Salts of pyrrolopyrimidinone derivatives and method of obtaining them

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) which is selected from gentisate, maleate, citrate, fumarate and semitartrate salts, which possess improved properties in their application, in particular higher stability.

EFFECT: invention also relates to method of obtaining acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) and to pharmaceutical composition, containing them, for treatment and prevention of erectile dysfunction, pulmonary arterial hypertension, chronic obstructive lung disease, benign prostate gland hypertrophy and diseases of lower urinary tract.

11 cl, 30 ex, 7 tbl

 

The technical field to which the invention relates

The present invention relates to salts of derivatives of pyrrolopyrimidine that are effective as inhibitors of PDE-5, and the way they are received.

The level of technology

In Korea patent No. 358083 disclosed derivatives of pyrrolopyrimidine having high inhibitory activity against PDE-5, the retrieval method, the intermediate connection used for their production, and their use for the prevention and treatment of erectile dysfunction, pulmonary hypertension, chronic obstructive pulmonary disease, benign prostate hypertrophy and diseases of the lower urinary tract.

From disclosed in Korea patent No. 358083 derivatives of pyrrolopyrimidine, 5-ethyl-2-{5-[4-(2-hydroxy-ethyl) - piperazine-1-ylsulphonyl]-2-n-propoxyphenyl}-7-n-propyl-1-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidine-4-one (hereinafter "SK-3530"), represented by the following formula (1), is an excellent selective inhibitor of PDE-5 compared with other PDE and is undergoing clinical trials for the treatment of erectile dysfunction, after he has passed preclinical stage of research.

Dihydrochloride salt (2HCl) SK-3530 is undergoing preclinical and clinical stages of research.

Digital the native salt SK-3530 has a good solubility and can be easily stabilized for a pharmaceutical product. But it has the following disadvantages.

First, as dihydrochloride salt SK-3530 is hygroscopic, it readily absorbs moisture from the environment and changes color when the moisture content is high. And, due to the hygroscopicity, to obtain a stable product must be provided by the conditions of use of the anhydrous solvent and dry air.

Secondly, dihydrochloride salt SK-3530 should be stored at temperatures below room temperature, as it does not possess sufficient stability at room temperature. In particular, dihydrochloride salt SK-3530 is unstable to heat or light, and therefore, any prolonged exposure to heat or light leads to the formation of various impurities.

Thirdly, dihydrochloride salt SK-3530 due to some corrosion properties may cause corrosion of the punch during the pressing of tablets. The reason is that dihydrochloride salt SK-3530 is a simple amorphous salt, and is not stable crystalline acid additive salt or its hydrate form. Therefore, one of the two groups chloride-hydrogen of the acid with a relatively weak ionic bond can leave the molecule under stringent conditions.

As mentioned above, dihydrochloride salt SK-3530 can give appropriate stabiles the ü, necessary for use as a pharmaceutical. But, because of the lack of connection physico-chemical properties and stability needed some additional techniques and costs.

The authors of this invention have conducted various studies to solve the aforementioned problems associated with the use of dihydrochloride salt SK-3530. However, they found that crystalline acid additive salt SK-3530 suitable for use in the pharmaceutical preparation can be obtained when SK-3530 receive in the form of an acid additive salt in the form of gentisate, maleate, citrate, fumarata or polytetra instead hydrochloride.

In the reaction of the free base of SK-3530 with a pharmaceutically acceptable acid selected from hentaimovi acid, maleic acid, citric acid, fumaric acid and tartaric acid, the authors of the present invention were able to synthesize new salts of acids with sufficient stability to heat, moisture and light. Thus, they have accomplished the present invention by obtaining a new crystalline acid salt additive SK-3530, which shows sufficient stability, and which is easy to use in pharmaceutical preparations.

Description of the invention

The purpose of this is th invention is to provide a salt SK-3530, meet physical and chemical requirements of pharmaceutically acceptable salts.

Another objective of the present invention is to develop a method of obtaining satisfactory physical and chemical requirements of salt SK-3530 by reacting the free base of SK-3530 with a specific acid.

Another objective of the present invention to provide pharmaceutical compositions for the treatment and prevention of erectile dysfunction, pulmonary hypertension, chronic obstructive pulmonary disease, benign prostate hypertrophy and diseases of the lower urinary tract, which contains the above salt SK-3530 as the active ingredient.

The following is a more detailed description of the present invention.

The present invention offers five non-hygroscopic pharmaceutically acceptable salts, such as gentisate, maleate, citrate, fumarate and polytetra SK-3530, represented by the following formula (1), which possess excellent stability and therapeutic effect. They also create the maximum concentration in the blood when a physiologically acceptable time and, therefore, are suitable for the treatment and prevention of erectile dysfunction, pulmonary hypertension, chronic obstructive for the of Alemania lungs, benign hypertrophy of the prostate gland and diseases of the lower urinary tract:

The present invention also provides a method of obtaining salt SK-3530, which includes the stage of interaction of the free base of SK-3530 represented by the formula (1), with a pharmaceutically acceptable acid selected from hentaimovi acid, maleic acid, citric acid, fumaric acid and tartaric acid.

A method of obtaining a crystalline acid salt additive SK-3530 according to the present invention includes:

the dissolution or suspension of the acid selected from hentaimovi acid, maleic acid, citric acid, fumaric acid and tartaric acid, to obtain the acid solution;

mixing the acid solution with the free base of SK-3530; and

filtration, washing and drying the solid substance obtained by mixing the above mixture with obtaining crystalline acid additive salt.

Upon receipt of a mixture of the free base of SK-3530 and acid in obtaining crystalline acid salt additive SK-3530 according to the present invention, pharmaceutically acceptable acid selected from hentaimovi acid, maleic acid, citric acid, fumaric acid and tartaric acid may be added to the WWTP is one base of SK-3530, or the free base of SK-3530 can be added to the acid.

The following is a detailed description of each phase retrieval method according to the present invention.

At the first stage of obtaining the acid solution is important to the regulation of the acid concentration. Preferably, the concentration of acid was adjusted so that it was in the range of 1-30 wt.%, which contributes to the effective conduct of further crystallization.

