Novel indazole derivative or its salt and intermediate compound for obtaining thereof, and antioxidant with application thereof, and application of indazole derivatives or its salt

FIELD: chemistry.

SUBSTANCE: invention relates to compound for formula (1) , antioxidant, containing formula (1) compound or its salt as active ingredient, and to application of formula (1) compound or its salt for oxidant manufacturing. Invention also relates to formula (2) compound, which is intermediate for obtaining formula (1) compound.

EFFECT: formula compound, demonstrating antioxidant properties.

4 cl, 1 tbl, 13 ex

 

The technical field to which the invention relates.

The present invention relates to a new derived indazole or its salt, and an intermediate connection to receive them. The present invention also relates to the antioxidant containing as active ingredient at least one of the derived indazole or its salt. Further, the present invention also relates to the use of such derived indazole or its salt to obtain antioxidants.

The level of technology

In recent years it was shown that lipid peroxidation in biological body and the accompanying radical reactions that cause various negative effects in the biological body due to irregularities in the membrane irregularities in the cell, etc. In this regard, various attempts have been made to use drugs, antioxidants or agents that suppress lipid peroxidation, has been much research on antioxidants.

For example, such typical antioxidants like vitamin C, vitamin E, polyphenols and the like, are used in food and cosmetics. Also SOD (superoxide dismutase) or similar enzymes, which convert active oxygen molecules into oxygen and hydrogen peroxide, is well known as antioxidants. In addition, edaravone is used as terapeutiche is some means to prevent the increase of the area of infarction after cerebral infarction with antioxidant action, and it is known that probucol and similar substances, which are therapeutic agents in hyperlipidemia, inhibit the oxidation of LDL (low density lipoprotein) and have an inhibitory effect on the development of atherosclerosis. However, little of this work satisfactorily in practice because of the low level of side effects and the like.

On the other hand, European patent publication No. 1679308 (Patent document 1) describes a group of compounds represented by the General formula that includes compounds represented by the following formula (1). Patent document 1 discloses that this group of compounds has the activity of inhibiting Rho-kinase and are useful as a therapeutic agent for glaucoma and other European patent publication No. 1870099 (Patent document 2) describes a means of having protective properties for neurons of the retina, comprising as active ingredient the group of compounds represented by the General formula that includes compounds represented by the following formula (1):

However, in these Patent documents 1 and 2 covered enough information about the compound represented by formula (1), and no description and assumptions in the application of the compounds represented by formula (1) above, the quality of the ve antioxidant.

The documents of the prior art,

Patent documents

Patent document 1: European patent publication No. 1679308.

Patent document 2: European patent publication No. 1870099.

The invention

The tasks to be solved by the inventions

Very interesting subject is the search for a new antioxidant and create a new connection with such action and effect, or its salts and intermediate compounds for obtaining such a new connection.

Means of solving problems

The authors of the present invention have made considerable efforts to search for antioxidant and as a result succeeded in obtaining a new derived indazole represented by the formula (1)or its salts and found that this new compound has excellent antioxidant effect in the measurement system of microsomal lipid peroxidation using microsomes of rat liver. In particular, the present invention is as follows.

The present invention is an antioxidant, which contains as active ingredient at least one compound represented by the following formula (1)or its salt. In this document, the compound represented by the following formula (1)or its salt is called "Connect the s according to the invention (1)".

The present invention also relates to the compound of the invention (1).

In addition, the present invention also relates to the compound represented by the following formula (2), or its salt. In this document, the compound represented by the following formula (2), which is an intermediate compound to obtain a compound of the invention (1) or its salt, is called "the connection according to the invention (2)", and the connection according to the invention (1) and the compound of the invention (2) in General referred to as "compound of the invention".

(where Boc is tert-butoxycarbonyl group, THP represents tetrahydropyranyloxy group).

The present invention also relates to the use of at least one of the compounds represented by formula (1)or their pharmaceutically acceptable salts to obtain antioxidant.

The effects of the invention

The connection according to the invention (1) showed excellent antioxidant effect in the measurement system microsomal peroxide oxidation of lipids using microsomes of rat liver. That is, the compound of the invention (1) is useful as an antioxidant. In addition, also provides the use of at least one of the compounds represented by formula (1) or their pharmaceutically acceptable salts to obtain antioxidant.

Ways of carrying out the invention

The connection according to the invention (1) is 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine, which is a derivative of indazole, represented by the following formula (1) and its salt, a compound of the invention (2) is 1-{6-[4-cyclopropyl-1-(tetrahydropyran-2-yl)-1H-indazol-5-yl]pyridine-3-yl}-1-ethylpropylamine acid tert-butyl ester, which is an intermediate compound to obtain a compound of the invention (1), represented by the following formula (2), and its salt:

"Salt" of the compound according to the invention is preferably a pharmaceutically acceptable salt, and, for example, lists salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, nitric acid, sulfuric acid or phosphoric acid, salts of organic acids such as acetic acid, triperoxonane acid, oxalic acid, malonic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid (D-isomer, L-isomer, meso-isomer), adipic acid, gluconic acid, glucoheptonate acid, glucuronic acid, benzoic acid, phthalic acid, terephthalic the I acid, lactic acid, hippuric acid, glutamic acid, aspartic acid, 1,2-ethicality acid, setinova acid, lactobionic acid, oleic acid, pamula acid, polygalacturonase acid, stearic acid, tannic acid, methanesulfonate acid, econsultancy acid, triftormetilfullerenov acid, benzolsulfonat acid, p-toluensulfonate acid, lauryl ester, methyl sulfate, naphthalenesulfonate acid or sulfosalicylic acid, salts of alkali metals such as lithium or potassium, salts of alkaline earth metals such as calcium or magnesium, and salts of Quaternary ammonium compounds, so what ammonia. Preferably, lists of salt, which forms hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid (D-isomer, L-isomer, meso-isomer) or methansulfonate acid, and particularly preferable are listed hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, maleic acid, succinic acid, tartaric acid (L-isomer) and methanesulfonate acid. The connection according to the invention (1) may form a salt in any proportion with inorganic what Isletas, organic acid, an alkaline metal, alkaline earth metal or the like, and each of such salts or a mixture of the means in the present invention.

