Using pentaaminofullerenes as antimicrobial agents and antimicrobial composition based thereon

FIELD: chemistry.

SUBSTANCE: in formula 1 , X denotes a negative charge which is localised on a fullerene skeleton, a chlorine atom bonded to a carbon skeleton or a hydrogen atom; the NR1R2 moiety denotes an amine residue, where R1 and R2 are hydrogen atoms or linear or branched alkyl radicals (CmH2m+1; n=1-20) that are substituted with protonated (NH3+) or unprotonated (NH2) amine groups, or a piperazine residue of general formula 1c-1 , where R, R'1, R'2, R'3 and R'4 are hydrogen atoms or linear or branched alkyl (CmH2m+1; n=1-20) radicals, as well as residues of aliphatic alcohols -(CH2)nOH, ethers -(CH2)nOR'5, thiols -(CH2)nSH, acids -(CH2)nCOOH, esters thereof -(CH2)nCOOR'5 or amides -(CH2)nCONR'5R'6, for which n=0-20, R'5 and R'6 are hydrogen atoms or linear alkyl (CmH2m+1; n=1-20) radicals.

EFFECT: stronger or prolonged antibacterial action.

2 cl, 2 dwg, 2 tbl, 3 ex

 

The invention relates to the chemical and pharmaceutical industry and relates to antimicrobial agents and compositions based on derivatives of fullerene C60. The invention can find application in biomedical research and in the production of new drugs intended for the treatment and prevention of infectious diseases. In addition, the invention can be used to create disinfection agents intended for disinfection and sterilization of contaminated microorganisms environments and surfaces.

After the discovery of fullerenes in 1985 [1 - W. Kroto, J.R. Heath, S.C. O'brien, R.F. Curl, R.E. Smalley. With60: Buckminsterfullerene, Nature 318, 162-163 (1985)], the development of the method of obtaining them in macroscopic quantities by arc evaporation of graphite [2 - W. ICratchmer, L.D. Lamb, K. Fostiropoulos, D.R. Huffman. BTS: a new form of carbon. Nature, 347, 354-358 (1990)] or by the incomplete combustion of hydrocarbons [3 - II. Murayama. S. Tomonoh, J.M. Alford, M.H. Karpuk. Fullerene production in tons and more: From science to industry. FuH. Nunotub Curbon Nanostruct., 12, 1-9 (2004)] and effective methods of separation of fullerenes [4 - K. Nagala. C. Dejima. Y. Kjkuchi, M. Hashiguchi. Being held-scale [60] fullerene separation from a fullerene mixture: Selective complexation of tullerenes with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Chem. Lett., 34, 178-179 (2005)] lower fullerene C60high purity became available in kilogram quantities for less than 15€/g [5 - http://www.neotechproduct.ru/str6.php?lang=rus].

The availability of fullerenes for which the waves made it possible to find a number of areas of practical use of these compounds, including pharmaceutical chemistry - new medicinal drugs with a broad spectrum of action. The most promising results were obtained with the use of chemically modified fullerenes With60and C70mainly containing ionogenic groups - amine [6 - Troshina, O., P. Troshin, A. Peregudov, V. Kozlovski, R. Lyubovskaya. Photoaddition of N-Substituted Piperazines to BTS: An Efficient Approach to the Synthesis of Water-Soluble Fullerene Derivatives. Chem. Eur Journal, 12, 5569-5577 (2006)] and carboxyl [7 - M. Brettereich, A. Hirsch. A highly water-soluble dendro[60]fullerene. Tetrahedron Letters, 39, 2731-2734 (1998); 8 - 0. Troshina, P. Troshin, A. Peregudov, V. K-ozlovskiy, J. Balzarini, R. Lyubovskaya. Chlorofullerene60CL6: a precursor for straightforward preparation of highly water-soluble polycarboxylic fullerene derivatives active against HIV. Org. Biomol. Chem., 5. 2783-2791 (2007)].

Fullerenes and their derivatives exhibit a pronounced antiviral, anticancer, neuroprotective, anti-amyloid remedy and other activities [9 - LB Piotrovsky, I. Kiselev. Fullerenes in biology. SPb, Rostock, 2006]. A unique combination of membrane and amphiphilic properties of functionalized fullerenes, determines their ability to easily pass through the cell membrane, favour the establishment of effective medicines on the basis of this class of compounds. In addition, fullerenes can be used as a means of delivery other drugs in living tissues and cells.