In the second stage of obtaining a mixture of the free base of SK-3530 and acid, preferably the acid used in an equivalent ratio of from 0.5 to 3.0 compared to SK-3530. Upon receipt of a mixture of the acid may be added to the free base of SK-3530, or the free base of SK-3530 can be added to the acid. The free base of SK-3530 can be added in solid form or dissolved in an appropriate reaction solvent. More specifically, the free base of SK-3530 in the solid state or dissolved in an appropriate solvent may be added to the acid solution to obtain a mixture. Alternatively, the acid solution may be added to the free base of SK-3530 in solid form or in solution, the free base of SK-3530, dissolved in an appropriate solvent.

On the second and third stages as the reaction is about solvent use water or a commonly used organic solvent. In particular, it is preferable to use water or an organic solvent selected from acetone, methanol, ethanol, isopropanol and acetonitrile, and combinations thereof.

The third stage is formed crystalline acid additive salt at a temperature of from -30 to 50°C, preferably from 0 to 30°C, particularly preferably at room temperature between 15 and 25°C.

Proposed by the present invention gentisate, Malatya, citrate, fumaric and polytetra salt SK-3530 represented by the formula (1), satisfy the following all five physico-chemical requirements of pharmaceutically acceptable salts: (1) low water absorption, (2) the corresponding solubility, (3) lower the ability of the tablet to stick together, (4) excellent stability, and (5) ease of mass production.

Accordingly, the present invention includes a pharmaceutical composition for the treatment of erectile dysfunction, which contains gentisate, maleato, citrate, fumaric or polytechneiou salt above SK-3530 represented by the formula (1), as the active ingredient.

The pharmaceutical composition according to the present invention can be administered orally or neironalna, and can be converted into the usual formulations of. Thus, it can be recip is on in various pharmaceutical forms for oral and refererlog introduction. To obtain the drugs used commonly used diluent or excipient, including filler, extender, binder, wetting agent, disintegrant, surfactant, and other substances. Solid dosage forms for oral administration include tablet, pill, powder, granule and capsule. These solid dosage forms obtained by mixing at least one excipient, such as starch, sucrose or lactose, gelatin, and other substances, with the active ingredient. Furthermore, in addition to the common excipients used lubricant such as magnesium stearate and talc. Liquid dosage forms for oral administration include suspensions, solution, emulsion and syrup. In addition to the commonly used diluent, such as water and liquid paraffin, may be used various excipients such as wetting agent, a sweetener, a flavouring agent, preservative, and other substances. Dosage forms for refererlog injection include sterile aqueous solution, a nonaqueous solution, suspension, emulsion, dried product, and suppositories. For non-aqueous solution and suspension can be used propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester type ethyloleate, and others in the society. For the base of the suppository can be used Witepsol, Macrogol, Tween 61, fat cocoa, lauric fat, glycoregulation, and other substances.

Dose injection of the pharmaceutical composition according to the present invention may depend on the patient's age, body weight, sex, method of administration, physical condition and the severity of the disease. Effective dose injection of salt SK-3530 is 10.0-200.0 mg, preferably 20-150 mg, calculated on the weight of the free base of SK-3530.

The best option of carrying out the invention

Practical and presently preferred embodiments of the present invention are illustrated by the following examples. However, it should be borne in mind that the experts in this area on the basis of this description to make modifications and improvements within the essence and scope of the present invention.

Example 1: Getting gentisate salt SK-3530

2,44 g hentaimovi acid was dissolved in 100 ml of acetone, and the resulting solution was stirred at room temperature. 8.0 g of the free base of SK-3530 was dissolved in 100 ml of acetone and slowly added to the solution hentaimovi acid. The mixture was stirred for 1 hour at room temperature and the resulting solid was filtered, washed with 20 ml of acetone and dried under vacuum at 50 the C with the receipt of 7.96 g (yield: 77.1 percent) of white crystalline target connection.

1H-NMR (300 MHz, DMSO-d6) δ (ppm) 11,70 (s, 1H), 7,89 (d, 1H), 7,80 (DD, 1H), 7,38 (d, 1H), 7,31 (s, 1H), 7,14 (d, 1H), 6.87 in (DD, 1H), of 6.71 (d, 1H), 4,37 (square, 2H), 4,12 (t, 2H), 3,47 (t, 2H), 2.95 and (m, 4H), to 2.66 (m, 4H), 2,59-2,48 (m, 4H), 1.77 in-to 1.59 (m, 4H), of 1.35 (t, 3H), of 0.96 (t, 3H), of 0.92 (t, 3H).

Example 2: Getting gentisate salt SK-3530

2,44 g hentaimovi acid was dissolved in 100 ml of acetone, and the resulting solution was stirred at room temperature. 8.0 g of the free base of SK-3530 was slowly added to a solution of hentaimovi acid. The mixture was stirred for 1 hour at room temperature and the resulting solid was filtered, washed with 20 ml of acetone and dried under vacuum at 50°C to obtain a white crystal of the target connection.

Example 3: Getting gentisate salt SK-3530

200 mg of the free base of SK-3530 suspended in 1 ml of acetone, and the resulting solution was stirred at room temperature. 61 mg hentaimovi acid was dissolved in a mixed solvent of acetone (1 ml) and water (2 ml) and slowly added to a solution of the free base of SK-3530. The mixture was stirred for 30 minutes at room temperature and was further stirred for 30 minutes after adding 12 ml of water. The obtained solid substance was filtered off, washed with 10 ml of water and dried under vacuum at 50°C with getting 249 mg (yield: 96.5 percent) of white crystalline target connection.

Use the 4: Obtain tablets, containing gentisate salt SK-3530

Anhydrous hydroalcoholic calcium (315 g) was mixed with microcrystalline cellulose (525 g, 90 μm) and transferred into the drum mixer. Then gentisate salt SK-3530 (70 g) was mixed with microcrystalline cellulose (187.5 g, 50 μm) and sieved through a sieve into the bowl containing the above-mentioned powder mixture. The sieve was purified using microcrystalline cellulose (525 g, 90 μm). Anhydrous hydroalcoholic calcium (315 g) was added to the mixture and was stirred for 10 minutes. Then to the mixture was added sodium starch glycolate (40 g)and was stirred for 6 minutes. And, finally, was added magnesium stearate (20 g) and was stirred for 3 minutes. The obtained powder mixture was pressed into tablets in the usual method.

Example 5: Receiving capsules containing gentisate salt SK-3530

Microcrystalline cellulose (525 g, 90 μm) was mixed with dry corn starch. Gentisate salt SK-3530 (70 g) was mixed with pre-mix and sift through a sieve. Added the remaining corn starch and after 10 minutes of mixing was conducted screening and then further mixed for 5 minutes. Filled product capsule of appropriate size.

