Salt of condensed heterocyclic derivative and its crystals

FIELD: chemistry.

SUBSTANCE: invention relates to novel choline salt of 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid, corresponding to formula and to its crystalline form. Crystalline form of salt (A) has characteristic peaks at diffraction angles (2θ(E)) 7.1, 11.5, 19.4, 20.3, 21.5, 22.0, 22.6, 23.5 and 26.2 in diagram of powder diffraction of X-rays, characteristic peaks of values of chemical shifts (δ(ppm)) 155.8, 149.8, 145.3, 118.0, 113.7, 111.6, 110.3, 98.1, 69.8, 58.7, 57.1 and 55.5 in solid-state 13C NMR spectrum and characteristic peaks of values of chemical shifts (δ(ppm)) -131.6, -145, and -151.8 in solid-state 19F NMR spectrum, as well as endothermic peak about 213°C in diagram of differential-thermal analysis.

EFFECT: compound has excellent solubility and stability in storage.

5 cl, 5 dwg, 3 tbl, 8 ex

 

Area of technology

The present invention relates to the compound (chemical name choline salt of 3-[2-fluoro-5-(2,3-debtor-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-diokso-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid; hereinafter referred to as "compound a") represented by a formula:

which has antagonistic activity against gonadotroponogo-releasing hormone, and is useful as a preventive or therapeutic agent for the treatment of sex hormone-dependent diseases such as benign prostatic hypertrophy, hysteromyoma, endometriosis, uterine fibroids, early puberty, amenorea, premenstrual syndrome, dysmenorrhea or similar.

Prior art

The compound (hereinafter referred to as "compound (B)") represented by a formula:

which has antagonistic activity against gonadotroponogo-releasing hormone, and is useful as a preventive or therapeutic agent for the treatment of sex hormone-dependent diseases such as benign prostatic hypertrophy, hysteromyoma, endometriosis, uterine fibroids, early puberty, amenorea, premenstrual syndrome, dysmenorrhea or p�daubney, described in the patent reference 1.

The publication contains only a General description of salts, such as pharmaceutically acceptable salts, and does not inform about the specific salts of the compound (B).

Patent reference 1: International Publication pamphlet 2007/046392

Description of the invention

The problem solved by the present invention

The authors of the present invention conducted diligent work confirmed that the compound (B) described in the patent reference 1 is amorphous or crystalline. One of the aspects of an amorphous state is that it is difficult, for example, to isolate and purify on an industrial scale in accordance with certain requirements, so the crystals are more preferable as the substance of the medicinal product. However, as will be described below in the example test (the test for limit of solubility), in crystals of the compound (B), there is the problem of solubility. Poor solubility often causes problems absorbability of the drug and may require ingenuity in the development of the formulation with compound (B) used as a medicinal drug. Therefore, for the application of the compound (B) as substances of a medicinal product requires the improvement of its solubility.

Means for solving the problems.

The authors of the present invention have conducted intensive�s studies to solve the aforementioned problems and found that what is the choline salt of 3-[2-fluoro-5-(2,3-debtor-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-diokso-l,2,3,4-tetrahydrothieno-[3,4-d]pyrimidine-5-carboxylic acid has a significantly higher solubility and desirable storage stability and, therefore, represents a preferred compound as the substance of the medicinal product. The present invention is entirely based on these received data.

That is, the present invention relates to:

(1) the compound represented by the aforementioned formula (A);

(2) the compound according to claim(1), which is crystalline;

(3) the compound according to claim(2), which has characteristic peaks at angles of diffraction (2θ(°)) 7,1, 11,5, 19,4, 20,3, 21,5, 22,0, 22,6, 23,5 and 26.2 on the graph of powder x-ray diffraction;

(4) the compound according to claim(2), which has characteristic peaks at values of chemical shifts (δ(ppm)) 1558, 149,8, 145,3, 118,0, 113,7, 111,6, 110,3, 98,1, 69,8, 58,7, 57,1 and 55.5 in the diagram of solid-state NMR spectra of13C;

(5) the compound according to claim(2), which has characteristic peaks at values of chemical shifts (δ(ppm)) 131,6, -145,2 and -151,8 in the diagram of solid-state NMR spectra of19F;

(6) the compound described in any one of the above claims.(2) to(5), which has an endothermic peak level 213ºC on thermogram of differential thermal analysis;

(7) pharmaceutical compositions containing�th as an active ingredient the compound, as described in any one of the above claims.(1)-(6);

(8) the pharmaceutical composition according to claim(7), which is an antagonist of gonadotropin-releasing hormone;

(9) the pharmaceutical composition according to claim(7), which is an agent for preventing or treating sex hormone-dependent diseases, a regulator of reproduction, contraceptive, medium, causing ovulation, or means for preventing postoperative recurrence of sex hormone-dependent organs;

(10) use of the compound as described in any one of the above claims. (1) to(6), in the production of means for preventing or treating sex hormone-dependent diseases, regulator of reproduction, contraceptive agent that causes ovulation, or means for preventing postoperative recurrence of sex hormone-dependent organs;

(11) the method of preventing or treating sex hormone-dependent diseases, reproductive method of reproduction, method of contraception, the method of inducing ovulation, or prevent postoperative recurrence of sex hormone-dependent organs, comprising administering an effective amount of the compound that is described in one of above paragraphs. (1) to(6) or similar.

