Method of producing polymerised coordination complexes of platinum

FIELD: chemistry.

SUBSTANCE: method involves reaction in aqueous medium of a diaquaplatinum or bis(nitrato)platinum complex in a mixture with dihalogenoplatinum with a block-copolymer of formula (1): or (2):, where R1 represents hydrogen or C1-C12-alkyl, L1 and L2 - connecting groups, R3 - hydrogen, a protective group for amino groups, a hydrophobic or polymerised group, R4 represents hydroxy-, carboxy- or a hydrophobic group, R5 represents hydrogen, an alkali metal ion or a protective group for the carboxylic group, m=5-20000, n=10-60, under the condition that, R5 - hydrogen or an alkali metal ion constitutes 50% or more in n links.

EFFECT: obtaining a conjugate which does not contain silver ions, the solution of which has lower particle-size distribution.

17 cl, 11 dwg, 7 ex

 

The technical field

The present invention relates to a method for producing a conjugate, in particular coordination compounds, complex platinum, suitable for use as antitumor agents, and the block copolymer.

The level of technology

A certain type of platinum complexes suitable for use as antineoplastic agents, and some of them have already been introduced into clinical use. In particular, we have developed specific stereoisomers of sodium dichloro(1,2-cyclohexanediamine)platinum (II) (here and later in this document in some cases, you may have the abbreviation "DACH-Pt(chlorate)") as analogues of cisplatin, which has found its clinical use as anti-cancer agents, and they showed great interest due to their antitumor action, superior antitumor activity of cisplatin. DACH-Pt(chlorate) is not introduced into clinical use, mainly due to its low solubility in water. At that time, as CIS-[(1R2R)]-1,2-cyclohexanediamine-N,N']oxalate(2-)-o,O-platinum (II) (it is also called oxaliplatin) is one of the various derivatives of the modified DACH-Pt(chlorate), in which two groups chlorate that are going ligands in the molecule, substituted group is, and oxalate, - currently widely used for clinical therapy due to its good solubility in water and strong antitumor action.

With regard to giving even more improved properties have also been proposed conjugates DACH-Pt and, for example, oxidized dextran or carboxymethylcysteine, which are the result of the substitution groups chlorate in DACH-Pt(chlorate) a polymer having carboxyl groups in its side chains (see non-patent document 1; these documents together are listed below), and conjugate block copolymer poly(ethylene glycol)-poly(glutamic acid) and DACH-Pt (see non-patent document 2). In particular, in non-patent document 2 reports that the conjugate described herein, forms a micelle polymer and solubilizated in the aquatic environment and demonstrates antitumor activity comparable to the antitumor effect oxaliplatin, but also high stability of drugs and long-lasting high level of accumulation in the tumor.

In non-patent document 1, the substitution of the polymer groups chlorate in DACH-Pt(chlorate) is carried out in the processing DACH-Pt(chlorate) silver nitrate, removing the resulting silver chloride in the filtering, transformation of the filtrate in line is the existing diavonex (sometimes abbreviated denoted as DACH-Pt(hydroxo)), demonstrating improved solubility in water, resulting in by-passing through the anion-exchange resin and the reaction between the complex and the polymer in water (see page 1088). In non-patent document 2 also implements almost the same method except that the silver chloride is removed in the centrifuge (see right-hand column on page 226 of the document).

The list of mentioned documents

Non-patent document 1: Y. OHYA et al., J. Biomater. Sci. Polymer Edn., Vol. 7, pp. 1085-1096 (1996).

Non-patent document 2: H. Cabral et al., J. Controlled Release 101 (2005) 223-232.

Description of the invention

Conjugate block copolymer poly(ethylene glycol)-poly(glutamic acid) and DACH-Pt, which was received in accordance with the method described in non-patent document 2, in the aquatic environment formed micelles of the polymer, which, specifically, was a micelle polymer obtained in [DACH-Pt]/[Glu]=0,75, and their cumulant diameter was 40 nm, and the cumulant polydispersity was very low (μ2/T2=0,03) in accordance with the measurement for them dynamic light scattering (DS). When the inventors of the present invention have reproduced this way, it was recorded the presence of silver ion, mixed with the conjugate DACH-Pt, and delete so the th ion of silver from the conjugate using conventional methods, it was impossible or extremely difficult. This is probably due to the fact that silver ion, which was not removed as a result of centrifugation, was taken in micelles of the polymer. In the case of medical drugs introduced into a living organism, the presence of this ion in the mixture of silver should be avoided as far as possible.

Thus, the purpose of the present invention is to provide essentially not containing silver ion conjugate (or coordination compound) block-copolymer complex of platinum, in particular, the conjugate block copolymer and DACH-Pt. One way to achieve the goal is to carefully remove the silver ion to be obtained conjugate block-copolymer complex of platinum. As described in non-patent document 1 may be used in complex declaratin from which silver ion was carefully removed. At that time, as the inventors of the present invention have found that achieving the goal of the present invention can also be achieved with thorough removal of silver ion on the stage of the complex bis(nitrato)platinum, which corresponds to the precursor complex declaratin, and the resulting product was used as source material for platinum.

In addition, applicants have also discovered that it is possible to obtain the solution, the soda is containing micelles of the polymer, characterized by one peak, reduce or eliminate those peaks that could be attributed to the polydisperse or aggregated micelles in the analysis of the micelles of the polymer obtained in the aquatic environment of the conjugate polymer/complex of platinum, according to the method gel chromatography (GPC), if the ratio of the complex bis(nitrato)platinum and the block copolymer will be installed on level concrete numerical values.

In addition, applicants unexpectedly discovered that the use as starting material for the complex mixture of platinum complex declaratin or complex bis(nitrato)platinum complex dehalogenation (complex of sodium dichloro-, diiodo or dibromobutane) could allow to obtain a solution containing micelles of the polymer, characterized by similar single peak and a more narrow distribution of particle sizes.

Thus, in accordance with this invention proposes a method of preparation of coordination compounds the reaction between the platinum complex and the polymer having carboxyl groups in its side chains, where the complex of platinum, a mixture of complex declaratin or complex bis(nitrato)platinum, in particular, the last complex on halogenating (complex of sodium dichloro-, diiodo or dibromobutane), and the polymer used as the block copolymer, vpisivaushiesya following General formula (1) or (2):

where R1represents a hydrogen atom or unsubstituted or substituted linear or branched C1-C12alkyl group; each of L1and L2independently represents a connecting group; R2represents a methylene group or ethylene group; R3represents a hydrogen atom, a blocking group to an amino group, a hydrophobic group or a polymerized group; R4represents a hydroxyl group, a blocked carboxyl group formed together with the end-WITH, or a hydrophobic group; each of R5independently represents a hydrogen atom, alkali metal ion or a blocking group for carboxyl group; m is an integer in the range from 5 to 20000, n is an integer in the range from 2 to 5000; and x represents an integer in the range from 0 to 5,000, with the proviso that x is not greater than n, and a hydrogen atom or alkali metal ion is 50% or more, preferably 80% or more, and more preferably 100%, from R5for n-x and x, the method includes a step of carrying out the reaction in an aqueous medium under conditions in which the complex of platinum (including platinum complexes in the state of the mixture) and the block copolymer form with each other the coordination compound, and the stage extract thus obtained coordination compounds.

