Complex comprising calcium and phosphorus-containing ethylenediamine derivatives

FIELD: coordination compounds synthesis.

SUBSTANCE: invention provides complex comprising calcium and [[(4R)-4[bis[carboxy.kappa.O)methyl]amino-.kappa.N]-6,9-bis[carboxy-.kappa.O)methyl]-1-[(4,4-diphenylcyclohexyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecane-11-ylic acid-.kappa.N6,.kappa.N9,-kappa.011]-oxydato(6-)]-,6H, (MS-325) or its salt with physiologically acceptable cation in each case containing essentially no Gf-MS-325. Also described are pharmaceutical agent based on compounds according to claim 1 and a method for preparing galena composition, complex or its salt with physiologically acceptable cation according to claim 1 intended for preparation of pharmaceutical agent reducing effect produced by heavy metals as well as complex or its salt with physiologically acceptable cation according to claim 1 intended for preparation of pharmaceutical agent suitable for NMR diagnostics and/or diagnostic radiology, a method for amplifying patient's image in NMR tomography based on compounds according to claim 1 and above defined complex or its salt with physiologically acceptable cation in each case containing essentially no visualizing metal chelates and MS-325.

EFFECT: increased assortment of complexes with useful medicine-destination properties.

14 cl, 4 dwg, 30 ex

 

The objects of the invention described in the claims, are complex, including calcium and [[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid. the Kappa. N6,. the Kappa. N9,. the Kappa. 011]-1-oxalato(6-)]-,6N, its salts, pharmaceutical agents containing such complexes intended for receiving agents used to reduce effects caused by heavy metals and methods for their preparation.

In medicine complex compounds are used, in particular, for the treatment of poisoning by heavy metals, pathological excess iron, as well as for the preparation of pharmaceutical agents intended for diagnostic use visualization.

In EP 71564 described inter alia Leguminosae salt complex of gadolinium(III) and diethylenetriaminepentaacetic acid (DTPC) as a contrast medium for NMR imaging. The composition comprising the complex, is used worldwide as a basic contrast medium for NMR under the name Magnevist ®. This contrast medium after intravenous dispersed in the extracellular space and is excreted via the kidneys through glomerular secretion. Almost no penetration through the intact cleto the major membrane. Magnevist ® most suitable for the visualization of areas subjected to pathological changes (for example, areas of inflammation, tumors).

In addition, compounds containing DTPC or Sa-DTPC apply in a clinical setting in case of poisoning metals.

Thus, there is a need for the creation of agents, allowing to reduce the impacts from heavy metals.

The task of the invention to provide such compounds and agents, and the method of their derivation. This task is solved by the present invention.

In lined with the patent application WO 96/23526 described the use of complex gadolinite(3-) and [[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-. .N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid. the Kappa. N6, the Kappa. N9,. the Kappa. 011]-1-oxalato(6-)]-, 3H), also known as Gd-MS-325, as agent for “blood depot. Gd-MS-325 is different in that it binds to human serum albumin (CSA) and the result is stored in the intravascular space. In WO 96/23526 also described a composition comprising Gd-MS-325. Thus, in example 10 describes the obtaining of 200 malamulo solution of Gd-MS-325 (Leguminosae salt)containing 5%excess complexing agent MS-325. Adding calcium is o salts to the composition claimed in p, however, it is not specifically mentioned in the text and examples.

In WO 96/23526 described a composition comprising Gd-MS-325, which contains 5%excess complexing agent MS-325 (example 10). Attempt to get the Ca-MS-325 for such compositions have been unsuccessful (see the tests I-III).

An attempt was made to obtain in situ complex with calcium hydroxide or calcium carbonate, including 5%excess complexing agent. In this case, there was a formation of turbidity, especially in the case of large quantities (1-10 l). AAS analysis of this turbid product has allowed to establish that in this case it is a component containing Gd. (Probably in the process of complexation MS-325 forms an intermediate product, which is preferable from the viewpoint of reaction kinetics, which due to their low solubility leads to the formation of turbidity. This product is essentially the Sa complexes with phosphate ester. The fact that it is an intermediate product resulting from the kinetic reaction, confirmed by the fact that, if this turbid solution was boiled under reflux for 48 h, then the precipitate dissolves and forms a clear solution). In addition, using GHUR revealed that this is already happening partial decomposition. Because there is outnote, to resolve which you want to filter, the intensity of which, in particular, depends on how quickly added to a solution of calcium, failed to obtain reproducible content of Ca-MS-325 and Gd-MS-325 in the composition. Thus, this procedure is completely unacceptable for the preparation of galenic forms on the basis of such pharmaceutical compositions.

Thus, the task is to develop a composition containing Gd-MS-325, which satisfies the requirements for galenical forms, ie, in particular, is not muddy. This task is solved by the present invention.

It was found that the above problem is solved by a separate receiving calcium complex and ligand MS-325, almost not containing chelate complexes of MS-325 with the metals used in diagnostic imaging, for example, paramagnetic metals and metals which can be used for x-ray or ultrasound imaging, i.e. metals with atomic numbers 21-29, 42, 44, 57-83, and radioactive metals, such as Cu, Re, Co, cu, AU, Ag, Pb, Bi, In, Ga, or in General to imaging in the ultraviolet/visible/infrared the spectrum of any chelate complexes with metals (generally called “metals that can be used for visualization”) (see WO 96/23526). After the addition of their type, for example, to a solution of Gd-MS-325. The data, for example, in the examples 14-29, indicate that in each case, the resulting solution is clear and not muddy.

