Binuclear nitrosyl iron complexes with benzazeheterocyclic derivatives, ways of its production

FIELD: pharmacology.

SUBSTANCE: invention refers to binuclear nitrosyl iron complexes with benzazeheterocyclic derivatives with general formula [Fe2(SR)2(NO)4] where R is And where X is NH, S, R1 is lower alkyl. Also there is proposed method for its production, nitrogen monoxide donor, application as oncology drug and for production of oncology drug, pharmaceutical composition and set used for treatment of oncology diseased.

EFFECT: production of binuclear nitrosyl iron complex that is used as an oncology drug with increased effectiveness and decreased toxicity.

15 cl, 3 ex, 4 tbl, 3 dwg

 

The technical field

The invention relates to a binuclear nitrosyl complexes of iron and can be used in medical practice to create a new generation medications for the treatment of cancer.

Prior art

In recent years, with the aim of creating drugs of new generation, used in the treatment of cancer, is an intensive search for anticancer agents based on transition metal complexes with improved spectrum of activity and reduced side effects in comparison with the already used clinical drugs, such as cisplatin, sodium nitroprusside, etc.

Interest in nitrosyl complexes of metals has increased due to open possibilities for their use as an effective NO-donors in medicine, in particular for the treatment of neoplastic diseases. The use of NO donors as a new class of antitumor agents is associated with the important role of NO in the process of growth of malignant tumors [Wink D., Vodovoz J., Cook, J., Biochemistry, 1998, 63, 7, pp. 948-957]. It is shown that the nitric monoxide changes the level of apoptosis of tumor cells, the activity of a gene p53 and neoangiogenesis [Brune B., Scheneiderhan N., Nitric oxide evoked p53 accumulation and apoptosis, Toxicol Letters, 2003, 193, 2, RR-23], and inhibits the activity of key repair protein O6-methylguanine-the NC-methyltransferase mammals [L. Liu, M. Xu-Welliver, S. Kanagula, H.E. Pegg, Inactivation and degradation of O6-alkylguanine-DNA alkyltransferase after reaction with nitric oxide., Canser. Res., 2002, 62, R-3043].

Binding of NO to the active centers of metallothionen, in particular with megamovie iron-containing proteins, has been studied intensively [Ford P.C., Lorkovic I.M., Chem. Rev., 2002, 102, 993; Hoshino, M.; Laverman LE, Ford P.C., Coord. Chem. Rev., 1999, 187, R]. It is established that one of the forms of natural reservoirs are NO nitrosyl iron complexes with tolstushki ligands [A.R. Butler, Megson I.I., Chem. Rev.,2002, 102, pp.1155-1165].

Their synthetic models - ethers “red salt” Russa have the composition [Fe2(SR)2(NO)4], where R = Et, t-Bu, (CH2)4-CH3C6H5F, Ph [T. Thomas, J.H. Robertson, E.G. Cox, Acta. Crystalogr., 1958, 11, p.599; C. Glidewell, M.E. Harman, M.B. Hursthouse, I.L. Johnson, M. Motevalli, J. Chem.Res., 1998, 212, p.1676; R.E. Marsh, A.L. Spek, Acta. Crystalogr., Sect. B. Struct. Sci., 2001, 57, p.800; C. Jinhua, M. Shaoping, H. Jinling, L. Jiaxi, Chinese J. Struct. Chem., 1983, 2, p. 263; T. B. Rauchfuss, T.D. Weatherill,Inorg. Chem., 1982, 21, pp. 827-830].

These binuclear diamagnetic serenadasunny complexes with R = Alk generate NO in thermo - or photoactivation [J.L. Bourassa, P.C. Ford, Coord. Chem. Rev., 2000, 200-202, pp. 887-900] and can serve as a new promising anticancer NO-generousity agents.

Also known binuclear paramagnetic serenadasunny iron complexes with ligands of the type μ-N-C-S, which are synthetic analogs of natural NO-donors-dinitrosyl iron complexes (DNIC)with cysteine, the glutathione and other tolstushki ligands of low molecular weight [O.A. Rakova, N.A. Sanina, S.M. Aldoshin, N.A. Goncharova, G.V.Shilov, Yu.M. Shulga, N.S. Ovanesyan, Inorganic Chemistry Communications 2003, 6, 145-148; A. F.Vanin, N.A. Sanina, V. A. Serezhenkov, D. Sh. Burbaev, V.I. Lozinsky and S.M. Aldoshin, Nitric oxide: biology &chemistry 2007, 16, 82-93].

However, the known synthetic NO donors in different classes are used as therapeutic agents for the treatment of cancer, and are used only for reinforcement (in varying degrees depending on the chemical nature of existing chemotherapeutic agents or radiotherapy [Wink D., Vodovoz J., Cook, J., Biochemistry, 1998, 63, 7, pp. 948-957; N.P. Konovalova, S.A. Goncharova, L.M. Volkova, T.A. Raevskaya, L. T. Eremenko, A.M. Korolev, Nitric Oxide: Biology and Chemistry, 2003, 8, pp. 59-64; Yang, W., Rogers P.A., H. Ding, J. Biol. Chem., 2002, 277, pp. 12868-12873; O. Siri, A. Tabard, P. Pullumbi, R. Guilard, Inorg. Chim. Acta 2003, 350, p. 633; J.L. Burgaud, E. Jngini, Del Soldato P. Ann, N.Y. Acad. Sci. 2002, 962, p.360; T.I. Karu, L.V. Pyatibrat, G.-S. Kalendo, Toxicology Letters, 2001, 121, p.57].

In the work of A. Janczyk et al. Nitric Oxide, 2004, 10, 1, pp. 42-50, studied the direct cytotoxic action of nitrosyl iron complex Na[Fe4S3(NO)7] on human melanoma cells in human and mouse. However, the nitrosyl complex of iron generates NO by photoactivation (even in darkness), and may not be used as anticancer drugs because of the high toxicity against normal cells.

That is they way there is a need for other antitumor tools with increased efficacy and reduced toxicity.

The present invention is to expand the Arsenal of anticancer agents and the creation of anticancer drugs based on transition metal complexes with improved spectrum of activity and reduced side effects, in particular, the medicinal product on the basis of binuclear nitrosyl iron complexes with besuseradminclient derivatives acting as donors of NO, with increased activity and reduced toxicity.

A brief description of the nature of the invention

In one aspect the invention relates to new binuclear nitrosyl complexes of iron with besuseradminclient derivative of the formula [Fe2(SR)2(NO)4]where R represents a

where X represents NH, S or O, R1represents lower alkyl.

In another aspect the invention relates to a method for binuclear nitrosyl iron complexes with besuseradminclient derivative of the formula [Fe2(SR)2(NO)4] processing thiosulfate nitrosyl iron complex corresponding besuseradminclient the thiol in the stoichiometric ratio in the presence rebuild the El, in an alkaline environment. This method allows for the first time to obtain the claimed complexes in crystalline form.

In an additional aspect, the present invention relates to a donor monoxide nitrogen, which represents a binuclear nitrosyl complex of iron with besuseradminclient derived as described above.

In the following aspect the present invention relates to the use of binuclear nitrosyl iron complexes with besuseradminclient derivative of the formula [Fe2(SR)2(NO)4] as anticancer drugs.

In an additional aspect, the present invention relates to the use of binuclear nitrosyl iron complexes with besuseradminclient derivative of the formula [Fe2(SR)2(NO)4] for anticancer drugs.

In the following aspect the present invention relates to pharmaceutical compositions containing an effective amount binuclear nitrosyl iron complex with besuseradminclient derivative of the formula [Fe2(SR)2(NO)4] and a pharmaceutically acceptable carrier.

In the following aspect the present invention relates to a kit used for the treatment of cancer, comprising: (1) a pharmaceutical composition comprising bieder the first nitrosyl complex of iron with besuseradminclient derivative of the formula [Fe 2(SR)2(NO)4], where R has the above meanings, in a sealed package; and (2) auxiliary tools.

