Perfluoroalkyl-containing complexes with polar residues, method for their preparing, pharmaceutical agent

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes perfluoroalkyl-containing complexes with polar residues of the general formula (I):

wherein R means a polar residue; G means a trifunctional residue, a perfluorinated carbon chain; K means a metal complex; Z means a linker group. Proposed complexes can be used for intravenous lymphography, tumor diagnosis and for visualization of infarctions and necrosis. Also, invention describes a method for synthesis of these complexes.

EFFECT: valuable medicinal properties of complexes.

16 cl, 1 tbl, 26 ex

 

The present invention relates to the object characterized in the claims, namely perftorsilanami metal complexes with polar residues of the General formula I, to a method for their production and to their use in NMR and x-ray, radionuclide diagnostics and radiation therapy, MRI limfografii (MRI=magnetic resonance imaging), as well as contrast media for the visualization of the pools of blood. Proposed in the invention compounds are most suitable for use in intravenous limfografii, for the diagnosis of tumors and for the visualization of infarction and necrosis.

In the methods based on nuclear magnetic resonance, second most important element after hydrogen is fluorine, due to the following factors:

1) fluorine has a high susceptibility constituting 83% of the susceptibility of hydrogen

2) fluorine has only one NMR active isotope,

3) fluorine has similar hydrogen resonance frequency, which allows to analyze both using the same equipment,

4) the fluorine is biologically inert,

5) the fluorine is not contained in the biological material (except teeth) and can therefore be used as probes or contrast agents to not generate spurious signals background.

Due to these properties, the fluorine content is it widely used in the diagnosis, based on the method of nuclear magnetic resonance, for example in19F-tomography, functional diagnostics and spectroscopy, as reflected in the relevant patent literature.

For example, in patent US 4639364 (name Mallinckrodt) were proposed triftoratsetofenona for use as contrast agents in19F-tomography:

CF3SO2NH2and

CF3SO2NH-CH2(SNON)4-CH2OH.

Similarly to the19F-tomography refers patent DE 4203254 (in the name of the Max-Planck-Gesellschaft, in which an aniline derivative of the following formula:

19F-tomography is an object of the application WO 93/07907 (name Mallinckrodt), which also suggested that derivatives of phenyl for use as contrast agents:

For use in19F-tomography have been proposed connections with a much simpler structure. For example, in patent US 4586511 (in the name of Children's Hospital Medical Center) described performancebased formula

CF3(CF2)7-Br,

in the patent EP 307863 (in the name of Air Products) claimed PERFLUORO-15-crown-5-ether of the formula

in the patent US 4588279 (in the name of the University of Cincinnati, Children's Hospital Research Foundation) described perfluorocarbon compounds such as PERFLUORO clonony or-octane, simple perforated ethers, such as tetrahydrofuran of the formula

or simple diesters, such as fluids of performability formula

Similarly, for use in19F-tomography are described in the application WO 94/22368 (name Molecular Biosystems) connection, for example

which as a fluorine-containing residue contains PERFLUORO-1H,1H-neopentylene group.

Structure of another type with a wider range of applications in the diagnosis presented in the patent US 5362478 (in the name of VIVORX), which States intended for use in imaging the combination of the fluorocarbon/polymer shell. According to this patent it is proposed to apply perftoran and serum albumin human. This combination has been found, allows, furthermore, to use a fluorine atom as a probe for local temperature measurement and for determining the partial pressure of oxygen.

Perfluorocarbons, for determining the oxygen content, also described in the patent US 4586511.

In the patent DE 4008179 (in the name of Schering) proposed to use the fluorine-containing benzosulfimide as pH probes:

For use in NMR diagnosis in which the quality-enhancing contrast substances are also connections containing atoms of iodine and fluorine and are described, for example, in applications WO 94/05335 and WO 94/22368 (both in the name of a Molecular Biosystems):

For use in19F-tomography is also a combination of the fluorine-paramagnetic metal ion, in this case we are talking about complexes with open-chain, as an example, in the application WO 94/22368 (name Molecular Biosystems) named compounds of formula

and in EP 292306 (name TERUMO Kabushiki Kaisha) are compounds of formula

and cyclic compounds described in EP 628316 (name TERUMO Kabushiki Kaisha):

For NMR-spectroscopic temperature measurements in DE 4317588 (in the name of Schering) was also proposed to use the following combination of fluorine atom and rare earth element:

where Ln represents a rare earth element is La, Pr, Dy or Eu.

If in the compounds containing fluorine and iodine, between the two nuclei interaction does not occur, the compounds containing fluorine and paramagnetic centers (radicals, ions of metals), is quite intensive interaction, which results in the reduction of the relaxation time of the nucleus of fluorine. The degree of manifestation of this effect depends on the number of unpaired electrons and is on metal (Gd 3+>Mn2+>Fe3+>Cu2+and the distance between the paramagnetic ion and19F-atom.

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

The reduction of the relaxation time as a function of distance from the paramagnetic ion is observed in all nuclei with odd spin number, including the proton, and therefore gadolinium compounds are widely used as contrast agents in NMR imaging (Magnevist®, Prohance®, Omniscan®, Dotarem®).

When1N-Mr-tomography, however, determine the relaxation time T1or T2protons, i.e. primarily protons of water, rather than the relaxation time of the nuclei of fluorine, and use the obtained data for visualization. A quantitative measure characterizing the reduction of the relaxation time T1is relaxationof, expressed in l/mmol-C. To reduce the relaxation time applied with success complexes of paramagnetic ions. The following table shows relaxational some commercially available preparations:

T1-relaxational in water [l/mmol, 39°C 0,47 T]T1-relaxational in PLA is IU [l/mmol, 39°C 0,47 T]
Magnevist®the 3.84,8
Dotarem®3,54,3
Omniscan®the 3.84,4
Prohance®3,7a 4.9

In these compounds occurs only interaction between protons and ion gadolinium. Identified for these contrast agents relaxational in water is about 4 l/mmol-C.

Thus, Mr imaging can be successfully applied and fluorine-containing compounds intended for19F-tomography, which uses the short relaxation time of the nucleus of fluorine and fluorine compounds, which determine the relaxation time of water protons.

An unexpected effect associated with the introduction of perftoruglerodnaya balance paramagnetic contrast agent, i.e. the eect of making the compounds used in the methods of the proton imaging properties of those compounds, which were hitherto considered as suitable only for use in the methods of visualization based on the use of fluoride, is also evident in the rapid increase in relaxational protons of water. As a result, this figure reaches values constituting 10-50 l/the mole, while similar values in some commercially available products are, as noted in the above table, from 3.5 to 3.8 l/mmol-C.

From the application DE 19603033.1 already known performancecriteria metal complexes. However, the potential application of these compounds is limited because in many cases they do not allow to achieve satisfactory results. With this in mind, now, as before, there remains a need in contrasting substances intended for visualization of malignant tumors, lymph nodes and necrotic tissue.

Malignant tumors often metastasize to the regional lymph nodes, and this process may also encompass several levels of lymph nodes. Thus, in particular, lymph node metastases were detected in approximately 50-69% of all patients with malignant tumors (see Elke, Lymphographie, Radiologische Diagnostik in Klinik und Praxis, edited by Frommhold, Stender, Thurn, volume IV, published by Thieme Verlag, Stuttgart, 7th ed., 1984, cc.434-496). The possibility of diagnosis of metastasis in lymph nodes is important for therapy of cancer and prediction of their development. Modern imaging techniques (computed tomography, ultrasound and magnetic resonance imaging (MRI) do not allow sufficient high accuracy and reliable the capacity to recognize lymphogenous metastasis of malignant tumors, as in most such cases as criteria of proper diagnosis can only be used the size of the lymph node. As a result, such methods simply do not allow to distinguish small metastases in the unaugmented lymph nodes (<2 cm) from hyperplasia of the lymph nodes are not affected by a malignant tumor (see Steinkamp and others, Sonographie und Kernspintomographie: Differentialdiagnostik von reaktiver Lymphknotenvergröberung und Lymphknotenmetastasen am Hals, Radiol. diagn. 33 (1992), s).

With this in mind, it seems appropriate to provide for the use of specific contrast agents the ability to differentiate lymph nodes, metastases, and hyperplastic lymph nodes.

As an example of known invasive imaging method can be called directly importtemplate (injection oil suspension of contrast medium into the prepared accordingly lymphatic vessel), which, however, is currently used only in rare cases and which allows you to visualize only some ways of lymph drainage.

In experiments conducted on animals, used for dextrans with a fluorescent label to ensure that after interstitial administration surveillance of lymphatic circulation. All labels used after their interstitial/intradermal call is placed to visualize the lymph ducts and lymph nodes, are substances in the form of solid particles ("particulate", such as emulsions and suspensions of nanocrystals) or large polymers (see also WO 90/14846). However, all currently known from the literature compositions due to their lack of local and systemic tolerability, as well as their low mobility in the lymph, causing poor efficiency of diagnosis, are still not optimal for use in indirect limfografii.

Because visualization of the lymph nodes is important for early detection of metastases in cancer patients, there is a need to impositively compositions of contrast agents, which would allow timely and reliable manner, to diagnose the corresponding changes in the lymphatic system.

To achieve the desired effect when using contrast agents, it is advisable to ensure not only their extremely high concentration in the lymph and high stability, but also the most uniform accumulation in the lymph in several levels of the lymphatic system, which is important for accurate diagnosis value. However, the contrast agent must rapidly and completely excreted from the body in order to minimize its negative impact on the whole body. The effect of the contrast of the CSOs of the substance must appear possible within a few hours after its introduction, what is important in radiological practice. Equally important requirement of contrast agents is their good tolerability.

Equally important is the need for impositively contrast substances, which would allow for one session of the diagnostic study to visualize and primary tumor and its possible metastasis in the lymph nodes.

Another important task of medicine is the detection, localization and monitoring of necrosis and infarction. Thus, in particular, myocardial infarction is not stationary and dynamic process, which lasts for an extended period of time (from several weeks to several months). This cardiovascular disease occurs in about three stages, which are impossible to clearly distinguish, because they are superimposed on one another, respectively smoothly one into the other. The duration of the first stage, which is the development of myocardial infarction, approximately the first 24 hours after it began, during which the tissue destruction is spreading like a shock wave (similar to the phenomenon of wave front) from subendocardium to the myocardium. The second stage in which the development of heart attack, as such, has already ended, includes the stabilization of the area in which the process saille the Oia affected heart tissue is the formation of fibers (fibrosis). The third stage, which corresponds to the complete healing of the affected heart tissue begins after replacing all the destroyed tissue fibrous scar tissue. During this period, an active restructuring.

To date there is no method that would allow high accuracy and reliability to diagnose the current phase of myocardial infarction in a human patient. To evaluate myocardial infarction crucial information about how big the share lost in the myocardial tissue and in what place, because this information depends on the type of therapy.

Heart attacks are known to affect not only the myocardium, and other tissues, especially the brain.

If the affected heart tissue to some extent amenable to healing, while necrosis, i.e. when the locally limited necrosis of tissue, you can only prevent or at least mitigate its harmful consequences for the rest of the body. The occurrence of necrosis may be due to a variety of reasons and, in particular, injuries, exposure to chemicals, oxygen deficiency or exposure. Similar to a heart attack information on the extent and type of necrosis is important to select the subsequent medical measures.

With this in mind a long time ago attempts were made to improve e the efficiency of localization, i.e. location, infarction and necrosis through the use of contrast agents in non-invasive methods such as scintigraphy or magnetic resonance imaging. While a large number of published works devoted to experimental research on the use of porphyrins for visualization of necrosis. However, obtained in the course of such research results are contradictory. Thus, in particular, Winkelman and Hoyes, published in Nature, 200 (1967), s, talks about the selective accumulation of manganese-5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (TPPS) in the necrotic area of the tumor.

In contrast, in the work of Lyon and others (Magn. Res. Med. 4 (1987), p. 24) suggests observed by these authors to the effect that the manganese-TFPS distributed essentially throughout the body and accumulate in the kidneys, liver, tumor, and only slightly in muscle tissue. Of particular interest is the fact that the concentration of the indicated substances in the tumor reaches its maximum only on the 4th day after injection and then only after raising dose of 0.12 mmol/kg to 0.2 mmol/kg Therefore, the authors made the conclusion about non-specific accumulation TFPS in tumor tissue. In the work Bockhurst and others, published in Acta Neurochir. 60 (1994, more.), s reiterated the selective binding of Mn-TPPS with tumor cells.

In the howling of all the results of the research, conducted by Foster and others (J. Nucl. Med. 26 (1985), s), it was found that111In-5,10,15,20-tetrakis(4-N-methylpyridinium)porphyrin (Tmip) does not accumulate in the necrotic area and its surrounding living boundary layers. Based on this we could make the obvious conclusion about the presence of interaction between the porphyrin and cloth, which, however, does not necessarily correspond to reality.

In the work of Ni and others, published in Circulation, t, No. 4, part 2, s, Abstract No. 2512 (1994), reported on the possibility of visualization of the affected myocardial regions using manganese-tetraphenylporphyrin (Mn-DFT) and gadolinium-mesoporphyrin (Gd-MP). According to the application WO 95/31219 both of these substances were used for visualization of infarction and necrosis. In this proposal, authored by Marchal and Ni, said (see example 3)that when the connection is used Gd-MP metal content in the diseased heart kidney were on the same level as in neinvazivnoi the body, whereas in the myocardium metal content in invertirovannoi tissue (see example 1) to nine times higher than its content in neinvazivnoi tissue. Unexpected is the fact that with MRI correlation between the intensity of the signal generated invertirovannoi tissue, and the intensity of the signal generated by healthy tissue, in both cases was relatively high in the Aries and was 2,10 and 2,19 respectively. Other metalloporphyrins as described in the application DE 19835082 (name Sobering AG).

Porphyrins have a tendency to accumulate in the skin, which leads to its photosensitivity. Such sensitization may persist for several days, and sometimes within a few weeks. This is an unwanted side effect, manifested in the use of porphyrins as diagnostics. In addition, porphyrins have only a very low therapeutic index, because, for example, in the case of Mn-TPPS its effect is manifested only when it is used in a dose of 0.2 mmole/kg, whereas the lethal dose LD50is already 0.5 mmole/kg

Other contrast agents are non-derivative porphyrin skeleton and intended for visualization of necrosis and heart attacks described in the application DE 19744003 (in the name of Schering AG), DE 19744004 (in the name of Schering AG) and WO 99/17809 (name EPIX). However, to date there is still no connection, which could effectively be used as contrast agents for imaging of heart attacks and necrosis.

Based on the foregoing, the present invention was based on the task to offer a contrast agent that would be suitable for use primarily in MRI limfografii, as well as for diagnosis and visualization of necrosis and heart attacks.

p> This task is solved according to the invention using performanceeasy complexes with polar residues of the General formula I

in which

Rfdenotes a perfluorinated, straight or branched carbon chain of the formula-CnF2nE,

where E represents a terminal fluorine atom, chlorine, bromine, iodine or hydrogen

n denotes the number 4-30,

K stands for a metal complex of General formula II

in which

R1represents a hydrogen atom or an equivalent of a metal ion with atomic number 21-29 and 58-71,

provided that at least two radicals R1represent the equivalents of metal ions,

R2and R3independently of one another denote hydrogen, C1-C7alkyl, benzyl, phenyl, -CH2HE or-CH2Och3and

U represents-C6H4-O-CH2-ω-, -(CH2)1-5-ω-, fenelonov group, -CH2-NHCO-CH2-CH(CH2COOH)-C6H4-ω-, -C6H4-(OCH2CH2)0-1-N(CH2COOH)-CH2-ωor optionally interrupted by one or more oxygen atoms, 1-3-NHCO-groups, 1-3-CONH groups and/or substituted by 1-3 -(CH2)0-5COOH-groups1-C12alkylenes or7-sub> 12-C6H4-O-group, when it ω refers to the place of joining-CO-,

or the General formula III

in which

R1have the above values,

R4denotes hydrogen or specified for R1the equivalent of a metal ion and

U1denotes-C6H4-O-CH2-ω-where ω refers to the place of joining-CO-,

or the General formula IV

in which R1and R2have the above values,

or the General formula VA or VB

in which R1has the above values

or the General formula VI

in which R1has the above values

or the General formula VII

in which

R1has the above values, and

U1denotes-C6H4-O-CH2-ω-where ω refers to the place of joining-CO-,

this is not necessarily present in the residue To the free acid groups optionally can be represented in the form of salts of organic and/or inorganic bases or amino acids or amides of amino acids,

G denotes at least three of functionalityand the balance, selected from the following residues (a)-(i):

(a)

(b)

(C)

(d)

(e)

(About

(g)

where α indicates the place of attachment G to the complex K β indicates the place of attachment G to the residue R, and γ indicates the place of attachment G to the residue Z,

Z denotes a group

γ-C(O)CH2O(CH2)2-ε,

where γ indicates the place of attachment of Z to the remainder of G, and ε indicates the place of attachment of Z to perfluorinated residue Rf,

R is a polar residue selected from complexes of General formulas II-VII, and in this case, R1denotes the hydrogen atom or the equivalent of a metal ion with a serial number 20-29, 31-33, 37-39, 42-44, 49 or 57-83, and the remaining R2, R3, R4U and U1have the above values, and in the case when G is a residue of formula (C) or (d), and R is a compound selected from complexes of General formulas II and V, R may not be identical to the balance To the General formula I, if Z represents δ-C(O)CH2O(CH2)2-ε,

and the and represents the balance of folic acid or attached via a-CO-, SO2or a direct link to the residue G carbon chain with 2 to 30 C-atoms, which is straight or branched, saturated or unsaturated and which is optionally interrupted by 1-10 oxygen atoms, 1-5-NHCO-groups, 1-5-CONH-groups, 1-2 sulfur atoms, 1-5-NH-groups or 1-2 phenylanaline groups, which optionally can be substituted by 1-2 HE-groups, 1-2 NH2groups, 1-2-COOH groups, or 1-2-SO3N-groups, or optionally substituted 1-8 HE-groups, 1-5-COOH groups, 1-2 SO3N-groups, 1-5 NH2groups 1-51-C4alkoxygroup, and

l, m, p independently of one another denote integers of 1 or 2.

