UA75364C2 - Perfluoroalkyl-containing complexes with remainders of sugars, a method for obtaining and use thereof - Google Patents

Abstract

The invention relates to perfluoroalkyl-containing complexes comprising sugar residues of the general formula (I), wherein R represents a mono- or oligosaccharide residue bound in the 1-OH or 1-SH position, Rf represents a perfluorated carbon chain, K is a metal complex and Y and Z are linker groups. The inventive complexes are suitable for use in intravenous lymphography, in tumor diagnosis and for infarct and necrosis imaging.

Description

Description of the invention

This invention relates to the objects described in the claims, namely, perfluoroalkyl-containing 2 metal complexes with residues of sugars of the general formula I, the method of their preparation and their use in NMR and X-ray diagnostics, radionuclide diagnostics and radiation therapy in MRI-lymphography (MRI- magnetic resonance imaging), as well as as contrast agents for visualization of blood pools. The compounds proposed in the invention are most suitable for use in intravenous lymphography, for diagnosing tumors and for visualization of infarctions and necrosis.

In methods based on nuclear magnetic resonance, the second most important element after hydrogen is fluorine, which is due to the following factors: 1) fluorine has a high susceptibility, which is 8395 of the susceptibility of hydrogen, 2) fluorine has only one NMR-active isotope,

C) fluorine is characterized by a resonance frequency similar to hydrogen, which allows analyzing both 75 elements using the same equipment, 4) fluorine is biologically inert, 5) fluorine is not contained in biological material (except teeth) and therefore can be used as a probe or contrast agent against a background that does not create spurious signals.

Thanks to these properties, fluorine is widely used in diagnostics based on the method of nuclear magnetic resonance, for example, in "UR-tomography, functional diagnostics and spectroscopy, which is reflected in the relevant patent literature.

So, (for example, in patent OZ 4639364 (in the name of MaiipsKgodO)| trifluoromethanesulfonamides were proposed for use as contrast agents in ""P-tomography: .

SEz35O»MN» I

SEZ35O2MH-СНоО-(СНОН))-СНоН. at

The same applies to "UE-tomography" (patent OE 4203254 (in the name of Makh-Riapsk-SezeiIzsnat), in which an aniline derivative of the following formula is proposed: "

SE, Fr

SE and from MNSOSN, And you and -

SE; . 19eg-tomography is an object (applications UUO 93/07907 (in the name of Maiyipskgoab), in which derivatives of "phenyl for use as contrast agents: - to no on c 6) are also proposed;"

SE, SE, no o Ev M -I n Sso,Nn sl os 2 | M SE, (95) No-

F SE; SE, but SE, M i» N (8) but on 19 n ! ! !

Compounds with a much simpler structure were also proposed for use in P-tomography.

GF) So, for example, in patent 5 4586511 (in the name of SPydgep'z Nozriai MeaisaI Sepieg)) described

HF perfluorooctyl bromide formula

SEZ(СЕ»2)7-VГг, in EU patent ER 307863 (in the name of Aig Rgodisiv))| claimed perfluoro-15-crown-5-ether of formula b5

IS

E and E

E o o E yu and E

R E

E E o o

E o E and E

IS

IS

E E

? and in patent 5 4588279 (in the name of Mopimegeyu oi Sipsippaiii, Spiidgepie Nozriiai Kezeagsp Rospaaiiop)| perfluorocarbon compounds described above, such as perfluorocyclononane or -octane, simple perfluorinated ethers, such as tetrahydrofuran of the formula i)

NO and t zo E s so

IS

E iv) o;

E E m. or simple diesters, such as the diester of perfluoropropylene glycol of the formula

CE, CE, and | shi - E O-SE,SE,SE--O E . » p

SE, SE, "

B. In a similar way, the compounds described (in the application UUO 94/22368 (in the name of MoIesciag Viozuvietv))| compounds, for example, (95) b 50 s" are prescribed for use in "UR-tomography"

F) name) 60 b5 o-so-sNn)k ; snusn.),sn-sN-(sno),so--0 o-so-snaB

SE, 70 / s-сSE, h

SE, g: ,

Ka

S y ,/ sv,

CE, which contain a perfluoro-1H,1H-neopentyl group as a fluorine-containing residue.

Structures of another type with a wider range of applications in diagnostics are presented in patent O5 5362478 (in the name of MIMOKH), which claims a combination of fluorocarbon/polymer shell intended for use in tomography. According to this patent, it is proposed to use perfluorononan and human serum albumin. A similar combination, as it was established, allows, in addition, to use a fluorine atom as a probe for local temperature measurement and for determining the partial pressure of oxygen.

Perfluorocarbons intended for determining oxygen content are also described in patent O5 45865111. (ze)

According to patent OE 4008179 (in the name of Zspegipo)| it is proposed to use fluorine-containing benzene sulfonamides as pH probes: m.

SE, cho E chnZOo,sn.sNnsON that s zad may nn: 2».

Compounds containing iodine and fluorine atoms are also intended for use in NMR diagnostics as contrast-enhancing substances and are described, for example, (in applications UMO 94/05335 and MO 94/22368 (both in the name of Moiiesshiag Viozuvietzv ))|: 1 (95) b 50 s»

F) name) 60 b5

AND

; snibn-so

EY

And I

MISSOSE,

And.

Sh 0 enxo C(SE,);

N.M. I and 2 oso-(сН,); (Fo 0 enxo (OR ) with sch o ny

The combination of fluorine-paramagnetic metal ion is also intended for use in UR-tomography, while we are talking about complexes with an open chain, as an example of which (in the application MO 94/22368 (in the name of MoYiIesshag Z

Viozuvzietzv))| the named compounds of the formula (Te) so, so g and

M i- n,v--nMos7 tn i it n Zosomn--sn, so. C 4 and so, so, Z c z

С(СЕ,.; С(СЕ,), soot С(СЕ) with С(СЕ)» ,

V. a (in EP 292306 (in the name of TEKOMO Kabryzpiki Kaizpa)) specified compounds of formula 1 (95) b 50 s»

F) name) 60 b5 i

M

; Fr7ltn ZY no, what Se o, so,

EE and E- --SN.SE, and -snya- U osv", ' sobu

SE, E. E

Yu-5 SE, -snsn--M still ron

SE, SEZ 6)

SE, "g that and also about cyclic compounds, (described in EP 628316 (in the name of TEKOMO Kabrizvnpiki Kaizpa)): re) also - ;

Sh with oyu MO So, oyu tk M20 so, How (S se" Z (S wai Z

M M M M ih - -ya - in - that giya :z» so, so, -I 1 in- m SE; SE, SE, (22) s» - -onesnA-M z

ZHUO-2 sleep; CE, ' 272 CE,

F) SE, name) se, 60 "

For NMR spectroscopic measurements of temperature (in OE 4317588 (in the name of Zspegipoa)| it was also proposed to use the following combination of a fluorine atom and a rare earth element: b5

- 2nd m

M M on

M M che

S. se,

So, where I n means the rare earth element ia, Rg, Оу or Эй. | If in compounds containing fluorine and iodine, there is no interaction between both nuclei, in compounds containing fluorine and paramagnetic centers (radicals, metal ions), there is a rather intense interaction, which is manifested in a reduction in the relaxation time of the fluorine nucleus. The degree of manifestation of this effect depends on the number of unpaired electrons of the metal ion (549"»Mp2"»Bed"»Su2) and on the distance between the paramagnetic ion and the "UR-atom.

The greater the number of unpaired electrons of a metal ion and the closer they are to fluorine, the more significantly the relaxation time of the fluorine nucleus decreases.

A reduction in the relaxation time as a function of the distance from the paramagnetic ion is observed in all nuclei with an odd spin number, including the proton, and therefore gadolinium compounds are widely used as contrast agents in NMR tomography (MadpemiviU, Rgopapse?, Otpizsap?U, Juoiaget U).

In "H-MeR-tomography, however, the relaxation time of T- or To protons, i.e. primarily water protons "I 30, and not the relaxation time of fluorine nuclei is determined and the obtained data are used for visualization. A quantitative measure that characterizes the reduction of the relaxation time of T. , is the relaxivity, which is expressed in l/mmol.s. Paramagnetic ion complexes are successfully used to shorten the relaxation time. The table below shows data on the relaxivity of some commercially available drugs: ггрепакационсть in the Hnmolche spot, 6, oatto) « с 7 что "» In these compounds, only the interaction between protons and the gadolinium ion takes place. The relaxivity in water found for the indicated "contrast substances" is approximately 4 l/mmol-s.

Thus, both fluorine-containing compounds intended 45 for UE-tomography, where a shortened relaxation time of the fluorine nucleus is used, and compounds that do not contain fluorine, in which the relaxation time of water protons is determined, can be successfully used in MR tomography. ос An unexpected effect associated with the introduction of a perfluorocarbon-containing residue into a paramagnetic contrast agent, i.e., an effect associated with giving compounds used in proton imaging methods the properties of those compounds that until now were considered suitable only for use in imaging methods,

Ge») 20 based on the use of fluorine, also manifests itself in a rapid increase in the relaxivity of water protons. As a result, this indicator reaches values of 10-5bl/mmol-s, while similar values in some

T» of commercially available products are, as follows from the above table, from 3.5 to 3.vl/mmol-s.

Perfluoroalkyl-containing metal complexes are already known from application OE 19603033.1). However, the possibilities of using these compounds are limited, since in many cases they do not allow to achieve satisfactory results. With this in mind, there is currently, as before, the need for contrast agents prescribed

HF) for visualization of malignant tumors, lymph nodes and necrotic tissues. ky Malignant tumors often metastasize to regional lymph nodes, and this process can also involve several levels of lymph nodes. Thus, in particular, metastases in the lymph nodes were detected in approximately 50-69905 of all patients with malignant tumors | see EiIKe, Gutrpodgarnie, Kadioiodizspe OiadpoviikK ip Kiipik 60 pa Rgahiv, under the editorship. EgottpPoi9, Ziepage, Tiigp, volume IM, ed. Tpiete Megiad, Bida, 7th ed., 1984, pp. 434-496). The possibility of diagnosing metastasis to the lymph nodes is important for the treatment of oncological diseases and forecasting their development. Modern imaging methods (computed tomography, ultrasound, and magnetic resonance imaging) do not allow to recognize lymphogenic metastasis of malignant tumors with sufficiently high accuracy and reliability, since in most such cases, only the size of the lymph node can be used as the criteria for the appropriate diagnosis. As a result, such methods simply do not allow to distinguish small metastases in non-enlarged lymph nodes ("2 cm) from hyperplasia of lymph nodes not affected by a malignant tumor | see. Z(eipkatr, etc., bopodharpie pa

Kegpzripiotodgarpieye: Oiyegepiiaidiadpovik mop geakiimeg I utryKpoiepmegoagoVegipud pa GutryKpoiepiteg (aviazep at Naiv5, Kadioi. aiadp. 33 (1992), p. 158).

Taking this into account, it seems reasonable to provide, when using specific contrast agents, the possibility of differentiating lymph nodes affected by metastases and hyperplastic lymph nodes.

As an example of a well-known invasive imaging method, we can mention direct lympho-radiography (injection of an oil suspension of a contrast agent into a suitably prepared lymphatic vessel), which, however, is currently used only in rare cases and allows visualization of only some lymph outflow pathways.

In the experiments conducted on animals, dextrans with a fluorescent label are also used in order to ensure, after their interstitial introduction, the possibility of observing the outflow of lymph. All labels used after their interstitial/intradermal administration to visualize lymphatic ducts and 7/5 lymph nodes are substances in the form of solid particles ("macroparticles", such as emulsions and suspensions of nanocrystals) or large polymers |see also MO 90/14846). However, all currently known compositions due to their insufficient local and systemic tolerance, as well as their low mobility in the lymph, which causes unsatisfactory diagnostic efficiency, still remain suboptimal for use in indirect lymphography.

Since visualization of lymph nodes is important for early detection of metastases in cancer patients, there is a need for lympho-specific compositions of contrast agents that would allow timely and reliable diagnosis of relevant changes in the lymphatic system. To achieve the desired effect when using contrast agents, it is advisable to ensure not only their extremely high concentration in the lymph and high stability, but also the maximum uniform accumulation in the lymph in several levels of the lymphatic system, which is important for making an accurate diagnosis. At the same time, the contrast agent must be quickly and completely removed from the body in order to minimize its negative impact on the entire body as a whole.

The effect of the contrast agent should begin to manifest itself, if possible, a few hours after its introduction, which is an important condition in radiological practice. An equally important requirement for contrast agents is their good tolerability. "No less important is the need for lymphospecific contrast agents, which would allow to visualize both the primary tumor and its possible metastasis to the lymph nodes in one session of the diagnostic study. ise)

One of the important tasks of medicine is the detection, localization and monitoring of necrosis and heart attacks. with

So, in particular, myocardial infarction is not a stationary, but a dynamic process that lasts for a long period of time (from several weeks to several months). This cardiovascular disease occurs in approximately three stages, which cannot be clearly distinguished, since they overlap one another, and accordingly, they smoothly transition from one to another. The duration of the first stage, in which the development of a myocardial infarction occurs, is approximately the first 24 hours after its onset, during which tissue destruction spreads like a shock wave (analogous to the phenomenon of a wave front) from the subendocardium to the myocardium. The second stage, in which the development of a heart attack as such has already ended, includes the stabilization of the area, in which the formation of fibers (fibrosis) occurs during the healing process of the tissue affected by the heart attack. The third stage, which corresponds to the complete healing of the infarcted tissue, begins after the replacement of all destroyed tissue with fibrous scar tissue. During this period, active restructuring takes place. c To date, there is no method that would allow diagnosing the current phase of a myocardial infarction in a living patient with high accuracy and reliability. For the assessment of a myocardial infarction, the information about how large a proportion of the tissue lost during a heart attack and in which exact place is of crucial importance, since the type of therapy depends on this information.

Heart attacks, as is known, affect not only the myocardium, but also other tissues, primarily the brain. o If the tissue affected by a heart attack is to some extent amenable to healing, then with necrosis, that is, with locally 2) limited dead tissue, it is only possible to prevent or at least mitigate its harmful consequences for the rest of the body. The occurrence of necrosis can be due to various reasons and, in particular, injuries,

Me, exposure to chemicals, lack of oxygen or radiation. Similarly to a heart attack, the availability of information about the degree and type of necrosis is important for the selection of subsequent medical measures.

With this in mind, attempts have long been made to increase the efficiency of localization, i.e. determining the location, infarcts and necrosis due to the use of contrast agents in non-invasive methods, such as scintigraphy or NMR-tomography. At the same time, a large number of published works are devoted to experimental studies on the use of porphyrins for visualization of necrosis. However (F, the results obtained in similar studies are contradictory. So, in particular, (In the work of MUipKeItap and Nowez, published in Mayishge, 200 (1967), p. 903), it is about the selective accumulation of manganese-5,10,15 ,20-tetrakis(4-sulfonatophenyl)porphyrin (TFPS) in the necrotic area of the tumor. 60 In contrast to this |in the work of Guop et al., Madp. Kez. May. 4 (1987), p. 24| it is said about that effect , which was observed by these authors, that manganese-TFPS is essentially distributed throughout the body, namely, it accumulates in the kidneys, liver, tumor and only slightly in muscle tissues. Of particular interest is the fact that the concentration of this substance in the tumor reaches a maximum only on the 4th day after administration, and then only after increasing the dose from 0.12 mmol/kg to 0.2 mmol/kg. Therefore, the authors also draw 65 Conclusions about the non-specific accumulation of TFPS in tumor tissue. GU work of VoskKpigvzi et al. , published in

Asia Meiyhospig. 60 (1994, addn.), p.347|, it is again about the selective binding of MP-TFPS to tumor cells.

In turn, according to the results of the researches that were carried out by Ovieg and others, U. Mysi. Mea. 26 (1985), p. 7561), it was established that 7111p-5,10,15,20-tetrakis(4-M-methylpyridinium) porphyrin (TMPIP) accumulates not in the necrotic area, but in the living marginal layers, which surround Based on this, it would be possible to draw an obvious conclusion about the presence of interaction between porphyrin and tissue, which, however, does not necessarily correspond to reality.

In the work of Mi et al., published in Sigstiayop, vol. 90, Mo4, part 2, p. 1468, Abstract Mo2512 (1994), it was reported about the possibility of visualization of infarcted areas with the help of 70 manganese-tetraphenylporphyrin (Mp-TFP) and gadolinium -mesoporphyrin (sa-mMmP). According to UMO application 95/312191, both of these substances were used to visualize infarctions and necrosis. (This application, authored by Magepyai! and Mee, states (see example 3)) that when compound 54-MP was used, the metal content in the infarcted kidney was at the same level as in the non-infarcted organ, whereas in myocardium, the content of metal in the infarcted tissue (see example 71) exceeded its content in non-infarcted tissue by nine times. 75 What is unexpected is the fact that in MRI the ratio between the intensity of the signal formed by the infarcted tissue and the intensity of the signal formed by the healthy tissue in both cases was at a relatively high level and amounted to 2.10 and 2.19, respectively. Other metalloporphyrins are described in application OE 19835082 (in the name of Zspegipd AS).

Porphyrins tend to accumulate in the skin, which leads to its photosensitization. Such sensitization can persist for several days, and sometimes for several weeks. This is an undesirable side effect that occurs when porphyrins are used as diagnostics. In addition, porphyrins have only an exceptionally low therapeutic index, since, for example, in the case of Mi-TFPS, its effect is detected only when it is used in a dose of 0.2 mmol/kg, while its lethal dose of LD is already 5o

Oh, bmmol/kg. Ha

Other contrast substances, which are not derivatives of the porphyrin framework and are intended for visualization of necrosis and infarcts, (described in applications OE 19744003 (in the name of 5spegipd AS), OE 19744004 (in the name of Zspegipd AS) and MO 99/17809 ( named ERICH)). However, until now there are still no compounds that can be used effectively enough as contrast agents for visualization of infarcts and necrosis.

Based on the above, the basis of this invention was the task of offering contrast "Its substances, which would be suitable for use primarily in MRI-lymphography, as well as for diagnosing tumors and visualization of necrosis and heart attacks. at

This problem is solved in accordance with the invention with the help of perfluoroalkyl-containing complexes with sugar residues of the general formula | o and i- (Ku-0-(2-K dm | (I), - c . i (U-Y and in which the K axis means a mono- or oligosaccharide residue attached through the 1-OH- or 1-5H-position , o Kro means a perfluorinated, straight or branched carbon chain of the formula -С.РонЕ, where

E is a terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, and

Ge") 20 p means numbers 4-30,

Their K means the metal complex of the general formula HER

Ф) име) 60 b5 soOog (well, we are not 70 I - Mu no

KbOosSs and

M o 1 » SsoOv I z (1) s (o) "I "so

Ge) yuyu - « - with z - and in which one about B! represents a hydrogen atom or the equivalent of a metal ion of serial number 21-29, 31-33, 37-39, 42-44, 49c or 57-83, provided that at least two radicals B! mean metal ion equivalents,

F B2 and BZ independently of each other mean hydrogen, C1-C7 alkyl, benzyl, phenyl, -СНоОН or -СНоОСН з and т» M represents -С 5Н/-О-СН»-о-, "(Р Но ) .5-o-, tenylene group, -"СНО-МНСО-СНО-СН(СНСООН)-С Nu -o-, -SenН-(оСНСНО)ю. -M(СНСООН)-СН»-о- or optionally interrupted by one or several oxygen atoms, 1-3 -МНнСО-groups, 1-3 -СОМН-groups and/or substituted by 1-3 -СНо).5СООН -groups of S.-S.oalkylene or

C7-C12-SeNu/-O-group, while o means the place of attachment to -СО-,

GF! or the general formula of HER ko bo b5

Owl! " i st 4 (U uesov at 70 K I i

Kgoos. p; (- sov: (PO, in which

B has the above values, p

VE stands for hydrogen or indicated for B! equivalent of a metal ion and o

SHY means -SveNa-О-СНо-о-, where oyu means the place of joining to -СО-, or the general formula IM (М «г зо СсооЕ Ф ( о и юю

FI YCHI U EE: y-tt ek « yu Koos Z s M o z She u y Ssoog: (U, 1 and in which B! and 22 have the above values, bu 70 or the general formula MA or UV s"

F) has) 60 b5 euros and ; with -soov' os ozh

M.

SO (ud), and mo boov, "nn ml Ov sch

Chen O)

СО (ув), з евро Shch y s -soov' y

And up and down and the owl! and

Vera 5

Also (UA), y ra sh 45 o « -saoE

I am 20; Mossoor"

And (UV), iF) in which VE! has the above values, ko or the general MI formula

(M) posy i bo pOo0s--7 -c008 (tsu z - in ! in which K' has the values indicated above, or of the general formula MYI (M) in v'sOos-- o "М A

Koos DY 1 pos vOos-7 (MI) . with o in which

Whew! has the above values, and

Shts means -СбН.-О-СН»-о-, be ою means the place of attachment to -СО-, т or the general formula МИИ (Се) со (мМ) 004, ю ( and - pyt

M « shi s ry pi

I» ES / r. o N ya I y - K - iy y I Ssoo UNI

Me, (U, c" in which B! has the above values, while the free acid groups optionally present in the K residue can optionally be represented in the form of salts of organic and/or inorganic bases or amino acids or in the form of amino acid amides, б у (Ф. in that case, if K means metal complexes of the formulas II-MY, is at least a three-fold co-functionalized residue selected from the following residues a)-Ж): 60 b5

(and)

And NN about (by CO -well and MN r with (6)

N u k-so--(SNurMy r

MN sch i o o " « « shi s y o 55

70 ; X -,

ZhK cho, i

In (o) and zozha and her x them blue

I - s sword;" R. » o Bay b) t and IV 25 ; nya n

What else ze 65 the bottom is nowhere and (t: in. see

What about her and 5 | And | WHAT | so on-enoemnyam - and Y Mn

T» Bl ; o vleh-K- NIKOM o0 Ye end "appeared

She m

0) 10 Che More

MN r.

MAS she s; sch 25 o'clock; - зо осаяМНА-ОН -СО -ем у Ф 3 со » РЕ и о In the event that K means a metal complex of the formula MI, is at least a three-fold functionalized residue selected from the residues K) and I): « с 40 ( Yu - and reMN-(sNursNn-Sosho from 45 chn i in) "y , t"

In o sy Sotenysntov sotu 60 GE bo R is)

while A means the place of attachment of o to complex K, B means the place of attachment of C to residue Y, and Г means the place of attachment of C to residue 7,

M means -CH»-, 5-X"HNO)CO-B (where n-1-5), 6-PHno-CHNON-CO-B or 5-CHN(ISNON-SNON)-CHON-CHNON-CO- B, where b means the place of attachment to the K sugar residue, and B means the place of attachment to the 0 residue, 27 means the group

U-M -5055 sho and z

Г-СОСНО-М(СоНВ)-505-Е, г-сОосСНно-О-(СНо»)»-505-Е, or о о О ИМ М-з05-6 in mech 2

Г-МНненНХсСНноО-О-СНХСН»О-Е, where Г means the site of attachment of 2 to the residue 0, and is the site of attachment of 7 to the perfluorinated residue

Kk with and ;. and

И, т independently of each other mean integers 1 or 2 and (о) р means integers from 1 to 4.

If the compound proposed in the invention is intended for use in NMR diagnostics, then the metal ion of the signal-forming group must be paramagnetic. Such ions primarily include divalent and trivalent ions of elements with serial numbers 21-29, 42, 44, and 58-70. As an example of ions suitable for use for the specified purposes, we can mention the ions of chromium (II), iron (II), cobalt (II), nickel (II), copper (II), (Ce), praseodymium (II), neodymium (II). , samarium(I) and ytterbium(). Given their high magnetic moment, the best ones are ions // gadolinium(II), terbium(II), dysprosium(II), holmium(II), erbium), iron!) and manganese). IF)

In order to use the compounds proposed in the invention in medical radiology (radioisotopic diagnostics and radiation therapy), the metal ion must be radioactive. For these purposes, for example, radioisotopes of elements with serial numbers 27, 29, 31-33, 37-39, 43, 49, 62, 64, 70, 75 and 77 are suitable. Technetium, gallium, indium, rhenium are better. and yttrium.

If the compound proposed in the invention is intended for its use in X-ray diagnostics, then as a metal ion it is preferable to use an element with a higher serial number in order to ensure a sufficiently high degree of absorption of X-rays. It was established that for this purpose, diagnostic agents containing physiologically compatible complex salt with metal ions of serial numbers 25, 26 and 39, and also 57-83 are suitable for this purpose. The best are manganese), iron (Ii), iron (I), praseodymium (IIi), neodymium|, samarium)), gadolinium), ytterbium (P!) or bismuth (P), primarily dysprosium ions!| ) and yttrium(P).

Present under certain conditions in B! acidic hydrogen atoms, that is, atoms that are not replaced by a central ion, -I may optionally be completely or partially replaced by cations of inorganic and/or organic bases or amino acids or amino acid amides. Examples of acceptable inorganic cations include lithium ion, potassium ion, calcium ion, and primarily sodium ion. Acceptable cations of organic bases are, in particular, those from primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine,

M,M-dimethylglucamine and primarily M-methylglucamine. Examples of acceptable amino acid cations include (2) cations of lysine, arginine, and ornithine, as well as amides of other acidic or neutral amino acids.

Their" To the best compounds of the general formula | belong to compounds containing the macrocycle K of the general formula II.

The residue ) in the metal complex K mainly means -СН»о- or -С8Н/-О-СНо-о-, where ою represents the place of attachment to -СО-.

Alkyl groups in the macrocycle of the general formula I indicated as B 2 and EZ values can have a direct or

F, branched chain. At the same time, methyl, ethyl, propyl, isopropyl, n-butyl, co 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl can be cited as examples.

Preferably, the 2nd C independently of each other mean hydrogen or C1-C6 alkyl. In one of the particularly preferred 60 variants, B2 is methyl and BZ is hydrogen.

The benzyl group or phenyl group in the macrocycle K of the general formula I is indicated as the value B 2 or C! can also be substituted in a ring.

The remainder K in the general formula | means a mono- or oligosaccharide residue or a thiosugar residue attached through the 1-0OH- or 1-5H-position, and in this case, according to the invention, we may also be talking about deoxysugars, which instead of one or more OH groups contain an H atom. In one of the best embodiments of the invention, K means a monosaccharide residue with 5 or 6 C atoms, preferably glucose, mannose,

galactose, ribose, arabinose or xylose or their deoxysugars, such as, for example, b-deoxygalactose (fucose) or b-deoxymannose (rhamnose), or their thiosugars, with glucose, mannose and galactose being the most preferred.

Among the compounds proposed in the invention of the general formula | compounds in which K; means 5000 7Spropyai. At the same time, n preferably means numbers from 4 to 15. The most preferred residues are -С/Ро, -СвЕ4з, -СвЕч7, -С12Е»2в and -С44Е2о, as well as the residues of the compounds considered in the examples.

The at least three-fold functionalized residue C in the general formula I, which is a "skeleton", in one of the best embodiments of the invention means | lysine residue (a) or (B).

My 7 represents the specified for the general formula I! linker, while independently of each other, 7 7/0 mainly means the y-m group. "M-505-E with 15 and ХУ mostly means group 5-ОНХОО-В.

The method of obtaining perfluoroalkyl-containing complexes with sugar residues of the general formula () 20 (К-0-(4-Ко)т (Й, с 25 о (СУ-К)р « 30 in which K means one of the metal complexes of the general formulas 1И-МИИ , (c represents one of the groups of formulas c a)-i), and M, 27, K, K, t, p and 1 have the above values, consists in the fact that the carboxylic acid of the general formula Ia (ze)

IS)

And soov and that (2 out of 7 p. ri vav: Fr

I" x m MI

Shk -T-Ch-N- And in ON with braids and about (95) b 50 5 of them owls (Pa)

Pas),

F) name) 60 b5

(pa) in which VE? means the equivalent of a metal ion with serial number 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or c a carboxy protecting group, and 2, BZ and y have the above values, or a carboxylic acid of the general formula Sha (o) (Sha) 5 « zo sok (Se) so m sov o / | i - 2 vioos7 7 Otto « shi s M g» and soov? with (Sha)

Sha), 1 o 50 in which 7, V and Sh! have the above values, or a carboxylic acid of the general formula Ma (22) c»

F) name) 60 b5

(Ma) 5 sok gy y ra ikh r2 kh on poto om;

MAM with;

AND"

And soov (Ma), with which V? and B? have the values indicated above, or a carboxylic acid of the general formula Ma or Mr o -«-c5o-oH - "So ke: ШЙ

And o so os OO

K moso ov M Fo -soov y z "-SOOK (uv), MBO (uv « -sko-Oon 3 s s M. sov r mo ooo, :" ---M v'sos noos7 X v met og M mo oo, and "-SOOK (Ua), MASOVU, (95) b 50 s"

F) name) 60 b5

(Ma) (MB) where is V? has the above values, or a carboxylic acid of the general formula Mia o (Ma) 5

Re osi ut So-oN h 7 5 r - 5 Te) kos SoOoKk (Ma), and

IS) in which E? has the above values, or a carboxylic acid of the general formula Ma - (Mpa) « 5 is vOOs--x. 9 z - 5 IM mk g» V'bos-- t on 5 ts R os s ni dk z pos (Ua), b 50 th» in which V her 0! have the above values, not necessarily in an activated form, are subjected to a known method of interaction under the conditions of a coupling reaction with an amine of the general formula ХХ (x)

F) yu N-b-(2Kp 60 (GO),

SU-KYU b5 in which Z stands for one of the groups of formulas a)-Y), and K, KT, M, 7, т and р have the values indicated above, and then, if necessary, the protective groups present under certain conditions are cleaved, resulting in metal complex of the general formula I or, if B? represents a protective group, after cleavage of such protective groups at the next stage, it is subjected to interaction according to a known method with at least one metal oxide or metal salt with serial number 21-29, 31-33, 37-39, 42-44, 49 or 57-83 , after which, if necessary, acidic hydrogen atoms present under certain conditions are replaced by cations of inorganic and/or organic bases, amino acids or amino acid amides.

The method of obtaining the compounds of the general formula I proposed in the invention, in which K means the complex of metal 70 of the general formula MI, and C is a group of the formula K) or I), consists in the fact that the amine of the general formula

MiMa sooye ( rt x pchishtchnym --H 5 M on sia this and 5 « ho sSook (USha, (Z (Mpa) Go)

IS) and - shi s ;" -I 1 (95) b 50 s" in which VZ means the equivalent of a metal ion of serial number 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or a carboxyl protecting group, is subjected to a known method of interaction in under the conditions of the coupling reaction with an optionally diactivated carboxylic acid of the general formula X

F) so m HO-0-(7-Vdt 60

СО, 65 ( )р in which C denotes a group of the formula K) or I), and K, K,, M, 7, т and р have the values indicated above, and then, if necessary, the protective groups present under certain conditions are cleaved with the obtaining of as a result of a metal complex of the general formula I or, if B? represents a protective group, after cleavage of such protective groups at the next stage, it is subjected to interaction according to a known method with at least one metal oxide or metal salt with serial number 21-29, 31-33, 37-39, 42-44, 49 or 57-83 , after which, if necessary, acidic hydrogen atoms present under certain conditions are replaced by cations of inorganic and/or organic bases, amino acids or amino acid amides. 70 The carboxylic acids of the general formulas Pa-MIa used in the reactions described above are either known compounds, or they are obtained by the methods described in the examples. So, in particular, the method of obtaining carboxylic acids of the general formula Pa is known from OE 19652386). Carboxylic acids of the general formula Xa can be obtained analogously to example C, given below in this description. The method of obtaining carboxylic acids of the general formula Ma is described in OE 19728954).

The precursor of compounds of the general formula MA is

M3-(2,6-dioxomorpholinoethyl)-M 9-(ethoxycarbonylmethyl)-3,6-diazaprobic acid, which is described (in EP 263059).

Compounds of the general formula MV are derivatives of isomeric diethylenetriaminepentaacetic acid (DTPA), which is attached through acetic acid located near the central M atom. This DTPK is described in IV OE 19507819 and

OE 19508058).

Compounds of the general formula MI are derivatives of M-(carboxymethyl)-M(2-(2,6-dioxo-4-morpholinyl)ethyl|uglycine, the method of preparation of which is described in 9. At. ОЙ. Spet. os, 59 (2 ) (1982), pp. 104-1071.

Compounds of the general formula MI! are derivatives of 1-(4-carboxymethoxybenzyl)ethylenediaminetetraacetic acid, which is described in patent 5 4622420).

The preparation of amines of the general formula IX and carboxylic acids of the general formula X is described in detail in Examples 1 and 2 below in this description, and therefore the specified compounds can be prepared analogously to the methods discussed in these examples. The amine of the general formula MiIa is a known starting compound. and)

The perbenzylated sugar acids used as starting materials can be obtained similarly to the method described |in GosKpoi in Apdem/. Spet., 110, Mo24 (1998), p. 3634) et seq. So, for example, 1-O-acetic acid is obtained from perbenzylglucose in two stages, namely, through trichloroacetimidate and interaction with ethyl alcohol with hydroxyacetic acid ester, catalyzed by VEZ in THF followed by saponification using maon in meon/tgF . ish

In one of the best options, perbenzylated sugar acids used as starting materials can also be obtained by dissolving perbenzylated 1-OH-sugar in an organic solvent that is immiscible with water, followed by interaction with an alkylating agent of the general formula XI -

Mi-I-SOO-89 (Xi) where Mi is a nucleophobe, and I means -(СНо)д- (where n-1-5), -СН.-СНОН-, -СН(ИСНОН-СНОН)-СНОН- CHOH-, and Zd represents a protective group, in the presence of a base and optionally an interphase catalyst. The alkylating "20" agent of the general formula XI can contain as a nucleophobe, for example, -СИ, -Вг, -У, -ОТв, -ОМ»8, -ОО50 СЕ», -в с -0505С/Ро or -О5О»СвЕ47. A protective group means an acid-protecting group commonly used for similar purposes. Such protective groups are well known to specialists | see, for example, Rgoiesiime Zgocrz ip Ogdapis :z» zZupipezez, T.MU. Sgeepe and R.O.M. MUtsiv, 2nd ed., ed-vo dopp UMPeu b 5opvz Ips., Mem Hogk 19911.

