RU2059642C1 - Gadolinium chelates and a method of their synthesis - Google Patents

Abstract

FIELD: organometallic compounds. SUBSTANCE: products: macrocyclic derivatives of 1,4,7,10-tetraazacyclodecane of the formula

given in description text. Reagent 1: gadolinium salt or oxide. Reagent 2: compound of the formula

Description

где А представляет собой группу формулы
-C

в которой R является водородом или линейной или разветвленной С₁-С₅алкильной группой или бензильной группой, которая может быть моно- или полизамещенной в ароматическом кольце галогеном, гидрокси-группой, карбокси-группой, карбамоилом, алкоксикарбонилом, сульфамоилом, низшим алкилом, низшим гидроксиалкилом, аминогруппой, ациламиногруппой, ацилом, гидроксиацилом или группой формулы Н(OCH₂CH₂)_1-4-, Ме(ОCH₂CH₂)_1-4 или Et(OCH₂CH₂)_1-4, где Х представляет собой группу O-R₁, в которой R₁является водородом или С₁-С₅ алкилом, гидроксиалкилом, алкоксиалкилом, алкоксигидроксиалкилом или полиоксаалкильной группой, имеющей 1-15 атомов кислорода и 3-45 атомов углерода, или Х представляет собой группу -NR₂R₃, в которой R₂ и R₃ могут быть одинаковыми или различными, являются С₁-С₆ алкилом, гидроксиалкилом, алкосиалкилом или алкоксигидроксигидроксиалкилом, имеющими вплоть до 5 гидроксильных групп и В₁, В₂ и В₃, которые могут быть одинаковыми или различными, имеют те же значения, что и А, или они являются водородом или группой формулы
-C

в которой R представляет собой водород или линейную или разветвленную С₁-С₅ алкильную группу, Y представляет собой группу O-R₅, в которой R₅является водородом или С₁-С₅ алкилом, гидроксиалкилом, алкоксиалкилом, алкоксигидроксиалкилом, или полиоксаалкильной группой, содержащей 1-15 атомов кислорода и 3-45 атомов углерода, или Y представляет собой группу -NR₆R₇, где R₆ и R₇, которые могут быть одинаковыми или различными, являются водородом или С₁-С₆ алкилом, гидроксиалкилом, алкоксиалкилом или алкоксигидроксиалкилом, имеющими вплоть до 5 гидроксильных групп, причем названные производные представляют собой, если требуется, соли с подходящими органическими или неорганическими основаниями, и комплексным солям названных хелатообразователей с подходящими ионами металлов в кислой, основной или нейтральной форме или, если требуется, нейтрализованных неорганическими или органическими кислыми или основными ионами, и, в конце концов, химически конъюгированными с макромолекулами или связанными с подходящими носителями.The invention relates to chelates of compounds representing new macrocyclic chelating agents which are derivatives of 1,4,7,10-tetraase-cyclododecane of the general formula I

where a represents a group of the formula
-C

in which R is hydrogen or a linear or branched C ₁ -C ₅ alkyl group or benzyl group, which may be mono- or polysubstituted in the aromatic ring with halogen, hydroxy group, carboxy group, carbamoyl, alkoxycarbonyl, sulfamoyl, lower alkyl, lower alkyl hydroxyalkyl, amino, acylamino, acyl, hydroxyacyl or a group of the formula H (OCH ₂ CH ₂ ) _1-4 -, Me (OCH ₂ CH ₂ ) _1-4 or Et (OCH ₂ CH ₂ ) _1-4 , where X represents an OR ₁ group in which R ₁ is hydrogen or C ₁ -C ₅ alkyl, hydroxyalkyl, alkoxyalkyl scrap, alkoxyhydroxyalkyl or a polyoxaalkyl group having 1-15 oxygen atoms and 3-45 carbon atoms, or X represents a —NR ₂ R ₃ group in which R ₂ and R ₃ may be the same or different, are C ₁ -C ₆ alkyl, hydroxyalkyl, alkoxyalkyl or alkoxyhydroxyhydroxyalkyl having up to 5 hydroxyl groups and B ₁ , B ₂ and B ₃ , which may be the same or different, have the same meanings as A, or they are hydrogen or a group of the formula
-C

in which R is hydrogen or a linear or branched C ₁ -C ₅ alkyl group, Y is an OR ₅ group in which R ₅ is hydrogen or C ₁ -C ₅ alkyl, hydroxyalkyl, alkoxyalkyl, alkoxyhydroxyalkyl, or a polyoxyalkyl group containing 1-15 oxygen atoms and 3-45 carbon atoms, or Y represents a group —NR ₆ R ₇ , where R ₆ and R ₇ , which may be the same or different, are hydrogen or C ₁ -C ₆ alkyl, hydroxyalkyl, alkoxyalkyl or alkoxyhydroxyalkyl having up to 5 hydroxy ln groups, wherein said derivatives are, if desired, salts with suitable organic or inorganic bases, and complex salts of said chelating agents with suitable metal ions in acidic, basic or neutral form or, if required, neutralized with inorganic or organic acidic or basic ions, and, after all, chemically conjugated to macromolecules or bound to suitable carriers.

 The invention also relates to a method for producing compounds of the general formula I and their complex salts.

The chelating agents of the invention and their complex salts can have a wide range of applications. Non-limiting examples of the use of these chelating agents are the extraction, separation and selective extraction of metal ions even at very low concentrations, their therapeutic use as detoxifying agents in the event of unintentional ingestion of metals or radioisotopes, or other examples that are obvious to a person skilled in the art. In such applications, chelating agents can be used directly or often being covalently or non-covalently bonded to macromolecules or insoluble surfaces, or being incorporated into structures that can deliver them to specific centers. In particular, complex salts of chelating agents of formula I with metal ions with atomic numbers from 20 to 31, 39, 42, 43, 44, 49 or 57 to 83, optionally in the form of salts with physiological biocompatible ions of organic or inorganic acids, or organic or inorganic bases, or amino acids, are strikingly suitable for use as contrasting agents in medical diagnostics in medical radiology and in NMR, EPR, X-ray and / or ultrasound methods. In order to optimize diagnostics, these derivatives can be covalently or non-covalently linked to biomolecules, macromolecules or aggregates of molecules characterized in that they can be selectively concentrated in the organ or tissue under study. At the same time, visualization of the internal structures of living objects is becoming more and more reliable in medical diagnostics. Among the newest techniques, the use of radioisotopes as internal radioactive labels in the body should be mentioned. One of the most important problems associated with the use of radioisotopes is the selectivity of their distribution, while another important aspect is their isolation over an acceptable period of time. Another imaging technique involves using ultrasound to measure differences in reflections at interfaces of tissues of different densities. The introduction of a suitable amount of a dense non-radioactive element or metal ion can lead to such a difference in reflection that even small, otherwise undetectable lesions can be distinguished. In the third diagnostic technique, nuclear magnetic resonance is used to create internal images of the human body. In this area, the development of contrast agents is of particular importance for the following reasons:
a) to increase the specificity of the diagnosis;
b) to detect minor lesions at an earlier stage;
c) to more accurately determine the spread of the tumor mass;
d) to improve the signal-to-noise ratio and shorten the imaging time, which also allows more efficient use of equipment;
f) to increase the contrast between those adjacent areas (for example, the abdominal or pelvic), where it is especially difficult to obtain high-quality images;
f) to obtain useful information on blood flow and tissue perfusion.