If the proposed invention the compound is intended for use in NMR diagnosis, the metal ion forming a signal group should be paramagnetic. Such ions are primarily two - and trivalent ions of elements with atomic numbers 21-29, 42, 44 and 58-70. As an example, suitable for use in the above order of the ions can be called ions of chromium(III), iron(II), cobalt(II), Nickel(II), copper(II), praseodymium(III), neodymium(III), samarium(III) and ytterbium(III). The most preferred with regard to their high magnetic moment of the ions of gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III), iron(III) and manganese(II).

For the application of the proposed invention is link is in medical radiology (radioisotope diagnostics and radiotherapy) metal ion must be radioactive. For use in this purpose, suitable, for example, radioisotopes of elements with atomic numbers 27, 29, 31-33, 37-39, 43, 49, 62, 64, 70, 75 77. Preferred in this technetium, gallium, indium, rhenium and yttrium.

If the proposed invention the compound is intended for use in x-rays, the metal ion is preferable to use an element with a higher sequence number in order to ensure a sufficiently high degree of absorption of x-rays. It was found that for this purpose, suitable diagnostic tools that contains a physiologically compatible complex salt with metal ions sequence numbers 25, 26 and 39, and 57-83. Preferred the ions of manganese(II), iron(II), iron(III), praseodymium(III), neodymium(III), samarium(III), gadolinium(III), ytterbium(III) or bismuth(III), first of all ions dysprosium(III) and yttrium(III).

Present under certain conditions in R acidic hydrogen atoms, i.e. atoms which are not substituted by the Central ion, optional can be completely or partially replaced by cations of inorganic and/or organic bases or amino acids or amides of amino acids. As an example of acceptable inorganic cations can be called a lithium ion, the potassium ion, calcium ion, and especially the sodium ion. Acceptable cations of organic bases are the Xia, in particular, any primary, secondary or tertiary amines, such as ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglycine and especially N-methylglucamine. As an example of acceptable cations of amino acids can be called cations lysine, arginine and ornithine, as well as amides mainly acidic or neutral amino acids.

The most preferred compounds of General formula I include compounds containing macrocycle To the General formula II, III, VB, or VII.

The remainder of U in the metal complex preferably denotes-CH2- or-C6H4-O-CH2-ω-where ω is a place of joining-WITH-.

Specified as values of R2and R3alkyl groups in the macrocycle of the General formula II can have straight or branched chain. The examples are methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl. Preferably R2and R3independently of one another denote hydrogen or C1-C4alkyl. In one particularly preferred options R2denotes methyl, and R3denotes hydrogen.

Specified as the values of R2or R3benzyl group or phenyl group in the macrocycle To the General form of the s II can also be substituted in the ring.

Polar residue R in the General formula I in one of the preferred options is a complex, which is preferably in addition to Gd3+- or Mn2+-complex may also be the CA2+-complex. Most preferred as the polar residues R complexes To General formulas II, III, VA and VII. As R1they are in a particularly preferred embodiment, contain the equivalent of a metal ion with a sequence number of 20, 25 or 64.

According to another preferred variant of the polar residue R has the following meanings: -C(O)CH2CH2SO3H, -C(O)CH2OCH2CH2OCH2CH2OH, -C(O)CH2OCH2CH2OH, -C(O)CH2OCH2CH(OH)CH2OH, -C(O)CH2NH-C(O)CH2COOH, -C(O)CH2CH(OH)CH2OH, -C(O)CH2OCH2COOH, -SO2CH2CH2COOH, -C(O)-C6H3-(m-COOH)2-C(O)CH2O(CH2)2-C6H3-(m-COOH)2-C(O)CH2O-C6H4-m-SO3H, -C(O)CH2NHC(O)CH2NHC(O)CH2OCH2COOH, -C(O)CH2OCH2CH2OCH2COOH, -C(O)CH2OCH2CH(OH)CH2O-CH2CH2OH, -C(O)CH2OCH2CH(OH)CH2OCH2-CH(OH)-CH2OH, -C(O)CH2SO3H, -C(O)CH2CH2COOH, -C(O)CH(OH)CH(OH)CH2OH, -C(O)CH2O[(CH2)2O]1-9CH 3-C(O)CH2O[(CH2)2O]1-9-H, -C(O)CH2OCH(CH2OH)2-C(O)CH2OCH(CH2OCH2COOH)2-C(O)-C6H3-(m-och2COOH)2, -CO-CH2O-(CH2)2O(CH2)2O-(CH2)2O(CH2)2OCH3preferably-C(O)CH2O[(CH2)2O]4-CH3.

In another preferred embodiment, the polar residue R represents the residue of folic acid.

Among proposed in the invention compounds of General formula I further preferred compounds in which Rfdenotes-CnF2n+1n preferably denotes a number from 4 to 15. The most preferred residues-C4F9- 6F13, -C8F17, -C12F29and-C14F29as well as balances considered in the examples of the compounds.

At least three functionalized balance G in General formula I, which is the "skeleton", in one of the preferred embodiments of the invention refers to a lysine residue (a) or (b).

Z denotes a specified General formula I linker, with the preferred group

The method of obtaining performanceeasy metal complexes with polar residues of the General formula I

in which K, G, R, Z, Rf, I, m and R have the above values, is that the carboxylic acid of General formula IIa

in which R5indicates the equivalent of a metal ion with atomic number 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or carboxyamide group, and R2, R3and U have the above values,

or carboxylic acid of General formula IIIa

in which R4, R5and U1have the above values,

or carboxylic acid of General formula IVa

in which R5and R2have the above values,

or carboxylic acid of General formula Va or Vb

where R5has the above values

or carboxylic acid of General formula VIa

in which R5has the above values

or carboxylic acid of General formula VIIa

in which R5and U1have the above values,

optionally in activated form, is subjected by well-known methods of interaction in terms of combination reaction with the amine of General formula VIII

in which G, R, Z, Rf, m and p have the t above values

and then, if necessary, otscheplaut present under certain conditions, the protective group to obtain the result of complex metal General formula I or, if R5represents a protective group, after removal of such protective groups at the next stage is subjected to interaction by well-known methods of at least one metal oxide or salt of the metal with atomic number 21-29, 31-33, 37-39, 42-44, 49 or 57-83, and then optionally present under certain conditions, the acidic hydrogen atoms are substituted by cations of inorganic and/or organic bases, amino acids or amides of amino acids.

Used in the above-described reactions of carboxylic acids of the General formulas IIa-VIIa are either known compounds or they are obtained as described in examples methods. Thus, in particular, a method of obtaining a carboxylic acid of General formula IIA are known from DE 19652386. Carboxylic acids of General formula IIIa can be obtained analogously to example 4, below in the present description. A method of obtaining a carboxylic acid of General formula IVa is described in DE 19728954.

The precursor compounds of General formula VA is N3-(2,6-dioxopentanoate)-N6(ethoxycarbonylmethyl)-3,6-disapprova acid, which is described in EP 263059.

Compounds of General formula VB are derived isomeric on etilendiamintetrauksusnoy acid (DTPC), which are attached via the Central N-atom of acetic acid. This DTPC described in DE 19507819 and DE 19508058.

Compounds of General formula VI are derived N-(carboxymethyl)-N-[2-(2,6-dioxo-4-morpholinyl)ethyl]glycine synthesis method described in J. Am. Oil. Chem. Soc., 59 (2) (1982), c.104-107.

Compounds of General formula VII are derived from 1-(4-carboxymethoxy)ethylenediaminetetraacetic acid synthesis method described in US 4622420.

Preparation of amines of General formula VIII is described in detail in the examples below in the present description, and therefore these compounds can be obtained similar to that described in these examples methods.

Proposed in the invention, metal complexes suitable as determined, for use in NMR and x-rays, as well as in radionuclide diagnostics and radiation therapy. The object of the invention in accordance with this is also the application of the proposed performanceeasy metal complexes with polar residues to obtain contrast agents intended for use in NMR and x-rays, especially when limfografii, for tumour diagnosis and visualization of infarction and necrosis, as well as in radionuclide diagnostics and radiation therapy. Proposed in the invention compounds are the most wearable is DNA for use in interstitial and primarily with intravenous limfografii. Along with this, they can also be used for visualization of intravascular cavity (as contrast agents for imaging pools of blood).

The object of the invention is also a pharmaceutical agent containing at least one physiologically compatible compound according to the invention, optionally in combination with commonly used in herbal preparations additives.

Proposed in the present invention compounds differ extremely good system compatibility and a high degree of accumulation (concentration) in the lymph nodes of three consecutive levels (which is especially important when intravenous limfografii). Due to this, they are particularly suitable for use in MRI limfografii.

Compounds according to the invention is also suitable for the detection and localization of vascular diseases, because they are at their introduction in intravascular cavity distributed. Proposed in the invention to allow connection with the use of NMR imaging to clearly differentiate fabric with good and poor blood flow, and thereby to diagnose ischemia. Equally in the application of contrast agents according to the invention it is also possible to clearly distinguish between invertirovannoi fabric due to her anemia and the surrounding healthy or ischemic tissue. Similar prob what the possibility is of particular importance in those cases, when, for example, need to determine exactly whether a myocardial infarction or talking about ischemia.

In comparison with used to date as contrast agents for imaging pools of blood macromolecular compounds, such as Gd-TPC-polylysin, the compounds according to the invention also have a higher T1-relaxational and accordingly they are characterized by a higher level of signal intensity in MRI imaging. Since, in addition, such compounds are retained in the blood for a longer period of time, they can be administered in relatively small doses (for example ≤50 mcmole Gd 1 l circulating in the body the blood). However, an important advantage of the invention compounds is that they are rapidly and almost completely excreted.

In addition, it was found that the compounds according to the invention accumulate in areas with increased vascular permeability, in particular in tumors, and in accordance with this, they allow you to get information about the perfusion of tissues, make it possible to determine the volume of blood in the tissues, selectively reduce the relaxation time, respectively the period thickening of the blood, and to visualize the permeability of blood vessels. To get this kind of physical and the ideological information when using extracellular contrast agents, such as Gd-DTPC (Magnevist®), it is impossible. With this in mind, there is also the opportunity to use the compounds according to the invention in such modern methods of visualization as magnetic resonance imaging and computed tomography, in particular for specific diagnosis of malignant tumors, for early monitoring of treatment with cytotoxic, anti-inflammatory or vasodilatation therapy for the early identification of areas with reduced blood flow (e.g., infarction), for angiography in vascular diseases and for the detection and diagnosis of aseptic or infection.

Proposed in the invention the pharmaceutical agents receive by known techniques by suspendirovanie or dissolution of the complex compounds according to the invention, optionally in combination with commonly used in herbal preparations additives in aqueous medium, after which the suspension or the solution so obtained is optionally subjected to sterilization. As these additives can be used, for example, physiologically compatible buffers such as tromethamine), complexing agents (such as diethylenetriaminepentaacetic acid) or weak complexes or the relevant proposed in the invention are metal complexes of CA-complexes or when dealing with electrolytes, such as sodium chloride, or, if necessary, antioxidants such as ascorbic acid.

If for enteral, respectively parenteral injection, or for other purposes, it is envisaged to apply suspensions or solutions proposed in the invention means water or a physiological saline solution, then they are mixed with one or more commonly used in herbal preparations auxiliary substances (for example, methylcellulose, lactose, mannitol) and/or one or more surface-active substances (for example, lecithin, Tween®, Myrj®and/or one or more korrigentami (e.g. essential oils).

In principle, the pharmaceutical agents according to the invention can also be obtained without isolating the complexes. But in any case, in the process of formation of chelate compounds should be particularly careful to comply with conditions that virtually eliminate the possibility of the presence in the proposed invention the complexes of metal ions, have not formed a complex and toxically. To this end, the process of obtaining complex compounds can be monitored by titration using, for example, color indicators, such as selenology orange. In accordance with this present invention relates also to the process for the preparation of complex compounds and their salts. In the extreme case highlighted the complex can be subjected to cleaning.

In the application proposed in the invention means in vivo they can be administered together with suitable for this purpose by the media, such as serum or physiological saline, and together with another protein, such as serum albumin human (SAC).

Proposed in the invention means are intended mainly for parenteral, preferably intravenous injection. However, depending on the studied object - vessels or tissues - they can also be used for intravascular or interstitial/intradermal injection.

The pharmaceutical agents according to the invention contain preferably from 0.1 μmol to 2 moles of the complex of 1 l and are intended for administration in doses, components, usually from 0.0001 to 5 mmol/kg

Proposed in the invention means meet various requirements, which determine their suitability for use as contrast agents in NMR imaging. Thus, in particular, such tools due to the increase in signal intensity after oral or parenteral administration to enhance images obtained using NMR imaging. In addition, these tools are highly effective the spine, which is necessary to reduce the concentration introduced into the body of foreign substances to the lowest possible level, and yet have a good tolerance, which is necessary to maintain the noninvasive nature of the studies.

Due to the high solubility of the proposed invention of funds in the water and their low osmolarity will be able to receive on the basis of highly concentrated solutions, which allows to maintain volume overload of the circulatory system within acceptable limits, and to compensate for the dilution of such fluids body fluids. Proposed in the invention means are further not only a high stability in vitro, but also show a surprisingly high stability in vivo, allowing the release or exchange of related ions in the complex, which in principle are toxic, there is only extremely slowly within the time period for which the new contrast agent is completely removed from the body.

Normally offered in the invention means when used as NMR-based assays used in doses of from 0.0001 to 5 mmol/kg, preferably 0.005 to 0.5 mmole/kg

Proposed in the invention of complex compounds may also be effectively used as reagents with the magnetic Veprik what ivascu and shift reagents in NMR spectroscopy in vivo.

The means according to the invention owing to their optimum radioactive properties and high stability contained complex compounds suitable for use as a diagnostic in radionuclide diagnostics. In more detail the application of such tools and their dosage are described, for example, in the publication "Radiotracers for Medical Applications", published by CRC-Press, Boca Raton, Florida.

Proposed in the invention compounds and tools can also be used in positron emission tomography, where to use the emitting protons isotopes, such as43Sc,44Sc,52Fe55Co.,68Ga and86Y (see W.D.Heiss and ..Phelps, Positron Emission Tomography of Brain, published by Springer Verlag, Berlin, Heidelberg, New York (1983)).

Compounds according to the invention can, as it has been unexpectedly found to apply also for the differentiation of malignant and benign tumors without the blood-brain barrier.

Compounds according to the invention differ in that they are completely eliminated from the body, thereby showing good tolerability.

As proposed in the invention compounds accumulate in malignant tumors (no diffusion in healthy tissue, but high permeability of tumor vessels), they can also be used in addition to radiation therapy of malignant tumors. The difference of radiation therapy with the appropriate diagnosis is only in the number and type of isotope. The objective is the destruction of tumor cells under the influence of powerful short-wave radiation with extremely small range. It uses the interaction is contained in the complex compounds of metals (such as iron or gadolinium) with ionizing radiation (e.g. x-ray or neutron radiation. This effect can significantly increase the local dose in the place where the metal complex (e.g., tumors). To ensure the same dose of irradiation in malignant tissue, the application of such metal complexes can significantly reduce the radiation dose to healthy tissue and thereby prevent undesirable for patients side effects. Therefore, proposed in the invention, the conjugates of metal complexes suitable for use as a radio-sensitizing substances in radiation therapy of malignant tumors (e.g., through the use of Mossbauer effects or neutron capture therapy). As an example of acceptable emitting β-radiation of ions can be called46Sc,47Sc,48Sc,72Ga73Ga and90Y. as acceptable emitting α-emission of ions with a small half-life can be called, for example,211Bi sup> 212Bi213Bi and214Bi, preferred of which212Bi. Emitting protons and electrons ion is158Gd, which can be obtained from157Gd by neutron capture.

If proposed in the invention, the tool is intended for use in radiation therapy in accordance with the methodology proposed R.L.Mills and others (see Nature, vol 336 (1988), s), the Central ion must be derived from the mössbauer isotope, such as57Fe or151Eu.

In the application proposed in the invention means in vivo they can be administered together with suitable for this purpose by the media, such as serum or physiological saline, and together with another protein, such as serum albumin human. Dosage depends on the type of hepatocellular disorders, used metal ion and the type of imaging method.

Proposed in the invention means are intended mainly for parenteral, preferably intravenous injection. However, as mentioned above, depending on the studied object - vessels or tissues - they can also be used for intravascular or interstitial/intradermal injection.

Proposed in the invention means are also suitable for use as contrast media in the substances it should be noted that in their application in biochemical and pharmacological research show no signs of anaphylactic reactions, known to iodine-containing contrast agents. These funds due to their optimum properties to absorb radiation in the range of higher voltages on the tube are most suitable for use in digital subtraction technique.

