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WO2008147243A1 - Complexes fer-nitrosyle binucléaires avec des dérivés benzohétérocycliques et procédé de production correspondant - Google Patents

Complexes fer-nitrosyle binucléaires avec des dérivés benzohétérocycliques et procédé de production correspondant Download PDF

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Publication number
WO2008147243A1
WO2008147243A1 PCT/RU2007/000286 RU2007000286W WO2008147243A1 WO 2008147243 A1 WO2008147243 A1 WO 2008147243A1 RU 2007000286 W RU2007000286 W RU 2007000286W WO 2008147243 A1 WO2008147243 A1 WO 2008147243A1
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Prior art keywords
binuclear
nitrosyl
benzazheterocyclic
pharmaceutical composition
iron complex
Prior art date
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Ceased
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PCT/RU2007/000286
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English (en)
Russian (ru)
Inventor
Natalia Alexeevna Sanina
Olga Stepanovna Zhukova
Zoya Sergeevna Smirnova
Tatyana Nikolaevna Rudneva
Gennady Viktorovich Shilov
Sergei Mikhailovich Aldoshin
Mikhail Ivanovich Davydov
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INSTITUT PROBLEM KHIMICHESKOI FIZIKI ROSSIISKOI AKADEMII NAUK
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INSTITUT PROBLEM KHIMICHESKOI FIZIKI ROSSIISKOI AKADEMII NAUK
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Priority to PCT/RU2007/000286 priority Critical patent/WO2008147243A1/fr
Publication of WO2008147243A1 publication Critical patent/WO2008147243A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/02—Iron compounds
    • C07F15/025—Iron compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to binuclear nitrosyl iron complexes and can be used in medical practice to create new generation drugs for the treatment of cancer.
  • State of the art
  • NO donors as a new class of antitumor agents is associated with the important role of NO in the growth of malignant tumors [Wipk D., Vodovoz J., Soc. J., Biochemistru, 1998, 63, 7, pp. 948-957].
  • Nitrogen monoxide has been shown to alter the level of tumor cell apoptosis, p53 gene activity, and neoangiogenesis [Vrupe V., Scheneiderhan N., Nitrirete okhide evoked p53-accumulation a d aportosis, Toxol Letters, 2003, 193, 2, pp.19-23], inhibits the activity of key repair protein
  • binuclear paramagnetic seranitrosyl iron complexes with ⁇ -N- ⁇ -S ligands which are synthetic analogues of natural donors of NO dinitrosyl iron complexes (DNIC) with cysteine, glutathione and other thiol-containing ligands of small molecular weight [O.A. Rakova, N.A. Sapipa, S.M.
  • the objective of the present invention is to expand the arsenal of antitumor agents and the creation of antitumor drugs based on transition metal complexes with an improved activity spectrum and reduced side effects, in particular, medicines based on binuclear nitrosyl iron complexes with benzazheterocyclic derivatives acting as NO donors with increased activity and reduced toxicity.
  • the invention relates to novel binuclear nitrosyl iron complexes with benzazheterocyclic derivatives of the formula [Fe 2 (SR) 2 (NO) 4 ], where R is
  • R 1 represents lower alkyl
  • the invention in another aspect, relates to a method for producing binuclear nitrosyl iron complexes with benzazheterocyclic derivatives of the formula [Fe 2 (SR) 2 (NO) 4 ] by treating the thiosulfate nitrosyl iron complex with an appropriate benzazheterocyclic thiol in a stoichiometric ratio in the presence of a reducing agent in an alkaline medium.
  • This method allows for the first time to obtain the claimed complexes in
  • the present invention relates to a donor of nitric oxide, which is a binuclear nitrosyl complex of iron with benzazheterocyclic derivatives, described above.
  • the present invention relates to the use of binuclear nitrosyl iron complexes with benzazheterocyclic derivatives of the formula [Fe 2 (SR) 2 (NO) 4 ] as an antitumor drug.