As for NMR diagnostics, contrast media containing paramagnetic complex salts of lanthanides and transition metals have already been described, for example, in US patent N 4639365 and EP 71564 and in patent applications DE 3401052, EP-A 135125, EP-A 130934, DE 3324236, EP-A124766, EP-F 165728, WO 87/02893, EP-A 230893. However, all the contrast agents for NMR developed so far are characterized by a number of problems in terms of their ability to influence the relaxation time of the atomic nuclei under consideration, their often insufficient selectivity when binding a metal ion, their stability, their selectively relative to the organ under study or their biological tolerance. The tendency of many complexes to exchange the central metal ion for metals important for the body, which are present in trace amounts, or ions, for example, Ca ²⁺ , which are in vivo present in relatively large quantities (see the work of Meya P.M. Current status of the use of chelating agents in medicine, p. 233) further restricts their use. In fact, in the case of insufficient stability of the complex, the body can lose the vital metals present in it in trace amounts and get unwanted and toxic heavy metals, such as Gd, Eu or Dy. Although it is true that the toxicity of the complex is often, but not always, lower than the toxicity of a free paramagnetic ion, it is also true that complexation usually leads to a decrease in the effectiveness of magnetic relaxation, which is responsible for some contrasting effects.

 Consequently, there are still several unresolved problems associated with the optimal contrast agent. These problems mainly concern the strong influence of the corresponding nuclei on the relaxation time; high stability of the complex both in solution and in the body; sufficient solubility in water; specificity of distribution in various parts of the body; appropriate rate of release from the test organ and tissue.

One of the most studied paramagnetic metal ions are Gd ³⁺ ions, especially where they are complexed with chelating agent diethylenetriaminopentaacetic acid (DTRA) (Runge et al. (1984), Am.J. Radiol. V. 141, p. 1209 and Weinman et al. (1984), Am. I. Radiol. 142, p. 619). The named complex in the form of a salt with D (-) N-methylglucamine is currently considered one of the most satisfactory in terms of activity, toxicity and its use in general.

 Despite these positive features, this compound cannot yet be considered as fully meeting the requirements for an optimal contrast agent for various reasons, among which, for example, the fact that Gd-DTRA-N-methyl-D-glucamine is removed too quickly from the blood stream and from the affected tissue sites during the study. This reduces the time available for imaging, which is important from a diagnostic point of view. In addition, the diffusion of the contrast agent between the healthy and the affected part is often so great that the contrast between the two areas may be too weak. To overcome these difficulties, the problem was approached in many ways, among which the most interesting are the following.

 a) We studied other chelating agents, in particular macrocyclic chelating agents, of which 1,4,7,10-tetraazacyclododecane-N, N ', N' ', N' '' - tetraacetic acid (DOTA) turned out to be the most effective. However, its complexes are characterized by problems similar to those examined by the example of DTPA.

 b) Gadolinium and its chelating agents were chemically conjugated with macromolecules, such as, for example, proteins (albumin, etc.), immunoglobulins, or with cellulose, or with other polymer matrices. On the one hand, this usually improved the relaxation of Gd, but on the other hand, it was necessarily accompanied by a sub-optimal dosage due to limitations in the solubility, toxicity and density of substitution of macromolecules. In addition, when one of the ligand centers of the chelating agents is used to form a chemical bond with the macromolecule, usually the stability of the resulting complex also decreases.

The chelating agents of formula I have shown excellent ability to trap metal ions even in very dilute solutions. An important example of this property is the ability to capture Cu ²⁺ ion from its aqueous solutions using 2- [1,4,7,10-tetraaza-4,7,10-tri (carboxymethyl) cyclododecan-1-yl] -3- benzyloxypropionic acid, a method for the preparation of which is given in examples 2 and 3.

As for their use in diagnostics, the metal complexes with chelating agents, which are the subject of the invention, were surprisingly suitable, for example, with respect to the requirements for the contrast agent used in the NMR method. Among such complexes, Gd ³⁺ complexes are most important, which are distinguished by their inherent excellent stability, relaxation, and selectivity with respect to the organ or tissue under study.

 These compounds have a wide range of applications, allowing intravascular administration (for example, intravenous, intraarterial, intracoronary, intraventricular, etc. administration), as well as intrathecal, intraperitoneal, intralymphatic, intracavitary and intraparenchymal routes. Both soluble and poorly soluble compounds are suitable for administration through the mouth or small intestine, which is therefore particularly suitable for visualizing the gastrointestinal tract. When administered parenchymally, they are preferably used in the form of a sterile aqueous suspension or solution, whose pH may vary, for example, from 6.0 to 8.5. The aforementioned sterile aqueous solutions or suspensions may be administered with concentrations ranging from 0.002 to 1.0 mol / L.

 The named formulations can also be lyophilized and delivered in such a form that allows them to be re-compiled immediately before use. When used in the gastrointestinal tract or when injected into body cavities, these agents can be used in the form of a suspension or solution containing additives necessary, for example, to increase viscosity.

 When administered orally, the formulations can be formulated in accordance with preparative methods commonly used in pharmacy, the formulations optionally coating from the surface so as to provide additional protection against the acidic environment in the stomach, thereby preventing the release of metal chelating ions, which occurs, in particular, at pH values typical of gastric juices. Other excipients, such as sweetening or flavoring agents, may be added in accordance with known pharmaceutical formulation techniques. Suspensions or solutions of complex salts may also be in the form of aerosols for use in aerosol bronchography.

 Some of the complex compounds of the invention have amazing specificity, which is manifested in that they are especially concentrated in the liver, in the spleen or after intralymphatic, intraparenchymal, intramuscular or subcutaneous administration, in the lymphatic vessels or in the lymph nodes. The resulting contrast between the organ under investigation and adjacent tissues allows a better visualization of the organ by NMR.

As for their use in diagnostics, metal complexes with chelating agents, which are the subject of the invention, can also be used as contrasting agents in medical radiology and electron paramagnetic resonance or sonography. In these cases, however, the central metal ions in the chelate complexes are, respectively, a radioisotope, for example ⁵¹ Cr, ⁶⁸ Ca, ¹¹¹ Ln, ^99m Tc, ¹⁴⁰ La, ¹⁶⁸ Yb, or not a radioisotope capable of changing the speed of passing and reflected ultrasonic waves.

 In the compounds of general formula IA, it is preferably a β-hydroxy-α-propionic, β-methoxy-α-propionic or β-benzyloxy-α-propionic group, optionally esterified or preferably substituted with an amide residue, which may be free, mono- or di- substituted alkyl, hydroxyalkyl, alkoxyalkyl or alkoxyhydroxyalkyl.