The interaction discussed above can be carried out at a temperature from 0 to 5029C, preferably from 09C to room temperature. The duration of the reaction is from 10 minutes. up to 24 hours, mostly from 2 Ohv. until 12 o'clock - The basis is added either in solid form, preferably in the form of finely ground powder, or in the form of a 10-70965, preferably 30-5096 aqueous solution. The best bases are Mmason and KOH. o As an organic solvent that is immiscible with water, in the alkylation method proposed in the invention, o can be used, for example, toluene, benzene, C3-benzene, hexane, cyclohexane, diethyl ether, tetrahydrofuran, dichloromethane, MTB or their mixtures. (2) As interphase catalysts in the method proposed in the invention, known for their use are used

For these purposes, quaternary ammonium or phosphonium salts or crown ethers, such as, for example, (15|-crown-5 or |(18|-crown-b6). Quaternary ammonium salts with four identical or different hydrocarbon groups near the cation selected from methyl, ethyl, propyl, isopropyl, butyl and isobutyl.

Hydrocarbon groups in the cation must be large enough to ensure good solubility of the alkylating agent in the organic solvent. According to the invention, it is most preferable to use M(butyl)d"-СІ", M(butyl)4"-НЗО 7, as well as M(methyl)y-СІ". as it was established, for use in NMR and X-ray diagnostics, as well as in radionuclide diagnostics and radiation therapy. The object of the invention 60, accordingly, is also the use of the proposed perfluoroalkyl-containing metal complexes with sugar residues for obtaining contrast agents intended for use in NMR and x-ray diagnostics, primarily in lymphography, for diagnosing tumors and for visualization of infarctions and necrosis, as well as in radionuclide diagnostics and radiation therapy. The compounds proposed in the invention are most suitable for use in interstitial and primarily in intravenous lymphography. 65 At the same time, they can also be used for visualization of the intravascular cavity (as contrast agents for visualization of blood pools).

The object of the invention is also pharmaceuticals that contain at least one physiologically compatible compound according to the invention, not necessarily in combination with additives that are usually used in galenic preparations.

The compounds proposed in this invention are characterized by exceptionally good systemic compatibility and a high degree of accumulation in the lymph nodes of three consecutive levels (which is especially important during intravenous lymphography). This makes them particularly suitable for use in MRI lymphography.

The compounds according to the invention are also suitable for detection and localization of vascular diseases, since they are distributed only in the intravascular cavity when they are introduced. The 7/0 compounds proposed in the invention allow using NMR tomography to clearly differentiate tissue with good and poor blood flow and thereby diagnose ischemia. To the same extent, when using contrast agents according to the invention, it is also possible to clearly distinguish the infarcted tissue due to its anemia and the healthy or ischemic tissue that surrounds it. Such an opportunity is of particular importance in cases where, for example, it is necessary to accurately establish whether a myocardial infarction has occurred or ischemia.

In comparison with the macromolecular compounds that have been used until now as contrast agents for imaging blood pools, such as, for example, aza-DTPK-polylysine, the compounds according to the invention also have a higher T.i-relaxation and, accordingly, they are characterized by a higher level signal intensity during NMR imaging. Since, in addition, such compounds are in the blood for a longer period of time, they can also be administered in relatively small doses (for example, "50 micromoles per liter of blood circulating in the body). However, an equally important advantage of the compounds proposed in the invention is that they are quickly and almost completely removed from the body.

In addition, it was established that the compounds according to the invention accumulate in areas with increased permeability of blood vessels, in particular in tumors, and accordingly, they allow obtaining information about tissue perfusion, make it possible to determine the volume of blood in tissues, selectively reduce the relaxation time, respectively, the period with blood thickening and visualize the permeability of blood vessels. It is impossible to obtain this kind of physiological information when using extracellular contrast agents, such as, for example, a-dtpk (Madpemivi U). Taking this into account, it is also possible to use the compounds according to the invention in such modern imaging methods as NMR tomography and computer tomography, in particular for the specific diagnosis of malignant tumors, for early control of the course of treatment during cytostatic, anti-inflammatory or vasodilation therapy , for early detection of areas with reduced blood supply (for example, in the myocardium), for angiography in vascular diseases, as well as for the detection and diagnosis of aseptic or infectious inflammations. co

The pharmaceutical products proposed in the invention are obtained according to known technology by suspending or dissolving the complex compounds according to the invention, if necessary in combination with additives usually used in galenic preparations, in an aqueous medium, after which the resulting suspension or the resulting solution is optionally subjected to sterilization. As specified additives can be used, for example, physiologically compatible buffers (such as tromethamine), complexing agents or weak complexes (such as diethylenetriaminepentaacetic acid or corresponding to the metal complexes proposed in the invention "

Ca-complexes) or, if necessary, electrolytes, such as sodium chloride, or, if necessary, antioxidants, such as ascorbic acid. - c If for enteral, respectively parenteral administration or for other purposes it is intended to use suspensions or solutions of the agents proposed in the invention in water or a physiological saline solution, then they are mixed with one or more auxiliary substances commonly used in galenic preparations (for example, with methyl cellulose , lactose, mannitol) and/or with one or more surfactants (for example, with lecithin, Tmeep?U, Mugi?) or with one or more correctors (for example, with essential oils). sl In principle, pharmaceutical agents according to the invention can also be obtained without the isolation of complexes. However, in any case, in the process of formation of chelate compounds, conditions should be especially carefully observed, which (95) almost completely exclude the possibility of the presence of metal ions in the complexes proposed in the invention, which did not form a complex and which have toxic effect. For these purposes, the process of obtaining complex compounds can be controlled by itration using, for example, color indicators, such as xylenol iz" yellow-hot. Accordingly, the present invention also relates to a method of obtaining complex compounds and their salts. In extreme cases, the selected complex can be subjected to purification.

When using the means proposed in the invention, they can be administered together with a carrier suitable for this purpose, such as, for example, serum or a physiological saline solution, and together with another protein, such as, for example, human serum albumin (SAL).

The means proposed in the invention are mainly intended for parenteral, preferably intravenous administration. However, depending on the investigated object - vessels or tissues - they can also be prescribed for intravascular or interstitial/intradermal administration. because Pharmaceuticals according to the invention contain preferably from 0.001 to 2 mol of the complex per liter and are intended for administration in doses that are, as a rule, from 0.0001 to 5 mmol/kg.

The means proposed in the invention meet the most diverse requirements that determine their suitability for use as contrast agents in NMR tomography. So, in particular, such means allow to increase the informativeness of the image obtained with the help of an NMR-tomograph due to an increase in signal intensity after their oral or parenteral administration. In addition, such means have high efficiency, which is necessary to reduce the concentration of foreign substances that are introduced into the body, to the minimum possible level, and at the same time have good tolerability, which is necessary to preserve the non-invasive nature of research.

Due to the high degree of solubility of the agents proposed in the invention in water and their low osmolality, it is possible to obtain highly concentrated solutions based on them, which allows maintaining the volumetric overload of the circulatory system within acceptable limits and compensating for the dilution of such solutions with body fluids. The means proposed in the invention also have not only a high ip mio stability, but also reveal an unexpectedly high ip mimo stability, due to which the release or exchange of ions bound in the complex, which are in principle toxic, occurs only extremely slowly during that time interval, which 7/0 New contrast agents are completely excreted from the body.

Usually, the agents proposed in the invention when used as NMR diagnostics are used in doses from 0.0001 to 5 mmol/kg, preferably from 0.005 to 0.5 mmol/kg.

The complex compounds proposed in the invention can, in addition, be effectively used as magnetic susceptibility reagents and shift reagents in ip mimo NMR spectroscopy.

Means according to the invention, due to their optimal radioactive properties and high stability of the complex compounds contained in them, are also suitable for use as diagnostics in radionuclide diagnostics. The use of such means and their dosage are described in more detail (for example, in the publication "Kadioigasegg Tog Medisa! Arriisayopvg", ed. in SKOS-Rhevzv, Vosa Kap, Riogiaa).

The compounds and means proposed in the invention can also be used in positron emission tomography, where isotopes that emit protons are used, such as, for example, 7Cs, "c, 52Re, 55Co, b8sza and 86u

went MU.O. Neivv and M.E. RIeirz, Rozygop Yeetivzviop Totodharpyu oi Vgaiipy, vid-vo Zrhipdeg Megiad, Vegiiy,

Neideirego, Mem/ HogKk (1983)).

Compounds according to the invention can, as it was unexpectedly established, also be used for the differentiation of malignant and benign tumors without a blood-brain barrier. Ha

The contrast agents proposed in the invention, after their intravenous administration, can also be used to quantify changes in the integrity of capillaries caused by hyperoxia (including "sharp capillary holes" and restoration of the integrity of the endothelium to a normal state after hyperoxic damage).

Regional microvascular hyperpermeability is confirmed by histological studies. With this in mind, the contrast agents proposed in the invention can also be used to visualize abnormal permeability of capillaries.

The compounds according to the invention are also distinguished by the fact that they are completely excreted from the body, thereby showing good tolerability. co

Since the compounds proposed in the invention accumulate in malignant tumors (lack of diffusion into healthy tissues, but high permeability of tumor vessels), they can also be used in addition to radiation therapy of malignant tumors. The difference between radiation therapy and corresponding diagnostics is only in the amount and type of isotope used. The goal is the destruction of tumor cells under the influence of powerful short-wave radiation with an extremely small radius of action. In this case, the interaction of metals contained in complex compounds (such as iron or gadolinium) with ionizing radiation (for example, X-rays) or neutron radiation is used. 70 Thanks to this effect, it is possible to significantly increase the local radiation dose in the place where the -c metal complex is located (for example, in tumors). To ensure the same dose of radiation in malignant tissue, the use of similar metal complexes allows to significantly reduce the dose of radiation to healthy tissues and "" prevent side effects that are undesirable for patients. Therefore, the conjugates of metal complexes proposed in the invention are also suitable for use as radiosensitizing substances in radiation therapy

Malignant tumors (for example, due to the use of Mössbauer effects or with neutron-capturing -I therapy). As an example of acceptable ions emitting B-rays, we can name 79Zs, 7"Zs, 85s, "ba, ba c and Оu. As acceptable ions emitting A-rays with a short half-life, we can name, for example, 211Bi, 212Vi, 213Vi and 214Vi, which 212Vi is better. The ion that emits protons and electrons is 129634,

Mami, which can be obtained from 127054 by capturing neutrons.

Ge") 20 If the tool proposed in the invention is intended for use in radiation therapy according to the method proposed by K.I. Miiiev and others. | see Maischge, vol. 336 (1988), p. 787), then the central ion must be a derivative of the I Mössbauer isotope, such as, for example, "Be" or "UEu,

When using the ip mimo agents proposed in the invention, they can be administered together with a carrier suitable for this purpose, such as, for example, serum or a physiological saline solution, and together with another protein, such as, for example, human serum albumin. The dosage depends on the cellular type

HF) violation, used metal ion and type of imaging method. 7 Means proposed in the invention are intended mainly for parenteral, preferably intravenous administration. However, as noted above, depending on the investigated object - vessels or tissues - they can also be prescribed for intravascular or interstitial/intradermal administration.

The agents proposed in the invention are also suitable for use as radiopaque substances, while it should be especially noted that when they are used in biochemical and pharmacological studies, no signs of anaphylactic reactions, known for iodine-containing contrast agents, are observed. These means, due to their optimal properties of absorbing rays in the range of higher voltages on the tube, are the most suitable for use in digital subtraction technology.

As a rule, the agents proposed in the invention when used as radiopaque substances are used similarly to, for example, meglumine diatrizoate in doses from 0.1 to bmmol/kg, preferably from 0.25 to immol/kg.

When using the compounds proposed in the invention, it is first of all possible to achieve their higher concentration in the blood compared to extracellular contrast agents. After intravenous administration, they are distributed only in the intravascular cavity, which is their main advantage over extracellular contrast agents.

Example 1 70 a) 2-M-trifluoroacetyl-6-M-benzyloxycarbonyl-1-lysine 100.0 g (356.7 mmol) of 6-M-benzyloxycarbonyl-1-lysine is dissolved in a mixture of 1000 ml of trifluoroacetic acid ethyl ether and 500 ml of ethanol and stir for 24 hours at room temperature. After that, it is evaporated to dryness and the residue is crystallized from diisopropyl ether.

Yield: 128.9 g (9695 from theory) of colorless crystalline powder.

Melting point: 98.59C.

Elemental analysis: solution: C 51.07 H 5.09 M 7.44 g 15.14 found: C 51.25 H 5.18 M 7.58 E 15.03 6) (1-(4-perfluorooctylsulfonyl )piperazine|amide 2-M-trifluoroacetyl-6-M-benzyloxycarbonyl-i-lysine

164.2 g (0, 66b4mmol) of EEDH (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred overnight at room temperature, then evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane/methanol 20:1 ).

Yield: 286.0 g (9396 from theory) of a colorless solid.

Melting point: 9296. i)

Elemental analysis: solution: C 36.30 H 2.83 M 6.05 E 41.01 53.46 found: C 36.18 H 2.94 M 5.98 E 40.87 53.40 "I in ) (1-«4-perfluorooctylsulfonyl)piperazine|6-M-benzyloxycarbonyl-i-lysine amide

A solution of 280.0 g (302.2 mol) of the compound indicated in the title of example 16 in 2000 ml of ethanol at 02C is bubbled with gaseous ammonia for one hour. Then the mixture is stirred for 4 hours. at 02C. After that, c is evaporated to dryness and the residue is separated from water by stirring. The solid substance is filtered off and dried in a vacuum at 502C.

Z Yield: 243.5 g (9790 from theory) of amorphous solid. in.

Elemental analysis: solution: C 37.60 H 3.28 M 6.75 E 38.89 5 3.86 found: C 37.55 H 3.33 M 6.68 ЕЗ38.78 53.81 « g) P1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-benzyloxycarbonyl-2-M-(1-0O-A-O-carbonylmethyl(2,3,4,6-tetra-O-benzylmannopyranose)|-I -lysine o) c To a solution of 100.0 g (1204 mol) of the compound indicated in the title of example iv, 72.1 g (1204 mol) "» 1-0-А-О-carboxymethyl-2,3,4,6-tetra-О- benzylmannopyranose and 13.86 g (120.4 mol) of M-hydroxysuccinimide in 500 ml of dimethylformamide at 02С add 41.27 g (200 mol) of M,M-dicyclohexylcarbodiimide. The mixture is stirred during the Agreement. at 029C and then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness under vacuum and chromatographed on silica gel (eluent: and dichloromethane/ethanol in a ratio of 20:1). os Yield: 136.1 g (87905 from theory) of viscous oil.

Elemental analysis: solution: C 57.32 H 4.89 M 4.31 P 24.86 5 2.47 b) 70 found: C 57.38 H 5.07 M 4.22 E 24.78 52 ,39 d) 1-K4-perfluorooctylsulfonyl)piperazine|amide 2-M-(I1-0O-A-O-carbonylmethylmannopyranose|-I-lysine

T» 130.0 g (100.0 mmol) of the compound indicated in the title of example 1g is dissolved in 2000 ml of ethanol and 10.0 g of palladium catalyst (10956 Pa/C) is added. After that, hydrogenate for 12 hours. at room temperature. Then the catalyst is filtered off and the filtrate is evaporated to dryness under vacuum. 29 Yield: 91.7 g (quantitative) of a colorless solid.

HF) Elemental analysis: solution: C 34.07 H 3.63 M 6.11 5 3.50 35.24 o detect.: C 33.91 H 3.72 M 6.04 5 3.40 35.31 f) P1-(4-perfluorooctylsulfonyl)piperazine|amide 60 6-M-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-M-(pentanoyl-3-aza- 4-oxo-5-methyl-5-yl)|-2-M-(1-0-A-O-carbonylmethylmannopyranose|-I-lysine, α-complex 50.0g (54.55mmol) of the compound specified in the title example of poison, 6.28 g (54.55 mmol) of M-hydroxysuccinimide, 4.62 g (109. mol) of lithium chloride and 34.35 g (54.55 mol) of the 1,4,7-tris(carboxylatomethyl)-10 -(carboxy-3-aza-4-oxo-5--methylpent-5-yl)-1,4,7,10-tetraazacyclododecane is dissolved under moderate heating in 400 ml of dimethyl sulfoxide. Then, at 102, 16.88 g (81, 8 moths)

M,M-dicyclohexylcarbodiimide and then stirred overnight at room temperature. The solution is poured into

300 Oml of acetone and stir for 1 hour. The precipitated solid is filtered and then purified by chromatography (KR-18, eluent: water/ethanol/acetonitrile gradient).

Yield: 75.9 g (91.095 from theory) of a colorless solid.

Water content: 8.695.

Elemental analysis (in terms of anhydrous substance): solution: С 35.34 Н 4.09 М 8.24 5 2.10 Р 21.12 ba 10.28 found.: С 35.28 Н 4.15 М 8 .19 5 2.15 P 21.03 ba 10.14 70 Example 2 a) P1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-(1,4,7-tris(carboxylatomethyl)-1,4,7 . (3a-5 complex of 50.0 g (54.55 mmol) of the compound indicated in the title of the example, 6.28 g (54.55 mmol) of M-hydroxysuccinimide, y75 2.82 g (109, .Omol) of lithium chloride and 34.35 g ( 54.55 mol) of the cCa complex of 1,4,7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methylpent-5-yl)-1,4,7,10-tetraazacyclododecane dissolve under moderate heating in 400 ml of dimethyl sulfoxide. Then, at 1093, add 16.88 g (81.8 mmol)

M,M-dicyclohexylcarbodiimide and then stirred overnight at room temperature. The solution is poured into

300 Oml of acetone and stir for 1 hour. The precipitated solid is filtered and then purified by chromatography (KR-18, eluent: water/ethanol/acetonitrile gradient).

Yield: 76.Og (92.095 from theory) of a colorless solid.

Water content: 6.8895.

Elemental analysis (in terms of anhydrous substance): solution: C 34.90 N 3.93 M 8.32 5 2.12 ER 21.33 ba 10.38 s detection: C 34.81 N 4.02 M 8.27 5 2.09 RE 21.22 sa10.19

Example C i) a) 2-I4-(3-oxaethylpropionate) methyl ether phenyl acetic acid

To 200.0g (1204.0mmol) of 4-hydroxyphenylacetic acid methyl ether and 212.0g (2000.0mmol) of sodium carbonate in 2000ml of acetone, 233.8g (1400.0mmol) of 2-bromoacetic acid ethyl ether are added and for 1 hour . boil under reflux. The solid substance is filtered off and evaporated to dryness under vacuum.

The residue is chromatographed on silica gel (eluent: n-hexane/ethyl acetic acid in a ratio of 15:1). at

Yield: 288.5 g (95.095 from theory) of colorless oil. co

Elemental analysis: soln.: C 61.90 H 6.39 o detect.: C 61.75 H 6.51 i-b) Methyl ether of 2-(4-(3-oxaethylpropionate)|phenyl-2-bromoacetic acid

To 285.0 g (1130, Ommol) of the compound specified in the title of Example B, dissolved in 2000 ml of carbon tetrachloride, add 201.0 g (1130, Ommol) of M-bromosuccinimide and 100.0 mg of dibenzoyl peroxide and for 8 hours. boil under reflux. Next, it is cooled in an ice bath, the precipitated succinimide is filtered off and the filtrate is evaporated to dryness under vacuum. The residue is purified on silica gel (eluent: n-hexane/acetone in a ratio of 15:1). and Yield: 359.2 g (96.095 from theory) of colorless viscous oil. "» Elemental analysis: soln.: C 47.28 H 4.57 Wg 24.16 found.: C 47.19 H 4.71 Wg 24.05 -i c) Methyl ether 2-I4-(3-oxaethylpropionate) |phenyl-2-(1-(1,4,7,10-tetraazacyclododecane-1-yl)) acetic acid o To 1,4,7,10-tetraazacyclododecane (3500, mol) of 1,4,7,10-tetraazacyclododecane in 10 ml of chloroform add 350.0 g

Ge) (1057, Ommol) of the compound indicated in the title of example 36, and stirred overnight at room temperature of 50 degrees. Next, it is extracted three times with water in portions of 300 Oml, the organic phase is dried over magnesium sulfate and

Pho is evaporated to dryness under vacuum. The residue without additional purification is used in the next reaction (example 3g).

Ta» Yield: 448,Og (quantitative) of viscous oil.

Elemental analysis: soln.: C 59.70 N 8.11 M 13.26 found: C 59.58 N 8.20 M 13.18 g) 2-I4-(3-oxapropionic acid)|phenyl- 2-(1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-10-yl|acetic acid with 445.0 g (1053.00 mmol) of the compound indicated in the title of example Zv, and 496, 0 g (5270, mol) of chloroacetic acid is dissolved in 4000 ml of water. The pH value is set to 10 using 3095 aqueous caustic sodium and stirred for 8 hours at 7020. After that, the pH of the reaction solution is set to 13 by mixing with 309 aqueous sodium hydroxide with caustic sodium and refluxed for 30 minutes. Then the solution was cooled in an ice bath and the pH value was set to 1 by adding concentrated hydrochloric acid. After that, it was evaporated to dryness under vacuum. The residue was dissolved in 4000 ml of methanol and stirred at room temperature for an hour. The common salt that has precipitated is filtered off, the filtrate is evaporated to dryness and the residue is purified on C KR-18 (eluent: gradient in di/ethanol/acetonitrile).

Yield: 403.Og (69.095 from theory) of a colorless solid.

Water content: 10.295.

Elemental analysis (in terms of anhydrous substance): solution: C 51.98 N 6.18 M 10.10 found: C 51.80 N 6.31 M 10.01 d) 2-I4-(Z-oxapropion acid)|phenyl-2-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-10-yl|acetic acid, sa-complex

130.7g of gadolinium oxide (360.65mmol) of gadolinium oxide is added to 400g (721.3mmol) of the compound indicated in the title of example 3g in 2000ml of water and stirred for 3h. at 80 C. The solution is filtered and the filtrate is lyophilized.

Yield: 511g (quantitative) of amorphous solid.

Water content: 11.095.

Elemental analysis (in terms of anhydrous substance): solution: C 40.67 N 4.41 M 7.98 sa 22.19 found: C 40.51 N 4.52 M 8.03 ba 22.05 e) P1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-(2-(4-(3-oxapropionyl)phenyl|/|-2-(1,4,7-tris(carboxylatomethyl)-1,4,7, 10-tetraazacyclododecane-10-yl|ioacetic acid)|-2-M-(1-0-A-O-carbonylmethylmannopyranose)-I-lysine, α-complex, sodium salt 50.0g (54.55mmol) of the specified compound in the heading of example I, 6.28 g (54.55 mmol) of M-hydroxysuccinimide, 4.62 g (109.Omol) of lithium chloride and 38.66 bg (54.55 mmol) of the compound indicated in the heading of example 3D are dissolved under moderate heating in 400 ml dimethyl sulfoxide. Then, at 109C, 16.88 g (81.8 mmol) are added

M,M-dicyclohexylcarbodiimide and then stirred overnight at room temperature. The solution is poured into

300 Oml of acetone and stir for 1 hour. The precipitated solid is filtered and then Ha is purified by chromatography (KR-18, eluent: water/ethanol/acetonitrile gradient). The obtained product is dissolved in a small amount of water and the pH value of the solution is set to 7.4 with the help of aqueous sodium caustic. After that, the solution containing the product is lyophilized.

Yield: 79.1 g (89965 from theory) of a colorless solid.

Water content: 10.395. hE

Elemental analysis (calculated per anhydrous substance): solution: С 36.86 Н 3.77 М 6.88 5 1.97 Е 19.82 ba 9.65 i-oi detection: С 36.75 Н 3, 84 M 6.80 5 2.03 R 19.75 ba 9.57 so

Example 4 a) P1-(4-perfluorooctylsulfonyl)piperazineamide 5-M-(11,4,1-tris(tert-butyloxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane-10-carbonylmethyl-2 M-(1-0-A-Yu-ka ch-rbonylmethylmannopyranose)-I-lysine 15.0 g (26.19 mmol) 1,4,7-tris(tert-butyloxycarbonylmethyl)-10-carboxymethyl-1,4,7 ,10-tetraazacyclododecane obtained according to MO 91/057621, 24.0 g (26.19 mmol) of the compound indicated in the title of the example, and 3.01 g (26.19 mmol)

M-hydroxysuccinimide is dissolved in 150 ml of dimethylformamide and at 0 C, 8.25 g (40.0 mmol) of M,M-dicyclohexylcarbodiimide are added. The mixture is stirred overnight at room temperature. The precipitated urea is filtered off and the filtrate is evaporated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: dichloromethane/methanol in a ratio of 20:1).

Yield: 35.45 g (92.0905 from theory) of a colorless solid.

Elemental analysis: - and resolution: C 44.08 H 5.69 M 7.62 E 21.95 5 2.18 s detection: C 44.01 H 5.81 M 7.53 E 21.87 5 2 ,03 b) (1-(4-perfluorooctylsulfonyl)piperazine|amide (95) 6-M-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-carbonylmethyl|/- 2-M-(1-0O-A-O-carbonylmet b» 50 ilmanopyranose|-I-lysine, sa-complex

30.0 g (20.39 mmol) of the compound indicated in the title of example 4a is dissolved in 50 ml of chloroform and added

TH» ZO00ml of trifluoroacetic acid. The mixture is stirred for 1 minute. at room temperature. After that, it is evaporated to dryness under vacuum and the residue is dissolved in ZOO ml of water. Next, add 3.69 g (10.19 mmol) of gadolinium oxide and stir for 5 hours. at 802. The solution is evaporated to dryness under vacuum and purified on silica gel (KR-18, eluent: water/ethanol/acetonitrile gradient). o Yield: 11.Og (37.095 from theory) of a colorless and amorphous solid.

Water content: 11.395. eat) Elemental analysis (in terms of anhydrous substance): solution: С 34.62 Н 3.87 М 7.69 Е 22.16 5 2.20 ba 10.97 60 detect.: С 34.57 Н 3, 95 M 7.60 R 22.05 5 2.13 ba 10.90

Example 5 a) P1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-(3,6,9-tris(carboxymethyl)-3,6,9-triazanone-dicarboxylic acid-1-carboxy-11-oyl|-2- M-(1-0-A-O-carbonylmethylmannopyranose)|-I-lysine 65 To 24.0 g (26.19 mmol) of the compound indicated in the title of the example, dissolved in a mixture of 100 ml of dimethylformamide and 30 ml of pyridine, add 12.10 g ( 30O, Ommoliv)

3-M-(2,6-dioxomorpholinoethyl)-6-M-(ethoxycarbonylmethyl)-3,6b-diazaprobic acid and stirred for 2 hours. at 5092C. After that, it is evaporated to dryness under vacuum. The residue is dissolved in 200 ml of water and the pH value of the resulting solution is set to 13 by adding 2095 aqueous caustic sodium. The mixture is stirred for 8 hours. at 229C and a pH of 13. Next, the pH of the solution is set to 7.2 by adding concentrated hydrochloric acid and then evaporated to dryness under vacuum. The residue is chromatographed on KR-18 silica gel (eluent: water/ethanol/acetonitrile gradient).

Yield: 17.26 g (51.095 from theory) of a colorless solid. Water content: 9.395.

Elemental analysis (in terms of anhydrous substance): 70 resolution: C37.19 H4.21 M7.59 g25.00 52.48 detection: C37.10 H4a.30 M7.48 P25.07 52.42 b) ( 1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-(3,6,9-tris(carboxylatomethyl)-3,6,9-triazanone dicarboxylic acid-1-carboxy-11-oyl|-2-M-(1 -O-А-О-carbonylmethylmannopyranose)-I -lysine, sa-complex, sodium salt

1.40 g (3.87 mmol) of gadolinium oxide is added to 10.0 g (7.74 mmol) of the compound indicated in the title of example 5a in 100 ml of water and stirred for 2 hours. at 7020. After that, the solution is filtered. The pH value of the filtrate is set to 7.4 using 2N. caustic sodium and lyophilized. Yield: 11.36 bg (quantitative) of amorphous solid. Water content: 10.590.

Elemental analysis (in terms of anhydrous substance): solution: С 32.72 Н 3.43 М 6.68 5 2.18 ba 10.71 Ма 1.57 Р 22.00 detect.: С 32.65 Н 3 .51 M 6.71 5 2.08 sa 10.61 Ma 1.68 ER 21.87

Example 6 a) P1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-benzyloxycarbonyl-2-M-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane|-10-( pentanoyl-3-az He a-4-oxo-5-methyl-5-yl)|-I -lysine, a complex of 50.0 g (60.20 mmol) of the compound indicated in the title of example 1c, 6.93 g ( 60.20 mmol) of M-hydroxysuccinimide, 5.09 g (120, Ommol) of lithium chloride and 37.91 g (60.20 mmol) of the cCa complex 1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane -10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl) is dissolved under moderate heating in 400 ml of dimethyl sulfoxide. Then, at 1023, 20.63 g (100, Ommol) of "Zh

M,M-dicyclohexylcarbodiimide and then stirred overnight at room temperature. The solution is poured into a so

300 Oml of acetone and stir for 1 hour. The precipitated solid is filtered off and then purified by chromatography (silica gel KR-18, eluent: water/ethanol/acetonitrile gradient). (ze)

Yield: 75.53g (87.0905 from theory) of a colorless solid. yu

Water content: 10.195.

Elemental analysis (in terms of anhydrous substance): - solution: C 37.48 N 3.84 M 8.74 5 2.22 ER 22.39 ba 10.90 detected: C 37.39 N 4.02 M 8.70 5 2.16 P 22.29 b 10.75 b) (1-(4-perfluorooctylsulfonyl)piperazine|amide " 2-M4-(11,4,7-tris(carboxylatomethyl)-1,4,7 ,10-tetraazacyclododecane-sa-complex, 10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)|-I -lysine - with 70.0 g (48.53 mmol) of the compound specified in the title of example 1g, dissolve in a mixture of 50 ml of water and 100 ml of ethanol, mix with 5.0 g of a palladium catalyst (1095 Pa/C) and hydrogenate at room temperature in a "" hydrogen atmosphere (Tatm.) until hydrogen absorption stops After separation of the catalyst by vacuum filtration, it is thoroughly washed with ethanol (two portions of 75 ml each) and concentrated to dryness under vacuum.

In this way, the compound specified in the title is obtained in the form of a highly viscous and colorless oil. Yield: 63.5 g - i (quantitative). Water content: 9.895. sl Elemental analysis (calculated per anhydrous substance): solution: С 37.48 Н 3.84 М 8.74 5 2.22 ER 22.39 ba 10.90 (65) detect.: С 37.39 Н 4 ,03 M 8.65 5 2.20 RE 22.31 ba 10.78

Fu 50 c) (1-4-perfluorooctylsulfonyl)piperazinamide 6-M-(1-0-A-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmannopyranose)-2-M-(1,4 ,7-tris(carboxylatomethyl)-1,4,7,10-t

I» tetraazacyclododecane, za-complex-10-(pentanoyl-3-aza-4oxo-5-methyl-5-yl)|-I-lysine 50.0 g (38.22 mmol) of the compound indicated in the title of example 66, 4, 40 g (38.22 mmol) of M-hydroxysuccinimide,

3.39 g (80 mmol) of lithium chloride and 22.88 g (38.22 mmol) of 1-O-A-O-carboxymethyl-2,3,4,6-tetra-O-benzyl-mannopyranose are dissolved under moderate heating (30 -402C) in

Gee! 400 ml of dimethyl sulfoxide. Next, at 109, 10.32 g (50.Omol) of M,M-dicyclohexylcarbodiimide are added and then stirred overnight at room temperature. After that, the solution is poured into 300 ml of acetone and stirred for 1 hour. The precipitated solid is filtered off and then purified by chromatography (silica gel KR-18, eluent: water/ethanol/acetonitrile gradient). Yield: 64.25g (89.095 of 60 theory) of a colorless solid. Water content: 10.995.

Elemental analysis (in terms of anhydrous substance): solution: С 46.42 Н 4.54 М 6.67 5 1.70 Р 17.10 са 8.33 found.: С 46.36 Н 4.71 М 6 .60 5 1.61 E 17.19 ba 8.21 g) P1-(4-perfluorooctylsulfonyl)piperazine|amide bo 6-M-(1-0-A-O-carbonylmethyl-2,3,4,6- tetra-O-benzylmannopyranose)-2-M-(1,4,7-tris(carboxylatomethyl)-1,4,8,10-tetraazacyclododecane,za-complex-10-(pentanoyl-3-aza-4-oxo -5-methyl-5-yl)|-I-lysine

60.0 g (31.77 mmol) of the compound indicated in the title of example bv is dissolved in 500 ml of ethanol and mixed with b.0 g of palladium catalyst (1096 Pa/C). After that, it is hydrogenated at room temperature in a hydrogen atmosphere (Tatm.) until hydrogen absorption stops. After that, the catalyst is removed by vacuum filtration, thoroughly washed with ethanol (two portions of 15 Oml) and concentrated to dryness in a vacuum.

