MXPA98010499A - Metalic chelates of macrocyclic derivatives polyaminocarboxilicos and its application in the formation of images for diagnost - Google Patents

Abstract

The present invention relates to the chelates of the compounds of the formula I in which R is a hydrophilic group comprising 3 or 4 successive phenyl rings and m is 1 or 2, with the metal ions, for use in diagnostic imaging.

Description

METAL-L7AT0S OF POLYAMINOCARBOXILIC MACROCYCLIC DERIVATIVES AND THEIR APPLICATION IN TRAINING OF 33TOGENES FOR DIAGNOSIS The present invention relates to the chelates formed by the macrocyclic polyaminocarboxylic acids with the metal cations and their use in the formation of diagnostic images, especially by magnetic resonance (MRI) for the magnetic cations. The relaxivities ri and r2 and particularly the first measure the magnetic efficiency of a chelate and allow to appreciate its usefulness as a contrast product. For currently marketed products, ri does not exceed 6 M ^ s "1 (at 20 MHz and 37 ° C), chelates are linear (gadopentetate or DTPA and gadoversetamide) or macrocyclic (gadoterate or DOTA and gadoteridol). these compounds, administered intravenously, diffuse rapidly out of the muscular domain into the extracellular interstitial compartment and there is not yet on the march of the product that remains sufficiently localized in the vessels to allow a good evaluation of tissue perfusion, of permeability capillary or blood volume.

REF .: 29103 The macromolecular derivatives result from the grafting of a classical chelate on a biocompatible polymer, such as that obtained by fixing the gadopentetate on polyethylene glycol or polylysine, or gadopentetate and gadoterate on a polysaccharide, described after more than 10 years and that have been tested on animals have not yet developed in man. The grafting of these classical chelates (DTPA or DOTA) on the branched polymers of single molecular mass, said in cascade or dendrimers, consisting of various repetitive units, as for example in EP-A-430863 or EP-A-, has been proposed. 607222. It has been mentioned that the relaxivities of these products are high and that they have a certain vascular remanence but these results remain limited because, for example, the polyamines bearing 24 or 48 molecules of gadopentetate described in EP-A-430863 do not have, despite of its size, but a relaxability of the order of 13 mM ^ s "1, for 4.8 M ^ s" 1, for the gadopentetato alone; furthermore, it seems difficult to isolate a single compound after synthesis, namely to obtain the substitution of all the terminal groups of such polyamine, assuming that the uniform molecular mass could be obtained, avoiding the dispersion of the physical-chemical properties and pharmacokinetics of the compounds of the administration dose, known drawback of the derivatives of classical polymers, which has limited their development. In the most recent works with the aim of obtaining molecules of strong relaxivity, of a single molecular mass, and which comprise only a single chelating group, mention may be made of EP-A-661279 and WO 97/01359 presenting the interest of the introduction in the known molecular structures, of at least 3 hydrophilic side arms of mass greater than 200 on the side substituents of the donor nitrogen atoms carrying the other coordination groups, which are the acid groups or derivatives, especially, it is indicated that gadolinium complexes of the compounds derived from the gadoterate of formula HOOC COOH have a relaxivity r_ > 20 mM'V1 at 20 MHz and 37 ° C. As compounds with strong relaxivity and that have a certain vascular remanence, it is necessary to mention those described in WO 96/23526, of structure significantly different from the preceding ones, where one of the representatives, MS325, gadolinium complex of the compound of formula it is reversibly fixed on the albumin of the plasma in such a way that its relaxivity ri in this medium is practically 10 times that of the gadopentetate where it is derived, for a half-life multiplied by 4 and a volume of distribution divided by 2.5 in the rabbits Acad . Radiol S356-S358 (1996). In contrast to MS325 and its homologs, the paramagnetic metal complexes of the present invention have high, equal relaxivities in water, since r_ is greater than 30 mM "ls" 1 (20 MHz, 37 ° C); In addition, Gomo does not fix virtually on plasma albumin, presents a net vascular location and is mainly eliminated by the kidneys, such that they can be advantageously used in MRI as contrast products, revealing the circulatory system. According to a first aspect, the invention relates to the chelates of paramagnetic, or radioactive, metal ions of the polyaminocarboxylic macrocycles of the formula wherein m is 1 or 2, R 'is H, a (C1-C4) alkyl group, optionally hydroxylated, a group CH2-COOH, CH2-CONZ? Z2, Zi and Z2 are independently of each other, H, or a (C1-C4) alkyl group, optionally hydroxylated, or R 'is a group HOOC-CH- (CH2) m-CONHR, R is a group where a is 1 or 2, Z is a bond CH2, CH2-CO-NH or (CH2) 2 ~ NHCO Z 'is a bond, 0, S, NQ, CH2, CO, CO-NQ, NQ-CO , NQ-CO- NQ, C0-NQ-CH2-C0NQ Z "is CO-NQ, NQ-CO or C0-NQ-CH2-C0-NQ, NQ-C0-CH2-NQ-C0 with Q and H or a alkylal group (C1-C4), optionally hydroxylated Ri, R2, R3, R4, R5, independently of each other are chosen from H, Br, Cl, and I, C0-NQ? Q2 0 N (Q_) -C0- C02- and Qi and Q2, identical or different, are selected from among the (C2-C6) alkyl groups optionally hydroxylated and optionally interrupted by the oxygen atom such that Qi and Q2 comprise those two from 4 to 10 OH groups, it being understood that at least 1 and when plus 2 groups Rt, R2, R3, 4, R5 are amide groups. The metal cations forming complexes in the chelates of the invention are chosen from the paramagnetic cations generally used in MRI, especially the trint cations where Fe3-, Cr3, Eu, Gd, Tb, and particularly Gd, or for a use in scintigraphy between cations of radioelements such as 99mtc or lllIn. The mineral bases which can give a physiologically acceptable salt with the possible free acid function of a metal complex of the compound of formula I, are preferably chosen from hydroxides and carbonates of alkali metals (FC Na ~) or alkaline earth metals (Ca ", Mg ") while the organic bases are chosen from amines such as aminoethanol, tromethamine or n-methylglucamine, or between amino acids such as lysine, glycine or arginine. Preferred are compounds in which m is 2 and is 1, R 'is not H or alkyl, Z is a bond, CH2 or CH2CONH, Z' is CONH, NHCO, C0NHCH2C0NH or NHCONH, Z "is CONH or CONHCH2CONH with R3 = CONQ? Q2 and R_, R2, R4, R5 are independently H, Br, Cl or I, or R2 = R4 = CONQ? Q2, in which case Ri, R3, R5 are independently H, Br, Cl or I, or Z "is .NHCO with R3 = N (Q?) COQ2 and R_, R2, R4, R5 are independently H, Br, Cl or I, or R2 = R4 = N (Q?) COQ2 in which case Ri, R3, R5, are independently H, Br, Cl or I.

Among those which are preferred are compounds in which Z 'is CONHCH2CONH or NHCONH, and better those for which Z' is CONH, a bond plus cut, R_, R3, R5 are all three Br or I and R2 = R4 = CONQ_Q2 with Qi and Q2 are the hydroxylated (C2-C) alkyl groups comprising those two of 6 to 10 OH groups or if Qi and / or Q2 is interrupted by a hydrogen atom, from 4 to 8 OH groups. According to a s. The invention relates to a process for the preparation of the metal chelates of the compounds of formula I, which consists of reacting on a chelate II, the metal cation M3"and the compound of the formula an amine of formula H2N-Z in which the letters have the same meaning as in formula I in the presence of a coupling agent, especially those used in the peptide synthesis, adapted to the reaction medium, aqueous or organic, in which the compounds of formula II and III are in solution, at least partially, under these conditions, the blocked carboxylic acid groups located on the alpha carbons of the nitrogen atoms of the compound II do not react. According to another aspect, the invention relates to contrast products for the formation of images in man or animals by scintigraphy when the chelate is radiolabelled or by magnetic resonance when the chelate comprises a paramagnetic ion, optionally ba or the salt form of a mineral or organic cation, in a pharmaceutically acceptable carrier, associated with the compatible excipients. According to a last aspect, the invention relates to methods of imaging the human or animal body comprising administering to a subject an effective unit dose of a composition of the invention and subjecting the tissue or area to be studied to a field magnetic field suitable for observing the magnetic resonance of the proton, or to a scintigraphy when the chelate contains a radioelement. The chelates of the compounds of formula I which comprise 4 identical substituents on the nitrogen atoms of the central macrocycle, 1,4,7,10-tetraazacyclododecane, or cyclen, are prepared with a number of steps lower than those of the case in the which R 'represents H, CH2C00H, CH2CONZjZ2, or an alkyl or hydroxyalkyl group with C1-C4 such that CH3, CH2CH2OH or CH2-CHOHCH2OH, since one of the four nitrogen atoms of the cyclen must be temporarily blocked, selectively by a group labile or previously make a substitution of the macrocycle for a group R '. The R groups of the compounds of the invention comprise 3 or 4 phenyl rings wherein the most elongated of the macrocycle is substituted by 1 or hydrophilic groups, which influence the aqueous solubility and biocompatibility of the chelate. Among these hydrophilic groups, tertiary amide groups are preferred, where the substituents are the hydroxylated (C2-C6) alkyl groups optionally interrupted by an oxygen atom and particularly those derived from the linear aminoalcohols HNQ? Q2 in which Qi and Q2 independently of one another are CH2 (CHOH) n (CH2OCH2) r (CHOH) pCH20H, and, if -in Q_ and Q2 r = O, then p = 0 and n can be 0 to 4 and Q_ and Q2 comprise conjuncts of 5. to 10 OH groups, which corresponds especially to HQ_Q2 a H-N [CH2 (CHOH) 4CH2OH] 2 and HN-CH2 (CHOH) 4"CH2OH I CH2-CHOH-CH2OH s i r = 1 in Qi and / or Q2, n and p are, independently of each other, 0 or 1 and Qi and Q2 comprise a group of 4 to 8 OH groups, what corresponds especially for HNQ_Q2 to HN-CH2 (CHOH) 3-CH2OH, HN-CH2 (CHOH) 2-CH2OH, (CH2) 2-OCH2-CH2OH CH2-CHOH-CH2OCH2-CH2OH and HN-CH2 (CHOH) 2-CH2OH CH2-CH2-OCH2 -CHOH-CH2OH.

These aminoalcohols precursors are commercially available or can be prepared - either from a suitable primary aminoalcohol, for example by the action of a sugar and reduction as described in EP-A-675105 when n = 4 and p = r = 0, or for those in which n = 3 and p = r = 0, as described in EP-A-558395, - either by the action of a sugar on the benzylamine followed by the introduction of the second hydroxylated substituent by the action of a halide or Suitable sulfonate after removal of benzyl by catalytic hydrogenation. When Q_ and / or Q2 comprise an oxygen atom in the chain, the aminoalcohols are, when n = p = 0, prepared from the 2-aminoethoxyethanol on which a suitable epoxide or a hydroxylated alkyl halide can be reacted or even a hydroxylated aliphatic aldehyde such as a monosaccharide to form an imine, is then reduced catalytically or chemically. When n is 1, the aminoalcohols can be prepared by the action of the epoxide C CH2-CH-CH2-0-CH2- (CHOH) p-CH2OH O on the suitable primary aminoalcohol, said epoxides are obtained by oxidation of the corresponding ethylenic derivatives, by a peracid or a peroxyimidic acid, as described by J. Org. Chem. 26 659-663 (1961) and 4_8 888-890 (1983). The presence of the halogen atoms on the sides of the amide groups on the phenyl ring is advantageous and R groups are preferred in which R? = R3 = R5 = Br or I and R2 = R4 = CO-NQ? Q2, especially for its stability. The point Z "can be formed between the 2 phenyl rings before or after the points Z '.