As a rule, proposed in the invention means when used as a radiopaque substances are used similarly, for example, diatrizoate of meglumine in doses from 0.1 to 5 mmol/kg, preferably from 0.25 to 1 mmole/kg

In the application proposed in the invention compounds is possible first of all to achieve their higher concentration in the blood compared with extracellular contrast agents. After intravenous they are distributed only in intravascular cavity, what is their main advantage over extracellular contrast agents.

Examples of carrying out the invention

Example 1A

2-N-TRIFLUOROACETYL-6-N-benzyloxycarbonylglycine

100 g (356,7 mmole) of 6-N-benzyloxycarbonylglycine dissolved in a mixture of 1000 ml of ethyl ether triperoxonane acid and 500 ml of ethanol for 24 h and stirred at room temperature. Thereafter evaporated to dryness and who headed the remainder of crystallized from diisopropyl ether.

Output: 128,9 g (96% of theory) of colorless crystalline powder.

Elemental analysis:

Rasch.:With 51,07N 5,09F 15,14N 7,44
the detection.:With 51,25N 5,18F 15,03N 7,58

Example 1B

[1-(4-PerformanceCounter)piperazine]amide of 2-N-TRIFLUOROACETYL-6-N-benzyloxycarbonylglycine

To 125 g (332 mmole) of the compound indicated in the heading of example 1A, and amounts to 188.7 g (332 mmole) 1-performancemonitoriterations (obtained according to DE 19603033) in 800 ml of tetrahydrofuran at 0°add 164,2 g (0,664 mmole) AEDH (ethyl ester of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) and stirred over night at room temperature. Thereafter evaporated to dryness in vacuum and chromatographic on silica gel (eluent: dichloromethane/methanol in a ratio of 20:1).

Output: 286 g (93% of theory) of colorless solid.

Elemental analysis:

Rasch.:With 36,30N 2,83F 41,01N 6,05S of 3.46
the detection.:With 36,18N 2,94F 40,87N 5,98S 3,40

Example 1V

[1-(4-PerformanceCounter)piperazine]amide of 6-N-be ilexibility

A solution of 280 g (302,2 mmole) of the compound indicated in the heading of example 1B, in 2000 ml of ethanol at 0°With bubbled for one hour with gaseous ammonia. The mixture is then stirred for 4 h at 0°C. then evaporated to dryness and the residue is separated from the water by stirring. The solid is filtered off and dried in vacuo (50°).

Output: 243,5 g (97% of theory) of an amorphous solid.

Elemental analysis:

Rasch.:With 37,60N 3,28F 38,89N 6,75S 3,86
the detection.:With 37,15N 3,33F 38,78N of 6.68S 3,81

Example 1G

[1-(4-PerformanceCounter)piperazine]amide of 6-N-benzyloxycarbonyl-2-N-(3,6,9,12,15-intoxikation)lysine

To 50 g (60,20 mmole) of the compound indicated in the heading of example 1, and 7.10 g (70 mmol) of triethylamine in 350 ml of dichloromethane at 0°With added dropwise a solution of 19.93 per g (70 mmol) of acid chloride of 3,6,9,12,15-pentaoxaoctadecane acid in 50 ml dichloromethane and stirred for 3 h at 0°C. Next, add 200 ml of 5%aqueous hydrochloric acid and stirred for 5 min at room temperature. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuum. The remainder of chromatog ayrout on silica gel (eluent: dichloromethane/acetone in a ratio of 15:1).

Output: 53,7 g (93% of theory) of colorless viscous oil.

Elemental analysis:

Rasch.:With 33,83N 4,94F 3.34N of 5.84S 33,69
the detection.:With 33,75N of 5.05F 3,29N 5,78S 33,75

Example 1D

[1-(4-PerformanceCounter)piperazine]amide of 2-N-(3,6,9,12,15-intoxikation)lysine

50 g (52,15 mmole) of the compound indicated in the heading of example 1, dissolved in 500 ml of ethanol and add 6 g of palladium catalyst (10%Pd/C). After that hydronaut at room temperature. Then the catalyst is filtered off and the filtrate evaporated to dryness in vacuum.

Output: 43,0 g (quantitative) of a colorless solid.

Elemental analysis:

Rasch.:With 27,68N 5,01F 39,17N 6,79S 3,89
the detection.:With 27,60N 5,13F 39,09N of 6.68S 3,81

Example 1E

[1-(4-PerformanceCounter)piperazine]amide of 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]-2-N-(3,6,9,12,15-intoxikation)lysine, Gd-complex

20 g (24,25 mmole) connect the tion, specified in the header of example 1D, and 2.79 g (24,25 mmole) of N-hydroxysuccinimide, 2,12 g (50 mmol) of lithium chloride and 15,27 g (24,25 mmole) Gd-complex of 1,4,7-Tris(carboxylatomethyl)-10-[(3-Aza-4-oxo-5-methyl-5-yl)]pentane acid]-1,4,7,10-tetraazacyclododecane dissolved under moderate heating in 200 ml of dimethylsulfoxide. Then, at 10°add to 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide and then stirred over night at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes Precipitated precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, eluent: gradient of water/ethanol/acetonitrile).

Output: 28,21 g (81% of theory) of colorless solid.

Water content: 11,0%.

Elemental analysis (based on anhydrous substance):

Rasch.:With 31,78N 4,84F 22,49N 8,78S of 2.23Gd 10,95
the detection.:With 31,74N to 4.98F 22,39N 8,69S 2,15Gd 10,87

Example 2A

[1-(4-PerformanceCounter)piperazine]amide of 6-N-[3,9-bis(tert-butyloxycarbonyl)-3,6,9-CreationDate-1,11-dicarboxylic acid bis(tert-butyl ether)-6-carbonylmethyl]-2-N-[3,6,9,12,15-intoxikation)whether the ina

To a solution of 20 g (24,08 mmole) of the compound indicated in the heading of example 1D, 14,88 g (24,08 mmole) of bis(tert-butyl ether) 3,9-bis(tert-butyloxycarbonyl-3,6,9-CreationDate-1,11-dicarboxylic acid and 2.77 g (24,08 mmole) of N-hydroxysuccinimide in 150 ml of dimethylformamide at 0°add to 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide. The mixture is stirred for 3 h at 0°and then overnight at room temperature. Precipitated precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuum and chromatographic on silica gel (eluent: dichloromethane/ethanol in a ratio of 20:1).

Output: 31,61 g (91% of theory) of a viscous oil.

Elemental analysis:

Rasch.:With 40,80N of 6.71F 22,39N 6,80S 2,22
the detection.:With 40,72N 6,82F 22,30N 6,75S 2,14

Example 2B

[1-(4-PerformanceCounter)piperazine]amide of 6-N-[6-carbonylmethyl-3,9-bis(carboxylatomethyl)-3,6,9-triazaundecamethylenediamine acid-1-carboxy-11-carboxylate]-2-N-(3,6,9,12,15-intoxikation)lysine, Gd-complex, sodium salt

30 g (20.8 mmole) of the compound indicated in the heading of example 2A are dissolved in 300 ml triperoxonane acid for 5 h and stirred at room temp is the temperature. Thereafter evaporated to dryness, the residue is dissolved in 300 ml of water and the value of the pH is adjusted to 2.5 with 10%aqueous NaOH. Next add 3.77 g (of 10.4 mmole) of gadolinium oxide and stirred for 3 h at 60°C. After this mixture is allowed to cool to room temperature and the pH value set by 7.4 with sodium hydroxide. Then evaporated to dryness and the residue purified on silica gel RP-18 (eluent: gradient of water/acetonitrile).

Output: MT 19 : 18 g (67% of theory) of a colourless, amorphous solid.

The water content of 9.8%.

Elemental analysis (based on anhydrous substance):

Rasch.:With 28,80N 4,25F 23,47N 7,12S 2,33Gd 11,48Na 1,67
the detection.:With 28,67N 4,34F 23,38N 7,03S 2,27Gd 11,37Na 1,74

Example 3A

[1-(4-performancecounterpermission]amide of lysine

20 g (24,08 mmole) of the compound indicated in the heading of example 1B, was dissolved in 300 ml of ethanol and add 4 g of palladium catalyst (10%Pd/C). After that hydronaut at room temperature. Then the catalyst is filtered off and the filtrate evaporated to dryness in vacuum.

Output: 16,77 g (quantitative) of a colorless solid in the society.

Elemental analysis:

Rasch.:With 31,04N 3.04 fromF 46,38N 8,04S 4,60
the detection.:With 30,97N 3,15F 46,31N 7,98S 4,51

Example 3b

[1-(4-performancecounterpermission]amide of 2,6-N,N'-bis[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]lysine, Gd-complex

10 g (14,36 mmole) of the compound indicated in the heading of example 3A, 3,34 g (29 mmol) of N-hydroxysuccinimide, of 2.54 g (mmole) of lithium chloride and 18,26 g (29 mmol) of the Gd-complex of 1,4,7-Tris(carboxylatomethyl)-10-(3-Aza-4-oxo-5-methyl-5-yl)-1,4,7,10-tetraazacyclododecane dissolved under moderate heating in 200 ml of dimethylsulfoxide. Then, at 10°add 12,38 g (60 mmol) of N,N-dicyclohexylcarbodiimide and then stirred over night at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes Precipitated precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, eluent: gradient of water/ethanol/acetonitrile).

Output: 19,02 g (69% of theory) of colorless solid.

Water content: 11.3 per cent.

Elemental analysis (based on anhydrous substance):

td align="left"> Rasch.:
With 35,03N 4,04F 16,82N of 10.21S 1,67Gd 16,38
the detection.:With 34,96N 4,13F 16,74N 10,16S 1,61Gd 16,33

Example 4A

Methyl ester 2-[4-(3-octaethylporphyrin)]phenylacetic acid

To 200 g (1,204 mole) of methyl ester of 4-hydroxyphenylarsonic acid and 212 g (2 mol) of sodium carbonate in 2000 ml of acetone add 233,8 g (1,4 mole) ethyl ester 2-bromoxynil acid for 5 h refluxed. The solid is filtered off and evaporated to dryness in vacuum. The remainder chromatographic on silica gel (eluent: n-hexane/ethyl ester of acetic acid in the ratio 15:1).

Output: 288,5 g (95% of theory) of colourless oil.

Elemental analysis:

Rasch.:With 61,90N 6,39
the detection.:With 61,75N 6,51

Example 4B

Methyl ester 2-[4-(3-octaethylporphyrin)]phenyl-2-bromoxynil acid

To 285 g (1,13 mole) specified in the header of example 4A compound dissolved in 2000 ml of carbon tetrachloride, add 201 g (1,13 mole) of N-bromosuccinimide and 100 mg dibenzoylperoxide and within 8 h refluxed. Next cool on l is danoy bath, fallen in sediment succinimide filtered and the filtrate evaporated to dryness in vacuum. The residue is purified on silica gel (eluent: n-hexane/acetone in a ratio of 15:1).

Output: 359,2 g (96% of theory) of colorless viscous oil.

Elemental analysis:

Rasch.:With 47,28N 4,57Br 24,16
the detection.:With 47,19N 4,71Br 24,05

Example 4B

Methyl ester 2-[4-(3-octaethylporphyrin)]phenyl-2-[1-(1,4,7,10-tetraazacyclododecane-7-yl]acetic acid

To 603 g (3.5 mol) of 1,4,7,10-tetraazacyclododecane in 6000 ml of chloroform, add 350 g (1,057 mol) of the compound indicated in the heading of example 4B, and stirred overnight at room temperature. Next three times extracted with 3000 ml of water, the organic phase is dried over magnesium sulfate and evaporated to dryness in vacuum. The residue is used without additional purification in the subsequent reaction (example 4G).

Output: 448 g (quantitative) of a viscous oil. Elemental analysis:

Rasch.:With 59,70N 8,11N 13,26
the detection.:With 59,58N 8,20N of 13.18

Example 4G

2-[4-(3-oxopropionate acid)]phenyl-2-[1,4,7-Tris(carboxymethyl)-1,4,7,10-tetr azacyclopentadecan-10-yl]acetic acid

445 g (1,053 mol) of the compound indicated in the heading of example 4B, and 496 g (5,27 mole) of Chloroacetic acid are dissolved in 4000 ml of water. Then the value of the pH is adjusted to 10 using 30%aqueous sodium hydroxide. Next, the mixture is heated to 70°and the pH value by addition of 30%aqueous sodium hydroxide is maintained at level 10. The mixture is stirred for 8 h at 70°C. thereafter, the pH value is set at 13 and within 30 minutes, refluxed. Then the solution is cooled in an ice bath and the addition of concentrated hydrochloric acid the pH value set to 1. Thereafter evaporated to dryness in vacuum. The residue is dissolved in 4000 ml of methanol and stirred for one hour at room temperature. Precipitated precipitated salt is filtered off, the filtrate is evaporated to dryness and the residue purified on silica gel RP-18 (eluent: gradient of water/ethanol/acetonitrile).

Output: 403 g (69% of theory) of colorless solid.

Water content: 10.2 per cent.

Elemental analysis (based on anhydrous substance):

Rasch.:With 51,98N 6,18N 10,10
the detection.:With 51,80N of 6.31N 10,01

Example 4D

2-[4-(3-oxopropionate acid)]phenyl-2-[1,4,7-Tris(carboxymethyl)-1,4,7,10-tetrazol logodesign-10-yl]acetic acid, Gd-complex

To 400 g (721,3 mmole) of the compound indicated in the heading of example 4G, in 2000 ml of water add 130,73 g (360,65 mmole) of gadolinium oxide and stirred for 5 h at 80°C. the Solution is filtered and the filtrate lyophilized.

Output: 511 g (quantitative) of amorphous solids.

Water content: 11,0%.

Elemental analysis (based on anhydrous substance):

Rasch.:With 40,67N to 4.41Gd 22,19N 7,98
the detection.:With 40,51N to 4.52Gd 22,05N 8,03

Example 4E

[4-PerformanceCounter)piperazine]amide of 2,6-N,N'-bis{2-[4-(3-oxopropyl)phenyl]-2-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-yl]acetic acid]lysine, digidelay complex, disodium salt

10 g (14,36 mmole) of the compound indicated in the heading of example 3A, of 3.45 g (30 mmol) of N-hydroxysuccinimide, of 2.54 g (60 mmol) of lithium chloride and 21,26 g (30 mmol) of the compound indicated in the heading of example 4D, dissolved under moderate heating in 250 ml of dimethylsulfoxide. Then, at 10°add 16,51 g (80 mmol) of N,N-dicyclohexylcarbodiimide and then stirred over night at room temperature. The solution is poured into 2000 ml of acetone and stirred for 10 minutes Drawn in solid precipitate ve is estvo filtered and then purified by chromatography (silica gel RP-18, eluent: gradient of water/ethanol/acetonitrile). This substance is dissolved in a small amount of water, the pH value set by 7.4 using sodium hydroxide and lyophilized.

Output: 21,02 g (69% of theory) of colorless solid.

Water content: 11.2 per cent.

Elemental analysis (based on anhydrous substance):

Rasch.:With 37,36N 3,66F 15,22Gd 14,82N a 7.92Na 2,17S 1,51
the detection.:With 37,28N 3,74F 15,14Gd 14,75N 8,03Na 2,23S 1,46

Example 5A

[1-(4-PerformanceCounter)piperazine]amide of 2,6-N,N'-bis[6-carbonylmethyl-3,9-bis(tert-butyloxycarbonyl)-3,6,9-CreationDate-1,11-dicarboxylic acid bis(tert-butyl ether)]lysine

To a solution of 10 g (14,36 mmole) of the compound indicated in the heading of example 3A, 18,53 g (30 mmol) of bis(tert-butyl ether) 3,9-bis(tert-butyloxycarbonyl)-6-carboxymethyl-3,6,9-CreationDate-1,11-dicarboxylic acid and 3.45 g (30 moles) of N-hydroxysuccinimide in 150 ml of dimethylformamide at 0°add 10,32 g (50 mmol) of N,N-dicyclohexylcarbodiimide. The mixture is stirred for 3 h at 0°and then overnight at room temperature. Precipitated precipitated urea is filtrowa, the filtrate is evaporated to dryness in vacuum and chromatographic on silica gel (eluent: dichloromethane/ethanol in a ratio of 20:1).

Output: 19,60 g (72% of theory) of a viscous oil.

Elemental analysis:

Rasch.:With 49,41N 6,75F 17,03N 7,39S 1,69
the detection.:With 49,35N 6,82F 16,92N to 7.32S 1,62

Example 5B

2,6-N,N-bis[6-carbonylmethyl-3,9-bis(carboxylatomethyl)-3,6,9-triazaundecamethylenediamine acid-1-carboxy-11-carboxylatomethyl-[1-(4-PerformanceCounter)piperazine]amide, Gd complex, sodium salt

15 g (to $ 7.91 mol) of the compound indicated in the heading of example 5A, dissolved in 50 ml of chloroform and add 200 ml triperoxonane acid. The mixture is stirred for 10 min at room temperature. Thereafter evaporated to dryness in vacuum and the residue is dissolved in 150 ml of water. Next add 2,87 g (to $ 7.91 mmole) of gadolinium oxide and stirred for 5 h at 80°C. the mixture is allowed to cool to room temperature and the pH value set by 7.4 with 2n. caustic soda. The solution is evaporated to dryness in vacuo and purified on RP-18 (eluent: gradient of water/ethanol/acetonitrile).

Output: 8,11 g (57% of theory) of colorless amorphous solid.

Sod is neigh water: 9,6%.