Important healthy lifestyles is of possible use of fullerenes is development on the basis of anti-infective (i.e. antiviral, antibacterial and antifungal) funds. In this case, an important target of their action is the lipid membrane of the pathogen: due to the high affinity to its internal hydrophobic part of fullerenes accumulate in the lipid bilayer, leading to violations associated with the membrane of metabolic processes [10 - A.K. Sirotkin, LB Piotrovsky, LN. Poznyakov, I. Kiselev. The effect of complexes of fullerene With60with polyvinylpyrrolidone on the morphology of influenza viruses. The matters. Biol. the honey. Pharm. chemistry, 2005, 3, 21-24; 11 - N. Tsao, T.Y. flood, S. Kaliev Chou, T.Y. Chang, J.J. Wu, C.C. Liu, H.Y. Lei. In vitro action of carboxyfullerene. J. Antimicrobial Chemother., 2002, 49, 641-649]. The antimicrobial effect of derivatives of fullerenes enhanced by simultaneous irradiation with visible or UV light, due to the ability of fullerenes to generate under the influence of light reactive oxygen species causing lipid peroxidation of biological membranes [12 - J. Lee, Y. Mackeyev, M. Cho, D. Li, J.-H. Kirn, L.J. Wilson, P. J.J. Alvarez. Photochemical and antimicrobial properties of novel60derivatives in aqueous systems. Environ. Sci. Technol., 43, 6604-6610 (2009)].

The objective of the invention is to develop compounds of fullerenes and compositions based on them, have a sustainable and significant biological activity against a wide range of pathogenic and conditionally pathogenic microorganisms.

In the present invention this task is PE is highlighted by the use of pantainorasingh fullerene C 60the General formula 1:

where in the General formula 1 X means:

- negative charge ("-"), localized on the fullerene cage, or

- atom of chlorine (-CL), attached to the carbon skeleton, or

- a hydrogen atom (-H);

where in the General formula 1 fragment NR1R2describes, but is not limited to the following definitions:

- the remainder of the amine, where R1and R2- hydrogen atoms or substituted protonated (NH3+or deprotonirovannymi (NH2) amino group, a linear or branched alkyl radicals (CmC2m+1; n=1-20);

- the rest of the piperazine of General formula Ic-1

where R, R'1, R'2, R'3and R'4are hydrogen atoms or linear or branched alkyl (CmC2m+1; n=1-20) radicals, as well as residues of aliphatic alcohols -(CH2)nOH, ethers -(CH2)nSH, acid -(CH2)nCOOH, their esters -(CH2)nCOOR'5or amides -(CH2)nCONR'5R'6for which n=0 to 20, and R'5and R'6are hydrogen atoms or linear alkyl (CmC2m+1; n=1-20) radicals.

The structure of the compounds of General formula 1 and a method for their synthesis have been described by us previously [13 - P.A. Troshin, A.B. Kornev, E.A. Hakina, V.F. Razumov "Aminophylline isposal their receipt of Application for invention No. 2010127788 from 07072019, RF and AV Komev, E.A. Khakina, S.I. Troyanov, A. A. Kushch, Deryabin D.G., A.S. Peregudov, A. Vasilchenko, V.M. Martynenko, P.A. Troshin, Facile preparation of amine and amino acid adducfs of [60] fullerene using chlorofullerene C60Cl6as a precursor. Chem. Commun., 2012, 48, 5461-5463]. The present invention discloses a method of practical application of those compounds of General formula 1 as an antimicrobial drugs in pure form and in compositions.

In accordance with the present invention, the antimicrobial composition of antibacterial action on the basis of amino derivatives of fullerene contains by weight from 0.0001 to 100% of compounds of General formula 1, and the rest - neutral components or substances, positively modifying (increasing, prolonging etc.) antimicrobial activity of the composition.

The closest known analogue of the invention is the use of fullerene derivatives of General formula 2 as an antibacterial and anticancer tools [18 - T. Mashino. Antibacterial agent and anticancer agent. Patent EP 1611889 A1 from 04.01.2006]. The compounds of formula 2 are complex mixtures of regioisomers of fullerene Preductal and work only with a very small yield of about 9%, which makes their practical use.

