UA74004C2 - Complexes containing perfluoroalkyl with polar radicals, their synthesis and application - Google Patents

Abstract

The invention relates to complexes containing perfluoroalkyl with polar radicals of general formula (I), wherein R represents the polar radical, Rf is a perfluorated carbon chain, ?? is a metal complex and Z is a linker group. The inventive complexes are suitable for intravenous lymphography, tumor diagnosis and infarct and necrosis imaging. , (??)

Description

Description of the invention

The present invention relates to the objects described in the claims, namely, perfluoroalkyl-containing 2 metal complexes with polar residues 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 83905 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 on the background that does not create spurious signals.

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

So, for example, in the patent O5 4639364 (in the name of MaiyipsKgodI) trifluoromethanesulfonamides were proposed for use as contrast agents in "UE-tomography: scher SEZ5OOMN" and

SEZ5OMN-СНО-(СНОН))-СНоОН. at

In the same way, patent OE 4203254 (in the name of Makh-Riapsk-SeveiIzpaty) belongs to ""E-tomography, in which an aniline derivative of the following formula is proposed:

SE o 19g-tomography is the object of the application UMO 93/07907 (in the name of MaiipskgodO), in which derivatives of "I phenyl for use as contrast agents are also proposed: but he and -

SE, SE, I o, Shk

I and no o st in Y « nos In so, ; what with st, | se, i g i i z". compounds with a much simpler structure were also proposed for use in E-tomography.

So, for example, in patent 05 4586511 (in the name of Spiidgep's Nozria! Medisa! Sepieg) described perfluorooctyl bromide of the formula o CEa(Ce2);-Bg, in patent ER 307863 (in the name of Aig Rhodisiv) is declared perfluoro-15-crown-5-ether of the formula

E h -e : E 60 MORE: in the patent 05 4588279 (in the name of MOpimegeyu oi Sipsippaiyi, SpPiidgep' Nozriiai Kezeagsp Eoshpaaiop) described perfluorocarbon compounds, such as perfluorocyclononane or -octane, simple perfluorinated ethers, such as tetrahydrofuran of the formula b5

EE E

E and E ve» DE

NI: or simple diesters, such as the perfluoropropylene glycol diester of the formula

se, se,

E --9- SEE vyt o --k 70 ov s,

Similarly, for use in "P-tomography" described in the application UMO 94/22368 (in the name of Moieszag

Viozuvietv) compounds, for example o-so-ondene. t snusndusnnsnenakoo- o

And "thistle ka. g с-СЕ, х o СЕ" in s ': z uv, s also o which as a fluorine-containing residue contain a perfluoro-1H,1H-neopentyl group.

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. Such a 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 4586511. | "in)

In patent OE 4008179 (in the name of Zspegipu) it is proposed to use fluorine-containing benzenesulfonamides as "pH-probes:

SE, m.

E mnZO; snn, so

Compounds containing iodine and fluorine atoms and described, for example, in applications MO 94/05335 and MO 94/22368 (both under the name Moiiesshiag Viozuvieptv) are also intended for use in NMR diagnostics as substances that increase contrast ):

I» ' y snysneso,n -I E me a o I

MNSOSE, o u y

And (U (SnaeSOor C(SE,);

Yes! and | 6.

And. eat

Y (5 (sneso (SE) o -k 7 N.M. I

For use in E-tomography, a combination of fluorine-paramagnetic metal ion is also intended, while 60 we are talking about complexes with an open chain, as an example of which in the application UMO 94/22368 (in the name of MoYiIesshag

Viozuvietv) named compounds of the formula b5 i nu--nuoyut i zy Z oomn-- sn,

In ; thank you

C(SE.). 0 О(СЕз ве С(СЕ С(СЕз)а 7 V i to a in EP 292306 (in the name of TEKOMO Kabrigpiki Kaizna) specified compounds of the formula и dod iz oou 12 , А С . сазя о со,

GOD

SE, EE; . -онсн--М se, и -сН; "In Go)

Sa ya-zh - y se « shk o and also about cyclic compounds described in EP 628316 (in the name of TEKOMO Kabryzgwnpiki Kaizna): t 2-5 y sl shi ah oyu tm Mo; From what (С сх и ДИ и ва Z им. Mo Me so; и Щ bo; : « shi s | ; ч Kk: f no stu SE; de; | se, U - -sn--0 U ov , -sne- M. se, z se, («c) se, (ав) 20 For NMR spectroscopic temperature measurements in OE 4317588 (in the name of Zspegipdu) it was proposed

GT" also use the following combination of a fluorine atom and a rare earth element: vd ikh and Toou

M. M. (S chih Z also

F) M F only about M. SE; co; because Y 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, then 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 65 unpaired electrons of the metal ion (sa » Mp? o» BeZi » Si?) and on the distance between the paramagnetic ion and the 19E 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 is shortened.

Reduction of 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 (Madpemizide, Rgopapse?b, OtpizzapF), Ooiaget).

In H-MR tomography, however, the relaxation time of Ti or To protons, i.e. primarily water protons, and not the relaxation time of fluorine nuclei is determined and the obtained data are used for visualization. The 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 have been successfully used to reduce the relaxation time by 70. The table below shows data on the relaxivity of some commercially available drugs:

Set re (l/mmol-s, 392C, 0.47 Tl (l/mmol-s, 392C, 0.47Tl

AND

In these compounds, only the interaction between protons and the gadolinium ion occurs. The relaxivity in water found for these contrast agents is approximately 4 l/mmol-s.

Thus, both fluorine-containing compounds intended 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.

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 techniques (o) properties of those compounds that were previously considered suitable only for use in imaging techniques , 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 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 application ("in") of these compounds are limited, since in many cases they do not allow to achieve satisfactory results. With this in mind, the need for contrast agents intended for visualization of malignant tumors, lymph nodes, and necrotic tissues remains today, as in the past. "

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 tspa Rgahiz, edited by EgottPoiI9, Z(epdeg, Tyigp, volume IM, ed. Tpiete Megiad, ZishNdag, 7th ed., 1984, pp. 434-496)|. The possibility of diagnosing metastasis to the lymph nodes is important for the therapy of 20 oncological diseases and forecasting their development. Modern methods of imaging (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, "z" can only be used as criteria for the appropriate diagnosis the size of the lymph node. 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 et al., bopodharpie pa - Ketgzripiotodharpie: Oiyegepiiaidiadpovik mop geakiimeg I utriKpoiepmegogoyegpud pa GutriKpoiiepteg(aviazep at Naiv, Kadioi. aiadp. 33 (1992), p. 1581. ve With this in mind, it is advisable to ensure when using specific contrast agents the ability to differentiate 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 ("in an oil suspension of a contrast agent into an appropriately prepared lymphatic vessel), which, however, in

T" is currently used only in rare cases and allows visualization of only some ways of lymph outflow.

In the experiments carried out on animals, dextran with a fluorescent label is 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 the lymphatic ducts and (F) lymph nodes are substances in the form of solid particles ("macroparticles", such as emulsions and

GI suspension 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. 65 To achieve the required 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 as early as 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.

One of the important tasks of medicine is the detection, localization and monitoring of necrosis and heart attacks. 7/o So, in particular, a myocardial infarction is not a stationary, but a dynamic process that occurs over a long period of time (from several weeks to several months). This cardiovascular disease occurs in approximately three stages, which cannot be clearly distinguished, because they overlap one another, and accordingly 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 /5 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.

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, information about how large a proportion of the tissue lost during a heart attack and in which location is crucial, as 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. high school

If the infarcted tissue is to some extent amenable to healing, then with necrosis, that is, with locally limited dead tissue, one can only prevent or at least mitigate its harmful consequences for (8) the rest of the body. The occurrence of necrosis can be caused by a wide variety of reasons and, in particular, injuries, exposure to chemicals, lack of oxygen, or radiation. Similarly to a heart attack, the presence of information about the degree and type of necrosis is important for the selection of subsequent medical measures. With this in mind, attempts have been made for a long time to increase the efficiency of localization, that is, determining the location of infarcts and necrosis due to the use of contrast agents with 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, the results obtained in such studies are contradictory. So, in particular, in work -

MuipKeItap and Nowez, published in Maishge, 200 (1967), p. 903, refers to the selective accumulation of manganese-5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (TFPS) in the necrotic area of the tumor.

In contrast to this, in the work of I uop et al. (Madp. Kez. Med. 4 (1987), p. 24) refers to the effect 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 the specified substance in the tumor reaches a maximum only on the 4th day after the first injection, and then only after increasing the dose from 0.12 mmol/kg to 0.2 mmol/kg. Therefore, the authors also conclude about the non-specific accumulation of TFPS in the tumor tissue. In the work of VoskKpytgvzi and others, published in ;" Asia Meigospig. 60 (1994, addn.), p. 347, again refers to the selective binding of MP-TFPS to tumor cells.

In turn, according to the results of research conducted by Eozieg et al. (9). MysiI. May 26 (1985), p. 756), -And it was established that 711Ip-5,10,15,20-tetrakis(4-M-methylpyridinium)porphyrin (TMPiP) accumulates not in the necrotic area, but in the living marginal layers, which surround her. On the basis of 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 av | reality

In the work of Mee et al., published in Sigstiaetsyop, vol. 90, Mo4, part 2, p. 1468, Abstract Mo2512 (1994), it was reported about the possibility of visualization of areas affected by a heart attack using

Chl» of manganese-tetraphenylporphyrin (Mp-TFP) and gadolinium-mesoporphyrin (54-MP). According to the application U/O 95/31219, both of these substances were used to visualize infarctions and necrosis. In this application, the authors of which are Magesnai! and Mi, it is said (see example 3) that when using the za-MP compound, the metal content in the infarcted kidney was at the same level as in the non-infarcted organ, while the metal content in the infarcted tissue was in the myocardium (see example 1 ) was nine times higher than its content in non-infarcted tissue.

F. 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 was 2.10 and 2.19, respectively . Other metalloporphyrins are described in the 6th application OE 19835082 (in the name of 5spegipud 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 appears when using porphyrins as a diagnosis of diseases. In addition, porphyrins have only an exceptionally low therapeutic index, since, for example, in the case of MP-TFPS, its 65 effect is manifested only when it is used in a dose of 0.2 mmol/kg, while its lethal dose of LD is already 5u

Oh, bmmol/kg.

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

Based on the above, the present invention was based on the task of offering contrast agents that would be suitable for use primarily in MRI-lymphography, as well as for diagnosing tumors and visualization of necrosis and infarctions.

This problem is solved in accordance with the invention with the help of perfluoroalkyl-containing complexes with 7/0 polar residues of the general formula I (K-6-(2-

Х х (FO in which t Kro denotes a perfluorinated, straight or branched carbon chain of the formula -СРоРЕ, where

E represents the terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, and n means the numbers 4-30,

K means a metal complex of the general formula ЯЙ in which shk p

I ozh-2 M M roi, p

KoOos and I o soov I. x Fu "

B" represents a hydrogen atom or the equivalent of a metal ion with the serial number 21-29, 31-33, 37-39, 42-44, 49 av! or 57-83, provided that at least two radicals EB! mean equivalents of metal ions , o

B2 and BZ independently of each other mean hydrogen, S-Alkyl, benzyl, phenyl, -СНоОН or -СНоОСН with "

O is -S. 5НА-О-СН»о-о-, -««ОН»)4.5-0-, phenylene group, -СНо-МНСО-СНО-СН(СНСООН)-СевНа-о-, chn -Сена(ОоСНоСНо)Юю . -M(СНСООН)-СНо-о- or optionally interrupted by one or more oxygen atoms, 1-3 -МНнСО-groups, 1-3 -СОМН-groups and/or substituted by 1-3 -СНо)5СООН-groups S.-Si»alkylenov or

С.-С12-СеН,-О-group, while o means the place of attachment to -СО-, or the general formula PI « sov g | shi s and Shk boon g» lady pan kOoos S, r. ; M. - shchi t "soor p

SO (PP), them (0) o in which o 50 V has the above values,

ВЕ means hydrogen or the equivalent of a metal ion indicated for B, and из" 7 means -SeН.-О-СН»о-о-, where o means the place of attachment to -СО-, or the general formula IM

SsosoKU : ( : o osi U vo S and sov ah in which B! and 22 have the above values, or of the general formula MA or MV b5 s k-soov vieoS 7 kdd " Zno evov:

Sov (ХАХ; ky obov o E k-sOOv 70 Y sya ky boov" in which E! has the values specified above, or of the general formula MI t5 pos ut to00- Z-сО0 0 ol, in which KE! has the values specified above, or the general formula MY

VieOS--. o ek M

Oo0- t oobt voo0A- - I (MI), p. 29 in which Ge)

Whew! has the above values, and

ШТ means -СеНа-О-СНо-о-, where ю means the place of attachment to -СО-, while the free acid groups optionally present in the К residue may optionally be represented in the form of organic and/or inorganic salts bases or amino acids or in the form of amides of amino acids, o means at least a three-fold functionalized residue selected from the following residues a)-Her): - (c) o i. everything - (SNO dreams Z

MA. m. i r z (B) « shk | v - s 7 t k-so-V.(snugnnnV ;" and s z. -I sh" ("c) at 50 s"

F) name) 60 b5

(c) se

Fe

And h / rya -M MA and shchi it; "4. p » B;

Wednesday | Met

Si sch

In (o) (e and U

Her father

So Ha") ah "

Shchi and Shchi -

For--4 Mem

Sh NN n , 83) « ! But N in what page M -(SNddDY-M-So o-(sndduAR s and so and I. shchi. I I MN . Z i 3 r , -I i (9 o NM M "MN

T» « 7 B. where o means the place of attachment of C to the complex K, p means the place of attachment of C to residue K, and y means the place of attachment of o to residue 2, o 4 means the group ko i-Mx. | UMO where y means the attachment site of 7 to residue 0, and y means the attachment site of 7 to the perfluorinated residue

Kk,

K is a polar residue selected from K complexes of the general formulas of II-MII, and in this case

Whew! means a hydrogen atom or the equivalent of a metal ion with serial number 20-29, 31-33, 37-39, 42-44, 49 or 57-83, and the residues K2, KZ, Kk, ) and 07! have the above values, and in the case when C is a residue of formula (c) or (4), and K is a complex selected from the complexes of general formulas P and M, K cannot be identical to residue K of general formula I , if 7 is 5-С(О)СНоО(СНо)»о-е, or is a residue of folic acid or attached via -СО-, 505- or a direct bond to a residue С carbon chain with 2-30 С - atoms, which is straight or branched, saturated or unsaturated and which is optionally interrupted by 1-10 oxygen atoms, 1-5 - МНСО-groups, 1-5 - СОМН-groups, 1-2 sulfur atoms, 1-5 - MH-groups or 1-2 phenylene groups, which may optionally be replaced by 1-2 OH-groups, 1-2 MH-o-groups, 1-2 -СООН-groups or 1-2 -505Н-groups, or necessarily substituted by 1-8 OH-groups, 1-5 -COOH-groups, 1-2 5О zH-groups, 1-5 70. МНо-groups, 1-5 C.-C. p independently of each other mean integers 1 or 2.