Elemental analysis (based on anhydrous substance):

Rasch.:With 30,70N is 3.08Gd 17,48N 7,78Na 2,56S 1,78
the detection.:With 30,58N 3,19Gd 17,42N 7,71Na 2,68S 1,72

Example 6A

[1-(4-PerformanceCounter)piperazine]amide of 6-N-benzyloxycarbonyl-2-N-[6-carboxy]methyl-3,9-bis(tert-butyloxycarbonyl)-3,6,9-CreationDate-1,11-dicarboxylic acid bis(tert-butyl ether)]lysine

To a solution of 20 g (24,08 mmole) of the compound indicated in the heading of example 1B, 14,88 g (24,08 mmole) of bis(tert-butyl ether) 3,9-bis(tert-butyloxycarbonyl)-6-carboxymethyl-3,6,9-CreationDate-1,11-dicarboxylic acid and 2.88 g (25 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide at 0°add to 8.25 g (40 moles) of N,N-dicyclohexylcarbodiimide. The mixture is stirred for 3 h at 0°and then overnight at room temperature. Precipitated precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuum and chromatographic on silica gel (eluent: dichloromethane/ethanol in a ratio of 20:1).

Output: 27,21 g (79% of theory) of a viscous oil.

Elemental analysis:

Rasch.: With 47,03N 5,64F 22,58N 6,85S 2,24
the detection.:With 46,94N 5,58F 22,65N 6,84S 2,31

Example 6b

[1-(4-PerformanceCounter)piperazine]amide of 2-N-[carbonylmethyl-3,9-bis(tert-butyloxycarbonyl)-3,6,9-CreationDate-1,11-dicarboxylic acid bis(tert-butyl ether)]lysine

25 g (17,48 mmole) of the compound indicated in the heading of example 6A, dissolved in 350 ml of ethanol and add 5 g of palladium catalyst (10%Pd/C). After that hydronaut at room temperature. Then the catalyst is filtered off and the filtrate evaporated to dryness in vacuum.

Output: cushion 22.66 g (quantitative) of a colorless solid.

Elemental analysis:

Rasch.:With 44,48N of 5.75F 24,92N 7,56S 2,47
the detection.:With 44,59N of 5.81F 25,03N 7,46S 2,52

Example 6b

[1-(4-PerformanceCounter)piperazine]amide of 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]-2-N-[6-carbonylmethyl-3,9-bis(tert-butyloxycarbonyl)-3,6,9-CreationDate-1,11-dicarboxylic acid bis(tert-butyl ether)]lysine, Gd-complex

20g (15,43 mmole) of the compound, specified in the header of example 6b, 1.78 g (15,43 mmole) of N-hydroxysuccinimide, 1.48 g (35 mmol) of lithium chloride and 9,72 g (15,43 mmole) Gd-complex of 1,4,7-Tris(carboxylatomethyl)-10-(3-Aza-4-oxo-5-methyl-5-yl)pentane acid-1,4,7,10-tetraazacyclododecane dissolved under moderate heating in 150 ml of dimethyl sulfoxide. Then, at 10°add 5,16 g (25 mmol) of N,N-dicyclohexylcarbodiimide and then stirred over night at room temperature. The solution is poured into 2500 ml of acetone and stirred for 10 minutes Precipitated precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, eluent: gradient of water/ethanol/acetonitrile).

Output: 22,94 g (78% of theory) of colorless solid.

Water content: 7.9 per cent.

Elemental analysis (based on anhydrous substance):

Rasch.:With 42,22N of 5.29F 16,95Gd 8,25N 8,82S 1,68
the detection.:With 42,15N 5,41F 16,87Gd 8,13N 8,70S 1,60

Example 6g

[1-(4-PerformanceCounter)piperazine]amide of 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(3-Aza-4-oxo-5-methyl-5-ilistener)]-2-N-[6-carbonylmethyl-3,9-bis(carboxylatomethyl)-3,6,9-CreationDate-dicarbo the OIC acid-carboxy-11-carboxylato-z]lysine, digidelay complex, sodium salt

20 g (10,49 mmole) of the compound indicated in the heading of example 6, is dissolved in 200 ml triperoxonane acid. The mixture is stirred for 60 min at room temperature. Further evaporated to dryness in vacuum and the residue is dissolved in 150 ml of water. Then add 1,90 g (a 5.25 mmole) of gadolinium oxide and stirred for 5 h at 80°C. the Mixture is allowed to cool to room temperature and the pH value set by 7.4 with sodium hydroxide. The solution is evaporated to dryness in vacuo and purified on silica gel RP-18 (eluent: gradient of water/ethanol/acetonitrile).

Output: 11,89 g (61% of theory) of colorless amorphous solid.

Water content: 10.2 per cent.

Elemental analysis (based on anhydrous substance):

Rasch.:With 32,97H 3,47F 17,39Gd 16,93N 9,05Na 1,24S 1,73
the detection.:With 32,90N 3,53F 17,31Gd 16,87N 8,92Na 1,33S 1,67

Example 7a

a) tert-butyl ether 5,6-bis(benzyloxy)-3-oxohexanoate acid

100 g (376,2 mmole) of 1,2-di-O-benzylglycine [obtained according to Chem. Phys. Lipids, 43(2) (1987), c.113-127 ] and 5 g of tetrabutylammonium hydrosulfate dissolved in a mixture of 40 ml of toluene and 200 ml of 50%aqueous sodium hydroxide. Further, when 0°C for 30 min added dropwise 78 g (400 mmol) of tert-butyl methyl ether 2-bromoxynil acid and then stirred for 3 h at 0°C. the Organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuum. The remainder chromatographic on silica gel (eluent: N-hexane/acetone in a ratio of 20:1).

Output: 133,4 g (94% of theory) of colourless oil.

Elemental analysis:

Rasch.:With 71,48N of 7.82
the detection.:With 71,61N a 7.92

Example 7b

5,6-bis(benzyloxy)-3-oxohexanoate acid

130 g (336,4 mmole) of the compound indicated in the heading of example 7a, dissolved in 200 ml dichloromethane and at 0°add 100 ml triperoxonane acid. The mixture is stirred for 4 h at room temperature and then evaporated to dryness. The residue is crystallized from pentane/diethyl ether.

Output: 102,2 g (92% of theory) of waxy solids.

Elemental analysis:

Rasch.:With 69,07N of 6.71
the detection.:With 69,19N 6,82

Example 7b

[1-(4-PerformanceCounter)piperazine]amide of 6-N-benzyloxycarbonyl-2-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraacetic dodecan-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]lysine, Gd-complex

50 g (60,20 mmole) of the compound indicated in the heading of example 1B, 6,93 g (60,20 mmole) of N-hydroxysuccinimide, 5,09 g (120 mmol) of lithium chloride and 37,91 g (60,20 mmole) Gd-complex of 1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane - 10-pentanoyl-3-Aza-4-oxo-5-methyl-5-sludge dissolved under moderate heating in 400 ml of dimethyl sulfoxide. Then, at 10°add 20,63 g (100 mmol) of N,N-dicyclohexylcarbodiimide and then stirred over night at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes Precipitated precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, eluent: gradient of water/ethanol/acetonitrile).

Output: 75,53 g (87% of theory) of colorless solid.

Water content: 10.1 per cent.

Elemental analysis (based on anhydrous substance):

Rasch.:With 37,48N 3,84F 22,39Gd 10,90N a total of 8.74S 2,22
the detection.:With 37,39N was 4.02F 22,29Gd is 10.75N 8,70S 2,22

Example 7G

[1-(4-PerformanceCounter)piperazine]amide of 2-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl]lysine, Gd-complex

70 g (48,53 mmol who) connection, specified in the header of example 7b, dissolved in a mixture of 500 ml of water and 100 ml of ethanol and add 5 g of palladium catalyst (10%Pd/C). After that hydronaut at room temperature. Then the catalyst is filtered off and the filtrate evaporated to dryness in vacuum.

Output: 63,5 g (quantitative) of a colorless solid.

Water content: 9.8 per cent.

Elemental analysis (based on anhydrous substance):

Rasch.:With 37,48N 3,84F 22,39Gd 10,90N a total of 8.74S 2,22
the detection.:With 37,39N 4,03F 22,31Gd 10,78N 8,65S 2,20

Example 7D

[1-(4-PerformanceCounter)piperazine]amide of 6-N-[5,6-bis(benzyloxy)-3-oxohexanoyl]-2-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]lysine, Gd-complex

10 g (of 7.64 mmole) of the compound indicated in the heading of example 7G, 3,30 g (10 mmol) of the compound indicated in the heading of example 7b, 0.85 grams (20 mmol) of lithium chloride and 1.15 g (10 mmol) of N-hydroxysuccinimide dissolved under moderate heating in 150 ml of dimethyl sulfoxide. Then, at 10°add 3,10 g (15 mmol) of N,N'-dicyclohexylcarbodiimide and stirred for 8 h at room temperature. React the solution was poured into 2000 ml of acetone and produce the precipitation. Specified in the title compound purified on silica gel RP-18 (eluent: gradient of water/ethanol/acetonitrile).

Output: 11,14 g (90% of theory) of colorless amorphous solid.

Water content: 4.3 per cent.

Elemental analysis (based on anhydrous substance):

Rasch.:With 41,51N 4,29F 19.93 perN 7,78Gd 9,70S 1,98
the detection.:With is 41.45N of 4.38F 19,84N of 7.70Gd 9,58S 1,90

Example 7E

[1-(4-PerformanceCounter)piperazine]amide of 6-N-(5,6,-dihydroxy-3-oxohexanoyl)-2-N-[1,4,7-tricarboxylate)-1,4,7,10-tetraazacyclododecane-10-pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]lysine, Gd-complex

10 g (6,17 mmole) of the compound indicated in the heading of example 7D, dissolved in 200 ml of ethanol and add 3 g of palladium catalyst (10%Pd/C). After that hydronaut at room temperature. Then the catalyst is filtered off and the filtrate evaporated to dryness in vacuum.

Output: 8,89 g (quantitative) of a colorless solid.

Water content: 3.1 per cent.

Elemental analysis (based on anhydrous substance):

Rasch.:With 35,03N 3,99F are 22.42 Gd 10,92N 8,75S of 2.23
the detection.:With 34,95N 4,12F 22,30Gd 10,78N 8,71S 2,18

Example 8A

1-(4-PerformanceCounter)piperazine]amide of 6-N-benzyloxycarbonyl-2-N-[5,6-bis(benzyloxy)-3-oxohexanoyl]lysine

To a solution of 20 g (24,08 mmole) of the compound indicated in the heading of example 1B, to 9.91 g (30 mmol) of the compound indicated in the heading of example 7b, and 3.45 g (30 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide at 0°add 9.28 are g (45 mmol) of N,N-dicyclohexylcarbodiimide. The mixture is stirred for 3 h at 0°and then overnight at room temperature. Precipitated precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuum and chromatographic on silica gel (eluent: dichloromethane/ethanol in a ratio of 20:1).

Output: 24,50 g (89% of theory) of a viscous oil.

Elemental analysis:

Rasch.:With 47,29N 4,14F of 28.26N 4,90S 2,81
the detection.:With 47,14N 4.26 deathsF 28,17N 4,91S 2,69

Example 8b

[1-(4-PerformanceCounter)piperazine]amide of 2-N-(5,6-dihydroxy-3-oxohexanoyl)lysine

20 g (of 17.5 mmole) of the compound specified in C is the cylinder of example 8A, dissolved in 300 ml of ethanol and add 5 g of palladium catalyst (10%Pd/C). After that hydronaut at room temperature. Then the catalyst is filtered off and the filtrate evaporated to dryness in vacuum.

Output: 17,65 g (quantitative) of a colorless solid.

Elemental analysis:

Rasch.:With 44,05N 4,10F 32,02N 5,55S 3,18
the detection.:With 43,96N 4,21F 31,94N 5,48S 3,24

Example 8b

[1-(4-PerformanceCounter)piperazine]amide of 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]lysine, Gd-complex

15 g (14,87 mmole) of the compound indicated in the heading of example 8b, 1.73 g (15 mmol) of N-hydroxysuccinimide, 1.27 g (30 mmol) of lithium chloride and 9,48 g (15 mmol) of the Gd-complex of 1,4,7-Tris(carboxylatomethyl)-10-(3-Aza-4-oxo-5-methyl-5-yl)pentane acid-1,4,7,10-tetraazacyclododecane dissolved under moderate heating in 100 ml of dimethyl sulfoxide. Then, at 10°add 5,16 g (25 mol) of N,N-dicyclohexylcarbodiimide and then stirred over night at room temperature. The solution is poured into 1500 ml of acetone and stirred for 10 minutes Precipitated precipitated solid is filtered off and is eaten purified by chromatography (silica gel RP-18, eluent: gradient of water/ethanol/acetonitrile).

Output: 19,28 g (80% of theory) of colorless solid.

Water content: 10,3%.

Elemental analysis (based on anhydrous substance):

Rasch.:With 41,51N 4,29F 19.93 perGd 9,70N 7,78S 1,98
the detection.:With 41,37N 4,40F fall of 19.88Gd 9,58N to 7.67S 1,85

Example 9a

[1-(4-PerformanceCounter)piperazine]amide of 6-N-benzyloxycarbonyl-2-N-[2,6-N,N'-bis(benzyloxycarbonyl)lysyl]lysine

20 g (24,08 mmole) of the compound indicated in the heading of example 1B, and of 2.53 g (25 mmol) of triethylamine are dissolved in 200 ml of tetrahydrofuran (THF) and type of 14.46 g (27 mmol) paranitrophenol ether di-N,N'-Z-lysine. The mixture is stirred for 5 h at 50°C. then evaporated to dryness in vacuum and the residue chromatographic on silica gel (eluent: dichloromethane/methanol in a ratio of 20:1).

Output: 28,07 g (95% of theory) of colorless solid.

Elemental analysis:

Rasch.:With 46,99N 4,19F 26,32N 6,85S 2,61
the detection.:With 47,08N 4,32F 2,21 N 6,75S 2,54

Example 9D

[1-(4-PerformanceCounter)piperazine]amide of 2-N-(lysyl)lysine, trihydrobromide

To 25 g (20,37 mmole) of the compound indicated in the heading of example 9a, add 100 ml of Hydrobromic acid in glacial acetic acid (48%) and stirred for 2 h at 40°C. Then cooled to 0°C, are added dropwise to 1500 ml of diethyl ether and precipitated precipitated solid is filtered off. After drying in vacuum (60° (C) receive 21,52 g (99% of theory) of crystalline solid of light yellow color.

Elemental analysis:

Rasch.:With 27,01N 3,40Br 22,46F 30,26N 7,87S 3,00
the detection.:With 26,92N 3,53Br 22,15F 30,14N of 7.69S 2,87

Example 9b

[1-(4-PerformanceCounter)piperazine]amide of 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]-2-N-[2,6-N,N'-bis[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]lysyl]lysine, tegadalay complex

31,49 g (50 mmol) of the Gd-complex of 1,4,7-Tris(carboxylatomethyl)-10-(3-Aza-4-oxo-5-methyl)-5-Il)pentanol acid, 6,91 g (60 mmol) of N-Hydra is keskliidu and 4,24 g (100 mmol) of lithium chloride are dissolved at moderate heat in 350 ml of dimethyl sulfoxide. Then, at 10°add 16,51 g (80 mmol) of N,N-dicyclohexylcarbodiimide and stirred for 5 h at 10°C. To this mixture is added 10 g (9,37 mmole) of the compound indicated in the heading of example 9b, and 3.03 g (30 mmol) of triethylamine and stirred for 12 h at 60°C. Next, the mixture is allowed to cool to room temperature and then it was poured into 3000 ml of acetone. The precipitation is filtered off and purified on silica gel RP-18 (eluent: gradient of water/ethanol/acetonitrile).

Output: 16.7 g (67% of theory) of colorless solid.

Water content: 7.9 per cent.

Elemental analysis (based on anhydrous substance):

Rasch.:With 36,58N 4,43F 12,14Gd 17,74N 11,06S 1,14
the detection.:With 36,47N 4,54F a 12.03Gd 17,65N 10,95S 1,21

Example 10A

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

To 18,13 g (68,1 mmole) 3,6,9,12,15-pentaoxaoctadecane acid and 30 g (68,1 mmole) of 1,7-di-Z-cyclen obtained according Z. Kovacs and .D. Sherry, J. Chem. Soc. chem. Commun., 2 (1995), p.185, 300 ml of tetrahydrofuran at 0°add 24,73 g (100 mmol) AEDH (ethyl ester of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) and p is remediat over night at room temperature. Thereafter evaporated to dryness in vacuum and chromatographic on silica gel (eluent: dichloromethane/methanol in a ratio of 20:1).

Output: 19,13 g (42% of theory) of colorless solid.

Elemental analysis:

Rasch.:With 61,03N to 7.61N 8,13
the detection.:With 60,92N of 7.75N 8,04

Example 10B

1,7-bis(benzyloxycarbonyl)-4-(3,6,9,12,15-intoxikation)-10-(2H,2H,4H,5H,5H-3-oxaprotiline)-1,4,7,10-tetraazacyclododecane

To 18 g (26,91 mmole) of the compound indicated in the heading of example 10A, and 14,05 g (26,91 mmole) of 2H,2H,4H,4H,5H,5H-3-oxaprotiline acid obtained according to DE 19603033, 300 ml of tetrahydrofuran at 0°add 12,36 g (50 mmol) AEDH (ethyl ester of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) and stirred over night at room temperature. Thereafter evaporated to dryness in vacuum and chromatographic on silica gel (eluent: dichloromethane/methanol in a ratio of 20:1).

Output: 21,51 g (67% of theory) of colorless solid.