In contrast to previously described compounds of fullerenes, exhibiting antimicrobial properties, derivatives of fullerenes, are suitable the e of General formula 1, easy to get and low cost, and therefore can be easily synthesized in large quantities with the purpose of practical use. In addition, the compounds in accordance with formula 1 are amphiphilic, as have hydrophobic and hydrophilic fragments that provides ease of their penetration through the cell membrane. This is an important advantage of these derivatives compared to most of the previously described compounds (for example, General formula 2), in which the skeleton of the fullerene coated evenly with charged groups.

Derivatives of fullerenes General formula 1, particularly those containing positively charged groups, for example, ammonia, possess high inhibitory activity against various gram-positive and gram-negative bacteria, which allows their use as chemotherapeutic agents of broad-spectrum antibiotics or disinfectants for disinfecting contaminated with microorganisms environments and surfaces. The basis of antimicrobial activity of derivatives of fullerenes General formula 1 is their membranotropic activity, i.e. high affinity to membranes of microbial cells, as detected using the method of atomic force microscopy (see example 1). The most pronounced activity in this region is give cationic derivatives of fullerenes, because they are more efficient contact with the negatively charged membranes of pathogenic microorganisms due to electrostatic attraction. The result of such interaction is the damage and destruction of microbial cells, which was established by a combination of bacteriological and bioluminescent methods.

Protected use of compounds of General formula 1 implies, including their use for the treatment and prevention of infectious diseases. With this purpose, the derivatives of fullerenes may be introduced into the body to provide a systemic effect, and also be applied topically to influence certain areas (for example, in the composition of dressings for the treatment of wounds, in the processing of the surgical field and so on). Compounds of fullerenes can be used in the form of solids, solutions or suspensions in water or other solvents, as well as printed on various media. It is also possible to use compounds of General formula 1 in compositions with other agents, including antimicrobial drugs of other classes (Quaternary ammonium compounds, and others).

Part patentable invention also includes the use of fullerene derivatives of General formula 1 for the disinfection of microbiologically contaminated environments and surfaces. To check the Denia disinfection liquid and gas derivatives of fullerenes can be entered in the specified environment in the form of solutions, suspensions or aerosols, as well as be used in the filtering processes in the form of pure substances or immobilized on different carriers. The purpose of disinfecting hard surfaces derivative 1 can be applied to them in the form of solids, solutions or suspensions. Thus to ensure long-term protection from the spread of microorganisms fullerene derivative may not be removed from the environment or from the surface, subjected to a disinfection treatment.

Antimicrobial activity of derivatives of fullerenes can be enhanced by simultaneous exposure to ultraviolet or visible light, which is associated with the ability of fullerenes to act as photosensitizers, translating contained in the oxygen environment in its active forms (for example, singlet oxygen or superoxide anion radical). Photochemical generation of reactive oxygen species, carried out by fullerene derivatives in close proximity to the lipid membrane or molecules of nucleic acids, leads to oxidative damage of these structures and, ultimately, to the loss of viability of microbial cells. The possibility of enhancing the antimicrobial activity of derivatives of fullerenes General formula 1 under the influence of light is illustrated by example 2. Due to this property of the compounds of fullerenes General formula 1 could the t to be used as vehicles for photodynamic therapy of infectious diseases, and for photochemical treatment of polluted environments, including the surfaces of medical devices and sewage.

Antimicrobial activity of derivatives of fullerenes can be modified (enhanced or prolonged) when used in combination with other source of inert or antimicrobial substances, including also showing trapnest to the membrane structures of the bacterial target cells. In the basis of such activity, on the one hand, lies Energeticheskiy antimicrobial effect of a fullerene derivative and a substance companion, and on the other, the possibility of formation between them of supramolecular complexes, the gradual release of the active principles of which leads to prolongation of antimicrobial effect. The possibility of modifying antimicrobial activity of derivatives of fullerenes General formula 1 in their compositions from Quaternary ammonium compounds is illustrated by example 3. Due to this action of the compounds of fullerenes General formula 1, depending on their molar ratio with substance-companion can be either enhanced or extended, depending on specific tasks is a positive effect in the treatment and prevention of infectious diseases or cleaning contaminated with microorganisms environments, including the surfaces of medical desig the treatment of sewage.

