Agent possessing cytotoxic activity on human cancer cells in culture

FIELD: medicine.

SUBSTANCE: invention refers to cell biology. Dopamine and/or its synthetic analogues, particularly substituted 3,4-dihydro-2(1H)-pyrimidinthione is applied as a cytotoxic agent having an effect on human cancer cells in culture.

EFFECT: presented substances can find application in medicine as a base for developing dosage forms used for therapy of malignant growths.

5 dwg, 3 ex

 

The invention relates to the field of cell biology and Biophysics and can be used in pharmacology to develop anti-cancer tools.

It is known (TSB, http://bse.sci-lib.com/article 121178.html)that cytotoxic funds (cyto... and GK. statikós - can stop, stop) it is different according to the chemical structure of the drug substance that blocks cell division. Mechanisms of suppression of certain stages of cell division, these drugs are different. So, alkylating means (for example, embihin, cyclophosphamide) directly interact with DNA; antimetabolites inhibit the metabolism in the cell, entering into competition with normal metabolites, precursors of nucleic acids (antagonists of folic acid with methotrexate; purine - 6-mercaptopurine, tioguanin; pyrimidine - 5-fluorouracil, cytosine arabinoside). Some antitumour antibiotics (for example, hrysomallis, rubomycin) block the synthesis of nucleic acids and vegetable alkaloids (eg, vincristine) - the chromosomes during cell division. The final effect of cytostatic funds - selective suppression of dividing cells. The cytotoxic ability of the funds to suppress the proliferation of cells is primarily used in the chemotherapy of malignant tumors. However, antitumoral the funds affected and normal tissue. In addition, many anti-cancer drugs have toxic effects and may cause side effects, associated or not associated with the main mechanism of suppression of cell multiplication: nausea, vomiting, loss of appetite, diarrhea, decrease in the number of leukocytes, platelets and erythrocytes in the blood, disease, cardiovascular disorders, temporary hair loss, and others. In some cases, this limits the dosage or even makes to suspend or terminate treatment.

The closest to the technical nature of the claimed connection is jasplakinolide (jasplakinolide) (see Jasplakinolide An Actin-Specific Reagent that Promotes Actin Polymerization, Methods in Molecular Biology, 2001, Volume 161, Part III, 109-120) is a natural product extracted from marine sponges and having antifungal and anticancer activity. Jasplakinolide associated with the protein responsible for the stability of the cells and incorporated in the mechanism of cell division, which is promising for the development of new anticancer drugs.

However jasplakinolide enters the cell only after dissolution in ethanol or dimethyl sulfoxide and manifests ambiguous, often the opposite effect on the intracellular actin, which limits its use.

In this regard, the task of finding the funds, on the one hand, highly effective to combat Raco the diversified diseases, on the other hand, is not toxic for normal cells and for the whole of the organism.

Experimentally it was found that for this task perspective is a well - known substance dopamine.

Dopamine - 3,4-dioxygenation, oksitiramin, C6H3(OH)2CH2CH2(NH2), an intermediate product in the biosynthesis of catecholamine formed by the decarboxylation of dioksifenilalanina (Dov). A number of organs and tissues (liver, lungs, intestines, and others) contain predominantly dopamine. Along with adrenaline and noradrenaline dopamine in small amounts are secreted by the adrenal glands, which indicates a possible independent of hormonal function of dopamine. In the Central nervous system dopamine is contained mainly in the motor centers, performing the function of a mediator. Dopamine has several pharmacological properties characteristic of hormones and adrenergic agents. However, the possibility of its use as cytotoxic funds are not described.

The technical result achieved by the invention is the discovery of a new non-obvious properties of a known substance - dopamine and its synthetic analogue - substituted 3,4-dihydro-2(1H)-pyrimidinethione.

The technical result is achieved by staisfactory dopamine General formula C 6H3(OH)2CH2CH2(NH2) or its synthetic analogue - substituted 3,4-dihydro-2(1H)-pyrimidinethione (hereinafter pyrimidinium) are used as cytotoxic means against cancerous human cells in culture.