R may preferably be hydrogen or a linear or branched alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or a benzyl or substituted benzyl group, as shown in formula I. R may also be an acyl or hydroxyacyl group . R may also be a polyoxaethylene group of the formula H (OHCH ₂ CH ₂ ) _2-4 -, Mt (OCH ₂ CH _{2) 2-4} -, Et (OCH ₂ CH ₂ ) _2-4 , where X may be a hydroxyl group or also the group —OR ₁ where R ₁ is as defined in formula 1. Non-limiting examples of R ₁ are: methyl, ethyl, isopropyl, 2-hydroxyethyl, 2-hydroxypropyl, 1,3-dihydroxyisopropyl, polyoxaalkyl. X may preferably also be a hydroxyalkylamino group of the formula —N ₂ R ₃ in which R ₂ and R ₃ are as defined in formula 1. Non-limiting examples of these groups are the following: amino, 2-hydroxyethylamino, 2-hydroxypropylamino, 2, 3-dihydroxypropylamino, 1,3-dihydroxyisopropylamino, 1,3-dihydroxy-2-methylisopropylamino, 2,3,4-trihydroxy-1-butylamino-1,3,4-trihydroxy-2-butylamino, 1,3 -dihydroxy-2-hydroxymethylisopropylamino, N-methyl-N-2-hydroxyethylamino, N-methyl-N-2,3-dihydroxypropylamino, N-methyl-N-1,3-dihydroxyisopropylamino -, N-methyl-N-2,3,4,5,6-pentahydroxyhexylamino, N-2-hydroxyethyl-N-2,3-dihydroxypropylamino, N-2-hydroxyethyl-N-1,3-dihydroxyisopropylamino , bis- (2-hydroxyethyl) amino, N, N-bis- (2,3-dihydroxypropyl) amino, N, N-bis- (1,3-dihydroxyisopropyl) amino.

In the compounds of general formula I, groups B ₁ , B ₂ , B ₃ are preferably an acetate or α-propionic group, ultimately esterified or substituted by an amide residue, which may be in free form or mono- or disubstituted by alkyl, hydroxyalkyl, alkoxyalkyl or alkoxyhydroxyhydroxyalkyl groups. R ₄ may preferably be hydrogen or linear or branched lower alkyl, preferably methyl. Non-limiting examples of R ₄ are: hydrogen, methyl, linear or branched propyl, butyl and pentyl, as defined in formula I. Y may preferably be a hydroxyl group or a group —O — R ₅ in which R ₅ has the meanings defined in the formula I. Non-limiting examples of R ₅ are: methyl, ethyl, isopropyl, 2-hydroxyethyl, 2-hydroxypropyl, 1,3-dihydroxyisopropyl, polyoxaalkyl. Y can preferably also be a hydroxyalkylamino group of the formula —NR ₆ R ₇ in which R ₆ and R ₇ are as defined in Formula 1. Non-limiting examples of these groups are the following: amino, 2-hydroxyethylamino, 2-hydroxypropylamino, 2,3 -dihydroxypropylamino, 1,3-dihydroxyisopropylamino, 1,3-dihydroxy-2-methylisopropylamino-2,3,4-trihydroxy-1-butylamino, 1,3,4-trihydroxy-2-butylamino, 1 , 3-dihydroxy-2-hydroxymethylisopropylamino, N-methyl-N-2-hydroxyethylamino-, N-methyl-N-2,3-dihydroxypropylamino, N-methyl-N-1,3-dihydroxyisoprop amylamino, N-methyl-N-2,3,4,5,6-pentahydroxyhexylamino, N-2-hydroxyethyl-N-2,3-dihydroxypropylamino, N-2-hydroxyethyl-N-1,3, dihydroxyisopropylamino -, N-bis- (2-hydroxyethyl) amino, N-bis- (2,3-dihydroxypropyl) amino, N-bis- (1,3-dihydroxyisopropyl) amino groups.

Metal ions suitable for the formation of complex salts with chelating agents of the general formula I are mainly bivalent or trivalent ions of elements having atomic numbers lying in the range from 20 to 31, 39, 42, 43, 44, 49 or from 57 up to 83 and particularly preferred are Fe ²⁺ , Fe ³⁺ , Cu ²⁺ , Cr ³⁺ , Gd ³⁺ , Eu ³⁺ , Dy ³⁺ or Mn ²⁺ . Among the metal radioisotopes, ⁵¹ Cr, ⁶⁸ Ga, ¹¹¹ Ln, ^99m Tc, ¹⁴⁰ La, ¹⁶⁸ Ib are particularly preferred.

 Preferred inorganic acid anions include ions such as chlorides, bromides, iodides or other ions such as sulfate. Preferred organic acid anions include acid ions that are commonly used in pharmacy to form salts with bases, such as acetate, succinate, citrate, fumarate, maleate. Preferred inorganic base cations include alkali metal ions such as lithium, potassium and sodium, the latter being particularly preferred. Preferred organic base cations include primary, secondary and tertiary amines, such as ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethiglucamine and N-methylglucamine, with the latter being preferred. Preferred amino acid cations include, for example, cations of lysine, arinine and ornithine.

 Non-limiting examples of macromolecules suitable for conjugation with the chelate complexes of the invention are the following: biomolecules, such as hormones (insulin), prostaglandins, steroid hormones, amino sugars, peptides, proteins (albumin, human serum albumin), lipids, antibodies, such like monoclonal antibodies, polysaccharide chains.

 The chelate complexes of the invention can also be incorporated into liposomes used in the form of mono-multilayer carriers.

(II)
R-O-CH₂-

H-CO-X (III) где Z является галогеном, а R и Х имеют значения, определенные выше, получая продукт присоединения IV

IV или соответствующие поли-замещенные, в зависимости от используемого избытка соединения III, по атомам азота соединения II продукты. Соединение IV также может быть получено, например, защитой диэтилентриамина V с помощью подходящей защитной группы Р, где Р может быть, например, фталоильной группой или другой подходящей защитной группой, известной из литературы (Т.У. Грин: "Защитные группы в органическом синтезе", 1980),
NH₂~ NH ~ NH₂ _→ P

N ~ NH ~ N

P путем алкилирования получающегося в результате соединения VI подходящим галоидным производным III
VI + I

I _→

P

N-CH₂-CH

N-CH

VII и окончательным конденсированием по- лучающегося в результате продукта VII, после снятия защиты и последующего тозилирования, с тозилдиэтаноламином.Chelating agents of the general formula I and their complex salts are preferably prepared by reacting 1,4,7,10-tetraazacyclododecane (II) synthesized according to the method proposed by Atkins et al. (JACS, 96, 2268 (1974)) with the desired α-halopropionyl derivative

(Ii)
RO-CH ₂ -

H-CO-X (III) where Z is halogen, and R and X are as defined above, obtaining the product of accession IV

IV or the corresponding poly-substituted, depending on the excess of compound III used, on the nitrogen atoms of compound II products. Compound IV can also be obtained, for example, by protecting diethylenetriamine V with a suitable protecting group P, where P can be, for example, a phthaloyl group or other suitable protecting group known from the literature (TU Green: "Protecting groups in organic synthesis ", 1980),
NH ₂ ~ NH ~ NH ₂ _ → P

N ~ NH ~ N

P by alkylation of the resulting compound VI with a suitable halogen derivative III
VI + I

I _ →

P

N-CH ₂ -CH

N-ch

VII and the final condensation of the resulting product VII, after deprotection and subsequent tosylation, with tosyl diethanolamine.

