Ketothiphen optically active isomers and their therapeutically active metabolites

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising S-isomer of compound of the formula (I) or its pharmaceutically acceptable salts and solvates in common with a pharmaceutically acceptable vehicle. Also, invention relates to a method for synthesis of compound S-isomer of the formula (I), and to a method for treatment of disease relating to the group comprising respiratory diseases, allergic diseases, dermatological diseases, gastroenteric diseases and ophthalmic diseases. The composition provides avoiding adverse sedative effects in treatment of indicated diseases.

EFFECT: valuable medicinal properties of compounds.

14 cl, 6 ex

 

The invention relates to a method of treatment of inflammatory and allergic diseases using norketamine, 10-hydroxy-ketotifen, 10-hydroxy-norketamine or optical active isomers ketotifen, norketamine, 10-hydroxy-ketotifen or 10-hydroxy-norketamine, or their pharmaceutically acceptable salts and solvate. More specifically, the present invention relates to methods for treating pulmonary diseases (such as asthma, bronchitis), skin diseases (such as urticaria and atopic dermatitis), gastrointestinal disorders (such as stomach irritation and enteritis) without sedative side effects and side effects affecting the cardiovascular system associated with the introduction of antihistamine drugs. Another variant implementation of the invention based on the discovery of the fact that normative and optically active isomers of norketamine are especially effective for the treatment of eye diseases such as conjunctivitis and keratitis.

Prior art

The present invention relates, in particular, to anti-inflammatory and antiallergic compounds that can be used to treat various diseases, particularly in patients suffering from pulmonary diseases, including asthma and bronchitis; skin diseases, VK is UCA urticaria and atopic dermatitis; and gastrointestinal disorders, including stomach irritation and enteritis.

The compounds described in this invention are metabolites of ketotifen (4-(1-methyl-4-piperidinyl)-4H-benzo(4,5)-cyclohepta-(1,2-b)thiophene-10-he). Due to severe sedative side effects associated with ketotifen, this connection has limited therapeutic use.

Ketotifen undergoes metabolism in the body in different ways:

Metabolite norketamine (also called normativism) is formed by demethylation of ketotifen:

Metabolites 10-hydroxy-ketotifen and 10-hydroxy-norketamine formed by recovery molecules ketotifen and norketamine, respectively.

Other metabolites ketotifen also formed in the body after administration of ketotifen. Thus, the molecule ketotifen may be N-glucuronidation and can turn into a N-oxide ketotifen. Received gidroksilirovanii isomers can then be subjected to metabolism with the formation of 10-hydroxy-glucuronidation. Can be formed and also other metabolites, and various types of road metabolism is different and may even be different in children and adults.

Not there is akih any known published pharmacological studies of racemates or of the isomers of ketotifen, 10-hydroxy-ketotifen or 10-hydroxy-norketamine. Pharmacological properties of the isomers ketotifen have been described Polivka et al.: 4H-benzo(4,5)cyclohepta(1,2-b)thiophenes and 9,10-dihydro derivatives-sulfonium analogues of pizotifen and ketotifen; chirality of ketotifen; synthesis of the 2-bromo derivative of ketotifen. Collect.Czech.Chem. Commun., 1989, 54, 2443-2469.

Brief description of the invention

Isomers ketotifen were synthesized and pharmacologically investigated in vitro and in vivo. Have also been synthesized and pharmacologically investigated various metabolites ketotifen. It was found that the antihistamine effect of racemic norketamine qualitatively similar antihistamine action racemic ketotifen. Thus, as ketotifen, and normative are antagonists of histamine H-1, with varying degrees of antagonism to histamine H-2. However, unexpectedly it was found that between the racemic ketotifen and compounds described in the present invention, there is an important and highly qualitative difference: these compounds do have a strong and DataGridView sedative activity of ketotifen. It was also found that racemic of normative, and in particular its isomer, possess strong anti-inflammatory and antihistamine properties, and they have a slight sedative effect or no such effect. Similarly, it was also obnarujeno, although both isomers ketotifen have the same antihistamine activity, but almost all of these sedative side effects inherent in R(+)-ketotifen. It was also found that the metabolites 10-hydroxy-norketamine and 10-hydroxy-ketotifen and isomers of both compounds inhibit inflammation and block the receptors of histamine H-1, while putting much less sedative effect than ketotifen.

Detailed description of the invention

Chemical synthesis of ketotifen, norketamine, 10-hydroxy-ketotifen and 10-hydroxy-norketamine, their stereochemical isomeric forms and diastereomers.

Racemic ketotifen and normativen be made by methods described by Waldvogel et al. (Helv.Chim.Acta, 59, 866-877, 1976), which is incorporated into this description by reference. R-(+)-ketotifen and S-(-)-ketotifen obtained by fractionated crystallization of salts racemic ketotifen with (-)-O,O'-di-(p-toluoyl)-R-tartaric acid and (+)-O',O-di(p-toluoyl)-S-tartaric acid, respectively, as described in the work Polivka et al. (Collect.Czech.Chem.Commun., 54, 2443-2469, 1989), which is introduced in the present description by reference.

The preferred method of obtaining optically active isomers of norketamine, 10-hydroxycytidine and 10-hydroxy-norketamine based on individual R - and S-enantiomers of ketotifen. Declared a new method for the synthesis of ketotifen, the cat is which avoids the use of harsh conditions, described Waldvogel and others, 1976, which can lead to racemization of the specified product. Other ways are stereoselective synthesis using chiral matrices, the separation of the corresponding racemates by standard methods, such as fractional crystallization of the diastereomeric salts with chiral acids, chromatography using a chiral media.

10-Hydroxy are obtained by catalytic reduction of the corresponding enantiomers ketotifen methods described Waldvogel et al., 1976. It should be noted that the 10-hydroxy-ketotifen have an additional chiral center, and what were the resulting diastereomers of the corresponding R - and S-enantiomers of ketotifen. These enantiomers can be separated by standard methods crystallization or chromatography, which is due to differences in solubility and chromatographic mobility of the diastereomeric isomers. Alternatively, the recovery of R - and S-enantiomers ketotifen chiral reducing agents can be carried out to obtain only the desired diastereomeric product (or highly enriched mixtures).

