2-nitroheterylthiocyanates for treating fungal infections, pharmaceutical composition for local application

FIELD: chemistry.

SUBSTANCE: invention relates to use of 2-nitroheterylthiocyanates, particularly 4-rhodano-5-nitropyrimidine and 2-rhodano-3-nitripyridine derivatives of general formula (I), optionally in crystalline form or in form of pharmaceutically acceptable addition salts thereof with acids or bases, having activity on fungal strains, fungal infection agents, for producing pharmaceutical compositions that are suitable for local application. The compounds are also active on strains that are resistant to existing drugs. In general formula (I) X=N or C-R3, R1 denotes a proton, a saturated or unsaturated linear alkoxy radical having 1-5 carbon atoms; a cycloalkyloxy radical having up to 6 carbon atoms; a saturated linear alkylmercapto radical having 1-3 carbon atoms; an amino radical having 1-10 carbon atoms, selected from a saturated or unsaturated linear mono- or dialkylamino radical or a cycloalkylamino radical, cyclic amino radical. Each of the cyclic groups can be substituted with 1-2 methyl groups, or a benzylamino group; R2 denotes a proton, a saturated or unsaturated linear alkyl radical having 1-5 carbon atoms, or a cyclic aliphatic radical having up to 6 carbon atoms, trifluoromethyl, styryl or methylmercapto group; R3 denotes a trifluoromethyl, formyl, acetyl, nitro, benzoyl, cyano group or an alkoxycarbonyl substitute having 1-3 carbon atoms in the alkoxy group.

EFFECT: improved properties of compounds.

5 cl, 3 tbl, 21 ex

 

The invention relates to the use of 2-nitromethylene, such as derivatives of 4-thiocyano-5-nitropyrimidine and 2-thiocyano-3-nitropyridine corresponding to General formula (I)below, with activity against fungal infections, for prevention and treatment of fungal infections of humans and animals using local method of application.

Various microorganisms, including bacteria and numerous microscopic fungi that form part of the usual ecological habitat of humans and animals, in addition to the use can cause various diseases. The causative agents of mycotic diseases recognized about four hundred species of pathogenic fungi, of which one hundred and stand out the most often.

Pathogenic fungi cause various diseases in humans and animals, especially of great importance are causative agents of dermatomycosis causing diseases of the skin, hair and nails: conditionally-pathogenic fungi that cause human disease only under certain conditions, activate their pathogenic properties with reduced immunity, cause diseases such as candidiasis, aspergillosis, and others. For example, this disease is a dysfunction or disorder of the structure of the nail, caused for example by onychomycosis. The latter is constantly who is alausa and resistant to late stage treatment of fungal infection of the nails. Bacteria such as Staphylococcus or yeast, can cause bacterial infection is paronychia (inflammation okolonogtevogo tissue), that is a superficial infection of the nail fold.

Marked increase in the share of fungal complications in the overall statistics for the structure of infectious diseases.

The factors predisposing to the development of fungal infections include: environmental degradation; increasing the number of oncological and hematological diseases; an increase in the number of patients suffering from diabetes; irrational use of hormonal preparations; irrational use of antibiotics; pregnancy; old age; alcohol dependence.

Mycosis gained great relevance in connection with the widespread use of powerful antibiotics, immunosuppression, malnutrition, environmental degradation. In recent years significantly increased the incidence of ringworm, especially in elderly and senile age. Moreover, fungal diseases of the skin are more common in patients with somatic and endocrine diseases, as well as in persons with impaired peripheral circulation. The treatment of fungal infections is complicated by the fact that these diseases often have a protracted course and prone to relapses.

Treatment of fungal infections such as onychomycosis, basically divided into three categories: a) systemic introduction of antifungal agents, b) surgical removal of the entire nail or part followed by local treatment of the open tissue or in the local application on the infected nail creams, lotions, gels or solutions, often using bandages to commit the specified dosage forms on the nails.

When the system mainly orally administered antifungal agent for the treatment requires long-term treatment (6 months or more), as well as the introduction of high doses (200-400 mg/day) antifungal agent. When surgical removal of the entire nail hands or feet, or part thereof, which is painful, you need to bandage the whole finger hands or feet, resulting in an undesirable appearance. The lack of local medicinal forms, such as gels, creams, solutions, lotions, lacquers and the like, is that the pharmaceutically active agent is not sufficiently close contact with the affected area.

Correct comprehensive treatment with antimycotic drugs with different mechanism and spectrum, is one of the major problems associated with fungal human pathology.

The mechanism of action of most antifungal agents associated with effects on key enzymes that affect the biosynthesis of ergosterol, which is part of the membrane CL is current mushroom, however, the level of impact varies, as different spectrum of antimycotic drugs and their bioavailability. The shape of the product for local use of medicinal antifungal agents may be different.

In the patent RU 2358748 A2 describes compositions for topical application, restore the structure of the nail, using herbaceous plants of the genus Equisetum together with one tool for education films and their application as a drug for topical application to the nails as nail Polish, cream, gel, lotion or foam. These compositions can be used for application in water-soluble medium for the formation of film as an additive in the product for local use for nail art. These compositions can be used to treat such specific damage to the structure of the nail, as reduced strength, animosity and brittle nails.

In the patent US 5464610 A describes a method of obtaining a sample of the patch with the use of salicylic acid or its salt, ester or mixtures thereof. The above sample patch attached to the carrier and contains salicylic acid, the content of which in the patch is from 10 to 80%, based on the mass of the sample.

In the patent US 5993790 A claimed composition of nail Polish local actions, including nail Polish water-based conser is ant, urea and natural Supplement. Mentioned composition of nail Polish suitable for the treatment of fungal, yeast and bacterial infections of the nail and the nail bed.

In the patent US 5753256 described A patch for the treatment of nail mycosis, and the patch includes a flexible protective film, a layer of matrix on the basis of acrylate polymer, which is firmly attached to the above-mentioned protective film and which includes an active compound selected from the group: miconazole, econazole, isoconazole, tioconazole, terconazole, oxiconazole, ketoconazole, Itraconazole, tolciclate, Albertin, haloprogin, griseofulvin, ciclopirox, terbinafine and salts of these compounds.

In the patent RU 2289570 (13) C2 describes the possibility of using Terbinafine, which is an effective antifungal agent, the local application. The specified connection is effective against a wide spectrum of fungal diseases, including fungal sinusitus infections and onychomycosis. Most preferably it is used to fight against dermatophytes, contagious fungi that infect the dead skin tissue or derivatives of the skin, such as the corneal layer, nails and hair.

In the patent RU 2337689 describes a tool for the treatment of superficial mycoses, which contains an antifungal ingredient - ketoconazole; emulsion media, including Amul gatory, castor oil, water, additives target stabilizer and preservative. The tool is made in the form of aerosol liniment.

In EN 2011106753 A describes how the introduction of topical antifungal agents for the treatment of fungal diseases such as onychomycosis. The method includes the local administration to the patient aqueous pharmaceutical preparation containing terbinafine, or its pharmaceutically acceptable salt, a phospholipid and a surfactant. The pharmaceutical preparation may be a cream, lotion, ointment, gel, solution, spray solution, lacquer or film-forming solution.

The present invention was to find new derivatives of heterocyclic compounds that possess high activity against fungal infections, including strains resistant to existing drugs (N.Berila, J.Subik., Epidemiol Mikrobiol Imunol. 2010, 59(2), 67-79; R.Di Santo, Nat. Prod. Rep., 2010, 27(7), 1084-98; R.Musiol, M.Serda, S.Hensel-Bielowka, J.Polanski. Curr. Med. Chem. 2010,17(18), 1960-73).

The result of this task was the synthesis of a series of derivatives of 4-thiocyano-5-nitropyrimidine and 2-thiocyano-3-nitropyridine, containing in its composition orthonormality fragment corresponding to General formula (I). Investigated for their activity against pathogenic fungal infections order to create the new antifungal drug.

The invention relates to the use of the new compounds of General formula (I):

where X=N or C-R3

R1 denotes a proton, saturated or not saturated linear alkoxy radical having 2-5 carbon atoms; cycloalkane radical having up to 6 carbon atoms; a saturated linear allylmercaptan radical having 1-3 carbon atoms; amino radical having 1-10 carbon atoms, selected from saturated or not saturated linear mono - or dialkylamino radical or cycloalkenyl radical, a cyclic amino radical, each of the cyclic groups may be substituted by 1-2 metal groups; or benzylamino;

R2 denotes a proton, saturated or not saturated, linear alkylaryl having 1-5 carbon atoms, or cyclic aliphatic radical having up to 6 carbon atoms, trifluoromethyl, styryl or methylmercapto;

R3 denotes trifluoromethyl, formyl, acetyl, nitro, benzoyl, cyano or alkoxycarbonyl Deputy having 1-3 carbon atoms in alkoxygroup possessing antifungal activity against strains of fungi, pathogens of fungal infections, for local usage.