For "example, the compound it can be prepared, when Z is a bond, from _T the diphenyl derivatives V or their esters in which Z 'has the same meaning as in formula I. The compound V in which Z' e 0 is described in Makromoleculare Chemie 130 103-144 (1969); that in C-J.1 Z 'is NH is described in Indian J. Chem. "1_3 35-37 (1975), that in which Z 'is CH2 or CO, in J. Pharm., Sci. 55 (3) 295-302 (1966) that in which Z' is a bond, in Synth. Comm. 24 (22) 3307-3313 (1994), and that in which Z 'is S is described in II Drug, 44 (7-8) 683-684 (1989). Other compounds V can be prepared by analogy procedures, for example when Z 'is HNCONH, by the action of 02NC6H4NCO on H2NC6H4COOH in anhydrous medium, or when Z' is NHCO or CONH, by reaction of the aromatic acid chloride on the suitable aniline in solution in an aprotic solvent such as CH2Cl2, C6HCH3, CH3CON (CH3), the aromatic acid on the aniline in the presence of a sulfonic acid chloride, triethylamine and dimethylaminopyridine as described in Synth. Communications 25 (18) 2877-2881 (1995). The reduction of the group NO 2 in NH 2 can be carried out, in a known manner, by hydrogen, in the presence of the catalyst or by chemical means. When Z in formula IV is CH2-CONH, the activated glycine in which the NH2 group is protected is reacted on the compound IV in which Z is a bond or on an aniline carrying a Z 'precursor group, eventually protected. Glycine is protected, for example, in the form of carbamate, in particular t-butylcarbamate (Synthesis, _48, 1986) and benzylcarbamate.

(Chem., Ber., 65, 1192 (1932)), in the form of phthalimide (Tetrahedron Letters 25, 20, 2093-2096 (1984)), with a benzyl (Bull. Soc. Chira. Fr., 1012- 1015, (1954)), an N-allyl (Tetrahedron Letters 22, 16, 1483-1486 (1981)). (See also Protective groups in Organic Synthesis 315-349, T. W. Green (John Wiley and Sons Inc.)). The elimination of the protective group of the NH2 fixed on Z is not in general, effected but in the stage of compound III. Classically, a phthalimido group is removed by the action of hydrazine, when a benzyloxycarbonyl or benzyl group is by catalytic hydrogenation. When Z = CH2 in compound IV and Z '= CONH or CONHCH2CONH, the 4-amino ethylbenzoic acid in which the NH2 group is protected in the form of carbamate or imide can be reacted as described in J. Org. Chem. 43, 2320-2325 (1978) or in Rec. Trav. Chi. The Netherlands, 7_9. 688 (1960) on the suitably substituted protected benzoic acid. When Z is (CH2) 2NHCO, compound III can be prepared by the action of an excess of ethylenediamine on a suitable benzoic ester, either by carrying the (Z '-phenyl) aZ "-phenyl substituted chain, either carrying only one precursor group of Z "eventually protected. On the other hand, when a is equal to 2, the compound IV can be reacted where the amino group is optionally protected on an aminobenzoic acid where the acid function is optionally protected, to obtain the compounds IV in which the second Z 'is CONH of formula The reaction is then carried out on the suitably substituted phenyl ring of the formula wherein R_, R2, R3, R4, R5 are H, halogen, CO-NQ? Q2, in formula I or are optionally protected and R "represents CO-CH2-NH2 or H, in organic or aqueous solution, the compounds IV or IV either in the form of acid chloride or in the presence of a coupling agent, such as those used in the peptide synthesis and for example a chloroformate, a sulfochloride, or an aliphatic carbodiimide, optionally carrying a group amine or solubilizing quaternary ammonium The amide of formula VI in which R "= H will be prepared by methods known to the person skilled in the art from the convenient, optionally halogenated, aromatic amino acid, in which each carboxylic group present is activated in the form of acid chloride or mixed anhydride, or from the nitrated aromatic acid which is amidated before reducing the NO2 group. Compounds VI in which R? = R3 = R5 = Br or?, And R2 and R4 = CO-NQ1Q2 with Q_ = CH2 (CHOH) 4CH2OH and Q2 = CH2CH2OH or CH2 (CHOH) _.3-CH2OH and R "= CO-CH-NH2 are described in WO 97/01359. The other derivatives, halogenated or not, and especially those in which the chains Q_ and Q2 are interrupted by an oxygen atom can be prepared analogously from suitable amino alcohols. When Z is a bond it is preferred to react the nitrated compound such that V on the aniline VI before effecting the reduction. It is thus possible to react compounds IV or IV on a VI precursor compound, carrying the COOH groups, optionally protected in the form of an ester instead of the CO-NQ1Q2 group, to make only the mono or diamide, or still make reacting a compound in which NL_L2 is an amino prot group. egi d, o, with e Z'i and Z'2 react to To prepare a compound III in which R3 or R2 and FU represent N (Q_) CO-Q2 and Z "= NH-CO or NH-CO-CH2-NH-._ the benzoic acid of the formula can be reacted in which the hydroxyls of the group N (Q_) C0Q2 are optionally protected on an amine wherein R "is H or COCH2-NH2, before reducing the nitro group to obtain a compound III in which Z is a bond.

Among the compounds of formula V there may be mentioned those prepared from CH (OCOCH) CH- (OCOCH.) COCÍ, described in Org. Synth 41, 79-82 (1961), and convenient benzoic acids, in which R = R = R = 1 R2 = described in Ep 357467 In the amide groups Z 'and Z ", Q can be introduced in a conventional manner by the action of the corresponding halide in the presence of a base on the compound in which Q = H, preferably in the stages of the intermediate compounds. The reaction of the compounds of the formula III on the salts of the chelates of the formula II takes place, preferably in an aqueous medium, optionally in the presence of a third polar aprotic solvent such as dioxane or tetrahydrofuran, in the presence of a soluble carbodiimide, such as those carrying the amine group described in J. Org. Chem. 21, 4 3 9 - 4 4 1 (1 9 5 6) and 2 6 r 2 5 2 5 -2 5 2 8. (1 9 6 1) or US 3, 1 3 5, 7 4 8, or from the ammonium group in O rg. S ynth V, 5 5 5 - 5 5 8, which is an undefined reactive of l-ethyl-3 (3-dimethylamino) propyl carbodiimide (EDCI) or its analogue, the 1-cyclohexyl 3- (2-morpholinyl) carbodiimide p-tolyl sulfonate. It can also be carried out in the presence of the N-hydroxy-sulfosuccinimide as described in Bioconjugate Chem. 5, 565-576 (1994) or of the tetraf luoroborate of 2-succinimido 1, 1, 3, 3-tetra-methyluronium. and the analogs described in Tetrahedron Letters 30, 1927-1930 (1988). Another method consists in forming an activated intermediate ester by reacting for example N-hydroxysulfosuccinimid (NHS) or hydroxybenzotria HOBT) in the presence of carbodiimide such as EDCI on urate II which can be solubilized by salification with a mineral cation, for example an ammonium or sodium. In the presence of 2-ethoxy-1-ethoxycarbonyl 1,2-dihydroquinoline (EEDQ), the reaction can be carried out in a hydroalcoholic medium. The compound of formula II in which m is 1, can be prepared from the cycle on which a diester of acetylene dicarboxylic acid is reacted to obtain an enamine which is reduced by a classical, catalytic or chemical method, followed by hydrolysis of the ester functions. In the case of the benzyl ester, it is preferred in a first step to carry out the chemical reduction of the enamines, for example by the action of a cyanoborohydride, followed by debenzylation by the hydrogen in the presence of the catalyst. The chelate II in which m = 2 and the 4 substituents of the nitrogen atoms are identical and M3 ~ is Gd "is a known compound, described especially in EP-A-661279. Chelate II in which m = 1 is prepared by the same procedures.Compounds II in which M + represents another metal cation will be prepared from analogous manner by the action of the metal salt, particularly the chloride, or the metal oxide on an aqueous solution of a ligand salt, as described in US 5,554,748 and the references which are cited, or in Helv. Chi. Acta 69, 2067-2074 (1986), or by cation exchange when the relative stability of the chelates allows, especially with an ion exchange resin For chelates with a radioelement, a radioisotope exchange can be effected by heating a chelate with a mineral salt of the radioactive metal in the ultrapure water and the elimination of the non-complex cations for the passage on a complex-forming resin, so that the metal cation of the chelate can be released by another ag excess complexing agent, preferably giving an insoluble Gd chelate, such as oxalic acid, to obtain the compound of the formula II pure, before forming the complex of another metallic cation. The compounds II 'in which m = 2 and R' is H, optionally hydroxylated alkyl, CH2COOH and CH2CONZ? Z2 can be prepared from a monosubstituted cyclin by R 'or by a removable protective group, in which case the introduction of R' in place after the I trialkylation with ROOC-CH- (CH2) 2-C00R. Among the monosubstitution processes, mention may be made of the monoalkylation reaction favored by the choice of solvent, described in J. Org. Chem. 5_8, 3869-3876 (1993), that with the complex formation of 3 nitrogen atoms by the boron or phosphorus derivatives, described respectively in Tetrahedron Letters 32 (5) 639-641 (1991) and Angew Chem. Int. Ed. 30 (5) 560-561 (1991), or that with the formation of an orthoamide intermediate described in US 5,410,043. When R 'is different from H, it is preferred to introduce it with R' instead of directly carrying out the trialkization of the I-cyclic by a reactive derivative of ROOC-CH- (CH2) 2C00R, the dialkylated and tetraalkylated derivatives formed simultaneously can not be eliminated by simple operations. The purification methods of different synthesis intermediates and of the final product are classic but they must obviously be adapted to the chemical nature of the product, its molecular mass, its solubilized salts and the viscosity of its solutions. Chemical (selective dissolution, crystallization) or physical separation methods can be applied by membrane filtration or by adsorbent, suspension or column treatment. Especially for compounds III which are soluble in an aqueous medium, it can be purified by passing on the anionic and cationic ion exchange resins or by ultrafiltration, by diafiltration or by reverse osmosis on a suitably chosen membrane to eliminate in the eluent the lower mass molecules, solvents and salts. For the compounds II ', it is preferable not to carry out a treatment that can modify the relative proportions of the isomers and to be able to purify the intermediate esters dissolved in an organic solvent not miscible by agitation with an aqueous acidic phase then, after decanting, by the contacting an adsorbent, such as Silica Gel, before carrying out its hydrolysis in a basic or acidic medium to obtain the acids II that will form the complex. The chelates of formula I are generally purified in the form of an alkaline salt soluble in aqueous medium by one of the methods mentioned above, and especially by treatment of its aqueous solution with carbon black or silanized silica. These chelates of the invention are characterized by the presence on the central core forming chelates of lateral arms comprising 3 or 4 successive phenyl rings, joined together by the points of shorter length, the last phenyl ring carries at least one hydrophilic group; Despite their high molecular mass, and the presence of several hydrophobic phenyl rings, these compounds are water soluble and biocompatible and can be administered intravenously to man. In addition, and this is a very important property, it crosses a little the vascular walls contrary to the commercialized compounds, which allows to obtain the images by magnetic resonance, a strong contrast between the vessels and the neighboring tissues; this property, associated with its strong relaxivity, allows either to inject the patient with inferior complex gadolinium doses, or to detect the pathological states that could only be detected.

