hydrolysed. After elimination of the ionic species, due to the passage through ion exchange resins, 41.4 g of l,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl)amino-5 carbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy- propane are obtained with a yield of 70%. c) This reaction may also be performed in ethyl alcohol (EtOH) instead of DMF: 588 g of 3-(L-2-acetoxy-propionyl)-amino-5-(1,3-dihydroxy-isopro-10 pyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.67 mol) in 5.8. 1 of EtOH are reacted at room temperature with 36.4 g of 1,3-diamino-2-hydroxy-propane (0.404 mol) dissolved in 2.9 1 of EtOH, in the presence of 144 g of tributylamine (0.777 15 mol). The obtained precipitate is filtered, suspended in water and treated with NaOH 2N up to pH 10.3 as previously described in a). 350 g of 1,3-bis-[3-(L-2-hydroxy-propionyl)-amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-20 benzoyl-amino]-2-hydroxy-propane are obtained with a yield of 62.2%. EXAMPLE 2 1,3-bis-[3-hydroxyacetylamino-5-(1,3-dihydroxy-isopropyl ) aminocarbonyl-2 ,4,6-triiodo-benzoyl-amino]-2,2-bis-25 hydroxymethyl-propane. a) 144 g of 3-acetoxyacetylamino-5-(1,3-dihydroxy-isopropyl )aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.192 mol), described in DE 2805928/Example 10, dissolved in 600 ml of DMF, 30 are dropwise added under stirring and between 5 to 10°C to a solution of 13.4 g of l,3-diamino-2,2- 240566 18 bis-hydroxymethyl-propane (0.10 mol) and 39 g of tributylamine (0.21 mol) in 80 ml of DMF. The reaction mixture is kept under stirring for some hours at 10-20°C. Hence it is poured under heavy 5 stirring into 5.5 1 of ethyl acetate from which the final product crystallizes. After filtration and drying, 140 g of raw 1,3-bis-[3-acetoxyacetyl- amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl- 2,4,6-triiodo-benzoyl-amino]-2,2-bis- 10 hydroxymethyl-propane are obtained. A sample crystallized from methyl alcohol has the following characteristics: m.p.: 284-287 °C Elemental Analysis (%) 15 CHIN Calculated: 26.91 2.58 48.74 5.37 Found: 26.82 2.70 48.45 5.37 b) 105 g of raw 1,3-bis-[3-acetoxyacetylamino-5-( 1,3- dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo- 20 benzoyl-amino]-2,2-bis-hydroxymethyl-propane are diluted in 1.9 1 of water and 0.8 1 of methyl alcohol (CH^OH) and slowly mixed with 170 ml of NaOH IN until a constant pH value of 10.3 is obtained. The mixture is kept under stirring for 25 about 10 h at 20°C. Then, the methyl alcohol is evaporated under vacuum. The resulting aqueous solution is made free from salts by passage R through ion exchange resins (160 ml of Amberlite IR 120 and 150 ml of DuoliteR A 30B). The eluate 30 is evaporated to dryness under vacuum, diluted again in 1.2 1 of water, bleached on active carbon 240 566 19 •D and percolated on 1200 ml of Amberlite XAD-2. The fractions containing the product are gathered and dried. 66 g of 1,3-bis-[3-hydroxyacetylamino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-tri-5 iodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane are obtained. The last impurities are eliminated by dissolving the product in aqueous ethyl alcohol 80% and filtering the turbid solution. 10 Yield: 62% m.p.: 285°C Elemental Analysis (%) CHIN Calculated: 25.19 2.45 51.51 5.68 Found: 25.26 2.60 51.36 5.57 15 TLC: (Silica Gel 60 F254, Merck) Eluent: CHC13/CH30H/NH40H 25% = 3/2/1 v/v/v. Rf = 0.23. HPLC: Rt = 9.6 min. Titre = 99% (on the area) Chromatographic conditions: Column: as reported in Example 1 20 Eluent: A) KH2P04 0.01 M B) H20 75%, CH3CN 25% Gradient (flow 1 ml/min; Detector UV 254 nm): time (min) = 0-5; 5-15; 15-25 %B = 20; 20 - 80; 80 In the same way the following compounds are obtained: 25 - l,3-bis-[3-hydroxyacetylamino-5-(2,3-dihydroxypro-pyl)aminocarbony1-2,4,6-triiodo-benzoyl-amino]- 2.2-bis-hydroxymethyl-propane. 1.3-bis-[3-hydroxyacetylamino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoylamino]- 30 2,2-bis-hydroxymethyl-propane. 240 566 20 EXAMPLE 3 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(2,3-dihydroxy -propyl ) aminocarbonyl-2,4,6-triiodo-benzoy1-amino]-2-hydroxy-propane. 5 197 g of 3-(L-2-acetoxy-propionyl)amino-5-(2,3- dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.25 mol), described in DE 2805928/Example 6, are reacted in 500 ml of DMF and in the presence of 55.6 g of tributylamine (0.30 mol) with 11.3 g of 1,3-10 diamino-2-hydroxy-propane (0.12 5 mol) according to the procedure described in the Example 2a). The condensation product is submitted to hydrolysis, as described in the Example 2b) . Similarly, the isolation and the purification of the final product are performed. 15 94.2 g of 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino ]-2-hydroxy -propane are obtained. Yield: 50% m.p.: 278-282°C Elemental Analysis (%) 20 CHIN Calculated: 25.47 2.48 52.09 5.75 Found: 25.21 2.53 51.89 5.59 TLC: (Silica Gel 60 *"254' Merck) Eluent: CHCl3/CH3OH/NH4OH 25% = 6/3/1 v/v/v. Rf = 0.24. 25 HPLC: Rt = 15.4 min. Titre = 99.4% (on the area) Chromatographic conditions: Column: LICHR0SPHERRRP18 (Merck), 5 p. (250 x 4 mm) Eluent: A) H3P04 0.1 M B) H20 50%, CH3CN 50 % Gradient (flow 1 ml/min; Detector CJV 254 nm): 30 time (min) = 0-5; 5 - 20; 20 - 30; 30 - 35 %B = 10; 10-28; 28-70; 70 40 56 6 21 . EXAMPLE 4 1, 3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(1,3, 4-tri-hydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino ] -2-hydroxy-propane. 5 24 g of 3-(L-2-acetoxy-propionyl)amino-5-(1,3,4- trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.03 mol), obtained by known methods described in DE 2805928, in 30 ml of DMF and in presence of 3.8 g of triethylamine (0.037 mol) are reacted with a 10 solution of 1.45 g of 1,3-diamino-2-hydroxy-propane (0.016 mol) in 30 ml of DMF at 5 to 8°C, according to the procedure described in Example 3. 