Determination of the absolute configurations

The enantiomers of ketotifen and norketamine have no asymmetric carbon atoms, which are typical for optical isomers. More precisely, specify the s enantiomers are formed in the result of molecular asymmetry, due to the difficulty vzaimoprevrascheny semichasnoho rings. (+)-Ketotifen is denoted by R and has the configuration observed in the x-ray crystal structure of (+)-ketotifen, (-)-O,O'-di(p-toluyl)-R-tartrate described Polivka and others, 1989. (-)-Ketotifen marked S.

The derivatives of 10-hydroxycytidine there is an additional chiral centre is a 10-carbon atom, and R - and S-configurations are determined in accordance with the standard rules of stereochemistry. In the name of diastereomers resulting from the recovery of enantiomers of ketotifen, the first letters R and S indicate the configuration semichasnoho ring, and the second letter R or S configuration means 10-carbon atom.

Synthesis of (R)- and (S)-norketamine and fumarate (R)- and (S)-norketamine

(These methods of synthesis are systematized in the diagrams).

(R)-4-(1-(2,2,2-Trichlorocyanuric)-4-piperidylidene)-9,10-dihydro-4H-benzo-(4,5)-cyclohepta(1,2-b)thiophene-10-he.

Anhydrous sodium carbonate (95,0 mg, 898 mmol), (+)-(R)-ketotifen (278 mg, 898 mmol) and chloride of benzyltriethylammonium (VTEUS) (205 mg, 898 mmol) were combined in a dry flask and placed in a high vacuum for two days. To the mixture was added freshly distilled dichloromethane (2 ml) in an atmosphere of N2 at room temperature and under stirring, and then was added 2,2,2-trihloretilamina (556 μl, 4.04 mmol). Two-phase react the mixture was boiled under reflux for one hour and after cooling to room temperature was suppressed by adding a saturated aqueous solution of sodium carbonate (7 ml). The resulting mixture was diluted with dichloromethane (50 ml) and the organic phase was separated, dried over sodium sulfate, filtered, evaporated and chromatographically (SiO2the mixture ethyl acetate-petroleum ether,). Fractions corresponding to the intermediate trichloromethylcarbonate, collected, evaporated, and placed in a high vacuum with getting 279 mg, 66% specified in the connection header.

1H NMR (400 MHz, CDCl3) δ 7,58 (s, 1H), 7,37-7,30 (m, 1H), 7.23 percent-7,19 (m, 2H), 7.18 in-7,11 (m, 1H), 7.03 is-7,00 (m, 1H), 4,88-4,69 (m, 2H), 4,20 (d, 1H, J=13,0 Hz), a 4.03-a-3.84 (m, 2H), 3,78 (d, 1H, J=13,0 Hz), 3,35-to 3.09 (m, 2H), 2,75-of 2.64 (m, 1H), 2,62-to 2.57 (m, 1H), 2,50-2,39 (m, 2H).

(R)-4-(4-Piperidylidene)-9,10-dihydro-4H-benzo-(4,5)-cyclopent(1,2-b)thiophene-10-he ((R)-normative).

Cadmium dust (178 mg, of 1.59 mmol) and 10% of a mixture of cadmium/lead (356 mg, 3,174 mmol) was added to the intensively stirred mixture of trichloromethylcarbonate (279 mg, 592 mmol) in THF (5.5 ml) and aqueous ammonium acetate (1 M, 3.0 ml) in nitrogen atmosphere. After 2 hours the mixture was filtered through celite and washed with a large amount of dichloromethane and water. The filtrate was podslushivaet saturated aqueous sodium carbonate and the organic layer was separated, dried over sodium sulfate, filtered and evaporated to obtain the crude (R)-norketamine (157 mg, 90%).

1H NMR (400 MHz, CDCl3) δ rate of 7.54 (d, 1H, J=5,2 Hz), 7,34-7,29 (m, 1H), 7.23 percent-7,13 (m, 3H), 7,02 (d, 1H, J=5,2 Hz), 4,20 (d, 1H,J=13,6 Hz), 3,76 (m, 1H, J=13,6 Hz), 3,21-3,14 (m, 1H), 3,13 was 3.05 (m, 1H), 2,86 was 2.76 (m, 1H), 2,75-of 2.58 (m, 3H), 2,47-2,39 (m, 2H).

Enantiomeric purity was determined by analytical chiral HPLC (5 μm, Merck Chiradex, the mobile phase a mixture of sodium phosphate-acetonitrile, 95:5, pH 4.0, flow rate 1 ml/min, the speed of movement of the chart paper of 0.3 cm/min, 254 nm): Rt 13,0 min, 95% EE

SCHEME

Synthesis fumarata (R)-norketamine ia (+)-(R)-ketotifen

Synthesis fumarata (S)-norketamine of (-)-(S)-ketotifen

Fumarate (R)-norketamine.

The crude (R)-normative (157 mg, 533 μmol) was dissolved in dichloromethane (1 ml) was added to a solution of fumaric acid (61,8 mg, 533 μmol) in ethanol (2 ml). After evaporation of 50% of the solvent crystals fumarata (R)-norketamine collected and washed with ethanol, and then, after drying in high vacuum, received 117 mg of product.

1H NMR (DMSO-d6) δ 7,99(m, 1H), 7,40-7,31 (m, 1H), 7,30-7,11 (m, 4H), to 6.43 (s, 2H), 4,35 (d, 1H, J=13,2 Hz), the 3.65 (d, 1H, J=13,2 Hz), 3.25 to is 3.08 (m, 2H), 2,99-2,89 (m, 1H), 2,83-to 2.74 (m, 1H), 2,70-of 2.54 (m, 2H), 2,50-2,40 (m, 1H), 2,38-of 2.28 (m, 1H).

