5,5'-/(1,3-PROPANEDIYL) BIS-/IMINO(2-OXO-2,1-ETHANEDIYL)ACETYLIMINO/BIS(2,4,6-TRIIODO-1,3-BENZENEDICARBOXYAMIDES), AND CONTRAST MEDIA CONTAINING THEM

Abstract: Compounds of formula (I), wherein R1, R2, R3, R'1, R'2, R'3 have the meanings defined in claim 1, are useful as opacifying components for X-ray contrast media.

Description: 5 , 5 ' -/( l , 3-PR0PANEDIYL) BIS-/IMIN0( 2-0X0-2, 1-ETHANEDIYL)ACETYLIMIN0 BIS(2 , 4, 6-TRII0D0-1 , 3-BENZENEDICARB0XYAMIDES) , AND CONTRAST MEDIA CONTAINING THEM This invention relates to symmetrical and asymme¬ trical 5,5 ■ -[ (l,3-propanediyl)bis [imino(2-oxo-2,1-etha- nediyl)acetylimino] ]bis(2,4,6-triiodo-l,3-benzenedicar- boxyamides), useful as opacifyng component of X-ray contrast media, of general formula (I) wherein : R>R'/ R ' R l'' which are the same or different, are H, "1~ C 4 alkyl, linear or branched c ι _c -4 mono- or polyhydroxyalkyl, 12; R 2' /R 3 ,R 3' ' which are the same or different, are one of the groups of formula -CH-Cϊ^OH, -CH 2 CH(OH)CH 2 OH, -CH(CH 2 OH)CH(OH)CH 2 OH, -CH 2 (CHOH) 4 CH 2 OH or -CH(CH 2 OH) 2 , X is one of the groups -CH(OH)-, -CH(CH 2 OH)-, -C(OH) (CH 2 OH)- or -C ( CH 2 OH) 2 - ; as well as enantiomers, diastereoisomers and/or rota- merε thereof. This inventions also includes the process for pre paring these non-ionic compounds, as well as the X-ra contrast media containing them as opacifying compo nents . Preferred compounds of formula (I) are those i which R, R', R χ , R χ ' are H or CH 3 and X is -CH(OH)- o -C(CH 2 0H) 2 -« Particularly preferred are those in whic R; R'» R χ , χ ! are H and X is -CH(OH)-. Compounds of formula (I) belong to the class o non-ionic contrast media for X-ray diagnosis, which are more and more replacing the salts of 2,4, 6-triiodo-ben- zoic acid derivatives, up to now widely used, in view of their better toler ability and minimum tendency to produce side effects. Thanks to the elimination of io- nic species, non-ionic solutions, in comparison with ionic agents, are characterized by the same iodine con¬ tent and a lower osmotic pressure, therefore a lower os olality. For this reason, for instance in angio- graphy, they cause less pain and lower endothelial da- mages. And in subarachnoidal administration used in myelography or cysternography, cases of arachnoiditis or epileptical episodes are very rare while they are frequent when ionic contrast media are used. Unfortunately, despite their remarkable physical arid pharmacological properties, non-ionic contrast media, basically consisting of monocyclic aromatic triiodina- ted nuclei, are too much hypertonic at the high dosages and concentrations required for many specific examina¬ tions. This fact led to the development of hexaiodina- ted dimeric products, in which osmolality is further reduced in accordance with iodine concentration. Howe- ver, the concentrated solutions of those compounds are often too much viscous. In addition, a large number of products, although theoretically promising, are not enough soluble. For this reason, research efforts have been paid on new hexaiodinated dimeric products characterized by high solubility, low viscosity and osmolality as well as i.v., intracisternal and intracerebral high tolera- bility and minimum side effects (pain, temperature raise, nausea, pressure lowering and vessel damages). In particular physicians need new contrast media covering many different uses, for instance urography, angiography, cardioangiography, phlebography , myelo- graphy, cysternography , ly phography , istersalpingo- graphy, bronchography and gastrography as well as arti¬ cular cavities visualization. The compounds of the present invention