The invention is illustrated graphics, where

figure 1 presents the dependence of the formation of monolayer culture of cancer cells BALB/3T3 clone A31 and 3T3B-Sv40 from the period of incubation and the concentration of dopamine in the environment;

figure 2 - dependence of the formation of monolayer culture of cancer cells ner-2 to the time of incubation and concentration in the environment of dopamine;

figure 3 - the ultrastructure of cancer cells ner-2 after 3-day incubation with dopamine at a concentration of 2×10-4M, where A is the control cancer cell, a portion of the surface with democompany pin (KDP) and the cortical layer (CS); mitochondria (M); B-E - cancerous cells, subjected to the action of dopamine. B - panoramic view, visible moire patterns (M) and lizanie lacunae (L); plot cytosole in the depth of the cells at higher magnification, see numerous actin filaments (an)associated with lacunae (L); G-E - damage to the contacts of two adjacent cells with the fusion of part of the cytoplasm (SC) in the field democompany contacts (G), merge adjacent microvilli (MB) (D), a bypass of the two cells through plazmaticeski the membrane actin bridge (arrows). Scale: a - 1 μm; B-D - 0.5 µm; E - 0.1 ám;

figure 4 - cytochemical visualization of dopamine in the cell culture ner-2 in control and after exposure to dopamine and haloperidol, painted by the reaction Falk, And where control cells ner-2; B - cell ner-2+10 mm haloperidol + dopamine at a concentration of 10-3M - cells of the ner-2+10 mm haloperidol;

figure 5 - dependence of the formation of monolayer culture of cancer cells ner-2 to the time of incubation and concentration in the environment of pyrimidinethione.

Example 1. To study the cytotoxic effect of dopamine took a culture of the cells of BALB/3T3 clone A31 mouse embryos, which is the normal cells characterized by the differentiation of actin cytoskeleton, and the line of these cells 3T3B-SV40 infected with a pathogenic virus SV-40, with the result that they malignities characterized pathologically undifferentiated cytoskeleton. Investigated the effect of dopamine on these two cultures, linked by our common origin, but qualitatively different properties.

Cell cultures derived from the Russian cell culture collection (Institute of Cytology RAS, St. Petersburg), was cultured in 5 ml Petri dishes at 37°C and 5% CO2in a medium containing RPMI-1640 and DMEM in the ratio of 1:1 with the addition of 10% bovine serum and gentamicin (80 mg/ml) to ensure sterility. To the involved side effect oxidation of dopamine (Orion, Pharma, Finland) in culture medium was added antioxidant sodium metabisulfite at a concentration of 200 μm (Pedrosa, Soares-da-Siva, 2002).

To evaluate the action of dopamine at the dopamine cells were made into cell suspension simultaneously with the sowing (up to rasplastyvanija cells at the bottom of the Cup). Thus the final concentrations of dopamine were to 1.0×10-4M to 1.0×10-3M. cell Survival, which was made in the amount of 150,000 in 2 ml of medium (Petri dish), was evaluated at 40 hours after inoculation and the results are shown in figure 1, which presents the dependence of the formation of monolayer culture of cancer cells BALB/3T3 clone A31 and 3T3B-Sv40 from the period of incubation and the concentration in the environment of dopamine.

As can be seen from figure 1, the dopamine has on the cells the cytotoxic effect of proportionally increasing with increasing concentration of dopamine. It is seen that the number of control cells progressively increased, reaching over 40 hours maximum, 100%fill monolayer entire surface of the bottom of the Petri dishes. The cultivation of both clones of cells in a medium containing dopamine concentration of 1×10-4M, causes the weakening of their growth, stronger, two times, the culture of tumor cells 3T3B-SV40 than her normal prototype BALB/3T3 clone A31 (confluently was 40% and 80%, respectively). The effect on the cells of dopamine at a concentration of 1×10-3 M had an even greater negative effect. And in this case, the cytotoxic effect of dopamine on cell culture 3T3B-SV40 was more pronounced than the cells of BALB/3T3 clone A31. Survival of tumor cells after 40 hours, according to the values of confluently amounted to 2%, which is 5 times lower than that characteristic in the same conditions for normal cells (filling degree 20%). When compared with the control, the viability of normal cells fell 5 times, and tumor cells in 50 times, respectively.

