Ca-ix specific radiopharmaceutical agents for treating and imaging malignant tumours

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I , II or IV , wherein the radical values W, V, Ra, Rb, X, L, Rt, A are presented in the patent claim.

EFFECT: declared compounds identify and bind the CA-IX protein; they can contain a radioactive element for radionuclide imaging or therapeutic application.

27 cl, 1 tbl, 5 dwg, 25 ex

 

The technical field to which the invention relates.

The present technology, in General, relates to the field of radiopharmaceuticals and their use in nuclear medicine as tracers, imaging means and for treatment of diseases in various States. It is well known that tumors can synthesize specific proteins associated with their malignant phenotype or can surgentes normal proteins in larger quantities than normal cells. The synthesis of individual proteins on the surface of malignant cells makes it possible to diagnose and characterize disease definition fenotipicheskoi identity and biochemical composition and activity of the tumor. Radioactive molecules that selectively associated with specific malignant cells provide an attractive way of imaging and treatment of tumors of non-invasive way. In particular, the authors of the present invention found that radiolabelled ligands for CA-IX protein, often as a result of sverginate many malignant cells, provide an attractive way of non-surgical imaging and selective effects on malignant target cells.

The level of technology

Carbonic anhydrase (CA) carbonatites is a family of enzymes, which is tasermiut rapid conversion of carbon dioxide to bicarbonate and a proton in the presence of water. Therefore, the carbonic anhydrase plays an important role in maintaining acid-base balance (pH) in the blood and tissues and also plays a role in the withdrawal of carbon dioxide from the tissues. SA is metalloenzymes containing zinc in the active site zinc is coordinated by three residues imidazole three his-tag side chains.

There are at least 16 isoenzymes in the family of carbonic anhydrase. Specific isoenzymes found in either the cytosol, fixed on the membrane, mitochondria, or sekretiruemyi cells. Well-studied constitutively expressing the enzyme, carbonic anhydrase II (CA-II), found in the cytosol of most types of cells and is the major isoform responsible for the regulation of intracellular pH.

CA-IX is the isoform of the enzyme, fixed membrane with its catalytic region in the extracellular space. It has a limited distribution in the tissue and is found in low concentrations mainly in the gastro-intestinal tract. Synthesis of CA-IX is controlled by HIF-1 α, and this enzyme significantly synthesized by tumour cells, under hypoxic conditions and in the laboratory and in the body. Increased synthesis of CA-IX was detected in carcinomas of the cervix, ovary, kidney, esophagus, lung, breast and brain. Low extracellular pH as a result of the activity of CA-IX, leads to carcinogenic t is informatsii, chromosomal rearrangement, extracellular tissue destruction, migration and invasion, induction of growth factors, activation of proteases, and chemoresistance. Accordingly, there may be a correlation between the content of CA-IX in cells and tumor development. Radiopharmaceuticals aimed at CA-IX protein, thus provide a new tool for non-surgical cancer treatment.

Selective effect on cancer cells by radiopharmaceuticals for imaging or therapeutic purposes is promising. A number of radionuclides known to be suitable for isotopic imaging, including Ga-67, Tc-99m, In-111, I-123 and 1-131. The preferred radioisotope for medical imaging is Tc-99m, because it has a short half-life (6 hours), easily available at a relatively low cost and emits gamma-rays of 140 Kev. In addition, the complexes of Tc-99m, such as resistant to water and air complex of Cu(I), [99mTC(HE2)3(CO)3]+the complex can be easily obtained in physiological solution at 1 ATM of carbon monoxide (CO). Accordingly, bifunctional molecules that activate specific receptor, acting on the biologically active molecule covalently associated with the coordination complex99mTC or186/188Re provide a new system for selecti the Noah visualization and exposure of the malignant cells.

Disclosure of inventions

In one aspect of the proposed compound of formula I

where: W is a bond, (C1-C8)alkyl, (C2-C8)alkenyl, aryl, heteroaryl, -NHC(O), -C(O)NH, -NH-C(O)-NH - or-NH-C(S)-NH-; V is a bond, (C1-C8)alkyl, (C2-C8)alkenyl, aryl, heteroaryl, -NH-C(O)-NH - or-NH-C(S)-NH-; NRaRbis a chelating group of the formula:

where Rtis H, C1-C8alkyl group, an ammonium ion or an ion of an alkaline or alkaline earth metal; Rvis alkyl; Rxand Ryeach independently selected from the group consisting of hydrogen, C1-C8of alkyl, aminoalkyl, hydroxyalkyl or carboxyethyl; m is an integer of 0-15; and n is an integer of 0-15; provided that W and V are both cannot be NH-C(O)-NH - or-NH-C(S)-NH-. In some implementations, Rvis stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl or tert-bootrom. In some implementations, Rvis stands. In some implementations, Rxis stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl or tert-bootrom. In some implementations, Ryis stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl or tert-bootrom. In some the implementation of each R tindependently is H or tert-bootrom. In some implementations, Rtis N. In some implementations, m is 0 or 1, and n is an integer of 0-8. In some implementations W is-NH-C(S)-NH-.

In some implementations NRaRbis a chelating group of the formula:

In some implementations NRaRbis a chelating group of the formula:

In some implementations NRaRbis a chelating group of the formula:

However, when NRaRbis bis(methylene)bis(1H-imidazole-2,1-diyl))luxusni acid (the above formula I does not include the following compounds 2,2'-(2,2'-(8-(3-(4-sulfamoylbenzoyl)touraid)activization) bis(methylene)bis(1H-imidazole-2,1-diyl))diuksusnoi acid; 2,2'-(2,2(4-sulfamoylbenzoyl) bis(1H-imidazole-2,1-diyl))diuksusnoi acid; or 2,2'-(2,2'-(5-(4-sulfamoylbenzoic)pentlandii) bis(methylene)bis(1H-imidazole-2,1-diyl))diuksusnoi acid.

In some implementations NRaRbis a chelating group of the formula:

In some implementations, the structure of the compounds of formula I is as follows:

In another aspect of the proposed compound of formula II:

where L-NRaRbis a chelate group defined for the compounds of formula I, or a group of the formula:

W and X are independently O or S; p is an integer from 0-5; q is an integer 0-8; Rtis H, C1-C8alkyl group, an ammonium ion or an ion of an alkaline or alkaline earth metal; and Rvis alkyl. In some implementations, Rvis stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl or tert-bootrom. In some implementations, Rvis stands. In some implementations, each Rtindependently is H or tert-bootrom. In some implementations, Rtis N.

In some implementations in compounds of formula II L group of the formula:

where iodine is 1-123 or 1-133. In other implementations L is a group of the formula:

In some such implementations iodine I-123 or I-133

In some implementations NRaRbis a chelating group of the formula:

In some implementations NRaRbis a chelating group of the formula:

In some implementations NRaRbis a chelating group of the formula:

In another aspect of the proposed compound of formula III:

where, J is aryl; Z is O or S; Lais NRaRbchelate group corresponding to the group of the formula I, or a group of the formula:

d is an integer from 0-5; e is an integer 0-8; Rtis H, C1-C8alkyl group, an ammonium ion or an ion of an alkaline or alkaline earth metal; and Rvis alkyl. In some implementations J is a phenyl, naphthyl or anthracene. In some implementations J is monosubstituted or duhsasana phenyl group. In some such implementations, the phenyl is monosubstituted I, (C1-C8) alkyl, (C2-C8) alkenyl, -CN, -NO2, -Oh, -SH, -SO2NH2or-NRcRd; where Rcand Rdindependently are H, (C1-C4) alkyl, or aryl; and the second Deputy is (C1-C8) alkyl, (C2-C8) alkenyl, -OH, -SH, or halogen. In some implementations, Rvis stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl or tert-bootrom. In some implementations, Rvis stands. In some implementations, each Rtindependently is H or tert-bootrom. In some implementation the s R tis N.

In some implementations in compounds of formula III Lais

In some implementations NRaRbis a chelating group of the formula:

In some implementations NRaRbis a chelating group of the formula:

In some implementations NRaRbis a chelating group of the formula:

In some implementations proposed complex comprising the compound of formula III, Lais NRaRbchelate group, and the connection is associated in a complex with the metal.

In another aspect of the proposed compounds of the formula IV:

where NRaRbis a chelate group corresponding to the group of formula I; Y is O or S; a is a (C1-C8) alkyl, -(CH2)x-(Och2CH2)y- or -(co2CH2)y(CH2)x-; x is an integer of 0-3; y is an integer of 0-3; y is an integer 0 to 5; s is an integer 0-10; Rtis H, C1-C8alkyl group, an ammonium ion or an ion of an alkaline or alkaline earth metal; and Rvis alkyl. In some implementations g is 0, 1 or 2. In some implementation is the thoughts of s is 0, 5, or 10. In some implementations, Rvis stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl or tert-bootrom. In some implementations, Rtis stands. In some implementations, each Rvindependently is H or tert-bootrom. In some implementations, Rtis N. In some implementations NRaRbis a chelating group of the formula:

In some implementations NRaRbis a chelating group of the formula:

In some implementations NRaRbis a chelating group of the formula:

In another aspect, a set of compounds of formula I, II, III or IV, containing NRaRbchelate group, and metal. In some implementations, the metal is Re, Te, Y, Lu, Ga, or In. In some implementations, the metal is a radionuclide. In some implementations, the metal is technetium-99m or rhenium-186m and/or rhenium-188m.

In another aspect, the complex comprises a compound of formula I, II, III or IV, where the connection includes NRaRbchelating group of the formula:

and a metal selected from the group consisting of Y, Ga, Lu and In. In another aspect, the complex includes a metal and a compound of formula I, II, III or IV, where the connection includes NR aRbchelating group of the formula:

In another aspect, the complex includes a metal and a compound of formula I, II, III or IV, where the connection includes NRaRbchelating group of the formula:

In another aspect of the proposed complex, namely:

its pharmaceutically acceptable salt and solvate; where M is TC or Re.

In another aspect of the proposed pharmaceutical composition, including any of the compounds of formulas I, II, III, IV, their pharmaceutically acceptable salt, or a solvate, pharmaceutically acceptable excipient, and the connection comprises a radionuclide. In some implementations radionuclide is iodine. In other implementations radionuclide is metal. In some implementations metal is Re, TC, Y, Lu, Ga, or In.

In another aspect, a method of imaging a region of a patient's body, comprising the stage of: introduction to the patient a quantity sufficient for the diagnosis of any of the compounds of formulas I, II, III, IV, and pharmaceutically acceptable salts, or their MES and the imaging region of the patient's body, in which the connection comprises a radionuclide. In some implementations, the radionuclide is iodine. In other implementations, the radionuclide is metal. In some Khujand is staliniach metal is Re, Those, Y, Lu, Ga, or In.

Brief description of drawings

Fig.1 is a graph of bearsdley in the tissues of HeLa xenograft mice99mTC analogue of the compound of example 8, expressed in % ID/g ± (SEM-standard error of the mean).

Fig.2 is a graph comparing the biodistribution in tissues of HeLa xenograft mouse99mTC analogues of examples 1, 3, 7, and 8, expressed in % ID/g ± (SEM).

Fig.3 is a graph of the distribution in the tissues of the complex99mTC compounds of example 7 in HeLa xenograft mice, expressed as % ID/g ± (SEM).

Fig.4 is a graph of the distribution in the tissues of the complex99mTC compound of example 3 in HeLa xenograft mice, expressed as % ID/g ± (SEM).

Fig.5 is a graph of the distribution in tissues connections99mTC of example 1 in HeLa xenografts, SKRC SKRC 52 and 59 of mice and compounds of examples 7 and 10 in HeLa xenograft mice, expressed as % ID/g ± (SEM).

The implementation of the invention

There are two categories of radiopharmaceuticals: (i) biological distribution is determined mainly by the blood flow or perfusion and affecting systems with high capacity, such as glomerular filtration in the kidneys, phagocytosis, clearance of the liver and absorption of bone tissue and (ii) with the distribution defined by the specific binding interaction of enzymes or receptors that t is Auda areas with low capacity. These radiopharmaceuticals belong to the second category and are synthesized by conjugation of the coordination complex of a radionuclide with a biologically active molecule, selective to a specific protein or receptor of interest.

While many biologically active molecules (Bamy) can be used as * possess advantages over antibodies or proteins. For example, small molecules and small peptides have a high diffusion, faster blood clearance, and lower background radiation. These holders allow you to easily synthesize analogues with high performance. In addition, small peptides can easily be turned into a mimetic peptides or analogues of small molecules, with increased stability and improved affinity for the target enzyme or receptor.

Accordingly, in one aspect of the proposed synthesis of compounds of formula I, II, III or IV. In some implementations, the connection comprises a radioactive element that can be used to apply compound in radioisotope imaging. In some implementations, the radioactive element is one of the unstable isotopes of Re, Cu, In, Ga, Y, Lu or I. Radioactive compound can also be used as radiopharmaceuticals for the treatment of visualisatie cancer cells. In particular, the connection can be used to influence carcinoma of the cervix, brain, kidney, ovary, breast, lung and esophagus.

Definition

For convenience, certain terms used in the description and in the appended claims are collected here.

In accordance with the use application, the term "about" is understood to the ordinary skilled in the field of engineering and varies to some extent depending on the context in which it is used. If the use of the term in this context is not clear to the ordinary specialists in this field of technology, "about" will mean up to plus or minus 10% of a certain term.

The implementation described in the illustrative application, respectively can be carried out in the absence of any element or elements, limitation or limitations, not specifically disclosed in the application. Thus, for example, the terms "comprising", "includes", etc. should be considered broad and without restrictions. In addition, the terms and expressions used in the application are used as terms of description and not of limitation, and are not intended for use of such terms and expressions, of excluding equivalents are presented and described signs or parts of them, but give the possibility of various modifications within the scope of the claim is the second of the claimed technology. In addition, the wording "consisting essentially of", it should be understood as including these elements, is definitely specified, and those additional elements that are not materially affect the basic and new features of the claimed technology. The phrase "consisting of" excludes any not specified element.

The use of indefinite and definite article and the like in the context of describing the elements (especially in the context of the subsequent patent claims) should be considered as including the singular and the plural, unless stated otherwise in the description or clearly contrary to the context.

The terms "lipophilic group" and "lipophilic part in accordance with the use in the description belong to the group, part or Deputy, with greater affinity to non-polar or non-aqueous environment compared to non-polar or aqueous medium. For example, online dictionary Merriam Webster's defines "lipophilic" as "having an affinity for lipids (fats)" Examples of lipophilic parts include aliphatic hydrocarbon radicals, for example, alkyl radicals, aromatic hydrocarbon radicals and acyl radicals of long-chain; they all have increased lipophilicity with the increasing number of contained carbon atoms. Usually, adding a lipophilic part to a specific connection increases the t of the affinity of compounds to the octanol in the standard method of determining the distribution coefficient octanol/water; this technique can be used to determine the relative hydrophobicity of the compounds (lipophilic) and hydrophilic properties.

The term "Lewis base" refers to a chemical substance that is able to return e-pairs under certain reaction conditions. The Lewis base can be characterized as a donor of a single electron in certain complexes, depending on the nature of the Foundation Lewis and the metal ion, but for most purposes, however, under the Lewis base basically refers to the donor of the two electrons. Examples of compounds of Lewis bases include uncharged compounds such as alcohols, thiols and amines and charged molecules, such as alkoxides, thiolate, carbanions and other organic anions. In certain examples, the Lewis base may consist of a single atom, such as an oxide (O2-). In certain, less normal circumstances, the Lewis base or ligand may be positively charged. The Lewis base, when coordinates the metal ion, usually referred to as the ligand.

The term "ligand" refers to a particle that interacts in some way with another particle. In one example, the ligand may be a Lewis base, which are capable of forming coordination with the Lewis acid. In other examples, the ligand are the two who is the particle often organic, which forms a coordination bond with a metal ion. The ligands in coordination with a metal ion can have multiple types of communication, known to experts in the art, which include, for example, end (i.e. the link with a single metal ion) and bridge (that is, one atom of base Lewis associated with more than one metal ion).

The term "chelating agent" refers to a molecule, often organic, and often the Lewis base having two or more unshared electron pairs that can be accepted by the metal ion. Metal ion usually coordinated by two or more electron pairs chelating agent. The term "bidentate chelating agent", "tridentate chelating agent" and "tetradentate chelating agent known in modern technology and belong to the chelating agents having, respectively, two, three, and four-electron pair available for simultaneous acceptance of a metal ion coordinated chelating agent. Typically, electron pair chelating agent forms a coordination with a single metal ion; however, in certain examples, the chelating agent can form a coordination relationship with more than one metal ion with a number of possible link types.

T is pmin "coordination" refers to the interaction, when multielectronic donor pairs coordination associated ("coordinated") with one metal ion.

The term "complex" refers to a compound formed by combining one or more rich in electrons and depleted by the electrons of the molecules or atoms that can exist separately with one or more molecules or atoms, depleted in electrons, each of which can exist separately.

The expression "therapeutically effective amount" in accordance with the use in the description indicates the number of connections, material, or composition containing the compound, which is effective for obtaining the desired therapeutic effect, at least in a subpopulation of cells of the animal with reasonable regard to the effect/risk applicable to any medical treatment.

In accordance with the use in the description, the terms "treating" or "treatment" are intended to include also the diagnosis, prevention, therapy and treatment. Patients receiving this therapy is optionally any animals, including primates, in particular humans and other mammals, such as horses, cattle, swine and sheep; and poultry and Pets in General.

The expression "pharmaceutically acceptable" is used in the description to refer to compounds, materials, compositions and/or forms doses of the programme, which are, under careful medical assessment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable regard to the effect/risk.

The expression "pharmaceutically acceptable carrier" in accordance with the use in the description means a pharmaceutically acceptable material, composition or filler, such as a liquid or solid filler, diluent, excipient or material to encapsulate the solvent involved in the transfer or delivery of the active compound from one organ, or body part to another body or body part. Each carrier must be "acceptable" in the sense of compatibility with other formulation ingredients and safe for the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives such as sodium carboxymethylcellulose, einzellage and cellulose acetate; (4) powder tragakant; (5) malt; (6) gelatin; (7) talc; (8) forming, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil is, - safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as etiloleat and tillaart; (13) agar; (14) buferiruemoi additives, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic solution; (18) ringer's solution; (19) ethanol; (20) pH buferiruemoi solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical compositions.