In a preferred implementation, the corresponding present invention, as complex declaratin use diaquo(1,2-cyclohexanediamine)platinum (II), as the complex bis(nitrato)use platinum bis(nitrato)(1,2-cyclohexanediamine)platinum (II), and as complex dehalogenating use of sodium dichloro(1,2-cyclohexanediamine)platinum (II).

In accordance with another alternative implementation of the present invention also proposes a method of preparation of coordination compounds the reaction between the platinum complex and the polymer having carboxyl groups in its side chains, where the source material used bis(nitrato)(1,2-cyclohexanediamine)platinum (II), diaquo(1,2-cyclohexanediamine)platinum (II) or a mixture of bis(nitrato)(1,2-cyclohexanediamine)platinum (II) and diaquo(1,2-cyclohexanediamine)platinum (II)complexes of platinum essentially do not contain silver ion and as the polymer used block copolymer, vpisivaushiesya the above General formula (1) or (2), and the method includes a step of carrying out the reaction in an aqueous medium under conditions in which the platinum complex (including a mixture of platinum complexes) and the block copolymer with each other form of coordination the e connection and the stage extract thus obtained coordination compounds. In a preferred implementation of the present invention, the ratio of platinum atoms in all the complexes (complex) of platinum, preferably bis(nitrato)(1,2-cyclohexanediamine)platinum (II) (which is hereinafter in this document may be the abbreviation DACH-Pt(nitrate)), and carboxylate groups in the block copolymer (based on the equivalents used later in this document) is set larger than 0.4, preferably in the range from 0.45 or more and 0.7 or less, more preferably from value (0.475) and more to 0.6 or less, and most preferably from 0.5 or more to 0.55 or less. The final concentration of total complexes (complex) of platinum in the reaction liquid water environment set equal to 2 mg/ml (approximately 4.6 mm) or less, preferably 1 mg/ml (approximately 2.3 mm) and less. Although these two set of conditions can be chosen independently, simultaneous selection of both conditions leads to a more preferable result.

If you wish to use as antitumor agents conjugate block-copolymer complex of platinum, which is produced in accordance with the present invention, an important factor in determining the accumulation of drugs in the tumor is Hanks to effect superior penetrating ability and retention (OOPS), is the distribution of particle sizes for micelles of the polymer. In accordance with the present invention offers a solution containing micelles of the polymer, which are characterized by a single peak when conducting measurement by GPC method and, in addition, the peak of the narrow distribution of the cumulant diameter that is one of the criteria of the diameter of the particles, namely, a narrow distribution of particle sizes. Therefore, in accordance with the present invention offers an effective way of obtaining conjugates or coordination compounds, which can profitably be used as anticancer agents, such as, for example, those that can form micelles polymer suitable for use in obtaining stable and excellent effect OOPS.

The following is a detailed description of the present invention.

Key terms used in the present description of the invention, which are considered to require standard definitions should be understood following manner, although thus any limitation and not impose.

The coordination compound is a compound which is considered to have coordination (communication), where the coordination relationship exists between the platinum complex of platinum and a carboxyl group block copolymer. In the description from the retene the term "conjugate" of the block-copolymer complex of platinum is used in this sense, it is interchangeable with the term “coordination compound”.

Complex declaratin, the complex bis(nitrato)platinum or complex dehalogenation (complex of sodium dichloro-, diiodo or dibromobutane), which are suitable for use by platinum complexes may contain any other ligands (ligand) in addition to the ligands diaquo, bis(nitrato) or dihalogen, if only they will meet the objectives of the present invention. Examples off the following, but are not limited to these. Complex declaratin may include diaquo(1,2-cyclohexanediamine)platinum (II), CIS-diamminedichloroplatinum (II), ammoniakkaskadenkglteanlage (II), CIS-mindeco(2-methylpyridine)platinum (II) and the like, and particularly preferred is diaquo(1,2-cyclohexanediamine)platinum (II). The complex bis(nitrato)platinum may include bis(nitrato)(1,2-cyclohexanediamine)platinum (II), CIS-diamminedichloroplatinum (II), aminodinitrotoluenes (II), CIS-lendinara(2-methylpyridine)platinum (II) and the like, and particularly preferred is bis(nitrato)(1,2-cyclohexanediamine)platinum (II). Among the complexes dehalogenation (complexes of sodium dichloro-, diiodo or dibromobutane) preferably can be used complex dichloroplatinum, it may include a complex of sodium dichloro(1,2-cycle is hexanediamine)platinum, CIS-diamminedichloroplatinum (II), amandaleporeonline (II) and CIS-amandala(2-methylpyridine)platinum (II) and the like, and particularly preferred is sodium dichloro(1,2-cyclohexanediamine)platinum (II).

"Essentially not containing silver ion" refers to a condition in which, as a maximum, contains not more than 20 hours/million silver, and preferably silver cannot be detected using conventional methods (for example, the method of atomic absorption), or it is not contained at all. Essentially not containing silver ion complex declaratin or complex bis(nitrato)platinum, which is used as a starting material for the platinum complex can be obtained by processing the corresponding complex dichloroplatinum silver nitrate, removing the obtained precipitate of silver chloride and further remove any remaining silver ion, for example, when using a reverse osmosis membrane that is described in the document JP Hei 5(1993)-301884 A. However, suitable for use by the retrieval method is not limited to only this. In addition, complexes of bis(nitrato)this platinum brand, for example, DACH-Pt(nitrato), commercially available in the company W. C. Heraeus GmbH & Co. KG. So DACH-Pt(nitrato) is bis(nitrato)(1,2-cyclohexanediamine)platinum (II) (it is also called dinitrate treatment deacon is about(1,2-cyclohexanediamine)platinum (II)). Despite the fact that these platinum complexes can be any existing stereoisomers, are preferred CIS-sodium dichloro(TRANS-L-1,2-cyclohexanediamine) and other platinum complexes having equivalent steric configuration.

In the present invention for achieving the objectives of the present invention can use any block-copolymer, vpisivaushiesya the above General formula (1) or (2). At that time, as the preferred block copolymers are those that are described by the following General formula (1) or (2-a)or their salts:

where R1L1L2, R3, R4and R5represent the same as defined for the General formula (1) and (2), respectively; m is an integer in the range from 5 to 20,000; and n is an integer in the range from 10 to 60, with the proviso that R5for the n atom of hydrogen or alkali metal ion is 50% or more, preferably 80% or more, more preferably 100%.

