Performancecriteria connection, the retrieval method (variants) and a pharmaceutical preparation containing these compounds

 

Describes performancecriteria metal complexes of the General formula I

RF-L-A

where RFis a perfluorinated, straight or branched carbon chain-CnF2nX, where x is the terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, and n denotes a number from 4 to 30,

L is a direct bond, methylene group, a group-NHCO group

,

while p denotes a number from 0 to 10, q and u, independently of one another denote 0 or 1, R1is a hydrogen atom, a methyl group, a group-CH2HE-, -CH2-CO2H - or circuit C2-C15which is optionally interrupted by 1 to 3 oxygen atoms, 1-2>CO-group or a phenyl group optionally substituted by 1 to 2 carboxyl groups and/or substituted 1-4-hydroxy groups, 1-2 s1-4alkoxygroup, 1-2-carboxyl groups, group-SO3H or is a straight, branched, saturated or unsaturated With2-30the carbon chain may contain 1-10 oxygen atoms, 1-3-NR’-groups, 1-2 sulfur atom, piperazine, -CONR’-group, -NR'r CO-group, a group of SO2the group-NR'r CO2, 1-2-CO-group, a group-CO-N-T-N(R’)-SOgroups, and/or possibly substituted 1-3-OR’groups, 1-2 exography, 1-2-NH-COR’groups, 1-2-CONHR’groups, 1-2-(CH2)p-CO2H-groups, 1-2 groups -(CH2)p-(O)q-CH2CH2-RFwhere R1, RFand p and q have the above values and T denotes the chain With2-C10which is optionally interrupted by 1-2 oxygen atoms, or 1-2-NHCO-group, And represents a variety of metal complexes or salts of organic and/or inorganic bases or amino acids, or amides of amino acids, processes for their preparation and a pharmaceutical agent containing, as contrast agents in vivo nuclear spynomore (MPT), preferably as an agent for blood depots and as infografica. 5 ad and 5 C.p. f-crystals, 5 tab., 6 silt.

The invention relates to the objects of the invention characterized in the claims, i.e., to the new Monomeric, performancemanagement, paramagnetic metal complexes and salts, complexes, pharmaceutical remedies containing these metal complexes, methods for their preparation and their use as contrast agents in1H-NMR diagnostics and spectroscopy, x-ray diagnostician is today widely used method of medical diagnosis, used to create images in vivo, using which it is possible to obtain an image of the blood vessels and tissues of the body (including malignancies), measuring the magnetic properties of the protons in the body fluids. For this purpose, for example, a contrast agent, which due to the effect of certain of the NMR parameters of the protons of the body (for example, the relaxation time T1and T2) enhance the contrast in the resulting image, or make these images readable. Primarily used complexes of paramagnetic ions, such as, for example, containing gadolinium complexes (e.g., Magnevist, Magnevist), due to the effect of paramagnetic ions, aimed at reducing the relaxation time. The criterion of reducing the relaxation time is relaxation, which is indicated in mm-1·s-1.

Paramagnetic ions, such as Gd3+, Mn2+, Cr3+, Fe3+and Cu2+cannot be used in a free form in the form of solutions, because they are highly toxic. In order to make them suitable for use in vivo, they usually are converted into complexes that was first described in European application EP 0071564 A1 (complexoriginally salt complex Gd-DTPA is known under the name Magnevist and is used along with other drugs for the diagnosis of malignant tumors of the human brain and kidneys.

Described in the French patent 2539996 Leguminosae Sol Gd-DOTA (gadolinium-III-complex of 1,4,7,10-tetracarboxylic-1,4,7,10-tetraazacyclododecane) is another contrast agent, which is very well proved in nuclear spectrometry and registered under the name of dotarem.

However, these contrast agents cannot be applied in all cases. So, currently used in the clinical setting of contrast to modern methods of obtaining images by nuclear spynomore (ASG) and computed tomography (CT), such as Magnevist® Pro Hance® , Ultravist® and Omniscan® , are distributed throughout the extracellular space of the body (in the intravascular space into the interstitial space).

In particular, for the image of the blood vessels, it is desirable to have a contrast agent, which upon introduction into the intravascular space exclusively it would be distributed, its thus marking (so-called. agent blood depot).

Attempts were made to solve these problems through the use of complexing agents that are associated with macro - or biomolecule. Still it was not enough successfully.

For example, the number of paramagnetic centers in set>p>If increasing the number of metal ions due to repeated introduction of integrated units in the macromolecular biomolecule, it is associated with an unacceptable deterioration of the affinity and/or specificity of this biomolecules [J. Nucl. Med. 24, 1158 (1983)].

Macromolecular contrast agents for angiography, such as albumin-Gd-DTPA, are described in the Radiology 1987; 162:205. However, the albumin-Gd-DTPA helps in rats 24 hours after intravenous injection enrichment in liver tissue, accounting for almost 30% of the dose. In addition, after 24 hours is displayed only 20% of the dose.

Macromolecule polylysine-Gd-DTPA (EP 0233619 A1) can also be used as an agent for blood depot. However, this connection is that due to the process of obtaining, from a mixture of molecules of various sizes. Attempts of their allocation in rats showed that this macromolecule is excreted by glomerular filtration through the kidneys unchanged. Thanks to the conditions of synthesis polylysine-Gd-DTPA has, however, also macromolecules, which have such a size that they are in the process of glomerular filtration cannot pass through the capillary vessels of the kidney and remain, therefore, in the body.

Described were also macromolecular contrast agent UFO contain only 5% of the signal amplifying paramagnetic cation.

The objective of the invention is to obtain new1H-NMR contrast agents, which do not have the mentioned disadvantages and, in particular, have a high rate of relaxation of protons and allow, therefore, with increasing intensity of the signal to reduce the dose. Further, the contrast agent must be stable, well-tolerated and, above all, to have organ-specific properties, and, on the one hand, their retention in the studied organs should be sufficient to at a lower dosage to maintain the number of images required for staging does not cause doubt of the diagnosis, but on the other hand, should ensure the possibility of rapid and complete elimination of metals from the body.

The problem is solved using Monomeric performanceeasy compounds of General formula I according to paragraph 1 of the claims, which are characterized by unexpectedly high rate of relaxation of protons equal to 20-50 [mm-1·s-1, 39°C, 0,47 T]. For comparison it is possible to bring the rate of relaxation of the protons for commercially available contrast agents1H-NMR, such as Medenine according to the invention is suitable for detection and localization of vascular diseases, as they have in the introduction in the intravascular space is distributed exclusively in it. Compounds according to the invention allow using nuclear spynomore to distinguish good Sabaudia blood tissue from the tissue, poorly Sabaudia blood, and thus to diagnose ischemia. Also infacirovania fabric because of its anemia can be separated from the surrounding healthy or ischemic tissue by the use of contrast agents according to the invention. This fact is of particular importance if we are talking about, for example, to distinguish a heart attack from ischemia.

In contrast, used as a blood agent depot macromolecular compounds, such as Gd-DTPA, polylysin, the compounds according to the invention are also characterized by higher relaxation T1(see table 3) and are, thus, a large increase in signal intensity in NMR imaging. Since they at the same time, have extended retention in the blood space, they can be administered in relatively small doses (for example,50 mmol Gd/kg body weight). But first of all connections according to izaberete is that the compounds of the present invention is suitable not only as an agent for blood depot, but also can be used as lifespecifically MRI contrast agents (infografica).

The image of the lymph nodes is important for the early detection of lesions metastases in patients with cancer. Contrast media according to the invention allow to distinguish small metastases in the unaugmented lymph nodes (<2 cm) hyperplasia of lymph nodes without malignant lesions.

This contrast agent can enter intravasal or interstitielle/intradermal. Introduction interstitielle/intradermal has the advantage, because the substance is transported directly from the source distribution (for example, from the primary tumor) through the appropriate Limpopo in potentially affected, the regional position of the lymph nodes. At the same time with the help of small doses it is possible to achieve a high concentration of contrast agent in the lymph nodes.

Compounds according to the invention satisfy all the conditions that apply to contrast agents in indirect Mr-limfografii: good local tolerability, rapid excretion from the site of injection, rapid and complete excretion from the body. Further, they are highly enriched place raspolagali Guinea pigs to demonstrate a high concentration in many locations of the lymph nodes (popliteal artery, groin, in Ilium) after injection subcutaneously (2.5 to 10 µmol/kg body weight, injection between the toes of the rear foot). In a particularly suitable cases were thus detected in the second (groin) and third (iliac) region and even the concentration of gadolinium, respectively200 or300 mmol/L. Usually using the compounds according to the invention can be detected concentration of lymph nodes ranging from 100 to 1000 mmol/L.

In the Mr images in Guinea pigs, it was possible to confirm the special suitability of the compounds according to the invention. After 120 min after subcutaneous administration of 10 mmol/kg body weight performancebased complex of gadolinium (Guinea pig, hind paw, the space between the fingers), T1-spin-echo images (TR 400 MS, TE 15 MS) showed a clear increase in the lymph nodes popliteal artery (270%), and lymph nodes in the groin (104%) (compare Fig. 1).

Compounds according to the invention can be injected to a person locally (either subcutaneously or directly in percutaneous tissue). There are many possible injection (with the appropriate injection volume of 0.2 to 1 ml, grouped around the region of interest (for example, appoints, that the medicinal product must be the concentration of the metal equal to 75 to 100 mmol/l, in order to use this amount, you can enter a potential clinical dose of 5-10 mmol/kg of the injection depends on whether specifically tinting specific area of the outflow of lymph from the tissues (for example, in the case of gynecological tumors or tumors of the rectum) or must be received unknown region of the outflow of a certain area of the lesion (arguablly possible therapeutic intervention, for example, in the case of melanoma or breast cancer).

For playing Mr images in normal tissue of the lymph nodes, where there is an increase in the concentration of compounds required concentration of gadolinium equal to at least 50 mmol/l and a maximum of 2500 mmol/L. Playback image may occur (depending on the site of injection and tissue) after 30 minutes or after 4-6 hours after injection of the compounds according to the invention. Because compounds of gadolinium complexes according to the invention is influenced primarily by relaxation times T1protons of water tissue lymph nodes defined as T1sequence meskie sites very often woven into adipose tissue, and it has a very high signal intensity with respect to such sequences, the available measurement methods that suppress adipose tissue. Paramagnetic gadolinium complexes in combination with suppressing adipose tissue, defined as T1measurement sequences are in contrast to ready-made forms super-paramagnetic particles of iron oxide one big advantage consisting in the fact that they allow you to get a MRI image with a high spatial resolution with minimal distortion artifacts (artifacts sensitivity) and short shooting time.

Since is positive labeling of lymph nodes (i.e., the rise of a signal), then the comparison is no more need for MRI-shootings in the absence of contrast agents, and the examination time per patient can be reduced.

New performancecriteria compounds of General formula I according to paragraph 1 of the claims include both complexing agents, and metal complexes. Compounds of General formula I with Z1as the hydrogen atom is known as the complexing agents, and compounds with at least one of the possible substituents Z1in the invention contain as the preferred residues L the following:

-CH2-

-CH2CH2-

-(CH2)s- S=3-15

-CH2-O-CH2CH2-

-CH2-(O-CH2-CH2-)tt=2-6

-CH2-NH-CO-

-CH2-NH-CO-CH2-N(CH2COOH)-SO2-

-CH2-NH-CO-CH2-N(C2H5)-SO2-

-CH2-NH-CO-CH2-N(C10H21)-SO2-

-CH2-NH-CO-CH2-N(C6H13)-SO2-

-CH2-NH-CO-(CH2)10-N(C2H5)-SO2-

-CH2-NH-CO-CH2-N(-CH2-C6H5)-SO2-

-CH2-NH-CO-CH2-N(-CH2-CH2-OH)SO2-

-CH2-NHCO-(CH2)10-S-CH2CH2-

-CH2NHCOCH2-O-CH2CH2-

-CH2NHCO(CH2)10-O-CH2CH2-

-CH2-C6H4-O-CH2CH2-

-CH2-O-CH2- (CH2-Och2CH2-C6F13)2-CH2-Och2-CH2-

-CH2-O-CH2-CH(OC10H21)-CH2-O-CH2CH2-

-(CH2NHCO)4-CH2O-CH2CH2-

-(CH2NHCO)3-CH2O-CH2CH2-

-CH2-Och2C(CH2OH)2-CHsub>)-SO2-

-NHCO-CH2-CH2-

-NHCO-CH2-O-CH2CH2-

-NH-CO-

-NH-CO-CH2-N(CH2COOH)-SO2-

-NH-CO-CH2-N(C2H5)-SO2-

-NH-CO-CH2-N(C10H21)-SO2-

-NH-CO-CH2-N(C6H13)-SO2-

-NH-CO-(CH2)10-N(C2H5)-SO2-

-NH-CO-CH2-N(-CH2-C6H5)-SO2-

-NH-CO-CH2-N(-CH2-CH2-OH)SO2-

-NH-CO-CH2-

-CH2-O-C6H4-O-CH2-CH2-

-CH2-C6H4-O-CH2-CH2-

-N(C2H5)-SO2-

-N(C6H5)-SO2-

-N(C10H21)-SO2-

-N(C6H13)-SO2-

-N(C2H4OH)-SO2-

-N(CH2COOH)-SO2-

-N(CH2With6H5)-SO2-

-N[CH(CH2OH)2]-SO2-

-N[CH(CH2OH)CH(CH2OH)]-SO2-

B according to the invention, very particular preference are the remains of L compounds named in the examples of the present description of the invention.

Other preferred compounds are those in which X in the formula-cn-F2nX represents fluorine, and n represents the number 4-15.

Connection obeys compounds of General formula 14

in which R3has the value of the Z1that is equivalent to the metal ion ordinal numbers 21-19, 39, 42, 44 or 57-83,

M1has a value of L

by reacting with compounds of General formula 15

in which RFhas the above value,

M2is the value of L, and

Nu is nucleofuge.

As nucleofuge are preferably remains

Cl, F, -OTs, -OMs,

The interaction is carried out in a mixture of water and organic solvents, such as isopropanol, ethanol, methanol, butanol, dioxane, tetrahydrofuran, dimethylformamide, dimethylacetamide, formamide or dichloromethane. Preferred ternary mixture of water, isopropanol and dichloromethane.

The interaction is carried out in the temperature range from -10°C to 100°C, preferably in the range from 0°C to 30°C.

As the catcher of the acid are inorganic and organic bases, such as triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, dimethylaminopyridine, hydroxide of alkali and alkaline earth metals, carbonates or bicarbonates, such as, naprimer of potassium hydroxide.

Compounds of General formula 15 are obtained from compounds of General formula 16

in which

RFM2has the above mentioned meaning according to the methods of activation acids, which are known to the specialist, as, for example, by reacting the acid with dicyclohexylcarbodiimide, N-hydroxysuccinimide/dicyclohexylcarbodiimide, carbonyl diimidazol, 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline, oxalic acid dichloride or isobutyl ether Harborview acid with the use described in the literature methods:

Activation of carboxylic acids. Overview in Houben-Weyl, Methods der Organischen Chemie, Band XV/2, Georg Thieme Verlag Stuttgart, 1-9.

Activating using carbodiimides. R. Schwyzer and H. Kappeler, Helv. 46: 1550 (1963).

E. Wunsch et al., B. 100: 173 (1967).

Activating using carbodiimide/hydroxysuccinimide: J. Am. Chem. Soc. 86: 1839 (1964) and J. Org. Chem. 53:3583 (1988). Synthesis 453 (1972).

Anhydrite way 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline: Century Belleau et al., J. Am. Chem. Soc., 90: 1651 (1986), H. Kunz et al., Int. J. Pept. Prot. Res., 26: 493 (1985) and J. R. Voughn, Am. Soc. 73: 3547 (1951).

Methods of acid chloride, thionyl chloride: Helv., 42: 1653 (1959).

Chloride of oxalyl: J. Org. Chem., 29: 843 (1964).

Compounds of General formula 16 are commercially available (Fluorochem, ABCR) or obtained from compounds of General formula 17

where M3is set to L, and

Q has the meaning of oxygen, sulfur, group, >CO, >N-R3,with the nitrogen atom to the hydrogen atom, by reacting with compounds of General formula 18

in which Hal denotes CL, Br, I, and

R4denotes H, methyl, ethyl, tert-butyl, benzyl, isopropyl, for example, according to C. F. Ward, Soc. 121 1161 (1922), according to well-known specialist methods, such as alkylation of alcohols with alkylhalogenide [Houben-Weyl Methods der Organischen Chemie (Methods of organic chemistry), Sauerstoffverbindungen I (oxygen compounds (I), Teil 3, Methods zur Herstellung und Umwandlung von Ethern (getter and conversion of ester), Georg Thieme Verlag, Stuttgart 1965, Alkylierung von Alkoholen mit Alkyl-halogeniden (Alkylation of alcohols with alkylhalogenide) S. 24, Alkylierung von Alkoholen mit Alkylsulfaten (Alkylation of alcohols with alkyl sulphates) S. 33] or N-alkylation sulfonamida using alkylsulfonate the S. 680; J. E. Rickman and T. Atkins, Am. Chem. Soc., 96: 2268, 1974, 96: 2268; F. Chavez and A. D. Sherry, J. Org. Chem. 1989, 54: 2990].

For the case where Q stands for a group >, the interaction is carried out with a Wittig reagent having the structure

r means the number of 0-16.

The resultant double bond-CH=CH - may be retained as an integral part of the structure or by catalytic hydrogenation (Pd 5%/C) can be translated into the grouping-CH2-CH2.

Compounds of General formula 18 are commercially available (Fluorochem, ABCR).

Alternatively, the compounds of formula I with the value And the General formula IX can be obtained from compounds of General formula 19

in which RF, R3and R4have the abovementioned meaning, and

L’ has a value of L, optionally protected hydroxyl or carboxyl functions, as, if necessary, existing protective group otscheplaut, and the thus obtained complexing agents enter into interaction with metal oxides or metal salts at room temperature or at elevated temperatures using a well-known specialist methods (EP 250358, EP 2 is their reason, amino acids or amides of amino acids.

Compounds of General formula 19 is obtained from compounds of General formula 20 (DO3A or esters)

in which R4has the above value,

by reacting with compounds of General formula 21

in which R3has a value of R1if necessary, in protected form, or -(CH2)m-L’-RF. and m is 0, 1 or 1, a L’ and RFhave the above significance. The interaction is carried out in alcohols, such as methanol, ethanol, isopropanol, butanol, ethers, such as dioxane, tetrahydrofuran, dimethoxyethane, or in water, or in mixtures of water and one of these organic solvents, as well as in acetonitrile, acetone, dimethylformamide, dimethylacetamide or dimethyl sulfoxide, dichloromethane, dichloroethane, chloroform, at temperatures between -10°C and 180°C, preferably at 20°-100°C. Preferably the addition of organic or inorganic bases, such as triethylamine, pyridine, dimethylaminopyridine, N-methylformamide, Diisopropylamine, hydroxide of alkali and alkaline earth metals, or carbon is Oia, potassium carbonate, sodium bicarbonate, potassium bicarbonate. In the case of low-boiling hydroxide exchange reaction is carried out in an autoclave.

Compounds of General formula 21 are commercially available (Fluorochem, ABCR) or obtained from compounds of General formula 22

by epoxidation using well-known specialist techniques, for example by oxidation catalisano a tungstate with H2O2according to the Pauna, cyclization of gelegenheden or by alkaline oxidation of N2O2in the presence of NITRILES.

Particularly suitable for this reaction are 3-chloroperbenzoic acid in dichloromethane at room temperature. Houben-Weyl, Methods der Organischen Chemie (Methods of organic chemistry), Sauerstoffverbindungen I (oxygen Compounds (I), Teil 3, Methods zur Herstellung und Umwandlung dreigliedriger cyclische Ether (1,2-Epoxide) (Methods of receiving and converting a three-membered cyclic ethers (1,2-epoxides)), Georg Thieme Verlag, Stuttgart, 1965; G. B. Payne and P. H. Williams, J. Org. Chem., 159, 24: 54; Y. Ogata and Y. Samaki, Tetrahedron 1964, 20; 2065; K. C. Sharpless et al., Pure Appl. Chem. 55, 589 (1983).

Compounds of General formula 22 receive preferably using the Wittig reaction, or by using the options on Horner, Slosser or Bestman, Houben-Weyl, Methods der Organischen Chemie XII/1 (oniumsalze (phosphonium Salts of) S. 79, Phosphoniumylide (Postnominal) S. 112, Wittig-Reaktion S. 121: A. W. Johnson, Ylides and Imines of Phosphorus, John Wiley & Sons, Inc., New York, Chichester, Brisbane, Toronto, Singapore, 1993, Wittig-Reaktion 221 S.; Schlosser-Modifikation der Wittig-Reaktion (Modification of slosser Wittig reaction) S. 240; Wadsworth-Emnions-Reaktion S. 313; Horner Reaktion S. 362, interaction ilide triarylphosphine

in which L’ and RF’ have the abovementioned meaning, and AG - is aryl, in particular phenyl, using known techniques (Merck Fluka) or in accordance with well-known specialist methods, for example by oxidation of primary alcohols with chromium trioxide/pyridine, Houben-Weyl, Methods der Organischen Chemie (Methods of organic chemistry), Sauerstoffverbindungen II (Oxygen compound (II), Teil 1, Aldehyde, Georg Thieme Verlag, Stuttgart, 1954, receive presents General formula 20 aldehydes

in which R3can also be oxygen.

The ylides triarylphosphine 23 is obtained from the corresponding halides of General formula 25

in which Hal, L’ and RFhave the above meaning, well-known specialist methods, for example by heating triarylphosphine with alkylhalogenide, Houben-Weyl, Methods der Organischen Chemie XII/1 (Methods of organic chemistry XII/1), Organische Phosphorv, ew York, Chichester, Brisbane, Toronto, Singapore, 1993. Compounds of General formula 25 are commercial products (Fluorochem, ABCR, 3M).

Compounds of General formula 21 in which R3=N, preferably derived from compounds of General formula 17

in which Q’ is Q, but may not mean the group >,

M3has a value of L with the exception of direct communications, and

RFhas the above value,

through the interaction of a well-known specialist method of synthesis of simple ether or by sulfonamidnuyu alkylation with epichlorhydrine (Houben-Weyl, Methods der Organischen Chemie (Methods of organic chemistry), Sauerstoffverbindungen I (oxygen Compounds (I), Teil 3, Methods zur Herstellung und Umwandlung von Ether (getter and conversion of ester), Georg hiem Verlag, Stuttgart, 1965, Alkylierung von Alkoholen (Alkylation of alcohols), S. 24, 33; Houben-Weyl, Methods der Organischen Chemie (Methods of organic chemistry), XI/2, Stickstoffverbindungen (Nitrogen compounds), Georg Thieme Verlag, Stuttgart, 1957, p. 680; J. E. Rickman and T. J. J. Atkins, Am. Chem. Soc. 1974, 96: 2268; F. Chave and A. D. Sherry, 1989, 54: 2990) get the connection of General formula 26

with l’ is Hal, F, -OTs, OMs.

In the case of low-boiling epoxides interaction is carried out in an autoclave.

Compounds of General formula

R2, R3, R4, L’ and RFhave the abovementioned meaning, by removal, if necessary, from each other protective groups and kompleksoobrazovanija well-known specialist way.

Compounds of General formula 27 are obtained by alkylation of compounds of General formula 20 with compounds of General formula 28

in which Hal, R2, R3, R4, L’ and RFhave the abovementioned meaning,

in a known manner, for example as described in patent EP 0232751 B1.

Compounds of General formula 28 are obtained from compounds of General formula 29

where L’, R3and RFhave the abovementioned meaning, and activated halogencarbonic acid of General formula 30

Nu, R2and Hal in the above value by the well-known specialist methods amidopolyamine through the activated carboxylic acid (cf. source of info.11).

Compounds of General formula 30 can be obtained from the acids in accordance with With. Hell, Century 14: 891 (1881); J. Volhard, A 242, 141 (1887); N. Zelinsky, Century 20: 2026, (1887) or halogenated acids in accordance with the methods of activation, as they are described General formula 15.

is ESA [Houben-Weyl, Methods der Organischen Chemie (Methods of organic chemistry), Stickstoffverbindungen II (Nitrogen compounds), Amino, 1. Herstellung, Georg Thieme Verlag, Stuttgart, 1957] easily from commercially available compounds (Fluorochem, ABCR) of General formula 31

or 32

for example, by alkylation of compound 31 with amine PhCH2Other3and subsequent removal of the protection of the amino group using catalytic hydrogenation or by reaction Mitsunobu [N. Ibner and E. Zbiral, Helv. 59 2100 (1976), A. K. Bose and C. Lal, Tetrahedron Lett. 3973 (1973)] connection 32 with phthalimide potassium and unprotect using hydrazine hydrate is added.

Compounds of General formula I with the value And the General formula VII are obtained from compounds of General formula 33

with L’, RFand R4in the above meaning and Y’ in Y, if necessary, the protective groups by removal of optionally available protection groups and by complex formation by the well-known specialist methods (Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, Inc., New York, 1991; EP 0130934, EP 0250358).

Compounds of General formula 33 are obtained from compounds of General formula 20 and compounds of General formula 34

known in itself, for example as described in EP 0232751 B1, EP 0292689 A2 or EP 0255471 A1.

Obtaining compounds of General formula 34 takes place by known methods, for example by hell-Volhard-Zelinska from commercial precursors (ABCR).

Compounds of General formula I with the value And the General formula VI are obtained from compounds of General formula 35

in which L’, R4and RFhave the above mentioned meaning, by, if necessary, removal of protective groups and complexing in a known manner [Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, Inc., New York, 1991 (EP 0130934, EP 0250358)].

Compounds of General formula 35 is produced by the interaction of esters-halogencarbonic acid or acids of General formula 18 with compounds of General formula 36

in which L’ and RFare above the value on the well-known specialist techniques as, for example, described in EP 0255471 or US 4885363.