H-CO-Y VIII где Z является галогеном, а R₄ и Y имеют значения определенные выше, получая искомые хелатообразователи общей формулы I.Compound IV or its polysubstituted analogues, in turn, may be condensed with a suitable α-haloacetate derivative VIII or with a suitable precursor thereof (such as an ester or nitrile),
R ₄ -

H-CO-Y VIII where Z is halogen, and R ₄ and Y are as defined above, obtaining the desired chelating agents of the general formula I.

 Finally, chelation with the desired metal ion is preferably carried out by reacting a suitable derivative of the formula I with a stoichiometric amount of the metal in the form of a salt or oxide, possibly in the presence of an acid or base necessary for neutralization.

Condensation of II with III can be carried out preferably in water or in a dipolar aprotic organic solvent such as dimethylformamide (DM F) or dimethylacetamide (DMAC), or a mixture thereof at a temperature from 30 to ¹⁵⁰ ° C, preferably from 40 to 100 ^C. Subsequent condensation of IV with VIII can be carried out in an aqueous medium or in an organic solvent in the presence of an inorganic or organic base, such as sodium hydroxide, potassium hydroxide, potassium carbonate or tetrabutylammonium hydroxide (TBAOH), at a pH ranging from 8 to 12, pr dpochtitelno from 9 to 11. The temperature can range from 40 ^to 100 ° C, preferably from 50 to 70 ° ^C.

Finally, the preparation of complex metal salt is preferably carried out in water or a suitable water-alcohol mixture, the temperature may range from 25 ^to 100 ° C, preferably from 40 to 80 ° ^C.

 The choice of a metal ion and, if necessary, a neutralizing ion is strictly related to the use of the resulting complex.

 PRI me R 1. 2- (1,4,7,10-Tetraazacyclododecan-1-yl) -3-benzyloxypropionic acid hydrochloride.

 A) 2-chloro-3-benzyloxypropionate

85 g of 2-chloro-3-benzyloxypropionic acid (0.396 mol) was suspended in 550 ml of water and neutralized to pH 7 with a 10% sodium hydroxide solution. After stirring for 15 minutes, the resulting aqueous solution was washed with diethyl ether and evaporated to dryness in vacuo to give the title compound. 90.6 g of sodium 2-chloro-3-benzyloxypropionate (0.383 mol) were obtained. Output: 96.7
Calculated, C 50.75; H 4.26; Cl 14.98.

 Found, C, 50.68; H 4.33; Cl 14.98.

 C) 2- (1,4,7,10-Tetraazacyclododecan-1-yl) -3-benzyloxypropionic acid trihydrochloride.

A suspension of 17.2 g of 1,4,7,10-tetraazacyclododecane (0.1 mol) and 71 g of 2-chloro-3-benziloksipropionata sodium (0.3 mol) in 70 mL of water was heated for 24 hours at 50 ^C. The resulting solution was diluted with water to 400 ml, was added dropwise in 200 ml of 2N. HCl solution was extracted several times with methylene chloride and then evaporated to dryness in vacuo.

The crude residue was combined with 400 ml of water and adsorbed on Amberlite 1R 120, from which it was eluted with sodium hydroxide solution. Concentration of the basic eluate 29 g of a residue was obtained which was dissolved in 400 ml of absolute ethanol at ⁶⁰ ° C; the solution was acidified with 200 ml of 6n. a solution of HCl in ethyl alcohol, and the resulting precipitate was stirred at 60 ^about C for 1 h. After cooling, the solid was filtered and dried, obtaining the desired compound. 33.5 g of 2- (1,4,7,10-tetraazacyclododecan-1-yl) -3-benzyloxypropionic acid trihydrochloride (0.0729 mol) were obtained. Yield: 72.9% Melting point: 221-224 ^C. Titers: (NaOH): 96,9% ( AgNO _3): 99.0%
Calculated, C 47.01; H 7.23; Cl 23.13; N, 12.18.

 Found C, 47.13; H 7.32; Cl 22.92; N, 12.09.

Thin layer chromatography: carrier: silica gel plate (Merck type G60), eluent: CHCl ₃ AcOH: H ₂ O 5: 5: 1; developer: Cl ₂ + ortho-toluidine; Rf 0.35.

¹ H-NMR- ¹³ C-NMR and IR spectra confirm the indicated structure.

 PRI me R 2. 2- [1,4,7,10-Tetraaza-7- (1-carboxy-2-benzyloxyethyl) -cyclododecane-1-yl] -3-benzyloxypropionic acid.

A solution of 12 g of 1,4,7,10-tetraazacyclododecane (0.069 mol) and 82.32 g of the sodium salt of 2-chloro-3-benzyloxypropionic acid (0.348 mol) obtained in the manner described in Example 1-A in 120 ml dimethylformamide were placed in a hermetically sealed vessel and heated ^at 50 ° C for 30 hours. The formed salt was filtered off and the solvent was distilled off under reduced pressure. The residue was combined with 300 ml of water, the pH was adjusted to 2.5 with 10% hydrochloric acid, then the mixture was extracted with four 50 ml portions of methylene chloride. The organic phase was evaporated to dryness and the residue was dissolved in 200 ml of 0.01 N. HCl and washed with diethyl ether. The pH was adjusted to 6 with a 10% sodium hydroxide solution and the aqueous solution was evaporated to dryness. The crude residue was combined with 30 ml of water and adsorbed on Amberlite 1R 120, from which it was eluted with 5N. ammonium hydroxide solution. Concentration of the basic eluant gave 7 g of a residue, which was recrystallized from water. 5.85 g of 2- [1,4,7,10-tetraaza-7- (1-carboxy-2-benzyloxyethyl) -cyclododecan-1-yl] -3-benzyloxypropionic acid (0.011 mol) was obtained .

Yield 16% Melting point 170-175 ^о С.

 Calculated, C 63.61; H 7.63; N, 10.60.

 Found C 63.48; H 7.82; N, 10.51.

The following compounds were prepared similarly:
2- [1,4,7,10-tetraase-4- (1-carboxy-2-benzyloxyethyl) -cyclododecan-1-yl] -3-benzyloxypropionic acid; 2- [1,4,7,10-tetraase-4,7-di (1-carboxy-2-benzyloxyethyl) -cyclododecan-1-yl] -3-benzyloxypropanoic acid.

 PRI me R 3. 2- [1,4,7,10-Tetraaza-4,7,10-tri (carboxymethyl) -cyclododecane-1-yl] -3-benzyloxy acid (Method A).

To a suspension of 23 g of 2- [1,4,7,10-tetraazacyclododecan-1-yl] -3-benzyloxypropionic acid trihydrochloride (0.05 mol) obtained by the procedure described in example 1 and 27.8 g of bromoacetic acid (0.2 mol) in 100 ml of water was added with stirring approximately 60 ml of 6N. sodium hydroxide solution, reaching a pH of 10. The mixture was heated at 50 ^about C for 17 h and a pH of 10 was maintained by further addition of 6 N. sodium hydroxide. The solution was cooled and treated with amberlite 1R 120, from which 5 N was eluted. ammonium hydroxide solution. The main eluate was evaporated to dryness, the resulting crude compound was dissolved in water, and the solution was acidified to pH 3 with 5N. HCl. The precipitate was filtered off and recrystallized from water to give the desired compound. 15.3 g of 2- [1,4,7,10-tetraase-4,7,10-tri (carboxymethyl) cyclododcan-1-yl] -3-benzyloxy acid (0.029 mol) were obtained.

