Functional nanomaterials with antibacterial and antiviral activity
SUBSTANCE: invention refers to nanocrystalline compounds of formula (I) AOx-(L-Men+)i where AOx represents metal oxide where A it specified from Ti or Zr, x=2; Men+ represents metal ion exhibiting antibacterial activity, specified from Ag+ and Cu++, where n=1 or 2; L represents a bifunctional molecule, or a organic or metal-organic molecule able to get bound with metal oxide and ion metal Men+ simultaneously; where the organic molecule is specified from pyridine, dipyridyl, tripyridyl, functionalized with carboxylic groups (-COOH), boronic groups (-B(OH)2), or phosphonic groups (-PO3H2), or 4-mercaptophenylboronic acids; where the metal-organic molecule represents a metal-organic complex containing organic ligand coordinated with central metal atom and containing boronic (-B(OH)2), phosphonic (-PO3H2) or carboxylic (-COOH) functional group, and the groups are coordinated with central metal atom and able to get bound with metal ions with antibacterial activity; where specified organic ligand coordinated with central metal atom is specified from pyridine, dipyridyl, tripyridyl functionalized with carboxylic groups (-COOH), boronic groups (-B(OH)2), or phosphonic groups (-PO3H2), or 4-mercaptophenylboronic acids; i represents a number of groups L-Men+ bound with nanoparticle AOx. Also, there are offered a composition exhibiting antibacterial and/or antiviral activity, dermatological compositions, application of nanocrystalline compounds, a method of nanocrystalline compounds regeneration.
EFFECT: nanocrystalline compounds show effective antibacterial action.
27 cl, 4 tbl, 4 dwg
The scope of the invention
The invention relates to nanomaterials consisting of metal oxides, United with nationalmuseum metals which possess antibacterial activity.
The level of technology
Known antibacterial activity of some metal ions, also called the oligodynamic effect.”
Metal ions with the highest antibacterial activity, are, in descending order of strength, ions of the following metals:
Hg > Ag > Cu > Zn > Fe > Pb > Bi.
The inclusion of such metals, in particular silver ions, plastics, ceramic materials and materials based on fibers or carbon creates the possibility of eliminating or reducing the growth of colonies of bacteria. This effect is particularly advantageous in light of the compatibility Ag+with the body and the increasing resistance of many bacteria to antibiotics. Thus, the use of materials which contain silver, may serve the purpose of avoiding or limiting bacterial proliferation.
As for the mechanism of action of silver, it is known that the antibacterial activity is implemented monovalent positive ion Ag+. It was noted that the presence of platinum mixed with silver promotiom oxidation of Ag to Ag+due to the galvanic E. the reaction; this leads to a corresponding strengthening of the antibacterial activity of the films consisting of platinum and silver. Moreover, the pharmaceutical preparations on the basis of silver, such as silver sulfadiazine used to prevent infections in the case of severe burns, acting through the gradual release of ions Ag+that are able to reversibly adsorb in bacterial cells by Association with groups-SH of cysteine in bacterial proteins present in the cell walls. The cytotoxic effect of Ag+also associated with the ability of the ion to displace essential ions from cells, such as calcium ions (CA2+) and zinc (Zn2+). Previous studies (see, for example, Carr H.S., Wlodkowski T.J. and H.S. Rosenkranz, 1973, “Antimicrobial agents and chemotherapy”, vol.4, p.585) showed that the antibacterial activity of ins Ag+directly proportional to their concentration and effective against many species of bacteria. Such considerations made for copper ion (Cu2+), which are known in agriculture as an antibacterial agent.
As of today in the technique known to produce nanocrystalline materials based on metal oxides (MOxhigh surface area, such as titanium dioxide, zinc oxide, tin oxide (SnO2), zirconium dioxide and colloi the hydrated silicon dioxide, you can bind to different substrate with strong coupling. Also known nanomaterials based on titanium dioxide, containing silver ions, which are produced by mixing suspensions of nanomaterials with solutions containing ions of Ag+. Adhesion of ions Ag+to the nanocrystalline structure of the metal oxide is very likely associated with the introduction of ions between the nanocrystals.
However, in order to obtain a homogeneous film, which detect effective antibacterial action, you need to use interop, which are distributed uniformly over the surface of the nanomaterial and which admit a homogeneous deposition of silver ions in a high concentration.
This problem is solved by the present invention, whereby it is also possible to obtain a film, which can precipitate on a variety of materials and filters used to clean the surrounding atmosphere.
The present invention relates to the production of new antibacterial and antiviral nanomaterials based on metal oxides, such as, for example, TiO2, ZrO2, SnO2, ZnO, SiO2, functionalized molecules of organic or inorganic nature, is able to simultaneously contact with the oxide ions of transition metals, such as Ag or Cu2+.
For purposes of illustration blocks of such new materials can be present, for example, formula (I)
where AOxis a metal oxide or metalloid oxide, where x = 1 or 2;
Men+represents a metal ion having antibacterial activity, where n = 1 or 2, preferably Ag+or Cu++;
L is a bifunctional molecule, or an organic or ORGANOMETALLIC capable of simultaneously contacting the metal oxide or metalloid oxide and a metal ion IUn+;
i represents the number of groups L-Men+associated with nanoparticle AOx.
The metal oxide or oxides of metalloids AOxfor use in the present invention are, for example, colloidal silicon dioxide, titanium dioxide, zirconium dioxide, tin oxide and zinc oxide. They are insulating materials or semiconductors that are able to shape themselves, or using a suitable substrate, with a large number of materials, including wood, plastic, glass, metals, ceramics, cement and inner and outer surfaces of buildings, and can be obtained in the form of nanoparticles with sizes of the order of nanometers. Such nanomaterials are able to adsorb due to electrostatic or chemical the ski interactions, such as essential communication molecules with suitable functional groups, such as the following groups: carboxyl (-COOH) (or carboxylate), phosphonic (-RHO3H2) (or phosphonate) or baronova (-B(OH)2or bornata), which can provide a bifunctional molecule L. taking into account the small size of the ligands L and metal ions Men+for example, silver ions or copper, which may be the size of the order of picometers, the result is that kakeda of nanoparticles of metal oxide can be uniformly coated metal ions, such as Ag+or Cu2+that is schematically illustrated, for example, Fig. 1.
As a result, such nanomaterials containing positively charged nanoparticles can form a suspension or in aqueous solvents, or in polar solvents organic nature, which are sustainable and transparent.
Another significant aspect is connected with the possibility of mixing suspensions of nanomaterials according to the invention with cationogenic surface-active substances, such as alkylammonium salt. With this in mind, the bactericidal activity of nanomaterials according to the invention can be enhanced due to the presence of alkylammonium salt. Indeed, surfactants of this type show bactericidal activity, which can be set is mentary antibacterial activity of the active metal ions. Unexpectedly, the authors found that alkylammonium salts, such as benzalkonium chloride, which has a tendency to precipitate in alkaline medium or in the presence of high concentrations of anions, stable in the presence of suspensions obtained from positively charged nanoparticles according to the present invention.
The experimental data described in this description below, also show that cationogenic surfactant, such as benzalkonium chloride, may cause adsorption on nanomaterials on the basis of titanium dioxide at pH values close to neutral. This provides the additional advantage of reducing volatility alkylammonium salts after the application of them to the surface.
Because of the wide spectrum of antibacterial action of materials containing silver ions and copper, the use of such materials as coatings for interior decoration of buildings, bathrooms, kitchens, fittings and valves in General, glass surfaces such as doors and Windows) and working rooms, and filters used for air purification in different environments, as well as water filters, undoubtedly represents the area of applications of essential importance. Receiving filters made of ceramic, glass or cellulose material and containing silver ions or ions IU the and and the inclusion of these materials in the conditioning units or devices forced air circulation provide an opportunity to prevent many diseases.
The design of such filters requires that the material that is applied as a coating on the filters allow high speed air flow and to bactericidal activity can be achieved under conditions of short time of contact.