are gene¬ rally characterized by a good water solubility, in some cases exceeding 100 g of compound per 100 ml of solu- tion at 30°C. Furthermore their solutions are low osmolar but surprisingly without bringing about the expected incre¬ ase in viscosity. For instance, one of the preferred compounds of this invention, 5,5 ' -[ (2-hydroxy-l, 3-propanediyl)bis- [imino(2-oxo-2 , 1-ethanediyl )acetylimino] ]bis-[N,N'-bis- (2, 3-dihydroxypropyl)-2 ,4 , 6-triiodo-l ; 3-benzenedicarbo- xyamide], produces stable aqueous solutions at 30°C containing more than 100 g of product per 100 ml of so- lution, as indicated in Table 1 which also includes the good values of osmolality and viscosity obtained for said compound. Table 1 - Chemico-physical characteristics of the com¬ pound of formula (I): 5,5'-[ (2-hydroxy-l,3- propanediyl)bis[imino(2-oxo-2,1-ethanediyl)-a- cetylimino]]bis[N, '-bis(2,3-dihydroxypropyl)- 2,4,6-triiodo-l,3-benzenedicarboxyamide] Solubility in H 2 o at 30°C: > 100 g in 100 ml Osmolality a) Iodine concentration 200 mgl/ml 300 mgl/πύ 400 mgl/ml Osmolality 0,17 0,25 0,72 r (osmol/kg H 2 0) a): Calculated with a steam-pressure osmometer We- scor v ' mod 5500, calibrated w th NaCl aqueous so¬ lutions. b): Calculated with ROTOVISCO (R) RV100-CV100-LV100, sensor ZB15. The process for the preparation of 5,5'-[(2-hydro- xy-1,3-propanediyl)bis[imino(2-oxo-2,1-ethanediyl)-ace- tylimino]]biε(2,4,6-triiodo-l,3-benzenedicarboxyami- des) of formula (I) is characterised in that a ,N'- 1,3-propanediyl-bis(2-chloroacetamide) of formula (II) C1CH 2 0C-NH-CH 2 -X-CH 2 -NH-C0CH 2 C1 (II) , where X is one of the groups -CH(OH)-, -CH(CH_OH)-, -C(OH) (CH 2 OH)- or -C(CH 2 OH) 2 -, in which hydroxy groups have been protected by an adequate protective group, is reacted, directly or through a multistep process, with a 5-acetylamino-2,4,6-triiodo-isophthaldiamide reactive derivative of general formula (III) wherein : R and R, which are the same or different, are H, < ~ -, -C 4 alkyl, linear or branched C.-c 4 mono- or polyhydroxyalkyl, R and R,, which are the same or different, are one of the groups of formula -CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 OH, -CH(CH 2 OH}CH(OH)CH 2 OH, -CH 2 (CHOH) 4 CH 2 OH or -CH(CH 2 OH) 2 , Z is an alkali metal ion, preferably Na + or K + , and, after deprotecting the hydroxy groups, the corre¬ sponding compound of general formula (I) is obtained, according to one of the two preferred procedures: a) a compound of formula (II) is reacted in a solvent with a compound of formula (III) in a molar ratio ranging from 1:2 to 1:2.5, thereafter the remaining protective groups are hydrolysed in an acid mediu in order to directly obtain the corresponding com pound of formula (I), b) a compound of formula (II) is reacted in a solvent with a compound of formula (III) in a molar ratio ranging from 1:1 to 1:0.5 to give the compound of formula (IV) wherein R, R.. , R_ . R,, X are as previously descri¬ bed, and said compound (IV) is then reacted in a solvent with another compound of formula (III) in a molar ratio ranging from 1:1 to 1:1.2, thereafter the remaining protective groups are hydrolysed in an acid medium to give the corresponding compound of formula (I) . If a direct reaction of the compound of formula (II) with a compound of formula (III) is performed ac¬ cording to synthesis a), symmetrical products with two identical aromatic iodinated residues are obtained. If a multistep reaction is performed according to synthesis b), asymmetrical products with two different iodinated aromatic residues are obtained. The reaction intermediate (II) is common to the two already mentioned synthesis and can