7.2 g of the title compound are obtained. Yield: 30% m.p.: 250-256°C 15 Elemental Analysis (%) CHIN Calculated: 26.05 2.65 50.02 5.52 Found: 26.04 2.95 49.15 5.33 [*]20436 = -5.01° (c = 10.13% H20) 20 Solubility in H^O at 20°C: 100% w/v TLC: (Silica Gel 60 F254' MercIc) Eluent: CHCl3/CH3OH/NH4OH 25% = 5/4/1 v/v/v. Rf = 0.24. 1 13 H-and C-NMR spectra are in accordance wxth the proposed structure. 2 5 EXAMPLE 5 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-[N-methyl-N-(D-l-deoxy-gluc itol)]aminocarbonyl-2,4,6-triiodo-benzoyl-amino ]-2-hydroxy-propane. 20.6 g of 3-(L-2-acetoxy-propionyl)amino-5-[N-me-30 thyl-N-(D-l-deoxy-glucitol)]aminocarbonyl-2,4,6-tri- iodo-benzoyl-chloride (0.024 mol), obtained by known 240566 22 methods described in DE 28 05928, in 100 ml of DMF are reacted with a solution of 1.124 g of 1,3-diamino-2-hy-droxy-propane (0.012 mol) and 2.53 g of triethylamine (0.02 5 mol) in 30 ml of DMF, according to the procedure 5 described in Example 3. 9.26 g of the title compound are obtained. Yield: 47% m.p.: 266°C (dec.) Elemental Analysis (%) CHIN 10 Calculated: 28.04 3.14 45.58 5.03 Found: 28.19 3.29 45.48 5.03 13. P02°436 = -19° (c = 7.04% H20) C-NMR spectrum is in accordance with the proposed structure. 15 In the same way the following compounds are obtained: 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-[N-me-thy1-N-(1,3-dihydroxy-isopropyl)]aminocarbony1-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane. 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-[N-me-20 thy1-N-(2,3-dihydroxy-propyl)]aminocarbonyl-2,4,6- triiodo-benzoy1-amino]-2-hydroxy-propane. EXAMPLE 6 1,3-bis-[N-methy1-N-[3-(L-2-hydroxy-propionyl)amino-5-(2-hydroxy-ethyl) aminocarbonyl-2,4,6-triiodo-benzoyl ]-2 5 amino]-2-hydroxy-propane. 20.85 g of 3-(L-2-acetoxy-propionyl)amino-5-(2-hy-droxy-ethyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.025 mol), obtained by known methods described in DE 2805928, in 80 ml of DMF are reacted with a solution 30 of 1.47 g of 1,3-bis-(methylamino)-2-hydroxy-propane (0.012 mol) and 2.63 g of triethylamine (0.026 mol) in 240566 23 30 ml of DMF at 5°C to room temperature, according to the procedure described in Example 3. 9.6 g of the title compound are obtained. Yield: 56% m.p.: 285°C (dec.) 5 Elemental Analysis (%) CHIN Calculated: 26.03 2.54 53.24 5.88 Found: 25.86 2.43 52.81 5.78 ^]2°436 = -3.85° (c = 9.95% H20) 1 13 10 H-and C-NMR spectra are in accordance with the proposed structure. EXAMPLE 7 I,3-bis-[N-methy1-N-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo- 15 benzoyl]amino]-2-hydroxy-propane. 21.4 g of 3-(L-2-acetoxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-ben-zoylchloride (0.02 5 mol), obtained by known methods described in DE 2805928, in 85 ml of DMF are reacted 20 with a solution of 1.47 g of 1,3-bis-(methylamino)-2-hydroxy-propane (0.012 mol) and 2.63 g of triethylamine (0.026 mol) in 30 ml of DMF at 5°C to room temperature, according to the procedure described in Example 3. II.1 g of the title compound are obtained. 25 Yield: 62% m.p.: 295°C (dec.) Elemental Analysis (%) CHIN Calculated: 26.60 2.70 51.09 5.64 Found: 26.31 2.95 50.68 5.48 on 30 [*] 436 = -3.54° (c = 10.44% H20) Solubility in H20 at 22®C: > 100% w/v 2 4 0 5 6 24 1 13 H-and C-NMR spectra are in accordance with the proposed structure. EXAMPLE 8 1,3-b is - [ N-methy1-N- [ 3 - (L-2-hydroxy-propionyl) amino-5- 5 (2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodoben- zoy1]amino]-2-hydroxy-propane. Title compound is obtained by reacting the desired reagents in the same quantities disclosed in Example 7 and following the same procedure. 7.9 g of final com- 10 pound are obtained. Yield: 44% m.p.: 280°C (dec.) Elemental Analysis (%) C H IN Calc.: 26.60 2.70 51.09 5.64 15 Found: 26.32 2.81 50.24 5.44 (H20=1.54%) W]20436 = -3.2° (c = 9.8% H20) Solubility in H20 at 20°C: >100% w/v 13 C-NMR spectrum is in accordance with the proposed structure. 20 EXAMPLE 9 1,3-bis- [ N-methy 1-N- [ 3 - (L-2-hydr oxy-propionyl) amino-5-(1,3,4-trihydroxy-2-butyl) aminocarbonyl-2,4,6-triiodo-benzoyl ] amino]-2-hydroxy-propane. 19.9 g of 3-(L-2-acetoxy-propionyl)amino-5-(1,3,4-25 trihydroxy-2-butyl) aminocarbonyl-2,4 ,6-triiodo-benzoyl-chloride (0.025 mol), obtained by known methods described in DE 28 05928, in 30 ml of DMF are mixed with 3.8 g of triethylamine (0.037 mol), then are reacted with a solution of 1.5 g of 1,3-bis-(methylamino)-2-hydroxy-30 propane (0.013 mol) in 25 ml of DMF at 5° C to room temperature, according to the procedure described in 240566 25 Example 3. 5.68 g of the title compound are obtained. Yield: 29.5% m.p.: 256°C Elemental Analysis (%) 5 CHIN Calculated: 27.12 2.86 49.12 5.42 Found: 27.46 3.15 48.55 5.24 C*]2°436 = -3.16° (c = 9.93% H20) "^H-and ^C-NMR spectra are in accordance with the 10 proposed structure. EXAMPLE 10 1-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxyiso-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-3-[3-hydroxyacetylamino-5-(2,3-dihydroxy-propyl)aminocarbo-15 ny1-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane. a) 125 g of 3-(L-2-acetoxy-propionyl)amino-5-(1,3-di-hydroxy-isopropyl)aminocarbonyl-2,4, 6-triiodoben-zoyl-chloride (0.163 mol), diluted in 150 ml of DMF, are dropwise added, while keeping the 20 temperature between 0 and 10°C, to a solution of 45.6 g of l-trifluoroacetylamino-2-hydroxy-3-ami-nopropane trifluoroacetate (0.152 mol) and 35.8 g of triethylamine (0.35 mol) in 280 ml of DMF. The resulting mixture is stirred at 10 °C for 8 h. 25 After filtration, the solution is