The paramagnetic chelates of the invention can be formulated for parenteral or enteral administration, associated with pharmaceutical vehicles and conventional excipients of this field. For an intravenous or intraarterial administration, the compounds of the invention are presented in sterile aqueous solution at the concentration of 0.001 to 0.5 mol / liter, optionally associated with a pH stabilizing agent around 7, such as the TRIS or C02 buffer, to an agent isotonizing agent such as mannitol, glycerol or glucose preferably with NaCl which can modify the solubility of the chelate dispersion, or to another complex former such as EDTA. In order to eliminate the endotoxins which can contaminate the finished product, especially especially the purification by liquid chromatography, an ultrafiltration, possibly tangentially at a substantially constant volume, is preferably carried out on the membranes where the nature and the cut-off threshold are a function of the molecular mass of the product and the pressure of the viscosity of the solution. This purification can also be carried out in certain intermediary stages on the smallest compounds, by microfiltration, especially on the charged membrane, or by ultrafiltration. Treatments can thus be considered for an absorbent, specific or not of endotoxins such as carbon black. For an intravaginal administration, the aqueous solutions preferably comprise a viscosifying agent, such as a natural gum, a polysaccharide or a cellulose derivative. For a rectal administration, the chelate will be formulated in the form of suppositories or viscous solution. Finally, for an oral administration, it could be present in the form of capsules, tablets or syrups, prepared with the usual excipients. Formulation examples can be found in Remington's for Pharmaceutical Science, 18e Edition (1990), Mack. Pub. Cy. The unit dose and its concentration are a function of the size of the patient, the type of imaging performed, but all of the solubility, the solution viscosity, the magnetic efficiency, the capillary permeability and the compound's pharmacokinetics. . They will be used in magnetic resonance imaging, applying rapid or non-rapid techniques, to study perfusion, particularly the myocardium, cerebral, renal or hepatic, for angiography or to locate or characterize permeability abnormalities, in particular tumorai, inflammatory and ischemic or cartilage. These products could also be used in nuclear medicine after the introduction of a radioactive atom, for example by isotopic exchange of the halogens or complex forming cation; A scintigraphy of the areas where images will be formed will be made after the administration of the chelates of the invention. In this context, the examples of the compounds of the invention are described as well as a method of preparing the gadolinium chelates of the compounds of the formula II in which R '= HOOC-CK (CH2) mCOOH, R' = CH2COOH, and compounds VI precursors of phenyls. The isolated products are, depending on the case, characterized by their retention distance in chromatography on thin layers or their retention times (tr) in high performance liquid chromatography (HPLC) or in spherical exclusion chromatography (CES).

Their molecular masses have been determined by mass spectrometry (electro-spraying).

A. _ "Gadolinium chelate of [1,4,7,10-tetraazacyclododecane] 1,4,, 10-tetra (2-glutaric acid) (sodium salt): 1. In a solution of 25 g of 1, 4, 7, 10-tetraaza-cyclododecane in 280 ml of acetonitrile, are introduced g of sodium carbonate then 78 g of ethyl 2-bromoglutarate, is prepared for example is described in Acta Chim. Acad. Sci. Hung 4_1 (3) 331-6 (1964); the medium is brought to its reflux temperature one day in the course of which 78 g of the brominated derivative is added twice with 30 g of sodium carbonate. The precipitate is filtered after cooling and the organic phase is rinsed with water before extraction with a dilute aqueous solution of hydrochloric acid. It is then extracted from the aqueous phase brought to a pH of 3-4 with toluene. The desired product is purified by chromatography on silica eluting with methylene chloride, optionally mixed with acetone. 2. Hydrolysis of the ester functions: 46 g of the octaester are introduced in solution in 52 ml of ethanol in 350 ml of water in which 50 g of NaOH are added, in the form of beads. After two days under stirring at 80 ° C, 500 ml of cation exchange resin is introduced into the cooled solution in the form of weak acid to neutralize after separation of the solid phase, 500 ml of anion exchange resin under the strong base form. The resin is separated and introduced into 500 ml of 6N aqueous acetic acid solution; the final product, passed in solution, is isolated in the form of a powder by evaporation under vacuum of the solvent. HPLC: column 25 cm x 4.6 mm silica gel Nucleosil® C18 100-5. Eluent No. 1: aqueous H2S? 4 (0.1%) for 10 minutes then with 0 to 10% (V / V) of CH3CN in 10 minutes: d = 1 ml / min; T = 25 ° C; tr = 5.4; 8.7; 10.2; 14 min (isomers) (CH3COOH-tr = 4.5 minutes). 3. Complex formation: by gadolinium oxide: in 30 ml of a solution of a pH of 5.5 to 6 of 2 g of the preceding octaacid, 0.47 g of gadolinium oxide are introduced and the mixture is kept at 80 ° C for 3 hours , in the course of which the pH is adjusted if necessary. After cooling, at pH = 6.5, 2 g of Chelex® 100 resin marketed by Sigma under the form Na ""; after a few hours of contact, the resin is separated and the solution is poured over 10 volumes of ethanol to precipitate the chelate. For gadolinium chloride: a pH of 6.5 is obtained by adding aqueous NaOH (1N), the mixture of 6.5 g of octaacid and 3.5 g of Gd CI3, 6 H2O in 130 ml of water, and it is brought to 60 ° C during 2 hours in the course of which the pH is maintained at 6.5 for the total addition of 21 ml of 1N aqueous NaOH. After a few hours at room temperature, concentrate to 25 ml and precipitate the final product in 10 volumes of C2HsOH.

B. Gadolinium chelate of 1,4,4,7,10-tetra-azacyclododecane 1,4-, 7-tri- (2-glutaric) acid (formula II: R = HOOC-CH- (CH2) 2COOH, R '= H , M = Gd): 1. 10-benzyl 1, 4, 7, 10-tetraazacyclododecane: 30.5 g of benzyl chloride are introduced dropwise into a solution of 50 g of 1, 4, 7, 10-tetraazacyclo-dodecane in 500 ml of chloroform. After 24 hours of stirring at room temperature, the reaction medium is filtered; the filtrate is concentrated to dryness. The residue is taken up in 350 ml of water and 75 ml of toluene and after the decanting of the toluene phase, the aqueous phase is extracted twice with 200 ml of dichloromethane. The organic phase is dried over sodium sulfate and then concentrated to dryness. 21 g of the product are obtained in the form of oil. 2. 10-Benzyl 1, 4, 7, 10-tetraazacyclododecane 1,4,7-tri- (2-methyl giutarate): A solution of 56.3 g of methyl 2-bromoglutarate in 50 ml of acetonitrile are introduced dropwise into a suspension of 18.7 g of the preceding product with 24.7 g of sodium carbonate in 300 ml of acetonitrile. The reaction medium is brought to its reflux temperature which is maintained for 36 hours; After filtration at room temperature the solvent is removed by evaporation and the residue is dissolved in a minimum amount of ethyl acetate and purified by chromatography on a silica column eluting with a mixture of ethyl acetate and petroleum ether (40 g. / 60 to 70/30 V / V). 20.7 g of the product are thus obtained in the form of oil. 3. 10-Benzyl [1,4,7,7-tetraazacyclododecane] 1,4-, 7-tris- (2-glutaric acid): 16.7 g of the oil obtained above in solution in 40 ml of methanol are introduced into 125 ml of water in which 25 g of NaOH have been dissolved; The mixture is kept under stirring at 70 ° C for 48 hours. S- "immediately removes the methanol under reduced pressure before introducing 400 ml of cation exchange resin in the form of weak acid (Amberlite-IR 50 marketed by Rohm and Haas) then, after separation, of the anions under the strong base form (Amberlite® - IRA 458), the desired product is fixed on the anionic resin, it is isolated by elution with 2 liters of an aqueous solution of 3N acetic acid then 2 liters of 6N solution. solvents are obtained 13.5 g of white crystals, mixture of isomers HPLC: column No. 1: 25 cm x 4 mm Lichrospher® 100-RP18 -5 m (Merck, DE); Eluent No. 1. tr = 28, 30 minutes (2 masses of 75/25 isomers on the surface) 4. 1, 4, 7, 10-tetraazacyclododecane 1,4,7-tris- (2-glutaric acid): 13 g of the preceding compound in the solution in 210 ml of water and 90 ml of methanol are hydrogenated for 3 hours at room temperature under a pressure of 28 x 10 Pa in the presence of 10% palladium on 50% wet carbon. After removal of the catalyst and the solvents by evaporation, 11 g of the white powder are obtained. HPLC: column No. 1; Eluent No. 1. tr = 8, 9 minutes (2 masses of isomers 75/25 on the surface).

. Complex formation: At 60 ° C, a solution of 1.6 g of the above compound and 1 g of Gd CI3, 6 H20 in 30 ml of water is maintained at pH 5 by addition of 3N aqueous NaOH, for 4 hours. Concentrate to a volume of 10 ml and precipitate the residue in 100 ml of ethanol. 1.6 g of the desired gadolinium complex is isolated by filtration. HPLC: column No. 1; Eluent No. 1; tr = 24, 26 minutes.

C. Gadolinium chelate of 1,4,4,7,10-tetra-azacyclododecane 1,4-, 7-tris- (2-glutaric) -acetic acid: 1. 1 g of the acid obtained in step 4 of preparation B it is placed in solution in 8 ml of water, with 270 mg of bromoacetic acid and the mixture is kept 3 hours at 70 ° C and pH 10 controlled by the addition of 1N aqueous NaOH. 100 ml of water and 10 ml of Amberlite® IRC 50 resin are immediately added at room temperature; After 1 hour of contact the resin is separated and 50 ml of Amberlite® IRA 458 resin are introduced into the medium. After 12 hours, the resin is separated and introduced into a column. The desired product is extracted by elution with 500 ml of an aqueous solution of 1N acetic acid. 0.8 g of white crystals are thus obtained. HPLC: column No. 2: 25 cm x 4 mm Symetry® - RP 18 - 5 um (Waters); Eluent No. 1; tr = 4 minutes. 2. Complex formation: 13.4 g of water, 0.45 g of GdCl3, 6 H20 and 0.75 g of the preceding compound are introduced; the pH is brought to 6 by the addition of an aqueous solution of NaOH (IN); the reaction medium is then maintained at 60 ° C for 5 hours during which the pH is adjusted several times by addition of the NaOH solution. After cooling, the medium is introduced into 130 ml of ethanol and the precipitate is isolated to give 0.75 g of the chelate.

D. N, N '- (2,3,4,5-tetrahydroxyphenyl) N, N' - [2- (hydroxyethoxy) ethyl] 2,4,6-triiodo 5- (glycylamino) -isophthalamide: 1. 5- [2- (hydroxyethoxy) ethylamino: pentane 1,2,3,4-tetraol: 8 g of 2-aminoethoxyethanol and 150 g of D-xylose are dissolved in 2.5 liters of methanol; the mixture is hydrogenated at room temperature under a pressure of 6 x 105 Pa, in the presence of 50 g of 10% palladium on carbon. The catalyst is removed by filtration and the solvent is distilled. The residue is dissolved in a minimum amount of water, chromatographed on 100 ml of Amberlite® IRN 77 (H ~) resin eluting with a solution of NH 4 OH then on 1 kg of silica gel Geduran® SI 60 to give 170 g of the aminoalcohol in the form of a brown oil. CCM: CH3OH / 25% NH4OH - (7/3 - V / V) - Rf = 0.3. 10 I3C NMR: (DMSO-d6 - 50.3 MHz); d (ppm): 51.4; 48.9 (2 x CH2NH); 62.9; 60.5 (2x CH2OH); 71.9; 71.2; 70.6 (3 x CHCH); 72.3; 69.7 (CH2OCH2). The arabinose derivative of ribose can be prepared in the same way. - c 2. N, N'- (2, 3, 4, 5-tetrahydroxypentyl) N, N '- [2- (hydroxyethoxy) ethyl] 2,4,6-triiodo 5- (phthala idoacetamido) -isophthalamide: Dissolve 30 g of the aminoalcohol above Prepared in 100 ml of dimethylacetamide at 45 ° C, then 22 g of the dichloride of the isophthalic acid derivative and 12 g of triethylamine are introduced and the medium is left under stirring at this temperature for 24 hours. The formed precipitate is isolated at room temperature and the solvent is removed by vacuum distillation. The residue in solution in 50 ml of water is eluted on 100 ml of Amberlite® IMAC HP 1110 (H +) resin; After concentration of the solution to 10 ml, it is poured into 1500 ml of isopropyl alcohol and the formed precipitate is isolated after 24 hours. 3. Amine release: The mixture is introduced at 80 ° C into a solution of 40 ml of water and 2.7 ml of hydrazine hydrate, 42 g of the product prepared above in solution in 60 ml of water. After stirring for 5 hours at this temperature, it is then filtered, the medium is acidified to a pH of 1 by the addition of hydrochloric acid concentration. The formed precipitate is separated and the filtrate is concentrated. The residue d ~ - the solution in 30 ml of water is chromatographed on 30 ml of Amberlite IMAC HP 111E (H ~) resin then on 55 ml of Amberlite® IRA 67 (OH ") resin.The concentrated eluent is fixed on 350 ml of resin Amberlite® 252 Na (H +), where it is eluted by an aqueous solution of NH4OH (2N), p = 20 g.

