lODINATED O IGOMERIC COMPOUNDS AND DIAGNOSTIC COMPOSITIONS CONTAINING THE SAME

This invention refers to contrast agents particularly useful for X-ray diagnostic examinations of vascular system of the human and animal body. X-ray imaging is a diagnostic technique widely used to rapidly detect a series of anomalies and/or pathological conditions of living tissues.

An important improvement in images obtained through the same diagnostic procedure was achieved thanks to the use as contrast media of pharmaceutical formulations of suitable opacifying agents. These compounds became unavoidable in the production of images of organs or tissues which, otherwise, couldn't be distinguished from the near regions.

Present X-ray contrast media preferably contain, as opacifying molecules, polyiodinated neutral aromatic compounds. D.P. Swanson e coll. in "Pharmaceuticals in Medical Imaging", 1990, Mac Millan Publ. Company, wrote an extensive and up-dated publication on the state of the art of these diagnostic agents. Today, the most common opacifying agents show a general use: as a consequence one of the most pressing request by the medical class concerns the availability of contrast media aiming at specific biological or anatomical parts. Opacifying formulations able to selectively or preferentially direct to organs such as, for instance, liver, kidneys, gall-bladder or endowed with the characteristic of remaining for a sufficiently long

time in the cardiocirculatory system before dispersing into the extra-vascular space or being excreted, for instance due to glomerular filtration, will be positively hailed by those investigating on the pathologies of the above mentioned districts. In fact, through such agents, the amount of active principle administered could be reduced, and at the same time it could be obtained the desired image enhancement and a decrease of possible toxic effects. Opacifying products for the cardiovascular system are particularly requested. As a matter of fact the contrast agents currently used show a quite unsatisfactory pharmacokinetic behaviour. After intravenous administration, they rapidly distribute in a volume, called central distribution volume, corresponding to plasma and interstitial fluid in open- fenestrae endothelial organs such as liver or kidneys. At a slower rate they distribute into extravascular tissues and structures with continuous endothelia, that's to say the remaining tissues except for brain. Contrast media are excreted through renal filtration from plasmatic region.

Due to this behaviour, the administered dosis to a human being is diluted in a volume of about 14 litres (central department) in less than 1 minute and its concentration further decreases in the following minutes due to diffusion in the remaining extracellular spaces, previously discussed.

Then the opacifying agent is uniformly distributed in a total body volume of about 25 litres and its concentration keeps decreasing due to kidney

elimination.

Contrast diversification between different structures and tissues extensively depends on this aspecific pharmacokinetic behaviour. For these reasons in computed tomography a high dosis of contrast agent is necessarily administered in bolus to obtain a considerable starting vascular phase.

The ideal contrastographic vascular agent should have some properties which allow it to get a series of diagnostic advantages such as for instance: a better anatomic definition of small vases, a prolonged contrast enhancement which allows the investigation of various anatomical structure with a unique dosis, - the detection of haemorrhages, the possibility of obtaining functional quantitative information on the perfusion grade of the structures under examination.

Up to now, researchers have substantially investigated the possible use of two general classes of product: emulsions and polymers.

For instance among emulsions we can mention: a) radiopaque liposomes, b) iodinated ester of seed oils, i.e. of poppy-flower (EOE-13), c) perfluoro derivatives such as perfluorooctyl bromide (PFOB) (see H.W. Fischer, Invest. Radiol. , 25, Suppl. 1, S2-S6, 1990). None of these contrastographic fluids was able to efficiently solve the technical problem previously disclosed. X-ray opaque contrast agents encapsulating liposomes (i.e. diatrizoate) generally show a low

encapsulating capacity and/or poor stability to sterilization.

Iodinated esters b) are metabolised and eliminated quite rapidly by the organism (more than 95% in about 5 min) and in addition they resulted quite toxic involving a high number of side reactions (about 4%).

As far as c) is concerned, perfluoro derivatives need very high dosages to produce the desired contrast in vascular structures. Iodinated polymers, i.e. polymeric chains, such as polyvynil or polysaccharide chains, binding to their framework, aromatic molecules preferably triiodinated, are still under investigation.

Said polymers highlighted a series of problems basically connected with high dosages, polymer potential immunogenicity, and particularly with imprecise range of molecular weight and therefore the correct iodine dosage to be administered.

This invention refers to a new family of polyiodinated compounds which has been particularly useful for the solution of the previously discussed problems.

It concerns compounds, described in the following formula I, constituted by a polyfunctionalized organic central nucleus covalently bound, by means of suitable bivalent functional residues, to polyiodinated aromatic neutral or ionic molecules, such as those already known as X-ray opacifying agents.

Other polyiodinated aromatic derivatives can be covalently bound to that molecules.

Alternatively, said molecules can be obtained by

binding to the central nucleus, through successive levels, non-iodinated aromatic precursors and then by performing a iodination on the obtained intermediate: this procedure has the advantage of using a total lower amount of toxic reagents in a terminal phase, in such way involving a better industrial exploitation and a more favourable environmental impact.

Polyiodinated oligomers are produced endowed with high opacifying properties, good tolerability and well- defined molecular weight. In particular the oligomer size can be increased through successive synthetic steps, thus spotting the corresponding ideal diagnostic application. Whsn it is useful to include in the oligomer structure also some ionic species, for instance iodinated aromatic nuclei with one or more free carboxylic or phenolic functions, these can be salified with a physiologically tolerable organic base preferably selected from primary, secondary or tertiary amines, or basic amino acids. Preferred organic bases can be for instance selected from ethanolamine, diethanolamine, morpholine, glucamine, N-methyl-glucamine, N,N-dimethyl-glucamine, lysine, arginine, ornithine.

Salifying agents equally preferred are selected from physiologically tolerable inorganic bases, in particular those with alkali metal cations, such as lithium, potassium and sodium.

Should the oligomer central nucleus include a structure with chelating properties with regards to bi- or trivalent metal ions, this property can be used to prepare chelates of oligomers with metal ions of atomic

number included between 20 and 31, 39, between 42 and 44, 49 and between 57 and 83, preferably with paramagnetic metal ions such as Fe(2+), Cu(2+), Mn(2+), Fe(3+), Gd(3+), Dy(3+), Yb(3+), Eu(3+).

This invention refers to compounds of formula (I)

wherein:

1 is an integer from 2 to 20, m is an integer from 1 to 100, n is an integer from 0 to 2, A is an organic core, which can be aliphatic, heterocyclic or aromatic and carries 2 to 20 groups B, as hereinbelow defined, or 2 to 20 organic residues ending with B, B is a single bond or a group selected from -CO-, - N(R)CO-, -CON(R)-, _N(R1)-, -NHCO-O-, -NH-CO-NH-,

-0-, -S-, -SO-, -PO-,

in which R is H, or a straight or branched (c,-c ₆ ) alkyl residue, or a straight or branched (C._c _β ) hydroxyalkyl residue with 1 to 5 -OH groups, is R or a -COR ₂ group, wherein R ₂ is a straight or branched (C^Cg) alkyl residue, or a straight or

branched (C^-Cg) hydroxyalkyl residue with 1 to 5

-OH groups, and wherein: a) if n = 0, the compounds of formula (I) are represented by sub-formula (la)

wherein:

A, B and 1 are as previously defined and

L is a group of general formula (II)

wherein:

P and Q, which are the same or different, are one of the groups -C0N(R)R ₃ , -N(R)-CO-R ₄ , -O-X wherein

R is as previously defined,

R3 is H, or a straight or branched ( ^-Cg) alkyl residue, or a straight or branched (C.- _C --) hydroxyalkyl residue with 1-5 OH groups,

R4 is a cyclic or acyclic, straight or branched (C^- C ₂ ) residue, interrupted or not by -0-, -N-, -P-, -S- or by imino, aryl, heteroaryl groups and/or with 1 to 6 hydroxy, alkoxy, amino, oxo, aryl, alkylaryl, heteroaryl groups,

X is a negative charge, or H, or a -CH_-CO-Y group,

where Y is one of the residues -0-R _ς or -N(R)R , where R and R^ are as previously defined and R ₅ is a negative charge, or H, or a straight or branched (C._Cg) alkyl residue, or straight or branched

⁽ ^-Cg) hydroxyalkyl residue with 1-5 OH groups, or an alkoxy-alkyl or alkoxyhydroxy-alkyl residue, or X can also be a polyoxaalkyl group of formula

wherein G is H, -CH ₃ or -CH ₂ -CH ₃ , or: b) if n-1, the compounds of formula (I) are represented by sub-formula (lb)

wherein:

A,B,1 and m are as above defined, and

L is a group of formula (II) as above defined, with the proviso that one of the two groups P and Q corresponds to an -E-F- residue wherein

E is one the groups -N(R)-C0-, -CO-N(R)-, -0-, wherein R is as above defined, and

F is a straight or branched (C -CJQ) residue, which is interrupted or not by -0- , -S-, -P- , -N(R _β )- groups, being R _{g a} residue R as above defined, or a -C0-R ₇ group wherein R ₇ is a straight or branched (C^Cg) alkyl with 1-6 OH groups or which

can carry from 1 to 6 substituents such as hydroxy, alkoxy, amino, oxo, aryl, heteroaryl groups, being F further characterized by a terminal group selected from -CO-, -0-, -N(R _β) _ _; _ CO-N(R)-, -N(R)CO-, ureido, urethane, being R and

Rg as above defined, in which said terminal group is the linker between F and the subsequent part of the molecule,

M is a repetition unity, which can have different meanings for each unity, of general formula (III)

wherein:

P _] _ and Qi are the same as P and Q as above defined, or one or both of them are an -E-F- residue as above defined, being each M group linked to the previous one through the terminal group of an F residue of the same, or through an ether bond in case said previous group contains hydroxy functions, or: c) if n-2 , the compounds of formula (I) are represented by sub-formula (Ic)

wherein :

A,B,M,1 and m are as above defined, and

L is a group of formula (II) in which both P and Q correspond to an -E-F- residue as above defined. 5 Should compounds of formula (I) include one or more free phenolic and/or carboxylic functions, this invention also include the salts of said compounds with physiologically acceptable organic bases selected from primary, secondary and tertiary amines or basic amino 0 acids or inorganic bases whose cations are sodium, potassium, magnesium, calcium or their mixtures.