This problem is solved by using nanomaterials according to the invention in that they cause a noticeable increase in surface area with indicators surface area, increasing on the order of 103and they can really be bactericidal action when the contact time of about 5 minutes, as provide in the standards UNI-EN 1276, April 2000, and UNI-EN 13697, December 2001.
Filters with a coating of nanomaterials according to the invention can also be easily restored to their initial antibacterial efficiency by immersion in ethanol solutions containing metal ions, such as Ag+or Cu2+.
Brief description of drawings
Fig. 1 schematically illustrates the structure of the nanoparticles according to the invention;
Fig. 2 illustrates the electronic absorption spectrum, showing the degree of adsorption of 4-mercaptophenylacetic acid on TiO2;
Fig. 3 illustrates the electronic absorption spectrum, showing the degree of adsorption of TBA (Hdcb) TiO2;
Fig. 4 is a schematic view of a specific implementation of the nano is astitsy according to the invention.
Detailed description of the invention
According to the features of the present invention receive nanocrystalline substrates containing AOxthat modifies the bifunctional ligands L, consisting of organic molecules containing functional groups capable of binding organic molecule with a nanocrystalline substrate and functional groups which are able to bind with metal ions, which have antibacterial activity, for example ions Ag+or Cu2+.
According to another features of the present invention receive nanocrystalline substrates containing AOxthat modifies the bifunctional ligands L, consisting of ORGANOMETALLIC molecules, such as transition metal complexes containing functional groups capable of binding complex with nanocrystalline substrate and functional groups which are able to bind with metal ions, which have antibacterial activity, for example ions Ag+or Cu2+.
Such nanocrystalline compounds represented by formula (I)
where AOxis a metal oxide or metalloid oxide, where x = 1 or 2;
Men+represents a metal ion having antibacterial activity, where n =1 or 2, preferably, Ag+or Cu++;
L is a bifunctional molecule, or an organic or ORGANOMETALLIC capable of simultaneously contacting the metal oxide or metalloid oxide and a metal ion IUn+;
irepresents the number of groups L-Men+associated with nanoparticle AOx.
The value of the parameteriwill depend on various factors such as the size of the nanoparticles AOxthe nature of the ligand L and the method used to obtain it. In the context of the present inventionicorresponds to the number of ligands L, with which the nanoparticles are able to bind, when specified nanoparticle AOxenter into contact with a solution of ligand L during the time interval from 10 minutes to 72 hours, preferably in the range of 3-24 hours.
The nanoparticles according to the invention have a size less than 40 nm, preferably less than 30 nm, preferably less than 15 nm. Nanoparticles of size less than 15 nm give transparent suspensions, which have a relatively wide range of applications.
The metal oxide or oxides of metalloids AOxthat can be used according to the present invention, are, for example, colloidal silicon dioxide, titanium dioxide, zirconium dioxide, tin dioxide and zinc oxide.
According to the General features of the present invention antibacter the social and antiviral activity described nanomaterials is evident even in the absence of weak radiation.
According to another features of the present invention nanocrystalline materials according to the invention or nanocrystalline materials, consisting only of oxide AOxmixed with cationogenic surface-active substances having antibacterial activity, which are able to adsorb onto the surface of nanoparticles AOxor which are able to form a mixture, stable in time, containing suspensions described nanomaterials.
According to another feature of the present invention it is possible to recover the initial bactericidal activity of the substrates in the case of depletion antibacterial metal ions (Ag+or Cu2+) to its initial value simply by immersing the substrate in an alcoholic solution containing a certain(s) ion(s) of metal(s).
According to another feature the present invention relates to dermatological compositions for the treatment of dermatological disorders such as acne and sores.
Bifunctional ligands L based on transition metal complexes
Complexes of transition metals that can be used for the described purpose, must contain organic ligands coordinated to the Central metal atom, with one of the following functional groups: Bronevoy (-B(OH)2), phosphonyl the Oh (RHO 3H2) or carboxyl (-COOH). Such functional groups are used to link the complex with the nanocrystalline substrate AOx. The other group, which coordinates to the Central metal atom, are able to bind with metal ions with antibacterial activity. Examples of such groups are ligands such as Cl-, Br-I-, CNS-, NH2CN-and NCS-.
ORGANOMETALLIC complexes of L according to the invention preferably contain organic ligands of the type dipyridyl and/or tripedia coordinated Central metal atom (M) and containing the following functional groups: carboxyl (-COOH), phosphonic (-RHO3H2or baronova (-B(OH)2), the ability to communicate with nanoparticles composed of JSCx; and also containing the following functional groups: Cl-, Br-I-, CNS-, NH2, SP-and NCS-coordinated specified by the Central metal atom (M) and the ability to communicate with ions Ag+or Cu2+. Preferably these dipyridine and tripolidine group, substituted carboxyl groups, preferably inpair-position to the nitrogen of the pyridine. When specified in the ORGANOMETALLIC complex of L contains more than one dipyridine or tripolidine groups who, optionally, one of these groups may be unsubstituted.
As for the metal ions (M)present in L, having octahedral coordination type, or have other types of coordination, corresponding to the tetrahedral configuration, the configuration of a flat rectangle or square planar configuration, the configuration of the trigonal pyramid or the configuration of a pyramid with a square or rectangular base, the candidates are any metals that are in the first, second or third row transition metals in the Periodic table of elements, which can form a stable bifunctional molecules of the type described.
Preferably, described ORGANOMETALLIC complexes L have octahedral coordination type. Preferably, the transition metals, coordinating such complexes, which are selected from Cr, Mn, Fe, Co, Ni, Cu, Zn, Ru, Rh, Pd, Re, Os, Ir and Pt.
On the other hand, ORGANOMETALLIC complexes of L according to the invention can have a negative charge and can form salts with cations, preferably organic cations, such as tetraalkylammonium cations. Such cations create the ability to solubilize such particles in organic solvents, which contribute to the adsorption process of nanomaterials based on metal oxides or oxides of metalloids.
Thus, these molecules can serve as bifunctional ligands, forming a homogeneous adsorbed layer on the nanoparticles AOxand at the same time may contact with metal ions with antibacterial activity.
Examples of such complexes with octahedral coordination presented in this description below.
TBA = tetrabutylammonium cation
N3Tcterpy = 4,4',4”-tricarboxylate
Group TION can be substituted by other tetraalkylammonium cations, which create the ability to solubilize complex in organic solvents.
H2dcb = 2,2'-dipyridyl-4,4'-dicarboxylic acid
Bifunctional ligands L on the basis of organic compounds
Bifunctional ligands L of the organic type, which are applicable in the context of the present invention include species of molecules containing groups, which can lead to interaction with nanoparticles AOxand also contain functional groups that can bind with ions having antibacterial activity. Examples of such molecules include organic molecules containing functional groups: carboxyl (-COOH), phosphonic (-RAN) and baronova (-B(Oh)2), which are able to contribute to the adsorption on the oxide surface AOx ; and a functional group >N >NH2, -CN, -NCS or-SH, which are able to bind with metal ions with antibacterial activity, such as Ag+or Cu2+.
Such organic ligands, preferably selected from
-- nitrogen-containing heterocycles with 6-18 members, preferably pyridine, dipyridyl or tripedia substituted by one or more substituents selected from carboxyl (-COOH), Bronevoy group (-B(Oh)2), phosphonic group (-RAN), mercaptan groups (-SH), and hydroxyl (-OH);
-- arrow C6-C18, preferably selected from phenyl, naphthyl and biphenyl, substituted by one or more substituents selected from carboxyl (-COOH), Bronevoy group (-B(Oh)2), phosphonic group (-RAN), mercaptan groups (-SH), and hydroxyl (-OH); and
-- monocarboxylic and dicarboxylic acids, C2-C18 substituted by one or more mercaptane groups (-SH) and/or hydroxyl groups (-OH).