The phrase "parenteral administration" and "introduced parenterally in accordance with the use in the description indicate the routes of administration other than enteral and local administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardially, intradermal, intraperitoneal, transtracheal, subcutaneous, podkategorie, intra-articular, podkapsulnaya, subarachnoid, intraspinal and epigastric injection and infusion.

The wording "somatic introduction, input associated diseases", "peripheral introduction" and "enter perifericheskie" in accordance with the use in the description of the research Institute means introducing the compound, drug or other material that is different from the direct administration of the Central nervous system, so that it enters the system of the patient and, thus, is subject to metabolism and other processes, for example, subcutaneous administration.

The term "amino acid" refers to all compounds of natural or synthetic, which include functional amino group and the functional group of the acid including analogs of amino acids and derivatives.

The term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Examples of heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

Basically, the term "substituted" refers to alkyl or alkenylphenol group, as defined herein (e.g., alkyl group), in which one or more links to a hydrogen atom contained therein are replaced by communication with non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more links with the atom(AMI) carbon or hydrogen, substituted one or more links, including double or triple bond with heteroatoms. Thus, the substituted group is substituted by one or more substituents, unless otherwise indicated. In some implementations substituted group is substituted by 1, 2, 3, 4, 5, or 6 substituents. Examples of groups of the substituents include the: halogen (i.e. F, Cl, Br and I); hydroxyl; alkoxy, alkenone, alkyloxy, aryloxy, aralkylated, heterocyclics, geterotsiklicheskikh group; CARBONYLS (oxo; carboxy; esters; urethanes; oximes; hydroxylamine; alkoxyamine; arelaxing; thiols; sulfides; sulfoxidov; sulfones; sulfonyl; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; urea; amidine; guanidine; enamines; imides; isocyanates; isothiocyanates; cyanate; thiocyanates; imine; nitro group; the NITRILES (i.e. CN); and so on

Alkyl groups include alkyl groups are straight-chain and branched - chain 1-12 carbon atoms, and typically 1-10 carbons or, in some realizations, 1-8, 1-6 or 1-4 carbon atoms. Examples of the alkyl group with a straight chain include groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl group. Examples of branched alkyl groups include, but are not limited to, ISO-propyl, isobutylene, second-butilkoi, tert-butilkoi, neopentylene, isopentane and 2,2-methylpropyloxy group. Alkyl groups can be substituted or unsubstituted. If the number of carbon atoms is not specified, "lower alkyl" refers to alkyl group, as defined above, but having about 1-10 carbon atoms, alternatively about 1 to 6 carbon atoms in the structure of its main chain. Similarly in "nizhegolenko", and "lower quinil" similar chain length.

The term "hydroxyalkyl" refers to an alkyl group with the specified number of carbon atoms in which one or more hydrogen atoms of the alkyl groups substituted-HE group. Examples of hydroxyalkyl groups include, but are not limited to, -CH2HE, -CH2CH2HE, -CH2CH2CH2HE, -CH2CH2CH2CH2HE, -CH2CH2CH2CH2CH2HE, -CH2CH2CH2CH2CH2CH2HE and extensive options.

The term "aminoalkyl" refers to an alkyl group with the specified number of carbon atoms in which one or more hydrogen atoms of the alkyl group substituted by-NR1R2the group, in which R1and R2each independently is hydrogen, unsubstituted (C1-C8) alkyl, the unsubstituted aryl and aryl substituted by one to three substituents selected from halogen, unsubstituted alkoxy, thiol, and CN. When R1and R2attached to the same nitrogen atom they may be linked to the nitrogen atom for forming a 5-, 6 - or 7-membered cycle. Non-limiting examples aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, -CH2CH2 CH2CH2CH2NH2CH2CH2CH2CH2CH2CH2NH2and their extensive options.

The term "alkylaryl" means -(C1-C8)alkyl-C(O) group, in which one or more metileno in the alkyl group, a C1-C8substituted With(O) group. Representative examples include, but are not limited to, acetyl, propionyloxy and CH3(CH2)2C(O)- group.

The terms "cyclic alkyl" or "cycloalkyl" refer to saturated or partially saturated non-aromatic cyclic alkyl groups with 3 to 14 carbon atoms and heteroatoms outside the ring with a single ring or polycyclic, including condensed and bridged cyclic system. Cycloalkyl or cyclic alkyl groups can be substituted or unsubstituted. Cycloalkyl or cyclic alkyl groups include mono - bi - or tricyclic alkyl groups with 3 to 14 carbon atoms in the ring(Zach) or, in some implementations, 3-12, 3-10, 3-8, or 3-4, 5, 6 or 7 carbon atoms. Examples of monocyclic cycloalkyl groups include, but are not limited cyclopropenes, cyclobutenes, cyclopentyloxy, tsiklogeksilnogo, cycloheptene and cyclooctene group. Bi - and tricyclic systems include bridge and Cycloalkyl group and condensed cycle is, such as, but not limited to bicyclo[2.1.1]hexane, adamantium, dequalinium etc.

Alkeneamine groups include straight and branched chain and Cycloalkyl group, as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkeline groups have about 2-12 carbon atoms in some implementations, 2-10 carbon atoms, in other implementations and 2-8 carbon atoms in other implementations. Examples include, but are not limited to vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2- (CH3)=CH2- (CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl and hexadienyl among others. Alkeneamine groups can be substituted or unsubstituted. Examples of substituted alkenyl groups can be monosubstituted or substituted more than once, such as, but not limited to, mono -, di - or tri-substituted by substituents such as are indicated above.

Alkyline groups include straight and branched chain and Cycloalkyl group, as defined above, except that at least one triple bond exists between two carbon atoms. Examples (C1-C8)alkenylphenol groups include, but are not limited to the, acetylene, propyne, 1-butane, 2-Butina, 1-pentenol, 2-penita, 1-hexyne, 2 - hexyne, 3-hexyne, 1-heptanol, 2 - heptanol, 3 - heptanol, 1-actinon, 2-actinon, 3-actinon and 4-actinon. Actinella group can be unsubstituted or optionally substituted by one or more substituents as described in the application next.

Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Aryl groups include monocyclic, bicyclic and polycyclic systems. Thus, the aryl groups include, but are not limited to, phenyl, ashleyrenee, heptylaniline, biphenylamine, inductile, fluoroanilino, phenanthroline, triphenylantimony, perenlei, naphthazarine, presenilins, biphenylenes, entrecanales, indenolol, indanernas, pentadienyl and naftilos group. In some implementations aryl group containing 6-14 carbon and other 6-12 or even 6-10 carbon atoms in the cyclic parts of the group. The aryl group includes substituted and unsubstituted aryl groups. Substituted aryl groups can be monosubstituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to 2-, 3-, 4-, 5- or 6-substituted phenyl or naftilos group which may be substituted by substituents, such as the above.

Kalkilya groups are alkyl groups as defined above, in which the connection of the hydrogen or carbon alkyl group substituted connection with the aryl group defined above. In some implementations kalkilya group containing 7-20 carbon atoms, a 7-14 carbon atoms or 7-10 carbon atoms.

Heterocyclic groups include non-aromatic cyclic compounds containing 3 or more members of the cycle, from which one or more is a heteroatom such as, but not limited to, N, O and S. In some implementations, heterocyclic groups include 3-20 members of the cycle, whereas other such groups have 3-6, 3-10, 3-12, or 3-15 members of the cycle. Heterocyclic groups include unsaturated, partially saturated and saturated cyclic systems, such as, for example, imidazolidine, imidazolidinone and imidazolidinyl group. Heterocyclic groups can be substituted or unsubstituted. Heterocyclic groups include, but are not limited to, aziridinyl, azetidinone, pyrrolidinyloxy, imidazolidinyl, pyrazolidinone, thiazolidinones, tetrahydrothiophene, tetrahydrofuranyl, dioxolanes, fernilee, tofanelli, pyrrolidino, pyrrolidine, imidazolidine, imidazolinones, pyrazolidine, pyrazolidine, thiazolidine, tetrazolyl, oxazolyl is, isoxazolidine, thiazolidine, thiazolidines, isothiazolines, thiadiazolidine, oxadiazolidine, piperidine, piperazinilnom, morpholino, thiomorpholine, tetrahydropyranyloxy, tetrahydropyranyloxy, occationally, dioxines, dianilino, perenlei, peredelnoj, pyrimidines, pyridazinyl, personalni, triazinyl, dihydropyridines, dihydrolinalool, dihydrolinalool, homopiperazine, genocidally, indolines, indolenines, isoindolines, isoindolines (pyrrolopyridine), indazolinone, indolizinyl, benzothiazoline, benzimidazolyl, benzofuranyl, benzothiophene, benzthiazoles, benzoxadiazole, benzoxazinones, benzodithiophene, benzoxadiazole, benzothiazinones, benzoxazolyl, benzothiazolyl, benzothiadiazoles, benzo[1,3]dioxolane, pyrazolopyrimidines, imidazopyridines (asianshemales), triazolopyridines, isoxazolidine, perenlei, xanminelay, adreniline, guanidines, hyalinella, ethanolamines, chinoiseries, khinoksalinona, chineselovelinks, indolenines, phthalazinone, naphthyridinone, pteridinyl, tianeptine, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydroindole, dihydroergotoxine, tetrahydrobenzo the ilen, tetrahydroindazole, tetrahydroaminoacridine, tetrahydroisoquinolines, tetrahydropyrimidines, tetrahydroprotoberberine, tetrahydroaminoacridine, tetrahydroaminoacridine and tetrahydropyranyloxy groups. Heterocyclic groups can be substituted or unsubstituted. Examples of substituted heterocyclic groups can be monosubstituted or substituted more than once, such as, but not limited to peredelnoj or morpholino groups, which are 2-, 3-, 4-, 5- or 6-substituted, or twice substituted by various substituents, such as described above.

Heteroaryl groups are cyclic aromatic compounds containing 5 or more members of the cycle, of which one or more is a heteroatom such as, but not limited to N, O, and S. Heteroaryl groups can be substituted or unsubstituted. Heteroaryl groups include, but are not limited to groups such as pyrrolidine, pyrazolidine, thiazolidine, tetrataenia, oxazolidine, isoxazolidine, thiazolidine, perederina, pyridinoline, piramidalnaya, piratininga, teofilina, benzothiazoline, furazilina, benzofuranyl, indayla, asiandaily (pyrrolopyridine), indazolinone, benzimidazolyl, imidazopyridine (azobenzene solila), pyrazolopyrimidine, triazolopyridine, benzothiazoline, benzoxazolinone, benzothiazoline, benzothiadiazole, imidazopyridine, isoxazolidine, tunately, polylina, Centinela, adreniline, huarinilla, hyalinella, sochineniia, tetrahydropyrimidine, khinoksalinona and chinadaily group.

Alkoxy groups are hydroxyl groups (-OH), in which communication with the hydrogen atom substituted on the link with the carbon atom substituted or unsubstituted alkyl group as defined above. Examples of linear alkoxy groups include, but are not limited to methoxy, ethoxy, propoxy, butoxy, pentox, hexose, etc., Examples of branched alkoxy groups include, but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isobutoxy, isohexane, etc. are Examples of cycloalkane groups include, but are not limited to cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy, etc., Alkoxy groups can be substituted or unsubstituted. Examples of substituted alkoxy groups may be substituted by one or more substituents, such as described above.

The terms "politikil" or "polycyclic group" refer to two or more cycles (e.g., cycloalkyl, cycloalkenyl, cycloalkenyl, Ariely and/or heterocyclyl), in which two or more and the Ohm carbon are common to two adjacent cycles, for example, "condensed cycles". Cycles associated through non-adjacent atoms, are called "bridge" cycles. Each cycle of polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, quinil, cycloalkyl, hydroxyl, amino, monoalkylamines, dialkylamino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, simple ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic group, -CF3, -CN, or the like.

The term "carbocycle" refers to aromatic or nonaromatic cycle, in which each atom of the cycle is carbon.

The term "nitro" refers to-NO2;

the term "halogen" is accepted in the art and refers to-F, -CL, -Br or-I;

the term "sulfhydryl" is accepted in the art and refers to-SH;

the term "hydroxyl" means-HE and the term "sulfonyl" is accepted in the art and refers to-SO2-.

"Halide" defines the corresponding anion of halogen and the definition of "pseudohalide" formulated by S. 560 "Modern Inorganic Chemistry" cotton and Wilkinson Advanced Inorganic Chemistry, Cotton and Wilkinson).

The term "amine or amino" refers to-NRcRdthe group, in which Rcand Rdeach the first is independently hydrogen, (C1-C8) alkyl, aryl, heteroaryl and heteroseksualci. When R0and R1linked to the same nitrogen atom, they may be connected with the nitrogen atom to form a 5-, 6 - or 7-membered cycle. For example, -NRcRdmay include cycle 1-pyrrolidinyl, pyridinyl or 4-morpholyl.

The term "amido" is accepted in the art as amino substituted carbonyl and includes a part, which may be represented by the General formula-C(O)NRcRdgroup in which Rcand Rddefined above. According to some implementations, amide does not include imides which may be unstable.

The terms "carboxyl" and "carboxylate" include such groups that can be represented by the General formula:

or

where E is a bond or is O or S, and Rfand Rf'independently are H, alkyl, alkenyl, aryl, or a pharmaceutically acceptable salt. When E is Oh, and Rfas defined above, the group is in the description of the carboxyl group, and, in particular, when R is hydrogen, the formula represents a "carboxylic acid". Usually, when clearly marked oxygen is replaced by sulfur, the formula represents a "thiocarbonyl" group.

The terms "alkoxyl" or "alkoxy" refers to alkyl GRU is PHE, defined above, with an associated oxygen radical. Examples of CNS groups include methoxy, ethoxy, propoxy, butoxy, tert-butoxy etc.

"Plain air" consists of two hydrocarbon covalently linked by oxygen. "Simple ether" also includes polyesters, where more than one ether group or Association may be present in this group. "Simple ether" also includes cyclic ethers and crown ethers, where the ester linkage is a cyclic group.

The term "sulfonate" refers to a group that may be represented by the General formula-S(O)2ORgin which Rgis the electron pair, hydrogen, alkyl, cycloalkyl or aryl. The term "sulfate" includes a group which can be represented by the General formula-OS(O)2ORgin which Rgdefined above. The term "sulfonamide" includes a group which can be represented by the General formula: -N(Rf)S(O)2ORf'in which Rfand Rf'defined above. The term "sulphonamide" refers to a group that may be represented by the General formula-S(O)2NReRfin which Reand Rfare hydrogen, (C1-C8) alkyl or aryl. The term "sulfonyl" refers to a group that may be represented by the General formula: -S(O)2Rhin which RhI have is one of the following: hydrogen, alkyl, alkenyl, quinil, cycloalkyl, heterocyclyl, aryl or heteroaryl.

The definition of each of the formulations, such as alkyl, m, n, etc. when they occur more than once in any structure, are considered to be independent of its definition elsewhere in the same structure.

Terms trifles, tosyl, mesyl and neatly refer to trifloromethyl, p-lololololololol, methanesulfonyl and nonafterburning group, respectively. The terms triplet, toilet, mesilate and nonflat are accepted in this field of technology and belong to the functional groups of ether triftoratsetata, ether p-toluensulfonate, ether metasulfite and ether nonattributable and, accordingly, molecules that contain group. The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifloromethyl, nonattributable, p-toluensulfonyl and methanesulfonyl, respectively. A more detailed list of abbreviations and acronyms used by chemists organically specialists in the field of technology, published in the first issue of each volume of the Journal of Organic Chemistry Journal of Organic Chemistry): this list is typically presented in a table, called the standard list of abbreviations.

Some compounds contained in the compositions may exist in particular geometric or stereoisomeric form is. In addition, the connection can also be optically active. The connection can also include CIS - and TRANS-isomers, R - and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures and other mixtures. Additional asymmetric carbon atoms may be present in the Deputy, such as an alkyl group. If, for example, a particular enantiomer of the compound, it can be obtained by asymmetric synthesis or derived from chiral auxiliary elements, where the resulting diastereomeric mixture is separated and the auxiliary group otscheplaut to obtain the pure desired enantiomers. Alternatively, when the molecule contains a basic functional group such as amino, or an acidic functional group, such as carboxyl, diastereomeric salt formed with an appropriate optically active acid or base, followed by separation of the diastereomers thus obtained, by fractional crystallization or chromatographic means well known to the prior art, and the subsequent isolation of pure enantiomers.

The expression "protective group" in accordance with the use in the description means temporary deputies, which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protection is the shaft groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of chemistry of the protective groups represented in the survey (Greene, T. C. P. Cotton, J. M. (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis (Protective Groups in OrganicSynthesis), 3rd edition; Wiley: new York, 1999).

Unless otherwise specified, "stereoisomer" means one stereoisomer of a compound that is essentially free of other stereoisomers of the compound. Thus, stereometrical a pure compound with one chiral center, will be substantially free of the opposite enantiomer of the compound. Stereometrical a pure compound with two chiral centers, will be essentially free of other diastereomers of the compounds. Normal stereometrical net connection comprises more than about 80% of the mass. one stereoisomer of the compound and less than about 20% of the mass. other stereoisomers of the compound, for example, more than about 90% of the mass. one stereoisomer of the compound and less than about 10% of the mass. other stereoisomers of the compound, or more than about 95% of the mass. one stereoisomer of the compound and less than about 5% of the mass. other stereoisomers of the compound or more than about 97% of the mass. one stereoisomer of the compound and less than about 3% of the mass. other stereoisomers of the compound.

If there is a mismatch between the image patterns and the name given to this structure, the image is depicting the structure is a priority. Additionally, if the stereochemistry of a structure or part of structure is not specified, for example, bold or dashed lines, the structure or part of a structure should be interpreted as including all stereoisomers.

Chelate compounds and their synthesis

In one aspect of the proposed compound of formula I, its pharmaceutically acceptable salt and solvate:

According to some implementations of the formula I, W is a bond, (C1-C8) alkyl, (C2-C8) alkenyl, aryl, heteroaryl, -NHC(O), urea (-NH-C(O)-NH-) or thiourea (-NH-C(S)-NH-); V is a bond, (C1-C8) alkyl, (C2-C8) alkenyl, aryl, heteroaryl, -NHC(O), urea (-NH-C(O)-NH-) or timesaving (-NH-C(S)-NH-); m is an integer of 0-15, and n is an integer of 0-15. In some realizations, W and V both are not urea or timesaving.