  • the present invention relates to the use of binuclear nitrosyl iron complexes with benzazheterocyclic derivatives of the formula [Fe 2 (SR) 2 (NO) 4 ] for the preparation of antitumor drugs.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a binuclear nitrosyl iron complex with benzazheterocyclic derivatives of the formula [Fe 2 (SR) 2 (NO) 4 ] and a pharmaceutically acceptable carrier.
  • the present invention relates to a kit used to treat cancer, comprising: (1) a pharmaceutical composition comprising a binuclear nitrosyl iron complex with benzazheterocyclic derivatives of the formula [Fe 2 (SR) 2 (NO) 4 ], where R has the above meanings in sealed packaging; and (2) auxiliaries.
  • Figure l shows the molecular structure of the complex (Fe 2 S 2 N 8 C 14 H 10 O 4 ) [complex I].
  • the complex has a centrosymmetric dimeric binuclear structure (Fig. 1). In the dimer, two tetrahedrally coordinated two NO groups and two benzazheterocyclic thiol iron atoms are connected by a bridge: Fe-S-C-N-Fe '.
  • the complex contains two solvent molecules - acetone.
  • Figure 2 shows the crystal structure of the complex
  • Fig. 3 shows the change in the difference absorption spectra over time.
  • novel binuclear nitrosyl iron complexes with the benzazheterocyclic derivatives of the present invention have the general formula [Fe 2 (SR) 2 (NO) 4 ], where R is
  • R 1 represents lower alkyl
  • R is benzimidazol-2-yl, 5-methyl-benzimidazol-2-yl or benzyl thiazol-2-yl.
  • lower alkyl as used herein means a straight or branched chain alkyl radical containing from 1 to 6 carbon atoms.
  • alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl.
  • the method for producing new binuclear nitrosyl iron complexes with benzazheterocyclic derivatives of the formula [Fe 2 (SR) 2 (NO) 4 ], where R has the above meanings, is that the thiosulfate nitrosyl iron complex is bis ( ⁇ -thiocylphato-S) -bis ( dinitrosylphosphate) (2-) sodium Na 2 [Fe 2 (S 2 O 3 ) 2 (NO) 4 ] (TNLC) is treated with the corresponding benzazheterocyclic thiol in a stoichiometric ratio in the presence of a reducing agent, and the process is carried out in an alkaline medium followed by isolation of the target product by known receptions.
  • the process is carried out at room temperature, preferably at 18-25 ° C.
  • the process is conducted in an oxygen free atmosphere.
  • benzazheterocyclic thiol preferably
  • SUBSTITUTE SHEET (RULE 26) use benzimidazole-2-thiol, 5-methylbenzimidazole-2-thiol or benzethiazole-2-thiol.
  • Hydrogen, metal thiosulfate, for example, Na 2 S 2 O 3 -5H 2 O, hydrogen sulfide and aliphatic thiols are used as reducing agent in the method of the present invention.
  • binuclear nitrosyl iron complexes with the benzazheterocyclic derivatives of the present invention are effective NO donors, generating nitrogen monoxide spontaneously when decomposed in proton media (such as water, blood and its components, physiological solutions, etc.), in the absence of chemo, photo, or enzymatic activation.
  • the complexes of the present invention represent a new promising class of nitrogen monoxide donors — synthetic analogues of active sites of nitrosyl non-heme iron-sulfur proteins — natural NO depots. Therefore, the present invention in an additional aspect relates to nitric oxide donors, which are binuclear nitrosyl iron complexes with benzazheterocyclic derivatives described above.
  • Binuclear nitrosyl iron complexes with the benzazheterocyclic derivatives of the natural aromatic thiols of the present invention possess antitumor activity against tumor cells of a mammal, in particular a human.
  • the present invention is further directed to the use of binuclear nitrosyl iron complexes with benzazheterocyclic derivatives of the formula [Fe 2 (SR) 2 (NO) 4 ], where R has the above meanings, as an antitumor drug.