In addition should the central nucleus A of the compounds of formula (I) shcv: a chelating ability with respect to bi- or trivalent metal ions, this invention 5 also include chelate complexes of said compounds with metal ions of elements having atomic number included between 20-31, 39, 42-44, 49 and 57-83.

As non-limiting examples of this invention, the organic core A can be derived from one of the following 0 compounds:

tetramino- and tetracarboxy-adamantane , and their corresponding iodinated derivatives . 0 As preferred L and M groups of this invention , precursors , or derivatives of all iodinated contrast

media known in the state of the art, ionic and non- ionic, monomers, dimers and trimers, can be used, of course modified with suitable reactive groups well known to the skilled chemist.

A non-limiting list of preferred compounds of this invention is herein below reported to show the wide potential applications of this invention.

GENERAL FORMULA

Compound 1 a) (Example 1)

Compound 1 b) R'-H ; R- (Example 1)

GENERAL FORMULA

wherein R

Compound 2 X = H (Example 2) Compound 3 X * (CH ₂ -CH ₂ -0) ₃ -CH ₃ (Example 3) Compound 4 X - (CH ₂ _CH ₂ -0) ₃ -H (Example 4) Compound 5 X = (CH ₂ -CH ₂ -0) ₇ -CH ₃ (Example 5) Compound 6 X = CH ₂ CONHCH ₂ CHOHCH ₂ OH (Example 6) Compound 7 H s CH ₂ CON(CH ₃ )CH ₂ (CHOH) ₄ CH ₂ 0 (Example 7)

GENERAL FORMULA

Compound 8 (Example 8)

Compound 9 (Example 9)

Compound 10 R (Example 10)

Compound 11 R (Example 11)

GENERAL FORMULA

Compound 12

-NHCOCH(OH)CH. (Example 12)

Compound 13

-NHCOCH ₂ QH

(Example 13) Compound 14

-N(CH )CH(CHOH) CH OH -NHCOCH(OHX-H

(Example 14)

Compound 15

(Example 15)

Compound 16 (Example 16) -0-(CH cH ₇ -0) ₇ -CH,

OTHER STRUCTURES

Compound 17 (Example 17)

Compound 18 (Example 18)

wherein R-

Compound 19 (Example 18)

wherein R = R of compound 18

Compound 20 (Example 18)

wherein R — R of compound 18 Compound 21 (Example 19)

whe ein R-

Meglumine H ,Θ

Compound 22 (Example 20

wherein R =

By using the compounds of this invention a highly selective and opacifying contrastographic composition can be prepared and administered to patients, in which composition the active ingredient/s has/have well- defined structures and iodine content. As a matter of fact the dosage of the opacifying material results to be completely reproducible.

In particular, and this is one of the main features of the present invention, the compounds of formula (I) are extremely interesting because of their capability of remaining in plasma for a very long period. Their retention time values in plasma are quite similar, if not even higher, to those disclosed by Doucet et al., Invest. Radiol. , 1991, for dextrane- based iodinated polymers.

For instance, compound 22 (described in Example 20), i.e. 3,3' ,3"-[ (hexahydro-lH-1,4,7-triazonin-l,4,7- triyl)tricarbonyl]tris[ [ [ (5-hydroxy-2,4,6-triiodo-3,1- phenylene)carbonyl]amino]methyl]tris[5-(acetylamino)-N- [2-hydroxy-l-(hydroxymethyl)ethyl] ]-2,4 ,6- triiodobenzamide] , showed a retention time value in plasma, in rats, of 300 min, at a dosage of 100 ngl/kg.

As various changes could be made in the above compositions and methods without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense. EXAMPLE 1 3,3' ,3' •-[ (Hexahydro-lH-1,4,7-triazonin-l,4,7-triyl)- tricarbonyl]tris[N-[2-hydroxy-1-(hydroxymethyl)ethyl]- 5-[ (S)-(2-hydroxy-l-oxopropyl)amino]-2,4,6-triiodo-

benzamide] (a) .

3 ,3'-[ (Hexahydro-lH-1,4,7-triazonin-l,4-diyl)dicar- bonyl]bis[N-[2-hydroxy-l-(hydroxymethyl)ethyl]-5-[ (S)- (2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodobenzamide] (b).

To a solution of 15 g of octahydro-lH-1,4,7- triazonine (obtained according to Atkins T.J., Richman J.E., Org. Synth., 1978, 58, 56) (0.012 mol) in 70 ml of DMF, cooled at 5°C and under nitrogen atmosphere, 5.94 g of triethylamine (TEA) (0.059 mol) and then a solution of 33.79 g of (S)-3-[2-(acetyloxy)-l- oxopropyl]amino-5-[ [ [ (2-hydroxy-l-(hydrcxymethyl)- ethyl]amino]carbonyl]-2,4,6-triiodobenzoy1 chloride (prepared according to DE 2,805,928) (0.041 mol) in 120 ml of dimethylformamide (DMF) are added. The temperature is gradually raised to 40 ^β C and kept constant during 48 h. The solvent is evaporated under reduced pressure and the residue is treated with three 250 ml portions of CH ₂ ci ₂ to give a solid which is dissolved in 350 ml of a H ₂ o/MeOH - 4/1 solution. The solution is adjusted to pH 10.3 and kept at this value by addition of 71 ml of IN sodium hydroxide (0.071 mol) during 2 h at 45°C. Then the aqueous solution is neutralized at pH 7 with 37% HC1 then evaporated to dryness. The crude residue is dissolved in 30 ml of H_o and percolated through Amberlite^ IR 120 and on Duolit S^ A 30 B. The eluate is concentrated to obtain a residue which is chromatographed on silica gel. In this way, two main products are obtained, which are then purified by percolating them first through Amberlit

IR 120, then through Duolite^ 30 B. By concentration of the eluate 3.2 g of compound (a) (0.0015 mol) and

2.7 g of compound (b) (0.0018 mol) are obtained.

Yield in (a): 12% m.p.: 285 °C (dec.) K.F.: 2.46 %(w/w)

[0y ^D ₂ = -3.59° (c = 2.01; DMF)

Elemental analysis:

% calc: C 26.36; H 2.49; I 52.22; N 5.76

% found: C 25.04; H 2.80; I 50.38; N 5.46; H ₂ o 2.46 TLC: silica gel plate 60 F 254 Merck

Eluent: CHC1 ₃ :MeOH:25% NH ₄ OH = 6:3:1

Detector: UV light (254 nm)

R _f = 0.06

¹ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure.

Yield in (b): 15% m.p.: 265 °C (dec.)

K.F.: 2.30% (w/w)

Elemental analysis: % calc: C 27.20; H 2.76; I 50.72; N 6.53

% found: C 26.77; H 2.95; I 49.84; N 6.27

TLC: silica gel plate 60 F 254 Merck

Eluent: ^CHC 1 ₃ :MeOH: 25% NH ₄ OH - 6:3:1

Detector: UV light (254 nm) Rf- 0.17

^ ^■ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure.

EXAMPLE 2

3,3' ,3' ^• -[ (Hexahydro-lH-1,4,7-triazonin-l,4,7-triyl)- tricarbonyl]tris[N-[2-hydroxy-l-(hydroxymethyl)ethyl]-

5-hydroxy-2 ,4 ,6-triiodobenzamide]

A) 5-hydroxy-l,3-benzenedicarboxylic acid monomethyl ester

This product is obtained according to well-known methods by monosaponification of the corresponding di- methyl ester with sodium hydroxide.

Yield: 45% m.p.: 242 °C

Elemental analysis: calc: C 55.11; H 4.11; 0 40.78

% found: C 55.36; H 4.02; 0 40.65 TLC: silica gel plate 60 F 254 Merck

Eluent: CHC1 ₃ :MeOH:25% NH ₄ OH = 6:3:1

Detector: 1% KMn0 ₄ in IN NaOH

R _f = 0.18

¹ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure.