Group NRaRbformula I is one of the following chelating groups, where Rtis H, alkyl group of C1-R8, ammonium ion or an ion of an alkaline or alkaline earth metal; and Rvis alkyl:

or

According to some realizations, Rvis stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl or tert-bootrom. In other implementations At the two who is the stands. In some implementations, each Rvindependently is H or tert-bootrom. In other implementations, Rtis N.

According to some implementations, the group NRaRbthe compounds of formula I consists of:

or

In implementations where NRaRbis bis(methylene)bis(1H-imidazole-2,1-diyl))luxusni acid, compound of formula I is not 2,2'-(2,2'-(8-(3-(4-sulfamoylbenzoyl)touraid)activization) bis(methylene)bis(1H-imidazole-2,1-diyl))luxusni acid; 2,2'-(2,2(4-sulfamoylbenzoyl) bis(1H-imidazole-2,1-diyl))luxusni acid; or 2,2'-(2,2'-(5-(4-sulfamoylbenzoic)pentlandii) bis(methylene)bis(1H-imidazole-2,1-diyl))luxusni acid.

According to various implementations, the group NRaRbconnections can optionally form a chelate with the metal. In some implementations, the metal is a radionuclide. For example, the metal may be a technetium-99m or rhenium-186m/188m. Complexes such as [NEt4]2[MBr3(CO)3]; M is TC or Re, can interact with the compounds of formula I in an alcohol solvent to obtain compounds of formula 1-M, as described below.

Examples of compounds of formula IM, include, but are not limited to any one of the trace of the operating connections:

assuming that the complex of formula I-M" is not:

[Re(CO)3[2,2'-(8-(3-(4-sulfamoylbenzoyl)touraid)activization)bis(methylene)bis(1H-imidazole-2,1-diyl))luxusni acid

[Re(CO)3][2-(2-((((1H-imidazol-2-yl)methyl)(4-sulfamoylbenzoyl)-amino)methyl)-1H-imidazol-1-yl)acetic acid],

[TC(CO)3][2-(2-((((1H-imidazol-2-yl)methyl)(4-sulfamoylbenzoyl)-amino)methyl)-1H-imidazol-1-yl)acetic acid]:

or

[Re(CO)3[2,2'-(8-(3-(4-sulfamoylbenzoyl)touraid)activization)bis(methylene)bis(1H-imidazole-2,1-diyl))luxusni acid.

In some implementations also proposed pharmaceutically acceptable salt, solvate, stereoisomer, tautomers, and prodrugs of such compounds. In another implementation, a pharmaceutical composition includes the compound of formula 1 and pharmaceutically acceptable excipient.

In another aspect of the proposed compound of formula II, as well as pharmaceutically acceptable salts thereof and a solvate.

In Formula II, L is a group NRaRbdefined above for formula I, or a group of the formula

where iodine can be in the op is about, meta or para position to carboxamide group; W and X are independently oxygen or sulfur; each Rtindependently is H, alkyl group of C1-C8, ammonium ion or an ion of an alkaline or alkaline earth metal; R is an integer from 0-5; and q is an integer of 0-8. In some implementations, each Rtindependently is H or tert-bootrom. In other implementations, Rtis N. In some realizations, W and X both represent oxygen. In some implementations, where L is a group of the formula

iodine is a radioactive isotope of iodine, for example, 1-123 or 1-131. In some implementations L is a group of the formula

According to some implementations, the compound of formula II in which L is a 3-jogesuido, iodine is a radioactive isotope, for example, 1-123 or I-131, and can be used in therapeutic preparations for the treatment of cancer. According to another aspect of the proposed pharmaceutical composition, which includes 3-identity similar to the compounds of formula II, and pharmaceutically acceptable excipient for cancer treatment.

According to various implementations of the connection can be optionally chelated with the metal used for the complex. In some implementation, the metal is a radionuclide. For example, the metal may be a technetium-t, or rhenium-186/188. Complexes such as [NE4]2[MBr3(CO)3]; M is TC or Re, can interact with the compounds of formula II in an alcohol solvent to obtain the chelated compounds of formula II-M, as described below.

Examples of compounds of formula II and II-M, include, but are not limited to any one of the following connections:

In some implementations proposed pharmaceutically acceptable salt, solvate, stereoisomer, tautomers and prodrugs of the compounds of formula II-M. In another implementation, a pharmaceutical composition includes the compound of formula II and pharmaceutically acceptable excipient.

In another aspect of the proposed compound of formula III, a pharmaceutically acceptable salt thereof or a solvate:

According to the formula III, Rtdefined above; d is an integer 0-5, e is an integer 0-8; J is an optionally substituted aryl group; and Lais a group NRaRbdefined above for formula I, or a group of the formula

According to some realizations J is phenyl, naphthyl, or anthracene. In one implementation J is monosubstituted or disubstituted Hairdryer is scrap. For example, the phenyl can be substituted by I, (C1-C8) alkyl, (C1-C8) alkenyl, -CN, -NO2, -OH, -SH, -SO2NH2or-NRcRdwhere R0and Rdindependently are H, (C1-C4) alkyl, or aryl. When J is disubstituted, the additional substituent R" is a (C1-C8) alkyl, (C2-C8) alkenyl, -OH, -SH, or halogen. In addition, the group additional substituent may be either ortho, meta or para relative to the group's first Deputy. In addition, one or more of the substituents can be modified by adding one or more other groups.

Illustrative examples of compounds of formula III include, but are not limited to:

According to various implementations of the compounds of formula III can then be optionally chelated to a metal, where Larepresents-NRaRbchelate group that is defined above. In some implementations, the metal is a radionuclide. For example, the metal may be a technetium-99m or rhenium-186/188.

Complexes such as [NEt4]2[MBr3(CO)3]; M is TC or Re, can interact with the compounds of the formula III in an alcohol solvent to obtain compounds of formula III-M, as described on the.

Examples of chelated compounds of formula III-M, include, but are not limited to:

In another aspect of the proposed compound of formula IV:

where NRaRbdefined above for the compounds of formula I; Y is O or S; a is a (C1-C8) alkyl, -(CH2)x(Och2CH2)y- or -(co2CH2)y(CH2)x-; x and y are independent integers 0-3; r is an integer of 0-5; and s is an integer of 0-5.

According to various implementations, the group NRaRbconnections can optionally form a chelate with the metal. In some implementations, the metal is a radionuclide. For example, the metal may be a technetium-t, or rhenium-186m/188m. Complexes such as [NEt4]2[MBr3(CO)3]; M is TC or Re, can interact with the compounds of formula IV in an alcohol solvent to obtain compounds of formula IV, as described below.

Examples of compounds of formula IV-M include, but are not limited to

Pharmaceutical compositions

Compounds of formulas I-M II-M III-M IV-M may contain one or more of radionuclides, which are suitable for use in the project as a means of radionuclide imaging and therapy for the treatment of rapidly proliferating cells. Accordingly, in one implementation of the proposed pharmaceutical composition comprising a compound of formula I-M II-M III-M IV-M, its salt, MES, stereoisomer or tautomer and a pharmaceutically acceptable carrier.

Mainly compounds of formulas I-M II-M III-M IV-M, or their pharmaceutical compositions can be used orally or parenterally, usually by injection. Parenteral route include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecally, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, podkategorie, intra-articular, podkapsulnaya, subarachnoid, intraspinal and epigastric injection and infusion. In some implementations, the compound or pharmaceutical composition are introduced orally. Such compounds can be in the form of tablets, pills, capsules, semi-liquid products, powders, solutions, suspensions, elixirs, aerosols, or any other suitable compositions.

According to another aspect of the proposed pharmaceutical composition that is suitable for visualization in the body. Such suitable pharmaceutical compositions contain the renderer, in which there is a radionuclide or as part of, from. that is, radioactive iodine, or at kachestvenaia radioactive metal, accordingly, the compounds of formulas I, II, III or IV, in a quantity sufficient to render, together with a pharmaceutically acceptable radiological vehicle. Radiological carrier should be suitable for injection or aspiration, such as albumin human serum; aqueous buffer solutions such as Tris(hydromethyl)aminomethane (and its salts), phosphate, citrate, bicarbonate, etc; sterile water; saline solution; and balanced ionic solutions containing chloride and / or salts of bicarbonate or normal cations blood plasma, such as calcium, potassium, sodium and magnesium.

The concentration of the renderer in radiological carrier should be sufficient to provide a satisfactory visualization. For example, when using an aqueous solution, the dosage is about 1.0-50 mcure. The renderer should be introduced so that was left in the patient for about 1-3 hours, although longer and shorter periods of time are acceptable. Therefore, can be manufactured in convenient capsules containing 1-10 ml of an aqueous solution.

Visualization can be performed in the usual way, for example by introducing a sufficient number of visualization tools to provide adequate visualization and subsequent scanning of a suitable apparatus, for example, a gamma camera. In about the certain implementations, the method of imaging a region of a patient's body includes stages: introduction to the patient a diagnostically effective amount of the compounds associated in complex with the radionuclide; the irradiation region of the patient's body; and the imaging region of the patient's body. In certain implementations rendered areas of the body are the head or thorax.

The present invention described thus in General, it will be easier understood with reference to the following examples, which are provided for illustration and are not intended to limit the present invention.

Examples

General methods of synthesis

The General procedure of alkylation of the imidazole-2-carboxaldehyde. To a solution of imidazol-2-carboxaldehyde dissolved in DMF (1 ml), was added 1 equivalent of allylbromide, excess potassium carbonate and a catalytic amount of potassium iodide. The reaction mixture is heated to 110°C for 18 h, followed by evaporation to dryness and purification using a Biotage SP4 method gradient of methanol 5-50% in DHM.

General methodology for the formation of homogeneous chelator by reductive amination. In the usual method of solution of the desired amine, dissolved in EDC (2 ml), add to 2.1 per equivalent of aldehyde. The reaction mixture is heated to 50°C for one hour, followed by the addition of triacetoxyborohydride sodium (36 mg, 0,19 mmol). After stirring at room temperature for 12 h, the solution is evaporated to dryness and purified using the Biotage SP4; with a gradient of methanol 5-50% in DHM Protective group of the purified compound (24 mg, 0,034 mmol) remove the processing piperidine/DMF 1:1 (1 ml) at room temperature for 2 h, followed by evaporation to dryness. The residue is dissolved in DHM and extracted with water. The aqueous layer was extravert excess DHM. Evaporation of the organic layer gives the desired compound as off-white solids.

Total synthesis of analogues of benzosulfimide with amide bond. To a solution of carboxylic acid (1 EQ) in DMF is added with tea (2 EQ) followed by addition of 2-(1-N-7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate methanamine (HATU, 1.4 EQ), and sulfonamide, respectively, substituted (1 EQ). The reaction mixture was stirred at 40°C during the night. Concentration followed by purification using a Biotage SP4 method gradient of methanol 5-50% in DHM give the desired free ligands.

General methodology for the synthesis of complexes of the compounds with the metal. Used as an example in the description of the rhenium is used as the metal, taking into account the availability of non-radioactive isotopes and safety of employees. However, it should be understood that such methods of synthesis can be repeated using technicaly analogues as technetium and rhenium come in the same reaction and have similar dimensions because of the lanthanide contraction. Therefore, when it can be definitely presents Re, it should be understood, Thu is also included Those complexes.

Unless otherwise specified, the synthesis of complexes of Re(I) carry out the reaction [NEt4]2[ReBr3(CO)3] (or [99mTC(CO)3With(H2O)3]+] with the appropriate ligand (10-6-10-4M) in the ratio of 1:1.2 in 10 ml of methanol. The closed tube is heated and leave heated at 100°C for 4 hours. After cooling analyze the purity of the reaction product RP-HPLC (high performance liquid chromatography with reversed phase), and the product was then purified using a column of silica with methanol as eluent. Radiochemical purity (RCP) after HPLC purification, leading to products without media", define HPLC that constantly gives ≥ 95%. Although the initial results of the introduction of a radioactive label is shown at concentrations below 10-6M, RCY is ≤80%. RCY is an abbreviation radiochemical yield. To achieve RCY> 95% at 75°C, the concentration in the reaction mixture had to be increased to 10-4M. In many cases, the corresponding complexes of Those and get tested on the example of the Re complexes to obtain non-radioactive analogues for testing and treatment.

Examples of synthesis of compounds of formula I

Scheme 1 illustrates a General route for the synthesis of analogues of 4-aminoethylethanolamine. Reductive amination of imine obtained vzaimodejstvie-aminoethylethanolamine with the appropriate aldehyde, with the subsequent reaction of the tridentate ligand with a radionuclide, network connections, which correspond to the formula I. Scheme 1

where (i) 2-pyridinecarboxaldehyde - (1)2-pyridinecarboxamide;

2-pyridinecarboxaldehyde or 1-methyl-1H-imidazole-2-carbaldehyde - 2-pyridinecarboxamide or 1-methyl-1 H-imidazole-2-carbaldehyde;

reflux - boiled under reflux;

pyridyl - pyridyl;

R=N-methylimidazole - K=K-Mei;

R=2-pyridyl; N-methylimidazolyl; 2-qwnolinyl; or acetyl - K=2-pyridyl; N-methylimidazole; 2-chinoline; or acetyl;

R-2-quinolinyl - R-2-chinoline;

R=acetyl - R=acetyl

Scheme 2 illustrates the General path of the synthesis of analogues of benzosulfimide thiourea. The reaction of N,N-bis(pyridine-2-ylmethyl)alkyl-1,6-diamine with 4-isothiocyanatobenzene with subsequent reaction with the radionuclide give the corresponding thiourea analogues, which also corresponds to the formula I.

Scheme 2

Example 1. [Re(CO)3][2-((pyridin-2-ylmethyl)(4-sulfamoylbenzoyl)amino)acetic acid]:

A. Synthesis of tert-butyl 2-((pyridin-2-ylmethyl)(4-sulfamoylbenzoyl)amino)acetate and tert-butyl 2,2'-(4-sulfamoylbenzoyl)diacetate:

A solution of 4-(2-amino-ethyl)benzosulfimide (1.60 g, 8.0 mmol), Asón (0,30 ml) and 2-pyridinecarboxamide (0,76 ml ,0 mmol) in EDC (50 ml) is heated to 75°C for 30 minutes in nitrogen atmosphere. The reaction mixture was cooled to 0°C. and sequentially treated with NaBH(OAc)3 (6,36 g, 30 mmol) and the crude tert-butylpyrocatechol (Yao Z., Bhaumik J., Dhanalakshmi S., Birds M., Rodriguez, P. A., Lindsay, J. With. (Yao, Z.; Bhaumik, J.; Dhanalekshmi, S.; Ptaszek, M.; Rodriguez, P. A.; Lindsey, J. S.) Tetrahedron, 2007, 63, 10657-10670) (2,08 g). The reaction mixture was stirred at room temperature overnight and treated with water. The reaction mixture was extracted with DHM. The organic layer is dried and concentrated under reduced pressure. The residue is purified flash chromatography on silica gel to obtain tert-butyl 2-((pyridin-2-ylmethyl)(4-sulfamoylbenzoyl)aminoacetate (1.04 g, 32%) and mpem-butyl 2,2'-(4-sulfamoylbenzoyl)diacetate (0,624 g, 18%).1H NMR (400 MHz, CD3OD): tert-butyl 2-((pyridin-2-ylmethyl)(4-sulfamoylbenzoyl)amino)acetate: δ to 8.45 (d, J=4,8 Hz, 0,42 H) of 8.40 (d, J=4,8 Hz, 0.58 N), 7,83 (t, J=6,4 Hz, 0,42 N), to 7.77 (d, J=8,4 Hz, 1,58 N) of 7.69 (t, J=8.0 Hz), 0.58 N), 7,56 (d, J=7,6 Hz, 0.58 N), 7,34-7,24 (m, 4H), 5,49 (s, 1H), 4,70 (s, 1H), 3,93 (s, 2H), only 2.91 (t, J=6,8 Hz, 2H), and 2.83 (t, J=6,8 Hz, 2H), 1,47 (s, 9H); MSER m/z: 406 (M+N)+.1H NMR (400 MHz, CD3CL3): tert-butyl 2,2'-(4-sulfamoylbenzoyl)diacetate: δ 7,83 (d, J= 8,4 Hz, 2H), 3.45 points (s, 4H), of 2.97 (t, J=5.6 Hz, 2H), 2,87 (t, J=6.0 Hz, 2H), for 1.49 (s, 18H); MSER m/z: 429 (M+H)+.

C. Synthesis of 2-((pyridin-2-ylmethyl)(4-sulfamoylbenzoyl)amino)acetic acid:

To a solution of tert-butyl 2-((pyridin-2-ylmethyl)(4-sulfamoylbenzoyl) the Mino)acetate (150 mg, of 0.37 mmol) in DHM (3.0 ml) and TFU (3.0 ml) was stirred at room temperature overnight. The solvent is removed under reduced pressure to obtain 2-((pyridin-2-ylmethyl)(4-sulfamoylbenzoyl)amino)acetic acid (129 mg, 100%).1H NMR (400 MHz, CD3OD) δ 8,73 (d, J=5.6 Hz, 0,46 N), 8,58 (d, J=4.4 Hz, 1H), to 8.57 (t, J=8.0 Hz, 0,46 N), 8,16 (t, J=7,6 Hz, 1H), 8,01 (d, J=8,4 Hz, 0.54 N), of 7.96 (t, J=6,8 Hz, 0.54), 7,79 (d, J=8,4 Hz, 2H), 7,66 (d, J=7.2 Hz, 2H), 7,35 (d, J=8,4 Hz, 2H), 4,51 (s, 2H), 4,06 (s, 2H), 3,36 (t, J=7,6 Hz, 2H), 3,05 (t, J=7,6 Hz, 2H); MSER m/z: 355 (M+N)+.