conventionally be obtained by reacting a 1,3-diamino-propyl derivative of general formula (V) NH 2 -CH 2 -X-CH 2 -NH 2 (V), wherein X is as previously described, with methyl or ethyl chloroacetate in a preferably alcoholic solvent and subsequently protecting the hydroxy groups with suitable protecting groups. Preferred X groups in compounds of formula (V) are -CH(OH)- and -C(CH 2 OH) 2 - residues. The protection of hydroxy groups in compounds of formula (V) can be also preferably obtained by reacting said compounds with 3,4-dihydro-2H-pyran in an aprotic organic solvent and in the presence of a suitable ca¬ talyst, such as for instance pyridinium p-toluenesulfonate (PPTS). Isophthaldiamides of formula (III) are preferably obtained by reacting 5-acetylamino-2,4,6-triiodo- isophthalic acid dichloride with the following hy- droxyalkylamines : 2-hydroxy-ethylamine, 1,3-dihydroxy- isopropylamine (serinol), 2, 3-dihydroxy-propylamine (isoserinol) , 2-amino-l,3,4-butanetriol or N-methyl- glucamine, following known synthetic processes such as those described in US 4,001,323 and EP 26281. Condensation reaction of the compounds of formula (II) with the isophthaldiamide reactive derivatives of formula (III) is preferably carried out in an inert or¬ ganic solvent. Dimethylformamide (DMF) is particularly preferred for most of the compounds of the present in¬ vention. The temperature ranges from room to solvent boiling temperature, preferably between 20 and 60°C. Final hydrolysis of hydroxy protecting groups is prefe¬ rably performed at room temperature in an aqueous sol- vent acidified at pH values ranging from 1 to 3, prefe¬ rably 2. The compounds of the present invention can be used as opacifying agents in non-ionic contrast media for X- ray analysis. They can be formulated in an appropriate pharmaco¬ logically acceptable carrier. Suitable carriers com¬ prise, for instance, those useful for enteral or pa- renteral administration. Examples of suitable carriers are sterile buffered aqueous solutions containing tro- methamine; phosphate, citrate, and/or bicarbonate ions, ionically balanced solutions containing physiologically tolerable anions and cations such as Cl^ ~ ', HCO_^~', Ca (2+) , Na (+) , K (+ ) and g (2+) . The solutions of the contrast media of the present invention can also con¬ tain a small amount of a physiologically tolerable che- lating agent, such as EDTA sodium and calcium salts, in concentratio s between 0.05 and 2 mM/1, or even hepa- rin, at a dosage ranging between 5 and 500 units per 100 ml of solution, or in another suitable anticoagu¬ lant agent. Hypotonic solutions of the contrast media of the present invention can be made isotonic by adding a correct amount of erlis liquid (Am. J. Phy. Vol. 131, 1940 p 67-72). useful iodine concentrations of said contrast media can range, according to the use, between 140 and 500 mgl/ml at a dosage of 10-300 ml. The following experimental examples illustrate the basic features of this invention. EXAMPLE 1 5,5*-[ (2-hydroxy-l,3-propanediyl)bis[imino(2-oxo-2,l- ethanediyl)acetylimino] ]bis[ , '-bis(2,3-dihydroxy- propyl)-2,4,6-triiodo-l,3-benzenedicarbox amide] . a) 2-hydroxy- ,N'-l,3-propanediyl-bis(2-chloroaceta- mide) . Into a three-necked 500 ml flask, equipped with a stirrer, thermometer and a calcium chloride valve, a methyl chloroacetate solution (47 g; 0.433 mol) in 100 ml of CH 3 OH is placed and temperature is kept between 0 and 5°C. A 1,3-diamino-2-hydroxy-propane (18 g; 0.2 mol) (Rif: Beil. 4H290, E II 739, E IV 1694) solution in 50 ml of CH^OH is added dropwise into the mixture, under stirring, during three hours while keeping the temperature between 0 and 