Example 2. Investigated the influence of dopamine on the cells of cancer of the larynx ner-2, derived from the Russian cell culture collection (Institute of Cytology RAS, St. Petersburg).

Cells taken in the amount of 100000 2 ml of medium (Petri dish)were cultured in 5 ml Petri dishes at 37°C and 5% CO2in a medium containing RPMI-1640 and DMEM in the ratio of 1:1 with the addition of 10% bovine serum and gentamicin (80 mg/ml) to ensure sterility. To avoid the side effect of oxidation of dopamine (Orion Pharma, Finland) in culture medium was added antioxidant sodium metabisulfite at a concentration of 200 μm (Pedrosa, Soares-da-Siva, 2002).

For evaluating the effect of dopamine on the cells of cancer of the larynx ner-2 was introduced into the cell suspension simultaneously with the sowing (up to rasplastyvanija cells at the bottom of the Cup). Thus the final concentrations of dopamine were of 1.5×10-4M, and 1.6×10-4M to 2.0×10-4the, 5,0×10-4M to 1.0×10-3M and 5.0×10-3M cell Survival was evaluated at 3 days after sowing.

The dynamics of the cell culture was examined after 24 and 29 hours, 48 and 72 hours after seeding. The dependence of the formation of monolayer culture of cancer cells ner-2 to the time of incubation and concentration in the environment of dopamine presented in figure 2. As can be seen from figure 2 cell viability under the action of dopamine at a concentration of 2.0×10-4M compared with control taken as 100%, almost unchanged, at concentrations of dopamine 5,0×10-4M is reduced to 12%and at a concentration of 1.0×10-3M is reduced to 5.4%, that is, 8.3 and 18.5 times, respectively. When the concentration of dopamine to 2.0×10-4M 72 hours of cultivation, the culture was recovered and the density has reached the reference value, and at a concentration of 5.0×10-4M and 1×10-3M density sharply decreased almost to zero, which indicates massive cell death.

To study ultrastructural changes in cells under the action of dopamine was preparing drugs for microscopy, which were fixed and processed as follows (Moshkov D.A. "Adaptation and the structure of the neuron", M: Nauka. (1985): 200 pages).