Description of figures:

Figure 1 shows the molecular structure of the complex (Fe2S2N8C14H10O4) [complex I].

The complex has having a center of inversion dimer binuclear structure (figure 1). In the dimer of two tetrahedrally coordinated by two groups and NO two besuseradminclient Mililani of the iron atom linked by a bridge: Fe-S-C-N-Fe. The complex contains two molecules of the solvent is acetone.

Figure 2 presents the crystal structure of the complex (Fe2S2N8C14H10O4) [complex I].

Figure 3 shows the variation in the differential absorption spectra in time during the interaction of complex I (Fe2S2N8C14H10O4) hemoglobin (b). The solvent is 0.05% phosphate buffer, pH 7.0, containing 3,3% DMSO, 25°C.

Detailed description of the invention

New binuclear nitrosyl iron complexes with besuseradminclient derivatives according to the present invention have the General formula [Fe2(SR)2(NO)4]where R represents a

where X represents NH, S, R1represents lower alkyl.

Preferably R represents the nd benzimidazole-2-yl, 5-methyl-benzimidazole-2-yl or benzothiazol-2-yl.

Used herein, the term "lower alkyl" means an alkyl radical with a straight or branched chain, containing from 1 to 6 carbon atoms. Examples of such alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl.

In the prior art there is no information about the claimed compounds and the way they are received.

Way to generate new binuclear nitrosyl iron complexes with besuseradminclient derivative of the formula [Fe2(SR)2(NO)4], where R has the above significance, is that thiosulfate nitrosyl complex of iron bis(μ-thiosulfate-S)-bis(dinitrodiphenyl)(2-) sodium Na2[Fe2(S2O3)2(NO)4] (TNCG) are processed with the proper besuseradminclient the thiol in the stoichiometric ratio in the presence of a reducing agent, and the process is conducted in an alkaline medium, followed by separation of the target product by known methods.

Preferably, the process is carried out at room temperature, preferentially at 18-25°C.

Preferably, the process is conducted in an oxygen-free atmosphere.

As besuseradminclient of thiol, preferably, use of benzimidazole-2-thiol, 5-methylbenzimidazole-2-thiol or benzothiazol-2-thiol.

is as a reducing agent in the method according to the present invention using hydrogen, thiosulfate metals, such as Na2S2O3·5H2O, hydrogen sulfide and aliphatic thiols.

The inventors have found that the binuclear nitrosyl iron complexes with besuseradminclient derivatives of the present invention are effective NO donors, generating nitric monoxide spontaneous decomposition in proton environments (such as water, blood and its components, physiological solutions, and the like), in the absence of chemo-, photo - or enzyme activation. Thus, the complexes of the present invention represent a promising new class of donors of nitrogen monoxide - synthetic analogues of the active sites nitrosyl Nehemiah iron-sulphur proteins - natural “depot” NO. Therefore, the present invention in an additional aspect relates to the donors of nitrogen monoxide, which represents a binuclear nitrosyl iron complexes with besuseradminclient derived above.

Binuclear nitrosyl iron complexes with besuseradminclient derivatives of natural aromatic thiols of the present invention have antitumor activity against tumor cells of a mammal, in particular humans.

The present invention is further directed to the use of binuclear nitrosyl iron complexes with be zasaharivshegosya derivative of the formula [Fe 2(SR)2(NO)4], where R has the above significance, as anticancer drugs.

In particular, the compounds of the present invention can be used to treat the following cancer: cancer of the ovary, adenocarcinoma of the breast, melanoma B-16, epidermoid carcinoma Lewis.

The iron complexes according to the present invention are suitable for inhibiting the growth of tumors in mammals and is preferably introduced in the form of a pharmaceutical composition comprising an effective antitumor amount of a compound according to the present invention in combination with at least one pharmaceutically or pharmacologically acceptable carrier and/or excipient. The media is also known from the prior art, as excipient, filler, excipient, additive or diluent, is any substance which is pharmaceutically inert, gives the appropriate consistency or form to the composition, and does not reduce therapeutic efficacy of antitumor compounds. The media is a "pharmaceutically or pharmacologically acceptable"if it does not cause any adverse, allergic or other adverse reactions when administered to a mammal or human, respectively.

The present invention relations is seeking also to the use of binuclear nitrosyl iron complexes with besuseradminclient derivative of the formula [Fe 2(SR)2(NO)4], where R has the above significance, to obtain antitumor drugs.

The present invention additionally provides pharmaceutical compositions containing an effective amount binuclear nitrosyl iron complex with besuseradminclient derivative of the formula [Fe2(SR)2(NO)4], where R has the above significance, and a pharmaceutically acceptable carrier.

Preferably as a pharmaceutically acceptable carrier in a composition according to the invention is used protonotariou environment.

As the pharmaceutically acceptable carrier in a composition according to the invention is used, preferably, the mixture protonotaria environment and dimethyl sulfoxide.

Preferably, as protonotaria environment using water, saline solution, water-soluble biopolymers.

Preferably, binuclear nitrosyl complex of iron with besuseradminclient derivative is present in the composition in amount of 50-100 microns.

Pharmaceutical compositions containing protivoopuxolevye compounds according to the present invention can be obtained by any conventional method. Necessary preparative form chosen depending on the selected method of administration. Compositions according to the invention can is be prepared for any way of introduction so, to the target tissue was available in this route of administration. Suitable routes of administration include, but are not limited to, oral, parenteral (e.g. intravenous, intraarterial, subcutaneous, rectal, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal or intrasternally), local (nasal, percutaneous, ocular), vnutrishkolnoe, vnutriobolochechnoe, small intestine, lung, intralymphatically, intracavitary, vaginal, transurethrally, intradermal, ear, intramammary, transbukkalno, orthotopic, intratracheal, intranidus, percutaneous, endoscopic, cressilia, sublingual and intestinal injection.

Pharmaceutically acceptable carriers for use in the compositions according to the present invention are well known to the specialist and they are chosen depending on a number of factors: specific antitumor compound and its concentration, stability and expected bioavailability; the disease, disorder or condition of the person being treated with the composition; the subject, its age, weight and General condition; and the route of administration. Suitable carriers are easily determined by the expert (J.G. Nairn in: Remington''s Pharmaceutical Science (ed. A. Gennaro), Mack Publishing Co., Easton, Pa, 1985, PP. 1492-1517).

Of the composition, preferably, the floor is up in the form of tablets, dispergiruyushchie powders, pills, capsules, gelatin capsules, dripping with the floor, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, tablets, pills, cakes or any other dosage forms that can be administered orally.

Compositions according to the present invention for oral administration include an effective antitumor amount of a compound according to the invention in a pharmaceutically acceptable carrier. Suitable carriers for solid dosage forms include sugars, starches, and other common substances, including lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, lures, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, gum Arabic, corn starch, potato starch, sodium saccharinate, magnesium carbonate, tragakant, microcrystalline cellulose, colloidal silicon dioxide, nitrocresols, talc, magnesium stearate and stearic acid. Further, such solid dosage forms may be uncoated or can be coated with a known coating methods, for example, to delay disintegration and absorption.

Antitumor compounds according to the present invention is also preferably used for the preparation of dosage forms for parenteral administration, in the example, as dosage forms for injection intravenous, intraarterial, subcutaneous, rectal, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal or intrasternally ways. Compositions according to the invention for parenteral administration include an effective antitumor amount of antitumor compounds in a pharmaceutically acceptable carrier. Suitable for parenteral dosage forms include solutions, suspensions, dispersions, emulsions, or any other dosage form, which may be introduced parenterally. Methods and compositions for receiving parenteral dosage forms are known from the prior art.