B) Methyl 3-(chlorocarbonyl)-5-hydroxybenzoate

To a suspension of 30.2 g of compound A) (0.154 mol) in 580 ml of CHC1 ₃ , 119 g of thionyl chloride (1 mole) are dropwise added at a temperature of 35-40°C. After stirring during 3h at 65°C, the suspension is cooled and the solvent is evaporated under reduced pressure. The residue is dissolved in 300 ml of ethyl ether and extracted seven times with 40 ml portions of a 4% NaHC0 ₃ solution. The organic layer is evaporated to dryness to give 28.4 g (0.132 mol) of compound B). Yield: 86% m.p.: 120-123° C

AgN0 ₃ 0.1 N: 98.3% Elemental analysis: % calc: C 50.37; H 3.29; Cl 16.52 % found: C 50.41; H 3.32; Cl 16.32 TLC: silica gel plate 60 F 254 Merck

Eluent: CHC1 ₃ :MeOH:25% NH ₄ OH = 6:3:1 Detector: 1% KMn0 ₄ i _n IN NaOH R _f = 0.77

The chro atographic analysis is performed by transforming methyl 3-(chlorocarbonyl)-5-hydroxybenzo- ate into the corresponding methyl ester by reaction with a 3% MeOH solution, which is sprayed on the plate, after 30 min at R.T.. ¹ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure.

C) 3,3',3• '-[ (hexahydro-lH-1,4,7-triazonin-l,4,7- triyl)tricarbonyl]tris[N-[2-hydroxy-1-(hydroxy- methy1)ethyl]-5-hydroxybenzamide] A solution of 8 g of compound B) (0.0357 mol) in 35 ml of CHC1 ₃ and 15 ml of dimethylacetamide (DMA) is dropwise added to a solution of 1.54 g of octahydro-lH- 1,4,7-triazonine (0.0112 mol) and 3.6 g of TEA (0.0357 mol) in 47 ml of CHC1 ₃ , under nitrogen atmosphere and at a temperature of 7-10°C. After 30 min at the same temperature and one night at 25°C, the solvent is evaporated under reduced pressure. The residue is dissolved in 400 ml of a 0.03M NaHC03 solution and the resulting precipitate is filtered, washed with H ₂ o an _d stirred in 150 ml of AcOEt at a temperature of 70°C during 30 minutes. After cooling the solid is filtered and dried to give 6.2 g of 3,3' ,3• '-[ (hexahydro-lH- 1,4,7-triazonin-l,4,7-triyl)tricarbonyl]tris[methyl 5- hydroxybenzoate] . The product is mixed with 12.8 g of 2-amino-l,3 propanediol (commercial product) (0.14 mol) and heated to a temperature of 110°C under vacuum. After 3.5 h at the same temperature, the solution is

cooled, and 60 ml of H ₂ o are added and the whole is percolated through Amberlite® IR 120 and Duolit<=® A 30

B. The eluate is concentrated to give a crude residue which is crystallised from EtOH. 3.95 g of (0.0045 mol) of compound C) are obtained.

Yield: 53% m.p.: >280 °C

K.F.: 3.73 %(w/w)

Elemental analysis:

^~ calc: C 55.53; H 6.15; N 9.48 % found: C 52.97; H 6.30; N 9.30; H ₂ 0 3.73

TLC: silica gel plate 60 F 254 Merck

Eluent: CHC1 ₃ :AcOH:H ₂ 0 - 5:5:1

Detector: 1% KMn0 ₄ in 1M NaOH

R _f = 0.12 ¹ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure.

D) title compound

To a solution of 13.2 g of the above described compound C) (0.015 mol) in 210 ml of H ₂ o, in about 3 h, 34.31 g of IC1 (commercial product) (0.122 mol) and

147.5 ml of 2N NaOH are simultaneously added to keep pH at 7.5-8. The mixture is kept under stirring during 70 min at R.T.. The solution is then acidified to pH 2 by addition of 37% HC1 thus obtaining a crude precipitate which is filtered and purified by reprecipitation with

37% HC1 from a basic solution at pH 8, to give the desired product.

23.18 g (0.012 mol) of the title compound are obtained.

Yield: 79% m.p.: 260°C (dec) K.F.: 0.88 %(w/w)

Elemental analysis:

% calc: C 23.73; H 1.99; I 57.87; N 4.26 % found: C 23.87; H 2.01; I 57.31; N 4.27; H ₂ o 0.88 TLC: silica gel plate 60 F 254 Merck Eluent: CHC1 _{3 :} AcOH:H ₂ 0 - 5:5:1 Detector: UV light (254 nm)

R _f = 0.20

^ ^• H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure.

EXAMPLE 3 3,3' ,3' •-[ (Hexahydro-lH-1,4,7-triazonin-l,4,7-triyl )- tricarbonyl]tris[N-[2-hydroxy-l-(hydroxymethyl)ethyl]-

5-[2-[ 2-(2-methoxyethoxy)ethoxy]ethoxy]-2,4 ,6-triiodo- benzamide]

A) 4-nitrobenzenesulfonic acid 2-[2-(2-methoxy- ethoxy)ethoxy]ethyl ester

48.15 g of TEA (0.47 mol) are dropwise added, during 30 min, to a solution of 99.45 g of 4- nitrobenzenesulfonyl chloride (prepared according to F.

Gialdi, R. Ponci "II Farmaco" Vol XIV, 751, 1959) (0.45 mol) in 90 g of triethylene glycol monomethyl ether

(0.45 mol) and 450 ml of AcOEt. After 90 min at 20 ^β C, the precipitated TEA hydrochloride is filtered off and washed three times with 90 ml portions of AcOEt.

Filtrates are collected, washed with 90 ml of H ₂ o, 60 ml of 2N HC1 and then with H ₂ o to neutrality. The organic layer is evaporated to dryness, to give a dense oil which, by cold germination, becomes solid and can be recovered by filtration.

112 g (0.305 mol) of compound A) are obtained. Yield: 67.7 % m.p.: 44 ^β C

TLC: silica gel plate 60 F 254 Merck

Eluent: AcOBu:AcOH:H ₂ o = 5:5:1 (upper phase) Detector: UV light (254 nm) R _f = 0.60

¹ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure.

B) 3,3',3''-[ (Hexahydro-lH-1,4,7-triazonin-l,4,7- triyl )tricarbonyl ]tris [N-[2-hydroxy-l-(hydroxy- methyl )ethyl ]-5-hydroxy-2 ,4 ,6-triiodobenzamide] trisodium salt The product was prepared by reacting 3,3 ',3' '- [ (hexahydro-lH-l,4,7-triazonin-l,4,7-triyl )tri¬ carbonyl]tris [N-[2-hydroxy-l-(hydroxymethyl)ethyl ]-5- hydroxy-2 ,4,6-triiodobenzamide] (prepared according to Example 2) with NaOH at pH 8. The solvent was evaporated and the residue was directly used in the successive step without any further purification.

C) title compound

To a solution of 8.10 g (0.004 mol) of compound B) in 70 ml of DMA, at a temperature of 50 ^β C and under nitrogen atmosphere, a solution of 4.16 g (0.012 mol) of compound A) in 10 ml of DMA is added. The mixture is heated to 70 ^β C during 2.5 h. After cooling, the solvent is evaporated under reduced pressure. The crude residue is treated with two 75 ml portions of CH_ci _? to give a solid which is filtered off. The filtrates are collected and evaporated to dryness and the final residue is purified by column chromatography on silica gel to give 1.19 g (0.0005 mol) of the title compound. Yield: 12% m.p.: 170 °C K.F.: 1.52 %(w/w) Elemental analysis:

% calc: C 29.87; H 3.38; I 47.34; N 3.48 % found: C 30.40; H 3.62; I 45.15; N 3.71; H ₂ 0 1.52 TLC: silica gel plate 60 F 254 Merck Eluent: CHC1 ₃ :MeOH:H 0 = 5:5:1 Detector: UV light (254 nm) R _f - 0.50

^H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure. EXAMPLE 4 3,3' ,3' '-[ (Hexahydro-lH-1,4,7-triazonin-l,4,7-triyl)- tricarbonyl]tris[N-[2-hydroxy-l-(hydroxymethy1)ethyl ]- 5-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]-2 ,4 ,6- triiodobenzamide]

To a solution of 10.20 g of 3 ,3 ^• ,3 • ^• -[ (hexahydro- 1H-1,4,7-triazonin-l,4,7-triyl )tricarbonyl]tris[N-[2- hydroxy-l-(hydroxymethyl)ethyl ]-5-hydroxy-2 ,4 ,6-triio- dobenzamide] trisodium salt (prepared according to Example 3) (0.005 mol) in 100 ml of DMA, 3.37 g of 2- (2-(2-chloroethoxy)ethoxy) ethanol (commercial product) (0.020 mol) and 2.25 g of Nal (0.015 mol) in 10 ml of DMA are added. The mixture is heated to 50°C for 45 h and at 90 ^β C for 47 h. After cooling the solvent is evaporated under reduced pressure. The crude residue is treated with five 100 ml portions of CH ₂ ci ₂ giving a solid which is filtered and dissolved in 50 ml of H-O. The aqueous solution is percolated through AmberliteS) IR 120 and Duolit4-9 A 30 B. The eluate is concentrated to obtain a residue, which is crystallised from abs. EtOH. 6.8 g (0.003 mol) of the title compound are obtained. Yield: 57% m.p.: 235 ^β C

K.F.: 1.52 %(w/w) Elemental analysis:

% calc: C 28.88; H 3.19; I 48.18; N 3.55 % found: C 28.69; H 3.33; I 46.91; N 3.57; H ₂ o 1.52 TLC: silica gel plate 60 F 254 Merck Eluent: CHC1 ₃ :MeOH:H ₂ 0 = 6:3:1 Detector: UV light (254 nm) R _f - 0.35 ^H-NMR, C-NMR, IR and MS spectra are consistent with the assigned structure. EXAMPLE 5