If the compound proposed in the invention is intended for its 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 ordinal 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, iron(Ii), cobalt(Ii), nickel), 75 copper(I), praseodymium(Ii), neodymium(Ii), samarium(Ii) and ytterbium(I ). Given their high magnetic moment, gadolinium(I), terbium(I), dysprosium(I), holmium(II), erbium), iron!) and manganese) ions are the best.

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 p

Means that contain a physiologically compatible complex salt with metal ions of serial numbers 25, 26 and 39, as well as 57-83. Manganese), iron(s), iron(I), praseodymium(II), neodymium(II), samarium), gadolinium), ytterbium(I) or bismuth(Ii) ions, primarily dysprosium ions, are the best. ) and yttrium(I).

Under certain conditions, acidic hydrogen atoms present in BC, i.e. atoms that are not replaced by a central ion, may optionally be completely or partially replaced by cations of inorganic and/or organic bases or amino acids or amino acid amides. As an example of acceptable inorganic cations may include lithium ion, potassium ion, calcium ion and especially sodium ion Acceptable cations of organic bases are, in particular, those of primary, secondary or tertiary amines such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, av

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

To the best compounds of the general formula | belong to compounds that contain macrocycle K of the general formula II, I, MV or MI.

The residue I in the metal complex K preferably means -СНо- or -СН/-О-СН»о-о-, where ой represents the place of attachment to -СО-. "

Alkyl groups in the macrocycle of the general formula II indicated as the values of K 2 and KZ can have a straight or branched chain. At the same time, methyl, ethyl, propyl, isopropyl, n-butyl, ts 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl can be cited as examples. Preferably, 2 and BZ independently of each other mean hydrogen or C.-C.alkyl. In one of the particularly preferred variants, 22 means methyl, and BZ means hydrogen.

The benzyl group or phenyl group in the macrocycle K of the general formula I is indicated as the value of K 2 or KZ! - 15 can also be substituted in the ring.

The polar residue K in the general formula I in one of the preferred variants is a complex K, which, in addition to Ba437- or Mp"-complexes, can also be a Ca"-complex. The most preferable polar residues are the K complexes of general formulas II . . (Оо)Ссн.ОосносСООн, -802СнН.СснсСООоНн, -5(0)-SeNaz-(m-СООН)», -FKO)СНоО(СНо)»-SeNai(m-СООН)», -FO)СнН»Оо -SeNu-m-5OZN, in B(Оо)СНоМНеосн.Мне(оснооснон, -(Оо)Ссн.осСносноосноБсСоон, -косносн.н(ОнсНноо-СНо.СНоОН, -ко)сн.осн.сн(оншесносНно-СН( ОН)-СНоОН, -Ф«О)СНоЖЗОзЗН,

Ф) -"0сСнН.сСнНьсСОоОон, -"Оо)Ссн(ншеснонеНноонон, -ФК«О)СНоОСН2)»О.а-СН», -ФК«О)СНоОСН2)»ОИ.о-Н, ka -«О) SnNoOosn(СНоОН)», -«Оо)СsnoОосн(СНоОСНоСООН)», -С(0)-SeNaz-(m-ОСНОСООН)», -бе0-сныо-(снНИЙо(СНИ»О-(СНИ»ЯС(СНОИ)) ОСсН», preferably -Ф(О)СНО(СН2И»О0-СНу. 60 In another, better version, the polar residue K is a residue of folic acid.

Among the compounds proposed in the invention of the general formula | compounds in which K; means -CaE2a444. n preferably means numbers from 4 to 15. The most preferred residues are -С/Ре, -СеР4з, -СвЕ47, -С412Еов and -045Его, 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 65 best embodiments of the invention means a lysine residue (a) or (B). 7 means the linker indicated for the general formula I, and the group is better

7-M. and M-5026

The method of obtaining perfluoroalkyl-containing metal complexes with polar residues of the general formula

F-O-(2-Kd (U

FO, in which K, b, K, 7, K,, 1, t and p have the above values, consists in the fact that the carboxylic acid of the general

II

70 of formula Ia

M

SK

"vost" ti and swot (Pa), in which RE? means the equivalent of a metal ion with serial number 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or a carboxyl protecting group, and 7, VZ and y have the above values, or a carboxylic acid of the general formula Sha sosv

PA sch "z - o I will add I to ON,

Shk that r am KO 5 -

С « sov (Ша), in which В», ВУ 0 have the above values, or a carboxylic acid of the general formula ma av!

U, ve volya Men koOos uy "zhi y - Tsny shshch s Chesov am) " in which B? and 22 have the above values, or a carboxylic acid of the general formula Ma or Mr

SHHI te V lek SOS, - s oov s M sov

What --fi - oh khan. -soor (Ma), ongevove (uv) o " where KE? has the values indicated above, or a carboxylic acid of the general formula Mia s» kosy у bo-оН vobs- З-бООЖ (la, in which E? has the values indicated above, or a carboxylic acid of the general formula Ma o vyuyus--k o o in PRI ob2-7 7 On vo oo ch te i ih . voo0- Supvu in which VZ Her 0! have the values indicated above, not necessarily in the activated form, subjected to a known method of interaction under the conditions of a coupling reaction with an amine of the general formula M b5

H-O-(YAKdv p.

And (MIV); in which b, K, 27, K,, t, and p have the values indicated above, and then, if necessary, the protective groups present under certain conditions are cleaved off, resulting in a metal complex of the general formula I or, if B 9 is a protective group, after cleavage of such protective groups at the next stage 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, present under certain conditions, acidic hydrogen atoms 70 are replaced by cations of inorganic and/or organic bases, amino acids or amino acid amides.

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 Sha can be obtained similarly to example 4, given below in this description. The method of obtaining carboxylic acids 72 of the general formula Ma is described in OE 19728954.

The precursor of compounds of the general formula MA is

MZ-(2,6-dioxomorpholinoethyl)-M 9U-(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 DTPC is described in OE 19507819 and 70 OE 19508058.

Compounds of the general formula MI are derivatives of M-(carboxymethyl)-M-(2-(2,6-dioxo-4-morpholinyl)ethylglycine, the method of preparation of which is described in -). At. OH Spent os, 59 (2) (1982), pp. 104-107.

Compounds of the general formula MI! are derivatives of 1-(4-carboxymethoxybenzyl)ethylenediaminetetraacetic acid, the method of preparation of which is described in OZ 4622420. ch. 29 The preparation of amines of the general formula MIII is described in detail in the examples given below in this description, and Ge) therefore, the specified compounds can be obtained similarly to those considered in these examples of methods.

The metal complexes proposed in the invention are suitable, as it was found, for use in NMR and X-ray diagnostics, as well as in radionuclide diagnostics and radiation therapy. In accordance with this, the object of the invention is also the use of the proposed perfluoroalkyl-containing metal complexes with polar residues for the preparation of contrast agents intended for use in NMR and (ab) X-ray diagnostics, primarily in lymphography, for diagnosing tumors and visualization of infarctions and necrosis, as well as with radionuclide diagnostics and radiation therapy. The compounds proposed in the invention are most suitable for use in interstitial and primarily in intravenous lymphography. Along with this, “And they can also be used for visualization of the intravascular cavity (as contrast agents for visualization of blood pools). -

The object of the invention are 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 (concentration) in the lymph nodes of three sequentially located levels (which is especially important for intravenous lymphography). Due to this, they are particularly suitable for use in MRI-lymphography. :z» 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 compounds proposed in the invention allow using NMR tomography to clearly differentiate tissue with good and poor blood flow and thereby diagnose ischemia. Likewise, 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 a possibility 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 contrast agents used until now as contrast agents for (av) 50 visualization of blood pools with macromolecular compounds, such as, for example, ca-DTPK-polylysine, the compounds of

GT" according to the invention also have a higher T.-relaxation and, accordingly, they are characterized by a higher level of signal intensity during NMR imaging. Since, in addition, such compounds are retained in the blood for a longer period of time, they can also be administered in relatively small doses (for example, 5 µmole per liter of blood circulating in the body). However, an equally important advantage of the 59 compounds proposed in the invention is that they are quickly and almost completely removed from the body.

GF) In addition, it was established that the compounds according to the invention accumulate in areas with increased permeability of 7 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, and selectively reduce the relaxation time , respectively, the period of blood thickening and visualize the permeability of blood vessels. It is impossible to obtain this kind of physiological information 60 when using extracellular contrast agents, such as, for example, Ca-DTPK (Madpemiziv). 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 monitoring of the course of treatment during cytostatic, anti-inflammatory or vasodilating 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.

The pharmaceutical products proposed in the invention are obtained according to known technology by suspending or dissolving complex compounds according to the invention, if necessary in combination with additives commonly 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, for example, physiologically compatible buffers (such as tromethamine), complexing agents (such as diethylenetriaminepentaacetic acid) or weak complexes or Ca-complexes corresponding to the metal complexes proposed in the invention or, if necessary, electrolytes such as sodium chloride, or at necessary antioxidants, such as ascorbic acid. 70 If it is intended to use suspensions or solutions of the agents proposed in the invention in water or physiological saline solution for enteral, respectively parenteral administration or for other purposes, then they are mixed with one or more auxiliary substances commonly used in galenic preparations (for example, with methylcellulose, lactose, mannitol ) and/or with one or more surfactants (for example, with lecithin, HmeepF, Mougier) and/or with one or more 7/5 Corrigents (for example, with essential oils).

In principle, the pharmaceutical means according to the invention can also be obtained without isolating the complexes. However, in any case, in the process of formation of chelate compounds, the conditions should be especially carefully observed, which 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 a toxic effect. For these purposes, the process of obtaining complex compounds is possible

Monitor by titration using, for example, colored indicators such as xylenol yellow-brown. 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 i) intravenous administration. However, depending on the investigated object - vessels or tissues - they can also be prescribed for intravascular or interstitial/intradermal administration.

Pharmaceutical products according to the invention contain preferably from 0.1 μmol to 2 mol of the complex per l and are intended for "g

Zzor 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 make it possible to increase the informativeness of the image obtained with the help of an NMR-tomograph by increasing the intensity of the signal after their oral or parenteral administration. In addition, such means have high efficiency, which is necessary to reduce the concentration of foreign substances 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 osmolarity, it is possible to obtain highly concentrated solutions based on them, which allows you to maintain the volumetric overload of the circulatory system within acceptable limits and compensate for the dilution of such solutions with body fluids. The means proposed in the invention also have not only high ip mio stability, but also reveal an unexpectedly high ip mimo stability, due to which the release or exchange of bound in the complex;" ions, which in principle are toxic, occurs only extremely slowly during the period of time during which the new contrast substances are completely removed from the body.

Usually, the agents proposed in the invention when used as NMR diagnostics are used in doses of 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 reagents with ve magnetic susceptibility and shift reagents in NMR-spectroscopy ip mimo. o Means according to the invention, due to their optimal radioactive properties and high stability of 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 "Kadioiigasegg Tog Meadisa! Arriisaiopeg", ed. SKS-Rgezv, Vosa Kap, Riogida.

The compounds and means proposed in the invention can also be used in positron emission tomography, which uses emitting protons of isotopes, such as, for example, C, "Bs, Ee, Co, 98(za) and 86U, see M.O. Neivv and M. E. Rieirv, Rozygop Etivviop Totodgarpu oi Vgaiip, ed-vo Zrgipdeg Mepad, Vegiip, Neideiregd, Mem mogk (1983)).

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

The compounds according to the invention also differ in that they are completely excreted from the body, thus exhibiting good tolerability.

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 appropriate diagnostics is only in the amount and type of isotope used. The goal is the destruction of tumor cells under the influence of 65 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 with neutron radiation is used.

Thanks to this effect, it is possible to significantly increase the local radiation dose in the place where the metal complex is located (for example, in tumors). To ensure the same radiation dose in malignant tissue

The use of such metal complexes allows you to significantly reduce the dose of radiation to healthy tissues and thereby prevent unwanted side effects for patients. Therefore, the conjugates of metal complexes proposed in the invention are also suitable for use as radiosensitizing substances in radiation therapy of malignant tumors (for example, due to the use of Mössbauer effects or in neutron capture therapy). As an example of acceptable ions emitting B-rays, 465c, 4756c, 85c, "7(Za, "Za and Ou can be named. Acceptable ions emitting o-rays with a short half-life can be named, for example, Vi .

If the tool proposed in the invention is intended for use in radiation therapy according to the method proposed by K.Yi. Miiiev and others. see Mayte, vol. 336 (1988), p. 787)|), then the central ion 719 must be a derivative of the Mössbauer isotope, such as, for example, Re or y,

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 type of cellular disorder, the used metal ion and the type of imaging method.

The 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 intended for intravascular or interstitial/intradermal administration.

The agents proposed in the invention are also suitable for use as radiopaque substances, and 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 to absorb radiation in the range of higher voltages on the tube, are most suitable for use in digital subtraction techniques.

As a rule, the means proposed in the invention when used as radiopaque substances C are used similarly to, for example, meglumine diatrizoate in doses from 0.1 to 1 mmol/kg, preferably from 0.25 to 1 mmol/kg.

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

Examples of implementation of the invention

Example And 2-M-trifluoroacetyl-6-M-benzyloxycarbonyllysine 100g (356.7mmol) of 6-M-benzyloxycarbonyllysine is dissolved in a mixture of 100000ml of ethyl ether from trifluoroacetic acid and 500ml of ethanol and stirred for 24 hours at room temperature. After that, c is evaporated to dryness and the residue is crystallized from diisopropyl ether. :z» Yield: 128.9 g (9695 from theory) of colorless crystalline powder.