Enantiomeric purity was determined by analytical chiral HPLC (5 μm, Merck Chiradex, the mobile phase a mixture of sodium phosphate-acetonitrile, 95:5, pH 4.0, flow rate 1 ml/min, the speed of movement of the chart paper of 0.3 cm/min, 254 nm): Rt13,0 min, 95% EE

(S)-4-(1-(2,2,2-trial methoxycarbonyl)-4-piperidylidene)-9,10-dihydro-4H-benzo-(4,5)-cyclohepta(1,2-b)-thiophene-10-he.

In accordance with the procedure described above for (R)-enantiomer was obtained (S)-enantiomer with the same output:

1H NMR (400 MHz, CDCl3) δ 7,58 (s, 1H), 7,37-7,30 (m, 1H), 7.23 percent-7,19 (m, 2H), 7.18 in-7,11 (m, 1H), 7.03 is-7,00 (m, 1H), 4,88-4,69 (m, 2H), 4,20 (d, 1H, J=13,0 Hz), a 4.03-a-3.84 (m, 2H), 3,78 (d, 1H, J=13,0 Hz), 3,35-to 3.09 (m, 2H), 2,75-of 2.64 (m, 1H), 2,62-to 2.57 (m, 1H), 2,50-2,39 (m, 2H).

(S)-4-(4-piperidylidene)-9,10-dihydro-4H-benzo-(4,5)-cyclohepta-(1,2-b)thiophene-10-he.

In accordance with the procedure described above for (R)-enantiomer was obtained (S)-enantiomer with the same output:

1H NMR (400 MHz, CDCl3) δ rate of 7.54 (d, 1H, J=5,2 Hz), 7,34-7,29 (m, 1H), 7.23 percent-7,13 (m, 3H), 7,02 (d, 1H, J=5,2 Hz), 4,20 (d, 1H, J=13,6 Hz), 3,76 (m, 1H, J=13,6 Hz), 3,21-3,14 (m, 1H), 3,13 was 3.05 (m, 1H), 2,86 was 2.76 (m, 1H), 2,75-of 2.58 (m, 3H), 2,47-2,39 (m, 2H).

Enantiomeric purity was determined by analytical chiral HPLC (5 μm, Merck Chiradex, the mobile phase a mixture of sodium phosphate-acetonitrile, 95:5, pH 4.0, flow rate 1 ml/min, the speed of movement of the chart paper of 0.3 cm/min, 254 nm): Rt7,5 min, 95% EE

Fumarate (S)-norketamine.

In accordance with the procedure described above for (R)-enantiomer was obtained (S)-enantiomer with the same output:

1H NMR (400 MHz, DMSO-d6) δ 7,99 (m, 1H), 7,40-7,31 (m, 1H), 7,30-7,11 (m, 4H), to 6.43 (s, 2H), 4,35 (d, 1H, J=13,2 Hz), the 3.65 (d, 1H, J=13,2 Hz), 3.25 to is 3.08 (m, 2H), 2,99-2,89 (m, 1H), 2,83-to 2.74 (m, 1H), 2,70-of 2.54 (m, 2H), 2,50-2,40 (m, 1H), 2,38-of 2.28 (m, 1H).

Enantiomeric purity was determined using the Ana is eticheskoi chiral HPLC (5 μm, Merck Chiradex, the mobile phase a mixture of sodium phosphate-acetonitrile, 95:5, pH 4.0, flow rate 1 ml/min, the speed of movement of the chart paper of 0.3 cm/min, 254 nm): Rt7,5 min, 95% EE

Pharmacological studies ketotifen, norketamine, 10-HE-ketotifen or 10-HE-norketamine and their optically active isomers

As discussed above, it was shown that the S-isomer of ketotifen and racemates and isomeric forms norketamine, 10-HE-ketotifen or 10-HE-norketamine have favorable pharmacological properties, which can be used to treat diseases such as, for example, allergic diseases, lung diseases, skin diseases and gastrointestinal disorders, but they do not have significant sedative side effects of ketotifen. Were installed unexpected facts that are described in the following examples.

Test method 1. Linking gistaminergicheskie receptors

The affinity of racemic and isomeric tested compounds against the histamine receptor Hi assessed using analysis of binding3H-pyrilamine as described Dini et al. (Agents and Actions, 1991, 33: 181-184). For this membrane, obtained from the cerebellum of Guinea pigs, incubated with3H-pyrilamine and with various concentrations of the test(s) connection(s). Specific binding of radio is active ligand to the receptor was determined in the presence of excess its ligand. The results were expressed as percentage of specific binding in the presence of compounds. The value of the IC50(concentration required for 50%inhibition of specific binding) and hill coefficients (nH) were determined using nonlinear regression analysis of the curve of competitive binding. These parameters were derived from the curve according to the hill equation using the software Sigmaplot™.

Test method 2. Antihistamine effects in vitro

Strips bronchial tissue or tissue other smooth muscle was dissected from the body of male Guinea pigs weighing 400-600, These tissues are suspended in the oxidized buffer having the composition (mm): NaCl, 133; KCl, 4,7; CaCl2, 2,5; MgSO4, 0,6; NaH2PO4, 1,3; NaHCO3, 16,3; and glucose, 7,7, or in solution with the same composition. This solution was maintained at 37,5°C. Reduction was recorded using isometric transducers (Model FT-10) on a grass polygraph.

To assess the viability of each tissue and to use it as a reference system was first registered reduction of each strip of fabric in response to exposure of the oxidized buffer, in which NaCl was replaced by KCl to obtain the concentration 137,7 mm KCl. Then back to the standard oxidized buffer, and then processed growing in the relevant progress and concentrations of histamine, moreover, a separate treatment of each concentration was carried out until then, until it is registered with the maximum response. Then, leaving one strip of tissue untreated, each of the remaining strips of fabric were treated for a predetermined time interval by a single concentration of antagonist. Finally, responses to increasing concentrations of histamine with subsequent processing 137,7 mm KCl were recorded a second time.