Yield: 48.55 g (quantitative) of a colorless solid.

Water content: 3.995.

Elemental analysis (in terms of anhydrous substance): solution: C 35.37 N 4.02 M 8.25 5 2.10 P 21.13 ba 10.29 70 detection: C 35.28 N 4.13 M 8.17 5 2.03 PE 21.05 ba 10.20

Example 7 a) 1,7-bis(benzyloxycarbonyl)-4-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino)acetyl-1,4,7,10-tetraazacyclododecane

To 50.0 g (113.5 mmol) of 1,7-bis(benzyloxycarbonyl)-1,4,7,10-tetraazacyclododecane and 66.42 g (113.5 mmol) of 2-(M-ethyl-M-perfluorooctylsulfonyl)aminoacetic acid ( obtained according to OE 19603033)| 49.46 g (200, Ommol) of EEDH (ethyl ether of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) is added to ZOO ml of tetrahydrofuran at 0 and stirred overnight at room temperature.

After that, it is evaporated to dryness in a vacuum and chromatographed on silica gel (eluent: dichloromethane/methanol in a ratio of 20:1).

Yield: 65.2 g (5795 from theory) of a colorless solid.

Elemental analysis: solution: C 42.91 H 3.80 M 6.95 E 32.05 5 3.18 found: C 42.85 H 3.90 M 6.87 E 31.98 5 3.15 s b) 5) 1,7-bis(benzyloxy)-4-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|acetyl-10-(I1-0O-A-YO-carbonylmethyl-2,3,4, 6-tetra a-O-benzylmannopyranose|-1,4,7,10-tetraazacyclododecane

To God (59.53 mmol) of the compound indicated in the title of example 7a and 35.64 g (59.53 mmol) of 1-0-A-O-carboxymethyl-2,3,4,6-tetra-O-benzylmannopyranose, obtained according to (from OEE 19728954), 24.73 g (100 mmoles) of EEDH (ethyl ether of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) are added to 30 ml of tetrahydrofuran at room temperature and stirred overnight at room temperature. ish

After that, it is evaporated to dryness in a vacuum and chromatographed on silica gel (eluent: dichloromethane/methanol in a ratio of 20:1).

Yield: 76.6 bg (81.095 from theory) of a colorless solid. i am

Elemental analysis: h- resolution: С 54.44 Н 4.70 М 4.41 Р 20.33 52.02 found.: С 54.37 Н 4.81 М 4.35 РЕ 20.27 5 1.96 c) « 1-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|acetyl-7-(1-0-A-O-carbonylmethylmannopyranose)-1,4,7,10-tetraazac iclododecane - with 7Og (44 .07 mmol) of the compound indicated in the title of Example 76 is dissolved in 800 ml of ethanol and 8 g of palladium catalyst (1095 Pa/C) is added. After that, it is hydrogenated at room temperature. Then the catalyst "" is filtered off and the filtrate is evaporated to dryness under vacuum.

Yield: 42.3 g (quantitative) of a colorless solid.

Elemental analysis: -I solution: C 35.04 H 3.99 M 7.30 E 33.65 5 3.34 detection: C 35.15 H 4.13 M 7.13 E 33.48 5 3, 26 1 c

OO 1,7-bis(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-sa-complex-10-(pentanoyl-3-aza-4-oxo-5-methyl-5 -yl)-4-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino)b acetyl-10-(1-0-A-O-carbonylmethylmannopyranose)-1,4,7,10-tetraazacyclododecane "z" 20g (20.84 mmol) of the compound indicated in the title of example 7c, 5.09 g (120 mmol) of lithium chloride and 37.78 g (bommol) of the 1,4,7-tris(carboxylatomethyl)-10-(pentanoyl-3-aza) complex -4-oxo-5-methyl-5-yl)-1,4,7,10-tetraazacyclododecane is dissolved under moderate heating in 400 ml of dimethyl sulfoxide. Then, at 1023, 29.67 g (120 mmol) are added

The EEDHs are then stirred overnight at room temperature. The solution is poured into 300 ml of acetone and stirred for 1 hour. The precipitated solid is filtered off and then purified by chromatography (silica gel KR-18, eluent: water/ethanol/acetonitrile gradient).

Yield: 13.2 g (29.095 from theory) of a colorless solid. 60 Water content: 11.895.

Elemental analysis (in terms of anhydrous substance): solution: C 36.31 H 4.34 M 9.62 5 1.47 E 14.79 ba 14.41 detect.: C 36.24 H 4.27 M 9 ,58 5 1,51 E 14,85 ba 14,25

Example 8 65 a) 1,7-bis(benzyloxycarbonyl)-4-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino)acetyl-10-(pentanoyl-3-aza-4-oxo-5-m ethyl- 5-yl-(/1,4,7-tris(carboxylatomethyl)-sa-complex-1,4,7,10-tetraazacyclododecane-10-ylI|-1,4,7,10-tetraazacyclododecane 50.0g (49.61 mmol) of the compound specified in the title of example 7a, 5.71 g (49.61 mmol) of M-hydroxysuccinimide, 4.24 g (100 mmol) of lithium chloride and 31.24 g (49.6 mmol) of CCa-complex 1,4,7 -tris(carboxylatomethyl)-10-(pentanoyl-3-azaoxo-5-methyl-5-yl)-1,4,7,10-tetraazacyclododecane is dissolved under moderate heating in 35 ml of dimethyl sulfoxide. Then, at 102, 15.47 g (/ 5 mmol)

M,M-dicyclohexylcarbodiimide and then stirred overnight at room temperature. The solution is poured into 2000 ml of acetone and stirred for 1 hour. The precipitated solid is filtered and then 7/0 is purified by chromatography (silica gel KR-18, eluent: water/ethanol/acetonitrile gradient).

Yield: 65.1 g (81.095 from theory) of a colorless solid.

Water content: 7.995.

Elemental analysis (in terms of anhydrous substance): solution: C 40.79 H 4.11 M 8.65 5 1.98 E 19.94 ba 9.72 found: C 40.71 H 4.20 M 8 .58 5 2.03 P 19.87 b 9.68 b) 1-2-(M-ethyl-M-perfluorooctylsulfonyl)amino|acetyl-7-pentanoyl-3-aza-4-oxo-5-methyl- b-yl-|(1,4,7-tris(carboxy latomethyl)-1,4,7,10-tetraazacyclododecane-10-yl|-za-complex)-1,4,7,10-tetraazacyclododecane 60,Og (37.05 mmol) of the compound indicated in the title of example va is dissolved in bbOml of ethanol and 6.0 g of 20 palladium catalyst (1095 Pa/C) is added. After that, they are hydrogenated at room temperature. Then the catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.

Yield: 50.06 g (quantitative) of a colorless solid.

Water content: 3.995.

Elemental analysis (calculated on the anhydrous substance): c solution: C 34.67 N 4.03 M 10.37 5 2.37 P 23.90 ba 11.64 detection: C 4.58 N 4.15 M 10.28 5 2.30 E 23.84 b 11.57 o c) 1-2-(M-ethyl-M-perfluorooctylsulfonyl)amino|acetyl-4,10-bisI1-0-A-O-carbonylmethyl-2 . )-1,4,7,10-tetraazacyclododecane (I n-10-yl|-sa-complex)-1,4,7,10-tetraazacyclododecane 40.00 g (29.600 mmol) of the compound indicated in the title of example 86, 2.54 g (60.Omol) of lithium chloride and 44.9 g (75.Omol) of 1-O-A-O-carboxymethyl-2,3,4,6-tetra-O-benzylmannopyranose are dissolved under moderate heating in 10 ml of dimethyl sulfoxide. Next, 24.73 g (100 mmol) of EEDH are added at 1023 and then stirred overnight at room temperature. The solution is poured into 300 ml of acetone and stirred for 10 min. The precipitated solid is filtered off and then purified by chromatography ( silica gel KR-18, eluent: water/ethanol gradient in/acetonitrile).

Yield: 31.98 g (43.095 from theory) of a colorless solid.

Water content: 3.595. "

Elemental analysis (in terms of anhydrous substance): solution: C 53.06 N 5.05 M 5.57 5 1.28 E 12.85 ba 6.26 - s detection: C 52.95 N 5.19 M 5.48 51.23 R 12.77 5 ab,14 g)1 ; » -(2-(M-ethyl-M-perfluorooctylsulfonyl)amino)acetyl-4,10-bisI1-0O-A-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmannopyranose|-7- -pentanoyl-3-aza-4-oxo-5-methyl-b-yl-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-yl|-a-complex) -1,4,7,10-tetraazacyclododecane -I 30.0 g (11.94 mmol) of the compound indicated in the title of example 8b is dissolved in a mixture of 30 ml of ethanol and 30 ml of water and 4.0 g of palladium catalyst (1095 Ra/ WITH). After that, hydrogenate at room temperature,

The Mn catalyst is filtered off and the filtrate is evaporated to dryness under vacuum. oz. Yield: 21.39 g (quantitative) of a colorless solid.

Water content: 3.495. b Elemental analysis (in terms of anhydrous substance): с» resolution: С 36.87 Н 4.39 М 7.82 5 1.79 Е 18.03 са 8.78 detection: С 36.80 Н 4, 50 M 7.85 5 1.68 E 17.91 ba 8.70

Example 9 a) (1-«4-perfluorooctylsulfonyl)piperazine|amide 6-M-(3,6-bis(carboxymethyl)octane-1,8-dicarboxylic acid-1-carboxy-8-oyl-1|-2-M- (1-0-A-O-carboxymethylmannopyranose)lysine o To 27.5 g (30, Ommol) of the compound indicated in the title of the example, dissolved in a mixture of 30 ml of dimethylformamide and 100 ml of pyridine, add 25.62 g (100, Ommol) of dianhydride of ethylenediamine-M,M,M' M'-tetraacetic acid and stirred for two hours at 50 2C. After that, 60 is evaporated to dryness in a vacuum. The residue is dissolved in 300 ml of water, the pH value is set to 10 by adding 2096 aqueous caustic sodium, then the pH value of the alkaline solution containing the product is set to 3 by adding concentrated hydrochloric acid and evaporated to dryness under vacuum.The residue is chromatographed on silica gel KR-18 (eluent: water/ethanol/acetonitrile gradient).

Yield: 18.22 g (51.0965 from theory) of a colorless solid. 65 Water content: 7.995.

Elemental analysis (in terms of anhydrous substance):

solution: C 36.31 H 3.98 M 7.06 R 27.12 5 2.69 found: C 36.23 H 4.07 M 6.98 RE 27.05 5 2.62 b) (1 -«4-perfluorooctylsulfonyl)piperazine|amide 6-M-(3,6-bis(carboxylatomethyl)octane-1,8-dicarboxylic acid-1-carboxylato-8-oyl-Mn-complex, sodium salt|)-2- M-(1-0-A-O-carboxymethylmannopyranose)-I-lysine 10 g (8.397 mmol) of the compound indicated in the title of example 3 is dissolved in 200 ml of water. Next, add 9b5 mg (8.397 mmol) of manganese carbonate (I!) and stir for 1 hour. at 60 C. Then the pH value of the solution is set to 7.4 with the help of 595 aqueous caustic sodium, filtered and then lyophilized.

Yield: 10.52 g (99.095 from theory) of a colorless solid. 70 Water content: 7.895.

Elemental analysis (in terms of anhydrous substance): solution: C 34.16 N 3.50 M 6.64 5 2.53 ER 25.52 Mp 4.34 Ma 1.82 detect.: C 34.06 N 3 .61 M 6.58 5 2.47 E 25.47 Mp 4.30 Ma 1.97

Example 10 a) 1,2,3,4,6-penta-O-acetyl-A,B-Y-mannopyranose

Similarly to the method described in the literature | МХ. Muoytot and A. Tpotrzop, "Meiyodz ip Sagropuagayie

Spetivigu" (under the editorship of K.G. MUpizMTseg, M... MMoytot and 9U.M. VemMiSheg), ed. Asadetis Rgevzv, Mem/ MogkK, vol. II, 53, pp. 211-215 (1963)) , as a result of the interaction of 150 g (832.5 mmol) of A,B-O-mannopyranose with a mixture of 1500 ml of absolute pyridine and 1500 ml of acetic anhydride after processing, 315 g (96.790) of the compound indicated above in the title is obtained in the form of a crude product in the form of a viscous and colorless The ratio between both A- and B-anomers in the title compound obtained in this way is 4:11 according to "H-NMR-spectroscopic analysis. To carry out the following reactions, the compound indicated above in the title may not be divided into separate A, B-anomers.

Elemental analysis: He solution: С 49.21 Н 5.68 o detection: С 49.12 Н 5.78 b) 1-0О-А-О0-(5-ethoxycarbonyl)pentyl-2,3,4, 6-tetra-O-acetylmannopyranose

Analogously to the method described in the literature for the synthesis of arylglycopyranosides (U. Sopspie and O. A. Eumu, "Meiyodz ip Sagropuadgage SPeptivighu" (edited by K.G. MUpivTseg, M.I. MMoytot and 9U.M. VemMiyeg) , ed. Asadetis "Zh Rgevzv, Mem MogK, vol. II, 90, p. 345-347 (1963)), as a result of the interaction of 156.2 g (400 mmol) of the compound indicated in the title of example 170a in the form of a mixture of A, B- of anomers with b/ml (400 mmol) of ethyl ether of b-hydroxyhexanoic acid and 60, bml (520 mmol) of stannous chloride (IM) in 1,2-dichloroethane with a total amount of "U bOOml after purification by column chromatography (eluent: hexane/ethyl acetate acid in a ratio of 2:11) yield 100.05 g (5195 from theory) of the compound indicated above in the title in the form of a colorless and viscous oil. The data of the H-NMR spectroscopic analysis of the compound obtained in this way indicated in the title indicate that this compound is only the pure A-anomer.

Elemental analysis: soln.: C 52.94 H 6.77 " detect.: C 52.80 H 6.78 c) 1-0-A-O-(5-carboxy)pentyl-2,3,4,6 -tetra-O-benzylmannopyranose - c A mixed suspension of 141.0 g (289 mmol) of the compound indicated in the title of example 106 in 200 ml of dioxane at room temperature and with simultaneous intensive stirring is mixed in portions with highly dispersed powder potassium hydroxide in a total amount of 238.5 g (4.2 bmol). To increase its miscibility, the reaction mixture is mixed with another 200 ml of dioxane, the suspension obtained as a result is then heated to the boiling point and at this temperature for two hours it is mixed dropwise with benzyl bromide - and the total amount is 372 ml (3.128 mol). After conducting the reaction for 4 hours. at 110 2С, and then within 12 hours. at room temperature, the reaction mixture for its processing is slowly poured into a mixture of water and ice in a total amount of 2.5 l, and the aqueous phase is then completely extracted with diethyl ether. After washing with the ether phase obtained in this way and its subsequent drying over sodium sulfate, the salt is separated

FO 20 is vacuum-filtered and diegyl ether is removed in a vacuum. After that, the excess benzyl bromide is quantitatively distilled off from the reaction mixture in a vacuum created by an oil pump at an oil bath temperature of 18020. The resinous-oily residue obtained in this way is purified on silica gel using ethyl acetic acid/hexane (in a ratio of 1:10) as an eluent.

Yield: 172.2g (91.095 from theory) of the compound indicated above in the title in the form of a colorless and highly viscous 29 Oil.

F! Elemental analysis: soln.: С75.68 Н7.16 di detect.: С75.79 Н7.04 g) P1-(4-perfluorooctylsulfonyl)piperazine|amide 60 6-M-benzyloxycarbonyl-2-M-(1-O- A-O-(5-carbonyl)pentyl-2,3,4,6-tetra-O-benzylmannopyranose!|-I -lysine 100.0 g (134.0 mmol) of the carboxylic acid obtained in example OV and 32.4 g (281 .4 mmol)

M-hydroxysuccinimide is dissolved in 500 ml of dimethylformamide, mixed with

M,M'-dicyclohexylcarbodiimide in a total amount of 58.0 g (281.4 mmol) and then stirred for 1 h. at this temperature. A solution of 111.3 g (134.0 mmol) of the compound indicated in the title of the example in 00 ml of dimethylformamide, cooled to 09C, is added dropwise to the solution of the activated ester obtained in this way and stirred for 2 hours. at 02C, and then for 12 hours. at room temperature.

To process dicyclohexylurea, which has precipitated, it is filtered and then the solvent is distilled off to obtain a dry residue. The residue obtained in this way is then chromatographed on silica gel (eluent: dichloromethane/ethanol in a ratio of 20:11, chromatography is carried out using a solvent gradient, continuously increasing the proportion of ethanol).

Yield: 132.5 g (67.490 from theory) of the title compound in the form of a colorless and highly viscous oil.

Elemental analysis: soln.: C 54.02 H 4.88 M 3.82 ER 22.01 5 2.19 70 found: C 53.87 H 4.85 M 4.02 P 22.55 5 2.06 e) 11-(4-perfluorooctylsulfonyl)piperazinamide 2-M-(1-0O-A-0-(5-carbonyl)pentylmannopyranose|-I-lysine 120.0g (81.77mmol) of the compound obtained in example 1Og is dissolved in 80O0ml of ethanol, mixed with 4.5 g of Perlman's catalyst (2095 Pa/sС) and hydrogenated at room temperature in a hydrogen atmosphere (Tatm) until hydrogen absorption stops (approximately within an hour). After that, the catalyst is removed 7/5 vacuum by filtration, then thoroughly washed with ethanol (approximately 200 ml) and concentrated to dryness under vacuum.

In this way, the compound specified in the title is obtained in the form of a highly viscous and colorless oil.

Yield: 78.5g (98.7905 from theory).

Elemental analysis: solution: C 37.04 H 4.25 M 5.76 RE 33.20 5 3.30 found: C 36.96 H 4.85 M 5.41 E 34.13 5 3.22 e ) P1-(4-perfluorooctylsulfonyl)piperazine|amide 2-M-(1-0-A-0-(5-carbonyl)pentylmannopyranose|-6-M-(1,4,7-tris(carboxylatomethyl)-10- (3-aza-4-oxo-5-methyl-5-yl pentanoyl)-1,4,7,10-tetraazacyclododecane|-I -lysine, α-complex 99.8g (158.4mmol, 2.2molar equivalents in conversion to the amount of used amine c

The component from example Од) described |in the application OE 19728954 SI| in example 3 ba-complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and b,7g i) of anhydrous lithium chloride (158.4 mmol) at 40 C is dissolved with stirring in 8000 ml of absolute dimethyl sulfoxide. Then, at this temperature, the total amount of 18.2 g (158.4 mmol) and 70.0 g (71.9 mmol) of the compound indicated in the title of Example 1, dissolved in 250 ml of absolute "I dimethyl sulfoxide, is mixed with M-hydroxysuccinimide. After cooling to room temperature, the reaction solution is mixed with 32.7 g (158.4 mmol) of M,M'-dicyclohexylcarbodiimide and stirred for 12 hours. at room temperature. Then the resulting suspension is mixed with a sufficient amount of acetone until the complete precipitation of the compound indicated above in the title "From the compound, the precipitate is separated by vacuum filtration, dried, dissolved in water, filtered dicyclohexylurea, which has not dissolved, and the filtrate for its desalination and purification from low molecular weight components pass through an ultrafiltration membrane AMISOM UM-3 (limiting /-ich permeability: ЗО0ODa) Retentate (substance that did not pass through the filtration membrane) is finally lyophilized.

Yield: 93.Og (81.69 from theory) in the form of a colorless lyophilizate. "

H2O content (when using Karl Fischer's reagent): 9.5390.

Elemental analysis (in terms of the anhydrous substance): - c solution: C 37.15 N 4.39 M 7.96 E 20.38 5 2.02 ba 9.92 a detection: C 36.92 N 4, 50 M 7.68 E 19.77 5 1.91 ba 10.08 "» Example 11 a) (1-(4-perfluorooctylsulfonyl)piperazine| amide 2-M-1-0O-A-0-(5-carbonyl )upentylmannopyranose|-6-M-2-I4-(Z-oxapropionyl)phenyl|/-2-(1,4,7-tris(carboxylatomethyl -i )-1,4,7,10-tetraazacyclododecan-10-yl (acetic acid) -I -lysine, Ca-complex, sodium salt sl A stirred suspension of 5.0 g (9.0 mmol) of the compound indicated in the title) of Example 3d in 15 ml of absolute dimethyl sulfoxide at 702C is mixed with 0.68 g (15.9 mmol ) of lithium chloride. After stirring for 30 minutes and 95) at 702C, the clear reaction solution is mixed in portions with M-hydroxysuccinimide in a total amount of 1.83 g

F 50 (15.9 mmol) and the reaction mixture is kept for another hour. at this temperature. After cooling to 0 C, it is mixed with 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide and the reaction solution is stirred for another hour.

T" at 09C, and then for 12 hours. at 22 9Sb. The reaction solution obtained in this way

M-hydroxysuccinimidoether of the compound specified in the title of example 3d is mixed dropwise at 2292C with a solution of 4.0 g (4.12 mmol) of the compound specified in the title of example OD in 1 bml of absolute 25 dimethyl sulfoxide and stirred for another 12 hours. at room temperature. Reactive for processing

HF) solution at 2292С is added dropwise to 300 ml of acetone, while the compound indicated in the title precipitates as a colorless precipitate. This precipitate is separated by vacuum filtration, dissolved in 200 ml of distilled water, and then the pH value of this solution is set exactly to 7.2 with the help of 1-molar caustic sodium.

The aqueous solution obtained in this way, which contains the product, is subjected to ultrafiltration three times through an ultrafiltration membrane KhMZ3 (AMISOMU, limit permeability: 3000Da) for desalination and for the separation of low molecular weight components. The resulting retentate is finally lyophilized.

Yield: 6.3 g (92.495 from theory based on the amount of the amine component used) in the form of a colorless lyophilizate with a water content of 7.38905. ve Elemental analysis (in terms of anhydrous substance): solution: C 38.48 N 4.13 M 6.65 E 19.16 5 1.90 sa 9.33 Ma 1.36 detect.: C 39.52 N 4.12 M 6.67 E 19.70 5 1.89 Ba 9.30 Ma 1.41

Example 12 a) M-(Z-oxa-1H1H,2H,2H4H4H,5H,5H-perfluorotridecyl)amide of 3,5-bisbenzyloxycarbonylaminobenzoic acid

Acids 20 g (47.5 mmol) of 3,5-bisbenzyloxycarbonylaminobenzoic acid (synthesis according to the method, (described in eKytsYpisk Nagmeu I., doipvop Rash O., Agivoy Rash A., Mogitiv deapetse K., Iomavz: K'givipe O. and etc., 9.

Honey. Spet., 40, 7, (1997), pp. 1149-1164), as well as 4.78 g (47.5 mmol) of triethylamine are dissolved in a solvent mixture consisting of 125 ml of dry tetrahydrofuran and 125 ml of dry dioxane. After cooling to 7/0 7199C, a solution of 6.56 mg (48 mmol) of isobutyl ether of chloroformic acid in 30 ml of dry tetrahydrofuran is slowly added dropwise with stirring, while the internal temperature should be maintained below -102C. After conducting the reaction for 15 min. at -15 "C, a solution of 58.6 g (47.5 mmol) of 1-amino-THIAN,1H,2H2H,4H,4H,5H,5H-3-oxoperfluorotridecane and 4.78 g (47.5 mmol) is added dropwise at -2092C of triethylamine in 100 ml of dry tetrahydrofuran. After conducting the reaction for one hour at -15 2С, and then for 75 two hours at room temperature, the reaction solution is concentrated to dryness in a vacuum. The resulting residue is dissolved in ZOO ml of ethyl acetic acid and washed twice with a saturated solution of sodium bicarbonate in portions of 200 ml and once with water in a portion of ZOO0 ml. After drying the organic phase over sodium sulfate, the salt is separated by vacuum filtration and the ethyl acetic acid is distilled off under vacuum.

The resulting oily residue is purified on silica gel using dichloromethane/hexane/2-propanol (10:5:1 ratio) as eluent.

Yield: 36.2 g (82.590 from theory) of the title compound as a colorless oil.

Elemental analysis: solution: C 46.82 H 3.27 M 4.55 P 34.97 found: C 47.21 H 3.31 M 4.61 E 34.48 Ge! b) M-(3-oxa-1Н,1Н2Н,2Н,4Н4Н,5Н,5Н-perfluorotridecyl)amide of 3,5-diaminobenzoic acid

30.0 g (32.4 mmol) of the amide obtained in example 12a is dissolved in 10 ml of ethanol and mixed with 1.2 g of Perlman's catalyst (2095 Pa/C). After that, it is hydrogenated at room temperature in a hydrogen atmosphere (Tatm.) until hydrogen absorption stops. After that, the catalyst is removed by vacuum filtration, thoroughly washed with ethanol (approximately Zb0Oml) and concentrated to dryness under vacuum. In this way, the compound specified in the title is obtained in the form of a highly viscous yellowish oil.

Yield: 20.12g (94.890 from theory). what

Elemental analysis: solution: C 36.66 H 2.77 M 6.41 P 49.28 found: C 36.07 H 2.87 M 6.23 E 49.43 and c) M-(3Z- oxa-АН,1Н,2Н2Н,4Н,4Н,5Н,5Н-perfluorotridecyl)amide h- 3-M-(1-0-А-О-carbonylmethyl-2,3,4,6-tetra-О-benzylmannopyranose) -5-aminobenzoic acid 10.95 g (18.30 mmol) of 1-carboxymethyloxy-2,3,4,6-tetra-O-benzyl-А-О-mannopyranoside (obtained according to patent OE 19728954 СИ| dissolve in 150 ml of dimethylformamide and mixed with M-hydroxysuccinimide " in a total amount of 2.09 g (18.3 mmol). Then it is cooled to 0 9C and 3.78 g (18.3 mmol) of dicyclohexylcarbodiimide is added. After that, it is stirred for an hour at 0 C, and then for 4 hours at - with room temperature. Next, it is cooled to 02°C, and during the course of the Agreement, a solution of 24.0 g (36.bmmol, 2 molar equivalents in terms of the amount of carboxylic acid used) of the diamino compound obtained in Example 126 in 3500 ml of dimethylformamide is slowly added dropwise. stir for another hour at 02C, and then overnight at ki mnat temperature. The mixture is evaporated to dryness under vacuum and the residue is dissolved in ZOO ml of ethyl acetic acid. The precipitated urea is filtered off and the filtrate is washed twice. with a 5% aqueous solution of soda in portions of 100 ml. The organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: n-hexane/isopropanol in the ratio 13:11). In this way, 16.8 g (74.395 from theory, in terms of the amount of carboxylic acid used) of the title compound are obtained in the form of a colorless oil. By increasing the polarity of the eluent

Ф 20 by changing the ratio between n-hexane and isopropanol to 5:1 in the following chromatographic fractions, a total of 10.15 g of the unreacted diamino compound from example 126 is recovered, which can be used again in the reaction according to the method discussed above.

Elemental analysis: solution: C 54.42 H 4.40 M3.40 P 26.13 29 found: C 54.32 H 4.49 M3.48 E 25.94

HF) d) M-(Z-oxa-1H1H,2H,2H,4H an,5H,5H-perfluorotridecyl)amide 3-M-(1-0-A-O-carbonylmethylmannopyranose)-5-aminobenzoic acid di Similarly to method of synthesis of the compound specified in the title of example 226, as a result of hydrogenolysis of 12.0 g (9.70 mmol) of the compound specified in the title of example 12b, using 0.5 g of Perlman's catalyst (20965-60 Ra/s) in a mixture of ethanol and water (in a ratio of 9:1) after processing, 8.08 g (96.795 from the theory) of the above title compound are obtained in the form of a viscous yellow oil.

Elemental analysis: solution: C 37.64 H 3.28 M 4.88 E 37.49 found: C 37.32 H 3.17 M 4.97 E 37.55 bo d). M-(3-oxa-1H,1H,2H,2H,4H 4H,5H,5H-perfluorotridecyl)amide

3-M-(1-0-A-O-carbonylmethylmannopyranose)-5-M-12-I4-(3-oxapropionyl)phenyl|/|-2-(1,4,7-tris(carboxylatomethyl)-1, 4,7,10-tetraazacyclododecane-10-yl|acetic acid) of benzoic acid, (za-complex, sodium salt 13.6 g (19.2 mmol, 2.2 molar equivalents in terms of the amount of used amine

The component from example 12d) of the cCa complex described in example 23d and 0.81 g of anhydrous lithium chloride (19.2 mmol) at 402 are dissolved with stirring in 1000 ml of absolute dimethyl sulfoxide and at this temperature are mixed with M-hydroxysuccinimide in a total amount of 2.2 g (19, 2 mmol) and from 7.5 g (8.7 mmol) of the 12 g compound indicated in the title of the example, dissolved in 100 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 3.96 mg (19.2 mmol) of M,M'-dicyclohexylcarbodiimide and stirred for 12 hours. at room temperature. The resulting suspension is then mixed with a sufficient amount of acetone until the compound specified above in the title is completely precipitated, the precipitate is separated by vacuum filtration, dried, dissolved in water, dicyclohexylurea that has not dissolved is filtered, and the filtrate is passed through an AMISOM ultrafiltration membrane for desalting and purification from low molecular weight components UM-3 (limit permeability: 3000Da) Retentate at the end of 75 lyophilized.

Yield: 11.51 g (84.595 from theory) in the form of a colorless lyophilisate.

H2O content (when using Karl Fischer's reagent): 6.7 7905.

Elemental analysis (in terms of anhydrous substance): solution: C 40.05 N 3.94 M 6.29 E 20.71 sa 10.08 Ma 1.47 found: C 39.98 N 4.00 M 6 ,31 E 20.73 ba 10.11 Ma 1.42

Example 13 a) 3,5-bis(benzyloxycarbonylamino)-1-4M-(1-(4-perfluorooctylsulfonyl)piperazine) benzamide 10 g (23.75 mmol) of 3,5-bisbenzyloxycarbonylaminobenzoic acid (synthesis according to the method described in eKycYpisk Nagmeu I., doipvop Rush O., Agivoy Rush A., Mogitov deapetsCe K., Iomavz: K'givipe O. and others, 9. Ge

May Spet., 40, 7 (1997), pp. 1149-1164), as well as 2.39 g (23.75 mmol) of triethylamine are dissolved in a mixture of solvents consisting of bOml of dry tetrahydrofuran and 7Oml of dry dioxane. After cooling to -459C7, a solution of 3.28 g (24 mmol) of isobutyl ether of chloroform and acid in 20 ml of dry tetrahydrofuran is slowly added dropwise while stirring, while the internal temperature does not exceed -1402C7. After conducting the reaction for 15 min. at -15 oC dropwise at -209C add a solution of 23.0 g (23.75 mmol) of perfluorooctylsulfonylpiperazine and 2.39 g (23.75 mmol) of triethylamine in bBOml of dry He tetrahydrofuran. After conducting the reaction for an hour at -15 C, | and then for two hours at room temperature the reaction solution is concentrated to dryness in a vacuum. The resulting residue is dissolved in about 200 ml of ethyl acetic acid and washed twice with a saturated solution of sodium bicarbonate in portions of 100 ml and once with water in a portion of ZOO ml. After drying the organic phase over sodium sulfate, the salt is separated by vacuum filtration and the ethyl ether of acetic acid is distilled off in a vacuum. The resulting oily residue is purified on silica gel using dichloromethane/hexane/2-propanol (in a 15:5:1 ratio) as an eluent.

Yield: 18.35 g (79.695 from theory) of the title compound as a colorless oil, | Elemental "analysis: solution: C 43.31 H 2.80 M 5.77 E 33.27 5 3.30 not) with detection: C 43.21 H 2.75 M 5.61 E 33.38 5 3.22 "» b) C3,5-diamino-1-4M4-(1-(4-perfluorooctylsulfonyl)piperazine|i)benzamide 9.70 g (10.0 mmol) obtained in " example 1 According to the amide is dissolved in 100 ml of ethanol and mixed with 0.4 g of Perlman's catalyst (2096 Ra/sС). After that, it is hydrogenated at room temperature in a hydrogen atmosphere (Tatm.) until hydrogen absorption stops. After that, the catalyst is removed by vacuum filtration, thoroughly washed with ethanol (approx

She 15O0ml) and concentrated to dryness in a vacuum. In this way, the compound indicated in the title is obtained in the form of a highly viscous yellowish oil.