5°C. When the operation is completed, temperature is raised to 20-25 c C and the mixture is kept under stirring overnight. As the reaction is completed, pH is neutral and a white crystalline precipitate is obtained, which is filtered, washed with CH,OH and dried under vacuum to obtain 37 g of crude 2- hydroxy-N,N'-1, 3-propanediyl-bis(2-chloroaceta- mide). After crystallization from 96% EtOH, 30 g of pure product are obtained. Yield: 61,7% m.p.: 115°C Elemental analysis (%) C H Cl N Calc: 34.59 4.98 29.17 11.52 Found: 34.45 4.95 28.54 11.26 IR, H and C-NMR spectra are in accordance with the structures. b) 2-[ (tetrahydro-2H-pyran-2-yl)oxy]-N,N'-l,3-propa- nediyl-biε(2-chloroacetamide) . To a suspension of 2-hydroxy-N,N'-1,3-propanediyl bis(2-chloroacetamide) (12.16 g; 0.050 mol) an 3,4-dihydro-2H-pyran (6.31 g; 0.075 mol) in 350 m of CH 2 C1 2 , 1.25 g of pyridinium p-toluenesulfonat (PPTS) (0.005 mol) are added in portions under stirring at a temperature of 5°C. After 30 minutes, temperature raises up to 20-25°C and the stirring is continued during 72 h; the solution is washed with 20% aqueous NaCl (2 x 100 ml), dried over 10 Na 2 S0. and concentrated to dryness under vacuum. The residue solidifies in n-hexane, and then after filtration, is crystallized from EtOH (115 ml) to obtain 14.1 g of 2-[ (tetrahydro-2H-pyran-2-yl)ox ]- N,N'-1,3-propanediyl-bis(2-chloroacetamide) . 15 Yield: 86% m.p.: 100°C Elemental analysiε (%) C H Cl N Calc: 44.05 6.16 21.67 8.56 Found: 44.16 6.20 20.70 8.53 20 IR, H and 13 C-NMR spectra are in accordance with the structures. c) N,N l -bis(2,3-dihydroxypropyl)-5-acetylamino-2,4,6- triiodo-1,3-benzenedicarboxyamide. In a three-necked 500 ml flask, 13.6 g (0.15 mol) 25 of l-amino-2,3-dihydroxy-propane are dissolved in 100 ml of dime hylacetamide (DMAC). The temperature is decreased to +3 - +5°C. Then a solution of 19.1 g (0.03 mol) of 5-acetylamino-2,4,6-triiodo-iso- phthalic acid dichloride (obtained according to the 30 synthesis scheme described in US 4,001,323 and EP 26281) in 60 ml of DMAC iε added dropwise under stirring for 1 h. The temperature raises between 20 and 25 C C, and 3 h later the solvent is evaporated and an oily reεi- due is obtained, which is diluted with water and kept under stirring up to its transformation into a white solid. After filtration, the product is suspended in 150 ml of CH OH and boiled for 2 h more. After cooling, the crystalline solid is filtered and dried to ob- tain 14.9 g of ,N'-bis (2, 3-dihydroxypropyl)-5-ace- tyl-amino-2,4,6-triiodo-l,3-benzenedicarboxyamide. Yield: 66.5% m.p.: 292-295°C (dec) d) 5,5'-[ (2-hydroxy-l,3-propanediyl)bis [imino(2-ox'o- 2,1-ethanediyl)acetylimino] ]bis[N,N'-bis(2,3-dihy- droxypropyl)-2,4,6-triiodo-l,3-benzenedicarboxya- mide] . 9.13 g (0.012 mol) of N,N'-bis (2,3-dihydroxypro- pyl)-5-acetylamino-2,4,6-triiodo-l,3-benzenedicar- boxyamide, obtained according to procedure c), are εuεpended in 130 ml of DMF at 40 C C, under εtirring and inert atmoεphere (N 2 ). 12.2 ml (0.012 mol) of 1M CH^ONa in CHgOH are εlowly added dropwiεe to the suspension. As soon as a clear solution is obtained the alcoholic solvent is removed under reduced pressure, therefore 2 g (0.006 mol) of 2- [ (tetrahydro-2H-pyran-2-yl)oxy]-N,N'-l,3-propane- diyl-biε(2-chloroacetamide) are added a-ccording to procedure b). The mixture is reacted at 40°C under stirring for 17 h, then the solvent is evaporated under vacuum and the oily residue is diluted many times with H 2 ci 2 and dried to remove totally the residual solvent. A solid product is obtained which is diluted in 75 ml of H 2 o. The pH of the solution is adjusted to 2 with IN HCl and kept constant