Yield 58.4%
Melting point 173 ° C with decomposition.

Titers: (NaOH), 99.6% (ZnSO4) 99.5% (high performance liquid chromatography): 09.0%
Calculated, C 54.95; H 6.92; N 10-68.

 Found, C 54.77; H 6.96; N, 10.77.

 13C-NMR and IR spectra confirm the indicated structure.

 PRI me R 4. 2- [1,4,7,10-Tetraaza-4,7,10-tri (carboxymethyl) -cyclododecane-1-yl] -3-benzyloxy acid (Method B).

 A mixture of 10 g of 2- (1,4,7,10-tetraazacyclododecan-1-yl) -3-benzyloxypropionic acid (0.028 mol) obtained according to the procedure described in example 1, but without the formation of hydrochloride, and 15.57 g of bromoacetic acid (0.112 mol) in 60 ml of water was treated according to the procedure similar to that described in example 3, obtaining the desired compound. 7.93 g of 2- [1,4,7,10-tetraaza-4,7,10-tri (carboxymethyl) -cyclododecan-1-yl] -3-benzyloxypropionic acid (0.015 mol) were obtained.

Yield 54% Melting point 169-172 ^{° C} with decomposition.

Titers: (NaOH): 99.3% (ZnSO ₄ ) 99.5%
Calculated, C 54.95; H 6.92; N, 10.68.

 Found, C, 54.71; H, 7.00; N, 10.64.

 Other physicochemical properties are consistent with the properties of the compound obtained according to method A (example 3).

 Similarly, the following compounds were prepared: 2-1,4,7,10-tetraase-4,7,10-tri (1-carboxyethyl) -cyclododecane -1-yl-3-benzyloxy acid, 2- [1,4,7, 10-tetraase-4- (1-carboxy-2-benzyloxyethyl) - 4,10-di (carboxymethyl) cyclic acid, 2- [1,4,7,10-tetraase-7- (1-carboxy-2-benzyloxyethyl ) -7,10-di (carboxymethyl) -cyc3-benzyloxypropionic acid, 2- [1,4,7,10-tetraase-4,7-di (1-carboxy-2-benzyloxyethyl) -10-carboxymethylcycloic acid.

PRI me R 5. Salt D (-) - N-methylglucamine and complex Gd ³⁺ -2- [1,4,7,10-tetraase-4,7,10-tri (carboxymethyl) -cyclododecane-1 -yl] -3-benzyloxy acid.

To a suspension of 100 g of 2- [1,4,7,10-tetraase-4,7,10-tri (carboxymethyl) -cyclododecan-1-yl] -3-benzyloxypropionic acid (0.19 mol) obtained by the procedure, described in example 3, in 150 ml of water was added 36.6 g of D (-) - N-methylglucamine (0.187 mol). To the solution were added 19.47 g of Gd ₂ O ₃ (0.095 mol) and the resulting the resulting suspension was heated ^at 50 ° C for 4 hours. The reaction mixture was filtered and the pH was adjusted to 6.5 with 10% aqueous solution D (-) - N-methylglucamine. The resulting solution was then evaporated and dried, obtaining the desired compound. 159 g of the salt of D (-) - N-methylglucamine and the complex Gd ³⁺ (2- [1,4,7,10-tetraaza-4,7,10-tri (carboxymethyl) -cyclododecan-1-yl] - 3-benzyloxy acid (0.182 mol).

Yield 95.8%
Melting point 137 ^about C. Title: (high performance liquid chromatography): 99.3%
Calculated, C 42.56; H 5.76; Gd 17.99; N, 8.01.

 Found, C, 42.42; H 5.96; Gd 17.63; N, 7.92.

[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{369}}$ -15.36 ^o , [α] ₄₃₆ ²⁰ = -11.22 ^o ,
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{546}}$ -6.7 ^o , [α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{280}}$ -5.7 ^about (C = 5% H ₂ O).

PRI me R 6. Salt D (-) - N-methylglucamine with the complex Gd ³⁺ 2- [1,4,7,10-tetraase-4,7,10-tri (carboxymethyl) -cyclododecane-1- silt] -3-hydroxy hydroxy acid.

A solution of 92 g of 0.105 mol of the salt of D (-) - N-methylglucamine with the complex Gd ³⁺ / 2- [1,4,7,10-tetraase-4,7,10-tri (carboxymethyl) -cyclododecane-1- yl] -3-benzyloxypropionic acid obtained by the procedure described in Example 5 in 550 ml of water, to which 153 g of 5% palladium on activated carbon was added, was hydrogenated for 5 hours at room temperature. The catalyst was removed by filtration and the aqueous solution was evaporated in vacuo at 50 ^C. The residue Drying to constant weight gave the title debenzylated compound. 67 g of the D (-) - N-methiglucamine salt was obtained with the complex Gd ³⁺ / 2- [1,4,7,10-tetraaza-4,7,10-tri (carboxymethyl) -cyclododecan-1-yl] - 3-hydroxypropionic acid (0.084 mol).

Yield 80%
Melting point 180 ^about C (decomposes).

 Calculated, C 36.77; H 5.65; Gd 20.06; N, 8.93.

 Found, C 36.47; H 5.47; Gd 20.29; N, 8.83.

[α $\genfrac{}{}{0ex}{}{\text{20}}{\text{] 365}}$ -16.7 ^about , [α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{436}}$ -11.2 ^about [α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{546}}$ -6.7 ^about , [α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{589}}$ = -5.8 ^about (with 5% H ₂ O).

 The following compounds were prepared analogously: 2- [1,4,7,10-tetraazocyclododecan-1-yl] -3-hydroxypropionic acid, 2- [1,4,7,10-tetraaza-4- (1-carboxy-2 -hydroxyethyl) -cyclododecan-1-yl] -3-hydroxy-propionic acid, 2- [1,4,7,10-tetraaza-7- (1-carboxy-2-hydroxyethyl) -cyclododecane-1-yl ] -3-hydroxypropionic acid, 2- [1,4,7,10-tetraaza-4,7-di (1-carboxy-2-hydroxyethyl) cyclododecan-1-yl] -3-hydroxypropionic acid, 2- [1,4,7,10-tetraase-4- (1-carboxy-2-hydroxyethyl) - 7,10-di- (carboxymethyl) cyclododecan-1-yl] -3-hydroxypropionic acid, 2 - [1,4,7,10-tetraase-4,7-di (1-carboxy-2 -hydroxyethyl) -10-carboxymethyl-cyclododecan-1-yl] -3-hydroxypropionic acid, 2- [1,4,7,10-tetraase-4,7,10-tri (carboxymethyl ) -cyclododecan-1-yl] -3-hydroxypropionic acid.

 PRI me R 7. 2- [1,4,7,10-Tetraazacyclododecan-1-yl] -3-benzyloxy-N- (1,3, -dihydroxyisopropyl) propionamide.