Compounds of the present invention also possess antifungal activity against fungal strains resistant to existing us Aasee time medicines.

Compounds of General formula (I) are mostly new and have never been known for their receipt or use to a specified destination.

In General structural formula along with the new compounds also included several known compounds: 4-isopropyl-amino-5-nitro-6-tizanidin (Demina G.R. et al, PLoS One, 2009, 4(12), 8174), 4-asokan-5-nitro-6-tizanidin (CA # 847188-01-6), 2-methylthio-4-methoxy-5-nitro-6-thiocyano-pyrimidine (US 2007/0270433), 4-methoxy-5-nitro-6-thiocyano-pyrimidine (EN 2312104 C1), 2-thiocyanato-3-nitropyridine (Ulrich H. Sci. Synth., 202, 11, 835), 4-thiocyanato-5-nitropyrimidin and 2-ethylmercaptan-4-thiocyanato-5-nitropyrimidin (Takahashi N., Torizo I. Che. Phar. Bull., 1958, 6, 334) and 3,5-dinitro-2-tizanidin (Z. Talik, Plazek E. Bulletin de Academie Polonaise des Sciences, Serie des Sciences Chimiques, 1960, 8(5), 219). However, the use of these compounds to a specified destination not previously been known.

Compounds represented by the General formula (I)capable of forming additive salts with acids. Salts with pharmaceutically active non-toxic acid can be formed by treating compound in the form of bases represented by the General formula (I), the appropriate acid selected from inorganic acids, for example: kaleidotrope acid, hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric or phosphoric acid; organic acids, for example: the criminal code is usnei acid, hydroxyoctanoic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, maleic and fumaric acids, malic, tartaric or citric acid.

Compounds represented by the General formula (I)containing an acidic proton may also be converted into their pharmaceutically active salt additive form with bases by treatment with appropriate organic and inorganic bases. Suitable salt forms include, for example, ammonium salts, salts of alkali and alkaline earth metals, in particular, salts of sodium, potassium, magnesium and calcium, salts with organic bases, for example, guanidine, triethylamine and salts with amino acids, e.g. arginine or lysine.

Used in the context of this invention, the term "additive salt" includes various solvate, which is able to form compounds of General formula (I). The compounds may be in amorphous form or in the form of crystals.

The invention also relates to a pharmaceutical composition having anti-fungal activity for local usage. The composition comprises as an active ingredient a compound of General formula (I) or its pharmaceutically acceptable additive salt with acid or base, in a pharmacologically effective if the este, as well as pharmaceutically acceptable carrier and adjuvants.

The pharmaceutical composition according to the present invention is made in a form suitable for local use. Examples of such forms can be creams, ointments, pastes, lotions, lipsticks, gels, liniments, plasters, shampoos, emulsions, etc.

Used compounds of the present invention can be used in crystalline form.

The object of the invention is a method of treating or preventing a fungal infection in a human or animal, comprising local administration to a patient compounds of formula (I) or its pharmaceutically acceptable salts, or pharmaceutical compositions specified above in an effective amount in a form suitable for local use.

These forms, as described above, can be creams, ointments, pastes, lotions, lipsticks, gels, liniments, plasters, shampoos, emulsions, etc.

The term "effective amount" means an amount of active ingredient, which when administered to patients provides prevention, reduction or elimination of symptoms of the diseases to be prevented or treated.

Compounds or their pharmaceutically acceptable salts, pharmaceutical composition in the form of ointments and creams and other ready-made forms for external PR the application can be used for the treatment and prevention of diseases or disorders in humans and animals, caused by strains of pathogens fungal infections (mycoses), including those resistant to current drugs.

Introduction compounds of formula (I) or their pharmaceutically acceptable salts, pharmaceutical compositions or drugs based on them in the treatment or prevention of human or animal can be carried out by conventional methods in the form of a form suitable for external use, for example, in the form of ointments, creams, pastes, lotions, nail Polish and liniments, placed in the package or patch.

As pharmaceutically acceptable excipients in the form of pharmaceutical compositions according to the invention can be any pharmaceutically acceptable components that are compatible with the active ingredient, do not harm patients and traditionally used for the preparation of dosage forms. These include, for example, fillers, binding agents, plasticizing agents, such as camphor, triphenyl or pentenyl diisobutyrate, diisobutylphthalate and others, pigments, solubilizing agents, stabilizers, diluents, adjuvants, preservatives, buffer components systems, solvents, dispersing agents, preservatives, thickeners, dyes, emulsifiers, film-forming substances, such as Hydra is xitil or propylethylene, hydroxypropiophenone, prolongator, substances that improve the penetration of drugs, for example, benzyl alcohol, etc.

Pharmaceutically acceptable excipients are, for example, gum Arabic, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, ester of fatty acids and of sorbitol, sodium lauryl sulphate, glycerin, glycerin fatty acid ester, lanolin, glycoregulation, Polysorbate, macrogol, vegetable oil, wax, paraffin, propylene glycol, polyethylene glycol, water, ethanol, polyalcohol, polyoxyethylenesorbitan castor oil, sodium chloride, sodium hydroxide, hydrochloric acid, dibasic sodium phosphate, monotony sodium phosphate, citric acid, glutamic acid, benzyl alcohol, methyl p-oxybenzoic, ethyl p-oxybenzoic and other

Soljubilizatory help to increase the solubility of sparingly soluble substances in water. With their help it is possible to adjust the viscosity of the solution, to produce products in other forms (liquid instead of solid), to develop new formulations, to improve the quality of cosmetics. As solubilization you can use any appropriate and compatible soljubilizatory usually use what has been created in the cosmetic industry for shampoos, shower gels, foam baths for creams, lotions, type oil/water co-emulsifiers for emulsion. These include, for example, derivatives of glycerides, Polysorbate 80, ethoxylated hydrogenated castor oil, paglierani oils, such as castor oil or paglierani hydrogenated castor oil and water or propylene glycol.

Composition for topical application may also contain as an additive vegetable oil, such as jojoba oil, olive oil, sunflower oil, soybean oil, peanut oil, rapeseed oil, almond oil, palm oil, coconut oil or stone fruit oil palm.

The composition may contain as emulsifiers, for example, glycerin, possibly in a mixture with laurate sucrose or sorbitol, emulsifier M/(oil/water), for example, hydrolyzed vegetable protein.

The composition can also be used in the form of liniment (.linimentum) - thick or gelatinous dosage forms for external use, which is rubbed into the skin. As auxiliary substances liniment may contain, for example, propylene glycols, benzalkonium chloride. Emulsion oily liniments may have the structure of the emulsions of the type oil-in-water" or "water in oil". Emulsion liniments, as well as suspension, need to be stable is Itachi, which can be improved by means of an emulsifier, for example, emulsifier T-2. (Emulsifier T-2 represents the esters of fatty acid and a polymer of glycerol, Tween 80 and other surfactants. In some cases, the emulsifiers can be formed by the interaction of the ingredients included in the composition of the liniment.

Pharmaceutically acceptable excipients in obtaining pharmaceutical compositions for external use are, for example, natural or rejected oil, for example, cocoa butter, waxes, fats, ester of glycerol and a saturated fatty acid, glycoregulation, macrogol, semi-solid or liquid polyols, triglycerides and other Basis of the pharmaceutical composition for external application may also include a surfactant or stabilizer.

The patches contain a hermetic protective layer and a layer that is attached to the above-mentioned protective layer, this layer is in direct contact with the affected place, for example, with the nail and optionally with the surrounding skin. The layer is usually made of adhesive amplifier penetration through the skin and/or the layer of the nail.

The implementation of the invention

Compounds according to the invention of formula (I) can be obtained from the corresponding intermediate compounds containing mobile halogen atom on the well-known re the work of nucleophilic substitution, where as the nucleophile acts thiocyanate ion, and which can be introduced into the reaction in the form of its sodium, potassium or ammonium salt (scheme 1). The reaction takes place in a suitable solvent, such as lower alcohols, acetone, ethylmethylketone. All radicals have the definitions as in the formula (I). Mixing can increase the reaction rate. The reaction can be easily carried out at a temperature in the range from +10 to +100°C. the Obtained product may be purified by crystallization, for example, from lower alcohols. It is possible to obtain various crystalline modifications.