Example 6: Obtaining injectable solution containing gentisate salt SK-3530

The sodium chloride was dissolved in trilinos water for injection and mixed with propylene glycol. Added gentisate salt SK-3530 and, after dilution, was additionally added sterile water for injection to obtain a solution with the required concentration. The resulting solution was filtered through a sterilizing filter and filled them sterile vials, used as a container for injection.

Example 7: Getting maleate salt SK-3530

1.44 g of maleic acid was dissolved in 100 ml of acetone, and the resulting solution was stirred at room temperature. 6.0 g of the free base of SK-3530 was slowly added to a solution of maleic acid. The mixture was stirred for 1 hour at room temperature, and 50 ml acetone was removed by condensation under reduced pressure. The obtained solid substance was filtered off, washed with 20 ml of ether and was dried under vacuum at 50°C with getting 7,02 g (yield: 96,0%) of white crystalline target connection.

1H-NMR (300 MHz, DMSO-d6) δ (ppm) 11,73 (s, 1H), 7,94 (d, 1H), to 7.84 (DD, 1H), 7,42 (d, 1H), 7,32 (s, 1H), between 6.08 (s, 2H), 4,37 (square, 2H), 4,14 (t, 2H), 3,62 (t, 2H), 3,52-2,70 (m, 10H), to 2.57 (t, 2H), 1,79 is 1.60 (m, 4H), of 1.36 (t, 3H), to 0.97 (t, 3H), of 0.92 (t, 3H).

Example 8: Getting maleate salt SK-3530

1.44 g of maleic acid was dissolved in 100 ml of acetone, and the resulting solution was stirred at room temperature. 6.0 g of the free base of SK-3530 was dissolved in 100 ml of acetone and slowly added to a solution of malé is the new acid. The mixture was stirred for 1 hour at room temperature, and 50 ml acetone was removed by condensation under reduced pressure. The obtained solid substance was filtered off, washed with 20 ml of ether and was dried under vacuum at 50°C to obtain a white crystal of the target connection.

Example 9: Getting maleate salt SK-3530

60 mg of the free base of SK-3530 suspended in 1 ml of acetone, and the resulting solution was stirred at room temperature. 14.4 mg of maleic acid was dissolved in a mixed solvent of acetone (1 ml) and water (2 ml) and slowly added to a solution of the free base of SK-3530. The mixture was stirred for 1 hour at room temperature and the resulting solid was filtered, washed with 20 ml of acetone and dried under vacuum at 50°C to obtain a white crystal of the target connection.

Example 10: Obtaining tablets containing maleato salt SK-3530

Anhydrous hydroalcoholic calcium (315 g) was mixed with microcrystalline cellulose (525 g, 90 μm) and transferred into the drum mixer. Then maleato salt SK-3530 (70 g) was mixed with microcrystalline cellulose (187.5 g, 50 μm) and sieved through a sieve into the bowl containing the above-mentioned powder mixture. The sieve was purified using microcrystalline cellulose (525 g, 90 μm). Was added to a mixture of anhydrous hydrocortisone (315 g) and was stirred for 10 minutes. Then to the mixture was added sodium starch glycolate (40 g) and was stirred for 6 minutes. And, finally, was added magnesium stearate (20 g) and was stirred for 3 minutes. The obtained powder mixture was pressed into tablets in the usual method.

Example 11: Obtain capsules containing maleato salt SK-3530

Microcrystalline cellulose (525 g, 90 μm) was mixed with dry corn starch. Maleato salt SK-3530 (70 g) was mixed with pre-mix and sift through a sieve. Added the remaining corn starch and after 10 minutes of mixing was conducted screening and then further mixed for 5 minutes. The product was filled capsule of appropriate size.

Example 12: Obtaining injectable solution containing maleato salt SK-3530

The sodium chloride was dissolved in sterile water for injection and mixed with propylene glycol. Added maleato salt SK-3530 and, after dilution, was additionally added sterile water for injection to obtain a solution with the required concentration. The resulting solution was filtered through a sterilizing filter and filled them sterile vials, used as a container for injection.

Example 13: Getting citrate salt SK-3530

totaling 3.04 g of citric acid was dissolved in 100 ml of acetone, and the obtained races the thief was stirred at room temperature. 8.0 g of the free base of SK-3530 was dissolved in 100 ml of acetone and slowly added to a solution of citric acid. The mixture was stirred for 1 hour at room temperature and the resulting solid was filtered, washed with 20 ml of acetone and dried under vacuum at 50°C to obtain 10.5 g (yield: 96.4 per cent) of white crystalline target connection.

1H-NMR (300 MHz, DMSO-d6) δ (ppm) 11,70 (s, 1H), 7,88 (d, 1H), 7,80 (DD, 1H), 7,38 (d, 1H), 7,31 (s, 1H), 4,37 (square, 2H), 4,12 (t, 2H), 3,44 (t, 2H), 3.00 and-and 2.83 (m, 4H), 2,75-of 2.54 (m, 8H), of 2.51-2,47 (m, 4H), 1,75-of 1.62 (m, 4H), 1,35 (t, 3H), of 0.96 (t, 3H), of 0.92 (t, 3H).

Example 14: Getting citrate salt SK-3530

totaling 3.04 g of citric acid was dissolved in 100 ml of acetone, and the resulting solution was stirred at room temperature. 8.0 g of the free base of SK-3530 was dissolved in 100 ml of acetone and slowly added to a solution of citric acid. The mixture was stirred for 1 hour at room temperature and the resulting solid was filtered, washed with 20 ml of acetone and dried under vacuum at 50°C to obtain a white crystal of the target connection.

Example 15: Getting citrate salt SK-3530

80 mg of the free base of SK-3530 suspended in 1 ml of acetone, and the resulting solution was stirred at room temperature. 30,4 mg of citric acid was dissolved in a mixed solvent of acetone (1 ml) and water (2 ml) and slowly added to the solution slobodnog the base of SK-3530. The mixture was stirred for 30 minutes at room temperature and was further stirred for 30 minutes after adding 12 ml of water. The obtained solid substance was filtered off, washed with 10 ml of water and dried under vacuum at 50°C to obtain a white crystal of the target connection.