evaporated to dryness, then is diluted with 3 1 of methylene chloride (CHjC^). The condensation product precipitates, then, after filtration, the protective groups are removed by hydrolysis, according to the 30 procedure described in Example 2b). The resulting product is purified by means of fixation on a 240 566 26 D strongly acidic resin (950 ml of Amberlite IR 120) and subsequent elution with about 6 1 of NH^OH 2M. After evaporation of the solvent, 76.5 g of 1-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihy-5 droxyisopropyl)aminocarbonyl-2,4,6-triiodo-ben- zoylamino]-2-hydroxy-3-amino-propane are obtained with a yield of 65%. Acidimetric titre = 99.4% m.p.: 211°C b) 73.5 g of 3-acetoxyacetylamino-5-(2,3-dihydroxy-10 propyl)aminocarbonyl-2,4, 6-triiodo-benzoyl-chlori- de (0.098 mol) in 500 ml of DMF are slowly added dropwise, at a temperature between 5 and 10°C, to a solution of 76 g of the product obtained at point a) (0.098 mol) and 11.1 g of triethylamine 15 (0.11 mol) in 500 ml of DMF. The mixture is kept under stirring for 20 h, then filtered and dried. The residue is dissolved in 1.9 1 of water and 0.8 1 of methyl alcohol, then it is submitted to hydrolysis and purification according to the 20 procedure described in Example 2b). 92 g of 1— [3— (L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl )aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-3-[3-hydroxyacetylamino-5-(2 f 3-dihydroxypropyl)-aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hy-25 droxypropane are obtained. Yield: 64.8% m.p.: 300°C Elemental Analysis (%) CHIN Calculated: 24.88 2.37 52.58 5.80 30 Found: 24.70 2.29 52.15 5.74 [^]2°436 = "2*9° (C = 10% H20) 4 0 5 6 6 27 TLC: (Silica Gel 60 ^54' Merck) Eluent: CHCl3/CH3OH/NH4OH 25% = 6/3/1 v/v/v. Rf = 0.18. HPLC: Rt = 13.6 min. Titre = 97.5% (on the area) Chromatographic conditions: 5 Column: as reported in Example 1 Eluents: A) K2P04 0.01 M B) KH2P04 0.01M 50%, CH3CN 50% Gradient (flow 1 ml/min; Detector UV 254 nm): time (min) = 0-6; 6 - 25; 25 - 30 %B = 2; 2-80; 80 10 EXAMPLE 11 1-[3-hydroxyacetylamino-5-(1,3,4-trihydroxy-2-butyl)-aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-3-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2 ,4,6-triiodo-benzoyl-amino]-2-hydroxypropa-15 ne. Title compound is obtained following the procedure described in Example 10. So 8.58 g of 3-acetoxyacetylamino-5-(1,3,4-trihy-droxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoy1-chlo-20 ride (0.011 mol) in 60 ml of DMF are reacted with a solution of 8.54 g l-[3-(L-2-hydroxy-propionyl)amino~5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino] -2-hydroxy-3-amino-propane (0.011 mol), obtained according to Example 10 a), and 2.22 g of 25 triethylamine (0.022 mol) in 60 ml of DMF to give the desired compound. 8.75 g of the title compound are obtained. Yield: 51% m.p.: 283°C (dec.) Elemental Analysis (%) 30 CHIN Calc.: 25.19 2.45 51.51 5.68 2 A 0 5 6 6 28 Pound: 24.13 2.72 48.88 5.32 (H20 = 2.71%) [C*]2°436 = ~2*6° (c = 10*44% H20) Solubility in H20 at 25°C: >100% w/v C-NMR spectrum is in accordance with the proposed 5 structure. EXAMPLE 12 1- [ 3- (L-2-hydroxy-propionyl) amino-5- (1,3-dihydroxyiso-propyl) aminocarbonyl-2 ,4, 6-triiodo-benzoyl-amino ]-3- [ 3-(L-2-hydroxy-propionyl) amino-5- (2 , 3-dihydroxypropy 1) -10 aminocarbonyl-2 , 4,6-triiodo-benzoyl-amino]-2-hydroxy-propane. Following the procedure described in Example 10, 8.75 g of 3-(L-2-acetoxy-propionyl)amino-5-(2,3-dihy-droxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chlo-15 ride (0.01 mol) in 60 ml of DMF are reacted with a solution of 7.76 g l-[3-(L-2-hydroxy-propionyl)amino-5-(1, 3-dihydroxy-isopropyl) aminocarbonyl-2,4, 6-triiodo-benzoyl-amino ]-2-hydroxy-3-amino-propane (0.01 mol), obtained according to Example 10 a), and 2.02 g of 20 triethylamine (0.02 mol) in 60 ml of DMF to give the desired compound. 8.15 g of the title compound are obtained. Yield: 55% m.p.: 287°C (dec.) Elemental Analysis (%) 25 CHIN Calculated: 25.46 2.48 52.08 5.75 Found: 25.49 2.34 51.67 5.73 20 436 " "5.67° (c = 10.01% H20) Solubility in H20 at 20°C: >100% w/v 13 30 C-NMR spectrum is in accordance with the proposed structure. ? 4 29 EXAMPLE 13 1-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxyiso-propyl)aminocarbonyl-2, 4,6-triiodo-benzoyl-amino]-3-[3-(L-2-hydroxy-propionyl)amino-5-[N-methy1-N-(D-l-deoxy-5 glucitol)]aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane. Following the procedure described in Example 10, 6.9 g of 3-(L-2-acetoxy-propionyl)-5-[N-methyl-N-(D-l-deoxy-glucito1)]aminocarbonyl-2,4,6-triiodo-benzoyl-10 chloride (0.008 mol) in 50 ml of DMF are reacted with a solution of 6.13 g l-[(L-2-hydroxy-propionyl)-5-(l,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino ]-2-hydroxy-3-amino-propane (0.008 mol), obtained according to Example 10 a), and 1.6 g of 15 triethylamine (0.016 mol) in 50 ml of DMF to give the desired compound. 4.2 g of the title compound are obtained. Yield: 34% m.p.: 285°C (dec.) Elemental Analysis (%) 20 CHIN Calculated: 26.84 2.83 48.62 5.37 Found: 27.29 2.92 48.62 5.22 [(X]20436 = -11-9° (c = 5.0% H.O) Solubility in H20 at 20°C: >100% w/v 13 25 C-NMR spectrum is in accordance with the proposed structure. EXAMPLE 14 1,3-bis-[3-hydroxyacetylamino-5-(1,3-dihydroxy-isopro-pyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-30 hydroxy-propane. 112.5 g of 3-acetoxyacetylamino-5-(l,3-dihydroxy- 30 40 5 6 6 isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.15 mol), described in DE 2805928/Example 10, in 400 ml of DMF are reacted with 16.7 g of triethylamine (0.165 mol) and with 7.13 g of 1,3-diamino-2-hydroxy-5 propane (0.075 mol), according to the procedure described in Example 2. 