Scheme 1

The source and intermediate compounds of the formula (II) are compounds that are either commercially available or can be obtained from a conventional widely known methods described in the literature.

The following are examples of preparing compounds according to the invention, which do not limit the scope of the present invention.

Example 1.

4-Dimethylamino-5-nitro-6-thiocyanatopropyl (compound 1)

A solution of 2 g (9 mmol) of 4,6-Dior-5-nitropyrimidine (F. Girard, Demaison S., Lee, M.-G., Agrofoglio L.A. Tetrahedron, 54 (1998) 30, 8745-8952; Scharn Dirk, Lothar Germeroth, Schneider-Mergener Jens, Holger Wenschuh, J. Org. Chem., 66 (2001) No. 2, 507-513) in 40 ml dioxane was treated previously prepared solution of dimethylamine acetate, the content is the future of 2.9 ml of aqueous 40% dimethylamine (22 mmol) and neutralized with acetic acid to pH 7. The reaction mass to stand 3 hours at room temperature and slowly diluted with 200 ml of cold water. The precipitation of 4-dimethylamino-5-nitro-6-chloropyrimidine filtered off, washed with water and used in the next stage without additional purification.

A solution of 1.3 g (6.4 mmol) of 4-dimethylamino-5-nitro-6-chloropyrimidine in 30 ml of ethanol was treated with 0.7 g (7 mmol) of potassium thiocyanate at room temperature. The reaction mass is boiled for 4 hours, treated with 0.1 g of activated charcoal and hot filtered. The filtrate is cooled and diluted with 100 ml of water. Loose light yellow precipitate of 4-dimethylamino-5-nitro-6-thiocyanatopropyl (compound 1) was washed with cold water and recrystallized from ethanol.

Yield: 78%.

T square: 142-144°C(EtOH)

MS (m/z: 225 (M+)

1H NMR (DMS0-d6): δ8.37 (1H, s, H), 3.48(6H, s, N(CH3)) ppm

Elemental analysis of C7H7N5O2S:

Calc.: C, 37.33; H, 3.13; N, 31.09

Found: C, 37.23; H, 3.27; N, 29.97

Example 2.

4-Methylamino-5-nitro-6-thiocyanatopropyl (compound 2)

Compound 2 was synthesized similarly to compound 1 but using as the amine 40% aqueous solution of methylamine.

Yield: 64%.

T square: 187-189°C(EtOH)

MS(m/z):211 (M+)

1H NMR (DMSO-d6): δ13.03 (1H, broad s, NH), 8.22 (1H, s, H), 3.12 (3H, s, CH3) ppm

Elemental analysis of C6H5N5O2S:

Calc: C, 34.12; H, 2.39; N, 33.16

Found: C, 3431; H, 2.41; N, 33.15

Example 3.

4 Isopropylamino-5-nitro-6-thiocyanatopropyl (compound 3)

Compound 3 was synthesized according to the method described in Demina G.R. et al, PLoS One, 2009, 4(12), 8174, and its spectral and analytical characteristics match those specified in the literature.

Yield: 81%.

T square: 151-153°C(EtOH)

MS (m/z): 239 (M+)

1H NMR (DMSO-d6): δ13.16 (1H, broad s, NH), 8.16 (1H, s, H), 4.86 (1H, m, CH), 1.37 (6H, s, 3CH3) ppm

Elemental analysis of C6H5N5O2S:

Calc: C, 40.16; H, 3.79; N, 29.27

Found: C, 40.03; H, 3.88; N, 29.11

Example 4.

4 Hexahydropyrazino-5-nitro-6-thiocyanatopropyl (compound 4)

Compound 4 was synthesized similarly to compound 1 but using as the amine prepared aqueous solution hexahydropyridine.

Yield: 48%.

T square: 107-109°C (ethyl Acetate)

MS (m/z): 279 (M+)

1H NMR (DMSO-d6): δ8.32 (1H, s, H), 3,85 (4H, m, N(CH2)2), 1.95 (4H, m, 2CH2), 1.57 (4H, t, CH2CH2) ppm

Elemental analysis of C11H13N5O2S:

Calc: C, 47.30; H, 4.69; N, 25.07

Found: C, 47.18; H, 4.53; N, 24.92

Example 5.

4-N-asokan-5-nitro-6-thiocyanatopropyl (compound 5)

Compound 5 was synthesized similarly to compound 1 but using as the amine prepared aqueous solution asokan.

Yield: 76%.

T square: 95-98°C (methanol)

MS (m/z): 293 (M+)

1H NMR (DMSO-d6): δ8.27 (1H, s, H), 3.91 (2H, broad s, N(CH2)2), 1.18-1.82 10H, broad m, 5CH2) ppm

Elemental analysis of C12H15N5O2S:

Calc: C, 49.13; H, 5.15; N, 23.87

Found: C, at 49.01; H, 5.26; N, is at 23.94

Example 6.

4-(3,5-Dimethylpiperidin-1-yl)-5-nitro-6-thiocyanatopropyl (compound 6)

Compound 6 was synthesized similarly to compound 1 but using as the amine prepared aqueous solution of 3,5-dimethylpiperidine.

Yield: 67%.

T square: 123-125°C (methanol)

MS (m/z): 293 (M+)

1H NMR (DMS0-d6): δ 8.34 (1H, s, H), 3.97 and 3.02 (4H, 2 broad m, N(CH2)2), 1.97 (2H, m, 2 CH), 1,21 (2H, m, CH2), 0.88 (6H, s, 2CH3) ppm

Elemental analysis of C12H15N5O2S:

Calc.: C, 49.13; H, 5.15; N, 23.87

Found: C, 49.13; H, 5.23; N, at 23.97

Example 7.

4-(2-Methylpiperidin-1-yl)-5-nitro-6-thiocyanatopropyl (compound 7)

Compound 7 was synthesized similarly to compound 1 but using as the amine prepared aqueous solution of 2-methylpiperidine.

Yield: 54%.

T square: 158-160°C (Ethanol)

MS (m/z): 293 (M+)

1H NMR (DMSO-d6): δ 8.21 (1H, s, H), 3,65 and 1.70 (M, two broad m, CH(CH2)4), 1.33 (3H, s, CH3)ppm

Elemental analysis of C11H13N5O2S:

Calc: C, 47.30; H, 4.69; N, 25.07

Found: C, 47.11; H, 4.54; N, 25.12

Example 8.

4 Diethylamino-5-nitro-6-thiocyanatopropyl (compound 8)

Compound 8 was synthesized similarly to compound 1 but using as the amine prepared 40% aqueous solution of diethylamine.

In the progress: 74%.

T square: 114-116°C (methanol)

MS (m/z): 253 (M+)

1H NMR (DMSO-d6): δ 8.31 (1H, s, H), OF 3.46 (4H, m, 2CH2), 1.01 (6N, m, 2CH3) ppm

Elemental analysis of C9H11N5O2S:

Calc: C, at 42.68; H, 4.38; N, 27.65

Found: C, 42.60; H, 4.33; N, 27.74

Example 9.

4-N-Benzylamino-5-nitro-6-thiocyanatopropyl (compound 9)

Compound 9 was synthesized similarly to compound 1 but using as the amine prepared aqueous solution of benzylamine.

Yield: 43%.

T square: 144-146°C (isopropanol)

MS (m/z): 287 (M+)

1H NMR (DMSO-d6): δ8.38 (1H, s, H), 7.38-7.25 (5H, m, Ph), 4.41 (2H, s, CH2) ppm

Elemental analysis of C12H9N5O2S:

Calc: C, 50.17; H, 3.16; N, 24.38

Found: C, 50.29; H, 3.24; N, 24.29

Example 10.

4-(N-benzyl-N-methylamino)-5-nitro-6-thiocyanatopropyl (compound 10)

Compound 10 was synthesized similarly to compound 1 but using as the amine prepared aqueous solution of N-methyl-N-benzylamine.

Yield: 46%.

T square: 127-129°C (ethanol)

MS (m/z): 301 (M+)

1H NMR (DMSO-d6): δ 8.31 (1H, s, H), 7.4-7.20 (5H, m, Ph), 4.34(2H, s, CH2),3.15(3H, s, CH3) ppm

Elemental analysis of C13H11N5O2S:

Calc: C, 51.82; H, 3.68; N, 23.24

Found: C, 51.76; H, 3.57; N, 23.19

Example 11.