The invention is illustrated by, but not limited to the following examples.

Example 1. Evaluation of antimicrobial activity of derivatives of fullerenes as examples of derivatives of fullerenes corresponding to General formula 1, were used for compounds 1A-C.

Determination of antimicrobial activity (concentration LD50, which causes the death of 50% of the bacterial target cells after 60 minutes of contact) was conducted on the model gram (Eschenchia coli) and gram positive (Bacillus subtilis) microorganisms in bacteriological tests of plating on a nutrient dense environment at the same time we studied the suppression of fullerene derivatives 1a-in the glow of bioluminescent sensor systems based on recombinant strains Eschenchia coli K12 TG1 and Bacillus subtilis In-10548 with cloned luxCD(AB)E-genes natural marine luminescense microorganism Photobactenum leiognathi Characteristic of antimicrobial action in this case was the value AS - concentration of the investigated derivatives of fullerenes, causing inhibition of bioluminescence in the 60th minute of contact for 50% of control values

The results of the determination of antimicrobial activity are shown in table 1

Table 1
Evaluation of antibacterial activity derived From60-fullerene in tests of viability (LD50) and bioluminescence (ES) model gram-negative and gram-positive microorganisms
ConnectionEschenchia coliBacillus subtilif
LD50, mcmES, mcmLD50, mcmES, mcm
1A18285155
1B28273331,5

Of the activity values shows that cationic derivatives of fullerene C60able to effectively inhibit both gram-positive and gram-negative microorganisms in the micromolar concentration range

Direct interaction of amino derivatives of fullerenes with bacterial cells demonstrated by atomic force microscopy acquired images of intact bacterial cells and cells after contact with aminor iswalnum fullerene 1A shown in Fig 1 after incubation with amino derivatives of fullerene-1A cells of Escherichia coli K 12 TG1 has undergone significant morphological changes: in close communication with them was recorded convex formation of irregular shape with a size from 47,3±3,11 nm to 276,0±14,9 nm, presumably representing the associates of fullerene derivatives 1A, established contact with the bacterial surface.

Example 2. Strengthening antibacterial activity of derivatives of fullerenes under the action of irradiation

Photosensitizing properties of fullerene derivatives With60were studied using the touch luminescense strain of Escherichia coli K 12 TG1 with cloned luxCDABE-geami marine luminescense organism Photobacterium leiognathi.

Suspension cells touch the bacterial system was mixed with an aqueous solution derivatives of fullerenes 1A-relevant concentrations, followed by their irradiation with light of a mercury-quartz lamp for 5, 10 or 15 minutes. After additional incubation for 15 minutes was measured level of bioluminescence of the investigated samples and the expected values AS characterizing effective concentration derivatives of fullerenes, causing quenching of bioluminescence touch microorganism by 50% compared to control.

The results of determination of the antimicrobial activity of derivatives of fullerenes in the dark and under irradiation of UV light are presented in table 2. It is seen that the antibacterial action of the investigated derivatives AV is greatly enhanced by exposure to UV irradiation, which is manifested in a significant reduction of the recorded values IS.

Table 2
The results of the determination of antibacterial activity (parameter ES, μm) derived From60-fullerene influence on the level of bioluminescence touch of Escherichia coli K 12 TG1 with cloned luxCDABE-renuMvi Photobacterium leiognathi by UV irradiation
ConnectionES, mcm
without UV irradiationafter UV irradiation for
5 min10 min15 min
1A281842,147,8
1B2719,618,89,3

Example 3. Modification of antibacterial activity of derivatives of fullerenes in combination with Quaternary ammonium compounds of didecyldimethylammonium bromide by clathrate (DDAB-K).

Modification of the properties of aminoplast the underwater fullerene 1A was studied in the test suppression bioluminescence touch of Escherichia coli K 12 TG1 with cloned luxCDABE genes marine luminescense organism Photobacterium leiognathi.