In the case of a hydrate and/or solvate of the compound of the present invention, the hydrate and/or solvate also included in the scope of compounds of the present invention. In the case of crystalline polymorphism and the group of crystalline polymorphisms (crystalline polymorphism) of the compounds according to the invention such crystalline polymorphisms and groups crystalline polymorphisms (crystalline polymorphisms) are also included in the scope of the compounds according to the invention. Here the group of crystalline polymorphisms (system crystalline polymorphisms) means crystalline form at the appropriate stages and (for) the whole process, when crystalline form various image changes in accordance with the terms and conditions of production, storage, etc. of such crystals (here state includes the state of the dosage forms).

Preferred specific examples of the compounds according to the invention can include the following compounds and their salts:

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine hydrochloride (hereinafter referred to in this document also appears the text as "compound a"),

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine hydrobromide,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine sulfate

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine phosphate

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine fumarate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine maleate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine succinate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine L-tartrate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine methanesulfonate,

- 1-{6-[4-cyclopropyl-1-(tetrahydropyran-2-yl)-1H-indazol-5-yl]pyridine-3-yl}-1-ethylpropylamine acid tert-butyl ester.

More preferred specific examples of the compounds according to the invention can include the following compounds and their salts:

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 1 hydrochloride

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 2 hydrochloride

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 3 hydrochloride

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 1 hydrobromide,

- 1-[6-(4-cyclopropyl-IH-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine hydrobromide,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 3 hydrobromide,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 1 sulfate

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 1 phosphate

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 0.5 fumarate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 1 fumarate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 1.5 fumarate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 0.5 maleate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 1 maleate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 1.5 maleate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 0.5 succinate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 1 succinate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 1.5 succinate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 0.5 l-tartrate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 1 l-tartrate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 1.5 l-tartrate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 1 methanesulfonate,

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 2 methanesulfonate

- 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine 3 methanesulfonate,

- 1-{6-[4-cyclopropyl-1-(tetrahydropyran-2-yl)-1H-indazol-5-yl]pyridine-3-yl}-1-ethylpropylamine acid tert-butyl ester.

While a specific method of obtaining the compounds according to the invention will be described in detail in the Example section" [Example retrieve] below as a typical way of receiving, after receiving the connection according to the invention (2) in accordance with the method described in WO 2007/142323, with compound leaves protection is usually applied by the method and/or transformation in Sol simultaneously and/or after removal of the protection, to obtain the compound of the invention (1).

While the details will be disclosed in described later in the section "pharmacological test", the connection according to the invention (1) showed excellent antioxidant effect in the measurement system microsomal peroxide oxidation of lipids using microsomes of rat liver. In other words, the connection according to the invention (1) is useful as an antioxidant. The present invention also provides the use of compounds represented by the above formula (1)or its salt to obtain antioxidant.

A useful application of the antioxidant of the present invention includes not only medical, but also beauty, pexeva is, industrial (such as paint), etc. applications. It is preferably useful as a medicine, more preferably as a drug, useful for the prevention or treatment of diseases in which the antioxidant is effective, particularly preferably as a drug for prevention or treatment of cardiovascular diseases such as atherosclerosis, arteriosclerosis, myocardial infarction, arrhythmia, chronic renal failure, nephritis, hypertension, and hyperlipidemia; diseases of the cranial nervous system, such as intracranial hemorrhage, cerebral infarction, subarachnoid hemorrhage, ischemic reperfusion injury, Alzheimer's disease, Parkinson's disease and dementia; diseases of the digestive system such as stomach ulcers, inflammatory disease bowel, reflux esophagitis, ulcerative colitis, Crohn's disease, diabetes, pancreatitis, hepatitis, cirrhosis of the liver and nonalcoholic steatohepatitis; respiratory diseases such as pneumonia, emphysema, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma; inflammatory/autoimmune diseases such as collagen disease, rheumatism, Behcet's disease, and sepsis; skin diseases such as atopic dermatitis, skin inflammation, psoriasis and jog; infections such as herpes infection and AIDS; cancer; cancer therapy, such as adriamycin-induced cardiotoxicity; ophthalmic inflammatory diseases, such as inflammation of the cornea, conjunctivitis, scleritis, and blepharitis; dry eyes; Parigi; cataract; eye diseases associated with oxidative stress, such as visual fatigue; retinal diseases such as age-related macular degeneration, age-related edema yellow spots (dry type, wet type) and diabetic retinopathy, and glaucoma.

The antioxidant of the present invention may be presented in one of the drug and/or mixed drug using commonly used technique, while the other active ingredient and/or additive (preferably, other pharmaceutically acceptable active ingredient and/or additive) is added as necessary.