3,3' ,3' '-[ (Hexahydro-lH-1,4,7-triazonin-l,4,7-triyl)- tricarbonyl]tris[N- [ 2-hydroxy-1- (hydroxymethyl)ethyl]- 5-(3,6,9,12,15,18,21-heptaoxadocos-l-yloxy)-2,4,6- triiodobenzamide]

A) 4-nitrobenzenesulfonic acid 3 , 6,9 ,12 ,15, 18 ,21-hep- taoxadocos-1-yl ester

6.7 g of TEA (0.06 mol) are dropwise added during 10 min, to a solution of 20.4 g of 4-nitrobenzenesul- fonyl chloride (obtained according to F. Gialdi, R. Ponci, "II Farmaco" Vol XIV, 751, 1959) (0.06 mol) and 20.4 g of 3,6,9,12,15,18,21-heptaoxadocoxan-l-ol (obtained according to Liebigs Ann. Chem. 1980. 858- 862) (0.06 mol) in 60 ml of AcOEt. After 2 h at a temperature of 20°C, the precipitated TEA hydrochloride is filtered off and washed three times with 10 ml portions of AcOEt. Filtrates are collected, washed with 30 ml of H ₂ o, 20 ml of 2N HC1 and then with H ₂ 0 to neutrality. The organic layer is evaporated to dryness to give a dense oil which is directly used in the successive step without any further purification.

25 g (0.047 mol) of compound A) are obtained. Yield: 79 %

TLC: silica gel plate 60 F 254 Merck Eluent: MeOH Detector: UV light (254 nm) R _f - 0.76

¹ H-NMR, ¹ C-NMR, IR and MS spectra are consistent with the assigned structure. B) title compound To a suspension of 7.55 g of 3,3' ,3' '-[ (hexahydro- 1H-1,4,7-triazonin-l,4,7-triyl)tricarbonyl]tris[N-[2- hydroxy-1-(hydroxymethy1)ethyl]-5-hydroxy-2,4,6-triio- dobenzamide] trisodium salt (prepared according to Example 3) (0.0037 mol) in 75 ml of DMA, at a temperature of 50°C and under nitrogen atmosphere, 7.78 g of compound A) (0.0148 mol) are added. The mixture is heated to 70°C during 6 h. After cooling, the solvent is evaporated under reduced pressure. The crude is treated with two 35 ml portions of CH_ci ₂ giving a solid which is filtered off. Filtrates are collected and evaporated to dryness. The final residue is purified by column chromatography on silica gel to give 2.5 g (0.00085 mol) of the title compound. Yield:23%.: m.p.: 78°C Elemental analysis:

% calc: C 34.30; H 4.42; I 38.83; N 2.86 % found: C 33.61; H 4.48; I 37.17; N 2.92 TLC: silica gel plate 60 F 254 Merck Eluent: CHC1 ₃ :MeOH:25% H ₄ OH = 6:3:1 Detector: UV light (254 nm) R _f = 0.76

^• ' ^• H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure.

EXAMPLE 6

3,3' ,3' '-[ (Hexahydro-lH-1,4,7-triazonin-l,4,7-triyl)- tricarbonyl]tris[5-[2-[ (2, 3-dihydroxypropyl)amino]-2- oxoethoxy]-N-[2-hydroxy-l-(hydroxymethy1)ethyl]-2 ,4 ,6- triiodobenzamide]

A) 2,2',2''-[ (hexahydro-lH-1,4,7-triazonin-l,4,7- triyl)trisfcarbonyl [ [ [5-[2-hydroxy-l-(hydroxy- methyl)ethyl ]aminoJcarbonyl ]-2 ,4 ,6-triiodo-3 ,1- phenylene]oxy] ]trisacetic acid methyl ester To a suspension of 10 g of 3,3' ,3 ' '-[ (hexahydro-

1H-1 ,4,7-triazonin-l ,4,7-triyl)tricarbonyl ]tris[N-[2- hydroxy-1-(hydroxymethy1)ethyl]-5-hydroxy-2,4 ,6-triio- dobenzamide] trisodium salt (prepared according to

Example 3) (0.0049 mol) in 100 ml of DMA, 3.75 g of methyl bromoacetate (0.0240 mol) are added and the mixture is heated to 60°C during 2 h. After cooling, the solvent is evaporated under reduced pressure and an oily residue is obtained which solidifies by treatment with 100 ml of H ₂ o. The precipitate is filtered and purified by silica gel chromatography to give 4.09 g

(0.0019 mol) of compound A).

Yield: 38% m.p.: 258°C K.F.: 1,89 %(w/w)

Elemental analysis:

% calc: C 26.32; H 2.35; I 52.15; N 3.84

% found: C 25.74; H 2.48; I 50.99; N 3.73; H ₂ o 1.89

TLC: silica gel plate 60 F 254 Merck Eluent: CH ₂ ci ₂ :MeOH = 4:1

Detector: UV light (254 nm)

R _f = 0.24

^■ ' ^■ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure.

B) title compound A solution of 2 g (0.00091 mol) of compound A) and

0.75 g of isoserinol (commercial product) (0.0082 mol) in 15 ml of MeOH, is heated to 70°C. After 3 h the solution is cooled to 10 ^β C during 1 h, then the precipitate is filtered. The crude is dissolved in 40 ml of H^o and percolated through Amberlite^ IR 120 and

Duolitt® A 30 B.

By concentration of the eluate 1.70 g (0.000718 mol) of the title compound are obtained.

Yield: 79% m.p.: 235-240 ^β C (dec) K.F.: 0.54 %(w/w)

Elemental analysis:

% calc: C 27.40; H 2.82; I 48.25; N 5.33

% found: C 27.41; H 2.88; I 47.38; N 5.25; H ₂ 0 0.54

TLC: silica gel plate 60 F 254 Merck Eluent: CHC1 ₃ : MeOH:25% NH40H - 2:2:1

Detector: UV light (254 nm)

R _f - 0.28

¹ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure. EXAMPLE 7

1,1' ,1' '-[ (Hexahydro-lH-1,4,7-triazonin-l,4,7- triyl)tris[carbonyl[5-[ [ [2-hydroxy-l-(hydroxymethy1)- ethyl]amino]carbonyl]-2,4,6-triiodo-3,1-phenylene]- oxy(l-oxo-2,1-ethanediyl)methylimino) ] ]tris[1-deoxy-D- glucitol]

A solution of 3 g of 2,2 ' ,2• '-[ (hexahydro-lH-

1,4 ,7-triazonin-l,4 ,7-triyl)tris [carbonyl [ [ [5-[2-hy¬ droxy-l-(hydroxymethyl)ethyl]amino]carbonyl]-2,4, 6- triiodo-3 ,l-phenylene]oxy] ]trisacetic acid methyl ester (prepared according to Example 6) (0.00137 mol) and of 2.4 g of 1-methylamino-l-deoxy-D-glucitol (0.01229 mol) (commercial product) in 100 ml of MeOH, is heated to reflux during 12 h. After cooling at 10°C during 2 h, a solid precipitates and is then filtered. The crude is dissolved in 15 ml H ₂ o and treated with 2 ml of NaOH 0.1N. The resulting solution is percolated through Amberlite® IR 120 and Duolite® A 30 B. By concentration of the eluate a crude is obtained which is purified by column chromatography on silica gel to give 1.30 g (0.00049 mol) of the title compound. Yield: 35% m.p.: 227-230°C (dec)

Elemental analysis:

% calc: C 29.58; H 3.39; I 42.62; N 4.70 % found: C 28.31; H 3.50; I 39.47; N 4.51 TLC: silica gel plate 60 F 254 Merck Eluent: CHC1 ₃ :MeOH:25% NH40H - 2: 2: 1 Detector: UV light (254 nm)

R _f s 0.02 H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure. EXAMPLE 8

5,5' ,5' '-[ (Hexahydro-lH-1,4,7-triazonin-l,4,7- triyl)tris[ (2-oxo-2,1-ethanediyl)amino] ]tris[N,N' -bis-

(2 ,3-dihydroxypropyl)-2 ,4 ,6-triiodo-l,3-benzenedi- carboxamide] A) Hexahydro-1,4 ,7-tris(chloroacetyl)-lH-l,4 ,7-tria- zonine

In a solution of 13 g of chloroacetyl chloride (0.115 mol) in 60 ml of CHC1 ₃ , _a t a temperature of 3°C and under nitrogen atmosphere, a solution of 4.72 g of octahydro-lH-1,4 ,7-triazonine (obtained according to Atkins T.J., Richman J.E., Org. Synth, 1978, 58, 56) (0.0365 mol) and 11.64 g of TEA (0.115 mol) are dropwise added in 90 ml of CHC1 ₃ during 1 h. After having kept the solution during 18 h at R.T., a solid precipitates which is then filtered. The filtrate is concentrated under reduced pressure to produce the precipitation of the hydrochloride of triethylamine. The salt is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in Et20 to give a precipitate, which is then filtered, washed with two 25 ml portions of CHC1 ₃ and united to the previous one. 5.8 g (0.016 mol) of compound A) are obtained. Yield: 44% m.p.: 155-157°C (dec.)