In the composition according to the invention may be included for various purposes a small number of additional components that are well known in the pharmaceutical industry. These components are for the most part give properties that increase the retention time of antitumor compounds in the introduction, we contribute to the stability of the composition, regulate pH value, facilitate the introduction of antitumor compounds in pharmaceutical compositions, etc. Each of these components individually is present in amounts of, preferably, less than about 15 wt.%, over predpochtitelno, less than about 5 wt.% and, most preferably, less than about 0.5 wt.% calculated on the total weight of the composition. Some components, such as fillers or diluents, can be up to 90 wt.% calculated on the total weight of the composition, as is well known in the technology of preparation of medicines. Such additives include createsite components to prevent the deposition of iron complex with thiophenols, surfactants, wetting or emulsifying agents (e.g. lecithin, Polysorbate-80, tween®80, pluronic-60, polyoxyethylenated), preservatives (e.g., ethyl-p-hydroxybenzoate), protects from the effects of microbes means (for example, benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal, and paraben), agents for adjusting the pH or buferiruemoi agents (e.g., acids, bases, sodium acetate, sorbitan-monolaurate), components for control osmolarity (for example, glycerin), thickeners (for example, aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methylcellulose, hydroxypropylcellulose, tristearin, complex citylove esters wax, polyethylene glycol), pigments, dyes, additives, giving fluidity, non-volatile silicones (for example, cyclomethicone), clay (e.g. bentonite), adhesives, which increases the amount of agents, flavorings, sweeteners, adsorbents, fillers (for example, water, saline, solutions of electrolytes), binders (for example, starches such as corn starch, wheat starch, rice starch or potato starch, gelatin, tragakant, methylcellulose, hypromellose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers, gum Arabic), loosening agents (e.g., starches such as corn starch, wheat starch, rice starch, potato starch or carboximetilkrahmal, structured polyvinylpyrrolidone, agar, alginic acid or its salt, such as sodium alginate, nitrocresols or crosspovidone), lubricating agents (for example, silicon dioxide, talc, stearic acid or its salts, such as magnesium stearate, or polyethylene glycol), agents for coatings (for example, concentrated solutions of sugar, including gum Arabic, talc, polyvinylpyrrolidone, carbopol, polyethylene glycol, or titanium dioxide) and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenols and thiophenol).

In accordance with a preferred embodiment of the pharmaceutical composition according to the invention includes at least one net in the first pharmaceutically acceptable solvent and anti-tumor compound, possessing solubility therein at least about 10-60 mg/ml Without regard to any particular theory believe that the solubility in dimethyl sulfoxide antitumor compounds can be directly related to its effectiveness. Also preferred is that the antitumor compound has an ID value100(that is, the concentration of drug causing 100%inhibition of the formation of the colony), at least 4 times less than that of cisplatin, when carrying out measurements in accordance with the methodology described in the book "Experimental evaluation of anticancer drugs in the USSR and the USA" Ed. by Z.P. Sofianou, A.B. sarcina (USSR), A. Goldin, A. Klein (USA) M.: Medicine, 1979, S. 71-105.

The introduction of the dosage forms listed ways can be continuous or intermittent, depending, for example, on the physiological state of the patient, whether the purpose of the introduction of therapeutic or prophylactic, and other factors, known or estimated practitioner.

Dose and scheme to introduce the pharmaceutical compositions according to the invention can be easily determined by the oncologist. It is clear that the dose of anticancer compounds depends on age, sex, health and weight of the recipient, type the concurrent treatment, if any, is astate processing and the nature of the desired effect. For any way of introduction, the exact amount used anticancer compounds, as well as appointed by the dose required to achieve the described here useful effects, also depends, in part, on factors such as bioavailability of anticancer compounds, a human disease that is treated, the desired therapeutic dose, and other factors that are obvious to the expert.

The concentration of anticancer compounds in the liquid pharmaceutical composition is most preferably 50-100 μm. Generally, the preferred relatively low concentration, so as anticancer compound is most soluble at low concentrations.

Emulsion for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., DMSO, dichloromethane), with formation of a solution. To the solution was added with stirring with an appropriate volume of media, which is an emulsion, such as emulsion (Liposyn II or Liposyn III, getting a pharmaceutically acceptable emulsions for parenteral administration to a patient. If desirable, such emulsions can be prepared with support of minimum or without solution of Cremophor®.

Dissolve the s for parenterale injection can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent, capable of dissolving the compound (e.g., DMSO), with formation of a solution. To the solution was added with stirring with an appropriate volume of media that represents protonotariou environment (salt solutions, solutions of sugars, water-soluble polymers, proteins, electrolytes) for parenteral administration to a patient.

So, for example, preparative liquid forms as a carrier typically use non-aqueous pharmaceutically acceptable polar solvents, such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, and water, salt solutions, solutions of dextrose (for example, DW5), solutions of electrolytes or any other proton pharmaceutically acceptable environment.

Suitable non-aqueous pharmaceutically acceptable polar solvents include, but are not limited to, amides (for example, dimethylacetamide (DMA), diethylenetriaminepenta, dimethylformamide, N-(β-hydroxyethyl) lactamide, N,N-dimethylacetamide, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone or polyvinylpyrrolidone); esters (e.g. esters of acetic acid such as monoacetin, diacetin and triacetin; aliphatic or aromatic esters, such as ethylcaproic or ethyloctanoic, alkyllead, benzyl benzoate, benzoylacetate, dimethylsulfoxide (DMSO), esters of glycerol, such as what it is, di - or triglyceriderich or tartratami, ethylbenzoic, ethyl acetate, ethylcarbonate, ethyllactate, etiloleat, esters of fatty acids sorbitan, esters of fatty acids and of polyethylene glycol (PEG), glycerylmonostearate, esters of glycerides such as mono-, di - or triglycerides, fatty acid esters, such as isopropylmyristate, esters based on fatty acids and PEG, such as PEG-hydroxyoleic and PEG-hydroxystearate, N-methylpyrrolidinone, pluronic-60, polyoxyethylenated polyesters based on sorbitol and oleic acid, such as poly(oksietilenom)30-60sorbitol(oleate)2-4, poly(oksietilenom)15-20monooleate, poly(oksietilenom)15-20mono-12-hydroxystearate and poly(oksietilenom)15-20monoricinoleate; polyoxyethylenesorbitan esters such as polyoxyethylene sorbitan monooleate, polyoxyethylenesorbitan, polyoxyethylenesorbitan, polyoxyethylenesorbitan and Polysorbate® 20, 40, 60 or 80 company ICI Americas, Wilmington, DE; polyvinylpyrrolidone; modified acceleratedly esters of fatty acids, such as gidrirovannoe polyoxyl(40)-castor oil and polyoxyethylene castor oil (for example, a solution of Cremophor® EL or a solution of Cremophor® RH 40); esters of fatty acid and saccharide (i.e., the condensation product of a monosaccharide (e.g., pentoses such as ribose, ribulose, ar is benosa, xylose, lyxose, xylulose; hexose, such as glucose, fructose, galactose, mannose and sorbose; triose, tetrose, heptose and actoz), disaccharide (e.g. sucrose, maltose, lactose and trehalose) or oligosaccharide, or a mixture thereof with a fatty acid (fatty acids) with 4 to 22 carbon atoms (for example, saturated fatty acids such as Caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid, and saturated fatty acids, such as palmitoleic acid, oleic acid, elaidic acid, erucic acid and linoleic acid)), or steroid esters); alkalemia, aryl, or cyclic ethers with 2-30 carbon atoms (for example, diethyl ether, tetrahydrofuran, dimethyldithiocarba, monotropy ether of diethylene glycol); glycoluril (simple ester of polyethylene glycol and tetrahydrofurfuryl alcohol); ketones with 3 to 30 carbon atoms (for example, acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4-30 carbon atoms (for example, benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane, sulfolan, tetramethylarsonium, tetramethylsilane, toluene, dimethylsulfoxide (DMSO) or tetramethylsilane); alkyl or aryl halides, the content is the following 1-30 carbon atoms and optionally more than one halogen atom as a substituent; dichloromethane; monoethanolamine; petroleum ether; trolamine; omega-3-polyunsaturated fatty acids (for example, alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid or docosahexaenoic acid); polyglycidyl ester 12-hydroxystearate acid and polyethylene glycol (Solutol® HS-15 BASF, Ludwigshafen, Germany); polyoxyethyleneglycol; sodium laurate; sodium oleate; or servicemanual.