The antioxidant of the present invention can be administered to the patient orally or parenterally, when it is used for prevention or treatment of diseases in which the antioxidant is effective, and as a form of introduction lists oral administration, topical introduction to the eye (for example, the introduction of eye drops, the introduction into the conjunctival SAC, the introduction into the vitreous body, subconjuctival introduction the s and subtenancies introduction), intravenous, transdermal introduction, etc. and the antioxidant is a part of the dosage forms suitable for injection, together with a pharmaceutically acceptable additive as necessary. As a dosage form suitable for oral administration, are listed, for example, tablet, capsule, granule, fine granule, powder and the like, and as a dosage form suitable for parenteral administration are listed, for example, injection, eye drops, eye ointment, patch, gel, intercalator etc. you can get Them using conventional methods generally used in this field. The antioxidant of the present invention can also be obtained in a unit dosage form comprising DDS (SDLS, the delivery system of the medicinal product, such as dosage form for intraocular implants and microspheres in addition to the above dosage forms.

For example, a tablet may be obtained by appropriate selection and use of excipient, such as lactose, glucose, D-mannitol, calcium hydrogenphosphate anhydrous, starch or sucrose; disintegrants, such as carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crosspovidone, starch, partially generowanie starch, or hydroxypropylcellulose with a low degree of replacement is to be placed; lubricant, such as hydroxypropylcellulose, ethylcellulose, gum Arabic, starch, partially generowanie starch, polyvinylpyrrolidone or polyvinyl alcohol; a lubricant such as magnesium stearate, calcium stearate, talc, water, silicon dioxide or utverjdenie oil; covering means, such as purified sucrose, hypromellose, hydroxypropylcellulose, methylcellulose or pyrrolidone; corrective substance such as citric acid, aspartame, ascorbic acid or menthol.

The injection can be obtained by selecting and using as needed to ensure that isotonicity, such as sodium chloride; a buffer such as sodium phosphate; a surfactant, such as polyoxyethylene sorbitan monooleate; a thickener such as methyl cellulose, etc.

Eye drops can be obtained by selecting and using as needed to ensure that isotonicity, such as sodium chloride or concentrated glycerin; a buffer such as sodium phosphate or sodium acetate; a surfactant, such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate or polyoxyethylene-utverjdenie castor oil; a stabilizer such as sodium citrate or edetate sodium; and a preservative, such as benzalkonium chloride or paraben, and pH may var is activated within acceptable ophthalmic composition, and, as a rule, preferably in the range from 4 to 8. Also eye ointment can be obtained using the commonly used basis, like as white petrolatum or paraffin oil.

Intercalator can be obtained by rubbing and mixing biodegradable polymers such as hydroxypropylcellulose, hypromellose, carboxyvinyl polymer or polyacrylic acid together with an active ingredient, followed by molding under pressure of the obtained powder, and excipient linking agent, a stabilizer, and a pH Converter can be used as needed.

The composition for the intraocular implant can be obtained by using a biodegradable polymer, for example, a biodegradable polymer such as polylactic acid, polyglycolic acid, copolymer of lactic acid and glycolic acid, or hydroxypropylcellulose.

The dose of the antioxidant according to the present invention can be varied appropriately depending on the dosage form, severity of condition, age, body mass of the patient, which is entered active substance, the decision of the doctor and so on, but in the case of oral administration, as a rule, from 0.01 to 5000 mg, preferably from 0.1 to 2500 mg, and more preferably from 0.5 to 1000 mg, you can enter per day for an adult single dose or in multiple with the MOU. In the case of injections, usually from 0.0001 to 2000 mg you can enter adult single dose or in several doses. Further, in the case of eye drops or intercalator, the substance containing the active ingredient with a concentration of 0.000001 to 10% (wt./vol.), preferably from 0.00001 to 1% (wt./vol.), more preferably from 0.0001 to 0.1% (wt./about.) you can enter one or more times per day. In the case of plaster, the plaster containing from 0.0001 to 2000 mg, can be attached to an adult, and in the case of the composition for the intraocular implant composition for an intraocular implant containing 0.0001 to 2000 mg per adult can be implanted in the eye.

Examples getting, examples, pharmacological test examples of dosage forms below are given for a better understanding of the present invention and not to limit the scope of the present invention.

Examples retrieve

<Example 1: Synthesis of 1-{6-[4-cyclopropyl-1-(tetrahydropyran-2-yl)-1H-indazol-5-yl]pyridine-3-yl}-1-ethylpropylamine acid tert-butyl ether complex>

To a solution of 4-cyclopropyl-1-(tetrahydropyran-2-yl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-1H-indazole (130 g, 353 mmol, see WO 2007/142323) in toluene (720 g) was added ethanol (140 ml), water (140 ml), potassium phosphate dehydrate (230 g, 933 mmol) and 2-bromo-5-(1-tert-butoxycarbonylamino-1-ethylpropyl)pyridine (100 g, 291 mmol, see WO 2005/03556) in the stream of argon gas. The reaction solution was aeronavali for 10 minutes with argon gas. Then in the gas stream of argon was added 20% of the mass. tricyclohexylphosphine/toluene solution (10 ml, from 6.22 mmol) and palladium acetate (700 mg, 3.11 mmol), and heated and stirred at 75°C for 6 hours.

After completion of the reaction solution was added water (200 ml) and separated. The organic layer was washed with saturated saline (300 ml) and ran through celite (trade name) (20 g) and then concentrated under reduced pressure. To the obtained residue was added heptane (1000 ml) and the obtained solid substance was collected by filtration and washed with heptane. The obtained solid substance was dried under reduced pressure at 48°C, to obtain 1-{6-[4-cyclopropyl-1-(tetrahydropyran-2-yl)-1H-indazol-5-yl]pyridine-3-yl)-1-ethylpropylamine acid tert-butyl ester (example compound 1) (104 g), represented by the following formula, in the form of a white powder (yield 66%).