Yield: 6.9g (98.295 from theory). o Elemental analysis: bu 70 resolution: C 32.49 H 2.15 M 7.98 E 45.98 5 4.56 detection: C 32.56 H 2.17 M 8.09 E 45.63 5 4 ,61

T" c). M-(I1--4-perfluorooctylsulfonyl)piperazinamide 5-amino-3-M-(1-0-A-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmannopyranose)benzoic acid 5.48g ( 9.15 mmol) of 1-carboxymethyloxy-2,3,4,-tetra-O-benzyl-А-ХО-mannopyranoside (obtained according to the method described in patent OE 19728954 SI is dissolved in 700 ml of dimethylformamide and mixed with (FI M-hydroxysuccinimide with a total amount of 1.04g (9.15mmol). Then it is cooled to 09C and 1.89g (9.15mmol) of dicyclohexylcarbodiimide is added. After that, it is stirred for one hour at 02C, and then for 4h at room temperature. After re-cooling to 0 "С during the period of the Agreement, a solution of 12.85 g (18.30 mmol, 2 molar equivalents in terms of the amount of carboxylic acid used) of the diamino compound described in Example 136 in 250 ml of dimethylformamide is slowly added dropwise. After that, it is stirred for another hour at 02С, and then overnight at room temperature.The mixture is evaporated in vacuo to dryness and the residue is dissolved in 100 ml et acetic acid silt ether. The precipitated urea is filtered and the filtrate is washed twice with a 595% aqueous solution of soda in portions of 100 ml. The organic phase is stirred over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: n-hexane/isopropanol in a ratio of 13:1). In this way, 8.14 g (69.495 from the theory, calculated on the amount of carboxylic acid used) of the title compound in the form of a colorless oil are obtained. By increasing the polarity of the eluent by changing the ratio between its components (n-hexane and isopropanol) to 6:11 in the chromatography process, a total of 4.36 bg of the unreacted diamino compound from example 136, which can be used again in the reaction, is recovered in the following chromatographic fractions according to the method discussed above.

Elemental analysis: solution: C 51.49 H 4.01 M 4.37 P 25.17 5 2.50 found: C 51.60 H 4.19 M 4.28 E 25.14 5 2.44 70 d). M-(1-(4-perfluorooctylsulfonyl)piperazine|amide of 5-amino-3-M-(1-0-A-O-carbonylmethylmannopyranose)benzoic acid

Analogously to the method described for the synthesis of the compound specified in the title of example 136, as a result of hydrogenolysis of 6.4 g (5.00 mmol) of the compound specified in the title 5 of example 13b using 0.3 g of a catalyst

Perlman (2095th Ra/s) in a mixture of ethanol and water (in a ratio of 8:1) after processing, 4.43 g (96.290 7/5 From theory) of the above-mentioned compound in the form of a viscous yellow oil are obtained.

Elemental analysis: solution: C 35.15 H 2.95 M 6.07 ER 35.01 5 3.48 found: C 35.32 H 3.02 M 5.89 E 35.05 5 3.58 d ). M-1-(4-perfluorooctylsulfonyl)piperazinamide 3-M-(1-0-A-O-carbonylmethylmannopyranose)-5-M-(1,4,7-tris(carboxylatomethyl)-10-(3-aza -4-oxo-5-methyl-5-ylpentanoyl)-1,4,7,10-tetraazacyclo do decan) benzoic acid, 15 for complex 5.54 g (8.6 mmol, 2.2 molar equivalents in terms of the amount of the used amine component from example 13d) described |in the application OE 19728954 SI| in example 31, the ba-complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (and 0.37 g of of anhydrous lithium chloride (8.9 mmol) at 40 C is dissolved with stirring in bOml of absolute dimethyl sulfoxide and at this temperature is mixed with M-hydroxysuccinimide in a total amount of 1.01 g (8.8 mmol) and with 3.7 g (4.0 mmol) specified in of the title of example 13g of the compound dissolved in 40 ml of absolute dimethylsulfoxide. After cooling to room temperature, the reaction solution is mixed with 1.82 g (8.mmol) of M,M'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting "I suspension is then mixed with with a sufficient amount of acetone until the compound specified above in the title is completely precipitated, the precipitate is separated by vacuum filtration, dried, dissolved in water, filtered through undissolved dicyclohexylurea, and the filtrate is passed through an ultrafiltration m AMISOM UM-3 membrane (limiting permeability: З000Da)

Finally, the retentate is lyophilized. at

Yield: 5.36 g (87.490 from theory) in the form of a colorless lyophilisate. what-

H2O content (when using Karl Fischer's reagent): 6.7 7905.

Elemental analysis (in terms of anhydrous substance): solution: C 36.01 N 3.61 M 8.22 E 21.05 sa 10.25 5 2.09 " detected: C 35.87 N 3.70 M 8.22 E 20.91 ba 10.18 5 2.16

Example 14 - c a) Diamide 1,4,7-triazaheygan-1,7-bis(2-Motrifluoroadetyl-6-M-benzyloxycarbonyl-y-lysine) c 100 g (107.9 μmol) of the carboxylic acid obtained in example Ia and 26 1 g (226.59 mmol) of M-hydroxysuccinimide is dissolved in 500 ml of dimethylformamide, at 0 2С it is mixed with M,M'-dicyclohexylcarbodiimide in a total amount of 46.7 g (226.59 mmol) in portions and then stirred for hours. at this temperature. A solution of 5.57 g - (53.95 mmol) of diethylenetriamine in bbml of dimethylformamide, cooled to 0 2C, is added dropwise to the solution of the activated ester obtained in this way and stirred for 2 hours. at 0 2C, and then with for 12 hours. at room temperature. To process the precipitated dicyclohexylurea, it is filtered and then the solvent is distilled off to obtain a dry residue. The residue thus obtained is then chromatographed on silica gel (eluent: dichloromethane/ethanol in a ratio of 15:11; chromatography

FO 20 is carried out using a solvent gradient, continuously increasing the proportion of ethanol).

Yield: 26.0 g (58.85 from theory based on the amount of the amine component used) of the compound specified in the title in the form of a colorless and highly viscous oil.

Elemental analysis: solution: C 52.74 H 5.78 M 11.96 E 13.90 29 found: C 52.66 H 5.89 M 11.88 E 14.02 o 5) 1,7-bis (2-M-trifluoroacetyl-6-H-benzyloxycarbonyl-i-lysine)diamide-4-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino) co acetyl-1,4,7-triazaheptane

16.18 g (27.Omol) of 2-(M-ethyl-M-perfluorooctylsulfonyl)aminoacetic acid is added to a solution of 20 g (244 mmol) of the diamide obtained in Example 14a in a mixture containing 150 ml of 60 tetrahydrofuran and 100 ml of chloroform at 09C in a nitrogen atmosphere acid (obtained according to OE 19603033), dissolved in 5 Oml of tetrahydrofuran. After that, a total of 18.0 g (3b,bmmol) of EEDH (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) is added in portions at 0 9С, left overnight for stirring at room temperature and then concentrated in a vacuum. The resulting oil is chromatographed on silica gel (eluent: n-hexane/isopropanol in the ratio of 15:11).In this way, 24.74 g (72495 from theory, calculated on the amount of secondary amine used) of the title compound are obtained as a colorless oil.

Elemental analysis: solution: C 42.01 H 3.96 E 31.19 M 8.00 5 2.29 found: C 41.92 H 4.07 E 31.22 M 7.87 5 2.34 in ) 1,7-bis(6-M-benzyloxycarbonyl-i-lysine)diamide-4-I(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|acetyl-1,4,7-triazageptane 22.0g ( 15.7 mmol) of the compound obtained in example 146 is dissolved in 100 ml of ethanol and this 7/0 solution is bubbled with gaseous ammonia for 40 minutes at 0 C. After that, it is stirred for 4 hours at 0 2 C, and then for 1 hour at room temperature and concentrated to dryness in a vacuum at a bath temperature of 402. The resulting oily residue is purified on silica gel using dichloromethane/hexane/2-propanol (in a ratio of 20:10:1) as an eluent.

Yield: 12.92 g (98.495 from theory) of the above title compound in the form of a colorless and highly viscous 75 oil.

Elemental analysis: solution: C 44.22 H 4.64 M 9.38 5 2.68 E 27.03 found: C 44.31 H 4.72 M 9.30 5 2.74 E 26.99 g ) 1,7-bis|6-M-benzyloxycarbonyl-2-IM-(1-0-A-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmannopyranose)-I -lysine|diamide- 4 -(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|acetyl-1,4,7-triazaheptane 5.47 g (915 mmol) 1-carboxymethyloxy-2,3,4,6-tetra-O-benzyl-A- UO-mannopyranoside (obtained according to the method described in patent OE 19728954 SI) is dissolved in 10 ml of dimethylformamide and mixed with M-hydroxysuccinimide in a total amount of 1.05g (9.1bmmol). Then it is cooled to 0 9C and 1.9g (9.15mmol) is added ) He dicyclohexylcarbodiimide. After that, it is stirred for an hour at 0 C, and then for 4 hours at (5) room temperature. Then it is cooled to 09 C and during the time, a solution of 7.65 g (9.15 mmol) obtained in example 148 is slowly added dropwise amino compounds in 50 ml of dimethylformamide. After that, it is stirred for an hour at 02C, and then overnight at room temperature. The mixture is evaporated to dryness t in a vacuum and the residue is dissolved in 100 ml of ethyl acetic acid. The precipitated urea is filtered off and - the filtrate is washed twice with a 596 aqueous solution of soda in portions of 5 Oml. The organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: n-hexane/isopropanol in a ratio of 20:11). In this way, 17.01 g (78.990 from the theory, in terms of She for the amount of used carboxylic acid) of the compound indicated in the title in the form of a colorless oil are obtained. yu

Elemental analysis: solution: C 59.13 H5.43 M 4.76 E 13.71 5 1.36 - found: C 59.22 H 5.39 M 4.85 E 13.70 5 1.40 d ) 1,7-bis|(2-M-(1-0-A-O-carbonylmethylmannopyranose)-I!-lysine|diamide-4-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|ac « ethyl -1,4,7-triazaheptane 15.0 g (6b.3bmmol) of the amide obtained in example 14m is dissolved in 150 ml of ethanol and mixed with 0.5 g of Perlman's catalyst (2095 Ra/C). After that, it is hydrogenated at room temperature in a hydrogen atmosphere "with (Tatm.) until hydrogen absorption stops. After that, the catalyst is removed by vacuum filtration, "washed thoroughly with ethanol (approximately 10 Oml) and concentrated to dryness under vacuum. In this way, the title compound is obtained in the form of a high viscous yellowish oil.

Yield: 8.54g (97.295 from theory). it. Elemental analysis: c solution: C 39.13 H 5.04 M 8.11 P 23.38 5 2.32 found: C 39.07 H 4.98 M 8.18 E 23.40 5 2.30 (95) e)

F 20 1,7-bis(2-M-(1-0-A-O-carbonylmethylmannotranose)-6-M-I1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo- 5-methyl-5-ylpentanoyl)-1,4,7,10-tetraazacyclododecani-I -lysinidiamide-4-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|)acetyl

T»-1,4,7-triazaheptane, digadolinium-complex

A mixed suspension of 5.7 g (9.0 bmmol) described |in the application OE 19728954 SI| in example 31n of the Ca-complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid in 7 bml of absolute dimethylsulfoxide at 702С mixed with 0.68 g (15.9 mmol) of lithium chloride. After 30 minutes

HF) stirring at 702, the clear reaction solution is mixed in portions with M-hydroxysuccinimide in a total amount of 1.83 g (15.9 mmol) and the reaction mixture is kept for another hour. at this temperature. After cooling to 02C, it is mixed with 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide and the reaction solution is stirred for another hour. at 02C, and then for 12 hours. at 222C. The reaction solution of M-hydroxysuccinimidoether Ca-complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid obtained in this way at 2290 is mixed dropwise with a solution of 2.84 g (2.0 mmol) of the compound specified in the title of example 14d in 15 ml of absolute dimethyl sulfoxide and then stirred for 12 hours. at room temperature. For processing, the reaction solution is added dropwise at 222C to 500 ml of acetone, while the title compound falls out as a colorless precipitate. This sediment is separated by vacuum filtration, dissolved in 200 ml of distilled water, and for desalination and separation of low-molecular components, it is subjected to ultrafiltration three times through an ultrafiltration membrane UM3 (AMISOMU, limit permeability: 3000Da). The resulting retentate is finally lyophilized.

Yield: 4.80 g (89.695 from theory based on the amount of the amine component used) in the form of a colorless lyophilizate with a water content of 8.9895.

Elemental analysis (in terms of anhydrous substance): solution: C 38.28 N 4.84 M 9.68 E 12.40 5 1.23 ba 12.07 found: C 38.20 N 4.91 M 9 .77 E 12.45 5 1.19 ba 12.10 70 Example 15 a) 1,7-bis(benzyloxycarbonyl)-4-y3-oxapentane-1,5-dicarboxylic acid-1-oyl-5-(1- -4-perfluorooctylsulfonyl)piperazinamide)-1,4,7,10-tetraazacyclododecane

To a solution of 10.75 g (24.4 mmol) of 1,7-bis(benzyloxycarbonyl)-1,4,7,10-tetraazacyclododecane in a mixture consisting of 1500 ml of tetrahydrofuran and 15 ml of chloroform, at 09C in a nitrogen atmosphere, add 16.56 g 75 (24.4 mmol) of the compound indicated in the title of example 15d, dissolved in 1500 ml of tetrahydrofuran. After that, a total of 18.0 g (3b,bmmol) of EEDH (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) is added in portions at 02C, left overnight at room temperature for stirring and then concentrated in a vacuum. The resulting oil is chromatographed on silica gel (eluent: n-hexane/isopropanol in a ratio of 12:1). In this way, 17.22 g (64.3905 from theory, based on the amount of secondary amine used) of monoamide and also 3.8 g (8.895 from theory) of diamide are obtained as a byproduct The title compound was isolated as a colorless oil.

Elemental analysis: solution: C 43.41 H 3.92 E 29.18 M 7.59 5 2.60 found: C 43.52 H 4.07 E 29.24 M 7.67 5 2.55 Ge ! b) 1,7-bis(benzyloxycarbonyl)-4--3-oxapentane-1,5-dicarboxylic acid-1-oyl-5-(1--4-perfluorooctylsulfonyl)piperazinamide)-10-(I1-0О- A-O-(5-carbonyl)pentyl-2,3,4,6-tetra-O-benzylmannopyranose|-1,4,7,10-tetraazacyclododecane 10.0 g (13.4 mmol) of the carboxylic acid obtained in example 1O and 3.24 g (28.1 mmol) of M-hydroxysuccinimide are dissolved in 100 ml of dimethylformamide, mixed with M,M'-dicyclohexylcarbodiimide "I" in a total amount of 5.8 g (28.1 mmol) in portions at 0 9C and then stirred for 1 h at this temperature A solution of 14.83 g (13.4 mmol) of the compound indicated in the title of Example 15a in 100 ml of dimethylformamide, cooled to 09C, is added dropwise to the solution of the activated ester obtained in this way and stirred for 2 hours at 02C, and then for 12 hours at room temperature. To process the precipitated dicyclohexylurea, filter and then distill off the solvent until a dry residue is obtained.

The residue is then chromatographed on silica gel (eluent: dichloromethane/ethyl acetic acid in the ratio of 20:1; chromatography is carried out using a solvent gradient, continuously increasing the proportion of ethyl acetic acid).

Yield: 18.3 g (78.295 from theory) of the title compound in the form of a colorless and highly viscous oil. "

Elemental analysis: solution: С 55.11 Н 5.03 М 4.82 РЕ 18.52 5 1.84 З with detection: С 54.87 Н 4.85 М 4.92 Е 18.55 З 1, 86 "» c) 1-43-oxapentane-1,5-dicarboxylic acid-1-oyl-5-(1--4-perfluorooctylsulfonyl)piperazinamide)-7-(1-0O-А-Ю-(5- carbonyl)pentylmannopyranose|-1,4,7, 10-tetraazacyclododecane 17.0 g (9.7 bmmol) of the compound obtained in example 146 is dissolved in 150 ml of ethanol, mixed with 1.0 g of Perlman's catalyst (2090 Ra/cС) and hydrogenated at room temperature in a hydrogen atmosphere (Tatm.) until hydrogen absorption stops. After that, the catalyst is removed by vacuum filtration, washed thoroughly with ethanol (two portions of 7 bml) and concentrated to dryness under vacuum. In this way, the title compound is obtained in the form of highly viscous and colorless oil.bu 70 Yield: 10.76g (99.095 from theory).

Elemental analysis: i» resolution: C 38.78 H 4.61 M 7.54 E 8.97 5 2.88 found: C 38.86 H 4.65 M 7.41 RE 29.02 52.92 d) 1,7-bis| 1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclodo 29 decan-Oa-complex-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)-4 -(2-M-ethyl-M-perfluorooctylsulfonyl)amino|)acets

HF) l-2-oxaacetyl/)|-10-(/1-0O-A-0-6-carbonylpentylmannopyranose|-1,4,7,10-tetraazacyclododecane 24.86g (39.4bmmol, 4.4 molar equivalents in terms of the amount of the used amine de component from example 15c) described |in application OE 19728954 SI| in example 31 of the ba-complex 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4, 7,10-tetraazacyclododecane-1,4,7-triacetic acid (and 1.67 g of 60 anhydrous lithium chloride (39.4 mmol) at 40 C are dissolved with stirring in 200 ml of absolute dimethyl sulfoxide and at this temperature are mixed with M-hydroxysuccinimide in a total amount of 4 .53g (39.4bmmol) and from 10.0g (8.97mmol) of the compound indicated in the title of example 14c, dissolved in 100ml of absolute dimethylsulfoxide. After cooling to room temperature, the reaction solution is mixed with 8.14g (394bmmol) M,M'- of dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The obtained suspension is then mixed with a sufficient amount of acetone until complete precipitation of the specified above in the title of the compound, the precipitate is separated by vacuum filtration, dried, dissolved in water, filtered off dicyclohexylurea, which did not dissolve, and the filtrate for desalting and for cleaning from low molecular weight components is passed through an ultrafiltration membrane AMISOM U UM-3 (permeability limit: З000Da) Retentate finally lyophilized.

Yield: 16.37 g (79.390 from theory) in the form of a colorless lyophilisate.

H2O content (when using Karl Fischer's reagent): 7.65905.

Elemental analysis (in terms of anhydrous substance): solution: C 38.01 N 4.61 M 9.58 E 13.81 5 1.37 ba 13.45 found: C 37.92 N 4.55 M 9 ,58 E 13.77 5 1.31 ba 13.48 d) Mono|1-(4-perfluorooctylsulfonyl)piperazinamide of 3-oxapentane-1,5-dicarboxylic acid 25 g (44.0 mmol) of 1-perfluorooctylsulfonylpiperazine are dissolved in 150 ml of tetrahydrofuran, mixed at room temperature with diglycolic acid anhydride in a total amount of 5.1 g (44.0 mmol) and the reaction solution obtained in this way for 12 hours. boil under reflux. After cooling to 75 room temperature, it is concentrated to dryness and the obtained oily residue is purified on silica gel using dichloromethane/2-propanol (16:1 ratio) as eluent.

Yield: 27.94 g (92.890 from theory) of the compound indicated above in the title in the form of a colorless and viscous oil.

Elemental analysis: solution: C 58.52 H 4.27 M 1.98 52.26 R 22.80 found: C 58.42 H 4.41 M 1.80 52.28 E 23.02

Example 16 a) 1,7-bis(benzyloxycarbonyl)-4-yl3-oxapentane-1,5-dicarboxylic acid-1-oyl-5-(1--4-perfluorooctylsulfonyl)piperazinamide)-(10-(1-0 -8-O-6-carbonylpentyl-2,3,4,b-tetra-O-benzylglucopyranose|-1,4,7,10-tetraazacyclododecane) Ha

In 750 ml of dry tetrahydrofuran, dissolve 68.5 g (91.7 μmol) of 1-carboxymethyloxy-2,3,4,6-tetra-O-benzyl-A-Y-mannopyranoside (obtained by the method described in the patent

ORE 19728954 SI| and then add 9.25 g (91.79 mmol) of triethylamine. After cooling the reaction solution to a temperature in the range from -15 to -202C, at this temperature and with stirring, a solution of 12.64 g (92.5 mmol) of isobutyl ether of chloroformic acid in 150 ml of dry tetrahydrofuran is slowly added dropwise, while the rate of dropwise addition is should be such that the internal temperature does not exceed -10207. After conducting the reaction for 15 min. at -1592C dropwise at -202C slowly add a solution of 101.6bg (91.7Umole) of the compound indicated in the title of example 15a and 9.25g (91./7Umole) of triethylamine in 50O0ml of dry SO tetrahydrofuran. After conducting the reaction for one hour at -15 29C, and then for two hours at room temperature, the reaction solution is concentrated to dryness in a vacuum. The resulting residue is dissolved in 450 ml of ethyl acetic acid and washed twice with a saturated solution of sodium bicarbonate in portions. by 30 Oml and once with water in a portion of 40 Oml. After drying the organic phase over sodium sulfate, the salt is separated by vacuum filtration and the ethyl acetic acid is distilled off under vacuum. The obtained oily residue is purified on silica gel using dichloromethane/hexane/2-propanol (in the ratio 10:20:1) as an eluent.

Yield: 130.6 bg (81.695 from theory) of the compound indicated above in the title in the form of a colorless and highly viscous Z c oil. "» Elemental analysis: " solution: С 55.11 Н 5.03 М 4.82 РЕ 18.52 5 1.84 found.: С 55.20 Н 5.09 М 4.91 Е 18.48 5 1 ,80 b) 1--3-oxapentane-1,5-dicarboxylic acid-1-oyl-5-(1--4-perfluorooctylsulfonyl)piperazinamide)-7-(1-O-А-Ю-(5- carbonyl)pentylmannopyranose|-1,4,7, with 10-tetraazacyclododecane 110.0 g (63.08 mmol) of the compound obtained in example 11ba is dissolved in 10000 ml of ethanol, mixed with 5.0 g of Perlman's catalyst (20956 Ra/cС) and hydrogenate until quantitative hydrogen absorption After that, the catalyst

F 250 is removed by vacuum filtration, then washed with ethanol and concentrated to dryness under vacuum. In this way, the compound specified in the title is obtained in the form of a viscous and colorless oil. yield: 92.61g (99.590 from theory).

Elemental analysis: solution: C 52.10 H 5.12 M 5.70 E 21.89 5 2.17 29 found: C 52.20 H 5.09 M 5.71 E 21.87 5 2.20

F c) 1,7-bis(1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-ylpentanoyl)-4-73-oxapentane-1,5- dicarboxylic acid-1-oyl-5-(1--4-perfluorooctylsulfonyl)piperazinamide)-10-(I1-0O-A-0-(5-carbonyl)pentylmannopyranose!|-1,4,7"10-tetraazacyclodo decane, digadolinium complex bo 55.4 g (88.0 mmol, 4.4 molar equivalents in terms of the amount of the used diamine component from example 33 g) described |in the applicant OE 19728954 SI| in example 31 of the ba-complex 10-(4- carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 3, 7 g of anhydrous lithium chloride (88.0 mmol) at 409C are dissolved with stirring in 5000 ml of absolute dimethyl sulfoxide and at this temperature is mixed with M-hydroxysuccinimide in a total amount of 10.1 g (88.0 mmol) and with 29.5 g (20.0 mmol) of the compound specified in the title of example 166, dissolved in 200 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 18.2 g (88.00 mm oil) of M,M'-dicyclohexylcarbodiimide and stirred for 12 hours. at room temperature.

The resulting suspension is then mixed with a sufficient amount of acetone to completely precipitate the compound indicated above in the Title, the precipitate is separated by vacuum filtration, dried, dissolved in water, dicyclohexylurea that has not dissolved is filtered off, and the filtrate is passed through an ultrafiltration membrane for desalting and for purification from low molecular weight components AMISOM IN UM-3 (limiting permeability: 300ODa) Finally, the retentate is lyophilized.

Yield: 35.96g (76.990o from theory) in the form of a colorless lyophilizate. 70 H2O content (when using Karl Fischer's reagent): 5.9890.

Elemental analysis (in terms of anhydrous substance): solution: C 38.01 N 4.61 M 8.22 E 13.81 sa 13.45 5 1.37 found: C 37.87 N 4.70 M 8 ,22 E 13.90 ba 13.48 5 1.36

Example 17 a) 5-(ethoxycarbonyl)pentyl-2,3,4,6-tetra-O-acetyl-A-O-mannopyranoside

Similarly to the method described in the literature for the synthesis of arylglycopyranosides (U. Sopspie and O. A. Imu, "Meijodz ip Sagropudgaie Spetivigu (edited by K.Y. MUpizMCeg, M.I. MUoigtot and 9U.M. VemiShpeg), Asadetis species

Rgezv, Mem MogKk, vol. II, 90, p. 345-347 (1963) as a result of the interaction of 156.2 g (400 mmol) of pentaacetate

O-mannose in the form of a mixture of A,B-anomers (the ratio between A and B is 4:1) (see the synthesis of 1,2,3,4,6-penta-O-acetyl-A,B-Y-mannopyranose in M.S. Muoytot and A. Trotrzop, "Meijoaz ip SagroNuagaie

Spetivigu" (under the editorship of K.G. MUpizMTseg, M... MMoytot and 9U.M. VemMiSheg), ed. Asadetis Rgevzv, Mem/ MogkK, vol. II, 53, p. 211-215 (1963)| with b/ml (400 mmol) ethyl ether of b-hydroxyhexanoic acid and 60.vml (520 mmol) tin(IM) chloride in 1,2-dichloroethane in a total amount of bOOml after purification by column chromatography (eluent: hexane/oethyl acetic acid in the ratio 2:1) obtain 100.05 g (5195 from theory) of the compound indicated above in the title in the form of a colorless and viscous oil. The data of "H-NMR spectroscopic analysis of the compound obtained in this way indicated in the title indicate that this the compound is only pure A-anomer.

Elemental analysis: solution: C 52.94 H 6.77 "I detected: C 52.80 H 6.78 b) 5-(carboxy)pentyl-2,3,4,6-tetra-O-benzyl- А-ХО-mannopyranoside и-о

A mixed suspension of 141.0 g (289 mmol) of the compound indicated in the title of example 17a in 200 ml of dioxane is mixed with highly dispersed powdered potassium hydroxide in a total amount of 238.5 g (4.2 bmol) at 9 room temperature and at the same time intensive stirring. To increase its miscibility, the reaction mixture is mixed with another 20 ml of dioxane, and the suspension obtained as a result is then heated to the boiling point and at this temperature for two hours it is mixed dropwise with benzyl bromide in a total amount of 372 ml (3.128 mol). After conducting the reaction for 4 hours. at 110 C, and then for 12 hours. at room temperature, the reaction mixture for processing is slowly poured into a mixture of water and ice in a total amount of 2.5 l, and the aqueous phase is then completely extracted with diethyl ether. After washing the ether phase obtained in this way and its subsequent drying over sodium sulfate, the salt is separated - with vacuum filtration and the diethyl ether is distilled off in a vacuum. After that, the excess of benzyl bromide is quantitatively distilled from the reaction mixture in a vacuum created by an oil pump, at an oil bath temperature of -" 18020. The tarry-oily residue obtained in this way is purified on silica gel using ethyl acetic acid/hexane (in a ratio of 1:10 ) as an eluent.

Yield: 172.2 g (91.095 from theory) of the compound indicated above in the title in the form of a colorless and highly viscous oil. sl Elemental analysis: solution: C 75.68 H 7.16 and detection: C 75.79 H 7.04

FO 20 c) 5-Kcarboxy)pentyl-2,3,4,6-tetra-O-benzyl-A-YUO-mannotranoside-M-hydroxysuccinimidoether 60.0 g (91.5 mmol) of the compound indicated in the title of example 176, dissolve in 75 ml of dimethylformamide and mixed with M-hydroxysuccinimide in a total amount of 10.4 g (91.5 mmol). Next, it is cooled to 02C and 18.9 g (91.5 mmol) of dicyclohexylcarbodiimide are added. After that, it is stirred for an hour at 0 29C, and then for 4 hours. at room temperature. The solvent is distilled off in a vacuum, the obtained residue is mixed with 100 ml of 22 ethyl ether of acetic acid and cooled to 02C. The precipitated urea is filtered and

HF) the resulting filtrate is concentrated to dryness in a vacuum. The resinous-oily residue obtained in this way is purified on silica gel using ethyl acetic acid/hexane (in a ratio of 1:20) as an eluent.

Yield: 61.23g (89.095 from theory) of the above title compound in the form of a colorless and viscous oil. 60 Elemental analysis: solution: C 70.29 N 6.57 M 1.86 detected: C 70.39 N 5.64 M 1.91 g) Methyl ether 2,6-6is16-M is-2-MA -(1-O-A-O-6-carbonylpentyl-(2,3,4,6-tetra-O-benzyl)mannopyranose|-I -lysine) bo To a solution cooled to 02С with 4.26g (18.30mmol , 0.5 molar equivalents in terms of the amount of carboxylic acid used) of dihydrochloride methyl ether I-lysine (which is supplied by the company

Vaspet) and 4.05g (40.2bmmol) of triethylamine in 100ml of dimethylformamide are added dropwise to a solution of 27.51g (36.bmmol) of the compound indicated in the title of example 17c in 150ml of dimethylformamide. After this addition is complete, the mixture is stirred for another hour at 02C and then overnight at room temperature. The mixture is evaporated to dryness under vacuum and the residue is dissolved in ZOO ml of ethyl acetic acid. The precipitated urea is filtered off and the filtrate is washed twice with a 595% aqueous soda solution in portions of 100 ml.

The organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: n-hexane/isopropanol in the ratio 25:11). In this way, 39.56 g (75.490 from 70 theory) of the title compound are obtained as a colorless oil.

Elemental analysis: solution: C 72.88 N 7.31 M 1.95 detected: C 72.90 N 7.29 M 2.02 d) 2,6-bisIb-Me-2-MA-(1-0О) -А-О-6-carbonylpentyl-(2,3,4,6-tetra-O-benzyl)mannopyranose)||-I -lysine

30.0 g (20.92 mmol) of the compound obtained in example 17 is dissolved in 150 ml of ethanol. Next, add a solution of 4g (100, Ommol) of sodium hydroxide in 1Oml of distilled water and mix for 1 hour. at 5020. According to the chromatogram of thin-layer chromatography, saponification is quantitative. After that, the mixture is concentrated to dryness in a vacuum, the resulting residue is dissolved in 300 ml of ethyl acetic acid, and the organic phase is extracted twice with a dilute aqueous solution of citric acid in portions of 10 ml. After drying over sodium sulfate, it is filtered and concentrated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: n-hexane/isopropanol in the ratio 13:11). In this way, 25.56 bg (88.5905 from theory) of the title compound are obtained as a colorless oil.

Elemental analysis: soln.: C 72.88 H 7.31 M 1.95 Ha detect.: C 72.78 H 7.33 M 1.96 e) M-hydroxysuccinimidoether i) 2,6-bis|6-M is-2-Md-(1-0O-A-O-6-carbonylpentyl-(2,3,4,6-tetra-O-benzyl)mannopyranose|-I-lysine) 14.Og (9.15 mmol) of compounds , specified in the title of example 17d, is dissolved in 100 ml of dimethylformamide and mixed with M-hydroxysuccinimide in a total amount of 1.04 g (915 mmol). Next, it is cooled to 092C and 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide is added. After that, it is stirred for an hour at 0 2C, and then at room temperature for 4 hours. at room temperature. Next, the solvent is distilled off in a vacuum, the resulting residue is mixed with 100 ml of ethyl acetic acid and cooled to 02C. The precipitated urea is filtered and the resulting filtrate is concentrated to dryness in a vacuum. The resinous-oily residue obtained in this way is purified on silica gel using ethyl acetic acid/n-hexane (in a ratio of 1:20) as an eluent. -

Yield: 12.94 g (92.490 from theory) of the compound indicated above in the title in the form of a colorless and viscous oil.

Elemental analysis: soln.: C 71.40 H 7.05 M 2.74 " detect.: C 71.39 H 7.14 M 2.81 g) 1,7-(1,4,7-triazaheptane)diamide - with 2,6-M,M'-bisi1-0O-A-0-(6-carbonyl)pentyl-2,3,4,6-tetra-O-benzylmannopyranose|-I-lysine h» To cooled to 02 of a solution of 0.47g (4.57mmol) of diethylenetriamine in 25ml of dimethylformamide" slowly add a solution of 14.0g (9.1bmmol; 2 molar equivalents in terms of the amount of amine used) of the compound indicated in the title of example 17e in 100ml of dimethylformamide dropwise. After this is completed the addition is stirred for another hour at 0 2C, and then overnight at room temperature. The mixture is evaporated to dryness in a vacuum and the residue is dissolved in 200 ml of ethyl acetic acid. "sl The precipitated urea is filtered off and the filtrate is washed twice with 590 with an aqueous soda solution in portions of 5 Oml. The organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: n-hexane/isopropanol in a ratio of 25:1 1). In this way it is obtained

He») 20 9.53 g (71.495 from theory) of the compound indicated in the title in the form of a colorless oil.

Elemental analysis: solution: C 72.79 H 7.42 M 3.36 found: C 72.90 H 7.39 M 3.32 z) Methyl ether 2-M-(2-(M-ethyl) -M-perfluorooctylsulfonyl)amino|acetyl-6-M-(benzyloxycarbonyl)-I-lysine 20.8 g (35.bmmol) 2-(M-ethyl-M-perfluorooctylsulfonyl)aminoacetic acid, as well as 3.bOg (35, hmmm)

HF) of triethylamine is dissolved in 200 ml of dimethylformamide and 4.09 g (35 bmol) of M-hydroxysuccinimide is added. Then it is cooled to 09C and 7.34 g (35.bmmol) of dicyclohexylcarbodiimide is added. After that, it is stirred for an hour at 02C, and then for 4 hours. at room temperature. Then it is cooled to 029C and for 1 hour. a solution of 11.77g (335.bmmol) of methyl ether hydrochloride 60 6-M-benzyloxycarbonyl-I-lysine and 4.0g (40.00mmol) of triethylamine in 170000ml of dimethylformamide is added dropwise. The mixture is stirred for an hour at 02C, and then overnight at room temperature. The mixture is evaporated to dryness in a vacuum and the residue is dissolved in 100 ml of ethyl acetic acid. The precipitated urea is filtered off and the filtrate is washed twice with a 595% aqueous soda solution in portions of 100 ml. The organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: n-hexane/ethyl acetic acid in a ratio of 20:11). In this way, 27.43 g (88.095 from theory) of colorless oil are obtained.