The result of the invention

The compound (A) of the present invention dissolves perfectly and has oral absorbability. In addition, the compound (A) has an excellent crystallinity, excellent storage stability and fluidity. The compound (A) is also easy to handle, for example in the technology of preparation of medicines.

Best mode of carrying out the invention

The compound (A) of the present invention can be obtained, for example, using the following method. In particular, for example, in pure form compound (B), which can be obtained using the method described in the patent reference 1, or by using methods corresponding to the present method, mixed with an equal amount (1.0 equivalent), or a small excess of choline hydroxide in a suitable solvent. Then the mixture was dissolved by heating, and the solvent is evaporated or added accordingly as needed. The compound (A) is precipitated when cooled and can then be selected. In addition, the compound (A) can be purified by recrystallization using the same or similar solvent.

The solvent may be any, provided that it does not interfere with the formation of salts. Examples of usable solvents include organic solvents, including alcohols such as methanol, ethanol, 1-prop�ol, 2-propanol, 1-butanol and 2-butanol; ethers, such as tetrahydrofuran and diisopropyl ether, and water. Can also be used a mixture of these solvents.

The compound (A) of the present invention is extremely useful as a means to prevent or treat genital garmoyle-dependent diseases such as benign prostatic hypertrophy, hysteromyoma, endometriosis, fibroids, early puberty, amenorea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, lupus erythematosis, hirsutism, lack of growth, sleep disturbance, acne, baldness, Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer and pituitary tumor, the regulator of reproduction as a means of contraception, means, causing ovulation, an agent for preventing postoperative recurrence of sex hormone-dependent organs, or the like.

The compound (A) according to the present invention can suitably be mixed with a pharmaceutical carrier, traditionally used for the preparation of pharmaceutical compositions.

Pharmaceutical media may be, respectively, in combination with an appropriate dosage form, as described below. As Pharma�eticeskaja media can for example, applied to an inert fillers such as lactose or the like; lubricants such as magnesium stearate or the like; disintegrators such as carboxymethyl cellulose or the like; binders such as hydroxypropyl methylcellulose or the like; surfactants such as macrogol or the like; foaming agents such as sodium bicarbonate or the like; auxiliary means, such as cyclodextrin or the like; acids such as citric acid or the like; stabilizers, such edental sodium or the like; pH regulators such as salt of phosphoric acid or the like.

Examples of dosage forms of the pharmaceutical compositions according to the present invention include oral-used tools, such as powders, granules, fine granules, anhydrous syrups, tablets, capsules and the like; parenteral-used tools, such as injections, poultices, suppositories, and the like; and oral tools are preferred.

Preferably, the above medicines prepared so that the compound (A) according to the present invention was applied in an amount of from 0.1 to 1000 mg per day per adult human in case of oral input means and from 0.01 to 100 mg / day for adults in the case of injections.

P�emery

The present invention is further illustrated in more detail by the following examples and examples of tests. However, the present invention is not limited.

Example 1

The compound (A)

3-[2-fluoro-5-(2,3-debtor-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-diokso-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (of 3.07 g) and 46% aqueous solution of choline hydroxide (1.64 g) was suspendirovanie in a mixed solution of 1-propanol and water (volume ratio of approximately 1:1; 30 ml), the mixture was heated and stirred for 15 min at 60°C. 1-propanol (30 ml) was added to the mixture at 60ºC and the mixture was stirred at room temperature for 1 hour and within the next one hour, was cooled by ice. After precipitation, the precipitate was collected by filtration and washed twice with 1-propanol (1 ml). The obtained solid substance was dried under reduced pressure at 40ºC with the preparation of the compound (A) (2,93 g). Next, this compound was heated and stirred at 60ºC in a mixed solvent of 1-propanol and water (volume ratio of approximately 1:1; 30 ml) and then 1-propanol (30 ml) was added to the solution obtained after hot filtration. The resulting mixture was cooled to room temperature and stirred for 1 hour and within the next one hour, was cooled by ice. The precipitated crystals were isolated by filtration and washed �each mixed solvent of 1-propanol and water (volume ratio of about 3:1; 1 ml). The obtained crystals were air dried for 4 days to produce a compound (A) (2,16 g).

1H-NMR (DMSO-d6)(δ(ppm)): 3,10 (9H, s), 3,35 is-3.45 (2H, m), 3.70 to 3.90 (8H, m), of 4.95 (2H, s), 5,47 (1H, Shir.C), 6,44 (1H, s), of 6.85-to 6.95 (1H, m), 7,05 (1H, d, J=11.5 Hz), 7,11 (1H, d, J=7,4 Hz), of 7.48 (1H, DD, J=9,7 Hz to 19.5 Hz), 11,14 (1H, Shir.C).

The resulting compound (A) was investigated using x-ray powder diffraction, thermal analysis, solid-state NMR spectra of13C and solid-state NMR spectra of19F when the following conditions to obtain relevant data.

For powder x-ray diffraction crystals were crushed in a mortar and measured with the aid of x-ray powder diffraction X Pert Pro MPD (Spectris pic, PANalytical Department) (reflection method; CuKα rays, the tube voltage 45 kV, tube current 40 mA).