C. Synthesis of [Re(CO)3][2-((pyridin-2-ylmethyl)(4-sulfamoylbenzoyl)amino)acetic acid]. A solution of 2-((pyridin-2-ylmethyl)(4-sulfamoylbenzoyl)amino)acetic acid (61 mg, 0,173 mmol), [NEt4]2[ReBr3(CO)3] (192 mg, 0.25 mmol) and K2CO3(30 mg) in the Meon (6.0 ml) was stirred at 100°C 5 h in a sealed tube under pressure. The reaction mixture was purified using a resin Amberchrom™ (CG 161), elwira Meon/N2O to obtain the specified connection (18,9 mg, 18%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8,77 (d, J=5,6 Hz, 1H), 8,17 (t, J=7,8 Hz, 1H), 7,79 (d, J=8,0 Hz, 2H), 7,74 (d, J=7,6 Hz, 1H), to 7.59 (d, J=8,0 Hz, 2H), 7,58 (d, J=6,0 Hz, 1H), 7.29 (s, 2H), 4.92 in (d, J=16,0 Hz, 1H), 4,77 (d, J=16,0 Hz, 1H), 4,10 (d, J=a 16.4 Hz, 1H), 3,74-3,68 (m, 1H), 3,64-to 3.58 (m, 1H), 3,53 (d, J=16,8 Hz, 1H), 3,14-is 3.08 (m, 2H); MSER m/z 620 (M+H)+.

Example 2. [Re(CO)3][2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylbenzoyl)-amino)acetic acid]:

A. Synthesis of tert-butyl 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylbenzoyl)amino)acetate:

A solution of 4-(2-amino-ethyl)benzosulfimide (1.40 g, 7.0 mmol), Asón (0,30 ml) and 1-methyl-1H-imidazol-2-carboxaldehyde (0,77 g, 7.0 mmol) in EDC (40 ml) is heated to 80°C for 30 minutes in nitrogen atmosphere. The reaction mixture was cooled to 0°C. and sequentially treated with NaBH(OAc)3(4,45 g, 21 mmol) and tert-butylpyrocatechol (1.80 g). The reaction mixture was stirred at room temperature overnight and treated with water. The reaction mixture was extracted with DHM and the organic layer dried and concentrated under reduced pressure. The resulting residue is purified flash chromatography on silica gel to tert-butyl 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylbenzoyl)amino)acetate (0,63 g, 22%).1H NMR (400 MHz, DMSO-d6) δ the 7.65 (d, J=8,4 Hz, 2H), 7,26 (s, 2H), 7,21 (d, J=8.0 Hz, 2H), 6,99 (d, J=0.8 Hz, 1H), 6.73 x (d, J=0.8 Hz, 1H), 3,76 (s, 2 H), to 3.38 (s, 3H), of 3.28 (s, 2H), and 2.79 (t, J=7.2 Hz, 2H), 2,69 (t, J=6,8 Hz, 2H), 1,40 (s, N); MSER m/z: 409 (M+H)+.

C. Synthesis of [Re(CO)3][2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylbenzoyl)-amino)acetic acid]. A solution of tert-butyl 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylbenzoyl)amino)acetate (110 mg, 0.27 mmol) in DHM (3.0 ml) and TFU (3.0 ml) was stirred at room temperature overnight. The solvent is removed under reduced davleniya obtain 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylbenzoyl)amino)acetic acid. A solution of 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylbenzoyl)amino)acetic acid, [NEt4]2[ReBr3(CO)3] (270 mg, 0.35 mmol) and K2CO3(78 mg) in Meon (6.0 ml) was stirred at 90°C for 4 h in vitro under pressure. The reaction mixture was purified using a resin Amberchrom™ (CG 161), elwira Meon/N2O to obtain the compound (105 mg, 63%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7,79 (d, J= 8.0 Hz, 2H), EUR 7.57 (d, J= 8.0 Hz, 2H), was 7.36 (d, J= 0.8 Hz, 1H), 7,25 (s, 2H), 7,15 (d, J=1.2 Hz, 1H), amounts to 4.76 (d, J= 16.4 Hz, 1H), 4,58 (d, J=16.0 Hz, 1H), a 4.03 (d, J=16,8 Hz, 1H), 3,67 (d, J=a 16.8 Hz, 1H), 3,65-to 3.49 (m, 2H), 3,17-to 3.09 (m, 2H); MSER m/z 623 (M+H)+.

Example 3. [Re(CO)3][2,2'-(2,2'-(4-sulfamoylbenzoyl)bis(methylene)bis(1H-imidazole-2,1-diyl))dioxyna acid]:

A. Tert-butyl 2,2'-(2,2'-(4-sulfamoylbenzoyl)bis(methylene)bis(1H-imidazole-2,1-diyl))diacetate:

A solution of 4-(2-amino-ethyl)benzosulfimide (110 mg, 0.55 mmol), Asón (0.10 ml) and tert-butyl 2-(2-formyl-1H-imidazol-1-yl)acetate (250 mg, 1,19 mmol) in EDC (20 ml) was stirred at 80°C for 30 minutes in nitrogen atmosphere. The reaction mixture was cooled to 0°C and treated with NaBH(SLA)3(0,423 g, 2.0 mmol). The reaction mixture was stirred at room temperature overnight and treated with water. The reaction mixture was extracted with DHM. Organic with the Oh is dried and concentrated under reduced pressure. The residue is purified flash chromatography on silica gel to obtain tert-butyl 2,2'-(2,2'-(4-sulfamoylbenzoyl)bis(methylene)bis( 1H-imidazole-2,1-diyl))diacetate (132 mg, 41%).1H NMR (400 MHz, CD3OD) δ of 7.75 (d, J=8,4 Hz, 2H), 7,18 (d, J=8,4 Hz, 2H), 7,07 (s, 2H), 6,93 (s, 2H), 4,58 (s, 4H), 3,68 (s, 4H), 2,84-to 2.74 (m, 4H), of 1.44 (s, 18H); MSER m/z: 589,4 (M+H)+.

Century [Re(CO)3][tert-butyl 2,2'-(2,2'-(4-sulfamoylbenzoyl)bis(methylene)bis(1H-imidazole-2,1-diyl))diacetate].

A solution of tert-butyl 2,2'-(2,2'-(4-sulfamoylbenzoyl)bis(methylene)bis(1H-imidazole-2,1-diyl))diacetate (65 mg, 0.11 mmol) and [NEt4]2[ReBr3(CO)3] (with 92.4 mg, 0.12 mmol) in Meon (3.0 ml), stirred at 95°C for 4 h in vitro under pressure. The reaction mixture was purified by Amberchrom resin™ (CG 161), elwira Meon/N2O to obtain the compound (51 mg, 54%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7,81 (d, J=8,4 Hz, 2H), 7,60 (d, J=8,4 Hz, 2H), 7,31 (s, 2H), 7,26 (d, J=1.2 Hz, 2H), 7,12 (d, J=1.2 Hz, 2H), 4.95 points (s, 4H), 4,74 (d, J=16.4 Hz, 2H), to 4.62 (d, J=16.4 Hz, 2H), 3,90-3,86 (m, 2H), 3,16-3,14 (m, 2H), 1,45 (s, 18H); MSER m/z: 859,3 M+.

C. [Re(CO)3][2,2'-(2,2'-(4-sulfamoylbenzoyl)bis(methylene)bis(1H-imidazole-2,1-diyl))dioxyna acid]. A solution of [Re(CO)3][tert-butyl 2,2'-(2,2(4-sulfamoylbenzoyl) bis(methylene)bis(1H-imidazole-2,1-diyl))diacetate] (20 mg) in TFU (1.0 ml) and DHM (1.0 ml) was stirred at room temp is the temperature 4 hours The solvent is removed under reduced pressure to obtain the specified connection (21,5 mg).1H NMR (400 MHz, DMSO-d6) δ 7,81 (d, J=8.0 Hz, 2H), 7,60 (d, J=8,4 Hz, 2H), 7,30 (s, 2H), 7.23 percent (d, J=1.2 Hz, 2H), was 7.08 (d, J=1.2 Hz, 2H), 4,91 (s, 4H), 4.72 in (s, 4H), 3,89-of 3.85 (m, 2H), 3,18-3,14 (m, 2H); MSER m/z: 7471,2.

Example 4. [Re(CO)3][2,2'-(2,2'-(4-sulfamoylbenzoyl)bis(methylene)bis(1H-imidazole-2,1-diyl))dioxyna acid]:

A. Synthesis of tert-butyl 2,2'-(2,2'-(4-sulfamoylbenzoyl)bis(methylene)bis(1H-imidazole-2,1-diyl))diacetate:

A solution of the hydrochloride of 4-(2-aminomethyl)benzosulfimide (223 mg, 1.0 mmol) and tert-butyl 2-(2-formyl-1H-imidazol-1-yl)acetate (441 mg, 2.1 mmol) in EDC (20 ml) was stirred at 75°C for 30 minutes in nitrogen atmosphere. The reaction mixture was cooled to 0°C and treated with NaBH(OAc)3(0,633 g, 3.0 mmol). The reaction mixture was stirred at room temperature overnight and treated with water. The reaction mixture was concentrated under reduced pressure. The residue is purified on a flash chromatography system biotage gradient Meon 0-10% in DHM to tert-butyl 2,2'-(2,2'-(4-sulfamoylbenzoyl)bis(methylene)bis(1H-imidazole-2,1-diyl))diacetate (569 mg, 99%) as a yellow oil.1H NMR (400 MHz, CD3CL3) δ 7,83 (d, J=8,4 Hz, 2H), 7,41 (d, J=8,4 Hz, 2H), 6,97 (s, 2H), PC 6.82 (s, 2H), of 4.66 (s, 2H), 4,43 (s, 2H), 3,83 (s, 1H), of 3.73 (s, 1H), 3,61 (s, 2H), 3,48 (s, 4H), of 1.39 (s, 18H); M (IES)(M8 (ESI)), 575,3 (M+H)+.

Century [Re(CO)3][2,2'-(2,2'-(4-sulfamoylbenzoyl)bis(methylene)bis(1H-imidazole-2,1-diyl))dioxyna acid]. A solution of tert-butyl 2,2'-(2,2'-(4-sulfamoylbenzoyl)bis(methylene)bis(1H-imidazole-2,1-diyl))diacetate (40 mg, 0,070 mmol) and [NEt4]2[ReBr3(CO)3] (60 mg, 0,077 mmol) in Meon (3.0 ml) was stirred at 90°C 5 h in vitro under pressure. The solvent is evaporated under reduced pressure to obtain a residue. The solution of the above residue in TFU (3.0 ml) and DHM (3.0 ml) was stirred at room temperature for 3 hours the Solvent is removed under reduced pressure to a residue, which was purified HPLC to obtain the compound (23 mg, 45% over 2 stages) as a white solid.1H NMR (400 MHz, DMSO-d6) δ to 7.93 (d, J=8.0 Hz, 2H), 7,86 (d, J=8,4 Hz, 2H), 7,47 (s, 2H), 7,14 (d, J=1.2 Hz, 2H), 7,06 (d, J=1.2 Hz, 2H), 4.92 in (s, 2H), 4,79 (d, J=16.0 Hz, 2H), amounts to 4.76 (s, 4H), 4,20 (d, J=16.0 Hz, 2H); MSER m/z: 733,1.

Example 5. [Re(CO)3][4-(2-(bis (isoquinoline-1-ylmethyl)amino)ethyl)benzosulfimide]

A. 4-(2-(bis(isoquinoline-1-ylmethyl)amino) ethyl)benzosulfimide:

A solution of 4-(2-amino-ethyl)benzosulfimide (1.0 g, 5.0 mmol), Asón (1.0 ml) and isoquinoline-1-carbaldehyde (2,09 g, 13.3 mmol) in EDC (50 ml) was stirred at 75°C for 30 minutes in nitrogen atmosphere. The reaction mixture was cooled to 0°C and treated with NaBH (The AU) 3(3,165 g, 15 mmol). The reaction mixture was stirred at room temperature overnight and treated with water. The reaction mixture was extracted with DHM. The organic layer is dried and concentrated under reduced pressure. The residue is purified flash chromatography on silica gel to obtain 4-(2-(bis(isoquinoline-1-ylmethyl)amino)ethyl)benzosulfimide (1.86 g, 77%).1H NMR (400 MHz, DMSO-d6) δ 8,24 (d, J=8,8 Hz, 2H), of 7.96 (d, J=8,4 Hz, 2H), to $ 7.91 (d, J=8.0 Hz, 2H), 7,72 (t, J= 7.8 Hz, 2H), 7,65 (d, J=8,4 Hz, 2H), 7,55 (t, J=7,6 Hz, 2H), 7,50 (d, J= 8,4 Hz, 2H), 7,30 (d, J=6.0 Hz, 2H), 7,29 (s, 2H), 4,01 (s, 4 H), to 2.94 (t, J=7,0 Hz, 2H), 2,78 (t, J=7,0 Hz, 2H); MSER m/z: 483,3 (M+N)+.

Century [Re(CO)3][4-(2-(bis(isoquinoline-1-ylmethyl)amino)ethyl)benzosulfimide]. A solution of 4-(2-(bis(isoquinoline-1-ylmethyl)amino)ethyl)benzosulfimide (230 mg, 0,477 mmol) and [NEt4]2[ReBr3(CO)3] (367 mg, 0,477 mmol) in Meon (6.0 ml) was stirred at 100°C for 3 hours in a tube under pressure. The reaction mixture was purified by Amberchrom resin™, elwira Meon/N2About to obtain the product (173 mg, 48%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8,69 (d, J=8,4 Hz, 2H), at 8.36 (d, J=8,8 Hz, 2H), 8,12 (d, J=8,4 Hz, 2H), 7,95 (t, J=7.4 Hz, 2H), 7,82 (d, J=8,4 Hz, 2H), of 7.75 (t, J=7,6 Hz, 2H), of 7.70 (d, J=8,4 Hz, 2H), 7.62mm (d, J=8,4 Hz, 2H), 7,34 (s, 2H), 5,46 (d, J=18,0 Hz, 2H), 5.25-inch (d, J=18,0 Hz, 2H), 4,07-a 4.03(m, 2H), 3,32-2,99, (m, 2H), MSER m/z: 7534,2 M+.

Example 6. [Re(CO)3][2-(2-(((carboxymethyl)(4-sulfamoylbenzoyl)AMI is about)methyl)-1H-imidazol-1-yl)acetic acid]:

A. Tert-butyl 2-(2-(((2-tert-butoxy-2-oxoethyl)(4-sulfamoylbenzoyl)amino)methyl)-1H-imidazol-1-yl)acetate

A solution of 4-(2-amino-ethyl)benzosulfimide (0,70 g, 3.5 mmol), Asón (0,20 ml) and tert-butyl 2-(2-formyl-1H-imidazol-1-yl)acetate (0,735 g, 3.5 mmol) in EDC (20 ml) is heated to 80°C for 30 minutes in nitrogen atmosphere. The reaction mixture was cooled to 0°C. and sequentially treated with NaBH(SLA)3(2.25 g, 10.5 mmol) and tert-butylperoxide (1.80 g). The reaction mixture was stirred at room temperature overnight and treated with water. The reaction mixture was extracted with DHM and the organic layer dried and concentrated under reduced pressure. The residue is purified flash chromatography on silica gel to obtain tert-butyl 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylbenzoyl)amino)acetate (0,63 g, 35%).1H NMR (400 MHz, DMSO-d6) δ to 7.67 (d, J=8,4 Hz, 2H), 7,25 (s, 2H), 7.23 percent (d, J=8,4 Hz, 2H),? 7.04 baby mortality (d, J=1.2 Hz, 1H), 6,76 (d, J=1.2 Hz, 1H), 4,82 (s, 2H), 3,74 (s, 2H), 3,24 (s, 2H), 2,69-of 2.66 (m, 4H), of 1.41 (s, 9H), of 1.40 (s, 9H); MSER m/z: 509 (M+H)+.

Century [Re(CO)3][2-(2-(((carboxymethyl)(4-sulfamoylbenzoyl)amino)methyl)-1H-imidazol-1-yl)acetic acid]. A solution of tert-butyl 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylbenzoyl)amino)acetate (40 mg, 0.079 in mmol) in DHM (2.0 ml) and TFU (2.0 ml) was stirred at room temperature for 3 hours. Dissolve Itel removed under reduced pressure to obtain 2-(2-(((carboxymethyl)(4-sulfamoylbenzoyl)amino)methyl)-1H-imidazol-1-yl)acetic acid. In a solution of 2-(2-(((carboxymethyl)(4-sulfamoylbenzoyl)amino)methyl)-1H-imidazol-1-yl)acetic acid and [NEt4]2[ReBr3(CO)3] (70 mg, 0.09 mmol) in Meon (2.0 ml) and N2O (2.0 ml) and the pH adjusted to 9 with 2 N NaOH. The mixture was stirred at 95°C during the night in vitro under pressure. The reaction mixture was purified HPLC to obtain the product (20 mg, 38%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7,76 (d, J=8.0 Hz, 2H), EUR 7.57 (d, J=8.0 Hz, 2H), was 7.36 (d, J=1.6 Hz, 1H), 7,26 (s, 2H), 7,16 (d, J=1.6 Hz, 1H), of 5.05 (d, J=16.4 Hz, 1H), to 4.98 (d, J=16.4 Hz, 1H), 4,73 (d, J=16.0 Hz, 1H), 4,43 (d, J=16.0 Hz, 1H), 4.00 points (d, J=16,8 Hz, 1H), 3,60-3,51 (m, 3H), 3,10 was 3.05 (m, 2H); MSER m/z: 667,2 (M+H)+.

Example 7. [Re(CO)3][2,2'-(4-sulfamoylbenzoyl)dioxyna acid]:

A solution of tert-butyl 2,2'-(4-sulfamoylbenzoyl)diacetate (40 mg, 0,094 mmol) in DHM (2.0 ml) and TFU (2.0 ml) was stirred at room temperature overnight. The solvent is removed under reduced pressure to obtain 2,2'-(4-sulfamoylbenzoyl)luxusni acid. In a solution of 2,2'-(4-sulfamoylbenzoyl)luxusni acid and Re(CO)3(H2O)3OTf (1.5 ml, 0.10 mmol/ml in water, 0.15 mmol) in water (3.0 ml), the pH value was adjusted to 9 using 2N NaOH. The mixture is stirred at room temperature overnight. The reaction mixture was purified HPLC to obtain the product (19.2 mg, 31%) as below is solid. 1H NMR (400 MHz, DMSO-d6) δ 7,73 (d, J=8,4 Hz, 2H), 7,53 (d, J=8,4 Hz, 2H), 7,24 (s, 2H), 3,74 (d, J=15.6 Hz, 2H), 3,47 (d, J=15.6 Hz, 2H).