Example 16: Obtaining tablets containing citrate salt SK-3530

Anhydrous hydroalcoholic calcium (315 g) was mixed with microcrystalline cellulose (525 g, 90 μm) and transferred into the drum mixer. Then citrate salt SK-3530 (70 g) was mixed with microcrystalline cellulose (187.5 g, 50 μm) and sieved through a sieve into the bowl containing the above-mentioned powder mixture. The sieve was purified using microcrystalline cellulose (525 g, 90 μm). Was added to a mixture of anhydrous hydroalcoholic calcium (315 g) and was stirred for 10 minutes. Then added to the mixture of sodium starch glycolate (40 g) and was stirred for 6 minutes. And, finally, was added magnesium stearate (20 g) and was stirred for 3 minutes. The obtained powder mixture was pressed into tablets in the usual method.

Example 17: Receive capsules containing citrate salt SK-3530

Microcrystalline cellulose (525 g, 90 μm) was mixed with dry corn starch. Citrate salt of SK-3530 (70 g) was mixed with pre-mix and sift through a sieve. To allali remaining cornstarch and after 10 minutes of mixing was conducted screening and then further mixed for 5 minutes. The product was filled capsule of appropriate size.

Example 18: Obtaining injectable solution containing citrate salt SK-3530

The sodium chloride was dissolved in sterile water for injection and mixed with propylene glycol. Added citrate salt SK-3530 and, after dilution, was additionally added sterile water for injection to obtain a solution with the required concentration. The resulting solution was filtered through a sterilizing filter and filled them sterile vials, used as a container for injection.

Example 19: Obtaining fumaric salt SK-3530

1.44 g of fumaric acid was dissolved in 100 ml of acetone, and the resulting solution was stirred at room temperature. 6.0 g of the free base of SK-3530 was slowly added to a solution of fumaric acid. The mixture was stirred for 1 hour at room temperature and after removal of 50 ml of acetone by condensation under reduced pressure, the obtained solid substance was filtered off, washed with 20 ml of ether and was dried under vacuum at 50°C with getting 6,92 g (yield: 94.7 percent) of white crystalline target connection.

1H-NMR (300 MHz, DMSO-d6) δ (ppm) of 11.69 (s, 1H), 7,88 (d, 1H), 7,79 (DD, 1H), 7,37 (d, 1H), 7,30 (s, 1H), 6,62 (s, 2H), 4,37 (square, 2H), 4,12 (t, 2H), 3.43 points (t, 2H), 2,90 (m, 4H), 2,59-2,48 (m, 6H), 2.40 a (t, 2H), 1,75-to 1.59 (m, 4H), of 1.35 (t, 3H), of 0.96 (t, 3H), of 0.92 (t, 3H).

Primer: Getting fumaric salt SK-3530

1.44 g of fumaric acid was dissolved in 100 ml of acetone, and the resulting solution was stirred at room temperature. 8.0 g of the free base of SK-3530 was dissolved in 100 ml of acetone and slowly added to a solution of fumaric acid. The mixture was stirred for 1 hour at room temperature and the resulting solid was filtered, washed with 20 ml of acetone and dried under vacuum at 50°C to obtain a white crystal of the target connection.

Example 21: Getting fumaric salt SK-3530

80 mg of the free base of SK-3530 suspended in 1 ml of acetone, and the resulting solution was stirred at room temperature. 14.4 mg of fumaric acid was dissolved in a mixed solvent of acetone (1 ml) and water (2 ml) and slowly added to a solution of the free base of SK-3530. The mixture was stirred for 30 minutes at room temperature and was further stirred for 30 minutes after adding 12 ml of water. The obtained solid substance was filtered off, washed with 10 ml of water and dried under vacuum at 50°C to obtain a white crystal of the target connection.

Example 22: Obtaining tablets containing fumaric salt SK-3530

Anhydrous hydroalcoholic calcium (315 g) was mixed with microcrystalline cellulose (525 g, 90 μm) and transferred into the drum mixer. Then fumaric salt SK-3530 (70 g) was mixed with microcr starecheski cellulose (187.5 g, 50 µm) and sieved through a sieve into the bowl containing the above-mentioned powder mixture. The sieve was purified using microcrystalline cellulose (525 g, 90 μm). Anhydrous hydroalcoholic calcium (315 g) was added to the mixture and was stirred for 10 minutes. Then to the mixture was added sodium starch glycolate (40 g) and was stirred for 6 minutes. And, finally, was added magnesium stearate (20 g) and was stirred for 3 minutes. The obtained powder mixture was pressed into tablets in the usual method.

Example 23: Obtain capsules containing fumaric salt SK-3530

Microcrystalline cellulose (525 g, 90 μm) was mixed with dry corn starch. Fumaric salt SK-3530 (70 g) was mixed with pre-mix and sift through a sieve. Added the remaining corn starch and after 10 minutes of mixing was conducted screening and then further mixed for 5 minutes. The product was filled capsule of appropriate size.

Example 24: Obtaining injectable solution containing fumaric salt SK-3530

The sodium chloride was dissolved in sterile water for injection and mixed with propylene glycol. Added fumaric salt SK-3530 and, after dilution, was additionally added sterile water for injection to obtain a solution with the required concentration. The resulting solution was filtered through art is religouse filter and filled them sterile ampoule, used as a container for injection.

Example 25: Getting protectrate salt SK-3530

1.19 g of tartaric acid was dissolved in 100 ml of acetone, and the resulting solution was stirred at room temperature. 8.0 g of the free base of SK-3530 was dissolved in 100 ml of acetone and slowly added to a solution of tartaric acid. The mixture was stirred for 1 hour at room temperature and the resulting solid was filtered, washed with 20 ml of acetone and dried under vacuum at 50°C to obtain 7.6 g (yield: 83,2%) of white crystalline target connection.

1H-NMR (300 MHz, DMSO-d6) δ (ppm) 11,70 (s, 1H), 7,87 (d, 1H), 7,79 (DD, 1H), 7,38 (d, 1H), 7,31 (s, 1H), 4,36 (square, 2H), 4.26 deaths (s, 1H), 4,12 (t, 2H), 3,42 (t, 2H), 2,89 (m, 4H), 2,59-2,47 (m, 6H), 2,39 (t, 2H), 1,80-of 1.56 (m, 4H), of 1.35 (t, 3H), of 0.96 (t, 3H), of 0.92 (t, 3H).