  • the compounds of the present invention can be used to treat the following oncological diseases: ovarian cancer, breast adenocarcinoma, B-16 melanoma, Lewis epidermoid carcinoma.
  • the iron complexes of the present invention are suitable for inhibiting the growth of tumors in mammals, and are preferably administered in the form of a pharmaceutical composition comprising an effective
  • SUBSTITUTE SHEET (RULE 26) an antitumor amount of a compound of the present invention in combination with at least one pharmaceutically or pharmacologically acceptable carrier and / or excipient.
  • a carrier also known in the art as an excipient, excipient, excipient, additive or diluent, is any substance that is pharmaceutically inert, gives the appropriate consistency or form of the composition and does not impair the therapeutic efficacy of the antitumor compounds.
  • a carrier is “pharmaceutically or pharmacologically acceptable” if it does not cause an adverse, allergic or other adverse reaction when administered to a mammal or human, respectively.
  • the present invention also relates to the use of binuclear nitrosyl iron complexes with benzazheterocyclic derivatives of the formula [Fe 2 (SR) 2 (NO) 4 ], where R has the above meanings, to obtain an antitumor drug.
  • a proton-containing medium is used as a pharmaceutically acceptable carrier in the composition of the invention.
  • a mixture of a proton-containing medium and dimethyl sulfoxide is also preferably used in the composition of the invention.
  • water, physiological saline, and water-soluble biopolymers are used as the proton-containing medium.
  • a binuclear nitrosyl iron complex with a benzazheterocyclic derivative is present in the composition in an amount of 50-100 ⁇ M.
  • compositions containing antitumor compounds of the present invention can be prepared by any method known in the art.
  • compositions containing antitumor compounds of the present invention can be prepared by any method known in the art.
  • compositions according to the invention can be prepared for any route of administration so that the target tissue is accessible with this route of administration.
  • routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal or intrasternal), local (nasal, percutaneous, intraocular, intraocular) into the small intestine, pulmonary, intralymphatic, intracavitary, vaginal, trasurethral, intradermal, auricular, intramammary, buccal, orthotopic, intratracheal, intrafocal, percutaneous, endoscopic, transmucosal, sublingual and intestinal injections.
  • parenteral e.g., intravenous, intraarterial, subcutaneous, rectal, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal or intrasternal
  • compositions of the present invention are well known to those skilled in the art and are selected depending on a number of factors: the particular antitumor compound used and its concentration, stability and expected bioavailability; the disease, disorder or condition of the person being treated with the composition; subject, his age, weight and general condition; and method of administration. Suitable carriers are readily identifiable by a person skilled in the art (J.G. Nairp at: Remptop's Pharmaceut Scalse (published by A. Gepparo), Mask Publishing Co., Eastop, Pa, 1985, pp. 1492-1517).
  • compositions are preferably prepared in the form of tablets, dispersible powders, pills, capsules, gelatin capsules, coated droplets, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, lozenges, dragees, lozenges, or any other dosage form, which can be administered orally.
  • compositions of the present invention for oral administration comprise an effective antitumor amount of a compound of the invention in a pharmaceutically acceptable carrier.
  • suitable carriers for solid dosage forms include sugars, starches and other conventional substances including lactose, talc, sucrose, gelatin,
  • SUBSTITUTE SHEET (RULE 26) carboxymethyl cellulose, agar, beckon, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, gum arabic, corn starch, potato starch, sodium saccharinate, magnesium carbonate, tragacanth, microcrystalline cellulose, colloidal sodium silica, colloidal sodium hydroxide, magnesium and stearic acid. Further, such solid dosage forms may be uncoated or may be coated by known methods, for example, to delay disruption and absorption.
  • the antitumor compounds of the present invention are also preferably used for the preparation of a parenteral dosage form, for example, in the form of a dosage form for injection by intravenous, intraarterial, subcutaneous, rectal, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal or intrasterial route.