Elemental analysis: % calc: C 40.19; H 5.06; Cl 29.66; N 11.72 % found: C 40.17; H 5.03; Cl 29.61; N 11.64 ¹ 1HH--NNMMRR,, IIRR aannd MS spectra are consistent with the assigned structure.

Scheme

B ) N , N ' -Bis ( 2 , 3-dihydroxypropyl ) -5 - [ ( trif luoro- acetyl ) amino ] -2 , 4 , 6-triiodo-l , 3-benzenedicarbo- 5 xamide

4 ml of MeONa 2 N in MeOH (0.008 mol) are added, at R.T. and under nitrogen atmosphere, to a solution of 9.69 g of N,N'-bis[ [2,3-bis (acetyloxy) ]propyl]-5- [(trifluoroacetyl)amino]-2,4,6-triiodo-l,3-benzenedi- 0 carboxamide (prepared according to known methods as shown in the above synthesis scheme starting from N,N'- bis(2,3-dihydroxypropyl)-5-amino-2,4,6-triodo-l,3- benzenedicarboxamide, obtained according to the procedure of patent US 4 250 113) (0.01 mol). The 5 solution is kept during 20 h, while 6 ml of MeONa 2 N in MeOH are added and then concentrated to dryness. The crude is dissolved in 150 ml of H ₂ o and the aqueous solution is extracted with eight 20 ml portions of

CH ₂ ci ₂ , concentrated at 100 ml and acidified to pH 2.4 0 with HCl to crystallize 6.9 g (0.0086 mol) of compound B).

Yield: 86% m.p.: 285°C (dec.)

Elemental analysis:

% calc: C 23.99; H 2.14; F 7.11; I 47.53; N 5.26 % found: C 23.82; H 2.02; F 7.31; I 47.64; N 5.29 ¹ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure. C) title compound

In a solution of 22.71 g (0.0283 mol) of compound B) in 180 ml of DMF, under nitrogen atmosphere, 14.17 ml of MeONa 2N in MeOH (0.0283 mol) are dropwise added and after 20 min MeOH is evaporated under reduced pressure. The residue is treated with 3.2 g (0.0089 mol) of compound (A) and with 4.047 g of Nal and the mixture is kept at 50°C during 75 h. After distilling the solvent, the crude is dissolved in 300 ml of CH ₂ ci ₂ to give a solid, which is filtered and purified by column chromatography on silica gel. By evaporation of the eluate, a solid is obtained which is dissolved in

10 ml of then percolated through Amberlite^ IR 120 and Duolite^ A 30

B.

By evaporation of the eluate to dryness, 1.9 g

(0.0008 mol) of the title compound are obtained.

Yield: 9% m.p.: 235°C (dec.) K.F.: 4.65% (w/w)

Elemental analysis:

% calc: C 27.43; H 2.94; I 48.30; N 7.11

% found: C 26.05; H 3.02; I 46.01; N 6.86; H ₂ o 4.65

TLC: silica gel plate 60 F 254 Merck Eluent: CHC1 ₃ :MeOH:25% H ₄ OH = 3:3:1

Detector: UV light (254 nm)

Rf - 0.11

¹ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure.

EXAMPLE 9 5,5' ,5' '-[ (Hexahydro-lH-1,4,7-triazonin-l,4,7-triyl)- tris[ (2-oxo-2,1-ethanediyl) (acetylimino) ] ]tris[N,N'- bis(2,3-dihydroxypropyl) -2,4,6-triiodo-l,3-benzene- dicarboxamide]

Following the procedure described in Example 8, 23.90 g of N,N ^• -bis-[2,3-dihydroxypropyl]-5-acetyla- mino-2,4,6-triiodo-l,3-benzenedicarboxamide (prepared according to US 3,701,771) (0.032 mol) in 300 ml of DMF are reacted with 16 ml of 2N MeONa in MeOH (0.032 mol) and 3.58 g of hexahydro-1,4,7-tris(chloroacetyl)-lH- 1,4,7-triazonine (prepared according to Example 8)

(0.01 mol) and 4.50 g of Nal (0.03 mol).

8 g (0.0032 mol) of the title compound are obtained.

Yield: 32% m.p.: 270°C (dec.)

K.F.: 1.38 %(w/w) Elemental analysis:

% calc: C 28.94; H 3.03; I 45.86; N 6.75

% found: C 28.36; H 3.25; I 45.18; N 6.60; H ₂ o 1.38

TLC: silica gel plate 60 F 254 Merck

Eluent: CHC1 ₃ :MeOH:25% NH ₄ OH = 2:2:1 Detector: UV light (254 nm)

R _f - 0.25

^■ ' ^■ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure.

EXAMPLE 10 5,5',5"-[ (Hexahydro-lH-1,4,7-triazonin-l,4,7-triyl)- tris[ (2-oxo-2,1-ethanediyl) (acetylimino) ] ]tris[N,N'-

bis[2-hydroxy-l-(hydroxymethyl) ethyl]-2,4 ,6-triiodo- 1,3-benzenedicarboxamide]

Following the procedure described in Example 8, 14.94 g of N,N'-bis[2-hydroxy-l-(hydroxymethyl)ethyl]- 5-acetylamino-2,4,6-triiodo-l,3-benzenedicarboxamide

(prepared according to US 4,001,323) (0.02 mol) in 225 ml of DMF are reacted with 10 ml of MeONa 2 N ^" in MeOH (0.02 mol) and 2.15 g of hexahydro-1,4,7-tris- (chloroacetyl)-lH-l,4,7-triazonine (prepared according to Example 8) (0.01 mol) and 2.70 g of Nal (0.018 mol). 4.3 g (0.0017 mol) of the title compound are obtained. Yield: 29% m.p.: 280-283°C (dec)

K.F.: 2.43 %(w/w) Elemental analysis: % calc: C 28.93; H 3.04; I 45.87; N 6.75

% found: C 28.38; H 3.34; I 44.27; N 6.64; H ₂ o 2.43 ^H-NMR, * ³ C-NMR, IR and MS spectra are consistent with the assigned structure. EXAMPLE 11 5,5' ,5' '-[ (Hexahydro-lH-1,4,7-triazonin-l,4,7-triyl)- tris[ (2-oxo-2,1-ethanediyl)oxy] ]tris[N,N'-bis[2- hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-l,3-ben¬ zenedicarboxamide]

Following the procedure described in Example 8, 15.53 g of N,N'-bis[2-hydroxy-l-(hydroxymethyl)ethyl]- 5-hydroxy-2,4,6-triiodo-l,3-benzenedicarboxamide (prepared according to EP 185130) (0.022 mol), in 140 ml of DMA are reacted with 11 ml of 2N MeONa in MeOH (0.022 mol) and 2.49 g of hexahydro-1,4,7-tris- (chloroacetyl)-lH-l,4,7-triazonine (prepared according Example 8) (0.01 mol) and 3.15 g of Nal (0.021 mol).

7.2 g (0.003 mol) of title compound are obtained.

Yield: 43% m.p.: 265°C (dec)

K.F.: 2.95 %(w/w)

Elemental analysis: % calc: C 27.39; H 2.81; I 48.24; N 5.32

% found: C 26.56; H 3.16; I 46.20; N 5.12; H ₂ o 1.38

TLC: silica gel plate 60 F 254 Merck

Eluent: CHC1 ₃ :MeOH:25% NH ₄ OH - 2:2:1

Detector: UV light (254 nm) R _f = 0.30

^H-NMR, C-NMR, IR and MS spectra are consistent with the assigned structure.

EXAMPLE 12 ,N" -[2 ,2-Bis[ [ [3-[ [ [2-hydroxy-l-(hydroxymethy1)- ethyl]amino]carbonyl]-5-[ (S)-(2-hydroxy-l-oxopropyl)- amino]-2 ,4 ,6-triiodobenzoyl ]amino]methyl]-l,3- propanediyl]bis[N'-[2-hydroxy-l-(hydroxymethyl)ethyl ] ]-

5-[ (S)-(2-hydroxy-l-oxopropyl)amino]-2,4 ,6-triiodo-l,3- benzenedicarboxamide A suspension of 1.43 g of 2,2-bis (aminomethyl)- l,3-propanediamine.4 HCl (prepared according to

Hodkin,J.H; Heller J. , J.Macromol.Sci.Chem. A3 1969,

1067-1086) (0.0051 mol) in 20.57 ml of a solution of

MeONa IN in MeOH is stirred during 45 min at R.T. and under nitrogen atmosphere. After cooling at 0°C, 2.3 g of TEA (0.0267 mol) are added and then a solution of

19.49 g of (S)-3-[[2-(acetyloxy)-l-oxopropyl]amino]-5-

[ [ [ (2-hydroxy-l-(hydroxymethyl)ethyl]amino]carbonyl ]-

2 ,4,6-triiodobenzoyl chloride (prepared according to DE 2805928) (0.0255 mol) in 100 ml of DMF. After 18 h at

25°C the precipitate is filtered, which is constituted

by triethylammonium chloride and sodium chloride. The filtrate is treated with 600 ml of AcOEt to give a solid which is filtered and dissolved in 100 ml of H ₂ o.

The solution is heated to 35°C, pH is adjusted to 12.5 by addition of 55 ml of 2N NaOH and pH is kept constant during 10 h by addition of further 55 ml of 2N NaOH.

After neutralizing the solution by addition of 10%HC1, a solid precipitates which is purified by column chromatography on silica gel to give the desired product.