Test method 3. Binding to muscarinic receptors

These experiments were performed on membranes derived from SF9 cells infected with baculovirus for the expression of subtypes of human recombinant muscarinic receptor. After incubation with the test material and the corresponding radioligand and after washing was determined associated radioactivity in a liquid scintillation counter using commercially available scintillation mixture. Specific binding of radioligand with each receptor was determined as the difference between total binding and nonspecific binding determined in the presence of excess its ligand. The value of the IC50(concentration required for 50%inhibition of specific binding) were determined using nonlinear regression analysis of the curve to nkuringo binding.

Test method 4. Inhibition of bronchial accumulation of eosinophils

Inhibition of the accumulation of eosinophils in the lungs were determined in sensitized Guinea pigs (400-600 g) after intraperitoneal injection of allergen, such as, for example, PAF (factor platelet aggregation) or bovine serum albumin. After a predefined period of time the animals were killed by injection of the barbiturate. The trachea was removed and annulirovano. Then successively introduced 6×10 ml aliquot of modified buffered solution of Tyrode (composition: NaHCO3, 11,9; NaCl, 136,9; KCl 2.7; The Na2HPO4, 0,4; glucose, 5.6 and EDTA 19,8; gelatin, 0.1% wt./about; pH 7.4) and was aspirated by gentle squeezing of the lungs. The total discharge of fluid generally exceeded 80%. Cell suspension was concentrated by centrifugation at low speed (200 G for 10 minutes) and the cell sediment resuspendable in 1 ml of modified mortar Tirade. The total number of cells was determined by diluting 10 ál of cell suspension in 90 µl of liquid Tarka. Leukocyte counts were determined from smears fixed in methanol (100%) and stained with the dye of Leishman. The total number of at least 500 cells per stroke was calculated at 1000-fold increase for the differentiation of cell types. Drugs were injected in viceprocesorovem subcutaneous infusion from an implanted Minnesota Alza (Alzet 2001 or equivalent) or by repeated oral or repeated parenteral injection.

Test method 5. Anti-inflammatory effect on the skin

Anti-inflammatory effect on the skin was tested by the method of induction of inflammation by applying a cretonne easy oil on the ears of mice. This test method described Tarrida J. et al., Meth. Find.Exp.Clin.Pharmacol., (1996) 18(4):233-234 and Blazzo et al., Prostaglandins, (1995) 50:161-168. Briefly, male mice (25-30 g) was treated with 5 ml/kg 2 mg/ml solution of each test compound in saline by intraperitoneal injection. Thirty minutes after injection in both ears of each mouse topically applied Croton oil (0,20 μl of 1.0% Croton oil in acetone or acetone (control). During the application of Croton oil or acetone animals were fixed, and then they were released and put it in a cage. Before the application of Croton oil or acetone, and at a pre-determined period of time after their application groups of animals were anestesiologi the halothane gas and subjected to euthanasia by displacement of the cervical vertebrae. The ears were removed and weighed. Then build a graph of average weight ear from time to time. Just, every time, tested 4 animals for each connection and control of the media.

Test method 6. Studies on sedative side effects

In the studies of the present invention uses a test on physostigmine-induced death. This t is article is a modified analysis on sedative effect, described by VILLANI et al., in U.S. patent No. 4659716. Briefly, physostigmine (1.9 mg/kg s.c.) in his introduction mice, divided into groups of 10 animals in each plastic cage (11 cm × 26 cm × 13 cm)in 90-100% of cases resulted in a fatal outcome. The mouse, which before the introduction of physostigmine was administered a sedative, such as, for example, sedative antihistamine, were protected from death and survived. In these studies, test compounds were administered orally 60 minutes before administration of physostigmine. The number of surviving individuals was counted after 30 minutes after administration of physostigmine.

The pharmaceutical composition

The terms "pharmaceutically acceptable salts or its pharmaceutically acceptable salt" means a salt or solvate obtained from pharmaceutically acceptable non-toxic acids. Suitable pharmaceutically acceptable acid additive salts of the compounds of the present invention are salts of acetic acid, benzosulfimide (besylate), benzoic, camphorsulfonic, lemon, econsultancy, fumaric, gluconic, glutamic, Hydrobromic, chloride-hydrogen, isetionate, lactic, maleic, malic, almond, methansulfonate, mucus, nitrogen, pambou, Pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluensulfonate acids and the like, Especially preferred is fumarate.

The present invention relates to pharmaceutical compositions containing one or more compounds of the present invention together with one or more pharmaceutically acceptable carriers. These pharmaceutical compositions may be specially prepared for oral administration, instillation in a conjunctiva, sublingual administration, parenteral administration, intradermal administration, rectal administration, transbukkalno injection or local administration, or for administration by inhalation or insufflation powder or aerosol.

The pharmaceutical compositions of the present invention can be administered to the human or other mammal oral, sublingual, parenteral, subcutaneous, transcutaneous, rectal, transbukkalno, topically, by instillation into the conjunctiva or in the form of oral or intranasal spray or aerosol. The term "parenteral" introduction means intravenous, intraarterial, intramuscular, intraperitoneal, intradermal, subcutaneous, or intra-articular injection or infusion. The term "cutaneous" refers to the use of various devices ("patches" and the like)that can facilitate or modify the transport or absorption of drugs through the skin. The term "local" refers to coating compositions containing medicinal cf is the rotary, on the skin and mucous membranes.

Forms for oral administration

The pharmaceutical compositions of the present invention for oral administration of solid dosage forms are capsules, granules, pills, powders and tablets. In these solid dosage forms, the active compound may be mixed with one or more pharmaceutical excipients or carriers (for example, sodium citrate, calcium diphosphate), fillers or additives, which give the volume (for example, starch, lactose, sucrose, glucose, mannitol, silicic acid), binders (for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, Arabic gum), humectants (e.g. glycerin), agents that slow dissolution (e.g., paraffin), leavening agents (for example, agar-agar, calcium carbonate, starch, alginic acid, silicates, sodium carbonate), absorption accelerators (for example, Quaternary ammonium compounds), wetting agents (for example, etilovym alcohol, glycerol monostearate), absorbents (for example, kaolin, bentonite), sizing (for example, talc, calcium stearate, magnesium stearate, polyethylene glycols, lauryl sulfate) and/or sautereau agents.