4-N-methylcyclohexylamine-5-nitro-6-thiocyanatopropyl (compound 11)

Compound 11 was synthesized similarly to compound 1 but using as and is prepared in an aqueous solution of N-methylcyclohexylamine.

Yield: 34%.

T square: 112-114°C (ethanol)

MS (m/z): 293 (M+)

1H NMR (DMSO-d6): δ 8.32 (1H, s, CH), to 3.64 (1H, m, CH), of 3.12 (3H, s, CH3), 2.0-1.0 (10H, broad m, SN2) ppm

Elemental analysis of C12H15N5O2S:

Calc.: C, 49.13; H, 5.15; N, 23.87

Found: C, 49.17; H, 5.08; N, at 23.84

Example 12.

A solution of 3.8 g (16,8 mmol) of 4,6-Dior-2-methyl-5-nitropyrimidine (Hurst Derek T., J. Heterocycl. Chem., 32, 1995, 697-699) in 40 ml dioxane was treated previously prepared solution of dimethylamine acetate, containing a 5.1 ml of aqueous 40% dimethylamine (42 mmol) and neutralized with acetic acid to pH 7, when the temperature of the reaction mass not higher than 15°C. the Reaction mass to stand 3 hours at room temperature and slowly diluted with 200 ml of cold water. The precipitation of 4-dimethylamino-2-methyl-5-nitro-6-chloropyrimidine filtered off, washed with water and used in the next stage without additional purification.

A solution of 2.7 g (12.5 mmol) of 4-dimethylamino-2-methyl-5-nitro-6-chloropyrimidine in 30 ml of ethanol was treated with 1.3 g (13 mmol) of potassium thiocyanate at room temperature. The reaction mass is boiled for 4 hours, treated with 0.1 g of activated charcoal and hot filtered. The filtrate is cooled and diluted with 100 ml of water. Loose light yellow precipitate of 4-dimethylamino-2-methyl-5-nitro-6-thiocyanatopropyl (compound 12) was washed with cold in the Oh and recrystallized from ethanol.

Yield: 86%.

MP.: 159-161°C (ethanol)

MS (m/z): 239 (M+)

1H NMR (DMSO-d6): δ 3.48 (6N, s, 2CH3), 2.36 (3H, s, CH3) ppm

Elemental analysis of C8H9N5O2S:

Calc.: C, 40.16; H, 3.79; N, 29.27

Found: C, 40.26; H, 3.88; N, 29.34

Example 13.

4-Amino-2-methyl-5-nitro-6-thiocyanatopropyl (compound 13)

Compound 13 was synthesized similarly to compound 12, but using as the amine prepared 25% aqueous ammonia solution.

Yield: 39%.

T square: 209-212°C (ethanol)

MS (m/z): 211 (M+)

1H NMR (DMSO-d6): δ 8.19 (2H, broad s, NH2), 2.43 (3H, s, CH3) ppm

Elemental analysis of C6H5N5O2S:

Calc: C, 34.12; H, 2.39; N 33.16

Found: C, at 34.25; H, 2.47; N, 33.04

Example 14.

4-Methylamino-2-methyl-5-nitro-6-thiocyanatopropyl (compound 14) Compound 14 was synthesized similarly to compound 12, but using as the amine prepared 40% aqueous solution of methylamine.

Yield: 76%.

T square: 200-202°C (methanol)

MS (m/z: 225 (M+)

1HNMR (DMSO-d6): δ 3.12 (3H, s, CH3), 2.35(3H, s, CH3) ppm

Elemental analysis of C6H5N5O2S:

Calc: C, 37.33; H, 3.13; N, 31.09

Found: C, 37.21; H, 3.27; N, 31.22

Example 15.

4-Pyrrolidino-2-methyl-5-nitro-6-thiocyanatopropyl (compound 15)

Compound 15 was synthesized similarly to compound 12, but using as the amine prepared aqueous solution of pyrrolidine.

Yield: 68%

T square: 142-144°C (methanol)

MS (m/z): 265 (M+)

1HNMR (DMSO-d6): δ 3.50 (4H, m, N(CH2)2), 2.41 (3H, s, CH3), 1.91 (4H, m, CH2CH2) ppm

Elemental analysis of C10H11N5O2S:

Calc: C, 45.27; H, 4.18; N, 26.40

Found: C, 45.29; H, 4.34; N, 26.43

Example 16.

4 Diethylamino-2-methyl-5-nitro-6-thiocyanatopropyl (compound 16) Compound 16 was synthesized similarly to compound 12, but using as the amine prepared 40% aqueous solution of diethylamine.

Yield: 53%.

T square: 69-70°C (methanol)

MS (m/z): 267 (M+)

1H NMR (DMSO-d6): 5 3.44 (4H, m, N(CH2)2), 2.56 (3H, s, CH3), 1.10 (6N, m, 2CH3) ppm

Elemental analysis of C10H11N5O2S:

Calc: C, 44.93; H, 4.90; N, 26.20

Found: C, 45.08; H, 4.93; N, at 26.32

Example 17.

A solution of 4.0 g (19.2 mmol) of 4,6-Dior-2-methyl-5-nitropyrimidine (Hurst Derek T., J. Heterocycl. Chem., 32, 1995, 697-699) in 40 ml of anhydrous ethanol was treated with 20 ml of the previously prepared solution of ateleta sodium (0.4 g (19.2 mmol) of metallic sodium and 20 ml of anhydrous ethanol)at a temperature of the reaction mixture below 0°C. After addition of the entire amount of sodium methylate the reaction mass incubated 2 hours at room temperature and slowly diluted with 200 ml of cold water. The precipitation 4 ethoxy-2-methyl-5-nitro-6-chloropyrimidine filtered off, washed with water and recrystallized the C benzene.

A solution of 3.2 g (14.7 mmol) of 4-ethoxy-2-methyl-5-nitro-6-chloropyrimidine in 30 ml of ethanol was treated with 1.5 g (15 mmol) of potassium thiocyanate at room temperature. The reaction mass is boiled for 4 hours, treated with 0.1 g of activated charcoal and hot FilterOutputStream cooled and diluted with 100 ml of water. Precipitated white precipitate 4-ethoxy-2-methyl-5-nitro-6-thiocyanatopropyl (compound 17) was washed with cold water and recrystallized from ethanol.

Yield: 42%.

T square: 60-62°C (ethanol)

MS (m/z): 240 (M+)

1H NMR (DMSO-d6): δ 4.64 (2H, q, CH2), 2.66 (3H, s, CH3), 1.43 (3H, t, CH3) ppm

Elemental analysis of C8H8N4O3S:

Calc: C, 40.00; H, 3.36; N, 23.32

Found: C, 39.93; H, 3.46; N, 23.31

Example 18.

4-Propoxy-2-methyl-5-nitro-6-thiocyanatopropyl (compound 18) Compound 18 was synthesized similarly to compound 17, but using at all stages of n-propyl alcohol instead of ethanol.

Yield: 26%.

T square: 50-52°C (methanol)

MS (m/z): 254 (M+)

1H NMR (DMSO-d6): 8 4.32 (2H, t, och2), 2.58 (3H, s, CH3), 1.77 (2H, m, CH2), 1.17 (3H, t, CH3) ppm

Elemental analysis of C9H10N4O3S:

Calc: C, 42.51; H, 3.96; N, 23.03

Found: C, 42.45; H, 3.89; N, 23.09

Example 19.

3,5-Dinitro-2-thiocyanatopropyl (compound 18)

Compound 19 was obtained by well-known methods Z. Talik, Plazek E. Roczniki Chemii(1960), 34, 165-75 in accordance with the following procedure: a solution of 2.0 g (9.8 mmol) of commercially available 3,5-dinitro-2-chloropyridine in a mixture of 20 ml ethanol and 20 ml of acetone was treated with 1.1 g (11 mmol) of potassium thiocyanate at room temperature. The reaction mass is boiled for 8 hours, treated with 0.1 g of activated charcoal and hot filtered. The filtrate is cooled and diluted with 100 ml of water.

Yield: 55%.

T square: 160-62°C (ethanol)

MS (m/z): 226 (M+)

1H NMR (DMSO-d6): δ 9.42 and 9.15 (two 1H, two s, 2CH) ppm

Elemental analysis of C8H8N4O3S:

Calc: C, 31.86; H, 0.89; N, at 24.77

Found: C, at 31.71; H, 1.01; N, 24.70

Example 20.