63 g of 1,3-bis-[3-hydroxyacetylamino-5-(1,3-dihydroxy-isopropyl )aminocarbonyl-2,4,6-triiodo-benzoyl-amino] -2-hydroxy-propane are obtained. 10 Yield: 56% m.p.: > 280°C Elemental Analysis (%) CHIN Calculated: 24.49 2.25 53.10 5.86 Found: 24.19 2.28 53.26 5.83 15 TLC: (Silica Gel 60 ^254' Merc^) Eluent: CHC13/CH3OH/NH4OH 25% = 3/2/1 v/v. Rf = 0.60. HPLC: Rt = 7.1 min. Titre = 99% (on the area) Chromatographic conditions: as reported in Example 2. EXAMPLE 15 20 l,3-bis-[3-hydroxyacetylamino-5-(1,3,4-trihydroxy-2-bu-tyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane . 23.4 g of 3-acetoxyacetylamino-5-(1,3,4-trihydro-xy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride 25 (0.03 mol), obtained by known methods described in DE 2805928, in 25 ml of DMF are reacted with 3.8 g of triethylamine (0.037 mol) and with 1.45 g of 1,3-dia-mino-2-hydroxy-propane (0.016 mol), according to the procedure described in Example 2. 30 4.7 g of the title compound are obtained. Yield: 21% m.p.: 275°C 2 4 0 5 31 Elemental Analysis (%) CHIN Calculated: 24.92 2.43 50.96 5.62 Found: 24.93 2.50 49.98 5.53 5 Solubility in HjO at 20°C: 100% w/v In the same way the following compounds are obtained: 1,3-bis-[3-hydroxyacetylamino-5-(2,3-dihydroxypro-pyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane. 10 - l,3-bis-[3-hydroxyacetylamino-5-[N-methy1-N-(1,3-dihydroxy-isopropyl)]aminocarbonyl-2,4,6-triiodo-benzoyl-amino ]-2-hydroxy-propane. 1,3-bis-[3-hydroxyacetylamino-5-[N-methy1-N-(2,3-dihydroxy-propyl)]aminocarbonyl-2,4,6-triiodo-ben-15 zoyl-amino]-2-hydroxy-propane. EXAMPLE 16 1,3-bis-[N-methy1-N-[3-hydroxyacetylamino-5-(1,3,4-tri-hydroxy-2-buty1)aminocarbonyl-2,4,6-triiodo-benzoyl]-amino]-2-hydroxy-propane. 20 23.4 g of 3-acetoxyacetylamino-5-(1,3,4-trihydro- xy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.03 mol), in 25 ml of DMF are reacted with 3.8 g of triethylamine (0.037 mol) and with 1.9 g of 1,3-bis-(methylamino)-2-hydroxy-propane (0.016 mol), according 25 to the procedure described in Example 2. 7 g of the title compound are obtained. Yield: 30% m.p.: 263°C Elemental Analysis (%) C H I N 30 Calculated: 26.04 2.65 50.02 5.52 Found: 26.12 2.69 50.86 5.57 ? 4 0 5 32 Solubility in H20 at 20°C: 100% w/v EXAMPLE 17 1,3-bis-[N-methyl-N-[3-hydroxyacetylamino-5-[N-methyl-N-(D-l-deoxy-glucitol)]aminocarbonyl-2,4,6-triiodo-5 benzoyl]amino]-2-hydroxy-propane. 24 g of 3-acetoxyacetylamino-5-[N-methy1-N-(D-l-deoxy-glucitol)]aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.028 mol), obtained by known methods described in DE 2805928, in 100 ml of DMF are reacted with a 10 solution of 1.65 g of 1,3-bis-(methylamino)-2-hydroxy-propane (0.014 mol) and 2.93 g of triethylamine (0.029 mol) in 30 ml of DMF, according to the procedure described in Example 2. 10.14 g of the title compound are obtained. 15 Yield: 41% m.p.: 276°C (dec.) Elemental Analysis (%) CHIN Calculated: 28.04 3.14 45.58 5.03 Found: 27.95 3.21 45.48 4.97 20 [°(] 2°436 88 -12. 6° (c = 10.6% H20) Solubility in H20 at 25°C: >100% w/v 13 C-NMR spectrum is in accordance with the proposed structure. In the same way the following compounds are obtained: 25 - 1,3-bis-[N-methy1-N-[3-hydroxyacetylamino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl ]amino]-2-hydroxypropane. 1,3-bis-[N-methy1-N-[3-hydroxyacetylamino-5-(2,3— dihydroxy-propyl) aminocarbonyl-2,4,6-triiodo-ben-3 0 zoy1]amino]-2-hydroxy-propane. 24 0 5 33 EXAMPLE 18 1,3-bis- [N-methy 1-N-[ 3-hydr oxyacety lamino-5-[N-methy 1-N-(1,3-dihydroxy-isopropyl)]aminocarbonyl-2,4,6-triiodo-benzoyl ]amino]-2-hydroxy-propane. 5 21.31 g of 3-acetoxyacetylamino-5-[N-methy1-N- (1,3-dihydroxy-isopropyl)]aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.02 5 mol), obtained by known methods described in DE 2805928, in 95 ml of DMF are reacted with a solution of 1.4 7 g of l,3-bis-(methylamino)-2-10 hydroxy-propane (0.12 mol) and 2.63 g of triethylamine (0.026 mol) in 30 ml of DMF, according to the procedure described in Example 2. 8.1 g of the title compound are obtained. Yield: 45% m.p.: 290°C 15 Elemental Analysis (%) C H IN Calc.: 26.98 2.86 50.33 5.55 Found: 26.29 3.01 50.21 5.24 (H20 = 1.02%) Solubility in H20 at 25°C: 100% w/v 13 20 C-NMR spectrum is in accordance with the proposed structure. EXAMPLE 19 1,3-bis-[3-(N-methy1-N-hydroxyacetyl)amino-5-(1,3-dihydroxy-isopropyl )aminocarbonyl-2,4,6-triiodo-benzoyl-25 amino]-2-hydroxy-propane. a) 46 g of 3-(N-methy1-N-acetoxyacetyl)amino-2,4,6-triiodo-isophthaloyl-dichloride (0.065 mol), described in EP 26281/Example 11, in 2 50 ml of anhydrous tetrahydrofuran (THF) are added dropwise 30 to 12.6 g of 1,3-dihydroxy-isopropylamine (0.138 mol) in 100 ml of THF. The mixture is kept for 3 h 140 5 34 at room temperature under stirring. Then it is filtered and evaporated to dryness under vacuum. The residue is constituted by 50.4 g of 3-(N-methy1-N-acetoxyacetyl)amino-5-(1,3-dihydroxy-iso-5 propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chlori de. b) 50 g of 3-(N-methyl-N-acetoxyacetyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (about 0.065 mol), obtained 10 according to a), diluted in 200 ml of DMF, are reacted with 3 g of 1,3-diamino-2-hydroxy-propane (0.034 mol) in 100 ml of DMF, according to the procedure described in Example 1. 21 g of 1,3-bis-[3-(N-methyl-N-hydroxyacetyl)ami-15 no-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-tri-iodo-benzoyl-amino]-2-hydroxy-propane are obtained. Yield: 44.2% m.p.: > 250°C Elemental Analysis (%) CHIN 20 Calculated: 25.47 2.48 52.08 5.75 Found: 25.82 2.60 52.37 5.62 TLC: (Silica Gel 60 F254> Merck) Eluent: CHCl3/CH3OH/NH4OH 25% = 6/3/1 v/v/v. Rf = 0.23 HPLC: Rt = 14.6 min. Titre = 96.7% (on the area) 25 Chromatographic conditions: as reported in Example 2. c) This product may be also obtained by N-methylation of the compound already described in Example 14. 