Cells were washed from the culture medium and recorded, with the tabs (as aldehydes and osmaboy acid) was dissolved in 0.1 M cacodylate is the buffer (pH 7.4), this used a mixture of glutaraldehyde and paraform (formaldehyde). Then they were zafiksirovali in 1%solution of camerahouse OS on cacodylate buffer (pH 7.4) for 1 h Then the drugs were obezvozhivani in solutions of alcohols of increasing concentration and embedded in epoxy resin Epone-812 in the same vessels, which carried out the cultivation. Cells were examined directly in flooded monolayer in the light microscope NU-2E (Carl Zeiss)equipped with a digital camera the Nikon CoolPix 995, and in the electron microscope Tesia BS-500 after their ultra-thin cutting through ultratome EM UC6 (Leica). The results of microscopic studies of the ultrastructure presented on figure 3. Revealed details of the damage to the cells observed under a light microscope. As can be seen in the photographs (magnification X14000), the cytoplasm of control cells dense because of the many free ribosomes and large elongated mitochondria with dark electron-dense matrix. A characteristic feature of the control cells ner-2 (A) is very narrow cortical layer representing a congestion under the plasma membrane actin filaments along its profile, and the absence of deep in the cytoplasm of long actin filaments, indicating predominantly globular form of actin in the cytosol. It's not tipin is to spread cells, which are known to have powerful bundles of actin filaments in stress fibers (Fulton A. "the Cytoskeleton: Architecture and choreography cells", M.: Mir, 1987, 120 pages). The effects of dopamine significantly modifies the ultra-structure of cells ner-2. They are rounded, the surface is smoothed by the disappearance or merger of microvilli, profiles nuclei become tortuous, inside the cytoplasm are formed extensive transparent gaps, representing a specific region (B). Also in the cytoplasm are formed distinct moire patterns resulting from irregular condensation of actin filaments (B). It is essential that in cancer cells the formation of specific gaps and moire pattern associated with the appearance here of long actin filaments (B), which implies the involvement caused by dopamine polymerization of actin in the formation of these lesions. A more detailed study of ultrastructural changes in cells of the ner-2 showed that the fusion of adjacent cells to each other occurs in different ways. It is either the ingrowth of individual microvilli in the cytoplasm of neighboring cells are melting and loss of membranes in the contact zone, thus microforming becomes narrow cytoplasmic bridge between them (D). Or merger occurs in an area where desmosomal the output contacts, initially rich filamentous actin (D). Finally, revealed a single actin bridges between contacting cells (E), along which can also be pathological exchange of substrates.

Also explored cytochemical visualization of dopamine inside the cells ner-2. For this cell ner-2 were incubated in culture medium with dopamine at a concentration of 10-3M for 30 min and 5 h in Petri dishes at 37°C in an atmosphere of 95% O2and 5% CO2at the bottom of which was placed top of the glass to which the cells were attached during incubation. After incubation of the cells in the presence of dopamine unattached cells were besieged by centrifugation and the precipitate washed three times from dopamine by resuspending environment D. The washed cells were applied in the form of a smear on a glass slide and examined under a fluorescent microscope (AXIO Imager Zl (Carl Zeiss) at magnification X40). Cells adhered to the cover glass, studied directly on it, rinsing them three times by immersion in the environment D.

As control was used cells ner-2, incubated without dopamine. As a control to establish the effect of dopamine receptors penetration of dopamine inside the cells investigated cells pre-exposed to haloperidol - blocker of dopamine receptors, and cells, inquire the data in the presence of joint actions of haloperidol and dopamine. Haloperidol (drug injection) was used at a concentration of 10 μm. The concentration of haloperidol was expecting so that was guaranteed to blockade all of dopamine receptors with the maximum multiplication culture. Cytochemical reactions of biogenic amines was carried out according to the method of Falk (O. Lindvall Friday, February, Björklund, A., Falck Century, Svensson L.A. Letters to the editor: New principles for microspectrofluorometric differentiation between DOPA, dopamine and noradrenaline J Histochem Cytochem. 1975, V.23 supported, No. 9, p.697-699), which received the strokes and monolayers of cells were dried for 2 days. over concentrated sulfuric acid and heated to 80°C over paraformaldehyde. Isoquinolines formed during condensation of catecholamines and vapors, formaldehyde, visualized by fluorescence at 490-500 nm (λ=330, 375 nm) using a microscope AXIO Imager Z1 (Carl Zeiss, Germany). The results are presented in figure 4. As can be seen from figure 4, fluorescence microscopy of cells ner-2, used for visualization of dopamine in the cytosol detected by cytochemical reaction Falk, showed that the rate of catecholamines within cells there is little, as evidenced by the almost complete absence of luminescence (A). Incubation of cells in medium containing dopamine in combination with haloperidol, leads to an increase in the intensity of fluorescence throughout the cell volume, showing the content of dopamine in high concentrations in C is toplasma and nuclei (B). A high level of luminescence was not possible to distinguish between the illumination of the surface cells on the background of the cytoplasm. However, in the preparations of cells ner-2, subjected to the action of one of haloperidol (In)visible luminescence revealed exclusively at the periphery of the cells, in full accordance with the idea of the blockade of dopamine receptors located on the plasma membrane, through ligand interactions.