Example 8. [Re(CO)3][2,2'-(2,2'-(4-sulfamoylbenzoyl)bis(methylene)bis(1H-imidazole-2,1-diyl-acetylsalicyl))dioxyna acid]:

A. Synthesis of tert-butyl 2,2'-(2-bromoacetylation)diacetate

To a solution of tert-butyl 2,2'-azanediyldiethanol (3.00 g, 12,24 mmol) and 2-bromoacetamide (1.39 ml, 3,23 g 16,00 mmol) in DHM (100 ml) was added Et3N (2.0 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, the Reaction mixture was diluted with DHM (300 ml), washed with water and dried over sodium sulfate. The solvent is evaporated under reduced pressure to obtain a residue, which was purified Biotage SP4, elwira 10% hexane in ethyl acetate to 50% hexane in EtOAc to tert-butyl 2,2'-(2-bromoacetylation)diacetate (4.68 g, 100%).1H NMR (400 MHz, CDCl3) δ 4.09 to (s, 2H), 4,07 (s, 2H), 3,86 (s, 2H), 1,49 (s, 9H), of 1.46 (s, 9H); MSER m/z: 388,390 (M+Na)+.

C. Synthesis of tert-butyl 2,2'-(2-(2-formyl-1H-imidazol-1-yl)acetylsalicyl)diacetate:

A solution of tert-butyl 2,2'-(2-bromoacetylation)diacetate (4,55 g, 12,43 mmol), 1H-imidazole-2-carbaldehyde (1.54 g, 16.0 mmol), DIPEA (5.0 ml) and potassium iodide (0.64 g, 4.0 mmol) was stirred at 80°C during the night. After evaporation of the solvent is at reduced pressure, the reaction mixture was diluted with DHM, washed with water and dried. The solvent is evaporated under reduced pressure to obtain a residue, which was purified using a Biotage SP4, elwira DHM - 3% Meon in DHM to tert-butyl 2,2'-(2-(2-formyl-1H-imidazol-1-yl)acetylsalicyl)diacetate (3,96 g, 84%).1H NMR (400 MHz, CDCl3) δ 9,76 (s, 1H), 7,31 (s, 1H), 7,25 (s, 1H), and 5.30 (s, 2H), 4,14 (s, 2H), 4,07 (s, 2H) and 1.51 (s, 9H), USD 1.43 (s, 9H); MSER m/z: 382 (M+H)+.

C. Synthesis of tert-butyl 2,2'-(2,2'-(4-sulfamoylbenzoyl)bis(methylene)bis(1H-imidazole-2,1-diyl-acetylsalicyl))diacetate:

A solution of 4-(2-amino-ethyl)benzosulfimide (100 mg, 0.50 mmol), Asón (0.10 ml) and tert-butyl 2,2'-(2-(2-formyl-1H-imidazol-1-yl)acetylsalicyl)diacetate (457 mg, 1.2 mmol) in EDC (30 ml) was stirred at 75°C for 30 minutes in nitrogen atmosphere. The reaction mixture was cooled to 0°C and treated with NaBH(SLA)3(0,423 g, 2.0 mmol). The reaction mixture was stirred at room temperature overnight and treated with water. The reaction is then extracted with DHM and the organic layer dried and concentrated under reduced pressure. The residue is purified Biotage SP4 on silica gel to obtain compound (465 mg, 100%).1H NMR (400 MHz, DMSO-d6) δ 7,63 (d, J=8.0 Hz, 2H), 7.23 percent-7,21 (m, 4H), of 6.96 (s, 2H), 6,79 (s, 2H), 5,00 (s, 4H), 4,30 (s, 4H), of 3.95 (s, 4H) and 3.59 (s, 4H), 2,70-of 2.66 (m, 2H), 2,59 is 2.55 (m, 2H), of 1.42 (s, 18H), of 1.33 (s, 18H); MSER m/z: 466,4 (M/2+H)+.

D. [Re(CO)3][2,2'-(2,2'-(4-sulfamoylbenzoyl NDIR)bis(methylene)bis(1H-imidazole-2,1-diyl-acetylsalicyl))dioxyna acid]. A solution of tert-butyl 2,2'-(2,2'-(4-sulfamoylbenzoyl)bis(methylene)bis(1H-imidazole-2,1-diyl-acetylsalicyl))diacetate (32 mg, 0.34 mmol) and [NEt4]2[ReBr3(CO)3] (30 mg, 0,39 mmol) in Meon (3.0 ml), stirred at 95°C for 4 h in a sealed tube under pressure. The solvent is evaporated under reduced pressure to obtain the crude product. A solution of the crude product in TFU (1.0 ml) and DHM (1.0 ml) was stirred at room temperature for 3 hours the Solvent is removed under reduced pressure to obtain a residue, which was purified HPLC, to obtain the specified connection in the form of a white solid (33 mg, 27%).1H NMR (400 MHz, DMSO-d6) δ 7,79 (d, J=8,4 Hz, 2H), 7,58 (d, J=8.0 Hz, 2H), 7,29 (s, 2H), 7,13 (s, 2H), 7,06 (s, 2H), is 5.06 (s, 4H) and 4.65 (d, J=16.4 Hz, 2H), and 4.40 (d, J=16.4 Hz, 2H), 4.29 (s, 4H), of 4.05 (d, J= 5.6 Hz. 4H), a 3.87-a 3.83 (m, 2H), 3,11-is 3.08 (m, 2H); MSER m/z: 978 M+.

Example 9. [Re(CO)3][4-(3-(5-(bis(pyridine-2-ylmethyl)amino)pentyl)touraid)benzosulfimide]:

A. 4-(3-(5-(Bis(pyridine-2-ylmethyl)amino)pentyl)touraid)benzosulfimide:

A solution of tert-butyl 5-(bis(pyridine-2-ylmethyl)amino)intercorporate (0,63 g of 1.64 mmol) in DHM (10 ml) and TFU (1.0 ml) was stirred at room temperature for 3 hours After the solvent is evaporated and the reaction mixture is diluted with DHM, washed with saturated aqueous potassium carbonate is concentrated in vacuo to obtain N,N-bis(pyridine-2-ylmethyl)pentane-1,5-diamine. The solution of the above product N,N-bis(pyridine-2-ylmethyl)pentane-1,5-diamine, 4-isothiocyanatobenzene (0.35 g, of 1.64 mmol) in acetonitrile (10 ml) and DIPEA (0,40 ml) was stirred at 50°C. in a nitrogen atmosphere for 3 hours the Solvent is evaporated under reduced pressure to obtain the crude product, which was purified flash chromatography, elwira using 5% Meon in DHM, with a further 15% Meon in DHM to obtain 4-(3-(5-(bis(pyridine-2-ylmethyl)amino)pentyl)touraid)benzosulfimide (0,145 g, 19%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ of 9.75 (s, 1H), 8,48 (d, 2H), 7,98 (s, 1H), 7,78-of 7.69 (m, 4H), 7,63 (d, 2H), 7,53 (d, 2H), 7,29-7,21 (m, 4H), 3,55 (s, 4H), 3.46 in-3,44 (m, 2H), 2,49-2,47 (m, 2H), 1.56 to to 1.42 (m, 2H), 1,32 of 1.28 (m, 2H); MSER m/z: 499,5 (M+H)+.

Century [Re(CO)3][4-(3-(5-(bis(pyridine-2-ylmethyl)amino)pentyl)touraid)benzosulfimide]. A solution of 4-(3-(5-(bis(pyridine-2-ylmethyl)amino)pentyl)touraid)benzosulfimide (30 mg, to 0.060 mmol) and [NEt4]2[ReBr3(CO)3] (43 mg, 0.06 mmol) in Meon (6.0 ml) was stirred at 100°C 5 h in a sealed tube under pressure. The reaction mixture was purified by Amberchrom resin™, elwira Meon/N2O to get [Re(CO)3][2-((pyridin-2-ylmethyl)(4-sulfamoylbenzoyl)amino)acetic acid] (31 mg, 67%) as a white solid in 51 substances. MSER m/z: 769,2 (M+H)+.

Example 10. [Re(CO)3][2-((pyridin-2-ylmethyl)(8-(3-(4-sulfamoylbenzoyl)touraid)octyl)amino)UKS is SNA acid]:

A. Tert-butyl 2-((8-(tert-butoxycarbonylamino)octyl)(pyridine-2-ylmethyl)amino)acetate:

A solution of tert-butyl 8-aminoantipyrine (1,61 g 6,588 mmol), 2-pyridinecarboxamide (0.63 ml, 6,588 mmol) and Asón (0.10 ml) in EDC (30 ml) is heated to 75°C for 30 minutes in nitrogen atmosphere. The reaction mixture was cooled to 0°C. and sequentially treated with NaBH(SLA)3(3,708 g, 17.5 mmol) and tert-butylperoxide (1,53 g)1. The reaction mixture was stirred at room temperature overnight and treated with water. The reaction mixture was then extracted with DHM, and the organic layers dried and concentrated under reduced pressure. The residue is purified flash chromatography on silica gel to obtain tert-butyl 2-((8-(tert-butoxycarbonylamino)octyl)(pyridine-2-ylmethyl)amino)acetate (1,71 g, 58%) as a yellow oil.1H NMR (400 MHz, CD3Cl3) δ charged 8.52 (d, J= 4,8 Hz, 1H), 7,65 (td, J=7,8,1,6 Hz, 1H), 7,56 (d, J=1,6, 1H), 7.18 in for 7.12 (m, 1H), 4,50 (s, 1H), 3,90 (s, 2H), or 3.28 (s, 2H), of 3.07 (q, J= 6.3 Hz, 2H), 2,61 (t, J= 7,6 Hz, 2H), 1,50-1,24 (M, N); MSER m/z: 450,4 (M+N)+.

C. 2-((Pyridin-2-ylmethyl)(8-(3-(4-sulfamoylbenzoyl)touraid)octyl)amino)acetic acid. A solution of tert-butyl 2-((8-(tert-butoxycarbonylamino)octyl)(pyridine-2-ylmethyl)amino)acetate (0,449 g, 1.0 mmol) in DHM (4 ml) and TFU (4.0 ml) was stirred at room temperature overnight. RA is the solvent evaporated to obtain 2-((8-aminoacetyl)(pyridine-2-ylmethyl)amino)acetic acid. The solution of the above product 2-((8-aminoacetyl)(pyridine-2-ylmethyl)amino)acetic acid, 4-isothiocyanatobenzene (0,278 g, 1.3 mmol) in CH3SC (40 ml) and DIPEA (3.0 ml), stirred at 50°C. in a nitrogen atmosphere for 48 hours, the Solvent is evaporated under reduced pressure to obtain crude product, which was purified Amberchrom™ elwira acetonitrile/water to obtain 2-((pyridin-2-ylmethyl)(8-(3-(4-sulfamoylbenzoyl)touraid)octyl)amino)acetic acid (0,500 g) as a colourless oil.1H NMR (400 MHz, DMSO-d6) δ 9,84 (s, 1H), 8,65 (d, J=4.4 Hz, 1H), 8,11 (s, 1H), 7,94 (td, J=7,6, and 1.6 Hz, 1H), of 7.70 (d, J=8,8 Hz, 2 H), 7,63 (d, J=8,8 Hz, 2H), EUR 7.57 (d, J=7,6 Hz, 1H), 7,50-7,47 (m, 1H), 7,26 (s, 2H), 4.53-in (s, 2H), 4,14 (s, 2H), 3,44 is 3.40 (m, 2H), 3,14-is 3.08 (m, 2H), 1,64-1,24 (m, 1 H); MSER m/z: 508,3 (M+N)+.

C. [Re(CO)3][2-((pyridin-2-ylmethyl)(8-(3-(4-sulfamoylbenzoyl)touraid)octyl)amino)acetic acid]. A solution of 2-((pyridin-2-ylmethyl)(8-(3-(4-sulfamoylbenzoyl)touraid)octyl)amino)acetic acid (60 mg) and [NEt4]2[ReBr3(CO)3] (77 mg, 0.10 mmol) in Meon (4.0 ml) and water (0,20 ml) was stirred at 90°C overnight in a test tube under pressure. The reaction mixture was purified HPLC to obtain the compound (7.2 mg) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9,76 (s, 1H), total of 8.74 (d, J=5,2 Hz, 1H), 8,13 (td, J=7,6, and 1.2 Hz, 1H), 8,04 (s, 1H), 7,72 to 7.62 (m, 5H), 7,56 (t, J=6,4 Hz, 1H), 7,25 (s, 2H), 4,74 (d, J=15,6 Hz, 1H), to 4.52 (d, J=15,6 Hz, 1H), 3,80 (d, J=a 16.8 Hz, 1H), 3,54 is 3.40 (m, 4H), to 3.38 (d, J=16,8 Hz, 1H), 1,7-to 1.31 (m, 12H); MSER m/z: 778,1 (M+H)+.

Examples of synthesis of compounds of formula II

Example 11. [Re(CO)3][(8)-6-(bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino)-2-(3-((S)-1-carboxy-4-oxo-4-(4-sulfamoylanthranilic)butyl)ureido)hexanoic acid]:

A. Synthesis of (9S,13)-15-benzyl 13,9-di-tert-butyl 3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadiene-9,13,15-tricarboxylate:

To a solution of the hydrochloride of L-Glu(OBn)-OtBu (3,13 mg, 9,49 mmol) and triphosgene (923 mg, of 3.13 mmol) in EDC (70 ml), cooled to -78°C. add triethylamine (2,80 ml) in nitrogen atmosphere. After stirring at -78°C, 2 h, add a solution of L-Lys(Z)-OtBu (3.88 g, the 10.40 mmol) and tea (1.5 ml) in EDC (10 ml). The mixture allowed to reach room temperature over 1 h and stirred at room temperature overnight. The reaction mixture is treated with 1N HCl and extracted with DHM. The organic layer is dried and concentrated under reduced pressure and the residue purified using the Biotage SP4 to obtain (9S,13)-15-benzyl 13,9-di-tert-butyl 3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadiene-9,13,15-tricarboxylate in the form of a colorless oil (4.71 g, 76%).1H NMR (400 MHz, CDCl3) δ 7,34-7,29 (m, 10H), 5,13-5,04 (m, 6H), equal to 4.97 (brs, 1H), to 4.38-to 4.28 (m, 2H), 3,18-3,14 (m, 2H), 2,50 to 2.35 (m, 2H), 2,19 is 2.10 (m, 1H), 1,94-of 1.85 (m, 1H), 1,79-1,72 (m, 1H), 1,58-of 1.33 (m, 21H).

C. Synthesis of (S)-4-(3-((S)-6-amino-1-tert-butoxy-1-oxohexyl-2-yl)ureido)-5-tert-BU is hydroxy-5-oxovalerate acid:

A suspension of (9S,13)-15-benzyl 13,9-di-tert-butyl 3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadiene-9,13,15-tricarboxylate (4,30 g, only 6.64 mmol), 10% Pd/C (1.0 g) and ammonium formate (4.0 g) in EtOH (70 ml) under a vacuum bell was stirred at room temperature overnight. The reaction mixture was filtered through a layer of Celite and washed with EtOAc. The solvent is evaporated to obtain(8)-4-(3-((8)-b-amino-1-tert-butoxy-1-oxohexyl-2-yl)ureido)-5-tert-butoxy-5-oxovalerate acid (4,07 g, 70%), which is used without further purification. MSER m/z: 432,3 (M/2+N)+.

C. Synthesis of (S)-4-(3-((S)-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)-1-tert-butoxy-1-oxohexyl-2-yl)ureido)-5-tert-butoxy-5-oxovalerate acid:

A solution of (S)-4-(3-((S)-6-amino-1-tert-butoxy-1-oxohexyl-2-yl)ureido)-5-tert-butoxy-5-oxovalerate acid (432 mg, 70% purity, 0.70 mmol), Asón (0.10 ml) and tert-butyl 2-(2-formyl-1H-imidazol-1-yl)acetate (470 mg, 2.0 mmol) in EDC (20 ml) stirred at 75°C for 30 minutes in nitrogen atmosphere. The reaction mixture was cooled to 0°C and treated with NaBH(SLA)3(0,633 g, 3.0 mmol). The reaction is left overnight with stirring at room temperature. The reaction mixture is treated with water and concentrated under reduced pressure to obtain a residue, which was purified on Biotage SP4 to use the drug gradient Meon 5-50% in DHM to obtain (S)-4-(3-((S)-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)-1-tert-butoxy-1-oxohexyl-2-yl)ureido)-5-tert-butoxy-5 - oxovalerate acid (300 mg, 52%) as a colourless oil.1H NMR (400 MHz, CDCl3) of 6.99 (s, 2H), 6,84 (s, 2H), 4,57 (s, 4H), 4,29-4,19 (m, 2H), 3,66 of 3.56 (m, 4H), 2,98-2,90 (m, 2H), 2,49-is 2.37 (m, 4H), 1,95-of 1.41 (m, 42H); MSER m/z: 410,8 (M/2+H)+.

D. Synthesis of (S)-tert-butyl 6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)-2-(3-((S)-1-tert-butoxy-1.5-dioxo-5-(4-sulfamoylanthranilic)pentane-2-yl)ureido)hexanoate:

A solution of (S)-4-(3-((S)-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)-1-tert-butoxy-1-oxohexyl-2-yl)ureido)-5-tert-butoxy-5-oxovalerate acid (80 mg, 0,098 mmol), 4-(2-amino-ethyl)benzosulfimide (30 mg, 0.15 mmol), HATU (50 mg, 0,17 mmol) and DIPEA (0,50 ml) in DMF (5 ml) was stirred at 40°C during the night. The solvent is evaporated under reduced pressure to obtain a residue, which was purified Biotage SP4 using gradient Meon 0 - 20% in DHM to obtain (S)-tert-butyl 6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)-2-(3-((S)-1-tert-butoxy-1.5-dioxo-5-(4-sulfamoylanthranilic)pentane-2-yl)ureido)hexanoate (100 mg, 100%). MSER m/z: 501,9 (M/2+N)+.