Mass spectrum (CI, mass/charge): 505([M+H]+).

1H-NMR spectrum (CDCl3): δ 0,50-0,55 (m, 2H), 0.75 to 0.87 (m, 8H), 1,40 (USS, 9H), 1,63-is 2.37 (m, 10H), 2,53-of 2.66 (m, 1H), 3,71-with 3.79 (m, 1H), 4,01-4,07 (m, 1H), 4,81 (USS, 1H), 5,72 (DD, J=9,3, 2, 7, 1H), 7,47-to 7.59 (m, 3H), 7,68 (DD, J=to 8.2, 2.4 Hz, 1H), 8,21 (s, 1H), 8,69 (DD, J=2,4, 0.7 Hz, 1H).

<Example 2: Synthesis of 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine hydrochloride>

The reaction solution was cooled to 12°C, was stirred for 0.3 hours at the same temperature. The precipitated solid was collected by filtration, and then washed with ethanol (100 ml). To the obtained solid substance (90 g) was added ethanol (270 ml) and was heated to 75°C. Then was added water (35 ml) and was heated and stirred for 0.5 hours. The reaction was cooled to 10°C and the obtained solid substance was collected by filtration, washed with ethanol (200 ml) and then dried at 40°C for 10 hours to obtain a white solid (71 g).

To the obtained solid substance (70 g) was added to a mixed solution (234 ml) of ethanol/water = 2/1 (vol./about.) and was heated and stirred at a temperature of from 70°C to 75°C for 0.5 hours in a stream of argon gas. The reaction was cooled to 10°C, the precipitated solid was collected by filtration and washed with 90 ml of ethanol. Drying at 50°C for 2 hours 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine hydrochloride (Example compound 2) (46 g) was obtained as a white powder (yield 62%).

Melting point: >250°C (decomposition).

Mass spectrum (CI, mass/charge): 321([M+H]+).

1H-NMR spectrum (CD3OD): δ 0,44-0,50 (m, 2H), 0,9-1,04 (m, 8H), 2,16-of 2.54 (m, 5H), 7,58-of 7.69 (m, 2H), scored 8.38-to 8.41 (m, 2H), 8,73 (DD, J=8,5, 2.4 Hz, 1H), 9,02 (DD, J=2,4, 0.5 Hz, 1H).

<Example 3: Synthesis of 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine hydrobromide>

To 1-{6-[4-cyclopropyl-1-(tetrahydropyran-2-yl)-1H-indazol-5-yl]pyridine-3-yl}-1-ethylpropylamine acid tert-butyl ether complex (connection Example 1, 2.1 g, 4.2 mmol) was added ethanol (20 ml) and 48% of the mass. solution of hydrogen bromide (10 ml), was heated and stirred for 4 hours at 40°C. the Solvent is kept under reduced pressure and to the residue was added at 50°C ethanol (10 ml) and water (2 ml). After cooling, water ice, the precipitated solid was collected by filtration and washed with ethanol to obtain a white solid (883 mg).

To the obtained white solid substance (530 mg) was added ethanol (5 ml) and water (200 ml) and was heated and stirred at 70°C for 0.5 hours. After cooling to room temperature the precipitated solid was collected by filtration, washed with ethanol and then dried at 60°C for 1.25 hours, to obtain 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine hydrobromide (Example compound 3) (273 mg) as a white powder (yield 22%).

Melting point: >221-223°C (decomposition).

Mass spectrum (CI, mass/charge): 321([M+H]+).

1H-NMR spectrum (CD3OD): δ 0,45-0,50 (m, 2H), 0,97 of-1.04 (m, 8H), 2,17 of $ 2.53 (m, 5H), ,60 (d, J=8,8 Hz, 1H), 7,65-of 7.69 (m, 1H), 8,39-8,42 (m, 2H), 8,72 (DD, J=8,8, 2.4 Hz, 1H), 9,02 (DD, J=2,4, 0.5 Hz, 1H).

<Example 4: Synthesis of 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine>

To 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine hydrochloride (Example compound 2, 30.0 g, to 76.3 mmol) was added n-butanol (300 ml) and 4M aqueous sodium hydroxide solution (370 ml) and stirred at room temperature for 1.5 hours. The organic layer was separated, washed with water (150 ml) and then the organic layer was concentrated to obtain a solid substance (22,6 g).

To the obtained solid substance (22,6 g) was added methanol (160 ml) and increased the temperature to 60°C. Water (160 ml) was added at the same temperature, and after stirring for 0.5 hours, the stirring was carried out for 1 hour at a temperature of from 10 to 15°C. After filtering the reaction solution obtained solid substance was washed mixed with a cold solution (46 ml) of methanol/water = 1/1 (vol./vol.). Drying for 11 hours at 80°C under reduced pressure of 1-[6-(4-cyclopropyl)-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine (Example compound 4) (21,5 g), represented by the following formula was obtained as a white powder (yield 88%):

Melting point: 208°C.

Mass spectrum (CI, mass/charge): 321 ([M+H]+).

1H-NMR spectrum (CD3OD): δ 0,41 of 0.47 (m, 2H), 0,7 is 0.86 (m, 8H), 1,75-2,04 (m, 4H), 2,28-is 2.37 (m, 1H), 7,42-7,49 (m, 2H), 7.62mm (DD, J=8,3, 0,7 Hz, 1H), to 7.93 (DD, J=8,3, 2,4 Hz, 1H), 8,24 (d, J=0.7 Hz, 1H), 8,67 (DD, J=2,4, 0.7 Hz, 1H).