Solid forms such as capsules,pills, granules, pills and tablets can be coated and/or shell (for example, intersolubility cover), known in the art. These compositions can also be prepared so that the active(s) ingredient(s) would be released in certain parts of the gastrointestinal tract by controlled release, delayed release or sustained release.

These compositions can also be prepared so that was performed lymphatic absorption of the active ingredient(s).

The specified active compound(I) can also be microencapsulation with one or more of the foregoing fillers.

Liquid dosage forms for oral administration are pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. The liquid dosage form may also contain well-known diluents (e.g., water, other solvents, solubilizing agents), emulsifiers (for example, ethanol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, butyleneglycol, dimethylformamide, oils, oleic acid, glycerine, glycols, esters sorbitan and fatty acids and mixtures thereof).

Besides inert diluents, the oral compositions can also include duvante, such as wetting agents, emulsifiers, suspendresume agents, sweetening agents or flavoring agents.

Suspensions can contain one or more suspendida agents known to experts in the pharmaceutical field.

Forms for local introduction

Compositions for topical administration of the compounds of the present invention are solutions, suspensions, drops, sprays, ointments, creams and powders. Compositions intended for application to the skin, may contain stimulants permeability and other agents known in the art. For application to the skin can also be used plasters, bandages, etc.

In addition to therapeutically active ingredients of the composition of the present invention for topical administration, including various preparations for local ophthalmic injection, may also include various ingredients of drugs, such as antimicrobial preservatives and agents, regulatory isotonicity. Examples of suitable antimicrobial preservatives are benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenethyl alcohol, dimitriades, sorbic acid, ONAMER M and other agents known in the art. These preservatives, when used, can be introduced in amounts of from 0.001 to 1.0 wt.%. Examples of suitable AG is now, which can be used to make this composition isotonicity or osmolarity are sodium chloride, potassium chloride, mannitol, dextrose, glycerin and propylene glycol. These agents, when used, can be introduced in amounts of from 0.1% to 10.0 % by weight (wt.%). These compositions preferably are water and have a pH in the range from 3.5 to 8.0.

Obviously for each expert, the composition can be manufactured in a variety of dosage forms suitable for local ophthalmic delivery, including solutions, suspensions, emulsions, gels and biodegradable solid ophthalmic strip.

Parenteral form for introduction

Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, emulsions, and sterile powders for the preparation of sterile injectable solutions or dispersions prior to use. Can be used in a variety of aqueous or anhydrous carriers, diluents, solvents and carriers (for example, water, ethanol, glycerin, glycol), vegetable oils (e.g. olive oil) and organic esters (for example, etiloleat) or mixtures thereof. Fluidity can be maintained with the use of a coating such as lecithin, by limiting the size of the particles and with the use of surface-active substances.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersing agents, antibacterial agents, antifungal agents, agents, giving isotonicity and/or agents that slow down the absorption. Effects of prolonged absorption or slow absorption can be achieved by injection of crystalline or amorphous suspensions with low solubility. Delayed absorption can also be achieved by dissolution or suspension of the specified drug in an oil carrier, or through the use of injectable demoform (for example, microencapsulating matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, polyarteritis, polyanhydride) or use different types of liposomes or microemulsions containing a drug. Compositions for injection may be sterilized by various methods.

Maintenance by inhalation

Compounds of the present invention, for example, normative, can be introduced by inhalation, which may be the preferred route of administration for some patients, for example patients suffering which their asthma. Can be used in various devices for inhalation, such as, for example, inhalers with a metering valve, a device for spraying a dry powder or aerosol inhalers, known to specialists.

Forms for rectal injection

Compositions for rectal administration, preferably, are suppositories.

Forms for buccal injection

Compositions for buccal injection, preferably, are toothpastes, liquid for rinsing the mouth, preparations for sublingual administration, chewing gum, etc.

Forms for sublingual introduction

Can be used in a variety glenavy drugs, namely concentrated solutions or suspensions of drugs that can be entered sublingual with various drip devices for spraying medicines on the mucous membranes of the mouth can be used in a variety of aerosol devices; and for the quick delivery of the full dose can also be used specially designed tablets, capsules or powders rapid dissolution.

Form for intradermal injection

Compositions for percutaneous introduction of the compounds of the present invention are various known plasters, bandages, etc.

Aerosol drug or drops for oral (buccal) or intra who analnogo introduction

Compositions for oral or intranasal sprays or drops can be prepared in the form of solutions, suspensions or dry powders and can be developed for intranasal, transbukkalno, bronchial/pulmonary and/or gastrointestinal absorption of the drug.

Therapeutic doses

Since the compounds of the present invention does not have a strong and DataGridView sedative side effects of ketotifen, they can be introduced in higher doses than typically used doses of ketotifen.

The actual dose of active ingredients in the pharmaceutical compositions of the present invention can be varied to achieve the desired therapeutic effect. Thus, the number of drugs can vary depending on such factors as the form of administration, disease severity, frequency, dose, etc. For administration as a drug to patients suffering from mild disorders of the respiratory tract or bronchial disorders (such as asthma, bronchitis and the like), oral dose of the compounds of the present invention is administered in amounts from 0.5 mg to about 200 mg, and preferably from 1 mg to 20 mg, one to four times daily based on patient weight of 60 kg, the Daily dose may be uvelichenie reduced according to from various factors, such as the weight and seriousness of the disease of the patient.

Examples of the use of drugs for the treatment of patients suffering from seasonal allergic conditions such as allergic rhinitis, is the introduction of oral doses of the compounds of the present invention in quantities of from 0.1 mg to about 100 mg, and preferably from 1 mg to 20 mg, one to four times daily based on patient weight of 60 kg For patients suffering from seasonal allergic conjunctivitis, the concentration of the solution containing the compounds of the present invention for instillation in into the conjunctival SAC, may be from 0.01% to 4.0%, and preferably from 0.02% to 2.0%, the active ingredient. Patients suffering from asthma, the compounds of the present invention is administered in the form of an oral dose of from 2 mg to 100 mg, and preferably from 2 mg to 20 mg, one to four times daily based on patient weight of 60 kg, the Frequency of administration and the number of doses can be determined by a medical practitioner with regard to various clinical factors, such as, for example, the body weight of the patient and the severity of the disease. Ophthalmic application typically provides local introduction of one or two drops (or a certain amount of solid or semi-solid dosage forms) in the affected eye one to four times per day. Skin note the work usually involves the application of skin creams, containing from 0.1% to 10.0% of the compound of the present invention.