Aqueous solutions of fullerene 1a c concentrations from 0,0078 to 0.125 mm in equal volumes were mixed with a solution of didecyldimethylammonium bromide clathrate (DDAB) in concentrations from 0,0156 to 0.125 mm and was maintained for 10-30 minutes In the obtained compositions were made of cell suspension sensory bacterial system, and then for 60 min dynamically measured the intensity of bioluminescence, reflecting the development of antibacterial effect. The result of this modification antibacterial activity of fullerene 1A was evaluated as "amplification effect" when more significant suppression of the level of bacterial bioluminescence composition compared to the isolated effect of equimolar amounts of fullerene and DDAB-K, and as a "rollover effect" with increasing time the complete suppression of bacterial bioluminescence compared to similar effect equimolar amounts of fullerene and DDAB-K.

The results of the study of the nature of the modification of the antimicrobial effect of the fullerene derivative 1A in combination with DDAB IS presented in figure 2.

When the molar ratio of the fullerene 1A: DDAB-K is greater than 1 (to the right of the slanted line), including the range of concentrations of fullerene 1A from 0,0078 to 0,03125 mm and DDAB-from 0,0078 to 0,0156 mm, each of which alone causes only a partial suppression of bacterial bi the luminescence, registered strengthening antibacterial effect formed compositions, potentially defined by the synergistic effect of constituent substances in the cells of the sensory bacterial system.

In turn, when the molar ratio of the fullerene 1A: DDB TO less than 1 (to the left of the slanted line), including the range of concentrations of fullerene 1A from 0,0039 to 0,0156 mm and DDAB-from 0,0078 to 0,0625 mm, recorded rollover effect, potentially defined primary formation of supramolecular complexes of substances companions, followed by a gradual release of active principles and defined it more smooth dynamics for the development of antibacterial effect.

Thus, depending on the molar ratio of the fullerene 1a c DAB TO the antibacterial effect can be either enhanced, or extended, depending on specific tasks is a positive effect in the treatment and prevention of infectious diseases or the treatment of polluted environments microorganisms, including surfaces of medical devices and sewage.

1. The use of fullerene derivatives of General formula 1 as an antimicrobial drugs

where in the General formula 1 X means:
- negative charge ("-"), localized on the fullerene Karka is e, or
- atom of chlorine (-Cl), attached to the carbon skeleton, or
- a hydrogen atom (-H);
where in the General formula 1 fragment NR1R2describes, but is not limited to the following definitions:
- the remainder of the amine, where R1and R2- hydrogen atoms or substituted protonated (NH3+or deprotonirovannymi (NH2) amino group, a linear or branched alkyl radicals (CmH2m+1; n=1-20);
- the rest of the piperazine of General formula Ic-1

where R, R'1, R'2R'3and R'4are hydrogen atoms or linear or branched alkyl (CmH2m+1; n=1-20) radicals, as well as residues of aliphatic alcohols -(CH2)nOH, ethers -(CH2)nOR'5, thiols -(CH2)nSH, acid -(CH2)nCOOH, their esters -(CH2)nCOOR'5or amides -(CH2)nCONR'5R'6for which n=0-20, a R'5and R'6are hydrogen atoms or linear alkyl (CmH2m+1; n=1-20) radicals.

2. Antibacterial composition comprising an effective concentration of the fullerene derivatives of General formula 1, and an inert diluent and components, intensifying or prolonging the antibacterial action of fullerene derivative of General formula 1.



 

Same patents:

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SUBSTANCE: present invention refers to a compound of formula (I), including any stereochemical isomer forms thereof, or a pharmaceutically acceptable salt thereof, , wherein A is phenyl or 6-member aromatic heterocycle containing 1 or 2 nitrogen atom; wherein said phenyl or 6-member aromatic heterocycle may be optionally condensed with phenyl; Z is CH2 or O; R1 is halogen, hydroxyl, C1-4alkyl, C1-4alkyloxy, or provided A is phenyl, then two neighbour substitutes R1 may be taken together to produce a radical of formula: -O-CH2-O- (a-1) or -O-CH2-CH2-O- (a-2); R2 is hydrogen or C1-4alkyl; each R3 and R4 independently is hydrogen, C1-6alkyl, C1-4alklyloxyC1-6alkyl or phenylC1-4alkyl; or R3 and R4 taken together with a nitrogen atom whereto attached form a radical of formula or , wherein X1 is CH2 or CHOH; and X2 is CH2, O or NR6; R5 is hydrogen, halogen, C1-4alkyl or C1-4alkyloxy; R6 is hydrogen, C1-4alkyl, C1-4alkylcarbonyl; n is equal to an integer 0, 1 or 2; provided the compound is other than , or a pharmaceutically acceptable salt thereof.