E. [Re(CO)3][(S)-6-(bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino)-2-(3-((S)-1-carboxy-4-oxo-4-(4-sulfamoylanthranilic)butyl)ureido)hexanoic acid]. A solution of (S)-tert-butyl 6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)-2-(3-((S)-1-tert-butoxy-1.5-dioxo-5-(4-sulfamoylanthranilic)pentane-2-is)ureido)hexanoate (60 mg, to 0.060 mmol) and [NEt4]2[ReBr3(CO)3] (60 mg, 0,077 mmol) in Meon (4.0 ml) was stirred at 80°C overnight in a sealed tube under pressure. The solvent is evaporated under reduced pressure to obtain a residue. The solution above the selected residue is dissolved in DHM (2.0 ml) and add TFU (2.0 ml), the reaction mixture was stirred at room temperature for 2 hours the Solvent is removed under reduced pressure to obtain a residue, which was purified HPLC, to obtain the compound (16 mg, 25% over 2 stages) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7,94 (brs, 1H), 7,71 (d, J=8,4 Hz, 2H), 7,35 (d, J=8,4 Hz, 2H), 7,26 (s, 2H), 7,17 (s, 2H), 7,03 (s, 2H), 6,37-6,33 (m, 2H), a 4.83 (s, 4H), 4,55 (d, J=a 16.4 Hz, 2H), 4,39 (d, J=a 16.4 Hz, 2H), 4,14-was 4.02 (m, 2H), 3,65-3,61 (m, 2H), 3.25 to up 3.22 (m, 2H), 2,74 (t, J=7,0 Hz, 2H), 2.05 is-of 1.30 (m, 10H); MSER m/z: 524,8 (M/2+H)+.

Example 12. (S)-2-(3-((S)-1-carboxy-4-oxo-4-(4-sulfhemoglobinemia)butyl)ureido)-6-(3-jogesuido)hexanoic acid:

A. 2,5-Dioxopiperidin-1-yl 3-identit:

A solution of 3-identies acid (744 mg, 3.0 mmol), carbonate N, N'-disuccinimidyl (920 mg, 3.6 mmol) and pyridine (0,30 ml) in acetonitrile (30 ml) was stirred at room temperature overnight. The solvent is removed under reduced pressure to obtain a residue, which was purified using a Biotage SP4, elwira 10%-00% EtOAc in hexane to obtain 3-identita 2,5-dioxopiperidin-1-yl (946 mg, 91%) as a white solid.1H NMR (400 MHz, CDCl3) δ 8,46 (s, 1H), 8,10 (d, J=7,6, 1H), 8,00 (d, J=8,0 Hz, 1H), 7,26 (t, J=7,8 Hz, 1H), 2.91 in (s, 4 H); MSER m/z: 368 (M+Na)+.

C. (S)-5-tert-butoxy-4-(3-((S)-1-tert-butoxy-6-(3-jogesuido)-1-oxohexyl-2-yl)ureido)-5-oxovalerate acid:

A solution of (S)-4-(3-((S)-6-amino-1-tert-butoxy-1-oxohexyl-2-yl)ureido)-5-tert-butoxy-5-oxovalerate acid (260 mg, of 0.60 mmol), 5-dioxopiperidin-1-yl-3-identita (276 mg, 0.80 mmol) and DIPEA (1.0 ml) in DMF (5.0 ml) was stirred at room temperature overnight. The solvent is removed under reduced pressure to obtain a residue, which was purified using a Biotage SP4, elwira 10-100% EtOAc in hexane to obtain (S)-5-tert-butoxy-4-(3-((S)-1-tert-butoxy-6-(3-jogesuido)-1-oxohexyl-2-yl)ureido)-5-oxovalerate acid (343 mg, 86%) as a colourless oil. MSER m/z: 332 (M+N)/2+.

C. (S)-2-(3-((S)-1-carboxy-4-oxo-4-(4-sulfhemoglobinemia)butyl)ureido)-6-(3-jogesuido)hexanoic acid. A solution of (S)-5-tert-butoxy-4-(3-((S)-l-tert-butoxy-6-(3-jogesuido)-1-oxohexyl-2-yl)ureido)-5-oxovalerate acid (98 mg, 0,148 mmol), sulfanilamide (to 34.4 mg, 0.20 mmol), HATU (76 mg, 0.20 mmol) and DIPEA (0,50 ml) in DMF (5 ml) was stirred at 50°C during the night. The solvent is evaporated under reduced pressure to obtain a residue, which was purified using a Biotage SP4 with g is adiantum EtOAc 10-100% in hexane to obtain (S)-tert-butyl 2-(3-((S)-1-tert-butoxy-1.5-dioxo-5-(4-sulfhemoglobinemia)pentane-2-yl)ureido)-b-(3-jogesuido)hexanoate. The solution above the selected material dissolved in a mixture of TFU (2.0 ml)/DGM (2.0 ml) and stirred at room temperature for 3 hours the Solvent is removed under reduced pressure to obtain a residue, which was purified HPLC to obtain the compound (20 mg, 19% over 2 stages) as a white solid. MSER m/z: 704,2 (M+N)+.

Example 13. (S)-2-(3-((S)-1-carboxy-4-oxo-4-(4-sulfamoylanthranilic)butyl)ureido)-6-(3-jogesuido)hexanoic acid:

A solution of (S)-5-tert-butoxy-4-(3-((S)-1-tert-butoxy-6-(3-jogesuido)-1-oxohexyl-2-yl)ureido)-5-oxovalerate acid (212 mg, 0.32 mmol), 4-(2-amino-ethyl)benzosulfimide (80 mg, 0.40 mmol), HATU (152 mg, 0.40 mmol) and DIPEA (0,50 ml) in DMF (5 ml) stirred at 50°C during the night. The solvent is evaporated under reduced pressure to obtain a residue, which was purified using Biotage SP4 with EtOAc gradient 10-100% in hexane to obtain (S)-tert-butyl 2-(3-((S)-1-tert-butoxy-1.5-dioxo-5-(4-sulfhemoglobinemia)pentane-2-yl)ureido)-6-(3-jogesuido)hexanoate. The solution of the above product is dissolved in TFU (2.0 ml)/DGM (2.0 ml) and stirred at room temperature for 3 hours the Solvent is removed under reduced pressure to obtain a residue, which was purified Amberchrom™ to obtain ((S)-2-(3-((S)-1-carboxy-4-oxo-4-(4-sulfamoylanthranilic)butyl)ureido)-6-(3-identitydocuments acid (40 mg, 17% over 2 stages) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8,54 (t, J=5,4 Hz, 1H), 8,17 (s, 1H), 7,97 (t, J=5,4 Hz, 1H), 7,86 (d, J=8,0 Hz, 1H), 7,83 (d, 7=8,0 Hz, 1H), 7,72 (d, J=8,4 Hz, 2H), 7,37 (d, J=8,0 Hz, 2H), 7,28-of 7.23 (m, 3H), 6,32 (t, J=7,0 Hz, 2H), 4,07-to 3.99 (m, 2 H), 3.27 to 2,80 (m, 2H), 2,75 (t, J=7,2 Hz, 2H), 2,10-of 1.29 (m, 10H); MSER m/z: 732,2 (M+H)+.

Examples of synthesis of compounds of formula IV

Example 14. [Re(CO)3] [2-((6-oxo-6-(4-sulfhemoglobinemia)hexyl)(pyridine-2-ylmethyl)amino)acetic acid]:

A. 6-((2-Tert-butoxy-2-oxoethyl)(pyridine-2-ylmethyl)amino)hexanoic acid:

A solution of 6-aminocaproic acid (1.97 g, 15 mmol) and 2-pyridinecarboxamide (1,61 g, 15 mmol) in EDC (30 ml) is heated to 75°C for 30 minutes in nitrogen atmosphere. The reaction mixture was cooled to 0°C. and sequentially treated with NaBH(OAc)3(of 7.95 g, 37.5 mmol) and tert-butylpyrocatechol (2,80 g)1. The reaction mixture was stirred at room temperature overnight and treated with water. The reaction mixture was extracted with DHM and the combined organic layers dried and concentrated under reduced pressure. The residue is purified flash chromatography on silica gel to obtain 6-((2-treat-butoxy-2-oxoethyl)(pyridine-2-ylmethyl) amino)Caproic acid (1.78 g, 35%) as a yellow oil.1H NMR (400 MHz, CD3CL3) δ 8,57 (ddd, J=4,8,1,6, 0.8 Hz, 1H), of 7.70 (td, J=7,6, and 1.6 Hz, H), 7,56 (d, J=7,6, 1H), 7,22-to 7.18 (m, 1H), 3,93 (s, 2H), 3,29 (s, 2H), 2,65 (t, J= 7,4 Hz, 2H), 2,33 (t, J= 7,6 Hz, 2H), 1,67-of 1.32 (m, 15H); MSER m/z: 337,2 (M+H)+.

C. Tert-butyl 2-((6-oxo-6-(4-sulfhemoglobinemia)hexyl)(pyridine-2-ylmethyl)amino)acetate

A solution of 6-((2-tert-butoxy-2-oxoethyl)(pyridine-2-ylmethyl)amino)Caproic acid (0,6545 g of 1.95 mmol), sulfanilamide (0,362 g, 2.10 mmol) and HATU (0,798 g, 2.10 mmol) in DMF (10 ml) and Et3N (1.0 ml) was stirred at 40°C during the night. The reaction mixture was purified flash chromatography on silica gel, elwira Meon/DHM to obtain tert-butyl 2-((6-oxo-6-(4-sulfhemoglobinemia)hexyl)(pyridine-2-ylmethyl)amino)acetate (297 mg, 31%). MSER m/z: 491,3 (M+N)+.

C. [Re(CO)3][2-((6-oxo-6-(4-sulfhemoglobinemia)hexyl)(pyridine-2-ylmethyl)amino)acetic acid]. A solution of tert-butyl 2-((6-oxo-6-(4-sulfhemoglobinemia)hexyl)(pyridine-2-ylmethyl) amino)acetate (70 mg, 0.14 mmol) in DHM (1.0 ml) and TFU (1.0 ml) was stirred at room temperature overnight. The solvent is removed under reduced pressure to obtain 2-((6-oxo-6-(4-sulfhemoglobinemia)hexyl)(pyridine-2-ylmethyl)amino)acetic acid. The solution above the selected product, 2-((6-oxo-6-(4-sulfhemoglobinemia)hexyl)(pyridine-2-ylmethyl)amino)acetic acid, [NEt4]2[ReBr3(CO)3] (108 mg, 0.14 mmol) and potassium carbonate (30 mg) in the Meon (4.0 ml) and water (1.0 ml) 100 is 4 h in a sealed tube under pressure. The reaction mixture was purified Amberchrom™, elwira Meon/N2About to obtain the compound (64 mg, 65%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ of 10.25 (s, 1H), total of 8.74 (d, J= 5,2 Hz, 1H), 8,13 (td, J= 7,6, and 1.2 Hz, 1H), 7,76-of 7.55 (m, 5H), 7,56 (t, J= 6,4 Hz, 1H), 7.23 percent (s, 2H), 4,74 (d, J= 16,0 Hz, 1H), 4,53 (d, J= 16,0 Hz, 1H), 3,82 (d, J= 16,8 Hz, 1H), 3,54 is 3.40 (m, 2H), 3,38 (d, J= 16,8 Hz, 1H), of 2.38 (t, J= 7,4 Hz, 2H), 1.76 staff to 1.31 (m, 6H); MSER m/z: 705,3 (M+H)+.

Example 15. Rhenium(tricarbonyl)(11-(bis(pyridine-2-ylmethyl)amino)-N-(4-sulfamoylbenzoyl)undecanone):

A. 11-(Bis(pyridine-2-ylmethyl)amino)-N-(4-sulfamoylbenzoyl)undecayed get the techniques described in the section"General synthetic methods" (139 mg, 31%). MSER m/z: 568 (M+N)+.

Century Rhenium(tricarbonyl)(11-(bis(pyridine-2-ylmethyl)amino)-N-(4-sulfamoylbenzoyl)undecanone)) is produced from compound stage And, according to the method described in General methods of synthesis of rhenium complexes", and allocate (10 mg, 19%) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ is 8.75 (d, 2H), 7,95 (m, 2H), of 7.90 (t, H), and 7.7 (d, 2H), 7,55 (d, 2H), and 7.3 (m, 4H), 7,2 (m, 2H), 4,8 (m, 4H), to 4.15 (d, 2H, in), 3.75 (m, 2H), 3,3 (m, 2H), and 2.83 (m, 2H), of 1.85 (m, 2H), of 1.35 (m, 14H). MSER m/z: 460 (M+H)+.

Example 16. Rhenium(tricarbonyl)(11-(bis(pyridine-2-ylmethyl)amino)-N-(4-sulfamoylbenzoyl)undecanone):

A. 11-(Bis(pyridine-2-ylmethyl)amino)-N-(4-sulfamoylbenzoyl)undecayed receive according to the method described Viseu under "General methods of synthesis (100 mg, 23%). MSER m/z: 552 (M+N)+.

Century Rhenium(tricarbonyl)(11-(bis(pyridine-2-ylmethyl)amino)-N-(4-sulfamoylbenzoyl)undecanone)) is produced from compound stage And, as described above under "General methods of synthesis of rhenium complexes", and allocate (22 mg, 36%) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8,82 (d, 2H), 8,45 (t, 1H), 8.0 a (m, 2H), and 7.8 (d, 2H), 7,55 (d, 2H), 7,40 (m, 4H), 7,30 (s, 2H), 4,90 (d, 4H), 4,30 (m, 2H), 3,70 (m, 2H), 1,80 (bs, 2H), 1.57 in (m, 2H), 1,38 (m, 14H). MSER m/z: 823 (M+H)+.

Example 17. Rhenium(tricarbonyl)(11-(bis(pyridine-2-ylmethyl)amino)-N-(4-sulfamoylbenzoyl)undecanone):

A. 11-(Bis(pyridine-2-ylmethyl)amino)-N-(4-sulfamoylbenzoyl)undecayed receive as described above under "General synthetic methods" (41 mg, 15%). MSER m/z: 538 (M+N)+.

Century Rhenium(tricarbonyl)(11-(bis(pyridine-2-ylmethyl)amino)-N-(4-sulfamoylbenzoyl)undecanone) is produced from compound a as described above under "General methods of synthesis of rhenium complexes" (15 mg, 33%) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ of 10.25 (s, 1H), 8,83 (d, 2H), 8,00 (m, 2H), 7,80 (s, 4H), at 7.55 (d, 2H), 7,40 (m, 2H), 7,20 (s, 2H), 4,90 (d, 4H), 4,30 (m, 2H), 3,60 (m, 2H), 2,30 (m, 2H), 1,80 (bs, 2H), 1.57 in (m, 2H), 1,38 (m, 10H). MSER m/z: 808 (M+N)+.

Example 18. Rhenium(tricarbonyl)(3-(2-(2-(bis(pyridine-2-ylmethyl)amino) ethoxy) ethoxy)-N-(4-sulfamoylbenzoyl)propanamide):

A. 3-(2-(2-(Bis(pyridine-2-ylmethyl)amino)it is C)ethoxy)-N-(4-sulfamoylbenzoyl)propanamide get as described above under "General methods of synthesis, giving the desired product (70 mg, 16%). MAR tons/year 542 (M+N)+.

Century Rhenium(tricarbonyl)(3-(2-(2-(bis(pyridine-2-ylmethyl)amino)ethoxy)ethoxy)-N-(4-sulfamoylbenzoyl)propanamide), is obtained from the connection stage And, as described above under "General methods of synthesis of rhenium complexes" (36 mg, 44%) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ is 8.75 (d, 2H), 7,95 (m, 3H), and 7.7 (d, 4H), at 7.55 (d, 2H), 7,30 (m, 6H), of 4.90 (d, 4H), 4,30 (m, H), of 3.80 (m, 2H), 3,55 (m, 4H) 3,40 (m, 2H), 3,30 (s, 2H), 3,17 (m, 2H), rating of 2.72 (t, 2H, in), 2.25 (t, 2H). MSER m/z: 812 (M+H)+.

Example 19. Rhenium(tricarbonyl)(3-(2-(2-(bis(pyridine-2-ylmethyl)amino)ethoxy)ethoxy)-N-(4-sulfamoylbenzoyl)propanamide):

A. 3-(2-(2-(Bis(pyridine-2-ylmethyl)amino)ethoxy)ethoxy)-N-(4-sulfamoylbenzoyl)propanamide receive, as described above under "General methods of synthesis, providing the desired product (126 mg, 43%). MSER m/z: 542 (M+N)+.

Century Rhenium(tricarbonyl)(3-(2-(2-(bis(pyridine-2-ylmethyl)amino)ethoxy)ethoxy)-N-(4-sulfamoylbenzoyl)propanamide) is produced from compound stage And, as described above under "General methods of synthesis of rhenium complexes" (31 mg, 41%) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ at 8.60 (d, 2H), 8,55 (m, H), of 7.75 (m, 2H), 7,55 (d, 2H), 7,35 (d, 2H), 7,15 (m, 4H), and 4.8 (d, 4H), to 4.15 (d, 2H, in), 3.75 (m, 4H), 3,6 (m, 2H), of 3.45 (m, 4H), 3,2 (m, H in), 2.25 (t, 2H). MSER m/z: 798 (M+H)+.

Example 20. Rhenium(Proc. of the carbonyl)(3-(2-(2-(bis(pyridine-2-ylmethyl)amino)ethoxy)ethoxy)-N-(4-sulfamoylbenzoyl)propanamide:

A. 3-(2-(2-(Bis(pyridine-2-ylmethyl)amino)ethoxy)ethoxy)-N-(4-sulfamoylbenzoyl)propanamide receive, as described above under "General methods of synthesis, representing the desired product (41 mg, 10%). MSER m/z: 512 (M+N)+.

Century Rhenium(tricarbonyl)(3-(2-(2-(bis(pyridine-2-ylmethyl)amino)ethoxy)ethoxy)-N-(4-sulfamoylbenzoyl)propanamide produced from compound stage And, as described above under "General methods of synthesis of rhenium complexes" (24 mg, 52%) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8,80 (m, 2H), 7,95 (m, 2H), 7,60 (m, 4H), to 7.4 (m, 4H), of 4.95 (m, 4H), 3,95 (m, 4H), of 3.65 (m, 4H), to 2.65 (m, 4H). MSER m/z: 798 (M+H)+.