Preferable examples of such bifunctional organic ligands include
-- pyridine, dipyridyl or trapidil, functionalityand carboxyl groups, baronowie groups or phosphonic groups; mercaptoethanol acid, mercaptoundecanoic acid, mercaptoethanol, mercaptonicotinic acid, 5-carboxypentyl, mercaptoethanol acid and 4-mercaptopurine the second acid.
Now will be described the experimental methods pertaining to producing nanomaterials consisting of AOxused in the development of the present invention, the characteristics of these nanomaterials and antibacterial properties of these nanomaterials.
Get a transparent suspensions of nanomaterials on the basis of titanium dioxide and zirconium dioxide
Nanomaterials based on titanium dioxide can be obtained with nanoparticles such a size that they form a transparent or opaque suspension in water or organic solvents. Suspension of TiO2consisting of nanoparticles of less than 15 nanometers, are usually transparent and when applied on the surface they do not change its color. Commercial products are titanium dioxides, such as “Biossido di Titanio P 25” (supplied by Degussa), give a suspension, which are white and opaque, because the average diameter of the nanoparticles of TiO2is in the range of 25-30 nm. For the purposes of the present invention can be used either opaque or transparent nanomaterials. However, transparent nanomaterials are of more interest because they provide a greater range of possible applications. Transparent colloidal suspension of colloidal silicon oxide or dioxide ol the VA are commercially available.
Methods of obtaining suspensions on the basis of titanium dioxide and zirconium dioxide will be described next. The given amounts of reactants can be modified without departing from the novelty and scope of the present invention.
(A) a Transparent suspension based on TiO2
In chemical glass download 300 ml of distilled H2Oh and 2.1 ml of a strong acid, for example concentrated HNO3(65%, wt./wt.). After 10 minutes with stirring via an addition funnel, add 50 ml of isopropoxide titanium (supplied by Fluka). Immediately formed precipitated TiO2milky color. The mixture is then heat at 80°C for 8-12 hours, providing continuing stirring and maintaining the temperature constant. During heating the precipitate is again dissolved and the mixture becomes opal. During the phase of heating of the colloidal suspension concentrate to a final volume of 100-200 ml, which corresponds to the concentration of TiO2150-75 g/l Nanoparticles of titanium dioxide, obtained at the end of the process, have a diameter in the range of 6-15 nm. Then, the suspension is concentrated to 100 ml, diluted with distilled water and ethanol, and get the final clear solution (pH ≈ 2), which contains, in a volume of 1 liter, TiO2at a concentration of 1.5% and alcohol in the range of 10-50%, preferably 25%.
(C) a Transparent suspension on the basis of ZrO
In chemical glass download 300 ml of distilled H2Oh and 2.1 ml of a strong acid, for example concentrated HNO3(65%). After about 10 minutes under stirring using a dropping funnel add 76 ml of 70% solution of tetraisopropoxide zirconium in isopropanol.
Immediately one can see the formation of precipitated ZrO2white-the color of milk. The mixture is then heat at 90°C for 8-12 hours, providing continuing stirring and maintaining the temperature constant. During heating the precipitate is again dissolved, and the formed suspension looks milky color, which concentrate to 140-280 ml, which corresponds to the concentration of ZrO2150-75 g/L. Then, the suspension is concentrated to 140 ml, diluted with distilled water and ethanol, and get opalescense suspension (pH ≈ 2), which contains ZrO2at a concentration of 1.5% and alcohol in the range of 10-50%, preferably 25%.
(C) an Opaque suspension based on TiO2
Neutral water opaque suspension on the basis of titanium dioxide can be obtained by adding titanium dioxide P 25 in aqueous solutions “Triton X 100” (supplied by Fluka).
Neutral water opalescent suspension on the basis of titanium dioxide can also be obtained from peroxotitanic acid by modification of the procedures described in the literature (H. Ichinose, M. Tersaki and Katsuki H., 1996,J. Ceramic Soc. Japan,104, 715).
In a typical receiving 150 ml of TiCl4in 20% HCl loaded into a 1-l chemical glass and to the resulting solution was added 826 ml of NH4OH, diluted 1:9 with distilled water. The resulting solution has a neutral pH (pH 7), and precipitates of titanium acid, Ti(OH)4. The resulting precipitate is white in color and has the consistency of a gel. The precipitate collected on the filter porosity G3 and washed 750-1000 ml of distilled water (as long as there is a complete removal of chloride that can show the processing liquid filtrate AgNO3). If chloride is present, mark the precipitation of a white cheesy AgCl. The precipitate containing titanium acid (Ti(OH)4), harvested and suspended in 200 ml of distilled water having a conductivity of less than 1.5 µs with a pH in the range 5-7; to the mixture slowly over 20-30 minutes add 92 ml of 30% H2About2. Celebrate the dissolution of the precipitate and formation of yellow coloured solution containing peroxotitanic acid of General formula
where x is equal to the value in the range of 3-6.
Finally, the solution warm for 1 hour at 70°C for the decomposition of excess H2About2and then treated in an autoclave for 8 hours at 120°C. At this stage of the procedure proximityout acid times ageda to titanium dioxide, mainly, in the allotropic form of anatase. The resulting suspension of the nanoparticles has a pH close to neutral, opaque in appearance and is stable in time.
The suspensions of nanomaterials that have antibacterial and antiviral activity
In order to give suspensions of nanomaterials bactericidal activity and antiviral activity, carry out the first stage of adsorption, which is adsorbed bifunctional ligand L, followed by mixing with an aqueous or alcoholic solution containing ions Ag+or Cu2+. Then to suspensions of nanomaterials functionalized ions Ag+or Cu2+you can add ammonium salt acting as econogene surface-active substance which has antibacterial activity, or can be added independently to or adsorbed on nanomaterials that are the subject of the present invention; such reception described above.
Generally, adsorption of bifunctional ligand L on the nanomaterial AOxdescribed in the present invention requires about 12-36 hours, while the binding of ions Ag+or Cu2+with ligand L is stabilized almost immediately by adding solutions containing these ions, for suspensions of nanomaterials, the functionality of the inpatient ligand L. The accumulated experimental data described in this description below, show that cationogenic surfactants, such as alkylammonium salts, can also be partially adsorbed on the surface of the nanomaterials.
Methods of preparation, are described below in detail show preparative methodology for producing suspensions of nanomaterials with bifunctional ligands L, ions Ag+and with cationogenic surfactants. Similar ways of getting you can use to obtain such suspensions with ions of Cu2+. The given amounts of reactants can be modified within the scope of the present invention.
(D) Adsorption of 4-mercaptophenylacetic acid and ions Ag+“TiO2P25” (supplied by Degussa)
To a solution containing 2×10-5moles of 4-mercaptophenylacetic acid, dissolved in 50 ml of ethanol was added 1 g of TiO2P25 (supplied by Degussa). The suspension is stirred for 24 hours. 4-Mercaptopropionate acid has an absorption band at 255 nm, which can be attributed to the transition of the π-π* phenolic cycle. This band electronic absorption creates the possibility of monitoring the adsorption Bronevoy acid on the surface of the nanomaterial as a function of time. It is known that adsorption occurs due to the interaction Bronevoy functional g is uppy with the surface of the semiconductor. Spectra electronic absorption in Fig. 2 show that the number 4 is mercaptophenylacetic acid adsorbed on the surface of TiO2P25”, reaches 35% of the initial concentration for 24 hours.
The solution is centrifuged 10 min at 4000 rpm, obtaining a clear solution, the solid is washed with 20 ml of ethanol and then resuspended in 50 ml of ethanol under stirring. To the resulting suspension add to 7.2×10-6of moles of the soluble silver salt, preferably silver lactate or silver acetate. The suspension obtained is white in color, odorless and stable in time.