The composition obtained in this way, also have a constant and reproducible analytical characteristics when preparing large quantities. In addition, they have more compatibility, more complete excretion of the metal and a more favorable impact on the cardiovascular system compared with the original composition based on Gd-MS-325.

Thus, the invention relates to a complex comprising calcium and [[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,. .N9,. Kappa]-1-oxalato(6-)]-, 6N, to receive his blessing and to salts of such complexes with physiologically compatible inorganic and/or organic cations such as sodium, calcium, potassium, meglumin, ethanolamine, diethanolamine, morpholine, glucamine, dimethylglycine, lysine, arginine and/or ornithine, and to the thus obtained Galanova compositions containing Gd-MS-325.

The invention relates also to the use of Ca-MS-325 and its salts for pharmaceutical agents, especially the antidotes used in poisoning the heavy metals.

Obtaining the compounds according to the invention

Complexing agent is converted into a complex containing calcium (Ca-MS-325), by reacting with a solution of calcium hydroxide, calcium oxide, calcium carbonate, or bicarbonate of calcium. Then optionally present acid hydrogen atoms of the acid groups are substituted by cations of inorganic and/or organic bases or amino acids.

In this case, the neutralization is carried out with the help of inorganic bases (for example, hydroxides, carbonates or bicarbonates, such as sodium, potassium, lithium or calcium and/or organic bases, such as primary, secondary and tertiary amines, such as ethanolamine, glucamine, N-methyl - and N,N-dimethylglycine, as well as basic amino acids, such as lysine, arginine and ornithine.

As containing CA complex includes four free acid groups, it may be advisable to obtain a neutral mixed salts, which as counterions contain both inorganic and organic cations.

This can be accomplished, for example, by interaction of Ca-MS-325 in aqueous solution with the oxide or salt of the desired metal, and optionally with a number of inorganic or organic bases, which is required for neutralization, PEFC is then formed complex salt is isolated and optionally purified. The base can be added in any order.

Obtaining compositions according to the invention, containing Gd-MS-325, carried out by dissolving in an aqueous medium containing calcium complex compounds according to the invention together with Gd-MS-325, optionally in combination with additives commonly used in the technology of preparation of galenical forms, after which the solution is not necessarily subjected to sterilization. It may be appropriate to obtain them, exposing the interaction of calcium-containing complex compounds according to the invention with the free complexing agent MS-325 and the stoichiometric quantity of the oxide or salt of gadolinium, as well as a number of inorganic or organic bases in aqueous medium required for neutralization of the complex containing gadolinium. The additives can be applied, for example, physiologically acceptable buffers (such as, for example, tromethamine), electrolytes (such as sodium chloride), and antioxidants (such as ascorbic acid).

The pharmaceutical agents according to the invention include 1 mkmol/l - 1 mol/l of the complex salt containing Gd, preferably 0.5 to 500 mmol/l, and 0.05 to 15 mol.%, preferably 0.5 to 5 mol.%, Ca-MS-325 and, as a rule, used in doses, comprising from 0.005 to 2 mmol/kg body weight, preferably 50-500 mmol/kg

Given neither the e examples serve to further illustrate the invention.

Experience illustrating obtaining in situ Gd-MS-325 using 5 mol.% Ca-MS-325

I. Obtaining in situ compositions containing the complex, which includes gadolinium and MS-325 in the form of meglumine salt (200 mmol) using a 5%excess complexing agent Ca-MS-325

In 3500 ml of deionized water add 181,25 g (0.5 mol) of gadolinium oxide, 815,35 g (of 1.05 mol, 95 wt.%-Noah contents) of MS-325 (ligand) and 683,25 g (3.5 mol) of N-methylglucamine, and then add 3,70 g (50 mmol) of calcium hydroxide. The mixture is stirred for 6 h at 95°C. Formed a cloudy solution. After cooling, the solution was adjusted with deionized water to a volume of 5000 ml and then filtered turbid product (filter pore size 2 μm).

Muddy residue is dried in vacuum (60°C.) (yield 2.86 g) and dissolved in a mixture of nitric acid/hydrogen peroxide (microwave) for the implementation of the AAS analysis. In this experience it was found that the content of Gd is 8.1% (relative to the solid product).

II. Obtaining in situ compositions containing the complex, which includes gadolinium and MS-325 in the form of meglumine salt (200 mmol) using a 5%excess complexing agent Ca-MS-325

In 3500 ml of deionized water add 181,25 g (0.5 mol) of gadolinium oxide, 815,35 g (of 1.05 mol, approximately 95 wt.%-Noah contents) of MS-325 (ligand) and 683,25 g (3.5 mol) of N-methylglucamine, the village is E. what type of 5.00 g (50 mmol) of calcium carbonate. The mixture is stirred for 6 h at 95°C. Formed a cloudy opaque solution. After cooling, the solution was adjusted with deionized water to a total volume of 5000 ml and then filtered turbid product (filter pore size 2 μm). Filtered cloudy precipitate is dried in vacuo (60°C.), the yield of 3.14 g (For the implementation of the AAS analysis it is dissolved in a mixture of nitric acid/hydrogen peroxide (microwave)). In this experience it was found that the content of Gd is 9.6% (relative to the solid product).