Compounds of General formula 36 can be obtained by removal of optionally available protection groups and by subsequent recovery using DIBORANE according the th L’, RFOh, q have the above significance, and

It denotes a protective group.

Compounds of General formula 37 are available through the condensation reaction of an activated, N-protected iminodiacetic acid 38 and amine 39:

in which L’, RF, o, q, Nu and K have the abovementioned meaning. As nucleofuge suitable preferably N-hydroxysuccinimide, as a protective group benzyloxycarbonyl, trifluoracetyl or tert-butyloxycarbonyl group.

Compounds of General formula 38 can be obtained by known specialist ways of protecting the amino group and the activated carboxylic acid [Protective Groups Aktivierung von Carboxylgruppen, S. 11] via a secure iminodiethanol acid 40.

in which K stands For a protective group from iminodiacetic acid 41

An alternative can be obtained from compounds of General formula 36 by, if necessary, removal of protective groups and recovery using DIBORANE according to the method described for formula 37, from compounds of General formula 42

mg_data/86/867553.gif" border="0">

in which L’ and RFhave the abovementioned meaning, can be obtained in a standard way, for example by reacting with a reagent Mukaiyama tosylate 2-fluoro-1-methylpyridine

[J. Org. Chem. 1994, 59, 415; Synthetic Commununications 1995, 25, 1401], or with azide complex of diphenyl ether phosphoric acid

[J. Am. Chem. Soc. 1993, 115, 3420; WO 94/15925].

Compounds of General formula 43 are available by condensation of the activated acid 44

Nu and To the aforementioned value, with the compound of General formula 45

in which L’, R4and RFhave the above significance, according to the described method.

Compounds of General formula 44 is obtained from commercially available triglycine (Bachem, Fluka) 46

by protecting the amino group with subsequent activation of the acid function by the well-known specialist methods to protect the amine and to activate the carboxylic acid (East. INF.12).

Compounds of General formula 45 can be easily obtained from compounds of formula 62 by introducing a protective group, R4according to the famous Spa with the value And the General formula II are obtained from compounds of General formula 47

with L’, R3, R4, RFand Y’ with the above value, if necessary, by removal of protective groups and complexing well-known specialist way (Protective Groups, EP 0250358, EP 0130934).

If Y’ in the General formula 47 means HE, the connection is produced by the interaction of compounds 48

with R4with the above value obtained in accordance with DE 3633243, with an amine of General formula 29 already described conditions and subsequent removal of the protective groups.

If Y’ in the formula 47 is a group

the interaction with bisengimana DTPA (commercial product of Merck) 49

carried out in similar conditions.

Compounds of General formula I with the value And the General formula III are obtained from compounds of General formula 50

in which L’, R2, R3, R4and RFwith the above value, if necessary, by removal of protective groups and complexing well-known specialist way [Protective Groups, EP 0071564, EP 0130934, DE-OS 3401052].

Compounds of General "https://img.russianpatents.com/img_data/86/867563.gif" border="0">

and derivatives halogencarbonic acid of formula 52

in which R4and Hal have the above-described value. Compounds of General formula 51 obtained by atsilirovaniya amine of General formula 29 with activated N-protected amino acid of General formula 53

in which Nu has the abovementioned meaning, and denotes a protective group, such as Z-BOC, FMOC, -F3and by subsequent removal of the protective group.

Compounds of General formula I with the value And the General formula IV are obtained from compounds of General formula 54

in which L’, RFand R4have the above mentioned meaning, by, if necessary, removal of protective groups and complexing in well-known specialist method, as it was already described [Protective Groups, EP 0071564, EP 0130934, DE-OS 3401052].

Compounds of General formula 54 can be obtained in a known manner from halogenated compounds of General formula 55

which can be obtained as commercial products (Fluorochem, ABCR) by reacting with hydroxy acids 56

c R4with the above value, and esters halogencarbonic acid 58

Compounds of General formula I with the value And the General formula V are obtained from compounds of General formula 59

in which L’, o, q, R4and RFhave the abovementioned meaning, if necessary, by removal of protective groups and by complex formation by the well-known specialist technique [Protective Groups, EP 0071564, EP 0130934, DE-OS 3401052].

Compounds of General formula 59 can be obtained in a known manner, for example, in accordance with J. Org. Chem. 58, 1151 (1993) by the interaction of esters halogencarbonic acid 18

with Hal and R4with the above value and compounds of General formula 39

in which L’, o, q, and RFhave the above significance. Compounds of General formula 39 can be obtained for the case q=0 of the compounds of General formula 60

with L’, RFand To the above value, a famous General formula 60 produced by aminolysis activated compounds of General formula 61

in which L’, Nu, RFand To have the above significance, with Ethylenediamine.

Compounds of General formula 61 receive by known methods protective groups of the unprotected acid of General formula 62

namely, the first stage is protected amino group, followed in the second stage by activating the acid group.

Compounds of General formula 62 receive according to the methods of amino acid synthesis [Houben-Weyl, Methods der organischen Chemie (Methods of organic chemistry), XI/2 Stickstoffverbindungen (Nitrogen compounds) II und III, II(Amino acids); Georg Thieme Verlag Stuttgart, 1958, Strecker-Reaktion, S. 305; Erlenmeyer-Reaktion, S. 306; Aminolyse von-Halogencarbonsauren (Aminals and-halogencarbonic acids), S. 309] from commercially available aldehydes of General formula

for example, Striker through aslacton or through cyanhydrin.

Compounds of General formula 39 receive for the case of=0 of the compounds of General formula 64

with RF, L’ and the aforementioned values, in a known manner by removal of protective groups and recovery using DIBORANE.

in which RFand L’ have the above values.

Compounds of General formula 65 receive a simple way of compounds of General formula 61 by amidopolyamine using ammonia and by subsequent removal of the protective group.

Compounds of General formula XIII can be obtained analogously to the compounds of General formula III by reacting derivatives halogencarbonic acid of General formula 52 with a compound of General formula 66

in which RF, L’ and R2have the above values.

Compounds of General formula 66 is produced by the interaction of the compounds of General formula 67

activated, N-protected amino acid of General formula 53 by analogy with the interaction of the amine 29 connection 53.

Compounds of General formula 67 can be obtained by reacting piperazine-free or, if necessary, partial protected, with fluorides or chlorides performancelevel acid (Sulfonamidnuyu the formation of amine and sulfofluoride described in DOS 2118190, DOS 2153270).

Compounds of General formula XI with a value of q equal to 0 or 1, get similarly soy

in which RF, L’, R2and Hal have the abovementioned meanings, or with compounds of General formula 68A

in which RF, L’, R2, p and Hal have the above values.

Compounds of General formula 68 can be obtained from compounds of General formula 30 and piperazine derivatives of General formula 67 in a known manner.

Compounds of General formula 68A can be obtained from compounds of General formula 67 by amide bonding with the compounds of General formula b

Compounds of General formula XII receive similarly, compounds of General formula II, for example, by reacting compounds of formula 49 with piperazine derivatives of General formula 67.

Compounds of General formula I with the value And the General formula X are obtained from compounds of General formula 69

in which L’, R3, R4and RFhave the above value, a Sg denotes a protective group by, if necessary, removal of protective groups and complexing in a known manner [Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, Inc., New York, 1991 (EP 0130934, EP 0250358)].

Connect is about acid or acids of General formula 18 with compounds of General formula 70

with L’, RF, R3and Sg have the above mentioned values are in accordance with well-known specialist methods, such as described in EP 0255471 or US 4885363.

Compounds of General formula 70 can be obtained by removal of optionally available protection groups and by subsequent recovery using DIBORANE in accordance with known methods from compounds of General formula 71

in which L’, RF, R3and Sg have the above-mentioned value.

Compounds of General formula 71 obtained by the condensation reaction of an activated derivative iminodiacetic acid of General formula 72 and Diethylenetriamine formula 73

in which L’, RF, R3, Sg and Nu have the above-mentioned value.

As nucleofuge is preferably N-hydroxysuccinimide.

Compounds of General formula 72 obtained from compounds of General formula 74

in which L’, RFand Sg have the abovementioned meaning, by activating carboxylic acids as described above.

Compounds of General formula 74 receive the General formula 18 with compounds of General formula 75

in which L’, RF, R3and Sg have the abovementioned meaning,

moreover, if necessary, existing ester group Malaysia.

Compounds of General formula 75 obtained from compounds of General formula 76

in which L’, RF, R3, Sg, and To have the above-mentioned value,

by removal of the protective group in accordance with known methods.

Compounds of General formula 76 is obtained from compounds of General formula 77

in which L’, RF, R3and To have the above-mentioned value,

by introducing a protective group Sg-known specialist way.

Compounds of General formula 77 is obtained from compounds of General formula 78

in which L’, RFand To have the above-mentioned value,

in accordance with well-known specialist methods (uben-Weyl, Methods der Organischen Chemie (Methods of organic chemistry), XII 2A, Metallorganische Acidic, Georg Thieme Verlag Stuttgart, 1973, s.285 ff, Umsetzung magnesiumorganischer Acidic mit Aldehyden (Interaction magnetogenesis compounds with aldehydes); s. 809 ff, Umsetzung von zinkorganischen Acidic mit Aldehyden (Interaction encourgaing sedicesima connection) Georg Thieme Verlag Stuttgart, 1970; S. 175 ff, Umsetzung lithiumorganischer Acidic mit Aldehiden (Interaction of organolithium compounds with aldehydes) by interacting with ORGANOMETALLIC compounds, which can be obtained from compounds of General formula 79

in which Hal and R3have the above meaning, such as compounds of magnesium, lithium or zinc.

Compounds of General formula 79 are commercial products (ABCR, Fluka).

Compounds of General formula 78 obtained from compounds of General formula 80

in which L’, RFand To have the above-mentioned value,

by restoring hydride diisobutylaluminum (Tett. Lett., 1962, 619; Tett. Lett., 1969, 1779; Sythesis, 1975, 617).

Compounds of General formula 80 obtained from compounds of General formula 45

in which L’ and RFhave specified above is known to the specialist way by introducing a protective group K.

Neutralization, if possible, remaining free carboxyl groups is carried out with the help of inorganic bases (for example, hydroxides, carbonates or bicarbonates, for example sodium, potassium, lithium, magnesium or calcium and/or organic, glucamine, N-methyl - and N,N-dimethylglycine, and also amino acids, such as lysine, angina and ornithine or of amides of originally neutral or acidic amino acid.

To obtain a neutral complex compounds can be added, for example, to the acid complex salts in aqueous solution or suspension sufficient basis to reach the neutral point. The resulting solution may then be one stripped off in vacuum to dryness. Often the advantage is that the obtained neutral salt by adding solvents, miscible with water, such as lower alcohols (methanol, ethanol, isopropanol and others), lower ketones (acetone and others), simple polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane and others), precipitated and get so easily allocated and well cleaned crystals. Especially preferred was adding the desired base during the complexation reaction mixture and as a consequence saving a single process step.

The subject invention are further pharmaceutical agents that contain at least one physiologically acceptable compound of General formula I, optionally with conventional galenovye add the integrated connection according to the invention, if necessary, with additives conventional galenic additives, suspended or dissolved in aqueous medium and then the suspension or solution optionally sterilized. Suitable additives are, for example, physiologically acceptable buffers (such as, for example, tromethamine), additives, complexing agents or weak complexes (such as, for example, diethylenetriaminepentaacetic acid or complexes of Sa related to the metal complexes according to the invention), or, if necessary, electrolytes, such as sodium chloride, or, if necessary, antioxidants, such as ascorbic acid.

If for enteral or parenteral administration, or for other purposes desired suspension or solution means according to the invention in water or physiological salt solution, then they are mixed with one or more traditional galenovye auxiliary substances [for example, methylcellulose, lactose, mannitol] and/or detergents [for example, lecithins, Tween® , Myrj® ], and/or aromatic substance (substances) for the correction of taste [for example, essential oils].

In principle it is also possible to obtain pharmaceutical without allocation of complexes. In each case must be one from uncomplexed toxic metal ions.

This can be, for example, is provided with color indicators, such as xrenovy orange, through the control titration during the retrieval process. The invention relates also to a method for production of complex compounds and their salts. For security you can remove the selected set.

The pharmaceutical agents according to the invention preferably contain 0.1 µmol - 1 Mol/l of the complex and injected, typically in amounts of 0.0001-5 mmol/kg They are intended for enteral and parenteral administration. Complex compounds according to the invention are applied:

1) for NMR diagnostics in the form of their complexes with the ions of elements with atomic numbers 21-29, 39, 42, 44 and 57-83;

2) for radiodiagnostics and radiotherapy in the form of their complexes with the radioisotopes of elements with atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70, 75 77.

The means according to the invention meet the diverse requirements of suitability as contrast media for nuclear spynomore. So, they are preferably suitable for improving the sharpness of the obtained image obtained by nuclear spynomore, after oral or parenteral administration by increasing intensively small number of foreign particles, and good tolerability, which is necessary to maintain the noninvasive nature of the research.

Good solubility and low osmolarity means according to the invention allows to obtain a highly concentrated solutions in order to keep the volume load of the circulation in the required boundaries and to compensate for the dilution due to body fluids. Further, the means according to the invention have not only a high stability in vitro, but also remarkably high stability in vivo, so that the release or exchange of ions, which are themselves poisonous associated in the complex during the time when the new contrast agent will be fully withdrawn, occurs extremely slowly.

In General, the means according to the invention for use as NMR diagnostic dispensed in quantities from 0.0001-5 mmol/kg, the preferred way of 0.005-0.5 mmol/kg, Particularly low doses (below 1 mg/kg body weight) organ-specific NMR-diagnostico used, for example, for the detection of malignant tumors and heart attacks heart.

Further, the complex compounds according to the invention can be used preferably as a reagent sensitivity and as reagents funds due to its favorable radioactive properties and good stability contained in complex compounds. The details of this application and dosage are described, for example, in "Radiotracers for Medical Applications", CRC Press, Boca Raton, Florida.

Connection and means according to the invention can also be used in positron emission tomography, which uses positron-emitting isotopes, such as43Sc,44Sc,52Fe55And68Ga (Heiss, W. D.; Phelps, M. E.; Positron Emission Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York, 1983).

Compounds according to the invention are suitable for the differentiation of malignant and benign tumors in hematoencephalic barrier.

They differ in that fully removed from the body and, thus, are well-tolerated.

Because of the substances according to the invention are concentrated in malignant tumors (there is no diffusion in healthy tissue, but remains high transmission ability of tumor vessels), they can contribute to the radiation therapy of malignant tumors. It differs from the corresponding diagnosis only by the number and type of isotopes. The objective is the destruction of tumor cells due to the energetically enriched shortwave radiation with the minor radius of action is INIA) with ionizing radiation (e.g., x-ray or neutron radiation. Due to this effect significantly increases the local radiation dose on the place where is located the complex of metals (for example, malignant tumors). In order to create the same dose of radiation in malignant tissues, the use of such metal complexes can significantly reduce radiation exposure to healthy tissue and, thereby, to avoid side effects for patients. Conjugates of metal complexes according to the invention therefore also suitable as radiosensitive tool in radiation therapy of malignant tumors (e.g., using Mossbauer effects or therapy associated with the capture of neutrons). Suitable-emitting ions are, for example,46Sc,47Se48Sc,72Ga73Ga and90Y. Corresponding with low half-life time-emitting ions are, for example,211Bi212Bi213Bi and214Bi, preferably212Bi. Suitable ion radiating protons and electrons is158Gd, which can be obtained from the158Gd by capture of neutrons.

If the application is 6, (1968), page 787], the Central ion must be derived from the Mossbauer isotope, such as57Fe or151Unit.

With the introduction of the means according to the invention in vivo can be used together with an appropriate carrier, e.g., serum or physiological saline, and together with another protein, such as serum albumin human. The dosage will depend on the type cellulare violations, used metal ion and method of forming image.

The means according to the invention is usually introduced parenterally, preferably intravenously. They can also be entered, as previously explained, intravasal or interstitielle/interdermal depending on the vessels or tissue of the body should be examined.

The means according to the invention is suitable as contrast agents for x-rays, and it should be particularly emphasized that using these drugs in the process of biochemical and pharmacological research does not appear signs of reactions anafilaktichesky of the type known from iodine-containing contrast agents. Especially valuable they are due to adsorption properties in the areas of higher stress in the tube for digital strcontrolid funds by analogy, for example, with meglumin-diatrizoate in the amount of 0.1-5 mmol/kg, preferably 0.25 to 1 mmol/kg

This way it was possible to synthesize new complexing agents, metal complexes and salts of metal complexes, which open new possibilities in diagnostic and therapeutic medicine.

The following examples explain the invention.

EXAMPLE 1

a) Complex tert-butyl ether N-ethyl-N-(performancelevel)-aminouksusnoy acid

20 g (37,94 mmol) N-atyperatyshem and 15,73 g (113,8 mmol) of potassium carbonate are suspended in 200 ml of acetone and pinned at 60°From 14.80 g (75,87 mmol) of a compound tert-butyl ether bromoxynil acid. Stirred for three hours at 60°C. the salt is Filtered off and the filtrate is evaporated in vacuum. The remainder chromatographic on silica gel (solvent: hexane/dichloromethane/acetone = 10/10/1). After evaporation of the fractions containing the target product, the residue is crystallized from methanol/ethyl acetate.

Output: 21,66 g (89% of theory) of a colorless waxy solid.

Elemental analysis:

Rasch.: With 29,96; N. Of 2.51; F 50,36; N 2,18; S 5,0

found: 29,81; N 2,70; F 50,15; N 2,30; S a 4.83

b) N-ethyl-N-(performancelevel)-aminouksusnoy acid

20 g (31,18 mmol) is connected to the temperature during the night. Evaporation to dryness is carried out in the vacuum. The residue is recrystallized from methanol/ether.

Yield 17,34 g (95% of theory) of colourless crystalline solid.

Elemental analysis:

Rasch.: With 24,63; N 1,38; F 55,19; N 2,39; S 5,48

found: 24,48; H 1,50; F 55,01; N 2,17; S 5,59

C) Gadolinium complex of 10-[2-hydroxy-4-Aza-5-oxo-7-Aza-7-(PerformanceCounter)-nonyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (17,09 mmol) of the compound shown in the title of example 1B), and 1.97 g (18,79 mmol) of N-hydroxysuccinimide dissolved in a mixture of 50 ml of dimethylformamide and 50 ml of chloroform. At 0°C add 3.88 g (18,79 mmol) dicyclohexylcarbodiimide and stirred for 1 hour at 0°C, then 3 hours at room temperature. Cooled again to 0°C and add 5,19 g (51,27 mmol) triethylamine/50 ml 2-propanol. Then add 10,78 g (18,79 mmol) of the gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (WO 95/17451), dissolved in 50 ml of water, and stirred for 3 hours at room temperature. Evaporated to dryness, absorb the residue in a mixture of 200 ml methanol/100 ml of chloroform and filtered from dicyclohexylamine. The filtrate is evaporated to dryness and purified using RP chromatography is th product: 16,37 g (78% of theory.) colorless glassy solid.

Water content: 7,1%

Relaxation T1(L/mmol· sec) at 20 MHz, 37°C:

41 (water)

49 (human plasma)

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 30,58; N 3,18; F 28,31; Gd 13,78; N 7,37; S 2,81

found: 30,40; N 3,29; F 28,14; Gd 13,55; N 7,28; S 2,65

d) 10-[2-hydroxy-4-Aza-5-oxo-7-Aza-7-(PerformanceCounter)-nonyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (8,76 mmol) of the compound shown in the title of example 1B) were dissolved in a mixture of 100 ml water/100 ml ethanol and added 1.73 g (13,71 mmol) of oxalic acid dihydrate. Heated 8 hours to 80°C. is Cooled to 0°C and filtered from the precipitated precipitate of oxalate of gadolinium. The filtrate is evaporated to dryness and the residue is purified on RP-18 (RP-18/Solvent: gradient of a mixture of water/isopropanol/acetonitrile).

Yield: 8,96 g (94% of theory) of a vitreous solid.

Water content: 9,3%

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 35,30; N 3,98; F 32,73; charged 8.52 N; S 3,25;

found: 35,10; N 4,15; F 32,51; N 8,35; S 3,15.

d) Manganese complex of 10-[2-hydroxy-4-Aza-5-oxo-7-Aza-7-(PerformanceCounter)-nonyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (as sodium salt)

5 g (5,07 mmol) of the compound shown in n the and at 80°C. The solution is filtered, and the filtrate was adjusted using 1 N sodium hydroxide to a pH of 7.2, and then dried by freezing.

Yield: by 5.87 g (quantitative) of a colorless amorphous powder.

Water content: 8,4%

Relaxation T1(L/mmol· sec) at 20 MHz, 37°C:

2,7 (water)

4,2 (human plasma)

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 32,81; N 3,42; F 30,42; Mn 5,17; N 7,92; Na 2,17;

S 3,02;

found: 32,62; N 3,57; F 30,21; Mn Is 5.06; N 7,80; Na 2,01;

S 2,90.

(e) ytterbium Complex of 10-[2-hydroxy-4-Aza-5-oxo-7-Aza-7-(PerformanceCounter)-nonyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

To 5 g (5,07 mmole) of the compound shown in the title of example 1 g) in a mixture of 100 ml water/30 ml ethanol add to 1.33 g (2,53 mmol) of ytterbium carbonate and stirred for 3 hours at 80°C. the Solution is filtered, and the filtrate is evaporated to dryness in a vacuum.

Yield: 6,36 g (quantitative) of a glassy solid.

Water content: 7.8 per cent.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 30,11; N 3,14; F 27,92; N 7,27; S 2,77; Yb 14,96;

found: 30,02; N 3,27; F 27,80; N 7,10; S 2,68; Yb 14,75.

g) dysprosium Complex of 10-[2-hydroxy-4-Aza-5-oxo-7-Aza-7-(PerformanceCounter)-nonyl]-1,4,7-Tris(carboxy of 100 ml water/30 ml of ethanol is added 0.95 g (2,53 mmol) of dysprosium oxide and stirred for 3 hours at 80°C. The solution is filtered, and the filtrate is evaporated to dryness in a vacuum.

Yield: 6,35 g (quantitative) of a colorless glassy solid.

Water content: 8.5 per cent.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With a 30.39; N 3,17; F as opposed to 28.18 per; N 7,33; S 2,80; Dy 14,18;

found: 30,17; N 3,25; F 28,03; N 7,21; S 2,65; Dy 14,00.

EXAMPLE 2

a) Complex tert-butyl ether 13,13,13,12,12,11,11, 10,10,9,9,8,8,7,7,6,6-heptadecafluoro-3-oxalidaceae acid

To a mixture of 10 g (21,55 mmol) of 1H,1H,2H,2H-perftoran-1-ol and 0.73 g (2,15 mmol) hydroxysulfate tetrabutylammonium 100 ml of 60% aqueous solution of caustic potassium/50 ml of toluene with vigorous stirring at 0°C is added dropwise 10,51 g (53,9 mmol) tert-butyl ether bromoxynil acid. Stirred for 1 hour at 0°C. Add 200 ml of toluene, the aqueous phase is separated and extracted 2 times - each time with 50 ml of toluene. The combined organic phases are dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic (Solvent: hexane/dichloromethane/acetone=20/10/1) over silica gel.

Yield: 9,72 g (78% of theory) of colorless viscous oil.

Elemental analysis:

Rasch.: With 33,23; N 2,61; F 55,85;

found: 33,09; N 2,78; F 55,71.

b) 13,13,12,12,11,11,10,10,9,9,8,8,7,7,6,6-heptade is in 180 ml triperoxonane acid and stirred at room temperature overnight. Produce evaporation in vacuo to dryness. The residue is recrystallized from a mixture of methanol/simple ether.

Yield: 7,80 g (96% of theory) of colorless solid.

Elemental analysis:

Rasch.: With 27,60; N 1,35; F 61,85;

found: 27,48; N 1,49; F 61,66.

C) Gadolinium complex of 10-[2-hydroxy-4-Aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17,17-heptadecafluoro-heptadecyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

7.0 g (13,41 mmol) of the compound shown in the title of example 2B), and 1.70 g (14,75 mmol) of N-hydroxysuccinimide dissolved in a mixture of 30 ml of dimethylformamide/20 ml of chloroform. At 0°C add 3.04 from g (14,75 mmol) dicyclohexylcarbodiimide and stirred for 1 hour at 0°C, then 3 hours at room temperature. Cooled again to 0°C and add 4,48 g (44,25 mmol) triethylamine/50 ml 2-propanol. Then add 8,46 g (14,75 mmol) of the gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-Tris(carboxymethyl)-1,4,7, 10-tetraazacyclododecane dissolved in 40 ml of water, and stirred for 3 hours at room temperature. Evaporated to dryness, absorb the residue in a mixture of 100 ml of methanol/30 ml of chloroform and filtered from dicyclohexylamine. The filtrate is evaporated to dryness and purified using RP-chromatogr Teoret.) colorless glassy solid.

Water content: 8.2% of

Relaxation T1(L/mmol· sec) at 20 MHz, 37°C:

19 (water)

33 (human plasma)

Elemental analysis:

Rasch.: With 32,32; N 3,27; F 29,96; Gd 14,59; N 6,50;

found: 32,16; N 3,42; F 29,78; Gd 14,39; N 6,40.

EXAMPLE 3

a) 1,2-epoxy-4-oxa-1H,1H,2H,3H,3H,5H,5N,6N,6N-performation

To a mixture of 20 g (43,09 mmole) of 1H,1H,2H,2H-perftoran-1-ol and 0.79 g (2,32 mmole) of tetrabutylammonium hydrosulfate in 200 ml of 60% aqueous solution of caustic potassium/100 ml of toluene with vigorous stirring at 10°C. are added dropwise of 7.97 g (86,18 mmole) of epichlorohydrin, and the temperature of the reaction solution becomes not more than 20°C. Stirred for 2 hours at 15°C and then added dropwise as described above, 3,99 g (43,09 mmole) of epichlorohydrin. After this was stirred at room temperature overnight. Add to 100 ml of methyl tert-butyl ether and the separated aqueous phase. It is extracted 2 times - each time with 50 ml of toluene. The combined organic phases, dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (Solvent: dichloromethane/hexane/acetone=20/10/1).