The obtained diffraction chart is shown in figure 1, the angles of diffraction (2θ(°)) and relative peak intensities (%), peaks whose relative intensity is approximately 20% or higher are shown in table 1.

7,1
Table 1
The diffraction angle (2θ(°))Relative intensity (%)The diffraction angle (2θ(°))Relative intensity (%)
3821,031
10,432A 21.583
11,54822,082
13,93122,646
14,12923,229
14,32423,539
15,53125,122
16,12326,257
A 16.42026,722
Of 17.42228,329
19,03429,627
19,48630,127
20,02231,222
20,3100--

For reasons connected with the nature of the data of powder x-ray diffraction, 2θ values and the full picture of diffraction are important results to confirm the crystalline identity. It is well known that the relative intensity of x-ray diffraction bands varies depending on the conditions of sample preparation and measurement conditions. It should be noted that the 2θ value of a diffraction pattern in powder x-ray diffraction may vary slightly, depending on the conditions of sample preparation and measurement conditions.

For thermal analysis measurements were conducted using a thermogravimetric/differential thermal analyzer TG-DTA TG8120 (Rigaku Corporation) (heating Rate: 10°C/min; standard: aluminium oxide). The resulting diagram is shown in figure 2.

Endothermic peak: about 213ºC.

It is noticed that the endothermic peak in thermal analysis may be slightly �to rebetica depending on the conditions of sample preparation and measurement conditions.

For measurements of solid-state NMR spectra of13C the sample was loaded into a 4 mm doxycyclinebuy rotor and a measurement was performed using a spectrometer Bruker Avance DRX500 (speed 10 kHz), using the CP/MAS technique. Diagram is obtained spectra are shown in figure 3.

It should be noted that the value of the chemical shift solid-state NMR spectrum of13With may slightly vary depending on the conditions of sample preparation and measurement conditions.

For measurements of solid-state NMR spectra of19F the sample was loaded into a 2.5 mm doxycyclinebuy rotor and a measurement was performed using a spectrometer Bruker Avance III 400 WideBore (rotation speed 30 kHz), with the use of MAS technology. Using a sample of polyvinylidene fluoride(PVDF) as the external standard sample, observed range, which gave resonance to -91,2 ppm. Diagram is obtained spectra are shown in figure 5.

It should be noted that the value of the chemical shift solid-state NMR spectrum of19F may slightly vary depending on the conditions of sample preparation and measurement conditions.

Example 2

The compound (A)

3-[2-fluoro-5-(2,3-debtor-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-diokso-l,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (4.07 g), 46% aqueous solution of choline hydroxide (2.18 g), 2-propanol (200 ml) and water (100 ml) were mixed and heated in the Techa�s 15 min at 40ºC. After removing insoluble substances by filtration, the resulting solution was concentrated and added 2-propanol (80 ml) and diisopropyl ether (80 ml). The mixture is then stirred at room temperature for approximately 1 hour, and then for 4 hours and cooled with ice. The precipitated solid was collected and dried at 90ºC overnight under reduced pressure (yield 3.59 g). To the obtained solid substance (3,56 g) was then added to a mixed solution of ethanol and water (volume ratio of approximately 1:1; 25 ml). The mixture was heated to 65ºC and after the addition at the same temperature of the mixed solution of ethanol and water (volume ratio 1:1; 10 ml) of hot mixture was filtered. The resulting solution was stirred, while at the same time to cool down to room temperature, for 2 hours, and then after addition of ethanol (20 ml) was additionally stirred at room temperature for about 1 hour. Then the mixture was stirred at room temperature for about 1 hour after addition of ethanol (20 ml) and then stirred overnight while cooling with ice. Solid material was isolated from the mixture, washed with ethanol (5 ml) and dried by purging with nitrogen. The solid is further dried at 40ºC overnight under reduced pressure to produce a compound (A) (2,43 g). The floor�Chennai compound (A) was measured powder x-rays diffraction in the same way, as in example 1. The result confirmed that the compound (A) was the same crystalline form, as was observed in example 1.

1H-NMR (DMSO-d6)(δ(ppm)): 3,10 (9H, s), 3,35 is-3.45 (2H, m), 3.70 to 3.90 (8H, m), of 4.95 (2H, s), 5,47 (1H, Shir.C), 6,44 (1H, s), of 6.85-to 6.95 (1H, m), 7,05 (1H, d, J=11.5 Hz), 7,10 (1H, d, J=7,4 Hz), 7,47 (1H, DD, J=9,7 Hz to 19.5 Hz) to 11.11 (1H, Shir.C).

Comparative example 1

The crystals of compound (B)

Ethyl acetate (0.1 ml) was added to an amorphous solid of 3-[2-fluoro-5-(2,3-debtor-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-diokso-l,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (10 mg) and the suspension was heated to 50ºC. The mixture is then dried by purging with nitrogen. The dry residue is then heated to 70ºC and dried over night under reduced pressure to obtain crystals of compound (B) (10 mg). The resulting crystals of the compound (B) was measured on the apparatus of the powder x-ray diffraction in the same manner as in example 1. The obtained diffraction chart is shown in figure 4.