Oral pharmaceutical composition

Examples of manufacturing tablets

Ingredientspillsa lot of 10,000 tablets
Normativen3 mg30 g
Microcrystalline cellulose30 mg300 g
Lactose70 mg700 g
Calcium stearate2 mg20 g
Lac FD&C Blue #10.03 mg300 mg

Active ingredient (in the example above compound is racemic of normative) is mixed with lactose and cellulose to form a homogeneous mixture. Then add the paint and mix again. And finally mixed with calcium stearate and the resulting mixture is pressed into tablets using a 9/32-inch (7 mm) PLANO-concave stamp. Tablets with different concentrations of drugs can be obtained by changing the ratio of active ingredient to the number of fillers or to the final weight of the tablet. In addition to the ingredients specified in this example, the desired composition for oral administration can contain other or to anitelea ingredients described above under "Forms for oral administration".

Therapeutic indications

Compounds of the present invention can be used for various therapeutic indications, including such statements, which can be used ketotifen. Compounds of the present invention possess pharmacological action similar to that of ketotifen, but the compounds of the present invention are not significant and datagridviews sedative side effects of starting compound (ketotifen), which is used for therapeutic purposes.

The present invention relates to a method of treatment and/or prevention of all forms of allergic disorders, including, but not limited to, allergic rhinitis, polyvalent Allergy, skin and eye allergies. These methods include the introduction to the mammal of a medicinal product according to the present invention either in the form of a single isomer or as a mixture of isomers, or pharmaceutically acceptable salt or MES.

The present invention also relates to methods of treatment and/or prevention of bronchial and pulmonary diseases, including, but not limited to, asthma, bronchitis, bronchial Hyper-reactivity, cough and chronic obstructive pulmonary disease (COPD). These methods include in the introduction to the mammal drugs of the present invention either in the form of a single isomer, either in the form of mixtures of isomers, or pharmaceutically acceptable salt or MES.

The present invention also relates to methods of treatment and/or prevention of skin diseases, including, but not limited to, atopic dermatitis, urticaria, other types of itching or inflammatory conditions, and psoriasis. These methods include the introduction of the mammal drugs of the present invention either in the form of a single isomer or as a mixture of isomers, or pharmaceutically acceptable salt or MES.

The present invention relates to a method of treatment and/or prevention of some forms of eye diseases such as conjunctivitis, keratitis, blepharitis, episcleritis, scleritis, anterior uveitis, posterior uveitis, endophthalmitis, optic neuritis, cranial Takayasu, sympathetic ophthalmia in mammals, such as man, where these methods allow you to avoid irritation of the eyes, as well as sedative and other toxic effects of ketotifen and steroids. These methods include the introduction to the mammal of a medicinal product according to the present invention either in the form of a single isomer or as a mixture of isomers, or pharmaceutically acceptable salt or MES.

The present invention relates to a method of treatment and/or prevention of certain Faure the gastro-intestinal diseases, such as, for example, syndromes of hyperactivity or hypersecretion, including the syndrome of Zollinger-Ellison, irritation of the stomach, enteritis, gastric ulcer or duodenal ulcer, hyperchlorhydria, heartburn, motility disorders, gastric reflux or unwanted secretion of gastric juice. These methods include the introduction of the mammal drugs of the present invention either in the form of a single isomer or as a mixture of isomers, or pharmaceutically acceptable salt or MES.

Joint introduction

The present invention also relates to methods of introducing one or more compounds of the present invention together with adrenergic agonists, including, but not limited to, albuterol, terbutaline, fenoterol, formoterol or salmeterol, which helps to eliminate or reduce side effects that may be induced by the specified therapy with beta-agonists.

The present invention also relates to methods of joint introduction of one or more compounds of the present invention with agents or drugs that cause bronchial Hyper-reactivity, including, but not limited to, agents that block adrenergic beta-receptors or inhibitors of cyclooxygenase, which helps to eliminate or reduce the build bronchial Hyper-reactivity, induced specified therapy. The present invention also relates to methods of joint introduction of one or more compounds of the present invention at least one of the drugs of the following classes: agents that reduce eye pressure, adrenergic antagonists, antibiotic agents, antiviral agents, steroids, cyclo-oxygenase inhibitors, leukotriene antagonists, inhibitors of lipoxygenase, local anaesthetics and ophthalmic therapeutic drugs. The present invention also relates to the joint introduction of the compounds of the present invention with anti means, such as, for example, phenylephedrine, nafazolina, tetrahydrozoline, or with antibacterial agents such as bacitracin, neomycin and polymyxin.

Equivalents

Many equivalents described herein specific embodiments of the invention are obvious or can be received by each specialist only through routine experimentation. Such equivalents are therapeutic use of one isomer and compositions containing the specified(e) isomer(s), not with(f) side effects, inherent to the respective(them) isomer(s) or source connection (ketotifen) or its isomer. Such equivalents I have are also many pharmaceutically acceptable salt forms, for example, sulfate, hydrobromide, hydrochloride, dihydrochloride, methansulfonate, fumarata, hydroxynaphthoate, or, if possible, one or the other of the hydrated forms of these salts, see Merck Index llth edition (1989) items 9089, 209, 3927, 4628, 8223, 5053, 5836, 8142, 2347, 7765, 1840, 9720, 7461, 1317, 4159 and 963, and cited in their work, and Am.Rev.Resp.Dis. 1988, 137: (4;2/2) 32. Equivalents is administered together with at least one compound of the present invention with any other drug used for the treatment of diseases in mammals, referred to in this document. For each health practitioner it is obvious that it may also be preferable to use higher or lower doses than those indicated in the present description, and these doses can be introduced with greater or lesser frequency than the frequency specified in the present description.