5-Methyl-3-nitro-2-thiocyanatopropyl (compound 20)

Compound 20 was synthesized similarly to compound 19, proceeding from commercially available 5-methyl-3-nitro-2-chloropyridine.

Yield: 53%.

T square: 135-139°C (methanol)

MS (m/z: 195 (M+)

1H NMR (DMSO-d6): δ 8.37 and 8.08 (two 1H, two s, 2CH), 2.43 (3H, s, CH3) ppm

Elemental analysis of C7H5N3O2S:

Calc: C, 43.07; H, 2.58; N, 21.53

Found: C, 43.21; H, 2.52; N, 21.70

Example 21.

6-Methoxy-3-nitro-2-thiocyanatopropyl (compound 21)

Compound 21 was synthesized similarly to compound 19 on the basis of commercially available 6-methoxy-3-nitro-2-chloropyridine.

Yield: 42%.

T square: 121-123°C (methanol)

MS (m/z): 211 (M+)

1H NMR (DMSO-d6): δ 8.41 (1H, d, CH), 6.89 (1H, d, CH), 3.91 (3H, s, CH3) ppm

Elemental analysis C 7H5N3O3S:

Calc: C, 39.81; H, 2.39; N, 19.90

Found: C, 39.68; H, 2.47; N, at 19.92

Description antifungal activity of the compounds according to the invention.

1. The activity of compounds of General formula (I) against pathogenic fungi and yeast.

The compounds of General formula (I) showed significant activity against pathogenic fungi and yeast, as well as against clinically isolated strains of fungi, including those that are sensitive to fluconazole, and also in relation resistant to antifungal drugs of cultures.

The activity of the tested compounds was determined by the method of twofold serial dilutions (micromethod) in a liquid nutrient medium with the identification of the minimum overwhelming concentration (MIC) against various laboratory and clinical strains of fungi [National Committee for Clinical Laboratory Standards. 1997. Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard M27-A. National Committee for Clinical Laboratory Standards, Wayne, PA, USA.; National Committee for Clinical Laboratory Standards. 2002. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Conidium-Forming Filamentous Fungi: Approved Standard M38-A. NCCLS, Wayne, PA, USA].

For preparation of inoculum used a suspension of yeast cells and a suspension of spores in sterile saline (0.85 per cent NaCl). The density of the suspensions was monitored spectrophotometrically. To obtain the inoculum source suspensions of yeast and fungal spores razvedyvatelnoye medium (RPMI 1640). The final concentration of cells in the experiment were (1-5)×103 cells/ml for yeast and (0,4-5)×104 cells/ml for fungi. The number of cells in the inoculum was verified by plating on agar Saburo and counting of grown colonies. The test substance was dissolved in dimethyl sulfoxide (DMSO) with initial concentration of 1600 mcg/ml in the same solvent was preparing a series of dilutions from 1600 to of 3.13 μg/ml For the production experiment the obtained solutions were diluted 50 times in the standard used to experience medium RPMI 1640. All the test solutions of drugs were prepared immediately prior to use.

Experiments were performed in sterile 96-well flat-bottom plates in RPMI medium 1640 in the wells containing 200 μl of medium. The final concentration of drug experience after making microbial inoculum ranged from 16 to 0.03 μg/ml when the concentration of the solvent (DMSO) 1%. Each drug in the experiment was attended not less than three times. In the panel of the experiment as a control were included wells that do not contain the tested preparations.

The plates were incubated at 35°C (Candida albicans and fungi), or 25°C (Cryptococcus humicolus) without shaking. Evaluation of the growth of the cultures was performed visually, using 4-stage scale: 0=optical transparency, a complete lack of growth, 1=weak growth (25% of control levels), 2=significant suppression of ROS is a (50% of control levels), 3=weak growth inhibition (75% of control levels), 4=no inhibition of growth. Minimal inhibitory concentration (MIC) of antifungal drugs were read at 24 h of cultivation for Candida albicans and Cryptococcus humicolus and 48 h of cultivation for Aspergillus niger and Fusarium oxysporum.

MBC was defined as the lowest concentration of drug that completely prevents the growth of the test organism (scale=0).

The result of this experiment, we investigated the ability of compounds of General formula (I) derivatives the group 2 nitroanilines to suppress the growth of pathogenic fungi and yeast and identified the values of their BMD (table 1).

Table 1
The activity of compounds of General formula (I) with respect to laboratory strains of pathogenic fungi and yeast. The minimum inhibitory concentration indicated in μg/ml
The connection number (example no.) Candida albicans was ATSS 14053Candida humicolus ADS 9949Aspergillus niger was ATSS 16404Fusarium oxysporum VKMF-140
14412
24482
32822
4161614
5>16828
6161624
7>16848
82824
92482
1020,524
1140,524
124824
1341622
144411
15>16>162>16
1641648
172412
184244
1910,521
Amphotericin B0,50,2512

2. The activity of compounds of General formula (I) against clinically isolated drug-resistant strains of yeast laboratory strains of fungi.

To determine the activity of compounds of General formula (I) against clinically isolated multidrug resistant strains of pathogenic fungi and yeast was used in the test culture fungi from RKG - dimorphic (yeast phase, Y): Candida albicans, strain 1244, .albicans, strain 1242, Ctropicalis, strain 531, .krusei, strain 526, .parapsilosis, strain 897, .guilliermondii, strain 594, .glabrata, strain 1188; filamentous (F): Aspergillus fumigatus, strain 1248, A.niger, strain 1249, A.flavus, strain 1247. All test cultures are clinical isolates from the respective patients, isolates of the pathogens persist in the Russian collection of pathogenic fungi research Institute of medical Mycology them. P.N. Institute, St. Petersburg maps.

Nutrient medium: agar and liquid medium Saburo. Solvents and suspension medium: distilled water, dimethyl sulfoxide (DMSO), a solution of phosphate buffer. Determination of antifungal activity of the above substances was performed by macromethod (GFH, issue 2, 2002) for serial twofold dilutions. Suspension of yeast organisms of the genus Candida were prepared from duhat is cnyh cultures, grown at 37°C on agar Saburo in test tubes. The culture was washed with a solution of phosphate buffer, the density of the sediment brought up to 10 Units on the turbidity standard. Prepared suspension of the test culture was diluted 100 times with the same solution phosphate buffer in each tube of the series of dilutions of the tested compounds in a liquid environment Saburo contributed 0.1 ml (2 drops) working suspension suspension cells. Culture of filamentous fungi were grown for 2-3 days at 37°C on agar Saburo in test tubes, then the cell mass was collected from the surface of the agar was placed in a sterile tube and rubbed, gradually adding a solution of phosphate buffer to the density of the working suspensions 5 Ed by the turbidity standard. The quantity of the working suspension in each tube of the series was also of 0.1 ml.

In each experiment was set controls:

1 culture of test organism (1 ml of culture medium +0.1 ml of the working suspension of micromycete; there were no test substance);

2 culture medium (1 ml of medium without culture and without substance);

3 test substance (0.9 ml of a nutrient medium +0.1 ml of the initial dilution of the test substance, i.e. in 1 ml contained 100 μg of the substance).

All series have been prepared in dilutions test tubes with test cultures of control and kept at 37°C until growth of the fungus in the first control. Minimum fungus eticheskoi concentration antimycotics considered to be breeding in the last tube, which are not visually see the growth of micromycete. For example, the growth is not in 1-9-th test tubes and the last of them breeding will be 214×104 (2140000) times, when the concentration of the substance has dropped to 0.39 µg/ml in the remaining five test tubes culture growth was almost (or is) the same as in the first control. Then the indicated concentration of 0.39 µg/ml is fungistatic title (or concentration).

If necessary, determine the biocidal action of antimycotics make seeding strokes microbiological loop on the sectors agarized medium Saburo in Petri dishes from each tube, which are not visually marked the growth of culture, and of the first control tube. After this Cup of sectoral sowing leave thermostat at the desired temperature for a period before the growth of colonies in the control sector. If the sowing was also positive, for example, from 7-9 th tubes, it means that the fungicidal effect is manifested at a concentration of antimycotics 3,14 µg/ml.