Example 26: Getting protectrate salt SK-3530

1.19 g of tartaric acid was dissolved in 100 ml of acetone, and the resulting solution was stirred at room temperature. 8.0 g of the free base of SK-3530 was slowly added to a solution of tartaric acid. The mixture was stirred for 1 hour at room temperature and the resulting solid was filtered, washed with 20 ml of acetone and dried under vacuum at 50°C to obtain a white crystal of the target connection.

Example 27: Obtaining tablets containing polytechneiou salt SK-3530

todny hydroalcoholic calcium (315 g) was mixed with microcrystalline cellulose (525 g, 90 µm) and transferred into the drum mixer. Then polytechneiou salt SK-3530 (70 g) was mixed with microcrystalline cellulose (187.5 g, 50 μm) and sieved through a sieve into the bowl containing the above-mentioned powder mixture. The sieve was purified using microcrystalline cellulose (525 g, 90 μm). Anhydrous hydroalcoholic calcium (315 g) was added to the mixture and was stirred for 10 minutes. Then added to the mixture of sodium starch glycolate (40 g) and was stirred for 6 minutes. And, finally, was added magnesium stearate (20 g) and was stirred for 3 minutes. The obtained powder mixture was pressed into tablets in the usual method.

Example 28: Receive capsules containing polytechneiou salt SK-3530

Microcrystalline cellulose (525 g, 90 μm) was mixed with dry corn starch. Polytechneiou salt SK-3530 (70 g) was mixed with pre-mix and sift through a sieve. Added the remaining corn starch and after 10 minutes of mixing was conducted screening and then further mixed for 5 minutes. The product was filled capsule of appropriate size.

Example 29: Obtaining injectable solution containing polytechneiou salt SK-3530

The sodium chloride was dissolved in sterile water for injection and mixed with propylene glycol. Added polytechneiou salt SK-3530 and, after dissolution, the more were added to sterile water for injection to obtain a solution with the required concentration. The resulting solution was filtered through a sterilizing filter and filled them sterile vials, used as a container for injection.

The test example 1: Test for stability

This test is used to confirm the stability during storage of salt SK-3530.

1) Resistance to water and weathering

In the process of obtaining a specific pharmaceutical form of the medicinal product therefore it should be quite stable. For example, tablets or capsules requires resistance to weathering, and receiving the injection solution requires resistance to the action of water.

In the following table 1 (25°C, humidity 75%), table 2 (40°C, humidity 60%) and table 3 (50°C, humidity 75%) presents the total content of impurities, as measured by liquid chromatography after storage dihydrochloride (2HCl), gentisate, maleate, citrate, fumaric and protectrate salts SK-3530 within 1 week and 3 weeks.

Table 1
Salt SK-3530The content of impurities (%) at 25°C. and humidity of 75%
Source1 week 3 weeks
Dihydrochloride salt SK-35300,200,240,31
Gentisate salt SK-35300,090,090,12
Malata salt SK-35300,120,120,12
Citrate salt of SK-35300,120,150,15
Fumaric salt SK-35300,020,020,03
Polytetra salt SK-35300,070,090,13

Table 2
Salt SK-3530The content of impurities (%) at 40°C and humidity 60%
Source1 week3 weeks
Dihydrochloride salt SK-3530 0,200,240,38
Gentisate salt SK-35300,090,100,10
Malata salt SK-35300,120,120,12
Citrate salt of SK-35300,120,130,14
Fumaric salt SK-35300,020,020,05
Polytetra salt SK-35300,070,100,14

Table 3
Salt SK-3530The content of impurities (%) at 50°C and relative humidity 75%
Source1 week3 weeks
Dihydrochloride salt SK-35300,200,270,42
Gentisate salt SK-35300,090,090,10
Malata salt SK-35300,120,150,19
Citrate salt of SK-35300,120,140,14
Fumaric salt SK-35300,020,020,05
Polytetra salt SK-35300,070,110,13

2) Test for resistance to the action of light

In the following table 4 and table 5 shows the results of testing for resistance to the action of light for dihydrochloride (2HCl), gentisate, maleate, citrate, fumaric and protectrate salts SK-3530. The total ultraviolet (UV) radiation was 200 watt-hours/m2and the total radiation in the visible part of the spectrum was 1080 kilolux/m2hour. Each salt was kept in a Petri dish at 25°C and humidity 60%.

Table 4
Salt SK-3530 The content of impurities (%)
SourceUVVisible
Dihydrochloride salt SK-35300,20of 5.921,37
Gentisate salt SK-35300,090,360,17
Malata salt SK-35300,120,350,14
Citrate salt of SK-35300,120,370,14
Fumaric salt SK-35300,020,080,07
Polytetra salt SK-35300,070,520,21

Table 5
Salt SK-3530Color change
Source UVVisible
Dihydrochloride salt SK-3530WhiteBrownYellow
Gentisate salt SK-3530WhitePale-yellowPale-yellow
Malata salt SK-3530WhiteWhiteWhite
Citrate salt of SK-3530WhiteWhiteWhite
Fumaric salt SK-3530WhitePale-yellowWhite
Polytetra salt SK-3530WhiteWhiteWhite

3) Test thermostability

In the following table 6 and table 7 shows the test result of thermal stability for dihydrochloride (2HCl), gentisate, maleate, citrate, fumaric and protectrate salts SK-3530. Each salt was placed on a Petri dish and kept in a drying Cabinet at 105°C. At which lugenia spent 3 hours and 48 hours, the content of impurities was measured using liquid chromatography.

Table 6
Salt SK-3530The content of impurities (%)
Source3 hours48 hours
Dihydrochloride salt SK-35300,203,0614,37
Gentisate salt SK-35300,090,090,13
Malata salt SK-35300,120,150,74
Citrate salt of SK-35300,120,301,81
Fumaric salt SK-35300,020,110,61
Polytetra salt SK-35300,070,140,70

Table 7
Salt SK-3530Color change
Source3 hours48 hours
Dihydrochloride salt SK-3530WhiteWhiteYellow
Gentisate salt SK-3530WhiteWhiteWhite
Malata salt SK-3530WhiteWhiteWhite
Citrate salt of SK-3530WhiteWhiteWhite
Fumaric salt SK-3530WhiteWhiteWhite
Polytetra salt SK-3530WhiteWhiteWhite

As can be seen from tables 1-7, gentisate, Malatya, citrate, fumaric or polytetra salt SK-3530 in accordance with the present invention thus is has antirouille significantly higher stability during storage, resistance to UV and visible light and thermal stability compared to dihydrochloride salt SK-3530.