(E) Adsorption of 4-mercaptophenylacetic acid and ions Ag+on a transparent suspensions of TiO2according to the method (a) and on the products of the company NM Tech
Dilute 100 ml of a clear solution of titanium dioxide obtained according to method (a) and containing 15% of TiO2, 100 ml of distilled water and 200 ml 0,052 g of 4-mercaptophenylacetic acid in ethanol. The suspension is stirred for 24 hours, and after the specified period spectrophotometric determination shows that boranova acid is completely adsorbed on the nanoparticles of the semiconductor. The small size of the nanoparticles relative to the “TiO2P25 and resulting large surface area of the suspended substances responsible for complete adsorption of bi is funkcionalnogo ligand. To a transparent, odorless, suspension while stirring, a stoichiometric quantity (relative to L) salts of silver, such as silver lactate (0.06 g) or silver acetate (0.05 g). After 1 hour of continuous mixing add 10-20 ml, preferably 12 ml, 50% (wt./about.) an aqueous solution of benzalkonium chloride, and the suspension is stirred for 1 hour. Then a concentrated suspension is diluted with distilled water and ethanol and receive 1 liter of opal suspension (pH ≈ 2), which contains TiO2at a concentration of 1.5% and the ethanol in the range of 10-50%, preferably 25%.
Found that the transparent suspension indefinitely sustainable. Below this description, such a product for the sake of brevity called “bakerline” (“Bactercline”).
The same procedure can be used for modification of transparent suspensions of nanomaterials sold NM Tech. Ltd. and called “PSO 419”, when the number of bifunctional ligand and silver ions are picked based on the amount of titanium dioxide in the product. For example, the product “PSO 419”, which is similar to the product obtained according to method (A), and in which the content of TiO2is 2%, and the pH is approximately equal to 2, can be transformed into anti-bacterial and anti-virus product by using a method similar to that described above.
In particular, 50 ml of the solution “PSO 41D2”, contains 2% TiO2, diluted with 2.2 mg 4-mercaptophenylacetic acid (2,05×10-5M), and the suspension is stirred for 24 hours. To the obtained solution, odorless, add 2,05×10-5M silver lactate or silver acetate. Finally, after 1-hour nepreryvnogo stirring 8-20 ml, preferably 12 ml of an aqueous solution of benzalkonium chloride, and the suspension is stirred for 1 hour. The obtained transparent suspension indefinitely sustainable.
It should be noted that other opaque products on the basis of TiO2sold NM Tech. Ltd., such as “AT-01” and “AT-03”, can be processed according to the described methods of the present invention and to obtain stable suspensions or powders, which have antibacterial and antiviral activity. For example, the sample in 50 ml of the solution “AT-01”, containing 1.7% of TiO2, diluted with 50 ml of ethanol containing 3.8 mg dissolved 4-mercaptophenylacetic acid (1,9×10-5M), the suspension is stirred for 24 hours, and receive the product, no smell. Then add to 1.9×10-5M silver lactate or silver acetate. The resulting suspension over time gives a fine precipitate.
(F) Adsorption cationogenic surfactants on the titanium dioxide
Cationogenic surface-active substances with antibacterial activity, as a rule, barberousse on nanomaterials on the basis of TiO 2, ZrO2, SnO2, ZnO, SiO2. Adsorption on negatively charged or neutral nanoparticles is almost instantaneous. In the case of suspensions of nanomaterials with alkaline pH, the addition of salts such as benzalkonium salts, such as, for example, chloride of benzyldodecyldimethylammonium or chloride of benzyloxycarbonylamino or benzalkonium chloride, causes sedimentation of suspensions; while in the case of suspensions of nanomaterials with neutral or acid pH of the suspension is stable.
In indirect tests on adsorption of benzalkonium chloride on nanomaterials on the basis of TiO2at neutral pH using conductometric measurements. The Association via adsorption of the cation of benzyldimethylamine on TiO2should, as expected, to cause a decrease in conductivity, which is confirmed by the experiment described below.
Diluted 1:10 with 50% (wt./about.) a solution of benzalkonium chloride has a conductivity of 4.7 MSM. If the volume of such solution to increase from 10 to 15 ml by adding distilled water, the conductivity is reduced to 3.90 MSM. If, instead, dilute the solution by adding 5 ml of neutral suspensions of titanium dioxide obtained from peroxotitanic acid according to method (C), or equivalent product AT-03” at neutral pH, the measured conductivity is of 3.60 MSM. The decrease in conductivity is and 300 µs can be attributed to the adsorption cationogenic surfactants on the surface of titanium dioxide.
(G) the Adsorption of 2,2'-dipyridyl-4-carboxy-4'-carboxyglutamate, Ag+and Cu2+“TiO2P25” (supplied by Degussa)
The anion of 2,2'-dipyridyl-4-carboxy-4'-carboxyglutamate (abbreviated “Hdcb”) receive, adding one equivalent of tetrabutylammonium hydroxide (abbreviated TWAIN) to 2,2'-dipyridyl-4,4'-dicarboxylic acid (abbreviated as “H2dcb”), which is poorly soluble in water and is in solid form. The ligand in the form of monocarboxylate (also called “monoprotonated form”) and tetrabutylammonium salt (abbreviated as TBA(Hdcb)”) so you can solubilisate in methanol or ethanol and can be adsorbed on the titanium dioxide.
To a solution of 1x10-4moles of TBA(Hdcb) in 100 ml of ethanol is added 5 g TiO2P25” (supplied by Degussa). The suspension is stirred for 24 hours. Ligand TBA(Hdcb) has an absorption band at 294 nm due to transitions of the π-π*, which allows control over its adsorption on nanomaterials as a function of time.
The spectra in Fig. 3 shows that after 24 hours, the ligand is completely adsorbed on the surface of the nanocrystalline substrate. It is known that adsorption occurs due to the interaction of carboxyl functional groups to the surface of the semiconductor.
Then the suspension is centrifuged 10 min at 4000 rpm, and the solid is washed with 50 ml of methanol. Then the nanomaterial, functionalliteracy ligand (abbreviated TiO 2/TBA(Hdcb)), and finally dried in vacuum at ambient temperature.
Two portions of TiO2/TBA(Hdcb) 2 g each resuspended in 100 ml of ethanol. One suspension was added with stirring 8 mg lactate silver; and another suspension type 7 mg CuCl2. Two suspensions have different substituents: suspension, functionalized copper ion - TiO2/TBA[Hdcb]/Cu2+- remains stable, TiO2/TBA[Hdcb]/Ag+over time, sludge forms.
(H) Adsorption of ORGANOMETALLIC ligands (L) and ions Ag+on a neutral suspensions of TiO2
Bifunctional ORGANOMETALLIC ligands L, described above, can be mounted on neutral suspensions of titanium dioxide obtained according to method (C), and nanomaterials suspended in ethanol solutions of ORGANOMETALLIC ligand concentration of about 10-3-10-4M. the Suspension was stirred for 12 h, during which the ORGANOMETALLIC ligand L is completely adsorbed on the surface of the nanomaterials.
Adding stoichiometric amounts of silver relative to the ligand L in ethanol solution corresponds to the formation of adducts in which the silver ion Ag+pinned on inorganic ligand, which is schematically illustrated in Fig. 4 in the case of the complex (H2dcb)2Ru(NCS)2(H2dcb = 2,2'-dipyridyl-4,4'-di is Urbanova acid). The presence of carboxyl functional groups makes possible the adsorption complex and uniform coating of nanocrystalline material for about 2-3 hours at 50°C. and for 12 hours at ambient temperature. At the next stage to a methanol solution add salt cerbère, such as silver nitrate, silver lactate or silver acetate, in a stoichiometric ratio of 2:1 to the number of moles (H2dcb)2Ru(NCS)2. The presence of two groups of NCS allows ions Ag+to connect instantly, as shown in Fig. 4.
According to the private variant of implementation of the present invention nanocrystalline materials of the formula (I) can be incorporated in a dermatological composition for the treatment of bacterial dermatological diseases such as acne or sores.
Getting some of these compositions are described herein below in the examples.