HPLC: column No. 1; Eluent No. 2; H20 / CF3COOH (pH 3.4) with acetonitrile gradient 95/5 at 50/50 V / V in 50 minutes; tr = 10-20 minutes (mixture of isomers).

E. N, N'- [bis (2,3,4,5,6-pentahydroxyhexyl)] 2,4,6-tribromo-5- (glycylamino) isophthalimide: 1. 5-amino-2,4,6-tribophthalic acid isophthalic: 156 g of bromine are slowly introduced into 300 ml of an aqueous solution of 50 g of 5-aminoisophthalic acid and 55 ml of 37% hydrochloric acid. After 1 night of stirring the excess bromine is neutralized by the addition of an aqueous solution of sodium bisulfite before isolating the precipitate. Performance: 90%. 2. 5- (Phthaloidoacetamido) 2,4,6-tribophthophthalic acid: 27 ml of thionyl chloride are slowly introduced into a solution of 69 g of N-phthaloylglycine, 200 ml of dimethylacetamide at 10 ° C, after 2 hours of stirring, 100 g of the acid obtained above are introduced at 15-20 ° C. After 1 night at room temperature, the mixture is poured into 800 ml of hot water. Thus 140 g of the final product are isolated. 3. Chloride of the preceding diacid: A solution of 100 g of diacid in 300 ml of dioxane and 50 ml of dimethylformamide, 70 ml of thionyl chloride is slowly introduced at 18 ° C. The yellow precipitate formed after 3 days of stirring at room temperature is filtered and washed with methyl and t-butyl oxide. 70 g of the beige solid are thus obtained. 4. N, N '[-bis (2, 3, 4, 5, 6-pentahydroxyhexyl)] 2,4,6-tribromo-5- (phthalimidoacetamido) isophthalimide: 150 g of disorbitylamine are dissolved in 600 ml of N-metrlpyrrolidone at 80 ° C and 16 g of dry sodium carbonate, then 96 of chloride of the preceding acid are introduced into the medium at 6 ° C. After 1 hour of stirring at this temperature and 16 hours at room temperature, the precipitate is removed and the solution is poured into 1.6 liters of isopropanol. The precipitate is isolated weighing 2700 g.

. Hydrazinolysis: 200 g of the preceding product and 17 ml of hydrazipa hydrate are introduced into 400 ml of water at 70 ° C. After stirring for 3 hours, it is acidified to pH 4 by the addition of 6N hydrochloric acid at room temperature.

The precipitate formed is then removed and the filtrate is neutralized by the addition of an aqueous solution of 1N NaOH. The excess hydrazine is removed by reverse osmosis. The residual solution is treated with 10 ml of strong cationic resin then 65 ml of weak anionic resin. The final product is then extracted from the solution by fixation on a strong cationic resin under the form H ", where it is eluted by a dilute aqueous solution of NaCl (0.1 M) p = 80 g HPLC: column No. 1, Eluent No. 2; tr = around 1 minute.

F. N, N '- [bis (2, 3,4,5, 6-pentahydrox_hexyl)] 2,4,6-triiodo-5-glycylamino) isophthalmide: 1. Chloride of 5- (phthalamidoacetamido) 2,4,6-triiodo-isophthalic acid: 149 ml of S0C12 are introduced into a solution of 335 g of N-phthaloylglycine in 1 liter of N-methylpyrrolidone at 10 ° C after 3 hours add 700 g of 2,4,6-triiodo-5-aminoisophthalic acid dichloride. After 3 days of stirring at room temperature, the medium is poured into 4.5 liters of aqueous ethanol (2/1 V / V), the pH is brought to 5 by the addition of triethylamine before isolating the formed precipitate, which may be purified by washing isopropanol p = 850 g. 2. Amidification by disorbitylamine H-N [CH2 (CHOH) 4CH2OH] 2 The operation is carried out as for the tribrominated analog, the product is obtained with 85% yield. 3. Hydrazinolysis 420 g of the triiodinated phthalimide in the solution in 1 liter of water and 300 ml of hydrazine hydrate are kept for several hours at 80 ° C. After acidification of the medium at pH 3.6 the excess of hydrazine is removed by chromatography on a cation exchange resin (H +) such as IMAC® HP111E marketed by Rohm and Haas, then the chlorides with an anion exchange resin (OH) The final product can be purified by chromatography on cation exchange resin (H ~ strong) and precipitated from its aqueous solution in ethanol 50% yield HPLC: column No. 1; Eluent No. 4: CH3CN / P. I. C.® B8 (0.05 M) (Waters) 15/85; I spend 1 ml / min. 3 minutes.

G. 1-deoxy 1- [(2,3-dihydroxypropyl) amino] D-galactitol 27 g 3-aminopropane 1,2-diol and 50 g of D-galactose in 140 ml of methanol are kept under stirring at 40 ° C for 16 hours. 60 ml of water are then added and the hydrogenation of the imine is carried out for 7 hours at 60 ° C. under a pressure of 20 x 105 Pa of hydrogen in the presence of 7 g of parylium on carbon (ai 10 *). The catalyst is then separated by filtration over Celite. After removal of the solvent under reduced pressure, the residue, dissolved in a minimum amount of water (50 ml), is slowly introduced into 600 ml of isopropanol. The formed precipitate is isolated. F = 132 ° C, 90% yield. This can be done before the precipitate in isopropanol, chromatograph the crude product, in solution, in 200 ml of water on 500 ml of an ion exchange resin in the form of sulfonic acid, eluting with an aqueous solution of diluted NH40H. Under these conditions, the aminoalcohol is a practically 50/50 mixture of two diastereoisomers. By recirculation, fractional precipitation or suspension, the mixture of one or other of the isomers can be enriched. Thus, by treatment of methanol at its reflux temperature (25 g of aminoaicol in 500 ml of solvent) a mixture is obtained which contains an excess of one of the isomers: 65% of the isomer having the largest type of reter. Then the surfaces are measured on the chromatograms obtained under the following conditions: Gas-phase chromatography (totally tri-fluorouracetylated derivative by the action of trifluoroacetic anhydride at 60 ° C): Apparatus: Variate Star 3400; Column: DB 1701 of J & W (0.25 μm - 30 x 0.25 mm); Gas' vector He - T injector (division l / 40e) = 290 ° C T column = 150 ° C to 280 ° C (5 ° C / min) - Volume: 1 μl; tr: 14.5 and 14.9 minutes (5.6 min for starting aminopropandiol) 13 C NMR (200 MHz - DMSO d6 - Ref DMSO - T = 30 ° C) d (ppm): "" 71.7; 71.6; 70.5; 70.1; 69.5; 68.5; 68.2 - (CHOH) 64.6; 63.2; (CH2OH) - 53.4; 53; 52.9 (NCH2). It is thus possible to obtain each diastereomer by condensing the D-galactose on the pure enantiomer of aminopropanediol or by the action of the enantiomers of glycidol on the N- (2, 3, 4, 5, 6-pentahydroxyhexyl) -benzylamide as follows: a) N-benzyl N- (2, 3, 4, 5, 6-pentahydroxyhexyl) amine: Dissolve in 230 ml of methanol 29 of D-galactose, 17 ml of benzylamine and keep the mixture at 50 ° C for 7 hours under a hydrogen pressure of 8 x 1 3 Pa after the addition of 5 g of carbon with 5% palladium. After hydrogenation, it is introduced at 40 ° C, ur.3. aqueous solution of hydrochloric acid to an acidic pH in the reaction medium. The mixture is filtered over Celite at room temperature to remove the catalyst, and after partial concentration, an aqueous solution of 5N NaOH is introduced until basic pH. The formed precipitate is isolated and recrystallized from ethanol. 13 C NMR (200 MHz - DMSO d6 - Re f DMSO - T = 30 ° C) d (ppm): "4040.8 (C CH2N) - 128.8; 128.4; 126.9 (phenyl) - 72; 70.6; 69.9; 68.8; (CHOH) - 63.2 (CH2OH) - 53.1; 52.4 (CH2NH). b) N-benzyl N- (2,3-dihydroxypropyl) (2, 3, 4, 5, 6-pentahydroxyhexyl) amine: 6.5 g of the secondary amine obtained in the preceding step are dissolved in 200 ml of 60 ° methanol. C, then 2.5 g of glycidol (racemic or pure enantiomer) is introduced into the solution at this temperature and the mixture is kept under stirring for 24 hours. The solvent is then removed by distillation under reduced pressure and the residue is chromatographed after dissolution in 200 ml of water on a column of Amberlite® IMAC 110 resin under the form H "eluting with an aqueous solution of dilute NH + OH (0.1 %), Thus obtaining 5.5 g of ia amine. c) N- (2,3-dihydroxypropyl) N- (2, 3, 4, 5, 6-pentahydroxyhexyl) amine: 2 g of the tertiary amine obtained in the preceding step in solution in 30 ml of water are hydrogenated at 45 ° C under hydrogen pressure of 100 x 105 Pa for 5 hours in the presence of 0.6 g of carbon with 10% palladium.

The solution is filtered immediately over Celite® to remove the catalyst and concentrated under reduced pressure. The residue can be recrystallized from ethanol.

When the (S) -glycidol is condensed, the diastereomeric amino alcohol is obtained, wherein the retention time under the preceding gas phase chromatography conditions is the longest. From the D-glucose and the D-mannose, it will be obtained by applying these procedures of the diastereomers of these alcohols, then other amino alcohols can be obtained from primary amino alcohols or different sugars.

H. Gadolinium chelate of (1, 4,, 10-tetra-azabicyclododecane) 1,4,4,7,10-tetra (2-succinic) acid: 1. Condensation of the benzyl acetylene dicarboxylate on the 4 nitrogen atoms of the cyclin: 23 g of benzyl acetylene dicarboxylate prepared at 20 ° C, prepared as described in J.C.S. Perkin I, p. 2024-2029 (1973), in solution in 25 ml of acetonitrile on a solution of 2.7 g of cyclen in 50 ml of acetonitrile; After 3 hours of stirring at 50 ° C, the solvent is removed under reduced pressure and purified by chromatography on silica by diluting with a dichloromethane / methanol mixture (98/2).

V / V) to isolate 19 g of the yellow solid. 2. Reduction of the enamine: 7 g of sodium cyanoborohydride in a solution of 19 g of the solid in 500 ml of acetonitrile and 50 ml of acetic acid are introduced portionwise with stirring and the mixture is kept under stirring overnight at room temperature. After removal of the solvent under reduced pressure, the residue as an oil is dissolved in a dichloromethane / methanol (99/1) mixture and filtered on silica. After evaporation of the solvent, 19 g of the yellow oil are isolated. 3. Debenzylation 8 g of the obtained octaester in a water / methanol mixture (175 ml / 75 ml) are hydrogenated for 6 hours in the presence of 4 g of 10% palladium on carbon (pressure: 3.5 x 105 Pa). After separation of the catalyst by filtration and removal of the solvent by distillation, 3 g of the octaacid are obtained in the form of a white powder. HPLC: Column No. 1; Eluent No. 1; tr = 18 to 19 minutes. 4. Complex formation: 1 g of the octaacid obtained is suspended in ml of water, the pH carrying 5.5 by the addition of an aqueous solution of 1N NaOH and 0.285 g of Gd203 are added.

After 4 hours of stirring at 70 ° C of the reaction medium where the pH is maintained between 5.5 and 6.5 by the addition of an aqueous solution of 1N HCl, it is filtered and the filtrate is concentrated to dryness to give the sodium salt of the chelate. .

