Metal-salen complex derivatives and method of obtaining thereof

FIELD: chemistry.

SUBSTANCE: invention relates to a metal-salen complex derivative. The complex is represented as A-B-C, where A is the metal-salen complex, B is a bond zone, including at least one disulphide bond; and C is a functional molecule, consisting of at least one of enzymes, antibodies, antigens, peptides, amino acids, oliginucleotides, proteins, nucleic acids and medication molecules. The bond zone (B) includes a molecule of a cross-linking agent to form a cross-linking between the said metal-salen complex (A) and the said functional molecule (C). The said metal-salen complex (A) and the said molecule of the cross-linking agent are bound together via at least one disulphide bond; and the said molecule of the cross-linking agent and the said functional molecule (C) are bound together via at least one disulphide bond. The zone of the disulphide bond (B) results from the formation of a bond between a SH group, introduced as a substituent into the said metal-salen complex, and the SH group of the said functional molecule (C), or results from the formation of a bond between the SH group of the said metal-salen complex (A) or the said functional molecule (C) and the SH group of the cross-linking agent molecule. Also claimed is a method of obtaining the metal-salen complex derivative.

EFFECT: invention makes it possible to obtain the derivative of a metal-salen complex, characterised by an excellent output and stability.

3 cl, 2 ex

 

The technical field to which the present invention

The present invention relates to the derivatives of complex metal-Salins and to a method for producing derivatives of complex metal-Salins.

Prior art

Complex iron-Salins, which is known as the metal catalyst, known as the complex metal-Salins. The applicant found that by itself, the complex iron-Salins has magnetic properties and, in addition, has an antitumor effect; and an assumption was made that the complex iron-Salins can be sent to the affected site of the target, and the pharmacological effects of the specified complex iron-Salins can be concentrated locally by introducing a complex iron-Salins person or an animal and then create an external magnetic field around the body of a person/animal.

In addition, the applicant has discovered that molecules of medicines can be sent to the affected area of tissue using magnetic fields, carrying out communication of complex iron-Salins with molecules of drugs. This complex iron-Salins disclosed in Japanese laid patent application (Kokai) Publication No. 2009-173631, in Japanese laid patent application (Kokai) Publication No. 2009-196913, in Japanese laid patent application (Kokai) Publication No. 2009-196914, in Japanese laid patent application (Kokai) Publication No. 2009-256232, in Japanese laid patent application (Kokai) Publication No. 2009-256233, and in Japanese laid patent application (Kokai) Publication No. 2009-274962.

In addition, in Japanese laid patent application (Kokai) Publication No. 2009-287949, the applicant proposes a method of detecting antibodies or antigens, allowing to separate the bound antigen or antibody from free angilena or antibodies, using a magnetic field, by combining the antigen and the antibody with the specified complex iron-Salins, using the reaction of the Biotin-avidin.

List of links

Patent literature

[Patent literature 1] Japanese published patent application (Kokai) Publication No. 2009-173631,

[Patent literature 2] Japanese published patent application (Kokai) Publication No. 2009-196913,

[Patent literature 3] Japanese published patent application (Kokai) Publication No. 2009-196914,

[Patent literature 4] Japanese published patent application (Kokai) Publication No. 2009-256232,

[Patent literature 5] Japanese published patent application (Kokai) Publication No. 2009-256233,

[Patent literature 6] Japanese published patent application (Kokai) Publication No. 2009-274962.

[Patent literature 7] Japanese published patent application (Kokai) Publication No. 2009-287949

The invention

However, described is use conventional technology does not allow for sufficient binding between the complex metal-Salins and for example, the molecule drug, an antigen and an antibody, and is characterized by the problem of output and stability of the derived complex metal-Salins. Thus, the aim of the present invention is the creation of derived complex metal-Salins, kharakterizuyushchegosya excellent yield and stability, and creating a method of producing such a derivative of the complex metal-Salins.