Elemental analysis:

Rasch.:With 47,32N 4,82F 27,07N 4,70
the detection.:With 47,26N 5,01 F 26,94N 4,59

Primarv

1-(3,6,9,12,15-intoxikation)-7-(2H,2H,4H,4H,5H,5H-3-oxaprotiline)-1,4,7,10-tetraazacyclododecane

20 g (16,77 mmole) of the compound indicated in the heading of example 1, dissolved in 200 ml of ethanol and add 2.5 g of palladium catalyst (10%Pd/C). After that hydronaut at room temperature. Then the catalyst is filtered off and the filtrate evaporated to dryness in vacuum.

Yield: 15.5 g (quantitative) of a colorless solid.

Elemental analysis:

Rasch.:With 40,27N 4,90F 34,93N 6,06
the detection.:With 40,15N 4,99F 34,87N 5,94

Example 10g

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-intoxikation)-10-(2H,2H,4H,4H,5H,5H-3-oxaprotiline)-1,4,7,10-tetraazacyclododecane, Gd-complex

15 g (16,22 mmole) of the compound indicated in the heading of example 10B, 4,60 g (40 mmol) of N-hydroxysuccinimide, 3,39 g (80 mmol) of lithium chloride and 25,19 g (40 mmol) of the Gd-complex of 1,4,7-Tris(carboxylatomethyl)-10-(3-Aza-4-oxo-5-methyl-5-yl)pentanol acid are dissolved under moderate heating in 300 ml of dimethyl sulfoxide. Then, at 10°add 24,73 g (100 IMO is her) EACH and then stirred over night at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes Precipitated precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, eluent: gradient of water/ethanol/acetonitrile).

Output: 19,86 g (57% of theory) of colorless solid.

Water content: 11.3 per cent.

Elemental analysis (based on anhydrous substance):

Rasch.:With 38,58N 4,74F 15,04Gd 14,64N 9,13
the detection.:With 38,47N 4,91F 14,95Gd of 14.57N 9,04

Example 11a

1-[(4-PerformanceCounter)piperazine]amide 3,5-dinitrobenzoic acid

To 20 g (35,2 mmole) performancemonitoriterations and 8.1 g (80 mmol) of triethylamine, dissolved in 200 ml of dichloromethane, at 0°With added dropwise a solution of 8,76 g (38 mmol) of 3,5-dinitrobenzotrifluoride in 55 ml of dichloromethane and stirred for 3 h at 0°C. Next, add 200 ml of 5%aqueous hydrochloric acid and stirred for 5 min at room temperature. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuum. The remainder chromatographic on silica gel (eluent: dichloromethane/acetone in a ratio of 15:1).

Output: 24,96 g (93% of theory) of colorless solid matter what.

Elemental analysis:

Rasch.:With 29,35N 1,45F 42,37N 7,35S 4,21
the detection.:With 29,28N 1,61F 42,15N of 7.25S 4,15

Example 11b

[1-(4-PerformanceCounter)piperazine]amide 3,5-diaminobenzoic acid

20 g (26,23 mmole) of the compound indicated in the heading of example 11a was dissolved in 400 ml of ethanol and add 6 g of palladium catalyst (10%Pd/C). After that hydronaut at room temperature. Then the catalyst is filtered off and the filtrate evaporated to dryness in vacuum.

Output: 18,43 g (quantitative) of a cream solid color.

Elemental analysis:

Rasch.:With 32,49N 2,15F 45,98N 7,98S 4,57
the detection.:With 32,29H 2,35F 45,69N 7,81S 4,40

Example 11b

[1-(4-PerformanceCounter)piperazine]amide 3,5-N,N'-bis[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]benzoic acid, Gd-complex

10 g (14.24 from mmole) of the compound indicated in the heading of example 11b, of 3.45 g (30 mmol) of N-hydroxysuccinimide, 2.5 g (60 moles) of lithium chloride and rate 18.89 g (30 mmol) of the Gd-complex of 1,4,7-Tris(carboxylatomethyl)-10-(3-Aza-4-oxo-5-methyl-5-yl)pentanol acid are dissolved under moderate heating in 200 ml of dimethylsulfoxide. Then, at 10°add 10,32 g (50 mmol) of N,N-dicyclohexylcarbodiimide and then stirred over night at room temperature. The solution is poured into 2000 ml of acetone and stirred for 10 minutes Precipitated precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, eluent: gradient of water/ethanol/acetonitrile).

Output: to 19.74 g (72% of theory) of colorless solid.

Water content: 11,8%.

Elemental analysis (based on anhydrous substance):

Rasch.:With 35,55N 3,72F 16,77Gd 16,33N 10,18S 1,67
the detection.:With 35,48N 3,84F 16,58Gd 16,24N 10,07S 1,58

Example 12

a) tert-Butyl ether 3-oxa-2H,2H,4H,4H,5H,5H-performancecountervalues acid

25,0 g (53,8 mmole) of 1H,1H,2H,2H-PERFLUORO-1-decanol [supplied by company Lancaster] was dissolved in 250 ml of absolute toluene and, at room temperature is mixed with a catalytic amount (about 0.75 g) of hydrosulphate of Tetra-n-butylamine. Further, when 0°add in the whole of 7.55 g (134,6 mmole, 2.5 equivalent in terms of the amount of alcohol component) fine powder of potassium hydroxide, and tatem,73 g (80,7 mmole, 1.5 equivalent in terms of the amount of alcohol component) of tert-butyl methyl ether bromoxynil acid and leave for 2 hours stirring at 0°C. the thus Obtained reaction solution is then stirred for 12 h at room temperature and for processing mixed with ethyl ether acetic acid total amount of 500 ml and 250 ml water. The organic phase is separated and washed twice with water. After drying the organic phase over sodium sulfate salt is separated by vacuum filtration and the solvent is distilled off in vacuum. The obtained oily residue is purified on silica gel using ethyl ester acetic acid/hexane (ratio 1:10) as eluent.

Output: 26,3 g (84.6% of theory) of the above in the title compounds as a colorless and viscous oil.

Elemental analysis:

Rasch.:With 33,23N 2,61F 55,85
the detection.:With 33,29N 2,61F 55,90

b) 3-oxa-2H,2H,4H,4H,5H,5H-performancebuy acid

20,0 g (34,58 mmole) of the compound indicated in the heading of example 12A, suspended under stirring at room temperature in 200 ml of a mixture consisting of methanol and 0.5-molar sodium hydroxide in the ratio of 2:1, click heated to 60° C. After the reaction for 12 h at 60°With transparent reaction mixture for processing neutralize the mixture with a cation exchange resin Amberlite®IR 120 (H+-form), the ion exchanger is removed by vacuum filtration and the thus obtained methanolic-aqueous filtrate is distilled in a vacuum to obtain a dry residue. The obtained amorphous-oily residue purified on silica gel using ethyl ester acetic acid/n-hexane (1:3) as eluent.

Yield: 16.0 g (88,6% of theory) of the above in the title compounds as a colorless and viscous oil.

Elemental analysis:

Rasch.:With 27,60N 1,35F 61,85
the detection.:With 27,58N 1,36F 61,90

C) 1,7-bis{[1,4,7-Tris(carboxylatomethyl)-10-(3-Aza-4-oxo-5-methyl-5-ilistener)]-1,4,7,10-tetraazacyclododecane}Diethylenetriamine, digidelay complex

2,48 g (3.94 mmole, 2,05 molar equivalent in terms of the number of Diethylenetriamine) described in the application DE 19728954 C1 in example 31h Gd complex of 10-(4-carboxy-1-methyl-2-oxo-3-isobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-trioxanes acid and 167 mg of anhydrous lithium chloride (3.94 mmole) in 40°With dissolved with stirring in 40 ml of abs is the currency of dimethyl sulfoxide and at this temperature, mixed with N-hydroxysuccinimide total number of 453 mg (3.94 mmole). After cooling to room temperature thus obtained reaction solution was mixed with 814 mg (3,946 mmole) N,N'-dicyclohexylcarbodiimide and within 2 hours and stirred at room temperature. The resulting suspension of the activated ester is then mixed with 198,3 mg (1,92 mmole) Diethylenetriamine dissolved in 5 ml of absolute dimethyl sulfoxide, and stirred for 12 h at room temperature. For processing the reaction mixture is mixed with sufficient acetone until complete precipitation of the above in the title compound, the precipitate was separated by vacuum filtration, dried, dissolved in water, filtered nerastvorim dicyclohexylamine and the filtrate is for desalting and purification from low molecular weight components pass through the ultrafiltration membrane AMICON®YM-3 (limiting the permeability of 3000 Da). Retentate (a substance that is not passed through the filtration membrane) at the end lyophilized.

Yield: 1.85 g (72.7% of theory) as a colourless lyophilisate.

H2About the content (using the Karl Fischer reagent): 3,89%.

Elemental analysis (based on anhydrous substance):

Rasch.:With 38,03N 5,24N 13,73Gd 23,71
the detection.:From 37.9 N 5,20N 13,69Gd 23,78

g) 1,7-bis{[1,4,7-Tris(carboxylatomethyl)-10-(3-Aza-4-oxo-5-methyl-5-ilistener)]-1,4,7,10-tetraazacyclododecane}-4-(3-oxa-2H,2H,4H,4H,5H,5H-perventricular)Diethylenetriamine, digidelay complex

To a solution of 3.23 g (2,44 mmole) of the compound indicated in the heading of example 12, in a mixture of 30 ml of DMSO and 3 ml of tetrahydrofuran at 50°C in nitrogen atmosphere are added dropwise 1.27 g (2,44 mmole) specified in the header of example 12B compounds dissolved in a mixture of 15 ml of tetrahydrofuran and 15 ml of dimethyl sulfoxide. After that, when 0°With portions add in the whole of 1.80 g (3,66 mmole) EACH [2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline] and left overnight stirring at room temperature. The resulting reaction solution was then mixed with sufficient acetone until complete precipitation of the above in the title compound, the precipitate was separated by vacuum filtration, dried, dissolved in water, filtered off any insoluble components and the filtrate is subjected to ultrafiltration through AMICON ultrafiltration membrane®YM-3 (marginal permeability: 3000 Da), which ensures complete desalting specified in the connection header and simultaneously it to remove low molecular weight components. Retentate at the end lyophilized.

O the d: of 3.54 g (79,4% of theory) as a colourless lyophilisate.

H2About the content (using the Karl Fischer reagent): 5.87 per cent.

Elemental analysis (based on anhydrous substance):

Rasch.:With 35,43N 4,07N 9,95F 17,64Gd 17,18
the detection.:With 35,42N 4,01N 9,89F 17,67Gd 17,18

Example 13

a) 2-N-TRIFLUOROACETYL-6-N-benzyloxycarbonyl-L-lysine

100.0 g (356,7 mmole) of 6-N-benzyloxycarbonyl-L-lysine dissolved in a mixture of 1000 ml of ethyl ether triperoxonane acid and 500 ml of ethanol for 24 h and stirred at room temperature. Thereafter evaporated to dryness and the residue is crystallized from diisopropyl ether.

Output: 128,9 g (96% of theory) of colorless crystalline powder.

Melting point: 98,5°C.

Elemental analysis:

Rasch.:With 51,07N 5,09N 7,44F 15,14
the detection.:With 51,25N 5,18N 7,58F 15,03

b) [1-(4-PerformanceCounter)piperazine]amide of 2-N-TRIFLUOROACETYL-6-N-benzyloxycarbonyl-L-lysine

To 125.0 g (332,0 mmole) of the compound indicated in the heading of example 1A, and amounts to 188.7 g (332,0 mmole) 1-perferential phenylpiperazine (obtained according to DE 19603033) in 750 ml of tetrahydrofuran at 0° To add 164,2 g (0,664 mmole) AEDH (ethyl ester of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) and stirred over night at room temperature. Thereafter evaporated to dryness in vacuum and chromatographic on silica gel (eluent: dichloromethane/methanol in a ratio of 20:1).

Output: 286,0 g (93% of theory) of colorless solid.

Melting point: 92°C.

Elemental analysis:

Rasch.:With 36,30N 2,83N 6,05F 41,01S of 3.46
the detection.:With 36,18N 2,94N 5,98F 40,87S 3,40

C) [1-(4-PerformanceCounter)piperazine]amide of 6-N-benzyloxycarbonyl-L-lysine

The solution 280,0 g (302,2 mol) of the compound indicated in the heading of example 1B, in 2000 ml of ethanol at 0°With bubbled for one hour with gaseous ammonia. After that, the mixture is stirred for 4 h at 0°C. Then evaporated to dryness and the residue is separated from the water by stirring. The solid is filtered off and dried in vacuum at 50°C.

Output: 243,5 g (97.0% of theory) of an amorphous solid.

Elemental analysis:

Rasch.:With 37,60N 3,28N 6,75F 38,89 S 3,86
The detection.:With 37,55N 3,33N of 6.68F 38,78S 3,81

g) [1-(4-PerformanceCounter)piperazine]amide of L-lysine

to 200.0 g (240,8 mmole) obtained in example 13B compounds dissolved in 1000 ml of ethanol, mixed with 5.0 g of catalyst Perlman (20%Pd/C) and hydronaut at room temperature in hydrogen atmosphere (1 ATM) until then, until there is no further absorption of hydrogen. Thereafter, the catalyst was removed by vacuum filtration, washed thoroughly with ethanol (three portions of approximately 100 ml) and concentrated to dryness in vacuum. This way, get listed in the title compound in the form of a highly viscous yellow oil.

Output: 162,5 g (96.9% of theory).

Elemental analysis:

Rasch.:With 31,04N 3.04 fromN 8,05F 46,38S 4,60
the detection.:With 31,11N 3,09N 8,08F 46,33S to 4.62

e) [1-(4-PerformanceCounter)piperazine]amide 6N-2N-bis{4-[2,3-bis(N,N-bis(tert-butyloxycarbonyl)amino)propyl]phenyl}-3-oxopropyl-L-lysine

the 5.25 g (7,72 mmole) 4-[2,3-bis-(N,N-bis(tert-butyloxycarbonyl)amino)propyl]phenyl}-3-oxopropanoic acid and 781,0 mg (7,72 mmole) of triethylamine dissolved in 50 ml is milenaria. Then at -15°With dropwise within 5 minutes and add a solution of 1.16 g (8.5 mmole) of isobutyl ether of Harborview acid in 10 ml of methyl chloride and stirred for 20 min at -15°C. Then, the solution is cooled to -25°C, for 30 min added dropwise a solution of 2.68 g (3,86 mmole) specified in the header of example 13G connection and 2.12 g (21,0 mmol) of triethylamine in 70 ml of tetrahydrofuran, and then stirred for 30 min at -15°and then overnight at room temperature. For recycling the solvent is distilled off in vacuum and the resulting oily residue is dissolved in 250 ml of chloroform. The chloroform phase is twice extracted with 10%aqueous solution of ammonium chloride in portions of 100 ml, the organic phase is dried over magnesium sulfate and evaporated to dryness in vacuum. The remainder chromatographic on silica gel (eluent: methylene chloride/ethanol in a ratio of 20:1).

Output: lower than the 5.37 g (68,8% of theory) of colorless and viscous oil.

Elemental analysis:

Rasch.:With 52,27N to 6.43N 5,54F 15,97S 1,59
the detection.:With 52,22N 6,51N 5,49F 15,99S 1,63

e) [1-(4-PerformanceCounter)piperazine]amide 6N-2N-bis{4-[2,3-bis(N,N-bis(carboxylatomethyl the l)amino)propyl]phenyl}-3-oxopropyl-L-lysine, octonaria salt

5.0 g (2,47 mmole) of the compound indicated in the heading of example d, dissolved in 60 ml of absolute dichloromethane. After that, the resulting solution at 0°With dropwise mixed with triperoxonane acid total 75 ml After the reaction for 12 h at room temperature the mixture is concentrated to dryness in vacuum. The resulting residue is mixed with 100 ml of water and again distilled in vacuum to obtain a dry residue. Thus obtained residue is dissolved in 200 ml of distilled water and water-containing product solution of the above in the connection header twice extracted with diethyl ether portions 60 ml. Total volume of the obtained water-containing product solution was adjusted by mixing with water to 300 ml, filtered off any insoluble components and the filtrate is subjected to ultrafiltration through AMICON ultrafiltration membrane®YM-3 (marginal permeability: 3000 Da), which ensures complete desalting specified in the connection header and simultaneously it to remove low molecular weight components. Total retentate by mixing with water adjusted to 200 ml and then the pH value of this solution is set at 10.0 with 15%aqueous sodium hydroxide. Alkaline water containing product solution at the end lyophilized.

This way obtain 4.0 g (92.8% in teorii) specified in the connection header in the form octanethiol salt in the form of amorphous freeze-dried.

Water content: 5.37 percent.

Elemental analysis (based on anhydrous substance):

Rasch.:With 38,46N 3,28N 6,41F 18,47S 1,83Na 10,52
the detection.With 38,42N 3,31N 6,39F 18,51S 1,87Na 10,38

W) [1-(4-PerformanceCounter)piperazine]amide 6N-2N-bis{4-[2,3-bis(N,N-bis(carboxymethyl)amino)propyl]phenyl}-3-oxopropyl-L-lysine, demergency complex, Terentieva salt

of 1.94 g (1,11 mmole) of the compound indicated in the heading of example, the 13th, is dissolved in 100 ml of distilled water and the pH value of the obtained solution set by 4.0 by mixing with 1-molar aqueous hydrochloric acid. Next, at 80°With portions mixed with 0.25 g (2,22 mmole) carbonate manganese(II). Thus obtained reaction solution is then for 5 h refluxed. After cooling to room temperature, the pH value of the water-containing product solution set with vigorous stirring 7.2 mixed with 1H. caustic soda and for desalting and purification from low molecular weight components pass through the ultrafiltration membrane AMICON®YM-3 (marginal permeability: 3000 Da). Retentate in conclusion, iiilist.