Preferably as a pharmaceutically acceptable carrier in the present invention to use protostegana environment, such as water, saline solutions, water-soluble polymers, proteins, solutions of dextrose (for example, DW5), electrolyte solutions or alcohols from the catalogue “PAA Laboratory's” (2006) R.26.

The following aspect of the present invention features a kit for the treatment of cancer, which includes: (1) a pharmaceutical composition comprising a binuclear nitrosyl complex of iron with besuseradminclient derivatives of the present invention, in a sealed package; and (2) auxiliary tools.

The set can contain the composition in the form of a single dosage form or in multiple doses. The set can include forms for oral or parenteral administration.

Pharmaceutical composition in the kit can be placed in glass or polymer is Ozerki, ampoules, vials, measured cartridges for injectors, blisters, capsules, sachets with the composition used, respectively, for oral or parenteral form.

Auxiliary means include fluid recovery composition introduced parenterally, if she's in the set is presented in a concentrated form, for example in the form of solids, dried drug etc.; means for receiving oral liquid forms and forms for injectionex tempore. As a liquid for recovery can be used water for injection, saline solution, lidocaine and the like To restore the composition applied in liquid form by mouth, can be used glucose, sugars, syrups, etc.

Optional auxiliary tool set includes tools for dissection of youporon, means for sealing the opened reusable youporon, liners statement.

Pharmaceutical composition, which represents a solid dosage form for oral administration may be presented as a set in the form of tablets, capsules in blisters, vials, bottles, vials, bags, etc. Pharmaceutical composition constituting the liquid dosage form for parenteral or oral administration may be presented in kit in a bottle is x, capsules, ampoules, cartridges, etc.

Example set for parenteral administration includes packaging, which includes instructions for use, ampoules or vials with dry composition, and vials with saline solution for injection. In the packaging goes a device for opening ampoules. The ampoules are Packed in blisters of 10 vials.

Other options set obvious to the person skilled in the art from the above description.

The following examples are provided only as an additional illustration of the invention and they should not be construed as limitations of the invention.

Examples of the synthesis of complexes

Example 1

Synthesis of complex (I), where R = benzimidazole-2-yl (Fe2S2N8C14H10O4)

For the synthesis used the original reagents Na2S2O3·5H2O (Aldrich), NaOH (analytical grade), 2-mercaptobenzimidazole (Aldrich). All operations on the preparation, mixing of solutions and selection of the complexes was carried out in an atmosphere of technical argon at room temperature. For recrystallization of the used organic solvent.

The mixture 0,992 g (4 mmol) of Na2S2O3·5H2O and 1,074 g (2 mmol) thiosulfate nitrosyl iron complex of bis(μ-thiosulfate-S)-bis(dinitrodiphenyl)(2-) sodium Na2[e 2(S2O3)2(NO)4] (TNCG) was dissolved in distilled water. A mixture of 1,500 g (10 mmol) of 2-mercaptobenzimidazole and 0.44 g (11 mmol) of NaOH, was also dissolved in the water.

Both solutions were mixed. The precipitate was filtered and dried in the air. The output of the intermediate was 0,719, the next day the precipitate was recrystallized.

The complex is soluble in ethanol, methanol, acetone, DMSO and DMF. Not soluble in dichloromethane, water, heptane and ether.

Output: 63,50%;

For Fe2S2N8C14H10O4found, %: Fe, 19,27; S, 10,69; N, 18,54; C, 43,40; H, 4,78; calculated, %: Fe, 18,99; S, 10,90; N, 19,05; C,44,93, Oh, 16,32; H, 4.45 and later.

IR spectrum (cm-1): 3207, 1787, 1738, 1515, 1467, 1428, 1384, 1272, 1218, 1183, 1002, 742, 713, 603.

Example 2

Synthesis of complex (II), where R = 5-methylbenzimidazole-2-yl (Fe2S2N8C16H14O4)

For the synthesis used the original reagents Na2S2O3·5H2O (Aldrich), NaOH (analytical grade), 2-mercapto-5-methylbenzimidazole (Aldrich). All operations on the preparation, mixing of solutions and selection of the complexes was carried out in an atmosphere of technical argon at room temperature. For recrystallization of the used organic solvent. For synthesis were prepared distilled water passing through it for 30 minutes, the current technical argon is.

The mixture 0,4960 g (2 mmol) of Na2S2O3·5H2O and 0,5740 g (1 mmol) thiosulfate nitrosyl iron complex of bis(μ-thiosulfate-S)-bis(dinitrodiphenyl)(2-) sodium Na2[Fe2(S2O3)2(NO)4] (TNCG) was dissolved in distilled water. A mixture consisting of 0,8250 g (5 mmol) of 2-mercapto-5-methylbenzimidazole and 0,2890 g (7 mmol) of NaOH, was also dissolved in the water.

Both solutions were mixed. The precipitate was filtered and dried in the air. The output of the intermediate was 2,2017, the next day the precipitate was recrystallized.

The complex is soluble in acetone, DMSO and DMF. Not soluble in dichloromethane, water, heptane and ether.

Output: 45,53%;

For Fe2S2N8C16H14O4found, %: Fe, 19,27; S, 10,69; N, 19,54; C, 34,26; H, 2,48; calculated, %: Fe, 20,01; S, 11,49; N, 20,08; C,34,43, Oh, 11,47; H, 2,53.

IR spectrum (cm-1): 3133, 1790, 1724, 1619, 1490, 1443, 1411, 1373, 1276, 1223, 1189, 1011, 854, 800, 720, 596, 543.

Example 3

Synthesis of complex (III), where R = benzothiazol-2-yl (Fe2S4N6C14H8O4)

For the synthesis used the original reagents Na2S2O3·5H2O (Aldrich), NaOH (analytical grade), 2-mercaptobenzthiazole (Aldrich). All operations on the preparation, mixing of solutions and selection of the complexes was carried out in an atmosphere of technical argon at room temperature. For re is cristallization used organic solvent. For synthesis were prepared distilled water passing through it for 30 minutes, the current technical argon.

The mixture 0,4960 g (2 mmol) of Na2S2O3·5H2O and 0,5740 g (1 mmol) thiosulfate nitrosyl iron complex of bis(μ-thiosulfate-S)-bis(dinitrodiphenyl)(2-) sodium Na2[Fe2(S2O3)2(NO)4] (TNCG) was dissolved in distilled water. A mixture consisting of 0,8402 g (5 mmol) 2-mercaptobenzthiazole and 0,2890 g (7 mmol) of NaOH, was also dissolved in the water.

Both solutions were mixed. The precipitate was filtered and dried in the air. The output of the intermediate was 1,1182, the next day the precipitate was recrystallized.

The complex is soluble in ethanol, methanol, acetone, methylene chloride, acetonitrile, ether, THF, DMSO and DMF. Not soluble in water, heptane.

For Fe2S4N6C14H8O4found, %: Fe, 18,96; S 22,01; N, 14,54; C, 29,39; H, 1,57; calculated, %: Fe, 19,78; S, 22,72; N, 14,89; C RUR 29.79, Oh, 11,34; H, 1,43.

IR spectrum (cm-1): 3448, 2923, 2852, 2379, 1787, 1721, 1468, 1429, 1384, 1313, 1270, 1006, 852, 754, 724, 706, 611.

The IR spectra of all samples were recorded on a spectrometer Fourier SPECTRUM BX-II. The sample was prepared in the form of tablets with KBr (1 mg analyte in 300 mg KBr).