  • Compositions according to the invention for parenteral administration include an effective antitumor amount of an antitumor compound in a pharmaceutically acceptable carrier.
  • Formulations suitable for parenteral administration include solutions, suspensions, dispersions, emulsions, or any other dosage form that can be administered parenterally. Techniques and compositions for preparing parenteral dosage forms are known in the art.
  • compositions of the invention may be included in the compositions of the invention for various purposes. These components for the most part give properties that increase the retention time of the antitumor compound at the injection site, contribute to the stability of the composition, provide pH control, facilitate the introduction of the antitumor compound into pharmaceutical compositions, and the like. Each of these components is individually present in an amount, preferably, less than about 15 mass%, more preferably less than about 5 mass%, and most preferably less than about 0.5 mass%, based on the total weight of the composition. Some components, such as
  • SUBSTITUTE SHEET (RULE 26) fillers or diluents can be up to 90 mass%, based on the total weight of the composition, as is well known in the technology for the preparation of medicines.
  • Such additives include cryoprotective component to prevent precipitation of the iron complex with thiophenol, surfactants, wetting or emulsifying agents (e.g. lecithin, policopbat-80, Tween ® 80, plyuponik-60, polyoxyethylene stearate), preservatives (e.g., ethyl-n- hydroxybenzoate), anti-microbial agents (e.g.
  • non-volatile silicones e.g. cyclomethicone
  • clays e.g.
  • binders e.g. starches, such as corn starch, wheat starch, rice starch or potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, polyvinyl chloride, polyvinyl gum arabic
  • disintegrating agents e.g.
  • starches such as corn starch, wheat starch, rice starch, potato starch or carboxymethyl starch, structured polyvinylpyrrolidone, agar, algae hydrochloric acid or its salt, such as sodium alginate, croscarmellose sodium or crospovidone), lubricants (e.g., silica, talc, stearic acid or its salts, such as magnesium stearate, or polyethylene glycol), coating agents (e.g., concentrated sugar solutions, including gum arabic, talc, polyvinylpyrrolidone, carbopolgel, polyethylene glycol or titanium dioxide) and antioxidants (e.g. sodium metabisulfite, sodium bisulfite, sulfite
  • lubricants e.g., silica, talc, stearic acid or its salts, such as magnesium stearate, or polyethylene glycol
  • coating agents e.g., concentrated sugar solutions, including gum arabic, talc, polyvinyl
  • SUBSTITUTE SHEET (RULE 26) sodium, dextrose, phenols and thiophenols).
  • the pharmaceutical composition according to the invention comprises at least one non-aqueous pharmaceutically acceptable solvent and an antitumor compound having a solubility therein of at least about 10-60 mg / ml.
  • an antitumor compound having a solubility therein of at least about 10-60 mg / ml.
  • the solubility of the antitumor compound in dimethyl sulfoxide can be directly related to its effectiveness.
  • the antitumor compound has an ID 100 value (i.e., a drug concentration that causes 100% inhibition of colony formation) at least 4 times less than cisplatin when measured according to the procedure described in the book “An Experimental Assessment of Antineoplastic Drugs in the USSR and the United States” edited by Z. P. Sof'ina, A.B. Syrkina (USSR), A. Goldin, A. Klein (USA) M.: “Medicine”, 1979, pp. 71 - 105.
  • the introduction of the dosage form in these ways can be continuous or periodic, depending, for example, on the physiological condition of the patient, on whether the purpose of the introduction of therapeutic or prophylactic, and other factors known or evaluated by the practitioner.
  • the dose and administration regimen of the pharmaceutical compositions of the invention can be easily determined by an oncologist. It is understood that the dose of antitumor compounds depends on the age, gender, state of health and weight of the recipient, the type of treatment carried out simultaneously, if any, the frequency of treatment and the nature of the desired effect. For any route of administration, the exact amount of the antitumor compound used, as well as the prescribed dose necessary to achieve the beneficial effects described here, also depends, in particular, on factors such as the bioavailability of the antitumor compound, the human disease being treated, the desired therapeutic dose, and others factors that are obvious to the specialist.