Industrial applicability

As described above, gentisate, Malatya, citrate, fumaric or polytetra salt SK-3530 in accordance with the present invention is a crystalline acid salt additive, suitable for a pharmaceutical product, and with excellent PDE-5 inhibitory activity, can be used for the treatment and prevention of erectile dysfunction, pulmonary hypertension, chronic obstructive pulmonary disease, benign prostate hypertrophy and diseases of the lower urinary tract.

Have been described and illustrated preferred embodiments of the present invention. However, they are not limitations to the present invention. In addition, it should be borne in mind that various modifications and variations of the present invention can be made by specialists in this field without deviating from the essence and scope of the present invention defined by the attached claims.

1. An acid additive salt derived pyrrolopyrimidine, represented by the following formula (1),

you choose from gentisate, maleate, citrate, fu is aratoi and protectrate salts.

2. The method of obtaining the acid additive salts derived pyrrolopyrimidine interaction derived pyrrolopyrimidine, represented by the following formula (1)

with a pharmaceutically acceptable acid selected from hentaimovi acid, maleic acid, citric acid, fumaric acid and tartaric acid.

3. The method according to claim 2, which includes:
the dissolution of the pharmaceutically acceptable acid selected from hentaimovi acid, maleic acid, citric acid, fumaric acid and tartaric acid in a solvent selected from the group consisting of water, acetone, methanol, ethanol, isopropanol and acetonitrile, or a mixed solvent to obtain a solution of the acid;
the mixture derived pyrrolopyrimidine represented by the above formula (1), with the acid solution; and
filtration, washing and drying the solid substance obtained by mixing the above mixture with obtaining crystalline acid additive salt.

4. The method according to claim 3, where the concentration of acid in the acid solution is from 1 to 30 wt.%.

5. The method according to claim 2 or 3, where the acid is used in amounts of from 0.5 to 1.3 equivalents relative to the derived pyrrolopyrimidine represented by the formula (1).

6. The method according to claim 2 or 3, where the reaction provocate temperatures from -30 to 50°C.

7. The method according to claim 2 or 3, where the derivative of pyrrolopyrimidine represented by the formula (1), used in solid form or dissolved in a solvent.

8. The method according to claim 7, where the solvent used for dissolving the derivative of pyrrolopyrimidine represented by the formula (1)is one solvent selected from the group consisting of water, acetone, methanol, ethanol, isopropanol and acetonitrile, or a mixed solvent.

9. Pharmaceutical composition for the treatment and prevention of erectile dysfunction, containing an effective amount of an acid additive salt derived pyrrolopyrimidine, represented by the following formula (1)which is selected from gentisate, maleate, citrate, fumaric and protectrate salts, as an active ingredient:

10. Pharmaceutical composition for the treatment and prevention of pulmonary hypertension, chronic obstructive pulmonary disease, benign prostate hypertrophy and diseases of the lower urinary tract, containing an effective amount of an acid additive salt derived pyrrolopyrimidine, represented by the following formula (1)

you choose from gentisate, maleate, citrate, fumaric and polute trutnau salts, as the active ingredient.

11. The pharmaceutical composition according to claim 9 or 10, which is obtained in the form of tablets, capsules or solution for injection.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I): X denotes a single bond or a binding group selected from -CO, -SO2-, -CS- or -CH2-; Y denotes a single bond or a divalent binding group obtained from a cyclic structure selected from benzene, pyridine, pyrimidine, pyrazole, imidazole, thiazole, thiophene, quinoline, benzoimidazole, benzothiazole, benzopyrazole, naphthalene and benzothiophene; X and Y are simultaneously single bonds; Z denotes a hydrogen atom or a substitute selected from a group A; m equals 1 or 2; n equals 0-3; in group A and group B, R, R' and R" can, respectively and independently, be identical or different and denote a hydrogen atom or -C1-6-alkyl; said -C1-6-alkyl can be substituted with a group selected from -OH, -O(C1-6-alkyl),-CONH2, -CONH(C1-6-alkyl), -CON(C1-6-alkyl)2, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2); Sus denotes a C3-C7 saturated or a C5-C10 unsaturated hydrocarbon ring or a nitrogen-containing C3-C7 heterocyclic ring containing 1-4 nitrogen atoms or containing an additional O, S atom; said C1-6 alkylene in groups A and B can be substituted in positions 1-3 with a -N(C1-6- alkyl)2 group, values of radicals R1, A1, T, B and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, a PI3K inhibitor and a medicinal agent having PI3K inhibitor properties against a proliferative diseases such as a malignant tumour.

EFFECT: high efficiency of using the compounds.

21 cl, 645 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to polymorph of 2-[4-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazol-1-yl]ethanol, particularly to a new crystalline phosphate salt of 2-[4-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazol-1-yl]ethanol.

EFFECT: preparing the pharmaceutical composition and using the new salt in treating cell growth abnormalities, such as cancer in mammals.

10 cl, 10 dwg, 6 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I in which: X8 denotes N, and X5 and X6 denote CH; R7 denotes phenyl or C5-6-heteroaryl group which is optionally substituted with one or more groups selected from halogen, hydroxy group, nitro group, cyano group, carboxy group and thiol, or phenyl or a methoxy group -C(=O)CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHCH2CH3, -C(=O)N(CH2CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHCH(CH3)2, -N(CH2CH3)2 or C1-4-alkyl, optionally substituted with a hydroxy group; RN3 and RN4, together with the nitrogen atom with which they are bonded, form a heterocyclic ring selected from morpholine, thiomorpholine, piperidinyl, piperazinyl, homopiperazinyl and a pyrrolidinyl ring, optionally substituted at the carbon atom with one or two C1-4-alkyl groups; R2 denotes NRN5RN6, where RN5 and RN6, together with the nitrogen atom with which they are bonded, form a heterocyclic ring selected from morpholine, thiomorpholine, piperdinyl, piperazinyl, homopiperazinyl and a pyrrolidinyl ring, optionally substituted at the carbon atom with one or two C1-4-alkyl groups; or a pharmaceutically acceptable salt thereof, and where "C5-6-heteroaryl" denotes a heteroaryl group selected from furan, thiophene, pyrrole, imidazole, pyrazole, triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, tetrazole, octatriazole, isoxazine, pyridine, pyridazine, pyrimidine, pyrazine and triazine; and where "C3-5-heterocyclyl", as used here, relates to a univalent structure obtained by removing a hydrogen atom from the ring of the heterocyclic compound, where that structure contains 5 or 6 ring atoms, 1-4 of which are ring heteroatoms selected from oxygen, nitrogen and sulphur; and under the condition that when R2 denotes an unsubstituted morpholine group, RN3 and RN4, together with the nitrogen atom with which they are bonded, form a morpholine group, R7 does not denote an unsubstituted phenyl, and when R2 denotes an unsubstituted piperidinyl, RN3 and RN4, together with the nitrogen atom with which they are bonded, form an unsubstituted piperidinyl, R7 does not denote unsubstituted phenyl. The invention also relates to a pharmaceutical composition based on compounds of formula I and having mTOR inhibiting activity.