Comparative example 2

The crystals of compound (B)

3-[2-fluoro-5-(2,3-debtor-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-diokso-l,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (0,69 g) was suspended in diisopropyl ether (10 ml) and the mixture was stirred at 60ºC for 3 hours under heating. The mixture is then stirred at room temperature over night, then during the hour while cooling with ice. The solid is collected by filtration and dried under reduced pressure to obtain crystals of compound (B) (0.65 g). The resulting crystals of the compound (B) was measured on the apparatus of the powder x-ray diffraction in the same manner as in example 1. The result confirmed that the compound (B) was the same crystalline form, as was observed in comparative example 1.

Comparative example 3

3-[2-fluoro-5-(2,3-debtor-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-diokso-l,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid N 1/2,N'-dibenzylethylenediamine salt (hereinafter referred to as "compound (C)").

Mixed acetonitrile (10 ml), N,N'-dibenziletilendiaminom (94,5 mg) and 3-[2-fluoro-5-(2,3-debtor-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-diokso-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (200 mg). The suspended mixture at a temperature of approximately 60ºC and stirred, allowing to cool to room temperature. Solid (247 mg) was isolated from the mixture by filtration, and dried at a temperature of approximately 60ºC overnight under reduced pressure.

1H-NMR (DMSO-d6)(δ(ppm)): USD 2.83 (2H, s), with 3.79 (3H, s), of 3.80 (3H, s), a 3.87 (2H, s), of 4.95 (2H, s), of 6.85-to 6.95 (1H, m), 6,98 (1H, s), to 7.09 (1H, d, J=11.5 Hz), of 7.19 (1H, d, J=7.5 Hz), 7,25-to 7.55 (6H, m).

Test example 1

Test of solubility limit

The compound (A) obtained in example 2, Krist�and we compounds (B), obtained in comparative example 2, the compound (C) obtained in comparative example 3 was suspended in water or in the 1st fluid for testing solubility (hereinafter referred to as "the 1st liquid") or the 2nd fluid (hereinafter referred to as "2nd fluid"), as described in Reagents Test Solutions for General Tests of the Japanese Pharmacopoeia, 15th Edition. The suspensions were incubated at 37ºC. After filtering part of the suspensions of the concentration of the obtained filtrates were studied using HPLC (high performance liquid chromatography) and the limit of solubility was calculated and compared.

The HPLC conditions are the following:

Detector: ultraviolet spectrophotometer-visible area/wavelength: 225 nm

Column: GL Science Inertsil ODS-3.5 µm, a 4.6×250 mm

Column temperature: constant at approximately 35ºC

Flow rate: 1.0 ml/min

Mobile phase A: 10 mm aqueous solution of potassium dihydrogen phosphate, brought to pH 5.5 with an aqueous solution of potassium hydroxide

Mobile phase B: Acetonitrile;

Mobile phase ratio of from 0 to 30 min: Mobile phase A/Mobile phase B=70/30.

The values of the solubility limit of the compound (A) crystal connections (B) and compound (C) in water, the 1st liquid 2nd liquid shown in table 2. In the water connection (A) has a solubility limit of approximately 600 times and about 60 times higher than that of the crystals of the compound (B) and compound (C), respectively. The solubility limit of the compound (A) in the 1st fluid was about 30 times and about 2 times higher than that of the crystals of compound (B) and compound (C), respectively. In the 2nd fluid the solubility limit of the compound (A) was about 10 times and about 70 times higher than that of the crystals of compound (B) and compound (C), respectively. These results thus confirm a significant improvement in the solubility of the compound (A) compared with crystals of the compound (B) and compound (C).

Table 2
The compound (A) obtained in example 2The crystals of compound(B) obtained in comparative example 2The compound (C) obtained in comparative example 3
Water4165768
1-I fluid40,142
2-I fluid373836752

Unit of measure: mg/ml

Test �reamer 2

Test oral suction capacity

1) Preparation of sample for measuring the concentration of a drug by injecting it through the tail vein

Female SD rats (Charles River, male, age-7 weeks, from 170 to 210 g) were used as experimental animals immediately after an overnight fast. N,N-dimethylacetamide (0.2 ml), brine (of 0.798 ml) and 2N-NaOH (0.002 ml) were added respectively to those amounts to 1 mg of compound (B) to prepare a 1.0 mg/ml solution. The solution is then injected at a dose of 1 ml/kg (1 mg/kg) via the tail vein without anesthesia (3 samples). Intravenous injection through the tail performed using a 26G injection needle and 1 ml syringe. Blood was collected via the subclavian vein at 2, 15, 60, 120, 240 and 360 minutes after intravenous injection through the tail. The blood was centrifuged and plasma was used as a sample for measuring the concentration of the drug in the blood.

2) Preparation of sample for measurement of drug concentration in oral administration

Female SD rats (Charles River, male, age-7 weeks, from 220 to 290 g) were used as experimental animals immediately after an overnight fast. 0.5% aqueous methylcellulose solution (5 ml) were respectively added to 3 mg of compound (A) or compound (B) (calculated on the pure substance) for the preparation of 0.6 mg/ml solution lekarstvennoj� drug. Each solution was orally given to rats at a dose of 5 ml/kg (3 mg/kg) (3 samples each). Oral administration was performed using a probe for rats and 2.5-ml syringe. Blood was collected via the subclavian vein without anesthesia 15, 30, 60, 120, 240, 360 and 480 minutes after oral administration. The blood was centrifuged and plasma was used as a sample for measuring the concentration of a therapeutic drug in the blood.