X-ray diffraction analysis of the complex Fe2S2N8C14H10O4(I) was carried out automatically by directone the d P-4 (BRUKER) (graphite monochromator, λ(Mo-Kα)=0,71073 Å, the temperature of 200 K, θ/2θ-scan). The experiment used a single crystal of black color in the form of a parallelepiped with dimensions of 0.35×0,20×0,15 mm Crystals are unstable at room temperature and dissolved at a rate of 10% for 1 hour. Structure deciphered by the direct method. Positions and thermal parameters for non-hydrogen atoms refined in isotropic and then anisotropic approximation full-fabric by the method of ordinary least squares (OLS). Hydrogen atoms were revealed from direct Fourier syntheses and refined in isotropic approximation.

The molecular structure of complex I is presented in figure 1. The complex has having a center of inversion dimer binuclear structure. In the dimer of two tetrahedrally coordinated by two groups and NO two besuseradminclient tilelli, the iron atoms are linked by bridge: Fe-S-C-N-Fe. The complex contains two molecules of the solvent is acetone.

Crystallographic data and the main parameters of the refinement are presented in table 1.

Interatomic distances and angles are presented in table 2.

All calculations were performed using the SHELXTL program complex (G.M. Sheldrick, SHELXTL v.6.14, Structure Determination Software Suite, Bruker AXS, Madison, Wisconsin, USA, 2000).

The distance Fe(1)Fe.....(1a) - 4,057 Ǻ see (table 2).

Table 1
Crystallographica is the cue data and characteristics analysis for complex I
Brutto-formulaC20H22Fe2N8O6S2
Molecular weight646,28
Temperature200(2) K
Wavelength0,71073 Ǻ
The crystal system, space grouptriclinic, P(-1)
a8,737(1) Ǻ
b9,072(1) Ǻ
c9,083(1) Ǻ
alpha74,82(1)°
beta73,10(1)°
gamma86,62(1)°
V664,70(13) Å3
Z, dthe calc.1; near 1.615 g/cm3
μ13,00 cm-1
F(000)330
The crystal size0,35×0,2×0.15 mm
The image area for θ2,33-25,00°
The total number of reflexes/ independent2572/2080 [R(int) = 0,0205]
N/a number of arguments2080/216
GOOF on F^20,994
R factor for reflections with I>2(σ)(I)R1 = 0,0270, wR2 = 0,0705
R factor for all reflectionsR1 = 0,0312, wR2 = 0,0731

Table 2
Interatomic distances and valence angles in the structure of complex I
Linkd, ÅLinkd, Å
Fe(1)-N(1)1,682(2)N(2)-O(2)1,172(3)
Fe(1)-N(2)1,687(2)Fe(1)-N(3)#12,0215(18)
O(1)-N(1)1,165(3)Fe(1)-S(3)2,3029(7)
S(3)-C(1) 1,736(2)
AngleΩ deg.AngleΩ deg.
O(2)-N(2)-Fe(1)161,6(2)N(2)-Fe(1)-S(3)107,52(7)
O(1)-N(1)-Fe(1)164,7(2)N(3)#1-Fe(1)-S(3)109,73(6)
N(1)-Fe(1)-N(2)111,05(10)C(1)-S(3)-Fe(1)102,48(7)
N(1)-Fe(1)-N(3)#1117,32(9)C(1)-N(3)-Fe(1)#1to 126.14(14)
N(2)-Fe(1)-N(3)#1106,94(9)C(3)-N(3)-Fe(1)#1grew by 127.76(15)
N(1)-Fe(1)-S(3)103,92(7)
Linkd, ÅLinkd, Å
N(3)-C(1)1,338(3)C(7)-C(6) 1,378(4)
N(3)-C(3)1,409(3)C(3)-C(4)1,387(4)
C(1)-N(4)1,354(3)C(4)-C(5)KZT 1,394(3)
N(4)-C(2)1,375(3)C(2)-C(3)1,401(3)
C(2)-C(7)1,387(3)C(6)-C(5)1,389(4)
C(8)-C(10)1,488(4)C(8)-C(9)1,492(4)
O(3)-C(8)1,220(3)
AngleΩ deg.AngleΩ deg.
C(1)-N(3)-C(3)105,98(17)C(4)-C(3)-C(2)120,2(2)
N(3)-C(1)-N(4)111,1(2)C(4)-C(3)-N(3)131, 5mm(2)
N(3)-C(1)-S(3)12,47(16) C(2)-C(3)-N(3)108,3(2)
N(4)-C(1)-S(3)122,39(19)C(3)-C(4)-C(5)117,4(2)
C(1)-N(4)-C(2)108,7(2)O(3)-C(8)-C(10)121,3(2)
N(4)-C(2)-C(7)132,1(2)O(3)-C(8)-C(9)121,4(2)
N(4)-C(2)-C(3)105,84(19)C(10)-C(8)-C(9)117,2(3)
C(7)-C(2)-C(3)122,0(2)C(7)-C(6)-C(5)120,8(2)
C(6)-C(7)-C(2)117,6(2)
Linkd, ÅLinkd, Å
C(4)-H(4)0,96(3)C(9)-H(9A)0,96(4)
N(4)-H(1)0,82(3)C(9)-H(9B)0,8(4)
C(6)-H(6)0,95(3)C(9)-H(9C)0,90(4)
C(7)-H(7)0,94(3)C(10)-H(10A)0,87(6)
C(5)-H(5)0,88(3)C(10)-H(10B)0,99(5)
C(10)-H(10C)0,96(4)
AngleΩ deg.AngleΩ deg.
C(1)-N(4)-H(1)124(2)C(6)-C(5)-H(5)120,4(17)
C(2)-N(4)-H(1)127(2)C(4)-C(5)-H(5)117,6(17)
C(6)-C(7)-H(7)to 126.8(18)C(8)-C(9)-H(9A)110(2)
C(2)-C(7)-H(7)115,5(18)C(8)-C(9)-H(9B)109(2)
C(3)-C(4)-H(4)122,716) C(8)-C(9)-H(9C)109(2)
C(5)-C(4)-H(4)119,9(16)C(8)-C(10)-H(10A)114(3)
C(7)-C(6)-H(6)121(2)C(8)-C(10)-H(10B)111(3)
C(5)-C(6)-H(6)118(2)C(8)-C(10)-H(10C)111(2)
C(6)-C(5)-C(4)122,0(3)

Matrix generation equivalent positions of atoms:

#1-x, -y, -z

Crystal structure of complex I is presented in figure 2.

Mössbauer absorption spectra were shot on installing WissEl, working in a mode of constant acceleration. Source served as the Co57in the matrix Rh. Measurements of the spectra at low temperatures was performed using flow helium cryostat CF-506 (Oxford Instruments) with controlled temperature. Processing mössbauer spectra was performed using the least squares method assuming Lorentzian form of individual spectral components.

The results are presented in table 3.

Table 3
Parameters NGR spectra of Fe57complexes I-III at T=290 K
ComplexδFemm/c-1ΔEQmm/c-1
I0,2020,954
II0,2320,805
III0,2170,994

The study of NO-donor activity of binuclear nitrosyl iron complexes with besuseradminclient derivatives

NO-donor activity of complexes I-III first established in the study of their reactions with hemoglobin (Hb). The method of research is the response of the education Hb-NO in the interaction of hemoglobin with free NO in solution [R. Cassoly, Q.H. Gibson, Conformation, co-operativity and ligand binding to human hemoglobin, J. Mol. Biol. 91 (1975) 301-313; T.J. McMahon, J.S. Stamler, Concerted nitric oxide/oxygen delivery by hemoglobin, in: L. Packer (Ed.), Methods In Enzymology, Academic Press, 301 (1999) Part C, 99-114]. The binding constant of the Hb c NO is 3·1010M-1that is three orders of magnitude higher than the constant for CO, and six orders of magnitude of the binding constant for O2[E. Antonini, M. Brunori, Hemoglobin and myoglobin in the reactions with ligands, in: A. Neuberger, E.L. Tatum (Eds.) North-Holland research monographs. Fronties of biology. Vol. 21, North-Holland Publishingcompany, Amsterdam-London, 21 (1971) 276]. Bimolecular constant interaction of Hb with NO close to diffusion: 1,02·108M-1·with-1in 0.05 M phosphate buffer, rn,0 at 20°C. Therefore, the Hb is a very easy trap for NO and is actively used for the study of NO-donor compounds that generate nitric monoxide. While the spectra of optical absorption of free Hb and Hb-NO vary greatly, making it easy to detect the formation of the nitrosyl adduct.