EFFECT: novel compound which can be suitable for treating malignant growths is obtained and described.

10 cl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine, particularly to application of an antiviral agent - 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazin-7-one dehydrate sodium salt (hereinafter - the Agent) for preventing and treating viral diseases caused by a tick-borne encephalitis virus. Also, there is described method for preventing and treating conditions caused by the tick-borne encephalitis virus in humans and animals involving introduction of the Agent presented above to humans and animals.

EFFECT: extended range of the drug preparations possessing a wide spectrum of action and used for treating and preventing tick-borne encephalitis.

20 cl, 2 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolo-[1,2-a]benzimidazole derivatives of formula I , where NR2 assumes morpholino or diethylamino values, and Ar is 4-methoxyphenyl or 4-chlorophenyl, having antioxidant and antiradical properties.

EFFECT: obtaining novel sulphates possessing useful biological properties.

2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: present invention refers to the field of organic chemistry, notably to derivatives of dihydroimidazole with the general formula (I) and to its pharmaceutically acceptable salts where X1 and X2 denote halogen; R1 and R2 are chosen from the group including -H, -CH3, -CH2CH3 on the condition that both R1 and R2 do not denote hydrogen; R3 denotes -H or -C(=O)-R7; and if R6 denotes hydrogen, then R4 denotes -OCH3, -OCH2CH3 or -OCH(CH3)2; R5 denotes -H, - halogen, -CF3, -OCH3, -C(CH3)2, - cyclopropyl, - cyano group, -C(CH3)3, -C(CH3)2OR (where R denotes -H), -C(CH3)2CH-OR (where R denotes -CH3), -C(CH3)2CN, -C(CH3)2COR (where R denotes -CH3), -SR (where R denotes -CH2CH3) or -SO2R (where R denotes -CH3, -CH2CH3, 1-pyrrolidine, -NH-tert-butyl); and if R6 does not denote hydrogen, then R4 denotes -OCH2CH3; R5 denotes hydrogen, -Cl, -OCH3, tert butyl; R6 denotes -Cl, cyclopropyl, -SO2R (where R denotes -CH3, 1-pyrrolidine, -NH-tert-butyl or -N(CH3)2); and R7 is chosen from the group including i) -CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, cyclobutyl, -CH2CH2Ph, 2-furanyl, phenyl or phenyl substituted with chlorine, -OCH3 or cyano group, ii) 1-piperidinyl, iii) -NRc2 (where Rc denotes -CH2CH2OH, -CH2CH2OCH3 or -CH2CH(OH)CH2OH, iv) substituted piperazidine with the formula where R is chosen from the group including a) hydrogen, c) -CH(CH3)2, k) -CH2CH2Rd (where Rd denotes -OH, -OCH3, -CF3, -SO2CH3, -NH2, -NHCOCH3, -NHSO2CH3, 4-morfolinil, 2-izotiazolidinil-1, 1-dioxide), l) -CH2CH2CH2Re (where Re denotes -OCH3, -SO2CH3, -SO2CH2CH3, -CN), m) -CH2-CO-Rh (where Rh denotes -NH2, 1-pyrrolidinyl, 4-morfolinil), n) -SO2Ri (where Ri denotes -CH3, -CH2CH3), o) -CORj (where Rj denotes -CH3, 2-tetrahydrofuranyl, -NH2, -N(CH3)2), p) 4-tetrahydro-2H-thiopiranyl-1,1-dioxide, q) 4-piperidinyl-1-acetyl, r) 4-piperidinyl-1-dimethylcarboxamide, and s) 3-tetrahydrothiophenyl-1,1-dioxide; v) substituted oxopiperazine with the formula where R denotes -H; and vi) substituted piperidine with the formula where R denotes -CONH2, -OH, -CH2OH, -CH2CH2OH, 1-pyrrolidinyl, 1-piperidinyl, 1-(4-methylpiperazinyl) or 4-morfolinil. Moreover, the invention refers to the pharmaceutical composition based on the compound with the formula (I), to application of the formula (I) compound for production of a drug, to the production process of the formula (I) compound.

EFFECT: new derivatives of dihydroimidazole that may be used as anticancer drugs.

40 cl, 204 ex

FIELD: pharmachology.

SUBSTANCE: invention describes new compounds with general formula (I-c) Where R1 is a radical (d-1) or (d-2) (radical values are given in the invention formula) and pharmaceutical composition containing them. The described compounds are the hepatitis C inhibitors and can be used in medicine.

EFFECT: enhanced hepatitis C inhibition.

5 cl, 1 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds selected from a group consisting of compounds of formula: and or to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition, as well as to using at least one compound under cl.1 and/or its pharmaceutically acceptable salts.

EFFECT: preparing new biologically active compounds which exhibit the properties of cycline-dependent kinase inhibitors.

11 cl, 86 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of novel 4-(azacycloalkyl)phthalonitriles. Novel 4-(azacycloalkyl)phthalonitriles of general formula

are obtained. The method of obtaining said compounds involves nucleophilic substitution of the bromine atom in 4-bromophthalonitrile (BPN) with N,N-cycloalkyleneamines.

.

The reaction takes place in the presence of a deprotonation agent K2CO3 and a catalytic complex Cul/dipyridyl formed in situ at temperature 90-95°C for 12 hours. Molar ratio of reactants BPN: amine: Cul: dipyridyl: K2CO3=1:1.2:0.1:0.1:1.5. After the reaction, the mixture is cooled and filtered. The filtered residue is washed with water and recrystallised.

EFFECT: obtaining novel 4-(azacycloalkyl)phthalonitriles using a method which is safe for this class of compounds.