Elemental analysis: solution: C 38.41 H 3.45 M 4.80 ER 36.89 5 3.66 found: C 38.45 H 3.38 M 4.88 E 37.02 5 3.71 ) 2-MA-(C2-(M-ethyl-M-perfluorooctylsulfonyl|aminoacetyl)-6-M rv-(benzyloxycarbonyl)-I -lysine

25.0 g (28.55 mmol) of the compound obtained in example 173 is dissolved in 150 ml of ethanol. Next, add a solution of 4g (100, Ommol) of sodium hydroxide in 1Oml of distilled water and mix for 1 hour. at 5020. According to the chromatogram of thin-layer chromatography, saponification is quantitative. After that, it is concentrated to dryness in a vacuum, the 7/0 obtained residue is dissolved in ZOO ml of ethyl acetic acid and the organic phase is extracted twice with a dilute aqueous solution of citric acid in portions of 10 ml. After drying over sodium sulfate, it is filtered and concentrated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: n-hexane/isopropanol in the ratio 10:11). In this way, 22.73 g (92.4905 from theory) of the title compound are obtained in the form of a colorless oil.

Elemental analysis: solution: C 37.64 H 3.28 M 4.88 E 37.49 5 3.72 found: C 37.65 H 3.38 M 4.88 E 37.52 5 3.73

Kk) 1,4,7-triazaheptan-4-2-M-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|acetyl-6-M-benzyloxycarbonyl)-I-lysine 1d-1,7-bis( 2,6-M,M'-bis(i1-O-A-O-(5-carbonyl)pentyl-2,3,4,6-tetra-O-benzylmannopyranose)|-I--lysindiamide) 15.33g (17.8 mmol) of the compound indicated in the title of example 17i, as well as 1.80 g (17.8 mmol) of triethylamine are dissolved in 250 ml of dry tetrahydrofuran. After cooling the reaction solution to a temperature in the range from -15 to -202C, at this temperature, a solution of 4.92g (35.bmmol) isobutyl ether of chloroformic acid in 50ml of dry tetrahydrofuran is slowly added dropwise while stirring, while the rate of dropwise addition should be as follows , so that the internal temperature does not exceed -10 °C. After conducting the reaction for 15 min. at -159C dropwise at -202C slowly add a solution of 52.0g (17.8mmol) of the compound indicated in the title of Example 17g and 1.80g (17.8mmol) of triethylamine in ZOOml of dry tetrahydrofuran.

After carrying out the reaction for an hour at -15 C, and then for two hours at room temperature, the reaction solution is concentrated to dryness in a vacuum. The obtained residue is dissolved in 5X0O0ml of ethyl ether of acetic acid and washed twice with a saturated solution of sodium bicarbonate in portions of 200Oml and once with water in a portion of 20OOml. After drying the organic phase over sodium sulfate, the salt is separated by vacuum filtration and the ethyl acetic acid is distilled off under vacuum. The resulting oily residue was purified on silica gel using ethyl acetic acid/n-hexane (1:20 ratio) as an eluent.

Yield: 54.bg (81.695 from theory) of the compound indicated above in the title in the form of a colorless and highly viscous oil.

Elemental analysis: solution: C 65.09 H 6.45 M 3.72 E 8.58 5 0.85 " found: C 65.13 H 4.41 M 3.69 E 8.52 5 0.90 l) o, c 1,4,7-triazaheptan-4-(2-M-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|acetyl)-i-lysinamide-1,7-bis/2,6 -M,M'-bis|1-h O-A-O-(5-carbonyl)pentylmannopyranose)/-I -lysindiamide) » 50.0 g (13.28 mmol) of the compound obtained in example 17k is dissolved in 500 ml of ethanol, mixed with 4.0 g of Perlman's catalyst (2090 Ra/sС) and hydrogenate at room temperature in a hydrogen atmosphere (Tatm.) until hydrogen absorption stops. After that, the catalyst is removed by vacuum filtration, thoroughly washed with ethanol (approximately 40 Oml) and concentrated to dryness under vacuum. In this way, the compound specified in the title is obtained in the form of a highly viscous and colorless oil.

Yield: 26.85g (93.090o from theory). o Elemental analysis: bu 50 resolution: C 45.85 H 6.35 M 6.44 GE 14.86 5 1.47 detection: C 45.76 H 6.35 M 6.41 E 14.92 5 1 .39 m) 1,4,7-triazaheptan-4-12-M-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|acetyl-6-M-(1,4,7-tris(carboxylatomethyl )-10-(3-aza-4-oxo-5-m ethyl-5-ylpentanoyl)-1,4,7,10-tetraazacyclododecane)-I -lysinamide-1,7-bis(2,6-M, M'-bisI1-0O-A-O-(5-carbonyl)pentyl mannopyranose|-I -lysindiamide), gadolinium complex

Gee! 5.54 g (8.6 mmol, 2.2 molar equivalents in terms of the amount of the used amine component from example 17l) described in the application OE 19728954 SSC in example III ba-complex ko 10-(4-carboxy-1-methyl-2 -oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (and 0.37 g of anhydrous lithium chloride (8.9 mmol) at 40 C are dissolved with stirring in bOml of absolute 60 dimethyl sulfoxide and at this temperature is mixed with M-hydroxysuccinimide in a total amount of 1.01 g (8.8 mmol) from 1.84 g (4.00 mmol) of the compound indicated in the title of Example 17l dissolved in 40 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 1.82 g (8.mmol) of M,M'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension was then mixed with a sufficient amount of acetone until the compound indicated above in the title was completely precipitated, the precipitate was separated by vacuum filtration, dried, dissolved in water, filter Dicyclohexylurea, which has not dissolved, and the filtrate for desalting and for cleaning from low-molecular components are passed through an ultrafiltration membrane AMISOM U UM-3 (limit permeability: 300ODa). The retentate is finally lyophilized.

Yield: 8.77g (78.790o from theory) in the form of a colorless lyophilisate.

H2O content (when using Karl Fischer's reagent): 4.4390.

Elemental analysis (in terms of anhydrous substance): solution: C 43.98 H 5.97 M 7.54 E 11.59 sa 5.64 5 1.15 found: C 43.97 Nb.02 M 7.62 E 11.61 sa 10.18 5 1.15

Example 18 a) Methyl ether of 2-MA-6-Me-bisI1-0O-A-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmannopyranose (/-I-lysine) 10.95 g. (18.30 mmol) of 1-carboxymethyloxy-2,3,4,6-tetra-O-benzyl-А-ХО-mannopyranoside (obtained according to the method described in patent OE 19728954 Si) is dissolved in 150 ml of dimethylformamide and mixed with

M-hydroxysuccinimide in a total amount of 2.09 g (18.3 mmol). Next, it is cooled to 09C and 3.78 g (18.3 mmol) of dicyclohexylcarbodiimide are added. After that, it is stirred for an hour at 0 2С, and then for 75 4 hours. at room temperature. Then it is cooled to 02C and within an hour a solution of 2.13g (9.1bmmol, 0.5 molar equivalents in terms of the amount of carboxylic acid used) of dihydrochloride of methyl ether I-lysine (supplied by Vaspet) and 2.02g (20, 133 mmol) of triethylamine in 7 Oml of dimethylformamide. After this addition is complete, the mixture is stirred for another hour at 0 2°C, and then overnight at room temperature. The mixture is evaporated to dryness under vacuum and the residue is dissolved in ZOO ml of ethyl acetic acid. The precipitated urea is filtered and the filtrate is washed twice with a 5% aqueous solution of soda in portions of 100 ml. The organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: n-hexane/isopropanol in the ratio 25:11). In this way, 10.05 g (82.395 from theory) of the title compound are obtained in the form of a colorless oil. with

Elemental analysis: solution: C 71.94 N 6.79 M 2.10 detected: C 71.90 N 6.79 M 2.09 b) 2-MA-6-Me-bisI1-O-A- O-carbonylmethyl-2,3,4,6-tetra-O-benzylmannopyranose|-I-lysine

Similarly to the method described in example 17d for the synthesis of the compound specified in its title, as a result of saponification of 15 g (11.2 mmol) of the methyl ether of the compound specified in the title of example 18a, 13.89 g (93.69 from theory) of the specified above in the title of the compound in the form of a colorless and viscous oil.

Elemental analysis: i) solution: C 71.80 N 6.71 M 2.12 and detection: C 71.84 N 6.69 M 2.15

From c) M-hydroxysuccinimidoether c. 2-Ma-6-Me-bis(I1-0O-A-OB-carbonylmethyl-2,3,4,6-tetra-O-benzylmannopyranose|-I-lysine 12.09 g (9.15 mmol) of the compound specified in of the title of example 186, dissolved in 100 ml of dimethylformamide and mixed with M-hydroxysuccinimide in a total amount of 1.04 g (9.15 mmol). Then it was cooled to 02C and 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide was added. After that, it was stirred for an hour at 0 29C , and then 40 for 4 hours at room temperature. Next, the solvent is distilled off under vacuum, the resulting residue is mixed with 100 ml of ethyl acetic acid and cooled to 02. The precipitated urea is filtered off and the obtained filtrate is concentrated to dryness in vacuum The resinous-oily residue obtained in this way is purified on silica gel using ethyl acetic acid/n-hexane (in a ratio of 1:20) as an eluent.

Yield: 12.24 g (94490 from theory) of the compound indicated above in the title in the form of a colorless and viscous oil. - Elemental analysis: 1 solution: C 70.27 N 6.47 M 2.96 detected: C 70.31 N 6.44 M 3.01

Mami d) P1-(4-perfluorooctylsulfonyl)piperazine|amide

Ge) 20 6-M-benzyloxycarbonyl-2-M-(2,6-M,M'-bis(1-0O-A-O-carbotlmethyl-2,3,4,6-tetra-O-benzylmannopyranose)| -I -lysyl)-

Their Y-lysine 19.0 g (13.4 mmol) of M-hydroxysuccinimidoether carboxylic acid obtained in example 18b is dissolved in 75 ml of dimethylformamide and mixed dropwise at 09 with a cooled to 02 solution of 11.13 g (13.4 mmol) of the compound indicated in the title of the example in 500O0ml of dimethylformamide. The resulting reaction solution 59 is stirred for another 2 hours. at 02C, and then for 12 hours. at room temperature. For processing

HF) dicyclohexylurea, which has precipitated, is filtered and then the solvent is distilled off in a vacuum to

GF of obtaining a dry residue. The residue obtained in this way is chromatographed on silica gel (eluent: dichloromethane/ethanol in a ratio of 28:11, while the chromatography is carried out using a solvent gradient, continuously increasing the proportion of its polar component used in the eluent (in this case, ethanol) during the chromatography process).

Yield: 25.28 g (88.490 from theory) of the title compound in the form of a colorless and highly viscous oil.

Elemental analysis: solution: C 59.10 H 5.34 M 3.94 RE 15.13 5 1.50 found: C 59.18 H 5.35 M 4.02 E 15.15 5 1.56 b5 si. and d) (1-(4-perfluorooctylsulfonyl)piperazine|amide

2-M4-Х2,6-М,М'-bis(1-0О-А-О-carbonylmethylmannopyranose)|-I -lysyl-I -lysine 20.0 g (9.37 mmol) of the compound obtained in example 18 are dissolved in 200 ml of ethanol, mixed with 1.5 g of Perlman's catalyst (2090 Ra/sС) and hydrogenated at room temperature in a hydrogen atmosphere (Tatm.) until hydrogen absorption stops. After that, the catalyst is removed by vacuum filtration, thoroughly washed with ethanol (two portions of approximately 100 ml) and concentrated to dryness under vacuum. In this way, the compound specified in the title is obtained in the form of a highly viscous and colorless oil.

Yield: 11.62g (97.090 from theory).

Elemental analysis: 70 resolution: C 38.50 H 4.65 M 6.57 RE 25.25 5 2.51 found: C 38.46 H 4.65 M 6.51 E 25.23 52.52 e ) P1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-(1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-ylpentanoyl)-1,4 ,7,10-tetraazacyclododecane)-2-M-42,6-M,M'-bis(1-0O-A-O-carbonylmethylmannopyranose)|-I -lysyl)-I -lysine, α-complex 9.98g (15.84 mmol, 2.2 molar equivalents in terms of the amount of the used amine component from example 18e) described |in the application OE 19728954 SI| in example 31 of the ba-complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (and 0.6b7g of anhydrous of lithium chloride (15.84 mmol) at 40 C is dissolved with stirring in 10000 ml of absolute dimethyl sulfoxide and at this temperature is mixed with M-hydroxysuccinimide in a total amount of 1.82 g (15.4 mmol) and with 9.19 g (7.19 mmol) of the example indicated in the title 18d of the compound dissolved in 50 ml of absolute dimethyl sulfoxide After cooling to room temperature, the reaction solution was mixed with 3.27 g (15.864 mmol) of M,M'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature.

The resulting suspension is then mixed with a sufficient amount of acetone to completely precipitate the above-mentioned compound, the precipitate is separated by vacuum filtration, dried, dissolved in water, filtered with dicyclohexylurea, which has not dissolved, and the filtrate for desalting and for simultaneous purification from possibly still present in in it, low-molecular components are subjected to ultrafiltration through an AMISOM UM-3 ultrafiltration membrane (limit permeability: 3000 Da). The retentate is finally lyophilized.

Yield: 11.85 g (87290 from theory) in the form of a colorless lyophilisate. h;E

H2O content (when using Karl Fischer's reagent): 5.5490.

Elemental analysis (calculated per anhydrous substance): so solution: С 38.12 Н 4.64 М 8.15 Е 20.38 5 1.70 са 8.32 со detection: С 38.16 Н 4.59 M 8.18 E 20.37 5 1.68 ba 8.28

Example 19 a) M. 1,7-bis(benzyloxycarbonyl)-4-(3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoyl)-1,4,7,10-tetraazacyclododecane

To a solution of 10.75 g (24 4 mmol) of 1,7-bisbenzyloxycarbonyl)-1,4,7,10-tetraazacyclododecane in a mixture with 150 ml of tetrahydrofuran and 1 bml of chloroform at 09C in a nitrogen atmosphere, add 12.74 g (24.4 mmol) of " of the title of example 19g of the compound dissolved in 150 ml of tetrahydrofuran. After that, a total of 18.0 g (3b,bmmol) of EEDH (|2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline|) is added in portions at 02C, left overnight for 3 s stirring at room temperature and then concentrated in a vacuum . The obtained oil is chromatographed on m silica gel (eluent: n-hexane/isopropanol in the ratio 16:11). In this way, 15.89 g (69.095 from theory, in terms of the amount of secondary amine used) of monoamide, as well as 3.8 g (8.895 from theory) of diamide are obtained as a by-product. The title compound is isolated as a colorless oil.

Elemental analysis: - solution: C 45.77 H 3.95 E 34.19 M 5.93 5 sl detect.: C 45.72 H 4.01 E 34.22 M 5.88 b) i95) 1, 7-bis(benzyloxycarbonyl)-4-(3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoyl)-10-(1-5-A-Y-(2-carbonyl)ethyl-2,3 , because 50 4,6-tetra-O-acetylmannopyranose!|-1,4,7,10-tetraazacyclododecane 7.09 g (13.4 mmol) of M-hydroxysuccinimidoether

I» 3-(2,3,4,6-tetra-O-acetyl-1-thio-A-Y-mannopyranosyl)propionic acid (obtained according to the method described in U. Naepwieg et al., Viosopiddaee Speth. 4, 85 (1993); Spirozhek 5. and ee U.S., Zupipevov oi 1-pio-acidozidez, Sagropuadgaye Kezeagsp 31 (1973), pp. 339-346Y) are dissolved in 100 ml of dimethylformamide and mixed dropwise at 09С with the previously cooled to 02C with a solution of 12.65 g (13.4 mmol) of the substance indicated in the title

HF) of the compound of example 19a in 100 ml of dimethylformamide. The mixture is stirred for 2 hours. at 0 9C, and then for 12 hours. at room temperature. For processing, the solvent is distilled off in a vacuum until a dry residue is obtained, which is then chromatographed on silica gel (eluent: dichloromethane/ethyl acetic acid in a ratio of 20:1; chromatography is carried out using a solvent gradient, continuously increasing the proportion of ethyl acetic acid).

Yield: 16.23 g (88.990 from theory) of the title compound in the form of a colorless and highly viscous oil.

Elemental analysis: solution: C 46.70 H 4.36 M 4.11 P 23.69 5 2.35 found: C 46.66 H 4.35 M 4.12 RE 23.65 5 2.30 b5 in)

1-(3-oxa-2H,2H,4H.4H,5H,5H-perfluorotridecanoyl)-7-I1-5-A-O0-(2-carbonyl)ethyl-2,3,4,6-tetra-O -acetylmannopyran oza|-1,4,7,10-tetraazacyclododecane 15.0 g (11.0 mmol) of the compound obtained in example 196 is dissolved in 1500 ml of ethanol, mixed with 1.0 g of Perlman's catalyst (2090 Ra/sС) and hydrogenated at room temperature in a hydrogen atmosphere (Tatm.) until hydrogen absorption stops. After that, the catalyst is removed by vacuum filtration, thoroughly washed with ethanol (two portions of 7 bml) and concentrated to dryness under vacuum. In this way, the compound specified in the title is obtained in the form of a highly viscous and colorless oil.

Yield: 11.56g (96.090 from theory). 70 Elemental analysis: solution: C 40.59 H 4.33 M 5.12 E 29.50 5 2.93 found: C 40.63 H 4.35 M 5.11 E 29.52 52.92 g ) 1-(3-oxa-2H,2H,4H.4H,5H,5H-perfluorotridecanoyl)-7-I1-5-А-О0-(2-carbonyl)ethylmannopyranose/|-1,4,7,10- tetraazac /5 Mclododecane 10.0g (9x13mmol) of the compound indicated in the title of example 19c is suspended in 100ml of absolute methanol and mixed with a catalytic amount of sodium methanolate at 593. After carrying out the reaction within the Agreement at room temperature, the data of control of the course of the reaction by thin-layer chromatography (eluent: chloroform/methanol in the ratio 4:11) already indicate a quantitative transformation. For processing, the transparent reaction solution is neutralized by mixing it with the cation exchange resin Atregiye IV 120 (H "-form), the ionite is removed by vacuum filtration, then washed with methanol, and the methanol filtrate obtained in this way is distilled in a vacuum until a dry residue is obtained. The obtained oily residue is purified by column chromatography on silica gel (eluent: dichloromethane/n-hexanoethyl acetic acid in a ratio of 15:20:11; chromatography is carried out using a solvent gradient, continuously increasing the fraction of ethyl acetic acid). Data of "H-NMR spectroscopic analysis of the indicated in compounds, based on the value of the interaction constants 4 2-0.9 Hz, make it possible to draw an unambiguous conclusion about the presence of the A-configuration in the anomeric center of O-mannopyranose. A similar A-configuration is the only configuration present in the center of anomerism, that is, the number of possible anomers of the title compound with

B-configuration therefore lies below the threshold of detection in "H-NMR-spectroscopic analysis. Accordingly, the compound indicated above in the title is obtained only in the form of a pure anomer with A-configuration.

Yield: 8.28 g (98.095 from theory) of the title compound in the form of a colorless and highly viscous oil.

Elemental analysis: and solution: C 37.59Н 4.24 М 6.05 Е 34.85 З 3.46 and found.: С 37.57 Н 4.28 М 6.02 Е 34.85 З 3.44 e) - 1-(3-oxa-2H,2H,4H.4H,5H,5H-perfluorotridecanoyl)-7-I1-5-A-0-(2-carbonyl)ethylmannopyranose/1|-4,10-bis |(1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-ylpentanoyl)|-1,4,7,10-tetraazacyclododecane, digadolinium complex « 2.A8g (3.94 mmol, 4.4 molar equivalents in terms of the amount of the used diamine component from example 719g) described |in the application OE 19728954 SI| in example 31 of the Ca-complex o) with 10-(4-carboxy-1-methyl-2 -oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 167 mg of anhydrous lithium chloride (3.94 mmol) at 40 °C are dissolved with stirring in 4 Oml of absolute dimethyl sulfoxide and at this temperature is mixed with M-hydroxysuccinimide in a total amount of 453 mg (3.94 mmol) and with 980 mg (0.895 mmol) of the compound indicated in the title of example 19g, dissolved in 10 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 814 mg - (3.94 mmol) of M,M'-dicyclohexylcarbodiimide and stirred for 12 hours. at room temperature. "sl The obtained suspension is then mixed with a sufficient amount of acetone until the compound indicated above in the title is completely precipitated, the precipitate is separated by vacuum filtration, dried, dissolved in water, filtered through undissolved dicyclohexylurea, and the filtrate for desalting and for purification from

Ge) 20 low-molecular components are passed through the ultrafiltration membrane AMISOM IN UM-3 (limit

Their permeability: 300 OD) Finally, the retentate is lyophilized.

Yield: 1.32 g (69.19 from theory) in the form of a colorless lyophilisate.

H2O content (when using Karl Fischer's reagent): 7.65905.

Elemental analysis (in terms of anhydrous substance): 99 resolution: С 37.43 Н 4.45 M 9.12 Р 15.02 5 1.49 ba 14.63

HF) detected: C 37.42 H 4.50 M 9.18 P 15.07 5 1.51 sa 14.58 yuyu e) tert-Butyl ether 3-oxa-2H,2H.4H.4H,5H, 5H-perfluorotridecanoic acid 25.0 g (53.8 mmol) 1H,1H,2H,2H-perfluoro-1-decanol |supplied by I Apsavieg company| dissolved in 250 ml of absolute toluene and mixed at room temperature with a catalytic amount (approximately 0.75 g) of 60 tetra-n-butyl ammonium hydrosulfate. After that, at 02С, a total of 7.55 g (134.0 mmol, 2.5 equivalents based on the amount of the alcohol component used) of highly dispersed powdered potassium hydroxide is added, and then 15.73 g (80.0 mmol, 1.5 equivalents based on on the used amount of the alcohol component) of tert-butyl ether of bromoacetic acid and stir for another 2 hours. at 029C. b The reaction solution obtained in this way is stirred for 12 hours. at room temperature and then mixed with ethyl acetic acid in a total amount of 50 ml and with 250 ml of water for processing. The organic phase is separated and washed twice with water. After drying the organic phase over sodium sulfate, the salt is separated by vacuum filtration and the solvent is distilled off under vacuum. The obtained oily residue is purified on silica gel using ethyl acetic acid/hexane (1:10 ratio) as an eluent.

Yield: 26.3 g (84.695 from theory) of the compound indicated above in the title in the form of a colorless and highly viscous oil.

Elemental analysis: solution: С 33.23 Н 2.61 РЕ 55.85 70 detected: С 33.29 Н 2.61 Е 55.90 g) 3-oxa-2Н,2Н,4Н,4Н,5Н, 5H-perfluorotridecanecarboxylic acid 20.0 g (34.58 mmol) of the compound indicated in the title of example 19e is suspended at room temperature with stirring in 200 ml of a mixture consisting of methanol and 0.5 molar caustic sodium in a ratio of 271, and then heated to 602C. After conducting the reaction for 12 hours. at 60 "C, the transparent reaction mixture for its 75 processing is neutralized by mixing it with the cation exchange resin Atregiye IV 120 (H"-form), the ionite is removed by vacuum filtration, and the resulting methanol-water filtrate is distilled in a vacuum until a dry residue is obtained. The obtained amorphous the oily residue is purified on silica gel using ethyl acetate/n-hexane (1:3 ratio) as eluent.

Yield: 16.0 g (88.695 from theory) of the compound indicated above in the title in the form of a colorless and highly viscous oil.

Elemental analysis: solution: C 27.60 H 1.35 R 61.85 found: C 27.58 H 1.36 E 61.90

Example 20 Ge a) Methyl ether of b-benzyloxycarbonyl-2-I(I2-(M-ethyl-M-perfluorooctylsulfonyl)amino)acetyl-i-lysine o

Up to 8.0 g (24.4 mmol) of E-carbonyloxybenzyl ether hydrochloride! -lysine (supplied by the company

Vaspet), dissolved in a mixture of 150 ml of tetrahydrofuran, 15 ml of chloroform and 2.62 g (26.0 mmol) of triethylamine, 16.18 g (27.0 mmol) of 2-(M-ethyl-M-perfluorooctylsulfonyl) are added dropwise at 0 in a nitrogen atmosphere aminoacetic acid, obtained according to (OJEU 19603033), dissolved in "I 5Oml of tetrahydrofuran. After that, a total of 18.00 g (3b,bmmol) of EEDH with (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) are added in portions at 0 9C and left overnight for stirring at room temperature. After that, it is concentrated in a vacuum and the resulting oil was chromatographed on silica gel (eluent: so n-hexane/isopropanol in a ratio of 15:1) to give 17.0 g (79.695 of theory, based on the amount of primary amine used) of the title compound as a colorless oil.

Elemental analysis: - resolved: C 38.41 H 3.45 E 36.89 M 4.80 5 3.66 found: C 38.42 H 3.47 E 36.92 M 4.87 5 3.64 b) Methyl ether of 2-I(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|acetyl-l-lysine) 15.0 g (20.23 mmol) of the compound obtained in example 204 is dissolved in 200 ml of ethanol, mixed with 800 mg of Perlman's catalyst (2095 Pa on activated carbon) and hydrogenated until the calculated amount of hydrogen is absorbed. After that, the catalyst is removed by vacuum filtration, washed thoroughly with ethanol and concentrated to dryness under vacuum. In this way, the title compound is obtained in the form of a colorless oil." Output: 14.68 Pho vi her output: 14.68g (97.995 from theory)

Elemental analysis: solution: C 32.40 H 3.26 E 43.56 M 5.67 54.32 - found: C 32.42 H 3.27 E 43.60 M 5.67 5 4.34 sl c) Methyl ether 6-(1-0-A-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmannopyranose)-2-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|ac i95 ) ethyl-i-lysine bo 50 In 50 Oml of dry tetrahydrofuran dissolve 21.31 g (35.bmmol) of 1-carboxymethyloxy-2,3,4,6-tetra-O-benzyl-a-Y-mannopyranoside (obtained by the method described in the patent OE 19728954 SI), as well as 3.b0g (35.bmmol) of triethylamine. After cooling the reaction solution to a temperature in the range from -15 to -202C, at this temperature, a solution of 4.92g (35.bmmol) of isobutyl ether of chloroformic acid in 7bml of dry tetrahydrofuran is slowly added dropwise with stirring, while the rate of dropwise addition should be as follows , so that the internal temperature does not exceed

GF) -10207. After conducting the reaction for 15 min. at -1592C dropwise at -202C slowly add a solution of 26.39g (35.bmmol) of the compound specified in the title of example 206 and 3.bOg (35.bmmol) of triethylamine in 100ml of dry tetrahydrofuran. After carrying out the reaction for an hour at -15 C, and then for two hours at room temperature, the reaction solution is concentrated to dryness in a vacuum. The obtained residue is dissolved in 60 25 OMl of ethyl ether of acetic acid and washed twice with a saturated solution of sodium bicarbonate in portions of 10 OMl and once with water in a portion of 20 OMl.

After drying the organic phase over sodium sulfate, the salt is separated by vacuum filtration and the ethyl acetic acid is distilled off under vacuum. The obtained oily residue is purified on silica gel using ethyl acetic acid/n-hexane (in a ratio of 1:10) as an eluent. for Yield: 38.12 g (81.095 from theory) of the compound indicated above in the title in the form of a colorless and highly viscous oil.

Elemental analysis: solution: C 49.92 H 3.92 M 2.53 P 29.18 5 2.90 found: C 49.99 H 4.11 M 2.69 ER 29.22 5 3.01 g ) 6-(1-0-A-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmannopyranose)-2-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|ac ethyl-i - lysine 27.65g (20.92mmol) of the compound obtained in example 208 is dissolved in 250ml of methanol. Then a solution of 70.80g (100.0mmol) of sodium hydroxide in 1TOml of distilled water is added and stirred for 10 minutes at 50°C.

Control of the course of the reaction by thin-layer chromatography indicates already quantitative saponification of methyl ether. After that, the mixture is concentrated to dryness in a vacuum, the obtained residue is dissolved in 300 ml of ethyl acetic acid, and the organic phase is extracted twice with a dilute aqueous solution of citric acid in portions of 1700 ml. After drying over sodium sulfate, it is filtered and concentrated to dryness under vacuum. 75 The obtained residue is chromatographed on silica gel (eluent: n-hexane/chloroform/isopropanol in the ratio 15:10:11). In this way, 24.31 g (88.990 from theory) of the title compound are obtained in the form of a colorless and viscous oil.

Elemental analysis: solution: C 51.46 H 4.70 M 3.21 P 24.71 5 2.45 found: C 51.49 H 4.71 M 3.19 g 24.72 52.41 d). 6-(1-0-A-O-carbonylmethylmannopyranose)-2-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino)acetyl-y-lysine 20.0 g (15.30 mmol) of the compound indicated in the title of the example 20 g , dissolved in a mixture of 250 ml of 2-propanol and 2 B ml of water and mixed with 1.0 g of palladium catalyst (1096 Pa on activated carbon). After that, hydrogenate for 12 hours. at room temperature and pressure of hydrogen one atmosphere. Next, the catalyst

It is filtered and the filtrate is evaporated to dryness in a vacuum. The residue is dissolved in 200 ml of methanol and the reaction product is precipitated by mixing with diethyl ether in a total amount of 800 ml. After separation of the solid obtained in this way by vacuum filtration, it is dried in a vacuum at 5096.

Yield: 14.32 g (99.096 from theory) of amorphous solid.

Elemental analysis: "I solution: C 35.56 H 3.84 M 4.44 5 3.39 E 34.15 detected: C 35.58 H 3.81 M 4.45 5 3.40 E 34, 17 i-oi e) M-(2-hydroxyprop-3-yl-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacycl ododecan-10-yl)amide co 6-(1 -O-A-O-carbonylmethylmannopyranose)-2-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino)acetyl-i-lysine, a complex of 7.48 g (7.9 mmol) of the compound indicated in the title of the example 20 units at 40 C are dissolved in 500 ml of h-dimethylsulfoxide and 1.00 g (8.7 mmol) of M-hydroxysuccinimide is added. Then it is cooled to 202 C and 1.795 g (8.7 mmol) of dicyclohexylcarbodiimide is added. After that, it is stirred for an hour at 20 oC, and then for 4 hours at 402 C. Then, at this temperature, a solution of 4.53 g (7.91 mmol) of gadolinium complex 10-(2-hydroxy-3-aminopropyl)-4,7,10-tris( carboxymethyl)-1,4,7,10-tetraazacyclododecane (for the preparation, see p) with MO 97/020511) in 20 ml of dimethyl sulfoxide. The mixture is stirred for an hour at 402C, and then overnight at room temperature. The suspension obtained in this way is then mixed with a sufficient amount of acetone until the compound indicated above in the title is completely precipitated, the precipitate is separated by vacuum filtration, dried, dissolved in water, filtered undissolved dicyclohexylurea and the filtrate for desalination and for purification from low molecular weight components are passed through an ultrafiltration membrane AMISOM UM-3 (permeability limit: 3000Da). The retentate is finally lyophilized. c Yield: 9.71 g (81.790 from theory) in the form of a colorless lyophilisate.

H2O content (when using Karl Fischer's reagent): 3.970.

Mami Elemental analysis (in terms of anhydrous substance):

He») 50 resolution: C 35.16 H 4.16 M 7.45 E 21.48 sa 10.46 5 2.13 detected: C 35.17 H 4.20 M 7.42 E 21.49 ba 10.48 5 2.09 t» p 21 ryklad a) 6-M-(1-0O-A-O-(5-carbonyl)pentyl-2,3,4,6-tetra-O-benzylmannopyranose) methyl ether |-2M-(2-(M-ethyl-M-perfluorooctylsulfonyl) 25 amino)acetyl-y-lysine

HF) 5.23 g (8.0 mmol) of the 5-(carboxy)pentyl-2,3,4,6-tetra-O-benzyl-A-XO-mannopyranoside described in Example 1, and 1.9 g (8.0 mmol ) of 1-hydroxybenzotriazole and 2.6 g (8.0 mmol) of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU; the company Rebos and Itiied, Great Britain) are dissolved in 75 ml of DMF and stir for 15 minutes. This solution is then mixed with 5.1 bml (ZOmmol) of M-ethyldiisopropylamine 60 with 5.93 g (8.0 mmol) of the amine described in example 206 and stirred for 1.5 days at room temperature. For processing, the solvent is distilled off in a vacuum until a dry residue is obtained, which is then chromatographed on silica gel (eluent: dichloromethane/ethyl acetic acid in a ratio of 30:1; chromatography is carried out using a solvent gradient, continuously increasing the proportion of ethyl acetic acid). : 9.7Og (88.095 from theory) of the compound specified in the title in the form of a colorless and highly viscous oil.