Example 1 Gadolinium chelate of the formula I in which m = 2 C02H R '= CH- (CH2) 2CCNHR R = (sodium salt) 1. 4- [N '- (4-nitrophenyl) ureido] benzoic acid: At 10 ° C, 24.6 g of 4-nitrophenylisocyanate are introduced under stirring into 80 ml of tetrahydrofuran, then slowly 20.5 g of 4-aminobenzoic acid in solution in 70 ml. ml of tetrahydrofuran. the mixture is allowed to come to room temperature and stirring is continued 1 hour before isolating the formed precipitate, p = 45 g. HPLC: column Nc. 1; Eluent No. 2: H20 / CF3COOH; pH = 3.4 with g; Acetonitrile (95/5 to 50/50 - V / V in 50 min); I spend 1 ml / min; tr = 44 minutes. 2. 4- [N '- (4-aminophenyl) ureido] benzoic acid: 22 g of the above product and 37 ml of the aqueous solution of 1N NaOH are introduced into 230 ml of water with 3 g of palladium on carbon (5%). The medium is maintained under a hydrogen pressure of 0.6 MPa for 6 hours at c? ' . After returning to room temperature, the pH is brought to 10 and the catalyst is filtered over Celite® before acidifying to a pH of 5.3 by the addition of a KCi 6N acucsa solution; the precipitate obtained is washed with acetone, p = 13.2 g. HPLC: column No. 1; Eluent No. 2; tr = 33 minutes. 3. _ 4- [N '[4- (phthalimidoacetamido) phenyl] ureido] -benzoic acid: 5.3 g of phthalimidoacetic acid are dissolved in 26 ml of dimethylacetamide at 10 ° C and, while maintaining the temperature, 2 ml of sodium chloride are added. thionyl, then, after 2 hours of stirring, 7 g of the compound of the preceding step. After 12 hours at room temperature, the reaction medium is poured into 250 ml of water and the formed precipitate is washed until neutral with water at 25 ° C then at 95 ° C. p = 10.4 g. HPLC: column No. 1; ? Luyente No. 2; tr = 40 minutes. 4. N, N'-; 2, 3, 4, 5-tetrahydroxypentyl) N-N '- [2-hydroxyethoxy; etii] 2,, 6-triiodo 5- [4- [N '- (4-phthalimido-acetamideienyl, benzoyl glycylamino] iso-phthalimide 40 g of dimethylacetamide are dissolved in 4 ml of the compound obtained above with 1.7 g of HOBT, H2C and 9.3 g of N, N'-bis- (2, 3,, 5-tetrahydroxypenth) N, N'-bis. Idrcxethoxyethyl * 2,4,6-triiodo 5- (glycylamino) -isophthalide after 2.4 g of EDCl, HC! at 0 ° C. After stirring at room temperature, the medium is poured into 300 ml of dicyrochrometan.The precipitate is isolated and washed with diethyl ether HPLC: column No. i; Eluent No. 2; tr = 30-33 minutes isomer mixture).

. Elimination of the phthalimido group: The product of formula III in which Z = CKCCNH; Z '= NHCONH; Z "= CCNHCH2CONH; R? = R3 - "Pj = I; R2 = P = CONCH2 (CHOH) 3CH2OH i (CH2) 2OCH2CH2OH In 45 ml of water, 11.5 g of the preceding compound and then 1.12 ml of hydrazine hydrate (0.023 mol) are introduced at 80 ° C. After 2 hours 45 to 80 ° C, it is cooled to Q ° C and acidified to pH 1 by the addition of HCl aqueous I2N. The mixture is then filtered over Celite® at room temperature then filtered over 16 ml of cationic resin (H ") IMAC® HP111E and 80 ml of resin weak ar.iónica ', OH ~; IMAC HP661, marketed by Rohm and Haas. , After a final purification by filtration on silica = cast, 4.6 g of the product are obtained HrLC: column Nc. I; ? Luyente No. 2; tr = 24-27 minutes mixture of isomers). 6. C Densation of products A and III They are introduced at 40 ° C in 20 ml of an aqueous solution at pH 6, 4.5 g of the previous amine and 0.63 g of chelate A, 0.057 g of NHS (sodium salt) and 0.76 g of? DCI, HCl. After 15 minutes the mixture is poured into water and the precipitate is isolated. After elimination of the starting products, the compounds of formula I are obtained. Steric exclusion chromatography: (CES). Conditions No. I: performed on a succession of 4 columns (30 cm x 8 mm) marketed by Shodex (JP) under the references CH Pak SB-HQ, containing poiihydroxymethacrylate gel where the exclusion limits, determined with swarm, are successively 106 Kdaltons Í5B-304); I05 Kdaltons (SB-303); 104 Kdaltons (SB-802-5); 104 Kdaltons (SB-302-5). ? luant: aqueous NaCl (0.16 M) / acetonitrile (70/30-V / V); I spend 0.3 mi / min. T = 30 ° C; tr: 33 minutes (50-53 min by the starting amine). HPLC: Column No. 3, 25 cm x 4.6 mm Platinum EPS C18 100 TO; 5 u (Alltech); # 3: water / CH3CN from 98/2 to 60/40 - V / V in 50 r.ir .; expense: 1 mi / min; T = 25 ° C; tr = 26 minutes.

Example 2 Gadolinium chelate of the formula I in which ra = 2 C02H - "I R '= CH- (CH2) 2CGNHR 1. A. 4- [4- (phthalimidomethyl) benzamido] benzoic acid It is introduced into a solution prepared with 25 g of 4-aminomethylbenzoic acid, 18 g of Na 2 CO 3 and 165 ml of water, 37 g of N-carbethoxy alimide. The precipitate formed is isolated and then suspended in 60 ml of α-irylacetamide in which 4.7 ml of thionium chloride are introduced slowly at 17 ° C. After 3 hours at this temperature, 9 g of 4-amir.ober.wracking acid are introduced and the medium is maintained 12 hours at room temperature, before pouring into 600 ml of water. The formed precipitate is isolated. H? LC: column No. 1; Eluent No. 2; t. = 48 minutes 2. N, N'-bis [2, 3,, 5, 6-pentahydroxylhexyl) 2,4,6-t-iodo 5- [4-4-amino methylbenzamido) benzoylglycylamino] - ii ma: a) Stir until dissolved 160 ml of di-ethylacetamide with 39 g of 5-gl. .lamino N, N'-bis- [2, 3, 4, 5, 6"-pentahydroxyhexyl) 2,4,6-triiodo isophthalamide, 4. 6 ml of triethylamine, 5.7 g of HOBT, H20 and 12 g of the product obtained above, before cooling to 0 ° C and adding 8 g of? DCl, HCl. At the end of the reaction, the tiedium is poured into 1000 ml of dichloromethane. The isolated precipitate was purified by precipitation in methanol from its aqueous solution, p = 43 g. b) Hydrazinolysis: 25 g of phthalimide obtained above are dissolved in 50 ml of water at 80 ° C before adding 2.2 ml of hydrazine hydrate. After 3 hours of stirring, the medium is cooled and acidified to pH 1 by the addition of 12N HCi. The medium is then filtered over Celote® then purified by chromatography on weak cationic resin, H ~) then on weak anionic resin Thus 15 g of the desired product are isolated. HPLC: column No. 1; Eluent No. 2; tr = 19 minutes. c) Condensation on the gadolinium chelate A: 15 g of the amine thus obtained and 1.9 g of the chelate A and sodium salt) are dissolved in 40 ml of water. After acidification to pH 6 by the addition of 1N aqueous HCl, 2.3 g of EDC1, HCl are introduced at 40 ° C. After 2 hours of stirring, the medium is introduced into 400 ml of ethanol; The precipitate formed is placed in aqueous solution, filtered on Norit carbon black. Thus, 8.5 g of the pure product are obtained.

CES: conditions No. 1: tr = 36 minutes. HPLC: column and eluent No. 3; tr = 23 minutes.

Example 3 Gadolinium chelate of the formula I in which = 2 R '= CH- (CH2) 2CCNHR a) 4- [4-Nitrobenzamido] benzoic acid: Gradually, 100 g of the 4-nitrobenzoic acid chloride are introduced into 74 g of 4-aminobenzoic acid and 360 ml of dimethylacetamide, keeping the temperature below 25 ° C . After stirring for 24 hours, 500 ml of methylene chloride are added at 10 ° C to precipitate the desired product. After washing with water and drying, 145 g of the product are isolated. b) 4- (4-Aminobenzamido) benzoic acid: A suspension of 136 g of preceding acid in 1 liter of water is added to which 240 ml of 1N aqueous NaOH solution and 14 g of palladium on charcoal are added ( 10%) at a hydrogen pressure of 0.6 MPa for 4 streams. The pH of the final suspension is then brought to 10 before the filtration on Celite® to remove the catalyst. The precipitate formed after acidification of the filtrate to pH 5.3 is isolated and dried. p = 106 g; F > 260 ° C. c) 4- [4- 'f -imidoacetamido) benzamido) -benzoic acid: They are introduced into a solution of 90 g of phthalimidoacetic acid in 400 ml of dimethylacetamide at 10 ° C, 32 ml of thionyl chloride, then after 3 hours of agitation, 105 g of the amino acid previously obtained at a temperature lower than 20 ° C. After 12 hours of stirring, the medium is poured into 4 liters of water and the precipitate is isolated, washed with hot water. The weight after drying: 176 g. F > 260 ° C. d) Chloride of the preceding acid: 2. ml of thionyl chloride in 10 g of the acid in suspension are introduced into 50 ml of dioxane, and 1 ml of dimethylformamide is added and the mixture is kept under stirring at 50 ° C for 5 hours. After the addition of the volume of diisopropyl ether, 10 g of the precipitate are isolated. It is thus possible to place the acid in suspension in toluene with tricaprylamimethylammonium chloride as cat. e N, '-bis (2, 3, 4, 5, c-pentahydroxyhexyl) 2,4,6-tr romo 5- (4- [4- (phthalimidoacetamido) benzamido] benzoyl-1-glycylamino) isophthalimide: A solution of 2.25 g of acid chloride with 5 g of N, N'-bis (2, 3, 4, 5, 6-pentahydroxyhexyl) 2,4,6-tribromo? -; giicylamino) isophthalimide and 0.7 ml of triethylamine in 25 ml of dimethylacetamide or of N-methylpyrrolidone is kept for 12 hours under stirring then it is poured into 60 ml of ethanol. 6.2 g of the precipitate is thus isolated. HPLC: column No. 1; Eluent No. 2: tr = 27-35 min. (mixture of isomers). f) Hydrazinolysis A solution of 0.6 ml of idrazrna hydrate in 10 ml of water in a solution of 10 g of the above phthalimide in 40 ml of dimethylacetamide at 80 ° C is introduced. After 3 hours of stirring at this temperature, the mixture is cooled and poured into 125 ml of ethanol. 9 g of the precipitate are isolated and purified by treatment of its aqueous solution by a strong anionic resin OHOH ") then weak cationic (H ~) p = 8 g.The reaction medium can then be acidified to remove the precipitated phthalohydrazide and remove the solvent and the lower mass molecules by ultrafiltration before a final precipitation in aqueous ethanol HP1C: column No. I, Eluent No. 2 but 90/10 V / V without rad; tr = 28-35 min. g) Coupling on chelate A to obtain the compound of formula I: Dissolve in 135 ml of water 5 of the compound obtained in step (f) with 0.65 g of chelate A (sodium salt); The pH of the medium is reduced to 6 by the addition of 1N aqueous HCl before introducing at 40 ° C 0.8 g of EDCl, HCl in the medium. After 2 hours of stirring and returning to room temperature, the medium is poured into 135 ml of ethanol. It is thus possible to introduce 1.6 g of chelate A (salt of soa or j in 25 ml of aqueous solution of 10 g of the amine obtained in step f then to pH 6.5, successively 18 ml of dioxane, 1.4 g of EDCl and 0.08 g of HOBT After 2 hours at room temperature, the reaction medium is poured into 100 ml of ethanol and the precipitate is isolated, redissolved in 100 ml of water, treated twice with 1 g of carbon black before being reprecipitated. in 3 volumes of ethanol.The precipitate formed is purified by treatment of 5 ml of Chelex 100 ion exchange ream.