Example 3. Investigated the influence of dihydropyrimidinase - synthetic analogue of dopamine on the cells of cancer of the larynx ner-2.

Cells ner-2 was cultured in 5 ml Petri dishes at 37°C and 5% CO2in a medium containing RPMI-1640 and DMEM in the ratio of 1:1 with the addition of 10% bovine serum and gentamicin (80 mg/ml) to ensure sterility. Substituted 3,4-dihydro-2(1H)-pyrimidinethione (pyrimidinium), synthesized on the basis of dopamine and courtesy Professor, Ph.D. Astikyam (Omsk state University), was used in 100%solution of dimethyl sulfoxide at a concentration of 10-3Meters To measure the performance of pyrimidinethione cells ner-2 was introduced into the cell suspension simultaneously with the sowing (up to rasplastyvanija cells at the bottom of the Cup). Cell survival was assessed after 3 days after sowing. The dependence of the formation of monolayer culture of cancer cells ner-2 from the period of incubation and the concentration in the environment pyrimidine is presented in figure 5. As can be seen from figure 5, the effect of pyrimidinethione concentrations of 1.0×10-3M reduces cell viability to 31% or 3.2 times compared to control.

Examples 2, 3 show that cancer cells ner-2 exposed to the cytotoxic action of dopamine and pyrimidinethione, which increases with increasing concentration of these substances and the duration of cultivation (figure 2, 5). It is established that the greatest effect of dopamine, and also of pyrimidinethione its synthetic analogue of the morphological and functional effects on cells observed after 72 hours of incubation, with the introduction in the environment of metabisulfite did not affect cell viability ner-2. The viability of cells under the action of dopamine at a concentration of 2.0×10-4M compared with control taken as 100%, almost unchanged, at a concentration of 5.0×10-4M reduces it to 12%and at a concentration of 1.0×10-3M to 5.4%, that is, 8.3 and 18.5 times, respectively. To compare the effect of pyrimidinethione concentrations of 1.0×10-3M reduces cell viability to 31% or 3.2 times.

So these examples show that dopamine and pyrimidinium have a cytotoxic effect on cancer cells. The use of dopamine and pyrimidinedione as promises to be not only effective, but also selective. Predpolozhitelnomu associated with a primary sensitivity to dopamine primary malignant and metastatic cells, rich globular actin. In General, dopamine can be seen as penetrating the drug with polymerizes actin mechanism of action, similar to the already well-known substances with the same properties, bicycloheptane phalloidin (Wieland T., Faulstich x Phalloidin. In kN. "Results and prospects of development of Bioorganic chemistry and molecular biology. Moscow, "Nauka", 1978, p.98-110) and cyclodepsipeptide jasplakinolide (Holzinger A. "Jasplakinolide. An Actin-Specific Reagent that Promotes Actin Polymerization". In Cytoskeleton Methods and Protocols, Ray H. Gavin, ed., SpringerLink. 2001, v.161, pt.3, p.109-120). However, dopamine on action on cells is different from them. Phalloidin in a cage does not penetrate, it is injected (Cooper J.A. Effects of cytochalasin and phalloidin on actin. J. Cell Biol. 1987, v.105, No. 4, p.1473-1478). Jasplakinolide, and used as an antitumor drug (Takeuchi H., Ara G., Sausville E., Teicher Century Jasplakinolide: interaction with radiation and hyperthermia in human prostate carcinoma and Lewis lung carcinoma. Cancer Chemother. Pharmacol. 1998, v.42, №6, p.491-496), enters the cell only after dissolution in ethanol or dimethyl sulfoxide, which limits its use. At the same time, dopamine easily penetrates the cell that exhibits the same properties in vitro and in vivo and directly visualized in the cell, making it not only promising cytotoxic funds, but also for research in cell biology.