To achieve the above objectives the present invention is characterized by the fact that it is a derivative of complex metal-Salins, the resulting ensure binding of functional molecules consisting of at least one enzyme, antibody, antigen, peptide, amino acid, oligonucleotide, protein, nucleic acid molecule drugs with complex metal-Salins through at least one disulfide bond, ether bond, ester bond and an amide bond; and the method of obtaining such a derivative of the complex metal-Salins. The binding of the complex metal-Salins and functional molecules preferably occurs through a crosslinking agent that is designed to create a linkage between them.

More specifically, the present invention is characterized by the fact that it is a derivative of the complex metal-Salins, represented by the formula A-B-C (where A: is the Wallpaper of complex metal-Salins; B: represents the communication area, comprising at least one disulfide bond, ether bond, ester bond and an amide bond; C: represents a functional molecule comprising at least one enzyme, antibody, antigen, peptide, amino acid, oligonucleotide, protein, nucleic acid molecule drugs).

The preferred implementation of the present invention is that the area of the binding (B) includes a molecule cross-linking agent to create a linkage between the complex metal-Salins (A) and the functional molecule (C), and complex metal-Salins (A) and the specified molecule cross-linking agent are linked together by a disulfide bond, ether bond, ester bond or amide bond, and this molecule cross-linking agent and the specified functional molecule (C) are connected together by a disulfide bond, ether bond, ester bond or amide bond.

This complex metal-Salins (A) is not specifically limited and, for example, represented by the following formula (I).

At least one of a-h represents "a-B-C" and the rest is a hydrogen or an arbitrary substituent. Specified by the Deputy can be any Deputy, capable of forming a communication area with the specified cross-linking molecule and the enta and/or specified functional molecule, and may be, for example, at least one of hydroxyl groups, carboxyl groups and SH groups. For example, a monomer as represented by formula (I), or a polymer including a dimer, where 'part' of the metal atom is interconnected with each of them directly or through another atom (such as an enzyme).

M represents a metal atom such as Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd.

Area disulfide bond (B) results in the formation of ties between the SH group is introduced as a substituent in the specified complex metal-Salins (A), and SH group indicated functional molecule (C) or occurs as a result of the formation of ties between the SH group of the specified complex metal-Salins (A) or specified functional molecule (C) and SH group in the molecule cross-linking agent.

The area of broadcasting communications (B) results in the formation of ties between the hydroxyl group is introduced as a substituent in the specified complex metal-Salins (A), and a hydroxyl group indicated functional molecule (C), or occurs as a result of the formation of ties between the hydroxyl group of the specified complex metal-Salins (A) or specified functional molecule (C) and the hydroxyl group of the molecule cross-linking agent.

Zone ester bonds (B) results in the formation of ties between the hydroxyl group is whether a carboxyl group, introduced as a substituent in the specified complex metal-Salins (A), and a carboxyl group and a hydroxyl group indicated functional molecule (C) or occurs as a result of the formation of ties between the hydroxyl group or carboxyl group of the specified complex metal-Salins (A) or specified functional molecule (C) and a carboxyl group or a hydroxyl group indicated functional molecule (C).

Area amide bond (B) results in the formation of ties between the amide group or carboxyl group is introduced as a substituent in the specified complex metal-Salins (A), and a carboxyl group or an amide group indicated functional molecule (C), or occurs by the formation of a connection between a carboxyl group or an amide group of the specified complex metal-Salins (A) or specified functional molecule (C) and amide group and a carboxyl group of the specified functional molecule (C).

Advantageous effects of invention

Derivatives of complex metal-Salins, which are characterized by good yield and stability, and consist of a combination of functional molecules, such as molecule drugs, and complex metal-Salins, can be obtained in accordance with the present invention, as disclosed above.

Predpochtite is further embodiments of the present invention

Area disulfide bond (B) includes, for example, a molecule cross-linking agent of the following formula (II).

This complex metal-Salins (A) is associated with "∙O-in (II) and a disulfide group (-S-S-), which is associated with the specified functional molecule (C), associated with at least one of i and j.

Another example of a binding agent in the area of the disulfide bond (B) has the following structure (III).

This complex metal-Salins (A) binds "∙C(O) - (III), and a disulfide group, which is associated with the specified functional molecule (C), associated with at least one of i and j.

Another binding agent in the area of the disulfide bond (B) has the following structure (IV).