EFFECT: compounds are used to treat the diseases the treatment of which is affected, mediated or promoted by GHSlA-r receptor activation The present invention also refers to pharmaceutical compositions and an intermediate compound of formula II: .

22 cl, 10 tbl, 11 ex

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SUBSTANCE: invention refers to compounds of formula I

or its pharmaceutically acceptable salts wherein R1-3, R5-7, a, X, Y, Y', Y" and Z have the values specified in cl. 1 of the patent claim which are muscarinic receptor antagonists. The invention also refers to pharmaceutical compounds, methods for preparing and methods for using such compounds.

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25 cl, 18 ex

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SUBSTANCE: invention relates to a method of producing amines and/or alkanolamines mainly containing mono- and diamine alkanols, alkyldiamines and triamines and cyclic amines by reacting glycerine with hydrogen and an aminating agent selected from the group: ammonia, methylamine and diethylamine, in the presence of a catalyst which contains a metal selected from Cu, Co, Ni, Mn, Mo, Cr, Zr, or a mixture thereof, at temperature ranging from 150°C to 300°C and pressure ranging from 20 to 300 bar, followed by separation of the end product. The process is carried out until 40-80% conversion of glycerine. The invention also relates to a method of producing amines and/or alkanolamines mainly containing mono- and diamine alkanols, alkyldiamines by reacting glycerine with hydrogen and aminating agent selected from ammonia, methylamine and diethylamine, in the presence of a catalyst which contains iridium, at temperature ranging from 150°C to 300°C and pressure ranging from 20 to 300 bar.

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11 cl, 2 tbl, 32 ex

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SUBSTANCE: invention refers to new piperazine amide derivatives of formula wherein X represents N or CH; Y represents N or CH; R1 represents lower alkyl, phenyl, phenyl-lower alkyl wherein phenyl can be optionally substituted by 1-2 substitutes independently specified in a group consisting of halogen, lower alkyl; R2 represents lower alkyl, phenyl, naphthyl or heteroaryl specified in dimethylisoxazolyl, quinolinyl, thiophenyl or pyridinyl wherein phenyl or heteroaryl are optionally substituted by 1 substitute optionally specified in a group consisting of halogen, lower alkoxy group, fluor-lower alkyl, lower alkoxy-carbonyl and phenyl; R3 represents phenyl, pyridinyl or pyrazinyl wherein phenyl, pyridinyl or pyrazinyl are substituted by 1-2 substituted optionally specified in a group consisting of halogen, lower alkyl and fluor-lower alkyl; R4, R5, R6, R7, R8, R9, R10 and R11 independently represent hydrogen, as well as to their physiologically acceptable salts. These compounds are bound with LXR alpha and LXR beta, and are applicable as therapeutic agents for treatment and/or prevention of high lipid levels, high cholesterol levels, low HDL cholesterol, high LDL cholesterol, atherosclerotic diseases, diabetes, non insulin dependent diabetes mellitus, metabolic syndrome, dislipidemia, sepsis, inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis, liver fibrosis, psoriasis, Alzheimer's disease, etc.

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15 cl, 88 ex

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1 cl, 13 ex

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11 cl, 30 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of novel 4-(azacycloalkyl)phthalonitriles. Novel 4-(azacycloalkyl)phthalonitriles of general formula

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.

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2 cl, 4 ex

FIELD: medicine, pharmaceutics.

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14 cl, 4 ex

FIELD: medicine, pharmaceutics.

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EFFECT: preparation of new compounds.

30 cl, 9 tbl, 944 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

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32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 1-amino-3,5-dimethyladamantane, involving reaction of 1,3-dimethyladamantane with formamide in concentrated acids to obtain 1-formamido-3,5-dimethyladamantane, provided that neither SO3-containing sulphuric acid nor 100% nitric acid is used, wherein the concentrated acids are 30-70% nitric acid and 90-100% sulphuric acid and further conversion of 1-formamido-3,5-dimethyladamantane to 1-amino-3,5-dimethyladamantane through hydrolysis with aqueous hydrochloric acid.