Elemental analysis: det. C 51.07 H 5.09 P 15.14 M 7.44 7 detection: C 51.25 H 5.18 ER 15.03 M 7.58 sh»

Example 16 o (1-4-perfluorooctylsulfonyl)piperazine|amide. 2-M-trifluoroacetyl-6-M-benzyloxycarbonyllysine o 20 To 125g (332mMmmMole) of the compound indicated in the title of the example and, and 188./7g (332mmol) of 1-perfluorooctylsulfonylpiperazine (obtained according to OE 19603033) in 800ml of tetrahydrofuran at 0gС and » add 164.2g (0.66b4mmol) of EEDH (ethyl ether of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) and stir 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). 52 Yield: 286g (9395 from theory) of a colorless solid.

HF) Elemental analysis: where dist.. C 36.30 H 2.83 R 41.01 M 6.05 8 3.46 found: C 36.18 H 2.94 R 40.87 M 5.98 Z 3 ,40 60

Example 1c (1-4-perfluorooctylsulfonyl)piperazine|amide of 6-M-benzyloxycarbonyllysine

A solution of 280 g (302.2 mmol) of the compound indicated in the title of example 16 in 2000 ml of ethanol at 09 is bubbled for an hour with gaseous ammonia. Then the mixture is stirred for 4 hours at 02C. After that, b5 is evaporated to dryness and the residue is isolated from water by stirring. The solid was filtered off and dried in vacuo (5025).

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

Elemental analysis: det. C 37.60 H 3.28 P 38.89 M 6.75 8 3.86 found: C 37.15 H 3.33 is 38.78 M 6.68 Z 3.81

Example 1g (1-(4-perfluorooctylsulfonyl)piperazinamide 6-M-benzyloxycarbonyl-2-M-(3,6,9,12,15-pentaoxahexadecanoyl)lysine to 50g (60.20mmol) of the compound indicated in the title of example c, and 7.10 g (/Omol) of triethylamine in ZbOml of dichloromethane at 0 is added dropwise to a solution of 19.93 g (7Omol) of 3,6,9,12,15-pentaoxahexadecanoic acid chloride in 5HOml of dichloromethane and stirred for 2 hours at 090. Next, 200 ml of 595 aqueous hydrochloric acid is added and stirred for 5 min at room temperature. The organic 75 phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: dichloromethane/acetone in a ratio of 15:1)

Yield: 53.7g (93905 from theory) of colorless viscous oil.

Elemental analysis: det. C 33.83 H 4.94 R 3.34 M 5.84 8 33.69 found: C 33.75 H 5.05 R 3.29 M 5.78 Z 33.75

Example td (1-(4-perfluorooctylsulfonyl)piperazine|amide | 2-M-(3,6,9,12,15-pentaoxahexadecanoyl)lysine 5Og (52.15 mmol) of the compound indicated in the title of example 1g is dissolved in 50 ml of ethanol and add bg s of palladium catalyst (1096 Pa/s). After that, hydrogenate at room temperature. Then the catalyst (he) is filtered off and the filtrate is evaporated to dryness under vacuum.

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

Elemental analysis: " det.. C 27.68 H 5.01 E 39.17 M 6.79 5 3.89 o detect.: C 27.60 H 5.13 E 39.09 M 6.68 Z 3, 81 "c)

Example Te (1-4-perfluorooctylsulfonyl)piperazineamide C 6-M-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4 -oxo-5-methyl-5-yl)|-2-M y -(3,6,9,12,15-pentaoxahexadecanoyl)lysine, a complex of 20 g (24.25 mmol) of the compound indicated in the title of example Id . aza-4-oxo-5-methyl-5-yl)|pentanoic acid|-1,4,7,10-tetraazacyclododecane is dissolved under moderate heating in 200 ml of dimethyl sulfoxide. - s Then, at 102C, add 8.25 g (40 mmol) of M, of M-dicyclohexylcarbodiimide and then stirred overnight at room temperature. The solution was poured into 300 mL of acetone and stirred for 1 h. The precipitated solid was filtered off and then purified by chromatography (silica gel KR-18, eluent: water/ethanol gradient /acetonitrile).

Yield: 28.21 g (8195 from theory) of a colorless solid. - and Water content: 11.095. Elemental analysis (in terms of anhydrous substance): av) solution. C 31.78 H 4.84 E 22.49 M 8.78 5 2.23 ba 10.95 o 50 detection: C 31.74 H 4.98 g 22.39 M 8.69 Z 2.15 ba 10.87

T» Example 2a (1-(4-perfluorooctylsulfonyl)piperazineamide 6-M-(3,9-bis(tert-butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid-bis(tert- butyl diether)-6-carbonylmethyl)-2-M-(3,6,9,12,15-pentaoxahexadecanoyl)lysine

To a solution of 20 g (24.08 mmol) of the compound indicated in the title of example d, 14.88 g (24.08 mmol) (F, bis(tert-butyl ether) 3,9-bis(tert-butyloxycarbonylmethyl-3,6,9- of triazaundecane-1,11-dicarboxylic acid ka and 2.77g (24.08mmol) of M-hydroxysuccinimide in 150ml of dimethylformamide at 09С add 8.25g (4Omol)

M,M-dicyclohexylcarbodiimide. The mixture is stirred for 3 hours at 0 2C, and then overnight at 60 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: 31.61 g (9195 from theory) of viscous oil.

Elemental analysis: 65 resolution. C 40.80 H 6.71 P 22.39 M 6.80 8 2.22 detection: C 40.72 H 6.82 E 22.30 M 6.75 Z 214

Example 26 (1-4-perfluorooctylsulfonyl)piperazineamide 6-M-(b-carbonylmethyl-3,9-bis(carboxylatomethyl)-3,6,9-triazaundecanedicarboxylic acid-1-carboxy-11-carboxylato|-2 -M-(3,6,9,12,15-pentaoxahexadecanoyl)lysine, Ca-complex, sodium salt

Zog (20.8 mmol) of the compound indicated in the title of example 2a is dissolved in 30 ml of trifluoroacetic acid and stirred at room temperature for 2 hours. After that, it is evaporated to dryness, the residue is dissolved in

ZOOml of water and the pH value is set to 2.5 using 10906 aqueous Mahon. Next, add 33.77 g (10.4 mmol) of gadolinium oxides and stir for 10 minutes at 60 es. After that, the mixture is allowed to cool to room temperature and the pH value is set to 7.4 with caustic sodium. Then it is evaporated to dryness and the residue is purified on silica gel KR-18 (eluent: water/acetonitrile gradient).

Yield: 19.18 g (6790 from theory) of a colorless, amorphous solid.

Water content 9.895. 75 Elemental analysis (in terms of anhydrous substance): cal. C28.80 NA,25 P23,AT M7.12 82.33 ba11.48 Ma1.67 detect.: С28.67 NA,34 g23.38 M7.03 52.27 411.37. Ma1.74

Example For (1-4-perfluorooctylsulfonylpiperazinamide of lysine) 20g (24.0v8mmol) of the compound indicated in the title of the example was dissolved in 100ml of ethanol and 4g of a palladium catalyst (1095 Pa/C) was added. After that, it was hydrogenated at room temperature. the catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.

Yield: 16.77 g (quantitative) of a colorless solid. with

Elemental analysis: o dist. C 31.04 H 3.04 P 46.38 M 8.04 8 4.60 found: C 30.97 H 3.15 P 46.31 M 7.98 8 4.51 "

Example 36 (1-4-perfluorooctylsulfonylpiperazinamide o 2,6-M,M'-bis1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4 -oxo-5-methyl-5-(α)yl)lysine, α-complex 10g (14.3bmmol) of the compound indicated in the title of example 3a, 3.34g (29mmol) M-hydroxysuccinimide, 2.54g C (mmol) lithium chloride and 18.26 g (29 mmol) of the cCa-complex y-1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl)-1,4,7 ,10-tetraazacyclododecane is dissolved under moderate heating in 2000 ml of dimethyl sulfoxide. Then, at 109C, 12.38 g (bOmol) 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 off and then purified by chromatography (silica gel KR-18, eluent: water/ethanol/acetonitrile gradient). - s Yield: 19.02 g (6995 from theory) of a colorless solid. and Water content: 11.395. -» Elemental analysis (in terms of anhydrous substance): solution. С 35.03 Н 4.04 Р 16.82 М 10.21 5 1.67 са 16.38 -I detection: С 34.96 Н 4 ,13 P 16.74 M 10.16 5 1.61 sa 16.33 ve Example 4a o Methyl ether of 2-I4-(3-oxaethylpropionate))phenylacetic acid

233.8 g (1.4 mol) of 2-bromoacetic acid ethyl ether are added to 200 g (1.204 mol) of 4-hydroxyphenylacetic acid methyl ether and 212 g (2 mol) of sodium carbonate in about 2000 ml of acetone and boiled for 5 hours with

T" reflux refrigerator. 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).

Yield: 288.5 g (9596 from theory) of colorless oil.

Elemental analysis: (F) solution: С 61.90 Н 6.39 ka detection: С 61.75 Н 6.51

Example 46 bo Phenyl-2-bromoacetic acid methyl ester 2-I4-(3-oxaethylpropionate)

201g (1.13mol) of M-bromosuccinimide and 100mg of dibenzyl peroxide are added to 285g (1.1mol) of the compound indicated in the title of example 4a, dissolved in 2000ml of carbon tetrachloride, and refluxed for 8 hours. Then 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 the ratio 65 157).

Yield: 359.2 g (9695 from theory) of colorless viscous oil.

Elemental analysis: det. C 47.28 H 4.57 Hg 24.16 found: C 47.19 H 4.71 Hg 24.05

Example 4c

Methyl ether 2-I4-(3-oxaethylpropionate)|phenyl-2-(1-(1,4,7,10-tetraazacyclododecan-7-yl|acetic acid)

350 g (1.057 mol) of the compound 70 specified in the title of example 4b is added to 33.5 mol of 1,4,7,10-tetraazacyclododecane in bbbOml of chloroform and stirred overnight at room temperature. Next, 300 ml of water is extracted three times, the organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum. The residue without additional purification is used in the next reaction (example 4Hg).

Yield: 448g (quantitative) of viscous oil.

Elemental analysis: div. C 59.70 H 8.11 M 13.26 found: C 59.58 H 8.20 M 13.18

Example 4g 2-I(4-(3-oxapropionic acid)|phenyl-2-(1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-10-yl)|acetic acid 4457 ( 1.0533 mol) of the compound indicated in the title of Example 4c and 496 g (5.27 mol) of chloroacetic acid are dissolved in 4000 ml of water. The pH value is then adjusted to 10 using 309b00 aqueous caustic sodium. The mixture is then heated to 702C and the pH value is added 3095 aqueous caustic sodium is maintained at a CM level of 10. The mixture is stirred for 8 hours at 702 C. After that, the pH value is set to 13 and for about

ZOHV is boiled under reflux. Then the solution is cooled in an ice bath and the pH value is set to 1 by adding concentrated hydrochloric acid. After that, it is evaporated to dryness in a vacuum.

The residue is dissolved in 4000 ml of methanol and stirred for one hour at room temperature. The common salt that precipitated is filtered off, the filtrate is evaporated to dryness and the residue is purified on silica gel KR-18 in (eluent: water/ethanol/acetonitrile gradient). at

Yield: 40Zg (6995 from theory) of a colorless solid.

Water content: 10.295. at

Elemental analysis (in terms of anhydrous substance): "solved. C 51.98 N 6.18 M 10.10 - detected: C 51.80 N 6.31 M 10.01

Example 4d "2-I4-(3-oxapropionic acid) phenyl-2-[1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-10-yl]acetic acid, Са-complex - 130.7g (360.65mmol) of gadolinium oxide is added to 400g (721.3mmol) of the compound indicated in the title of example 4g in 2000ml of water and stirred for two hours at 80 2C. The solution is filtered and the filtrate is lyophilized.

Yield: 511g (quantitative) of amorphous solid.

Water content: 11.095. -i Elemental analysis (in terms of anhydrous substance): е distr. C 40.67 N 4.41 sa 22.19 M 7.98 "in detection: C 40.51 N 4.52 ba 22.05 M 8.03 o 29 Example where

T» 14-perfluorooctylsulfonyl)piperazine|amide 2,6-M,M'-bis(2-I(4-(3-oxapropionyl)phenyl)-2-(1,4,7-tris(carboxylatomethyl)-1, 4,7,10-tetraazacyclododecan-10-yl acetic acid/lysine, digadolinium complex, disodium salt 10g (14.3bmmol) of the compound indicated in the title of Example 1a, 3.45g (ZOmol) M-hydroxysuccinimide, 2.54g (boOmol) ) of lithium chloride and 21.26 g (30 mmol) of the compound indicated in the title of example 4d are dissolved at (F) with moderate heating in 250 ml of dimethyl sulfoxide. Then, at 109C, 16.51 g (8 mmol) of M,M-dicyclohexylcarbodiimide are added and then stirred overnight at room temperature. The solution is poured into 2000 ml of acetone and stirred for 1 h. The precipitated solid is filtered off and then purified by chromatography (silica gel KR-18, eluent: water/ethanol/acetonitrile gradient). This substance is dissolved in a small amount of water, the pH value is set to 7.4 with caustic sodium and lyophilized.

Yield: 21.02 g (6995 from theory) of a colorless solid.

Water content: 11.295. 65 Elemental analysis (in terms of anhydrous substance):

distr.. С37.36 НЗ,6b Р15.22 414.82 М7.92 Ма?,17 81.51 found.: С37.28 НЗ,74 Е15.14 ба14.75 М8.03 Ма2.23 81.46

Example 5a (1-4-perfluorooctylsulfonyl)piperazineamide 2,6-M,M'-bisIb-carbonylmethyl-3,9-bis(tert-butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dicarbonate acid-bis(tert-butyl ether)|lysine

To a solution of 10 g (14.3 mmol) of the compound indicated in the title of Example 3a, 18.53 g (3 mmol) of bis(tert-butyl ether) 3,9-bis(tert-butyloxycarbonylmethyl)-6-carboxymethyl-3,6, 10.32 g (5 mol) of 9-triazaundecane-1,11-dicarboxylic acid and 3.45 g (ZOmol) of M-hydroxysuccinimide in 1500 ml of dimethylformamide at 09Сb are added

M,M-dicyclohexylcarbodiimide. The mixture is stirred for hours 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).

Output: 19.60 Ohms (72905 from theory) of viscous oil.