This complex metal-Salins (A) is associated with "∙CH2-" in (IV), and a disulfide group, which is associated with the specified functional molecule (C), associated with at least one of i and j.

In the preferred embodiment, where the specified functional molecule (C), such as the enzyme is directly related to the specified complex metal-Salins, and the specified complex metal-Salins and the molecule agent that promotes condensation, can be digidrirovanny and condensed with the formation of the active complex ether (between the exact connection) and the amino group of the specified functional molecules (3) can be made to interact with the obtained active ester, thereby replacing the molecule agent that promotes condensation of the active ester, forming an amide linkage, and wiring specified complex metal-Salins component of the target through an amide bond. This process is represented in the following reaction scheme.

In the above circumstances, N,N'-dicyclohexylcarbodiimide (DCC) is a molecule dehydrating condensing agent and N-hydroxysuccinimide (HONSu) is a molecule agent that promotes condensation.

The above molecule agent that promotes condensation (HONSu), can be used as a molecule cross-linking agent to link the specified complex metal-Salins (A) with the specified functional molecule (C). This complex metal-Salins and molecule agent that promotes condensation, condense, and SH group in the molecule agent that promotes condensation, and SH group indicated functional molecules interact with each other, resulting in the formation of disulfide bonds and the binding of the specified complex metal-Salins and the specified functional molecules together via disulfide bonds.

This complex metal-Salins contains a functional group for condensation with the functional group of the molecule cross-linking agent, at least one of the above (a-h side chains, so that it can be condensed with one molecule of crosslinking agent. For example, the complex metal-Salins contains a functional group (carboxyl group or hydroxyl group) for dehydration and condensation with a hydroxyl group of the molecule cross-linking agent, at least one of the above (a-h side chains so that said complex metal-Salins could be condensed with the specified molecule cross-linking agent (molecule agent that promotes condensation: HONSu)).

Examples of these molecules cross-linking agent (molecule agent that promotes condensation) include the following:

Carbodiimide condensing agents:

diisopropylcarbodiimide (DIPC);

1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDC=WSCI);

hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSCI•HCl); and

dicyclohexylcarbodiimide (DCC)

Perphosphate condensing agents:

O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyleneglutaric;

O-benzotriazol-1-yl-N,N,N',N'-tetramethylpropylenediamine;

benzotriazol-1 and oxytrol-pyrrolidinedithiocarbamate; and

benzotriazol-1-iltis(dimethylamino)phosphodiesterase (BOP).

Other:

diphenylphosphinite (DPPA).

Examples of the above agents that promote condensation, include the following.

N-hydroxy polyvalent imides of carboxylic acids:

N-hydroxysuccinimide (HONSu); and

imide, N-hydroxy-5-norbornene-2,3-dicarboxylic acid (HONB).

N-hydroxytriazolam:

1-hydroxybenzotriazole(HOBt).

Other:

3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazin (HO Obt);

2 hydroxyimino-2-ethylcyanoacrylate, ether;

p-NITROPHENOL (HONp); and

pentafluorophenol (HOPfp).

The ratio of the specified complex metal-Salins, agent, contributing condensing and condensing agent may be, for example, as follows:

complex metal-Salins: an agent that promotes condensation of the condensing agent = 1:1 to 2:1 to 2.

The fact of the formation of ties between the target component and the specified complex metal-Salins can be confirmed using mass spectrometry. The formation of the amide bond and disulfide bond can be confirmed using mass spectrometry and IR spectroscopy.

Examples

Examples preparation of complexes the metal-Salins

Complex metal-Salins, including the amino group as a substituent, get as disclosed below.

A mixture of 4-nitrophen is a (25 g, 0.18 mol)and hexamethylenetetramine (25 g, 0.18 mole) and polyphosphoric acid (200 ml) is stirred for 1 hour at 100°C. Then the mixture is introduced into 500 ml of ethyl acetate and 1 l of water and stirred until dissolved. After optionally added to a solution of 400 ml of ethyl acetate, the resulting solution is divided into two phases, and the aqueous phase is removed and the remaining connection twice washed with the main solvent, and dried over anhydrous MgSO4getting 17 g of compound 2 (57% yield).