3) measurement of the concentration of the drug

The corresponding solution of internal standard substance (0.1 ml) was added to plasma (0,025 ml) obtained in PP.1 and 2 using the conventional method. Then was added acetonitrile (0,875 ml) to remove protein. After centrifugation the supernatant (supernatant) (0,005 ml) was injected into LC-MS/MS. The concentration of drug in plasma was measured using the equipment LC-MS/MS under the conditions given below. Note that the standard curve was created by adding the appropriate internal standard substance and the substance of the study to clean the blood plasma (0.05 ml) using a conventional method in accordance with the previous procedures of measurements.

LC

Device: Agilent 1100

Column: Capcellpak MGIII 5 µm, a 4.6×50 mm

Mobile phase A: 10 mm aqueous ammonium acetate

Mobile phase B: Acetonitrile;

(The ratio of mobile phases are shown in the�face 3)

Column temperature: 40ºC

Flow rate: 0.5 ml/min MS/MS

Device: API-4000

The ionization method: ESI (ionization) (Turbo Ion Spray) to(turbo-electric ionizer)

Table 3
Time (minutes)A(%)B (%)
0,09010
3,09010
4,01090
7,01090
7,19010
12,09010

The biological availability of the compound (A) was approximately 59% and the desired absorption in oral administration was confirmed. In addition, the time to reach maximum concentration of the drug (T max) was 35 min for compound (A) compared to 200 min for compound (B), due to the fact that the compound (A) is rapidly absorbed after ingestion and are expected to exercise quick�beginning of the action.

Bioavailability (%) was calculated by measuring the area under the curve values of the concentration of the drug in the blood from time to time, determined with using software WinNonlin Professional firms (Pharsight Corporation), based on the concentration of the drug in the blood at each time point, obtained, as indicated above, after intravenous administration of compounds (B) through the tail and oral administration of compound (A) or compound (B).

Test example 3

Test

The compound (A) obtained in example 2 were stored in the clear at 90ºC for studying stability. When measuring stability, the purity of the sample was measured using HPLC at the beginning and after 8 days, the results were compared.

Conditions of measurements using HPLC were as follows:

Detector: spectrophotometer for ultraviolet and visible region, wavelength: 225 nm

Column: GL Science Inertsil ODS-3, 5 µm, a 4.6×250 mm

Column temperature: a constant temperature of about 35ºC

Flow rate: 1.0 ml/min

Mobile phase A: 10 mm aqueous solution of potassium dihydrogen phosphate was adjusted with an aqueous solution of potassium hydroxide to pH 5,5

Mobile phase B: Acetonitrile (the ratio of mobile phases are shown in table 4)

Measuring range: 54 minutes from the beginning of the analysis. Square empty peaks from the calculation were excluded.

The results of measurements of the PR�dstanley in table 5.

Table 4
Time (minutes)A (%)B (%)
07030
207030
403070
603070
60,17030
807030

Table 5
The compound (A) obtained in example 2
Measurement timeStarting pointAfter 8 days
Purity (%)99,699,6

As described above, the test results of examples 1-3 show that the compounds (A) of this from�retenu excellent solubility, oral absorbability and storage stability and, therefore, it represents a perfect Union, with which it is possible to solve the problems associated with the physical properties of the pure compounds (B).

Application in industry

The compound (A) according to the present invention has excellent solubility and other desirable physical properties, therefore, is suitable as the material of the medicinal product and is suitable for industrial production of medicines.

Brief description of diagrams

Fig.1 shows a chart of powdered x-ray diffraction of compound (A) obtained in example 1. The vertical axis shows the intensity of x-ray diffraction (number of intervals discredit the measured signal); the horizontal axis shows a diffraction angle (2θ(°)).

Fig. 2 shows a diagram representing the TG-DTA measurement of the compound (A) obtained in example 1. On the vertical axis (left) shows the masses. % thermogravimetric curve (TG); on the vertical axis (right) shows the heat flow (UV) on the curve of differential thermal analysis (DTA) and the horizontal axis shows temperature (°C).

Fig. 3 shows the spectra of solid-state NMR13With the compound (A) obtained in example 1. On the vertical axis showing�and intensity; the horizontal axis shows the value of the chemical shift (δ ppm). Characteristic peaks values of chemical shifts (δ(ppm)) in the NMR spectrum19F in the solid phase are -131,6, -145 and -151,8.

Fig. 4 shows a chart of powdered x-ray diffraction of compound (A) obtained in comparative example 1. The vertical axis shows the intensity of x-ray diffraction (number of intervals discredit the measured signal); the horizontal axis shows a diffraction angle (2θ(°)).

Fig. 5 shows the spectra of solid-state NMR19F compound (A) obtained in example 1. The vertical axis shows the intensity; the horizontal axis shows the value of the chemical shift (δ ppm). The connection is characterized by an endothermic peak at about 213°C in the chart of differential thermal analysis.

1. The connection represented by the formula

2. The compound according to claim 1, in crystalline form having characteristic peaks at angles of diffraction (2θ(Å)) 7,1, 11,5, 19,4, 20,3, 21,5, 22,0, 22,6, 23,5 and 26.2 in the chart of powdered x-ray diffraction.