Yield: 19,05 g (85% of theory.) a colorless oil.

Elemental analysis:

Rasch.: With 30,02; N 1,74; F 62,09;

found: 29,87; N 1,95; F 61,81.

To 12.0 g (34,60 mmole) of 1,4,7-Tris(carboxymethyl)-1,4, 7,10-tetraazacyclododecane in 50 ml of water is added to 8.3 g (207,6 mmole) of sodium hydroxide. Added dropwise a solution of 18.0 g (34,60 mmole) of the compound indicated in the title of example 3A), dissolved in 60 ml of n-butanol/60 ml of 2-propanol and the solution is heated overnight to 70°C. Evaporated in vacuum to dryness, absorb the residue in 300 ml of water and 3 N hydrochloric acid to establish a pH value of 3. Then 2 times extracted with 200 ml of n-butanol. United butanolide phase evaporated in vacuum to dryness, and the residue is purified by RP-chromatography (RP-18/Solvent: gradient of water/n-butanol/acetonitrile).

Yield: 26,61 g (79% of theory.)

Water content: 11,0%.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 37,42; N 4,07; F 37,27; N 6,47;

found: 37,25; N 4,19; F 37,08; N 6,30.

C) Gadolinium complex of 10-[-2-hydroxy-4-oxa-1H,1H, 2H,3H,3H,5H,5N,6N,6N-perforatrice]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (11,54 mmol) of the compound shown in the title of example 3b), dissolved in a mixture of 100 ml of water/50 ml of 2-propanol and type of 2.09 g (5,77 mmol) of gadolinium oxide. Stirred for 3 hours at 80°C. the Solution is filtered and evaporated to dryness in a vacuum.

Vilakazi T1(L/mmol· sec) at 20 MHz, 37°C:

15,2 (water)

27,5 (human plasma)

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 31,77; N 3,16; F 31,64; Gd 15,40; N 5,49;

found: 31,55; H 3,30; F 31,49; Gd 15,28; N 5,35.

EXAMPLE 4

a) 1,2-epoxy-4-oxa-1H,1H,2H,3H,3H,5H,5N,6N,6N-performancecan

To a mixture of 20 g (54,93 mmole) of 1H,1H,2H,2H-perfluorooctane-1-ol and of 1.87 g (5.5 mmole) of tetrabutylammonium hydrosulfate in 200 ml of 60% aqueous solution of caustic potassium/100 ml of toluene with vigorous stirring at 10°C. added dropwise to 10,17 g (109,9 mmole) of epichlorohydrin, and the temperature of the reaction solution becomes not more than 20°C. Stirred for 2 hours at 15°C and then added dropwise as described above, to 5.08 g (54,93 mmole) of epichlorohydrin. After this was stirred at room temperature overnight. Add 100 ml of toluene and 100 ml of methyl tert-butyl ether and the separated aqueous phase. It is extracted 2 times - each time with 50 ml of toluene. The combined organic phases, dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (Solvent: dichloromethane/hexane/acetone=20/10/1).

Yield: 19,15 g (83% of theory) of colourless oil.

Elemental analysis:

Rasch.: With 31,44; N 2,16; F 58,78;

found: 31,40; N is iododecane

To 14,84 g (42,84 mmole) of 1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (D3A) in 70 ml of water is added 10.3 g (257,0 mmole) of sodium hydroxide. Added dropwise a solution of 18.0 g (42,84 mmole) of the compound indicated in the title of the example 4A) are dissolved in 80 ml of n-butanol/60 ml of 2-propanol and the solution is heated overnight to 70°C. Evaporated in vacuum to dryness, absorb the residue in 300 ml of water and with 3N hydrochloric acid to establish a pH value of 3. Then 2 times extracted with 200 ml of n-butanol. United butanolide phase evaporated in vacuum to dryness, and the residue is purified by RP-chromatography (RP-18/Solvent: gradient of water/n-butanol/acetonitrile).

Yield: 27.4 g (75% of theory.) glassy solids.

Water content: 10.1 per cent.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 39,17; N 4,60; F 32,22; N 7,31;

found: 39,05; N Is 4.85; F 32,05; N 7,19.

C) gadolinium Complex of 10-[2-hydroxy-4-oxa-1H,1H,2H, 3H,3H,5H,5N,6N,6N-perforater]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (13,04 mmol) of the compound shown in the title of example 4B), dissolved in a mixture of 100 ml of water/50 ml of 2-propanol and type of 2.36 g (of 6.52 mmol) of gadolinium oxide. Stirred for 3 hours at 80°C. the Solution is filtered and upar

Water content: 6.1 per cent.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 32,61; N 3,50; F 26,82; Gd 17,08; N between 6.08;

found: 32,43; N 3,69; F 26,67; Gd 16,85; N 5,91.

EXAMPLE 5

a) Tert-butyl ether 9,9,9,8,8,7,7,6,6-nomatter-3-oksanalove acid

To a mixture of 20 g (75,73 mmole) of 1H,1H,2H,2H-perference-1-ol and 2.57 g (EUR 7.57 mmole) of tetrabutylammonium hydrosulfate in 300 ml of 60% aqueous solution of caustic potassium/200 ml of toluene with vigorous stirring at 0°C is added dropwise to 29,54 g (151,5 mmole) of tert-butyl methyl ether bromoxynil acid. After stirred at 0°C for one hour. Add 100 ml of toluene, separating the aqueous phase and extracted 2 times - each time with 50 ml of toluene. The combined organic phases are dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (Solvent: hexane/dichloromethane/acetone=20/10/1).

Yield: 21,48 g (75% of theory) of colourless oil.

Elemental analysis:

Rasch.: With 38,11; 4,00; F 45,21;

found: 37,95; N 4,18; F 45,03.

b) 9,9,9,8,8,7,7,6,6-nomatter-3-Aksyonova acid

20 g (52,88 mmol) of the compound shown in the title of the example 5A), dissolved in 300 ml triperoxonane acid and stirred overnight at room the suitable product: 14,82 g (87% of theory) of colourless crystalline solid.

Elemental analysis:

Rasch.: With 29,83; N 2,19; F 53,08;

found: 29,71; 2.40 A; F 52,90.

C) gadolinium Complex of 10-[2-hydroxy-4-Aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,13-nonformulary]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

7,41 g (23,01 mmole) connection name example 5B) and only 2.91 g (25,31 mmole) of N-hydroxysuccinimide dissolved in a mixture of 40 ml of dimethylformamide/20 ml of chloroform. At 0°C add with 5.22 g (25,31 mmole) dicyclohexylcarbodiimide and stirred for 1 hour at 0°C, then 3 hours at room temperature. Again cooled to 0°C, add 6,98 g (69 mmol) of triethylamine/30 ml 2-propanol. After this type of 13.2 g (23,01 mmol) of the gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane dissolved in 40 ml of water, and stirred for 3 hours at room temperature. Evaporated to dryness. Absorb residue in a mixture of 200 ml of methanol/50 ml of chloroform and filtered from dicyclohexylamine. The filtrate is evaporated to dryness and purified using RP-chromatography (RP-18/Solvent used in chromatography: a gradient of water/n-propanol/acetonitrile).

Yield: 15,20 g (71% of theory.) colorless glassy solid.

The water content is 5.7%.

Element the 17,74; N 7,87.

EXAMPLE 6

a) N-(2-amino-ethyl)amide-N-ethyl-N-(PerformanceCounter)-aminouksusnoy acid

15 g (25,63 mmole) of the compound indicated in the title of example 1B), or 3.24 g (28,19 mmole) of N-hydroxysuccinimide dissolved in 80 ml of dimethylformamide and at 0°C type of 5.82 g (28,19 mmole) dicyclohexylcarbodiimide. Stirred for 1 hour at 0°C and then 2 hours at room temperature. Filter from the fall in the sediment of dicyclohexylamine, and the filtrate for 30 minutes added to a solution of 46,21 g (768,9 mmol) of ethylene diamine in 300 ml of dichloromethane. Stirred for 5 hours at room temperature. Add 1000 ml of H2O and the organic phase is separated. It washed 2 times, each time with 500 ml water, then dried over magnesium sulfate and evaporated to dryness in a vacuum. Cleaning is carried out using chromatography on silica gel (Solvent: dichloromethane/2-propanol=15/1).

Yield: to 11.79 g (75% of theory) of colorless, waxy solid.

Elemental analysis:

Rasch.: With 27,42; H 2,30; F 52,66; N 4,57; S 5,23;

found: 27,20; N 2,41; F 52,48; N To 4.38; S 5,10.

b) N-[2-(bromoacetyl)-amino-ethyl]-amide-N-ethyl-N-(PERFLUORO-octylsilane)-aminouksusnoy acid

10 g (16.3 mmol) of the compound shown in the title ol the Ute 3,29 g (16.3 mmole) of bromoacetamide and stirred for 2 hours at 0°C. The solution is poured into 300 ml of 1 N hydrochloric acid and mix well. The organic phase is separated, dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (Solvent: dichloromethane/acetone=20/1).

Yield: 11.1 g (91% of theory) of a light yellow waxy solid.

Elemental analysis:

Rasch.: With 25,68; N 2,02; VG Is 10.68; F 43,16; N 5,62; S 4,29;

found: 25,47; N 2,18; Br 10,45; F 43,29; N 5,47; S 4,10.

b) 10-[2-Oxo-3-Aza-6-Aza-7-oxo-9-Aza-9-(PerformanceCounter)-undecyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

To 10 g (made 13.36 mmol) of the compound indicated in the title of example 6b) in 180 ml of methanol add 4,63 g (made 13.36 mmol) of 1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DO3A) and 18.5 g (133,6 mmol) of potassium carbonate. Boiled for 12 hours under reflux. Inorganic salts are filtered and the filtrate pariveda dry. The residue is absorbed in 100 ml of water, its acidity is installed with 5 N hydrochloric acid to pH 3. The extraction is carried out 2 times - each time with 150 ml of n-butanol. The combined organic phases warialda in vacuum to dryness, and the residue is purified by RP-chromatography (RP-18/solvent gradient of water/n-butanol water: 13,0%.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 35,55; N 3,98; F 31,86; N 9,67; S 3,16;

found: 35,37; N 3,75; F 31,64; N 9,78; S 3,25.

d) gadolinium Complex of 10-[2-Oxo-3-Aza-6-Aza-7-oxo-9-Aza-9-(PerformanceCounter)-undecyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (9,86 mmol) of the compound indicated in the title of example 6A), dissolved in a mixture of 50 ml of water/20 ml of ethanol and 1.79 g (is 4.93 mmol) of gadolinium oxide. Stirred for 4 hours at 80°C. the Solution is filtered and vacuum evaporated to dryness.

Yield: 14.4 g (quantitatively).

Water content: 7,1%.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 30,85; N 3,19; F 27,65; Gd 13,46; N 8,39; S 2,75;

found: 30,64; N 3,35; F 27,58; Gd To 13.29; N 8,28; S 2,65.

EXAMPLE 7

a) an ester of 1H,1H,2H,2H-perftoran-1-ol-p-toluene-sulfonic acid

To 30 g (64,64 mmole) of 1H, 1H, 2H,2H-perftoran-1-ol in 300 ml of dichloromethane and 10,12 g (100 mmol) of triethylamine added at 0°C 12,57 g (65,93 mmole) chloride p-toluensulfonate acid. Stirred for 2 hours at 0°C, then stirred for 2 hours at room temperature. The solution is poured into 500 ml of cold 2 N hydrochloric acid and vigorously stirred. The organic phase is stirred, dried over magnesium sulfate and evaporated the dosa is eerie) a colorless crystalline powder.

Elemental analysis:

Rasch.: With 33,02; N 1,7; F 52,2; S 5,1;

found: From 32.8; N 1,93; F 52,04; S of 5.05.

b) 10-[(1-hydroxymethyl-1-carboxy)-methyl]-1,4,7-Tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecane

To a solution of 20 g (57,78 mmol) of 1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DO3), 31,21 g (780 mmole) of sodium hydroxide and 2 g (12 mmole) of potassium iodide in 100 ml of dimethylformamide add to 37.2 g (173,4 mmole) of 2-chloro-3-benzyloxypropionic acid and stirred for 3 days at 60°C. Evaporated to dryness and the residue is evaporated in 300 ml of water. Then with 3 N hydrochloric acid installing the acidity of pH 3 and produce extracted 2 times, each time with 250 ml dichloromethane. For the aqueous phase to give 4 g of palladium catalyst (10% Pd/C) and hydronaut 5 hours at 60°C. the Catalyst is filtered off and the filtrate evaporated to dryness. The residue is purified using RP-chromatography (RP-18/Solvent: gradient of water/2-propanol/acetonitrile).

Yield: of 5.92 g (21% of theory relative DO3A) colorless glassy solid.

Water content: 11,1%.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 47,00; N. Of 6.96; N 12,90;

found: 46.81 / Bbl; N Is 6.78; N 12,99.

b) 10-[1-hydroxymethyl-1-(methoxycarbonyl)-methyl]-1,4,7-Tris(methoxycarbonylmethyl is E. this type of 5.8 g (13,35 mmol) of the compound, which is stated in the title of example 7b), and stirred for 1 hour at 0°C. and Then heated for 6 hours to a temperature of 60°C. Evaporated to dryness, absorb the residue in 150 ml of methylene chloride and extracted 3 times - each time with 200 ml of 8% aqueous soda solution. The organic phase is dried and pariveda dry. Get 6,09 g (93% of theory) of the target compound in the form of a slightly yellow oil.

Elemental analysis:

Rasch.: With 51,42; N 7,81; N 11,42;

found: 51,20; N. Of 7.95; N 11,28.

d) 10-[1-methoxycarbonyl)-3-oxa-1H,2H,2H,4H,4H,5H,5H-pervertedly]-1,4,7-Tris(methoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane

To 6 g (12,23 mmol) of the compound indicated in the title of example 7b), in 40 ml of dimethylformamide type of 0.44 g (14,68 mmol) of sodium hydride (80% suspension in mineral oil) and stirred for 30 min at -10°C. Then add 8,32 g (13,45 mmol) of the compound indicated in the title of example 7a), and stirred for 8 hours at room temperature. Carefully add 400 ml of ice water and extracted twice with - each time with 300 ml ethyl ester of acetic acid. Combined phase ethyl ester acetic acid, washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporated in vacuum to dryness and chromatographic ccli yellow oil.

Elemental analysis:

Rasch.: With 39,75; N To 4.41; F 34,48; N 5,98;

found: 39,58; N 4,60; F 34,27; N 5,75.

d) 10-[1-carboxy-3-oxa-1H,2H,2H,4H,4H,5H,5H-pervertedly]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

7.5 g (8,01 mmol) of the compound shown in the title from example 7G), suspended in a mixture of 50 ml water/30 ml ethanol, and then add 3,84 (96 mmol) of sodium hydroxide. Boil over night under reflux. Cooled to room temperature and with 3 N hydrochloric acid to establish a pH of 3. Evaporated in vacuum to dryness, and the residue is purified using RP-chromatography (RP-18/Solvent: gradient of a mixture of water/n-butanol/acetonitrile).

Yield: 6,84 g (87% of theory.) glassy solids.

Water content: 10,3%.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 36,83; N 3,78; F 36,68; N 6,36;

found: 36,67; N 3,90; F 36,49; N 6,25.

e) gadolinium Complex of 10-[1-carboxy-3-oxa-1H,2H,2H,4H,4H,5H,5H-pervertedly]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (as sodium salt)

6 g (for 6.81 mmol) of the compound shown in the title of example 7D), are suspended in 80 ml of water and add to 1.23 g (3.4 mmol) of gadolinium oxide. Heated 3 hours to a temperature of 90°C. is Cooled down to room those who sutured with freezing.

Yield: 7,83 g (quantitative) of a colorless powder in the form of flakes.

Water content: 8,1%.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 30,69; N 2,77; F 30,56; Gd 14,88; N 5,30; Na 2,18;

found: 30,48; N 2,85; F 30.37 Per; Gd 14,69; N 5,17; Na 1,95.

EXAMPLE 8

a) 2H,2H-perforaciones

30 g (82,4 mmole) of 1H,1H,2H,2H-perfluorooctane-1-ol are dissolved in 500 ml of dichloromethane and add 17,76 g (82,4 mmole) chlorochromate pyridinium. Stirred at room temperature overnight. The solution is filtered through a short column filled with alumina (neutral), the filtrate is evaporated to dryness and the residue chromatographic on silica gel (Solvent: dichloromethane/hexane/acetone=10/10/1).

Yield: 26,55 g (89% of theory.) waxy solids.

Elemental analysis:

Rasch.: With 26,54; N 0,84; F 68,21;

found: 26,47; H 1,05; F 68,10.

b) 2-amino-2H,3H,3H-parfionova acid (as hydrochloride)

? 7.04 baby mortality g (143,6 mmol) of sodium cyanide and 8,45 g (158 mmol) of ammonium chloride dissolved in 30 ml of water. To this solution was added 40 ml of ethanol and 26 g (71,8 mmole) of the compound indicated in the title of example 8A). Heated 2 hours to a temperature of 45°C. Add 300 ml of water and extracted 3 times, each time with 200 ml of water. Obyedinennaya absorb 100 ml of 6 N aqueous hydrochloric acid/50 ml of methanol and 2 hours and heated at the reflux. Evaporated in vacuum to dryness. The residue is recrystallized from a small amount of 2-propanol/methyl tert-butyl ether.

Yield: of 11.15 g of crystalline solids.

Elemental analysis:

Rasch.: With 24,37; N 1,59; CL 7,99; F 55,68; N 3,16;

found: 24,15; N 1,72; Cl 7,65; F 55,51; N 3,05.

a) 2-[(N-benzyloxycarbonyl)-triglycidyl]-amino-2H,3H,3H-parfionova acid

of 8.37 g (24,8 mmol) of N-benzyloxycarbonylglycine 3.14 g (27,28 mmol) of N-hydroxysuccinimide dissolved in 80 ml of dimethylformamide and at 0°C add 5,63 g (27,28 mmole) dicyclohexylcarbodiimide. Stirred for 1 hour at 0°C and then 2 hours at room temperature. Cooled to 0°C, add 7,53 g (74.4 mmole) of triethylamine and 11 g (24.8 mmole) of the compound shown in the title of example 8b), and then stirred over night at room temperature. Evaporated in vacuum to dryness, absorb the residue in 300 ml of 5% aqueous citric acid and extracted 3 times, each time with 200 ml of ethyl ether, acetic acid and mix well. The combined organic phases are dried over magnesium sulfate and evaporated in vacuum to dryness. The remainder chromatographic on silica gel (Solvent:dichloromethane/n-propanol=20/1).

Yield: 11,83 g (67% of those>ideno: 38,59; N 2,85; F 34,48; N to $ 7.91.

g) 2-[triglycidyl]-amino-2H,3H,3H-parfionova acid

11.5g (16,14 mmole) of the compound shown in the title of example 8b), dissolved in 200 ml of 2-propanol and add 3 g of palladium catalyst (10% Pd/C). Hydronaut over night at room temperature. Filtered from the catalyst and the filtrate evaporated to dryness.

Yield: was 9.33 g (quantitative) of a colorless solid product.

Elemental analysis:

Rasch.: With 31,15; N 2,61; F 42,71; N RS 9.69;

found: 31,29; H 2,80; F 42,53; N 9,48.

d) 2-(1H,1H-perforated)-1,4,7,10-Teresa-3,6,9,12-tetrasociological

9.2 grams (15,91 mmol) of the compound shown in the title of example 8b), dissolved in 1000 ml of dimethylformamide and add 3,93 g (15,91 mmole) 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline. Stirred 3 days at room temperature. Evaporated to dryness and the residue chromatographic on silica gel (Solvent: dichloromethane/2-propanol=20/1).

Yield: 4,54 g (51% of theory) of a waxy solid product.

Elemental analysis:

Rasch.: With 32,16; N 2,34; F 44,08; N 10,00;

found: 32,05; N 2,47; F 43,87; N 9,89.

e) 2-(1H,lH-perforated)-1,4,7,10-tetraazacyclododecane (tetrahydrochloride)

To 4.4 g (a 7.85 mmole) of the compound, given what whether a reverse refrigerator. Evaporated to dryness in vacuo, and the residue is absorbed in 50 ml conc. of hydrochloric acid. Add 100 ml of ethanol and boiled for 8 hours using a reflux apparatus. Evaporated to dryness in vacuo, and the residue is recrystallized from ethanol.

Yield: 4,75 g (93% of theory) of colorless crystalline powder.

Elemental analysis:

Rasch.: With 27,71; N 3,88; CL 21,81; F 37,99; N 8,62;

found: 27,65; N 3,95; Cl 21,40; F 37,69; N to 8.41.

W) 2-(1H,1H-perforated)-1,4,7,10-Tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane

4.6 g (7,07 mmol) of the compound shown in the title of example 8E), and 4.0 g (42,4 mmol) Chloroacetic acid resturaunt in 40 ml of water, and the pH value is adjusted by adding 30% aqueous solution of caustic potassium equal to pH 10. Heated 8 hours to a temperature of 70°C and keep the pH value between 8 and 10 by adding 30% aqueous solution of caustic potash). The solution is cooled to room temperature using conc. hydrochloric acid, acidity it is set to pH 2 and evaporation to dryness. Absorb residue in 150 ml of methanol, the salt is filtered off and the filtrate evaporated in vacuum to dryness. The residue is purified using RP-chromatography (RP-18/Solvent: gradient of water/2-propanol/ACE water: 10.1 per cent.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 37,51; N. Of 3.97; F 33,53; N to 7.61;

found: 37,35; N 4,12; F 33,40; N 7,45.

C) gadolinium Complex of 2-(1H,1H-perforated)-1,4,7,10-Tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane (as sodium salt)

4.5 g (6,11 mmol) of the compound shown in the title of the example g), suspended in 100 ml of water and add 1,107 g (3,05 mmol) of gadolinium oxide. Heated 3 hours to a temperature of 90°C. is Cooled to room temperature and a solution of 2 N sodium hydroxide establish a pH value of 7.2. The solution is filtered, and then dried by freezing.

Yield: 6,03 g (quantitative) of a colorless powder.

Water content: 7,5%.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 30,23; N 2,87; F 27,03; Gd 17,21; N 6,13; Na 2,52;

found: 30,10; N 3,05; F 26,81; Gd 17,15; N 5,95; Na 2,30.

EXAMPLE 9

a) 10-[2-hydroxy-1H,1H,2H,3H,3H-perpersonal]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

To 15 g (43,3 mmole) of 1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 50 ml of water is added 13,85 g (346,4 mmol) of sodium hydroxide. Add dropwise a solution of 27,68 g (64,95 mmol) 1,2-epoxy-1H,1H,2H,3H,3H-perfornance dissolved in 50 ml of n-butanol/50 ml 2-propanol, and the solution is heated during the night by means of 3 N hydrochloric acid, equal to pH 3. After that 2 times extracted with 200 ml of n-butanol. United butanolide phase evaporated in vacuum to dryness, and the residue is purified using RP-chromatography (RP-18/Solvent: gradient of water/n-butanol/acetonitrile).

Yield: 30,34 g (78% of theory) of a vitreous solid.

Water content: 13.7 percent.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 37,32; N. Of 4.04; F 36,89; N 7,25;

found: 37,15; N 4,21; F 36,70; N 7,19.

b) Complexation 10-[2-hydroxy-1H,1H,2H,3H,3H-perpersonal]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (12,94 mmol) of the compound shown in the title of example 9a), dissolved in 100 ml of water/50 ml of ethanol and add 2,34 g (6.47 mmole) of gadolinium oxide. Stirred for 3 hours at 80°C. the Solution is filtered and evaporated in vacuum to dryness.

Yield: 13,16 g (quantitative) of a colorless glassy solid.

Water content: 9.1 per cent.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 31,11; N 3,05; F 30,75; Gd 16,97; N 6,05;

found: 31,01; N 3,19; F 30,55; Gd 16,71; N 5,88.

EXAMPLE 10

a) N,N,10H,11N,N,N-perforans-10-ene

24,77 g (52,26 mmol) of 1H,1H,2H,2H-peritonitis-1-iodide and 13,71 g (52,26 mmole) of triphenylphosphine are heated in 500 ml acetete colorless phosphonium salt. The phosphonium salts filtered off, dried in vacuum at 40°C.

Yield: 38,9 g (89% of theory).

This phosphonium salt is used directly without purification in the next stage: to salt obtained above phosphine, of 38.9 g (46.5 mmol) in 250 ml dichloromethane added with 5.22 g (46.5 mmol) of potassium tert-butylate, 0.20 g (0.75 mmol) of 18-crown-6 and 19,54 g (42,28 mmol) of 2H,2H-performcance and stirred for 10 hours at room temperature. Evaporated to dryness and the residue chromatographic on silica gel (Solvent: dichloromethane/n-hexane/diethyl ether=10/20/1).

Yield: 30,3 g (65% of theory calculated on used iodide) colorless waxy solid.

Elemental analysis:

Rasch.: With 26,92; N 0,68; F 72,40;

found: 26,81; H 0,79; F 72,20.

b) 10,11-epoxy-N,N,10H,11N,N,N-perforacion

To 25 g (28,02 mmol) of the compound shown in the title of example 10A), dissolved in 250 ml of dichloromethane, is added at 0°C of 10.47 g (36,42 mmol) 3-chloroperoxybenzoic acid (approximately 60%) and stirred overnight at room temperature. Add 300 ml of 5% aqueous sodium carbonate solution and mix well. The organic phase is separated, dried over sodium sulfate and UPA the new ether=10/10/1).