III. Obtaining in situ compositions containing the complex, which includes gadolinium and MS-325 in the form of meglumine salt (200 mmol) using a 5%excess complexing agent Ca-MS-325

In 350 ml deionized water add 18,12 g (50 mmol) of gadolinium oxide, 81,54 g (105 moles, approximately 95 wt.%-Noah contents) ligand MS-325 and of 68.3 g (350 mmol) of N-methylglucamine, and then add 0,37 g (5 mmol) of calcium hydroxide. The mixture is refluxed for 48 h (in this case, the original cloudy colorless solution slowly becomes transparent and becomes light yellow color), cooled and using deionized water adjusted to a total volume of 500 ml. Solution light yellow color filter and analyzed by GHWR. The content of Gd-MS-325 determines, taking as 100% the contents of the specified soy is inane external standard (external standard: Gd-MS-325, purified using IHVR). This experience revealed that the content is 96,3%. The fact that the identified content is less than 100% and the presence of yellow color indicate that the decomposition.

For comparison: the content according GHWR/95°C (6 h): 98,9%.

Examples illustrating the invention

Example 1

Calcium(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid. .N6,. .N9,. Kappa]-1-oxalato(6-)]-,4N

In 2000 ml of deionized water dissolve 10.0 g (12,88 mmole, a content of 95 wt.%) ligand MS-325, 0,954 g (12,88 mmole) of calcium hydroxide and 1,546 g (38,64 mmole) of sodium hydroxide and stirred for 5 h at 95°C. the Mixture is allowed to cool and add 0,515 g (12,88 mmole) of sodium hydroxide, filtered through a filter with a pore size of 2 microns and from the filtrate by freeze-drying receive specified in title product as a colourless amorphous powder.

Output 12,40 g (quantitative), the water content of 10.3%.

Elementary analysis (anhydrous substance)

Calculated: 45,89, N 4,43, N 4,87, CA With 4.64, Na 10,65, P 3,59%.

Found: 46,01, N To 4.52, N 4,99, CA 4,53, Na 10,77, P 3,70%.

Example 2

Calcium(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylchlorosilane]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid. the Kappa. N6,. .N9,. Kappa]-1-oxalato(6-)]-,Sa,2N

In 2000 ml of deionized water dissolve 10.0 g (12,88 mmole, a content of 95 wt.%) ligand MS-325, 2,578 g (25,76 mmole) of calcium carbonate and 0,515 g (12,88 mmole) of sodium hydroxide and stirred for 5 h at 95°C. the Mixture is allowed to cool and add 0,515 g (12,88 mmole) of sodium hydroxide, filtered through a filter with a pore size of 2 microns and from the filtrate by freeze-drying receive specified in title product as a colourless amorphous powder.

Output 12,25 g (quantitative), the water content of 9.8%.

Elementary analysis (anhydrous substance)

Calculated: 46,21, N 4,47, N 4,90, CA 9,34, Na Are 5.36, P 3,61%.

Found: 46,32, N 4,55, N 5,00, CA 9.22, Na The 5.45, P to 3.73%.

Example 3

Calcium(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid, .N6,. .N9,. the Kappa. 011]-1-oxalato(6-)]-,CA

In 200 ml of deionized water dissolve 10.0 g (12,88 mmole, a content of 95 wt.%) ligand MS-325, 3,867 g (38,64 mmole) of calcium carbonate and stirred for 5 h at 95°C. the Mixture is allowed to cool, filtered through a filter with a pore size of 2 microns and from the filtrate by freeze-drying receive specified in title product as a colourless amorphous powder.

Output 11,91 g (quantitative), the water content of 7.9.

Elementary analysis (anhydrous substance)

Calculated: 46,53, N 4,50, N Is 4.93, CA 14,11, P 3,64%.

Found: 46,41. N Br4.61, N 5,02, CA 14,22, P 3,75%.

Example 4

Calcium(4-), [[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-. .N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,. .N9,. the Kappa. 011]-1-oxalato(6-)]-,tetraselmis

In 2000 ml of deionized water dissolve 10.0 g (12,88 mmole, a content of 95 wt.%) ligand MS-325, 1,288 g (12,88 mmole) of calcium carbonate and 8,80 g (45,08 mmole) of meglumine and stirred for 5 h at 95°C. the Mixture is allowed to cool, add 1,257 g (6,44 mmole) of meglumine, filtered through a filter with a pore size of 2 microns and from the filtrate by freeze-drying receive specified in title product as a colourless amorphous powder.

Output 22,27 g (quantitative), the water content of 10.0%.

Elementary analysis (anhydrous substance)

Calculated: 47,07, N 7,12, N 6,30, CA To 2.57, P 1,99%.

Found: 47,20, N 7,21, N To 6.43, CA 2,69, P 2,10%.

Example 5

Calcium(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,. .N9,. the Kappa. 011]-1-oxalato(6-)]-,Sa, dimeglumine

In 200 ml of deionized water dissolve 10.0 g (12,88 mmole, a content of 95 wt.%) is Uganda MS-325, 1,91 g (25,76 mmole) of calcium hydroxide and 3.77 g (19,32 mmole) of meglumine and stirred for 5 h at 95°C. the Mixture is allowed to cool, add 1,257 g (6,44 mmole) of meglumine, filtered through a filter with a pore size of 2 microns and from the filtrate by freeze-drying receive specified in title product as a colourless amorphous powder.

Output 17,06 g (quantitative), the water content of 9.1%.