Example 21. Rhenium(tricarbonyl)11-(bis((1-methyl-1H-imidazol-2-yl)methyl)amino)-N-(4-sulfamoylbenzoyl)undecayed:

A. 11-(Bis((1-methyl-1H-imidazol-2-yl)methyl)amino)-N-(4-sulfamoylbenzoyl)undecayed receive as described above under "General methods of synthesis, leading to 1 (38 mg, 10%). MSER m/z: 544 (M+N)+.

Century Rhenium(tricarbonyl) 11-(bis((1-methyl-1H-imidazol-2-yl)methyl)amino)-N(4-sulfamoylbenzoyl)undecayed produced from compound stage And, as described above under "General methods of synthesis of rhenium complexes" (18 mg, 36%) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ 10.30 a.m. (s, H), 7,30 (d, 2H), 7,05 (d, 2H), to 6.43 (d, 2H), 5,65 (d, 2H) and 4.65 (m, 2H), 3,60 (s, 6H), is 2.30 (m, 2H), of 1.85 (m, 2H), of 1.35 (m, 14H). MSER m/z: 817 (M+H) .

Example 21A. Rhenium(tricarbonyl) 11 -(bis((1-methyl-1H-imidazol-2-yl)methyl)amino)-N-(4-sulfamoylbenzoyl)octanamide can be obtained by the method similar to example 22:

.

Example 22. Rhenium(tricarbonyl)6-(bis(pyridine-2-ylmethyl)amino)-N-(4-sulfamoylbenzoyl)hexanamide:

A. 6-(Bis(pyridine-2-ylmethyl)amino)-N-(4-sulfamoylbenzoyl)hexanamide receive the same method that is described in the section "General synthetic methods" (162 mg, 22%). MSER m/z: 468 (M+N)+.

Century Rhenium(tricarbonyl)6-(bis(pyridine-2-ylmethyl)amino)-N-(4-sulfamoylbenzoyl)hexanamide obtained from compounds of the above stages a, and then the techniques described in "General methods of synthesis of rhenium complexes" (13 mg, 11%) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ 10.30 a.m. (s, N), 8,82 (d, 2H), 7,98 (t, 2H), to 7.75 (m, 4H), at 7.55 (d, 2H), 7,40 (m, 2H), 7,20 (d, 2H), 4,90 (m, 4H), of 2.45 (m, 4H), of 1.85 (m, 2H), 1,65 (m, 2H), 1,35 (m, 2H). MSER m/z: 742 (M+H)+.

Analogues of benzosulfimide with ethylenediaminetetraacetic acid as a linker

Compounds synthesized using the methodology presented in the following scheme 3. The reaction of 4,4'-(ethane-1,2-diyl)dimorpholino-2,6-dione with the equivalent 4-aminobenzenesulfonamide, then the equivalent of N,N-bis(pyridine-2-ylmethyl)alkyl-1,6 diamine gives the specified connection, which then coordinate with the radionuclide, the use is of a General methodology, discussed above.

Scheme 3

where: reflux - boiled under reflux

Example 23A. A solution of EDTA dianhydride (130 mg, 0.50 mmol) and sulfanilamide (86 mg, 0.50 mmol) in DMF (3.0 ml) was stirred at room temperature for 4 h N1N1bis(pyridine-2-ylmethyl)octane-1,8-diamine (162 mg, 0.50 mmol) are added to the reaction mixture and the reaction mixture was stirred at room temperature overnight. The solvent is evaporated under reduced pressure and purified HPLC to obtain the desired product (110 mg, 29%) as a white solid. MSER m/z: 378,2 (M/2+N)+.

C. Solution of the above compound phase A (20 mg, was 0.026 mmol), [NEt4]2[ReBr3(CO)3] (23 mg, 0,030 mmol) and potassium carbonate (5 mg) in the Meon (5.0 ml) was stirred at 100°C overnight in a test tube under pressure. The reaction mixture was then concentrated and purified HPLC to obtain the desired compound (5.3 mg) as a white solid. MSER m/z: was 513.3 (M/2+N)+.

Example 24. The compound of the following formula get by the method similar to example 24:

Example 25. Rhenium(tricarbonyl)[4-[3-(2-{2-[2-(bis-pyridine-2-ylmethyl-amino)-ethoxy]-ethoxy}-ethyl)-touraid]-benzosulfimide] can be obtained corresponding to modify which of the above methods of synthesis.

Selective inhibition of the activity of carbonic anhydrase

Compounds are tested for their ability to inhibit the isozyme II and IX carbonic anhydrase in vitro. Purified enzymes person put R&D Systems (Minneapolis, MN (Minneapolis, Minnesota). The inhibition constants (Kifor SA and CA-IX is determined by the method of Poker and stone (Pocker and Stone) [25]. The initial velocity of hydrolysis of 4-nitrophenylacetate catalyzed by a variety of carbonic anhydrase isozyme, measured spectrophotometrically at 400 nm. Substrate solution (1×10-2-1×10-6M) was prepared in anhydrous acetonitrile. Use the molar ratio of repayment of 18,000 M-1·cm-14-nitrophenolate formed by hydrolysis under the conditions of the experiment (9 mmol Tris-HCl, 81-mmol NaCl, pH of 7.4, 25°C). The concentration of the enzyme are 100 nmol for CA-IX and 30 nmol for SA-II. Speed reanimating hydrolysis defined in the absence of added enzyme, is subtracted from the observed velocity. Spare inhibitor solution prepared in deionized water with 10-20% DMSO (which is not inhibited enzimatico activity) [12]. Dilution of inhibitor added to the enzyme solutions and pre-incubated for 10 minutes to allow formation of a complex E-I before adding the substrate. Acetazolamide include all tests as positive to the of ntrolle.

Table 1. The results of the IC50(nmol) some of the examples and comparative examples

ExampleIC50(nmol)
CA-IICA-IX
Comparative example 1 (see below)37777
Comparative example 2 (see below)12254
626130
5360172
357943
9237153
857793
Comparative example with acetazolamide (see below)4632

The structure of comparative example 1:

The structure of the comparative example 2:

The structure with anitelea acetazolamide:

The biodistribution in tissues of mice with xenograft human Introduction of CA-IX inhibitors with radioactive label in xenograft models of human tumor perform to published methods [20]. Based on data from Western blotting and cell culture are described in particular goal 3, we decided to investigate the ability of our compounds to achieve CA-IX in the HeLa xenografts as well as in SK-RC-52 xenografts. Briefly, HeLa, SK-RC-52 and SK-RC-59 cells incubated according to the method of the provider. Prior to inoculation of cells trypsinized, counted and suspended in 50% PBS with 1 mg/ml D-glucose, 36 mg/ml of sodium pyruvate, 50% Matrigel (BD Biosciences, Franklin Lakes, NJ). Mice NCrnu/nuanaesthetize intraperitoneal injection of 0.5 ml of Avertin (20 mg/ml) (Sigma-Aldrich, St. Louis, MO), then subcutaneously inoculant in the rear groin 2×106cells in a volume of 0.25 ml of the suspension. Research uptake by tumor spend to achieve tumor size 100-200 mm3. Tissue distribution analyze the introduction of tail vein injection dose of about 2 µci/mouse CA-IX inhibitors with radioactive label in a constant volume of 0.1 ml. of a Group of five animals subjected to euthanasia by Aspicia carbon dioxide after 1, 4 and 24 hours after injection. Determining specific binding of CA-IX reach co-injection of a dose of acetazolamide 10 mg/kg of Tissue (tumor, CR is V, heart, liver, lungs, spleen, large intestine and small intestine, stomach, kidney, skeletal muscle and brain) prepare, cut, weighed wet, placed in plastic tubes and determine the activity of automated γ-counter (LKB Model 282, Wallac Oy, Finland). Radioactivity in tissues over time expressed as % of the injected into the tissue dose per gram tissue (% ID/g) and % entered dose to organ (% DPO).

Samples analogs99mTC injected into the tail vein of Nude mice NCr containing CA-IX, synthesizing SK-RC-52 xenografts or HeLa cells. Groups of mice (n=5) is removed from the experiment after injection after 1 and 4 hours and collect the following tissues: blood, heart, lungs, liver, spleen, kidneys, stomach, thick and small intestine (with contents), testes, skeletal muscle, bone, brain, adipose tissue and the tumor. At both time points additional group of mice (n=5) carry out the co-injection of 10 mg/kg of acetazolamide to block the binding of carbamides. Fig.1 and 2 show the distribution in tissues of different radiopharmaceuticals.

Data distribution in the tissue are obtained from99mTC analogue compounds of example 8 in the HeLa HeLa xenograft mice, expressed as % ID/g ±(SEM). The data shown in Fig.1.

For reference, in Fig.2 the tested compounds are99mTC analogues of the compounds of examples 1, 3, 7 and 8 in xenotransplant the Tata HeLa mouse.

Data distribution in the tissue are obtained from99mTC analogue compounds of example 7 in the HeLa HeLa xenograft mice. The data shown in Fig.3.

Data distribution in the tissue are obtained from99mTC analogue compound of example 3 in HeLa xenograft mice, expressed as % ID/g ±(SEM). The data shown in Fig.4.

Data distribution in the tissue are obtained from99mTC analogue compounds of example 1 in HeLa xenograft, SKRC SKRC 52 and 59 of the mouse, the compounds of examples 7 and 10 in HeLa xenograft mice. The data shown in Fig.5.

Equivalents

At that time, as shown and described certain implementation, specialists in the art should be understood that changes and modifications may be made in the description, not going beyond the technology in its broader aspects as defined in the subsequent claims,

The present disclosure should not be limited to the specific implementations described in this application. Many modifications and changes can be made without leaving the scope of the claims as obvious to experts in the given field of technology. Functionally equivalent methods and connections within disclosure, in addition to those listed in the description, are obvious to experts in the art from the preceding description. Such modifications and changes PR is naznaczony to match the scope of the claims appended claims. The present disclosure should be limited only in accordance with the attached claims, together with all equivalents that are subject to the claims of the invention. It should be understood that this disclosure is not limited to particular methods, reagents, compounds, or biological systems, which of course can vary. You also need to understand that the terminology used in the application only for the purpose of describing particular implementations and is not intended to limit.

In addition, where features or aspects of the disclosure are described on the basis of Markush groups, specialists in the art should understand that therefore, the disclosure are also described on the basis of independent member or subgroup of members of the Markush group.

Specialists in the art should understand that for all purposes, in particular with respect to the written description, all ranges disclosed in the application, also include any and all possible subranges and combinations of these sub-bands. Any specified range can be easily recognized as sufficiently describing and enabling the splitting of this range, at least equal halves, thirds, quarters, fifths, tenths parts, etc. as a non-limiting example, each range discussed in the description, can be easily divided least one third, the middle third and most third and so on, Specialists in the art should also understand that all phrases such as "to", "at least," "greater", "less", etc. include a specified number and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, specialists in the art should understand that the range includes every independent member, including first and last number, the specified range.

All publications, patent applications, granted patents and other documents referred to in this application are included in the description by reference as if each independent publication, patent application, issued patent, or other document were specifically and independently specified, have been incorporated by reference in their entirety. Definitions contained in the text, incorporated by reference, is excluded so that they are not inconsistent with the definitions of the present disclosure.

Other implementation formulated in the following claims.

1. The compound of formula I or its pharmaceutically acceptable salt:

where W is a bond, (C1-C8)alkyl, (C2-C8)alkenyl, aryl, heteroaryl,
-NHC(O),
-C(O)NH, -NH-C(O)-NH - or-NH-C(S)-NH-;
V is a bond, (C1-C8)alkyl, (C2-C8)alkenyl is m, the aryl, heteroaryl, -NH-C(O)-NH - or-NH-C(S)-NH-;
NRaRbis a chelating group of the formula:

Rtis H, C1-C8alkyl group;
Rxand Ryeach independently is hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxylation;
Rvis alkyl;
m is an integer of 0-15; and
n is an integer of 0-15; provided that W and V are both cannot be NH-C(O)-NH - or-NH-C(S)-NH-; and provided that the compound is not 2,2'-(2,2'-(8-(3-(4-sulfamoylbenzoyl)touraid)activization) bis(methylene)bis(1H-imidazole-2,1-diyl))luxusni acid;
2,2'-(2,2-(4-sulfamoylbenzoyl) bis(1H-imidazole-2,1-diyl))luxusni acid; or 2,2'-(2,2'-(5-(4-sulfamoylbenzoic)pentlandii) bis(methylene)bis(1H-imidazole-2,1-diyl))luxusni acid.

2. Connection on p. 1, where NRaRbis a chelating group of the formula:

3. Connection on p. 1, in which Rvis stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl or tert-bootrom.

4. Connection on p. 1, in which each Rtindependently is H or tert-bootrom.

5. Connection on p. 1, in which m is 0 or 1 and n is an integer 0-8.

6. Connection on p. 1, having the structure:

7. Connection on p. 1, in which the PR NR aRbis

8. The complex containing the compound under item 1 and a radioactive metal selected from the group consisting of Re and Tc.

9. Complex p. 8, in which the radioactive metal is technetium-99m, rhenium-186m or rhenium-188m.

10. Complex p. 8, in which NRaRbis

11. Complex under item 8, which is selected from the group consisting of:

or its pharmaceutically acceptable salt; and
M is a radioactive metal selected from the group consisting of Re and Tc.

12. Complex on p. 11, in which M is technetium-99m, rhenium-186m or rhenium-188m.

13. The compound of formula II or its pharmaceutically acceptable salt:

where
L is NRaRbchelating group of the formula:

or a group of the formula:

W and X are independently O or S;
p is an integer from 0-5;
q is an integer 0-8;
Rtis H, C1-C8alkyl group;
Rxand Ryeach independently is hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxylation;
Rvis alkyl.

14. The complex containing the connection on p. 13, in which L is NRaRbchelate group, and radioactive the second metal, selected from the group consisting of Re and Tc.

15. The compound of formula IV:

where
NRaRbis a chelating group of the formula:

Y is O or S;
A is a (C1-C8) alkyl, -(CH2)x-(OCH2CH2)y- or -(OCH2CH2)y(CH2)x-;
x is an integer of 0-3;
y is an integer of 0-3;
r is an integer from 0-5;
s is an integer 0-10;
Rtis H, C1-C8alkyl group;
Rxand Ryeach independently is hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxylation; and
Rvis alkyl.

16. Connection on p. 15 in which r is 0, 1 or 2.

17. Connection on p. 15, in which s is 0, 5 or 10.

18. Connection on p. 15, in which NRaRbis

19. The complex containing the connection on p. 15 and radioactive metal selected from the group consisting of Re and TC.

20. Complex p. 19, in which the radioactive metal is technetium-99m, rhenium-186m or rhenium-188m.

21. Complex p. 19, in which NRaRbis

22. Connection on p. 15, in which Rvis stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl or tert-bootrom.

23. With the Association under item 15, in which each Rtindependently is H or tert-bootrom.

24. Pharmaceutical composition comprising the compound to be selectively associated with the protein carbonic anhydrase IX, according to any one of paragraphs.1-7, 13 or 15-18 or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.

25. Pharmaceutical composition for visualization of the tumor, which synthesizes carbonic anhydrase IX, comprising the complex according to any one of paragraphs.14, 19, 20 or 21 or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.

26. The use of the complex according to any one of paragraphs.8, 14, or 19, or its pharmaceutically acceptable salt for visualization of the tumor, which synthesizes carbonic anhydrase IX.

27. The use of the complex according to any one of paragraphs.8, 14, or 19, or its pharmaceutically acceptable salts for the treatment of tumors, which synthesizes carbonic anhydrase IX.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new radiopharmaceutical compounds of structural formula

.

In formula I, R means H or a (C1-C8)alkyl group; W means a bond, -CH(NH2)-, -C(O)-NH-CH(COOH)-, -O-(CH2)n-O-(CH2)n- or -(CH2)nO(CH2)nO(CH2)n; Z means -NHC(O)-, -NH-C(O)-CH(NH2)- or -C(O)-NH-CH(COOH)-; e is an integer from 1 to 4; f is an integer from 0 to 10; g is an integer from 0 to 10; n is an integer from 0 to 2; the radical NRaRb values are presented in the patent claim.

EFFECT: invention refers to the radionuclide complex containing a radioactive metal and the above compounds, to a pharmaceutical compound for visualising and to a method for visualising any patient's region, e.g. a tissue specified in the spleen tissue, kidney tissue or PSMA-expressing tumour tissue.

21 cl, 6 dwg, 1 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing binuclear 3,4,5-triaryl-1,2-diphosphacyclopentadienide manganese complexes of general formula where Ar=C6H5, para-F-C6H4, para-Cl-C6H4. The method involves reacting a dimer of manganese tetracarbonyl bromide [MnBr(CO)4]2 with 1-trimethylstannyl-3,4,5-triaryl-1,2-diphosphacyclopenta-2,4-diene in molar ratio of 1:2 in pure tetrahydrofuran for 30 minutes at room temperature.

EFFECT: invention increases output of the product and reduces time and power costs.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a refractory composition for making casting moulds. The composition contains (a) at least 85 pts.wt refractory material, (b) 0.5-10 pts.wt binder and (c) manganese cyclopentadienyl tricarbonyl, a derivative thereof, in amount of about 0.0005 pts.wt to about 4 pts.wt, where the parts by weight are given with respect to 100 pts.wt of the refractory composition. Also disclosed are methods of making a casting mould and a method of moulding metal parts.

EFFECT: invention enables to make casting moulds with improved exothermic properties.

13 cl, 4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a complex compound of a magnetisable metal and salen. The complex compound is presented by formula (I) , wherein M represents Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir or Pt, and a-f and Y represents hydrogen, or -NHR3-, -NHCOR3 respectively provided a-f and Y are not hydrogen simultaneously, wherein -R3 represents a pharmaceutical molecule with R3 provides the transport of a charge equivalent to max. 0.5 electron (e); or by formula (II) , wherein M represents Fe, Y, a, c, d, f, g, i, j, 1 represent hydrogen respectively; b and k represent -NH2, h and e represent -NHR3, wherein -R3 represents taxol (paclitaxel), or M represents Fe, Y, a, c, d, f, g, i, j, 1 represent hydrogen respectively; b, e, h and k represent -NHR3-, wherein -R3 represent gemfibrozil. There are also presented a local anaesthetic, an antineoplastic agent, a complex metal molecule, an intermediate compound, methods for preparing the magnetic substance, methods for preparing the magnetisable compound. The present invention enables preparing the therapeutic agent using the magnetic properties of the complex of metal and salen for the purpose of magnetising the specific therapeutic agent by chemical binding of the therapeutic agent to the complex of metal and salen so that to deliver the therapeutic agent to an affected area.