3. The compound according to claim 2, having characteristic peaks values of chemical shifts (δ(ppm)) 155,8, 149,8, 145,3, 118,0, 113,7, 111,6, 110,3, 98,1, 69,8, 58,7, 57,1 and 55.5 in solid-state NMR spectrum of13S.

4. The compound according to claim 2, having characteristic peaks values DM chemical�IG (δ(ppm)) -131,6, -145, and -151,8 in the NMR spectrum19F in the solid phase.

5. The compound according to any one of claims. 2-4, having endothermic peak at about 213°C in the chart of differential thermal analysis.



 

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,

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43 cl, 42 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula , wherein Y and Z are independently specified in a group of a) or b) so that one of Y or Z is specified in the group a), and another one - in the group b); the group a) represents i) substituted C6-10aryl; ii) C3-8cycloalkyl; iii) trifluoromethyl or iv) heteroaryl specified in a group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyridinyl, isoxazolyl, imidazolyl, furasan-3-yl, benzothienyl, thieno[3,2-b]thiophen-2-yl, pyrazolyl, triazolyl, tetrazolyl and [1,2,3]thiadiazolyl; the group b) represents i) C6-10aryl; ii) heteroaryl specified in a group consisting of thiazolyl, pyridinyl, indolyl, pyrrolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, imidazo[1,2-a]pyridin-2-yl, furo[2,3-b]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, thieno[2,3-b]pyridinyl, quinolinyl, quinazolinyl, thienyl and benzimidazolyl; iii) benzofused heterocyclyl attached through a carbon atom, and when a heterocyclyl component contains a nitrogen atom, the carbon atom is optionally substituted by one substitute specified in a group consisting of C3-7cycloalkylcarbonyl; C3-7cycloalkylsulphonyl; phenyl; phenylcarbonyl; pyrrolylcarbonyl; phenylsulphonyl; phenyl(C1-4)alkyl; C1-6alkylcarbonyl; C1-6alkylsulphonyl; pyrimidinyl and pyridinyl; C3-7cycloalkylcarbonyl, phenyl, phenylcarbonyl, phenyl(C1-4)alkyl and phenylsulphonyl are optionally substituted by trifluoromethyl, or by one or two fluor-substitutes; iv) phenoxatiynyl; vi) fluoren-9-on-2-yl; vii) 9,9-dimethyl-9H-fluorenyl; viii) 1-chlornaphtho[2,1-b]thiophen-2-yl; ix) xanthen-9-on-3-yl; x) 9-methyl-9H-carbazol-3-yl; xi) 6,7,8,9-tetrahydro-5H-carbazol-3-yl; xiii) 3-methyl-2-phenyl-4-oxochromen-8-yl; or xiv) 1,3-dihydrobenzimidazol-2-on-5-yl optionally substituted by 1-phenyl, 1-(2,2,2-trifluoroethyl), 1-(3,3,3-trifluoropropyl) or 1-(4,4-difluorocyclohexyl); 1-phenyl is optionally substituted by one or more fluor-substitutes or trifluoromethyl; or xv) 4-(3-chlorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl; R1 represents C6-10aryl, C1-3alkyl, benzyloxymethyl, hydroxy(C1-3)alkyl, aminocarbonyl, carboxy, trifluoromethyl, spirofused cyclopropyl, 3-oxo or aryl(C1-3)alkyl; or when s is equal to 2 and R1 represents C1-3alkyl, the substitutes C1-3akyl is taken with a piperazine ring to form 3,8-diazabicyclo[3.2.1]octanyl or 2,5-diazabicyclo[2.2.2]octanyl ring system, and its pharmaceutical compositions.

EFFECT: preparing the new pharmaceutical compositions.

20 cl, 7 tbl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula IV, VIII-A and X, and to their pharmaceutical acceptable salts possessing the inhibitory activity on PI3-kinase (phosphoinositide-3-kinase). In compounds of formula IV and IX and Wd is specified in a group consisting of, , , and each of which can be substituted. In formula VIII-A, the group Wd represents the group or , wherein Ra is hydrogen, R11 is amino; in compound IV, Wa2 represents CR5; Wa3 represents CR6; Wa4 represents N or CR7; in compound IX, Wa1 and Wa2 independently represent CR5, N or NR4, and Wa4 independently represents CR7 or S, wherein no more than two neighbouring atoms in a ring represent atom or sulphur; Wb5 represents N; B represents a grouping of formula II, as well as in case of compound IV, B means C1-C10alkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl having one to six ring heteroatoms specified in N, O and S; in case of compound IX, B also means C1-C10alkyl, C3-C10cycloalkyl or 6-merous heterocycloalkyl having nitrogen atom; Wc represents C6-C10aryl or 5-18-merous heteroaryl having one or more ring heteroatoms specified in N, O and S, or phenyl or 6-merous heteroaryl respectively is equal to an integer of 0, 1, 2, 3 or 4; X is absent or represents -(CH(R9))z-, respectively; z is equal to 1; Y is absent. The other radical values are specified in the patent claim.

EFFECT: compounds can be used for treating such diseases, as cancer, bone disorders, an inflammatory or immune disease, diseases of the nervous system, metabolic disorders, respiratory diseases, thrombosis or cardiac diseases mediated by PI3-kinase.