Elemental analysis: solution: C 52.29 H 4.97 M 3.05 P 23.43 5 2.33 found: C 52.33 H 4.95 M 3.12 E 23.50 5 2.30 585 6-M-(1-O-A-O-(5-carbonyl)pentyl-2,3,4,6-tetra-O-benzylmannopyranose|-2M-(2-(M-ethyl-M-perfluorooctylsulfonyl) amino )acetyl-y-lysine 9.0 g (12.400 mmol) of the compound obtained in example 21a is dissolved in 150 ml of methanol. Next, a solution of 2.48 g (62.00 mmol) of sodium hydroxide in 1 bml of distilled water is added and stirred for 1 hour at 50 260. 70 Control of the course of the reaction by thin-layer chromatography already indicates quantitative saponification of the methyl ether after the end of the above reaction time. Then the mixture is concentrated to dryness in a vacuum, the resulting residue is dissolved in 300 ml of ethyl acetic acid and the organic phase is extracted twice with a dilute aqueous solution of citric acid in portions of 100 ml After drying over sodium sulfate, it is filtered and concentrated to dryness under vacuum. The resulting residue is chromatographed on silica gel (eluent: 75 n-texane/chloroform/isopropanol in the ratio nni 25:10:11). In this way, 15.88 g (93.995 from theory) of the title compound are obtained in the form of a colorless and highly viscous oil.

Elemental analysis: solution: C 51.95 H 4.88 M 3.08 P 23.67 5 2.35 found: C 51.99 H 4.91 M 3.09 P 23.70 5 2.33 20 c) 6-M-(1-0O-A-0-(5-carbonyl)pentylmannopyranose|-2M-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|acetyl-y-lysine 13.0g (9, 52 mmol) of the compound indicated in the title of example 216 is dissolved in a mixture of 150 ml of 2-propanol and 25 ml of water and 1.0 g of palladium catalyst (1095 Pa on activated carbon) is added. After that, it is hydrogenated for 12 hours at a hydrogen pressure of 1 atmosphere and at room temperature. After that, the catalyst is filtered off with 25 1, the filtrate is evaporated to dryness in a vacuum. The resulting residue is chromatographed on silica gel (eluent: n-hexane/chloroform/isopropanol in the ratio 15:10:11). In this way, 9.09 g (95.195 from theory) are obtained about the compound indicated in the title in the form of a colorless and highly viscous oil.

Elemental analysis: solution: C 37.10 H 4.22 M 4.19 R 32.18 5 3.10 "I 30 detected: C 37.09 H 4.21 M 4.19 R 32.20 5 3 ,13 g) M-(2-hydroxyprop-3-yl-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-10-yl)amide o 6-M-(1- O-A-0-(5-carbonyl)pentylmannopyranose|-2M-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|acetyl-lysine-lysine, so sa-complex 7.93 g (7.9 mmol) of the compound, indicated in the title of example 21c, is dissolved at 40°C in 75 ml of dimethyl sulfoxide and mixed with 1.00 g (8.70 mol) of M-hydroxysuccinimide. Then it is cooled to room temperature and a total of 1.795 g (8.7 mmol) of dicyclohexylcarbodiimide is added After that, it is stirred for an hour at 202C, and then for 4 hours at 402C. To this solution of the activated complex ester of the compound indicated in the title of example 21c, then at 402 for 1 hour, a solution of 4.53 g " (7.9 mmol) is added dropwise gadolinium complex 40 .10-(2-hydroxy-3-aminopropyl)-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (see preparation in - with MO 97/020511) in 20 ml of dimethyl sulfoxide. The mixture is stirred for one hour at 402C, and then overnight at room temperature. The suspension obtained in this way is then mixed with a sufficient amount of the mixture » acetone/2-propanol (in a ratio of 2:1) until the compound indicated above in the title is completely precipitated, the precipitate is separated by vacuum filtration, after which it is washed with ethyl acetic acid, dried, dissolved in water, dicyclohexylurea, which has not dissolved, is filtered, and the filtrate for desalting and for purification from low-molecular components is passed through an ultrafiltration membrane AMISOM 9 s "UM-3 (limit permeability: 300ODa). The retentate is finally lyophilized.

Yield: 9.71 g (78.89 from theory) in the form of a colorless lyophilisate. o H2O content (when using Karl Fischer's reagent): 6.6590. b 20 Elemental analysis (in terms of anhydrous substance): solution: С 36.97 Н 4.52 М 7.19 Е 20.71 са 10.08 5 2.06 из» detect.: С 37.02 Н 4 .50 M 7.22 E 20.69 ba 10.08 5 2.09

Example 22 a) P1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-14-I(2,3-bis(M,M-bis(tert-butyloxycarbonylmethyl)amino)propyl|phenyl)-3-oxapropionyl-2 -M-(1-A-YUO-carbonylmeth

Gee! ilmanopyranose)-I-lysine 5.25 g (7.72 mmol) tetra-tert-butyl ether 1-(4-carboxymethoxybenzyl)-EDTC | see patent 05 4622420) and where 781 mg (7.72 mmol) of triethylamine is dissolved in 50 ml of methylene chloride. Then for 5 min. at -1529C, a solution of 1.1 mg (8.5 mmol) of isobutyl ether of chloroformic acid in 17 Oml of methyl chloride is added dropwise and 60 is stirred for another 20 minutes. at -152C. After that, the solution is cooled to -252C, during ЗОхв. a solution of 7.07 g (7.72 mmol) of the compound specified in the title of Example 1 and 2.12 g (21.0 mmol) of triethylamine in 7 Oml of tetrahydrofuran is added dropwise and then stirred for another 30 minutes. at -152C, and then overnight at room temperature. For processing, the solvent is distilled off in a vacuum and the obtained oily residue is dissolved in 250 ml of chloroform. The chloroform phase is extracted twice with a 1096-g aqueous solution of ammonium chloride in portions of 10 Oml, the organic phase is dried over magnesium sulfate and evaporated to dryness in a vacuum. The residue is chromatographed on silica gel (eluent: methylene chloride/ethanol in a ratio of 20:1).

Yield: 9.6Og (79.095 from theory) of colorless and highly viscous oil.

Elemental analysis: solution: C 46.39 H 5.55 M 5.32 ER 20.45 5 2.03 found: C 46.42 H 5.51 M 5.29 E 20.49 52.09 b) (1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-14-I(I2,3-bis(M,M-bis(carboxymethyl)amino)propyl|phenyl)-3-oxapropionyl-2-M-(1 -А-О-carbonylmethylmannopyranose a)-I-lysine 70 9.0 g (5.7 mol) of the compound obtained in example 22a is dissolved in 150 ml of methanol. Next, a solution of 4.0 g (100 mol) of sodium hydroxide in 25 ml of distilled water is added and mixed for two hours at 602°C. Control of the course of the reaction by thin-layer chromatography indicates already quantitative saponification of tetra-tert-butyl ether after the end of the above reaction time. After that, the mixture is concentrated to dryness in a vacuum, the resulting residue is dissolved under warm conditions in 500 ml of dimethyl sulfoxide and then mixed with a sufficient amount of 75% of a mixture of acetone and ethyl acetic acid (in a ratio of 1:1) until the compound indicated above in the title is completely precipitated, after which the precipitate obtained in this way is separated by vacuum - by filtration, thoroughly washed with acetic acid ethyl ether, dried, dissolved in water, the pH value of the solution containing the product is set to 3.5 with the help of 1-molar hydrochloric acid, the possibly present insoluble components and the filtrate are filtered for desalination and for cleaning from low-molecular components are passed through the ultrafiltration membrane AMISOM UM-3 (limit permeability: З000Da). Finally, the retentate is lyophilized.

Yield: 6.76 g (87.690 from theory) in the form of a colorless lyophilisate.

H2O content (when using Karl Fischer's reagent): 3,300.

Elemental analysis (in terms of anhydrous substance): He solution: C 39.89 N 4.09 M 6.20 ER 23.84 5 2.37 o detection: C 39.92 N 4.15 M 6.22 ER 23.92 52.29 c) (1-4-perfluorooctylsulfonyl)piperazine|amide 6-M-14-I(I2,3-bis(M,M-bis(carboxylatomethyl)amino)propyl|phenyl)-Z- oxapropionyl-2-M-(1-A-O-carbonylmethylmannopyranose)-I -lysine, Mp-complex, disodium salt part;E

C,Og (2.22 mmol) of the compound specified in the title of example 226 is dissolved at boiling temperature in 150 ml of a mixture of water and ethanol (in a ratio of 3:1) and mixed with 0.25 g (2.22 mmol) of manganese carbonate in 809 portions !) After that, the reaction solution obtained in this way for 5 hours. boil with reverse Ge) refrigerator. After cooling to room temperature, the mixture of solvents is completely distilled off in a vacuum, and the resulting residue is dissolved in a mixture of 200 ml of distilled water and n-butanol (in a ratio of 1:1). Further, the pH value with intensive mixing is set to 7.2 by mixing with In. caustic sodium. After - complete distillation of n-butanol in a vacuum, the remaining aqueous phase is passed through an ultrafiltration membrane AMISOM U UM-3 (limit permeability: 300ODa) for desalination and for purification from low molecular weight components. Finally, the retentate is lyophilized. "

Yield: 3.19 g (99.095 from theory) in the form of a colorless lyophilizate.

H2O content (when using Karl Fischer's reagent): 5.0890. o, c Elemental analysis (in terms of anhydrous substance): "» resolution: C 37.23 H 3.54 E 22.25 Mp 3.78 M 5.79 Ma 3.17 5 2.21 " detection: C 37.30 H 3.49 E 22.29 Mp 3.81 M 5.76 Ma 3.19 5 2.18

Example 23 a) 1-(4-perfluorooctylsulfonyl)piperazine|monoamide of 3-benzyloxycarbonylaminoglutaric acid - Stirred solution of 25.0 g (94.9 mmol) of 3-M-(benzyloxycarbonyl)glutaric acid anhydride | synthesis according to Naiapak Mipoga, Matatoiyu Mmy- ispi, Miya Naidite, Izpitagi Tozpiuazy, TEG EAM; Teigapedhop Gay, EM, 22, 39 (1981), p. 3883-3886 in 150 ml of absolute tetrahydrofuran, while stirring, is mixed dropwise with a solution of 53.97 g (95.00 mmol) of 1-perfluorooctylsulfonylpiperazine in 15 ml of tetrahydrofuran and the obtained

FO 20 in this way reaction solution for 12 hours. boil under reflux. After cooling to room temperature, it is concentrated to dryness and the resulting oily residue is purified on silica gel with dichloromethane/2-propanol (20:1 ratio) as eluent.

Yield: 75.80 g (96.095 from theory) of the compound indicated above in the title in the form of a colorless and viscous oil.

Elemental analysis: solution: C 36.11 H 2.67 M 5.05 5 3.86 E 38.84

Gee! found: C 36.12 H 2.61 M 5.08 5 3.88 E 38.82 b) (1-(4-perfluorooctylsulfonyl)piperazine|monoamide of 3-aminoglutaric acid) and 31.50g (37.8v8mmol) of the obtained in accordance with example 236, the compound is dissolved in ZOO ml of ethanol, mixed with 2.5 g of Perlman's catalyst (20906 Ra/s) and hydrogenated until quantitative absorption of hydrogen at a hydrogen pressure of 1 60 atmospheres.

After that, the catalyst is removed by vacuum filtration, washed with ethanol and concentrated to dryness under vacuum. In this way, the title compound is obtained in the form of a pale yellow viscous oil.

Yield: 25.22g (95.590 from theory).

Elemental analysis: 65 resolution: C 29.28 H 2.31 M 6.03 5 4.06 E 46.31 detection: C 29.32 H 2.29 M 6.08 5 4.08 E 46.28 in). (1-«4-perfluorooctylsulfonyl)piperazine|3-M-(1-A-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmannopyranose)glutaric acid monoamide 21.52g (18.9bmmol) 1- Carboxymethyloxy-2,3,4,6-tetra-O-benzyl-A-Y-mannopyranoside (obtained according to the method described in patent OE 19728954 SI| is dissolved at room temperature in 100 ml of absolute dimethylformamide and at 09 is mixed with 2.56 g ( 22.2 mmol) of M-hydroxysuccinimide, and then with 4.55 g (22.2 mmol) of dicyclohexylcarbodiimide. After carrying out the reaction for 1 h at 0 9 C and for 1 h at 222: dicyclohexylurea, which did not dissolve, is filtered off and the clear solution obtained in this way of the activated ether of the above title compound at 092 is slowly added dropwise to the mixed 70 solution of 13.22 g (18.9 mmol) of the compound from Example 236 in 100 ml of dimethylformamide. After the reaction has been carried out for 12 hours at room temperature, the solvent is distilled off under vacuum and the resulting residue is dissolved in

ZOO ml of acetic acid ethyl ether, after which the urea is filtered off and the organic filtrate is washed twice with a saturated solution of sodium bicarbonate in portions of 1000 ml, once with 100 ml of a 1095% aqueous solution of citric acid and once with 200 ml of water. After drying the organic phase over sodium sulfate 75, the salt is separated by vacuum filtration and the ethyl acetic acid is distilled off under vacuum.

The resulting oily residue is purified on silica gel using ethyl acetic acid/n-hexane (in a ratio of 1:15) as an eluent.

Yield: 21.39 g (88.395 from theory) of the compound indicated above in the title in the form of a colorless and highly viscous oil.

Elemental analysis: solution: C 49.81 H 4.10 M 3.29 P 25.27 5 2.51 found: C 49.89 H 4.11 M 3.32 ER 25.22 52.51 g) (1-«4-perfluorooctylsulfonyl)piperazine|monoamide of 3-M-(1-A-O-carbonylmethylmannopyranose)glutaric acid Ge! 19.55 g (15.30 mmol) of the compound specified in the title of example 23c is dissolved in a mixture of 250 ml of 2-propanol and 25 ml of water and mixed with 1.5 g of palladium catalyst (1096 Ra on activated carbon). After that, hydrogenate for 12 hours. at room temperature and pressure of hydrogen one atmosphere. Then the catalyst is filtered off and the filtrate is evaporated to dryness under vacuum. The residue is dissolved in 200 ml of methanol and the reaction product is precipitated by mixing with diethyl ether in a total amount of 800 ml. After the separation of the solid obtained in this way by vacuum filtration, it is dried in a vacuum at 4026.

Yield: 17.49 g (97.590 from theory) of amorphous solid.

Elemental analysis: solution: C 32.73 H 3.08 M 4.58 5 3.49 E 35.20 and found: C 32.68 H 3.15 M 4.55 5 3.50 E 35, 17 d). 3-M-(1-A-O-carbonylmethylmannopyranose)glutaric acid-(1-(4-perfluorooctylsulfonyl)piperazine|amide-5-M-2-hydroxyprop-3-yl-I(1,4,7-tris (carboxylatomethyl)-1, 4,7,10-tetraazacyclododecan-10-yl|) amide, a complex of 14.43 g (15.64 mmol) of the compound indicated in the title of example 23 gH and 0.67 g of anhydrous lithium chloride « (15.864 mmol) at 402С are dissolved with stirring in 100 ml of absolute dimethyl sulfoxide and at this temperature are mixed with M-hydroxysuccinimide in a total amount of 1.82 g (15.84 mmol) and with a solution of 9.08 g t s (15.84 mmol) of gadolinium complex h 10-(2 -hydroxy-3-aminopropyl)-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (see preparation in

MO 97/02051) in 3 ml of dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 3.27 g (15.84 mmol) of M,M'-dicyclohexylcarbodiimide and stirred for 12 hours. at room temperature. The resulting suspension is then mixed with a sufficient amount of acetone until the above-mentioned compound is completely precipitated, the precipitate is separated by vacuum filtration, dried, dissolved in water, the remaining dicyclohexylurea, which has not dissolved, and the filtrate for desalting and simultaneous purification from low molecular weight components are filtered off. which may still be present in it, are subjected to ultrafiltration through an ultrafiltration membrane AMISOM UM-3 (limit permeability: З000Da) Retentate at the end

Fu 20 is lyophilized.

Yield: 18.71 g (80.2905 from theory) in the form of a colorless lyophilisate.

T» H2O content (when using Karl Fischer's reagent): 4.870.

Elemental analysis (in terms of anhydrous substance): solution: C 34.24 N 3.83 M 7.61 E 21.92 5 2.18 ba 10.67 found: C 34.26 N 3.79 M 7 ,58 E 21.87 5 2.18 ba 10.68

HF) Example 24 a) 1,7-bis(benzyloxycarbonyl)-4-yl3-oxapentane-1,5-dicarboxylic acid-1-oyl-5-(1--4-perfluorooctylsulfonyl)piperazinamide)-10-(2 ,6-M,M'-bis(1-0O-A-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmannopyranose)|-I -lysyl-1,4,7,10-tetraazacyclododecane 6o To a solution of 27.0 g (24.4 mmol) of the secondary amine obtained in example 1542 in a mixture of 150 ml of tetrahydrofuran and ml of chloroform at 02С in a nitrogen atmosphere, add 33.04 g (25.00 mmol) of the compound indicated in the title of example 18c, dissolved in 250 ml of tetrahydrofuran After that, a total of 18.0 g (36.bmmol) of EEDH (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) are added in portions at 09C and left overnight for stirring at room temperature. Then the mixture is concentrated to dryness in a vacuum and the obtained oil is chromatographed on 62 silica gel (eluent: n-hexane/isopropanol in the ratio 25:11). In this way, 45.87 g (78.095 from theory, in terms of the amount of secondary amine used) of the title compound are obtained in the form of coloring oil

Elemental analysis: solution: C 59.30 H 5.39 E 13.40 M 4.65 5 1.33 found: C 59.32 H 5.37 E 13.37 M 4.70 5 1.34 b ) 1--3-oxapentane-1,5-dicarboxylic acid-1-oyl-5-(1--4-perfluorooctylsulfonyl)teraziniamide)-7-(2,6-M,M'-bis(1-0O- A-O-carbonylmethylmannopyranose)I-I-lysyl-1,4,7,10-tetraazaschudodecane 70 24.1 g (10.0 mmol) of the compound obtained in example 24a and indicated in its title is dissolved in 250 ml of ethanol and mixed with 1, 4 g of Perlman's catalyst (2096 Ra/C). After that, hydrogenation is carried out until the quantitative absorption of hydrogen, after which the catalyst is removed by vacuum filtration, washed thoroughly with ethanol and concentrated to dryness under vacuum. The product is obtained as a highly viscous yellow oil.

Yield: 12.80g (90.190 from theory).

Elemental analysis: solution: C 39.72 H 4.89 P 22.73 M 7.88 5 2.26 found: C 39.72 H 4.87 E 22.77 M 7.90 5 2.24 ) 1-43-oxapentane-1,5-dicarboxylic acid-1-oyl-5-(1--4-perfluorooctylsulfonyl)piperazinamide)-7-(2,6-M,M'-bis(1-0O-A -O-carbonylmethylmannopyranose a)|-I-lysyl-4,10-bis(1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-ylpentanoyl)|- 1,4,7,10-tetraazac cyclododecane, digadolinium-complex 5.54 g (8.6 mmol, 2.2 molar equivalents in terms of the amount of the used amine component from example 246) described |in application OE 19728954 SI| in example Ж1й ba -complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.37 g of sodium chloride (8.mmol ) of anhydrous lithium chloride at 40 C is dissolved with stirring in bOml of absolute dimethyl sulfoxide and at this temperature is mixed with M-hydroxysuccinimide in a total amount of 1.01 g (8.8 mmol) and with 5.68 g (4.0 mmol) of the compound indicated in the title of example 246 , dissolved in 40 ml of absolute g about dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 1.82 g (8.mmol) of M,M'-dicyclohexylcarbodiimide and stirred for 12 hours. at room temperature. The obtained "I" suspension is then mixed with a sufficient amount of acetone until the compound specified above in the title is completely precipitated, the precipitate is separated by vacuum filtration, dried, dissolved in water, filtered through undissolved dicyclohexylurea, and the filtrate is used for desalting and for cleaning from low molecular weight components pass through an ultrafiltration membrane AMISOM U UM-3 (limit permeability: 300 ODa). The retentate is finally lyophilized. at

Yield: 8.52 g (80.695 from theory; in terms of the amount of diamine component used) in the form of a colorless lyophilizate.

H2O content (when using Karl Fischer's reagent): 6.0990.

Elemental analysis (in terms of anhydrous substance): " solution: C 38.61 N 4.76 M 9.53 E 12.21 sa 11.89 5 1.12 detected: C 38.57 N 4.82 M 9.52 E 12.21 ba 11.93 5 1.15 - s Example 25 c a) 1,7-bis(benzyloxycarbonyl)-4-і3-oxapentane-1,5-dicarboxylic acid-1-oyl- 5-(1--4-perfluorooctylsulfonyl)piperazinamide)-10-(2,6-M,M'-bis(1-0O-A-O-(5-carbonyl)pentyl-2,3,4, b- tetra-O-benzylmannopyranose))-I -lysyl-1,4,7,10-tetraazacyclododecane

To a solution of 27.0 g (24.4 mmol) of the secondary amine obtained in Example 1542 in a mixture of 150 ml of tetrahydrofuran - I and 1 B ml of chloroform at 02С in a nitrogen atmosphere, add 35.80 g (25.0 mmol) of the compound indicated in the title of Example 17d, sl, dissolved in 250 ml of tetrahydrofuran. After that, a total of 18.0 g (36.bmmol) of EEDH (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) is added in portions at 09C and left overnight for stirring at 95°C at room temperature. Then the mixture is concentrated to dryness in a vacuum and the resulting oil is chromatographed on bo 50 silica gel (eluent: n-hexane/isopropanol in the ratio 20:11). In this way, 49.48 g (80.495 from theory, calculated on the amount of secondary amine used) of the title compound in the form of a colorless oil are obtained.

Elemental analysis: solution: C 60.47 H 5.79 E 12.80 M 4.44 5 1.27 found: C 60.52 H 5.77 E 12.77 M 4.50 5 1.30 o b) 1--3-oxapentane-1,5-dicarboxylic acid-1-oyl-5-(1--4-perfluorooctylsulfonyl)piperazinamide)-7-(2,6-H,M'-bis(1-0О -А-О-(5-carbonyl)pentylmanopyrimone)|-I-lysyl-1,4,7,10-tetraazacyclododecane 25.2 g (10.0 mmol) of the compound obtained in example 25a and specified in its title is dissolved in 250 ml of ethanol and mix with 1.8 g of Perlman's catalyst (2096 Pa/C). After that, it is hydrogenated until the quantitative absorption of hydrogen, after which the catalyst is removed by vacuum filtration, thoroughly washed with ethanol and concentrated to dryness under vacuum. The product is obtained in the form of a highly viscous yellow oil.

Yield: 14.11g (92.590 from theory).

Elemental analysis: 65 resolution: C 49.60 H 7.20 RE 21.17 M 7.34 5 2.10 detection: C 49.62 H 7.17 E 21.20 M 7.30 5 2.14 -B4-

c) 1-43-oxapentane-1,5-dicarboxylic acid-1-oyl-5-(1--4-perfluorooctylsulfonyl)piperazinamide)-7-(2,6-M,M'-bis(1-0O- А-О-(5-carbonyl)pentylmanopyranose)|-I -lysyl-4,10-bisI1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5- ylpentanoyl)|-1,4,7,10-tetraa

Zacyclododecane, digadolinium complex 5.54 g (8.6 mmol, 2.2 molar equivalents in terms of the amount of the used amine component from example 256) described |in the application OE 19728954 SI| in example 31 (a complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (and 0.37 g (8.mmol) of anhydrous lithium chloride at 40 9C is dissolved with stirring in bOml of absolute 7/0 dimethylsulfoxide and at this temperature is mixed with M-hydroxysuccinimide in a total amount of 1.01g (8.8mmol) and with 6.10g (4.0mmol) of the compound specified in the title of Example 256, dissolved in 40 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 1.82 g (8.mmol) of M,M'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension is then mixed with with a sufficient amount of acetone until the compound specified above in title 75 is completely precipitated, the precipitate is separated by vacuum filtration, dried, dissolved in water, the undissolved dicyclohexylurea is filtered off, and the filtrate for desalting and for purification from low molecular weight components is passed through an ultrafiltration membrane AMISOM U UM-3 (limit permeability: 300ODa) The retentate is lyophilized at the end.

Yield: 9.2 bg (84.095 from theory; in terms of the amount of diamine component used) in the form of a colorless lyophilizate.

H2O content (when using Karl Fischer's reagent): 5.8990.

Elemental analysis (in terms of anhydrous substance): solution: C 40.52 N 5.16 M 9.15 E 11.72 ba 11.41 5 1.16 found: C 40.57 N 5.20 M 9, 12 E 11.69 s 11.43 5 1.18 s

Example 26 o a) (1-(4-perfluorooctylsulfonyl)piperazinamide 6-M-tert-butyloxycarbonyl-2-M-benzyloxycarbonyl-i-lysine 19.02g (50.Omol). A-M-(benzyloxycarbonyl)-E- M'-(tert-butyloxycarbonyl)-I-lysine (supplied by the company

Vaspet) is dissolved in 1500 ml of absolute tetrahydrofuran. Then, at 0 9C, add 8.31 g (50.0 mmol) of carbonyldimidazole and 5.03 g (50.00 mmol) of triethylamine, dissolved in 7 bml of dry Ж tetrahydrofuran, dropwise, and for 10 minutes. stirred at this temperature. Then, at 092C, a solution of 48.42 g (50.00 mmol) of perfluorooctylsulfonylpiperazine and 5.03 g (50.00 mmol) of triethylamine in 250 ml of dry tetrahydrofuran is added dropwise. After stirring overnight, the tetrahydrofuran was distilled off in vacuo and the resulting oil was chromatographed on silica gel (eluent: n-hexane/isopropanol in the ratio 15:11). In this way, 49.48 g (80.495 from theory, in terms of the amount of secondary amine used) of the title compound in the form of a colorless oil are obtained. and -

Elemental analysis (in terms of anhydrous substance): solution: C 40.01 H 3.79 M 6.02 E 34.70 5 3.45 found: C 40.07 H 3.82 M 6.02 E 34 .67 5 3.48 « b) (1-4-perfluorooctylsulfonyl)piperazinamide of 6-M-tert-butyloxycarbonyl-i-lysine

30.0 g (32.2 mmol) of the compound indicated in the title of example 2ba is dissolved in 300 ml of isopropanol and mixed with 1.5 g of Perlman's catalyst (2095 palladium hydroxide on carbon). After that, hydrogenate for 10 hours. at m room temperature, while monitoring the course of the reaction by thin-layer chromatography already indicates quantitative hydrogenolytic cleavage of the benzyloxycarbonyl protecting group after the end of the above-mentioned reaction time. Then the catalyst is filtered off and the filtrate is concentrated to dryness under vacuum. Received balance

Chromatography on silica gel (eluent: n-hexane/isopropanol in a ratio of 25:1). In this way, 25.13 g (98.095 from theory) of the title compound are obtained in the form of a colorless oil. sl Elemental analysis: solution: C 34.68 H 3.67 E 40.55 M 7.03 5 4.03 (95) found: C 34.72 H 3.70 E 40.60 M 7.01 5 3.98 bo 50 c) (1-4-perfluorooctylsulfonyl)piperazine|amide 6-M-tert-butyloxycarbonyl-2-M-(1-5-A-0-(2-carbonyl)ethyl-2,3,4 ,6-tetra-O-acetyl mannopyranose|-I-lysine and» 15.53 g (35.6 mols) 3-(2,3,4,6-tetra-O-acetyl-1-thio-A-ХО- mannopyranosyl)propionic acid (obtained according to 9. Naepwieg et al., Viosopishdae Spet. 4 (1993), p. 855; SPirozhsheKu 5. and Yee U.S., BZupipeviv oi 1-(pio-aidovides, Sagropudgaie Kezeagsp 31 (1973) ), p.339-346), as well as 3,bOg (35.6 b0mmol) of triethylamine are dissolved in 30 ml of dry tetrahydrofuran. After cooling the reaction solution to a temperature in the range of -15 to -202C at this temperature dropwise with slow stirring add a solution of 4.92 g (35.600 mmol) of isobutyl ether of chloroformic acid in 75 ml of dry tetrahydrofuran, while the rate of dropwise addition should be such that the internal temperature does not exceed -102C. carrying out the reaction within 15 minutes. at -159C dropwise at 209C slowly add a solution of 28.35g (35.60mmol) of the compound indicated in the title of Example 226 and 3.6b0g (35.6bmmol) of triethylamine in 200ml of dry tetrahydrofuran. After carrying out the reaction for one hour at -15 C, and then for two hours at room temperature, the reaction solution is concentrated to dryness in a vacuum. The obtained residue is dissolved in 250 ml of ethyl acetic acid and washed twice with a saturated solution of sodium bicarbonate in portions of 100 ml and once with water in a portion of 20 ml. After drying the organic phase over sodium sulfate, the salt is separated by vacuum filtration and the ethyl ether of acetic acid is distilled off in a vacuum. The obtained oily residue is chromatographed on silica gel using ethyl acetic acid/n-hexane (1:25 ratio) as an eluent.

Yield: 34.21 g (79.195 from theory) of the compound indicated above in the title in the form of a colorless and highly viscous oil.

Elemental analysis: solution: C 39.54 H 4.23 M 4.61 P 26.58 5 5.28 found: C 39.49 H 4.21 M 4.59 P 26.52 5 5.31 g ) P1-(4-perfluorooctylsulfonyl)piperazine|amide 70 6-M-tert-butyloxycarbonyl-2-M-(1-5-A-0-(2-carbonyl)ethylmannopyranose|-I-lysine 29.93g (24, 64 mmol) of the compound indicated in the title of example 2bv is suspended in 400 ml of absolute methanol and mixed with a catalytic amount of sodium methanolate at 593. After carrying out the reaction for

According to at room temperature, control of the course of the reaction by thin-layer chromatography (eluent: chloroform/methanol in the ratio 9:11) indicates an already quantitative transformation. For processing, the clear 75 reaction solution is neutralized by mixing it with the cation exchange resin Atregije U|B 120 (H"-form), the ionite is removed by vacuum filtration, and the methanol filtrate obtained in this way is distilled off in a vacuum until a dry residue is obtained. The resulting amorphous residue is purified by chromatography on silica gel with using 2-propanol/ethyl acetic acid/n-hexane (in a 1:1:15 ratio) as an eluent.

Yield: 23.42 g (90.89 from theory) of colorless viscous oil.

Elemental analysis: solution: C 36.72 H 4.14 M 5.35 P 30.85 5 6.13 found: C 36.69 H 4.11 M 5.35 E 30.82 5 6.11 d ) (1-«(4-perfluorooctylsulfonyl)piperazinamide 2-M-(11-5-A-0-(2-carbonyl)ethylmannopyranose|-I-lysine 20.93 g (20.00 mmol) of the compound specified in the title of example 2b at 09C is dissolved under vigorous stirring in a mixture of 100 ml of trifluoroacetic acid and 100 ml of dichloromethane and stirred for 1 hour at (5) this temperature. After that, the mixture is evaporated to dryness under vacuum and the residue is dissolved in 150 ml of water. The pH value of this aqueous solution, which contains the product , set to 9.5, adding 2-molar aqueous caustic sodium drop by drop. Next, the aqueous solution containing the product is subjected to ultrafiltration through the AMISOM UM-3 ultrafiltration "I membrane" for desalination and simultaneous purification from possible low-molecular components still present in it (limiting permeability: C3000Da). Finally, the retentate is lyophilized

Yield: 17.79 g (942965 from theory) of free amine in the form of a colorless lyophilizate.

H2O content (when using Karl Fischer's reagent): 3.0990. at

Elemental analysis (in terms of anhydrous substance): solution: С 34.26 Н 3.73 М 5.92 Е 34.12 5 6.77 found.: С 34.26 Н 3.79 М 5.88 Е 34.07 5 6.80 - e) P1-(4-perfluorooctylsulfonyl)piperazine|amide 2-M-(11-8-A-0-(2-carbonyl)ethylmannopyranose|-6--(1,4,7 -tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-ylpentanoyl)-1,4,7,10-tetraazacyclododecane-I-lysine, gadolinium complex « 5.54 g (8, 6 mmol, 2.2 molar equivalents in terms of the amount of the used amine component from example 2bd) described |in the application OE 19728954 SI| in example 31 of the ba-complex ts 10-(4-carboxy-1-methyl-2-oxo-3 -azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (and 0.37 g of anhydrous lithium chloride (8.8 mmol) at 40 C are dissolved with stirring in bOml of absolute dimethyl sulfoxide and at at this temperature, it is mixed with M-hydroxysuccinimide in a total amount of 1.01 g (8.mmol) and with 3.78 g (4.0 mmol) of the compound specified in the title of example 2bd, dissolved in 40 ml of absolute dimethyl sulfoxide . After cooling to room temperature, the reaction solution is mixed with 1.82 g - (8.mmol) M,M'-dicyclohexylcarbodiimide and stirred for 12 hours. at room temperature. The resulting suspension is then mixed with a sufficient amount of acetone until the compound indicated above in the title is completely precipitated, the precipitate is separated by vacuum filtration, dissolved in water, dicyclohexylurea, which has not dissolved, is filtered off, and the filtrate is used for desalting and for cleaning from low molecular weight components

Gee! 20 is passed through an ultrafiltration membrane AMISOM UM-3 (permeability limit: 3000Da). The retentate is finally lyophilized.

T» Yield: 5.17 g (83.095 from theory) in the form of a colorless lyophilisate.

H2O content (when using Karl Fischer's reagent): 4.4390.