Obtaining gels and creams
Suspensions of nanomaterials on the basis of titanium dioxide according to the invention can be used as active ingredients in obtaining hydrophilic gels and creams for dermatological applications. Obtaining hydrophilic gels involves mixing the active ingredients with excipients and gelling components, such as, for example, glycerin, aminopropiophenone, magnesium silicate Seeley is at aluminum. Obtaining hydrophilic creams involves mixing pharmaceutically effective amount of the active ingredients with surfactants and emulsifiers, such as vaseline, liquid paraffin, stearyl alcohol, glycol stearate, carboxypolymethylene and sodium salt of ethylenediaminetetraacetic acid. Of course, any excipient adopted for such purposes (of the excipients, well known to experts in the art), can be used to obtain dermatological compositions according to the invention.
Antibacterial and antiviral activity of functionalized nanomaterials
Functionalityand nanomaterials obtained according to the methods (D), (E), (F), (G) and (H)have antibacterial activity against Escherichia coli. The tests were carried out depositing the film, consisting of various nanomaterials on Petri dishes in contact with a number of colonies of more than 104CFU (colony forming units). In all cases, see the complete destruction of the colonies.
More complete measurements carried out according to the standards UNI-EN 1276, April 2000, and UNI-EN 13697, December 2001, for a product synthesized according to the method (S) (product, called bakerline), which is transparent and, thus, applicable in a wider range of applications.
Evaluation of bactericidal and the performance suspension: method of dilution and neutralization (UNI-EN 1276, April 2000)
For testing use the following strains:
Sources of bacteria
All the tested bacterial strains provided by the Department of experimental and diagnostic medicine, section of Microbiology, University of Ferrara.
Experienced product bacterin diluted to 80%.
The test substance is considered bactericidal, if for each bacterial strain at 20°C. after a contact time of 5 min the result is decreased viability of at least 105units.
The results show that in all cases receive the decreased viability of greater than 105units.
On the basis of the obtained results and the criterion of applicability of the trials tested substance “bacterin is bactericidal against Escherichia coli, Enterococcus faecalis, Staphylococcus epidermidis, Staphylococcus aureus, Salmonella and Listeria, when used at a concentration of 80% (which is the maximum possible test concentration) at a contact time of 5 min in the presence of bovine albumin at a final concentration of 0.3%, according to the method of the standard UNI-EN 1276, April 2000.
Evaluation of bactericidal and the activity: surface tests (UNI-EN 13697, December 2001)
In addition to the strains used for testing suspensions, see above, in this case, the test applies to Legionella pneumophila.
Thus, the list of strains used in the test is as follows:
The test substance is considered bactericidal against stipulated by the bacterial strains according to the European standard, if for each bacterial strain at 20°C. after a contact time of 5 min the result is decreased viability of at least 104units.
The results in table 1 show that in all cases the decimal logarithm of antimicrobial activity greater than 4.
|The contact time and the logarithm of antimicrobial activity|
|The test microorganisms||5 minutes|
|Staphylococcus aureus||> was 4.02|
|Staphylococcus epidermidis||> 4,00|
|Pseudomonas aeruginosa||> 4,00|
|Escherichia coli||> 4,00|
|Enterococcus faecalis||> 4,19|
|Legionella pneumophila||> 4.26 deaths|
On the basis of the obtained results and the criterion of applicability of the test substance “bacterin”, tested in the specified test conditions, is bactericidal against Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus epidermidis, Staphylococcus aureus, Salmonella, Listeria and Legionella pneumophila, when used at a concentration of 100%, contact time of 5 min in the presence of bovine albumin at a final concentration of 0.3%, according to the method of the standard UNI-EN 13697, December 2001.
Evaluation of antifungal activity by the method of dilution and neutralization with suspension (standard UNI-EN 1650, October 2000)
For testing use the following strains:
The test strains were provided by the Department of experimental and diagnostic copper is ins, section of Microbiology, University of Ferrara.
The test substance is considered fungicidal, if for each fungal strain at 20°C. after a contact time of 15 min the result is decreased viability, at least at the 104units.
Decreased viability in the case of different concentrations of bakerline are presented in table 2.
|Contact time and decrease generosamente|
|The test microorganisms||15 minutes|
|Candida albicans||> of 1.13×104||> of 1.13×104||> of 1.13×104|
|Aspergillus niger||< 1,87×103||> to 1.37×104||> to 1.37×104|
On the basis of the obtained results and the criterion of applicability of the trials tested substance “bacterin isfungicidalagainstCandda albicans at concentrations of 25%, 50% and 80%, and againstAspergillus nigerat concentrations of 50% and 80% (which is the maximum possible test concentration) after 15 min of contact in the presence of bovine albumin at a final concentration of 0.3%, according to the method of the standard UNI-EN 1650, October 2000.
Evaluation of fungicidal activity: surface test (standard UNI-EN 13697, December 2001)
For testing use the following strains:
The test strains were provided by the Department of experimental and diagnostic medicine, section of Microbiology, University of Ferrara.
The test substance is considered fungicidal, if the decimal logarithm of antimicrobial activity against microbial strains obtained according to the European standard, equal to or greater than 3, in the case of the 15-minute contact at 20°C.
The logarithm of the reduction presented in table 3.
|The contact time and the logarithm of antimicrobial activity|
|Candida albicans||2,02||> 3,18|
|Aspergillus niger||1,14||> 3.04 from|
On the basis of the obtained results and the criterion of applicability of the trials tested substance “bacterin” installed in the test conditions is fungicidal against Candida albicans and Aspergillus niger, when used at a concentration of 100%, after 15 min of contact in the presence of bovine albumin at a final concentration of 0.3%, according to the method of the standard UNI-EN 13697, December 2001.
The experiments described in this description below, show that the product bacterin in very small concentrations has virucidal activity against the virus HSV-1 (the virus-1 herpes).
Receive different amounts of suspensions of viruses in a modified environment Dulbecco (D-MEM), to which was added 1% serum fetal cow (BFS). The virus used in the concentration (titer virus) 1x106cytolytic plaque-forming units (PFU, (Pfu)). Different numbers of bakerline added to different samples with pre-treatment 1 and 5 hours. Unhandled suspension viruses retain control. On Windows the years of incubation period at ambient temperature, all samples were diluted to a known volume to determine the titers of the virus. The titers of virus control and samples treated with bakerline, determined by the method described in this description below.
When determining the titer of virus calculate the number of infectious began present in 1 ml of solution. One way is to determine the number of cytolytic plaques produced significantly diluted suspension of viruses and brought into contact with the monolayer of cells. In this series of experiments, use of renal cells of African monkey (Vero). Cells were cultured at 37°C in the presence of 5% CO2in D-MEM”, which added 10% BFS, 1% L-glutamine and 1% penicillin/streptomycin. Determination of the titer carry on tablets with 12 holes. When culture is almost merge, viral mass is diluted to known concentrations in the medium containing 2% BFS. Each dilution make 2 holes on the tablet. After incubation for 1 hour at 37°C. the inoculum remove, and block infection by adding medium containing 1% BFS and 2% human gamma-globulin, which has the function of inhibiting the formation of secondary plaques.
Inoculated cultures are incubated at 37°C for 2 days and control up until the lysis plaques will not be visible. At this point, cells are fixed and stained gentianales purple. Under an optical microscope believe plaques present in the wells, and the received number is multiplied by the dilution factor, and get the titer of virus in units of PFU/ml
Results and discussion
Virucidal activity of the product of bakerline
Product bacterin of 10 and 50 microlitres enter into contact with HSV-1 titer virus 1x106the combat. Incubation is carried out in 1 ml of medium (D-MEM, to which was added 1% BFS. Use different incubation time: 1 hour and 5 hours. At the end of the specified incubation period, the virus was diluted to concentrations of 1x103and 1x102the battle, and inoculant almost fused culture. As can be seen from table 4 below, cells inoculated with virus pretreated with bakerline not have plaques of lysis for any time pre-treatment and any dilution of the virus.
|The number of the battle and the percentage of inhibition of the formation of cytolytic plaques after pretreatment of HSV-1, 1×106, bakerline, 1 μl/ml, compared to control|
|Pretreatment of HSV-1 titer of 1×10610 μl and 50 μl of the test product|
|Breeding HSV-1 (1×103the combat)|
|Secondary control (combat)||The average of the samples treated with 10 µl (combat)||Inhibition of Blasco education (%)||The average of the samples treated with 50 μl (combat)||Inhibition of Blasco education (%)||The titer of virus control|
|1 hour||5 hours||1 hour||5 hours||1 hour and 5 hours||1 hour||5 hours||1 hour and 5 hours||1 hour||5 hours|
The titer of the virus HSV-1 control, specified above in Table 4, calculated by multiplying the average number of plaques of cytolysis by the dilution factor (103). As can be seen from Table 4, the treated samples have 100% reduction in plaque formation cytolysis compared to control.