14.3 g of 1,3-bis-[3-hydroxyacetylamino-5-(l,3-di-hydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-ben- 30 zoyl-amino]-2-hydroxy-propane (0.01 mol) in 500 ml of anhydrous DMF are mixed under stirring with a 35 solution of 1.08 g of sodium methylate (0.02 mol) in 30 ml of methyl alcohol. After 3 h, methyl alcohol is removed by distillation. An excess of methyl iodide is added and the solution is stirred 5 for one day at room temperature. Then the reaction mixture is poured under stirring in 600 ml of ethyl acetate and the raw product precipitates. This one is filtered, diluted in water and made free from salts by passage through ion exchange 10 resins (AmberliteR IR 120 and IRA 400). The eluate is treated with active carbon and evaporated to dryness. 7 g of 1,3-bis-[3-(N-methy1-N-hydroxyacetyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-15 benzoyl-amino]-2-hydroxy-propane are obtained with a yield of 47.9%. This compound is identical to the one obtained through process b). In the same way the following compound is obtained: 20 - 1,3-bis-[3-[N-methyl-N-(L-2-hydroxy-propionyl)]-amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane. EXAMPLE 20 1,3-bis-[3-[N-methy1-N-(L-2-hydroxy-propionyl)]amino-5-25 (1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino ]-2-hydroxy-propane. 80.4 g of 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino] -2 -hydroxy -propane (0.055 mol), described 30 in Example 1, are dissolved in 900 ml of DMF and mixed under stirring with 132 ml of sodium methylate 1 M in U 5 8 36 methyl alcohol (0.132 mol). Methyl alcohol is removed by distillation. Hence, 23.7 g of dimethyIsulphate (0.188 mol) are dropwise added at a temperature of 5°C. Stirring is maintained for about 1 h, then the solvent 5 is removed by vacuum distillation. The raw material is diluted with ethyl acetate and forms a solid powder, which is filtered, diluted in water and made free from £ salts by percolation on ion exchange resins (Amberlite p IR 120 and Duolite A 30B) . The solution is evaporated 10 to dryness and then dissolved in boiling ethyl alcohol. After some days, 62 g of 1,3-bis-[3-[N-methy 1-N-(L-2-hydroxy-propionyl)] amino-5-(1,3-dihydroxy-isopropyl)-aminocarbonyl-2,4 , 6-triiodo-benzoyl-amino]-2-hydroxy-propane crystallize. 15 Yield: 75.6% m.p.: > 300°C (dec.) Elemental Analysis (%) CHIN Calculated: 26.60 2.70 51.10 5.64 20 Found: 26.58 2.75 50.95 5.60 [<*]2°436 = +29.7° (c = 10% H20) TLC: (Silica Gel 60 F254' Merc'c) Eluent: CHC13/CH3OH/NH4OH 25% = 6/3/1 v/v/v. Rf = 0.16. EXAMPLE 21 1,3-bis-[3-[N-methy1-N-(L-2-hydroxy-propionyl) ]amino-5-25 (2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodoben-zoyl-amino]-2-hydroxy-propane. In 2 50 ml of DMF, 102 g of the product described in Example 3 (0.07 mol) are reacted with 150 ml of sodium methylate 1M in methyl alcohol (0.15 mol) and with 30 30 g of metansulphonate methyl ester (0.27 mol), according to the procedure described in Example 20. HO 5 37 42.6 g of 1,3-bis-[3-[N-methy1-N-(L-2-hydroxy-pro-pionyl)]amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane are obtained. 5 Yield: 41% m.p.: 284°C Elemental Analysis (%) CHIN Calculated: 26.50 2.70 51.10 5.64 Found: 26.24 2.80 50.88 5.47 10 EXAMPLE 22 1,3-bis-[3-(N-methyl-N-hydroxyacetyl)amino-5-(2,3-dihy-droxy-propyl)aminocarbony1-2,4,6-triiodo-benzoyl-amino ]-2-hydroxy-propane. 23 g of 3-(N-methyl-N-acetoxyacetyl)amino-2,4,6-15 triiodo-isophthaloyl-dichloride (0.032 mol), described in EP 26281/Example 11, are reacted with 5.8 g of 2,3-dihydroxy-propylamine (0.064 mol) in THF according to the procedure described in Example 19a). The resulting product is 3-(N-methyl-N-acetoxyacetyl)amino-5-(2,3-di-20 hydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl- chloride, which is reacted in DMF with 1.5 g of 1,3-diamino-2-hydroxy-propane (0.016 mol). The resulting product is isolated and purified according to the procedure of Example 1. 11 g of 1,3-bis-[3-(N-methy1-N-hy-25 droxyacetyl)amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2 ,4 ,6-triiodo-benzoyl-amino]-2-hydroxy-propane are obtained. Yield: 47% m.p.: 295°C (dec.) Elemental Analysis (%) 30 CHIN Calculated: 25.47 2.48 52.08 5.75 ?40 5 38 Found: 25.97 2.50 51.71 5.77 In the same way the following compound is obtained: 1,3-bis-[3-(N-methy1-N-hydroxyacetyl)amino-5-(1,3,4-trihydroxy-2-buty1)]aminocarbonyl-2,4,6-5 triiodo-benzoy1-amino]-2-hydroxy-propane. EXAMPLE 23 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydro-xyisopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane. 10 Following the procedure described in Example 2, the 3-(L-2-acetoxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl )aminocarbonyl-2,4,6-triiodo-benzoyl-chloride is reacted in DMF with l,3-diamino-2,2-bis-hydroxyme-thyl-propane to give the desired product. 15 Yield: 65% m.p.: 285°C (dec.) Elemental Analysis (%) CHIN Calculated: 26.32 2.68 50.55 5.58 Found: 26.21 2.72 50.31 5.53 20 TLC: (Silica Gel 60 ^254' Merc^) Eluent: CHCl3/CH3OH/NH4OH 25% = 6/3/1 v/v/v. Rf = 0.12 HPLC: Rt = 17.7 min. Titre = 98% (on the area) Chromatographic conditions: as reported in Example 3. EXAMPLE 24 25 l,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-[N-methy1-N-(D-l-deoxy-glucitol)]aminocarbonyl-2,4,6-triiodo-ben-zoy1-amino]-2,2-bis-hydroxymethyl-propane. Following the procedure described in Example 2, 10 g of 3-(L-2-acetoxy-propionyl)amino-5-[N-methy1-N-(D-l-30 deoxy-glucitol)]aminocarbonyl-2,4,6-triiodo-benzoyl- chloride (0.011 mol) in 50 ml of DMF are reacted with 240566 39 I.19 g of 1,3-diamino-2,2-bis-hydroxymethyl-propane (0.006 mol) and 4.94 g of tributylamine (0.027 mol) in 20 ml of DMF. II.5 g of the title compound are obtained. 