 A) 3-Benzyloxy-2-chloropropionyl chloride.

119 g of thionyl chloride (1 mol) was added dropwise to 107.3 g of 3-benzyloxy-2-chloropropionic acid (0.5 mol) at 30 ^C. After heating the reaction mixture at reflux for 2 hours, further added 33 g of thionyl chloride (0.277 mol) and the mixture were refluxed for another 30 minutes. The excess thionyl chloride was distilled off under reduced pressure, and the title compound was obtained by distillation in vacuo. 95.8 g (0.41 mol) of 3-benzyloxy-2-chloropropionyl chloride were obtained. Yield 82% Boiling point 125-131 ^о С / 0.05 mbar. Titers: (reduction with Zn): 99.9% (argentometry): 96.0%
Calculated, C 51.53; H 4.32; Cl 30.42.

 Found, C, 51.30; H 4.46; Cl 29.48.

¹ H-NMR, ¹³ C-NMR and IR spectra confirmed the indicated structure.

 B) 2-chloro-3-benzyloxy-N- (1,3-dihydroxyisopropyl) propionamide.

 A solution of 70 g (0.3 mol) of 3-benzyloxy-2-chloropropionyl chloride in 150 ml of tetrahydrofuran was added dropwise over a period of approximately 2 hours to a solution of 32.6 g (0.36 mol) of 2-amino-1,3-dihydroxyisopropane in 150 ml of water and 250 ml of tetrahydrofuran. During the addition of the acid chloride, the pH of the solution was kept constant at 10 by the addition of 6N. sodium hydroxide solution. 250 ml of water was added to the reaction mixture. When concentrated to 450 ml, a white product precipitated, which was filtered off and recrystallized from water, yielding 4N after treatment with carbopuron. desired product. 62.2 g (0.218 mol) of 2-chloro-3-benzyloxy-N- (1,3-dihydroxy-isopropyl) -propionamide were obtained.

Yield 72.6%
Melting point 133-135 ^about C.

Titers (argentometry): 99.8%
Calculated, C 54.27; H 6.30; Cl 12.32; N, 4.87.

Found, C, 54.19; H 6.38; Cl 12.24; N, 4.84; H ₂ O 0.22.

High Performance Liquid Chromatography: 99%
¹ H-NMR, ¹³ C-NMR and IR spectra confirmed the indicated structure.

 C) 2- (1,4,7,10-tetraazacyclododecan-1-yl) -3-benzyloxy-N- (1,3-dihydroxyisopropyl) propionamide trihydrochloride.

51.6 g (0.3 mol) of 1,4,7,10-tetraazacyclododecane and 258.75 g (0.9 mol) of 2-chloro-3-benzyloxy-N- (1,3-dihydroxyisopropyl) -pro pionamida obtained by the procedure described in example 7-B, were reacted in dimethylformamide at ⁷⁰ ° C for 24 hours. After evaporation of the solvent in vacuo the residue was added water and adsorbed on an ion-exchange resin type 1R 120 from which it was eluted with using 5n. ammonium hydroxide solution. The ammonium solution was evaporated to dryness and the residue was taken up in the corresponding trihydrochloride as described in Example 1. 63.84 g (0.120 mol) of 2- (1,4,7,10-tetraazacyclododecan-1-yl) -3-ben- trihydrochloride was obtained. zyloxy-N- (1,3-dihydroxyisopropyl) -propionamide. Yield 40.0% Melting point: 125 ° ^C (decomposition).

 Calculated, C 47.33; H 7.56; Cl 19.96; N 13.14.

 Found, C, 47.41; H 7.68; Cl 19.85; N 13.08.

High performance liquid chromatography: 97.6%
The following compounds were prepared analogously: 2- (1,4,7,10-tetraazacyclododecan-1-yl) -3-benzyloxypropionamide, 2- (1,4,7,10-tetraazacyclododecan-1-yl) -3-ben- zyloxy-N- (2-hydroxyethyl) propionamide, 2- (1,4,7,10-tetrazacyclododecan-1-yl) -3-benzyloxy-N- (2,3-dihydroxypropyl) propionamide, 2- (1,4,7,10-tetraazacyclododecan-1-yl) -3-benzyloxy-N, N-di- (3-hydroxyethyl) propionamide.

PRI me R 8. 2- [1,4,7,10-Tetraaza-4,7,10-tri (carboxymethyl) -cyclododecan-1-yl] -3-benzyl si-N
A mixture of 16 g (0.038 mol) of 2- [1,4,7,10-tetraazacyclododecan-1-yl)] benzyloxy-N- (1,3-dihydroxyisopropiol) propionamide obtained according to the procedure described in example 7 and 21.13 g (0.152 mol) of bromoacetic acid in 100 ml of water were reacted in the same manner as described in Example 3 to give the title compound. 12.4 g of 2- [1,4,7,10-tetraaza-4,7,10-tri (carboxymethyl) -cyclododecan-1-yl] -3-benzyloxy-N- (1,3- dihydroxyisopropyl) propionamide.

54.4% yield
Melting point 137 ^C (decomposition).

Titers: (NaOH) 98.8%
Calculated, C 53.98; H 7.72; N, 11.66.

 Found, C, 53.91; H 7.85; N, 11.59.

 Similarly, the following compounds were prepared: 2- [1,4,7,10-tetraaza-4,7,10-tri (carboxymethyl) -cyclododecan-1-yl] -3-benzyl cypr2- [1,4,7,10 -tetraase-4,7,10-tri (carboxymethyl) -cyclododecan-1-yl] -3-benzyloxy-N- (2-hydroxyethyl) propionamide, 2- [1,4,7,10-tetraase-4 , 7,10-tri (carboxymethyl) -cyclododecan-1-yl] -3-benzyl si-Npionamide, 2- [1,4,7,10-tetraase-4,7,10-tri (carboxymethyl) -cyclododecane- 1-yl] -3-benzyloxy-N, N-di (2-hydroxyethyl) -propionamide.

PRI me R 9. Gd ³⁺ 2- [1,4,7,10-Tetraaza-4,7,10-tri (carboxymethyl) -cyclododecan-1-yl] -3-benzyloxy-N- (1 , 3-dihydroxyisopropyl) propionamide.

To a suspension of 8 g (0.013 mol) of 2- [1,4,7,10-tetraaza-4,7,10-tri (carboxymethyl) -cyclo-dodecan-1-yl] -3-benzyloxy-N- (1, 3 digid- roksiizopropil) -propionamide, prepared as described in example 8, in 30 ml of water was added Gd ₂ O ₃ 1.33 g (0.0065 mol) and the mixture was reacted ^at 50 ° C according to the procedure described in example 5. The resulting solution was evaporated to dryness, isolating the desired product. 9 g (0.012 mol) of Gd ³⁺ 2- [1,4,7,10-tetraaza-4,7,10-tri (carboxymethyl) -cyclododecan-1-yl] -3-benzyloxy-N- were obtained (1,3-dihydroxyisopropyl) propionamide. Yield 92.3%
Calculated, C 42.95; H 5.74; N, 9.28.

 Found C, 42.87; H 5.80; N, 9.23.