Yield: 24,17 (95% of theory) of colorless solid.

Elemental analysis:

Rasch.: With 26,45; N Of 0.67; F 71,12;

found: 26,25; N 0,88; F 71,35.

b) 10-[1-(1H,1H-perftoran)-2-hydroxy-1H,2H,3H,3H-perfcounter]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

To 7,63 g (22,02 mmole) of 1,4,7-Tris(carboxymethyl)1,4,7,10-tetraazacyclododecane in 35 ml of water is added? 7.04 baby mortality g (0,176 mmole) of sodium hydroxide. This added dropwise a solution of 20 g (for 22.02 mmol) of the compound shown in the title of example 10B), dissolved in 50 ml of a mixture n-butanol/40 ml of 2-propanol, and the solution is heated overnight to 120°C in an autoclave. Produce evaporation to dryness in vacuo, the residue is absorbed in 200 ml of water, and the acidity is set with 3 N hydrochloric acid to pH 3. After that 2 times extracted with 300 ml of n-butanol. United butanolide phase evaporated in vacuum to dryness, and the residue is purified using RP-chromatography (RP-18/Solvent: gradient of water/n-butanol/acetonitrile).

Yield: 9,79 g (31% of theory) of a colorless glassy solid.

Water content: 12,5%.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With worth 32.55; N To 2.57; F 51,49; N 4,47;

found: 32,38; H 2,75; F til)-1,4,7,10-tetraazacyclododecane

8 g (6.38 mmol) of the compound indicated in the title of example 10B), dissolved in 50 ml of water/40 ml ethanol/20 ml of chloroform and added to 1.16 g (3,19 mmol) of gadolinium oxide. Stirred for 4 hours at 90°C in an autoclave. The solution is filtered and evaporated in vacuum to dryness.

Yield: for 9.47 g (quantitatively) of glassy solids.

Water content: 5.2 per cent.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 28,99; N 2,07; F 45,85; Gd 11,16; N 3,98;

found: 28,81; N 2,19; F 45,71; Gd 11,03; N is 4.03.

EXAMPLE 11

a) 7H,7H,8H,N,10H,10H-perferences-8-ene

18.7 g (50 mmol) of 1H,1H,2H,2H-perforati-1-iodide and 13,11 g (50 mmol) of triphenyl of phosphine heated in 400 ml of acetone with stirring to 70°C. a Clear solution quickly becomes milky turbidity and is colorless phosphonium salt. The phosphonium salts filtered off, dried in vacuum at 40°C.

Yield: 28,95 g (91% of theory).

This phosphonium salt is used directly without purification in the following reaction: to the above salt of phosphonium, 28,95 g (to 45.5 mmol) in 200 ml dichloromethane type of 5.05 g (to 45.5 mmol) of potassium tert-butylate, 0.20 g (0.75 mmol) of 18-crown-6 and 14,98 g (41,36 mmol) of the compound shown in the title of example 8A), and stirred for 10 hours p is tan/n-hexane/diately ether=10/20/1).

Yield: 19,65 g (61% of theory) of colorless waxy solid.

Elemental analysis:

Rasch.: With 22,38; H 0,94; F 76,69;

found: 22,20; N 0,99; F 76,51.

b) 8,9-epoxy-7H,7H,8H,N,10H,10H-performancecan

To 19 g (29.5 mmol) of the compound shown in the title of example 11a), dissolved in 200 ml of dichloromethane, is added at 0°C 11,03 g (38,35 mmol) 3-chloroperoxybenzoic acid (approximately 60%) and stirred overnight at room temperature. Add 300 ml of 5% aqueous sodium carbonate solution and mix well. The organic phase is separated, dried over sodium sulfate and pariveda in vacuum to dryness. The remainder chromatographic on silica gel (Solvent: n-hexane/dichloromethane/diethyl ether=10/10/1).

Yield: 19,43 g (93% of theory) of colorless solid.

Elemental analysis:

Rasch.: With 27,14; H 0,85; F 69,75;

found: 27,01; H 0,97; F 69,60.

b) 10-[1-(1H,1H-perforated)-2-hydroxy-1H,2H,3H,3H-perpersonal]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

To 9.3 g (26,83 mmole) of 1,4,7-Tris(carboxymethyl)-1,4,1,10-tetraazacyclododecane in 50 ml of water is added 8,59 g (214,6 mmole) of sodium hydroxide. This added dropwise a solution of 19 g (26,83 mmol) coenagrion during the night up to 120°C in an autoclave. Produce evaporation to dryness in vacuo, the residue is absorbed in 200 ml of water, and the acidity is set with 3 N hydrochloric acid to pH 3. After that 2 times extracted with 300 ml of n-butanol. United butanolide phase evaporated in vacuum to dryness, and the residue is purified using RP-chromatography (RP-18/Solvent: gradient of water/n-butanol/acetonitrile).

Yield: 9.4 g (29% of theory) of a vitreous solid.

Water content: 12.7 per cent.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: From 34.17; H 3,06; F 46,84; N 5,31;

found: 33,98; N 3,18; F 46,65; N 5,20.

d) gadolinium Complex of 10-[1-(1H,1H-perforated)-2-hydroxy-1H,2H,3H,3H-perpersonal]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

9 g (8,53 mmol) of the compound shown in the title of example 11b), dissolved in a mixture of 60 ml of water/40 ml ethanol/30 ml of chloroform and added 1.54 g (4,27 mmole) of gadolinium oxide. Stirred for 4 hours at 90°C in an autoclave. The solution is filtered and evaporated to dryness in a vacuum.

Yield: of 11.45 g (quantitative) of a colorless, glassy solid.

Water content: 10.2 per cent.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 29,81; N 2,42; F 40,86; Gd 13,01; N 4,63;

naydeen

30 g (91,74 mmol) of 1H,1H,2H,2H-perferences-1-bromide dissolved in 100 ml of toluene, then add 3,23 g (to 36.7 mmol) of CIS-1,4-butanediol and 1 g (2,95 mmol) of tetrabutylammonium hydrosulfate. Produce cooled to 0°C and add 16 g (400 mmol) of sodium hydroxide in the form of fine powder. Then produce stirring for 1 hour at 0°C and overnight at room temperature. Filtered the solid, the filtrate is washed twice, each time with 200 ml of water, dried the organic phase over magnesium sulfate and then evaporated in vacuum to dryness. The remainder chromatographic on silica gel (Solvent: dichloromethane/n-hexane/acetone=15/15/1).

Yield: 11,71 g (55% of theory based on diol) waxy solid.

Elemental analysis:

Rasch.: With 33,12; N 2,43; F 58,93;

found: 33,05; N 2,61; F 5,73.

b) 9,10-epoxy-7,12-dioxo-5H,5N,6N,6N,8H,8H,N,10H,11N,11H,13H,13H,14H,14N-perforation

To 11 g (18,96 mmol) of the compound produced in the name of example 12A), dissolved in 100 ml of dichloromethane, is added at 0°From 7.08 g (24,64 mmol) 3-chloroperbenzoic acid (approximately 60%) and stirred overnight at room temperature. Add 150 ml of 5% aqueous sodium carbonate solution and well OK chromatographies on silica gel (Solvent: n-hexane/dichloromethane/diethyl ether=10/10/1).

Yield: a 10.74 g (95% of theory) of colorless solid.

Elemental analysis:

Rasch.: With 32,23; N 2,37; F 57,35;

found: 32,13; N. Of 2.51; F 57,20.

b) 10-[1-(2-oxa-1H,1H,3H,3H,4H,4H-perforati)-2-hydroxy-4-oxa-1H,2H,3H,3H,5H,5N,6N,6N-peritonitis)-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

To 6,1 g (17,61 mmol) of 1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 40 ml of water, add 5,63 g (141 mmole) of sodium hydroxide. Added dropwise a solution of 10.5 g (17,61 mmole) of the compound shown in the title of example 12B), dissolved in 50 ml of n-butanol/40 ml of 2-propanol and heated the solution during the night up to 120°C in an autoclave. In vacuum evaporated to dryness, absorb the residue in 200 ml of water and set the acidity with 3 N hydrochloric acid to pH 3. Then extracted 2 times, each time with 300 ml n-butanol. United butanolide phase evaporated in vacuum to dryness, and the residue is purified using RP-chromatography (RP-18/Solvent: gradient of water/n-butanol/acetonitrile).

Yield: 4,96 g (27% of theory) of a colorless glassy solid.

Water content: 9.7 per cent.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 38,27; N 4,17; F 36,32; N 5,95;

found: 38,12; N 4,20; F 36,20; N 5,81.

the IP(carboxymethyl)-1,4,7,10-tetraazacyclododecane

4.7 g (5 mmol) of the compound shown in the title of example 12B), dissolved in a mixture of water (30 ml/30 ml ethanol/20 ml of chloroform and add 0,90 g (2.5 mmole) of gadolinium oxide. Stirred for 3.5 hours at 90°C in an autoclave. The solution is filtered and evaporated to dryness in a vacuum.

Yield: of 5.89 g (quantitative) of a colorless glassy solid.

Water content: 7,1%.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 32,88; N 3,31; F 31,21; Gd 14,35; N 5,11;

found: 32,67; N 3,45; F 31,04; Gd 14,18; N 5,02.

EXAMPLE 13

a) 1-phenyl-2,6-dioxo-1H,1H,3H,3H,4H,5H,5H,7H,7H,8H,8H-performancedata-4-ol

To 7,14 g (39,2 mmol) glycerol-1-monobenzyl ether and 25 g (43,55 mmol) of 1H,1H,2H,2H-peritonitis-1-iodide in 100 ml of toluene was added 1 g (2,94 mmol) of tetrabutylammonium hydrosulfate and 15.6 g (390 mmol) of sodium hydroxide in the form of fine powder. Stirred for 24 hours at room temperature. From solids to separate the organic phase and washed twice, each time with 5% aqueous hydrochloric acid. The organic phase is dried over magnesium sulfate and evaporated in vacuum to dryness. The remainder chromatographic on silica gel (Solvent: n-hexane/acetone=15/1).

Yield: 19,95 g (81% of theory) of colorless m is-2,6-dioxo-1H,1H,3H,3H,4H,5H, 5H,7H,7H,8H,8H-performancecan

To 19.5 g (31,03 mmol) of the compound shown in the title of example 13A), dissolved in 100 ml of dimethylformamide, are added in several portions of 1.12 g (37,24 mmole) of sodium hydride (80% suspension in mineral oil) and stirred for 2 hours at room temperature. Then add 8,24 g (37,24 mmol) n-delivered and stirred over night at 50°C. Add 150 ml of ice water and extracted 2 times, each time with 150 ml of ethyl ester of acetic acid. The combined organic phases are washed with 2 times - each time with 150 ml of water, dried over magnesium sulfate and evaporated to dryness. The remainder chromatographic on silica gel (Solvent: n-hexane/acetone=20/1).

The output of finished product: cushion 22.66 g (95% of theory) of a waxy solid.

Elemental analysis:

Rasch.: With 46,88; N Is 4.85; F 42,02;

found: 46,64; N equal to 4.97; F 41,87.

a) 2-(decyloxy)-4-oxa-1H,1H,2H,3H,3H,5H,5N,6N,6N-performation-1-ol

20 g (to 26.02 mmol) of the compound shown in the title of example 13B), dissolved in 200 ml of isopropanol and add 3 g of palladium catalyst (10% Pd/C). Hydronaut over night at room temperature. The catalyst is filtered off and the filtrate evaporated to dryness in a vacuum.

Yield: 17,65 g (the number 4,76; F 47,43.

g) 1,2-epoxy-4-oxa-6-(decyloxy)-8-oxa-1H,1H,2H,3H,3H,5H,5N,6N,7N,7N,N,N,10H,10H-perforation

To a mixture of 17 g (25,06 mmol) of the compound shown in the title of example 13B), and 2 g (of 5.89 mmol) of tetrabutylammonium hydrosulfate in 300 ml of 60% aqueous solution of caustic potassium/100 ml of toluene with vigorous stirring at 10°C. are added dropwise to a 9.25 g (100 mmole) of epichlorohydrin and ensure that the temperature of the reaction solution did not exceed 20°C. is Stirred at a temperature of 15°C for two hours and then added dropwise as described above, 4,63 g (50 mmol) of epichlorohydrin. Then stirred over night at room temperature. Add 100 ml of toluene and methyl tert-butyl ether and the separated aqueous phase. It is extracted 2 times - each time with 100 ml of toluene. The combined organic phases, dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (Solvent: dichloromethane/hexane/acetone=20/10/1).

Yield: 14,91 g (81% of theory) of colorless solid.

Elemental analysis:

Rasch.: With 42,51; N 4,80; F 43,97;

found: 42,37; N 4,96; F 43,68.

d) 10-[2-hydroxy-4,8-dioxa-6-(decyloxy)-1H,1H,2H,3H,3H,5H,5N,6N,7N,7N,N,N,10H,10H-pertrochemical]-1,4,7-Tris(carboxym water add 6.11 g (152,8 mmol) of sodium hydroxide. This added dropwise a solution of 14 g (19,06 mmol) of the compound shown in the title of example 13 g), dissolved in 80 ml of n-butanol/40 ml of 2-propanol and heated the solution during the night up to 80°C in an autoclave. Produce evaporation in vacuo to dryness, absorb the residue in 200 ml of water and set the acidity with 3 N hydrochloric acid to a value of pH 3. Then twice extracted with 300 ml of n-butanol. United butanolide phase evaporated in vacuum to dryness, and the residue is purified using RP-chromatography (RP-18/Solvent: gradient of water/n-butanol/acetonitrile).

Yield: 17,88 g (76% of theory) of a vitreous solid.

Water content: 12,5%.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 44,49; N the ceiling of 5.60; F 29,91; N 5,19;

found: 44,31; N. Of 5.75; F 29,70; N to 5.03.

e) gadolinium Complex of 10-[2-hydroxy-4,8-dioxa-6-(decyloxy)-1H,1H,2H,3H,3H,5H,5N,6N,7N,7N,N,N,10H,10H-pertrochemical]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (9,26 mmol) of the compound shown in the title of the example d), dissolved in 30 ml of water/100 ml ethanol/30 ml of chloroform and added 1.68 g (4,63 mmol) of gadolinium oxide. Stirred for 3.5 hours at a temperature of 90°C in an autoclave. The solution is filtered and evaporated to dryness.

Water content: 7.8 per cent.

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 38,93; N 4,66; F 26,17; Gd 12,74; N 4,54;

found: 38,71; N 4,82; F 26,01; Gd 12,55; N of 4.38.

EXAMPLE 14

a) 1-phenyl-2-oxa-4,4,4-Tris(2-oxa-1H,1H,3H,3H,4H,4H-peritonitis)-butane

To 4,24 g (18,74 mmol) monobenzyl ether of pentaerythritol and 40 g (93,7 mmol) of 1H, 1H, 2H, 2H-perforati-1-bromide in 150 ml of toluene is added 2 g (of 5.89 mmol) of tetrabutylammonium hydrosulfate and 22,48 g (562 mmol) of finely dispersed powder of sodium hydroxide. Then produce stirring for 24 hours at room temperature. From solids to separate the organic phase and washed twice each time with 5% aqueous hydrochloric acid. The organic phase is dried over magnesium sulfate and evaporated in vacuum to dryness. The remainder chromatographic on silica gel (Solvent: n-hexane/acetone=25/1).

Yield: accounted for 14.45 g (61% of theory relative to the benzyl ether) colorless, waxy solid.

Elemental analysis:

Rasch.: With 34,19; N 2,15; F 58,59;

found: 34,02; N 2,31; F 58,41.

b) 2,2,2-Tris(2-oxa-1H,1H,3H,3H,4H,4H-peritonitis)-Ethan-1-ol

14 g (11,07 mmole) of the compound shown in the title of example 14a), dissolved in 100 ml isopropanol/100 ml tetrahydrofuranate filtered off, and the filtrate is evaporated to dryness in a vacuum.

Yield: 13 g (quantitative) of a colorless solid product.

Elemental analysis:

Rasch.: With 29,66; H 1,80; F 63,09;

found: 29,45; N 1,97; F 62,91.

C) 1,2-epoxy-4-oxa-6,6,6-Tris(2-oxa-1H,1H,3H,3H,4H,4H-peritonitis)-hexane

To a mixture of 12.5 g (at 10.64 mmol) of the compound shown in the title of example 14b), and 1 g (2,95 mmol) of tetrabutylammonium hydrosulfate in 150 ml of 60% aqueous solution of caustic potassium/50 ml of toluene with vigorous stirring at 10°C. are added dropwise 3.94 g (42,57 mmole) of epichlorohydrin and ensure that the temperature of the reaction solution did not exceed 20°C. is Stirred at a temperature of 15°C for two hours and then added dropwise as described above, of 1.97 g (21,29 mmol) of epichlorohydrin. Then stirred over night at room temperature. Add 100 ml of toluene and 100 ml of methyl tert-butyl ether and the separated aqueous phase. It is extracted 2 times - each time with 50 ml of toluene. The combined organic phases, dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (Solvent: dichloromethane/hexane/acetone=20/10/1).

Yield: 8,12 g (62% of theory) of colorless solid.

Ele is-1H,1H,3H,3H,4H,4H-peritonitis)-hexyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

To 2.25 g (6,50 mmole) of 1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 30 ml of water, add 2,08 g (52 mmole) of sodium hydroxide. This added dropwise a solution of 8.0 g (6,50 mmol) of the compound shown in the title of example 14C), dissolved in a mixture of 50 ml of n-butanol/30 ml 2-propanol, and the solution is heated overnight to 100°C in an autoclave. Produce evaporation to dryness in vacuo, the residue is absorbed in 200 ml of water, and the acidity is set with 3 N hydrochloric acid to pH 3. After that 2 times extracted with 100 ml of n-butanol. United butanolide phase evaporated in vacuum to dryness, and the residue is purified using RP-chromatography (RP-18/Solvent: gradient of water/n-butanol/acetonitrile).

Yield: 7,79 g (67% of theory) of a colorless glassy solid.

Water content: 11.9 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 35,06; N 3,20; F 47,02; N 3,56;

found: 34,90; N 3,38; F 46,86; N 3,47.

e) gadolinium Complex of 10-[2-hydroxy-4-oxa-6,6,6-Tris(2-oxa-1H,1H,3H,3H,4H,4H-peritonitis)hexyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

7 g (of 4.44 mmol) of the compound shown in the title of example 14 g), dissolved in 30 ml of water/50 ml of ethanol/50 ml of chloroform and the comfort and evaporated to dryness in a vacuum.

Yield: a 8.34 g (quantitative) of a colorless, glassy solid.

Water content: 8,1%.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 31,94; N Is 2.74; F 42,83; Gd Is 9.09; N 3,24;

found: 31,74; N 2,91; F 42,67; Gd cent to 8.85; N 3,15.

EXAMPLE 15

a) 1,7-bis[acetyl-(2-(N-ethyl-N-perftorgeksilsilanami)]-1,4,7-triathalete

20 g (34,17 mmol) of the compound shown in the title of example 1B), and to 4.33 g (37,59 mmol) of N-hydroxysuccinimide dissolved in 150 ml of dimethylformamide. At 0°C add 7,76 g (37,59 mmole) of dicyclohexylcarbodiimide and stirred for 3 hours at room temperature. Filtered dicyclohexylphosphino and pin the filtrate to a solution of 1.76 g (17,09 mmol) Diethylenetriamine and 13,83 g (136,7 mmol) of triethylamine in 200 ml of dimethylformamide at room temperature. Stirred over night at room temperature. Evaporated in vacuum to dryness, and the residue is absorbed in 200 ml of 5% aqueous soda solution. Extracted 2 times - each time with 150 ml of dichloromethane, dried the combined organic phases over magnesium sulfate and evaporated in vacuum to dryness. The remainder chromatographic on silica gel (Solvent: dichloromethane/2-propanol=20/1).

Yield: 16.5 g (78% of the teno: 27,03; N 2,17; F 52,04; N 5,49; S 5,07.

b) 4-(3-carboxypropanoyl)-1,7-bis-{acetyl-[2-(N-ethyl-N-perftorgeksilsilanami)]}-1,4,7-triathalete

To 16 g (12,93 mmol) of the compound shown in the title of example 15A), dissolved in 100 ml of methylene chloride, add to 3.92 g (38,78 mmole) of triethylamine, and the solution is cooled to 0°C. then add 2,59 g (25,86 mmol) of succinic acid anhydride and stirred for 3 hours at 0°C, over night at room temperature. Add 200 ml of 5% aqueous hydrochloric acid and shake well. The organic phase is separated and dried over magnesium sulfate. Evaporated in vacuum to dryness and the residue chromatographic on silica gel (Solvent: dichloromethane/2-propanol=15/1).

Yield: 15,74 g (91% of theory) of colorless solid.

Elemental analysis:

Rasch.: With 28,73; N 2,19; F 48,29; N 5,24; S 4,79;

found: 28,58; 2.40 A; F 48,17; N 5,17; S 4,65.

b) 10-[7-hydroxy-5-Aza-4-oxooctanoate acid-N,N-bis(3-Aza-4-oxo-6-Aza-6-(PerformanceCounter)-octyl)-amide]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

15 g (11,21 mmol) of the compound shown in the title of example 15B), and 1.42 g (of 12.33 mmol) of N-hydroxysuccinimide dissolved in a mixture of 80 ml of dimethylformamide/30 ml of chloroform. At 0°C type of 2.54 g (of 12.33 m is adout to 0°C and add 4,05 (40 mol) of triethylamine/50 ml 2-propanol. After that add 7,07 g (of 12.33 mmol) of the gadolinium complex of 10-[2-hydroxy-3-aminopropyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane dissolved in 30 ml of water, and stirred for 3 hours at room temperature. Evaporated to dryness and the residue is absorbed in a mixture of 100 ml of methanol/50 ml of chloroform and filtered from dicyclohexylamine. The filtrate is evaporated to dryness and purified by RP-chromatography (RP-18/Solvent: gradient of water/n-propanol/acetonitrile).

Yield: 17,76 g (78% of theory) of a colorless glassy solid.

Water content: 6.8 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 31,08; N 3,03; F volume of 34.12; Gd 8,31; N 7,40; S 3,39;

found: 30,89; N 3,15; F 34,01; Gd 8,14; N 7,25; S 3,24.

EXAMPLE 16

The gadolinium complex of 1, 4,7-Tris(carboxylatomethyl)-10-(2-hydroxy-19,19,20,20,21,21,22,22,23,23,24,24,25,25,26,26,26-heptadecafluoro-4,7,10,13,16-intoxikation)-1,4,7,10-tetraazacyclododecane

a) 16,16,17,17,18,18,19,19,20,20,21,21,22,22,22-heptadecafluoro-3,6,9,12-tetraoxygenated-1-ol

A mixture of 20 g (32,35 mmol) 1-p-toluensulfonate-1H,1H,2H,2H-perftoran [see example 7a], 1 g of tetrabutylammonium hydrosulfate, 62,83 g (323,5 mmole) tetraethyleneglycol, 300 ml of dichloromethane and 100 ml of 50% aqueous sodium hydroxide solution intensively paramashiva the deliver phase and washed with a dichloromethane phase water. The organic phase is dried over magnesium sulfate and evaporated in vacuum. Gain of 18.5 g of the desired specified in the title compound as a pale yellow oil.

b) 1,2-epoxy-19,19,20,20,21,21,22,22,23,23,24,24,25,25,26,26,26-heptadecafluoro-4,7,10,13,16-intoxikation

A mixture of 17 g (of 26.5 mmol) 16,16,17,17,18,18,19,19,20,20,21,21,22,22,22-heptadecafluoro-3,6,9,12-tetraoxygenated-1-ol

0.5 g of tetrabutylammonium hydrosulfate, 2,94 g of epichlorohydrin, 200 ml of dichloromethane and 50 ml of 50% aqueous sodium hydroxide solution intensively mixed at room temperature for 8 hours. Separate the phases, the aqueous phase is shaken out in 100 ml of dichloromethane, the combined organic phases are shaken with 50 ml of water, dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel using hexane/5 -50% ethyl acetate and get 12,92 g mentioned in the title compound in the form of oil.

Elemental analysis:

Rasch.: With 36,22; N 3,62; F 46,62;

found: 36,00; N 3,78; F 46,20.

in) 1,4,7-Tris(carboxylatomethyl)-10-(2-hydroxy-19,19,20,20,21,21,22,22,23,23,24,24,25,25,26,26,26-heptadecafluoro-4,7,10,13,16-intoxikation)-1,4,7,10-tetraazacyclododecane

To a solution of 6 g (17.3 mmol) of 1,4,7-(tricarboxylate)-1,4,7,10-tetraazacyclododecane and 4 g of sodium hydroxide in 30 ml water is added a solution of 12.0 is furan. Produce stirring overnight at 70°C., then evaporated in vacuum, absorb residue 150 ml of water and set the acidity with 6 N hydrochloric acid equal to pH 3, and repeatedly extracted with n-butanol. The combined extracts are evaporated in vacuum and the residue is purified by chromatography on RP-18 using a gradient of water/n-butanol/acetonitrile. Get 13,71 g of target compound in the form of a yellowish viscous oil.

Elemental analysis:

Rasch.: With 40,31; N Is 4.93; F 30,97; N lower than the 5.37;

found: 40,08; N To 5.21; F 30,77; N of 5.29.

d) gadolinium Complex 1,4,7-Tris(carboxylatomethyl)-10-(2-hydroxy-19,19,20,20,21,21,22,22,23,23,24,24,25,25,26,26,26-heptadecafluoro-4,7,10,13,16-intoxikation)-1,4,7,10-tetraazacyclododecane

Mix a mixture of 5 g (4,79 mmol) of 1,4,7-Tris(carboxylatomethyl)-10-(2-hydroxy-19,19,20,20,21,21,22,22,23,23,24,24,25,25,26,26,26-heptadecafluoro-4,7,10,13,16-pentoxyverine)-1,4,7,10-tetraazacyclododecane, 50 ml of water and 30 ml of ethanol with 869 mg (2,397 mmol) of gadolinium oxide and heated 5 hours at the reflux. The hot solution is filtered, evaporated in vacuum. Get the ceiling of 5.60 g of the compound shown in the title, as a glassy solid with a water content=4,1%.