EFFECT: preparing the complex compound of the magnetisable metal and salen.

16 cl, 20 dwg, 10 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: invention refers to photosensitisers, namely to a conjugate of RGD-containing peptide or RGD-peptidomimetic and a photosensitiser selected from tetraarylporphyrin of formula:

or chlorophyll or tbacteriochlorophyll of formulae , or wherein tetraarylporphyrin or said chlorophyll or bacteriochlorophyll derivative of formula I, II or III contains at least one residue of the RGD-containing peptide or RGD-peptidomimetic. The values of M and radicals is related with those specified in the patent claim. Also, there are offered a pharmaceutical composition, a diagnostic technique for tumours by dynamic fluorescent visualisation, molecular magnetic resonant tomography (MPT) for diagnosing tumours and a method of photodynamic therapy of tumours.

EFFECT: invention provides producing the conjugate of the RGD-containing peptide or RgD-peptidomimetic and the photosensitiser which is applied in methods of photodynamic therapy and diagnosing of tumours.

23 cl, 75 dwg, 43 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing bis(3,6-di(tert-butyl)benzosemiquinolates-1,2) of cobalt (II) or manganese (II) or nickel (II), of general formula: M(SQ)2 , where: SQ is 3,6-di(tert-butyl)benzoquinolate-1,2, and M = Mn(II) or Co(II) or Ni(II). The method is characterised by that a disubstituted salt of an alkali metal salt and 3,6-di(tert-butyl) pyrocatechol-1,2 is obtained, followed by reaction thereof with 3,6-di(tert-butyl)benzoquinoline-1,2. The formed 3,6-di(tert-butyl)benzosemiquinolate-1,2 of the alkali metal reacts with a Co(II) or Mn(II) or Ni(II) halide in an inert atmosphere in tetrahydrofuran.

EFFECT: simple synthesis of bis-semiquinolates of metals.

4 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: in the compound of formula I, M denotes identical or different metal atoms selected from a group comprising: Pd, Fe, Mn, Co, Ni, Cu, Zn or Mo, R1 and R2 independently denote hydrogen, amino, hydroxyl, carboxy, cyano, C1-12alkyl, C2-12alkenyl, C2-12alkynyl, C1-12alkoxy, C1-12alkylamino, C1-12alkoxycarbonyl, C1-12alkylamido,arylamido. Alkyl groups in the said substitutes may in turn be substituted with one or more of the following groups: hydroxyl, oxo, carboxy, amino or amido, R3-R10 independently denote hydrogen, or NHR3R4 and NHR5R6, taken together, and(or) NHR7R8 and NHR9R10, taken together, denote a ligand (or ligands) containing one or more donor aliphatic or aromatic nitrogen atoms and which occupy the cis-position near metal (M) atoms. The invention also discloses a pharmaceutical composition, use of the compound to prepare a medicinal drug and a therapeutic treatment method.

EFFECT: obtaining compounds capable of boosting efficiency of medicinal drugs.

25 cl, 17 ex, 23 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a radiopharmaceutical agent for diagnosing or treating (therapy) skeletal bone injury, containing a complex of zoledronic acid with 99mtechnetium or 188rhenium isotopes, zoledronic acid, tin halide or possibly an antioxidant - ascorbic or gentisic acid. The invention also relates to a method of preparing said radiopharmaceutical agent, involving mixing a lyophilisate, obtained by mixing a zoledronic acid solution and a solution of tin dichloride in hydrochloric acid in an inert gas atmosphere and adding a metal hydroxide, with a salt of a metal from the group of isotopes and a radionuclide solution.

EFFECT: more effective use of the compounds.

4 cl, 2 ex, 14 tbl

FIELD: chemistry.

SUBSTANCE: method involves reacting triethanol ammonium salts of o-cresoxyacetic and p-chloro-o-cresoxyacetic acid with the corresponding metal salt in alcohol or aqueous medium preferably at room temperature for 1-48 hours. The three-component complexes are extracted through solvent distillation with subsequent washing of the formed powder with ether and drying in a vacuum. The said complexes can be used as a base for making medicinal drugs.

EFFECT: design of a method of preparing complexes of o-cresoxy- and p-chloro-o-cresoxyacetic acid, triethanolamine and metals having formula n[R(o-CH3)-C6H3-OCH2COO-•N+H(CH2CH2OH)3]•MXm, where R = H, p-Cl; M = Mg, Ca, Mn, Co, Ni, Cu, Zn, Rh, Ag; X = CI, NO3, CH3COO; n = 1, 2; m = 1-3.

2 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of producing manganese (II) alcoholates which can be used in different syntheses, in purification of complex multicomponent mixtures from alcohols, in analytical control and in scientific research. The method involves direct reaction of metal with alcohol in a vertical bead mill. The liquid phase used is the corresponding alcohol taken in mass ratio to glass beads of 1:1.5. Manganese is taken in amount of 5.81-43.3 % of the mass of the liquid phase. The process is initiated at room temperature and is carried out while controlling by taking samples and determination of content of manganese (II) compounds until all the loaded metal is virtually exhausted, after which stirring in the glass bead is stopped. The suspension of the reaction mixture is separated from the glass beads and taken for filtering. The alcoholate residue is washed with a liquid phase solvent and taken for purification by recrystallisation, and the filtrate and washing liquid phase with traces of dissolved alcoholate are returned for a repeated process. As a rule, the alcohol used is C1-C5-alcohol with normal and isomeric structure, cyclohexanol, ethyl cellosolve and ethylene glycol.

EFFECT: method allows for reaction of manganese with alcohol in conditions where the reaction could have been quantitatively insufficient with respect to the reagent, could have taken place at technically acceptable rates and led to accumulation the main mass of the product in solid phase, which can be easily separated by simple filtering.

2 cl, 2 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new isatin-5-sulphonamide derivatives of general formula or their physiologically acceptable salts, wherein R represents phenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, tetrahydropyranyl, diazine or triazolyl methyl optionally substituted by one C1-6alkyl, which can be additionally substituted by one halogen; R' represents phenyl optionally substituted by one or two halogens, or triazolyl optionally substituted by one C1-6alkyl which can be additionally substituted by one halogen; provided R means phenyl, R' represents optionally substituted triazolyl, pharmaceutical compositions containing the above derivatives, using them as molecular imaging agents, using them in diagnosing or treating diseases or disorders related to apoptosis dysregulation, methods for synthesis of the above derivatives, methods for molecular imaging of caspase activity and apoptosis, and methods for assessing the therapeutic exposure of the analysed compound on caspase activity.

EFFECT: new isatin-5-sulphonamide derivatives are described.

27 cl, 26 dwg, 4 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula [1] or their pharmaceutically acceptable salts, which possess properties of an inhibitor of the JAK2 thyrokinase activity. In general formula radicals are selected from group (I) or (II). In group (I) X represents CH or N; R1 represents a halogen atom and R2 represents H, a halogen atom, CN, or is selected from the groups of formulas

,

or a group -ORP or 5-6-membered heteroaryl, containing 1-4 nitrogen atoms and optionally additionally containing an oxygen or sulphur atom or containing an oxygen atom as a heteroatom, optionally substituted; or (II) X represents -CRA; and RA represents a group of formula , RB represents (a) amino, optionally substituted with one or two groups, selected from the group, consisting of C1-6alkyl, C3-6cycloalkyl, (C3-6cycloalkyl)C1-6alkyl and C1-3alcoxyC1-3alkyl, (b) C1-3alcoxy, (c) hydroxy or (d) a 5-6-membered saturated cyclic amino group, which additionally can contain a heteroatom, selected from an oxygen atom; R1 represents a halogen atom and R2 represents H; R3 -R5 have values given above. Other values of the radicals are given in the invention formula.

EFFECT: compounds can be applied for the prevention or treatment of cancer, for instance hematologic cancer disease or a solid form of cancer, inflammatory disorder, for instance, rheumatoid arthritis, inflammatory intestinal disease, osteoporosis or multiple sclerosis and angiopathy, for instance, pulmonary hypertension, arteriosclerosis, aneurism or varicose veins.

14 cl, 19 tbl, 234 ex

FIELD: medicine, pharmaceitics.

SUBSTANCE: invention relates to particular derivatives of N-(phenylsulphonyl)benzamide, given in i.1 of the invention formula. The invention also relates to a pharmaceutical composition, possessing an inhibiting activity with respect to anti-apoptotic proteins Bcl-2, containing an effective quantity of one of the said compounds or a therapeutically acceptable salt of such a compound.

EFFECT: N-(phenylsulphonyl)benzamide derivatives as inhibitors of the anti-apoptotic proteins Bcl-2.

2 cl, 2 tbl, 458 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new radiopharmaceutical compounds of structural formula

.

In formula I, R means H or a (C1-C8)alkyl group; W means a bond, -CH(NH2)-, -C(O)-NH-CH(COOH)-, -O-(CH2)n-O-(CH2)n- or -(CH2)nO(CH2)nO(CH2)n; Z means -NHC(O)-, -NH-C(O)-CH(NH2)- or -C(O)-NH-CH(COOH)-; e is an integer from 1 to 4; f is an integer from 0 to 10; g is an integer from 0 to 10; n is an integer from 0 to 2; the radical NRaRb values are presented in the patent claim.

EFFECT: invention refers to the radionuclide complex containing a radioactive metal and the above compounds, to a pharmaceutical compound for visualising and to a method for visualising any patient's region, e.g. a tissue specified in the spleen tissue, kidney tissue or PSMA-expressing tumour tissue.

21 cl, 6 dwg, 1 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: described are novel heteroaryl-N-aryl-carbamates of general formula , where: Ar1 is phenyl, probably substituted with C1-C6halogenalkyl or C1-C6halogenalkoxy; Het is triazolyl; Ar2 is phenyl; X1 represents O or S; X2 - O; R4 - H or C1-C6alkyl; n=0, 1 or 2; and R1, R2 and R3 are independently selected from H, CN, C1-C6alkyl, C1-C6halogenalkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkinyl, C(=O)O(C1-C6alkyl), phenyl and Het-1, where Het-1 is a 5-membered unsaturated heterocyclic ring, containing one heteroatom, selected from sulphur or hydrogen, or a 6-membered unsaturated heterocyclic ring, containing one nitrogen atom as a heteroatom, and Het-1 can be substituted with F, Cl, C1-C6alkyl, C1-C6halogenalkyl or C1-C6alkoxy, and a method of fighting pest insects Lepidoptera or Homoptera with the application of the said compounds as insecticides and acaricides.

EFFECT: increased efficiency.

5 cl, 2 tbl, 80 ex

FIELD: chemistry.

SUBSTANCE: invention relates to methods of obtaining a compound of formula (4), which can be used as a serine protease inhibitor.

EFFECT: protease inhibitors are useful for treatment HCV infections.

7 cl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to a compound of Formula

,

where Y represents a group of formula -(CR9R10)-; X is selected from the group, consisting of -C(=O)-, -OC(=O)-, -NHC(=O)-, -(CR11R12)- and -S(-O)2-; Z represents a group of formula -(CR13R14)q-; R1 is selected from the group, consisting of C1-C12alkyl, optionally substituted with one substituent, selected from naphthyl, indole and biphenyl; C2-C12alkenyl, substituted with a substituent, selected from thienyl, naphthyl and phenyl, with the said phenyl being optionally substituted with 1-2 substituents; selected from halogen, trifluoroalkyl, C1-C6alkyl, methoxy and hydroxy; C3-C6cycloalkyl; C6-C10aryl, optionally substituted with 1-2 substituents, selected from halogen, phenyl, amino, phenoxy, C1-C6alkyl, methoxy, hydroxyl and carboxy; and C4-C9heteroaryl, selected from indole, quinoline, quinoxaline, benzofuranyl, benzothiophene, benzimidazole, benzotriazole, benzodioxin, benzothiasole, pyrazole, furyl and isoxazole, optionally substituted with a substituent, selected from C1-C6alkyl and phenyl; R2 and R3 each is independently selected from the group, consisting of H and C1-C12alkyl; R4a is selected from the group, consisting of H, C1-C12alkyl, optionally substituted with phenyl; C2-C12alkenyl, C3-C6cycloalkyl, C6aryl, C(=O)R15, C(=O)NR15R16, C(=O)OR15, SO2R15 and -C(=NR15)-NR16R17; R4d represents hydrogen or R4a and R4b, taken together with a nitrogen atom, which they are bound to, form an optionally substituted heterocyclic fragment, selected from piperidine, morpholine, pyrrolidine and azetidine, where the substituent is selected from C1-C12alkyl, hydroxy, halogen, carboxy and oxo; each R5a and R5b represents H, or R6, R7 and R8 each is independently selected from the group, consisting of H, C1-C12alkyl, C3-C6cycloalkyl, C6-C10aryl, optionally substituted with halogen, or taken together with a carbon atom, which they are bound to, two or more of R6, R7 and R8 form a fragment, selected from the group, consisting of C2-C12alkenyl; C3-C6cycloalkyl, optionally substituted with C1-C6alkyl; C6aryl, optionally substituted with 2 substituents, selected from halogen; each R9 and R10 represents H or C1-C12alkyl, substituted with naphthyl; each R11 and R12 represents H; R13 and R14 represent H, or each R15, R16 and R17 is independently selected from the group, consisting of H, C1-C12alkyl, C3-C6cycloalkyl, C6aryl, substituted with one substituent, selected from C1-C6alkyl; and C5-heteroaryl, additionally containing one nitrogen atom, with the said heteroaryl representing pyridyl; q represents an integer number, selected from the group, consisting of 2, 3 and 4; r represents 1; or its pharmaceutically acceptable salt. The invention also relates to particular compounds of 1,4-diazepan-2-one derivatives.

EFFECT: obtaining 3-aminoalkyl-1,4-diazepan-2-one melanocortin-5 receptor antagonists.

21 cl, 7 tbl, 110 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R1 and R2 have the following values: (i) R1 and R2 together form =O; (ii) R1 and R2 together with carbon atom, which they are bound with, form duoxacycloalkyl; R1 represents hydrogen or halogen; and R2 represents halogen; (iv) R1 represents C1-6alkyl, where alkyl is optionally substituted with cyano, -RxS(O)qRv or -RxNRyRz; and R2 represents hydrogen; (v) R1 represents -OR12 or -NR13R14; and R2 represents hydrogen, deutero or phenyl, which is optionally substituted with halogen; R3 represents hydrogen, halogen, C1-6alkyl, cyano, halogen C1-6alkyl, C3-10cycloalkyl or C1-6alkoxy; R4 and R5 represent hydrogen; R6 is independently selected from halogen, C1-6alkyl, halogenC1-6alkyl, -RxOR18 and -RxS(O)qRv; R7 independently represents halogen or -RxORw; R12 is selected from hydrogen and C1-6alkyl, R13 represents hydrogen; R14 is selected from hydrogen, C3-10cycloalkyl, -C(O)Rv and -C(O)ORw; R18 represents hydrogen, C1-6alkyl, or pyperidinyl, where R18 is optionally substituted with 1-3 Q1 groups, each Q1 is independenly selected from hydroxyl, C1-6alkoxy, C1-6alkoxycarbonyl, carboxyl and morpholinyl; Rx independently represents C1-6alkylene or simple bond; Rv and Rw represent hydrogen or C1-6alkyl; Ry and Rz represent hydrogen; n has value 0-4; p has value 0-5; and each q independently has value 0, 1 or 2. Invention also relates to compounds of formula (II) , where substituents have values, given in the invention formula, to pharmaceutical composition, possessing inhibiting activity with respect to JAK kinases, containing compounds of formula (I) or (II), methods of treating JAK-modulated disease, and application of compounds of formula (I) or (II).

EFFECT: compounds of formula (I) or (II) as inhibitors of JAK kinases.

32 cl, 6 dwg, 2 tbl, 84 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted isoquinolines and isoquinolinones of formula (I) and to their stereoisomer and/or tautomer forms and/or pharmaceutically acceptable salts, wherein R1 is H, OH or NH2; R3 is H; R4 is H, halogen or (C1-C6)alkylene-R'; R5 is H, halogen, (C1-C6)alkyl; R7 is H, halogen, (C1-C6)alkyl, O-(C1-C6)alkyl; R8 is H; R6 is absent; or is one of (C1-C4)alkylene related to a cycloalkyl ring related to a cycloalkyl ring, wherein (C1-C4)alkylene forms a second bond to another carbon atom of the cycloalkyl ring to form a bicyclic ring system, R10 is H, phenyl, or pyridine, wherein phenyl is unsubstituted or substituted; R11 is H, (C1-C6)alkyl; or R11 and R12 together with the carbon atom to which they are attached form (C3)cycloalkyl; R12 is (C1-C6)alkyl, (C3-C8)cycloalkyl or phenyl; or R12 is H, provided r=2 and another R12 is other than H; or R11 and R12 together with the carbon atom to which they are attached form (C3)cycloalkyl; R13 and R14 are independently H, (C1-C6)alkyl, (C1-C6)alkylene-R', C(O)O-(C1-C6)alkyl, n is equal to 0; m is equal to 1 or 2; s is equal to 1 or 2; r is equal to 1 or 2; L is O, NH; R' is (C3-C8)cycloalkyl, (C6-C10)aryl; wherein in R11 and R12 residues, alkyl is unsubstituted or optionally substituted by one OCH3; wherein in R11 and R12 residues, alkyl is unsubstituted or optionally substituted by one or more halogens; wherein in R10 and R12 residues, (C6-C10)aryl is unsubstituted or optionally substituted by one or two groups optionally specified in halogen, CN, (C1-C6)alkyl, O-(C1-C6)alkyl, SO2-(C1-C6)alkyl, CF3 and OCF3. Also, the invention refers to using a compound of formula (I).

EFFECT: there are prepared new isoquinoline and isoquinolinone derivatives effective in treating and preventing the diseases related to Rho-kinase inhibition.

38 cl, 132 ex

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