Professionals, pharmacologists known that bronchial Hyper-reactivity is usually observed in patients suffering from various pulmonary disorders, such as asthma. In addition, experts also know that bronchial Hyper-reactivity can be induced by drugs, such as, for example, agonists adrenergic beta-receptors.

Compounds of the present invention, with certain farmakologicheskogodeystviya (such as inhibiting activity, aimed at different types of histamine receptors, PHAT-antagonistic activity, the impact on (nitric oxide)-synthase activity, stabilizing mast cells and the like) can be used for other indications than those specified in this application. These indications are equivalents described herein specific embodiments of the invention.

The use of a single isomer of the compounds of the present invention avoids the side effects inherent to the corresponding diastereoisomer. Such side effects can be, for example, side effects acting on the cardiovascular system, such as, for example, heart failure and cardiac arrhythmia, side effects acting on the gastrointestinal tract, such as stomach irritation or side effects acting on the Central nervous system, such as, for example, sedation or drowsiness. All equivalents are included in the scope of the present invention.

1. The pharmaceutical composition does not have sedative side effect, containing an S-isomer of compounds of the structure

where R represents H,

or its pharmaceutically acceptable salt and solvate together with a pharmaceutically acceptable carrier.

2. The method of synthesis Stereogum the Cesky active compound according to claim 1, including the interaction of the stereochemical isomer of ketotifen with 2,2,2-trichlorethylphosphate in the presence of benzyltriethylammonium chloride to obtain 1-(2,2,2-trichlorocyanuric)-Nord-intermediate with subsequent Cd/Pb-catalyzed cleavage to stereochemical active compound according to claim 1 and the allocation of the specified connection.

3. The method of treatment of a disease selected from the group including respiratory diseases, allergic diseases, skin diseases, gastrointestinal diseases and eye diseases, which comprises the administration to a mammal in need of such treatment, a therapeutically effective amount of a compound selected from the group comprising S-isomer of norketamine and S-isomer ketotifen, or their pharmaceutically acceptable salt and solvate, avoiding sedative side effects, limiting the dose of racemic ketotifen.

4. The method according to claim 3, where the specified respiratory disease selected from the group comprising chronic obstructive pulmonary disease (COPD), bronchial asthma, cough, bronchitis and bronchial Hyper-reactivity.

5. The method according to claim 3, where the specified allergic disease selected from the group including allergic rhinitis, urticaria, allergic conjunctivitis and allergic keratitis.

6. The method according to claim 3, the de specified skin disease selected from the group including atopic dermatitis, urticaria, other types of itching or inflammatory conditions, and psoriasis.

7. The method according to claim 3, where the specified gastrointestinal disorder selected from the group comprising a syndrome of hypersecretion, including the syndrome of Zollinger-Ellison, irritation of the stomach, enteritis, gastric ulcer or duodenal ulcer, gastric reflux, hyperchlorhydria, motility disorders and heartburn.

8. The method according to claim 3, where the specified eye disease selected from the group including conjunctivitis, keratitis, blepharitis, episcleritis, scleritis, uveitis, neuritis, Takayasu and sympathetic ophthalmia.

9. The method according to claim 3, where the specified therapeutically active compound or its pharmaceutically acceptable salt or MES is administered through inhalation or intranasal insufflation or by parenteral, local, dermal, intradermal, rectal, sublingual, co or oral administration.

10. The method according to claim 3, where the specified therapeutically active compound or its pharmaceutically acceptable salt or MES administered orally.

11. The method according to claim 3, where the specified therapeutically active compound or its pharmaceutically acceptable salt or MES administered orally in the form of a composition sustained release.

12. The method according to claim 3, where the specified therapeutically active with the unity imposed in the amount of from about 0.5 mg to 200 mg one to four times per day.

13. The method according to claim 3, where the solid, semi-solid, liquid, suspension or aerosol pharmaceutical composition or the pharmaceutical composition of local or transcutaneous applications containing a therapeutically effective amount of a therapeutically active compound or its pharmaceutically acceptable salt or MES, is administered in combination with a pharmaceutically acceptable carrier or carriers.

14. The method according to claim 3, where the specified S-isomer of norketamine and S-isomer of ketotifen or their pharmaceutically acceptable salt and MES are administered together with one or more drugs of the class, including antagonists of adrenergic receptors, analgesics, antihypertensive agents, calcium antagonists, antihistamines, anticholinergic agents, antibacterial agents, antiviral agents, anti-inflammatory agents, bronchodilators, anti-inflammatory agents, steroids, leukotriene antagonists, inhibitors of lipoxygenase, local anesthetic agents, vasoconstrictor tools, vasodilator, anti-cough and expectorants.

Priority signs:

US 60/153566 from 13.09.1999 - refers to the racemic metabolites ketotifen covers of racemic normative;. US 60/197905 from 15.04.2000 - refers to R-norketamine;. US 60/197363 from 15.04.2000 - assigns the I to the S-norketamine; . US 60/197906 from 15.04.2000 - refers to R-ketotifen;. US 60/197985 from 15.04.2000 - refers to S-ketotifen.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

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

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

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

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

The invention relates to a method for producing a condensed 2-getreleasedate General formula

using the diamine of General formula

where A=

R=2-furyl, 2-thienyl, 2-(1-methyl)pyrrolyl, 3-(1-methyl)indolyl, and aldehydes in the presence of acetate or copper sulfate, characterized in that the interaction takes place by boiling in 50% acetic acid, followed by decomposition of the copper salt, the effect on its suspension in 50% acetic acid sodium thiosulfate in 100With

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to organic chemistry and pharmacology, namely a mixture of isomers of the potassium salt of 2-[5(6)-nitro-1-(titanyl-3)benzimidazolyl-2-thio] acetic acid in a molar ratio of 1:3, manifesting cardiotonic activity

The invention relates to organic chemistry and medicine, in particular to a new connection - 5(6)-nitro-1-(1,1-dissociator-3)-2-chlorobenzimidazole formula I, showing inflammatory and bronchodilatory activity

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

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

9 cl, 5 sch, 36 tbl, 70 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with applying antihistamine preparation named mebhydrolin. It is suggested to apply pharmaceutical composition that includes therapeutically efficient quantity of mebhydrolin and target additives as sugar, starch, polyvinyl pyrrolidone and salt of stearic acid. Pharmaceutical composition is designed in tableted form. The innovation provides correspondence of mebhydrolin tablets against all the standards of State pharmacopoeia XI, decreased quantity of additional substances and expiry period of 3 yr, not less.