<Example 5: Synthesis of 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine L-tartrate>

To a solution of 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine (Example compound 4, 4.0 g, 12 mmol) in ethanol (160 ml) was added dropwise a solution of L-tartaric acid (2.8 g, 19 mmol) in ethanol (85 ml) at room temperature for 0.5 hours and stirred at the same temperature for 0.67 hours. The reaction solution was cooled to 10°C and the precipitated solid substance was collected by filtration. After washing with ethanol (40 ml) the solid was dried under reduced pressure at 40°C for 1 hour, then the temperature was raised to 60°C and dried under reduced pressure for 11 hours to obtain 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine L-tartrate (Example compound 5) (5,4 g) as a white solid (yield 92%).

Melting point: 215-216°C.

Mass spectrum (CI, mass/charge): 321([M+H]+).

1H-NMR spectrum (CD3OD): δ 0,41-0,46 (m, 2H), 0,83-0,89 (m, 2H), of 0.95 (t, J=7.4 Hz, 6H), 2,10 (DQC., J=14,8, 7,4 Hz, 2H), 2.26 and (DQC., J=14,8, 7,4 Hz, 2H), 2,34-to 2.42 (m, 1H), and 4.40 (s, 2H), 7,46-7,52 (m, 2H), 7,81 (DD, J=8,3, 0.5 Hz, 1H), of 7.97 (DD, J=8,3, 2.7 Hz, 1H), 8,27 (d, J=0.7 Hz, 1H), 8,66-8,67 (m, 1H).

<Example 6: Synthesis of 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine maleate is>

To a solution of maleic acid (11 mg, 0,095 mmol) in tetrahydrofuran (110 ml) was added a solution of 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine (Example compound 4, 10 mg, 0,031 mmol) in tetrahydrofuran (800 ml) and left for 6 days at room temperature. The precipitated solid was collected by filtration and dried under reduced pressure at 50°C to obtain 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine maleate (Example compound 6) (11 mg) as a white solid (71%yield).

Melting point: 174-178°C.

1H-NMR spectrum (CD3OD): δ 0,41-0,46 (m, 2H), 0,83-of 0.90 (m, 2H), of 0.96 (t, J=7.5 Hz, 6H), 2,10 (DCV, J=14,8, 7.5 Hz, 2H), 2.21 are to 2.42 (m, 3H), 6,27 (s, 3H), 7,46-7,53 (m, 2H), 7,82 (DD, J=8,5, 0.6 Hz, 1H), 7,94 (DD, J=8,5, 2.7 Hz, 1H), of 8.27 (s, 1H), 8,65-8,66 (m, 1H).

<Example 7: Synthesis of 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine fumarata>

To a solution of fumaric acid (11 mg, 0,095 mmol) in tetrahydrofuran (275 ml) was added a solution of 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine (Example compound 4, 10 mg, 0,031 mmol) in tetrahydrofuran (667 μl) and left for 3 days at room temperature. The precipitated solid was collected by filtration and dried under reduced pressure at 50°C to obtain 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine fumarate (Example compound 7) (8,8 mg) as a white Tverdov the substance (yield 75%).

Melting point: 257°C.

1H-NMR spectrum (CD3OD): δ 0,41-0,46 (m, 2H), 0,82-0,94 (m, 8H), 1,94-2,07 (m, 2H), 2,18 (DCV, J=14,8, 7,3 Hz, 2H), 2,31-to 2.41 (m, 1H), of 6.68 (s, 1H), 7,45-7,51 (m, 2H), 7,76 (DD, J=8,3, 0.7 Hz, 1H), 7,95 (DD, J=8,3, 2.4 Hz, 1H), compared to 8.26 (d, J=0.7 Hz, 1H), 8,66 (DD, J=2,4, 0.7 Hz, 1H).

<Example 8: Synthesis of 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine succinate>

To a solution of succinic acid (11 mg, 0,093 mmol) in tetrahydrofuran (275 ml) was added a solution of 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine (Example compound 4, 10 mg, 0,031 mmol) in tetrahydrofuran (667 μl) and left for 6 days at room temperature. The precipitated solid was collected by filtration and dried under reduced pressure at 50°C to obtain 1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylpropylamine succinate (Example compound 8) (6.9 mg) as a white solid (yield 58%).

Melting point: 218°C.

1H-NMR spectrum (CD3OD): δ 0,41-0,46 (m, 2H), 0,82-of 0.90 (m, 8H), 1,94 (DCV, J=14,6, 7,3 Hz, 2H), 2,11 (DCV, J=14,6, 7,3 Hz, 2H), 2,30-to 2.40 (m, 1H), of 2.51 (s, 2H), 7,44-7,51 (m, 2H), 7,72 (d, J=8,3 Hz, 1H), 7,94 (DD, J=8,3, 2.4 Hz, 1H), to 8.25 (d, J=0.7 Hz, 1H), 8,66 (d, J=2.4 Hz, 1H).