The above definitions of groups or fragments in the General formula (1), (2), (1) and (2) must be interpreted in accordance with their values or content, generally recognized among experts in the relevant field of technology. Their specific examples are provided herein further but are not limited to these.

In the case of R1unsubstituted or substituted, linear or branched C1-C12the alkyl group includes methyl, ethyl, n-sawn, ISO-propyl, n-boutelou, second-boutelou, tert-boutelou, n-pentelow, n-hexoloy, decile and undecyloxy group. In the case of substituted R1Deputy includes azetilirovanny formyl group, cyano, formyl group, carboxyl group, amino group, With1-C6alkoxycarbonyl group2-C7allasitoror, three1-C6alkylsalicylate with the same or different alkyl substituents, siocsiwap or silylamine. Poly(etilenglikolevye) (PEG) segments having such a functional group in one of its limit positions, can conveniently be obtained in accordance with the methods of obtaining segments of PEG-block-polymers, which are described, for example, in documents WO 96/32434, WO 96/33233 and WO 97/06202.

Thus obtained block copolymers, vpisivaushiesya General formula (1), (2), (1) or (2-a), depending on the used method of obtaining can use any variant of connection and can be connected to any connecting group, if only they will meet the objectives of the invention. For example, the methods include a method of obtaining a target block copolymer, R is the result of the use of the derivative of PEG, with the end amino group, its polymerization with the use of its terminal amino group and, for example, anhydride N-carboxylic acid (NCA) of β-benzyl-L-Asparaginate and/or γ-benzyl-L-glutaminate for synthesizing a block copolymer, and then either turning benzyl groups of the side chains in other ester groups, or their partial or complete hydrolysis. In this case, the structure of the copolymer becomes the one that is described by the General formula (1) or (1-a)and the connecting group L1acquires the structure, resulting from the end structure of the used segment of the PEG, which preferably represents -(CH2)b-NH- (where b is an integer in the range from 1 to 5).

In addition, the copolymer corresponding to the present invention can be obtained by the method in which synthesize fragment in the form of a segment of the poly(carboxylic acid) or poly(amino acid or its derivative), and after that it is associated with a previously received fragment in the form of a segment of the PEG. In this case, the obtained copolymer, ultimately, may have the same structure as the structure of the copolymer obtained by the method described first, or a structure corresponding to the General formula (2) or (2-a). Despite the fact that the connecting group L2any particular Ogre is icene not impose, preferably it represents -(CH2)with-CO- (where C is an integer in the range from 1 to 5) group.

Each R5independently can be a hydrogen atom or a blocking group for the carboxyl group. A blocking group for the carboxyl group include the following, but is not limited to: benzyl, benzydamine or1 - 6alkyl group, with specific examples of alkyl groups are methyl, ethyl, n-sawn, ISO-propyl, n-bucilina, second-bucilina, tert-bucilina, n-pentilla and n-exilda group.

Each R3independently can be a hydrogen atom or a blocking group for the amino group, for example benzyloxycarbonyl, tert-butyloxycarbonyl, acetyl or trifluoracetyl group, and it can also represent a hydrophobic group, such as benzylcarbamoyl or benzylaminocarbonyl group and the like, or a polymerized group, such as calolina or methacryloyl group.

Each R4independently can represent a hydroxyl group; a blocked carboxyl group with end-WITH, for example benzyloxycarbonyl, tert-butyloxycarbonyl or methoxycarbonyl group; a hydrophobic group, such as benzilic the and - or benzhydrylamine; or polymerized hydrophobic group, such as allyloxy or VINYLTRIMETHOXYSILANE. m is an integer in the range from 5 to 20000, preferably from 10 to 5000, more preferably from 40 to 500, and n is an integer in the range from 2 to 5000, preferably from 5 to 1000, more preferably from 10 to 60, and most preferably from 15 to 40. Therefore, despite the fact that in the present description of the invention the fragment in the case referred to as poly(ethylene glycol) and the like, the prefix "poly" is used as a concept including also what is usually classified as "oligo".

At that time, as x, which determines the ratio in the chemical composition between the quantities of two types of repeating units, which may be present in the segment of poly(amino acid or its derivative), in particular, poly(aspartic acid), may be an integer in the range from 0 to 5000 (but not more than n). In this case, each of the repeating units may be distributed statistically or in blocks.

The conditions of the reaction when receiving the above-described coordination compounds containing the platinum complex and the block copolymer include complex declaratin, in particular, DACH-Pt(hydroxo), or the complex bis(nitrato)platinum, in particular, DACH-Pt(nitrato), PR is sutstvie in the aquatic environment, in particular, in the water, (which may be an aqueous solution containing mixed with water, an organic solvent, such as methanol, ethanol, acetonitrile, dimethylformamide and the like, as needed), in the amount soluble in the aqueous medium at temperatures in the range 5°C-90°C, although this is not a limitation; then the simultaneous presence of the block copolymer; and careful stirring of the mixture or leaving the mixture to defend within the period of time sufficient to obtain coordination compounds. Despite the impossibility of giving a sufficient period of time, because it varies depending on the reaction temperature, it can have a duration of from 10 to 96 hours at 37°C.

In the case of use as source material for platinum complex extremely complex declaratin, especially DACH-Pt(hydroxo), or complex bis(nitrato)platinum, in particular, DACH-Pt(nitrato)used the ratio of platinum atoms in the platinum complex and carboxylate groups in the block copolymer (based on equivalents, the same should be used in this document hereinafter) in the desirable case set larger than 0.4, preferably in the range from 0.45 or more and 0.7 or less, more predpochtitel the but from the value (0.475) or more to 0.6 or less, most preferably 0.5 or more to 0.55 or less. Coordination compounds obtained in such conditions, in an aqueous medium to form a little aggregated micelles polymer or do not form at all and can form micelles polymer, characterized by almost one peak in accordance with the measurement by GPC method. In addition, micelles can encapsulate approximately 80% or more of the platinum complex used in the reaction (number of downloads).

Another preferred implementation of the present invention is the way in which to ensure the presence in the aqueous medium mixtures as raw materials complex of platinum and passing the reaction of the block copolymer for complex declaratin or complex bis(nitrato)platinum, preferably DACH-Pt(hydroxo) or DACH-Pt(nitrato), in particular, DACH-Pt(nitrato), and complex dehalogenation, preferably DACH-Pt(halogeno), in particular, complex dichloroplatinum, preferably DACH-Pt(chlorate).