5 Yield: 58% Elemental Analysis (%) CHIN Calculated: 28.72 3.29 44.41 4.90 Found: 28.60 3.33 44.37 4.85 13 10 C-NMR spectrum is in accordance with the proposed structure. In the same way the following compounds are obtained: 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(2,3-dihydroxy-propyl )aminocarbonyl-2,4,6-triiodo-benzo-15 yl-amino]-2,2-bis-hydroxymethyl-propane. 1,3-bis[3-(L-2-hydroxy-propionyl)amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4, 6-triiodo-benzoyl-amino] -2 ,2-bis-hydroxymethyl-propane. EXAMPLE 25 20 1,3-bis-[3-[N-methy1-N-(L-2-hydroxy-propionyl)]amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino] -2 ,2-bis-hydroxymethyl-propane. The product described in Example 23 is submitted to N-methylation with sodium methylate and CH3I fol-25 lowing the procedure of Example 19c). Yield: 65.5% m.p.: > 300°C Elemental Analysis (%) CHIN Calculated: 27.40 2.89 49.63 5.48 30 Found: 27.38 2.91 49.47 5.45 [^2°436 = +26.7° (c = 10% H20) In the same way the following compounds are obtained: 1,3-bis-[3-[N-methyl-N-(L-2-hydroxy-propionyl)]-amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-pro-5 pane. 1,3-bis-[3-[N-methyl-N-(L-2-hydroxy-propionyl)]-amino-5-(1,3,4-trihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane. 10 EXAMPLE 26 1,3-bis-[N-methy1-N-[3-[N-methy1-N-(L-2-hydroxy-propionyl )]amino-5-(2-hydroxy-ethyl) aminocarbonyl-2,4,6-tri-iodo-benzoy1]amino]-2-hydroxy-propane. The product described in Example 6 is submitted to 15 N-methylation with sodium methylate and CH3I following the procedure of Example 19 c). Yield: 58% m.p.: 280°C Elemental Analysis (%) CHIN 20 Calculated: 27.18 2.76 52.22 5.76 Found: 27.25 2.77 52.14 5.91 13 C-NMR spectrum is m accordance with the proposed structure. EXAMPLE 27 25 1,3-bis-[N-methy1-N-[3-[N-methy1-N-(L-2-hydroxy-propionyl )]amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane. The product described in Example 7 is submitted to N-methylation with sodium methylate and CH^I following 30 the procedure of Example 19 c). Yield: 54% m.p.: 285°C (dec.) 240 5 6 41 Elemental Analysis (%) C H IN Calc.: 27.69 2.92 50.15 5.53 Found: 25.25 3.23 48.72 5.27 (H20 = 2.7%) 5 Solubility in H20 at 20°C: 100% w/v 13C-NMR spectrum is in accordance with the proposed structure. EXAMPLE 28 1,3-bis- [ 3 - (N-methy1-N-hydroxyacety1)amino-5-(1,3-dihy-10 droxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino ] -2 ,2-bis-hydroxymethyl-propane. The product described in Example 2 is reacted with 2 equivalent of NaOH, hence with an excess of CH^Br in DMF for one day under stirring in a sealed system. The 15 subsequent work follows the procedure described in Example 19 c). Yield: 54% m.p.: > 285-288°C Elemental Analysis (%) CHIN 20 Calculated: 26.32 2.68 50.55 5.58 Found: 25.90 2.80 50.12 5.53 TLC: (Silica Gel 60 F254' Merck) Eluent: CHCl3/CH3OH/NH4OH 25% = 3/2/1 v/v/v. Rf = 0.26 HPLC: Rt = 15.5 min. Titre = 97.7% (on the area) 25 Chromatographic conditions: as reported in Example 2. In the same way the following compounds are obtained: 1,3-bis-[3-(N-methyl-N-hydroxyacetyl)amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-ben-zoy1-amino]-2,2-bis-hydroxymethyl-propane. 30 - l,3-bis-[3-(N-methyl-N-hydroxyacetyl)amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6- triiodo-benzoyl-aiuino]-2,2-bis-hydroxymethylpro-pane. 240 5 43 Table 1 - Acute toxicity of an aqueous solution of 1,3-bis[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydro-xyisopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino] -2-hydroxy-propane . 5 Toxicity Doses Concentration Administered Dead/Treated LD50 mgl/kg mgl/ml Volume Ratio C.L. 95% ml/kg mgl/kg 900 300 30.0 0/10 a) 11600 300 38.7 0/10 > 15000 15000 300 50.0 0/10 b) 900 300 3.0 0/10 >900 a): Intravenous administration (14 days of observation) in mice. 15 b): Intracisternal administration (7 days of observation) in rats. Table 2 - Comparison among some preferred compounds of 20 the invention and IODIXANOL. Compound Osmolality 37°C. 300 mgl/ml mosm/kg H2O Viscosity 37°C. 300 mgl/ml mPa-s A 141 8.5 B 131 8.6 C 196 8.7 A: 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-di-hydroxy-isopropyl)aminocarbonyl-2,4, 6-triiodoben-zoy1-amino]-2-hydroxy-propane. 30 B: 1-[3-(L-2-hydroxy-propionyl) amino-5-(1,3-dihydro-xyisopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl- </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 240 566 44 amino]-3-[3-hydroxyacetylamino-5-(2,3-dihydroxy-propyl )aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane. 1,3-b is-[N-[3,5-bis-(2,3-dihydroxy-propyl)aminocarbonyl-2 ,4,6-triiodo-phenyl]-acetylamino]-2-hy-droxy-propane [IODIXANOL: EP 108638, Example 3] 45 10 WHAT WE CLAIM IS

1. Symmetrical and asymmetrical 1,3-bis-[3-(mono- or di-hydroxy)acylamino-5-(mono- or poly-hydroxyalkyl)-aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-hydroxy- or hydroxyalkyl-propanes of general formula (I) l?2* Afkyl(OK)i. Ov .N AlkyKOKJi.g A B wherein: R and R', which are the same or different, are a straight or branched mono- or di-hydroxyalkyl C^-C^ residue, (i). £/. .V ^ 20 25 30 R]_' R2 R^f which are the same or different, are H c-r . ^^'OYfOcj CH-, R.|,, R2i and R^,, which are the same or different, are H or or ch, 3 / Alkyl(OH) is a group of the formula -ch(ch2oh)ch(oh)ch2oh, -ch(ch2oh)2, -ch2ch(0h)- ch2oh, -ch2(choh)4ch2oh, or -ch2ch2oh, X is a group of the formula -CH(OH)-, -CH(CH20H)- -c(oh)(ch2oh)- or -c(ch2oh)2-; and A and B, may be the same or different, and enan- tiomers, diastereoisomers and/or rotamers thereof.