Sample drug test

1. Test antioxidant activity in liver microsomes of rats

Antioxidant activity of the tested compounds was evaluated using the measurement of lipid peroxidation in microsomes. This is eats determines the amount of reactive compounds thiobarbituric acid (TBARS), who receive during the reaction of lipid peroxidation caused by adding nikotinamidadenindinukleotida acid and sulphate of iron to microsome. This system adds test the connection, and evaluate the effect of suppression of the test substance in the formation of TBARS as an antioxidant effect. This method is a common way to measure the antioxidant activity of a compound or the like. (Reference documents: Yakugaku Zasshi 119, 93-99 (1999), Biochimica et Biophysics Acta, 1046, (1990) 207-213, Chemistry & Biology Experiment line 2, lipid peroxidation experimental method (Hirokawa shoten).)

<Preparation of reagents for testing antioxidant activity, the preparation of a solution of test compound and method of assessment>

Reagent preparation

Preparation of buffer solution

Buffer solution was prepared by mixing to obtain a 25 mm Tris(hydroxymethyl)aminomethane (Tris) (pH of 7.4) and 150 mm potassium chloride (KCl).

2) preparation of a 5 mm solution of iron sulfate

Iron sulfate (FeSO4•7H2O) was dissolved in distilled water to prepare a 5 mm solution.

3) preparation of a solution of 50 mm nikotinamidadenindinukleotida acid

Nikotinamidadenindinukleotida acid (NADP) was dissolved in distilled water to prepare a 50 mm solution.

4) the production of 200 mm solution of ethylenediaminetetraacetic acid

Ethylenediaminetetraacetic acid (EDTA) was dissolved in distilled water to prepare 200 mm solution.

5) Microsome rat liver

Used five μl of commercially available liver microsomes of rats [XENOTECH, catalog number R1000 (20 mg protein/ml)].

Preparation of the solution under test connection

As the test compound used compound A, which is a compound according to the invention [1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-ethylenepropylene hydrochloride (Example compound 2)], and compound B, which have a similar structure of compound [1-[6-(4-cyclopropyl-1H-indazol-5-yl)pyridine-3-yl]-1-methylethylamine hydrochloride (synthesized according to the method described in European Patent publication No. 1679308)]. Ten mm solutions of test compounds were prepared by dissolving 1.3 mg of compound A in 0,315 ml of dimethyl sulfoxide (DMSO) and the dissolution of 2.15 mg of compound B in 0,554 ml of dimethyl sulfoxide (DMSO):

Method of evaluation

1) Solution of the test compound (5 μl) were placed in the reaction tube.

2) buffer Solution (480 ml) was placed in the reaction tube.

3) Then in each reaction tube was added 5 μl of microsomes rat liver mixed and pre-aged in an incubator (37°C) for 5 minutes.

4) 50 mm Rast is the PR nikotinamidadenindinukleotida acid (5 ml) was added to each reaction tube, so the final concentration was 500 ám.

5) a Solution of 5 mm iron sulfate (5 ml) was added to each reaction tube, so that the final concentration was 50 μm, and the reaction was started.

6) Allowing the reaction to go in for 20 minutes, in each reaction tube was added 200 mm solution of ethylenediaminetetraacetic acid (25 μl)so that the final concentration was 10 mm to stop the reaction, and left in ice water.

7) Level of education by-products of lipid peroxidation (TBARS) in the solution after the reaction was measured using a commercially available measuring kit for TBARS [Cayman, catalog number 10009055].

As a group reactions non-lipid peroxidation, the test was made by adding distilled water instead of nikotinamidadenindinukleotida acid and sulphate of iron, and measured the level of TBARS formation. A number of examples of each group n=2 and the level of suppression of the formation of TBARS (%) was calculated from the mean values of n=2 in accordance with the following formula 1 and IC50the test compounds was measured using a nonlinear regression package for statistical analysis (EXSAS).

Formula 1

the level of suppression of the formation of TBARS (%)=[1-(Tx-T0)/(Tn-T0)]×100

where T0: TBARS level of education in the group of reactions is non-lipid peroxidation (μm);

Tn: TBARS level of education in the group with added control solution (μm);

Tx: TBARS level of education in the group with added test compound (μm).

How to add connection

- The group with added test compound: solution was added compound dissolved in a solution of dimethyl sulfoxide (DMSO).

The group added a control solution and a group of non-lipid peroxidation: was added a solution of dimethyl sulfoxide (DMSO).

Table 1
IC50
Connection Aof 3.8 microns
Compound B>100 mm

Discussion

From these results, compound a showed strong antioxidant activity. On the other hand, compound B has not demonstrated strong antioxidant action, although it has a structure similar to the structure of the compound A.

Examples of dosage forms

The drug of the present invention will be described more specifically by describing examples of dosage forms, however, it should be noted that the present invention is not is going to be restricted to these examples of dosage forms.

Example dosage forms 1: tablet

100 mg,

Connection A1 mg
Lactose66,4 mg
Corn starch20 mg
Carboxymethylcellulose calcium6 mg
Hydroxypropylcellulose6 mg
Magnesium stearate0.6 mg

The compound A and the lactose are mixed in a mixing installation, to the mixture carboxymethylcellulose calcium and hydroxypropylcellulose and granularit, and the resulting granules are governed by particle size after drying and adjusted according to the particle size of the granules add the magnesium stearate is added and stirred, followed by pelletizing in teletrauma car. Further, by varying the amount of added compound A, it is possible to prepare a tablet containing 0.1 mg, 10 mg or 50 mg 100 mg

Example dosage forms 2: eye ointment

In 100 g:

Connection A0.3 g
Parafi the TV oil 10.0 g
White petrolatumin sufficient quantity

To evenly melt white petrolatum and paraffin oil, add A connection, mix well and then slowly cooled to prepare eye ointment. Varying the amount of added compounds And can be prepared eye ointment with a concentration of 0.05% (wt./mass.), 0,1% (wt./mass.), of 0.5% (wt./mass.) or 1% (wt./mass.).