Elemental analysis: det. C 49.41 H 6.75 B 17.03 M 7.39 8 1.69 found: C 49.35 H 6.82 P 16.92 M 7.32 Z 1.62

Example 56 2,6-M,M-bis|Ib-carbonylmethyl-3,9-bis(carboxylatomethyl)-3,6,9-triazaundecanedicarboxylic acid-1-carboxy-11-carboxylatolysine-|(1-(4-perfluorooctylsulfonyl )piperazine|iamide, Ca-complex, sodium salt) 29 15 g (7.91 mol) of the compound indicated in the title of example 5a is dissolved in 500 ml of chloroform and 200 ml of He) trifluoroacetic acid is added. The mixture is stirred for 1 min at room temperature. After that, it is evaporated to dryness in a vacuum and the residue is dissolved in 150 ml of water. Next, add 2.87 g (7.9 mmol) of gadolinium oxide and stir for 5 hours at 802C. Then the mixture is allowed to cool to room temperature and the pH value is set to 7.4 using 2N. caustic sodium. The solution is evaporated to dryness under vacuum and purified on KR-18 Z 3o (eluent: water/ethanol/acetonitrile gradient). (av)

Yield: 8.11 g (5795 from theory) of a colorless amorphous solid.

Water content: 9.695. at

Elemental analysis (in terms of anhydrous substance): "I solution. C 30.70 N 3.08 Ca 17.48 M 7.78 Ma 2.56 5 1.78 - detected: C 30.58 N 3, 19 Ba 17.42 M 7.71 Ma 2.68 8 1.72

Example ba (1-(4-perfluorooctylsulfonyl)piperazinamide 6-M-benzyloxycarbonyl-2-M-1b-carboxy|methyl-3,9-bis(tert-butyloxycarbonylmethyl)-3,6,9-triazaundecane-1 ,11-di o) carboxylic acid-bis(tert-butyl ether)|lysine "» To a solution of 20 g (24.08 mmol) of the compound indicated in the title of example iv, 14.88 g (24.08 mmol) of " bis(tert- butyl ether) of 3,9-bis(tert-butyloxycarbonylmethyl)-6-carboxymethyl-3,6,9-triazaundecane-1,11-dicarboxylic acid and 2.88 g (25 mmol) of M-hydroxysuccinimide in 70000 ml of dimethylformamide at 09С add 8, 25g (4 mol) of M,M-dicyclohexylcarbodiimide. The mixture is stirred for hours 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). o Yield: 27.21 g (7995 from theory) of viscous oil. aw! 250 Elemental analysis: iz» dist. C 47.03 H 5.64 R 22.58 M 6.85 8 2.24 found: C 46.94 H 5.58 R 22.65 M 6.84 Z 2 ,31

Example 66 o (1-(4-perfluorooctylsulfonyl)piperazineamide 2-M-Icarbonylmethyl-3,9-bis(tert-butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid-bis(tert -butyl ether)|)lysine 25g (17.48mmol) of the compound indicated in the title of example ba is dissolved in 35O0ml of ethanol and 5g of 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: 22.66 g (quantitative) of a colorless solid.

Elemental analysis: 65 resolution. C 44.48 H 5.75 ER 24.92 M 7.56 8,247 detected: C 44.59 H 5.81 R 25.03 M 7.46 Z 2.52

Example bv (1-4-perfluorooctylsulfonyl)piperazineamide 6-M-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4- oxo-5-methyl-5-yl)|-2-M -I(b-carbonylmethyl-3,9-bis(tert-butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid-bis( tert-butyl ether)|lysine, vCa-complex of 20g (154Zmmol) of the compound indicated in the title of example 66, 1.78g (15.4Zmmol) of M-hydroxysuccinimide, 1.48g (ZbBmmol) of lithium chloride and 9.72g (154Zmmol) cCa complex of 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 150 ml of dimethyl sulfoxide. Then, at 1022, add 5.16 g (25 mmol)

M,M-dicyclohexylcarbodiimide and then stirred overnight at room temperature. The solution is poured into 2500 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: 22.94 g (7895 from theory) of a colorless solid. and

Water content: 7.995.

Elemental analysis (in terms of anhydrous substance): cal. C 42.22 H 5.29 E 16.95 Ca 8.25 M 8.82 Z 1.68 found: C 42.15 H 5.41 E 16 .87 sa 8.13 M 8.70 8 1.60

Example bg (1-(4-perfluorooctylsulfonyl)piperazinamide 6-M-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(3-aza-4-oxo-5- methyl-5-ylpentanoyl))|-2-M-

I(b-carbonylmethyl-3,9-bis(carboxylatomethyl)-3,6,9-triazaundecane-dicarboxylic acid-carboxy-11-carboxylato-2|lysine, digadolinium complex, sodium salt) 20g (10.49 mmol) ) of the compound indicated in the title of example bv is dissolved in 200 ml of trifluoroacetic acid.

The mixture is stirred for 50 minutes at room temperature. Then it is evaporated to dryness in a vacuum and the residue is dissolved in 150 ml of water. Then 1.90 g (5.25 mmol) of gadolinium oxide is added and stirred for 5 hours at 8020. The mixture is allowed to cool to room temperature and the pH value is adjusted to 7.4 using caustic sodium. The solution is evaporated to dryness under vacuum and purified on silica gel KR-18 (eluent: water/ethanol/acetonitrile gradient).

Yield: 11.89 g (6195 from theory) of a colorless amorphous solid. at

Water content: 10.295. "AND

Elemental analysis (in terms of anhydrous substance): and - solution. C 32.97 H 3.47 E 17.39 C4 16.93 M 9.05 Ma 1.24 Z 1.73 detection: C 32.90 H 3.53 E 17.31 ba 16.87 M 8.92 Ma 1.33 5 1.67

Example 7a h a) tert-Butyl ether of 5,6-bis(benzyloxy)-3-oxahexanoic acid - with 100 g (376.2 mmol) of 1,2-di-O-benzylglycerol (obtained according to Spec. RPuz. IGiridv, 43 (2) (1987), pp. 113-127)| and 5 g of tetrabutylammonium hydrosulfate are dissolved in a mixture of 400 ml of toluene and 200 ml of 50965 I aqueous caustic sodium. Next, 78 g (400 mmol) of tert-butyl ether of 2-bromoacetic acid are added dropwise at 09C for 300 minutes and then stirred for 30 minutes at 02. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: M-hexane/acetone in a ratio of 20:1). their Yield: 133.4 g (9496 from theory) of colorless oil.

Elemental analysis: (c) at 50 resolution: C 71.48 N 7.82 detection: C 71.61 N 7.92 s"

Example 76 5,6-bis(benzyloxy)-3-oxahexanoic acid 130 g (336.4 mmol) of the compound specified in the title of example 7a is dissolved in 200 ml of dichloromethane and 100 ml of trifluoroacetic acid is added at 02. The mixture is stirred for 4 hours at room temperature and then evaporated to dryness. The residue is crystallized from pentane/diethyl ether. yield: 102.2 g (9295 from theory) of a waxy solid.

Elemental analysis: 60 resolution: C 69.07 Nb, 1 detection: C 69.19 H 6.82

Example 7c 65 (1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-benzyloxycarbonyl-2-M-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclodo decane-10-( pentanoyl-3-aza-4-oxo-5-methyl-5-yl)|)lysine, complex 5O (60.20 mmol) of the compound indicated in the title of example 1c, 6.93 g (60.20 mmol) of M-hydroxysuccinimide . 4-oxo-5-methyl-5-yl is dissolved under moderate heating in 400 ml of dimethyl sulfoxide. Then, at 102, 20.63 g (1000 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 off and then purified by chromatography (silica gel KR-18, eluent: water/ethanol/acetonitrile gradient).

Yield: 75.53 g (8795 from theory) of a colorless solid.

Water content: 10.195.

Elemental analysis (in terms of anhydrous substance): cal. C 37.48 H 3.84 E 22.39 ba 10.90 M 8.74 5 2.22 found: C 37.39 H 4.02 P 22 ,29 ba 10.75 M 8.70 5 2.22

Example 7g (1-4-perfluorooctylsulfonyl)piperazineamide 2-M4-(11,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4- oxo-5methyl-5-yl|lysine y, va-complex 7Og (48.53 mmol) of the compound specified in the title of example 7c is dissolved in a mixture of 50Oml of water and 100ml of ethanol and 5g of a 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: 63.5 g (quantitative) of a colorless solid.

Water content: 9.895. sch - y

Elemental analysis (in terms of anhydrous substance): (o) soln. C 37.48 N 3.84 E 22.39 ba 10.90 M 8.74 5 2.22 detected: C 37.39 N 4, 03 g 22.31 ba 10.78 M 8.65 5 2.20 "

Example 7d o (1-"4-perfluorooctylsulfonyl)piperazine|amide 6-M-(5,6-bis(benzyloxy)-3-oxahexanoyl1|-2-M-(1,4,7-tris(carboxylatomethyl)-1 ,4,7,10-tetraazacyclododecane-10-o (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)lysine, sa-complex "g 10 g (7.64 mmol) of the compound indicated in the title of the example 7g, C, 30g (LOmmoles) of the compound indicated in the title

From example 76, 0.85 g (20 mmol) of lithium chloride and 1.15 g (1 mmol) of M-hydroxysuccinimide are dissolved under moderate heating in 150 ml of dimethyl sulfoxide. Then, at 1096, add Z10g (15 mmol)

M,M'-dicyclohexylcarbodiimide and stirred for 8 hours at room temperature. The reaction solution is poured into 2000 ml of acetone and the precipitate that has fallen out is isolated. The title compound is purified on silica gel "

KR-18 (eluent: water/ethanol/acetonitrile gradient).

Yield: 11.14 g (9095 from theory) of a colorless amorphous solid. no) s Water content: 4.395. with» Elemental analysis (in terms of anhydrous substance): solution. С 41.51 Н 4.29 Е 19.93 М 7.78 Са 9.70 З 1.98 found.: С 41.45 Н 4.38 P 19.84 M 7.70 sa 9.58 8 1.90 -I 1" Example 7e (1-"4-perfluorooctylsulfonyl)piperazine|amide (ав) 6-M-(5,6,-dihydroxy-3- oxahexanoyl)-2-IM-I(1,4,7-triscarboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-pentanoyl-3-aza-4-oxo-5-methyl-5-yl)lysine , sa-complex 10g (6b, 17mmol) of the compound indicated in the title of example 7d is dissolved in 200ml of ethanol and 3g chz" of palladium catalyst (1090o 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: 8.89 g (quantitative) of a colorless solid.

Water content: 3.195. o Elemental analysis (in terms of anhydrous substance): co dist. C 35.03 N 3.99 E 22.42 ba 10.92 M 8.75 5 2.23 detected: C 34.95 N 4.12 E 22.30 ba 10.78 M 8.71 5 2.18 60

Example va 1--4-perfluorooctylsulfonyl)piperazine|amide 6-M-benzyloxycarbonyl-2-IM-(5,6-bis(benzyloxy)-3-oxahexanoyl|lysine

To a solution of 20 g (24.08 mmol) of the compound indicated in the title of example 1c, 9.91 g (30 mmol) of the compound 65 indicated in the title of example 76, and 3.45 g (30 mmol) of M-hydroxysuccinimide in 100 ml of dimethylformamide at 09C are added 9, 28 g (45 mmol) of M,M-dicyclohexylcarbodiimide. The mixture is stirred for 2 hours at 02°C, 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: 24.50 g (8995 from theory) of viscous oil.

Elemental analysis: det. C 47.29 H 4.14 E 28.26 M 4.90 5 2.81 found: C 47.14 H 4.26 g 28.17 M 4.91 Z 2.69

Example 86 70 (1-(4-perfluorooctylsulfonyl)piperazine|amide 2-M-(5,6-dihydroxy-3-oxahexanoyl)lysine 20 g (17.5 mmol) of the compound indicated in the title of example va is dissolved in 00 ml of ethanol and added 5 g of palladium catalyst (1095 Pa/C). After that, hydrogenate at room temperature. Then the catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.

Yield: 17.65 g (quantitative) of a colorless solid. t Elemental analysis: det. C 44.05 H 4.10 P 32.02 M 5.55 8 3.18 found: C 43.96 H 4.21 E 31.94 M 5.48 Z 3.24

Example 8b (1-(4-perfluorooctylsulfonyl)piperazinamide 6-M-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4- oxo-5-methyl-5-yl)|lysine, va-complex 15 g (14.87 mmol) of the compound indicated in the title of example 86, 1.73 g (15 mmol) of M-hydroxysuccinimide, 1.27 g (3 mmol) of lithium chloride and 9.48 g (15 mmol) of the cCa-complex about 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 100 ml of dimethyl sulfoxide. Then, at 1092C, 5.16 g (25 mmol) are added

M,M-dicyclohexylcarbodiimide and then stirred overnight at room temperature. The solution is poured into 1500 ml of acetone and stirred for 1 hour. The precipitated solid is filtered and then purified by chromatography (silica gel EP-18, eluent: water/ethanol/acetonitrile gradient). at

Yield: 19.28 g (8095 from theory) of a colorless solid.

Water content: 10.395. at

Elemental analysis (in terms of anhydrous substance): "g div. C 41.51 H 4.29 P 19.93 sa 9.70 M 7.78 5 1.98 - found: C 41.37 H 4.40 is 19.88 Sa 9.58 M 7.67 8 1 ,85

Example 9a "(1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-benzyloxycarbonyl-2-M-(2,6-M,M'-bis(benzyloxycarbonyl)lysyl|lysine) - with 20 g (24.0 mmol) of compounds , indicated in the title of example c, and 2.53 g (25 mmol) of triethylamine are dissolved in 200 ml of tetrahydrofuran (THF) and 14.46 g (27 mmol) of di-M,M'-2-lysine paranitrophenol ether are added. The mixture is stirred for two hours at 5020. After that, it is evaporated to dryness under vacuum and the residue is chromatographed on silica gel (eluent: dichloromethane/methanol in a ratio of 20:1).

Yield: 28.07g (9595 from theory) of a colorless solid.

Ш- Elemental analysis: Ш» resolution. С 46.99 H 4.19 Р 26.32 M 6.85 5 2.61 (c) found: С 47.08 H 4.32 B 26.21 M 6.75 C 2.54 o Example 96 "c" (1-"4-perfluorooctylsulfonyl)piperazine|amide 2-M-I-(lysyl)lysine, trihydrobromide

100 ml of hydrobromic acid in glacial acetic acid (4895) is added to 25 g (20.37 mmol) of the compound indicated in the title of Example 3 and stirred for 2 hours at 402C. Next, it is cooled to 02C, 1500 ml of diethyl ether is added dropwise, and the precipitated solid is filtered off. After drying in a vacuum (6023), 21.52 g (9995 from theory) of a clear yellow crystalline solid are obtained.