  • the concentration of the antitumor compound in the liquid pharmaceutical composition is, most preferably, 50-100
  • Emulsions for parenteral administration can be prepared by dissolving the antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., DMSO, dichloromethane) to form a solution.
  • An appropriate volume of carrier is added to the solution with stirring, which is an emulsion, such as an emulsion of Lirosup II or Lirosup III, to obtain a pharmaceutically acceptable emulsion for parenteral administration to a patient.
  • an emulsion such as an emulsion of Lirosup II or Lirosup III, to obtain a pharmaceutically acceptable emulsion for parenteral administration to a patient.
  • such emulsions may be prepared with or without a minimum amount of a Cemorhor ® solution.
  • Solutions for parenteral administration can be prepared by dissolving the antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., DMSO) to form a solution.
  • a pharmaceutically acceptable solvent capable of dissolving the compound (e.g., DMSO)
  • the carrier which is a proton-containing medium (saline solutions, sugars, water-soluble polymers, proteins, electrolyte solutions) for parenteral administration to the patient.
  • saline solutions, sugars, water-soluble polymers, proteins, electrolyte solutions for parenteral administration to the patient.
  • non-aqueous pharmaceutically acceptable polar solvents are usually used as a carrier, such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, saline solutions, dextrose solutions (e.g. DW5), electrolyte solutions, or any other proton pharmaceutically acceptable medium.
  • Suitable non-aqueous pharmaceutically acceptable polar solvents include, but are not limited to, amides (e.g. dimethylacetamide (DMA), dimethylacetamide benzylbenzoate, dimethylformamide, N- ( ⁇ -hydroxyethyl) lactamide, N 5 N-dimethylacetamide, 2-pyrupolidinone-l-me - pyrrolidinone or polyvinylpyrrolidone); esters (e.g., acetic acid esters such as monoacetin, diacetin and triacetin; aliphatic or aromatic esters such as ethyl caprylate or ethyl octanoate,
  • amides e.g. dimethylacetamide (DMA), dimethylacetamide benzylbenzoate, dimethylformamide, N- ( ⁇ -hydroxyethyl) lactamide, N 5 N-dimethylacetamide, 2-pyrupolidinone-l-me - pyrroli
  • SUBSTITUTE SHEET (RULE 26) alkyl oleate, benzyl benzoate, benzyl acetate, dimethyl sulfoxide (DMSO), glycerol esters such as mono-, di- or triglyceryl citrates or tartrates, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, sorbitan fatty acid esters and polyethylene ethers ), r-glyceryl monostearate, esters of glycerides, such as mono-, di- or triglycerides, fatty acid esters, such as isopropyl myristate, fatty acid-based esters and PEG, such as PEG-hydroxyoleate and PEG-hydroxystearate, N-methylpyrrolidinone , plupnik-60, p oxyethylenated polyesters based on sorbito
  • polyoxyethyl sorbitan esters such as polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate and polysorbate ® 20, 40, 60 or 80 from ICI Américas, DEmig; polyvinylpyrrolidone; fatty acid esters modified with alkylene oxides, such as hydrogenated polio (40) castor oil and polyoxyethylene castor oils (for example, Cortorhor ® EL solution or Creamhorr ® RH 40 solution); fatty acid esters of a saccharide (i.e., the condensation product of a monosaccharide (e.g., pentoses, such as ribose, ribulose, arabinose, x
  • a saccharide i.e., the condensation product of a monosaccharide (e.g., pentoses, such as ribose, ribu
  • sucrose, maltose, lactose and trehalose or an oligosaccharide or mixtures thereof with a fatty acid (s) with 4-22 carbon atoms (e.g. 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 steroidal esters); alkyl, aryl or cyclic ethers with 2-30 carbon atoms (for example, diethyl ether, tetrahydrofuran, dimethyl isosorbite, diethylene glycol monoethyl ether); glycofurol (simple
  • SUBSTITUTE SHEET polyethylene glycol ether and tetrahydrofurfuryl alcohol); ketones with 3-30 carbon atoms (e.g. acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons with 4-30 carbon atoms (e.g.