Both times pre-treatment and both dilutions of the virus has the Xia almost complete reduction of the present virus particles. The product reduces the titer of the virus with about 300000 present viral particles (control) to a titer of less than 1000. Thus, when 1-hour contact bacterin, diluted to a concentration of 1% (10 µl/ml), causes almost complete loss of viral particles.
This study of antiviral activity of the product of bakerline shows that the product has antiviral activity in direct contact with the virus HSV-1 even under the most severe dilution of the product with contact time 1 hour.
Performed the experiments show that when the level of dilution of the product of the order of 1:100 is achieved by complete loss of viral particles.
The composition of the invention can be used in any applications in which it is desirable achievement antibacterial and/or antiviral activity, such as for treatment of surfaces, such as surfaces in the environment in health care (clinics, hospitals etc), in particular, floors, walls, tables, operating tables, etc. of Another application, in which case the composition according to the invention exhibit an advantageous activity is the treatment of air in various media, in particular public places and/or places health, or other environments in which it is desirable to have almost completely sterile air, such as plants for the manufacture of pharmaceutical preparations the practical preparations and plants for food processing. In these applications, the composition of the invention can be used for coating on the filters used in various types of ventilation systems for processing spaces large or small sizes.
According to another variant embodiment of the invention receive a dermatological composition for the treatment of bacterial infections, which contain or together with or instead of nanocrystalline materials of the formula (I) photocatalytic suspension of TiO2in combination with silver or a derivative of silver and/or copper, or a derivative of copper(II), such as those described as examples in the patent application Italy No. IS20052 filed 01 Sept. 2005.
1. Nanocrystalline compounds of formula (I)
where AOXis a metal oxide, where a is selected from Ti or Zr, x=2;
Men+represents a metal ion having antibacterial activity, selected from Ag+and C++where n=1 or 2;
L is a bifunctional molecule, or an organic or ORGANOMETALLIC capable of simultaneously contacting the metal oxide and the metal ion Men+; where the organic molecule is selected from pyridine, dipyridyl, tapiridae, functionalized with carboxyl groups (-COOH), baronowie groups (-B(OH)2or phosphonic groups (RHO3 H2), or 4-mercaptophenylacetic acid; where the ORGANOMETALLIC molecule is an ORGANOMETALLIC complex containing an organic ligand coordinated to the Central metal atom and containing Bronevoy
(-B(OH)2), phosphonic (-RHO3H2) or carboxyl (-COOH) functional group, and the group coordinated to the Central metal atom, are able to bind with metal ions with antibacterial activity; where the specified organic ligand coordinated to the Central metal atom selected from pyridine, dipyridyl, tapiridae, functionalized with carboxyl groups (-COOH), baronowie groups (-B(OH)2or phosphonic groups
(RHO3H2), or 4-mercaptophenylacetic acid;
i represents the number of groups L-Men+associated with nanoparticle AOX.
2. The nanocrystalline compounds according to claim 1, where Men+choose from Ag+and Cu++.
3. The nanocrystalline compounds according to claim 1 or 2, where these metal oxides or oxides of metalloids AOxchoose from titanium dioxide or zirconium dioxide.
4. The nanocrystalline compounds according to claim 1, where L is an ORGANOMETALLIC complex containing an organic ligand coordinated to the Central metal atom and containing baronova (-B(OH) ), phosphonic (-RHO3H2) or carboxyl (-COOH) functional group, and the group coordinated to the Central metal atom, are able to bind with metal ions with antibacterial activity.
5. The nanocrystalline compounds according to claim 4, where these groups are able to bind with metal ions with antibacterial activity, selected from CL-, VG-I-, CNS-, NH2CN-and NCS-.
6. The nanocrystalline compounds according to claim 4, where the specified organic ligand coordinated to the Central metal atom is dipyridyl and/or tripyridyltriazine the ligand functionalized with carboxyl groups (-COOH), Bronevoy (-B(OH)2or phosphonic (RHO3H2).
7. The nanocrystalline compounds according to claim 6, where these dipyridine and/or tripolidine group, substituted carboxyl groups, preferably in the para-position relative to the nitrogen of pyridine, and where, in the case when the ORGANOMETALLIC complex of L contains more than one dipyridine and/or tripolidine group, one of the above-mentioned groups optionally may be unsubstituted.
8. The nanocrystalline compounds according to any one of claims 4-7, where the specified metal coordinating organic ligands, and coordinating groups which are able to bind the metal ions with antibacterial activity, is a metal, which is first, second or third row transition metals of the Periodic table of elements, and which can form a stable bifunctional molecules of the type described; where the specified metal is chosen, preferably, from CR, Mn, Fe, Co, Ni, cu, Zn, Ru, Rh, Pd, Re, Os, Ir and Pt.
9. The nanocrystalline compounds according to any one of claims 4 to 7, where these ORGANOMETALLIC complexes have a coordination structure type octahedral, tetrahedral, flat rectangle or square planar, trigonal pyramid or pyramid with a square or rectangular base, and preferably, octahedral type.
10. The nanocrystalline compounds according to any one of claims 4 to 7, where these compounds are selected from [(H3Tcterpy)M(SP)3]TION, [(H3Tcterpy)M(S)3]TION, [M(H3Tcterpy)(bpy)NCS]TBA and M(H2dcb)2(NCS)2,
where N3Tcterpy is 4,4',4"-tricarboxylate,
TBA is tetrabutylammonium cation,
bpy is 2,2'-dipyridyl, and
H2dcb is 2,2'-dipyridyl-4,4'-dicarboxylic acid.
11. The nanocrystalline compounds according to claim 1, where L is an organic molecule containing functional carboxyl group (-COOH), fastonline (RHO3H2or baronova (-B(OH)3), are able to contribute in the BPA is rblu oxide AO X; group >N >NH2CN-, NCS-, CNS-or SH, are able to bind with metal ions with antibacterial activity.
12. The nanocrystalline compounds according to claim 11, where the ligand L is selected from
pyridine, dipyridyl and tapiridae, functionalized with carboxyl groups, baronowie groups or phosphonic groups;
13. The nanocrystalline compounds according to claim 1, and these nanocrystalline compounds contain particles smaller than 40 nm, preferably less than 30 nm.
14. The nanocrystalline compounds according to item 13, and these nanocrystalline compounds contain particles smaller than 15 nm.
15. The composition having antibacterial and/or antiviral activity, including nanocrystalline compounds according to any one of claims 1 to 14, together with cationogenic surface-active substance.
16. The composition according to item 15, where the specified cationogenic surfactant is a salt of alkylamine, preferably selected from: compounds Quaternary ammonium compounds, benzyl C12-AVI or benzalkonium chloride.
17. The composition according to item 15 or 16, which represents a clear solution.
18. The nanocrystalline compounds according to claim 1, where the surface molecules of these nanocrystalline with the joining of adsorbed salt alkylamine, preferably selected from salts of Quaternary ammonium bases, benzyl C12-AVI or benzalkonium chloride.
19. Dermatological compositions comprising at least one nanocrystal compound according to any one of claims 1 to 14 or 18 together with a pharmaceutically or kosmetologicheskii acceptable excipients.