High Performance Liquid Chromatography: 97.5%
PRI me R 10. Gd ³⁺ 2- [1,4,7,10-tetraaza-4,7,10-tri (carboxymethyl) -cyclododecan-1-yl] -3-hydroxy-N- (1 , 3-dihydroxyisopropyl) propionamide.

9 g (0.012 mol) Gd ³⁺ 2- [1,4,7,10-tetraaza-4,7,10-tri (carboxymethyl) -cyclododecan-1-yl] -3-benzyloxy-N- (1 The 3-dihydroxy-isopropyl) propionamide obtained by the procedure described in Example 9 was dissolved in 60 ml of water. After adding 15 g of palladium on activated carbon, the solution was hydrogenated according to the procedure of example 6, to obtain the desired compound. 6.22 g (0.0096 mol) of Gd ³⁺ 2- [1,4,7,10-tetraaza-4,7,10-tri (carboxymethyl) -cyclododecan-1-yl] -3- were obtained hydroxy-N - (1,3-dihydroxyisopropyl) propionamide.

Yield 80%
Calculated, C 36.13; H 5.61; N, 10.53.

 Found, C 36.06; H 5.64; N, 10.48.

 The following compounds were prepared analogously: 2- [1,4,7,10-tetraazacyclododecan-1-yl] -3-hydroxypropionamide, 2- (1,4,7,10-tetraazacyclododecan-1-yl) -3-hydroxy N- (2-hydroxyethyl) -propionamide 2- (1,4,7,10-tetraazacyclododecan-1-yl) -3-hydroxy-N- (2,3-dihydroxypropyl) propionamide, 2- ( 1,4,7,10-tetraazacyclododecan-1-yl) -3-hydroxy-NN-di- (2-hydroxymethyl) -propionamide, 2- [1,4,7,10-tetraase-4,7,10- tri (carboxymethyl) -cyclododecan-1-yl] -3-hydroxypropionamide, 2- [1,4,7,10-tetra-aza-4,7,10-tri (carboxymethyl) cyclododecan-1-yl] -3-hydroxy-N- (2-hydroxyethyl) - propionamide, 2- [1,4,7,10-tetraase-4,7,10-tri (car boxymethyl) -cyclododecan-1-yl] -3-hydroxy-N- (pionamide, 2- [1,4,7,10-tetraaza-4,7,10-tri (carboxymethyl) -cyclododecan-1-yl] - 3-hydroxy-N, N-di- (2-hydroxyethyl) propionamide).

 PRI me R 11. Determination of relaxation of the compounds according to the invention.

Working conditions
A) Equipment "MINISPEС PC 120" (Broker company)
B) Observed frequency 20 MHz (proton)
C) Temperature: 39 ^о С, with preliminary thermal stabilization -
NMR ampoules for 10 min at
operating temperature
D) Concentrations: in the range from 0 to 5 mmol with the following
with specific measuring points:
0 / 0.1 / 0.2 / 0.5 / 1.0 / 2.0 / 5.0 mmol
E) Solvent: 0.154 M NaOH solution (0.9%), water
F) pH: 7.3, check again potentiometrically
ki before measuring relaxation.

The longitudinal relaxation measurements (R ₁ ) were processed using a "reverse recovery" sequence with a minimum of 8 points and an approximation of 3 parameters in accordance with the program provided for the instrument of the type "MINISPEC 120 BRUKER", with which measurements were taken.

The lateral relaxation measurements (R ₂ ) were processed using the sequence of Carr, Purcell, Maybum and Gill, according to the program provided for the device type "MINISPEC 120 BRUKER", which was used to measure, adjusting the device so as to observe signal attenuation by approximately 1 / 3 of the initial value, and the number of points was greater than or equal to 10 and the approximation was carried out according to 2 parameters.

Table 1 shows, by way of non-limiting examples, the values of R ₁ and R ₂ calculated for compounds A and B in comparison with the Gd / DTPA complex neutralized with N-methylglucamine.

 Physicochemical data of the compounds are given in table.2.

PRI me R 12. Obtaining liposomes containing the complex: Gd ³⁺ / 2- [1,4,7,10-tetraaza-4,7,10-tri (carboxymethyl) -cyclodecodan-1-yl] -3-benzyloxypropionic acid, neutralized with N-methylglucamine.

An anhydrous lipid mixture was prepared as follows: egg phosphatidylcholine 75 mol. and cholesterol 25 mol. using the PEV method (F. Jock et al. (1978), Proc. Natl, Acad. Sci, USA, 75, 4194). 400 mg of the mixture was dissolved in 35 ml of chloroform, where 10 ml of a 0.05 M solution of N-methyl-D-glucamine salt with Gd ³⁺ / 2- [1,4,7,10-tetraase complex was added dropwise under the influence of ultrasound. -4,7,10-tri (carboxymethyl) -cyclododecan-1-yl] -3-benzyloxypropionic acid.

After complete addition, sonication was continued for 5 minutes. Then, the crude compound was heated ^to 50 ° C, and the solvent was distilled off in vacuo. The resulting gelled residue was suspended in a 1% NaCl solution and freed from unbound chelate using five successive centrifugation and resuspension operations (26000 g) for 10 minutes.

Example 13. Determination of LD ₅₀ in mice by intravenous administration of the compounds of the present invention.

Table 3 shows, by way of non-limiting examples, LD ₅₀ values for compounds A and B of the present invention compared to GdCl ₃ and c Gd / DTPA neutralized with N-methylglucamine.

From table 3 it is seen that in this pharmacological test, the complexes of gadolinium with macrocyclic chelating agents of the present invention are characterized by significantly reduced toxicity compared with both GdCl ₃ and Gd / DTPA.

PRI me R 14. Obtaining a salt solution of D (-) - N-methylglucamine with a complex of Gd ³⁺ / 2- [1,4,7,10-tetraase-4,7,10-three (carboxyme- tyl) -cyclododecan-1-yl] -3-benzyloxypropionic acid.

 436.8 g (0.500 mol) of the compound obtained according to the procedure described in Example 5 were dissolved in 300 ml of water for injection.

 The volume of the solution was adjusted to 500 ml by adding water for injection, then the solution was filtered, poured into test tubes and sterilized.

PRI me R 15. Obtaining a salt solution of D (-) - N-methylglucamine with the complex Gd ³⁺ / 2- [1,4,7,10-tetraase-4,7,10-three (carboxyme- tyl) -cyclododecan-1-yl] -3-hydroxypropionic acid.

 398.8 g (0.500 mol) of the compound obtained according to the procedure described in Example 6 were dissolved in 300 ml of water for injection. The volume of the solution was adjusted to 500 ml by adding water for injection, then the solution was filtered, poured into test tubes and sterilized.

PRI me R 16. Obtaining a salt solution of D (-) - N-methylglucamine with the complex Gd ³⁺ / 2- [1,4,7,10-tetraase-4,7,10-three (carboxy- methyl) -cyclododecan-1-yl] -3-benzyloxypropionic acid.

 218.4 g (0.250 mol) of the salt described in Example 14 was dissolved in 260 ml of water for injection, 0.6 g of ascorbic acid was added, and the solution was diluted to 500 ml with water for injection. The solution was sterilized by filtration and poured into tubes.