at room temperature for 20 h until the tetrahydropyranyl protecting group is completely hydrolysed. Finally, the aqueous solution is percolated in succession on 20 ml of Amberlite^ R ' IR 120 and on 50 ml of IRA^ R ' 400. The eluate obtained from ion- exchange resins is concentrated to about 100 ml, treated for 30 min with Amberlite^ R 'XAD-2 resin and finally concentrated to drynesε. The residue (7.18 g) is cromatographed on 50 ml of silica gel 60F Merck (230-400 mesh). Eluting mixture: CH 2 ci 2 /CH 3 OH of 3/1 to 0/1 (v/v) . The recovered product (5.46 g) is crystallized twice from CH 3 OH/EtOH to obtain 3.95 g of 5,5'-[(2- hydroxy-1,3-propanediyl)bis[imino(2-oxo-2,1-ethane- diyl)acetylimino]]bis [N,N'-bis(2,3-dihydroxypro- pyl)-2,4,6-triiodo-l,3-benzenedicarboxyamide]. Yield: 86% Elemental analyεis (%) C H I N Calc: 28.15 3.03 45.75 6.73 Found: 28.32 3.03 45.72 6.56 EXAMPLE 2 5,5 l -[(2-hydroxy-l,3-propanediyl)bis[imino(2-oxo-2,l- ethanediyl)acetylimino]]bis[ ,N'-biε(1,3-dihydroxyiso- propyl)-2,4,6-triiodo-l,3-benzenedicarboxyamide]. a) N,N'-bis(1,3-dihydroxypropyl)-5-acetylamino-2,4,6- triiodo-l,3-benzenedicarboxyamide. Following the procedure described in EXAMPLE 1 c), 4.53 g (0.05 mol) of l-hydroxymethyl-2-hydroxy- ethylamine are reacted in 40 ml of DMAC with 6.36 g (0.01 mol) of 5-acetylamino-2,4,6-triiodo-isophtha- lie acid dichloride in 50 ml of DMAC in order to obtain 4.5 g N,N'-bis(1,3-dihydroxyisopropyl)-5- acetylamino-2,4,6-triiodo-l,3-benzenedicarboxyamide which is controlled in H and ■LJ C-NMR spectroscopy and used without additional purification. b) 5,5'-[ (2-hydroxy-l,3-propanediyl)bis [imino(2-oxo- 2,1-ethanediyl)acetylimino] ]bis[N,N'-bis(l,3-dihy- droxyisopropyl)-2,4,6-triiodo-l,3-benzenedicar- boxyamide] . Following the procedure described in EXAMPLE 1 d), 4.2 g (0.0056 mol) of N,N'-bis(1,3-dihydroxyiso- propyl)-5-acetylamino-2,4,6-triiodo-l,3-benzenedi- carboxyamide, suspended in 50 ml of DMF, are reac¬ ted with 5.6 ml (0.0056 mol) of 1M CH 3 ONa in CH 3 OH. The resulting amide sodium salt is then reacted with 1 g (0.003 mol) of 2-[ (tetrahydro-2H-pyran-2- yl)oxy]-N,N'-1,3-propanediyl-bis(2-chloroacetamide) to obtain the desired condensation product that, after hydrolysiε of the protecting group and εubse- quent purification, yields 1.26 g of 5,5'-[(2-hy- droxy-1,3-propanediyl)bis[imino(2-oxo-2,1-ethane- diyl)acetylimino] ]bis[N,N'-bis(l,3-dihydroxyiso¬ propyl)-2,4 ,6-triiodo-l,3-benzenedicarboxyamide] . Yield: 25.2% Elemental analysis (%) C H I N Calc : 28 . 15 3 . 03 45 . 75 6 . 73 Found: 28.01 3.18 45.50 6.50 (H 2 0:1.75%) In a similar way the following compounds were ob¬ tained: - 5,5 ■ -[(2-hydroxy-l,3-propanediyl)bis[imino(2-oxo- 2,1-ethanediyl)acetylimino] ]bis[N,N'-bis-(2-hydro- xyethyl)-2,4, -triiodo-l,3-benzenedicarboxyamide]. 5,5'-[(2-hydroxy-l,3-propanediyl)bis[imino(2-oxo- 2,1-ethanediyl)acetylimino]]bis[N,N'-bis-(1,3,4- trihydroxy-2-butyl)-2,4,6-triiodo-l,3-benzenedicar- boxyamide]. 5,5*-[[2,2-bis (hydroxymethyl)-l,3-propanediyl]- bis-[imino(2-oxo-2,1-ethanediyl)acetylimino]]bis- [N,N ! -biε(2-hydroxyethyl)-2,4,6-triiodo-l,3-benze- nedicarboxyamide] . - 5,5'-[[2,2-biε(hydroxymethyl)-l,3-propanediyl]biε- [imino(2-oxo-2,1-ethanediyl)acetyl-imino]]biε[N,N'- bis(l,3-dihydroxyisopropyl)-2,4,6-triiodo-l,3-ben- zenedicarboxyamide] . 5,5'-[[2,2-bis(hydroxy ethy1)-1,3-propanediyl]bis- [imino(2-OXO-2,1-ethanediyl)acetyl-imino]]bis[N,N'- bis(2,3-dihydroxypropyl)-2,4,6-triiodo-l,3-benze- nedicarboxyamide] . 5,5'-[[2,2-bis (hydroxymethyl]-1,3-propanediyl]bis- [imino(2-oxo-2,1-ethanediyl)acetyl-imino]]bis[N,N"- bis(1,3,4-trihydroxy-2-butyl)-2,4,6-triiodo-l,3- benzenedicarboxyamide] .