  • the proton content of the medium such as water, saline solutions, water-soluble polymers, proteins, dextrose solutions (eg, DW5), electrolyte or alcohol solutions from the PAA Labotor's catalog (2006) p, is used as a pharmaceutically acceptable carrier in the present invention.
  • a pharmaceutical composition comprising a binuclear nitrosyl iron complex with the benzazheterocyclic derivatives of the present invention, in an airtight package; and (2) auxiliaries.
  • the kit may contain the composition in the form of a single dosage form or in the form of multiple doses.
  • the kit may include forms for oral or parenteral administration.
  • the pharmaceutical composition in the kit can be placed in glass or polymer vials, ampoules, vials, metered dose cartridges for injectors, blisters, capsules, sachets with the composition, used respectively for oral or parenteral form.
  • Aids include reconstitution fluids
  • SUBSTITUTE SHEET (RULE 26) a composition administered parenterally if it is presented in a kit in concentrated form, for example, in the form of a dry substance, a dried preparation, and the like; Means for the preparation of oral liquid forms and forms for injection ex-troter. Water for injection, physiological saline, lidocaine solution, etc., can be used as a recovery fluid. To restore the composition used in liquid form orally, a solution of glucose, sugars, syrups, etc. can be used.
  • Optional kit aids include openers for closures, means for sealing opened reusable closures, instruction inserts.
  • the pharmaceutical composition which is a solid dosage form for oral administration, can be presented in a kit in the form of tablets, capsules in blisters, ampoules, vials, vials, sachets, and the like.
  • the pharmaceutical composition which is a liquid dosage form for parenteral or oral administration, may be presented in a kit in bottles, capsules, ampoules, cartridges, and the like.
  • kits for parenteral administration includes a package that contains instructions for use, ampoules or vials with a dry composition and ampoules with saline for injection. A device for opening ampoules is inserted into the package. Ampoules are packed in blisters of 10 ampoules.
  • SUBSTITUTE SHEET (RULE 26) used an organic solvent.
  • the starting reagents Na 2 S 2 O 3 -5H 2 O (Aldrich), NaOH (analytical grade), 2-mercapto-5-methylbenzimidazole (Aldrich) were used. All operations for the preparation, mixing of solutions and the separation of complexes were carried out in an atmosphere of industrial argon at room temperature. An organic solvent was used for recrystallization. Distilled water was prepared for the synthesis by passing a stream of technical argon through it for 30 minutes.
  • the complex is well soluble in acetone, DMSO and DMF. Insoluble in dichloromethane, water, heptane and ether.
  • IR spectrum (cm "1 ): 3133, 1790, 1724, 1619, 1490, 1443, 1411, 1373, 1276, 1223, 1189, 1011, 854, 800, 720, 596, 543.
  • the starting reagents Na ⁇ S 2 O 3 -SH 2 O (Aldrich), NaOH (bhd), 2-mercaptobenzthiazole (Aldrich) were used. All operations for the preparation, mixing of solutions and the separation of complexes were carried out in an atmosphere of industrial argon at room temperature. An organic solvent was used for recrystallization. Distilled water was prepared for the synthesis by passing a stream of technical argon through it for 30 minutes.
  • the complex is well soluble in ethanol, methanol, acetone, methylene chloride, acetonitrile, ether, THF, DMSO and DMF. Not soluble in water, heptane.
  • IR spectrum (cm "1 ): 3448, 2923, 2852, 2379, 1787, 1721, 1468, 1429, 1384, 1313, 1270, 1006, 852, 754, 724, 706, 611.