Table 2
The activity of compounds of General formula I against clinical strains of fungi of the genus Aspergillus. The minimum inhibitory concentration indicated in μg/ml
Strains gr the scale of the genus Aspergillus Connection 3The connection 14Connection 19
IPCIFCIPCIFCIPCIFC
A.flavus ¥1247/109412,525255012,525
A.flavusY132412,525252512,525
A.flavusV 1382/80012,52512,512,56,2525
A.fumigatus F132725506,2512,52550

.fumigatus F13 84/461 2510012,5502550
A.fumigatus F1248/880-125100255012,550
A.niger ¥ 1249/880-225253,126,2512,550
A.niger F132225506,2512,52525
A.niger F132712,5503,126,2512,512,5
Table 3
The activity of compounds of General formula I against clinical strains of fungi of the genus Candida. The minimum inhibitory concentration indicated in μg/ml
Strains of fungi of the genus CandidaConnection 3The connection 14Connection 19
IPCIFCIPCIFCIPCIFC
C.albicansYl 129/131,563,130,390,780,780,78
C.albicans Y1353/12773,133,133,136,251,561,56
C.albicans Y1274/2486,25 12,51,563,130,780,78
C.glabrata Yl 188/106212,512,56,256,251,561,56
C.glabrata Y1352/37312,5253,136,251,566,25
C.glabrata Y1311/145212,5256,256,251,563,13
C.krusei Y11981,563,130,781,560,781,56
C.krusei Y1319/20461,563,130,781,561,561,56
C.krusei Y12000,781,560,781,561,561,56
C.tropicalis Y135V170,390,780,390,780,20,78
C.parapsilosis Y13 2112,52512,512,53,133,13

The following are examples of pharmaceutical compositions in the form of various shapes suitable for use as a medicine.

Example A. Preparation of pharmaceutical compositions in the form of ointments Il the cream.

Ointment and cream can be made as follows: 0.5 to 3 wt%. from the total mass of the active substance is melted in a small amount of ointment, cream or candlestick basis. The resulting melt is thoroughly mixed with the required quantity of base, preheated (35-80)°C. the resulting mixture was homogenized. Ready mix in the melted state is poured into the tubes.

Example B. a Pharmaceutical composition in the form of a gel.

The compound of formula 1-3 wt. -%, citric acid - 5%, hydroxyethylcellulose - 4%glycerol and 2.5%sodium hydroxide was 0.9%, water to 100%.

Dissolve citric acid and sodium hydroxide, add glycerine, acetone and the active substance. With vigorous stirring, hydroxyethyl cellulose and then aged for swelling. Get the gel, which then can be used as antifungal agents.

Example Century Pharmaceutical composition in the form of nail Polish.

Film-forming component of hydroxypropylmethyl 5%, active compound of the formula (1)1.0 to 1.5 wt. -%, 40%-aqueous-alcoholic solution, the rest to 100%. Use demineralized water.

Perhaps adding bentonite or citric acid as a stabilizer, a plasticizer compounds, such as camphor, triphenyl or pentenyl diisobutyrate, and pigment.

Example G Preparation of f is rmaceuticals composition in the form of liniment.

Liniment get 5% transparent yellow liquid with a weak peculiar smell, containing 1-2 mg of active compound of the formula (I), 50 mg benzalkonium chloride and 1,2-propylene glycol.

The liniment may be applied in a creamy moisturizing masks to restore and strengthen nails.

Propylene glycol is used as a humidifier.

Example D. the Pharmaceutical composition in the form of a fatty emulsion liniment.

3 g of the active substance, colloidal silicon dioxide (Aerosil) 5 g, castor oil 89, Possibly adding emulsifier, for example, Emulsifier T-2 or Tween 80.

Example E. Pharmaceutical composition in the form of lotion.

The active compound of the formula (I) 5% of the mass, diisopropylamide 12%, lactic acid 4%, ethyl alcohol - the rest. You can add benzyl alcohol as a substance that accelerates the penetration of the drug.

Tests were carried out with compounds of the present invention, the resistance of clinically isolated strains of Candida krusei. The tests were carried out according to the method described for fluconazole P. Pappas et al. Practical guidelines for treatment of candidiasis. Clinical Infection Diseases 2004 - vol.38 - p. 161-189.

1. The use of compounds of General formula (I):

where X=N or C-R3
R1 denotes a proton, a saturated or unsaturated linear is alkoxyalkyl, 1-5 carbon atoms; cycloalkylcarbonyl having up to 6 carbon atoms; a saturated linear allylmercaptan radical having 1-3 carbon atoms; aminoacyl having 1-10 carbon atoms, selected from saturated or unsaturated linear mono - or dialkylaminoalkyl, or cycloalkenyl radical, cyclic aminoadipyl, each of the cyclic groups may be substituted by 1-2 methyl groups; or benzylamino;
R2 denotes a proton, saturated or unsaturated, linear alkylaryl having 1-5 carbon atoms, or cyclic aliphatic radical having up to 6 carbon atoms, trifluoromethyl, styryl or methylmercapto;
R3 denotes trifluoromethyl, formyl, acetyl, nitro, benzoyl, cyano or alkoxycarbonyl Deputy having 1-3 carbon atoms in alkoxygroup, possibly in crystalline form, or their pharmaceutically acceptable additive salts with acids or bases, possessing antifungal activity against strains of fungi, pathogens of fungal infections, for local usage.

2. The use according to claim 1, according to which compounds have antifungal activity against fungal strains that are resistant to drugs.

3. Pharmaceutical composition having antifungal aktivnosti form suitable for local application, containing as an active ingredient a compound of General formula (I) according to claim 1 or its pharmaceutically acceptable additive salt with acid or base, in a pharmacologically effective amount.

4. The pharmaceutical composition according to claim 3 in the form of ointment, cream, paste, lotion, nail Polish, tape, shampoo, emulsion or liniment.

5. The pharmaceutical composition according to claim 4, in the form of ointment, cream, paste, lotion, nail Polish, tape, shampoo, emulsion or liniment placed in the package.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 6-(1-piperazinyl)-pyridazines of formula , where R1 is chlorine, trifluoromethyl or cyano; R2 is phenyl or phenyl substituted with a halogen; R*1 is hydrogen, C1-4-alkyl or pyridinylmethyl; X is -O-, -NH-, -CH2-, -CH(OH)-, -SO2-, -CO-, -NH-CH2-, -O-CH2-, 1,2-ethendiyl or ethyndiyl; or a pharmaceutically acceptable addition salt or solvate thereof as well as pharmaceutical compositions containing said novel compound as an active ingredient.

EFFECT: improved properties of derivatives.

8 cl, 4 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted quinoxaline-type bridge piperidine compounds of formula

,

or pharmaceutically acceptable derivatives thereof, where: a equals 0; b is an integer selected from 0 or 1; each R5 is independently selected from -H; R1 is -(C9-C14)bicycloalkyl, each substituted with 1 or 2 independently selected R3 groups; each R3 independently selected from -(C1-C4)alkyl. The invention also relates to a pharmaceutical composition, capable of modulating ORL-1 receptor function, based on said compound.

EFFECT: obtaining novel compounds which can be used in medicine to treat pain, memory disorder, obesity, constipation, depression, dementia, Parkinsonism, anxiety, cough, diarrhoea, high blood pressure, epilepsy, anorexia, urinary incontinence or drug dependence.

27 cl, 2 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrole derivatives of the formula (1): or pharmaceutically acceptable salts thereof, where: R1 denotes H, halogen; R2 denotes an 8-10-member bicyclic hydrocarbon group, optionally substituted, or a bicyclic heterocyclic group consisting of one or two atoms selected from nitrogen, oxygen and sulphur and 5-9 carbon atoms, optionally substituted, where the optional substitute is halogen, lower alkyl, OH, lower alkoxy, oxo, NO2, CN; R3 denotes H.

EFFECT: compounds have inhibiting action of production of IL-6, which enables use thereof in a pharmaceutical composition and when treating a range of diseases.

12 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of general formula (I), or pharmaceutically acceptable salts thereof, where X1 denotes N, N-R3, C-R3 or O; X2 denotes N, CH or C-CH3; X3 denotes N or C, where X1, X2 and X3 all do not simultaneously denote N; X4, X5 each independently denotes C or N; X6 denotes N or C-R1 ; where at least two and not more than four of X1, X2, X3, X4, X5 and X6 denotes N; and where the bonds between X1 and X2, X2 and X3, X3 and X4, X4 and X5, X5 and X1, as well as X5 and X6 can each independently be single or double, or , can form an aromatic ring, under the condition that a chemically stable structure is formed; R denotes -(cyclohexyl)R2; R1 denotes a halide, nitro group, -CN, -CH2CN, -OH, -NH2, -COOH or -Y1R4; Y1 denotes -O-, -SO2, -NHSO2-, -C(O)O- or a bond; R4 denotes (C1-C6)alkyl, phenyl or benzyl, each of which is substituted with 0-3 times with a hydroxy group or a halogen; n equals 0, 1 or 2; R3 denotes H or (C1-C6)alkyl; R2 denotes H, -OH, =O or -Y2-Y3-Y4-R5, where Y2 denotes -C(O)-, -C(O)NRa-, -NH- or a bond; Y3 denotes (C1-C6)alkylene or a bond; Y4 denotes -NRa-, -S-, -SO2-, -NRaC(O)-, -NHSO2- or a bond; R5 denotes (C1-C6)alkyl, (C3-C10)cycloalkyl, a 5-6-member heterocyclyl containing 1-2 heteroatoms selected from N and O, where R5 is optionally substituted with -OH or -NHRa; where each Ra independently denotes hydrogen or (C1-C6)alkyl; Z denotes hydrogen. The invention also relates to a pharmaceutical composition based on a compound of formula (I).