20. Dermatological composition according to claim 19, moreover, these compositions are in the form of gel or cream.
21. Dermatological composition according to claim 20, where, if the composition is in the form of a hydrophilic gel, excipients selected from glycerol, aminopropiophenone, magnesium silicate and aluminum silicate; and if the composition is in the form of a hydrophilic cream, excipients selected from surfactants and emulsifiers, such as vaseline, liquid paraffin, stearyl alcohol, glycol stearate, carboxypolymethylene and sodium salt of ethylenediaminetetraacetic acid.
22. The application of the nanocrystalline compounds according to one of claims 1 to 14 or 18 to obtain drugs having antibacterial and/or antiviral activity.
23. The application of the nanocrystalline compounds according to any one of claims 1 to 14 or 18 as an antibacterial and/or anti-virus tools to coatings for the interior of buildings, elements of the s accessories, glass surfaces and working rooms and filters to clean the air or water.
24. The regeneration method of the nanocrystalline compounds according to any one of claims 1 to 14 or 18, comprising a stage of contacting these nanocrystalline compounds with a salt solution of silver (I) or a salt solution of copper (II).
25. Dermatological compositions comprising at least one nanocrystal compound of formula (I) according to claim 1 together with a pharmaceutically or kosmetologicheskii acceptable excipients.
26. Dermatological compositions according A.25, and these compositions are in the form of gel or cream.
27. Dermatological compositions according p, where, if the compositions are in the form of a hydrophilic gel, excipients selected from glycerol, aminopropiophenone, magnesium silicate and aluminum silicate; and if these compositions are in the form of a hydrophilic cream, excipients selected from surfactants and emulsifiers, such as vaseline, liquid paraffin, stearyl alcohol, glycol stearate, carboxypolymethylene and sodium salt of ethylenediaminetetraacetic acid.
SUBSTANCE: invention relates to a novel carboranyl derivative of fluorinated porphyrins of general formula I , where Ia: M=2H, R=o-CB10H10C-, Ib: M=2M, R=o-C6H5-CB10H10C-, Ic: M=2H, R=-CB11H11 -Cs+, Id: M=Cu, R=-CB11H11 -Cs+, Ie: M=Pd, R=-CB11H11 -Cs+, If: M=2H, R=-CB11H11 -Na+, Ig: M=Cu, R=-CB11H11 -Na+, Ih: M=Pd, R=-CB11H11 -Na+,having photosensitiser properties. The invention also discloses methods for synthesis of said compounds.
EFFECT: compounds which exhibit photosensitiser properties can be used in boron neutron capture therapy (BNCT) and photodynamic therapy (PDT) of oncological diseases.
6 cl, 8 ex, 1 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: described are structure and manufacturing of antibiotics which include borinic acid complexes, in particular derivatives of hydroxyquinoline, imidazole and picolinic acid, together with compositions of said antibiotics and methods of application of antibiotics and compositions as bactericidal and fungicidal preparations as well as therapeutic medications for treatment of diseases caused by bacteria and fungi.
EFFECT: obtaining antibiotics which include borinic acid complexes.
51 cl, 1 ex, 4 tbl
SUBSTANCE: invention relates to chelate complexes of gadolinium (III). Complexes of Gd3+ with 4-dihydroxyborophenylamine (DHBPA) have formula Gd(DHBPA)3, and complexes of Gd3+ with DHBPA and monosaccharide (M), which is in the inner sphere of the complex, have formula: M3[Gd(DHBPA)3]. DHBPA molecules enter the coordination sphere of gadolinium through nitrogen and oxygen atoms of the alanine fragment. Monosaccharides, e.g. fructose and/or ribose, form outer-sphere complexes on hydroxyl groups of borophenyl in DHBPA, built in the inner coordination sphere of Gd3+.
EFFECT: obtaining new compounds.
2 cl, 3 ex, 4 dwg
SUBSTANCE: present invention relates to a method for synthesis of a compound of formula I , in which X1 is selected from O; and X2 is N; involving successive reaction of a formula II compound with (i) methyl- or optionally substituted aryl-lithium; then (ii) n-butyl-, sec-butyl-, tert-butyl- or n-hexyl-lithium; and then (iii) borate ester. The invention also relates to a method of obtaining formula IV compounds: , which involves combination of [4-(1,3,4-oxadiazol-2-yl)phenyl]boronic acid with a formula III compound, in which P is a nitrogen protecting group, and to a formula IV compound, where P is C1-6alkoxycarbonyl.
EFFECT: design of an efficient method of obtaining the said compound.
9 cl, 9 ex
SUBSTANCE: invention relates to a method of producing organoboron compounds, which can be used as components of catalyst systems in oligomerisation and polymerisation of olefin, diene and acetylene hydrocarbons, as well as in fine organic and organometallic synthesis. A method is described for producing 1-phenyl-2,3,4,5-tetraalkylborocyclopenta-2,4-dienes by reacting dialkyl substituted acetylenes with phenyldichloroborane and magnesium metal in the presence of zirconocene dichloride as a catalyst in an argon atmosphere in a tetrahydrofuran medium. The reaction time is 8 to 12 hours and total output of end products is 35 to 55%.
EFFECT: obtaining novel organoboron compounds in a single step, synthesis of which is difficult or impossible using known methods.
1 cl, 1 tbl, 10 ex
SUBSTANCE: invention relates to novel class of photosensibilisers for photodynamic therapy - N,N-difluorboryl complexes of N-(3-aryl-2H-isoindol-1-yl)-N-(3-aryl-1H-isoindol-1-ylidene)amines of general formula: , where R=H,C1-C4-alkyl, OC1-C4-alkyl, Ph, Br, as well as to method of obtaining them lying in processing of respective ligand with boron trifluoride etherate in presence of secondary or tertiary amine in boiling benzole.
EFFECT: described photosensibilisers possess high photoinduced activity and are promising for practical application in photodynamic therapy method.
2 cl, 7 ex, 2 tbl
SUBSTANCE: invention refers to improved method of producing complex lithium borate salt to be applied as conducting salt in electrolytes in making galvanic cells, particularly lithium-ion batteries. Parent components boric acid, oxalic acid and lithium compounds (carbonate, lithium hydroxide) taken in the equivalent ratio according to the chemical reaction equation, charged in a planetary-type mill cup and mechanically activated with centrifugal rotary acceleration 500-600 m/s2 within 15-20 seconds. Synthesis is ensured within 4-6 hours in a furnace at temperature 190-220°C. Furnace heating rate to working temperature is 15-30°C/min. The prepared salt is finished drying in a vacuum furnace, then unloaded and packed in a boxing filled with dry inert gas.
EFFECT: product with low element-impurity content.
1 cl, 1 ex, 1 tbl, 5 dwg
SUBSTANCE: method involves reaction synthesis of trihydrocarbylborane and aluminium oxide from trihydrocarbylboroxine and trihydrocarbylaluminium, and differs that reaction is performed in such a way that it results in trihydrocarbylaluminium in amount 0.5 or more per one mole of aluminium oxide formed from reaction thus preventing undesired gelling.
EFFECT: there is improved industrial production method for trihydrocarbylborane, the method is characterised with a number of quality and cost advantages.
4 cl, 7 ex
SUBSTANCE: invention describes method of obtaining novel intermediates, which are suitable for synthesis of amino acids, used for obtaining peptide receptor modulators, for instance agonists or partial agonists of said peptide receptors. Such modulators of peptide receptors include, for instance modulators of glucagon-like peptide receptors.
EFFECT: efficiency of application for relief of diabetic condition.
3 cl, 3 ex, 2 dwg
SUBSTANCE: regioselective synthesis of complex rapamycin 42-ether (CCI-779) involves: (a) acylation of 31-silyl rapamycin ether by compound of formula HOOC.CR7R8R9 or its combined anhydride, where: R7 is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, alkinyl with 2-7 carbon atoms, -(CR12R13)fOR10, -CF3, -F or -CO2R10; R10 is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, alkinyl with 2-7 carbon atoms, triphenylmethyl, benzyl, alcoxymethyl with 2-7 carbon atoms, chloroethyl or tetrahydropyranyl; R8 and R9 together form X; X is 2-phenyl-1,3,2-dioxaborinane-5-yl or 2-phenyl-1,3,2-dioxaborinane-4-yl, where phenyl can be optionally substituted; R12 and R13 each is independently hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, alkinyl with 2-7 carbon atoms, trifluormethyl or -F; and f=0-6; to obtain 42-ether boronate of 31-silyl rapamycin ether; (b) selective hydrolysis of 42-ether boronate of 31-silyl rapamycin ether in moderately acid environment to obtain rapamycin 42-ether boronate; and (c) diol treatment of rapamycin 42-etherboronate to obtain complex rapamycine 42-ether. Invention also claims new intermediate products applicable in this method.