Although some theoretical limitations on the scope of the present invention should not be applied, it can be assumed that, during simultaneous presence of complex dehalogenation in this way it becomes possible keeping the initial concentration of the complex bis(nitrato)p is Atina, which reacts with the block copolymer in the reaction solution, at a low level, such that the coordination compound formed in the reaction rate, suitable for receiving the polymer micelles. Therefore, in a wide range of used the ratio between the quantities of the platinum complex and the polymer can be obtained micelle polymer, characterized by almost one peak in accordance with the measurement by GPC method, with little formation of aggregated polymer micelles or no education themselves, which allows to obtain a liquid reaction mixture, which contains micelles of the polymer, characterized by a narrow distribution of particle sizes.

In example 10 of Japanese patent publication No. 2000-506855 And (or WO 97/33894) describes stating that the boiling equimolar amounts DACH-Pt(chlorate) and DACH-Pt(nitrato) in distilled water resulting in obtaining the dual complex of platinum (platinum complex containing in one molecule two atoms of platinum).

Thus, despite the occurrence of assumptions about the availability of the coordination compounds corresponding to the present invention, also with the participation of the dual complex in the presence of a block copolymer corresponding to the present invention, it is necessary under the TB, that the coordination compound obtained in the present invention and forming a micelle polymer mainly comprises mononuclear complex of platinum, if we consider factors including the nature of the reaction mixture.

In the present invention for the complex bis(nitrato)platinum, preferably DACH-Pt(nitrato), and complex dehalogenation, in particular, complex dichloroplatinum, preferably DACH-Pt(halogeno), especially DACH-Pt(chlorate), it is possible to carry out mixing, or to provide simultaneous presence in the aqueous medium at a molar ratio in the range from 1:9 to 9:1, preferably from 1:4 to 4:1, and more preferably is 1:1. This state of the mixture or the simultaneous presence of preferably causes the mixing of the complex bis(nitrato)platinum and complex dehalogenation in the aquatic environment, especially in water. At that time, as to the state of the mixture or the simultaneous presence can also lead to the simultaneous presence DACH-Pt(halogeno), in particular, complex dichloroplatinum, preferably DACH-Pt(chlorate), and strong acids, except hydrochloric acid, such as sulfuric acid, Perlina acid, triftormetilfullerenov acid, nitric acid, in particular, nitric acid; or the provision of content in water races is the thief of the complex bis(nitrato)platinum halide ion, selected from the group consisting of ions of chloride, iodide and bromide, to obtain the prescribed number of complex dehalogenation in situ. The source of the halide include the following, though not limited to: hydrochloric acid, sodium chloride and potassium chloride in the case of ion chloride; sodium iodide and potassium iodide in case of iodide ion; and potassium bromide, sodium bromide and Hydrobromic acid in the case of bromide ion. In the case of the simultaneous presence of these two complexes of platinum used the ratio of platinum complexes and the block copolymer may be in the range from 4:10 to 4:1, preferably from 4.5:10 to 2:1, more preferably from 5:10 to 3:2, when the expression ratio (the ratio in equivalents between the amounts of platinum atoms in the platinum complexes and carboxylate groups in the block copolymer.

Thus get the desired coordination compound. The coordination compound can effectively remove or clear the use of conventional methods of isolation of the polymer micelles, for example, dialysis or ultrafiltration or a combination, because the connection spontaneously associate and form stable micelles polymer encapsulating the platinum complexes in the reaction solution.

A brief description of hell is Jay

Fig. 1 is a GPC chart for containing micelles of the polymer solution obtained in Example 1. The x-axis represents retention time (minutes)and the ordinate axis represents the output signal (mV) for ultraviolet absorptiometer.

Fig. 2 is a graph showing the distribution of particle size of micelles in containing micelles of the polymer solution obtained in Example 1 measurement which was performed by the method of dynamic light scattering. The abscissa represents the diameter (nm)and the ordinate axis represents the relative intensity.

Fig. 3 is a GPC chart for containing micelles of the polymer solution obtained in Example 2. The x-axis and y-axis have the same values as in Fig. 1.

Fig. 4 is a graph showing the distribution of particle size of micelles in containing micelles of the polymer solution obtained in Example 2, the measurement which was performed by the method of dynamic light scattering. The x-axis and y-axis have the same values as in Fig. 2.

Fig. 5 is a GPC chart for each of the reaction solutions obtained with the use of platinum atoms in the platinum complex and carboxylate groups in the block copolymer at the ratios shown in Example 3. Axis AB of the CRSC and the y-axis have the same values that, and Fig. 1.

Fig. 6 is a graph showing the change of squares shown on the GPC charts of Fig. 5 in this space correspond to the amounts, respectively, of the obtained polymer micelles. The x-axis represents the used ratio of platinum atoms in the platinum complex and carboxylate groups in the block copolymer, and the ordinate axis represents the peak area [mV·sec] of the micelles.

Fig. 7 shows a GPC chart for the reaction solutions obtained using the two types of complexes of platinum when used in the proportions given in Example 4. The x-axis and y-axis have the same values as in Fig. 1.

Fig. 8 is a graph showing the change of squares shown on the GPC charts of Fig. 7, the square correspond to the amounts, respectively, of the obtained polymer micelles. The abscissa represents the ratio {[nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II)]/([CIS-sodium dichloro(TRANS-L-1,2-cyclohexanediamine)platinum (II)]+[CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II)]}, and the y-axis represents the peak area of the micelles [mV·sec].

Fig. 9 is a graph showing the change of the area corresponding to the number of micelles of the polymer in each of the reaction solutions obtained PR is changing used the ratio of platinum atoms in the equimolar mixture of two types of complexes of platinum and of the carboxylate in the block copolymer in Example 5. The x-axis represents the used ratio of platinum atoms in the platinum complexes and carboxylate in the block copolymer, and the y-axis has the same meaning as in Fig. 8.

Fig. 10 is a diagram for civil reaction solution obtained in Example 6, for the case of obtaining two platinum complexes in situ. The x-axis and y-axis have the same values as in Fig. 1.

Fig. 11 shows a GPC chart for the reaction solutions obtained in variable concentrations in the reaction solution of nitrate of CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II), for a variable ratio between the quantities of the platinum atom in the nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II) and carboxylate in the block copolymer. The x-axis and y-axis have the same values as in Fig. 1.

The best way of carrying out the invention

Hereafter in this document, the present invention is described more specifically with reference to specific examples, which, however, are not intended to limit the present invention. In addition, in the following examples used the platinum complexes, the levels of silver ion, which accounted for less than 5 hours/million

Example 1

In this example, describe a concrete example, in which the source materials are simultaneously present DACH-Pt(nitrato) and DACH-Pt(chlorate).