Elemental analysis: name) solution. C 27.01 H 3.40 Vg 22.46 E 30.26 M 7.87 5 3.00 60 found: C 26.92 H 3.53 Vg 22.15 P 30 .14 M 7.69 8 2.87

Example OV (1-(4-perfluorooctylsulfonyl)piperazine|amide 6-M-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4- oxo-5-methyl-5-yl)|-2-M bB 72,6-M,M -bisi1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl- 3-aza-4-oxo-5-methyl-5-yl) |lysine lysine, trigadolinium complex 31.49g (5Omol) of a-complex 1,4,7-tris(carboxylatomethyl)-10-(3-aza-4 -oxo-5-methyl)-5-yl)pentanoic acid, 6.91 g (bOmole) of M-hydroxysuccinimide and 4.24 g (10Omole) of lithium chloride are dissolved under moderate heating in 35Oml of dimethylsulfoxide. Then, at 1096, 16.51g (bOmole) are added )

M,M-dicyclohexylcarbodiimide and stir for 2 hours at 102C. 10 g (9.37 mmol) of the compound indicated in the title of example 96 and 3.03 g (ZO mmol) of triethylamine are added to this mixture and stirred for 12 hours at 602C. Then the mixture is allowed to cool to room temperature and after that it is poured into 300 ml of acetone. The deposited precipitate is filtered and purified on silica gel KR-18 (eluent: water/ethanol/acetonitrile gradient).

Yield: 16.7 g (6795 from theory) of a colorless solid.

Water content: 7.995.

Elemental analysis (in terms of anhydrous substance): cal. C 36.58 H 4.43 P 12.14 sa 17.74 M 11.06 8 114 detected: C 36.47 H 4.54 P 12.03 ba 17.65 M 10.95 5 1.21

Example 10a a) 1,7-bis(benzyloxycarbonyl)-4-(3,6,9,12,15-pentaoxahexadecanoyl)-1,4,7,10-tetraazacyclododecane

To 18.13 g (68.1 mmol) of 3,6,9,12,15-pentaoxahexadecanoic acid and 30 g (68.1 mmol) of 1,7-di-2-cyclene, 20 obtained according to 7. Komasv and A.O. Zpetu, U. Spet. Zos. sing Sottyp., 2 (1995), p. 185, 24.73 g (100 mmol) of EEDH (ethyl ether of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) is added to 300 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). p 25 Yield: 19.13 g (4295 from theory) of a colorless solid.

Elemental analysis: о solution. С 61.03 Н 7.61 М 8.13 found.: С 60.92 Н 7.75 М 8.04 «І 30 Example 106 (ав) 1,7-bis(benzyloxycarbonyl)-4 -(3,6,9,12,15-pentaoxahexadecanoyl)-10-(-2H,2H 4H,5H,5H-3-oxaperfluorotriodecanoyl)-1,4,7,10-tetraazacyclododecane

Up to 18 g (26.9 mmol) of the compound indicated in the title of example b, and 14.05 g (26.91 mmol) of "I 2H.2nH.4H,4H,5H,5H-3-oxaperfluorotridecanoic acid, obtained according to YuOE 19603033 , 12.36 g (5 mmoles) of EEDH (ethyl ether of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) are added to 35 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: 21.51 g (6795 from theory) of a colorless solid. -at

Elemental analysis: c "from solution. C 47.32 H 4.82 R 27.07 M 4.70 detection: C 47.26 H 5.01 R 26.94 M 4.59

Example 10c - 1-(3,6,9,12,15-pentaoxahexadecanoyl)-7-(2H,2H,4H4H,5H,5H-3-oxaperfluorotridecanoyl)-1,4,7,10-tetraazaz with cyclododecane 20g (16.7/mmol) of the compound indicated in the title of example 1g is dissolved in 200 ml of ethanol and 2.5 g of a 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: 15.5 g (quantitative) of a colorless solid. t» Elemental analysis: soln.. C 40.27 H 4.90 E 34.93 M 6.06 found: C 40.15 H 4.99 E 34.87 M 5.94 o Example 10g name) 1, 7-bis(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)-4- (3,6,9,12,15-pentaoxahexadecanoyl)-10-(2H,2H,4H.4H,5H,5H-3-oxaperfluorotridecanoyl)-1,4,7,10-tetraaza 60 cyclododecane, Ca-complex 15g (16.22 mmol) of the compound indicated in the title of example 10, 4.0 g (40 mmol) of M-hydroxysuccinimide,

3.39 g (vVOmole) of lithium chloride and 25719 g (4Omole) of the cCa complex of 1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl)pentanoic acid are dissolved at moderate heating in 3 mL of dimethylsulfoxide. Next, at 1023, 24.73 g (10 mol) of EEDH are added and then stirred 65 overnight at room temperature. The solution is poured into 300 ml of acetone and stirred for 10 minutes.

The precipitated solid is filtered and then purified by chromatography (silica gel KR-18,

eluent: water/ethanol/acetonitrile gradient).

Yield: 19.86 g (5795 from theory) of a colorless solid.

Water content: 11.395.

Elemental analysis (in terms of anhydrous substance): cal. C 38.58 H 4.74 E 15.04 sa 14.64 M 913 found: C 38.47 H 4.91 P 14.95 ba 14.57 M 9.04

Example 1t1a is 3,5-dinitrobenzoic acid 1-K4-perfluorooctylsulfonyl)piperazinamide

To 20 g (35.2 mmol) of perfluorooctylsulfonylpiperazine and 8.1 g (8 mmol) of triethylamine, dissolved in 200 ml of dichloromethane, a solution of 8.7 bg (Zvmmol) of 3,5-dinitrobenzoyl chloride in 5 ml of dichloromethane is added dropwise at 09C and stirred for 1 hour at 029C. Then add 200ml of 595% aqueous hydrochloric acid and mix for 5 minutes at room temperature. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: dichloromethane/acetone in a ratio of 15:1).

Yield: 24.96 g (9395 from theory) of a colorless solid.

Elemental analysis: det. C 29.35 H 1.45 P 42.37 M 7.35 5 4.21 found: C 29.28 H 1.61 g 42.15 M 7.25 8 415

Example 116 (1-4-perfluorooctylsulfonyl)piperazinamide of 3,5-diaminobenzoic acid with 29 20 g (26.23 mmol) of the compound indicated in the title of example 1182 is dissolved in 400 ml of ethanol and 10 g of palladium catalyst (1095 Ra/ WITH). After that, they are hydrogenated at room temperature. Then the catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.

Yield: 18.43 g (quantitative) of a cream-colored solid.

Elemental analysis: in o dist.. C 32.49 H 2.15 P 45.98 M 7.98 8 4.57 found: C 32.29 H 2.35 P 45.69 M 7.81 Z 4, 40 o

Example 11c h (1-4-perfluorooctylsulfonyl)piperazine 3,5-M,M'-bis| y-1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)|benzoic acid, according - a complex of 10 g (14.24 mmol) of the compound specified in the title of example 116, 3.45 g (ZOmole) of M-hydroxysuccinimide, 2.54 g (bOmol) of lithium chloride and 18.89 g (ZOmole) of CCa-complex 40. 1.4 ,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl)upentanoic acid is dissolved with moderate heating in 200 ml of dimethyl sulfoxide. Next, at 1096, 10.32 g (5 BOmmol) h of M,M-dicyclohexylcarbodiimide are added 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 off and then purified by chromatography (silica gel KR-18, eluent: water/ethanol/acetonitrile gradient).

Yield: 19.74 g (7295 from theory) of a colorless solid. - and Water content: 11.895. Elemental analysis (in terms of anhydrous substance): av) solution. С 35.55 Н 3.72 Е 16.77 са 16.33 М 10.18 5 1.67 о 50 detection: С 35.48 H 3.84 R 16.58 ba 16.24 M 10.07 8 1.58

T» Example 12 a) tert-Butyl ether of 3Z-oxa-2H,2H4H.4H,5H,5H-perfluorotridecanecarboxylic acid 25.0 g (53.8 mmol) 1H,1H,2H,2H-perfluoro-1-decanol | supplied by the company And apsavieg| dissolved in 250 ml of absolute toluene and mixed with a catalytic amount (approximately 0.75 g) of tetra-n-butylammonium hydrosulfate at room temperature. Then, at 09C, a total of 7.55g (134.bmmol, 2.5 equivalents in

F, calculated on the amount of the alcohol component used) of highly dispersed powdered potassium hydroxide, and then 15.73 g (80.7 mmol, 1.5 equivalents on the amount of the alcohol component used) of tert-butyl ether of bromoacetic acid and left for 2 hours for stirring at 0 2s. 60 The reaction solution obtained in this way is then stirred for 12 hours at room temperature and for processing it is mixed with ethyl acetic acid in a total amount of 50 ml and 250 ml of water. 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 (in a ratio of 1:10) as eluent. 65 Yield: 26.3 g (84.695 from theory) of the above title compound in the form of a colorless and highly viscous oil.

Elemental analysis: div. C 33.23 H 2.61 E 55.85 found: C 33.29 H 2.61 P 55.90 b) 3Z-oxa-2H,2H.4H,4H,5H,5H-perfluorotridecanecarboxylic acid 20.0g (34.58 mmol) of the compound indicated in the title of example 12a, with stirring, is suspended at room temperature in 200 Oml of a mixture consisting of methanol and 0.5 molar caustic sodium in a ratio of 2:1, and then heated to 6b02C. After carrying out the reaction for 12 hours at 60 C, the transparent reaction mixture for processing is neutralized by mixing with the cation exchange resin Atregije? IR 120 (H"-form), the ionite is removed by vacuum filtration, and the methanol-water filtrate obtained in this way is distilled in a vacuum until a dry residue is obtained. The resulting amorphous-oily residue is purified on silica gel using ethyl acetic acid/n-hexane (in 1:3 ratio) as eluent 15 Yield: 16.0 g (88.695 from theory) of the above title compound as a colorless and highly viscous oil.

Elemental analysis: div. C 27.60 H 1.35 ER 61.85 20 found: C 27.58 H 1.36 g 61.90 c) 1,7-bis(11,4,7-tris(carboxylatomethyl)-10-( 3-aza-4-oxo-5-methyl-5-ylpentanoyl)|-1,4,7,10-tetraazacyclododecane) diethylenetriamine, digadolinium complex 2.A8g (3.b9a4mmol, 2.05 molar equivalents based on the amount of used c 25 of diethylenetriamine) described in the application OEE 19728954 Si in example 31 0/0 Ca-complex He) 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 40 ml of absolute dimethyl sulfoxide and at this temperature are mixed with M-hydroxysuccinimide in a total amount of 453 mg (3.94 mmol). After cooling to room temperature, the reaction solution t 30 obtained in this way is mixed with 814 mg (3.94 mmol) of M,M'-dicyclohexylcarbodiimide and stirred at room temperature for 2 hours! temperature The resulting suspension of the activated ether is then mixed with 198.2 mg (1.92 mmol) of diethylenetriamine dissolved in 5 ml of absolute dimethyl sulfoxide and stirred for 12 hours at room temperature. at

For processing, the reaction mixture is mixed with a sufficient amount of acetone until complete precipitation of the compounds specified in the heading of the compound, the precipitate is separated by vacuum filtration, dried, dissolved in water, filtered

From the undissolved dicyclohexylurea and the filtrate for desalting and for cleaning from - low-molecular components, pass through an ultrafiltration membrane AMISOMF UM-3 (limit permeability Z000 Da). The retentate (substance that did not pass through the filtration membrane) is finally lyophilized. "

Yield: 1.85g (72.790o from theory) in the form of a colorless lyophilizate.

H2O content (when using Karl Fischer's reagent): 3.89905. n- s Elemental analysis (in terms of anhydrous substance): ;" distr. C 38.03 H 5.24 M 13.73 ba 23.71 revealed: C 37.98 H 5.20 M 13.69 sa 23.78 - and d) iz 1,7-bis(11.4, 7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-ylpentanoyl)|-1,4,7,10-tetraazacyclododecane)-4-(3-oxa-2H,2H). 4H,4H,5H,5H-perfluorotridecanoyl)diethylenetriamine, digadolinium complex (in To a solution of 3.23 g (2.444 mmol) of the compound indicated in the title of example 12c, in a mixture with 3 ml of 20 dimethyl sulfoxide and 3 ml of tetrahydrofuran at 5023 in a nitrogen atmosphere at 1.27 g (2.44 mmol) of the compound specified in the title of example 126, dissolved in a mixture of 1 ppm tetrahydrofuran and 15 mL dimethyl sulfoxide, is added dropwise. After that, at 0 9C, a total of 1.80 g (3. ppm) EEDH (2- ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline| and left overnight for stirring at room temperature. The resulting reaction solution is then mixed with a sufficient amount of acetone until complete 252 precipitation of the above title compound, the precipitate is separated by vacuum filtration, dried, dissolved in the water,

HF) filter the undissolved components, and the filtrate is subjected to ultrafiltration through an ultrafiltration membrane AMISOMEUE MM-3 (limit permeability: 3000 Da), which ensures complete desalting of the compound indicated in the title and, at the same time, its purification from low-molecular components.

The retentate is finally lyophilized. 60 Yield: 3.54 g (79.490 from theory) in the form of a colorless lyophilisate.

H2O content (when using Karl Fischer's reagent): 5.87905.

Elemental analysis (calculated per anhydrous substance): div. C 35.43 H 4.07 MO9.95 E 17.64 sa 17.18 65 found: С 35.42 H 4.01 MO.89 E 17.67 sa 17.18

Example 13 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 during 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: 98.520.

Elemental analysis: soln.. C 51.07 H 5.09 M 7.44 E 1514 found: C 51.25 H 5.18 M 7.58 E 15.03 b) (1--4-perfluorooctylsulfonyl)piperazine Iiamide 2-M-trifluoroacetyl-6-M-benzyloxycarbonyl-i-lysine

To 125.00 g (332.Omol) of the compound indicated in the title of example La and 188.7 g (332.Omol) of 1-perfluorooctylsulfonylpiperazine (obtained according to OE 19603033) in 750 ml of tetrahydrofuran at 0 °C add 164.2 g (0.66 b4 mmol ) EEDH (ethyl ether of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) 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: 286.0 g (9395 from theory) of a colorless solid.