EFFECT: obtaining novel pyrimidine derivatives which are useful for therapeutic or preventive treatment of a c-Jun N-terminal kinase-mediated disorder.

14 cl, 3 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (I): or to its pharmaceutically acceptable ester, amide, carbamate, solvate or salt, including salt of such ester, amide or carbamate and solvate of such ester, amide, carbamate or salt, where values R1, R2, R3, R4, R5 and R6 are given in item of the formula, with the exception: 4-[3-(4,5-dihydro-1H-imidazol-2-yl)-2-(3,5-dimethylisoxazol-4-yl)indole-1-yl]phenol; 1-(4-hydroxyphenyl)-2-(4-methylimidazol-1-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-(1H-pyrazol-3-yl)-1H-indole-3-carbonitryl; 1-(3-chloro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-prop-1-inyl-1H-indole-3-carboxylic acid amide.

EFFECT: compounds I possess affinity of binding with estrogen receptor of p-subtype, which makes it possible to use them in pharmaceutical composition and in treatment or prevention of state, associated with disease or disorder, associated with activity of estrogen receptors of β-subtype.

27 cl, 271 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to new salts of a compound 1:

,

which represents hemi- or monosalts with C4 organic dibasic acid, which have improved properties when used. The invention also refers to method of specified salts production.

EFFECT: improved acid stability.

24 cl, 8 dwg, 4 tbl, 39 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to new derivatives of 4-aminopyrimidine, having antagonistic activity in respect to the receptor H4. In the formula : R1 is selected from C1-8alkyl, C3-8cycloalkyl-C0-6alkyl, aryl-C1-6alkyl, the group of the formula R2 and R3 together with the atom N, with which they are linked, creating the saturated heterocyclic group, which may be a 4-7-member monocyclic or 9-member condensed bycyclic one, where the specified heterocyclic group may contain up to two atoms N and does not contain any other heteroatoms, and may be unnecessarily substituted with one or more substitutes, independently selected from C1-4alkyl and NRaRb, provided that if the heterocyclic group either contains 2 atoms N and is not substituted with the group NRaRb, or comprises 1 atom N and is substituted with one group NRaRb; or R2 is H, and R3 is pyrrolidinyl substituted with C1-4alkyl group; where Ra is H or C1-4alkyl; Rb is H or C1-4alkyl; R4 and R5 is H; R6 is aryl group; n is equal to 1; and aryl is phenyl group, unnecessarily substituted with halogen. The invention also relates to a pharmaceutical composition containing the specified compounds, to application of compounds for production of a medicinal agent for treatment of such diseases as an allergic, immunological or inflammatory diseases or pain, and also to a method for production of the specified compounds.

EFFECT: higher efficiency of application of compounds in treatment of diseases.

34 cl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: chemistry.

SUBSTANCE: described are novel chiral cis-imidazolines selected from a group which includes 2-{4-[(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-acetamide, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(1,1-dioxohexahydrothiopyran-4-yl)-piperazin-1-yl]-methanone, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(3-methanesulphonylpropyl)-piperazin-1-yl]-methanone, 2-{4-[(4S,5R)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxyethyl)-acetamide. 2-{1-[(48;5K)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidin-4-yl}-acetamide and others described by the general structural formula (I), and pharmaceutical composition containing said compounds.

EFFECT: compounds can be used as anti-cancer agents, particularly as agents for treating solid tumours.

8 cl, 217 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an improved method for preparing 2-arylamino-4-hetarylpyrimidines of formula (I) which possess inhibitory action on serine-threonine kinase Haspin on the enzymatic level, and may be used as drug substances for oncological diseases. In formula (I), wherein Het = , , , , , , , , , , ,

R=H; 2-Me; 3-Me; 4-Me; 2,3-di-Me; 2-MeO; 3-MeO; 4-MeO; 4-EtO; 4-PhO; 2-Cl; 3-Cl; 4-Cl; 4-F; 2-Me, 3-Cl. The method consists in a reaction of related hetarylmethylketone and N,N-dimethylformamide dimethylacetale on boiling of reagents in isopropyl alchohol for 6 hours to produce 3-dimethylamino-1-hetaryl-2-propen-1-ones with adding in situ related aryl guanidine and further boiling for 2 hours. The process is conducted at molar ratio (mole) of hetarylmethylketone: N,N-dimethylformamide dimethylacetale : aryl guanidine = 1:1.5:1.

EFFECT: method simplifies the process due to cutting a process time and reducing consumption of the initial ingredients.

6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a non-hydratable crystal form (polymorph A) of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-[4-cyano-2-methyl-6-[(methylamino)-carbonyl]phenyl]-1H-pyrazole-5-carboxamide (compound 1), which is characterised by an X-ray diffraction pattern having reflection angle peaks given in the claim. According to the invention, the method involves heating a hydratable crystal form of compound 1 (polymorph B), having X-ray diffraction characteristics given in the claim, at temperature from about 40°C to the boiling point of the solvent of the mixture, which contains a solvent selected from a group consisting of water, n-heptane, 1-chlorobutane, toluene, 1-butanol and 1-pentanol.

EFFECT: obtaining a stable polymorph A of compound 1, which enables to obtain stable solid insecticide compositions.

15 cl, 2 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: present compounds can be used, for example, in treating diseases of the central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal system and the endocrine system.

EFFECT: described compounds are useful in treating a range of diseases or conditions in which interaction with the histamine H3 receptor is beneficial.

9 cl, 216 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 4-(azacycloalkyl)benzene-1,3-diol compounds of general formula (I) given below:

,

where: R1 is: - C1-C5-alkyl radical, - C3-C6-cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, and C1-C5 alkoxy group, a fluorine atom or a trifluoromethyl group, - aralkyl radical, - C1-C5-alkoxy radical, -amine radical, having the structure (a):

,

where R2 is: - hydrogen, - C1-C5-alkyl radical, - C3-C6- cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, and C1-C5 alkoxy group, a fluorine atom and a trifluoromethyl group, - pyridyl radical, - aralkyl radical of the structure (b):

,

where p is equal to 1 or 2, - a radical of the structure (c):

,

where R4 is: - carboxymethyl, -COOCH3, or carboxyethyl, -COOEt, radical, - C1-C3-alkyl radica, - hydrogen, and R5 is: - an unsubstituted aryl radical or an aryl radical substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy group, fluorine atom or a trifluoromethyl group, - C3-C6-cycloalkyl radical, - pyridyl, and R3 is: - hydrogen, - C1-C5-alkyl radical; or R1 can also be a radical of formula (d):

,

where R6 is: - hydrogen, - C1-C5-alkyl radical, - C3-C6-cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy group, a fluorine atom and a trifluoromethyl group, - pyridyl radical, - aralkyl radical, R7 is: - hydrogen, - C1-C5-alkyl radical, and R8 is: - hydrogen, - hydroxyl, - amine radical, - C1-C3-alkoxy radical; Y is hydrogen or fluorine, and m and n are equal to 0, 1 or 2, as well as isomeric and enantiomeric forms of compounds of formula (I). The invention also relates to use of said compounds as a drug for treating pigmentation disorders.

EFFECT: novel compounds, which can be used in pharmacology or cosmetology to treat or prevent pigmentation disorders, are obtained and described.