To 217 mg of bis(nitrato)(TRANS-L-1,2-diaminocyclohexane)platinum (II) [which is also called nitrate of CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II), and this nomenclature is used in this document hereafter] and 189 mg sodium dichloro(TRANS-L-1,2-diaminocyclohexane)platinum (II) [or CIS-sodium dichloro(TRANS-L-1,2-cyclohexanediamine)platinum (II), and this nomenclature is used in this document here and below] added 220 ml of water and conducted joint is heated up to 70°C to dissolve both components. This solution was cooled to about 37°C, and dissolved 750 mg of block copolymer poly(ethylene glycol)-poly(glutamic acid) [hereinafter in this document abbreviated referred to as PEG-P(Glu), and if the molecular weight of PEG is 12×103and the degree of polymerization for P(Glu) is equal to 20, then the copolymer is abbreviated as PEG-P(Glu) 12-20] when the ratio {[nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II)+CIS-sodium dichloro(TRANS-L-1,2-cyclohexanediamine)platinum (II)]/[Glu]=1}, and the reaction was allowed to proceed at 37°C for 72 hours in a dark place. The resulting solution was subjected to repeated ultrafiltration using ultrafiltration apparatus (Nippon Millipore: Labscale·TFF system: cutoff molecular weight of 100000) for removing the bulk of the low molecular weight side is products NaNO3and NaCl and unreacted complex of platinum and a block copolymer, which did not form micelles. The filtrate was concentrated to obtain 55 ml of a solution of micelles. The amount of the platinum complex encapsulated in micelles, accounted for 38% of the added amount. Analysis of the solution by the GPC method using liquid chromatography (TOSOH Corporation, AS-8020 series) was performed using the following conditions for GPC. The GPC chart shown in Fig. 1. Separate measurements of dynamic light scattering (NICOMP.380ZLS) in accordance with the attached manual. The result is demonstrated in Fig. 2.

Conditions for GPC

Column: Waters Ultrahydrogel 500

10 μm of 7.8×300 mm

Detector: ultraviolet absorptiometer (wavelength measurement=240 nm)

The column temperature is approximately 40°C.

Mobile phase: 10 mmol/l phosphate buffer (pH 7.4)

The flow rate: 0.6 ml/min

The volume of injected sample: 10 ál

As clearly follows from Fig. 1, it is necessary to understand that aggregated polymer micelles or micelle polymer having a very large diameter, were not formed because of high-molecular wing (shorter retention time) no peak was not observed. On the basis of Fig. 2, it is also necessary to understand that the average particle diameter obtained for micelles of the polymer which was a 33.3 nm with a standard deviation of 7.9 nm (23.7 per cent).

Example 2

In this example, describe a specific example in which as the source of material used alone DACH-Pt(nitrato), and the coordination compound was obtained at a particular value when calculating the number of carboxylate (Glu) in the block copolymer.

To 227 mg of nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II) was added 120 ml of water and held their joint heated to 70°C. to obtain a solution. This solution was cooled to about 37°C, and dissolved 750 mg PEG-P(Glu) 12-20 when the ratio {[nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II)]/[Glu]=0,525} and the reaction solution was allowed to proceed at 37°C for 72 hours in a dark place. The thus obtained solution was subjected to repeated ultrafiltration (boundary molecular weight of 100000) for removing the bulk of the low molecular weight by-product - NaNO3and unreacted complex of platinum and a block copolymer, which did not form micelles. This solution was analyzed by GPC method as in Example 1. The GPC chart shown in Fig. 3. The result held for separately measuring dynamic light scattering (NICOMP 380ZLS) shown in Fig. 4.

It Is Evident From Fig. 3 it is clear that the aggregated micelles polymer or micelle polymer having a very large di is m, were not formed because of high-molecular wing no peak was not observed. It Is Evident From Fig. 4 it is also clear that the average particle diameter obtained for micelles of the polymer was 29.9 nm with a standard deviation of 20.7 nm (69,0%). Despite the fact that the micelles of the polymer was characterized by a broader size distribution in comparison with what took place for the case of reception in Example 1, no aggregated micelles polymer was not observed.

Example 3

In this example as starting material used alone DACH-Pt(nitrato) and investigated the influence of the used ratio between the quantities of platinum atoms in the platinum complex and carboxylate (Glu) in the block copolymer on the configuration of the micelles of the polymer obtained from coordination compounds.

Nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II) was dissolved in water at 70°C (9,238 mmol/l). This solution was cooled to about 37°C., then added an aqueous solution of PEG-P(Glu) 12-40 at the ratios {[nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II)]/[Glu]=7/10, a 6.5/10, 6/10, 5,5/10 and 5/10}. The final concentration of CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II) in each of the solutions was made equal to 2 mg/ml (4,620 mmol/ml) and the reaction solution was allowed to proceed at 37°C for 96 hours in a dark place. Of each and the resulting solutions were selected part and were analyzed by GPC method under the same conditions, as in Example 1. The thus obtained GPC chart shown in Fig. 5. The correlation between the size of the micelles and the ratio of [nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II)]/[Glu] was represented by that shown in Fig. 6. Area for micelles reached a maximum when the ratio of [nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II)]/[Glu] was 5.5/10. On the basis of Fig. 5, it should be concluded that when the ratio of the complex of platinum and carboxylate was in the range of from 7/10 to 6/10, was formed structures that are aggregated micelles of the polymer, because the high-molecular wing was observed peaks in the form of shoulders.

Example 4

In this example, examine the effect of the ratio in the mixture between the two types of platinum complexes on the configuration of the micelles of the polymer obtained from coordination compounds.

Nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II) and CIS-sodium dichloro(TRANS-L-1,2-cyclohexanediamine)platinum (II) was dissolved in water at 70°C at a molar ratio 9:1, 4:1, 2:1, 1:1, 1:2, 1:4 and 1:9 respectively (collectively, 2.5 mmol/l). These solutions were cooled to about 37°C. this was dissolved PEG-P(Glu) 12-20 when the ratio {[nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II)+CIS-sodium dichloro(TRANS-L,2-cyclohexanediamine)platinum (II)]/[Glu]=1}, and the reaction solutions was allowed to proceed at 37°C for 72 hours in a dark place. From each of the reaction solutions took part and were analyzed by GPC method under the same conditions as in Example 1. The thus obtained GPC chart shown in Fig. 7. The correlation between the size of the micelles and the ratio of nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II):CIS-sodium dichloro(TRANS-L-1,2-cyclohexanediamine)platinum (II) represented that shown in Fig. 8. Area for micelles reached a maximum when the ratio of nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II):CIS-sodium dichloro(TRANS-L-1,2-cyclohexanediamine)platinum (II) was 1:1.

Example 5

In this example, examine the effect used in the ratio between the amount of platinum atoms in the platinum complexes and carboxylate (Glu) in the block copolymer on the configuration of the micelles of the polymer obtained from coordination compounds, in the case of using two types of complexes of platinum.

Nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II) and CIS-sodium dichloro(TRANS-L-1,2-cyclohexanediamine)platinum (II) was dissolved in water at 70°C at a molar ratio of 1:1 (collectively, 2.5 mmol/l). This solution was cooled to about 37°C, and dissolved PEG-P(Glu) 12-20 at the ratios of [nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II)+CIS-sodium dichloro(TRANS-L-1,2-cyclohexanediamine)Platin is (II)]/[Glu] 1/4, 1/2, 1/1 or 1/0,5. After that, the reactions to the resulting solutions was allowed to proceed at 37°C for 24 hours in a dark place. From each of the reaction solutions took part and were analyzed by GPC method under the same conditions as in Example 1. The correlation between the size of the micelles and the ratio of [nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II)+CIS-sodium dichloro(TRANS-L-1,2-cyclohexanediamine)platinum (II)]/[Glu] shown in Fig. 9. Area for micelles reached a maximum when the ratio of [nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II)+CIS-sodium dichloro(TRANS-L-1,2-cyclohexanediamine)platinum (II)]/[Glu] was 1:1.

Example 6

In this example, describe a specific example in which the receiving condition of the simultaneous presence of two types of platinum complexes provide in sute.

Nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II) was dissolved in 10 ml of water at 70°C. This solution was cooled to about 37°C. to it was added 10 μl of 1 N. hydrochloric acid, it is dissolved 44 mg of PEG-P(Glu) 12-40 when the ratio {[nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II)]/[Glu]=0,5/1} and reactions to the resulting solution was allowed to flow at 37°C for 24 hours. From the reaction solution took part and were subjected to the analysis of the GPC method under the same conditions, as in Example 1. The GPC chart shown in Fig. 10. The area of polymer micelles were 8085 (mV/sec).

Example 7

In this example as starting material used alone DACH-Pt(nitrato)that allowed us to study the influence of its concentration in the reaction solution, intended for obtaining coordination compounds, and to investigate the influence of the used ratio between the quantities of platinum atoms in the platinum complex and carboxylate (Glu) in the block copolymer on the configuration of the micelles of the polymer obtained from coordination compounds.

Nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II) was dissolved at a concentration of 4,620 mmol/l, 2,309 mmol/l and 1,155 mmol/l at 70°C and the solution was cooled to about 37°C. In 30 ml of each of the cooled solution with different concentrations of dissolved PEG-P(Glu) 12-40 at the ratios {[nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II)]/[Glu]=7/10, 6/10, 5,5/10, 5/10 That is 4/10 and 3/10} and reactions to the resulting solutions was allowed to proceed at 37°C for 72 hours in a dark place. From each of the reaction solutions took part and were analyzed by GPC method under the same conditions as in Example 1. The obtained GPC chart shown in Fig. 11.

Although in positions corresponding to approximately 2 minutes, the peaks of the polymer micelles was observed for the reaction of the nitrate solution of CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II) at all levels of the concentrations of no presence peak of the polymer micelles were not confirmed, if the ratio of platinum atoms in the platinum complex and carboxylate was 4/10 and less.

In the case of the reaction solution is characterized by the concentration of nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II) 4,620 mmol/l, high-molecular wing peaks of polymer micelles was observed peaks in the shoulders, if the ratio of platinum atoms in the platinum complex and carboxylate was in the range of from 7/10 to 65/10, which leads to the conclusion about the formation of aggregated or polydisperse micelles of the polymer.

Similarly in the case of the reaction of the nitrate solution of CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II) concentration 2,309 mmol/l for high-molecular wing was observing a very small peak in the form of a shoulder, if the ratio of the complex of platinum and carboxylate was 7/10, but at the ratios of 6/10 and less peak in the shoulder disappeared, and was formed monodisperse micelles of the polymer.

In addition, in the case of the reaction of the nitrate solution of CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II) concentration 1,155 mmol/l was formed by the ü monodisperse micelles polymer regardless of the ratio between the quantities of a complex of platinum and carboxylate.

Based on the foregoing, it will be clear that monodisperse micelles polymer easier to get at concentrations of nitrate CIS-diaquo(TRANS-L-1,2-cyclohexanediamine)platinum (II), not more than 4,620 mmol/L.

1. The method of obtaining coordination compounds as a result of reaction between the platinum complex and the polymer having carboxyl groups in its side chains,
where as a complex of platinum use complex declaratin or complex bis(nitrato)platinum in the form of a mixture with complex dehalogenation, which is selected from complexes of sodium dichloro-, diiodo or dibromobutane, and the polymer used as the block copolymer, vpisivaushiesya following General formula (1) or (2):


where R1represents a hydrogen atom or unsubstituted or substituted linear or branched C1-C12alkyl group, L1and L2independently from each other represent a connecting group, R3represents a hydrogen atom, a protective group for an amino group, a hydrophobic group or a polymerized group, R4represents a hydroxyl group, a protected carboxyl group formed together with the end - WITH, or a hydrophobic group; each of R5independently represents FDS is th a hydrogen atom, ion of an alkali metal or a protective group for carboxyl group, m represents an integer in the range from 5 to 20000, n is an integer in the range from 10 to 60, with the proviso that the hydrogen atom or alkali metal ion, which is defined as R5is 50% or more of the n links,
the method includes a step of carrying out the reaction in an aqueous medium under conditions in which the complexes of platinum and a block copolymer with one another to form a coordination compound, and
stage extract thus obtained coordination compounds from the reaction mixture.

2. The method according to claim 1, where the complex declaratin is diaquo(1,2-cyclohexanediamine)platinum (II)complex of bis(nitrato)platinum is a bis(nitrato)(1,2-cyclohexanediamine)platinum (II)complex dehalogenating choose from the sodium dichloro(1,2-cyclohexanediamine)platinum (II), diiodo(1,2-cyclohexanediamine)platinum (II) and dibromo(1,2-cyclohexanediamine)platinum (II).

3. The method of claim 1, where the platinum complex in the form of a mixture produced by mixing the complex bis(nitrato)platinum and complex dehalogenating selected from complexes of sodium dichloro-, diiodo and dibromobutane.

4. The method according to claim 1, where the platinum complex in the form of a mixture produced by adding a halide ion selected from the group consisting of ion x is orida, iodide and bromide, in aqueous solution of the complex bis(nitrato)platinum.

5. The method according to claim 1, where the platinum complex in the form of a mixture produced by mixing bis(nitrato)(1,2-cyclohexanediamine)platinum (II) complex dehalogenating selected from the group consisting of sodium dichloro(1,2-cyclohexanediamine)platinum (II), diiodo(1,2-cyclohexanediamine)platinum (II) and dibromo(1,2-cyclohexanediamine)platinum (II).

6. The method according to claim 1, where the platinum complex in the form of a mixture produced by adding a halide ion selected from the group consisting of ions of chloride, iodide and bromide, an aqueous solution of bis(nitrato)(1,2-cyclohexanediamine)platinum (II).

7. The method according to claim 1, where the platinum complex in the form of a mixture produced by mixing the sodium dichloro(1,2-cyclohexanediamine)platinum (II) and an aqueous solution of bis(nitrato)(1,2-cyclohexanediamine)platinum (II).