Elemental analysis (in terms of anhydrous substance): 25 solutions: С 35.45 Н 4.07 М 8.09 Е 20.72 са 10.09 5 4.11

HF) detected: C 35.50 N 4.01 M 8.12 E 20.68 Ca 10.13 5 4.14

Example 27 o a) P1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-benzyloxycarbonyl-2-M-(1-0-8-O-carbonylmethyl-2,3,4,6-tetra-O-benzylglucopyranose) -I -lysine 60 8.02g (13.4mmol) of the compound specified in the title of the described |in the application OE 19728954 SI| of example 4ba (1-carboxymethyloxy-2,3,4,6-tetra-O-benzyl-B-ХО-glucopyranoside) and 3.24 g (28.14 mmol) of M-hydroxysuccinimide are dissolved in 100 ml of dimethylformamide and mixed at 09С in portions with M with ,M'-dicyclohexylcarbodiimide in a total amount of 5.80g (28.14mmol). Then it is stirred for 10 minutes at this temperature. To the solution of the activated complex ether obtained in this way, a solution of 11.13g (13.4mmol) of the specified in the title of the example, the compound was dissolved in 10 ml of dimethylformamide, and stirred -58v-

within 2 hours at 0 9C, and then for 12 hours. at room temperature. To process the precipitated dicyclohexylurea, it is filtered and then the solvent is distilled off to obtain a dry residue. The residue obtained in this way is then chromatographed on silica gel (eluent: dichloromethane/ethanol

In the ratio of 20:11; chromatography is performed using a solvent gradient, continuously increasing the proportion of ethanol).

Yield: 12.67 g (67.09 from theory) of the title compound in the form of a colorless and highly viscous oil.

Elemental analysis: solution: C 52.77 H 4.50 M 3.97 R 22.89 5 2.27 70 found: C 52.75 H 4.61 M 3.98 R 22.94 5 2.26 b) (1-4-perfluorooctylsulfonyl)piperazinamide. 2-M-(1-0-8-YOO-carbonylmethylglucopyranose)-I-lysine 11.52 g (8.17 mmol) of the compound obtained in example 27a is dissolved in 1000 ml of ethanol, mixed with 0.5 g of Perlman's catalyst (2090 Ra/ cС) and hydrogenated at room temperature in a hydrogen atmosphere (Tatm.) until hydrogen absorption stops. After that, the catalyst is removed by vacuum filtration, thoroughly washed 7/5 with ethanol (three portions of approximately 40 ml each) and concentrated to dryness under vacuum. In this way, the compound specified in the title is obtained in the form of a highly viscous and colorless oil.

Yield: 7.36 bg (98.495 from theory).

Elemental analysis: solution: C 34.07 H 3.63 M 6.11 E 35.24 5 3.50 found: C 34.11 H 3.59 M 6.08 E 35.23 5 3.52 ) (1-4-perfluorooctylsulfonyl)piperazine|amide 2-M4-(1-0-8-O-carbonylmethylglucopyranose)-6-M-I|1,4,7-tris(carboxylatomethyl)-10-(aza-4 -oxo-5-methyl-5-ylpenta noyl)-1,4,7,10-tetraazacyclododecani|-I -lysine, Ca-complex 9.98 g (15.84 mmol, 2.2 molar equivalents in terms of the amount of used amine with

The component from example 276) described |in the application OE 19728954 SI| in example Zp of the ba-complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (and 0.6b7g and ) (15.864 mmol) of anhydrous lithium chloride at 40 "С is dissolved with stirring in 8 Oml of absolute dimethylsulfoxide and at this temperature is mixed with M-hydroxysuccinimide in a total amount of 1.82 g (15.4 mmol) and with 7.25 g (7.19 mmol) specified in of the title of example 276 of the compound dissolved in 30 ml of absolute "I dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 3.27 g (15.864 mmol) of M,M'-dicyclohexylcarbodiimide and stirred for 12 hours. at room temperature. ish

The resulting suspension is then mixed with a sufficient amount of acetone to completely precipitate the above-mentioned compound, the precipitate is separated by vacuum filtration, dissolved in water, the undissolved dicyclohexylurea is filtered off, and the filtrate is passed through an ultrafiltration membrane for desalination and purification of low molecular weight components. AMISOM UM-3 (limiting permeability: 300 OD) Finally, the retentate is lyophilized.

Yield: 9.11 g (83.095 from theory) in the form of a colorless lyophilisate.

H2O content (when using Karl Fischer's reagent): 4.0296. "

Elemental analysis (in terms of anhydrous substance): solution: С 35.37 Н 4.02 M 8.25 Е 21.13 52.10 Са 10.29 - with detection: С 35.42 Н 4.07 М 8.18 E 21.09 5 2.06 b 10.34 i Example 28 ,» a) 1-(4-perfluorooctylsulfonyl)piperazine|amide of 2-M-trifluoroacetyl-y-lysine 10.0 g (11.4 bmmol) obtained in example 16, the compounds are dissolved in 100 ml of ethanol, mixed with 1.0 g of Perlman's catalyst (2095 Ra/s) and hydrogenated until quantitative absorption of hydrogen. After that, the catalyst is removed by vacuum filtration, washed with ethanol and concentrated to dryness under vacuum. In this way, the title compound is obtained in the form of a viscous and colorless oil.

Yield: 8.85g (97.595 from theory). (95) Elemental analysis: bu 50 resolution: C 30.31 H 2.54 M 7.07 E 47.95 5 4.05 detection: C 30.36 H 2.50 M 7.11 P 47.99 54.00 chz" b) (1-(4-perfluorooctylsulfonyl)piperazinamide 2-M-trifluoroacetyl-6-M-(1-0O-A-Y-(5-carbonyl)pentyl-2,3,4, 6-tetra-O-benzylmannopyranose|-I-lysine

To a solution of 29.0 g (36 b, mmol) of the compound indicated in the title of example 28a and 4.05 g (40.2 b mmol) of triethylamine in 100 ml of dimethylformamide, cooled to 02, a solution of 27.51 g (36, b mmol) of the compound indicated in the title is added dropwise of the compound of example 17c in 150 ml of dimethylformamide. After this addition is complete, the mixture is stirred for another hour at 02C and then overnight at room temperature. The mixture is evaporated to dryness in a vacuum and the residue is dissolved in 30 ml of ethyl acetic acid. The undissolved components are filtered and the filtrate is washed twice with a 595% aqueous soda solution in portions of 100 ml. The organic phase 60 is dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: n-hexane/isopropanol in the ratio 25:11). In this way, 42.05 g (80.4905 from theory) of the title compound are obtained in the form of a colorless oil.

Elemental analysis: solution: C 50.42 H 4.51 M 7.96 R 26.59 5 2.24 found: C 50.38 H 4.50 M 7.91 R 26.62 5 2.20 c) (1-4-perfluorooctylsulfonyl)piperazine|amide

6-M-(1-0O-A-O-(5-carbonyl)pentyl-2,3,4,6-tetra-O-benzylmannopyranose|-I-lysine 20.0 g (14, Ommol) obtained in example 286 compounds are dissolved in 150 ml of ethanol. Next, a solution of 2.8 g (70.Omol) of sodium hydroxide in 25 ml of distilled water is added and stirred for 0.5 h at 50260. According to

The chromatogram of thin-layer chromatography until this point in time is the quantitative cleavage of the protective group. Then the mixture is concentrated to dryness in a vacuum and traces of water are removed by repeated co-distillation with ethanol. The residue is chromatographed on silica gel (eluent: n-hexane/isopropanol in the ratio 20:11). In this way, 16.66 bg (89.395 from theory) of the title compound are obtained as a colorless oil. 70 Elemental analysis: solution: С 52.25Н 4.91 М 4.20 Р 24.22 5 2.41 detected: С 52.30 Н 4.90 М 4.18 Р 24.22 5 2.38 g ) (1-4-perfluorooctylsulfonyl)piperazinamide 6-M-(1-0O-A-O-(5-carbonyl)pentylmannopyranose|-I-lysine 15.0 g (11.25 mmol) of the compound obtained in example 288 is dissolved in 150 ml of the mixture of ethanol and water in a 10:11 ratio of 75 and mixed with 1.0 g of Perlman catalyst (2090 Pa/C). After that, hydrogenation is carried out until quantitative absorption of hydrogen at room temperature and at a hydrogen pressure of one atmosphere. After that, the catalyst is removed by vacuum filtration , the residue is washed with a mixture of ethanol and water (in a ratio of 10:1) and concentrated to dryness under vacuum. In this way, the title compound is obtained as a viscous

Eat colorless oil.

Yield: 10.77g (98.490 from theory).

Elemental analysis: solution: C 37.04 H 4.25 M 5.76 RE 33.20 5 3.30 found: C 37.06 H 4.20 M 5.81 E 33.19 5 3.30 d ) (1-(4-perfluorooctylsulfonyl)piperazine|amide with 8-M-(1-0O-A-O-(5-carbonyl)pentylmannopyranose/|-2-M-11,4,7-tris(carboxylatomethyl)- 10-(3-aza-4-oxo-5-methyl-5-yl pentanoyl)-1,4,7,10-tetraazacyclododecane|-I -lysine, a-complex i) 5.54g (8.6mmol, 2 ,2 molar equivalents in terms of the amount of the used amine component from example 28d) described |in the application OE 19728954 SI| in example 31 of the ba-complex 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1 . hydroxysuccinimide in a total amount of 1.01 g (8.8 mmol) and from 3.89 g (4.0 mmol) of the compound indicated in the title of Example 28, dissolved in bOml of absolute sodium dimethyl sulfoxide. After cooling to room temperature the reaction solution is mixed with 1.82 g (8.8 mmol) of M,M'-dicyclohexylcarbodiimide and stirred for 12 hours. at room temperature. The obtained suspension is then mixed with a sufficient amount of acetone until complete precipitation of the h-compound indicated above in the title, the precipitate is separated by vacuum filtration, dissolved in water, the undissolved dicyclohexylurea is filtered off, and the filtrate for desalting and for purification from low molecular weight components is passed through an ultrafiltration AMISOM UM-3 membrane (permeability limit: 3000Da) The retentate is lyophilized at the end.

Yield: 4.81 g (75.99 from theory) in the form of a colorless lyophilisate. - with H2O content (when using Karl Fischer's reagent): 8.9890. и Elemental analysis (in terms of anhydrous substance): yes" solution: С 37.15 Н 4.39 М 7.96 Е 20.38 са 9.92 52.02 detect.: С 37.27 Н 4.40 M 8.02 E 20.31 sa 10.00 5 1.98

Example 29 - and a) 1,7-bis(benzyloxycarbonyl)-4-(1-0-8-O-carbonylmethyl-2,3,4,6-tetra-O-benzylgalactopyranose)-10-73-oxapentane-1 ,5-dicarboxylic acid-1-oyl-5-(1-(4-perfluorooctylsulfonyl)piperazine)amide)-1,4,7,10-tetraazacyclo do decane (95) To a solution of 27.0 g (24.4 mmol) of the obtained in example 1542 secondary amine in a mixture with 150 ml of tetrahydrofuran

Fu 50 and 15 ml of chloroform at 02C in a nitrogen atmosphere add 35.80 g (25.0 mmol) of the compound indicated in the title of example 17d, dissolved in 250 ml of tetrahydrofuran. After that, a total of 18.0 g (36.bmmol) of EEDH (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) is added in portions at 09C and left overnight for stirring at room temperature. Then it is concentrated to dryness under vacuum and the obtained oil is chromatographed on silica gel (eluent: n-hexane/isopropanol in a ratio of 20:11). This way, 32.11 g (78.0905 from theory, calculated on the amount of secondary amine used) of the title compound are obtained as a colorless oil .

Elemental analysis: solution: C 54.09 H 4.72 E 19.14 M 4.98 5 1.90 found: C 54.12 H 4.77 E 19.17 M 5.03 5 1.90 because b). 1--1-0-8-O-carbonylmethylgalactopyranose)-7-(3-oxapentane-1,5-dicarboxylic acid-1-oyl-5-(1--4-perfluorooctylsulfonyl)piperazinamide)-1,4,7 ,10-tetraazacyclododecane

3,Og (17.77 mmol) of the compound obtained in example 29a and indicated in its title is dissolved in 250 ml of ethanol and mixed with 3,Og of Perlman's catalyst (2095 Pa/C). After that, it is hydrogenated until the quantitative absorption of hydrogen, after which the catalyst is removed by vacuum filtration, thoroughly washed with ethanol and then concentrated to dryness in a vacuum. The product is obtained in the form of a highly viscous yellow oil.

Yield: 17.89g (95.190o from theory).

Elemental analysis: solution: C 36.30 H 4.09 P 30.50 M 7.94 5 3.03 found: C 36.26 H 4.12 E 30.46 M 7.90 5 3.04 in ). 1-41-0-8-O-carbonylmethylgalactopyranose)-7-3-oxapentane-1,5-dicarboxylic acid-1-oyl-5-(1--4-perfluorooctylsulfonyl)piperazinamide)-4,10-bis(1 ,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-ylpentanoyl)-1,4,7,10-tetraazacyclododecane|-1,4,7,10-tetraazacyclododecane , digadolinium complex 5.54 g (8.6 mmol, 4.4 molar equivalents in terms of the amount of used amine 7/0 KHomponent from example 296) described |in application OE 19728954 CI| in example 31 of Ca-complex 10-(4-carboxy -1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (and 0.37 g (8.mmol) of anhydrous lithium chloride at 40 9С are dissolved at stirring in bOml of absolute dimethylsulfoxide and at this temperature is mixed with M-hydroxysuccinimide in a total amount of 1.01g (8.mmol) and with 2.11g (2.0mmol) of the compound indicated in the title of example 296, dissolved in 25ml of absolute 7/5 dimethylsulfoxide. After cooling to room temperature, the reaction solution is mixed with 1.82 g (8 ,mmol) of M,M'-dicyclohexylcarbodiimide and stirred for 12 hours. at room temperature. The resulting suspension is then mixed with a sufficient amount of acetone to completely precipitate the above-mentioned compound, the precipitate is separated by vacuum filtration, dried, dissolved in water, the undissolved dicyclohexylurea is filtered off, and the filtrate is passed through an ultrafiltration membrane for desalting and purification from low molecular weight components AMISOM IN UM-3 (limiting permeability: 300ODa) Finally, the retentate is lyophilized.

Yield: 3.29 g (72.20 from theory, based on the amount of the amine component used) in the form of a colorless lyophilizate.

H2O content (when using Karl Fischer's reagent): 5.9990. si

Elemental analysis (in terms of anhydrous substance): о solution: С 36.84 Н 4.37 М 9.82 Е 14.15 са 19.63 5 1.40 detection: С 36.87 Н 4.40 М 9.82 E 14.09 ba 19.59 5 1.38

Example 30 a) 3-(1-0-А-0-2,3,4,6-tetra-O-benzylmannopyranose)-2-M-benzyloxycarbonyl-I-serine methyl ester

21.42 g (39.61 mmol) of 2,3,4,6-tetra-O-benzyl-A-O-mannopyranose (obtained according to ER. Kopd et al., U. Sagropuag. Spet.) are dissolved in B500 ml of dry acetonitrile. 16, b (1997), pp. 877-890). After cooling the reaction solution to 59C at this temperature, a solution of 13.23g (59.52mmol) of trimethylsilyl ether of trifluoromethanesulfonic acid in 30ml of acetonitrile is slowly added dropwise with stirring, and then a solution of 20.06g (79.21mmol) of M-benzyloxycarbonyl-I-serine methyl ether (supplied by Vaspet) in 5 Oml of acetonitrile, while the rate of dropwise addition should be such that the internal temperature does not exceed 102. After conducting the reaction for 15 hours. at room temperature, the reaction solution is concentrated to dryness in a vacuum. The obtained residue is dissolved in 250 ml of ethyl acetic acid and washed twice with a saturated solution of sodium bicarbonate in portions of 100 ml and once with water in a portion of 200 ml. "

After drying the organic phase over sodium sulfate, the salt is separated by vacuum filtration and the ethyl acetic acid is distilled off under vacuum. The obtained oily residue is purified on silica gel using 300 ml of ethyl acetic acid/n-hexane (1:5 ratio) as an eluent. h Yield: 23.6Og (76.890 from theory) of the above title compound as a colorless oil. » Elemental analysis: soln.: C 71.21 H 6.37 M 1.81 detected: C 71.19 H 6.41 M 1.79 - b) 3-(1-0-A-0-2, 3,4,6-tetra-O-benzylmannopyranose)-2-M-benzyloxycarbonyl-l-serine 10.0 g (12.900 mmol) of the compound obtained in Example 3b is dissolved in a mixture of 20 ml of methanol, 20 ml of water and 5 ml of tetrahydrofuran. Next, at room temperature, add 0.47 g (19.35 mmol) of lithium hydroxide dissolved in i95) 25 ml of distilled water, and then stir for 2 hours. at 602. Control over the course of the reaction

Ф 50 by thin-layer chromatography (eluent: methylene chloride/methanol in a ratio of 10:1) indicates already quantitative saponification of the methyl ether from example Zba after the end of the above-mentioned reaction time. For processing, the solution containing the product is concentrated to dryness in a vacuum, and the resulting residue is dissolved in 250 ml of ethyl acetic acid under warm conditions (approximately 602). After that, the ethyl acetate phase obtained in this way is washed twice with 15956 aqueous hydrochloric acid in portions of 5 Oml and once with distilled water 29 in a portion of 100 ml. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under vacuum. Remainder

HF) is chromatographed on silica gel (eluent: n-hexane-ethyl acetic acid in a ratio of 5:1). In this way, 8.40 g (85.79 from theory) of the compound indicated in the title are obtained in the form of a colorless oil. o Elemental analysis: .: C 70.94 H 6.22 M 1.84 60 found.: C 70.97 H 6.30 M 1.78 c) (1-4-perfluorooctylsulfonyl)piperazine|amide 3-(1-0-А) -0-2,3,4,6-tetra-O-benzylmannopyranose)-2-M-benzyloxycarbonyl-I-serine

To 13.86 bg (244 mmol) of 1-perfluorooctylsulfonylpiperazine (obtained according to OE 19603033), dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, at 09C in a nitrogen atmosphere, 20.57 g (27.0 mmol) obtained according to example 306 are added dropwise. of carboxylic acid dissolved in 50 Oml of tetrahydrofuran. After that, a total of 18.0 g (36 b, bOmol) of EEDH (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) are added in portions at 0 9C and left overnight for stirring at room temperature. For processing, the reaction solution is concentrated in a vacuum and obtained extremely viscous oil

Chromatography on silica gel using a mixture of n-hexane/isopropanol (in a ratio of 15:1) as an eluent.

In this way, 17.0 g (79.6905 from theory, in terms of the amount of primary amine used) of the title compound are obtained in the form of a colorless viscous oil.

Elemental analysis: solution: C 51.53 H 4.23 M 3.15 P 25.65 5 2.41 70 found: C 51.48 H 4.27 M 3.10 RE 25.71 5 2.35 d) (1-(4-perfluorooctylsulfonyl)piperazinamide 3-(1-0-A-O-mannopyranose)-I-serine 15.0 g (11.41 mmol) of the compound obtained according to example 3b is dissolved in 200 ml of ethanol and mixed with 1 .5 g of Perlman's catalyst (2095 Ra/C). After that, the reaction solution is hydrogenated at room temperature in a hydrogen atmosphere (Tatm.) until hydrogen absorption stops (approximately within 8 hours). For 7/5 processing, the catalyst is removed under vacuum -filtration, washed thoroughly with ethanol (two portions of approximately 10 Oml) and the ethanol filtrate containing the product concentrated to dryness in a vacuum.Thus, the title compound is obtained as a highly viscous and colorless oil.

Yield: 8.79g (94.095 from theory).

Elemental analysis: solution: C 30.78 H 3.20 M 5.13 P 39.41 5 3.91 found: C 30.87 H 3.14 M 5.19 E 39.50 5 3.88 d ) (1-(4-perfluorooctylsulfonyl)piperazine|amide 3-(1-0-A-O-mannopyranose)-2-M-(1,4,7-tris(carboxylatomethyl)-10-(3-aza-4 -oxo-5-methyl-5-ylpentanoyl)-1,4,7,10-t tetraazacyclododecane-I-serine, sa-complex with

A mixed suspension of 5.7 g (9.0 bmmol, corresponds to 1.5 molar equivalents in terms of the amount of the compound used, indicated in the title of example 30 (primary amine)) described in the OE application of 19728954 CI in the example of Zp cCa-complex 10-( 4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid in 7 bml of absolute dimethyl sulfoxide at 702 is mixed with 0.68 g (15.9 mmol ) of lithium chloride. After stirring for 30 minutes at 702C, the clear reaction solution is mixed with M-hydroxysuccinimide in a total amount of 1.83 g (15.9 mmol) in portions, and the reaction mixture is kept for another hour. at 70 "С. After cooling the reaction solution to 102, it is mixed with 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide and the reaction solution (ze) is stirred for another hour. at 02C, and then for 12 hours. at 222C. The solution obtained in this way

M-hydroxysuccinimidoether of the Ca-complex

Zo /10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid then according to v. dropwise mixed at 222 with a solution of 4.94g (6b.03mmol) of the compound indicated in the title of Example 3g in 15ml of absolute dimethylsulfoxide and then stirred for another 12h. at room temperature. For processing, the reaction solution at 222С is slowly added dropwise to a mixture of solvents consisting of 250 ml of acetone and 250 ml of 2-propanol, while the compound specified in the title is added over 12 hours. completely precipitates in Z 70 at 102С in the form of light yellow oil. The supernatant eluent is carefully decanted and the oily product c is dissolved in 200 ml of distilled water, while this product is completely transformed into a solution with "with the formation of an aqueous solution of the compound indicated above in the title, which has a clear yellow color. Then this aqueous solution containing the product, first it is filtered through a membrane filter, and then, for desalination and to separate low-molecular components, it is subjected to ultrafiltration three times through an ultrafiltration membrane UM3 (AMISOMU, limit permeability: 3000Da). The retentate obtained as a result is finally lyophilized. 1 Yield: 8.63Zg ( 80.295 from the theory, in terms of the amount of the compound used, indicated in the title of this example (ZoOg) in the form of a colorless lyophilizate with a water content of 7.6595.

Elemental analysis (in terms of anhydrous substance): (o) 50 resolution: С 33.57 Н 3.80 М 7.83 Е 22.57 са 10.99 5 2.24

GT" revealed: C 33.57 H 3.76 M 7.82 E 22.63 sa 11.06 52.18

Example 31 a) (1-4-perfluorooctylsulfonyl)piperazinamide 6-M-benzyloxycarbonyl-2-M-(O-B-O-galactopyranosyl-(1-54)-gluconosyl|-I-lysine

A solution of 13.3 g (37.2 mmol) of О-в-О-galactopyranosyl- (1-»4)-O-glucono-1,5--lactone | lactobionolactone; production according to (a) UMShiatv

T.U., Riezzaz M.K., Soidvivip 1I.), Sagropuadg. Caves. 67, SI. (1978); (6) Korauavzpi K., Bcitioto N, Ipa U., Br Royut. U. 17 (1985), p. 567; (c) Nigoti Kpapo, Kaiziko Zopda and AuaKo Kozaka, Viosopiidaeeee Spet. 6 (1995), pp. 131-134)| in 40 ml of absolute dimethyl sulfoxide. The reaction solution obtained in this way is then stirred for 14 hours. at 402C. For processing, the solution is mixed at room temperature with 500 ml of absolute 2-propanol, the resulting colorless precipitate is separated by vacuum filtration using frit 4 and then thoroughly washed with absolute 2-propanol in a total amount of 250 ml. The 65 solid substance obtained in this way is further dissolved in ZbOml of distilled water and subjected to ultrafiltration three times through an ultrafiltration membrane UM3 (AMISOM, limit permeability: З000Da). Such a three-time ultrafiltration allows to separate the excess of lactobionolactone from the target product, as well as possible low molecular weight components. Finally, the precipitate on the ultrafiltration membrane is completely dissolved in 30 ml of distilled water and lyophilized.

Yield: 6.51 g (92.790 from theory) in the form of a colorless lyophilisate.

Water content: 10.0395.

Elemental analysis (in terms of anhydrous substance): solution: С 38.98 Н 4.05 М 4.79 Р 27.58 5 2.74 found.: С 39.04 Н 4.09 М 4.82 Е 27 ,61 52.71 70 b) (1-(4-perfluorooctylsulfonyl)piperazine|amide 2-M-(IO-B-ЮО-galactopyranosyl-(1-- 54)-gluconosyl-I-lysine 5.00 g (4.27 mmol) the compound obtained in example 31a is dissolved in 100000 ml of ethanol, mixed with 0.5 g of Perlman's catalyst (2095 Pa/C) and hydrogenated until the quantitative absorption of hydrogen at a hydrogen pressure of 1 atmosphere. After that, the catalyst is removed by vacuum filtration, then washed with ethanol and dried concentrated in vacuo.This way, the title compound is obtained as a colorless and viscous oil.

Yield: 4.36g (98.595 from theory).

Elemental analysis: solution: C 34.76 H 3.99 M 5.40 E 31.51 5 3.09 found: C 34.78 H 4.04 M 5.34 E 31.51 5 3.15 ) (1-4-perfluorooctylsulfonyl)piperazine|amide 2-M-(O-B-O-galactopyranosyl-(1.-54)-gluconosyl|/-6-I-(1,4,7-tris(carboxylatomethyl) -10-(3-aza-4-oxo-5-methyl-5-ylpentanoyl)-1,4,7,10-tetraazacyclododecane-I-lysine, Ca-complex 5.54 g (8.6 mmol, 2.2 molar equivalents in terms of the amount of the used amine component from example 316) described |in the application OE 19728954 SI| in example 31 (for complex He 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1, 4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.37 g (8.mmol) of anhydrous lithium chloride at 40 9С are dissolved with stirring in bOml of absolute dimethylsulfoxide and at this temperature are mixed with M-hydroxysuccinimide in a total amount 1.01 g (8.8 mmol) and from 3.85 g (4.0 mmol) of the title compound of Example 316 dissolved in bOml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction The aqueous solution is mixed with 1.82 g (8.mmol) of M,M'-dicyclohexylcarbodiimide and stirred for 12 hours. at room temperature. The resulting suspension is then mixed with a sufficient amount of acetone/2-propanol (in a 1:11 ratio) until the title compound is completely precipitated, and the precipitate is separated by vacuum filtration. The precipitate obtained in this way (ze) is then dissolved in 30 ml of water and dicyclohexylurea, which has not dissolved, is filtered off.

The filtrate is subjected to ultrafiltration three times through an ultrafiltration membrane AMISOM UM-3) (limit permeability: З00ODa). Such triple ultrafiltration allows to separate from the target product in an excess of the Z4a complex, as well as possible low-molecular components. Finally, the sediment on the ultrafiltration membrane is completely dissolved in 500 ml of distilled water and lyophilized.

Yield: 4.64 g (70.49 from theory) in the form of a colorless lyophilisate. "

H2O content (when using Karl Fischer's reagent): 10.08905.

Elemental analysis (in terms of anhydrous substance): C s solution: С 35.70 Н 4.22 М 7.65 Е 19.59 са 9.54 5 1.95 h detection: С 35.77 Н 4, 17 M 7.71 PE 19.61 sa 9.60 5 1.99 i?

Example 32 a) P1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-benzyloxycarbonyl-2-M-(2,3,4,5-pentahydroxyhexanoyl)-I-lysine and To a solution of 100.0g (120.4mol) a solution of 21.45 g (120.4 mol) of 5-gluconolactone in 5 Oml of tetrahydrofuran is added dropwise to the compound indicated in the title of the example in 50 Oml of dry tetrahydrofuran at 5027. The mixture is stirred during the Agreement. at 602C and then overnight at room temperature. After that, it is evaporated to dryness under vacuum and the residue is chromatographed on silica gel (eluent: dichloromethane/ethanol in a ratio of 7020).

Yield: 98.37 g (8295 from theory) of viscous oil.

T» Elemental analysis: solution: С 38.10 Н 3.70 РЕ 32.02 М 5.55 5 3.18 found.: С 38.22 Н 3.79 Е 32.02 М 5.42 5 3, 29 29 b) 1-K4-perfluorooctylsulfonyl)piperazine|amide 2-M-(2,3,4,5-pentahydroxyhexanoyl)-I-lysine (FI 100.9g (100.0 mmol) of the compound specified in the title of example 32a , dissolve in 2000 ml of ethanol and add 10.0 g of palladium catalyst (1090 Pa/C). After that, hydrogenate for 12 hours at room temperature. Then the catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.

Yield: 87.46 g (quantitative) of a colorless solid. bo Elemental analysis: solution: C 32.96 H 3.57 M 6.41 5 3.67 E 36.93 found: C 32.91 H 3.72 M 6.34 5 3.50 E 36.78 c) (1-4-perfluorooctylsulfonyl)piperazine|amide 6-M-(1,4,7-tris(carboxylatomethyl)|-1,4,7,10-tetraazacyclododecane-10-M-(pentanoyl-3-aza- 4-oxo-5-methyl-5-yl)|- 2-M-(11-0-A-O-carbonylmethylmannopyranose|-I-lysine, a-complex

50.0 g (54.55 mmol) of the compound indicated in the title of the example, 6.28 g (54.55 mmol) of M-hydroxysuccinimide, 4.62 g (109 mol) of lithium chloride and 34.35 g (54.55 mol) of the CCa complex 1,4,7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methylpent-5-yl)-1,4,7,10-tetraazacyclododecane

It is dissolved under moderate heating in 400 ml of dimethyl sulfoxide. Then, at 102, 16.88 g (81, moles) are added

M,M-dicyclohexylcarbodiimide and then stirred overnight at room temperature. The solution is poured into

300 Oml of acetone and stir for 1 hour. The precipitated solid is filtered and then purified by chromatography (KR-18, eluent: water/ethanol/acetonitrile gradient).

Yield: 75.9 g (91.095 from theory) of a colorless solid. 70 Water content: 8.695.

Elemental analysis (in terms of anhydrous substance): resolution:

C 35.34 H 4.09 M 8.24 5 2.10 g 21.12 ba 10.28 found: C 35.28 H 4.15 M 8.19 52.15 R 21.03 sa 10.14

Example 33 a) P1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-benzyloxycarbonyl-2-M-(2,3,4,5-pentapdroxyhexanos)-I-lysine

To a solution of 100.0 g (120.4 mmol) of the compound indicated in the title of example iv and 12.18 g (1204 mmol) of triethylamine in 500 ml of dry tetrahydrofuran at 5097 is added dropwise a solution of 21.45 g (120.4 mol) of β-gluconolactone in 500 ml of tetrahydrofuran . The mixture is stirred during the Agreement. at 602C and then overnight at room temperature. After that, add 400O0ml of 595 aqueous hydrochloric acid, stir for 5 minutes. at room temperature, mixed with sodium chloride, the organic phase is separated, dried over magnesium sulfate, evaporated to dryness under vacuum and the residue is chromatographed on silica gel (eluent: dichloromethane/ethanol in a ratio of 20:1).

Yield: 100.97 g (8295 from theory) of viscous oil. with

Elemental analysis: solution: C 37.58 H 3.45 E 31.58 M 5.48 5 3.14 found: C 37.72 H 3.59 E 31.72 M 5.42 5 3.29 b) 1-K4-perfluorooctylsulfonyl)piperazine|amide 2-M-(2,3,4,5-pentahydroxyhexanoyl)-I-lysine 100.9 g (100, Ommol) of the compound indicated in the title of example 32a is dissolved in 2000 ml of ethanol and add 10.0 g of palladium catalyst (1090 Ra/C). After that, hydrogenate for 12 hours. at room temperature. Then the catalyst is filtered off and the filtrate is evaporated to dryness under vacuum. oh

Yield: 87.46 g (quantitative) of a colorless solid. co

Elemental analysis: solution: C 32.96 H 3.57 M 6.41 5 3.67 E 36.93 and found: C 32.91 H 3.72 M 6.34 5 3.50 E 36.78 - c) (1-4-perfluorooctylsulfonyl)piperazine|amide 6-M-(1,4,7-tris(carboxylatomethyl)|-1,4,7,10-tetraazacyclododecane-10-M-(pentanoyl-3-aza) -4-oxo-5-methyl-5-yl)|- 2-M-(11-0-A-O-carbonylmethylmannopyranose|-I-lysine, α-complex « 50.0g (54.55mmol) of the specified compound in the title of the example of poison, 6.28 g (54.55 mmol) of M-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54.55 mol) of the CCa complex - with 1,4,7-tris (carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5--methylpent-5-yl)-1,4,7,10-tetraazacyclododecane and is dissolved under moderate heating in 400 ml of dimethyl sulfoxide. Then, at 102, 16 ,88 g (81.8 moles) of M,M-dicyclohexylcarbodiimide and then stirred overnight at room temperature. The solution was poured into

300 Oml of acetone and stir for 1 hour. The precipitated solid is filtered and then purified by chromatography (KR-18, eluent: water/ethanol/acetonitrile gradient). -and Yield: 75.9g (91.095 from theory) of a colorless solid. sl Water content: 8.695.