Elementary analysis (anhydrous substance)

Calculated: 46,88, N Is 6.19, N Of 5.82, CA 6,66, R To 2.57%.

Found: 47,01, N 6,29, N 5,93, CA To 6.58, P 2,69%.

Example 6

Calcium(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,. .N9,. the Kappa. 011]-1-oxalato(6-)]-,CA,2N

In 200 ml of deionized water dissolve 10.0 g (12,88 mmole, a content of 95 wt.%) ligand MS-325 and 1,91 g (25,76 mmole) of calcium hydroxide and stirred for 5 h at 95°C. the Mixture is allowed to cool, filtered through a filter with a pore size of 2 microns and from the filtrate by freeze-drying receive specified in title product as a colourless amorphous powder.

Output 11,30 g (quantitative), the water content of 7.3%.

Elementary analysis (anhydrous substance)

Calculated: 51,09, N 5,46, N 5,42, CA To 5.17, P 3,99%.

Found: 51,21, N Of 5.55, N Of 5.53, CA To 5.08, P 4,10%.

Example 7

Calcium(-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid. aa.N6,. .N9,. the Kappa. 011]-1-oxalato(6-)]-,4H

In 100 ml of water is added 10.0 g (12,88 mmole) of MS-325 and 0,954 g (12,88 mmole) of calcium hydroxide and added 1.55 g (38,64 mmole) of sodium hydroxide. The mixture was incubated for 5 h at 80°C. the Mixture is cooled to 10°C and the pH value was adjusted to 2.5 with 10%aqueous hydrochloric acid solution. Then add 200 ml of isopropanol and the mixture is cooled to 0°C. the Mixture is allowed to settle for 3 h at 0°C, then it is filtered off from the separated precipitate. Obtained by filtering the precipitate washed twice with 50 ml ethanol and twice with 100 ml of diethyl ether and dried in vacuum.

Output 8,76 g (87% of theoretical) of a colourless crystalline powder.

The water content of 7.6%.

Elementary analysis (anhydrous substance)

Calculated: 51,09, N 5,46, N 5,42, CA To 5.17, P 3,99%.

Found: 50,87, N 5,64, N 5,28, CA 5.01, P 3.72 per cent.

Example 8

Calcium(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,. .N9,. Kappa]-1-oxalato-)]-, 2N 2N

In 200 ml of deionized water dissolve 10.0 g (12,88 mmole, a content of 95 wt.%) ligand MS-325, 1,288 g (12,88 mmole) of calcium carbonate and 1.03 g (25,76 mmole) of sodium hydroxide and stirred for 5 h at 95°C. the Mixture is allowed to cool, filtered through a filter with pore size of 2 m is m, and from the filtrate by freeze-drying receive specified in title product as a colourless amorphous powder.

Output 11,70 g (quantitative), the water content of 9.8%.

Elementary analysis (anhydrous substance)

Calculated: 48,35, N 4,92, N 5,13, CA 4,89, Na 5,61, R Of 3.78%.

Found: 48,49, N 5,01, N 5,24, CA 5,00, Na 5,50, P 3,90%.

Example 9

Calcium(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,-.N9,. Kappa]-1-oxalato(6-)]-,3N,1H

In 200 ml of deionized water dissolve 10.0 g (12,88 mmole, a content of 95 wt.%) ligand MS-325, 0,954 g (12,88 mmole) of calcium hydroxide and 1,546 g (38,64 mmole) of sodium hydroxide and stirred for 5 h at 95°C. the Mixture is allowed to cool, filtered through a filter with a pore size of 2 microns and from the filtrate by freeze-drying receive specified in title product as a colourless amorphous powder.

Output 12,14 g (quantitative), the water content of 10.7%.

Elementary analysis (anhydrous substance)

Calculated: 47,09, N 4,67, N 4,99, CA 4,76, Na 8,19, P 3,68%.

Found: 47,22, N 4,78, N 5,12, CA 4,70, Na 8,27, R Of 3.80%.

Example 10

Calcium(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,. .N9,. Kappa]-1-oxalato(6-)]-,dimeglumine 2N

In 200 ml of deionized water dissolve 10.0 g (1288 mmole, content of 95 wt.%) ligand MS-325, 0,954 g (12,88 mmole) of calcium hydroxide and of 5.03 g (25,76 mmole) of meglumine and stirred for 5 h at 95°C. the Mixture is allowed to cool, filtered through a filter with a pore size of 2 microns and from the filtrate by freeze-drying receive specified in title product as a colourless amorphous powder.

Output 17,22 g (quantitative), water content, to 12.8%.

Elementary analysis (anhydrous substance)

Calculated: 48,41, N 6,57, N 6,01, CA 3,44, P 2,66%.

Found: 48,28, N 6,69, N 6,12, CA To 3.52, P 2,77%.

Example 11

Calcium(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,. .N9,-Kappa]-1-oxalato(6-)]-,dimeglumine,1H

In 200 ml of deionized water dissolve 10.0 g (12,88 mmole, a content of 95 wt.%) ligand MS-325, 1,288 g (12,88 mmole) of calcium carbonate and rate of 7.54 g (38,64 mmole) of meglumine and stirred for 5 h at 95°C. the Mixture is allowed to cool, filtered through a filter with a pore size of 2 microns and from the filtrate by freeze-drying receive specified in title product as a colourless amorphous powder.

Output 19,70 g (quantitative), the water content of 11.0%.