2. Compounds according to claim 1, where R2, R21, R3/and Rg1 represent hydrogen and the two residues A and B are equal. 2 46

3. Compounds according to claim 1, where R^, R^',R2, R2 1 » and 1 represent hydrogen and the two residues A and B are equal.

4. Compounds according to claim 1, where R2> R2 1 , R3 and 5 R3' represent hydrogen, Alkyl(OH)1_5 represents either 1,3-dihydroxy-isopropy1 or 2,3-dihydroxy-propy1, X represents the group -CH(OH)- and the two residues A and B are equal. 5* A compound according to any one of claims 1 to <(, 10 selected from the group constituted by: 1,3-bis-[3-(2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl) aminocarbonyl-2 ,4, 6-triiodo-benzoyl-amino] -2-hydroxy-propane,,. 1,3-b is-[3-(L-2-hydroxy-propionyl)amino-5-(1,3- .i 'I f •'*>, 15 dihydroxy-isopropyl) aminocarbonyl-2,4 , 6-triiodo-;:: ^ benzoyl-amino]-2-hydroxy-propane , \ 1,3-bis-[3-hydroxyacetylamino-5-(l,3-dihydroxy^ isopropyl)aminocarbonyl-2 ,4 , 6-triiodo-benzoyl- J? amino ]-2 ,2-bis-hydroxymethyl-propane , 20 - 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(2,3- dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino] -2-hydroxy-propane , l,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-25 benzoyl-amino]-2-hydroxy-propane , 1-13-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydro-xy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino ]-3-[3-hydroxyacetylamino-5-(2,3-dihydroxy-propyl )aminocarbonyl-2,4, 6-triiodo-benzoyl-amino]-30 2-hydroxy-propane , 1,3-bis-[3-hydroxyacetylamino-5-(2,3-dihydroxy- 24 0 5 6 6 V 47 propyl) aminocarbonyl-2,4,6-triiodo-benzoyl-amino ]- 2.2-bis-hydroxymethyl-propane, 1.3-bis-[3-hydroxyacetylamino-5-( 1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl- 5 amino]-2 ,2-bis-hydroxymethyl-propane -t 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-[N-me-thy1-N-(1,3-dihydroxy-isopropyl)]aminocarbony1-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane, 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-[N-me-10 thy1-N-(2,3-dihydroxy-propyl)]aminocarbonyl-2,4,6- triiodo-benzoy1-amino]-2-hydroxy-propane, 1,3-bis-[N-methy1-N-[3-(L-2-hydroxy-propionyl)-amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane, 15 - l,3-bis-[N-methyl-N-[3-(L-2-hydroxy-propionyl)- amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoy1]amino]-2-hydroxy-propane, 1,3-bis-[3-hydroxyacetylamino-5-(1,3-dihydroxy-isopropyl )aminocarbonyl-2,4,6-triiodo-benzoyl-20 amino]-2-hydroxy-propane,. l,3-bis-[3-hydroxyacetylamino-5-(2,3-dihydroxy-propyl )aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane , 1,3-bis-[3-hydroxyacetylamino-5-(1,3,4-trihydroxy-25 2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl- amino] -2-hydroxy-propane , 1,3-bis-[3-hydroxyacetylamino-5-[N-methy1-N-(1,3-dihydroxy-isopropyl)]aminocarbonyl-2,4,6-triiodo-benzoyl-amino ]-2-hydroxy-propane , 30 - l,3-bis-[3-hydroxyacetylamino-5-[N-methyl-N-l f/Jy dihydroxy-propyl) ]aminocarbony 1-2,4,6-triiod^.4n- s°crw3i 48 zoyl-amino]-2-hydroxy-propane, 1,3-bis-[N-methy1-N-[3-hydroxyacetylamino-5-(l,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane, 1,3 -bis- [N-methy1-N-[3-hydroxyacetylamino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodoben-zoyl]amino]-2-hydroxy-propane 5 1,3-bis-[3-(N-methy1-N-hydroxyacetyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino ]-2-hydroxy-propane, 1,3-b is-[3-[N-me thy1-N-(L-2-hydroxy-propiony1)]-amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane, 1,3-bis-[3-[N-methy1-N-(L-2-hydroxy-propionyl)]-amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane, 1,3-bis-[3-[N-methy1-N-(L-2-hydroxy-propionyl)]-amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane, 1,3-bis-[3-(N-methy1-N-hydroxyacetyl)amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-ben-zoy1-amino]-2-hydroxy-propane, 1,3-bis-[3-(N-methy1-N-hydroxy acetyl)amino-5-(1,3/4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane, 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino ] -2 , 2-bis-hydroxymethyl-propane, 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-(2,3-dihydroxy-propyl) aminocarbonyl-2,4 , 6-triiodo^B^l^^v;,^ zoyl-amino]-2,2-bis-hydroxymethyl-propane, ~

5 OCT 1993 49 1,3-bis - [ 3 - (L-2-hydroxy-propionyl)amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo- amino-5-(1,3-dihydroxy-isopropyl)aminocarbony1-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane , 1,3-bis-[3-[N-methy1-N-(L-2-hydroxy-propionyl)]-amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-pro-pane . , 1,3-bis-[3-[N-methy1-N-(L-2-hydroxy-propionyl)]-amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane , 1,3-bis-[3-(N-methy1-N-hydroxyacetyl)amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino] -2 ,2-bis-hydroxymethyl-propane, 1,3-bis-[3-(N-methy1-N-hydroxyacetyl)amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino ] -2 , 2-bis-hydroxymethyl-propane , 1,3-bis-[3-(N-methy1-N-hydroxyacetyl)amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2,2-bis-hydroxymethyl-propane , 1,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-[N-methy1-N-(D-l-deoxy-glucitol)]aminocarbonyl-2,4,6- triiodo-benzoy1-amino]-2-hydroxy-propane , 1,3-b is-[3-(L-2-hydroxy-propionyl)amino-5-f N-me- triiodo-benzoy1-amino]-2,2-bis-hydroxymethyl-pro- benzoyl-amino]-2,2-bis-hydroxymethyl-propane, 1,3-bis-[3-[N-methy1-N-(L-2-hydroxy-propionyl)]- thyl-N-(D-l-deoxy-glucitol)]aminocarbonyl- , . o 24 0 5 6 6 50 pane, 1-[3-hydroxyacetylamino-5-(1,3,4-trihydroxy-2-bu-tyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino ] -3 -[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy-isopropyl )aminocarbonyl-2,4,6-triiodo-benzoyl-amino ]-2-hydroxy-propane, 1-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydro-xy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino ] -3- [ 3- ( L-2-hydroxy-propionyl)amino-5-(2,3— dihydroxy-propyl)aminocarbonyl-2,4,6-triiodoben-zoy1-amino]-2-hydroxy-propane. 