Melting point: 9296.

Elemental analysis: det. C 36.30 H 2.83 M 6.05 E 41.01 8,346 found: C 36.18 H 2.94 M 5.98 P 40.87 Z 3.40 cm o in ) (1-«4-perfluorooctylsulfonyl)piperazine amide 6-M-benzyloxycarbonyl-i! -lysine

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 092C is bubbled for an hour with gaseous ammonia. After that, the mixture is stirred for 4 hours at 0 C. Then it is evaporated to dryness and the residue is separated from the water by stirring. The solid substance is filtered off and dried in a vacuum at 5026 h. (ав)

Yield: 243.5 g (97.090 from theory) of amorphous solid. at

Elemental analysis: div. 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 E 38.78 Z 3.81 - d) 1-(4-perfluorooctylsulfonyl)piperazinamide and -lysine 200.0g (240, mmol) of the compound obtained in example 13c is dissolved in 10000ml of ethanol, mixed with 5.0g of Perlman's catalyst (2095 Ra/s) and hydrogenated at room temperature in a hydrogen atmosphere (1 atm) until hydrogen absorption stops. After that, the catalyst is removed by vacuum filtration, thoroughly washed with ethanol (three portions of approximately 10 Oml) and concentrated to dryness under vacuum. In this way, the title compound is obtained in the form of a highly viscous yellow oil. Yield: 162.5 g (96.990 from theory).

Elemental analysis: - det. C 31.04 H 3.04 M 8.05 E 46.38 8 4.60 found: C 31.11 H 3.09 M 8.08 is 46.33 C 4, 62 (c) d) (1-(4-perfluorooctylsulfonyl)piperazine|amide about 50. 5M-2M-bis4-(2,3-bis(M,M-bis(tert-butyloxycarbonylmethyl)amino)propyl|phenyl) -3-oxa-propionyl-!-lysine 5.25 g (7.72 mmol) 4-(2,3-bis-(M,M-bis(tert-butyloxycarbonylmethyl)amino)propyl|phenyl)-3-oxapropion

I" acid and 781.0 mg (7.72 mmol) of triethylamine are dissolved in 5 Oml of methylene chloride. Then, at -15 °C, a solution of 1.1 mg (8.5 mmol) of isobutyl ether of chloroformic acid in 1 Oml of methyl chloride is added dropwise for 10 minutes and stirred for another 20 minutes at -1520. Next, the solution is cooled to -252C, a solution of 2.68 g (3.8 mmol) of the compound indicated in the title of Example 13 and 2.12 g (21.0 mmol) of triethylamine in 7 ml of tetrahydrofuran is added dropwise over 30 minutes, after which it is 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% aqueous solution of ammonium chloride in portions of 100 ml, the organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum. 60 The residue is chromatographed on silica gel (eluent: methylene chloride/ethanol in a ratio of 20:1).

Yield: 5.37 g (68.895 from theory) of colorless and highly viscous oil.

Elemental analysis: det.. C 52.27 N b.AZ M 5.BA B 15.97 8 1.59 65 found: C 52.22 H 6.51 M 5.49 R 15.99 Z 1.63 f) (1-4-perfluorooctylsulfonyl)piperazinamide 6M-2M-bis/t4-(2,3-bis(M,M-bis(carboxylatomethyl)amino)propyl|phenyl)-3-oxapropionyl-i-lysine, octasodium salt of 5.0 g (2.47 mmol) of the compound indicated in the title of example 1Zd is dissolved in bOml of absolute dichloromethane.

After that, the obtained solution at 02С is mixed dropwise with trifluoroacetic acid in a total amount of 75 ml. After carrying out the reaction for 12 hours at room temperature, the mixture is concentrated to dryness in a vacuum.

The resulting residue is mixed with 100 ml of water and distilled again under vacuum until a dry residue is obtained.

The residue obtained in this way is dissolved in 200 ml of distilled water and the aqueous solution of the compound indicated above in the title, which contains the product, is extracted twice with diethyl ether in bOml portions. The total 70 volume of the obtained aqueous solution containing the product is brought up to ZbOml by mixing with water, the components that have not dissolved are filtered, and the filtrate is subjected to ultrafiltration through an ultrafiltration membrane AMISOMEUE MM-3 (limit permeability: 3000 Da), which ensures complete desalination of the compound indicated in the title and at the same time its purification from low molecular weight components.

The total volume of the retentate is brought up to 200 ml by mixing with water, and then the pH value of this solution is 75. It is set to 10.0 with the help of 1595 caustic sodium. The alkaline aqueous solution containing the product is finally lyophilized.

In this way, 4.0g (92.89o from theory) of the compound specified in the title is obtained in the form of an octasodium salt in the form of an amorphous lyophilizate.

Water content: 5.37905.

Elemental analysis (in terms of anhydrous substance): cal. C 38.46 H 3.28 M 6.41 E 18.47 Z 1.83 Ma 10.52 found: C 38.42 H 3.31 M 6 .39 P 18.51 C 1.87 Ma 10.38 w) (1-"4-perfluorooctylsulfonyl)piperazinamide 6M-2M-bis/t4-(2,3-bis(M,M-bis(carboxymethyl)amino) propyl|phenyl)-3-oxapropionyl-! -lysine, dimanganese Ho) complex, tetrasodium salt 1.94 g (1.11 mmol) of the compound indicated in the title of example 1Ze is dissolved in 100 ml of distilled water and the pH value of the resulting solution is set to 4.0 by mixing with 1-molar aqueous hydrochloric acid. Then, at 8092C, it is mixed with 0.25 g (2.22 mmol) of manganese(I) carbonate in portions. The reaction solution obtained in this way is then refluxed for 5 hours. After cooling to room | "c) the temperature of the pH value of the aqueous solution containing the product is set with intensive stirring at 7.2 by mixing with In. with caustic sodium and for desalination and for purification from low-molecular components is passed through the AMISOMF UM-3 ultrafiltration membrane (permeability limit: 3000 Da). The retentate of the end is lyophilized. M

Yield: 1.8Og (92.095 from theory) of the title compound in the form of a colorless lyophilizate.

H2O content (when using Karl Fischer's reagent): 7.28905.

Elemental analysis (in terms of anhydrous substance): " solution. C 38.07 H 3.25 E 18.28 Mp 6.22 M 6.34 Ma 5.20 8 1.81 Z 70 detected: C 38, 01 H 3.29 P 18.29 Mp 6.21 M 6.36 Ma 5.28 5 1.78 s "» Example 14 " a) (1-4-perfluorooctylsulfonyl)piperazinamide 6-M-(benzyloxycarbonyl)-2 -M-(M-pteroyl)-I-glutaminyl)lysine 20 g (45.3 mmol) of folic acid are dissolved in 30 ml of dimethylsulfoxide and at 10 °C, 9.49 g (4 mmol) of M,M-dicyclohexylcarbodiimide are added. The mixture is stirred overnight at room temperature. Next, 29.1 g (Zb5 mmol) of the compound specified in the title of example c and 20 ml of pyridine are added to this mixture and stirred for 1 hour at 5020. Then it is cooled to room temperature and a mixture of 1500 ml of diethyl ether and 1500 ml of acetone is added. The precipitate that has fallen out is filtered and purified on silica gel KR-18 (eluent: water/ethanol/tetrahydrofuran gradient). (ав) 50 Yield: 21.59g (3895 from theory) of a yellow solid.

T» Water content: 2.195.

Elemental analysis (in terms of anhydrous substance): cal. C 43.10 H 3.54 E 25.76 M 11.29 8 2.56 29 found: C 43.02 H 3.62 E 25.68 M 11.21 5 2.48 b) (1-4-perfluorooctylsulfonyl)piperazinamide 2-M-((M-pteroyl)-I -glutaminyl|lysine de To 20 g (15.p95 mmol) of the compound indicated in the title of example 14a, add 200 ml of hydrobromic acid in glacial acetic acid (4895) and stirred for 2 hours at 402C. Then it is cooled to 02C, 2000 ml of diethyl ether is added dropwise and the precipitated solid is filtered off. After drying in a vacuum (6023) is obtained 18.96 g (9995 from theory) of yellow crystalline solid.

Elemental analysis: det. C 37.01 H 3.27 Vg 6.65 R 26.90 M 12.83 Z 2.67 bo found: C 36.91 H 3.42 Vg 6.31 R 29.75 M 12.72 5 2.56 c) (1-«4-perfluorooctylsulfonyl)piperazinamide 6-M-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl- 3-aza-4-oxo-5-methyl-5-yl|-2-M-

KM-pteroyl)-I -glutaminyl|lysine, α-complex 0.92g (8mmol) M-hydroxysuccinimide, 0.b8g (1bmol) lithium chloride and 5.04g (8mmol) ba-complex 1,4,7-tris( carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl)-1,4,7-10-tetraazacyclododecane is dissolved under moderate heating in 80 ml of dimethyl sulfoxide. Next, at 109Sb, add 2.0 bg (1Omol)

M,M-dicyclohexylcarbodiimide and then stirred for 2 hours at room temperature. 5 g (4.16 bmmol) of the compound indicated in the title of example 146 and 10 ml of pyridine are added to this reaction solution. The 7/0 mixture was stirred overnight at room temperature. Then the solution is poured into 1000 ml of acetone and stirred for 1 hour. The precipitated solid is filtered and then purified by chromatography (silica gel KR-18, eluent: water/ethanol/acetonitrile gradient). The product is dissolved in a small amount of water, the pH value is set to 7.4 with caustic sodium and lyophilized.

Yield: 3.87g (53905 from theory) of a yellow solid.

Water content: 5.895.

Elemental analysis (in terms of anhydrous substance): cal. C38.36 НЗ,74 Р18.42 Сав,7 М12.78 Ма1.31 81.83 found.: С38.28 НЗ,85 18.33 са8.85 М12 ,69 Ma1,42 81,75

Example 15 a) 6-M-benzyloxycarbonyl-2-IM-(3,6,9,12-tetraoxatridecanoyl)lysine (1-"4-perfluorooctylsulfonyl)piperazinamide

To 50 g (60.20 mmol) of the compound indicated in the title of example 1c and 7.10 g (/Omol) of triethylamine, dissolved in ZBOml of dichloromethane, a solution of 16.85 g (7/Omol) of hydrogen chloride, grade 3,6,9, is added dropwise at 09Сb. of 12-tetraoxatridecanoic acid in 50 ml of dichloromethane and stir for 1 hour at 020. Then (o) add 200 ml of 595 aqueous hydrochloric acid and stir for 5 minutes at room temperature. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: dichloromethane/acetone in a 15:1 ratio) yield: 30.94 g (9295 from theory) of a colorless, viscous oil.

Elemental analysis: o "c) solution. C 40.63 H 4.19 R 31.21 M 541 8 310 found: C 40.75 H 4.08 E 31.29 M 5.58 Z 3.25 " And b) (1-(4-perfluorooctylsulfonyl)piperazinamide 2-M-(3,6,9,12-tetraoxatridecanoyl)lysine - 53.96 g (52.15 mmol) of the compound indicated in the title of example 15a, dissolved in 500 ml of ethanol and BG 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: 43.0 g (quantitative) of a colorless solid. Z t0 Elemental analysis: с "» dist.. С 36.01 Н 4.14 Р 35.86 М 6.22 8 3.56 " found.: С 27.60 Н 5.13 Е 39.09 М 6, 68 C 3.81 c) (1-«4-perfluorooctylsulfonyl)piperazine|amide - and 6-M-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl -3-aza-4-oxo-5-methyl-5-yl)|-2-M i»-(3,6,9,12-tetraoxatridecanoyl)lysine, α-complex 21.84 (24.25 mmol) of compounds , indicated in the title of example 156, 2.79 g (24.25 mmol) of M-hydroxysuccinimide, (a) 2.12 g (5 BO mmol) of lithium chloride and 15.27 g (24.25 mmol) of the sa-complex about 50 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.

Then, 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 1 hour. The precipitated solid is filtered off and then purified by chromatography (silica gel KR-18, eluent: gradient of 5% water/ethanol/acetonitrile).

GF! Yield: 28.21 g (8195 from theory) of a colorless solid.

Water content: 11.095. Elemental analysis (in terms of anhydrous substance): bo soln. C 36.53 H 4.33 E 21.36 M 8.34 5 212 ba 1040 detected: C 37.74 H 4.98 g 22.39 M 8.69 Z 2.15 ba 10.87

Example 16 a) 1-"4-perfluorooctylsulfonyl)piperazinamide 65 /85-M-benzyloxycarbonyl-2-M-(propyl-3-sulfonic acid)lysine

To 5 g (60.20 mmol) of the compound indicated in the title of example iv and 7.10 g (7 mmol) of triethylamine,

dissolved in 25 Oml of dry tetrahydrofuran, at 5092С dropwise add a solution of 7.3 g (bOmol) of propanstalone in 50 ml of tetrahydrofuran and stir for 1 hour at 602С. Next, add 200 ml of 595% aqueous hydrochloric acid and stir for a few minutes at room temperature. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: dichloromethane/acetone in a ratio of 15:1).

Yield: 45.16 g (79905 from theory) of colorless viscous oil.

Elemental analysis: 70 resolution. C 36.56 H 3.49 R 33.90 M 5.88 8 6.73 detection: C 36.72 H 3.35 R 33.79 M 5.78 Z 6.75 b) (1-(4-perfluorooctylsulfonyl)piperazinamide 2-M-(propyl-3-sulfonic acid)lysine 49.68 g (52.15 mmol) of the compound indicated in the title of example 1ba is dissolved in 500 ml of ethanol and 1 g of palladium catalyst is added ( 1095 Pa/C).After that, hydrogenate at room temperature.The catalyst is then filtered off and the filtrate is evaporated to dryness under vacuum.

Yield: 42.69 g (quantitative) of a colorless solid.