Claims: CLAIMS 1. Symmetrical and asymmetrical 5,5'-[ (1,3-propane- diyl)bis[imino(2-oxo-2,1-ethanediyl)acetylimino]]bis- (2,4,6-triiodo-l,3-benzenedicarboxyamideε) of general formula (I) wherein: which can be the εame or different, are H, C^-C alkyl, linear or branched C^-C 4 mono- or polyhydroxyalkyl, R 2 ,R ' ,R 3 ,R 3 ' , which can be the εame or different, are one of the groupε of formula -CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 OH, -CH(CH 2 OH)CH(OH)CH 2 OH, -CH 2 (CHOH) 4 CH 2 OH or -CH(CH 2 OH) 2 , X iε one of the groupε -CH(OH)-, -CH(CH 2 OH)-, -C(OH)(CH 2 OH)- or -C(CH 2 OH) 2 -, aε well as enantiomers, diaεtereoisomers and/or rota- mers thereof. 2. Compounds according to claim 1, wherein R, R', R,, R^ are H and X is -CH(OH)-. 3. Compounds according to claim 1, wherein R, R', R,, R χ « are H and X is -C(CH 2 OH) 2 _. 4. Compounds according to claim 1, wherein R, R", R, ; - j _* are H, R 2 , R 2 « , , R 3 ' are groups of formula -CH(CH 2 OH) 2 and/or -CH 2 CH(OH)CH 2 OH, X is -CH(OH)-. 5. A compound according to claims 1-4, selected from: - 5,5'-[(2-hydroxy-l,3-propanediyl)bis[imino(2-oxo- 2,1-ethanediyl)acetylimino]]bis[N,N'-bis(2,3-dihy- droxypropyl)-2,4,6-triiodo-l,3-benzenedicarboxya- mide]. 5,5'-[(2-hydroxy-l,3-propanediyl)bis[imino(2-oxo- 2,1-ethanediyl)acetylimino]]bis[N,N'-biε(l,3-dihy- droxyisopropyl)-2,4, -triiodo-l,3-benzenedicar- boxyami e] . 5,5'-[(2-hydroxy-l,3-propanediyl)bis[imino(2-oxo- 2,1-ethanediyl)acetylimino]]bis[N^N'-bis(2-hy- ' droxyethyl)-2,4,6-triiodo-l,3-benzenedicarboxya- mide]. 5,5 r -[(2-hydroxy-l,3-propanediyl)biε[imino(2-oxo- 2,1-ethanediyl)acetylimino] ]bis[N,N « -bis(l,3,4- trihydroxy-2-butyl)-2,4,6-triiodo-l,3-benzenedicar- boxyamide]. - 5,5'-[[2,2-biε(hydroxymethyl)-l,3-propanediyl]- bis[imino(2-oxo-2,1-ethanediyl)acetylimino]]bis- [N,N » -bis(2-hydroxyethyl)-2,4,6-triiodo-l,3-ben-ze- nedicarboxyamide]. 5,5'-[[2,2-bis(hydroxymethyl)-1,3-propanediyl]- bis[imino(2-oxo-2,l-ethanediyl)acetylimino]]bis- [N,N f -bis(1,3-dihydroxyisopropyl)-2,4,6-triiodo- 1,3-benzenedicarboxyamide] . 5,5'-[[2,2-bis(hydroxymethyl)-l,3-propanediyl]bis- [imino(2-oxo-2,1-ethanediyl)acetylimino]]bis[N,N'- bis(2,3-dihydroxypropyl)-2,4,6-triiodo-l,3-benzene- dicarboxyamide] . 5,5'-[ [2,2-bis (hydroxymethyl)-l,3-propanediyl]bis- [imino(2-oxo-2,1-ethanediyl)acetylimino]]bis[N,N'- biε(l,3,4-trihydroxy-2-butyl)-2,4,6-triiodo-l,3- benzenedicarboxyamide] . 