68 cl, 11 dwg, 7 tbl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula wherein each of R1 and R2 is independently selected from a group consisting of a hydrogen atom, nitro and NR6R7; R3 is C1-C8alkyl; each of R4 and R5 is independently selected from a group consisting of C1-C8alkoxy, phenoxy and phenyl(C1-C8alkylene)oxy; each of R6 and R7 is independently selected from a group consisting of a hydrogen atom, C1-C8alkyl, C(O)R8 and SO2R8;R8 is selected from a group consisting of a hydrogen atom, C1-C8alkyl, halogen-substituted C1-C8-alkyl, C1-C8-alkyl, substituted (C1-C8-alkylsubstituted amino), C1-C8-alkyl, substituted with piperidine and C1-C8-alkyl, substituted with morpholine.

EFFECT: reduced PDE4 enzyme activity and treating PDE4 enzyme mediated diseases or conditions.

21 cl, 2 tbl, 32 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a compound of formula and to its pharmaceutically acceptable salt and its enantiomers, wherein D means pyridyl, which is substituted by 1-2 independently specified groups R38; M means , wherein * means an attachment position to D; and † means an attachment position to Z; Z means -O-; Ar means phenyl, which is optionally substituted by 0-4 groups R2; and G means ; wherein each R38 means -C0-C6-alkyl-(substituted by one group containing heterocyclyl, which means a monocyclic structure, and contains 5 to 7 atoms, wherein 1 or 2 atoms are independently specified in a group containing N, O and S optionally substituted by one or more oxo groups); in each specific case R2 is independently specified in -H and halogen; each R13 means -H; Q means cyclopropyl. The invention also refers to a pharmaceutical composition based on the composition of formula (I), a method for inhibiting the activity of protein kinase of the growth factor receptors and a method of treating choroidal neovascularisation.

EFFECT: there are prepared new compounds possessing the activity on protein kinase inhibitors.

7 cl, 8 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of obtaining compounds of formula . The compounds of formula 6 are intermediate products for obtaining dihydrothieno[3,2-d]pyrimidines, which produce an impact on the cardiovascular system, possess sedative action, or can be applied in treatment of inflammatory diseases of joints, skin, eyes or diseases of the peripheral or central nervous system, respiratory or gastrointestinal disorders. The method includes the following stages: a) interaction of reagents of formulas HS-CH2-CO2Ra and CHR5=CR4-CO2Ra with obtaining an intermediate product of formula ; and b) cyclisation of the intermediate product of formula 7 in a solvent in the presence of TiCl2(O-iPr)2, TiCl(O-iPr)3, TiCl3(O-iPr) and in the presence of a base-amine, with obtaining a product of formula 6. Ra stands for alkyl, R4 and R5 are independently selected from a group, including H, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C6-C10-aryl, C6-C10-aryl-C1-C6-alkylene, C5-C10-heteroaryl-C1-C6-alkylene, C3-C10-heterocycle and C5-C10-heteroaryl, -O-C1-C6-alkyl, -O-C6-C10-aryl, -O-C3-C10-heterocycle and -O-C5-C10-heteroaryl, -NR'R", fluorine, C1-C6-fluoroalkyl and C1-C6-fluoroalkoxygroup, where R' and R" are independently selected from a group, including H and C1-C6-alkyl, and where in each case the group can be optionally substituted with one or more groups, selected from a group, including OH, oxogroup, halogen, C1-C6-alkyl and O-C1-C6-alkyl. The method makes it possible to obtain the intermediate products 6, which do not require carrying out distillation and chromatographic purification between stages in realisation of processes suitable for wide-scale synthesis of dihydrothieno[3,2-d]pyrimidines.

EFFECT: invention results in higher total output of the final products as compared to that in realisation of methods of preceding level of technology.

6 cl

FIELD: chemistry.

SUBSTANCE: invention relates to compound with structural formula (I) or to its pharmaceutically acceptable salt, where R represents cyanogroup. Invention also relates to method of obtaining said compound and to pharmaceutical composition against platelet aggregation based on the compound.

EFFECT: obtained is novel compound and based on its pharmaceutical composition, which can be applied in medicine for production of medication for prevention or treatment of diseases of cardiac and cerebral vessels, such as coronary syndromes, myocardial infarction and myocardial ischemia, caused by aggregation of platelets.

13 cl, 3 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to thieno[3,2-d]pyrimidine derivative of formula (I) or to its pharmaceutically acceptable salt: (I), where Y stands for -CH=CR1-, -C≡C- or -C(=O)NR1-; L stands for -C(=O)NR2-, -NR2C(=O)- or -NR2C(=O)NR2-; R1 and R2, each independently stands for H; R stands for H, a halogen atom, methyl or methoxy; E stands for phenyl or C3-10heteroaryl, which is non-substituted or substituted with 1-2 substituents, consisting of a group, which includes a halogen atom, -CF3, C1-6alkyl, hydroxy-C1-6alkyl, C3-8cycloalkyl, -(CH2)n-C1-6alkylamino, -(CH2)n-diC1-6alkylamino, -(CH2)nC1-6alkoxy, -(CH2)n-OS(=O)2-C1-6-alkyl, -(CH2)n-phenyl, -(CH2)n-C2-5heteroaryl and -(CH2)n-C4-6heterocycloalkyl, where C3-10heteroaryl represents pyridine, isoquinoline, indole or isoxazole, C2-5heteroaryl of radical -(CH2)n-C2-5heteroaryl represents imidazole or pyrrol, C4-6heterocycloalkyl of radical -(CH2)n-C4-6heterocycloalkyl represents piperazine, morpholine, diazepam, pyrrolidine or piperidine, and phenyl, heteroaryl and heterocycloalkyl each independently, is non-substituted or substituted with substituent selected from a group, which consists of C1-6alkyl, hydroxy-C1-6alkyl, a halogen atom and diC1-6alkylamino, n is equal to 0 or 1; and Z stands for H, -C(=O)R3, C1-6alkyl, hydroxyC1-6alkyl, C3-8cycloalkyl, piperidine, phenyl or pyridine, where piperidine, phenyl and pyridine, each independently, is non-substituted or substituted with C1-6alkyl, C1-6alkoxy or R3-piperazinyl and R3 represents C1-6alkyl or phenyl. The invention also relates to an intermediate compound for obtaining the claimed final compound of formula (I).