Elemental analysis: det. C 30.81 H 3.32 P 39.46 M 6.84 8 7.83 found: C 30.64 H 4.1 g 39.29 M 6.68 C 7.89 ) (1-"4-perfluorooctylsulfonyl)piperazinamide 6-M-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5 -methyl-5-yl)|-2-M-(propyl-3-sulfonic acid)lysine, c-complex with 29 19.85g (24.25mmol) of the compound indicated in the title of example 166, 2.79g (24.25mmol ) of M-hydroxysuccinimide, he) 2.12 g (5 BOmmol) of lithium chloride and 15.27 g (24.25 mmol) of the cCa complex of 1,4,7-tris(carboxylatomethyl)-10-|(3-aza-4-oxo- 5-methyl-5-yl)pentanoic acid!|-1,4,7,10-tetraazacyclododecane is dissolved under moderate heating in 200 ml of dimethylsulfoxide.

Next, at 1023, 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 100 minutes. The solid substance that precipitated is filtered and then purified by chromatography (silica gel KR-18, eluent: water/ethanol/acetonitrile gradient).

Yield: 28.13 g (8195 from theory) of a colorless solid. "Her

Water content: 11.095.

З Elemental analysis (in terms of anhydrous substance) - solution. C 33.27 H 3.70 E 22.36 M 8.73 C 4.44 ba 10.89 found: C 32.41 H 3.88 P 22.49 M 8.69 Z 4.35 ba 10.97 "

Example 17 - c a) 1-"4-perfluorooctylsulfonyl)piperazinamide h 6-M-benzyloxycarbonyl-2-M,M-bis(propyl-3-sulfonic acid)lysine -" Up to 50 g (60.20 mmol) of the compound specified in the title of example iv, and 12.14 g (120 mmol) of triethylamine, dissolved in 250 ml of dry tetrahydrofuran, at 509С, a solution of 14.65 g (120 mmol) of 1,3-propanesultone in 100 ml of tetrahydrofuran is added dropwise and stirred for 2 hours at 602С. Then add 400 ml

of aqueous hydrochloric acid, stirred for 2 hours at room temperature, mixed with 15% sodium chloride, the organic phase was separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (eluent: dichloromethane/acetone in a ratio of 15:1). o Yield: 52.24 g (8196 from theory) of colorless viscous oil. with AI Elemental analysis:

I" dist.. C 35.76 H 3.66 R 30.05 M 5.21 8 8.95 found.: C 35.75 H 3.55 R 30.19 M 5.08 Z 9.04 b) (1-«4-perfluorooctylsulfonyl)piperazinamide 2-M,M-bis(propyl-3-sulfonic acid)lysine 53.74 g (52.15 mmol) of the compound specified in the title of example 17a are dissolved in 500 ml of ethanol and bg is added

IF) of a palladium catalyst (1095 Pa/C). After that, they are hydrogenated at room temperature. Then the catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.

Yield: 49.06 g (quantitative) of a colorless solid. 60 Elemental analysis: det. C 30.64 H 3.54 E 34.33 M 5.96 Z 10.23 found: C 30.69 H 3.71 E 34.19 M 6.08 8 10.38 65 c) P1-(4-perfluorooctylsulfonyl)piperazinamide 6-M-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo- 5-methyl-5-yl)|-2-M

"M-bis(propyl-3-sulfonic acid) lysine, Ca-complex, disodium salt 38.76 g (24.25 mmol) of the compound indicated in the title of example 176, 2.79 g (24.25 mmol) of M-hydroxysuccinimide, 2, 12 g (5 mmoles) of lithium chloride and 15.27 g (24.25 mmoles) of the cCa complex of 1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl)upentanoic acid |-1,4,7,10--etraazacyclo to decane is dissolved under moderate heating in 200 ml of dimethylsulfoxide. Next, at 109C, 8.25 g (4 mol) 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 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel KR-18, eluent: water/ethanol/acetonitrile gradient).

Yield: 31.63 g (8195 from theory) of a colorless solid.

Water content: 11.095.

Elemental analysis (in terms of anhydrous substance): solution. С 32.07 Н 3.57 Р 20.06 М 7.83 5 5.97 Са 9.76 Ма 2.86 detect.: С 31.94 Н 3 ,48 P 20.19 M 7.69 5 5.85 Sa 9.87 Ma 2.99

Example 18 a) 5-benzyl ether of T-trifluoroacetyl-1-glutamic acid 100 g (421.5 mmol) of 5-benzyl ether of I-glutamic acid is dissolved in a mixture of 1000 ml of ethyl trifluoroacetic acid and 500 ml of ethanol and stirred for 24 hours at room temperature. After that, it is evaporated to dryness and the residue is crystallized from diisopropyl ether.

Yield: 140.47 g (96905 from theory) of colorless crystalline powder.

Elemental analysis: det. C 50.46 H 4.23 P 17.10 M 4.20 s detected: C 51.35 H 4.18 E 17.03 M 4.28 Ge) b) M-bis( 2-M-trifluoroacetyl-i-glutamic acid 5-benzyl ether 2-hydroxyethyl)amide

8.25 g of " ( 4 Ommoliv). M,M-dicyclohexylcarbodiimide. The mixture is stirred for hours 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). at

Yield: 9.11 g (9095 from theory) of viscous oil. "AND

Elemental analysis: and - resolved. C 51.43 H 5.51 P 13.56 M 6.66 detected: C 51.22 H 5.41 E 13.40 M 6.75 c) M-bis(2 -hydroxyethyl)monoamide of M-trifluoroacetyl-y-glutamic acid h 21.92 g (52.15 mmol) of the compound specified in the title of example 186 is dissolved in 500 ml of ethanol and 3 g of 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: 43.Og (quantitative) of a colorless solid.

Elemental analysis: -I solution.. С 40.01 Н 5.19 Р 17.26 M 848 и» found.: С 39.84 Н 5.13 Е 17.09 М 8.68 o d) Trifluoroacetyl-i - glutamic boron/M-bis(2-hydroxyethyl)amide-5-(/1-(4-perfluorooctylsulfonyl)piperazine|amide o Up to 10.96 bg (33.2 mmol) of the compound indicated in the title of example 18a, and 18, 87 g (33.2 mmol)

T» of 1-perfluorooctylsulfonylpiperazine (obtained according to OE 19603033) in 8 Oml of tetrahydrofuran at 09C, add 16.42 g (bb4 mmol) of EEDH (ethyl ether of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) and stir overnight at room temperature . After that, it is evaporated to dryness in a vacuum and

Chromatograph on silica gel (eluent: dichloromethane/methanol in a ratio of 20:1).

Yield: 30.93 g (9395 from theory) of a colorless solid.

F, Elemental analysis: name) dist. C 39.61 H 2.89 P 35.66 M 6.19 8 3.54 in detection: C 39.68 H 2.74 P 35.81 M 6.13 From 3.40 d) I-glutamic acid-M-bis(2-hydroxyethyl)amide-5-(1--4-perfluorooctylsulfonyl)piperazinamide

A solution of 30.24 g (30.22 mmol) of Example 186 indicated in the title in 200 ml of ethanol at 02C is bubbled with gaseous ammonia for one hour. The mixture is then stirred for 4 hours at 02. After that, 65 is evaporated to dryness and the residue is separated from the water by stirring. The solid was filtered off and dried in vacuo (5025).

Yield: 26.55 g (9790 from theory) of amorphous solid.

Elemental analysis: det. C 41.12 H 2.89 P 35.66 M 6.19 8 3.54 found: C 41.15 H 2.83 E 35.78 M 6.28 8 3.71 e )

IR-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)|-I-glu tamic acid-M-bis(2-hydroxyethyl)amide-5-(1-(4-perfluorooctylsulfonyl)piperazinamide, sa-complex 211.96g (24.25mmol) of the compound indicated in the title of example 18d, 2.79g (24, 25 mmol)

M-hydroxysuccinimide, 2.12 g (5 mmoles) of lithium chloride and 15.27 g (24.25 mmoles) of Ca-complex 1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl- 5-yl)pentanoic acid (1,4,7,10-tetraazacyclododecane) is dissolved under moderate heating in 200 ml of dimethylsulfoxide.

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

Yield: 27.43 g (8195 from theory) of a colorless solid.

Water content: 11.095.

Elemental analysis (in terms of anhydrous substance): cal. C 34.41 H 3.83 E 23.13 M 9.03 5 2.30 ba 11.26 found: C 34.34 H 3.98 g 23 .29 M 9.19 Z 2.15 ba 11.07 s

Example 19 o a) M-dimethylbis(1,1-dihydroxymethyl)amide of 5-benzyl ether of M-trifluoroacetyl-iii-glutamic acid

To a solution of 8.03 g (24.08 mmol) of the compound indicated in the title of example 18a, 3.98 g (24.08 mmol) of dimethylbis(1,1-dihydroxymethyl)amine and 2.77 g (24.0 v8 mmol) of M-hydroxysuccinimide in 150 ml of dimethylformamide at 02С add 8.25 g (40 mmol) of M,M-dicyclohexylcarbodiimide. The mixture is stirred for hours 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: 110.53 g (9195 from theory) of viscous oil. at

Elemental analysis: "calc.. C 50.00 H 5.66 E 11.86 M 7.18 - detected: C 50.17 H 5.82 E 11.80 M 7.15 b) (1-4- perfluorooctylsulfonyl)piperazinamido-benzyl ether of M-trifluoroacetyl-iii-glutamic acid « 25.05 g (52.15 mmol) of the compound indicated in the title of example 192 is dissolved in 500 ml of ethanol and 1 g of palladium catalyst (1096 Pa/C) is added. After that, they are hydrogenated at room temperature. Then the catalyst - c is filtered off and the filtrate is evaporated to dryness under vacuum. a Yield: 20.36 g (quantitative) of a colorless solid. ,» Elemental analysis: soln.. C 40.00 H 5.42 E 14.60 M 7.18 -I detected: C 40.10 H 5.53 E 14.69 M 7.28 ve c) M- trifluoroacetyl-i-glutamic acid-M-dimethylbis(1,1-dihydroxymethyl)amide-5-(1-(4-perfluorooctylsulfonyl)piperazine|amide

To 12.96 g (33.2 mmol) of the compound indicated in the title of example 196 and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonylpiperazine (obtained according to OE 19603033) in 800 ml of tetrahydrofuran at 0°C

T" add 16.42 g (bb4 mmol) of EEDH (ethyl ether of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) and stir 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: 28.42 g (9195 from theory) of a colorless solid.

Elemental analysis:

F) d) dist.. C 31.93 H 3.00 RE 40.40 M 5.96 5 341 found.: C 32.08 H 2.94 E 40.57 M 5.88 Z 3.31 bo g ) -glutamic acid-M-|dimethylbis(1,1-dihydroxymethyl)|amide-5-(1--4-perfluorooctylsulfonyl)piperazinamide

A solution of 28.41 g (30.2 mmol) of the compound specified in the title of example 19c in 200 ml of ethanol at 02C is bubbled with gaseous ammonia for one 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 was filtered off and dried in vacuo (502).

Yield: 24.74 g (9790 from theory) of amorphous solid.

Elemental analysis: det. C 32.71 H 3.46 R 38.24 M 6.63 8 3.80 found: C 32.75 H 3.33 R 38.38 M 6.68 Z 3.81 d ) 2-M-(11,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)|- I -Hg lutamic acid-M-I|dimethylbis(1,1-dihydroxymethyl)amide)-5-(1-(4-perfluorooctylsulfonyl)piperazinamide, 70 ba-complex 20.48g (24.25mmol) of the compound specified in the title example 19g, 2.79g (24.25mmol) of M-hydroxysuccinimide, 2.12g (5BOmmol) of lithium chloride and 15.27g (24.25mmol) of the 1,4,7-tris(carboxylatomethyl)-10-(3 -aza-4-oxo-5-methyl-5-yl)pentanoic acid)|-1,4,7,10-tetraazacyclododecane is dissolved under moderate heating in 200 ml of dimethylsulfoxide. Then, 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 1 hour. The precipitated solid is filtered and then purified by chromatography (silica gel KR-18, eluent: water/ethanol/acetonitrile gradient).

Yield: 29.05 g (8395 from theory) of a colorless solid. and

Water content: 11.095.

Elemental analysis (in terms of anhydrous substance): cal. C 34.12 H 3.91 E 22.38 M 8.73 5 2.22 ba 10.90 found: C 34.24 H 3.98 g 22 .39 M 8.69 Z 2.15 ba 10.87 s (8)

Example 20 a). (1-(4-perfluorooctylsulfonyl)piperazinylamide of 5-benzyl ester of M-trifluoromethylacetyl-y-glutamic acid

To 11.0 bg (33.2 mmol) of the compound indicated in the title of example 18a and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonylpiperazine (obtained according to OE 19603033) in 8 vOml of tetrahydrofuran at 0С o 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 under vacuum and chromatographed on silica gel (eluent: dichloromethane/methanol in a ratio of 20:1). "

Yield: 27.28 g (9395 from theory) of a colorless solid. 325 Elemental analysis: - det. C 35.35 H 2.40 R 43.01 M 4.76 8 3.63 found: C 35.48 H 2.51 R 42.87 M 4.73 Z 3, 50 « b) 5-1-(4-perfluorooctylsulfonyl)piperazine-iamide of M-trifluoroacetyl-III-glutamic acid - with 21.92 g (52.15 mmol) of the compound indicated in the title of example 18a, dissolve in 500 ml of ethanol and add 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: 41.37 g (quantitative) of a colorless solid.

Elemental analysis: -I solution. C 28.76 H 1.91 R 47.89 M 5.30 8 4.04 e found.: C 28.84 H 2.03 R 47.79 M 5.28 Z 419 (c) c) M-trifluoroacetyl-i-glutamic acid-M-bis(2-hydroxyethyl)amide-5-(1--4-perfluorooctylsulfonyl)piperazinamide

T» To a solution of 24.9 g (24.08 mmol) of the compound indicated in the title of example 18a, 2.53 g (24.08 mmol) of diethanolamine and 2.77 g (24.08 mmol) of M-hydroxysuccinimide in 150 ml of dimethylformamide at 092С, 8.25 g is added (4 Ommol). M,M-dicyclohexylcarbodiimide. The mixture is stirred for 2 hours at 02°C, 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). iF) Yield: 9.11 g (9095 from theory) of viscous oil. elemental analysis: in solution. C 31.37 H 2.75 R 43.15 M 6.36 8 3.64 found: C 31.22 H 2.61 R 43.30 M 6.25 Z 3, 81 g) I-glutamic acid-M-bis(2-hydroxyethyl)amide-5-(1-(4-perfluorooctylsulfonyl)piperazinamide

A solution of 26.61 g (30.22 mmol) of the compound indicated in the title of example 18c in 200 ml of ethanol at 02C for 1 hour is bubbled with gaseous ammonia. 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 was filtered off and dried in vacuo (502).