Example dosage forms 3: injection

In 10 ml:

Connection A10 mg
Sodium chloride90 mg
Polysorbat 80in sufficient quantity
Sterile purified waterin sufficient quantity

The compound A and the sodium chloride is added to sterile purified water to prepare an injection. Varying the amount of added compounds And can be prepared in an injection containing 0.1 mg, 10 mg or 50 mg 10 ml

Example dosage forms 4: eye drops

100 ml

10 mg
Connection A
Sodium chloride900 mg
Polysorbat 80in sufficient quantity
Disodium hydrogenphosphatein sufficient quantity
Sodium dihydrogen phosphatein sufficient quantity
Sterile purified waterin sufficient quantity

To sterile purified water add the Compound A and other ingredients as described above and mixed well to prepare eye drops. Varying the amount of added compounds And can be prepared eye drops concentration of 0.05% (wt./vol.), 0,1% (wt./vol.), of 0.5% (wt./about.) or 1% (wt./vol.).

It should be understood that embodiments of, and examples described herein are for example and not for limitation in all respects. Scope of the present invention defined by formula rather than by the above description, and it should be understood that any modifications to the equivalent value and volume formulas included.

Industrial applicability

The connection according to the invention (1) showed excellent antioxidant activity in the system is IU measurement of microsomal peroxide oxidation of lipids using microsomes of rat liver. Thus, the connection according to the invention (1) is useful as an antioxidant.

1. Antioxidant-containing compound represented by the following formula (1)or its salt as an active ingredient:

2. The compound represented by the following formula (1)or its salt:

3. The compound represented by the following formula (2)or its salt:

(where BOC is tert-butoxycarbonyl group, and TPR is tetrahydropyranyloxy group).

4. The use of compounds represented by at least one of the following formula (1) or its pharmaceutically acceptable salt, to obtain antioxidant:



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula I , where R1 is a hydrogen atom, a lower alkyl, CD3, -(CH2)n-CHO, -(CH2)n-O-lower alkyl, -(CH2)n-OH, -(CH2)n-cycloalkyl or is a heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O); R2 is a hydrogen atom, a halogen atom, hydroxy, lower alkyl, di-lower alkyl, -OCH2-O-lower alkyl or lower alkoxy; or the piperidine ring along with R2 forms a spiro-ring selected from 4-aza-spiro[2,5]oct-6-yl; Ar is an aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), optionally having one, two or three substitutes selected from a halogen atom, lower alkyl, lower alkyl having as substitutes, a halogen atom, a lower alkoxy having as substitutes, a halogen atom, cycloalkyl, lower alkoxy, S-lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with N), or optionally having as substitutes, phenyl, optionally having R' as substitutes, and R' is a halogen atom, CF3, lower alkyl, lower alkoxy or a lower alkoxy having as substitutes, a halogen atom, or is a heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N and S); R is a lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O), aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), Where the aryl and heteroaryl optionally have as substitutes, one or two R'; n equals 0, 1, 2 or 3; or to a pharmaceutically acceptable acid addition salt, a racemic mixture or a corresponding enantiomer and/or optical isomer of said compound. The invention also relates to pharmaceutical compositions based on a glycine reuptake inhibitor of a compound of formula I.

EFFECT: obtaining novel compounds and a pharmaceutical composition based thereon, which can be used in medicine to treat neurological and psychoneurological disorders.

22 cl, 1 tbl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to phenyl alkyl piperazines of formula (I) , in which: R1 represents independently on each other hydrogen atom, halogen atom, (C1-C5)alkyl group, (C1-C5)halogenalkyl group, (C1-C2)perfluoroalkyl group, (C1-C5)alkoxyl group or (C1-C2)perfluoroalkoxyl group; R2 stands for (C1-C5)alkyl group or (C1-C5)alkoxyl group, R3 represents (C1-C5)alkyl group; A represents =CH- and =N-; in form of base or additive salt with acid. Invention also relates to pharmaceutical composition for modulation of activity of TNF-alpha, which contains claimed compounds, and to method of their obtaining.

EFFECT: obtained are novel compounds which can be applied in medicine as medications for treating or preventing pain and/or diseases, associated with inflammatory of immune disorders.

24 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, particularly novel pyridinone derivatives of formula (I) or stereochemically isomeric forms thereof, where R1 is C1-6alkyl or C1-3alkyl, substituted with C3-7cycloalkyl; R2 is a halogen, trifluoromethyl, C1-3alkyl or cyclopropyl; X is a covalent bond, O or O-CH2; Ar is an unsubstituted phenyl or phenyl substituted with n radicals R4, where n equals 1, 2 or 3; where each R4 is a halogen; or pharmaceutically acceptable addition salts or solvates thereof. The invention also relates to a pharmaceutical composition, having the activity of positive allosteric modulators of the metabotropic glutamate receptor subtype 2, based on compounds of formula I and use of compounds of formula I to prepare a medicinal agent for treating or preventing neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved.

EFFECT: novel compounds which can be useful in treating and preventing neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved are obtained and described.

15 cl, 4 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to N-[2,4-dioxo-6-(tetrahydrofuran-2-yl)-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]methanesulphonamide and N-[6-(1-isopropoxyethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H- quinazolin-3-yl] methanesulphonamide, having antagonistic activity on the AMPA receptor. The invention also relates to a pharmaceutical composition.