6. A proceεs for the preparation of compoundε of for¬ mula (I), characterized in that a N, '-1,3-propanediyl- biε(2-chloroacetamide) of formula (II) C1CH 2 0C-NH-CH 2 -X-CH 2 -NH-C0CH 2 C1 (II) , where X is one of the groups -CH(OH)-, -CH(CH 2 OH)-, -C(OH) (CH 2 OH)- or -C(CH 2 OH) 2 -, in which the hydroxy groups have been protected by a suitable protecting group, is reacted, directly or through a multistep pro¬ cess, with a 5-acetylamino-2,4,6-triiodo-isophthaldia- mide reactive derivative of general formula (III) wherein : R and R^, which are the same o different, are H, C ] _-C 4 alkyl, linear or branched C-,-C 4 mono- or polyhydroxyalkyl, 2 and R 3 , which are the same o different, are one of the groups of formula -CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 OH, -CH(CH 2 0H)CH(OH)CH 2 0H, -CH 2 (CHOH) 4 CH 2 OH or -CH(CH 2 OH) 2 . Z is an alkali metal ion, and, after deprotecting the hydroxy groups, the corre¬ sponding compound of general formula (I) is obtained, according to one of the following procedures: a) a compound of formula (II) is reacted in a solvent with a compound of formula (III) in a molar ratio ranging from 1:2 to 1:2.5, thereafter the remaining protecting groups are hydrolysed in an acid medium in order to obtain directly the corresponding com- pound of formula (I), b) a compound of formula (II) iε reacted in a solvent with a compound of formula (III) in a molar ratio ranging from 1:1 to 1:0.5 to give the compound of formula (IV) wherein R , R, ; R 2 . R 3 , X are as previously described , and said compound ( IV ) i s then reacted in a εolvent with another compound of formula ( III ) in a molar ratio ranging from 1: 1 to 1 : 1.2 , therafter the remaining pro¬ tective groups are hydrolysed in an aci d medium to give the corresponding compound of formula (I ) . 7. Non-ionic X-ray contrast media containing as opa- cifying component at least one iodinated compound ac- cording to claims 1 to 5. 8 . A X-ray contrast medium according to claim 7 con- taining as opacifying component 5,5 '-[ (2-hydroxy-l,3- propanediyl)bis[imino(2-oxo-2,1-ethanediyl)acetylimi¬ no] ]bis [N,N'-bis (2,3-dihydroxypropyl)-2,4,6-triiodo- 1,3-benzenedicarboxyamide] . 9. A X-ray contrast medium according to claim 7 con¬ taining as opacifying component 5,5 '-[ (2-hydroxy-l,3- propanediyl)biε [imino(2-oxo-2,1-ethanediyl)acetylimi¬ no] ]biε[N,N'-biε(l,3-dihydroxyisopropyl)-2,4, 6-triiodo- 1,3-benzenedicarboxyamide] .

Inventors: ANELLI PIERLUCIO, BROCCHETTA MARINO, UGGERI FULVIO, VISIGALLI MASSIMO, ANELLI, PIERLUCIO, BROCCHETTA, MARINO, UGGERI, FULVIO, VISIGALLI, MASSIMO
Applicants: BRACCO SPA, DIBRA SPA, BRACCO S.P.A., DIBRA S.P.A.
Application year: 1992
Main classification: A61K49
IPC codes: A61K49, C07C237