Elementary analysis (anhydrous substance)

Calculated: 47,64, N 6,89, N 6,17, CA 2,94, P 2,28%.

Found: 47,80, N 6,97, N 6,28, CA 3,00, P 240%.

Example 12

Calcium(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid. .N6,. aa.N9,. Kappa]-1-oxalato(6-)]-,3,5N,0,5N

In 200 ml of deionized water dissolve 10.0 g (12,88 mmole, a content of 95 wt.%) ligand MS-325, 1,288 g (12,88 mmole) of calcium carbonate and 1,546 g (38,64 mmole) of sodium hydroxide and stirred for 5 h at 95°C. the Mixture is allowed to cool and the pH value was adjusted to 7.4 by adding 5%aqueous sodium hydroxide solution. The mixture is filtered and by freeze-drying receive specified in the header of the product.

Output 12,01 g (quantitative)of a colorless powder, the water content of 8.6%.

Elementary analysis (anhydrous substance)conducted for connection in the form of 3,5N-salt

Calculated: Of 46.68, N 4,55, N Is 4.93, CA 4,70, Na 9,44, P 3.63 Percent.

Found: 46,61, N 4,43, N 5,02, CA 4,81, Na 9,51, P 3.71 Per Cent.

Example 13

Calcium(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,. Kappa]-1-oxalato(6-)]-,3,meglumin,0,5N

In 200 ml of deionized water dissolve 10.0 g (12,88 mmole, a content of 95 wt.%) ligand MS-325, 1,288 g (12,88 mmole) of calcium carbonate and rate of 7.54 g (38,64 mmole) of meglumine and stirred during the 5 h at 95°C. The mixture is allowed to cool and the pH value was adjusted to 7.4 by adding 5%aqueous solution of meglumine. The mixture is filtered and by freeze-drying receive specified in the header of the product.

Output 20,82 g (quantitative)of a colorless powder, the water content of 9.7%.

Elementary analysis (anhydrous substance)conducted for connection in the form of 3,meglumine salt

Calculated: 47,32, N? 7.04 Baby Mortality, N 6,24, CA 2,75, P 2,12%.

Found: 47,48, N 7,15, N 6,36, CA 2,87, P 2,17%.

Example 14

A composition containing a complex comprising gadolinium and MS-325 in the form of sodium salt (200 mmol) (5%excess complexing agent representing the connection specified in the header of example 1)

18,12 g (50 mmol) of gadolinium oxide, 77,65 g (100 mmol, 95 wt.%) MS-325, 4,318 g (5.0 mmol) of the compound indicated in the heading of example 1, and 11.2 g (280 mmol) of sodium hydroxide are stirred in 350 ml of Tris-Hcl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. the Mixture is allowed to cool to room temperature and the pH value was adjusted to 7.4 with 20%aqueous sodium hydroxide solution. Then, using Tris-HCl buffer (10 mmol/l, pH 7.4) the total volume adjusted to 500 ml, the solution is filtered through a filter with a pore size of 2 μm, and the filtrate is poured into the bubbles.

Example 15

A composition containing a complex comprising gadolinium and MS-325 in the de meglumine salt (200 mmol) (5%excess complexing agent, representing the connection specified in the header of example 4)

18,12 g (50 mmol) of gadolinium oxide, 77,65 g (100 mmol, 95 wt.%) MS-325, 7,783 g (5.0 mmol) of the compound indicated in the heading of example 4, and 54,66 g (280 mmol) of meglumine stirred in 350 ml of Tris-HCl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. the Mixture is allowed to cool to room temperature and the pH value was adjusted to 7.4 with 20%aqueous solution of meglumine. Then, using Tris-Hcl buffer (10 mmol/l, pH 7.4) the total volume adjusted to 500 ml, the solution is filtered through a filter with a pore size of 2 μm, and the filtrate is poured into the bubbles.

Example 16

A composition containing a complex comprising gadolinium and MS-325 in the form of sodium salt (200 mmol) (5%excess complexing agent representing the connection specified in the header of example 7)

18,12 g (50 mmol) of gadolinium oxide, 77,65 g(100 mmol, 95 wt.%) MS-325, 3,879 g (5.0 mmol) of the compound indicated in the heading of example 7, and 11.2 g (280 mmol) of sodium hydroxide are stirred in 350 ml of Tris-Hcl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. the Mixture is allowed to cool to room temperature and the pH value was adjusted to 7.4 with 20%aqueous sodium hydroxide solution. Then, using Tris-HCl buffer (10 mmol/l, pH 7.4) the total volume adjusted to 500 ml, the solution is filtered through a filter with razmara is then, 2 μm, and the filtrate is poured into the bubbles.

Example 17

A composition containing a complex comprising gadolinium and MS-325 in the form of sodium salt (200 mmol) (5%excess kompleksoobrazovanija agent representing the connection specified in the header of example 8)

18,12 g (50 mmol) of gadolinium oxide, 77,65 g (100 mmol, 95 wt.%) MS-325, 4,099 g (5.0 mmol) of the compound indicated in the heading of example 8, and 11.2 g (280 mmol) of sodium hydroxide are stirred in 350 ml of Tris-Hcl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. the Mixture is allowed to cool to room temperature and the pH value was adjusted to 7.4 with 20%aqueous sodium hydroxide solution. Then, using Tris-HCl buffer (10 mmol/l, pH 7.4) the total volume adjusted to 500 ml, the solution is filtered through a filter with a pore size of 2 μm, and the filtrate is poured into the bubbles.