Elemental analysis (relative to anhydrous substance):

Rass(carboxylatomethyl)-10-(4-Aza-2-hydroxy-26,26,26,25,25,24,24,23,23,22,22,21,21,20,20,19,19-heptadecafluoro-5-oxo-16-teghekacnel)-1,4,7,10-tetraazacyclododecane

a) 22,22,22,21,21,20,20,19,19,18,18,17,17,16,15,15-heptadecafluoro-12-tietokanava acid

Mix a solution of 10 g (37,71 mmol) 11-bromoundecanoic acid in 150 ml of dichloromethane with 11,43 g of triethylamine and 18,11 g (37,71 mmol) of 1H,1H,2H,2H-perpendicularity and stirred at room temperature overnight. The solution is extracted repeatedly with 2 N hydrochloric acid, washed with common salt solution, dried over magnesium sulfate and evaporated in vacuum. Get a 21.5 g of the compound shown in the title, in the form of a yellow oil.

Elemental analysis:

Rasch.: With 37,96; N 3,79; F 48,61; S a 4.83;

found: 38,30; N 4,01; F 48,40; S 5,20.

b) gadolinium Complex 1,4,7-Tris(carboxylatomethyl)-10-(4-Aza-2-hydroxy-26,26,26,25,25,24,24,23,23,22,22,21,21,20,20,19,19-heptadecafluoro-5-oxo-16-teghekacnel)-1,4,7,10-tetraazacyclododecane

5 g (7,52 mmol) of the compound indicated in the title of example 17A), and 0.95 g of N-hydroxysuccinimide dissolved in a mixture of 25 ml of dimethylformamide and 15 ml of chloroform. At 0°C add 1,71 g dicyclohexylcarbodiimide and stirred for 1 hour at 0°C, then 3 hours at room temperature. Then again cooled to 0°C. and mixed with 3 ml of triethylamine and 20 ml of n-propanol. After this type of 4.75 g (of 8.27 mmol) of the gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4 C. Evaporated to dryness, the residue absorbed in a mixture of 55 ml of methanol and 20 ml of chloroform and filtered from dicyclohexylamine. The filtrate is evaporated to dryness and purified by chromatography on RP-18 using a gradient of water/n-butanol/acetonitrile. Get 6,15 g of the compound shown in the title, in the form of a glassy solid with a water content=2,3%.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 37,41; N. Of 4.38; F 26,47; Gd 12,89; N 5,74; S 2,63;

found: 37,08; N 4,60; F 26,30; Gd 12,68; N 5,91; S 2,49.

EXAMPLE 18

The complex gadolinium 1,4,7-Tris(carboxylatomethyl)-10-[1-(1,2-dihydroxyethyl)-3-oxa-6,6,7,7,8,8,9,9,10,10,11,11,11-traducator]undecane-1,4,7,10-tetraazacyclododecane

a) 1-p-toluensulfonate-1H,1H,2H,2H-perfluorooctane

To a solution of 25 g (of 68.7 mmol) of 1H,1H,2H,2H-perfluorooctane-1-ol in 300 ml of dichloromethane at 0° C add 20 ml of pyridine and stirring portions add 13,49 g (70,76 mmol) p-chloride toluensulfonate acid. Produce stirring for further 3 hours at 0°C, at room temperature in vacuum pull dichloromethane. The remaining solution of pyridine is mixed with ice water, and the sediment falls out of the target product. The residue is dissolved in dichloromethane, the solution is washed with water, dried over magnesium sulfate are square 29,2 g connection mentioned in the title, in the form of foam.

Elemental analysis:

Rasch.: With 34,76; N 2,14; F 47,65; S to 6.19;

found: 34,98; N 2,38; F 47,39; S 6.42 per.

b) 1,4,7-Tris(benzyloxycarbonyl)-10-[1-(2,2-dimethyl-1,3-dioxolane-4-yl)-6,6,7,7,8,8,9,9,10,10,11,11,11-traducator-3-oxa]-undecane-1,4,7,10-tetraazacyclododecane

To 7,33 g (10 mmol) of 1,4,7-Tris(benzyloxycarbonyl)-10-[2-hydroxy-1-(2,2-dimethyl-1,3-dioxolane-4-yl)]-ethyl-1,4,7,10-tetraazacyclododecane [J. Mag. Res. Imag. 5:7-10, (1955)], dissolved in 100 ml of dichloromethane, add alternately 20 ml of 50% aqueous sodium hydroxide solution, 0.5 g of tetrabutylammonium hydrosulfate and is 5.18 g (10 mmol) 1-p-toluensulfonate-1H,1H,2H,2H-perfluorooctane [see example 18a)] and intensively stirred the mixture overnight at room temperature. The phases are separated, the organic phase is washed repeatedly with water, dried over magnesium sulfate and evaporated in vacuum. The residue is purified by chromatography on silica gel using dichloromethane/1-10% ethanol. Get 8,02 g of compound indicated in the title, in the form of a viscous oil.

Elemental analysis:

Rasch.: With 53,01; N 5,02; F 23,19; N 5,26;

found: 53,30; N 5,39; F 23,01; N 5,40.

C) 1-[1-(2,2-dimethyl-1,3-dioxolane-4-yl)-6,6,7,7,8,8,9,9,10,10,11,11,11-traducator-3-oxa]-undecane-1,4,7,10-tetraazacyclododecane

A solution of 7 g (to 6.57 mmol) of 1,4,7-Tris(benzyloxy the Cana 100 ml of isopropyl alcohol is mixed with 0.7 g of palladium on coal (10%) and shaken for 3 hours in hydrogen atmosphere. Make utilitrack from the catalyst and evaporated solution in vacuum. Get 4,20 g of compound indicated in the title, in the form of a glassy foam.

Elemental analysis:

Rasch.: With 41,70; N 5,32; F 37,28; N 8,46;

found: 41,61; N 5,57; F 37,10; N 8,59.

g) 1,4,7-Tris(carboxylatomethyl)-10-[1-(1,2-dihydroxyethyl)-3-oxa-6,6,7,7,8,8,9,9,10,10,11,11,11-traducator]-undecane-1,4,7,10-tetraazacyclododecane

Dissolve to 3.36 g (24,15 mmol) bromoxynil acid in 50 ml of water and mixed with 6 N sodium hydroxide to achieve a pH of 7. At 40°C under stirring simultaneously added dropwise a solution of 4 g (6,04 mmol) 1-[1-(2,2-dimethyl-1,3-dioxolane-4-yl)-6,6,7,7,8,8,9,9,10,10,11,11,11-traducator-3-oxa]-undecane-1,4,1,10-tetraazacyclododecane dissolved in 20 ml of isopropyl alcohol, and so 6 N sodium hydroxide, the pH value is kept at the level of 9-10. After this is mixed with policecontributing hydrochloric acid to obtain pH values of 1 and continue to mix the next 3 hours at 60°C. Cool to room temperature and the solution extracted many times with n-butanol. The organic extract is evaporated and the residue is purified by chromatography on RF-18 using a gradient of water/n-butanol/acetonitrile. Gain of 3.85 g of compound indicated in the title, in the form of the,20; N 4,68; F 31,00; N 7,03;

found: 39,08; N 4,98; F 30,72; N 7,29.

e) gadolinium Complex 1,4,7-Tris(carboxylatomethyl)-10-[1-(1,2-dihydroxyethyl)-3-oxa-6,6,7,7,8,8,9,9,10,10,11,11,11-traducator]-undecane-1,4,7,10-tetraazacyclododecane

Mix the mixture of 1.59 g (2 mmol) of 1,4,7-Tris-(carboxylatomethyl)-10-[1-(1,2-dihydroxyethyl)-3-oxa-6,6,7,7,8,8,9,9,10,10,11,11,11-traducator]undecane-1,4,7,10-tetraazacyclododecane, 25 ml of water and 15 ml of ethanol with 363 mg (1 mmol) of gadolinium oxide and heated for 5 hours under reflux. The hot solution is filtered, evaporated in vacuum and obtain 1.85 g of the compound indicated in the title, in the form of vitreous solids content of water=4.2 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 32,84; N 3,60; F 25,98; Gd 16,54; N of 5.89;

found: 32,53; N 3,71; F 25,72; Gd 16,39; N 5,93.

EXAMPLE 19

The complex gadolinium 1,4,7-Tris(carboxylatomethyl)-10-{2-hydroxy-4-oxa-4-[4-(2H,2H,3H,3H-1-oxopentanoic-1-yl)]-phenyl}-but-1-yl-1,4,7,10-tetraazacyclododecane

a) 1-hydroxy-4-(2H,2H,3H,3H-1-oxopentanoic-1-yl)-benzene

5 g (45,41 mmol) of hydroquinone are mixed with 100 ml of acetone and stirring in turn mixed with 13.8 g of potassium carbonate and 14,04 g (22.7 mmol) of 1-p-toluensulfonate-1H,1H,2H,2H-performacne [see example 7a)]. Heated 6 hours with reverse choleragenic several times with dichloromethane. The organic extract was dried over magnesium sulfate and evaporated in vacuum. The residue is purified by chromatography on silica gel using hexane/5-30% ethyl acetate. Get to 8.20 g of target compound indicated in the title, in the form of a viscous oil.

Elemental analysis:

Rasch.: With 34,55; N 1,63; F 58,07;

found: 34,31; N 1,79; F 58,01.

b) 1-(3,4-epoxy-1-exabot-1-yl)-4-(2H,2H,3H,3H-1-oxopentanoic-1-yl)-benzene

A mixture of 8 g (14,38 mmol) 1-hydroxy-4-(2H,2H,3H,3H-1-oxopentanoic-1-yl)-benzene, 0.4 g of tetrabutylammonium hydrosulfate, 1,60 g (17,26 mmol) of epichlorohydrin, 150 ml dichloromethane and 30 ml of 50% aqueous sodium hydroxide solution intensively stirred for 30 minutes in an ice bath, then intensively stirred for 5 hours at room temperature. Separate the phases, the organic phase is washed with water, dried over magnesium sulfate and evaporated in vacuum. The residue is purified by chromatography on silica gel using hexane/5-30% ethyl acetate and get 6.60 g of the compound indicated in the title, in the form of a viscous oil.

Elemental analysis:

Rasch.: With 37,27; N 2,41; F 52,75;

found: 37,10; N 2,66; F 52,80.

in) 1,4,7-Tris(carboxylatomethyl)-10-{2-hydroxy-4-oxa-4-[4-(2H,2H,3H,3H-1-oxopentanoic-1-yl)]-phenyl}-but-1-yl-1,4,7,10-tetraazacyclododecane

It races the add solution 6,12 g (10 mmol) of 1-(3,4-epoxy-1-exabot-1-yl)-4-(2H,2H,3H,3H-1-oxopentanoic-1-yl)-benzene in 25 ml of tetrahydrofuran and heated for 24 hours under reflux, then evaporated in vacuo, dissolve the residue in 100 ml of water, using 6 N hydrochloric acid to establish a pH value of 3 and repeatedly extracted with n-butanol. The combined extracts evaporated in vacuum. The residue is purified by chromatography on RP-18 using a gradient of water/n-butanol/acetonitrile. Get of 6.71 g of compound indicated in the title, in the form of a viscous oil.

Elemental analysis:

Rasch.: With 41,35; N 4,10; F 33,69; N of 5.84;

found: 41,58; N. Of 4.38; F 33,50; N 5,91.

d) gadolinium Complex 1,4,7-Tris(carboxylatomethyl)-10-{2-hydroxy-4-oxa-4-[4-(2H,2H,3H,3H-1-oxopentanoic-1-yl)]-phenyl}-but-1-yl-1,4,7,10-tetraazacyclododecane

Mix the mixture of 4,79 g (5 mmol) of 1,4,7-Tris(carboxylatomethyl)-10-{2-hydroxy-4-oxa-4-[4-(2H,2H,3H,3H-1-oxopentanoic-1-yl)]-phenyl}-but-1-yl-1,4,7,10-tetraazacyclododecane, 50 ml of water and 30 ml of ethanol 906 mg (2.5 mmol) of gadolinium oxide and heated for 5 hours under reflux. The hot solution is filtered and evaporated in vacuum. Get 5.50 g of the compound shown in the title, as a glassy solid with a water content of 4.9%.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 35,62; N 3,26; F 29,02; Gd. 14,13; N 5,03;

found: 35,40; N 3,50; F 28,81; Gd 14,01; N 5,18.

USE ecil]-3,6,9-creationcontext

a) Complex benzyl ester of N-tert-butoxycarbonylamino-(1H,1H,2H,2H-peritonitis)-simple ether

A solution of 2,953 g (10 mmol) of complex N-tert-butyloxycarbonyl ester (Bachem) in 30 ml of dry dimethylformamide partially administered 300 mg (10 mmol) of sodium hydride (80% in oil). After subsequent dissolution produce mixing with 6,072 g (10 mmol) of tosylate obtained in accordance with example 7a). Stirred for 12 hours at room temperature. Then poured into 500 ml of ice water, absorb the product in dichloromethane, the organic solution is washed with water, dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel. The solvent is a mixture of dichloromethane with increasing addition of methanol. The compound shown in the title, get in the form of syrup. Yield: 5,902 g (79.6% of theory).

Elemental analysis:

Rasch.: With 40,50; N 3,26; F 43,56; N 1,89;

found: 40,64; N 3,37; F 43,49; N, 1,83.

b) Benzyl ester serine-(1H,1H,2H,2H-peritonitis)-simple ether (in the form of a salt triperoxonane acid)

50 ml of a mixture of triperoxonane acid and dichloromethane in the ratio of 2:1 was dissolved 7,414 g (10 mmol) obtained in appropriate evaporated to dryness and remove the residues triperoxonane acid by codistillation using ethanol. Allocate a connection listed in the title, in the form of a salt triperoxonane acid.

Yield: 7,418 g (98.2% of theory).

Elemental analysis:

Rasch.: With 34,98; N 2,27; F 50,30; N 1,85;

found: 34,89; N 2,31; F 50,39; N 1,80.

in Complex di(tert-butyl)ether 3,9-bis(tert-butoxycarbonylmethyl)-6-[(1-benzyloxycarbonyl)-1H,2H,2H,4H,4H,5H,5H-3-ekspertirtizy)-3,6,9-creationcontext

In a mixture of 10 ml of acetonitrile and 20 ml of a phosphate buffer having a pH value of 8.0, add 3,777 g (5 mmol) obtained in accordance with 20B) trifenatate amine and 3,523 g (10 mmol) of N,N-bis(tert-butoxycarbonylmethyl)-2-(bromacil)-amine and 2 hours intensively stirred at room temperature. Then separate buffer phase is extracted with her 10 ml of acetonitrile and add it to the organic phase. After adding 20 ml of fresh buffer solution is stirred for further 20 hours at room temperature. Separate the organic phase evaporated to it, and distribute the rest among 100 ml of phosphate buffer solution (pH 8.0) and 100 ml of ether acetic acid. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The connection specified in the title, purify by chromatography on silica gel. the Noah in the name, obtained as a glassy solid.

Yield: 3,162 g (53.4% of theory).

Elemental analysis:

Rasch.: With 48,69; N 5,62; F 27,28; N 3,55;

found: 48,82; N 5,72; F 27,37; N 3,50.

g) 3,9-bis(carboxymethyl)-6-[(1-carboxy)-1H,2H,2H,4H,4H,5H,5H-3-ekspertirtizy]-3,6,9-creationdatetime

In a mixture of 25 ml triperoxonane acid/dichloromethane in the ratio 2:1 add 5,920 g (5 mmol) of the compound obtained according to 20V). Stirred at room temperature overnight, evaporated to dryness, absorb the residue in 100 ml with 3 N hydrochloric acid, heated for 3 hours under reflux and then evaporated in vacuum to dryness and absorb in 160 ml of a mixture of water, ethanol and chloroform (10:5:1). By adding ion exchanger IRA-67 (HE--form) in solution establish a constant pH value (equal to 3). Quickly produce suction and receive the connection specified in the title, in the form of a glassy solid.

Yield: 3,080 g (71,3% of theory).

Water content: 11.3 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 34,53; N 3,25; F 37,15; N a 4.83;

found: 34,41; N 3,32; F 37,29; N 4,90.

e) gadolinium Complex, disodium salt of 3,9-bis(carboxymethyl)-6-[(1-carboxy)-1H,2H,nanola add 2,941 g (3.0 mmol, designed by 11.3% water content) obtained in paragraph 20 (g) acid. Under stirring and heating to 50°C. add part by part 543,8 mg (1.5 mmole) of gadolinium oxide. After adding the mix to the formation of the solution. Then set the value of pH to 7.2 by adding sodium hydroxide. Then the solution pariveda, and there is a strong foaming. The remainder magisteriums distilled water. Get the connection specified in the title, in the form of a glassy solid.

Yield: 3,489 g (quantitative).

Water content: 8.2 percent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 28,12; N 2,17; F 30,25; Gd 14,73; N 3,94; Na or 4.31;

found: 28,25; N. Of 2.26; F 30,40; Gd 14,85; N 3,99; Na of 4.38.

EXAMPLE 21

The gadolinium complex, monosodium salt of 3,6,9-Tris(carboxymethyl)-3,6,9-creationcontext-mono-N-{ethyl-2-amino-[carboxymethylamino-(N-ethyl-N-PerformanceCounter)]-amide

a) 3,6,9-Tris(carboxymethyl)-3,6,9-creationcontext-mono-N-{ethyl-2-amino-[carboxymethylamino-(N-ethyl-N-PerformanceCounter)]}-amide

200 ml of a mixture of dimethylformamide and dichloromethane in the ratio of 4:1 is suspended 17,87 g (50 mmol) of bisengimana diethylenetriaminepentaacetic acids of the N-PerformanceCounter]-aminouksusnoy acid and 6.50 g (64,2 mmole) of triethylamine. 5 hours mix, evaporated to dryness, mixed with 300 ml of ice water, adjust the pH value of the mixture with 3 N hydrochloric acid equal to about 3. Extracted twice, each time with 200 ml of n-butanol, combine the organic solutions and evaporated. The product was then purified by chromatography on silica gel RP-18. As the solvent are water and tetrahydrofuran. Get the connection given in the title, in the form of a glassy solid.

Yield: 2,722 g (54,3% of theory).

Water content: 9.7 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 33,54; N 3,52; F 32,21; N Scored 8.38; S 3,20;

found: 33,65; N 3,60; F 32,14; N 8,51; S 3,29.

b) gadolinium Complex, monosodium salt of 3,6,9-Tris(carboxymethyl)-3,6,9-creationcontext-mono-N-{ethyl-2-amino-[carbonylmethyl-(N-ethyl-N-PerformanceCounter)]-amide

In 90 ml of a mixture of distilled water and ethanol (2:1) add 3,259 g (3 mmol, calculated by 9.7% water) of the compound obtained under paragraph 21A). Under stirring in parts add 543,8 mg (1.5 mmol) of gadolinium oxide. Mix to form a solution, then set the value of pH to 7.2 by adding sodium hydroxide and evaporated, and by name, in the form of a glassy solid.

Yield: 3,861 g (quantitative).

Water content: 8.4 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 28,53; N 2,65; F 27,40; Gd 13,34; N 7,13; Na 1,95;

S 2,72;

found: 28,61; N 2,68; F 27,48; Gd 13,40; N 7,08; Na 1,99;

S was 2.76.

EXAMPLE 22

The gadolinium complex, monosodium salt of 3,9-bis(carboxymethyl)-6-1H,1H,4H,4H,5H,5H,8H,8H,10H,10H,11N,11N,-2,7-dioxa-3,6-diaza-9-occupationall)-3,6,9-creationcontext

a) N-(2-amino-ethyl)-amide (1H,1H,2H,2H-peritonitis)-simple ester of glycolic acid

In 80 ml of dichloromethane is dissolved 10,44 g (20 mmol) of compound 2B) and mixed with 2.30 g (20 mmol) of N-hydroxysuccinimide, and of 4.13 g (20 mmol) of dicyclohexylcarbodiimide. Stirred over night, filtered from dicyclohexylamine and the filtrate is placed in a solution of 60.1 g (1000 mmol) of Ethylenediamine in 100 ml of dichloromethane. Stirred overnight, mixed with 1.5 liters of water and separate the organic phase. The dichloromethane solution is washed with water, dried over sodium sulfate, evaporated to dryness and purify the residue by chromatography on silica gel. The solvent is a mixture of dichloromethane with increasing addition of ISO-propanol.

Yield: 9p>b) N-[ethyl-2-(benzyloxycarbonylamino)]-amide (1H,1H,2H,2H-peritonitis) simple ester of glycolic acid

In 15 ml of dichloromethane is dissolved 2,092 g (10 mmol) of benzyloxycarbonylglycine and mixed with 1,151 g (10 mmol) of N-hydroxysuccinimide, as well as with 2,063 g (10 mmol) dicyclo-hexylcaine. Stirred over night, filtered from dicyclohexylamine and evaporated to dryness. The residue is purified on silica gel by chromatography on a column. The solvent is a mixture of dichloromethane and ethanol. Get the connection given in the title, in the form of a glassy solid.

Yield: 6,905 g (91,4% of theory).

Elemental analysis:

Rasch.: With 38,16; N 2,94; F 42,75; 5,56 N;

found: 38,28; N 2,98; F 42,82; N 5,50.

C) N-[ethyl(2-aminomethylpyrrolidine)]-amide (1H,1H,2H,2H-peritonitis)-simple ester of glycolic acid

100 ml of a mixture of tetrahydrofuran and ethanol in the ratio 2:1 hydronaut 3,777 g (5 mmol) of the compound obtained in paragraph 22b), in the presence of 0.2 g of Pearlman-catalyst (Pd 20%/S) to absorb 112 ml of hydrogen. Produce suction catalyst, well washed with ethanol and evaporated to dryness. Get the connection given in the title, in the form of a glassy solid is 1,98; N 6,76;

found: 30,87; N 2,64; F Br52.11; N 6,82.

d) Complex bis(tert-butyl ether) 3,9-bis(tert-butyloxycarbonyl)-6-(1H,1H,4H,4H,5H,5H,8H,8H,10H,10H,11N,11N-2,7-dioxa-3,6-diaza-9-oxopentanenitrile)-3,6,9-creationcontext

In a mixture of 10 ml of acetonitrile and 20 ml of phosphate buffer having a pH value of 8, enter 3,107 g (5 mmol) of the amine obtained in paragraph 22b), and 3,523 g (10 mmol) of N,N-bis(tert-butyloxycarbonyl)-2-(bromacil)-amine and 2 hours intensively stirred at room temperature. Then separate the buffer phase, exteriour her 10 ml of acetonitrile and add it to the organic phase. After adding 20 ml of fresh buffer is stirred for further 20 hours at room temperature. Separate the organic phase evaporated to it, and distribute the rest among 100 ml of phosphate buffer (pH 8.0) and 100 ml of acetic ether. The organic phase is washed with saturated common salt solution, dried on sodium sulfate and evaporated. Connection purified on silica gel using chromatography. The solvent is dichloromethane with increasing addition of methanol. Get the connection given in the title, in the form of a glassy solid.

Yield: 3,044 g (52.3% of theory).

Elemental Anan,8H,8H, 10H,10H,11N,11H-2,7-dioxa-3,6-diaza-9-occupationall)-3,6,9-creationdatetime

In a mixture of 120 ml triperoxonane acid/dichloromethane in the ratio 2:1 enter 5,820 g (5 mmol) of the compound obtained in paragraph 22 g). Left to mix overnight at room temperature, evaporated to dryness, remove the residues triperoxonane acid by codistillation ethanol and absorb in 240 ml of a mixture of water, ethanol and chloroform. The solution set by adding ion exchanger IRA-67 (HE--form) remain constant pH value (about 3). Quickly sucked off, evaporated and get the connection given in the title, in the form of a glassy solid.

Yield: 3,214 g (68.4% of theory).

Water content: 10,3%.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 35,79; N 3,65; F 34,37; N 7,45;

found: 35,90; N 3,72; F 34,31; N 7,51.

e) gadolinium Complex, monosodium salt of 3,9-bis(carboxymethyl)-6-(1H,1H,4H,4H,5H,5H,8H,8H,10H,10H,11N,11N,-2,7-dioxa-3,6-diaza-9-oxopentanenitrile)-3,6,9-creationcontext

In a mixture of 60 ml of distilled water and 30 ml ethanol add 3,143 g (3.0 mmol, calculated by 10.3% water content) obtained in paragraph d), acids. When peremeshivayte before the formation of the solution. Then set the pH of the solution to 7.2 by adding sodium hydroxide. Then the solution pariveda, and there is a strong foaming. The remainder magisteriums distilled water. Get the connection specified in the title, in the form of a glassy solid.

Yield: 3,635 g (quantitatively).

Water content: 7.9 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 30,14; N 2,71; F 28,75; Gd 14,09; N 6,28; Na to 2.06;

found: 30,21; N 2,78; F 29,03; Gd 14,16; N 6,22; Na 2,11.

EXAMPLE 23

The complex gadolinium 3,6,9-Tris(carboxymethyl)-3,6,9-creationcontext-bis{N-[2-amino-ethyl-(N-utilisationtechnologies]-amide}

(a) Amide N-ethyl-(2-benzyloxycarbonylamino)-performancelevel acid

In 30 ml of dimethylformamide is dissolved 5,272 g (10 mmol) of N-ethylamide performancelevel acid. Under exclusion of moisture mixed with 330 mg (11 mmol) of sodium hydride (80% in oil). After the evolution of gas added dropwise a solution of 2,093 g (10 mmol) of N-benzyloxycarbonylglycine. Poured into 300 ml ice water, extracted with dichloromethane, the organic solution is washed with water, dried over sodium sulfate and evaporated to dryness. The remainder chromatographic on silica gel with n the

Yield: 6,149 g (87,3% of theory).