Output: 1,80 g (92.0% of theory) specified in the title compounds as colourless lyophilisate.

H2About the content (using the Karl Fischer reagent): 7,28%.

Elemental analysis (based on anhydrous substance):

Rasch.:With 38,07N 3,25F 18,28Mn 6,22N 6,34Na 5,20S 1,81
the detection.:With 38,01N 3,29F 18,29Mn 6,21N 6,36Na 5,28S 1,78

Example 14

a) [1-(4-PerformanceCounter)piperazine]amide of 6-N-(benzyloxycarbonyl)-2-N-[(N-pteroyl)-L-glutaminyl]lysine

20 g (45,31 mmole) of folic acid are dissolved in 300 ml of dimethyl sulfoxide and 10°add 9,49 g (46 mmol) of N,N-dicyclohexylcarbodiimide. The mixture is stirred over night at room temperature. Further to this mixture of 29.1 g (35 mmol) of the compound indicated in the heading of example 1B, and 20 ml of pyridine and stirred for 3 h at 50°C. Then cooled to room temperature and add a mixture of 1500 ml of diethyl ether and 1500 ml of acetone. The precipitation is filtered off and purified on silica gel RP-18 (eluent: gradient of water/ethanol/tetrahydrofuran).

Output: 21,59 g (38% of theory) of a yellow solid.

With the actual content of the water: 2,1%.

Elemental analysis (based on anhydrous substance):

Rasch.:With 43,10N 3,54F 25,76N 11,29S 2,56
the detection.:With 43,02N 3,62F 25,68N 11,21S 2,48

6) [1-(4-PerformanceCounter)piperazine]amide of 2-N-[(N-pteroyl)-L-glutaminyl]lysine

To 20 g (15,95 mmole) of the compound indicated in the heading of example 14a, add 200 ml of Hydrobromic acid in glacial acetic acid (48%) and stirred for 2 h at 40°C. Then cooled to 0°With added dropwise 2000 ml of diethyl ether and precipitated precipitated solid is filtered off. After drying in vacuum (60° (C) receive 18,96 g (99% of theory) of crystalline solid yellow color.

Elemental analysis:

Rasch.:With 37,01N of 3.27Br 6,65F 26,90N 12,83S to 2.67
the detection.:With 36,91N 3,42Br of 6.31F 29,75N 12,72S 2,56

C) [1-(4-PerformanceCounter)piperazine]amide of 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl]-2-N-[(N-is terol)-L-glutaminyl]lysine, Gd-complex

0,92 g (8 mmol) of N-hydroxysuccinimide, of 0.68 g (16 moles) of lithium chloride and 5,04 g (8 mmol) of the Gd-complex of 1,4,7-Tris(carboxylatomethyl)-10-(3-Aza-4-oxo-5-methyl-5-yl)-1,4,7-10-tetraazacyclododecane dissolved under moderate heating in 80 ml of dimethyl sulfoxide. Then, at 10°add to 2.06 g (10 moles) of N,N-dicyclohexylcarbodiimide and then stirred for 3 h at room temperature. To this reaction solution was added 5 g (4,16 mmole) of the compound indicated in the heading of example 14b, and 10 ml of pyridine. The mixture is stirred over night at room temperature. Then the solution is poured into 1000 ml of acetone and stirred for 10 minutes Precipitated precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, eluent: gradient of water/ethanol/acetonitrile). The product is dissolved in a small amount of water, the pH value set by 7.4 using sodium hydroxide and lyophilized.

Output: a 3.87 g (53% of theory) of a yellow solid.

Water content: 5.8 per cent.

Elemental analysis (based on anhydrous substance):

Rasch.:With 38,36H3 74F 18,42Gd 8,97N 12,78Na 1,31S 1,83
the detection.:With 38,28H3 85F 18,33 Gd cent to 8.85N 12,69Na 1,42S 1,75

Example 15

a) [1-(4-PerformanceCounter)piperazine]amide of 6-N-benzyloxycarbonyl-2-N-(3,6,9,12-tetraaceticacid)lysine

To 50 g (60,20 mmole) specified in the header of example 1B connection and 7.10 g (70 mmol) of triethylamine, dissolved in 350 ml of dichloromethane, at 0°With added dropwise a solution of 16,85 g (70 mmol) of acid chloride of 3,6,9,12-tetraaceticacid acid in 50 ml dichloromethane and stirred for 3 h at 0°C. Next, add 200 ml of 5%aqueous hydrochloric acid and stirred for 5 min at room temperature. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuum. The remainder chromatographic on silica gel (eluent: dichloromethane/acetone in a ratio of 15:1).

Output: 30,94 g (92% of theory) of a colourless, viscous oil.

Elemental analysis:

Rasch.:With 40,63N 4,19F 31,21N 5,41S 3,10
the detection.:With 40,75N 4,08F 31,29N 5,58S 3,25

b) [1-(4-PerformanceCounter)piperazine]amide of 2-N-(3,6,9,12-tetraaceticacid)lysine

53,96 g (52,15 mmole) of the compound indicated in the heading of example 15A, dissolved in 500 ml of ethanol and add 6 g PAL is Diavolo catalyst (10%Pd/C). After that hydronaut at room temperature. Then the catalyst is filtered off and the filtrate evaporated to dryness in vacuum.

Output: 43,0 g (quantitative) of a colorless solid.

Elemental analysis:

Rasch.:With 36,01N 4,14F 35,86N 6,22S of 3.56
the detection.:With 27,60N 5,13F 39,09N of 6.68S 3,81

C) [1-(4-PerformanceCounter)piperazine]amide of 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]-2-N-(3,6,9,12-tetraaceticacid)lysine, Gd-complex

21,84 (24,25 mmole) of the compound indicated in the heading of example 15B, and 2.79 g (24,25 mmole) of N-hydroxysuccinimide, 2,12 g (50 mmol) of lithium chloride and 15,27 g (24,25 mmole) Gd-complex of 1,4,7-Tris(carboxylatomethyl)-10-[(3-Aza-4-oxo-5-methyl-5-yl)pentane acid]-1,4,7,10-tetraazacyclododecane dissolved under moderate heating in 200 ml of dimethylsulfoxide. Then, at 10°add to 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide and then stirred over night at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes Precipitated precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, eluent: gra is ient water/ethanol/acetonitrile).

Output: 28,21 g (81% of theory) of colorless solid.

Water content: 11,0%.

Elemental analysis (based on anhydrous substance):

Rasch.:With 36,53N 4,33F 21,36N a 8.34S 2,12Gd the 10.40
The detection.:With 37,74N to 4.98F 22,39N 8,69S 2,15Gd 10,87

Example 16

a) [1-(4-PerformanceCounter)piperazine]amide of 6-N-benzyloxycarbonyl-2-N-(propyl-3-sulfonic acid)lysine

To 50 g (60,20 mmole) of the compound indicated in the heading of example 1B, and 7.10 g (70 mmol) of triethylamine, dissolved in 250 ml of dry tetrahydrofuran at 50°With added dropwise a solution 7,33 g (60 moles) of propanesultone in 50 ml of tetrahydrofuran and stirred for 3 h at 60°C. Next, add 200 ml of 5%aqueous hydrochloric acid and stirred for 5 min at room temperature. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuum. The remainder chromatographic on silica gel (eluent: dichloromethane/acetone in a ratio of 15:1).

Output: 45,16 g (79% of theory) of colorless viscous oil.

Elemental analysis:

Rasch.:With 36,56N 3,49 F 33,90N 5,88S of 6.73
the detection.:With 36,72N 3,35F 33,79N 5,78S 6,75

b) [1-(4-PerformanceCounter)piperazine]amide of 2-N-(propyl-3-sulfonic acid)lysine

49,68 g (52,15 mmole) of the compound indicated in the heading of example 16A was dissolved in 500 ml of ethanol and add 6 g of palladium catalyst (10%Pd/C). After that hydronaut at room temperature. Then the catalyst is filtered off and the filtrate evaporated to dryness in vacuum.

Output: 42,69 g (quantitative) of a colorless solid.

Elemental analysis:

Rasch.:With 30,81N 3,32F 39,46N 6,84S 7,83
the detection.:With 30,64N 4,1F 39,29N of 6.68S 7,89

C) [1-(4-PerformanceCounter)piperazine]amide of 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]-2-N-(propyl-3-sulfonic acid)lysine, Gd-complex

19,85 g (24,25 mmole) of the compound indicated in the heading of example 16B, and 2.79 g (24,25 mmole) of N-hydroxysuccinimide, 2,12 g (50 mmol) of lithium chloride and 15,27 g (24,25 mmole) Gd-complex of 1,4,7-Tris(carboxylatomethyl)-10-[(3-Aza-4-oxo-5-methyl-5-yl)pentane acid]-1,4,7,10-t is triazacyclononane dissolved under moderate heating in 200 ml of dimethylsulfoxide. Then, at 10°add to 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide and then stirred over night at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes Precipitated precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, eluent: gradient of water/ethanol/acetonitrile).

Output: 28,13 g (81% of theory) of colorless solid.

Water content: 11,0%.

Elemental analysis (based on anhydrous substance)

Rasch.:With for 33.27N 3,70F 22,36N 8,73S of 4.44Gd 10,89
the detection.:With 32,41N 3,88F 22,49N 8,69S 4,35Gd 10,97

Example 17

a) [1-(4-PerformanceCounter)piperazine]amide of 6-N-benzyloxycarbonyl-2-N,N-bis(propyl-3-sulfonic acid)lysine

To 50 g (60,20 mmole) of the compound indicated in the heading of example 1B, 12,14 and g (120 mmol) of triethylamine, dissolved in 250 ml of dry tetrahydrofuran at 50°With added dropwise a solution of 14,65 g (120 mmol) of 1,3-propanesultone in 100 ml of tetrahydrofuran and stirred for 3 h at 60°C. Next, add 400 ml of 5%aqueous hydrochloric acid, stirred for 5 min at room temperature, mesilat with sodium chloride, the organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuum. The remainder chromatographic on silica gel (eluent: dichloromethane/acetone in a ratio of 15:1).

Output: 52,24 g (81% of theory) of colorless viscous oil.

Elemental analysis:

Rasch.:With 35,76N 3,66F 30,05N to 5.21S 8,95
the detection.:With 35,75N 3,55F 30,19N 5,08S 9,04

b) [1-(4-PerformanceCounter)piperazine]amide of 2-N,N-bis(propyl-3-sulfonic acid)lysine

53,74 g (52,15 mmole) of the compound indicated in the heading of example 17A, dissolved in 500 ml of ethanol and add 6 g of palladium catalyst (10%Pd/C). After that hydronaut at room temperature. Then the catalyst is filtered off and the filtrate evaporated to dryness in vacuum.

Output: 49,06 g (quantitative) of a colorless solid.

Elemental analysis:

Rasch.:With 30,64N 3,54F 34,33N 5,96S 10,23
the detection.:With 30,69N 3,71F 34,19N between 6.08S 10,38

C) [1-(4-PerformanceCounter)piperazine]amide of 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]-2-N,N-bis(propyl-3-sulfonic acid)lysine, Gd-complex, disodium salt

38,76 g (24,25 mmole) of the compound indicated in the heading of example 17B, and 2.79 g (24,25 mmole) of N-hydroxysuccinimide, 2,12 g (50 mmol) of lithium chloride and 15,27 g (24,25 mmole) Gd-complex of 1,4,7-Tris(carboxylatomethyl)-10-[(3-Aza-4-oxo-5-methyl-5-yl)pentane acid]-1,4,7,10-tetraazacyclododecane dissolved under moderate heating in 200 ml of dimethylsulfoxide. Then, at 10°add to 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide and then stirred over night at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes Precipitated precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, eluent: gradient of water/ethanol/acetonitrile).

Output: 31,63 g (81% of theory) of colorless solid.

Water content: 11,0%.

Elemental analysis (based on anhydrous substance):

Rasch.:With 32,07N 3,57F grade of 20.06N 7,83S 5,97Gd 9,76Na 2,86
the detection.:With 31,94N 3,48F 20,19N of 7.69S 5,85Gd 9,87Na 2,99

Example 18

a) 5-benzyl ester of N-TRIFLUOROACETYL-L-glutamic acid

100 g (421,5 mmole) of 5-benzyl ester L-glutamine the Oh of the acid dissolved in a mixture of 1000 ml of ethyl ether triperoxonane acid and 500 ml of ethanol and stirred for 24 h at room temperature. Thereafter evaporated to dryness and the residue is crystallized from diisopropyl ether.

Output: 140,47 g (96% of theory) of colorless crystalline powder.

Elemental analysis:

Rasch.:With 50,46N 4,23F 17,10N 4,20
the detection.:With 51,35N 4,18F 17,03N 4,28

b) N-bis(2-hydroxyethyl)amide 5-benzyl ester 2-N-TRIFLUOROACETYL-L-glutamic acid

To a solution 24,9 g (24,08 mmole) of the compound indicated in the heading of example 18a, 2,53 g (24,08 mmole) of diethanolamine and 2.77 g (24,08 mmole) of N-hydroxysuccinimide in 150 ml of dimethylformamide at 0°add to 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide. The mixture is stirred for 3 h at 0°and then overnight at room temperature. Precipitated precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuum and chromatographic on silica gel (eluent: dichloromethane/ethanol in a ratio of 20:1).

Output: 9,11 g (90% of theory) of a viscous oil.

Elemental analysis:

Rasch.:With 51,43N 5,51F 13.56MHzN 6,66
the detection.:With 51,22N 5,41F 13,40N 6,75

in) N-is IP(2-hydroxyethyl)monoamide N-TRIFLUOROACETYL-L-glutamic acid

21,92 g (52,15 mmole) of the compound indicated in the heading of example 18b, dissolved in 500 ml of ethanol and add 3 g of palladium catalyst (10%Pd/C). After that hydronaut at room temperature. Then the catalyst is filtered off and the filtrate evaporated to dryness in vacuum.

Output: 43,0 g (quantitative) of a colorless solid.

Elemental analysis:

Rasch.:With 40,01N 5,19F 17,26N 8,48
the detection.:With 39,84N 5,13F 17,19N 8,68

g) TRIFLUOROACETYL-L-glutamic acid-N-bis(2-hydroxyethyl)amide-5-[1-(4-PerformanceCounter)piperazine]amide

To 10,96 g (33,2 mmole) of the compound indicated in the heading of example 18a, and 18,87 g (33,2 mmole) 1-performancemonitoriterations (obtained according to DE 19603033) in 80 ml of tetrahydrofuran at 0°add 16,42 g (66,4 mmole) AEDH (ethyl ester of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) and stirred over night at room temperature. Thereafter evaporated to dryness in vacuum and chromatographic on silica gel (eluent: dichloromethane/methanol in a ratio of 20:1).

Output: 30,93 g (93% of theory) of colorless solid.

Elemental analysis:

Rasch. With 39,61N 2,89F 35,66N is 6.19S 3,54
the detection.:With 39,68N is 2.74F 35,81N 6,13S 3,40

d) L-glutamic acid-N-bis(2-hydroxyethyl)amide-5-[1-(4-PerformanceCounter)piperazine]amide

The solution 30,24 g (30,22 mmole) specified in the header of example 18b in 200 ml of ethanol at 0°within hours bubbled with gaseous ammonia. The mixture was then stirred for 4 h at 0°C. then evaporated to dryness and the residue is separated from the water by stirring. The solid is filtered off and dried in vacuo (50°).

Output: 26,55 g (97% of theory) of an amorphous solid.

Elemental analysis:

Rasch.:With 41,12N 2,89F 35,66N is 6.19S 3,54
the detection.:With 41,15N 2,83F 35,78N 6,28S 3,71

e) N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]-L-glutamic acid-N-bis(2-hydroxyethyl)amide-5-[1-(4-PerformanceCounter)piperazine]amide, Gd complex

211,96 g (24,25 mmole) of the compound indicated in the heading of example d, and 2.79 g (24,25 mmole) of N-hydroxysuccinimide, 2,12 g (50 mmol) chlorite is as lithium and 15,27 g (24,25 mmole) Gd-complex of 1,4,7-Tris(carboxylatomethyl)-10-[(3-Aza-4-oxo-5-methyl-5-yl)pentane acid]-1,4,7,10-tetraazacyclododecane dissolved under moderate heating in 200 ml of dimethylsulfoxide. Then, at 10°add to 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide and then stirred over night at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes Precipitated precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, eluent: gradient of water/ethanol/acetonitrile).

Output: 27,43 g (81% of theory) of colorless solid.

Water content: 11,0%.

Elemental analysis (based on anhydrous substance):

Rasch.:With 34,41N 3,83F 23,13N 9,03S 2,30Gd of 11.26
the detection.:With 34,34N 3,98F 23,29N 9,19S 2,15Gd 11,07

Example 19

a) N-dimetallic(1,1-dihydroxymethyl)amide 5-benzyl ester of N-TRIFLUOROACETYL-L-glutamic acid

To a solution 8,03 g (24,08 mmole) of the compound indicated in the heading of example 18a, 3,98 g (24,08 mmole) dimetallic(1,1-dihydroxymethyl)amine and 2.77 g (24,08 mmole) of N-hydroxysuccinimide in 150 ml of dimethylformamide at 0°add to 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide. The mixture is stirred for 3 h at 0°and then overnight at room temperature. Precipitated precipitated urea is filtered off, Phil is spending evaporated to dryness in vacuum and chromatographic on silica gel (eluent: dichloromethane/ethanol in a ratio of 20:1).