  • the molecular structure of complex I is shown in FIG.
  • the complex has a centrosymmetric dimeric binuclear structure.
  • the dimer two tetrahedrally coordinated by two NO groups and two benzazheterocyclic thiols, iron atoms are connected by a bridge: Fe-S-C-
  • the complex contains two solvent molecules - acetone.
  • the Mössbauer absorption spectra were recorded on a WissEl setup operating in a constant acceleration mode. Co 57 in the Rh matrix served as a source. Spectra were measured at low temperatures using a flow-controlled helium cryostat CF-506 (Oxford Istrumepts) with a controlled temperature. The Mössbauer spectra were processed using the least squares method under the assumption of the Lorentzian shape of individual spectral components.
  • the NO-donor activity of complexes I – III was first established by studying their reactions with hemoglobin (Hb).
  • the research method is based on the reaction of the formation of Hb-NO in the interaction of hemoglobin with free NO in solution [R. Sassolu, Q.N. Gibsop, Compormatiop, co-reactivit ap ligapd ipgip humap hemoglobip, J. MoI. Biol. 91 (1975) 301-313; TJ. MsMahop, JS Stalmer, Soppertit pitris okhide / okhuhep to a distributor, ip: L.
  • Hb is a very convenient trap for NO and is actively used to study an NO donor ktivnosti compounds, generating nitric oxide.
  • the optical absorption spectra of free Hb and Hb-NO vary greatly, making it easy to detect the formation of nitrosyl adduct.
  • a homogeneous preparation of bovine Hb was obtained from bovine hemoglobin from MP Biomedicals, which is a mixture of metHb and HbO 2 .
  • 0.05 M phosphate buffer, pH 7.0 was used.
  • Hb was stored frozen in the form of balls in liquid nitrogen. Before use, Hb was thawed in 5 ml vessels in a stream of nitrogen. In an anaerobic experimental cuvette with a volume of 4 ml with an optical path length of 1 cm
  • the cell line is SKO V3 human ovarian cancer. Cells were grown in
  • SUBSTITUTE SHEET (RULE 26) monolayer in RPMIl 640 medium containing 10% fetal calf serum at 37 ° C and 5% CO 2 .
  • cells were seeded in 96-well plates and grown under the same conditions.
  • the cytotoxic effect was tested using the MTT test based on the ability of living cell dehydrogenase to restore the unpainted tetrazolium salt into blue formazan crystals soluble in dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • the optical absorption of DMSO solutions was measured on an optical counter for multi-well plates at a wavelength of 540 nm. The results were expressed as mean values for 4 parallel measurements.
  • the cytotoxic effect was evaluated by cell survival in experimental samples relative to the control in%. A compound was considered active if, at a concentration of 100 ⁇ M, the number of living cells was 50% or less (IK50 ⁇ 100 ⁇ M). The measurement error did not exceed 5%.
  • cisplatin As a reference drug, cisplatin (cis-DDP), an antitumor drug used in clinics in Russia and abroad, was used
  • mice were transplantable tumors of mice on Ca-755, lymphocytic leukemia P-388 and melanoma B-16 (on first-generation hybrid mice BDF 1 (C 5 - 7 BI / 6 x DBA / 2 ) and DBA / 2 weighing 18-25 g, obtained from the department of laboratory animals of the State Research Center named after N.N. Blokhin RAMS). A statistically significant antitumor effect of the claimed drugs was revealed.

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  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne des complexes fer-nitrosyle binucléaires avec des dérivés benzohétérocycliques représentés par la formule générale [Fe2(SR)2(NO)4] dans laquelle R désigne (I), X désigne NH, S ou O et R1 désigne un alkyle inférieur. Cette invention concerne également un procédé de production correspondant, l'utilisation de ces complexes comme médicament antitumoral, un donneur de monoxyde d'azote à base de ces complexes, une composition pharmaceutique contenant lesdits complexes en une quantité efficace et une trousse servant au traitement de maladies oncologiques.