Elemental analysis:

Rasch.: With 34,10; N 2,43; F 45,85; N 3,98; S 4,55;

found: 34,00; N 2,49; F 45,97; N 4,06; S 4,49.

b) N-ethyl-N-2-(aminoethyl)-perftorgeksilsilanami

100 ml of a mixture of tetrahydrofuran and ethanol in the ratio 2:1 hydronaut 3,522 g (5 mmol) of the compound obtained in paragraph 23a), in the presence of 0.2 g of Pearlman/catalyst (Pd 20%/S) to absorb 112 ml of hydrogen. Produce suction catalyst, well washed with ethanol and evaporated to dryness. Get the connection given in the title, in the form of an amorphous solid.

Yield: 2,814 g (98,7% of theory).

Elemental analysis:

Rasch.: With 25,27; N 1,9; F 56,6; N 4,9; S 5,6;

found: From 25.3; N 1,9; F 56,5; N 4,9; S of 5.53.

b) 3,6,9-Tris(carboxymethyl)-3,6,9-creationcontext-bis{N-[2-amino-ethyl-(N-ethyl-N-PerformanceCounter)]-amide}

In 30 ml of dry dimethylformamide is dissolved 5,703 g (10 mmol) of the compound obtained in paragraph 23B), and 1,518 g (15 mmol) of triethylamine and parts under stirring and exclusion of moisture with 1,787 g (5 mmol) of bisengimana diethylenetriaminepentaacetic acid. Leave the mix overnight, then evaporated, mixed with water, and the pH value with 3 N hydrochloric acid is set to AP subjected to chromatography on silica gel RP-18. As the solvent are water and tetrahydrofuran. The connection specified in the title, is a glassy solid.

Yield: 6,172 g (82,4% of theory).

Water content: 9.8 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 30,47; N Was 2.76; F 43,12; N 6,55; S 4,28;

found: 30,59; N 2,81; F 43,00; N 6,61; S 4,33.

d) gadolinium Complex of 3,6, 9-Tris(carboxymethyl)-3,6,9-creationcontext-bis{N-[2-amino-ethyl-(N-utilisationtechnologies]-amide}

In a mixture of 120 ml of distilled water, 60 ml of ethanol and 20 ml of chloroform, add 6,570 g (4.0 mmol, calculated by 9.8% water content) of the compound obtained in paragraph 23C). Under stirring and heating to 50°C. add part by part 725 mg (82,0 mmole) of gadolinium oxide. Mix to form a solution, evaporated, and there is a strong foaming, and the remainder magisteriums distilled water. Codistillation repeated twice. Get the connection specified in the title, in the form of a glassy solid.

Yield: 7,191 g (quantitatively).

Water content: 8,1%.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 27,63; N 2,32; F 39,10; Gd 9,52; N 5,93; S 3,88;

found: Of 27.50; N 2,37; F To 39.22; Gd Being 9.61; N 5, the Teal-[glycolic acid-(1H,1H,2H,2H-peritonitis-simple ether)-amide]>-amide}

a) 3,6,9-Tris(carboxymethyl)-3,6,9-creationcontext-bis{N-<2-amino-ethyl-[glycolic acid-(1H,1H,2H,2H-peritonitis-simple ether)-amide]>-amide}

In 40 ml of dry dimethylformamide is dissolved 6,771 g (12 mmol) of the compound obtained in example 22A), as well as 1,821 g (18 mmol) of triethylamine and parts under stirring and exclusion of moisture with 2,144 g (6 mmol) of bisengimana diethylenetriaminepentaacetic acid. Leave the mix overnight, then evaporated, mixed with 20 ml of water, and the pH value with 3 N hydrochloric acid is set to approximately 3 and extracted twice each time with 150 ml of butanol. The organic solutions are combined evaporated and the residue is subjected chromatography on silica gel RP-18. As the solvent are water and tetrahydrofuran. Get the connection specified in the title, in the form of a glassy solid.

Yield: 6,989 g (78.4% of theory).

Water content: 7,1%.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 33,95; N 3,05; F 43,47; N 6,60;

found: To 34.06; N 3,11; F 43,40; 6,67 N.

b) gadolinium Complex 3,6,9-Tris(carboxymethyl)-3,6,9-creationcontext-bis{N-<2-amino-ethyl-[glycolic acid-(1H,1H,2H,2H-peritonitis-simple ether)-amide]>-icannga 7.1% water content) connection, obtained in item 24A). Under stirring and heating to 50°C. add part by part 543,8 g (1.5 mmole) of gadolinium oxide. Mix to form a solution, evaporated, and there is a strong foaming, and the remainder magisteriums several times with distilled water. Get the connection specified in the title, in the form of a glassy solid.

Yield: 5,285 g (quantitatively).

Water content: 6.9 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 30,76; N 2,58; F 39,39; Gd 9,59; N 5,98;

found: 30,87; N 2,65; F 39,51; Gd RS 9.69; N 6,11.

EXAMPLE 25

The gadolinium complex, sodium salt of 3,9-bis(carboxymethyl)-6-[N-(1H,1H,2H,2H-peritonitis)-aminocarbonylmethyl-3,6,9-creationcontext

a) N-(1H,1H,2H,2H-peritonitis)-amide N-benzyloxycarbonylglycine

In 70 ml of dichloromethane is dissolved 7,877 g (15 mmol) of 1H,1H,2H,2H-perpendiculaire [J. Fluor. Chem. 55, 85 (1991)] and mix with a cash consideration of USD 1,726 g (15 mmol) of N-hydroxysuccinimide, 3,095 g (15 mmol) of dicyclohexylcarbodiimide and 3,138 g (15 mmol) of N-benzyloxycarbonylglycine (Bachem). Leave the mix overnight, filtered off dicyclohexylamine, evaporated and the residue is subjected to chromatography on a column of silica gel. As solvents is the d of the finished product: 8,951 g (91.2% of theory).

Elemental analysis:

Rasch.: With 36,71; N 2,31; F 49,36; N 4,28;

found: 36,87; N 2,39; F 49,51; N 4,37.

b) Glycine-N-(1H,1H,2H,2H-peritonitis)-amide

150 ml of a mixture of tetrahydrofuran and ethanol in the ratio of 2:1 was dissolved 7,594 g (10 mmol) of the compound obtained in paragraph 28a), and in the presence of 0.25 g of Pearlman-catalyst (Pd 20%/S) prior to the acquisition 224 ml of hydrogen. Produce suction catalyst, well washed with ethanol and evaporated to dryness. Get the connection given in the title, in the form of an amorphous solid.

Yield: 6,21 g (99.3% of theory).

Elemental analysis:

Rasch.: With 25,37; N 1,60; F 56,84; N 4,93;

found: 25,28; N 1,65; F 56,92; N 4,99.

C) Di(tert-butyl ether) 3,9-bis(tert-butyloxycarbonyl)-6-N-[1H,1H,2H,2H-peritonitis)-aminocarbonylmethyl-3,6,9-creationcontext

In a mixture of 10 ml of acetonitrile and 20 ml of a phosphate buffer having a pH value of 8, enter 2,841 g (5 mmol) of the amine obtained in paragraph 25B), and 3,875 g (11 mmol) of N,N-bis(tert-butyloxycarbonyl)-2-(bromacil)-amine and 2 hours intensively stirred at room temperature. Then separate buffer phase is extracted with her 10 ml of acetonitrile and add it to the organic phase. After adding 20 ml of fresh buffer is stirred for further 20 hours at the o buffer (pH 8.0) and 100 ml of acetic ether. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The compound shown in the title, purified on silica gel using chromatography. The solvent is dichloromethane with increasing addition of methanol. Get the connection given in the title, in the form of a glassy solid.

Yield: 4,161 g (78.3% of theory).

Elemental analysis:

Rasch.: With 45,20; N 5,59; F A 30.39; N 5,27;

found: 45,35; N 5,67; F 30,47; N 5,34.

g) 3,9-bis(carboxymethyl)-6-N-(1H,1H,2H,2H-peritonitis)-aminocarbonylmethyl-3,6,9-creationdatetime

In a mixture of 100 ml triperoxonane acid/dichloromethane in the ratio 2:1 add 4,783 g (4.5 mmol) of the compound obtained according to paragraph (25V). Stirred at room temperature overnight, then evaporated to dryness, absorb the remains triperoxonane acid by codistillation ethanol and absorb in 160 ml of a mixture of water, ethanol and chloroform (10:5:1). By adding ion exchanger IRA-67 (HE--form) solution set (constant pH value), equal to approximately 3. Quickly produce suction and receive the connection specified in the title, in the form of a glassy solid.

Rasch.: With 34,38; N 3,25; F 38,52; N 6,68;

found: 34,29; N To 3.33; F 38,65; N 6,77.

e) gadolinium Complex, monosodium salt of 3,9-bis(carboxymethyl)-6-N-(1H,1H,2H,2H-peritonitis)-aminocarbonylmethyl-3,6,9-creationcontext

In a mixture of 60 ml of distilled water and 30 ml ethanol add 2,823 g (3.0 mmol, calculated by 10.9% water content) of the compound obtained under paragraph 25 g). Under stirring and heated to 50°C in parts add 543,8 mg (1.5 mmol) of gadolinium oxide. After adding the mix to the formation of the solution. Then set the value of pH to 7.2 by adding sodium hydroxide. The solution is evaporated. Thus, there is a strong foaming. The remainder magisteriums double-distilled water. Get the connection specified in the title, in the form of a glassy solid.

Yield: 3,353 g (Quant).

Water content: 9.2 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 28,41; N 2,28; F 31,83; Gd 15,50; N 5,52; Na 2,27;

found: 28,51; N 2,33; F 31,76; Gd 15,57; N 5,46; Na 2,35.

EXAMPLE 26

The gadolinium complex, disodium salt of 3,6,9-Tris(carboxymethyl)-4-[4-(1H,1H,2H,2H-perpendicularly)-benzyl]-3,6,9-creationcontext

a) Di(tert-butyl ether) 3,6,9-Tris(t is about dimethylformamide is dissolved 6,131 g (5 mmol) of di(tert-butyl ether) 3,6,9-Tris(tert-butyloxycarbonyl)-4-(4-hydroxybenzyl)-3,6,9-creationcontext, presents PCT WO 88/07521, and portions under stirring and exclusion of moisture mixed with 150 g (5 mmol) of sodium hydride (80% in oil). After dissolution mix 3,092 g (5 mmol) of tosylate obtained in example 7a). Stirred for 12 hours at 40°C. Then poured into 500 ml of ice water, absorb the product in dichloromethane, the organic solution is washed with water, dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel. The solvent is a mixture of dichloromethane, isopropanol, and hexane in a ratio of 20:1:5.

Get the connection specified in the title, in the form of an amorphous solid.

Yield: 5,015 g (81.8% of theory).

Elemental analysis:

Rasch.: With 49,96; N. Of 5.92; F 26,34; N 3,43;

found: 50,11; 6,00; F 26,43; N 3,38.

b) 3,6,9-Tris(carboxymethyl)-4-[4-(1H,1H,2H,2H-perpendicularly)-benzyl]-3,6,9-creationcontext

100 ml of a mixture of triperoxonane acid and dichloromethane in the ratio of 2:1 was dissolved 3,678 g (3 mmol) of the compound obtained according to paragraph 26a), stirred at room temperature overnight. Then evaporated to dryness, remove the residues triperoxonane acid by codistillation ethanol. Absorb residue in 160 ml of a mixture of water, ethanol, pH), equal to approximately 3. Quickly produce suction and receive the connection specified in the title, in the form of a glassy solid.

Yield: 2,357 g (83.1% of theory).

Water content: 11.3 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 39,38; N 3,41; F 34,16; N of 4.44;

found: 39,52; H 3,47; F 34,32; N 4,36.

C) gadolinium Complex, disodium salt of 3,6,9-Tris(carboxymethyl)-4-[N-{1H,1H,2H,2H-perpendicularly)-benzyl]-3,6,9-triaza-untenantability

In a mixture of 60 ml of distilled water and 30 ml ethanol add 3,145 g (3.0 mmol, calculated by 11.3% water content) of the compound obtained under paragraph 26B). Under stirring and heated to 50°C in parts add 543,8 mg (1.5 mmol) of gadolinium oxide. After adding the mix to the formation of the solution. Then set the value of pH to 7.2 by adding sodium hydroxide. The solution is evaporated. Thus, there is a strong foaming. The remainder magisteriums double-distilled water. Get the connection specified in the title, in the form of a glassy solid.

Yield: 3,804 g (quantitatively).

Water content: 9.8 per cent.

Elemental analysis (relative to anhydrous is

The gadolinium complex of 10-[(-PerformanceCounter)-piperazine-1-yl carboxymethyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

a) 1-performancecounterpermission

34,39 g (398,3 mmol) piperazine, 50 g (99,6 mmol) performancemonitoring and 10,12 g (100 mmol) of triethylamine are heated for 24 hours to a temperature of 85°C. Add 500 ml of water and extracted twice each time with 200 ml of dichloromethane. The organic phase is dried over magnesium sulfate and evaporated in vacuum to dryness. The remainder chromatographic on silica gel (Solvent: dichloromethane/2-propanol=25/1).

Yield: 17,55 g (31% of theory) of colorless amorphous solid.

Elemental analysis;

Rasch.: With 25,36; N 1,60; F 56,84; N 4,93; S 5,64;

found: To 25.15; H 1,80; F 56,65; N 4,81; S 5,70.

b) 1-(2-bromoacetyl)-4-performancecounterpermission

17 g (of 29.9 mmol) of the compound shown in the title of example 27A) and 5.1 g (50 mmol) of triethylamine are dissolved in 100 ml of dichloromethane. At -10°C for 30 minutes, added dropwise to 9.1 g (of 44.9 mmol) bromoacetamide and stirred for 2 hours at 0°C. the Solution is poured into 200 ml of 2 N hydrochloric acid and mix well. The organic phase is separated, dried over magnesium sulfate and evaporated in vacuum. The remainder chromatography yellowish waxy solid.

Elemental analysis:

Rasch.: With 24,40; N Of 1.46; F 46,86; N 4,06; S 4,65; Br 11,59;

found: 24.22 To; N 1,60; F 46,75; N 3,97; S 4,48; Br 11,41.

b) 10-[(-PerformanceCounter)-piperazine-1-yl-carbonylmethyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

To 17,78 g (20 mmol) of the compound indicated in the title of the example b) in 180 ml of methanol add 4,63 (made 13.36 mmole) of 1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (D3A) and 18.5 g (133,6 mmol) of potassium carbonate. Boil for 12 hours by using the reverse flow. The inorganic salt is filtered off and the filtrate evaporated to dryness. The residue is absorbed in 100 ml of water, and the acidity install 5 N hydrochloric acid equal to pH 3. Extracted 2 times with 150 ml of n-butanol. The combined organic phases are evaporated in vacuum to dryness, and the residue is purified by RP chromatography (RP-18/Solvent: gradient of water/n-butanol/acetonitrile).

Yield: 12,79 g (67% of theory) of colorless solid.

Water content: 8.5 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 35,23; N 3,70; F 33,83; N 8,80; S 3,36;

found: 35,17; H 3,81; F 33,67; N 8,65; S 3,18.

d) gadolinium Complex of 10-[(-PerformanceCounter)-piperazine-1-yl-carbonylmethyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-Tetris Prov./20 ml of ethanol and add 1,90 g (5,23 mmol) of gadolinium oxide. Stirred for 4 hours at 80°C. the Solution is filtered and evaporated to dryness in a vacuum.

Yield: 12.2 g (quantitatively).

Water content: 5,1%.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 30,33; N 2,91; F 29,13; Gd 14,18; S 2,89;

found: From A 30.39; N 2,81; F 29,02; Gd 14,01; S 2,78.

EXAMPLE 28

The gadolinium complex, monosodium salt of 3,9-bis(carboxymethyl)-6-[(4-PerformanceCounter)-piperazine-1-carbonylmethyl]-3,6,9-creationcontext

a) 1-(2-benzyloxycarbonylamino)-methyl-carbonyl-4-(PerformanceCounter)-piperazine

In 80 ml of dichloromethane is dissolved 8,524 g (15 mmol) of a derivative of piperazine obtained in paragraph 27A), and mixed with a cash consideration of USD 1,726 g (15 mmol) of N-hydroxysuccinimide, 3,095 g (15 mmol) of dicyclohexylcarbodiimide and 3,138 g (15 mmol) of N-benzyloxycarbonylglycine (Bachem). Leave the mix overnight, filtered off dicyclohexylamine, evaporated and the residue is subjected to chromatography on a column on silica gel. As solvents are a mixture of dichloromethane and ethanol. The compound shown in the title, get in the form of solids.

Yield: 10,16 g (89.2% of theory).

Elemental analysis:

Rasch.: With 34,79; N 2,39; F 42,53; N Of 5.53; S 4,22;

found: When rufuran and ethanol in the ratio of 2:1 was dissolved 7,594 g connection obtained in paragraph 28a), and hydronaut in the presence of 0.25 g of Pearlman-catalyst (Pd 20%/S) prior to the acquisition 224 ml of hydrogen. Produce suction catalyst, well washed with ethanol and evaporated to dryness. Get the connection given in the title, in the form of an amorphous solid.

Yield: 6,21 g (99.3% of theory).

Elemental analysis:

Rasch.: With 26,89; N 1,93; F 51,65; N 6,72; S 5,13;

found: 27,03; N 1,97; F 51,77; N To 6.58; S 5,20.

C) Di(tert-butyl ether) 3,9-bis(tert-butyloxycarbonyl)-6-[(4-PerformanceCounter)-piperazine-1-carbonylmethyl]-3,6,9-triazaundecamethylenediamine acid

In a mixture of 10 ml of acetonitrile and 20 ml of a phosphate buffer having a pH value of 8, enter 3,127 g (5 mmol) of the amine obtained in item 28B), and 3,875 g (11 mmol) of N,N-bis(tert-butyloxycarbonyl)-2-(bromacil)-amine and 2 hours intensively stirred at room temperature. Then separate buffer phase is extracted with her 10 ml of acetonitrile and add it to the organic phase. After adding 20 ml of fresh buffer is stirred for further 20 hours at room temperature. Separate the organic phase evaporated to it, and distribute the rest among 100 ml of phosphate buffer (pH 8.0) and 100 ml of acetic ether. The organic phase is washed with saturated is cidaut on silica gel using chromatography. The solvent is dichloromethane with increasing addition of methanol. Get the connection given in the title, in the form of a glassy solid.

Yield: 4,481 g (76,3% of theory).

Elemental analysis:

Rasch.: With 43,71; N 5,42; F 27,99; N 4,85; S 2,78;

found: 43,84; N 5,47; F 28,10; 5,00 N; S 2,69.

g) 3,9-bis(carboxymethyl)-6-[(4-PerformanceCounter)-piperazine-1-yl-carbonylmethyl]-3,6,9-creationcontext

In a mixture of 100 ml triperoxonane acid/dichloromethane in the ratio 2:1 add 5,193 g (4.5 mmol) of the compound obtained according to paragraph (28V). Stirred at room temperature overnight, then evaporated to dryness, absorb the remains triperoxonane acid by codistillation ethanol and absorb in 160 ml of a mixture of water, ethanol and chloroform (10:5:1). By adding ion exchanger IRA-67 (HE--form) solution set (constant pH), equal to approximately 3. Quickly produce suction and receive the connection specified in the title, in the form of a glassy solid.

Yield: RUB 3,718 g (79,2% of theory).

Water content: 10,9%.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 33,59; N 3,25; F 34,74; N 6,03; S 3,45;

found: 33,69; nil)-piperazine-1-carbonylmethyl]-3,6,9-creationcontext

In a mixture of 60 ml of distilled water and 30 ml ethanol add 3.13 g (3.0 mmol, calculated by 10.9% water content) of the compound obtained under paragraph 28 g). Under stirring and heated to 50°C in parts add 543,8 mg (1.5 mmol) of gadolinium oxide. After adding the mix to the formation of the solution. Then set the value of pH to 7.2 by adding sodium hydroxide. The solution is evaporated. Thus, there is a strong foaming. The remainder magisteriums double-distilled water. Get the connection specified in the title, in the form of a glassy solid.

Yield: 3,678 g (quantitatively).

Water content: 9.2 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 28,24; N 2,37; F 29,21; Gd 14,22; N 5,07; Na 2,08; S 2,90;

found: 28,36; N 2,41; F 29,14; Gd 14,30; N 5,15; Na 2,12; S 2,83

EXAMPLE 29

The complex gadolinium 3,6,9-Tris(carboxymethyl)-3,6,9-creationcontext-bis[(4-PerformanceCounter)-piperazine]-amide

a) Bis[(4-PerformanceCounter)-piperazine]-amide 3,6,9-Tris(carboxymethyl)-3,6,9-creationcontext

In 30 ml of dry dimethylformamide is dissolved 5,683 g (10 mmol) of the compound obtained according to paragraph 27A), and 1,518 g (15 mmol) of triethylamine s acid. Leave the mix overnight, then evaporated, mixed with water, and the pH value with 3 N hydrochloric acid is set to approximately 3 and extracted two times with 100 ml of n-butanol. The organic solutions are combined evaporated and subjected to chromatography on silica gel RP-18. As the solvent are water and tetrahydrofuran. The connection specified in the title, is a glassy solid.

Yield: 6,741 g (81,4% of theory).

Water content: 9.8 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 30,55; H 2,50; F 43,24; N 6,56; S 4,29;

found: 30,67; N To 2.55; F 43,33; N Of 6.49; S 4,21.

b) gadolinium Complex 3,6,9-Tris(carboxymethyl)-3,6,9-creationcontext-bis[(4-PerformanceCounter)-piperazine]-amide

In a mixture of 120 ml of distilled water, 60 ml of ethanol and 20 ml of chloroform, add 6,570 g (4 mmol, calculated by 9.8% water content) of the compound obtained under paragraph 23C). Under stirring and heated to 50°C in parts add 725 mg (82,0 mmol) of gadolinium oxide. Mix to form a solution, then evaporated. This forms a strong expansion, the residue is subjected to codistillation distilled water. Codistillation repeating what about the product: 7,191 g (quantitatively).

Water content: 8,1%.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 27,69; N 2,08; F 39,19; Gd 9,54; N 5,95; S 3,89;

found: 27,83; N 2,15; F 39,10; Gd 6,91; N 6,03; S 3,88.

EXAMPLE 30

a) Benzyl ether 11-[N-ethyl-N-(PerformanceCounter)-amino]undecanoate

20 g (37,94 mmol) N-ethyl-N-perftorgeksilsilanami and 15,73 g (113,8 mmol) of potassium carbonate are suspended in 200 ml of acetone and 60°C. are added dropwise 26,96 g (75,87 mmol) of benzyl ester 11-bromoxynil acid. Stirred for 3 hours at 60°C. is Filtered from the salts, the filtrate is evaporated in vacuum to dryness. The remainder chromatographic (solvent: hexane/dichloromethane/acetone=10/10/1) silicagel. After evaporation containing the product fractions, the residue is recrystallized from methanol/ethyl acetate.

Yield: 26,46 g (87% of theory) of colorless crystalline powder.

Elemental analysis:

Rasch.: With 41,95; N Was 4.02; N Of 1.75; F 40,29; S 4,00;

found: 41,78; N 4,17; N 1,68; F 40,12; S 3,88.

b) 11-[N-ethyl-N-(PerformanceCounter)-amino]-undecanoate acid

20 g (24,95 mmole) of the compound shown in the title of example 30A), dissolved in 300 ml isopropanol/200 ml dichloromethane and add 3 g of palladium catalyst (10% Pd/C). Hydronaut over night at room temperaturerange ether/hexane.

Yield: 16,69 g (94% of theory) of colourless crystalline solid product.

Elemental analysis:

Rasch.: With 35,45; N 3,68; N 1,97; F 45,39; S 4,51;

found: 35,31; H 3,81; N 1,85; F 45,25; S 4,42.

C) gadolinium Complex of 10-[2-hydroxy-4-Aza-5-oxo-16-Aza-16-(PerformanceCounter)-octadecyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

12,16 g (17,09 mmol) of the compound shown in the title of example 30B), and 1.97 g (18,79 mmol) of N-hydroxysuccinimide dissolved in a mixture of 50 ml of dimethylformamide/50 ml of chloroform. At 0°C add 3.88 g (18,79 mmol) dicyclohexylcarbodiimide and stirred for 1 hour at 0°C, then 3 hours at room temperature. Again cooled to 0°C and add 5,19 g (51,27 mmol) of triethylamine/50 ml 2-propanol. After that add 10,78 g (18,79 mmol) of the gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (WO 95/17451), dissolved in 50 ml of water, and stirred for 3 hours at room temperature. Evaporated to dryness and the residue is absorbed in a mixture of 200 ml methanol/100 ml of chloroform and filtered from dicyclohexylamine. The filtrate is evaporated to dryness and purified by RP-chromatography (RP-18/Solvent: gradient of water/n-propanol/acetonitrile).

The output ready productlis (relative to anhydrous substance):

Rasch.: With 36,02; N 4,30; F 25,49; Gd 12,41; N 6,63; S 2,53;

found: 35,87; N. Of 4.45; F 25,28; Gd 12,29; 6,50 N; S 2,41.

d) 10-[2-hydroxy-4-Aza-5-oxo-16-Aza-16-(perforater-sulfonyl-octadecyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

11.1 g (8,76 mmol) of the compound shown in the title of example 30B), dissolved in a mixture of 100 ml water/100 ml ethanol and added 1.73 g (13,71 mmol) of oxalic acid dihydrate. Heated 8 hours to 80°C. is Cooled to 0°C and filtered from the gadolinium oxalate. The filtrate is evaporated to dryness and the residue is purified on RP-18 (RP-18/Solvent: water/isopropanol/acetonitrile).