Output: 110,53 g (91% of theory) of a viscous oil.

Elemental analysis:

Rasch.:With 50,00N 5,66F up 11,86N 7,18
the detection.:With 50,17N of 5.82F 11,80N 7,15

b) [1-(4-PerformanceCounter)piperazine]amide 5-benzyl ester of N-TRIFLUOROACETYL-L-glutamic acid

25,05 g (52,15 mmole) of the compound indicated in the heading of example 19a, dissolved in 500 ml of ethanol and add 6 g of palladium catalyst (10%Pd/C). After that hydronaut at room temperature. Then the catalyst is filtered off and the filtrate evaporated to dryness in vacuum.

Output: 20,36 g (quantitative) of a colorless solid.

Elemental analysis:

Rasch.:From 40,00N 5,42F 14,60N 7,18
the detection.:With 40,10N of 5.53F 14,69N 7,28

in) N-TRIFLUOROACETYL-L-glutamic acid-N-dimetallic(1,1-dihydroxymethyl)amide-5-[1-(4-PerformanceCounter)piperazine]amide

To 12,96 g (33,2 mmole) of the compound indicated in the heading of example 19b, and 18,87 g (33,2 mmole) 1-performancemonitoriterations (obtained according to DE 19603033) in 800 ml of tetrahydrofuran is ri 0° To add 16,42 g (66,4 mmole) AEDH (ethyl ester of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) and stirred over night at room temperature. Thereafter evaporated to dryness in vacuum and chromatographic on silica gel (eluent: dichloromethane/methanol in a ratio of 20:1).

Output: 28,42 g (91% of theory) of colorless solid.

Elemental analysis:

Rasch.:With 31,93N 3,00F 40,40N 5,96S 3,41
the detection.:With 32,08N 2,94F 40,57N 5,88S 3,31

g) L-glutamic acid-N-[dimetilan(1,1-dihydroxymethyl)]amide-5-[1-(4-PerformanceCounter)piperazine]amide

The solution 28,41 g (30.2 mmole) of the compound indicated in the heading of example 19c, in 200 ml of ethanol at 0°within hours bubbled with gaseous ammonia. The mixture was then stirred for 4 h at 0°C. then evaporated to dryness and the residue is separated from the water by stirring. The solid is filtered off and dried in vacuo (50°).

Output: 24,74 g (97% of theory) of an amorphous solid.

Elemental analysis:

Rasch.:With 32,71N of 3.46F 38,24N 6,63S 3,80
the detection.:With 32,75N 3,33F 38,38N of 6.68S 3,81

d) 2-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]-L-glutamic acid-N-[dimetilan(1,1-dihydroxymethyl)amide]-5-[1-(4-PerformanceCounter)piperazine] amide, Gd complex

20,48 g (24,25 mmole) of the compound indicated in the heading of example 19g, and 2.79 g (24,25 mmole) of N-hydroxysuccinimide, 2,12 g (50 mmol) of lithium chloride and 15,27 g (24,25 mmole) Gd-complex of 1,4,7-Tris(carboxylatomethyl)-10-[(3-Aza-4-oxo-5-methyl-5-yl)pentane acid]-1,4,7,10-tetraazacyclododecane dissolved under moderate heating in 200 ml of dimethylsulfoxide. Then, at 10°add to 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide and then stirred over night at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes Precipitated precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, eluent: gradient of water/ataneli/acetonitrile).

Output: 29,05 g (83% of theory) of colorless solid.

Water content: 11,0%.

Elemental analysis (based on anhydrous substance):

Rasch.:With the volume of 34.12N 3,91F 22,38N 8,73S 2,22 Gd 10,90
the detection.:With 34,24N 3,98F 22,39N 8,69S 2,15Gd 10,87

Example 20

a) [1-(4-PerformanceCounter)piperazine]amide 5-benzyl ester N-cryptomailer-L-glutamic acid

To 11,06 g (33,2 mmole) of the compound indicated in the heading of example 18a, and 18,87 g (33,2 mmole) 1-performancemonitoriterations (obtained according to DE 19603033) in 80 ml of tetrahydrofuran at 0°add 16,42 g (66,4 mmole) AEDH (ethyl ester of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) and stirred over night at room temperature. Thereafter evaporated to dryness in vacuum and chromatographic on silica gel (eluent: dichloromethane/methanol in a ratio of 20:1).

Output: 27,28 g (93% of theory) of colorless solid.

Elemental analysis:

Rasch.:With 35,35H 2,40F 43,01N 4,76S 3,63
the detection.:With 35,48N of 2.51F 42,87N 4,73S 3,50

b) 5-[1-[4-PerformanceCounter)piperazine]amide N-TRIFLUOROACETYL-L-glutamic acid

21,92 g (52,15 mmole) of the compound indicated in the heading of example 18a, dissolved in 500 ml of ethanol and add 3 g of palladium catalyst (10%-n is th Pd/C). After that hydronaut at room temperature. Then the catalyst is filtered off and the filtrate evaporated to dryness in vacuum.

Output: 41,37 g (quantitative) of a colorless solid.

Elemental analysis:

Rasch.:With 28,76N 1,91F 47,89N and 5.30S 4,04
the detection.:With 28,84N 2,03F 47,79N 5,28S 4,19

in) N-TRIFLUOROACETYL-L-glutamic acid-N-bis(2-hydroxyethyl)amide-5-[1-(4-PerformanceCounter)piperazine]amide

To a solution 24,9 g (24,08 mmole) of the compound indicated in the heading of example 18a, 2,53 g (24,08 mmole) of diethanolamine and 2.77 g (24,08 mmole) of N-hydroxysuccinimide in 150 ml of dimethylformamide at 0°add to 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide. The mixture is stirred for 3 h at 0°and then overnight at room temperature. Precipitated precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuum and chromatographic on silica gel (eluent: dichloromethane/ethanol in a ratio of 20:1).

Output: 9,11 g (90% of theory) of a viscous oil.

Elemental analysis:

Rasch.:With 31,37N 2,75F 43,15N 6,36S of 3.64
the detection.:With 31,22N 2,61F 43,30N 6,25S 3,81

g) L-glutamic acid-N-bis(2-hydroxyethyl)amide-5-[1-(4-PerformanceCounter)piperazine]amide

The solution 26,61 g (30,22 mmole) of the compound indicated in the heading 18V example, in 200 ml of ethanol at 0°within hours bubbled with gaseous ammonia. The mixture was then stirred for 4 h at 0°C. then evaporated to dryness and the residue is separated from the water by stirring. The solid is filtered off and dried in vacuo (50°).

Output: 23,93 g (97% of theory) of an amorphous solid.

Elemental analysis:

Rasch.:With 30,89N 3,09F 39,56N 6,86S 3,93
the detection.:With 30,75N 3,13F 39,78N 6,75S 3,81

d) N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-Aza-4-oxo-5-methyl-5-yl)]-L-glutamic acid-N-bis(2-hydroxyethyl)amide-5-[1-(4-PerformanceCounter)piperazine]amide, Gd complex

16,43 g (24,25 mmole) of the compound indicated in the heading of example 20g, and 2.79 g (24,25 mmole) of N-hydroxysuccinimide, 2,12 g (50 mmol) of lithium chloride and 15,27 g (24,25 mmole) Gd-complex of 1,4,7-Tris(carboxylatomethyl)-10-[(3-Aza-4-oxo-methyl-5-yl)pentane acid]-1,4,7,10-tetraazacyclododecane dissolved under moderate heating in 200 ml of dimethylsulfoxide. Then, at 10°add to 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide and then stirred over night at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes Precipitated precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, eluent: gradient of water/ethanol/acetonitrile).

Output: 28,10 g (83% of theory) of colorless solid.

Water content: 11,0%.

Elemental analysis (based on anhydrous substance)

Rasch.:With 34,41N 3,83F 23,13N 9,03S 2,30Gd of 11.26
the detection.:With 34,44N to 4.98F 23,19N 8,89S 2,15Gd 11,17

Example 21

a) [1-(4-PerformanceCounter)piperazine]amide 5-benzyl ester N-triftoratsetilatsetonom acid

To 11,06 g (33,2 mmole) of the compound indicated in the heading of example 18a, and 18,87 g (33,2 mmole) 1-performancemonitoriterations (obtained according to DE 19603033) in 80 ml of tetrahydrofuran at 0°add 16,42 g (66,4 mmole) AEDH (ethyl ester of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) and stirred over night at room temperature. Thereafter evaporated to dryness in vacuum and chromatographic on when likehere (eluent: dichloromethane/methanol in a ratio of 20:1).

Output: 27,28 g (93% of theory) of colorless solid.

Elemental analysis:

Rasch.:With 35,35H 2,40F 43,01N 4,76S 3,63
the detection.:With 35,48N 2,54F 42,87N 4,73S 3,40

b) 5-[1-[4-PerformanceCounter)piperazine]amide N-TRIFLUOROACETYL-L-glutamic acid

21,92 g (52,15 mmole) of the compound indicated in the heading of example 21A, dissolved in 500 ml of ethanol and add 3 g of palladium catalyst (10%Pd/C). After that hydronaut at room temperature. Then the catalyst is filtered off and the filtrate evaporated to dryness in vacuum.

Output: 41,37 g (quantitative) of a colorless solid.

Elemental analysis:

Rasch.:With 28,76N 1,91F 47,89N and 5.30S 4,04
the detection.:With 28,84N is 1.81F 47,79N 5,28S 4,16

Example 22. The distribution proposed in the invention of a contrast agent from example 3 in the organs (including the accumulation in the tumor and lymph nodes) after intravenous administration to rats with prostate cancer

PEFC is intravenous administration to rats (copulatory inbreeding, 12 days prior to the experiments the animals intramuscularly implanted cells prostate cancer lines Dunning R3327 MAT-Lu) of the compound from example 3 at the rate of 100 mcmole total gadolinium per 1 kg of body weight after 10 min, 1 h and 24 h after injection (PV) was determined by the metal content in various organs, tumors, and lymph nodes (data on which the grouped data to brusheezy and peripheral lymph nodes (in the table are average values ± standard deviation, n=3).

Example 23. Picture of heart attack (MRT) after intravenous administration of contrast material to rats

The shots are MR-pictures of the heart (in vivo and post morten) 24 h after intravenous injection of 100 mcmole Gd/kg KGW connection specified in the header of example 6g, rats with induced acute heart attack. The contrast agent was injected 24 h after occlusion (blockage) of a coronary artery. Applied in this example, the model of myocardial infarction directly comparable with the model of experimentally induced myocardial kidneys, which results in the occlusion of branches of the renal artery. T1loaded, EKG-deployed spin-echo images (1.5 T, TR (effective): 400 MS, TE: 12 MS, NA: 4, matrix: 128"128, thickness: 2.5 mm) clearly show a strong amplification signal is La in the area of infarction. Subsequent induction of acute myocardial infarction confirmed by NBT-staining.

This experiment can demonstrate the suitability of the compounds according to the invention as markers of necrosis.

1. 24 h after injection, in vivo axial

2. 25 h after injection, post morten, axial

3. 25 h after injection, post morten, coronary

4. 25 h after injection, slice, ex vivo

5. 25 h after injection, slice, NBT-staining

6. The connection specified in the header of example 6g: 100 mcmole/kg, intravenously, SE, TR/TE 400/12 MS, arrow: myocardial infarction

Example 24 Shots lymph nodes (MRT) after intravenous administration of contrast material Guinea pigs

The shots are MR-pictures popliteal lymph nodes prior to the introduction of contrast medium and 24 h after intravenous injection of 100 mcmole Gd/kg KGW connection specified in the header of example 6g, cavies. The immune system of the animals stimulated by intramuscular injection of an emulsion of egg yolk (0.1 ml in the thigh and drumstick in 6 days) with the aim of increasing size and weight of the lymph nodes. T1-weighted turbo-spin-echo images (1.5 T, the sequence: T1-TSE, TR 666 MS, TE: 12 MS) illustrate the strong signal enhancement in healthy tissue, lymph nodes already after a short time after the injection. So the increase in popliteal and inguinal limfaticheskie the nodes is 201± 9% after 15 min after injection, 209±23% after 60 min and 82±24% after 24 h after injection. Factor signal intensity between lymph nodes and muscle is 1.5±0.1 to 15 after injection and at 24 h after injection, reaches a value of 1.6±0,1.

1. The baseline

2. 15 min after injection,

3. 24 h after injection,

4. The connection specified in the header of example 6g: 0.2 mmole/kg, intravenously, T1-TSE, TR/TE 666/12 MS, TA 3:49,

Guinea pigs with stimulated lymph nodes, arrow: popliteal lymph node.

Example 25. Picture of heart attack (MRT) after intravenous administration of contrast material to rats

The shots are MR-pictures of the heart (in vivo and post morten) after 25 h after intravenous injection of 100 mcmole Gd/kg KGW connection specified in the header of example 9b, rats with induced acute heart attack. The contrast agent was injected 24 h after occlusion (blockage) of a coronary artery. Applied in this example, the model of myocardial infarction directly comparable with the model of experimentally induced myocardial kidneys, which results in the occlusion of branches of the renal artery. T1loaded, EKG-deployed spin-echo images (1.5 T, TR (effective): 400 MS, TE: 12 MS, NA: 4, matrix: 128"128, thickness: 2.5 mm) illustrate the strong signal enhancement in the area of infarction. P the following induction of acute myocardial infarction confirmed by NBT-staining.

This experiment can demonstrate the suitability of the compounds according to the invention as markers of necrosis.

1. 25 h after injection, in vivo axial

2. 25 h after injection, post morten, axial

3. 25 h after injection, post morten, coronary

4. 25 h after injection, slice, ex vivo

5. 25 h after injection, slice, NBT-staining

6. The connection specified in the header of example 9b: 100 mcmole/kg, intravenously, SE, TR/TE 400/12 MS, arrow: myocardial infarction

Example 26. Pictures of lymph nodes (MRT) after intravenous administration of contrast material Guinea pigs

The shots are MR-pictures popliteal lymph nodes prior to the introduction of contrast medium and 24 h after intravenous injection of 50 mcmole Gd/kg KGW connection specified in the header of example 9 g, cavies. The immune system of the animals stimulated by intramuscular injection of an emulsion of egg yolk (0.1 ml in the thigh and drumstick in 6 days) with the aim of increasing size and weight of the lymph nodes. T1-weighted turbo-spin-echo images (1.5 T, the sequence: T1-TSE, TR 666 MS, TE: 12 MS) illustrate the strong signal enhancement in healthy tissue, lymph nodes already after a short time after the injection. So the increase in popliteal and inguinal lymph nodes is 84-87% after 15 min after injection, about 80 to 98% after 60 min and 48-69% at 24 h, p is the next injection. Factor signal intensity between lymph nodes and muscle is 1.5 through 15 after injection and at 24 h after injection, reaches a value of 1.8.

1. The baseline

2. 15 min after injection,

3. 24 h after injection,

4. The connection specified in the header of example 9b: 50 mcmole/kg, intravenously, T1-TSE, TR/TE 666/12 MS, TA 3:49, Guinea pigs with stimulated lymph nodes, arrow: popliteal lymph node.

1. Performancecriteria complexes with polar residues of the General formula I

in which Rfdenotes a perfluorinated, straight or branched carbon chain of the formula-CnF2nin which n denotes an integer from 4 to 30;

K stands for a metal complex of General formula II

in which R1represents a hydrogen atom or an equivalent of a metal ion with atomic number 21-29 and 58-71, provided that at least two radicals R1represent the equivalents of metal ions;

R2and R3independently of one another denote hydrogen, C1-C4alkyl, benzyl, phenyl, -CH2OH or-CH2Och3and

U represents-C6H4O-CH2-ω-, -(CH2)1-5-ω-, -C6H4-(OCH2CH2 )0-1-N(CH2COOH)-CH2-ωor optionally interrupted by one or more oxygen atoms, 1-3-NHCO-groups, 1-3-CONH groups and/or substituted by 1-3 -(CH2)0-5COOH-groups1-C12alkylenes or7-C12-C6H4-O-group, when it ω refers to the place of joining-CO-,

or the General formula III

in which R1have the above meanings;

R4denotes hydrogen or specified for R1the equivalent of a metal ion and

U1denotes-C6H4-O-CH2-ω-where ω refers to the place of joining-CO-,

or the General formula IV

in which R1and R2have the above values,

or of General formula VB

in which R1has the above values

or the General formula VII

in which R1has the above values, and

U1denotes-C6H4O-CH2-ω-where ω refers to the place of joining-CO-,

this is not necessarily present in the residue To the free acid groups optionally can be presented in view of the salts of organic and/or inorganic bases or amino acids or amides of amino acids,

G represents at least three-functionalized residue selected from the following residues (a)-(i):

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

where and denotes the place of attachment G to the complex;

β indicates the place of attachment G to the residue R;

γ indicates the place of attachment G to the residue Z,

Z denotes a group

γ-C(O)CH2O(CH2)2-ε,

where γ indicates the place of attachment of Z to the remainder of G;

ε indicates the place of attachment of Z to perfluorinated residue Rf,

R is a polar residue selected from complexes of General formulas II-VII, and in this case, R1denotes the hydrogen atom or the equivalent of a metal ion with atomic number 21-29 and 58-71, and the remaining R2, R3, R4U and U1have these vychutnajte, moreover, in the case when G is a residue of formula (C) or (d), a R is a compound selected from complexes of General formulas II and V, R may not be identical to the balance To the General formula I, if Z represents δ-C(O)CH2O(CH2)2-ε,

or represents the balance of folic acid or attached via a-CO-, SO2or a direct link to the residue G carbon chain with 2 to 30 C-atoms, which is straight or branched, saturated or unsaturated and which is optionally interrupted by 1-10 oxygen atoms, 1-5-NHCO-groups, 1-5-CONH-groups, 1-2 sulfur atoms, 1-5-NH-groups or 1-2 phenylanaline groups, which optionally can be substituted by 1-2 HE-groups, 1-2 NH2groups, 1-2-COOH groups, or 1-2-SO3N-groups, or optionally substituted 1-8 HE-groups, 1-5-COOH groups, 1-2 SO3N-groups, 1-5 NH2groups 1-51-C4alkoxygroup, and

l, m, p independently of one another denote integers of 1 or 2.