2.36 g (0.000820 mol) of the title compound are obtained.

Yield: 16% m.p.: 267°C (dec)

K.F.: 2.60 %(w/w) D t^] ₂₀ = +18.10° (c 10.03; 2N NaOH)

Elemental analysis:

% calc: C 25.47; H 2.38; I 52.95; N 5.84

% found: C 24.89; H 2.66; I 51.57; N 5.74 ; H ₂ 0 2.60

TLC: silica gel plate 60 F 254 Merck

Eluent: CHC1 ₃ :MeOH:25% NH ₄ OH = 6:4:2

Detector: UV light (254 nm)

R _f - 0.33

^ ^■ H-NMR, 1 ³ C-NMR, IR and MS spectra are consistent with the assigned structure. EXAMPLE 13

N, ' '-[2,2-Bis[ [ [3-[ [ [2,3-dihydroxy-l-(hydroxymethyl)- propyl]amino]carbonyl]-5-[ (hydroxyacetyl)amino]-2 ,4,6- triiodobenzoyl ]amino]methyl]-1,3-propanediyl]bis [N'- [2,3-dihydroxy-l-(hydroxymethyl)propyl] ]-5-[ (hydroxy- acetyl)amino]-2,4 ,6-triiodo-l,3-benzenedicarboxamide

A) 3-[ (2-Acetyloxyacetyl)amino]-5-[ [[ (2,3-dihydroxy-

1-hydroxymethyl)propyl]amino]carbonyl]-2,4,6- triiodobenzoyl chloride

A suspension of 97 g of (S)-5-[ [ (acetyloxy)-l- oxopropyl]amino]-2,4,6-triiodo-l,3-benzenedicarbonyl dichloride (prepared according to DE 2547789) (0.14 mol) in 400 ml of THF is added at 20°C under nitrogen atmosphere to a suspension of 34 g of 3-amino-l,2,4- butanetriol (product known in literature, Beil. IV, 4,

1903) (0.28 mol) in 200 ml of THF. The whole is heated during 2 h, then the resulting precipitate is filtered.

By dilution of the filtrate with 200 ml of CH ₂ ci ₂ a solid precipitated, which is filtered off. The filtrate is diluted with 2400 ml of CH ₂ ci ₂ thus obtaining the precipitation of a solid, that after 15h at 20°C, is isolated by filtration to give the desired product.

57.5 g (0.074 mol) of compound A) are obtained.

Yield: 53% m.p.: 234-240°C

Elemental analysis:

% calc: C 24.62; H 2.07; Cl 4.54; I 48.78; N 3.59 % found: C 24.75; H 2.09; Cl 4.63; I 48.48; N 3.57

TLC: silica gel plate 60 F 254 Merck

Eluent: dioxane:CHCl ₃ = 2:1

Detector: 2% starch

R _f - 0.31 H-NMR, ⁱ³ C-NMR, IR and MS spectra are consistent with the assigned structure.

B) title compound

To a suspension of 1.25 g of 2 ,2-bis(aminomethyl)- l,3-propanediamine.4HCl (prepared according to Hodkin, J.H, Heller J., J. Macromol.Sci.Chem.A3, 1969, 1067-

1086) (0.0045 mol) in 18 ml of a solution of MeONa IN

in MeOH stirred during 45 min at R.T. and under nitrogen atmosphere, 2.02 g of TEA (0.020 mol) are added. After cooling at 0°C a solution of 17.52 g (0.022 mol) of compound A) in 100 ml of DMF is added. After 16 h at 25°C the precipitated, constituted by triethylammonium chloride, is filtered. The filtrate is treated with 300 ml of AcOEt to give a solid. The resulting solid residue is filtered and dissolved in 100 ml of H ₂ o. The solution is heated to 35°C, pH is adjusted to 12.5 and kept constant during 10 h by addition of 51.46 ml of 2N NaOH. After neutralizing the solution by addition of 10% HCl, a solid precipitates, which is then purified by column chromatography on silica gel to give 1.89 g (0.000643 mol) of the title compound.

Yield: 14% m.p.: 258°C (dec)

K.F. : 3.76 %(w/w)

Elemental analysis:

% calc: C 24.92; H 2.33; I 51.79; N 5.72

% found: C 24.24; H 2.66; I 48.81; N 5.46; H ₂ o 3.76

TLC: silica gel plate 60 F 254 Merck

Eluent: CHC1 ₃ :MeOH:25% NH ₄ OH = 4:4:2

Detector: UV light (254 nm)

R _f = 0.12 ¹ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure. EXAMPLE 14

1,1 ^« -[ [2 ,2-Bis[ [ [3-[ [ [ 1-deoxy-D-glucitol-l-il ]methyl- amino]carbonyl]-5-[ (S)-(2-hydroxy-1-oxopropyl)amino]- 2,4 ,6-triiodobenzoyl]amino]methyl]-l,3-propanediyl ]- bis[iminocarbonyl[5-[ (S)-(2-hydroxy-l-oxopropyl )amino]-

2,4,6-triiodo-3 ,1-phenylene]carbonyl (methylimino) ] ]- bis[1-deoxy-D-glucitol]

A) l-Deoxy-l-[[5-[ (S)-2-acetyloxy-l-oxopropyl)amino]- 3-chlorocarbonyl-2,4,6-triiodobenzoylJmethyl- amino]-D-glucitol

33 g of l-deoxy-l-(methylamino)-D-glucitol (commercial product) (0.169 mol) are added to a solution of 60 g of (S)-5-[ [ (acetyloxy)-l-oxopropyl]- amino]-2,4,6-triiodo-l,3-benzenedicarbonyl dichloride (prepared according to DE 2547789) (0.084 mol) in 1500 ml of THF at a temperature of 40°C. The mixture is heated to 55°C during 2h and the amine hydrochloride is filtered. The filtrate is dissolved up to the volume of 500 ml and then diluted with 350 ml of CH.ci _? . The solvent is filtered and evaporated under reduced pressure and the resulting residue is treated with 500 ml of CH ₂ ci ₂ . The resulting precipitate is filtered to give 16.9 g (0.0194 mol) of compound A). Yield: 23% m.p.: 240°C (dec) K.F.: 1.07 %(w/w) Elemental analysis:

% calc: C 27.65; H 2.78; Cl 4.08; I 43.83; N 3.22 % found: C 27.33; H 2.77; Cl 4.19; I 43.52; N 3.15;

H ₂ 0 1.07 TLC: silica gel plate 60 F 254 Merck

Eluent: CHC1 ₃ :MeOH:25% NH ₄ OH = 6:3:1

Detector: UV light (254 nm)

R _f = 0.33

^H-NMR, 1 ³ C-NMR, IR and MS spectra are consistent with the assigned structure.

B) title compound

0.77 g of 2 ,2-bis (aminomethyl )-l, 3-propanediamine .4HC1 (prepared according to Hodkin, J.H, Heller J. , J. Macromol. Sci.Chem. A3, 1969, 1067-1086) (0.0028 mol) are suspended into 11.20 ml of a solution of MeONa IN in MeOH and stirred during 45 min at R.T. and under nitrogen atmosphere. After cooling at 0°C, a solution of 12 g (0.0138 mol) of compound A) in 72 ml of DMF is added. After 48h at 25°C the precipitate, constituted by triethylammonium chloride, is filtered. The filtrate is treated with 300 ml of AcOEt to give a solid which is filtered and dissolved in 75 ml of H ₂ o. The solution is heated to 40°C, pH is adjusted to 10 and kept constant during 18 h by addition of 26.5 ml of 2N NaOH. The aqueous solution is percolated through Amberlite® IR 120 and Duolite^ A 30 B. By concentration of the eluate, 2 g (0.00061 mol) of the title compound are obtained.

Yield: 22% m.p.: 270°C (dec)

K.F.: 0.90% ( /w) t00 ₂₀ = +20.65° (c - 10.05; 2N NaOH) Elemental analysis:

% calc: C 28.07; H 3.06; I 46.27; N 5.11 % found: C 27.83; H 3.24; I 45.22; N 5.02; H ₂ 0 0.90 ¹ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure. EXAMPLE 15

N,N' '-[2 ,2-Bis[ [ [3-[ [ [2-hydroxy-l- (hydroxymethyl)- ethyl]amino]carbonyl]-5-hydroxy-2 ,4 , 6-triiodobenzoyl ]- amino]methyl]-l,3-propanediyl]bis [N'-[2-hydroxy-l-(hy- droxymethyl)ethyl]-5-hydroxy-2,4 ,6-triiodo-l,3- benzenedicarboxamide]

Scheme

₉ H ₇ C10 ₄ C..H..N.O.,

^C 5 ^H 16 ^N 4 41 40 4 16 PM 214,61 PM 132,22 PM 844,80 a

^C 49 ^H 60 ^N 8°20

PM 1081,07 b

A) N,N' '-[2,2-Bis[ [ [3-[ [ [2-hydroxy-l-(hydroxymethyl)- ethyl ]amino]carbonyl ]-5-hydroxybenzoyl ]amino]- methyl]-l,3-propanediyl ]bis [N'-[2-hydroxy-l- (hydroxymethyl )ethyl ]-5-hydroxy-l,3-benze- nedicarboxamide]

A solution of 22.81 g of methyl 3- (chlorocarbonyl)-5-hydroxybenzoate (prepared according to Example 2) (0.104 mol) in 100 ml of CHC1 ₃ and 40 ml of DMA is dropwise added to a solution of 3.37 g of 2 ,2-bis (aminomethyl)-l,3-propanediamine (prepared according to Hodkin J.H., Heller J. , J. Macromol. Sci. Chem. A3, 1969, 1067-1086) (0.0245 mol) and of 10.53 g of TEA (0.104 mol) in 80 ml of CHC1 ₃ , at a temperature of 0-5°C and under nitrogen atmosphere. The mixture is kept at 20°C during 16 h. By concentration to dryness of the solution, a residue is obtained which is suspended in 700 ml of a 0.03M NaHC03 solution. The precipitate is filtered and treated at a temperature of 50°C with 700 ml of MeOH. After cooling, the precipitated is eliminated, by filtration. The methanol solution, after ebullition during lh, gives a solid, tetraester (see previous scheme), which is then filtered. The intermediate tetraester is mixed to 14.49 g of 2-amino-l, 3-propanediol (commercial product) (0.159 mol) and heated under reduced pressure (110°C;. 2.6kPa). After 5 h the oil is cooled at 40°C, dissolved in 100 ml of a mixture MeOH:H ₂ o nd percolated through Amberlite® IR 120 and A 30 B. By evaporation of the eluate a residue is obtained which is crystallised from 100 ml of MeOH to give 5.76 g (0.00532 mol) of compound A).