Yield: 23.93 g (9790 from theory) of amorphous solid.

Elemental analysis: det. C 30.89 H 3.09 R 39.56 M 6.86 8 3.93 found: C 30.75 H 3.13 R 39.78 M 6.75 Z 3.81 d )

IR-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)|-I-glu then tamic acid-M-bis(2-hydroxyethyl)amide-5-(1-(4-perfluorooctylsulfonyl)piperazinamide, a complex of 16.43 g (24.25 mmol) of the compound indicated in the title of example 20 g, 2.79 g (24 .25 mmol) of M-hydroxysuccinimide, 2.12 g (5 BO mmol) of lithium chloride and 15.27 g (24.25 mmol) of the 1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5 -methyl-5-yl)pentanoic acid)|-1,4,7,10-tetraazacyclododecane is dissolved under moderate heating in 200 ml of dimethylsulfoxide. t5 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 1 h. The precipitated solid is filtered off and then purified by chromatography (silica gel KR-18, eluent: water/ethanol/acetonitrile gradient).

Yield: 28.10 g (8395 from theory) of a colorless solid.

Water content: 11.095.

Elemental analysis (in terms of anhydrous substance) solution. C 34.41 H 3.83 E 23.13 M 9.03 5 2.30 ba 11.26 found: C 34.44 H 4.98 is 23, 19 M 8.89 5 2.15 ba 11.17 s o

Example 21 a) (1-"4-perfluorooctylsulfonyl)piperazinamide of 5-benzyl ether of M-trifluoroacetylglutamic acid

To 11.0 bg (33.2 mmol) of the compound indicated in the title of example 18a and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonylpiperazine (obtained according to OE 19603033) in 8 Oml of tetrahydrofuran at 09C in add 16.42 g (bb4 mmol) of EEDH (ethyl ether of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) and av! 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). at

Yield: 27.28 g (9395 from theory) of a colorless solid. "Her

Elemental analysis: and - solution. C 35.35 H 2.40 P 43.01 M 4.76 8 3.63 found: C 35.48 H 2.54 P 42.87 M 4.73 Z 3, 40 b) 5-1-(4-perfluorooctylsulfonyl)piperazine-iamide of M-trifluoroacetyl-iii-glutamic acid h 21.92 g (52.15 mmol) of the compound specified in the title of example 21a are dissolved in 500 ml of ethanol and 3 g - s of palladium catalyst are added (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: 41.37 g (quantitative) of a colorless solid.

Elemental analysis: -I solution. C 28.76 H 1.91 R 47.89 M 5.30 8 4.04 i" detection: C 28.84 H 1.81 R 47.79 M 5.28 5 416 o Example 22: Distribution of the contrast agent proposed in the invention from example C in organs (including 5p accumulation in the tumor and lymph nodes) after its intravenous administration to rats with prostate cancer

T» After intravenous administration to rats (copulatory inbreeding, 12 days before the experiment, prostate cancer cells of the Oippipd K3327 MAT-Gy line were intramuscularly implanted with the compound from example C at the rate of 100 μmol of total gadolinium per kg of body weight after 1 min, h and 24 hours

After administration (p.v.), the metal content was determined in various organs, in the tumor, as well as in lymph nodes (the data of which are grouped in the form of data for mesenteric and peripheral lymph nodes) (the table shows the average

F) value 4 mean square deviation, n-3). ime) th fabric of vv

Kidney 35988 39441 292318 1.70-0.39 2.00-0.21 1.38-0.07 and

Race 00100001 ovyayu iv pis: i shsheshii nin sv But Po VE pt: NIM NYM PENYA Os: NI POLON ON OURS

WE and developments in S

Note: "58 ml of blood per kg of body weight; ""only an aliquot sample of tissue from the muscle of the right leg; the sum of all organs after 10 and bOhv p.v. excluding the rest of the body. with

Claims (21)

Formula of the invention (o) 1. Perfluoroalkyl-containing complexes with polar residues of the general formula (Ua (I) « | o (c), in which K; means a perfluorinated, straight or branched carbon chain of the formula -СаРопЕ, where E is the terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, and "p" means the numbers 4-30, Y chn K means the metal complex of the general formula II i; (1): "she Sho iy Her 2 s I-aK Kesh spin, i" 0 Ob" Km More. Beu ke B - in which Э БЕ" represents a hydrogen atom or the equivalent of a metal ion with serial number 21-29, 31-33, 37-39, 42-44, 49 or 57-83, provided that at least two EB radicals ! mean the equivalents of metal ions, ("in") 20 22nd EZ independently of each other mean hydrogen, S.-Alkyl, benzyl, phenyl, -СНООН or -СНоОСН» and Their» M represents -СеН./-О- СН»о-о-, "(РНа) 4-5-о-, tenylene group, -"СН-АМНСО-СНО-СН(ИСНСООН)-С оНа-о-, -СенНА-(ОоСНоСНо)Ю -М (СНСООН)-СНо-о- or optionally interrupted by one or more oxygen atoms, 1-3 МНОСО-groups, 1-3 СОМН-groups and/or a substituted 1-3 (СН) 5СООН-group we C.-C.oalkylene or St-C12-SeH-O group, while o means the place of attachment to -СО-, or the general formula of ИЙ о борР,(и) scoops, ООН 60 га 7 and Mk OA lo Я 01 This jus i m -th 65 K. dl. in which В has the above values, В" means hydrogen or the metal ion equivalent specified for В!, and ШТ means -СеН.-О-СН»о-о-, where o means the place of attachment to -СО-, or the general formula IM i m n Su; B lo SO NK lju x 4. Me peri BOS Zhov Sh aries. in which B" and 2? have the values indicated above, or the general formula MA or MV --SHOKeA , (MA from Shiya U "Tr slya ov. zh di UYUNI! bo bor sch --"oh 225, (MV sikh chews Her (B) o visual DM and "y y o VOD. " lh I dido sy ee DVO: o in which В! has the above values, o or the general formula MI Pt 7 TE i Z Y te m widows t" swarms, in which KE! has the above values , or the general formula MY "tashose-. OO (M) s vve prn i" 00 VIbOb ey vovk -I 75 in which VE! has the above values, and pi i means -SeNi-O-SNo-o-, be o means the place of attachment to -СО-, while the free acid groups optionally present in the residue К can optionally be represented in the form of salts of organic and/or inorganic bases or amino acids or in the form of amides of amino acids, C means at least three times o a functionalized residue selected from the following residues a)-Her): T" (a) H (c) To 1 te, vk-or K-t 10 ay 15 (c) 20 i y: nki che B; M-"zh t 25 | o EZ (is) | "Her from what; o o sa « 35 y | i- ze not x 40 o) s pniynnia yayu MA YASNA - WE So stA-(Spyu Metr, che : - EZ EE и (о) о я !! Am M "M. Her" | and (F) TO Sny SN Ss ar, yu |. 60 And I () 65 The height of СОЕНя СНО мит, iv Е where 7 means the place of attachment of C to complex K, v means the place of attachment of C to residue K, and 7 means the place of attachment of o to residue 2, 27 means the group: - 85 p.-lyadya80 5. - then JENE NE where 7 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 K is a polar residue selected from the K complexes of the general formulas II-MII, and in this case ВЕ! means a hydrogen atom or the equivalent of a metal ion with serial number 20-29, 31-33, 37-39, 42-44, 49 or 57-83, and the residues B2, 23, 27, ) and 1 have the above values, and in in the case when C is a residue of the formula (c) or (4), and K is a complex selected from the complexes of the general formulas ІІ and М, К cannot be identical to the residue К of the general formula I, if 7 is all ( ОУсТ сн, or is a folic acid residue, or a carbon chain with 2-30 C atoms attached via -СО-, 5О.- or a direct bond to the С residue, with 29 being straight or branched, saturated or unsaturated and which optionally interrupted by 1-10 He) oxygen atoms, 1-5 MHSO-groups, 1-5 SOMN-groups, 1-2 sulfur atoms, 1-5 MH-groups or 1-2 phenylene groups, which may optionally be substituted by 1-2 OH-groups, 1-2 MH-groups, 1-2 COOH-groups or 1-2 ЗОзЗН-groups, or optionally substituted by 1-8 OH-groups, 1-5-BSOOH-groups , 1-2 5O zH-groups, 1-5 MH"-groups, 1-5 C.-C; alkoxy groups, and И, т, р independently of each other mean the integers 1 or 2. With 3о 2. Metal complexes according to claim 1, which differ in that the equivalent of the B" metal ion in the K residue is (а) an element with serial number 21-29, 39, 42, 44 or 57-83. o 3. Metal complexes according to claim 1, which differ in that the equivalent of the metal ion EK! in the remainder K is an element with sequence number 27, 29, 31-33, 37-39, 43, 49, 62, 64, 70, 75 or 77. " 4. Complexes of metals according to any of claims 1-3, which differ in that K is a metal complex of the general formula II, I, MV or MI. 5. Metal complexes according to any of claims 1-4, which differ in that the polar residue K has the values specified for the K complex. 6. Complexes of metals according to claim 5, which differ in that as polar residues K there are complexes K of general "20 formulas II, IP, MA or MI. - about the village 7. Metal complexes according to claim 5 or 6, which differ in that B is the equivalent of a metal ion with . serial number 20, 25 or 64. and?" 8. Metal complexes according to any of claims 1-4, which differ in that the polar residue K has the following values: --I((3СН 2СсНоЗОЗЗН, -Кко)сн»оСснН.снНосСносСНоон, -ФфкоОо)сн»Ооснсноон, "Ф(0)СНоОосСнНоСнН(ОНИСНоОН, -Ф(0)СНоМнНА-С(О)СНХСОоНН, -К(0)СнОССн(ОонНИСнНоОонН, -К(Оо)сноснЬсооНН, -И -5025СНоСНоСООН, /-С(0)- SeNa-(m-COOH)», /-С(О)СНоО(СНО)»-SeNa-(m-СООН)», 0 -Ф(0)СНО-СеНу-м-5ОЗН, -сон.Мнесн.Мне (сно.оснсСоонН, -«О0)СснНооснноснос.сСооН, o -Фсноосн.сн(онСНноо-СН.СНоОНн, -ко)осн.осн.сн(оншесносНноО-СнН(ОН)-СНоОН, -Ф«О)СНобЗОзЗН, o -"OsSnN.sSnNhsSOoOon, -"Oo)Ssn(nshesNoneNnooNn, -FK«O)СНоОСН2)»О.а-СН», -ФK«O)СНоОСН2)»ОИ.о-Н, 5o Ф(Ф)СНоОоСсНн (СНООН)», -«Оо)СсноОосн(СНоОСНоСООН)», -С(0)-СеНаз-(m-ОСНСООН)», о -бе0-снё-(снНИБо(СНИ»О-(СНИ»ЯС(СНОИ)) ОСсН», mainly -Ф(О)СНО(СН2И»О0-СНу. и» 9. Metal complexes according to any of claims 1-4, which differ in that the polar residue K is a residue of folic acid. 10. Metal complexes according to any of claims 1-9, which differ in that C in the general formula | is a residue of lysine (a) or (b). 11. Complexes of metals according to any of claims 1-10, which differ in that in the metal complex K is Ф) is a group -СНо- or -СН.-О-СН»-о-, b ой means the place of attachment to -CO-. km 12. A pharmaceutical agent containing at least one physiologically acceptable compound according to any of claims 1-11, optionally in combination with additives that are commonly used in galenic preparations. in 13. A pharmaceutical product according to claim 12, which is characterized by the fact 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. A pharmaceutical agent according to claim 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. A pharmaceutical product according to claim 12, which is characterized by the fact that it is a contrast agent for b5 use in radionuclide diagnostics and radiation therapy, which contains the compound according to point 3 as an active substance. 16. A pharmaceutical agent according to claim 12, which is characterized by the fact that it is a contrast agent for use in 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 claim 12, which is characterized by the fact that it is a contrast agent for use in indirect lymphography, which contains as an active substance the compound according to point 2. 18. A pharmaceutical product according to claim 12, which is characterized by the fact that it is a contrast agent for use in intravenous lymphography, which contains as an active substance the compound according to point 2. 19. A pharmaceutical product according to claim 12, which is characterized by the fact that it is a contrast agent for 7/o Visualization of the intravascular cavity, which contains as an active substance the compound according to item 2. 20. A pharmaceutical product according to claim 12, which is characterized by the fact that it is a contrast agent for imaging tumors, which contains the compound according to item 2 as an active substance. 21. The method of obtaining perfluoroalkyl-containing complexes with polar residues of the general formula (Kr Oad () (k, in which K, b, K, 7, K,, I, t and p have the values indicated in claim 1, which differs in that the carbon acid of the general formula Ia pAKAEY; (Pa) if t vne and 2 I are 25 BVOVKYA and what PE lo: i.e. (o) ooene in which B? means the equivalent of a metal ion with serial number 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or C 3o carboxy protecting group, and 7, BZ and y have the values indicated above, or a carboxylic acid of the general formula Sha (av) ren , (Na) o or KYY nan B; -f- 5 1 4. MY hundred YAM . g y "2 what shcha ha what 40 B evovy ts in which KU, B5 Her Sh! have the values indicated above, or a carboxylic acid of the general formula May y" ros (Mag) (Ma) PAM oh shchi s -a moe, F) and in evil them) in S. that I and OO pl: DVOVE. because pi ZbbOve (uv) oluscho ve M t, im 55 lev ove de VE? has the values indicated above, or a carboxylic acid of the general formula Mia Ed watered wasp vve a) in which E? has the values indicated above, or a carboxylic acid of the general formula MIT and caress 8 , (Mpa) ke that Y sii OV NI well well then 0 water in Sho in which Vo Her 0! have the values indicated above, not necessarily in the activated form, are subjected according to a known method of interaction under the conditions of the coupling reaction with an amine of the general formula M 75 rea pr "(Mu Fu; in which b, K, 7, K,, t and p have the indicated a higher value, 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 is a protective group, after the cleaving of such protective groups, at the next stage, they are subjected to interaction according to a known method with at least one oxide metal 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 amides of amino acids. 6) Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2005, M 10, 15.10.2005. State Department of Intellectual Property of the Ministry of education and science of Ukraine. " "c) "c) " m. - with . and? -I sh" ("c) o 50 s" F) ime) 60 b5