2. The metal complexes according to claim 1, characterized in that the equivalent of a metal ion, R1in the remainder It is the element with atomic number 21-29 and 58-71.

3. The metal complexes according to claim 1, characterized in that the equivalent of a metal ion, R1in the remainder It is the element with atomic number 27, 29, 62, 64, 70.

4. The complexes m is for metal according to any one of claims 1 to 3, characterized in that It is a complex of metal of General formula II, III, VB, or VII.

5. The metal complexes according to any one of claims 1 to 4, characterized in that a polar residue R is defined for complex values.

6. The metal complexes according to claim 5, characterized in that the polar residues R are the complexes of General formulas II, III, VA, or VII.

7. The metal complexes according to claim 5 or 6, wherein R1represents the equivalent of a metal ion with a serial number 21, 25 or 64.

8. The metal complexes according to any one of claims 1 to 4, characterized in that a polar residue R has the following meanings: -C(O)CH2CH2SO3H, -C(O)CH2JCH2CH2JCH2CH2OH, -C(O)CH2JCH2CH2OH, -C(O)CH2OCH2CH(OH)CH2OH, -C(O)CH2NH-C(O)CH2COOH, -C(O)CH2CH(OH)CH2OH, -C(O)CH2JCH2COOH, -SO2CH2CH2COOH, -C(O)-C6H3-(m-COOH)2-C(O)CH2O(CH2)2-C6H3-(m-COOH)2, -C(O)CH2O-C6H4-m-SO3H, -C(O)CH2NHC(O)CH2NHC(O)CH2OCH2COOH, -C(O)CH2JCH2CH2JCH2COOH, -C(O)CH2JCH2CH(OH)CH2O-CH2CH2OH, -C(O)CH2JCH2CH(OH)CH2JCH2-CH(OH)-CH2OH, -C(O)CH2SO3H, -C(O)CH2CH2COOH, -C(O)CH(OH)CH(OH)CH 2OH, -C(O)CH2O[(CH2)2O]1-9-CH3, -C(O)CH2O[(CH2)2O]1-9-H, -C(O)CH2OCH(CH2OH)2-C(O)CH2JCH(CH2JCH2COOH)2-C(O)-C6H3-(m-och2COOH)2, -CO-CH2O-(CH2)2O(CH2)2O-(CH2)2O(CH2)2JCH3preferably-C(O)CH2O[(CH2)2O]4-CH3.

9. The metal complexes according to any one of claims 1 to 4, characterized in that a polar residue R represents the residue of folic acid.

10. The metal complexes according to any one of claims 1 to 9, characterized in that the G in General formula I represents a lysine residue (a) or (b).

11. The metal complexes according to any one of claims 1 to 10, characterized in that the U in the metal complex is a group-CH2- or-C6H4-O-CH2-ω-where ω refers to the place of joining-WITH-.

12. Pharmaceutical preparation containing at least one physiologically acceptable compound according to any one of claims 1 to 11 optional in combination with commonly used in herbal preparations additives as a contrast agent for NMR and x-ray.

13. The means indicated in paragraph 12, characterized in that it contains the metal complexes according to claim 2, and is intended for use as a contrast agent for infogra the AI in the diagnosis of changes in the lymphatic system.

14. The means indicated in paragraph 12, characterized in that it contains the metal complexes according to claim 2, and is intended for use as a contrast agent for indirect limfografii.

15. The means indicated in paragraph 12, characterized in that it contains the metal complexes according to claim 2, and is intended for use as a contrast agent for intravenous limfografii.

16. The method of obtaining performanceeasy complexes with polar residues of the General formula I

in which K, G, R, Z, Rf, I, m and p are specified in claim 1 values

characterized in that the carboxylic acid of General formula IIa

in which R5indicates the equivalent of a metal ion with atomic number 21-29 and 58-71 or carboxyamide group, and R2, R3and U have the above values,

or carboxylic acid of General formula IIIa

in which R4, R5and U1have the above values,

or carboxylic acid of General formula IVa

where R5and R2have the above values,

or carboxylic acid of General formula Va or Vb

where R5has the above values

or carboxylic acid of General formula VIa

in which R5has the above values

or carboxylic acid of General formula VIIa

in which R5and U1have the above values,

optionally in activated form, is subjected by well-known methods of interaction in terms of combination reaction with the amine of General formula VIII

in which G, R, Z, Rf, m and p have the above values,

and then, if necessary, otscheplaut present under certain conditions, the protective group to obtain the result of complex metal General formula I or, if R5represents a protective group, after removal of such protective groups at the next stage is subjected to interaction by well-known methods of at least one metal oxide or metal salt with a serial number 21-29 and 58-71, then optionally present under certain conditions, the acidic hydrogen atoms are substituted by cations of inorganic bases.



 

Same patents:

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to chemistry of biologically active substances, in particular, to novel biologically active compounds, namely, 2-(5-R-aminomethylfuryl-2)-1,3-dioxalanes of the formula (I): wherein at (Ia) R means --Ts and at (Ib) R means -CO-Ph. These compounds show properties as activating agent with respect to germination of winter wheat grains of sort "Pobeda-50" possessing growth-regulating and anti-stress activity.

EFFECT: valuable biological properties of compounds.

1 cl, 2 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of aminoquinoline and aminopyridine. Invention describes compounds of the general formula (I): wherein R1 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R2 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R3 means hydrogen atom or direct or branched (C1-C4)-alkyl group or phenyl group, thienyl group or furyl group optionally substituted with one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 form in common 1,3-butadienyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group or halogen atom; R6 means hydrogen atom or cyano-group; R7 means hydrogen atom or direct or branched (C1-C4)-alkyl group, phenyl group, benzyl group, thienyl group, or furyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group, trifluoromethyl group, cyano-group or halogen atom; X means -NH-group, -NR8-group or sulfur atom, or oxygen atom, or sulfo-group, or sulfoxy-group wherein R8 means direct or branched (C1-C4)-alkyl group or (C3-C6)-cycloalkyl group; n = 0, 1 or 2, and their salts. Also, invention describes a method for preparing compounds of the formula (I). a pharmaceutical composition based on thereof, using compounds of the formula (I) as antagonists of A3 receptors for preparing a pharmaceutical composition used in treatment of different diseases (variants), compounds of the formula (IA), (II), (III) and (IV) given in the invention description. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

15 cl, 6 tbl, 6 dwg, 172 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of N-heterocyclic compounds of the formula: , wherein n and m mean independently a whole number from 1 to 4; A means -C(O)OR1 or -C(O)N(R1)R2; W means -CH; R1 means hydrogen atom or (C1-C8)-alkyl; R means hydrogen atom, (C1-C8)-alkyl, heterocyclyl-(C1-C4)-alkyl chosen from the group comprising benzodioxolyl-, benzodioxanyl- or dihydrobenzofuranylalkyl or phenyl-(C1-C4)-alkyl substituted possibly with alkoxy-group; R4 means cyano-group or heterocyclyl chosen from the group comprising pyridinyl, morpholinyl, benzodioxolyl or benzodioxanyl-radical if m = 1; if m means from 2 to 4 then R4 can mean additionally hydroxy-group, -NR1R2 wherein R1 and R2 mean independently hydrogen atom, (C1-C8)-alkyl or benzyl-radical, -N(R1)-C(O)-R1, -N(R1)-C(O)-OR1, -N(R1)-S(O)t-R1 wherein R1 means hydrogen atom or (C1-C8)-alkyl, -N(R1)-C(O)-N(R1)2 wherein R1 means hydrogen atom; R5 means (C1-C8)-alkyl; t = 2, and their stereoisomers and pharmaceutically acceptable salts, pharmaceutical composition based on thereof and a method for treatment of diseases, in particular, rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds and composition.

12 cl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

11 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

EFFECT: valuable medicinal properties of compounds and composition, improved method for treatment of infections.

24 cl, 14 tbl, 1 dwg, 45 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to quinazoline derivatives of the formula (I) or their pharmaceutically acceptable salts wherein m = 0 or 1; each group R1 can be similar or different and represents halogen atom, hydroxy- and (C1-C6)-alkoxy-group, or group of the formula Q3-X1 wherein X1 represents oxygen atom (O); Q3 represents phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl, and wherein heteroaryl group represents aromatic 5- or 6-membered monocyclic rings with one or two nitrogen heteroatoms, and any heterocyclyl group defined as the group R1 represents non-aromatic saturated or partially saturated 3-6-membered monocyclic ring with one or two heteroatoms chosen from oxygen and nitrogen atoms, and wherein adjacent carbon atoms in any (C2-C6)-alkylene chain in the substitute R1 are separated optionally by incorporation of oxygen atom (O) in the chain, and wherein any group CH2 or CH3 in the substitute R1 comprises optionally in each of indicated groups CH2 or CH3 one or some halogen substitutes or a substitute chosen from hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl or pyridyloxy-group, and wherein any heteroaryl or heterocyclyl group in the substitute R1 comprises optionally 1, 2 or 3 substitutes that can be similar or different and chosen from hydroxy-group, carbamoyl, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]-carbamoyl, (C1-C6)-alkoxy-(C1-C6)-alkyl and cyano-(C1-C6)-alkyl, or among group of the formula -X5-Q6 wherein X5 represents a direct bond or -CO, and Q6 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that comprises optionally (C1-C6)-alkyl as a substitute wherein heterocyclyl group represents non-aromatic, fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from nitrogen and oxygen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; Z represents a direct bond or oxygen atom; Q1 represents phenyl, (C3-C7)-cycloalkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl wherein heteroaryl group represents 5- or 6-membered aromatic monocyclic ring with I, 2 or 3 heteroatoms of nitrogen, and any heterocyclyl group represents non-aromatic fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from oxygen, nitrogen or sulfur atom, or when Z represents oxygen atom (O) then Q1 can represent (C1-C6)-alkyl or (C1-C6)-alkoxy-(C1-C6)-alkyl and wherein any heterocyclyl group in the group -Q1-Z- comprises substitutes chosen from (C1-C6)-alkyl, (C1-C)-alkoxycarbonyl and pyridylmethyl, and wherein any heterocyclyl group in the group -Q1-Z- comprises optionally 1 or 2 oxo-substitutes; Q2 represents aryl group of the formula (Ia): wherein G1 represents halogen atom, trifluoromethyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C2-C6)-alkanoyl, pyrrolyl, pyrrolidinyl, piperidinyl and morpholinomethyl, and each G2, G3, G4 and G5 that can be similar or different represents hydrogen, halogen atom, cyano-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group, or G1 and G2 form in common group of formulae -CH=CH-CH=CH-, -CH=CH-O- or -O-CH=CH- being each group carries optionally halogen atom as a substitute, or G1 and G2 form in common group of formulae -O-CH2-O- or -O-CH2-CH2-O-, or -O-CH2-CH2-O-, and each among G3 and G4 represents hydrogen atom, and G5 is chosen from hydrogen and halogen atom. Proposed compounds possess anti-tumor activity and designated for preparing a medicine preparation for its using as an anti-tumor agent for suppression and/or treatment of solid tumors. Also, invention relates to a pharmaceutical composition based on abovementioned compounds.

EFFECT: valuable medicinal properties of compounds.

20 cl, 7 tbl, 57 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention relates to a novel heterocyclic compound, in particular, 3-(5-nitrofuryl)-7-(5-nitrofurfurylidene-3,3a,4,5,6,7-hexahydro-2H-indazole of the formula (1): that elicits an antibacterial activity with respect to bacterium of genus Staphylococcus and can be used in medicine. The compound of the formula 91) is prepared by reaction of 2,6-di-(5-nitrofurfurylidene)-cyclohexanone with hydrazine hydrate in propanol-2 medium. The yield is 80%, m. p. at 193-195°C, empirical formula is C16H14N4O6, LD50 value at intraperitoneal administration is 500 mg/kg. This compound exceeds activity of furacilinum and furazolidone by 16 and 2-31 times, respectively. Invention provides preparing compound possessing the higher and selective antibacterial activity and low toxicity.

EFFECT: valuable properties of compound.

1 cl, 3 tbl, 1 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention describes perfluoroalkyl-containing complexes with residues of sugars of the general formula (I): wherein R means mono- or oligosaccharide residue added through 1-OH- or 1-SH-position; Rf means perfluorinated carbon chain; K means the metal complex of the formula (II) wherein R1 means hydrogen atom (H) or equivalent of metal ion with order number 21-29 or 58-71 under condition that at least two radicals of R1 represent metal ions; R2 and R3 mean independently hydrogen atom (H), (C1-C6)-alkyl, benzyl, phenyl; U means the group C6H4-O-CH2-ω- or (C2-C8)-alkylene, or (C6-C9-C6H4-O-group optionally broken with one oxygen atom (O), 1,2-NHCO-groups or 1,2-CONH-group wherein ω means a point of addition to -CO-; Y and Z represent linker-groups useful for using in intravenous lymphography, tumor diagnosis and for visualization of infarctions and necrosis.

EFFECT: valuable medicinal properties of complexes.

11 cl, 1 tbl, 2 dwg, 39 ex

The invention relates to arylpiperazines General formula I

< / BR>
where is phenyl, pyridyl or pyrimidyl; each R3- H, halogen, NO2, СООR, where R is H, C1-6alkyl, CN, CF3WITH1-6alkyl, -S - C1-6alkyl, -SO-Cl - C1-6alkyl, -SO2-Cl-C1-6alkyl, C1-6alkoxy and up to10aryloxy, n= 1, 2, or 3; R is a direct bond; And - piperazinil, X1and X2IS N; Y IS-SO2-; Z IS - N(OH)-CHO; Q - CH2-; R1- H, C1-6alkyl, C5-7cycloalkyl until10aryl, until10heteroaryl until1-2aralkyl or until12heteroallyl, R4- H, C1-6alkyl, and others; R2- H, C1-6alkyl, or together with R1- carbocyclic or heterocyclic Spiro 5-, 6 - or 7-membered ring containing at least one heteroatom selected from N, O or S, and the group Q can be associated either with R1or R2with the formation of 5,- 6 - or 7-membered alkyl or heteroalkyl ring that includes one or more O, S or N

The invention relates to compounds of the formula I

< / BR>
in which R1denotes-C(=NH)-NH2which may be substituted once by a group-COA, -CO-[C(R6)2]n-Ar, -COOA, -HE or normal aminosidine group

< / BR>
R2denotes H, A, OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSО2Ar, COOR6, SOPS(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,

R3means And, cycloalkyl, - [C(R6)2]nAr, - [C(R6)2]n-O-Ar, -[C(R6)2]nHet or-C(R6)2=C(R6)2-Ar,

R6denotes H, a or benzyl,

X is absent or represents-CO-, -C(R6)2-, -C(R6)2-C(R6)2-, -C(R6)2-CO-, -C(R6)2-C(R6)2-CO-, -C(R6)= C(R6)-CO-, NR6CO-, -N{[CR6)2]n-COOR6} -CO - or-C(COOR6R6-C(R6)2-CO-,

Y represents-C(R6)2-, -SO2-, -CO-, -COO - or-CONR6-,

And denotes alkyl with 1-20 C-atoms, where one or two CH2-groups can be replaced by O - or S-atom or single, two - or three-fold substituted by the group And, Ah', OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr', NHSO2A, NHSО2Ar', COOR6, CON(R6)2, CONHAr', COR6, COAr', S(O)nA or S(O)nAr is phenyl or naphthyl,

AG' refers to unsubstituted or one-, two - or three-fold substituted by a group A, OR6N(R6)2, NO2CN, Hal, NHCOA, COOR6, SOPS(R6)2, COR6or S(0)nA phenyl or naphthyl,

Het denotes a single or dual core unsubstituted or one - or multi-substituted by a group of Hal, A, Ar', COOR6, CN, N(R6)2, NO2, Ar-CONH-CH2and/or carbonyl oxygen saturated or unsaturated heterocyclic ring system containing one, two, three or four identical or different heteroatoms, such as nitrogen, oxygen or sulphur,

Hal denotes F, C1, Br or J,

n denotes 0, 1 or 2,

and their salts

The invention relates to biochemistry, in particular to the use of bromo derivatives known betterin-1,3-dioxide of the General formula I

< / BR>
where R1and R2different and mean hydrogen or Br,

as irreversible inhibitors of H, K-adenosinetriphosphatase (N,K-Atraz)

The invention relates to the objects of the invention characterized in the claims, i.e

The invention relates to metallogenica derivative containing four nitrogen atom of the macrocycle, fused with the pyridine cycle, methods for their preparation and their use in medicine to obtain an image
The invention relates to histochemistry
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