EFFECT: high efficiency of the method.

3 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of producing hydrochlorides of amine-derivatives of adamantane of general formula:

,

where R=H, CH3; n=0, 1. According to the disclosed method, biologically active compounds such as, for example, hydrochlorides of 1-aminoadamantane (R=H, n=0) (amantadine) and 1-amino-3,5-dimethyl-adamantane (R=CH3, n=0) (memantine) are obtained, which are used in the chemical and pharmaceutical industry to prepare medicinal agents for treating Parkinson's disease, Alzheimer's diseases, neurodegenerative diseases, glaucoma etc. The method involves reaction of adamantane carboxylic acid with thionyl chloride at its boiling point for 1.5 hours in molar ratio 1:1.1 respectively, to form an acyl chloride of adamantane carboxylic acid, which reacts with sodium azide in anhydrous toluene at its boiling point in molar ratio 1:1:15-20 respectively for 1.5-2 hours, followed by addition of concentrated hydrochloric acid and holding the reaction mass for 1 hour and extracting the end product.

EFFECT: method is more technologically effective and ecologically clean and enables to obtain a large number of homologues of hydrochlorides of amine-derivatives of adamantane with quantitative output of 92-95%.

4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing cycloalkylamines of general formula Alk-R, where

, , , , , , , , , . The method is realised by reacting a cyclic ketone with an amine derivative and formic acid in the presence of a catalyst. The cyclic ketones used include cyclopentanone, cyclohexanone and 2-adamantanone, and the amine derivative used is formamide, cyclohexylamine, piperidine, morpholine, piperazine, 2-aminoethanol, 1,2-ethylenediamine, and the catalyst used is copper nanoparticles. The process is carried out in molar ratio ketone: amine derivative: HCOOH equal to 1:3-4:5-10, at temperature 100°C for 3-9 hours. The copper nanoparticles can be obtained in situ, as well as beforehand.

EFFECT: high output of cycloalkylamines under milder conditions for carrying out the process.

3 cl, 11 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 3,5-dimethyladamantyl-1-amine or its salts. Method involves the bromination step of 1,3-dimethyladamantane with liquid bromine at boiling. The bromination reaction is carried out in the mole ratio 1,3-dimethyladamantane to bromine = 1:(2-8) but preferably in the ratio = 1:(3-6), and separation of bromine is carried out by distillation. Then the excessive amount of formamide is added to a synthesized residue and kept the mixture at temperature 120-180°C but preferably at 150-160°C. The end product is isolated in free form or as a salt. Proposed method allows simplifying the process based on decreasing non-utilizable waste and possibility for carrying out the process in a single apparatus to yield the end product of high quality and purity.

EFFECT: improved method of synthesis.

3 cl, 11 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of norbornylamine with exo-configuration of nitrogen atom and endo-anellated 5-6-membered cycles of the formula (I) and with exo-configuration of nitrogen atom and exo-anellated 5-6-membered cycles of the formula (Ia) , and their pharmaceutically acceptable salts or trifluoroacetates also. In compounds of the formula (I) or (Ia) A means (C1-C4)-alkylene; S1 means optionally (C1-C4)-alkyl; S2 means (C1-C4)-alkyl or hydrogen atom (H) being if S1 and S2 mean alkyl then X in the group [-N+(S1S2)-X-] corresponds to pharmacologically acceptable anion or trifluoroacetate; B means saturated or unsaturated carbon 5- or 6-membered cycle; R1, R2, R3, R4 and R5 have values given in the description. Also, invention relates to a method for preparing these compounds and to a medicinal agent. These compounds can be used for preparing medicinal agents useful for treatment or prophylaxis in breathing impulse disturbance, in particular, in breathing disturbance caused by sleep, transient breathing stop during sleep, snore, for treatment or prophylaxis of acute and chronic renal diseases, in particular, acute and chronic renal insufficiency and, disturbance in intestine, gallbladder, ischemic states of peripheral and central nervous system disturbances, severe attacks and others symptoms. Compounds are inhibitors of sodium-proton exchange, show effect on serum lipoprotein and therefore they can be used in prophylaxis and regression of atherosclerotic alterations.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