8. The method according to claim 1, where the bis(nitrato)(1,2-cyclohexanediamine)platinum (II) complex of bis(nitrato)platinum, sodium dichloro(1,2-cyclohexanediamine)platinum (II) complex dehalogenation are present at a molar ratio in the range from 1:9 to 9:1.

9. The method according to claim 1, where the bis(nitrato)(1,2-cyclohexanediamine)platinum (II) complex of bis(nitrato)platinum, sodium dichloro(1,2-cyclohexanediamine)platinum (II) complex dehalogenation are present at a molar ratio in the range of the zone from 1:4 to 4:1.

10. The method according to claim 1, where the bis(nitrato)(1,2-cyclohexanediamine)platinum (II) complex of bis(nitrato)platinum, sodium dichloro(1,2-cyclohexanediamine)platinum (II) complex dehalogenation are present at a molar ratio of 1:1.

11. The method according to claim 1, where the two reagent is used in such quantities that the ratio between the number of platinum atoms in total platinum complexes and the number of carboxylate groups in the block copolymer was in the range from 4:10 to 4:1.

12. The method according to claim 1, where the two reagent is used in such quantities that the ratio between the number of platinum atoms in total platinum complexes and the number of carboxylate groups in the block copolymer was in the range of from 4.5:10 to 2:1.

13. The method according to claim 1, where the two reagent is used in such quantities that the ratio between the number of platinum atoms in total platinum complexes and the number of carboxylate groups in the block copolymer was in the range from 5:10 to 3:2.

14. The method of obtaining coordination compounds as a result of reaction between the platinum complex and the polymer having carboxyl groups in its side chains,
where as source material for use platinum bis(nitrato)(1,2-cyclohexanediamine)platinum (II), diaquo(1,2-cyclohexanediamine)platinum (II) or a mixture of bi is(nitrato)(1,2-cyclohexanediamine)platinum (II) and diaquo(1,2-cyclohexanediamine)platinum (II), all of which essentially do not contain silver ion, and
in the polymer used as the block copolymer, vpisivaushiesya following General formula (1) or (2):


where R1represents a hydrogen atom or unsubstituted or substituted linear or branched C1-C12alkyl group, L1and L2independently from each other represent a connecting group, R3represents a hydrogen atom, a protective group for an amino group, a hydrophobic group or a polymerized group, R4represents a hydroxyl group, a protected carboxyl group formed together with the end-WITH, or a hydrophobic group; each of R5independently represents a hydrogen atom, alkali metal ion or a protective group for carboxyl group, m represents an integer in the range from 5 to 20000, n is an integer in the range from 10 to 60, with the proviso that the hydrogen atom or alkali metal ion, which is defined as R5is 50% or more of the n links,
the method includes a step of carrying out the reaction in an aqueous medium under conditions which a complex of platinum and a block copolymer formed with each other coordination compound, and
stage extract obtained is m-way coordination compounds from the reaction mixture,
where the ratio of platinum atoms in the platinum complex and carboxylate groups in the block copolymer in the reaction set in the range from the value (0.475) or more to 0.6 or less.

15. The method according to 14, where the platinum complex is bis(nitrato)(1,2-cyclohexanediamine)platinum (II).

16. The method according to 14, where the ratio of platinum atoms in the platinum complex and carboxylate groups in the block copolymer in the reaction set in the range from 0.5 or more to 0.55 or less.

17. The method according to 14, where the concentration of platinum complex in an aqueous medium in the reaction set equal to 4.62 mm and less.



 

Same patents:

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SUBSTANCE: method of preparing polyolefin nanocomposite includes mixing in melt mixture of polyolefin, filling agent and non-ionogenic surface-active substance. Claimed is method of preparing polyolefin nanocomposite, which includes mixing in melt mixture of polyolefin, filling agent representing natural or synthetic phyllosilicate or their mixture, or layered hydrocarbonate and non-ionogenic surface-active substance, such as sorbitan ester, dimethylsiloxane-ethyleneoxide or poly(methylmethacrylate)-poly(oxyethylene) blockcopolymer. Also claimed are versions of obtained by claimed method polyolefin nanocomposite and products from it.

EFFECT: nanocomposites with improved properties and possibility to use natural filling agent which is not modified before application.

17 cl, 12 tbl, 11 ex

FIELD: chemistry.

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35 cl, 6 tbl, 37 ex, dwg

FIELD: chemistry.

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20 cl, 2 ex, 1 tbl

Dispersion // 2320680

FIELD: chemistry of polymers, chemical technology.

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37 cl, 15 ex

FIELD: pharmaceutical chemistry.

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9 cl, 2 dwg, 2 tbl, 5 ex

FIELD: organic chemistry, chemistry of polymers.

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11 cl, 78 ex

FIELD: polymers.

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29 cl, 6 tbl, 23 ex

Rubber composition // 2254348

FIELD: rubber industry.

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14 cl, 5 dwg, 5 tbl, 3 ex

FIELD: chemistry.

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EFFECT: method increases output of product.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing iron (II) oxalate by directly reacting metal with acid in the presence of atmospheric oxygen and a liquid phase while stirring. The process is carried out in a bead mill. The liquid phase solvent used is water with mass ratio of the liquid phase to glass beads equal to 1:1, content of oxalic acid in the initial load is between 0.5 and 2.0 mol/kg, and content of stimulating sodium chloride additive is between 0.02 and 0.10 mol/kg. Crushed grey cast iron which is stirred by a blade mixer is taken in amount of 30% of the mass of the rest of the load. The process is started and carried out at temperature in the interval from (50±2) to (93±2)°C while bubbling air under conditions for stabilising temperature using a heated liquid bath and controlling using a sample taking method and determination of content of iron (II) and (III) salts in the samples, and residual quantity of acid up to virtually complete conversion of the latter into salt. After that air bubbling, external heat supply for stabilising temperature and stirring are stopped. The suspension of the reaction mixture is separated from the glass beads and particles of unreacted metal alloy and filtered. The filtration residue is washed with distilled water and taken for further purification through recrystallisation, while the filtrate and the washing water are returned to the load for the repeated process. Iron (II) oxalate, which is separated from the reaction mixture by traditional filtering, is virtually the only product of conversion.