Example 18

A composition containing a complex comprising gadolinium and MS-325 in the form of sodium salt (200 mmol) (5%excess complexing agent representing the connection specified in the header of the example 9)

18,12 g (50 mmol) of gadolinium oxide, 77,65 g (100 mmol, 95 wt.%) MS-325, 4,209 g (5.0 mmol) of the compound indicated in the heading of example 9, and 11.2 g (280 mmol) of sodium hydroxide are stirred in 350 ml of Tris-Hcl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. the Mixture is allowed to cool to room temperature and the pH value to the W ill result to 7.4 with 20%aqueous sodium hydroxide solution. Then, using Tris-HCl buffer (10 mmol, /l,pH 7.4) the total volume adjusted to 500 ml, the solution is filtered through a filter with a pore size of 2 μm, and the filtrate is poured into the bubbles.

Primer

A composition containing a complex comprising gadolinium and MS-325 in the form of sodium salt (200 mmol) (5%excess complexing agent representing the connection specified in the header of the example 12)

18,12 g (50 mmol) of gadolinium oxide, 77,65 g(100 mmol, the actual content of 95 wt.%) MS-325, 4.26 deaths g (5.0 mmol) of the compound indicated in the heading of example 12, and 11.2 g (280 mmol) of sodium hydroxide are stirred in 350 ml of Tris-Hcl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. the Mixture is allowed to cool to room temperature and the pH value was adjusted to 7.4 with 20%aqueous sodium hydroxide solution. Then, using Tris-HCl buffer (10 mmol/l, pH 7.4) the total volume adjusted to 500 ml, the solution is filtered through a filter with a pore size of 2 μm, and the filtrate is poured into the bubbles.

Example 20

A composition containing a complex comprising gadolinium and MS-325 in the form of meglumine salt (200 mmol) (5%excess complexing agent representing the connection specified in the header of the example 13)

18,12 g (50 mmol) of gadolinium oxide, 77,65 g (100 mmol, 95 wt.%) MS-325, 7,297 g (5.0 mmol) of the compound indicated in the heading of the use the and 13, and 54,66 g (280 mmol) of meglumine stirred in 350 ml of Tris-HCl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. the Mixture is allowed to cool to room temperature and the pH value was adjusted to 7.4 with 20%aqueous solution of meglumine. Then, using Tris-Hcl buffer (10 mmol/l, pH 7.4) the total volume adjusted to 500 ml, the solution is filtered through a filter with a pore size of 2 μm, and the filtrate is poured into the bubbles.

Example 21

A composition containing a complex comprising gadolinium and MS-325 in the form of meglumine salt (200 mmol) (5%excess complexing agent representing the connection specified in the header of example 10)

18,12 g (50 mmol) of gadolinium oxide, 77,65 g (100 mmol, 95 wt.%) MS-325, of 5.83 g (5.0 mmol) of the compound indicated in the heading of example 10, and 54,66 g (280 mmol) of meglumine stirred in 350 ml of Tris-Hcl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. the Mixture is allowed to cool to room temperature and the pH value was adjusted to 7.4 with 20%aqueous solution of meglumine. Then, using Tris-Hcl buffer (10 mmol/l, pH 7.4) the total volume adjusted to 500 ml, the solution is filtered through a filter with a pore size of 2 μm, and the filtrate is poured into the bubbles.

Example 22

A composition containing a complex comprising gadolinium and MS-325 in the form of sodium salt (200 mmol) (5%excess complexing agent, to depict allaudio a connection, specified in the header of example 1)

18,12 g (50 mmol) of gadolinium oxide, 77,65 g (100 mmol, the actual content of 95 wt.%) MS-325, 1.08 g (1.25 mmole) of the compound indicated in the heading of example 1, and 11.2 g (280 mmol) of sodium hydroxide are stirred in 350 ml of Tris-Hcl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. the Mixture is allowed to cool to room temperature and the pH value was adjusted to 7.4 with 20%aqueous sodium hydroxide solution. Then, using Tris-HCl buffer (10 mmol/l, pH 7.4) the total volume adjusted to 500 ml, the solution is filtered through a filter with a pore size of 2 μm, and the filtrate is poured into the bubbles.

Example 23

A composition containing a complex comprising gadolinium and MS-325 in the form of sodium salt (200 mmol) of (2,5%excess complexing agent representing the connection specified in the header of example 1)

18,12 g (50 mmol) of gadolinium oxide, 77,65 g (100 mmol, the actual content of 95 wt.%) MS-325, 2.16 g (2.5 mmole) of the compound indicated in the heading of example 12, and 11.2 g (280 mmol) of sodium hydroxide are stirred in 350 ml of Tris-Hcl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. the Mixture is allowed to cool to room temperature and the pH value was adjusted to 7.4 with 20%aqueous sodium hydroxide solution. Then, using Tris-HCl buffer (10 mmol/l, pH 7.4) the total volume adjusted to 500 ml, the solution is filtered through a filter is R with a pore size of 2 μm, and the filtrate is poured into the bubbles.