Compound 2 (17 g, 0.10 mol), acetic anhydride (200 ml) and sulfuric acid (minimum: approximately 15 ml) is stirred for 1 hour at room temperature. The resulting solution was stirred for 0.5 hour in ice water (2 l) to carry out hydrolysis. The resulting solution was filtered and air-dried, obtaining a white powder. The resulting powder was recrystallized from a solution containing ethyl acetate, receiving 24 g of compound 3 (yield 76%) in the form of white crystals.

The mixture of carbon (2.4 g) coated with 10% palladium compound 3 (24 g, 77 mmol) and methanol (500 ml) restore during the night in the healing atmosphere of hydrogen (1.5 ATM). After the restore process is complete, the resulting product is filtered, receiving compound 4 (21 g) as a brown oil which CSOs color.

Compound 4 (21 g, 75 mmol) and di(tert-butyl)dicarbonate (18 g, 82 mmol) is stirred overnight in anhydrous dichloromethane (DCM) (200 ml) under nitrogen atmosphere. The resulting solution was left to evaporate in a vacuum, and then dissolved in methanol (100 ml). Then add sodium hydroxide (15 g, 374 mmol) and water (50 ml)and the resulting solution was refluxed for 5 hours. Then the solution is cooled, filtered, washed with water and dried in vacuum, obtaining as a result, the connection brown. The compound obtained twice treated using flash-chromatography using silica gel to give 10 g of compound 6 (yield 58%).

Compound 6 (10 g, 42 mmol) is introduced into 400 ml of anhydrous ethanol, the mixture is refluxed and add a few drops of ethylene diamine (1.3 g, 21 mmol) with stirring for 0.5 hours in 20 ml of anhydrous ethanol. The obtained mixed solution is placed in a container with ice, where it is cooled and stirred for 15 minutes. The mixture is then washed with 200 ml of ethanol, filtered and dried in vacuum, obtaining 8.5 g (yield 82%) of compound 7.

Examples of the formation of links between complex iron-Salins and protein (disulfide bond)

STAGE 1:

Compound 7A

Link is 8

Compound 8 get in the way Manfred T. Reetz, Martin Rentzsch, Andreas Pletsch, Matthias Maywald, Peter Maiwald, Jerome j.-P. Peyralans, Andrea Maichele, Yu Fu, Ning Jiao, Frank Hollmann, Regis Mondiere and Andreas Taglieber, 'Direct evolution of enantioselective hybrid catalysis: a novel concept in asymmetric catalysis,' Tetrahedron 63 (2007) 6404-6414.

STAGE 2:

Compound 7A (134 mg, 0,338 mmol), compound 8 (122 mg, 0,721 mmol), the molecule cross-linking agent, diisopropylcarbodiimide (170 μmol), agent dehydration condensing and NaHCO3(75 mg; 0.89 mmol) is transferred into a solution in which 0.1 M N,N-4-dimethylaminopyridine dissolved in THF (tetrahydrofuran) (20 ml)and the resulting solution was stirred for 2 hours at room temperature. The resulting solution is mixed with a solution in which the ethyl acetate and hexane mixed in a ratio of 1:1, and the resulting solution is treated through column chromatography with silica gel (20 g), resulting in the connection 9 (yellow, 115 g, yield 62%).

Connection 9

STAGE 3:

Compound 9 (17 mg, 31 μmol) and FeCl3(11 mg) was placed in methanol (4 ml) and stirred for 16 hours in air at room temperature, resulting in the connection of brown. Then, the compound obtained is dried in vacuum. The compound obtained is diluted with 400 ml of dichloromethane, washed twice with saturated saline, dried over anhydrous Na2S0sub> 4and then dried in vacuum, obtaining as a result, the connection 10 (18 mg, yield 90%).

Connection 10

STAGE 4

The connection 10, the protein obtained from Sigma-Aldrich (papain-lyophilized, 10 mg), and L-cysteine (10 mg) is placed in water (H2O, 1 ml) and stirred for 30 minutes. Then the resulting solution was mixed with phosphate buffer (300 ál, 1 M) at pH=7,01. Six hours after mixing receive compound 11 and compound 12 (papain binds to SH groups in both of them).