The use of dopamine and/or its synthetic analogues, in particular zameshannogo,4-dihydro-2(1H)-pyrimidinethione, as cytotoxic means against cancerous human cells in culture.



 

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20 cl, 7 dwg, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound of formula I where: R1 represents a group selected from among -CH2OH, -NH(CO)H while R2 represents a hydrogen atom or R1, together with R2, forms group -NH-C(O)-CH=CH- where the nitrogen atom is bonded to the carbon atom in the phenyl ring whereto R1 is bonded, the carbon atom bonded to the carbon atom in the phenyl ring whereto R2 is bonded; R3a and R3b are independently selected from the group consisting of hydrogen atoms and C1-4alkyl groups; X and Y are independently selected from the group consisting of an ordinary bond and an oxygen atom; n, m and q (each) independently have a value selected from among 0, 1, 2 and 3; p has a value selected from among 1, 2 and 3; R4 and R5 are independently selected from the group consisting of hydrogen atoms, a halogen atoms, C1-4alcoxy, -CONH2, -NHCONH2, -SR7, -SO2R7 where R7 represents C3-4cycloalkyl; R6 is selected from the group consisting of hydrogen atoms, a halogen atoms, C1-4 alkyl and C1-4alcoxy or its pharmaceutically acceptable salt or a stereoisomer thereof. Additionally, the invention relates to a pharmaceutical composition based on the compound with formula I and to a method for β2-adrenergic receptor activity modulation.

EFFECT: produced are new 4-(2-amino-1-hydroxiethyl) phenol derivatives possessing the activity of β2-adrenergic receptor antagonists.

22 cl, 32 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically a pharmaceutical gel exhibiting antimicrobial and antifungal action. The presented gel contains as active ingredients betamethasone dipropionate (0.01-0.3 wt %), gentamycin sulphate (0.02-0.6 wt %) and terbinafine hydrochloride (0.8-5.0 wt %), and as excipients - propylene glycol (10.0-40.0 wt %), UV filter Escalol 567 (1.0-40.0 wt %), cyclomethicone DC 345 (5.0-20.0 wt %), organosilicone emulsifier DC 5329 - (1.0-4.0 wt %), organosilicone elastomer DC 9045 (5.0-50.0 wt %), antioxidant Tinogard NOA (0.02-0.1 wt %), acrylate emulsion of copolymer Salcare SC80 (1.0-3.5 wt %), trometamol (1.0-2.5 wt %), preservative Sharomix MCI (0.1-0.5 wt %), purified water (to 100.0 wt %).

EFFECT: due to said composition of excipients the invention provides skin protection against ultra-violet radiation and improved penetration of active ingredients in derma.

3 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry and discloses a pharmaceutical composition containing phenylephrine in a prolonged release dosage form, either alone, or in a combination with another active ingredient, such as an antihistamine, an analgesic, a febrifuge, a non-steroid anti-inflammatory drug or a mixture of two or more other active ingredients. In a preferential version of the invention, the composition contains a solid dosage form with hydroxypropyl methylcellulose and sodium-carboxymethyl cellulose as a prolonged release phenylephrine matrix. Phenylephrine is released from the solid dosage form during a long period of time, substantially irrespectively of pH.

EFFECT: development of the pharmaceutical composition containing phenylephrine in the prolonged release dosage form.

18 cl, 1 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely anaesthesiology and resuscitation, and orthopaedic surgery. A method involves complex pre-, intra- and prolonged postoperative drug-induced prevention which is implemented by the following scheme: preoperative drug-induced prevention by the introduction of the anticonvulsant preparation gabapentin or pregabalin 3-5 days before the operation, in the day of operation and for 6 postoperative months in decreasing doses; premedication 1 hour before anaesthesia by the intramuscular introduction of the glucocorticoid dexamethasone, intraoperative prevention by the introduction of the preparation kininogenesis inhibitor aprotinin (contrical) for the anaesthesia and to the end of the operative day in certain doses, and a NMDA receptor antagonist - ketamine for the anaesthesia and the operation, and for 2-3 postoperative days in certain doses, therapy with the antidepressant amitriptyline in decreasing doses from the first postoperative day for 2 months with additional graduated intra- and postoperative epidural anaesthesia for 5-7 postoperative days by infusion of 0.2% ropivacaine (naropin).