Example 24

A composition containing a complex comprising gadolinium and MS-325 in the form of meglumine salt (200 mmol) (1,25%excess complexing agent representing the connection specified in the header of example 4)

18,12 g (50 mmol) of gadolinium oxide, 77,65 g (100 mmol, 95 wt.%) MS-325, 1,946 g (1.25 mmole) of the compound indicated in the heading of example 4, and 54,66 g (280 mmol) of meglumine stirred in 350 ml of Tris-Hcl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. the Mixture is allowed to cool to room temperature and the pH value was adjusted to 7.4 with 20%aqueous solution of meglumine. Then, using Tris-Hcl buffer (10 mmol/l, pH 7.4) the total volume adjusted to 500 ml, the solution is filtered through a filter with a pore size of 2 μm, and the filtrate is poured into the bubbles.

Example 25

A composition containing a complex comprising gadolinium and MS-325 in the form of meglumine salt (200 mmol) of (2,5%excess complexing agent representing the connection specified in the header of example 4)

18,12 g (50 mmol) of gadolinium oxide, 77,65 g (100 mmol, 95 wt.%) MS-325, 3,891 g (2.5 mmole) of the compound indicated in the heading of example 4, and 54,66 g (280 mmol) of meglumine stirred in 350 ml of Tris-Hcl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. the Mixture is allowed to cool to room temperature and the pH value was adjusted to 7.4 with POM is using a 20%aqueous solution of meglumine. Then, using Tris-Hcl buffer (10 mmol/l, pH 7.4) the total volume adjusted to 500 ml, the solution is filtered through a filter with a pore size of 2 μm, and the filtrate is poured into the bubbles.

Example 26

A composition containing a complex comprising gadolinium and MS-325 in the form of sodium salt (200 mmol) (5%excess complexing agent representing the connection specified in the header of example 1)

An alternative method

18,12 g (50 mmol) of gadolinium oxide, 77,65 g(100 mmol, 95 wt.%) MS-325 and 11.2 g (280 mmol) of sodium hydroxide are stirred in 350 ml of Tris-Hcl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. the Mixture is allowed to cool to room temperature, add 4,318 g (5.0 mmol) of the compound indicated in the heading of example 1, and the pH value was adjusted to 7.4 with 20%aqueous sodium hydroxide solution. Then, using Tris-HCl buffer (10 mmol/l, pH 7.4) the total volume adjusted to 500 ml, the solution is filtered through a filter with a pore size of 2 μm, and the filtrate is poured into the bubbles.

Example 27

A composition containing a complex comprising gadolinium and MS-325 in the form of meglumine salt (200 mmol) (5%excess complexing agent representing the connection specified in the header of example 4)

An alternative method

18,12 g (50 mmol) of gadolinium oxide, 77,65 g (100 mmol, 95 wt.%) MS-325 and 54,66 g (280 m is Olga) meglumine stirred in 350 ml of Tris-HCl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. The mixture is allowed to cool to room temperature, add 7,783 g (5.0 mmol) of the compound indicated in the heading of example 4, and the pH value was adjusted to 7.4 with 20%aqueous solution of meglumine. Then, using Tris-HCl buffer (10 mmol/l, pH 7.4) the total volume adjusted to 500 ml, the solution is filtered through a filter with a pore size of 2 μm, and the filtrate is poured into the bubbles.

Example 28

A composition containing a complex comprising gadolinium and MS-325 in the form of sodium salt (200 mmol) of (2,5%excess complexing agent representing the connection specified in the header of example 1)

An alternative method

18,12 g (50 mmol) of gadolinium oxide, 77,65 g (100 mmol, 95 wt.%) MS-325 and 11.2 g (280 mmol) of sodium hydroxide are stirred in 350 ml of Tris-Hcl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. the Mixture is allowed to cool to room temperature, added 2.16 g (2.50 mmole) of the compound indicated in the heading of example 1, and the pH value was adjusted to 7.4 with 20%aqueous sodium hydroxide solution. Then, using Tris-HCl buffer (10 mmol/l,pH 7.4) the total volume adjusted to 500 ml, the solution is filtered through a filter with a pore size of 2 μm, and the filtrate is poured into the bubbles.

Example 29

A composition containing a complex comprising gadolinium and MS-325 in the form of meglumine salt (200 mmol) of (2,5%excess of complexones the promoting agent, representing the connection specified in the header of example 4)

An alternative method

18,12 g (50 mmol) of gadolinium oxide, 77,65 g (100 mmol, 95 wt.%) MS-325 and 54,66 g (280 mmol) of meglumine stirred in 350 ml of Tris-HCl buffer (10 mmol/l) at pH 7.4 for 6 h at 95°C. the Mixture is allowed to cool to room temperature, add 3,891 g (2.5 mmole) of the compound indicated in the heading of example 4, and the pH value was adjusted to 7.4 with 20%aqueous solution of meglumine. Then, using Tris-HCl buffer (10 mmol/l, pH 7.4) total volume adjusted to 500 ml, the solution is filtered through a filter with a pore size of 2 μm, and the filtrate is poured into the bubbles.

Example 30

1The h and31P-NMR spectra of compounds from examples 1 and 2

All measurements carried out using NMR-spectrometer type AMX 400 (400 MHz, firm Bruker).

Chemical shifts1N is specified as δ (part./million) relative to the solvent (D2O δ=4,8 frequent./million).

Chemical shifts31R is specified as δ (part./million) in relation to an external standard H3RHO4(85%, δ=0 part./million).

The connections defined in the headers of examples 1 and 2, is dissolved in D2O and the spectra measured at room temperature.