The results of the study for illustration presented in figure 3 for complex I.

Homogeneous preparation bovine Hb was obtained from bovine hemoglobin firm "MP Biomedicals, which is a mixture of metHb and HbO2. At all stages of receipt of Hb and in all experiments with Hb used 0.05 M phosphate buffer, pH 7.0. For the conversion of a mixture of metHb with HbO2in Hb was previously prepared column 2 x 15 cm) with Sephadex G-25 and translated it into an anaerobic state. At the outlet from the column was collected 5 ml of Hb with a concentration of 6·10-4mol l-1. Kept Hb frozen in the form of balls in liquid nitrogen. Before using Hb was unfrozen in containers with a volume of 5 ml in a stream of nitrogen. In anaerobic experienced a cuvette with a volume of 4 ml with optical path length of 1 cm was introduced to 2.8 ml of buffer, 0.1 ml Hb 6·10-4mol l-1and recorded absorption spectrum. To button nitrosyl complex in the vessel, Zap lannom nitrogen, added absolute anaerobic DMSO so as to obtain a solution of the complex with a concentration of 6·10-3mol l-1. Then, the solution was stirred for 3-5 minutes until fully dissolved and injected 0.1 ml of the obtained solution in the experimental cell with Hb and the cell comparison, containing 2.9 ml of anaerobic buffer. The final concentration of nitrosyl complex was equal to 2·10-4mol l-1, DMSO - 3.3 percent. It was further recorded differential absorption spectra, first - after 1 minute from the start of the reaction (shown in figure 3), then at intervals of 3 minutes for the first 30 minutes of the reaction, and then at intervals of 15, 30, 60 minutes (figure 3 are shown for clarity, only a portion of these spectra). Registration of the spectra was carried out before full conversion of Hb in HbNO, when the range was no longer change. The number of generated NO was assessed spectrophotometrically by the number formed HbNO. To determine the concentration HbNO absorption spectrum of the reaction system containing Hb and HbNO, using a computer processing program MathCad decomposed into its constituent spectrum of the Hb and HbNO. The calculation was performed in the wavelength range of 450-650 nm 200 experimental points. To register absorption spectra used the spectrophotometer Specord M-40 has an interface for computer recording of the spectra and thermostatted cuvette of the Department is the group. Spectra were recorded at 25°C.

As a result of these studies for the first time established that complexes generate NO in aqueous solutions of dimethysulfoxide spontaneously (i.e. in the absence of chemo-, photo - or enzymatic activation).

The study of cytotoxicity tetranitroaniline iron complexes with besuseradminclient tilille on tumor human cellsin vitro

The experimental technique

Before beginning the experiment, all compounds were dissolved in 200 µl of DMSO, and then brought to the desired concentration of the culture medium RPMI1640. The final concentration of DMSO in the sample did not exceed 0.2% and had no effect on cell growth.

Line cells - cancer human ovarian SKOV3. Cells were grown in monolayer in medium RPMI1640 containing 10% fetal calf serum, at 37°C and 5% CO2. For experiments cells were planted in 96-well plates and were grown in the same conditions.

Testing the cytotoxic effect was performed using the MTT-test based on the ability of the dehydrogenases of living cells to restore unpainted salt tetrazole in blue crystals formazan, soluble in dimethyl sulfoxide (DMSO).

All compounds were introduced into the wells in a volume of 20 μl in 4-end concentrations (µm) 100, 50, 25 and 10. The total volume of incubation was 200 ál. Cells with drugs incubated indicated in the data above conditions within 72 hours. After incubation, the cells were added MTT reagent and incubated under the same conditions for 2 hours. Then the resulting crystals formazan was dissolved in 100 μl DMSO at 37°C for 20 minutes. The optical absorption of DMSO solutions were measured on an optical counter to advance the plate at a wavelength of 540 nm. The results were expressed as average values for 4-parallel dimensions. The cytotoxic effect was evaluated by survival of cells in experimental samples relative to the control in %. A connection is considered active if at a concentration of 100 μm, the number of living cells was 50% or less (IR50≤ 100 µm). The measurement error did not exceed 5%.

The results of the study are presented in table 4.

Two of the studied nitrosyl iron complex I and III, containing dibenzylidene and tiobenzimidazola ligands, showed cytotoxic activity in cell line SCOV3. For I and III IR50amounted to 57 μm and 25 μm, respectively.

Studied nitrosyl iron complexes I and III showed different cytotoxic effect on tumor cells of a manin vitro. The maximum activity was shown by complex III (IR50= 25 μm).

As the comparison drug was used cisplatin (cis-DDP), an anticancer drug used in clinics in Russia and abroad (IR = 16 μm). It is established that at low concentrations two times complex III retains the same activity as the concentration of 100 μm (survival of tumor cells to 12.5% (table 4). The fact that the toxicity of complex III was significantly lower (its index of overall toxicity LD100is 50 mg/kg)than for cisplatin (LD100= 16 mg/kg), may be set in high-dose chemotherapy, with severe side effects, as a way of increasing the sensitivity of tumor cells to therapeutic treatment, and will reduce the concentration of the applied drugs.

Table 4
Cytotoxic activity of nitrosyl iron complexes I-III cell line SKOV3
№ p/pConcentration, µmConnection. Cell survival, %
IIIIII
110012,410012,5
25056,3210032587,510050,1
41010010088,5
5IR50, mcm57>10025

In accordance with the methodological guidelines for the study of antitumor activity of pharmacological substances studies on transplantable tumors of mice Ca-755, leukemia P-388 and melanoma B-16 (in mice-the first generation hybrids BDF1(C57Bl/6 × DBA/2) and DBA/2weighing 18-25 g, obtained from the Department of laboratory animals of the Russian them. N.N. Blokhin Russian Academy of medical Sciences). Statistically significant anti-tumor effect of the proposed remedies.

1. Binuclear nitrosyl complex of iron with besuseradminclient derivatives of the General formula [Fe2(SR)2(NO)4],
where R

and where X represents NH, S, R1is lower alkyl.

2. Binuclear nitrosyl complex of iron according to claim 1, where R represents a benzimidazole-2-yl, 5-methyl-benzimidazole-2-yl or benzothiazol-2-the l

3. A method of obtaining a binuclear nitrosyl iron complexes according to claim 1, which consists in the fact that thiosulfate nitrosyl complex of iron processed with the proper besuseradminclient the thiol in the stoichiometric ratio in the presence of a reducing agent, and the process is conducted in an alkaline medium, followed by separation of the target product by known methods.

4. The method of claim 3, wherein the process is conducted at room temperature, preferentially at 18-25°C.

5. The method according to claim 3, wherein the process is conducted in an oxygen-free atmosphere.

6. The method according to claim 3, characterized in that as besuseradminclient of thiol use of benzimidazole-2-thiol, 5-methyl-benzimidazole-2-thiol or benzothiazol-2-thiol.

7. The method according to claim 3, characterized in that in use as a reducing agent hydrogen, metal thiosulfate, hydrogen sulfide and aliphatic thiols.