PCT/RU2007/000286 2007-05-30 2007-05-30 Complexes fer-nitrosyle binucléaires avec des dérivés benzohétérocycliques et procédé de production correspondant Ceased WO2008147243A1 (fr)

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PCT/RU2007/000286 WO2008147243A1 (fr) 2007-05-30 2007-05-30 Complexes fer-nitrosyle binucléaires avec des dérivés benzohétérocycliques et procédé de production correspondant

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PCT/RU2007/000286 WO2008147243A1 (fr) 2007-05-30 2007-05-30 Complexes fer-nitrosyle binucléaires avec des dérivés benzohétérocycliques et procédé de production correspondant

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WO2008147243A1 true WO2008147243A1 (fr) 2008-12-04

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CN102558244A (zh) * 2012-01-10 2012-07-11 大连理工大学 邻苯二硫酚基和二氮烯架桥的双核铁配合物、其制备方法及应用
CN102617650A (zh) * 2012-03-13 2012-08-01 大连理工大学 烃硫基和氮/氨基架桥的双核铁配合物、其制备方法及应用
RU2494104C2 (ru) * 2011-10-20 2013-09-27 Учреждение Российской Академии Наук Институт Проблем Химической Физики Ран (Ипхф Ран) Моноядерные динитрозильные комплексы железа, способ получения моноядерных динитрозильных комплексов железа, донор монооксида азота, применение моноядерного динитрозильного комплекса железа в качестве противоопухолевого лекарственного средства
US8575382B2 (en) 2009-07-13 2013-11-05 “Ivy Pharm” LLC Low molecular weight pharmacological activity modulators
RU2843160C2 (ru) * 2023-10-27 2025-07-07 Федеральное Государственное Бюджетное Учреждение Науки Федеральный Исследовательский Центр Проблем Химической Физики И Медицинской Химии Российской Академии Наук (Фиц Пхф И Мх Ран) Фармацевтическая композиция на основе биядерного анионного нитрозильного комплекса и ее применение в таблетированной форме для лечения сердечно-сосудистых и онкологических заболеваний

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8575382B2 (en) 2009-07-13 2013-11-05 “Ivy Pharm” LLC Low molecular weight pharmacological activity modulators
RU2494104C2 (ru) * 2011-10-20 2013-09-27 Учреждение Российской Академии Наук Институт Проблем Химической Физики Ран (Ипхф Ран) Моноядерные динитрозильные комплексы железа, способ получения моноядерных динитрозильных комплексов железа, донор монооксида азота, применение моноядерного динитрозильного комплекса железа в качестве противоопухолевого лекарственного средства
CN102558244A (zh) * 2012-01-10 2012-07-11 大连理工大学 邻苯二硫酚基和二氮烯架桥的双核铁配合物、其制备方法及应用
CN102558244B (zh) * 2012-01-10 2014-06-25 大连理工大学 邻苯二硫酚基和二氮烯架桥的双核铁配合物、其制备方法及应用
CN102617650A (zh) * 2012-03-13 2012-08-01 大连理工大学 烃硫基和氮/氨基架桥的双核铁配合物、其制备方法及应用
CN102617650B (zh) * 2012-03-13 2014-08-27 大连理工大学 烃硫基和氮/氨基架桥的双核铁配合物、其制备方法及应用
RU2843160C2 (ru) * 2023-10-27 2025-07-07 Федеральное Государственное Бюджетное Учреждение Науки Федеральный Исследовательский Центр Проблем Химической Физики И Медицинской Химии Российской Академии Наук (Фиц Пхф И Мх Ран) Фармацевтическая композиция на основе биядерного анионного нитрозильного комплекса и ее применение в таблетированной форме для лечения сердечно-сосудистых и онкологических заболеваний

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