Yield: 9.80 g (92% of theory) of a vitreous solid.

Water content: 8.5 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 41,01; H 5,16; F 29,02; N 7,55; S 2,88;

found: 40,87; N 5,31; F 28,85; N 7,40; S 2,73.

e) ytterbium Complex of 10-[2-hydroxy-4-Aza-5-oxo-16-Aza-16-(performancecountercategory]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

To 5,64 g (5,07 mmol) of the compound shown in the title of the example 30g), in 100 ml of water/50 ml of ethanol is added to 1.33 g (2,53 mmole) of ytterbium carbonate and stirred for 3 hours at 80°C.

The solution is filtered, and the filtrate is evaporated to dryness in a vacuum.

Yield: 7,08 g (the number of the anhydrous substance):

Rasch.: With 35,58; N 4,24; F 25,17; N 6,55; S 2,50; Yb 13,49;

found: 35,43; N 4,37; F 25,05; N 6,48; S 2,39; Yb 13,35.

(e) dysprosium Complex of 10-[2-hydroxy-4-Aza-5-oxo-16-Aza-16-(performancecountercategory]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

To 5,64 g (5,07 mmol) of the compound shown in the title of the example 30g) in 100 ml of water/50 ml of ethanol is added 0.95 g (2,53 mmole) oxide dysprosium and stirred for 3 hours at 80°C. the Solution is filtered, and the filtrate is evaporated to dryness in a vacuum.

Yield: 7,10 g (quantitative) of a colorless glassy solid.

Water content: 9.1 per cent.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 35,87; N 4,28; F 25,38; N 6,60; S 2,52; Dy 12,77

found: 35,69; N 4,39; F 25,18; N Of 6.49; S 2,43; Dy 12,70

EXAMPLE 31

a) Tert-butyl ether 11,11,11,10,10,9,9,8,8,7,7-traducator-3-accountcasino acid

To a solution of 27,57 g (75,73 mmol) of 1H,1H,2H,2H-perfluorooctane-1-ol and 2.57 g (EUR 7.57 mmole) of tetrabutylammonium hydrosulfate in 300 ml of 60% aqueous solution of caustic potassium/200 ml of toluene was added dropwise with vigorous stirring at 0°C 19,51 g (100.0 mmol) of tert-butyl methyl ether bromoxynil acid. Produce stirring for one hour at 0°C. the organic phase is separated and the aqueous phase is extracted with 2 times every F vacuum. The residue is purified by chromatography on silica gel (Solvent: dichloromethane).

Yield: 28,97 g (80% of theory) of colourless oil.

Elemental analysis:

Rasch.: With 35,16; N 3,16; F to 51.64;

found: 35,08; N 3,20; F 51,70.

b) 11,11,11,10,10,9,9,8,8,7,7-traducator-3-accountequity acid

25,29 g (52,88 mmol) of the compound shown in the title of example 1A) is dissolved in 300 ml triperoxonane acid and stirred overnight at room temperature. Produce evaporation to dryness in vacuo and crystallization of the residue from hexane/diethyl ether.

Yield: 20,54 g (92% of theory) of colourless crystalline solid.

Elemental analysis:

Rasch.: With 28,45; N 1,67; F 58,51;

found: 28,36; N 1,60; F 58,62.

C) gadolinium Complex of 10-[2-hydroxy-4-Aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,14,14,15,15,15-tridecapeptide]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

7,21 g (17,09 mmol) of the compound shown in the title of example 31B), and 1.97 g (18,79 mmol) of N-hydroxysuccinimide dissolved in a mixture of 50 ml of dimethyl formamide/50 ml of chloroform. At 0°C add 3.88 g (18,79 mmol) dicyclohexylcarbodiimide and stirred for 1 hour at 0°C, then 3 hours at room temperature. Cooled again to 0°C and dobavleno-2-hydroxypropyl)-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (WO 95/17451), dissolved in 50 ml of water, and stirred for 3 hours at room temperature. Evaporated to dryness, absorb the residue in a mixture of 200 ml methanol/100 ml of chloroform and filtered from dicyclohexylamine. The filtrate is evaporated to dryness and purified using RP-chromatography (RP-18/Solvent: mixture of water/n-propanol/acetonitrile).

Yield: 12,68 g (71% of theory.) colorless glassy solid.

Water content: 6,4%.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 33,16; N 3,61; F 25,26; Gd 16,08; N 7,16;

found: 32,85; N 3,84; F 25,01; Gd trend of 15.87; N 7,03.

EXAMPLE 32

a) Tert-butyl ether 15,15,15,14,14,13,13,12,12,11,11,10,10,9,9,8,8,7,7-helicobater-3-oxopentanoic acid

To a mixture of 42,72 g (75,73 mmol) of 1H,1H.2N.2H-perfluorooctane-1-ol and 2.57 g (EUR 7.57 mmol) of tetrabutylammonium hydrosulfate in 300 ml of 60% aqueous solution of caustic potassium/200 ml of toluene with vigorous stirring at 0°C is added dropwise 19,51 g (100.0 mmol) of tert-butyl methyl ether bromoxynil acid. Stirred for 1 hour at 0°C, the organic phase is separated and the aqueous phase is extracted with two times, each time with 50 ml of toluene. The combined organic extracts dried over sodium sulfate and evaporated in vacuum. The remainder chromatographer is.

Elemental analysis:

Rasch.: With 31,87; N 2,23; F 58,82;

found: 31,73; H 2,20; F 58,90.

b) Tert-butyl ether 15,15,15,14,14,13,13,12,12,11,11,10,10,9,9,8,8,7,7-helicobater-3-oxopentanoic acid

35,87 g (52,88 mmol) of the compound indicated in the title of example 1A) is dissolved in 300 ml triperoxonane acid and stirred overnight at room temperature. Evaporated in vacuum to dryness and the residue is crystallized from hexane/diethylether.

Yield: 30,60 g (93% of theory) of colourless crystalline solid.

Elemental analysis:

Rasch.: With 27,03; N 1,13; F 64,12;

found: 26,91; H 1,20; F 64,02.

C) gadolinium Complex of 10-[2-hydroxy-4-Aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,14,14,15,15,15,16,16,17,17,18,18,19,19,19-henicopernis]-1,4,7-Tris(carboxymethyl)-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10,63 g (17,09 mmol) of the compound shown in the title of example 32b), and 1.97 g (18,79 mmol) of N-hydroxysuccinimide dissolved in a mixture of 50 ml of dimethyl formamide/50 ml of chloroform. At 0°C add 3,88 (18,79 mmol) dicyclohexylcarbodiimide and stirred for 1 hour at 0°C, then 3 hours at room temperature. Cooled again to 0°C and add 5,19 g (51, 27 mmol) triethylamine/50 ml 2-propanol. Then add 10,78 g (18,79 mmole) comp is extended in 50 ml of water, and stirred for 3 hours at room temperature. Evaporated to dryness, absorb the residue in a mixture of 200 ml methane/100 ml of chloroform and filtered from dicyclohexylamine. The filtrate is evaporated to dryness and purified using RP-chromatography (RP-18/Solvent: water/n-propanol/acetonitrile).

Yield: 14,73 g (69% of theory.) colorless glassy solid.

The water content is 5.7%.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 31,61; N 2,99; F 33,87; Gd 13,35; N 5,95;

found: 31,49; N 3,15; F 33,68; Gd 13,21; N 6,01.

EXAMPLE 33

a) Benzyl ester of N-(2-bromopropionyl)glycine

To 100 g (usd296.4 mmole) licensedialog ester salt of p-toluensulfonate acid and 33.0 g (to 326.1 mmole) of triethylamine in 400 ml of methylene chloride are added dropwise at 0°From 55.9 g (to 326.1 mmol) of the chloride of 2-bromopropionic acid. Ensure that the temperature did not rise above 5°C. After the addition is stirred one hour at 0°C., then 2 hours at room temperature. Add 500 ml of ice water and set the aqueous phase with 10% aqueous hydrochloric acid solution to pH 2. The organic phase is separated, each time washing her 300 ml of 5% aqueous soda solution and 400 ml of water. The organic phase wysu the/p>

Yield: 68,51 (75% of theory) of colorless crystalline powder.

Melting point: 69-70°C.

Elemental analysis:

Rasch.: With 48,02; N 4,70; N 4,67; Br 26,62;

found: 47,91; N 4,82; N 4,51; Br 26,47.

b) 1-[4-benzyloxycarbonyl)-1-methyl-2-oxo-3-isobutyl]-1,4,7,10-tetraazacyclododecane

To 55.8 g (324,4 mmol) of 1,4,7,10-tetraazacyclododecane dissolved in 600 ml of chloroform, add 50 g (162,2 mmole) of the compound indicated in the title of example 1A), and stirred overnight at room temperature. Add 500 ml of water, separate the organic phase and washed it 2 times with 400 ml of water. The organic phase is dried over magnesium sulfate and evaporated in vacuum to dryness. The remainder chromatographic on silicagel. (Solvent: chloroform/methanol/ aqueous 25% ammonia-=10/5/1).

Yield: 40,0 g [63% used in example 1A)] a slightly yellowish viscous oil.

Elemental analysis:

Rasch.: With 61,36; N. Of 8.50; N 17,89;

found: 61,54; N 8,68; N 17,68.

b) 10-[4-(benzyloxycarbonyl)-1-methyl-2-oxo-3-isobutyl]-1,4,7-Tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (Complex of sodium bromide)

To 20 g (51,08 mmol) of the compound shown in the title of example 1B), and 17,91 g (169 mmol) of sodium carbonate in 300 ml and is Cooled to 0°C, filter out salts and the filtrate evaporated to dryness. The remainder chromatographic on silica gel (Solvent: ethyl acetate/ethanol: 15/1). Containing the product fractions evaporated and the residue is recrystallized from Diisopropylamine.

Yield: 34,62 (81% of theory) of colorless crystalline powder.

Melting point: 116-117°C.

Elemental analysis:

Rasch.: With 54,54; N To 7.59; N Of 8.37; Na 2,74; Br 9,56;

found: 54,70; N. Of 7.65; N 8,24; Na 2,60; Br 9,37.

d) 10-[4-(carboxy)-1-methyl-2-oxo-3-isobutyl]-1,4,7-Tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (Complex of sodium bromide)

30 g (35,85 mmole) of the compound shown in the title of example 1B), dissolved in 500 ml isopropanol and add 3 g of palladium catalyst (10% Pd/C). Hydronaut over night at room temperature. Filtered from the catalyst and the filtrate evaporated in vacuum to dryness and recrystallized from acetone.

Yield: 22,75 g (85% of theory) of colorless crystalline powder.

Melting point: 225°C.

Elemental analysis:

Rasch.: With 49,86; N. Of 7.69; N 9,38; Na 3,07; Br 10,71;

found: 49,75; N 7,81; N 9,25; Na 2,94; Br of 10.58.

d) 10-[1-methyl-2-oxo-3-Aza-5-oxo-5-(4-performancecounterpermission-1-yl)-pentyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-Tetra is, given the title of example 27A), dissolved in 150 ml of tetrahydrofuran. At 0°C type of 3.97 g (16,07 mmol) N-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), stirred for 3 hours at 0°C, then 12 hours at room temperature. Evaporated in vacuum to dryness. The residue is absorbed in 150 ml triperoxonane acid and stirred for 12 hours at room temperature. Evaporated to dryness, the residue is dissolved in water and with 10% aqueous sodium hydroxide solution set pH of 3.2. For cleaning chromatographic on RP-18 (water/acetonitrile/tetrahydrofuran).

Yield: 9,67 g (63% of theory.) hygroscopic solid.

Water content: 10,5%.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 36,30; N 3,93; N 9,56; F 31,49; S 3,13;

found: 36,14; N 3,98; N 9,40; F 31,67; S to 3.02.

e) gadolinium Complex of 10-[1-methyl-2-oxo-3-Aza-5-oxo-5-(4-performancecounterpermission-1-yl)-pentyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

5 g (to 4.87 mmol) of the compound shown in the title of the example d), dissolved in 60 ml of water and add 0,883 g (2,44 mmol) of gadolinium oxide. Stirred for 3 hours at 90°C. the Solution is filtered, and the filtrate is dried by freezing.

Yield: 6,47 g (quantitatively) volume>p>Rasch.: With 31,56; N 3,16; N 8,31; F 27,37; S 2,72; Gd 13,33;

found: 31,37; N 3,35; N 8,18; F 27,19; S 2,92; Gd of 13.05.

EXAMPLE 34

a) 4-performanceorientierter-1-impotencia-acid

To a suspension of 11,41 g (100.0 mmol) of glutaric acid anhydride in 100 ml of tetrahydrofuran with stirring, added dropwise at 0°With a solution to 10.62 g (105,0 mmol) of triethylamine and 59,67 g (105,0 mmol) of the compound shown in the title of example 27A), in 50 ml of tetrahydrofuran and leave overnight at room temperature. The reaction mixture is acidified with 100 ml of 2 N Hcl and extracted with three times 100 ml of tetrahydrofuran. The combined organic extracts dried over sodium sulfate, filtered and evaporated. The residue is recrystallized from 2-propanol/ethyl acetate.

Yield: 52,30 g (73% of theory) of colourless crystalline solid.

Elemental analysis:

Rasch.: With 29,92; N 2,22; N 4,11; F 47,33; S 4,70;

found: 29,90; N 2,18; N 4,07; F 47,42; S 4,79.

b) gadolinium Complex of 10-[2-hydroxy-4-Aza-5,9-dioxo-9-{4-perforati)-piperazine-1-yl}-nonyl]-1,4,7-Tris(carboxymethyl)-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

11,66 g (17,09 mmole) connection name from example 34a) and 1.97 g (18,79 mmole) of N-hydroxysuccinimide dissolved in a mixture of 50 ml of the 1 h at 0°C, after 3 hours at room temperature. Again cooled to 0°C, add 5,19 g (51, 27 mmol) of triethylamine/50 ml 2-propanol. After that add 10,78 g (18,79 mmol) of the gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (WO 95/17451), dissolved in 50 ml of water, and stirred for 3 hours at room temperature. Evaporated to dryness, absorb the residue in a mixture of 200 ml methanol/100 ml of chloroform and filtered from dicyclohexylamine. The filtrate is evaporated to dryness and purified using RP-chromatography (RP-18/Solvent: water/n-propanol/acetonitrile).

Yield: 16.7 g (73% of theory.) colorless glassy solid material.

Water content: 7,5%.

Elemental analysis (relative to anhydrous substance):

Rasch.: With 32,99; N 3,50; F 26,09; Gd 12,70; N 7,92; S 2,59;

found: 32,75; N 3,68; F 25,88; Gd 12,55; N 7,84; S 2,63.

EXAMPLE 35

a) N-benzylphosphonate

To a mixture of to 10.62 g (105,0 mmol) of triethylamine and of 10.72 g (100,0 mmole) of benzylamine added dropwise at 80°C under powerful stirring 50,21 g (100.0 mmol) of performanceoriented. Stirred for 2 days at 80°C, mixing the reaction mixture with 300 ml of water and extracted 3 times with ethyl acetate. The combined organic extras is Itel: dichloromethane/methanol=4/1).

Yield: 45,96 g (78% of theory.) colourless liquid.

Elemental analysis:

Rasch.: With 30,57; N 1,37; N 2,38; S 5,44; F 54,81;

found: 30,49; N 1,30; N 2,42; S 5,50; F 54,90.

b) Tert-butyl ether N-benzyl-N-(PerformanceCounter)-aminouksusnoy acid

of 22.4 g (37,94 mmol) of the compound described in example 35A), and 15,73 g (113,8 mmol) of potassium carbonate are suspended in 200 ml of acetone and 60°C. are added dropwise 14,80 g (75,87 mmol) tert-butyl ether bromoxynil acid. Stirred for 3 hours at 60°C. is Filtered from the salts, the filtrate is washed under vacuum to dryness. The remainder chromatographic (solvent: hexane/dichloromethane/acetone=10/10/1) on silica gel. In the process of evaporation of the fractions of the residue from methanol/simple ester crystallized.

Yield: to 24.02 g (90% of theory) colorless resinous solids.

Elemental analysis:

Rasch.: With 35,86; N 2,59; N 1,99; S 4,56; F 45,91;

found: 35,67; N 2,71; N 2,13; S 4,45; F 45,83.

b) N-benzyl-N-(PerformanceCounter)-aminouksusnoy acid

20 g (28,43 mmol) of the compound indicated in the title of example 35B), dissolved in 200 ml triperoxonane acid and stirred overnight at room temperature. Evaporated in vacuum to dryness. The residue is recrystallized from methanol/etilatsetatnyj analysis:

Rasch.: With 31,54; N 1,56; N 2,16; S 4,95; F 49,89;

found: 31,38; H 1,70; N 2,05; S 4,87; F 49,71.

d) gadolinium Complex of 10-[2-hydroxy-4-Aza-5-oxo-7-Aza-7-(PerformanceCounter)-8-phenylethyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

11,06 g (17,09 mmole) of the compound named in the example 35V) and 1.97 g (18,79 mmole) of N-hydroxysuccinimide dissolved in a mixture of 50 ml of dimethylformamide/50 ml of chloroform. At 0°C add 3.88 g (18,79 mmole) dicyclohexylcarbodiimide and stirred for 1 hour at 0°C, then 3 hours at room temperature. Again cooled to 0°C, add 5,19 g (51,27 mmol) of triethylamine/50 ml 2-propanol. After that add 10,78 g (18,79 mmol) of the gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (WO 95/17451), dissolved in 50 ml of water, and stirred for 3 hours at room temperature. Evaporated to dryness, absorb the residue in a mixture of 200 ml methanol/100 ml of chloroform and filtered from dicyclohexylamine. The filtrate is evaporated to dryness and purified by means of RP-chromatography (RP-18/Solvent: water/n-propanol/acetonitrile).

Yield: 16,49 g (75% of theory.) colorless glassy solid material.

Water content: 6.5 per cent.

Elemental analysis:

Rasch.: With 33,95; N 3 is named

To a mixture of to 10.62 g (105,0 mmol) of triethylamine and 15,73 g (100,0 mmole) of decylamine added dropwise at 80°C under powerful stirring 50,21 g (100.0 mmol) of performanceoriented. Stirred for 2 days at 80°C, mixing the reaction mixture with 300 ml of water and extracted 3 times with ethyl acetate. The combined organic extracts dried over sodium sulfate, filtered and evaporated. The remainder chromatographic on silica gel (Solvent: dichloromethane/methanol=4/1).

Yield: 43,48 g (68% of theory.) colorless viscous liquid.

Elemental analysis:

Rasch.: With 33,81; H 3,47; N 2,19; S 5,02; F 50,51;

found: 33,71; N 3,39; N 2,15; S Is 4.93; F 50,31.

b) Tert-butyl ether N-decyl-N-(PerformanceCounter)-aminouksusnoy acid

24,26 g (37,94 mmol) of the compound described in example 36A), and 15,73 g (113,8 mmol) of potassium carbonate are suspended in 200 ml of acetone and 60°C. are added dropwise 14,80 g (75,87 mmol) tert-butyl ether bromoxynil acid. Stirred for 3 hours at 60°C. is Filtered from the salts, the filtrate is evaporated in vacuum to dryness. The remainder chromatographic (Solvent: hexane/dichloromethane/acetone=10/10/1) on silica gel)). After evaporation containing the product fractions, the residue from methanol/simple ester crystallized.

The output of finished PR is 38,25; N 4,28; N 1,86; S 4.26 Deaths; F 42,86;

found: 38,09; N To 4.41; N 1,74; S 4,10; F 42,67.

in) N-decyl-N-(PerformanceCounter)-aminouksusnoy acid

20 g (26,54 mmol) of the compound indicated in the title of example 36B), dissolved in 200 ml triperoxonane acid and stirred overnight at room temperature. Evaporated in vacuum to dryness. The residue is recrystallized from methanol/simple ether.

Yield: 17,22 (93% of theory) of colourless crystalline solid.

Elemental analysis:

Rasch.: With 34,44; H 3,47; N 2,01; S 4,60; F 46,31;

found: 34,28; H 3,30; N 1,95; S 4,65; F 46,28.

d) gadolinium Complex of 10-[2-hydroxy-4-Aza-5-oxo-7-Aza-7-(PerformanceCounter)-heptadecyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

11,92 g (17,09 mmole) of the compound named in the example 36V) and 1.97 g (18,79 mmole) of N-hydroxysuccinimide dissolved in a mixture of 50 ml of dimethylformamide/50 ml of chloroform. At 0°C add 3.88 g (18,79 mmole) dicyclohexylcarbodiimide and stirred for 1 hour at 0°C, then 3 hours at room temperature. Again cooled to 0°C, add 5,19 g (51,27 mmol) of triethylamine/50 ml 2-propanol. After that add 10,78 g (18,79 mmol) of the gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetrazocine, absorb residue in a mixture of 200 ml methanol/100 ml of chloroform and filtered from dicyclohexylamine. The filtrate is evaporated to dryness and purified using RP-chromatography (RP-18/Solvent: water/n-propanol/acetonitrile).

Yield: 16,76 g (71% of theory.) colorless glassy solid material.

Water content: 6.5 per cent.

Elemental analysis:

Rasch.: With 35,46; N 4,18; N Of 6.71; S 2,56; F 25,77; Gd 12,55;

found: 35,28; N 4,33; N 6,80; S 2,61; F 25,65; Gd 12,41.

EXAMPLE 37

a) N-hexylphosphonic

To a mixture of to 10.62 g (105,0 mmol) of triethylamine and 10,12 g (100,0 mmole) of benzylamine added dropwise at 80°C under powerful stirring 50,21 g (100.0 mmol) of performanceoriented. Stirred for 2 days at 80°C, mixing the reaction mixture with 300 ml of water and extracted 3 times with ethyl acetate. The combined organic extracts dried over sodium sulfate, filtered and evaporated. The remainder chromatographic on silica gel (Solvent: dichloromethane/methanol=4/1).

Yield: 45,50 g (78% of theory.) colourless liquid.

Elemental analysis:

Rasch.: With 28,83; N To 2.42; N, 2,40; S 5,50; F 55,37;

found: 28,29; N 2,39; N 2,44; S 5,55; F 55,50.

b) Tert-butyl ether N-hexyl-N-(PerformanceCounter)-aminouksusnoy acid

22,13 g (and at 60°C and added dropwise 14,80 g (75,87 mmol) tert-butyl ether bromoxynil acid. Stirred for 3 hours at 60°C. is Filtered from the salts, the filtrate is evaporated in vacuum to dryness. The remainder chromatographic (Solvent: hexane/dichloromethane/acetone=10/10/1) on silica gel). After evaporation containing the product fractions, the residue from methanol/simple ester crystallized.

Yield: 23,02 g (87% of theory) colorless resinous solids.

Elemental analysis:

Rasch.: With 34,44; H 3,47; N 2,01; S 4,60; F 46,31;

found: 34,31; N 3,61 N 1,97; S 4,65; F 46,25.

in) N-hexyl-N-(PerformanceCounter)-aminouksusnoy acid

20 g (28,43 mmol) of the compound indicated in the title of the example b), dissolved in 200 ml triperoxonane acid and stirred overnight at room temperature. Evaporated in vacuum to dryness. The residue is recrystallized from methanol/simple ether.

Yield: 16,74 (91% of theory) of colourless crystalline solid.

Elemental analysis:

Rasch.: With 29,96; N. Of 2.51; N 2,18; S 5,00; F 50,36;

found: 29,87; N 2,70; N 2,05; S 4,84; F 50,17.

d) gadolinium Complex of 10-[2-hydroxy-4-Aza-5-oxo-7-Aza-7-(PerformanceCounter)-tridecyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10,96 g (17,09 mmole) of the compound named in the example 37V) and 1.97 g (18,79 mmole) N-hydroxysuccinic is carbodiimide and stirred for 1 hour at 0°C, after 3 hours at room temperature. Again cooled to 0°C, add 5,19 g (51,27 mmol) of triethylamine/50 ml 2-propanol. After that add 10,78 g (18,79 mmol) of the gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (WO 95/17451), dissolved in 50 ml of water, and stirred for 3 hours at room temperature. Evaporated to dryness, absorb the residue in a mixture of 200 ml methanol/100 ml of chloroform and filtered from dicyclohexylamine. The filtrate is evaporated to dryness and purified using RP-chromatography (RP-18/Solvent: water/n-propanol/acetonitrile).

Yield: 16,46 g (75% of theory.) colorless glassy solid material.

Water content: 6.8 per cent.

Elemental analysis:

Rasch.: With 33,11; N 3,70; N 7,02; S 2,68; F 26,98; Gd 13,14;

found: 33,01; N. Of 3.84; N 6,95; S To 2.57; F 26,85; Gd 13,03.

EXAMPLE 38

a) Benzyl ether 11-[N-ethyl-N-(PerformanceCounter)-amino]-hexanoic acid

20 g (37,94 mmol) N-ethyl-N-perftorgeksilsilanami and 15,73 g (113,8 mmol) of potassium carbonate are suspended in 200 ml of acetone and 60°C. are added dropwise 21,64 g (75,87 mmol) of benzyl ester 6-Bromhexine acid. Stirred for 3 hours at 60°C. is Filtered from the salts, the filtrate is evaporated in vacuum to dryness. The remainder of the chromatography the shares of the residue from methanol/simple ester crystallized.

Yield: 25,26 g (91% of theory) of colorless crystalline powder.

Elemental analysis:

Rasch.: With 37,77; N 3,03; N 1,91; S Of 4.38; F 44,15;

found: 37,61; N 3,18; N 1,84; S 4,27; F 44,01.

b) 11-[N-3THA-N-(PerformanceCounter)-amino]-hexanoic acid

20 g (27,34 mmole) of the compound indicated in the title of example 38b), dissolved in 300 ml isopropanol/200 ml dichloromethane and add 3 g of palladium catalyst (10% Pd/C). Hydronaut over night at room temperature. The catalyst is filtered off and the filtrate evaporated in vacuum to dryness. The residue is recrystallized from a simple ether/hexane.