Connection 11

Connection 12

Complex iron-Salins, including carboxyl group are in accordance with the above stages, using 3-hydroxybenzoic acid as the starting material. Then carry out the reaction of interaction of the obtained complex iron-Salins, N'-dicyclohexylcarbodiimide (DCC) and hydroxysuccinimide (HONSu), getting active ester; and when the protein (papain-lyophilisate), which is micheneau substance is subjected to interaction with the active ester, this protein replaces hydroxysuccinimide and is associated with the specified complex iron-Salins amide bond. The formation of the amide bond was confirmed by IR spectroscopy.

1. The derived complex metal-Salins, the notion is Noah as a-b-C (A: complex metal-Salins; In: communication area, comprising at least one disulfide bond; and With: a functional molecule comprising at least one of the enzymes, antibodies, antigens, peptides, amino acids, oligonucleotides, proteins, nucleic acids and molecules of the drug),
moreover, the communication zone (C) includes the molecule cross-linking agent for the formation of a linkage between the specified complex metal-Salins (A) and the functional molecule (C); and the specified complex metal-Salins (A) and the specified molecule cross-linking agent are linked together via at least one disulfide bond; and the specified molecule cross-linking agent and the specified functional molecule (S) are linked together via at least one disulfide bond; and
where area disulfide bond (B) results in the formation of ties between the SH group is introduced as a substituent in the specified complex metal-Salins (A), and SH group indicated functional molecule (C), or occurs as a result of the formation of ties between the SH group of the specified complex metal-Salins (A) or specified functional molecule (C) and SH group in the molecule cross-linking agent.

2. The derived complex metal-Salins on p. 1, wherein said complex metal-Salins (A) represented by the following formula (I)where at least one of a-h is a"," OCTA is inoe represents hydrogen or an arbitrary Deputy, and M represents a metal atom

3. The method of deriving complex metal-Salins, by providing functional molecule comprising at least one of the enzymes, antibodies, antigens, peptides, amino acids, oligonucleotides, proteins, nucleic acids and molecules of the drug, contact a complex metal-Salins through at least one disulfide bond,
where specified complex metal-Salins and molecule agent that promotes condensation, dehydration and condense to generate their active complex ether, and carry out the reaction of the specified functional molecules and the active complex ether, thereby replacing the molecule agent, Pro-active condensation of ester and associating the specified complex metal-Salins with functional molecule and
where the molecule agent that promotes condensation, is an N-hydroxysuccinimide.



 

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28 cl, 1 dwg, 4 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing humin-containing iron chelates used in agriculture. The method involves mixing a chelating agent with an iron salt. The chelating component used is nitrosated ligno-humate formed at the chelate preparation step during reaction with iron (II) sulphate in ratio 1:2-1:3.

EFFECT: invention increases content of iron in the chelate with full solubility of the product in a weakly alkaline medium.

1 tbl, 6 ex

FIELD: pharmacology.

SUBSTANCE: invention refers to binuclear cation nitrosyl iron complexes with natural aliphatic thiolyls with general formula [Fe2(SR)2(NO)4]SO4 where R is aliphatic ligands of natural origin.

Also there is proposed method for production of binuclear cation nitrosyl iron complex, nitrogen monoxide donor, inductor of tumor cells apoptosis, application binuclear cation nitrosyl iron complex, pharmaceutical composition and set used for treatment of oncology diseased. The technical result is EFFECT: production of binuclear cation nitrosyl iron complex possessing cytotoxic, apoptotic and NO-donor activity.

15 cl, 2 ex, 4 tbl, 7 dwg

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

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.

EFFECT: invention ensures high efficiency of treatment.

8 cl, 1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention represents a pharmaceutical composition for treating demodectic blepharitis and blepharoconjunctivitis, containing recombinant interferon specified in a group: recombinant interferon alpha, recombinant interferon beta, recombinant interferon gamma, boric acid, fluconazole and/or voriconazole with the ingredients of the composition taken in certain ratio, g in 1 ml.

EFFECT: higher therapeutic effect.

2 cl, 6 ex

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