EFFECT: use of said compounds to produce drugs for treating AMPA mediated conditions and primarily for treating epilepsy or schizophrenia.

6 cl, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

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

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: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to a method for increasing the radioresistance in mice. The method for increasing the radioresistance in mice consisting in the fact that 20-30 min before a radiation exposure, parsley juice diluted with normal saline is introduced intramuscularly.

EFFECT: method increases the radioresistance in mice effectively.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine. A pharmaceutical formulation for the treating diseases associated with endothelial dysfunction contains an active ingredient presented by a methyl pyridine derivative - 1.0-6.0 wt %; purine - 10.0-80.0 wt % and additive agents - the rest. The active substance is presented by compounds of a group: 3 -(N,N-dimethyl carbamoyloxy)-2-ethyl-6-methylpyridinium succinate, 3-methylpyridinium succinate, 2-ethyl-6-methyl-3-hydroxypyridinium hydrochloride, 6-trichloromethyl-2-chloropyridine (nitrapyrin), 2-ethyl-6-methyl-3-hydroxypyridine succinate. Purine is presented by inosine, adenosine, hypoxanthine. The pharmaceutical formulation may be presented in the form of injections, lyophilisate, solid capsules, tablets and suppositories.

EFFECT: formulation according to the invention provides creating the stable drug dosage form which considerably exceeds the existing analogues in pharmacodynamics activity on the endothelial dysfunction and toxicological properties.

4 cl, 4 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to diastereomers of isobornyl compounds of the structural formula (I), where R1=H and isobornyl fragments have the configuration (1S, 2R, 4R, 1'S, 2'R, 4'R) and (1R, 2S, 4S, 1'R, 2'S, 4'S), where R1=CH3 and isobornyl fragments have the configuration (1S, 2R, 4R, 1'R, 2'S, 4'S) or the isobornyl fragments have the configuration (1S, 2R, 4R, 1'S, 2'R, 4'R) and (1R, 2S, 4S, 1'R, 2'S, 4'S).

EFFECT: high antioxidant activity.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cosmetology. What is presented is using a cell culture prepared of one or more homogenous cell lines originated from cambium Panax ginseng, or extract thereof when preparing an anti-aging cosmetic composition.

EFFECT: invention provides the effective agent for preventing or suppressing the aging ensured by the antioxidant effect of the natural materials being the ingredients of the above composition.

7 cl, 7 dwg, 20 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a polyphenol derivative formulation and is used in cosmetics, nutrition science and therapy. The polyphenol derivative formulation possessing antioxidant and antiradical activity and having an effect on carbonyl stress. A method for preparing the formulation. The cosmetic formulation possessing antioxidant and antiradical activity and having an effect on carbonyl stress. Using the formulation in nutrition science. The formulation to be used as a therapeutic agent possessing antioxidant and antiradical activity and having an effect on carbonyl stress. The pharmaceutical formulation possessing antioxidant and antiradical activity and having an effect on carbonyl stress.

EFFECT: formulation has an effect on carbonyl stress.

23 cl, 11 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to an antioxidant preparation containing 5-aminosalicylic acid, quercetic and 5% alcoholic extract of propolis as an active agent, and Lutrol F127, Cremophore RH-40 and glycerol as a base in certain proportions.

EFFECT: preparation has the pronounced antioxidant action and is recommended for the correction of the free-radical oxidation processes.

1 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to pharmacology, neurology and cell engineering. What is described is using Napelline as a cerebroprotective agent. The mode of action of the agent is activation of cerebral neural stem cells.

EFFECT: invention achieves extending the range of high-effective cereroprotective agents.

3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely preparing an agent of hindu lotus seed extract (Nelumbo nucifera) possessing immunotropic and antioxidant activity. The agent possessing immunotropic and antioxidant activity prepared by extraction of hindu lotus seed extract (Nelumbo nucifera) in 50% ethanol in a Soxhlet extraction apparatus in the specific proportions.

EFFECT: agent possesses manifested immunotropic and antioxidant activity.

6 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery, and may be used for prevention of acute postoperative pancreatitis. For this purpose, the underlying background therapy is combined with intravenous bolus administration of dalargin 0.002 g and the antioxidant thioctic acid depending on a risk level of the complication measured in terms of the area of intervention in abdominal operations. A high risk level requires thioctic acid to be administered in a dose of 600 mg intravenously drop-by-drop 1 hour before the operation and on the following day, and thioctic acid in a dose of 300 mg on the third day intravenously drop-by-drop. In a moderate risk level thioctic acid is administered intravenously drop-by-drop in a dose of 600 mg 1 hour before the operation and in a dose of 300 mg on the following day. And in a low risk level, thioctic acid is administered intravenously drop-by-drop in a dose of 300 mg 1 hour before the operation.

EFFECT: method enables the more effective prevention of acute postoperative pancreatitis ensured by the combined use of drugs with antisecretory and antioxidant activity.

2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and represents application of calix[6]arene of formula (1A) or (1B) for treatment of skin contamination with uranium, plutonium or americium.

EFFECT: invention ensures stability of calix[6]arenes with actinides in static mode.

5 cl, 4 ex, 11 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to biomedical compositions and methods of treating skin-affecting diseases, disorders and states.

EFFECT: compositions and methods of treating skin states, resulting from production of active forms of oxygen in a subject's skin, include application of local composition, containing an antioxidant compound with a lipophilic, mitochondria targeted cation, and which delivers therapeutically efficient quality of the antioxidant compound to fibroblasts and keratocytes of the skin.

13 cl, 2 tbl, 3 ex, 4 dwg

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