2 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula in which Q together with carbon and nitrogen atoms whereto attached forms a 9-10-member bicyclic heterocycle, and R1 and R2, R3, R4, R5 and R6 are as specified in cl.1 of the patent claim, or to its enantiomers, or a mixture of its enantiomers, or to its pharmaceutically acceptable salt. Also, an invention refers to a method for activation of glucokinase activity in mammals, by introduction of the compound described above, to a method of treating the pathological conditions associated with glucokinase activity and impaired glucose tolerance by means of introduction of the compound of formula I, to a pharmaceutical composition on the basis of the presented compounds, and also to application of the compounds of formula I for preparing the pharmaceutical composition.

EFFECT: there are produced and described new compounds which are activators of glucokinase activity and can be used as therapeutic agents for preventing and treating impaired glucose tolerance, insulin-independent diabetes and obesity.

14 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound of formula pharmaceutically acceptable salt or solvate of a compound or salt (I), ring Q represents optionally substituted monocyclic or condensed (C6-C12)aryl or optionally substituted monocyclic or condensed heteroaryl where said substitutes are chosen from: halogen; (C1-C6)alkyl optionally substituted by 1-3 halogen atoms; (C1-C6)alkylsulphonyl; phenyl optionally substituted by 1 or 2 substitutes chosen from halogen, (C1-C6)alkyl which can be substituted by 1-3 halogen atoms, groups (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and (C1-C6)alkylthio; monocyclic or condensed heteroaryl optionally substituted by halogen; or oxo; Y1 represents a bond or -NR6-CO-, where R6 represents hydrogen, ring A represents optionally substituted a nonaromatic heterocyclyldiyl where said substitutes are chosen from (C1-C6)alkyl optionally substituted by groups hydroxy, (C1-C6)alkylamino, di(C1-C6)alkylamino, morpholino, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl; cyano; (C3-C6)cycloalkyl; (C1-C6)alkoxy; (C1-C6)alkoxy(C1-C6)alkyl; phenyl; benzyl; benzyloxymethyl; thienyl; 4-8-members monocyclic nonaromatic heterocycle having 1 or 2 heteroatoms chosen from N or O, and optionally substituted by 1 or 2 substitutes chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and oxo; (C1-C6)alkylamino; di(C1-C6)alkylamino; a group of formula: -Y2Z'- represents a group of formula: [Formula 2] each R7 independently represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, each of R8 and R9 independently represents hydrogen or (C1-C6)alkyl, n is equal to an integer 0 to 3, Z1 represents a bond, -O-, -S- or-NR9 - where R9 represents hydrogen, (C1-C6)alkyl, acyl or (C1-C6)alkylsulphonyl, ring B represents optionally substituted aromatic carbocyclediyl or optionally substituted aromatic heterocyclediyl where said substitutes are chosen from (C1-C6)alkyl, halogen, (C1-C6)alkoxy and oxo; Y3 represents a bond optionally substituted (C1-C6)alkylene or (C3-C6)cycloalylene, optionally interrupted -O- or optionally substituted (C2-C6)alkenylene where said substitutes are chosen from (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen and (C1-C6)alkoxycarbonyl; Z2 represents COOR3; R3 represents hydrogen or (C1-C6)alkyl.

EFFECT: preparation of new compounds.

30 cl, 9 tbl, 944 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of benzene sulphonamide of formula (I), tautomeric and stereoisomeric forms and physiologically acceptable salts thereof: where X is O, S; R1 is H, halogen; R2 is H, halogen; halogen; R3 is NO2, CN; R4 is: ,

where R71 is H; R72 is H; Z1 is -[CH2]P-, where p = 2.

EFFECT: compounds have antagonistic activity towards CCR3, which enables for their use in making medicinal agents.

13 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: inventive subject matter is compouns and their pharmaceutically acceptable salts which can be applied in prevention and treatment of diseases caused by HCV infection. Structural formulae of the compounds are presented in the claim.

EFFECT: obtaining anti-HCV medicine including the claimed compound or its pharmaceutically acceptable salt as active component.

2 cl, 100 ex

FIELD: medicine; cosmetology.

SUBSTANCE: invention contains antiperspirant, continuous phase and structure-forming agent containing cyclic depeptide derivative, method of production thereof, method of hidropoiesis prevention or reduction, derivative of cyclic depeptide and gel base for antiperspirant.

EFFECT: compositions have higher activity.

46 cl, 10 tbl, 6 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compositions and methods for treatment of depressive disorder in subject using the therapeutically effective dose of agonist(s) of delta-receptors of the general formula: wherein Ar1 represents a 6-membered carbocyclic aromatic ring with a substitute Y at its carbon atom wherein Y represents carboxamide of the formula: CONR9R10 wherein both R9 and R10 represent ethyl group; Z is chosen from group consisting of hydrogen atom (H), -OH and alkoxy-group; Ar2 represents a 6-membered carbocyclic aromatic ring with a substitute X at its carbon atom wherein X represents H, or pharmaceutically acceptable ester or salt of such compound. Invention provides antidepressant effect in a patient in using indicated compounds in lower doses as compared with the known agonists of delta-receptors showing the related chemical structure with compounds proposed.

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

17 cl, 1 tbl, 21 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of formula I , wherein G is carbon or nitrogen atom; A is i) phenyl substituted with any from -COOH, -CONH2, COOCH3, -CN, -NH2 or -COCH3; ii) naphthyl, benzophuranyl, and quinolinyl; and iii) formulae , , .

Compounds of present invention are useful in particular in pain treatment.

EFFECT: new agents for pain treatment.

58 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered a pharmaceutical composition for treating and/or preventing arterial hypertension containing an angiotensin converting enzyme (ACE) inhibitor and N-acetyl-5-methoxytriptamine (melatonin) in the following proportions: ACE inhibitor - 2-4; N-acetyl-5-methoxytriptamine (melatonin) - 2-8; excipients - up to 100 mg with the ACE inhibitor being presented by the compounds specified in a group of enalapril, captopril, perindopril, lisinopril, fozinopril, quinapril, spirapril. The pharmaceutical composition may be presented by a solid dosage form - a tablet, a film-coated tablet, a softgel capsule, a solid gel capsule, by a soft dosage form - a rectal suppositorium.

EFFECT: providing a therapeutically significant effect (stable night-time blood pressure profile) and a lower risk of side effects due to using the doses low for the ACE inhibitors specified above have been shown.

3 cl, 3 tbl

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