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

10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: catalysts for metathesis polymerisation of dicyclopentadiene are described, which are represented by [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(o-N,N-diethylaminomethylphenylmethylene)ruthenium of formula (1) or [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(o-N-pyrrolidinylmethylphenylmethylene)ruthenium of formula (2) . A method is described for producing a catalyst of formula (1), involving successively reacting a first generation Grubb catalyst with 1,3-bis-(2,4,6-trimethylphenyl)-2-trichloromethylimidazolidine and N,N-diethyl-(2-vinylbenzyl)amine in an inert atmosphere at temperature between 40 and 70°C in the presence of a solvent. In another version of the said method, a second generation Grubb catalyst is reacted with N,N-diethyl-(2-vinylbenzyl)amine in an inert atmosphere at temperature between 40 and 70°C in the presence of a solvent. A method is described for producing a catalyst of formula (2), involving successively reacting a first generation Grubb catalyst with 1,3-bis-(2,4,6-trimethylphenyl)-2-trichloromethylimidazolidine and 1-(2-vinylbenzyl)pyrrolidine in an inert atmosphere at temperature between 40 and 70°C in the presence of a solvent. In another version of the method, a second generation Grubb catalyst is reacted with 1-(2-vinylbenzyl)pyrrolidine in an inert atmosphere at temperature between 40 and 70°C in the presence of a solvent. A method is described for metathesis polymerisation of dicyclopentadiene, involving polymerisation using catalysts of formulae (1) or (2) in molar ratio monomer:catalyst ranging from 70000:1 to 100000:1.

EFFECT: increased output of catalyst and simpler synthesis due to less number of stages, obtaining polydicyclopentadiene with good application properties with low catalyst consumption.

7 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: iron (II) fumarate can be used in different fields of chemical practice, in analytical control and in scientific research, through direct reaction of iron with fumaric acid in the presence of a catalyst, where the catalyst used is molecular iodine in amount of 0.025 to 0.1 mol/kg of the initial load, iron is taken in large excess in form of shells on the entire height of the reactor, false bottom and blade mixer, as well as in form of crushed cast iron and(or) reduced iron powder, the liquid phase solvent used is butylacetate, in which iodine and fumaric acid are at least partially dissolved, where fumaric acid is taken in amount of 0.8 to 1.2 mol/kg of the initial load, loading is done in the sequence: glass beads, liquid phase solvent, fumaric acid, iodine, and then crushed cast iron and(or) reduced iron powder; the process is started at room temperature and is carried out in a vertical type bead mill with ratio of mass of beads to mass of crushed cast iron and(or) reduced iron powder equal to 4:1, at temperature ranging from 18 to 45°C while bubbling air with flow rate of 0.95 l/min-kg of the liquid phase and using forced cooling and controlling using a sampling method until complete exhaustion of the loaded acid for formation of salt, after which stirring and cooling are stopped, the reaction mixture is separated from glass beads and unreacted crushed cast iron and(or) reduced iron powder and filtered, the residue is washed with butylacetate and taken for recrystallisation, and the filtrate and washing butylacetate are returned to the repeated process. Amount of acid used in extracting the product (without loss during purification) ranges from 89 to 96.5%, which depends on conditions for carrying out the process.

EFFECT: improved method of producing said product.

8 ex

FIELD: pharmacology.

SUBSTANCE: invention can be applied in medicine and pharmaceutics. Bioactive cis-dichlorodimethylaminoplatinum (II) is obtained by heating aqueous solution containing potassium tetrachloroplatinate (II), methylaminochloride and potassium acetate to 80°C for 4 hours.

EFFECT: cis-dichlorodimethylaminoplatinum (II) output reaching 69%, admixtures not detected.

4 ex

FIELD: chemistry.

SUBSTANCE: pure salt of cis-dichloroamonoplatinum (II) possesses the bioactivity and can be used in medicine and pharmaceutics as substance of anticancer agents. Potassium trichloroaminoplatinate (II) is dissolved in chloride methylamine water solution at temperature and added with methylamine. The reaction proceeds during 30 min, the precipitated cis-dichloroamonoplatinum (II) salt is filtered, washed with alcohol and dried.

EFFECT: yield increase and purity enhancing.

3 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the methods for preparation of nitroso derivatives of lignosulphonates. The solution of lignosulphonates and the salts of nitrous acid undergo the electrochemical treatment during 5…20 min at voltage 2…10 V and nitrite consumption 5…30% of lignosulphonates mass.

EFFECT: claimed method allows simplifying and acceleration of the nitrosation without evolving of toxic nitrogen oxides.

18 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: pure cis-dichlorodi(ethylamine)platinum (II) salt has anti-tumour activity and can be used in medicine and pharmaceutics. Potassium tetrachloroplatinate (II) is dissolved in an aqueous solution of ethylamine chloride at room temperature and ethylamine solution is then added. The precipitated cis-dichlorodi(ethylamine)platinum (II) salt is filtered off, washed with alcohol and dried.

EFFECT: increased output of product and prevention of product contamination.

3 ex

FIELD: chemistry.

SUBSTANCE: pure salt of cis-dichlorodiisopropylamineplatinum (II) has biological activity and can be applied in medicine and pharmaceutics. Potassium tetrachloroplatinate(II) is dissolved in water solution of isopropylamine chloride at room temperature, to obtained solution solution of isopropylamine is added. Deposited cis-dichlorodiisopropylamineplatinum (II) salt is filtered, washed with alcohol and dried.

EFFECT: increase of target product output and exclusion of product contamination.

3 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to obtaining etyheleneammonium bis(1-hydroxyethane-1,1-diphosphonato(2-))cuprate (+2), etyheleneammonium bis(1-hydroxyethane-1,1-diphosphonato(2-)) zincate(+2) and etyheleneammonium bis(1-hydroxyethane-1,1-diphosphonato(2-)) nickelate(+2) and can be used for processing toxic wastes of obtaining metal coatings - waste electrolytes of galvanic copper, zinc and nickel plating, waste solutions of chemical nickel plating and copper plating. Products, obtained by said method, can be used for preparation of electrolytes, metal corrosion inhibitors, for obtaining various copper, zinc and nickel compounds, including catalysts of organic and inorganic substance synthesis. Claimed method includes using liquid industrial wastes, containing metal(+2), ethyleneammonium and/or anion of 1-hydroxyethane-1,1-diphosphonic acid as reagents. Target products are obtained by crystallisation from reaction water solution with separation of sediment from solution, process is carried out at temperature from (-5) to 105°C and atmospheric pressure. Method allows to obtain pure crystalline products with yield up to 98%, to reduce expenditures on environment protection.

EFFECT: method simplification and increase of its manufacturability.

7 cl, 9 ex

FIELD: medicine.

SUBSTANCE: there is offered a monoclonal antibody specific to human interleukine-4 (hIL-4) containing two domains with the related CDR1-3 region. There are described versions thereof that contain specified CDR, polynucleotide coding said antibody. There are described an expression vector and a host-cell for preparing the antibody to human interleukine-4 (hIL-4). There are opened: application of the antibody for preparing a pharmaceutical agent for treating the diseases mediated by interleukine-4 and/or IgE. There is discovered the pharmaceutical composition for treating the diseases mediated by interleukine-4 and/or IgE is opened.

EFFECT: application of the invention ensured the high-affinity neutralised monoclonal antibodies to human interleukine-4.

14 cl, 1 tbl, 6 ex

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