Yield: 22% m.p.: 230°C

K.F.: 3.70% (w/w)

Elemental analysis:

% calc: C 54.42; H 5.60; N 10.37 % found: C 52.14; H 5.74; N 9.83

TLC: silica gel plate 60 F 254 Merck

Eluent: CHC1 ₃ :MeOH:25% NH ₄ OH - 5:4:2

Detector: UV light (254 nm)

R _f - 0.23 ¹ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure.

B) title compound

To a suspension of 5.76 g (0.00533 mol) of compound A) in 100 ml of H ₂ o, 18.03 g of ICl (0.0639 mol) and 167 ml of IN NaOH (0.1670 mol) are simultaneously added in 3 h at R.T. in such a way to keep pH at 7. After 1 h, pH is adjusted to 2.5 by addition of 37% HCl and a solid precipitates, which is then filtered. The crude is ' suspended in H ₂ o and dissolved by addition of 2N NaOH up to pH 7 and purified by column chromatography on silica gel . By evaporation of the eluate under reduced pressure a crude is obtained which is then dissolved in H_o. The aqueous solution pH is adjusted to 2.5 by addition of 37% HCl. A solid precipitates which is then filtered to give 9.12 g (0.00352 mol) of the title compound.

Yield: 66% m.p.: 200°C (dec)

Ag 0 ₃ 0.1 N: 98.6%

K.F.: 0.60% (w/w) Elemental analysis:

% calc: C 22.71; H 1.87; I 58.76; N 4.32

% found: C 22.45; H 1.97; I 57.94; N 4.39; H ₂ o 0.60 TLC: silica gel plate 60 F 254 Merck Eluent: CHC1 ₃ :MeOH:25% NH40H - 5:4:2 Detector: UV light (254 nm) R _f = 0.29

H-NMR, 1 ³ C-NMR, IR and MS spectra are consistent with the assigned structure. EXAMPLE 16 N,N' '-[2,2-Bis[ [ [3-[ [ [2-hydroxy-l-(hydroxymethyl)- ethyl]amino]carbonyl]-5-(3,6,9,12,15,18,21-heptaoxado- cos-l-yloxy)-2,4,6-triiodobenzoyl]amino]methyl]-1,3- propanediyl]bis[N ^• -[2-hydroxy-l-(hydroxymethyl)ethyl]- 5-(3,6,9,12,15,18,21-heptaoxadocos-i-yloxy)-2,4,6- triiodo-1,3-benzenedicarboxamide] To a suspension of 10.42 g of N,N' '-[2,2-bis[ [ [3- [ [[2-hydroxy-1-(hydroxymethyl)ethyl]amino]carbonyl]-5- hydroxy-2,4,6-triiodobenzoyl]amino]methy1]-1,3- propanediyl]bis[N'-[2-hydroxy-l-(hydroxymethyl)ethyl]- 5-hydroxy-2,4,6-triiodo-l,3-benzenedicarboxamide] so- dium salt (1:4) [prepared by reaction of 10.08 g of N,N"-[2,2-bis[[ [3-[[ [2-hydroxy-l-

(hydroxymethyl)ethyl]amino]carbonyl]-5-hydroxy-2,4,6- triiodobenzoyl]amino]methyl]-1,3-propanediyl]bis[N'-[2- hydroxy-1-(hydroxymethyl)ethyl]-5-hydroxy-2,4,6- triiodo-1,3-benzenedicarboxamide] (obtained following Example 15) (3.888 mmol) with 15.55 ml of IN NaOH (15.55 mmol). By evaporation of the solvent 10.42 g of the desired product (3.888 mmol)] in 100 ml of DMA, under nitrogen atmosphere, are added to 10.89 g of 4- nitrobenzenesulfonic acid-3,6,9,12,15,21-heptaoxadocos- 1-yl ester (prepared as previously described such as in

Example 4) (20.72 mmol). The reaction mixture is kept at a temperature of 70 °C during 6 h, then evaporated to dryness. The crude is dissolved in 50 ml of CH ₂ C1 ₂ to give a precipitate which is filtered off (sodium 4- nitrobenzenesulfonate) . The filtrate is extracted with

H ₂ o and the organic layer evaporated to dryness. The residue is purified by column chromatography on silica gel to give 5.8 g (1.494 mmol) of the title compound. Yield: 38% m.p.: 87°C K.F.: 0.38% (w/w) Elemental analysis:

% calc: C 33.73; H 4.36; I 39.23; N 2.88 % found: C 33.32; H 4.43; I 38.30; N 2.82; H ₂ o 0.38 TLC: silica gel plate 60 F 254 Merck Eluent: CHC1 ₃ :MeOH:25% NH ₄ OH - 84:14:2 Detector: UV light (254 nm) R _f = 0.20

¹ H-NMR, 1 ³ C-NMR, IR and MS spectra are consistent with the assigned structure. EXAMPLE 17

N,N' ,N' '-Tris[3-[ [ [2-hydroxy-l-(hydroxymethyl)- ethyl]amino]carbonyl]-5-[ (S)-(2-hydroxy-l-oxopropyl)- amino]-2 ,4,6-triiodobenzoyl ]tris (2-aminoethy1)amine

A solution of 72.5 g of (S)-3-[ (2-acetyloxy-l-oxo- propyl)amino]-5-[ [ [2-hydroxy-l-(hydroxymethyl)ethyl ]- amino]carbonyl]-2 ,4,6-triiodobenzoyl chloride (prepared according to DE 2805928) (0.075 mol) in 170 ml of DMA is dropwise added, in 10 min and at a temperature of 20°C, into a solution of 2.2 g of tris(2- aminoethyl)amine (commercial product) (0.015 mol) in 50 ml of DMA in the presence of 13.8 g of solid K2C03.

After 36h the suspension is filtered and the filtrate is evaporated to dryness. The crude is treated with 500 ml of CH ₂ ci and comes under a crystalline shape. The solid is filtered and dissolved in 750 ml of H ₂ o and 250 ml of MeOH. The solution is alkalinized and heated to 40°C during 18 h keeping pH at 10.7 by addition of 36 ml of 2N NaOH (0.072 mol). After dilution ^" at 2 1 with H ₂ o the solution is electrodyalized through salt elimination. The final solution is therefore diluted to a volume of 500 ml, percolated through IR 120 and DuoliteS) A 30 B. By evaporation of the eluate at a reduced pressure a crude is obtained, then is purified by column chromatography on silica gel to give 5.3 g (0.0024 mol) of the title compound. Yield: 17% m.p.: >240°C

K.F.: 6.8% (w/w) Elemental analysis:

% calc: C 26.16; H 2.61; I 51.81; N 6.36 ^' % found: C 26.07; H 2.64; I 51.69; N 6.33; H ₂ o 6.80 TLC: silica gel plate 60 F 254 Merck

Eluent: CHC1 ₃ :MeOH:25% NH ₄ OH = 9: 6: 1 Detector: UV light (254 nm) R _f = 0.25 H-NMR, ⁱ³ C-NMR, IR and MS spectra are consistent with the assigned structure. EXAMPLE 18

3 ,3' ,3' '-[ (1,4,7,10-tetrazaacyclododecan-l,4,7-triyl)- tricarbonyl] ris[N-[2-hydroxy-l-(hydroxymethyl)ethyl]- 5-[ (S)-(2-hydroxy-l-oxopropyl)amino]-2,4,6-triiodo- benzamide]

In a suspension of 1.72 g of 1,4,7,10-

tetraazacyclododecane (TAZA) (commercial product) (0.01 mol) and of 6.2 g of K2C03 (0.045 mol) in 30 ml of DMA, 38.8 g of (S)-3-[ [2-(acetyloxy)-l-oxopropyl ]amino]-5- [ [ [2-hydroxy-l-(hydroxymethyl )ethyl]amino]carbonyl]- 2 ,4 ,6-triiodobenzoyl chloride (prepared according to DE 2 805 928) (0.04 mol) in 70 ml of DMA, are dropwise added at a temperature of 20°C. The temperature is gradually increased up to 40°C and kept constant during 18 h. The solvent is evaporated under reduced pressure and the residue is diluted with CH ₂ ci ₂ portions, to precipitate a solid, which is then filtered. The crude is dissolved in 200 ml of H ₂ 0:MeOH - 2:1. The solution pH is adjusted to 10.5 with 20 ml of sodium hydroxide 2N and then heated to 40 ^β C during 4 h. The aqueous solution is concentrated under reduced pressure and percolated through Amberlite© IR 120 Duolit © A 30 B. By concentration of the eluate a residue of 22 g is obtained, then is purified on silica gel column to give 6.38 g (0.00219 mol) of the title compound. Yield: 28.6% m.p.: >240°C (dec.) K.F.: 4.95% (w/w) Elemental analysis:

% calc: C 26.93; H 2.67; I 51.21; N 6.28 % found: C 25.41; H 2.94; I 49.78; N 6.24; H ₂ o 4.95 H-NMR, 1 ³ C-NMR, IR and MS spectra are consistent with the assigned structure.