Elemental analysis (calculated per anhydrous substance): (65) solution: C 35.34 N 4.09 M 8.24 5 2.10 P 21.12 ba 10.28 bu 50 detection: C 35.28 N 4.15 M 8.19 5 2.15 E 21.03 sa 10.14

In the conditions described in example Te, mannose was replaced by glucose, respectively galactose. Example 34 a) P1-(4-perfluorooctylsulfonyl)piperazineamide 6-M-benzyloxycarbonyl-2-M-(1-0-A-O-carbonylmethyl-(2,3,4,6-tetra-O- benzylglucopyranose)|-I -lysine

To a solution of 100.00 g (120.4 mol) of the compound indicated in the title of example iv, 72.1 g (120.4 mol) of 1-0-A-O-carboxymethyl-2,3,4,6-tetra-O- of benzylglucopyranose and 13.86 g (120.4 mol) of M-hydroxysuccinimide in X0O0 ml of dimethylformamide at 02С add 41.27 g (200.0 mmol) of M,M-dicyclohexylcarbodiimide. The mixture is stirred where during the Agreement. at 029C and then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness under vacuum and chromatographed on silica gel (eluent: 60 dichloromethane/ethanol in a ratio of 20:1).

Yield: 136.1 g (87905 from theory) of viscous oil.

Elemental analysis: solution: C 57.32 H 4.89 M 4.31 P 24.86 5 2.47 found: C 57.48 H 5.04 M 4.20 E 24.69 5 2.38 bo b) 1-K4-perfluorooctylsulfonyl)piperazinamide. 2-M-(1-0O-A-O-carbonylmethylglucopyranose|-I-lysine) 130.0g (100, Ommol) of the compound indicated in the title of example 34a is dissolved in 2000 ml of ethanol and added

10.0 g of palladium catalyst (1090 Pa/C). After that, hydrogenate for 12 hours. at room temperature. Then the catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.

Yield: 91.7 g (quantitative) of a colorless solid.

Elemental analysis: solution: C 34.07 H 3.63 M 6.11 5 3.50 E 35.24 found: C 33.92 H 3.71 M 6.02 5 3.42 E 35.33 ) (1-4-perfluorooctylsulfonyl)piperazine|amide 6-M-(1,4,7-tris(carboxylatomethyl)|-1,4,7,10-tetraazacyclododecane-10-M-(pentanoyl-3-aza-4 -oxo-5-methyl-5-yl)|- 70 2-M-(11-0-A-O-carbonylmethylglucopyranose|-I-lysine, (for complex 50.0g (54.55mmol) of the compound specified in title of example 346, 6.28 g (54.55 mmol) of M-hydroxysuccinimide, 4.62 g (109 mol) of lithium chloride and 34.35 g (54.55 mol) of the 1,4,7-tris(carboxylatomethyl)- 10-(carboxy-3-aza-4-oxo-5-methylpent-5-yl)-1,4,7,10-tetraazacyclododecane is dissolved under moderate heating in 400 ml of dimethyl sulfoxide. Then, at 102, 16.88 g (81, 8 mol) of 75 M,M-dicyclohexylcarbodiimide and then stirred overnight at room temperature.

300 Oml of acetone and stir for 1 hour. The precipitated solid is filtered and then purified by chromatography (KR-18, eluent: water/ethanol/acetonitrile gradient).

Yield: 75.9 g (91.095 from theory) of a colorless solid.

Water content: 8.695.

Elemental analysis (calculated per anhydrous substance): solution: С 35.34 Н 4.09 М 8.24 5 2.10 Р 21.12 б 10.28 found.: С 35.26 Н 4.18 М 8 ,14 5 2,158 E 21,01 sa 10,13

Example 35 a) P1-(4-perfluorooctylsulfonyl)piperazine|amide with 8-M-benzyloxycarbonyl-2-M-(1-0-A-O-carbonylmethyl-(2,3,4,6-tetra-O-benzylgalactopyranose) )|-I -lysine

To a solution of 50.0 g (60.2 mol) of the compound indicated in the title of example iv, 36.05 g (60.2 mmol) of 1-O-A-O-carboxymethyl-2,3,4,6-tetra-O-benzylgalactopyranose and 20.64 g (100.0 mmol) of M,M-dicyclohexylcarbodiimide are added to 6.93 g (60.2 mmol) of M-hydroxysuccinimide in X0Oml of dimethylformamide at 02C. The mixture is stirred during the Agreement. at 029C and then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness under vacuum and chromatographed on silica gel (eluent: dichloromethane/ethanol in a ratio of 20:1). oh

Yield: 68.1 g (87905 from theory) of viscous oil. co

Elemental analysis: solution: C 57.32 H 4.89 M 4.31 P 24.86 5 2.47 and found: C 57.47 H 5.05 M 4.19 RE 24.72 5 2.29 - b) 1-K4-perfluorooctylsulfonyl)piperazinamide. 2-M-(I1-0O-A-O-carbonylmethylgalactopyranose|-I-lysine) 65.0g (50.Omol) of the compound specified in the title of example 35a is dissolved in 1000ml of ethanol and 5.0g of a palladium catalyst (1095 After that, hydrogenation is carried out for 12 hours at room temperature.

Then the catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.

Yield: 45.85 g (quantitative) of a colorless solid. - с Elemental analysis: ц resolution: С 34.07 Н 3.63 М 6.11 5 3.50 Е 35.24 "» detection: С 33.93 Н 3.74 М 6.01 5 3.39 E 35.05 c) (1-4-perfluorooctylsulfonyl)piperazine|amide 6-M-(1,4,7-tris(carboxylatomethyl))|-1,4,7,10-tetraazacyclododecane-10-M-(pentanoyl -3-aza-4-oxo-5-methyl-5-yl)|- -and 2-H-(1-0O-A-O-carbonylmethylgalactopyranose|-I-lysine, sa-complex sl 50.0g (54 .55 mmol) of the compound indicated in the title of example 356, 6.28 g (54.55 mmol) of M-hydroxysuccinimide, 4.62 g (109 .Omol) of lithium chloride and 34.35 g (54.55 mol) of the cCa-complex (95) 1, 4,7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5--methylpent-5-yl)-1,4,7,10-tetraazacyclododecane b" 50 is dissolved under moderate heating in 400 ml dimethyl sulfoxide. Then, at 102, 16.88 g (81, mol) are added

M,M-dicyclohexylcarbodiimide and then stirred overnight at room temperature. The solution is poured into

Add 300 ml of acetone and stir for 1 hour. The precipitated solid is filtered and then purified by chromatography (KR-18, eluent: water/ethanol/acetonitrile gradient).

Yield: 37.95 g (91.0965 from theory) of a colorless solid.

Water content: 8.695. o Elemental analysis (calculated per anhydrous substance): solution: С 35.34 Н 4.09 М 8.24 5 2.10 Р 21.12 ba 10.28 ko detect.: С 35.22 Н 4.17 M 8.18 5 2.19 R 20.91 ba 10.12

Example 36 60 a) Monobenzyl ether M-trifluoroacetyl-i! -glutamic acid, 100 g (421.5 mmol) of monobenzyl ether of I-glutamic acid are dissolved in a mixture of 1000 ml of trifluoroacetic acid ethyl ether and 500 ml of ethanol and for 24 hours. stir at room temperature. After that, it is evaporated to dryness and the residue is crystallized from the action of isopropyl ether.

Yield: 140.47 g (96905 from theory) of colorless crystalline powder. 65 Elemental analysis: resolved: C 5046H4I423E 17.10 M 4.20 detected: C 51.35 H4.18 E 17.03 M 4.28 b) 5-M-(methyl)-M-(2,3, 4,5,6-pentahydroxyhexyl)amide of monobenzyl ether 2-M-trifluoroacetyl-i! -glutamic acid

To a solution of 24.9 g (24.08 mmol) of the compound indicated in the title of example Zba, 2x g (24.08 mmol)

8.25 g (4 mmol) of M-methylglucamine and 2.77 g (24.0 in 8 mmol) of M-hydroxysuccinimide in 150 ml of dimethylformamide at 092 are added. M,M-dicyclohexylcarbodiimide. The mixture is stirred during the Agreement. at 02C and then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness under vacuum and chromatographed on silica gel (eluent: dichloromethane/ethanol in a ratio of 20:1).

Yield: 109.40 g (8995 from theory) of viscous oil.

Elemental analysis: solution: C51.43 H 5.51 E 13.56 M 6.66 found: C 51.22 H 5.41 E 13.40 M 6.75 c) M-(methyl)-IM- I-(2,3,4,5,6-pentahydroxyhexyl)amide M-trifluoroacetyl-i-glutamic acid 77.33 g (15.15 mmol) of the compound indicated in the title of example 366 is dissolved in 500 ml of ethanol and 3 g of palladium catalyst ( 1095th Ra/S). After that, they are hydrogenated at room temperature. Then the catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.

Yield: 43.0 g (quantitative) of a colorless solid.

Elemental analysis: solution: C 40.01 H 5.19 E 17.26 M 8.48 found: C 39.84 H 5.13 E 17.09 M 8.68 g) Trifluoroacetyl! -glutamic acid-5-M-(methyl)-M-(2,3,4,5,6-pentahydroxyhexyl)amide-(1--4-perfluorooctylsulfonyl)piperazinamidepiperase niamide Ha

To 10.96 bg (33.2 mmol) of the compound indicated in the title of example Zbv and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonylpiperazine (obtained according to OE 19603033 | in 10 ml of tetrahydrofuran at 0°C) add 16.42 g (bb4 mmol) EEDH (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred overnight at room temperature. After that, it is evaporated to dryness in a vacuum and chromatographed on silica gel (eluent: dichloromethane/methanol in a ratio of 20:1). "AND

Yield: 28.67 g (9296 from theory) of a colorless solid.

Elemental analysis: i-o resolution: C 39.61 H 2.89 E 35.66 M 6.19 5 3.54 Ho) found: C 39.68 H 2.74 E 35.81 M 6.13 5 3.40 d) I-glutamic acid-5-M-(methyl)-M-(2,3,4,5,6-pentahydroxyhexyl)amide-(1--4-perfluorooctylsulfonyl)piperazinamide i-

A solution of 28.36 g (30.22 mmol) of the compound indicated in the title of example Zbg in 200 ml of ethanol at 02 is bubbled with gaseous ammonia for an hour. The mixture is then stirred for 4 hours. at 02. After that, it is evaporated to dryness and the residue is separated from the water by stirring. The solid is filtered off and dried in vacuo (5020).

Yield: 24.19 g (95905 from theory) of amorphous solid. o) c Elemental analysis: "» resolution: C 41.12 H 2.89 E 35.66 M 6.19 5 3.54 " detection: C 41.15 H 2.83 E 35.78 M 6, 28 5 3.71 e)

M-11,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)|-I-glu - c tamic acid-5-M-(methyl)-M-(2,3,4,5,6-pentahydroxyhexyl)amide-5-(1-(4-perfluorooctylsulfonyl)piperazinamide, c-complex and 20.43 g (24 .25 mmol) of the compound indicated in the title of example Zbd, 2.79 g (24.25 mmol) of M-hydroxysuccinimide, b 20. 212 g (5 BO mmol) of lithium chloride and 15.27 g (24.25 mmol) of the cCa-complex 1,4,7- tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl)upentanoic acid)-1,4,7,10-tetraazacyclododecane is dissolved under moderate heating in 200 ml of dimethyl sulfoxide.

Next, at 102C, 8.25 g (40 mmol) of M,M-dicyclohexylcarbodiimide are added and then stirred overnight at room temperature. The solution is poured into 300 ml of acetone and stirred for 10 min. The solid substance that precipitated is filtered off and then purified by chromatography (silica gel KR-18, eluent: gradient

HF) water/ethanol/acetonitrile).

Yield: 28.45 g (79906 from theory) of a colorless solid. where Water content: 11.095.

Elemental analysis (in terms of anhydrous substance): 60 resolution: С 34.41 Н 3.83 Е 23.13 М 9.03 5 2.30 ba 11.26 detection: С 34.34 Н 3.98 Е 23.29 M 9.19 5 2.15 ba 11.07

Example 37 a) P1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-benzyloxycarbonyl-2-M-(1-0O-A-O-carbonylmethyl (2,3,4-tri-O-benzylglucuronic acid-benzyl bo ether)-I -lysine

To a solution of 100.0 g (120.4 mol) of the compound indicated in the title of example 1c, 73.77 g (120.4 mol) of benzyl ether of 1-0-A-O-carboxymethyl-2,3,4-tri-O-benzylglucuronic acid and 13.86 bg. (120.4 mol)

41.27 g (200.0 mmol) of M-hydroxysuccinimide is added to 50 O0 ml of dimethylformamide at 09Сb

M.M-dicyclohexylcarbodimid. The mixture is stirred during the Agreement. at 0 9C and then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness under vacuum and chromatographed on silica gel (eluent: dichloromethane/ethanol in a ratio of 20:1).

Yield: 147.58 g (8695 from theory) of viscous oil.

Elemental analysis: 70 resolution: C 52.25 H 4.31 M 3.93 P 22.66 5 2.45 detection: C 52.38 H 4.17 M 4.12 ER 22.78 5 2.39 b) 1-K4-perfluorooctylsulfonyl)piperazinamide. 2-M-(1-0O-A-O-carbonylmethylglucuronic acid)|-I-lysine 142.52 g (100.0 mmol) of the compound indicated in the title of example C37a is dissolved in 2000 ml of ethanol and 10.0 g of palladium catalyst (1090 -th Ra/S). After that, hydrogenate for 12 hours. at 75 room temperature. Then the catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.

Yield: 93.06 g (quantitative) of a colorless solid.

Elemental analysis: solution: C 33.56 H 3.36 M 6.02 5 3.45 E 34.71 found: C 33.31 H 3.42 M 6.04 5 3.40 E 35.51 ) (1-4-perfluorooctylsulfonyl)piperazine|amide 6-M-(1,4,7-tris(carboxylatomethyl)|-1,4,7,10-tetraazacyclododecane-10-M-(pentanoyl-3-aza-4 -oxo-5-methyl-5-yl)|- 2-I1-M-(I1-0O-A-O-carbonylmethylglucuronic acid)/-I -lysine, α-complex, sodium salt 50.76g (54.55mmol ) of the compound indicated in the title of example 376, 6.28 g (54.55 mmol) of M-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54.55 mol) of the CCa-complex Ga 1.4, 7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methylpent-5-yl)-1,4,7,10-tetraazacyclododecane is dissolved under moderate heating in 400 ml of dimethyl sulfoxide. Then, at 102, add 16.88 g (81.8 moles) and)

M,M-dicyclohexylcarbodiimide and then stirred overnight at room temperature. The solution is poured into

300 Oml of acetone and stir for 1 hour. The precipitated solid is filtered and then purified by chromatography (KR-18, eluent: water/ethanol/acetonitrile gradient). "AND

Yield: 75.14.9 g (88.095 from theory) of a colorless solid.

Water content: 8.695. what

Elemental analysis (in terms of anhydrous substance): so solution: С 34.53 Н 3.80 М 8.05 Ma 1.47 52.05 ЕР 20.63 са 10.05 detect.: С 34.38 Н 3 .95 M 8.19 Ma 1.63 52.15 E 20.83 ba 10.14 y

Example 38 h- a) 6-M-benzyloxycarbonyl-2-(2-(M-ethyl-M-perfluorooctylsulfonyl|amino|acetyl-y-lysine)

To a solution of 31.82 g (113.5 mmol) of 6-M-benzyloxycarbonyl-Y-lysine and 66.42 g (113.5 mmol) of 2-(M-ethyl-M-perfluorooctylsulfonyl)aminoacetic acid (obtained according to OE 19603033) | 49.46 g (200, Ommol) of EEDH (ethyl ether of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) is added to 0 ml of tetrahydrofuran at 0 and stirred overnight at room temperature. After that, it is evaporated to dryness in a vacuum and chromatographed on silica gel (eluent: dichloromethane/methanol in the ratio of 20:1). ,» Yield: 55.79 g (58905 from theory) of a colorless solid.

Elemental analysis: solution: C 36.85 H 3.09 M 4.96 E 38.11 Z 3.78 - and detection: C 36.85 H 3.19 M 4.87 E 38.28 5 3, 95 ml b) M-methyl-M-(2,3,4,5,6-pentahydroxyhexyl)amide 6-M-benzyloxycarbonyl-2-M-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino)acetyl- and -lysine (95) To a solution of 51.02 g (60.2 mol) of the compound indicated in the title of example C8a, 11.75 g (60.2 mol)

Fu 50 M-methylglucamine and 6.93 g (60.2 mol) of M-hydroxysuccinimide in 250 ml of dimethylformamide at 02С add 20.64 g (100.Omol). M,M-dicyclohexylcarbodiimide. The mixture is stirred during the Agreement. at 02C, and then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness under vacuum and chromatographed on silica gel (eluent: dichloromethane/ethanol in a ratio of 20:1).

Yield: 53.05 g (8695 from theory) of viscous oil. 99 Elemental analysis:

He) solution: C 38.68 H 4.03 M 5.47 E 31.52 5 3.13 found.: C 38.49 H 4.17 M 5.32 E31.70 5 3.29 c) M-methyl-M-(2,3,4,5,6-pentahydroxyhexyl)amide 2-M-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|acetyl-y-lysine bo 102.48g (100, mol) of the compound indicated in the title of Example 386 is dissolved in 2000 ml of ethanol and 10.0 g of palladium catalyst (1090 Pa/C) is added. After that, it is hydrogenated for 12 hours at room temperature. Then the catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.

Yield: 89.06 g (quantitative) of a colorless solid.

Elemental analysis: solution: C 33.72 H 3.96 M 6.29 5 3.60 E 36.26 found: C 33.91 H 3.82 M 6.14 5 3.47 E 36.31 d) M-methyl-M-(2,3,4,5,6-pentapdroxyhexyl)amine 6-M-(1,4,7-tris(carboxylatomethyl)|-1,4,7,10-tetraazacyclododecane-10 -M-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)|- 2-M-(2-(M-ethyl-M-perfluorooctylsulfonyl)amino|acetyl-i-lysine, Ca- a complex of 48.58 g (54.55 mmol) of the compound specified in the title of example C8c, 6.28 g (54.55 mmol) of M-hydroxysuccinimide, 4.62 g (109 .Omol) of lithium chloride and 34.35 g (54.55 mmol) of cCa- 1,4,7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methylpent-5-yl)-1,4,7,10-tetraazacyclododecane complex is dissolved under moderate heating in 400 ml dimethyl sulfoxide. Then, at 1023, 16.88 g (81.8 mol) are added

M,M-dicyclohexylcarbodiimide and then stirred overnight at room temperature. The solution is poured into 70 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered and then purified by chromatography (KR-18, eluent: water/ethanol/acetonitrile gradient).

Yield: 73.27g (89.495 from theory) of a colorless solid. Water content: 8.695.

Elemental analysis (in terms of anhydrous substance): solution: С 35.18Н 4.23 М 4.23 5 2.13 Е 21.50 са 10.47 found.: С 35.28 Н 4.15 М 4, 19 52.18 E 21.33 ba 10.61

Example 39:

Distribution of the contrast agent proposed in the invention from example 1 in organs (including accumulation in the tumor and lymph nodes) after its intravenous administration to rats with prostate cancer

After intravenous administration to rats (copulatory inbreeding, 12 days before the experiment, the animals were intramuscularly implanted with prostate cancer cells of the Oippipd K3327 MAT-y line) of the compound from example 1 at the rate of 225 μmol of total gadolinium per kg of body weight after 10 min., h. and 24 hours after administration (p.v.), the metal content was determined in various organs, in the tumor, as well as in the lymph nodes (data for which are grouped in the form of data for mesenteric and peripheral lymph nodes) (the table shows average values - standard deviation, p -3). about " "

F s s u z v « o z s i z z z z Belaya 02001000 89000100 sovomov sl bassa 010001000000001vnyu000000100010000 lom s cathode 00010011 mimo 00010001 evilo b 50 5 byayu 00000001 vya

NN

Note: "Bvml of blood per kg of body weight; "only an aliquot sample of tissue from the muscle of the right leg; """vum on all organs after 10 and bOkhv. p.v. without taking into account the rest of the body; the rest of the body also contains a residual volume of blood.

GF Example 40:

Visualization of lymph nodes (MRO) after intravenous administration of the contrast agent proposed in the invention from example 1 to rabbits with tumor cells UH2 b Fig. 1 shows images of iliac lymph nodes obtained during MR tomography, registered before the administration of the contrast agent, as well as at different time points during of a 24-hour period after intravenous administration to rabbits with intramuscularly (im) implanted tumor cells UH2 of the compound from example 1 at the rate of 200 micromoles of ba per kg of body weight. On T/-suspended images obtained on the basis of gradient echo (1, 5 Tl; sequence: MRKapde; TC 11.1ms, TE 4.Zms, A 152), a significant increase in signal intensity 65, which is formed by healthy tissues of the lymph nodes, is visible. Those areas within the lymph node, in which the signal intensity did not increase, were diagnosed as metastases, which was confirmed histologically (staining of lymph node sections with H/E). However, in later nths of time after the introduction of the contrast agent (after 24 hours), a reverse change in signal intensity was unexpectedly detected. In other words, in the healthy tissue of the lymph nodes, the intensity of the signal generated by them decreased, while in the metastasis, on the contrary, a significant increase in the intensity of the signal generated by them was observed.

It should be noted the unexpected fact that immediately after the introduction of the contrast agent, a clear increase in the intensity of the signal formed by the primary tumor (primarily in its periphery) was observed. At later time points (24 hours after the injection), the intensity of the signal gradually increased towards the center of the tumor.

Example 41:

Visualization of a heart attack (MRI) after intravenous administration of the contrast agent proposed in the invention from example 1 to rats

Fig. 2 shows images of the heart obtained by MR tomography (immediate and postmortem) after 24 hours. after intravenous administration to rats with acute induced myocardial infarction of compounds from example 1 at the rate of 100 micromoles of SA per kg of body weight. On T.-suspended images obtained on the basis of spin echo (1.5

Tl; TC: 40 Ohms, TE: bms; MA: 4; matrix: 128X128; layer thickness: 2.5 mm), a significant increase in signal intensity is visible in the infarcted area. Successful induction of acute myocardial infarction was confirmed by staining with the help of MW.

Claims (23)

Formula of the invention 25 1. Perfluoroalkyl-containing complexes with sugar residues of the general formula aganet, Co o Ce-PO a " in which K means a mono- or oligosaccharide residue attached through the 1-OH- or 1-5H-position, (Ce) means perfluorinated, direct or a branched carbon chain of the formula -С.РонЕ, where сЕ represents the terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, and п means the numbers 4-30, and c) K means the metal complex of the general formula ІІІ M that ов! ; (I) shvish - A- M sha - s Oobs M o . "» Shchi soov! -1 395 in which B! represents a hydrogen atom or the equivalent of a metal ion of serial number 21-29, 31-33, 37-39, 42-44, 49 1 or 57-83, provided that at least two radicals B! mean equivalents of metal ions, F 50 B2 and BZ independently of each other mean hydrogen, C.4-СТ7 alkyl, benzyl, phenyl, -СНоОН or -СНоОСН», and СО is Со с,н, -а - сн, -Фф-,- сн, у "-о-, phenylene group, и" І -сн,-Мнсео-сн,-сНСН.соОоБ- СН, - о-, зв -С,Н,-сСНеН. I- MONOH-CH, -o- HF! or optionally interrupted by one or more oxygen atoms, 1-3-MHSO-groups, 1-3-СОМН-groups and/or substituted by 1-3-(CH») 05СООН-groups C.-C.oalkylene or C7-C12-SeH.-O-group, while 0 means the place of attachment to -СО-, 60 or the general formula ИЙ b5 g РЕ; (1) -щ-- сх а ЧЬ Sherat, M toas ЧЧ and С is a compound in which В has the above values, ВЕ means hydrogen or the metal ion equivalent specified for В! and ШТ means -с 6Н.,-0-СН a --, where d means a place joining to -CO-, or the general formula IM that Ov!mM --7 » I rat M toas CHI / a MI SHCHI sch 29 soov! oh in which B! and 22 have the values indicated above, or the general formula MA or MV so (MA and stos MV - С tb -soov! e) A- topa CHI YASHYUZHYUK- I oo o mech I in pok shchi sao, (uv - - , (MV ) с - соов8 Per "e-- Y sook! a shi с -ооов;" in which V! has the above values, or the general formula MI MI) rRat- 5 ikh Sela, y -i M MA 5, vos-. t-- sooo! in which B! has the above values, (95) . or of the general formula MY (22) caste- - a ; (MI) II i» voob--7 ry 1 KE ny 29 va yb--tlo (F) in which ka В has the values indicated above, and Ц means -С ён. -0-СНа -Ф- where Ф means the place of attachment to -СО-, 6о or the general formula MY! b5 th ov ; (MIP) -Ch - na -oos g on to soov! in which B! has the above values, while the free acid groups optionally present in the K residue may optionally be represented in the form of salts of organic and/or inorganic bases or amino acids or in the form of amino acid amides, 15 C in the case that K means metal complexes of formulas II-MII, is at least a three-fold functionalized residue selected from the following residues a)-Y): (a) n sch 25 (c) n o T Arno Hn V IN « to and ge! and so (s) 0. , Io) 35 | and - " V A- I M MA t s M " 45 o She (a) R ' I Me, Z-M -- p CHI 0, goes - -I M MI u yu imme) E 60 (e) b5 t , 9 so 10 and | "M V same--Oh and No. (9 N ! mn--so--0--(SNUYU i s slav i N y and MO Z 2 same so- y - (sn 5y,- Male N | Н N s and o (9) : | « Min Ge) so mn--so--sn--("СНАр МН рой | и- mmMm-с0-en-А-(сСНЯАИ-МНемм о « и - s | ; ;" mmNA--со- сн - (SNAYA2-A- MNema r MN ih: s V (9) (p) FO shi - M (СН 6--D-so-6- (nar M--yav I HT» so o: t v o () t bo 65 yins 1 M n in SHU SNIN bosom M--y in MN KI SCHO ICH y and p (f o yaki ShCMNA- o - 00 - i o tro, E s in the event that K means the metal complex of the formula MI , is at least a three-fold functionalized residue selected from the residues K) and I): (yu E li --МН-- «SNAU СНА - СО lak o, МН Ge and (о) 7 () кы чме-ШВ со Сны сНИИ - Soy that "МН Е" со Е со at the same time s means the place of attachment of C to the complex K, p means the place of attachment of C to residue M, and ty means the place of attachment of C to residue 7, and M means /--СН »j»-, 5-(снН2)сОо -в (where //п-1-5), в-сСНа-сНОноН -со-рв or 5в-снНИсСнНОН -сНасНИ)-сСнНОнН -СНОН о -сSO -р, where 5 means the place of attachment to the sugar residue K, and p means the place of attachment to the residue 0, " 27 means the group - a seam." And " t-сОСН with -М(СоНе)- 502 -, 15 t-сОосСН 3-2 - (SN.) -502-, -I п и во я1--5 o M-VO and or Ф 20 Ж-МНеНОСН.-Оо -СНаСНі -х, ГТ" where t means the place of attachment of 7 to the C residue, and E means the place of attachment of 7 to the perfluorinated residue K,, Y, t independently of each other mean integers 1 or 2, and p means integers from 1 to 4. 2. Metal complexes according to claim 1, which differ in that the equivalent of the metal ion B! is an element with (F) sequence number 21-29, 39, 42, 44 or 57-83. to Z. Metal complexes according to claim 1, which differ in that the equivalent of the metal ion B is an element with serial number 27, 29, 31-33, 37-39, 43, 49, 62, 64, 70, 75 or 77. 4. Metal complexes according to any of claims 1-3, which differ in that K means a monosaccharide residue with 5-6 C atoms or its deoxy compound, preferably glucose, mannose or galactose. 5. Metal complexes according to any of claims 1-4, which differ in that K is a metal complex of the general formula II. 6. Complexes of metals according to claim 5, which differ in that 22 iv independently of each other mean hydrogen 65 or S.-Sualkil. 7. Metal complexes according to any of claims 1-6, which differ in that E in the formula -SuRodpE means a fluorine atom. 8. Metal complexes according to any of claims 1-7, which differ in that C in the general formula | means a lysine residue (a) or (b). 9. Metal complexes according to any of claims 1-8, which differ in that 7 in the general formula I means the group 7- - 5 0 -805- b where t means the place of attachment of 7 to the C residue, and E means the place of attachment 7 to the perfluorinated /o residue of KE. 10. Metal complexes according to any of claims 1-9, which differ in that MU in the general formula | means the group 5-сСН.асо -рД, where 5 means the place of attachment to the sugar residue K, and p means the place of attachment to the 0 residue. 11. Metal complexes according to any of claims 1-10, which differ in that I in the metal complex K means -СН-or -с еН,-0 -СНа -о, where 0(d means the place of attachment to -СО -. 12. A pharmaceutical agent containing at least one physiologically compatible compound according to any of claims 1-11, optionally in combination with additives commonly used in galenic preparations. 13. The pharmaceutical agent according to 12, which differs in that it is a contrast agent for use in NMR and X-ray diagnostics, which contains the compound according to item 2 as an active substance. 14. The pharmaceutical agent according to 12, which is characterized by the fact that it is a contrast agent for visualization of infarctions and necrosis, which contains as an active substance the compound according to point 2. 15. The pharmaceutical agent according to 12, which differs in that it is a contrast agent for use in radionuclide diagnostics and radiation therapy, which contains as an active substance the compound according to item 2. 16. The pharmaceutical agent according to 12, which is distinguished by the fact that it is a contrast agent for Go) use during lymphography for the diagnosis of changes in the lymphatic system, which contains as an active substance the compound according to point 2. 17. The pharmaceutical agent according to 12, which differs in that it is a contrast agent for use in indirect lymphography, which contains as an active substance the compound according to item 2. With 3o 18. The pharmaceutical agent according to 12, which is characterized by the fact that it is a contrast agent for (Ce) use in intravenous lymphography, which contains the compound according to item 2 as an active substance. 19. The pharmaceutical agent according to 12, which is characterized by the fact that it is a contrast agent for visualization of the intravascular cavity, which contains as an active substance the compound according to item 2. 20. The pharmaceutical agent according to 12, which is characterized by the fact that it is a contrast agent for visualization of tumors, which contains as an active substance the compound according to item 2. - 21. The pharmaceutical agent according to 12, which is characterized by the fact that it is a contrast agent for visualization of abnormal permeability of capillaries, which contains as an active substance the compound according to point 2. 22. The method of obtaining perfluoroalkyl-containing complexes with residual sugars of the general formula | " with Ogo (E-Vdv with c with Se-to in which K means one of the metal complexes of the general formulas 1II-MII according to claim 1, 5 represents one of the groups of formulas a)-i) of item 1, and M, 7 , K, K,, t, p and I have the meaning specified in claim 1, which differs in that the carboxylic acid of the general formula Ia V. his; (Pa) ; и 2 еще я А. Ф 8th Я гтну он T» voos ЧИ ХО ОЧ 25 обов (Ф; in which 2? means the equivalent of the metal ion of serial number 21-29, 31-33, 37-39, 42-44 , 49 or 57-83 or a carboxy protecting group, and B2, BZ and I) have the above values, or a carboxylic acid of the general formula Sha 60 b5 7 ee; (Sha) S Still soma ХШТ-О m A he as ЧИ ЧО And that Mosk in which 7, В и Ш! have the above values, or a carboxylic acid of the general formula Ma re te "(Ma) 15 , Also E2 an shoos 8 I 20 What is the difference in which B? and B? have the values indicated above, or a carboxylic acid of the general formula Ma or Mr Cso-Oon, Ma and - --- (Ma) сч с 7-оове о and п-еооне - 30 (Се) шию; (MB) with 7A-soone o iv) 5 zv NOO or Ya-sov Shchi p-hye0or5 de V? has the values indicated above, or a carboxylic acid of the general formula Mia « ; (Mia tob i - so-on (a) М M - s voos--7 7-- soore z" in which VE? has the values indicated above, or a carboxylic acid of the general formula Ma OO a ; (Mig) not ni VVOOS 3 ВШ on -I base 1 MI vs 5 (95) in which V? and SHO! have the above values, not necessarily in the activated form are subjected to interaction under the conditions of the coupling reaction with the amine of the general formula ХХ Х» n ) Set 59 in which ОС, К, К,, У, 7, т and р have the above values, and then, if necessary, the protective groups present under (Ф) certain conditions are removed with the result of obtaining a metal complex of the general formula I or, if В ? 7 is a protective group, after cleavage of the specified protective groups, at the next stage, they are subjected to interaction according to a known method with at least one metal oxide or metal salt with serial number 21-29, 31-33, в 37-39, 42-44, 49 or 57-83, after which, if necessary, acidic hydrogen atoms present under certain conditions are replaced by cations of inorganic and/or organic bases, amino acids or amino acid amides. 23. The method of obtaining perfluoroalkyl-containing complexes with sugar residues of the general formula и;() 65 Ср in which K means a metal complex of the general formula MI according to claim 1, C represents a group of the formula K) or I) according to claim 1, and M, 2, K . (MPa); и чо N ОВС С. ЧО М он spdydge in which VZ means the equivalent of a metal ion with serial number 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or 75 carboxy protecting group, is subjected to a known method of interaction under the conditions of a coupling reaction with an optionally activated carboxylic acid of the general formula X HO-o-(2-Roa (X) Se-Por in which b, K, K,, M, 7, t and p have the above values, and then, if necessary, the protective groups present under certain conditions are cleaved with the result of obtaining a metal complex of the general formula I or, if B 9 is a protective group, after cleaving such protective groups at the next stage, they are subjected to interaction according to a known method with at least one metal oxide or metal salt with the serial number 21-29, 31-33, ch 37-39, 42-44, 49 or 57-83, after which, if necessary, the acidic hydrogen atoms present under certain conditions are replaced by cations of inorganic and/or organic bases, amino acids or amino acid amides (o) « (Se) so IS) m. - with . and? -I 1 (95) b 50 s» F) ime) 60 b5