M marketed by Sigma, then per d ltrafiitration on membrane of the cutting threshold 5 KZ, at pH. "P = 4 g I:: Corctions No. i; tr = 34 minutes HPLC: column and eluent Nc 3; tr = 23 minutes.

Example 4 Gadolinium chelate of the formula I in which _r_ = 2?. ' = H and R = 5 hours at 40 ° C, under agitation, 0.3 g of the gadolinium complex of 1,4,4,7,10-tetraaza-cydododecane 1,4,7-triglutaric acid prepared according to (B), 2 g of the amine prepared in Example 3 (f) and 0.3 g of? L7C1, HCl in 5 ml of water, maintaining the pH at 7 by the addition of a 1N HCi aqueous solution. The medium is poured into 50 ml of ethanol and the precipitate formed is isolated. It is purified er. solution in 120 ml of water by ultrafiltration with a 3 KD membrane cut-off threshold to eliminate the start products that have not reacted. After the agitation on black of . When the solution is brought to dryness, give 1 g of the white solid. C? S: Conditions No. 1; tr = 36.3 minutes. HPLC: column and eluent No. 3; tr = 31 minutes.

The use of gadolinium chelate of the formula I in which m = 2 R '= CH2COOH and R = By applying the same operation mode as for example 4, 0.8 g of the final product is obtained from 0.3 g of starting chelate C and 2 g of the amine prepared in example 3 f. CES: Conditions No. 1; t. = 35.7 minutes. HPLC: column and eluent No. 3; tr = 22 minutes.

E p e 6 Gadolinium binding of the formula I in which m = 2 C H R '= CH- CH_: CCNHR CH2CHOHCH2OH 1. 5- [4- (4-Aminobenzamidoj benzamido] 2,4,6-tribophthophthalic acid: (a) 4- (4-Nitrobenzamido) benzoic acid chloride: They are kept for 8 hours at the reflux temperature in 250 ml of thionyl chloride and 0.1 ml of dimethylformamide, 70 g of the acid. The excess of thionyl chloride is distilled under reduced pressure and the residue is poured under stirring in 1.5 liters of ethyl acetate and 500 g of crushed ice. The final product is extracted into the organic phase, this is washed with water, an aqueous solution of sodium bicarbonate is then dried and concentrated, p = 64 g. 'b! -Acido i- [4- (4-nitrobenzamido) benzamido] 2,4,6-isortaic: 13 streams are maintained at the flow temperature of a solution of 64 g of the acid chloride with 67 g of 5-mino acid 2, 4, 5-isophthalic tribromine in 170 ml of dioxane. The solvent is evaporated and the residue, after washing with 300 ml of ethyl acetate, is heated, dissolved in 500 ml of water with a suffnt amount of 5N NaOH to obtain a pH of 7; After washing with ethyl acetate and acidification, the desired product is isolated, precipitated, p = 73 g. (c) Reduction: 19 q of the preceding product in aqueous solution at pH 6 is maintained for 7 hours under a hydrogen pressure of 0. 5 MPa in the presence of 2 g of platinum on carbon type 156; Johnson Matthey). After filtration, the solution is evaporated, p = 15 g. 2. N, N'- (2,3-dihydroxypropyl) N, N '- (2, 3, 4, 5, 6-pentahydrcxihexii) 2, 4, 6-tribromo 5- (4- [4- (glycylamido) -benzamido) ] isophthalimide: (a) 13 g of the preceding derivative are added, at ^ 1 C ° C, in 10 ml of a solution of prepared phthalic acid acetic acid chloride, with 4.7 g of phthaoiiglycine acid, 1.7 ml of SOCl2. hours of stirring at 20 ° C, the solution is poured into 150 ml of water at 377 ° C and the precipitate is isolated, p = 10.6 g. . { acid chloride: 16 ml of thionyl chloride are introduced into a solution of 12.4 g of the preceding derivative in 60 ml of dioxane and 10 ml of dimethylformamide, keeping the temperature below 10 ° C. After 30 minutes of stirring, the solution is poured into 200 ml of water and the precipitate is isolated and added to 100 ml of ethyl acetate, p = 12 g. te) Condensation on the aminoalcohol: At 60 ° C, 11.6 g of the acid dichloride are introduced into 120 ml of N-methylpyrrolidinone containing 13.5 g of 1-deoxy? 1- (2, 3-dihydroxypropyl-amino) D-galactitol prepared following step G. After 4 hours of stirring, the mixture is introduced into 1200 ml of dichloromethane and the precipitate is isolated, p = 35 g. 'd! Elimination of the phthalimide protecting group: 14 g of the preceding derivative are introduced into 30 ml of water at 80 ° C, containing 1.2 g of hydrate of J? Razir.a. After 3 hours at this temperature, the solution is acidified to pH i by the aqueous addition of 5N HCl. The precipitate formed after several hours was dried and the filtrate treated successively by the IMAC® H? 111C Na and HP 661 (Rchm and Hass). HP1C: column No. 1; Eluent No. 2; tr = 25-28 minutes product start 32-36 minutes). 3. Reaction with the chelate A: 0.6 g of the chelate ie gadolinium A (sodium salt), 0.7 g of EDCl, HCl and 4 g of the preceding amine are introduced into 15 ml of water; the pH is brought to 6 by the addition of an aqueous solution of 1N HCi and the mixture is kept for 2 hours at 40 ° C, before being introduced into 200 ml of ethanol. E_ 'formed precipitate is isolated and its solution in 100 ml of water is subjected to a uitrafiltration on a polyether sulfone membrane of the cut-off threshold 5 KDa.

HPLC: column and speaker No. 3; tr = 26 minutes. CE5: Conditions No. 1; tr = 36 minutes. was Diio gadolinium chelate of the formula I in which m = 2 CC2H R '= CH- •, CH2 /; CCNHR 1. 4- (4-aminophenylcarbamoii) benzoic acid: (a) methyl 4-- 4-nitrophenicarbomethylbenzoate: At 10 ° C, 10 ml of thionyl chloride are slowly added to a solution of 25 g of methyl monoester of terephthalic acid in 125 ml of dimethylacetamide: after 1 hour 30 minutes of stirring at 15 ° C, the mixture is slowly introduced into a solution of 19 g of 4-r.if canilir.a in 125 ml of the same solvent. After 2 hours at 50 ° C, the formed precipitate is isolated.

Performance: 97:; (b) Reduction: 10 g of the above nitrated derivative is suspended in 100 ml of dimethylacetamide in the presence of 2.5 g of 10% carbon palladium (moisture 50%) and maintained under a hydrogen pressure of 0.5 MPa for 7 days. hours. The catalyst is removed by filtration of the medium over Claree! and the filtrate is introduced in 500 ml of a 3 la. The formed precipitate is isolated. Performance: 9. c) Hydrolysis of the ester group: 9 g of the preceding compound, 50 ml of 2N1 aqueous NaOH and 25 ml of methanol are kept at 60 ° C for 2 hours. The solution is acidified at 20 ° C to pH 4.5 by the addition of a concentrated hydrochloric acid solution, and 7 g of the formed precipitate is isolated. HPLC: column No. 1; ? Urgent No. 2; tr = 29 minutes. 2. N, N'-bis (2,3,4,5,6-pentahydroxyhexyl) 5- [4- (4-a mcfenii carbamoyl) benzoylglycylamido] 2,4,6-triiodo isoftali ida: Stir for 2 hours at room temperature environment, 25 g of the amino acetamido isoftaimide iodide prepared in F with 3 i of tetylamine, 5.8 g of the preceding product, 4.3 g of HOBT and 6 g of EDCl, HCl, then poured into 700 ml of dichloromethane. The precipitate formed is isolated and purified by chromatography on a column of silanized silica RP-2 (Merck), eluting with water. 16 g of the desired product are isolated. HPLC: column No. I; Eluent No. 2; tr = 14 minutes. 3. Coupling with the gadolinium chelate A: A few days are kept under agitation, at 40 ° C 3.125 g of the chelate (sodium salt), 1.8 g of the preceding compound, 0.15 g 2 EDCi, HCl and 100 mg of NHS suifónico keeping the pH around 7, by addition of an aqueous solution of 1N KCl The precipitate formed by introducing 50 ml of ethanol is isolated and purified by uifrafiltration on a 5 kDa membrane to give 1 g to the expected product. Conditions No. 1, tr = 30 minutes HPLC: Column No. 3, Eluent No. 3, tr = 20 minutes.

Example 8 Gadolinium chelate of the formula I in which m = 2 C02H R '= CH- (CH2) 2CONHR R = 1. 3- [3- (Phthalimidoethylcarbamoyl) benzamido] benzoic acid: (a) 3- (Aminoethylcarbamcyl) benzoic acid: A solution of 9 g of methyl isophthalic acid methyl ester and 1.5 ml of ethylenediarin in 90 ml of methane! The mixture is stirred for 13 hours before the concentration to dryness and the residue is washed with methanol mixed with ice. ib) Protection of NH 2 ba or the phthalimide form: 9 g of amine and 14 g of N-carbethoxyphthalimide are introduced into a solution of 6.9 g of sodium carbonate in 130 ml of water. After stirring for 1 hour 30 minutes, the solid is isolated and the filtrate is acidified to pH 2. The phthalimide is precipitated in the form of white crystals. Performance: 80 *. HPLC: Column No. 1; Speaker No. 2; tr = 32 minutes. (c) 2.6 ml of thionyl chloride are added dropwise to 10 ° C to a solution of 12 g of the above phthalimide in 45 ml of dimethylacetamide. After 2 hours at 15 ° C, the orange solution is added slowly to a solution of 5 g of 3-aminobenzoic acid in 45 ml of dimethylacetamide. The reaction medium is kept at 55 ° C. for 3 hours, then 900 ml of water are poured. The precipitate is isolated. Performance: 96 2. N, '-bis (2, 3, 4, 5, 6-pentahydroxyhexyl) 5- [3- (3-ammoethylcarbamoyl) benzamido] benzamidoacetamido] 2,4,6-triiodinatephthalimide: a; 20 g of the iodated aminoacetamidoisophthalamide prepared according to F 2.5 ml of triethiamine, 3.3 g of the above compound, 3.4 g of HOBT and 4.9 g of EDCl, HCl in 100 ml of dimethylacetamide are kept stirring for 1 hour 30 minutes, then the reaction medium is poured into 700 ml of dichloromethane and 26 g of the formed precipitate are isolated HPLC: Column No. 1, Eluent No. 2, tr = 26 minutes. (b) Hydrazinciysis: 3.5 ml of hydrazine hydrate are introduced into a solution of 25 g of the preceding product in 55 ml of water at 30 ° C. After 8 hours at this temperature, the medium is acidified to pH 1 and the precipitate formed is isolated. It is purified by chromatography on a cationic resin (H ~) then anionic (OH ").

- "I", HPLC: Column Nc. 1; Eluent No. 2; tr = 23 minutes. 3. Copying with gadolinium chelate A: 2 g of chelate A (sodium sai), 2.3 g of? IC1, HCl and 16 g of the preceding compound are kept at pH for 1 hour at 40 ° C under agitation. 50 ml of water, before adding 200 mg of NH5 sulphonic and continuing stirring at 40 ° C for 3 hours. The medium is then poured into 500 ml of ethanol and the isolated precipitate is purified by ultrafiltration to give 10 g of sodium salt of the desired product. CES: Conditions No. 1; tr = 36 minutes. r.? C: Column No. 3; Eluent No. 3; tr = 21 minutes.