EFFECT: higher efficiency of application.

5 cl, 3 ex, 2 tbl

FIELD: medicine, allergology, toxins, pharmacy.

SUBSTANCE: invention relates to recombinant allergens of insect venom and to specific methods for their preparing, in particular, antigen 5 of wasp venom allergen. Recombinant antigen 5 is prepared in bacterial cells as insoluble aggregates followed by their denaturation and transfer to a soluble monomeric allergen. Transfer is carried out by dialysis using acid buffer solution (pH = 3.5-6.5) that can comprise guanidine hydrochloride, or by using a cysteine-containing solvent. Based on describes methods the practically pure recombinant antigen 5 of wasp venom allergen is isolated and used in pharmaceutical composition for hyposensibilization of body to wasp venom allergen. Invention provides preparing protein with reduced reaction capability JgE owing to it can be used in immunotherapy in treatment of allergy.

EFFECT: improved preparing method, valuable properties of allergen.

8 cl, 1 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to benzimidazole derivatives or their salts useful in medicine of the general formula (1): wherein R1 and R2 can comprise similar or different values and represent independently of one another hydrogen atom, halogen atom, cyano-group, hydroxyl group, alkyl group comprising 1-4 carbon atoms, alkoxy-group comprising 1-4 carbon atoms, trifluoromethyl group; A represents unsubstituted, linear alkylene group comprising 1-7 carbon atoms; E represents group -COOR3 comprising 1-6 carbon atoms; G represents unsubstituted, linear alkylene group comprising 1-6 carbon atoms; M represents a simple bond or -S(O)m- wherein m represents a whole number in the range 0, 1 or 2; J represents substituted or unsubstituted heterocyclic group comprising 4-10 carbon atoms and one heteroatom in ring taken among the group consisting of nitrogen atom or sulfur atom excluding unsubstituted pyridine ring; a substitute in indicated aromatic heterocyclic group is taken among halogen atom, cyano-group, linear alkyl group comprising 1-6 carbon atoms, linear alkoxy-group comprising 1-6 carbon atoms, trifluoromethyl group and trifluoromethoxy-group wherein one or more indicated substituted can be replaced by random positions in ring; X represents methane group (-CH=). Also, invention relates to a pharmaceutical composition used in inhibition of human chymase activity based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for prophylaxis and/or treatment of inflammatory disease, cardiovascular disease, allergic disease, respiratory disease or osseous either cartilaginous metabolic disease.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 3 tbl, 20 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, allergology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for treatment of patient suffering with allergic disease. Method involves administration to patient the therapeutically effective dose of pharmaceutical composition comprising compound of the formula (I)

. The compound elicits high effectiveness in treatment of allergy and shows low toxicity also.

EFFECT: improved method for treatment.

9 cl, 2 tbl, 2 dwg, 40 ex

FIELD: pharmaceutical industry.

SUBSTANCE: composition contains steroid as active principle, in particular 11-β,16-α,17-α,21-tetrahydroxy-9-α-fluoro-1,4-pregnadiene-3,20-dione or pharmaceutically acceptable salt thereof and special-destination additives including microcrystalline cellulose, crospovidone, and magnesium stearate.

EFFECT: optimized bioavailability, increased storage stability, and improved organoleptic properties.

3 cl, 1 tbl

Antiallergic drug // 2253451

FIELD: pharmaceutical industry.

SUBSTANCE: drug composition includes antihistamine agent as active principle, in particular 1-(p-chlorophenyl)-1-(pyrid-2-yl)-3-N,N-dimethylpropylamine or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carrier including microcrystalline cellulose, lactose, crospovidone, and magnesium stearate.

EFFECT: optimized bioavailability, increased storage stability, and improved organoleptic properties.

6 cl, 5 ex

FIELD: medicine.

SUBSTANCE: method involves introducing autologic mesenchyma trunk cells as a single intravenous drop dose or in the amount of 1 mln cells per 1 kg of patient body weight.

EFFECT: provided stable clinical remission.

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new aminobenzophenones of the formula (I):

or their pharmaceutically acceptable salts. These compounds elicit properties of inhibitors of cytokines secretion, in particular, 1β-interleukin (IL-1β) and tumor necrosis α-factor (TNF-α) and to secretion of polymorphonuclear superoxide that are useful for treatment of inflammatory diseases, for example, skin diseases, such as psoriasis, atopic dermatitis. In the formula (I) R1 is taken among the group consisting of halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, cyano-group, carbamoyl, phenyl or nitro-group under condition that when R1 means a single substitute then it at ortho-position, and when R1 means more one substitute then at least one substitute of R1 is at ortho-position; R2 means one substitute at ortho-position being indicated substitute is taken among the group consisting of (C1-C3)-alkyl, (C1-C3)-alkoxy-group; R3 means hydrogen, halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, phenyl, cyano-, carboxy-group or carbamoyl; R4 means hydrogen atom or (C1-C3)-alkyl; Q means a bond or -SO2-; Y means (C1-C15)-alkyl, (C3-C10)-carbocyclic group or phenyl being each of them can be substituted optionally with one or some similar or different substitutes designated by the formula R5; R5 means halogen atom, (C1-C4)-alkyl, amino-, (C1-C3)-alkoxy-group, (C1-C3)-alkoxycarbonyl or -COOH; X means oxygen or sulfur atom. Also, invention relates to a pharmaceutical composition and to a method for treatment and/or prophylaxis of inflammatory diseases.

EFFECT: valuable medicinal properties of compounds and composition.

9 cl, 2 sch, 2 tbl, 29 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

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