1-[3-(L-2-hydroxy-propionyl)amino-5-(1,3-dihydro-xy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino ]-3-[3-(L-2-hydroxy-propionyl)amino-5-[N-methy 1-N- (D-l-deoxy-glucitol)]aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane, 1,3-bis-[N-methy1-N-[3-hydroxyacetylamino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoy1]amino]-2-hydroxy-propane , 1,3-bis-[N-methy1-N-[3-hydroxyacetylamino-5- [N-methyl-N-(1,3-dihydroxy-isopropyl)]aminocarbony1-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane , 1,3-bis-[N-methy1-N-[3-hydroxyacetylamino-5-[N-methy1-N-(D-l-deoxy-gluc itol)]aminocarbonyl-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane , 1,3-bis-[N-methy1-N-[3-(L-2-hydroxy-propionyl)-amino-5-(2-hydroxy-ethy1)aminocarbonyl-2,4,6- triiodo-benzoyl]amino]-2-hydroxy-propane , . 1,3-bis-[N-methy 1-N-[ 3- (L-2-hy droxy-propionyl amino-5- (1,3,4-trihydroxy-2-butyl) aminocarbon^l- 2,4, 6-triiodo-benzoyl ] amino]-2-hydroxy-propane> 5OCT 19% & 51 1,3-bis-[N-methyl-N-[3-[N-methyl-N-(L-2-hydroxypropionyl) ]-amino-5-(2-hydroxy-ethyl)aminocarbonyl-2, 4,6-triiodo-benzoyl]amino]-2-hydroxy-propane, and l,3-bis-[N-methyl-N-[3-[N-niethyl-N-(L-2-hydoxypropionyl) ]-amino-5- (1,3-dihydroxy-isopropyl) aminocarbonyl-2,4,6-triiodo-benzoyl ] amino]-2-hydroxy-propane.

6. Process for the preparation of a 1,3-bis-[3-(mono- or di-hydroxy)acylamino-5-(mono- or poly-hydroxyalkyl) aminocarbonyl-2,4, 6-triiodo-benzoyl-amino]-hydroxy- or hydroxyalkyl-propane of general formula (I) as defined in claim 1, characterized in that either: a) a compound of general formula (II) R3-HN-CH2-X-CH2-NH-R3' (II) wherein: R3 and R3' are H or CH3, and X represents -CH(OH)-, -CH(CH2OH)-, -C(OH) (CH2OH) - or -C(CH2OH)2-, and one of the amino groups may be protected by a suitable protective group/ is reacted, with a reactive derivative of a 3-(mono- or di-acyloxy)acylamino-5-(mono- or poly-hydroxyalkyl) aminocarbonyl-2,4,6-triiodobenzoic acid of general formula (III) 12' ocTmsij V. / R4 is a straight or branched mono- or di-acyloxyalkyl Ci-Cia residue containing from 3 to 13 atoms of C and 1 or 2 acyloxy groups C2-C5/ (III), r i i o wherein: Rx and Rz represent H or CE3/ 52 4^56 61 Alkyl(OH)1_5 is a group of formula CH2 (CHOH) 4CH20H, -CH2CH(OH)CH2OH, -CH(CH20H)CH(0H)CH20H, -CH2CH2OH, or - ch(ch2oh)2, in which the hydroxy groups may be protected by acetalic or ketalic groups, and CO-Y is the residue of a mixed anhydride or a halogenocarbonyl group, in a molar ratio of 1:2, in a solvent and in the presence of a basic condensation agent to directly give a product of general formula (IV)/ A (IV). wherein Rx, R2, R3, R'ir R2', R'3r R4f AlkyltOH)^ and X have the previously described meaning and R5 corresponds to R4; or b) a compound of formula (II), in which one of the two amino groups is protected by a suitable protective group, is reacted with a compound of formula (III) in a molar ratio of 1:1 in a solvent and in the presence of a basic condensation agent to give, after hydrolysis of the protective groups, a corresponding l-[3-(mono- or di-hydroxy) acy lamino-5 -(mono- or poly-hydroxyalkyl ) -aminocarbonyl-2 ,4,6-triiodo-benzoyl-amino]-3-amino-hydroxyalkyl derivative of formula (V) o f\ T (V). r?Q *C,, wherein Rir R2, R3, R3', AlkylfOH)^ and X have been previously defined, and R is a straight or branched mono- or di-hydroxyalkyl Ci-Ca residue, and this compound of formula (v) is subsequently reacted with a derivative of formula (III) in the presence of a basic condensation agent to give the desired compound of formula IV where Rs corresponds to R4; £40566 53 then, the compound of formula IV prepared by either process a) or b) is transformed, by hydrolysis of the protective groups, into the corresponding compound of formula (I) and this last one, if the two Ri and R./ are H, may be, if desired, N-methylated in an alkaline medium.

7. Process for the preparation of compounds of general formula (I), where R2 and Ra' are CH3, characterized in that a compound of general formula (I), in which R2 and R2' are hydrogen, is methylated in an alkaline solution by means of treatment with methyl halide, dimethylsulphate, methylsulphonate, or dimethylcarbonate.

8. Non-ionic X-ray contrast agents containing as an opacifying component at least one 1,3-bis-[3-(mono- or dihydroxy)acylamino-5-(mono- or poly-hydroxyalkyl)amino-carbonyl-2,4,6-triiodo-benzoyl-amino] -hydroxy or hydroxyalkyl-propane according to any one of claims 1 to 5.

9. A process for the preparation of a compound of general formula (I) substantially as herein defined and with particular reference to the Examples.

10. A compound of general formula (I) as herein defined when prepared by any one of the processes of claims 6, 7 or 9. per: attorneys for the applicant </div>