21 cl, 70 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing 1-amino-3,5-dimethyladamantane hydrochloride (the preparation memantin or acatinol) used in medicinal practice as agent for treatment of such diseases as Parkinson's disease, neurodegenerative disorders, glaucoma. Method for preparing 1-amino-3,5-dimethyladamantane hydrochloride involves addition of nitric acid to preliminary prepared 1,3-dimethyladamantane emulsion in acetic acid at 10-30oC followed by addition of 30-55% urea solution in water in the mole ratio 1,3-dimethyladamantane : acetic acid : nitric acid : urea = (1:3)-(4:9)-(12:2.5)-5.0, respectively followed by neutralization of obtained reaction mass with alkali an aqueous solution, extraction and the following isolation of product as hydrochloride and its crystallization from water. Method provides preparing product of the high quality that satisfies requirements of Pharmacopoeia.

EFFECT: improved preparing method, enhanced quality of product.

5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 3 tbl, 35 ex

The invention relates to the chemistry of adamantane derivatives, and in particular to a new method of obtaining amino adamantane General formula AdR, where R=NH2, NHBu-t,

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which are biologically active substances and can find application in pharmacology and adamant-1-ylamine is the basis of the drug midantana"

FIELD: chemistry.

SUBSTANCE: luminescent composite material contains a polymer base 1 made of an optically transparent polymer material and a phosphor-containing multilayer polymer film consisting of three layers: optically transparent polymer film 2; polymer composition 3, including an inorganic phosphor - cerium-doped yttrium-aluminium garnet, or cerium-doped gallium-gadolinium garnet; polymer composition 4 with dispersed semiconductor nanocrystals made of a semiconductor nucleus, first and second semiconductor layers, and emitting a fluorescent signal with fluorescence peaks in the wavelength range of 580-650 nm. Layers of the multilayer polymer film can also be arranged in the following order: polymer composition 3 containing a phosphor, polymer composition 4 with dispersed semiconductor nanocrystals, optically transparent polymer film 2. The light-emitting device contains a luminescent composite material situated away from a light source. The light source is in form of a light-emitting diode with radiation wavelength of 430-470 nm. The light-emitting devices have service life longer than 50000 h, luminous efficacy higher than 100 lm/W and correlated colour temperature of 2500-5000 K.

EFFECT: invention enables to obtain white light with colour rendering index of more than 80.

48 cl, 14 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to obtaining biocompatible magnetic nano-particles and can be applied for therapeutic purposes, in particular, for fighting cancer. Method of obtaining nano-particles, including iron oxide and silicon-containing casing and having value of specific absorption rate (SAR) 10-40 W per g of Fe with field strength 4 kA/m and frequency of alternating magnetic field 100 kHz, contains the following stages: A1) preparation of composition of at least one iron-containing compound in at least one organic solvent; B1) heating of composition to temperature in range from 50°C to temperature 50°C lower than temperature of reaction of iron-containing compound according to stage C1 for minimal period 10 minutes; C1) heating composition to temperature between 200°C and 400°C; D1) purification of obtained particles; E1) suspending purified nano-particles in water or water acid solution; F1) addition of surface-active compound to water solution, obtained according to stage E1); G1) processing of water solution according to stage F1) by ultrasound; H1) purification of water dispersion of particles, obtained according to stage G1); I1) obtaining dispersion of particles according to stage H1) in mixture of solvent from water and water-mixable solvent; J1) addition of alkoxysilane into dispersion of particles in mixture of solvent according to stage I1); and K1) purification of particles.

EFFECT: invention makes it possible to obtain biocompatible magnetic particles with high value of specific absorption rate (SAR).

42 cl, 3 dwg, 9 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and may be used for tumour growth inhibition induction in experiment. For this purpose, the Pliss's lymphosarcoma cells 1 ml in the concentration of 20x106/ml proincubated for 30 min at 37°C with 100 mcl with a one-wall carbon nanotube suspension of the length of 100-200 nm functionalised by MH2-groups in the concentration of 10 mcg/ml. The tumour growth inhibition is specified as 97% for 20 days and prolonged life length is stated to increase in 1.68 times as compared to reference tumour carrier animals.

EFFECT: invention induces the tumour growth inhibition and prolongs life length of experimental animals ensured by the combined incubation of tumour cells and one-wall carbon nanotubes.

3 tbl

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