6 cl, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or a pharmaceutically acceptable salt thereof, wherein G1 is phenyl or pyridyl, each of which is optionally additionally substituted by one substitute presented by T; G2 is phenyl, 1,3-thiazolyl or 1,3-oxazolyl, wherein G2 is bound to G1 in the para position in relation to a place of attachment of G1 to group NH in formula (I), wherein G2 means phenyl, G3 is bound to G2 in the para position of G2 in relation to G1, and wherein provided G2 represents 1,3-thiazolyl or 1,3-oxazolyl, G2 is bound to G1 in the position of 5 G2 and G3 is bound to G2 in the position of 2 G2; T in each case is independently specified in a group containing C1-6alkyl and halogen; G3 is presented by formula or by formula ; W1 is -C(R3)(R4)-C(R3)(R4)-, and W2 represents N; or W3 represents O; W4 is -C(R3)(R4) -; each R3 and R4 is hydrogen; each R5 and R6 kis hydrogen; Rc and Rd together with a carbon atom whereto attached, are a 4-5-member cycloalkyl or monocyclic heterocycle of formula ; wherein one hydrogen atoms attached to the carbon atom of the cycloalkyl ring and monocyclic heterocycle is optionally substituted by a radical specified in a group -C(O)O(R8); W5 is -CH2- or -CH2-CH2-; W6 is O or N(RX), wherein Rx is hydrogen, C1-6alkyl or -C(O)O(Rz); RZ in each case is independently C1-6alkyl; R8 is hydrogen; L1 is O; and X is hydrogen, C1-6alkyl, or - (CRgRh)u-C(O)O(R10); or L1 is -CH2- and X is -C(O)OH; R10 is hydrogen; or Q is G4 or Y1-Y3; or Q is described for formula wherein Z is phenyl; G4 is benzothiazole or benzoxazole optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of C1-6alkyl, halogen and -OR1; Y1 in each case is independently -C(O)-, -C(O)O- or -C(O)N(Rw)-, wherein the right side -C(O)O- and -C(O)N(Rw)- of the groups is attached to Y3 or (CRJRk)v, Y3 in each case is independently phenyl, benzyl, piperidinyl or bicyclo[4.2.0]octa-1,3,5-triene, wherein the phenyl and benzyl residues are optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of halogen and haloC1-6alkyl; Rg and Rh in each case is independently hydrogen, or C1-6alkyl; R1 in each case is independently halogenC1-6alkyl; Rw is hydrogen; and u means 1.

EFFECT: compounds being the type 1 diacylglycerol O-acyltransferase (DGAT-1) enzyme inhibitors.

7 cl, 1 tbl, 61 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 4-(4-cyano-2-thioaryl)- dihydropyrimidin-2-one derivatives of formula (I), a method for preparing and using them. In formula , , both A and E mean C-R7, wherein R7 mean hydrogen, Z means O, n means the number 0,1 or 2, R1 means (C1-C6)-alkyl which may be substituted by the group hydroxy, (C1-C4)-alkoxy,(C3-C6)-cycloalkyl, phenyl or 5- or 6-member heteroaryl with two heteroatoms specified in nitrogen or sulphur, or may be substituted up to three times by fluorine, or means (C3-C6)-cycloalkyl or phenyl, R2 means hydrogen, R3 means cyano or a group of formulas -C(=O)-R8, -C(=O)-O-R8 or -C(=O)-NH2, wherein R8 means (C1-C6)-alkyl or (C3-C6)-alkenyl, R4 means methyl or ethyl, or R3 and R4 are linked to each other and together form an annulated group of formula (II), R9 means hydrogen, (C1-C6)-alkyl or (C3-C6)-cycloalkyl with (C1-C6)-alkyl may be substituted by a hydroxy group, aminocarbonylamino or (C1-C4)-acylamino, R5 means hydrogen or (C1-C6)-alkyl. The other group and radical values are specified in the patent claim.

EFFECT: compounds possess the properties of a neutrophil elastase (HNE) inhibitor and can find application in treating and/or preventing pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary emphysema, mediated by neutrophil elastase (HNE) activity.

16 cl, 4 tbl, 10 dwg, 202 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein: X and Y independently mean a nitrogen atom or the chain -CR4-, wherein R4 means a nitrogen atom; A means an aryl or heteroaryl group, with the above aryl or heteroaryl groups are optionally substituted by one or more groups specified in a halogen atom, a hydroxyl group, (C1-C4)alkyl group, (C3-C5)cycloalkyl group, (C1-C4)alkoxy group optionally substituted by (C1-C4)alkoxy group, a halogen alkyl group, a halogen alkoxy group; W means a halogen atom; Z means (C1-C4)alkylene group optionally substituted by one or more groups specified in a halogen atom and (C1-C4)alkyl group; B means the group -NR4R5, wherein R4 and R5 independently mean (C1-C4)alkyl group; R1 and R2 mean: - or R1 means a hydrogen atom and R2 mean (C1-C4)alkyl group, - or R1 and R2 together with a carbon atom whereto attached form a mono- or polycyclic system specified in: (C3-C8)cycloalkyl group, a bicyclic bridge group or a tetracyclic bridge group; the above system may be substituted by one or more hydroxyl groups; R3 means either the group C(O)R5, wherein R5 means (C1-C4)alkoxygroup optionally substituted by (C1-C4)alkoxygroup, or the group NR6R7, wherein R6 and R7 independently mean a hydrogen atom, (C1-C4)alkyl group, (C3-C5)cycloalkyl group, (C1-C4)alkylsulphonyl group, a halogenalkyl group, or the group -CH2XR8, wherein: - X means an oxygen atom and R8 means a hydrogen atom or (C1-C4)alkyl group, - or the nitrile group (CN); p means an integer equal to 0 or 1; the aryl group represents an aromatic monocyclic group containing 5 or 6 carbon atoms; the above cycle may be fused with a partially saturated heterocyclic group containing 5 or 6 atoms, including one or two heteroatoms, such as an oxygen atom; the heteroaryl group represents an aromatic cyclic group containing 5 or 6 atoms, including one or two heteroatoms, such as nitrogen; in the form of a base or an additive salt with an acid or base, as well as to their enantiomers and diastereoisomers, including to their racemic mixtures. Besides, the invention refers to methods for preparing the compound of formula I, as well as to a therapeutic agent and a pharmaceutical composition which possess antagonist action on an urotensin II receptor and contain the compound of formula I.

EFFECT: there are prepared and described the new compounds which possess urotensin II receptor antagonist action.

9 cl, 44 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel carboxyl- or hydroxyl-substituted benzimidazole derivatives of formula (I), or pharmaceutically acceptable salts thereof, where R1 is selected from and , R2 is hydrogen; R3 is cyclohexyl or bicyclo[2.2.1]heptyl; R4 is phenyl, which is substituted in the 4th position with a halogen or a lower fluoroalkyl, or a pyridyl, which is substituted with 1 or 2 substitutes independently selected from halogen and a lower alkoxy group; R5 and R6 independently denote hydrogen or fluorine; R7 and R9 are independently selected from a group consisting of hydrogen, lower alkyl, halogen, lower alkoxy group, lower fluoroalkyl, lower fluoroalkoxy group and cyano group; R8 is -(CR12R13)n-COOH, where n equals 0, 1 or 2, and R12 and R13 are independently hydrogen or lower alkyl, or -O-(CR14R15)p-COOH, where p equals 1 or 2, and R14 and R15 are independently hydrogen or lower alkyl, or R14 and R15 together with the carbon atom with which they are bonded form a cycloalkyl ring, or R8 is tetrazole; R10 is a hydroxy group or -(CH2)p-COOH, where p equals 0 or 1; m equals 0 or 1; R11 is -COOH. The invention also relates to specific carboxyl- or hydroxyl-substituted benzimidazole derivatives and a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel carboxyl- or hydroxyl-substituted benzimidazole derivatives, having selective activity with respect to farnesoid X receptor, are obtained.

26 cl, 126 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (I): or to its pharmaceutically acceptable ester, amide, carbamate, solvate or salt, including salt of such ester, amide or carbamate and solvate of such ester, amide, carbamate or salt, where values R1, R2, R3, R4, R5 and R6 are given in item of the formula, with the exception: 4-[3-(4,5-dihydro-1H-imidazol-2-yl)-2-(3,5-dimethylisoxazol-4-yl)indole-1-yl]phenol; 1-(4-hydroxyphenyl)-2-(4-methylimidazol-1-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-(1H-pyrazol-3-yl)-1H-indole-3-carbonitryl; 1-(3-chloro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-prop-1-inyl-1H-indole-3-carboxylic acid amide.

EFFECT: compounds I possess affinity of binding with estrogen receptor of p-subtype, which makes it possible to use them in pharmaceutical composition and in treatment or prevention of state, associated with disease or disorder, associated with activity of estrogen receptors of β-subtype.

27 cl, 271 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

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