Result

The connection specified in the header of the example 1

1N: 1,4-1,7 (m, 2H), 1,8-2,1 (m, 3H), 2,15 was 2.25 (m, 2H), 2,32 (t, 12 Hz, 1H), 2,5-of 2.92 (m, 7H), 2,95-3,4 (m, 8H), of 3.45 (d, 16 Hz, 1H), 3,66 (d, 16 Hz, 1H), 3,8-3,95 (m, 2H), 4,23 (m, 1H), 7,15-7,25 (m, 2H), 7,25-7,5 (m, 8H).

31P: 0,3 8 (q, 6 Hz), 0,51 (q, 6 Hz).

The connection specified in the header of the example 2

1H: 1,20-1,45 (broad, 2H), 1.5 and 1.7 (broad, 2H), 1,75-2,05 (m, 3H), to 2.1-2.5 (m, 6H), 2,65-3,20 (m, 8H), 3,24 (d, 16 Hz, b 1H), 3.45 points (d, 16 Hz, 1H), 3,50-of 3.80 (m, 4H), was 4.02 (m, 1H), 6.75 in-7,20 (m, 10H).

31P: 0,25 (q, 6 Hz), 0,10 (q, 5 Hz).

1. The complex, including calcium and [[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxy-.Kappa)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,. Kappa]-1-oxalato(6-)]-,6N (MS-325), or its salt with a physiologically acceptable cation, in each case containing no Gd-MS-325.

2. The compound according to claim 1, characterized in that there is at least one physiologically acceptable cation is a sodium, calcium, potassium, meglumin, ethanolamine, diethanolamine, morpholine, glucamine, dimethylglycine, lysine, arginine or ornithine.

3. The compound according to claim 1, selected from the group including

Sa(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxy-.Kappa)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,. Kappa]-1-oxalato(6-)]-,4Na

Sa(4-), [[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxy-.Kappa)methyl-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,. Kappa]-1-oxalato(6-)]-,Sa,2N;

Sa(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxy-.Kappa)methyl] -1- [(4,4-diphenylacetyl)oxy] -1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,. Kappa]-1-oxalato(6-)]-,sa;

Sa(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxy-.Kappa)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,.Kappa]-1-oxalato(6-)]-,tetramethrin;

Sa(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxy-.Kappa)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,.Kappa]-1-oxalato(6-)]-,Sa,dimeglumine;

Sa(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxy-.Kappa)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,.Kappa]-1-oxalato(6-)]-,CA,2N;

Sa(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxy-.Kappa)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,.Kappa]-1-oxalato(6-)]-,4H;

Sa(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxy-.Kappa)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-FOS is undecan-11-sludge acid..N6,..N9,.Kappa]-1-oxalato(6-)]-,2Na,2H;

Sa(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxy-.Kappa)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,.Kappa]-1-oxalato(6-)]-,3Na,H;

Ca(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxy-.Kappa)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,.Kappa]-1-oxalato(6-)]-,dimeglumine,2H;

Sa(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxy-.Kappa)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,.Kappa]-1-oxalato(6-)]-,dimeglumine,1H;

Sa(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxy-.Kappa)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,.Kappa]-1-oxalato(6-)]-,3,5Na,0,5H or

Sa(4-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxy-.Kappa)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,.Kappa]-1-oxalato(6-)]-,3,5 meglumin,0,5H,

in each case containing no Gd-MS-325.

4. A pharmaceutical agent containing at least one physiologically acceptable compound according to any and what claims 1 to 3 optionally in combination with additives, commonly used in the technology of preparation of galenic forms.

5. A method of obtaining a galenical compositions containing Gd-MS-325, characterized in that the oxide of gadolinium, [[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,.Kappa]-1-oxalato(6-)]-,6N, physiologically acceptable buffer and an organic or inorganic base is subjected to interaction with calcium-containing complex according to claim 1, or gadolinium oxide and salt [[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,.Kappa]-1-oxalato(6-)]-,6N, Tris buffer and sodium oxide is subjected to interaction with the receiving gadolinium

(3-),[[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxylato)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid-Kappa-N6,..N9,.Kappa]-1-oxalato(6-)] and then mixed with calcium-containing complex according to claim 1.

6. Pharmaceutical agent comprising Gd-MS-325 and the number of separately obtained containing calcium complex according to claim 1, comprising 0.05 to 15 mol.% in relation to the number of Gd-MS-325, which is not muddy.

7. Pharma is efticiency agent according to claim 6, where the amount of calcium-containing complex is 0.5-5 mol.% in relation to the number of Gd-MS-325.

8. The pharmaceutical agent according to claim 6, where the concentration of Gd-MS-325 in a solution of 200 mmol.

9. The compound or its salt with a physiologically acceptable cation according to claim 1, intended to receive pharmaceutical agent that reduces the effects caused by heavy metals.

10. The compound or its salt with a physiologically acceptable cation according to claim 1, intended to receive pharmaceutical agent for NMR diagnosis and/or diagnostic radiology.

11. Method of strengthening the image of the patient in NMR tomography, wherein the patient is administered an effective amount of an agent according to item 8.

12. The complex, including calcium and [[(4R)-4-[bis[(carboxy-.Kappa)methyl]amino-..N]-6,9-bis[carboxy-.Kappa)methyl]-1-[(4,4-diphenylacetyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-fashiondesign-11-sludge acid..N6,..N9,-Kappa]-1-oxalato(6-)]-,6N (MS-325), or its salt with a physiologically acceptable cation, in each case, almost not containing chelates of metals used for visualization, and MS-325.



 

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