Following the same procedure, the following compounds are prepared:

3,3'-[ (1,4 ,7,10-tetraazacyclododecan-l,7- diyl)dicarbonyl]bis[N-[2-hydroxy-l-(hydroxy¬ methy1)ethyl]-5-[ (S)-(2-hydroxy-l-oxopropyl)-

amino]-2,4 ,6-triiodobenzamide] , obtained with molar excess 2.5:1 of chloride (A) compared to TAZA.

3,3•3",3"•-[ (1,4,7,10-tetraazacyclododecan- 1,4,7,10-tetrayl)tetracarbonyl]-tetrakis[N-[2- hydroxy-1-(hydroxymethyl)ethyl]-5-[ (S)-(2-hydroxy- l-oxopropyl)amino]-2,4,6-triiodobenzamide] , obtained with a molar excess of chloride (A) 7:1 compared to TAZA. EXAMPLE 19

2,2' ,2"-[ (hexahydro-lH-1,4,7-triazonin-l ,4,7-triyl)- tris[carbonyl[5-[ [[2-hydroxy-1-(hydroxymethyl)ethy1]- amino]carbonyl]-2,4,6-triiodo-3,l-phenylene]oxy] ]- trisacetic acid To a solution of 20 g of 3,3' ,3"-[ (hexahydro-lH- 1,4,7-triazonin-l,4,7-triyl)tricarbonyl]tris[N-[2-hy¬ droxy-l-(hydroxymethyl)ethyl]-5-hydroxy-2,4,6- triiodobenzamide] (prepared according to Example 3) (0.010 mol) in 100 ml of DMA stirred at 20°C under N2 atmosphere, 14.5 ml of MeONa 2 N in MeOH (0.029 mol) are added. After 15 min MeOH is evaporated under vacuum and 8.46 g of ehtyl bromoacetate (0.054 mol) are added to the solution diluted with 100 ml of DMA. After heating to 60°C during 3 h, the reaction is evaporated under vacuum to give an oily residue which solidifies due to H ₂ 0 treatment. After filtration, H ₂ 0 washing and drying, a crude is obtained, which is then purified by flash chromatography on silica gel. The intermediate ethyl triester, isolated as white solid, is suspended in 75 ml of H ₂ 0 and treated with 17.1 ml of IN NaOH (0.0171 mol) at 20°C during 2 h, to dissolve gradually

the suspended solid. After the acidification of the solution to pH-1.5 with 37% HCl, and filtration and drying, 7.9 g (0.0037 mol) of the title compound are obtained. Yield: 36% m.p.: 282°C (dec.)

Acidimetric assay (0.1N NaOH): 96 Elemental analysis:

% calc: C 25.16; H 2.11; I 53.17; N 3.91 found: C 24.45; H 2.36; I 51.15; N 3.89; H o 2.38 TLC: silica gel plate 60 F 254 Merck Eluent: n-BuOH:AcOH:H ₂ o = 3:1:1 Detector: UV light (254 nm) R _f = 0.12 ¹ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure. EXAMPLE 20

3 ,3' ,3"-[[ (Hexahydro-lH-1,4,7-triazonin-l,4,7-triyl)- tricarbonyl]tris[ [[ (5-hydroxy-2,4,6-triiodo-3,1- phenylene)carbonyl]amino]methy1]tris[5-(acetylamino)-N- [2-hydroxy-l-(hydroxymethyl)-ethyl]-2,4,6-triiodobenza- mide] .

A) 3,3' ,3"-[ (hexahydro-lH-1,4,7-triazonin-l,4,7- triyl)tricarbonyl]tris(5-hydroxybenzoic) acid To a suspension of 114.45 g of 3,3' ,3"-[ (hexa- hydro-lH-1,4,7-triazonin-l,4,7-triyl)tricarbonyl]- tris(5-hydroxybenzoic)acid trimethyl ester (prepared according to Example 2) (0.172 mol) in 450 ml of H ₂ o heated to 50°C are added 450 ml of 2N NaOH (0.900 mol) during about 75 min. After 3.5 h the solution is decolorized, cooled at 25°C and dropwise added to 2N HCl (450 ml; 0.900 mol). The precipitated solid is

filtered, washed with H ₂ 0 and dried giving 94.9 g (0.153 mol) of compound A).

Yield: 89% m.p.: 230-235°C (dec.)

Acidimetric assay (0.1N NaOH): 94% Elemental analysis:

% calc: C 57.97; H 4.38; N 6.76; 0 30.89

% found: C 56.42; H 4.61; N 6.60; 0 31.55; H ₂ o 1.21

TLC: silica gel plate 60 F 254 Merck

Eluent: CHC1 _{3 :} AcOH:H ₂ 0 = 5:5:1 Detector: UV light (254 nm) R _f = 0.35

^■ ^H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure. B) 3,3' ,3"-[[ (hexahydro-lH-1,4,7-triazonin-l,4,7- triyl)tricarbonyl]tris[ [[ (5-hydroxy-3,1-pheny- lene)carbonyl]amino]methy1]tris[5-acetylamino)-N- [2-hydroxy-l-(hydroxymethyl)-ethyl] ]-2,4,6-triio- dobenzamide] To a suspension of 10.2 g (0.16 mol) of compound A) in 90.62 g of S0C1 ₂ (0.758 mol), 0.1 g of quinoline are added heating to ebullition for 3 h. The resulting clear solution is concentrated to dryness to give a glassy residue which is treated with Et ₂ o. _A fter filtration and drying, 11.35 g of 3,3' ,3"-[ (hexahydro- 1H-1,4,7-triazonin-l,4,7-triyl)tricarbonyl]tris (5- hydroxybenzoyl chloride) are obtained. The solution of a portion of said chloride (2.70 g; 0.0049 mol) in 20 ml of DMA is dropwise added to a solution of 19.77 g of 3-(acetylamino)-5-(aminomethy1)-N-[2-hydroxy-l- (hydroxymethyl)ethyl]-2,4,6-triiodobenzamide (0.030 mol) in DMA cooled at 5°C C. After 2 h at the same

temperature, the resulting solution is evaporated to oily residue which is dropwise added in 300 ml of H _? o containing 2 ml of 37% HCl. After filtration and dryness the resulting residue is suspended in H ₂ o and dissolved by addition of 25% NH40H. After 15 h at 25°C the solution is adjusted to pH 7 with 37% HCl giving a precipitate which is filtered and dried. The resulting crude is purified by column chromatography on silica gel and precipitated again from H ₂ o giving 4.52 g (0.018 mol) of compound B).

Yield: 46% m.p.: 268°C (dec.)

Elemental analysis:

% calc: C 37.57; H 2.73; I 44.89; N 6.61; 0 13.20

% found: C 31.83; H 2.72; I 44.64; N 6.59; 0 15.17; H ₂ o 2.38

TLC: silica gel plate 60 F 254 Merck

Eluent: CHC1 ₃ :MeOH:H 0 = 60:33:8

Detector: UV light (254 nm)

R _f = 0.20 H-NMR, 1 ³ C-NMR, IR and MS spectra are consistent with the assigned structure.

C) title compound

13.33 g of compound B) (0.052 mol) are dissolved in 120 ml of H ₂ o by addition of 6.5 ml of 2N NaOH (0.0013 mol) at 25°C. To the resulting solution during

6 h, 12.25 g of ICl (0.42 mol; 92% of the total) and

49.2 ml of 2N NaOH (0.098 mol; 92% of the total) are simultaneously added keeping pH at 9. At first the addition is performed at 25°C but after adding 70% of the iodinating reaction mixture the temperature is taken to 37-40°C during 9 h. After 15 h at 25°C, the

reaction mixture is treated with sodium bisulfite, filtered and acidified to pH 1 with 37% HCl. The precipitate is isolated by centrifugation, washed with

H ₂ 0 and dried. 17.9 g (0.0049 mol) of the title compound are obtained. Yield: 93% m.p.: 245°C (dec.)

Acidimetric assay (0.IN NaOH): 98.4% Elemental analysis:

% calc: C 22.54; H 1.64; I 62.11; N 4.57 % found: C 22.04; H 1.86; I 59.68; N 4.46; Na 0.15;

H ₂ 0 1.96

^ ^■ H-NMR, ¹³ C-NMR, IR and MS spectra are consistent with the assigned structure.