Example 9 Gadolinium chelate of the formula I in which = 2_C02H 'I R' = CH- (CH2) 2CCNHR (sodium salt) 1. 4- [4- [4- [ffalimidomethy] benzamido] benzoic acid: At 3.5 ° C, 3.5 ml of thionyl chloride are introduced into a solution of 19.3 g of 4- [4-phenylbenzoate] benzoic acid, then after 2 hours 45 minutes of stirring, 3 g of 4-aminobenzoic acid. After 12 hours at 20 ° C, the medium is poured into 500 ml ie water. The formed precipitate is washed with dioxane. p = 11.5 g. HPLC: Column No. 1; ? Luyente No. 2; tr = 53 minutes. 2. N, N '- (2, 3,, 5, 6-pentahydroxyhexyl) N, N' - (2-h-hydroxyethyl) 4- [4- [4-aminomethyl) benzamido] benzamido] -benzamide > a) At a temperature of 20 ° C, one night under stirring, 4.3 g of 1-deoxy-1- (2-hydroxyethylamino) D-glucitol, 4 g of HOBT, H20, II g of the preceding acid and 6.7 g of EDCl are maintained.

HCl. The reaction medium is then poured into 500 ml of dichloromethane and the precipitate formed is washed with 300 ml of diethyl ether. HPLC: Column No. 1; Eluent No. 2; tr = 39 minutes. jb) Hydrazinolysis: The preceding precipitate is introduced into 60 ml of dimethyacetamide and at 80 ° C, 3.2 ml of hydrazine hydrate in solution in 25 ml of water. After 3 hours the medium is concentrated and the residue is dissolved in water. The phase The aqueous solution is brought to pH 7.5 by the addition of a concentrated solution of HCl, then chromatographed on a strong cationic resin (H "") and then a weak anionic resin (OH "). After concretion in ethanoi, 3.5 are obtained. g of the precipitate .5 IHPLC: Column No. 1;? nant No. 2; tr = 27 minutes. 3. Ac to the gadolinium chelate A: At 40 ° C, 1.5 g of the above compound ccn 0.5 g of quelate A in 15 ml of water and 5 ml of '. J dimethylacetamide and 0.75 g of EDCl, HCl and 0.05 g of sulfonic NHS (sodium salt) are introduced. After 2 hours of stirring at this temperature, the reaction medium is poured onto 2 volumes of ethanol and 1.3 g of the precipitate are isolated.; 5 HPLC: Column No. 3; Eluent No. 3; tr = 31 minutes.

Example 10 Gadolinium chelate of the formula I in which C02H I R '= CH- (CH2) 2CONHR R = 1. 4- [4- [4-Nitrobenzamido] benzamido] benzoic acid: It is introduced in a solution at 5 ° C, 35 g of the acid 4- (4-amino-benzamido) benzoic acid in 140 ml of dimethylacetamide, 25.4 g of 4-methylbenzoic acid chloride. After one day of stirring at 20 ° C, the reaction medium is poured onto 500 ml of dielethermethane. p = 50 g. 2. Reduction of the nitro group: A suspension of 13 g of the preceding acid in 400 ml of dimethylacetamide is hydrogenated under a pressure of 0.15 MPa, for 4 hours in the presence of 3 g of Pd / C al - - and 50 * of water. After filtration and evaporation of the solvent, 12 g of the product are isolated. 3. A. 4- [4- [4- (Phthalimidoacetamido) benzamido] -benzamidoj benzoic acid: A solution of 16.4 g of phthalimidoacetic acid in 40 ml of thionyl chloride is maintained at reflux temperature for 4 hours. After concentration, the reaction medium is introduced into 100 ml of diis-propyl ether. 10 g of the precipitate of acid chloride are isolated. 3.5 g of this are introduced into a solution of 12 g of the aniline obtained in step 2, in solution in 50 ml of di-etiacetamide at 10 ° C. After returning to L'7 ° C, the solvent is removed by distillation and the residue is washed with diethyl ether. p = 16 g. 4. Condensation on the amine prepared in E and hydrazinólisis: 13 g of the E mine, 10 g of the preceding acid and 3.5 g of HOBT are put in solution in 80 ml of dimethylacetamide at 35 ° C; 4.9 g of? CCi, HCl are then introduced into the reaction medium cooled to 20 ° C, after one day, this is poured into 600 ml of dichloromethane and the precipitate formed is washed with 400 ml of ethanoi. dissolved in 90 ml of dimethylacetamide and 22 ml of water at 30 ° C, 1.85 ml of hydrazine hydrate are then introduced and the medium is stirred for 3 hours before evaporating the solvents.The residue is dissolved in 300 ml of water and the pH is brought to 1 by the addition of an aqueous solution of HCl Í12N).

After filtration on Celite® and chromatography on an anionic resin and on a cationic resin, after filtration of the eluent on charcoal, 13 g of the desired substance are isolated.

. Reaction of the products of formulas II and III: 1 g of chelate A and 3 g of the previous amine are dissolved in 40 ml of water. After acidification to pH 6 by addition of dilute aqueous HCi solution, the reaction medium is brought to 40 ° C and 0.09 g of sulphonic NHS and 1.2 g of EDCl, HCl are reduced. After 2 hours of stirring at this temperature, the medium is poured into 400 ml of ethanol and the precipitate After the usual purification treatments, 6 of the final product are isolated. CE5: Previous conditions; tr = 38 minutes.

Example 11 Gadolinium chainlet of the formula I in which m = z R '= CH- (CH 2) 2CONHR I C02H -Action 5- (4-nitrobenzamido) 2,4,6-tr? Bromo 18 hours at its reflux temperature, 50 g of para-nitrobenzoic acid chloride and 5 g of 5-amino 2, 6-tribophosphthalic acid in 400 ml of dioxane are maintained. After cooling, the precipitate is filtered, washed with 50 ml of dioxane and dried, p = 115 g. 2. Acide 5- (4-aminobenzamido) 2, 4, 6-tribromo A solution of 180 g of the above nitrated derivative in 600 ml of water is brought to pH 6 by the addition of an aqueous solution of 5N NaOH and hydrogenated under a pressure of 5 x 10 Pa in the presence of Pt type 156 (Johnson Matthey) for 7 hours. The catalyst is removed by filtration and the water is evaporated under reduced pressure, p = 80 g. HPLC: Column No. 1; Eluent No. 6; water / trifluoroacetic acid (pH 2.3) with methanol (99/1 - V / V); I spend 1 ml / in .; tr = 3.6 minutes (18.8 minutes for nitrate). 3. 5- (4- [4- (Phthalimidomethyl) benzamido] -benzarylated 2-, 4,6-tribophthophthalic acid A mixture of 10 g of 4-aminomethylbenzoic acid, 14.5 g of N-carbethoxylated aiimide and 9.2 ml of triethylamine e 140 ml of tetrahydrofuran is maintained at its reflux temperature for 72 hours The precipitate isolated by filtration at room temperature from the reaction medium is washed with diethyl ether and an aqueous solution of 1N hydrochloric acid, 14.5 g of the solid are obtained, where 12.2 g are dissolved at 10 ° C in 90 ml of N, N-dimethylacetamide and 3.5 ml of thionyl chloride, after 3 hours of stirring, 23.4 g of the aniline obtained in step 2 are introduced into the medium and left under The mixture is stirred for 1 night before the mixture is poured into 900 ml of water, the precipitate is isolated, washed with water and recrystallized in 200 ml of dioxane, p = 30 g.

- -HPLC: Column No. i; ? Luyente No. 5; water / CH3COONH4 (0.01 M) / CH3CN; I spend 1 ml / min .; gradient from 35/15 to 50/50 in 20 4. Acid dichloride: 30.3 g of the isophthalic derivative obtained in the preceding step are dissolved in 150 ml of dioxane containing 26 ml of dimethylformamide and at 5 ° C, 42 ml of thionium chloride are introduced dropwise. After 30 minutes at 0 ° C, the mixture is poured into 550 ml of water and the precipitate formed is filtered, washed with water and with diisopropyl ether. p = 26 g after drying.

. N, N '- .2, 3, 4, 5, 6-pentahydroxyhexyl) N, N' - (2,3-d hydroxypropyl) 2,4,6-tribromo 5- [4- [4-amincmethyl-cenoam ) benzamido] isophthalamide: a) 10 g of the acid dichloride are introduced into a solution of 15 g of i-deoxy-1- (2,3-dihydroxypropylamino) -D-galactit in 100 ml of N-methyl-pyrrolidine at 60 ° C. After 4 hours of stirring at this temperature, the medium is again brought to room temperature, poured into one liter of i = oprcpanol. The formed precipitate is isolated and dried. HPLC: Column No. 1; Eluent No. 5; tr = 16 minutes. (b) Elimination of the phthalimide group: 20.4 g of the preceding solid are introduced under stirring in 30 ml of N, N-dimethiacetamide at 80 ° C followed by 1.6 ml of hydrazine hydrate in solution in 20 ml of water. After 3 hours at this temperature, the reaction medium is poured at room temperature into 1 liter of ethanol. The precipitate formed is isolated, dried and then dissolved in 40 ml of water. At 0 ° C about 2 ml of the aqueous solution of 6N HCl are introduced to knock down the pH to 2; the medium is filtered over 2elite® then purified by the passage over ion exchange resins (anionic® anmberlite and IMAC® oe then retain the product HPLC: Column No. 1; ? Luyente No. 5; tr = 24 to 29 minutes. 6. Reaction with the queiate A: 5.3 g of the preceding amine and 1.1 g of the sodium sachet of sodium) are dissolved in 12.5 ml of water and the pH is lowered to 6 by the addition of an aqueous solution of 1N HCl. 12.5 ml of dioxane, 3.36 g of HCET then 1.8 g of EDCl are then introduced and the medium is kept at pH 6 for 4 hours before pouring into 150 ml of ethanoi. The precipitate formed is isolated and then purified by tangential uitrariltration on a 30 KD cutting threshold membrane in regenerated cellulose of 50 cm2 Labscale® module from Miilipore®). Thus, 5.6 g of the desired product are isolated: HPLC: Column No. 1; Eluent No. 3; tr = 16 minutes.

Example 12 Gadolinium chainlet of the formula I in which m = 2, R '- H- (CH 2) 2 CCNHR CC 2 H (sodium salt) N, N'-bis (2, 3, 4, 5, 6-pentahydroxyhexii) 2,4,6- -chromo-5- [4- 4-aminomethylbenzamido) benzamide] isofamide: (a) Stir during 4 hours at 60 ° C, a solution of 230 ml of N-methylpyrrolidone of 10 g of acid dichloride prepared as in step 4 of example 11 and 1 . or g .scrbitylamine. The reaction medium is then introduced into 1.5 liters of isopropanol where 17.5 g of the precipitate are isolated HPLC: Column No. I, Entitlement No. 5, tr = 15 minutes. ; b; Elimination of the phthalimide group: The operation as in the preceding example is carried out starting from 16 g of the product of "a stage (a) to obtain 6.2 g of the amine sought." HPLC: Column No. 1; tr = 15 to 20 minutes. 2. The procedure is as in example 11 above starting with 0.73 g of chelate A and 4.8 g of amma to obtain 2.5 g of the desired product. HPLC: Column No. 1; ? Luyente No. 3; tr = 13 minutes.