8. The donor of nitrogen monoxide, which represents a binuclear nitrosyl complex of iron according to claim 1.

9. The use of binuclear nitrosyl iron complex according to claim 1 as an antitumor drug.

10. The use of binuclear nitrosyl iron complexes according to claim 1 for receiving anticancer drugs.

11. Pharmaceutical composition comprising an effective amount binuclear nitrosyl the th complex of iron with besuseradminclient derivative according to claim 1 and a pharmaceutically acceptable carrier, as anticancer drugs.

12. The pharmaceutical composition according to claim 11, where the pharmaceutically acceptable carrier used protonotariou environment.

13. The pharmaceutical composition according to claim 11, where the pharmaceutically acceptable carrier, a mixture of protonotaria environment and dimethyl sulfoxide.

14. The pharmaceutical composition according to any one of p or 13, where protonotaria environment using water, saline solution, water-soluble biopolymers.

15. The pharmaceutical composition according to claim 11, where binuclear nitrosyl complex of iron with besuseradminclient derivative is present in the amount of 50-100 microns.

16. The set used for the treatment of cancer, comprising: (1) a pharmaceutical composition comprising a binuclear nitrosyl complex of iron with besuseradminclient derivative according to claim 1, in a sealed package; and (2) auxiliary components.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing mono-imine compounds of formula where radicals assume values given in claim 1 of the invention, involving reaction of a dicarbonyl compound with aniline in an aliphatic non-aromatic solvent. The invention also describes an asymmetric iron complex of formula , where radicals assume values given in claim 3 of the invention, as well as a catalyst system for polymerisation of olefins.

EFFECT: invention describes mono-imine compounds having electron-attracting substitutes in the ortho-position and asymmetric bis(imino)-compounds and asymmetric iron compounds obtained from said compounds, and use of the complexes in olefin polymerisation.

7 cl, 11 ex, 1 tbl

FIELD: information technology.

SUBSTANCE: article with an image includes a substrate having a masked or concealed protective image on at least part thereof, which reflects less than 50% of radiation at wavelength 800-900 nm. The protective image contains an infrared radiation absorbing compound selected from:

or salt or polymer thereof, where M is a metal selected from iron, cobalt, nickel, aluminium, scandium, chromium, vanadium, titanium, manganese and lanthanide. R1 is selected from hydrogen, phosphonate, sulphonate, nitro, halogen, cyano, thiocyano, thioalkyl, thioaryl, alkyl, alkoxy, aryl, aryloxy, amine, substituted amines and substituted aryl. One of R2 and R3 is oxygen and the other is NO; n is a number corresponding to half the coordination number of metal M; each of L and L' independently denotes a ligand which forms a complex with metal M, and y is a number which corresponds to the coordination number of metal M. The infrared radiation absorbing compound does not form an intensely coloured protective image, and the protective image is pale, colourless or tinted. The invention also discloses a method of making the article with the image, using the compound and a method of authenticating the said article.

EFFECT: obtaining a protective image which can reflect less than half the light at 800-900 nm, and a protective image which is not intensely coloured.

14 cl, 35 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to use of a tetranitrosyl complex of iron with thiophenol of formula [Fe2(SC6H5)2(NO)4] as an anti-tumour medicinal agent in order to prepare a medicinal agent for treating oncological diseases. The invention also relates to a pharmaceutical composition and a set containing said complex.

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8 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to complex compound of iron with carbohydrate. Complex compound, in addition to iron (III) contains iron (II). Per cent of iron (II) in terms of total amount of iron in complex compound constitutes, at least, 2 wt %. Carbohydrate is selected from group, consisting of natural carbohydrates or synthetic derivatives of carbohydrates, such as starch, hydrolysed starches, dextrins, in particular such as maltodextrin, maltose syrup, glucose syrup, cyclodextins, dextrans, saccharides. Per cent of carbohydrate in terms of complex compound of iron with carbohydrate constitutes from 10 to 80 wt %. Method of obtaining complex compound of iron with carbohydrate includes the following stages. Water solution of suspension of carbohydrate is prepared. After that, iron (III) salts are added at constant pH value within the range from 7 to 13. Iron (III) salt is selected from group, consisting of iron (III) chloride and iron (III) sulfate. Water solution or suspension is heated with further cooling. Formed complex compound of iron with carbohydrate if isolated. Precipitation of complex compound of iron with carbohydrate is performed by addition of one or more alcohols, such as ethanol or propanol. Obtained complex compound is used for production of medication for treatment of iron-deficient anemias, which is well absorbed in organism in case of peroral intake.

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26 cl, 1 tbl, 4 ex

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(II) Fe(C6H7O6)(C17H19O6N4)2H2O which is used as an additive.

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FIELD: chemistry.

SUBSTANCE: invention relates to 1-alkenylimidazole derivatives of general formula 1 , where R is vinyl, allenyl or isopropenyl, R1 is hydrogen or methyl, E is Zn (II) or Fe(III), An is chlorine or acetate, n equals 1, 2 or 4, except compounds where R is vinyl, R1 is hydrogen, E is Zn(II), An is chlorine or acetate and n equals 2.

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5 ex, 8 tbl

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6 cl, 2 tbl, 14 ex

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EFFECT: disclosed catalyst system enables production of polyethylene with given molecular weight distribution in a single reactor.

16 cl, 3 tbl, 3 ex

FIELD: chemistry.

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EFFECT: liquid phase used together with the sodium chloride additive can be repeatedly returned to the process.

10 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I) where the bond b represents a double bond; X represents -S-; each Z1 and Z3 independently represents a direct bond, -N(R5) - or - (CH2)q; Z2 represent -C(O)- or -C(S)-; m represents an integer equal to 1; n represents an integer equal to 1; each of q independently represents an integer varying within 1 to 4; R0 represents hydrogen, halogen, hydroxy, unsubstituted C1-C3alkyl or unsubstituted C1-C3alkoxy; R1 is independently selected from a group consisting of halogen, optionally substituted C1-C3alkyl, -R6OR7, -R6N(R7)2, -R6C(O)R7, -R6C(O)OR7, -R6C(O)N(R7)R9N(R7)2, -R6OC(O)R8, -R6C(O)N(R7)2 or -R6OR9N(R7)2; R2 represents hydrogen; R4 is selected from a group consisting of morpholine, isoxazolyl, thiazolyl, oxazolyl, benzisoxazolyl, benzothiazolyl, dioxynyl, dioxolyl, and optionally substituted phenyl. Also, the invention refers to pharmaceutically acceptable salts of the compounds of formula (I) and to a pharmaceutical composition exhibiting antiproliferative activity and containing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) exhibiting antiproliferative activity.

21 cl, 11 dwg, 5 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new camptothecin derivatives, i.e. 4,5-dihydrotriazolyl [5,4-c]16a-deoxocamptothecin and triazolyl[5,4-c]16a-deoxocamptothecin showing anticancer activity, a pharmaceutical composition containing them and applying them as anticancer drugs.

EFFECT: preparing the anticancer pharmaceutical composition.

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SUBSTANCE: invention refers to compounds of formula (I) exhibiting the properties of proteinkinase Plk1 inhibitors. In formula (I): the ring A is a 5-member heteroaryl ring which contains atoms N as heteroatoms where the ring is optionally substituted by C1-6alkyl; X1 is NR8-; R1 is H, C1-10 aliphatic, C3-10 cycloaliphatic, phenyl, 5-6- member heteroaryl group containing atom S, N as a heteroatom where said R1 is optionally substituted by 0-5 J1; each R2 and R3, is independently H, C1-10 aliphatic group; R4 is C3-10 cycloaliphatic group; R8 is H, -C(O)OR; each J1 is independently C1-6 halogenalkyl, halogen, Q or -Z-Q; each Z is independently C1-6 aliphatic group where 0-3 -CH2- links in the specified C1-6 aliphatic group are optionally replaced by -NR-, -O-, -C(O)-, where any of the unsubstituted -CH2- links in the specified C1-6 aliphatic group is optionally substituted by 0-2 Jz ; each Q is independently H, C1-6 aliphatic group, 3-8- member aromatic or non-aromatic monocyclic ring having 0-3 heteroatoms independently selected from O and N where each Q is independently and optionally substituted by 0-2 JQ; Jz is halogen; JQ is -M; each M is independently H, C1-6 aliphatic group, halogen; each R is independently H or unsubstituted C1-6 aliphatic group.