EFFECT: application as antitumour medication.
48 cl, 3 ex
SUBSTANCE: invention relates to tetra-(5-acetylamino-7-heptyloxy)anthraquinonoporphyrazines of copper and cobalt of formula .
EFFECT: obtained compounds can be used as dyes and catalysts.
4 ex, 5 dwg,
SUBSTANCE: invention relates to tetra-(5-acetylamino-7-hydroxy)anthraquinonoporphyrazines of copper and cobalt of formula
EFFECT: compounds can be used as dyes and catalysts.
4 ex, 6 dwg
FIELD: process engineering.
SUBSTANCE: invention relates to compound that represents a multimetal complex comprising assemblage of metal complexes wherein ligand is coordinated by one metal atom or assemblage of atoms of one metal. Note here that assemblage of metal complexes are bound together by polydentant ligand which substitutes partially the ligands of metal complex assemblage and contains 2 to 1000 ligand atoms wherein each metal complex has carboxylic ligand and aforesaid polydentant ligand that represents dicarboxylic acid ligand, while metal is selected from the group consisting of Pt, Ni or Pd. Invention covers also the method of producing clusters of metal or metal oxide, the method of producing compound containing multimetal complex, and metal complex.
EFFECT: invention allows producing larger amount of controlled-size clusters.
25 cl, 3 ex, 8 dwg
SUBSTANCE: invention relates to an iridium-platinum complex of formula (I) , where Cp* is selected from a group consisting of a cyclopentadienyl ligand, pentamethylcyclopentapentadienyl ligand, pentaethylcyclopentadienyl ligand and pentapropylcyclopentadienyl ligand, X is a hydrogen atom or a substitute group selected from a group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxyl group and an organic group located in the ortho, meta or para position relative the phenyl group or a combination of these positions, and Y is selected from a group consisting of a methyl group, an ethyl group and a propyl group, wherein said organic group is selected from a group consisting of an alkyl group, alkoxy group, alkenyl group, alkenyloxy group, alkynyl group, alkynyloxy group, aryl group, aryloxy group, aralkyl group and an aralkyloxy group, which can have a heteroatom or an ether bond, which are substituted or unsubstituted and which are C1-C30 The invention also discloses a method for synthesis of the iridium-platinum complex.
EFFECT: invention enables preparation of an iridium-platinum complex capable of giving iridium-platinum clusters, having a controlled cluster size and controlled alloy composition
3 ex, 1 dwg, 10 cl
SUBSTANCE: invention relates to an organonickel sigma-complex of formula ([NiBr(Xy)(bpy)], where Xy=2,6-dimethylphenyl, bry=2,2'-bipyridyl). Said complex exhibits high catalytic activity during oligomerisation of ethylene with retention of good solubility in carbon solvents.
EFFECT: possibility of oligomerisation in completely homogeneous conditions.
2 cl, 7 ex, 1 tbl, 1 dwg
SUBSTANCE: invention relates to a novel compound - dihydrate of iron (II) hydroascorbate riboflavinate
(II) Fe(C6H7O6)(C17H19O6N4)2H2O which is used as an additive.
EFFECT: improved development and growth of chickens.
1 cl, 1 ex, 1 tbl
SUBSTANCE: invention relates to 1-alkenylimidazole derivatives of general formula 1 , where R is vinyl, allenyl or isopropenyl, R1 is hydrogen or methyl, E is Zn (II) or Fe(III), An is chlorine or acetate, n equals 1, 2 or 4, except compounds where R is vinyl, R1 is hydrogen, E is Zn(II), An is chlorine or acetate and n equals 2.
EFFECT: compounds have antihypoxic properties for different types of hypoxia.
5 ex, 8 tbl
SUBSTANCE: enhanced catalysts useful in a range of reactions in organic synthesis, such as olefin substitution and atom or group transfer reactions, are described. The catalysts are obtained by bringing a poly-coordination complex of a group VIII metal - ruthenium, including a Schiff base polydentate ligand and one or more other ligands, into contact with an acid under such conditions that the said acid can partially break the bond between the metal and the Schiff base polydentate ligand of the said metal complex, optionally through intermediate protonation of the said Schiff base ligand.
EFFECT: improved method.
17 cl, 43 ex, 3 tbl
SUBSTANCE: method involves reacting triethanol ammonium salts of o-cresoxyacetic and p-chloro-o-cresoxyacetic acid with the corresponding metal salt in alcohol or aqueous medium preferably at room temperature for 1-48 hours. The three-component complexes are extracted through solvent distillation with subsequent washing of the formed powder with ether and drying in a vacuum. The said complexes can be used as a base for making medicinal drugs.
EFFECT: design of a method of preparing complexes of o-cresoxy- and p-chloro-o-cresoxyacetic acid, triethanolamine and metals having formula n[R(o-CH3)-C6H3-OCH2COO-•N+H(CH2CH2OH)3]•MXm, where R = H, p-Cl; M = Mg, Ca, Mn, Co, Ni, Cu, Zn, Rh, Ag; X = CI, NO3, CH3COO; n = 1, 2; m = 1-3.
2 cl, 11 ex
SUBSTANCE: invention relates to catalysis and preparation of dicyclopentadiene metathesis polymerisation catalysts. The metathesis polymerisation catalyst has the formula: , where L is a substitute selected from the group: , , . Several methods of preparing the catalyst are disclosed. The method of preparing the catalyst having formula , where , , is characterised by that, a second generation Grubbs catalyst is reacted with N,N-dialkyl-(2-vinylbenzyl)amine or 4-(2-vinylbenzyl)morpholine in an inert atmosphere at 60-85°C in the presence of a solvent, where the dialkyl- is methylethyl- or methyl(2-methoxyethyl). The method of preparing the catalyst formula , where L is a substitute selected from the group: , , , , involves reacting a ruthenium triphenylphosphine complex with 1,1-diphenyl-2-propyn-1-ol in tetrahydrofuran at boiling point of the solvent in an inert atmosphere and then with tricyclohexylphosphine at room temperature in an inert atmosphere. The ruthenium indenylidene complex formed is extracted and then, successively in the same reactor, reacted with 1,3-bis-(2,4,6-trimethylphenyl)-2-trichloromethylimidazolidine and 2-(N,N-dialkylaminomethyl)styrene or 1-(2-vinylbenzyl)pyrrolidine or 4-(2-vinylbenzyl)morpholine in toluene while heating to 60-70°C in an inert atmosphere. The dialkyl- is diethyl-, methylethyl- or methyl(2-methoxyethyl)-. A dicyclopentadiene metathesis polymerisation method is disclosed, which involves polymerisation using the catalyst in paragraph 1 in molar ratio substrate: catalyst ranging from 70000:1 to 200000:1.
EFFECT: invention increases catalyst output and simplifies synthesis by reducing the number of steps, and also enables to obtain polydicyclopentadiene with good application properties.
4 cl, 1 tbl, 22 ex
SUBSTANCE: present invention relates to a novel organic silver complex containing silver, ammonium carbamate or ammonium carbonate of formula 2 AgnX, where X is oxygen, halogen, cyano, carbonate, nitrate, nitrite or sulphate etc, and to a method of preparing the said complex by reacting a silver compound with a corresponding carbamate or carbonate compound of ammonia.
EFFECT: complex is highly stable and can be used when making thin layers for making metallisation patterns or electrodes.
19 cl, 50 ex, 14 dwg