PRI me R 17. Obtaining a salt solution of D (-) - N-methylglucamine with a complex of Gd ³⁺ / 2- [1,4,7,10-tetraase-4,7,10-three (carboxyme- tyl) -cyclododecan-1-yl] -3-benzyloxypropionic acid.

 218.4 g (0.250 mol) of the salt described in Example 14 was dissolved in 200 ml of water for injection, 0.45 g of tromethamine hydrochloride was added, and the solution was diluted with water for injection to 500 ml. The solution was filtered, poured into test tubes and sterilized.

PRI me R 18. Obtaining a salt solution of D (-) - N-methylglucamine with the complex Gd ³⁺ / 2- [1,4,7,10-tetraase-4,7,10-tri (carboxymethyl) β-cyclododecan-1-yl] -3-hydroxy-propionic acid.

 199.4 g (0.250 mol) of the salt described in Example 15 was dissolved in 200 ml of water for injection, 0.6 g of ascorbic acid was added, and the solution was diluted with water for injection to 500 ml. The solution was sterilized by filtration and poured into tubes.

PRI me R 19. Obtaining a salt solution of D (-) - N-methylglucamine with a complex of Gd ³⁺ / 2- [1,4,7,10-tetraase-4,7,10-three (carboxymethyl) - cyclododecan-1-yl] -3-hydroxypropionic acid.

 199.4 g (0.250 mol) of the salt described in Example 15 was dissolved in 200 ml of water for injection, 0.45 g of tromethamine hydrochloride was added, and the solution was diluted to 500 ml with water for injection. The solution was filtered, poured into test tubes and sterilized.

Claims (6)

1. Gadolinium chelates with a compound of the general formula

where A is a group of the general formula

where R is hydrogen, benzyl;
X is hydroxyl or a group NR ₁ R ₂ , where R _{1 is} hydrogen or methyl, and R _{2 is} hydroxy (C ₁ C ₆ ) is an alkyl group optionally containing up to 5 hydroxyl groups;
B ₁ B ₂ B ₃ are CH ₂ COOH groups, optionally B ₁ or B ₂ A or B ₁ B ₂ A,
or their salts with N alkylglucamine. 2. Chelates according to claim 1, characterized in that the compounds have the general formula

where R and X have the indicated meanings. 3. Chelates according to claim 2, characterized in that the compounds have the general formula

where R has the indicated meanings;
X is OH, NHCH (CHOH) ₂ , -NHCH ₂ CH (OH) CH ₂ OH-, NHCH ₂ CH (OH). CH (OH) CH ₂ OH. 4. Chelates 1 3, characterized in that gadolinium is a radioisotope of ^{6 8} Gd.  5. Chelates 1 3 or 4, characterized in that the compounds are selected from the group consisting of 2- (1,4,7,10-tetraase-4-) 1-carboxy-2-benzyloxyethyl (-7,10-di) carboxymethyl (- cyclododecan-1-yl) -3-benzyloxy-propionic acid, 2- (1,4,7,10-tetraase-4-) 1-carboxy-2-hydroxyethyl) -7, 10-di- (carboxymethyl) cyclododecane -1-yl) -3-hydroxypropionic acid, 2- (1,4,7,10-tetraase-7-) 1-carboxy-2-benzyloxyethyl) -4, 10-di- (carboxymethyl) -cyclododecane-1- il) -3-benzyloxypropionic acid, 2- (1,4,7,10-tetraase-7-) 1-carboxy-2-hydroxyethyl (-4, 10-di) carboxymethyl (-cyclododecan-1-yl) -3 -hydroxypropionic acid, 2- (1,4,7,10- etraaza-4,7-di) 1-carboxy-2-benzyloxyethyl (10-carboxymethyl-cyclododecan-1-yl) -3-benzyloxypropionic acid, 2- (1,4,7,10-tetraase-4,7-di ) 1-carboxy-2-hydroxyethyl (-10-carboxymethyl-cyclododecan-1-yl) -3-hydroxypropionic acid, 2- (1,4,7,10-tetraase-4,7,10-tri (carboxymethyl) - cyclododecan-1-yl) -3-benzyloxypropionic acid, 2- (1,4,7,10-tetraase-4,7,10-tri (carboxymethyl) -cyclododecan-1-yl) -3-hydroxypropionic acid, 2- (1,4,7,10-tetraazacyclododecan-1-yl) -3-benzyloxy-N- (2-hydroxyethyl) propionamide, 2- (1,4,7,10-tetraazacyclododecan-1-yl) -3- hydroxy-N- (2-hydroxyethyl) prop onamide, 2- (1,4,7,10-tetraazacyclododecan-1-yl) -3-benzyloxy-N- (1,3-dihydroxyisopropyl) propionamide, 2- (1,4,7,10-tetraazacyclododecane-1 -yl) -3- hydroxy-N- (1,3-dihydroxyisopropyl) propionamide, 2- (1,4,7,10-tetraazacyclododecan-1-yl) -3-benzyloxy-N- (2,3-dihydroxypropyl ) -propionamide, 2- (1,4,7,10-tetraazacyclododecan-1-yl) -3-hydroxy-N- (2,3-dihydroxypropyl) propionamide, 2- (1,4,7,10-tetraase -4,7,10-tri) carboxymethyl (-cyclododecan-1-yl) -3-benzyloxy-N- (2-hydroxyethyl) propionamide, 2- (1,4,7,10-tetraase-4.7, 10-three) carboxymethyl (-cyclododecan-1-yl) -3-hydroxy-N- (2-hydroxyethyl) propionamide, 2- (1,4,7,10-tetraaza-4,7,10-tri) carboxymethyl (-cyclododecan-1-yl) - 3-benzyloxy-N- (1,3-dihydroxyisopropyl) propionamide, 2- (1, 4,7,10-tetraaza-4,7,10-tri) carboxymethyl (-cyclododecan-1-yl) -3-hydroxy-N- (1,3-dihydroxyisopropyl) propionamide, 2- (1,4,7 , 10-tetraaza-4,7,10-tri) carboxymethyl (- cyclododecan-1-yl) -3-benzyloxy-N- (2,3-dihydroxypropyl) propionamide, 2- (1,4,7,10- tetraaza-4,7,10-tri) carboxymethyl (- cyclododecan-1-yl) -3-hydroxy-N- (2,3-dihydroxypropyl) propionamide, or their salts with N-methylglucamine. 6. A method of obtaining gadolinium chelates with a compound of General formula I

where a group of General formula II

where R is hydrogen, benzyl;
X is hydroxy or an NR ₁ R ₂ group, where R _{1 is} hydrogen or methyl, R ₂ hydroxy (C ₁ C ₆ ) is an alkyl group optionally containing up to 5 hydroxy groups,
B ₁ B ₂ = B ₃ groups —CH ₂ COOH, optionally B ₁ or B ₂ A or B ₁ B ₂ A,
or their salts with N-alkylglucamine, characterized in that the gadolinium salt or oxide is reacted with a compound of the general formula I or its salt, followed by, if necessary, neutralizing the resulting product with N-lower alkylglucamine.

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