Example 13 Gadciinium chelate of formula I in which C02H CH- (CH2) 2C3NHR 1. 4- (Phthalimidomethylaminocarbonylamino) benzoic acid: 3.9 ml of thionyl chloride in a solution of 10 g of phthaloylglycine in 30 ml of N, N-dir.-thiacetamide are introduced at 3 ° C after stirring for 3 hours. temperature, 4 g of 4-aminobenzoic acid. After one night at room temperature, the medium is poured into 500 ml of water at 30 ° C. The formed precipitate is isolated. 2. 5- (4- [4- (Phthalimidomethylcarbonylamino) benzamido] benzamidc 2,4,6-tribothiophthalic acid. 4.8 ml of thionyl chloride in a solution of 19.5 g of the preceding acid in 120 ml of water are introduced at 10 ° C. N, N-dimethiacetamide, then after 2 hours 30 minutes, 38 g of 5- (4-amino) benzamido-2,4,6-t-isophilic acid, After one night at room temperature, the medium pour over 1 liter of water and the precipitate formed is isolated and washed with 400 ml of hot dioxane, p = 7.4 g. 3. N, N'-bis (2, 3,, 5, 6-pentahydroxyhexyl) 2,4,6-tribremo 5- [4- [4-talimidomethylcarbonylamino] benzamido) benzamido) isophthalamide: Are introduced at 5 ° C, 21 ml of thionyl chloride in a solution of 16.5 g of the above diacid in 90 ml of dioxane and 13.6 ml of dimethylformamide. After stirring for 2 hours 30 minutes, the medium is poured into 400 ml of water and the precipitate formed is dried and then introduced into a 70 ° C solution of 29.3 g of disorbitylamine in 150 ml of N-methypyrrolidine. 4 hours of stirring at this temperature, the medium is brought to room temperature, the salts are isolated and the filtrate is poured into 1 liter of isopropanol The precipitate formed is washed with 1.2 liters of ethanol p = 23 g HPLC: Column No. 1, Eluent No. 2, tr = 28 to 33 minutes. 4. Elimination of the phthalimide group: They are introduced into a mixture of 80 ml of N, N-di-ethylacetamide and 20 ml of water at 80 ° C, 22 g of preceding phthalic acid and 1.4 ml of hydrazma hydrate. After 3 hours at this temperature the medium is brought to 20 ° C then it is poured over 300 ml of ethanol. The precipitate formed, dried, is dissolved in 40 ml of water, the solution is cooled to 0 ° C and 3 ml of 6N hydrochloric acid are adjusted to pH 1.5. After filtration over Celite®, the filtrate is eluted on 45 ml of anionic resin Amberlite® IRA67 (Rohm and Hass), 50 ml of cationic resin IMAC® HPIIIE then 16 ml of anionic resin Amberlite® IRA458. After neutralization and filtration on a membrane of 0. 22 um, the solution is brought to dryness, p = 11.7 g. HPLC: Column No. 1; Eluent No. 2; tr = 16 to 20 minutes.

. Condensation on the chelate A: 11.2 g of the previous amma and 1.9 g of the chelate A sai of sodium) are put into solution in 24 ml of water. The pH of the solution is brought 6.1 by the addition of a 2N HCl solution. 24 ml of dioxane are then introduced, then 2.7 g of l- (3-dimethylamin.cpropii, -3-ethylcarbodiimide hydrochloride and 0.094 g of hydroxy benzotriazole.) After 3 hours of stirring at room temperature, the mixture is poured into 300 ml. of ethanol and the formed precipitate is isolated, after iltrafiltration with a Labscale® module where the membrane has a cut-off of 10 KD, the solution is iiofilized, p = 10.2 g HPLC: Column No. 1; Eluent No. 7; CH3CN / PIC A *? Aters®! Gradient in 25 minutes from 25/75 to 30/70; PICA = H2O / H3PC4 / (C HQ> 4N "HS0"; tr = 14 minutes ^.

Example 14 Gadolinium chelate of the formula I in which = 1 co2ri = CH-CH2 ~ CONHR 1.8 g of gadolinium chelate of the acid are dissolved! 1, 4,, 10-tetraazacyclododecane) 1, 4, 7, 10-tetra- (2-succinic acid) and 13.5 g of N, '-bis * 2, 3, 4, 5, 6-pentah? Drox? -r Extract 2, 4, 6-c ibro.no 5- (4- [4-ammoacetam? dobenzam? do i cepoeilglicilammo) isoftaiamida prepared as in step f of Example 3 in "O ml of water and introduced into a aqueous solution of HCl IN up to a pH of 6. After the addition of 2 g of EDCI, the mixture is maintained at 4 ° C. for 2 hours, then a tangential ultrafiltration is carried out on a Minisette® Filtron® cassette, a polyethersulfone membrane with a threshold of cut 5 KD, up to 2 liters of filtrate, the retentate is immediately contacted for 2 hours with 15 g of black Darco G60 marketed by A.idrich After separation of the -black by filtration and concentration to dryness, they are isolated 5 g of the white solid, CES: Conditions No. 1, tr = 35 minutes.

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

Claims (12)

RE IVINDICATIONS

1 . - Chelate of a cation of a paramagnetic metal; n a compound of formula characterized because: it is 1 or 2, ?. ' is H, a (C1-C4) alkyl group, or hydroxyalkyl, CH2-CCCH or CH2-CONZZ2 group, Zi and Z2 are independently one to the other, H, or an alkyl group (C.-C.), optionally idroxilado, I o?. ' is a group HGCC-CH- (CH2) m-CONHR, R is a group where a is 1 or 2, Z is a bond, CH2, CH2CONH or (CH2) 2NHCO Z 'is a bond, O, S, NQ, CH2, CO, CO-NQ, NQ-CO, NQ-CO- NQ or CO-NQ-CH2-CONQ S "is CO-NQ, NQ-CO or CO-NQ-CH2-CO-NQ, NQ-CO-CH2-NQ-CO with Q and H or an alkyl group (C.-Ci), optionally hydrolyzed Ri, R2 , 3, R4, R5, independently of one another are chosen from H, Br, Cl, I, CO-NQ? Q2 0 N (Q?) - CO-Q2 and Qi and Q2 / identical or different, are chosen from among the (C2-C6) alkyl groups, optionally hydroxylated, optionally interrupted by an oxygen atom, so that Qi and Q2 comprise those two from 4 to 10 OH groups, it being understood that at least I, and when more 2 groups i, R2, R3, R4, Rj are amide groups, and their salts with a mineral base, or an organic, pharmacologically acceptable base.

2. - The chelate of a cation of a paramagnetic metal with a compound of the formula I, and its salts, according to claim 1, characterized in that it is 2 IR 'is HCOC-CH- (CH2) 2CONHR, CH2COOH, or CH2CONZ .Z2, a is 1, Z is a bond, CH2, or CH2CONH, Z 'is CONH, NHCO, CONH-CH2-CONH, or NHCONH, Z "is CCNH or CONH-CH2-CONH, and then R2 = R4 = CONQ? Q2 or R3 = CCNQ? Q2, and R., R2, R4, R5 are H, Br, Cl or I, or Z "is NHCC, and then R2 = R4 = N (Q?) COQ2 or R3 = N (Q.) - CCQ2, and Ri, R2, R4, R5 sc t H, Br, Cl or I.

3. - The chelate of a paramagnetic metal cation of a compound of the formula I, and its salts, according to claim 1, characterized in that m is 2 R 'is HCOC-CH-? CH2? 2C_NHR or CH2COOH, a is I, Z is a bond, CH2, or CH2CONH, Z' is CONH, NHCCNH, or CCNH-CK2-CONH, Z "is CCNH, or CONH-CH2 -CONH, Ri, R3 and R5 all three Br or I, R2 and R4 are CCNQ1C2 with Qi and Q2 chosen from the hydroxylated (C2-C6) alkyl groups comprising them two of 6 to 10 OH groups, or comprising 4 to 8 OH groups if Qi and / or Qz are interrupted by an oxygen atom.

4. -. The chelate of a paramagnetic metal cation of a compound of formula I, and its salts, according to claim 1, characterized in that m is 2 I R 'is HCOC-CH-; CH2) 2CQNHR, a is 1, Z is CH2, or CH2CCNH, Z 'is CONH, NHCONH, Z "is CCNH, or CONH-CH2-CONH, Ri, R3 and 5 are all three Br or I, R2 and R are CCNQ1C2 with Qi and Q2 chosen from the hydroxylated (C2-C2) alkyl groups comprising the two from 6 to 13 CH groups, or comprising 4 to 3 OH groups if Qi / or Q2 are interrupted by an oxygen atom.

5. - The chelate of a paramagnetic metal cation of a compound of formula I, and its salts, according to claim 1, characterized in that m e s 2 I? 'is CH2CO2H, or HCCC-CH- (CH2) 2CONHR. a is i, Z is CH2, or CH2CONH, Z 'and Z "is CONH, Ri, 3 and R5 are all three Br or I, R2 and R4 are CONQ? Q2 with Qi and Q2 chosen from the hydroxylated (C2-C6) alkyl groups comprising them two of 6 to 10 CH groups, or that comprise 4 to 8 OH groups if Qi and / or Q2 are interrupted by an oxygen atom.

6. - The chelate of a paramagnetic metal cation of a compound of the formula I, and its salts, according to claim 1, characterized in that m is 2 I R 'is CH2CO2H, or HOOC-CH- (CH2) 2CONHR, a is 2, 1 is CH2 or CH2CONH, Z 'is CONH, or NHCO, Z "is CONH, or CGNH-CH2-CONH, and Ri, R3 and R5 are all three Br or I, and then R2 and R4 are all the two CONQ1Q2, or R3 is CONQ1Q2 and then Ri, R2, R4 and R5 are H, Br, or I.

7. The queiate of a paramagnetic metal cation of a compound of formula I, and its salts, according to claim 1, characterized in that m is 1"IR" is HOOC-CH-CH2-CONHR, a is 1, Z is CH2, or CH2CONH, Z 'is CONH, Z "is CONH, or CONH-CH2-CONH, Ri, R3 and R5 are Br, R2 and R are CONQ? Q2 with Qi and Q2 are the hydroxylated ICH2-C02 alkyl groups comprising them two from 6 to 10 OH groups.

8. - The queiate according to one of claims 1 to 7, characterized in that the metal cation is Gd3 ~.

9. - The gadolinium chelate, and its salts, of the compound of the formula I according to claim 1, characterized in that m is 2 I R 'is HOOC-CH- (CH2) 2CONHR and R is 1

10. The gadolinium chelate, and its salts, of the compound of the formula I according to claim 1, characterized in that it is 3 I R 'is HOOC-CH- (CH2) 2CONHR - with Z "is CONH-CH2CCNH and Qi and Q2 are CH2 (CHOH) 4CH2OH, 'then, whether Z is CH2 and Ri, R3 and Rj are already oca eo or Z is CH2CONH and Pi, R3 and R5 are Br , - or with Z "is CCNH, Z is CH2 or CH2CCNH, and Ri, R3, R5 are Br and Qi is CH2 (CHOH) 4CH2COH, and Q2 is CH2CHOH-CH2OH, or CH2 (CHOH) 4CH2OH.

11. - The contrast product for the magnetic resonance diagnostic imaging characterized in that it comprises an effective amount of a story according to one of claims 1 to 10 in a. pharmaceutically acceptable vehicle.

12. - The scintigraphy product, characterized in that it comprises a radiolabelled chelate of a metal cation with a compound of the formula HOOC COOH! I RHN-OC-. { CH2) m-HC-N-CHrCH2-N-CH- (CH2) rn-CO-NHR I I CH2 CH2 i l CH2 CH2 ir R'N-CH2-CH2-N- CH- (CH2) m-CO-NHR I COOH where m is 1 or 2, R 'is H, a (C1-C4) alkyl group, or hydroxyquinyl, a CH2-COCK or CH2-CONZ? Z2 group, Zi and Z2 are independently one of the other, H, or a (C 1 -C 4) alkyl group, optionally hydrexylated, or R 'is a group HOOC-CH- (CH2) m-CONHR, R is a group where a is 1 or 2, Z 'is a bond, O, S, NQ, CH2, CO, CO-NQ, NQ-CO, NQ-CO- NQ or CO-NQ-CH2-CONQ Z "is CO -NQ, NQ-CO or CO-NQ-CH2-CO-NQ, NQ-CO-CH2-NQ-CO with Q and H or an alkyl group (C? -C4), optionally hydroxylated Ri, R2, R3, R4 , R5, independently of one another are chosen from among H, 3r, Cl, I, CO-NQ1Q2 ON (Q?) - CO-Q2 and Oi and Qir identical or different, are chosen from among the groups C2-C6 alkyl ), possibly hydroxylated, optionally interrupted by an oxygen atom, such that Qi and Q2 comprise two of 4 to 10 OH groups, it being understood that at least 1, and when more 2 Ri groups, 2, R 3, P 4, 5 are amide groups, and their salts with a mineral base, or an organic, pharmacologically acceptable base.