EFFECT: preparing the pharmaceutical composition and method for inhibiting proteinkinase Plk1 activity.

31 cl, 43 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds selected from a group consisting of compounds of formula: and or to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition, as well as to using at least one compound under cl.1 and/or its pharmaceutically acceptable salts.

EFFECT: preparing new biologically active compounds which exhibit the properties of cycline-dependent kinase inhibitors.

11 cl, 86 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to imidazopyridines of formula I

and to their pharmaceutically acceptable salts where Z1 represents CR1; R1 represents H; R1' represents H; Z2 represents CR2; Z3 represents CR3 or N; R2 and R3 are independently selected from H, halogen; R4 represents H; Y represents W-C(O)-; W represents or , R5 represents H; X1 is selected from R11' and -OR11'; each R11 independently represents H, C1-C12alkyl, C2-C8alkenyl; X4 represents , R6 represents H, halogen, cyclopropyl or -(CR19R20)n-SR16; R6 represents H, halogen; p represents 0, 1, 2 or 3; n represents 0, 1 or 2; where each specified alkyl in R11 is independently substituted by one or two groups independently selected from halogen, -(CR19R20)nOR16 and R21; each R16 independently represents H, C1-C12alkyl; R19 and R20 are independently selected from H, C1-C12alkyl; R21 represents cyclopropyl.

EFFECT: invention refers to a pharmaceutical composition for treating hyperproliferative disorder.

10 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula:

in which: X represents one of the following groups: - a phenyl group optionally substituted by one or more groups, optionally selected from one of the following atoms and groups: halogen, (C1-C6)alkoxy, (C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, NRaRb, R1 represents hydrogen atom, halogen, (C1-C6)alkoxy, (C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, amino, the group NRcRd; with the alkyl and alkoxy groups being optionally substituted by one or more halogens, hydroxy, amino or (C1-C6)alkoxy, R2 represents one of the following groups: -hydrogen atom, - (C1-C6)alkyl group optionally substituted by one or more groups optionally substituted by hydroxy, halogen, amino, the group NRaRb, the phenyl group, the - (C1-C3)alkoxygroup optionally substituted by one or more groups independently selected from hydroxy, halogen, amino, the group NRaRb, - (C3-C7)cycloalkyl((C1-C6)alkyl, - (C3-C7)cycloalkyl(C1-C6)alkoxy, -(C2-C6)alkenyl, - (C2-C6)alkinyl, - the group -CO-R5,- the group -CO-NR6R7,- the group -CO-O-R8,- the group -NR9-CO-R10,- the group -NR11R12,- halogen atom,- the cyanogroup,- the phenyl group optionally substituted by one or more groups optionally selected from the following atoms and groups: halogen, (C1-C6)alkoxy, NRaRb, -CO-R5, -CO-NR6R7, -CO-O-R8, (C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkoxy, (C1-C6)alkyl group optionally substituted by one or more hydroxy groups or NRaRb R3 represents hydrogen atom, (C1-C6)alkyl, (C1-C6)alkoxy or halogen atom, R4 represents hydrogen atom, (C1-C4)alkyl, (C1-C4)alkoxy or fluorine atom, R5 represents hydrogen atom, the phenyl group or (C1-C6)alkyl, R6 and R7, the same or different represents hydrogen atom or (C1-C6)alkyl, or together with nitrogen atom forms a 4-7-member cycle optionally containing the other heteroatom selected from N, O or S,R8 represents (C1-C6)alkyl, R9 and R10, the same or different, represent hydrogen atom or (C1-C6)alkyl, R11 and R12, the same or different, represent (C1-C6)alkyl, or together with nitrogen atom form a 4-7-member cycle optionally containing the other heteroatom selected from N, O or S, Ra and Rb independently represent hydrogen atom, (C1-C6)alkyl or together with nitrogen atom form a 4-7-member cycle, Rc represent hydrogen atom, and Rd represents (C1-C6)alkyl and at least one of the substitutes R1, R2, R3 and R4 are different from hydrogen; and when R3 means methyl, X is unsubstituted; when R1 means methyl, X is unsubstituted; when R2 means chlorine, X is other than parafluorophenyl; in the form of a base or an acid addition salt. The invention also refers to the compounds selected from the group, to a drug, to a pharmaceutical composition, as well as to application of the compounds of formula (I) by any of cl. 1-4.

EFFECT: preparing new biologically active compounds for treating or preventing the diseases associated with nuclear receptor NOT.

13 cl, 18 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound 4-(1-(4-(4-methoxyphenylthio)-2,5-dioxo-2,5-dihydro-1H-pyrro-3-yl)-1H-indol-3-yl)butyl carbamimidothioate (the compound "ЛХТА-1833") which can be used in therapy of colon cancer, breast cancer, melanoma, leucosis.

EFFECT: preparing the new compounds for treating cancer.

2 cl, 2 tbl, 3 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 4-arylcumarine derivatives and a based drug which can be used for treating tumours of general formula

, where A means a group , where CnHm represents residual fatty acids of saturate and olefin series, n represents number 13, 15 or 17, m represents number 27, 31 or 33, while R1, R2, R3 represent hydrogen atoms and/or methoxygroup OCH3. The drug contains said 4-arylcumarine derivatives contained in liposomes containing phosphatidylcholine, phosphatidylinositol and lipid oligopolysaccharide.

EFFECT: there are prepared the new oncology compounds and the new drug showing lesser systemic toxicity and greater membrane affinity.

12 cl, 9 ex, 1 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to composition for prevention and treatment of cancer. Pharmaceutical composition for prevention and treatment of cancer, which contains one or more components selected from group, consisting of cell line obtained from Taxus cambium or procambium with specified characteristics. Functional food product for prevention or improvement of state in case of cancer, which contains one or more components selected from group, consisting of cell line obtained from Taxus cambium or procambium with specified characteristics.

EFFECT: composition and product efficiently induce death of cancer cells, have minimal side effects.

11 cl, 22 dwg, 4 tbl, 8 ex

Kinase inhibitors // 2440352

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula : a pharmaceutically acceptable salt or solvate thereof, having Syk kinase inhibiting properties. The invention also relates to a pharmaceutical composition containing said compound, methods of treating diseases whose development is aided by c-kit receptor activity, such as arthritis, rheumatoid arthritis, tumours, mantle cell lymphoma, as well as a method of inhibiting angiogenesis.

EFFECT: improved method.

13 cl, 4 tbl, 10 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and chemical-pharmaceutical industry, in particular, to medication, applied in case of myocardial infarction and operations on heart in conditions of artificial blood circulation. Water-soluble composition for intravenous introduction, contains ingredients with the following component ratio in wt %: D-glucose 23.40-28.60; potassium chloride 0.14-0.16; potassium salt of L-asparaginic acid 0.81-0.99; semi-magnesium salt of L-asparagenic acid (magnesium L-aspartate) 0.72-0.88; human insulin genetically engineered (in IU/l) 54.00-66.00; dinitrosyl complex of iron (II) with glutathione 0.19-0.23; water for injections - remaining part, with solution pH 7.4±0.1 at 22°C.

EFFECT: application of composition ensures limitation of myocardial infraction size, recovery of metabolic condition of heart at reperfusion, reduces injury of membranes of post-ischemic cardiomyocytes with smaller haemodinamics disorders as compared with traditionally applied medications.

2 dwg, 7 tbl, 4 ex

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