EFFECT: method completely prevents developing phantom pain syndrome, related physical suffering and psychological stress, relieves invalid's adaptation to life and social useful activity.

3 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, and concerns a composition for treating attention deficit hyperactivity disorder, which contains L-lysine-d-amphetamine dimesylate, microcrystalline cellulose, croscarmellose sodium and magnesium stearate. The invention also concerns a method of treating attention deficit hyperactivity disorder in a subject including aged 6-12 years old, with using the offered compositions.

EFFECT: invention provides the compositions effective to reduce the probability or to prevent misuse of amphetamine and overdose of amphetamine.

18 cl, 50 dwg, 72 tbl, 37 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly pulmonology, laboratory diagnostics and immunology, and can be used for treating bronchial asthma. That is ensured by evaluating a bronchial asthma control level by GINA 2006 criteria and a related therapeutic stage; additionally, patient's peripheral blood is examined for CD 25+ antigen expressed on an membrane of activated lymphocytes by indirect immunofluorescence test, and if the CD 25+ cell level is 11 or more, then the combined therapy with iGCS and long-acting β2-antagonist is recommended.

EFFECT: method ensured bronchial asthma control ensured by reflected effectiveness of the basic anti-inflammatory therapy.

1 ex, 1 tbl

Purification method // 2444511

FIELD: chemistry.

SUBSTANCE: present invention relates to versions of a method of purifying terbinafine from nonmetallic impurities, primarily a substance A of formula

, as well as to use of said methods to obtain purified terbinafine. One of the versions of the method involves molecular distillation of crude terbinafine in form of a free base and extraction the obtained purified terbinafine in form of a free base or acid-addition salt (method A). In another version (method B), crude terbinafine in form a free base undergoes molecular distillation combined with formation of a salt of the obtained product with simultaneous deposition of a purified trans-isomer, and the obtained highly pure terbinafine is extracted in form of a free base or acid addition salt.

EFFECT: method enables to obtain terbinafine containing less than approximately 5 ppm of substance A.

13 cl, 2 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly ophthalmology, and concerns prevention of myopia progression. That is ensured by using lenses, accommodation exercises, instillations of 2.5% irifrin in both eyes at bedtime for 4 weeks. Additionally, there are assessed a vegetative regulation type of the nervous system by A.M. Wein's technique, calculating a Kerdo index, evaluating a vegetative responsiveness by a zone exposure method by evaluating an Aschner-Dagnini eyeball-heart reflex and a celiac-plexus reflex, examining a psychological status by Eysenck and Taylor techniques. If observing vegetative nervous system dysfunction syndrome, the Kerdo index exceeding 0, the sympathetic vegetative responsiveness, the emotional instability level exceeding 7 points, trait anxiety exceeding 5 points, the therapy is added with grandaxin 100 a day twice over in the morning and in the afternoon for 4 weeks twice a year.

EFFECT: method enhances main parameters of the accommodative function both in vagotonic and normotonic patients, and in sympatotonic patients, reliably provides higher visual acuity.

1 tbl, 1 ex

FIELD: drugs.

SUBSTANCE: invention relates to drugs and complexes for the treatment killing the pain comprising the following components: (a) (1K, 2K.) -3 - (3 'dimethylamin-1-ethyl-2-methylpropyl)-phenol of formula (G) or its acid addition salt and (b) paracetamol. There were also disclosed a pharmaceutical composition and dosage form containing the specified combination, a method of killing pain for mammals, and the combination for the drug manufacture for the killing of pain.

EFFECT: proposed group of inventions provides a synergistic effect in the killing of pain.

13 cl, 1 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

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