Yield: 16,13 g (92% of theory) of colourless crystalline solid.

Elemental analysis:

Rasch.: With 29,96; N. Of 2.51; N 2,18; S 5,00; F 50,36;

found: 29,81; N 2,70; N 2,09; S Is 4.93; F 50,14.

C) gadolinium Complex of 10-[2-hydroxy-4-Aza-5-oxo-11-Aza-11-(PerformanceCounter)-tridecyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10,96 g (17,09 mmole) connection name from example 38b), and 1.97 g (18,79 mmole) of N-hydroxysuccinimide dissolved in a mixture of 50 ml of dimethylformamide/50 ml of chloroform. At 0°C add 3.88 g (18,79 mmole) dicyclohexylcarbodiimide and stirred for 1 hour at 0°C, then 3 hours at room those who t 10,78 g (18,79 mmol) of the gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (WO 95/17451), dissolved in 50 ml of water, and stirred for 3 hours at room temperature. Evaporated to dryness, absorb the residue in a mixture of 200 ml methanol/100 ml of chloroform and filtered from dicyclohexylamine. The filtrate is evaporated to dryness and purified by RP-chromatography (RP-18/Solvent: water/n-propanol/acetonitrile).

Yield: 15.0 g (69% of theory.) colorless glassy solid material. Water content: 5.9 per cent.

Elemental analysis:

Rasch.: With 33,11; N 3,70; N 7,02; S 2,68; F 26,98; Gd 13,14;

found: 33,01; N 3,83; N 6,91; S 2,49; F 26,83; Gd of 13.05.

EXAMPLE 39

a) Tert-butyl ether N-cyclohexylmethyl-N-(perforater-sulfonyl)aminouksusnoy acid

22,59 g (37,94 mmole) of N-cyclohexyltrichlorosilane and 15,73 g (113,8 mmole) of potassium carbonate are suspended in 200 ml of acetone at 60°C is added dropwise 14,80 g (75,87 mmole) of tert-butyl methyl ether bromoxynil acid and stirred at 60°C for 3 hours Salt is separated by filtration, the filtrate is evaporated in vacuum to dryness. The residue is purified by chromatography on silica gel (eluent hexane/dichloromethane/acetone =10:10:1). The fractions containing the product, evaporated, the residue is crystallized from methanol/ether. The product obtained as a colorless waxy solid (22,62 g, yield-Cyclohexylmethyl-N-(PerformanceCounter)aminouksusnoy acid

21,12 g (31,18 mmole) of the compound indicated in the heading of example 39 (a), dissolved in 200 ml triperoxonane acid and stirred at room temperature overnight and then evaporated in vacuum to dryness. The residue is recrystallized from methanol/ether. The product is obtained in the form of a colorless crystalline substance (18,21 g, yield 94%).

Elemental analysis:

Rasch.: With 32,86%; N 2,60%; F 51,98%; N 2,25%; S 5,16%;

calc.: WITH 33,02%; N 2,56%; F 52,01%; N 2,27%; S OF 5.24%.

C) gadolinium Complex of 10-[2-hydroxy-4-Aza-5-oxo-7-Aza-7-(PerformanceCounter)-8-cyclohexylethyl-1,4,7-Tris(carboxymethyl]-1,4,7,10-tetraazacyclododecane

to 10.62 g (17,09 mmole) of the compound indicated in the heading of example 39B), and 1.97 g (18,79 mmole) of N-hydroxysuccinimide dissolved in a mixture of 50 ml of dimethylformamide and 50 ml of chloroform. Then at 0°C add 3.88 g (18,79 mmole) dicyclohexylcarbodiimide and stirred at 0°C for 1 h and then at room temperature for 3 hours Again cooled to 0°C and add 5,19 g (51,27 mmole) of triethylamine/50 ml 2-propanol. Then add 10,78 g (18,79 mmole) of the gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (WO 95/17451), dissolved in 50 ml of water and stirred at room temperature for 3 Cawino by filtration. The filtrate is evaporated to dryness, the residue purified by reversed-phase chromatography on RP-18 (eluent gradient of water/n-propanol/acetonitrile). The product is obtained as a colourless glassy solid (16,69 g, yield 80%, the water content of 7.1%).

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 33,77%; N To 3.67%; F 26,71%; Gd 13,01%; N 6,95%; S 2,65%;

calc.: With 33,91%; N 3,80%; F 26,58%; Gd 13,01%; N 7,02%; S 2,74%.

EXAMPLE 40

a) Complex gadolinia 10-[2-hydroxy-4-Aza-4-(2,2-dimethyl-5-hydroxy-1,3-doxipan-6-yl)butyl]1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

To a mixture of 28.5 ml of distilled water and 14.3 ml (102,78 mmole) of triethylamine added under stirring 20 g (34,86 mmole) of the gadolinium complex of 10-[2-hydroxy-3-aminopropane)-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (obtained as described in WO 95/17451), as well as of 20.1 g (139,44 mmole) of 2,2-dimethyl-1,3,6-dioxabicyclo[5.1.0]octane (synthesized as described in EN 101980810) and refluxed for 5 h, and then stirred at room temperature overnight. Then concentrated in vacuo, the residue is purified by chromatography on silica gel with elution in an increasing gradient of methanol/ammonia. Specified in the title compound obtained as a viscous MS 40,16%; N 5,90%; Gd To 21.91%; N 9,76%;

calc.: With 40,28%; N 6,03%; Gd 22,07%; N 9,88%.

b) gadolinium Complex of 10-[2-hydroxy-4-Aza-(2,2-dimethyl-5-hydroxy-1,3-doxipan-6-yl)-N-performancelevel]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

To a solution of 2.0 g (2,79 mmole) of the compound indicated in the heading of example 40A), in 20 ml of dimethyl sulfoxide add 2,77 g (4,74 mmole) of N-ethyl-N-performancecountercategory acid. Then mixed with 2,40 g (9.73 mmole) of EEDQ (ethyl ester of 1,2-dihydro-2-ethoxyquinoline-1-carboxylic acid) and stirred at room temperature overnight. Then add 200 ml of water, approximately 50 g of sodium chloride and twice with portions of 200 ml extracted with n-butanol. The organic phase is again exagerate saturated saline solution, dried over sodium sulfate and evaporated to dryness in a vacuum. The residue is purified by chromatography on silica gel. Specified in the title compound obtained as a colorless foam (1,83 g, yield of 51.1%, the water content of 7.3%).

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 33,65%; N Of 3.77%; F 25,13%; Gd 12,24%; N 6,45%; S 2,50%;

calc.: With 33,82%; N 3,91%; F 25,01%; Gd 12,37%; N 6,66%; S 2,62%.

C) gadolinium Complex of 10-[2-hydroxy-4-Aza-4-N-(2,3-dihydroxy-1-hydroxymethylpropane)-N-perforagricultural the Yong 1 ml of distilled water, add 1.4 g (1.09 mmole) of the compound indicated in the heading of example 40B), and stirred at room temperature for 10 minutes Then the solvent is evaporated in vacuum, the residue is distilled three times with 15 ml of distilled water, transferred into 60 ml of distilled water and freeze-dried. Specified in the title compound obtained as white foam (1,21 g, yield 89.4% of the water content of 9.2%).

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 31,84%; N 3,56%; F 25,94%; Gd 12,63%; N 6,75%; S 2,58%;

calc.: With 31,68%; N 3,68%; F 26,11%; Gd Was 12.75%; N 6,87%; S 2,44%.

EXAMPLE 41

The gadolinium complex of 10-[4-PerformanceCounter)piperazine-1-ylcarbonyl(carboxy)methyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (sodium salt)

In 100 ml of dimethyl sulfoxide was dissolved by heating 10.0 g (16,21 mmole) of the gadolinium complex of 10-[(carboxy)carbonylmethyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (obtained by kompleksoobrazovaniem acid with oxide of gadolinium) and 3.0 g of lithium chloride. After cooling, add of 9.21 g (16,21 mmole) of the compound indicated in the heading of example 27A). The mixture is then cooled to 0°C, added 12.3 g (48,63 mole) of EEDQ (ethyl ester of 1,2-dihydro-2-ethoxyquinoline-1-carboxylic acid) and stirred at to the mix. The residue purified by chromatography on silica gel with elution with a mixture of dichloromethane/methanol/ammonia, 2:2:1. The fractions containing the product are combined and concentrated, the residue is dissolved in 200 ml of distilled water, add NaOH to pH 7.2 and freeze-dried. The product is obtained as a white foam (of 7.64 g, yield to 39.6%, the water content of 7.8%).

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 30,31%; H 2,80%; F 27,17%; Gd 13,23%; N 7,07%; Na 1,93%; S 2,70%;

calc.: With 30,42%; N 2,91%; F 27,04%; Gd To 13.29%; N, 7.16 Percent; Na 2,04%; S 2,59%.

10-(3-carboxy-3-ylpropionic acid)-1,4,7,10-tetraazacyclododecane

150 g (761 mmol) Bromantane acid is neutralized 10% NaOH solution and the solution evaporated to dryness. In 300 ml of distilled water dissolve 65,55 g (380 mmol) cyclina add disodium salt (obtained from 150 g bromantane acid=761 mmol). The mixture is heated at 50°C and stirred overnight. Then the solution is evaporated to dryness and the residue is distilled with ethanol. The residue is transferred into butanol and extracted with water. The aqueous phase is concentrated and the residue purified by chromatography on silica gel with elution with a mixture of methanol with ammonia (20:1 to 2:1). The fractions containing the product are combined and evaporated to dryness. The product yield is 54.8 g (50.4 percent).

Elemental pianova acid)-1,4,7,10-tetraazacyclododecane

In 60 ml of distilled water dissolve 11 g (38,14 mmol) of 10-(3-carboxy-3-ylpropionic acid)-1,4,7,10-tetraazacyclododecane and mixed with 18,03 g (190,74 mmole) of Chloroacetic acid. The mixture is heated to 70°C and add 32% NaOH solution to pH 9-10. Then stirred at 70°C during the night, alkalinized to pH 10, added 7.2 g (76,19 mmole) of Chloroacetic acid and stirred at 70°C for 3 hours the Mixture is evaporated to dryness, and then evaporated with methanol, transferred into methanol and the salt is separated by filtration. The filtrate is concentrated and purified by chromatography on an ion exchanger Amberlite 252 With the elution with water/ammonia. The fractions containing the product are pooled, concentrated, re-transferred into distilled water and freeze-dried. Specified in the title compound obtained as a white foam (13,12 g, yield 82.3 per cent water content of 9.6%).

Elemental analysis (calculated on the anhydrous substance):

Rasch.: With 46,75%; N 6,54%; N 12,12%;

calc.: WITH 45,87%; N 6,62%; N 12,24%.

EXAMPLE 42

Kinematics excretion from the blood contrast agents

Kinematics excretion from the blood of contrast agents was investigated in rats (Han. Wistar, Schering SPF, approximately 250 g body weight). To do this, after a single intravenous injection (via a Caudalvene) substance (dose) is determined during the time up to 300 min p.i using ICP-AES. Pharmacokinetic parameters: volume of distribution (Vss), total factor purification (CLtot) and the period of providentia (t) was calculated using special computer programs (TOPFIT 2.0; Thomae, Schering, Godecke), and it is based on one - and twocompartment distribution model.

Compared to Dy-DTPA (analog dysprosium Magnevist) fluoride compounds according to the invention (for example, example 1B) is clearly more slowly eliminated from the blood and, in addition, have a smaller distribution (see also Fig. 1 and table 1).

It should be noted that these compounds unexpectedly have extended rately in the blood and therefore, being a "contrast agent blood depots are suitable for imaging of blood vessels using the appropriate technique, in relatively small dosages50 mmol per kg of body weight.

Fig.1:

Elimination from the blood (as % of injected dose) Dy-DTPA (dose: 100 mmol Dy per kg body weight, n=3) and fluoride compounds according to the invention of example 1B (dose: 50 mmol Gd / kg body weight, n=2) after repeated intravenous injection of substances in rats (Wistar Han, Schering SPF250 g body weight).

Other details in the text to Fig.1.

EXAMPLE 43

Enrichment of lymph nodes in Guinea pigs

Various fluorine-containing complexes of gadolinium and manganese have been tested over time from 90 minutes to 24 hours after injection subcutaneously (2.5 to 10 mmol of total gadolinium/kg of body weight, hind paw s.c.) on the subject of stimulation Guinea pigs (complete Freund-adjuvant; accordingly 0.1 ml i.m. at right and left femora and tibia; two weeks before giving control of the dose of the substance to enrich lymph nodes in three contiguous lymph nodes (popliteal, inguinal, iliac). Thus were obtained the results given in table 2 (the determination of concentrations of gadolinium using ICP-AES).

Table 2 shows that a high concentration of contrast agents observed in three successive lymph node.

EXAMPLE 44

The image of the lymph nodes (MRI) after interstitial administration of contrast material

In Fig.1.1 shows Mr images of lymph nodes: popliteal and inguinal before (left side: precontrast), and after 120 minutes (right side) after subcutaneous (Guinea pig, hind paw, space, Breakfast is minimizetotray ether) (10 mmol Gd/kg body weight). T1-spin-echo images (TR 400 ms, TE 15 MS) make more evident the strong increase of the signal in the lymph nodes, popliteal and inguinal - injected (straight arrow) compared with penjelasannya (curved arrow) side of the body or with precontrast image.

EXAMPLE 45

Excretion of contrast medium after introduction i.p.

After the introduction of the perforated gadolinium complex according to the invention (100 mmol of total gadolinium/kg of body weight) in the peritoneal region of the rat was investigated within 14 days after the introduction of the delay of the metal in the liver and in the body. While this study used a fluoride compound 2B). After 14 days after the injection, the concentration of gadolinium in the liver was 0.22%, while in the rest of the body 1/1% of the administered dose.

In contrast, Gd-DPTA-polylysin as the polymer material is not fully displayed. After 14 days, the body is still 7% of the administered dose.

EXAMPLE 46

Definition T1relaxation of selected compounds

Relaxation following compounds determined using a Minispec pc 20 (20 MHz, 0,47 T) at 37°C in water and in human plasma and compared to Gd-DTPA-polylysine and mud-nevist® as a comparative substance. (see tab.3).

In this experiment, on the body of negritude was to identify the minimum effective dose of the compound of example 33 for use in interstitial limfografii. In the first part of the experience directly on one animal (in each case with the introduction on the one hand, the 6 points above or below the hips) compared two doses (10,0 and 2.5 mmol Gd/kg). In the second part of the experiment was performed in a single dose of 1.0 µmol/kg and was administered subcutaneously standardized in two places (5 cm below the knee) with outer and inner side of hind limbs.

Confirmed the excellent suitability of the compounds according to example 33 to obtain regional lymph nodes (inguinal, iliac and para-aortic) after intersticialnom injection in the hind leg of the dog. Achieved significant increase in signal right after the introduction, through which approximately 60-90 min, reached a maximum. Along with contrast lymph nodes up to the maximum intensity projection was possible to observe a clear enhancement of the image of the lymphatic vessels.

With the direct comparison of two doses of 10.0 and 2.5 mmol Gd/kg not found virtually no difference in the signal intensity. On the contrary, the minimum dose of 1 çmol/kg (with an amended scheme, in the representation of the lymph glands (MRT) after intersticialnom contrast to the Guinea pig

In Fig. 3 and 4 show Mr images of the popliteal, inguinal and iliac lymph nodes before (baseline: precontrast) and after 30 min, 5 or 6 h after interstitial injection (subcutaneously in the interdigital space of the hind legs) Guinea pig 10,0 and respectively 2.5 mmol Gd/kg of body weight of the compound of example 33 to stimulate the lymph nodes (full beta-blockers: 0.1 ml intramuscularly in the right and left side above and below the hip; 2 weeks prior to the introduction of the analyzed compounds). Images of T1-balanced gradient echo (TR 10 MS, TE 5 MS,26°) revealed a strong increase of the signal in different groups of lymph nodes (arrows) compared with precontrast image. Corresponding values of the signal gain (in % of value of precontrast) are given in table 4.

EXAMPLE 49

The image of the tumor (MRT) after intravenous administration of contrast material rabbit

In this experiment investigated the suitability of the compound of example 33 to obtain images of liver tumors and compared with the effect of the standard contrast agent Magnevist 0 company Schering AG, Berlin). This used the rabbit, which is 4 weeks prior to injection of 100 mmol/kg Magnevist after 30 min after injection in healthy liver, and in the tumor could be observed only a slight increase of the signal. Signal enhancement in healthy liver ranged from 5-30 min after injection of approximately 25% in tumor 35-66%.

In contrast, injection of the compound from example 33 was led to significantly greater signal amplification in a healthy liver (approximately 150% after 15-60 min after injection) compared with tumors (approximately 65-85% after 15 min - 24 h after injection). Therefore, the contrast between healthy tissue and tumor increases (increase in the ratio of the signal intensity of the liver/tumor from 1.6 (0 min) to 2.6 (15 after injection)).

In Fig. 5 and 6 shows precontrast Mr image of the liver (tumor) and after 15 min, 30 min and 60 min after intravenous administration of 100 μmol Gd/kg of body weight in the form of the compound of example 33 and drug Magnevist. Images of T1-balanced gradient echo (1.5 T; TR/TE 100/4,6 MS,70°) revealed a strong signal rise in healthy liver tissue compared to tissue tumors after administration of the compound of example 33. Corresponding values of the signal gain (in % of precontrast) are given in table 5.

Claims<>is a perfluorinated, straight or branched carbon chain with formula-CnF2nX, where x is the terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, and n denotes a number from 4 to 30,

L is a direct bond, methylene group, a group-NHCO group

while p denotes a number from 0 to 10, q and u, independently of one another denote 0 or 1,

R1is a hydrogen atom, a methyl group, a group-CH2HE-, -CH2-CO2N-, or a chain With2-C15which is optionally interrupted by 1 to 3 oxygen atoms, 1-2>CO-group or phenyl group, optionally substituted by 1-2 carboxy groups and/or substituted by 1-4 hydroxy groups, 1-2 s1-C4alkoxygroup, 1-2 carboxyl groups, group-SO3H or is a straight, branched, saturated or unsaturated C2-C30-carbon chain, which optionally contains 1 to 10 oxygen atoms, 1-3-NR1groups, 1-2 sulfur atom, piperazine, -CONR1group, -NR1CO-group, group-SO2the group-NR1-CO2, 1-2-CO-group, a group-CO-N-T-N(R1)-SO2-RF, phenyl group, not necessarily the 1-3-OR1groups, 1-2 exography, 1-2-NH-COR1groups, 1-2-CONHR1groups, 1-2 -(CH2)p-CO2N-groups, 1-2 groups -(CH2)p-(O)q-CH2CH2-RFand R1, RFand p and q have the above meanings;

T denotes the chain With2-C10which is optionally interrupted by 1-2 oxygen atoms, or 1-2-NH-groups

A represents a metal complex or salt of organic and/or inorganic bases or amino acids or amides of amino acids of General formula II

in which R3, Z1and Y do not depend on each other;

R3has a value of R1or means -(CH2)m-L-RFwhere m means 0, 1 or 2, a L and RFhave the above values;

Z1independently of each other means the equivalent of a metal ion with atomic number 21-29, 39, 42, 44 or 57-83;

Y means-OZ1or

and Z1, L, RFand R3have the above meanings; or the General formula III

in which R3and Z1have the above meanings;

Torah Z1has the above meaning; or

the General formula V

in which Z1has the above meaning, and o and q means the number 0 or 1, and the sum o+q=1; or

the General formula VI

in which Z1has the above meaning; or

the General formula VII

in which Z1and Y have the above meanings; or

the General formula VIII

in which R3and Z1have the above values, a R2has the above value for R1; or

the General formula IX

in which R3and Z1have the above meanings; or

the General formula X

in which R3and Z1have the above meanings; or

the General formula XI

in which Z1that p and q have the above significance, and R2has a value of R1; or

the General formula XII

in which L, RFand Z1have the above meanings; or

the General formula XIII

1denotes a hydrogen atom.

3. Connection under item 1 or 2, wherein n in the formula-CnF2nX denotes a number from 4 to 15.

4. Join one of the PP.1-3, characterized in that X in formula CnF2nX denotes a fluorine atom.

5. Join one of the PP.1-4, wherein L represents-CH2-

-CH2-CH2

-(CH2)sis, s=3-15

-CH2-O-CH2CH2-

-CH2-(O-CH2-CH2-)tt=2-6,

-CH2-NH-CO-

-CH2-NH-CO-CH2-N(CH2COOH)-SO2-

-CH2-NH-CO-CH2-N(C2H5)-SO2-

-CH2-NH-CO-CH2-N(C10H21)-SO2-

-CH2-NH-CO-CH2-N(C6H13)-SO2-

-CH2-NH-CO-(CH2)10-N(C2H5)-SO2-

-CH2-NH-CO-CH2-N(-CH2-C6H5)-SO2-

-CH2-NH-CO-CH2-N(-CH2-CH2-OH)-SO2-

-CH2-NHCO-(CH2)10-S-CH2CH2-

-CH2NHCOCH2-O-CH2CH2-

-CH2NHCO(CH2)10-O-CH2CH2-

-CH2-C6H4-O-CH2CH2-

-CH2-O-CH2- (CH2-Och2CH2-Csub>-O-CH2-CH-(OS10H21)-CH2-O-CH2CH2-

-(CH2NHCO)4-CH2O-CH2CH2-

-(CH2NHCO)3-CH2O-CH2CH2-

-CH2-Och2C(CH2OH)2-CH2-O-CH2CH2-

-CH2NHCOCH2N(C6H5)-SO2-

-NHCO-CH2-CH2-

-N-CH2-O-CH2CH2-

-NH-CO-

-NH-CO-CH2-N(CH2COOH)-SO2-

-NH-CO-CH2-N(C2H5)-SO2-

-NH-CO-CH2-N(C10H21)-SO2-

-NH-CO-CH2-N(C6H13)-SO2-

-NH-CO-(CH2)10-N(C2H5)-SO2-

-NH-CO-CH2-N(-CH2-C6H5)-SO2-

-NH-CO-CH2-N(-CH2-CH2-OH)SO2-

-NH-CO-CH2-

-CH2-O-C6H4-O-CH2-CH2-

-CH2-C6H4-O-CH2-CH2-

-N(C2H5)-SO2-

-N(C6H5)-SO2-

-N(C10H21)-SO2-

-N(C6H13)-SO2-

-N(C2H4OH)-SO2-

-N(CH2COOH)-SO2-

-N(CH2C6H5)-SO2-

-N[CH(CH2OH)2]-SO2-

-N[CH(CH is 10-[2-hydroxy-4-Aza-5-oxo-7-Aza-7-(PerformanceCounter)-nonyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, the gadolinium complex of 10-[2-hydroxy-4-Aza-5-oxo-7-oxa-10,1-0,11,11,12,12,13,13,14,14,15,15,16,16,17,17,17-heptadecafluoro-heptadecyl]-1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane.

7. The method of obtaining performanceeasy compounds of General formula I on p. 1, where a represents a fragment of General formula XI with a value of q equal to 0 and in which Z’ represents an ion of a metal selected from the group comprising manganese, gadolinium, ytterbium and dysprosium, and the remaining radicals have the meanings specified in paragraph 1, which consists in the fact that the compound of General formula 20

where R4means hydrogen, methyl, ethyl, isopropyl, tert-butyl or benzyl is subjected to interaction with the compound of General formula 68

in which RF, L’, R2and Hal have the above values, with stirring in an organic solvent at elevated temperatures for several hours, after which otscheplaut existing protective group, and the thus obtained complexing agents enter into a reaction with at least one oxide or salt of a metal selected from the group comprising manganese, gadolinium, ytterbium and dysprosium, at room or elevated temperatures, and Zech grounds amino acids or amides of amino acids.

8. The method of obtaining performanceeasy compounds of General formula I on p. 1, where a has the General formula XI with a value of q equal to 1, and in which Z’ represents an ion of a metal selected from the group comprising manganese, gadolinium, ytterbium and dysprosium, and the remaining radicals have the meanings specified in paragraph 1, which consists in the fact that the compound of General formula 20

where R4means hydrogen, methyl, ethyl, isopropyl, tert-butyl or benzyl is subjected to interaction with compounds of General formula 68A

in which RF, L’, R3, p and Hal have the abovementioned meaning, in an organic solvent at elevated temperatures for several hours, and then, if necessary, otscheplaut existing protective group, and the thus obtained complexing agents enter into a reaction with at least one oxide or salt of a metal selected from the group comprising manganese, gadolinium, ytterbium and dysprosium, at room or elevated temperature, and then, if necessary, available acidic hydrogen atom is substituted by cations of inorganic and/or organic bases, amino acid is e a indicates a fragment of General formula IV, in which Z’ represents an ion of a metal selected from the group comprising manganese, gadolinium, ytterbium and dysprosium, and the remaining radicals have the meanings specified in paragraph 1, namely, that interact hydroxyacids or hydroxyether General formula 56

in which R4has the above significance, with a halogen-containing compounds of General formula 55

in which RF, L’ and l’ have the above meanings, in a mixture of organic solvent and buffer at alkaline pH at room temperature for several hours, and then, if necessary, otscheplaut existing protective group, and the thus obtained complexing agents are interacting with at least one oxide or salt of a metal selected from the group comprising manganese, gadolinium, ytterbium and dysprosium, at room temperature or elevated temperature, and then, if necessary, replace existing acidic hydrogen atoms of the cations of inorganic and/or organic bases, amino acids or amides of amino acids.

10. Pharmaceutical drug intended to identify subroutinename under item 1, if necessary, conventional galenovye additives.



 

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