EFFECT: novel compound, which can be applied in medicine for the prevention or treatment of diseases, characterised by an anomalous growth of cells as a result of an excessive expression of proteinkinase, is obtained.

8 cl, 2 tbl, 128 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new hydrate of 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol hydrochloride salt in the crystalline form with the characteristics below. The hydrate can be used for producing a drug or for treating or preventing a transplanted organ or tissue rejection, or autoimmune diseases in a therapeutically effective amount. The above hydrate is characterised by an X-ray powder diffractogram having peaks at approximately 2.9, 17.2, 30.6, 28.2, 24.4, 8.6 and 25.9 degrees 2-Theta with a limit of error of ±0.2 degrees for each value of 2θ, having a purity of 90% or more, and containing 5.2 to 5.9% of water.

EFFECT: invention also characterises a pharmaceutical composition with using the above hydrate.

4 cl, 4 dwg, 8 tbl, 14 ex

Fingolimod salts // 2543621

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propan-1,3-diol salts specified in tartrate, lactate benzoate, succinate, malonate, acetate and propionate in the crystalline form. Each of the above salts is characterised by powder X-ray pattern data. Compounds in the therapeutically effective amount can be used in treating autoimmune diseases.

EFFECT: crystalline salts of the present invention possess higher stability, better solubility, more convenient to store and handle.

11 cl, 7 dwg, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a free-running form of powdered choline chloride from an aqueous solution thereof. Squeezed beet pulp with moisture content of 82…84% is preheated in a heating chamber to temperature of 80…90°C, and then dried in a vibration drier which is superheated with steam at atmospheric pressure with temperature of 135…140°C and speed of 1.5 m/s. Drying is carried out in a pulsed vibrofluidised bed to moisture content of 12…13%, wherein in the working chamber of the vibration drier, the layer of the product is brought into a vibrofluidised state for 3 s every 60 s by a gas-distributing array. The array has amplitude and frequency of vibration of 7 mm and 12.5 Hz, respectively. Spent superheated steam at temperature of 105…110°C from the vibration drier is first fed into a cyclone purifier for purification from a fine fraction which is combined with dried beet chips, and the purified spent superheated steam is then divided into two streams. One stream, formed when drying the product, is fed into a calorifier, where it is condensed and atmospheric air is heated through the separating wall of the calorifier to temperature of 65…70°C. The other stream is fed by a fan into a steam superheater in order to be superheated to temperature of 13.5…140°C with heating steam obtained in a steam generator at temperature of 150…155°C, and then into the vibration drier to form a recirculation loop. The condensate of the heating steam at temperature of 140…145°C, after the steam superheater, is combined with the condensate of the spent superheated steam at temperature of 95…100°C after the calorifier and fed into a condensate collecting tank. The obtained condensate mixture at temperature of 120…125°C from the condensate collecting tank is fed into the heating chamber for preliminary heating of the squeezed beet pulp, followed by returning into the steam generator to form a recirculation loop and removing excess condensate from the recirculation loop. The obtained dried beet pulp is ground to particle size of 1 mm and fractionated on a sieving machine. Sieve screenings are taken for regrinding, and the substance passing through the sieve is mixed with the starting 70% aqueous choline chloride solution, preheated to temperature of 35…40°C, in ratio of 2:3. The obtained mixture with moisture content of 47…50% is fed into the drier, where it is dried in a fluidised bed to final moisture content of 10% with atmospheric air, which is heated in the calorifier to temperature of 65…70°C with air flow rate in the working chamber of the drier of 0.8…1.0 m/s. Spent atmospheric air at temperature of 40…45°C from the drier is first fed for purification into the cyclone purifier, and then into the heater for heating the starting choline chloride solution before feeding into the mixture. The fine fraction of choline chloride obtained after purification is combined with a stream of ready powdered choline chloride after drying and taken for cooling.

EFFECT: method enables to obtain powdered choline chloride of high quality, enables preservation of vitamin B4 in the end product and prevents thermal decomposition of vitamin B4 in the initial 70% aqueous solution.

1 dwg

FIELD: food industry.

SUBSTANCE: invention relates to methods for manufacture of a free-flowing form of powdered choline chloride produced from a water solution having a biological action. The method envisages mixing 70% water solution of choline chloride with an active adsorbent. The adsorbent is represented by dry apple refuses produced as a result of two-stage drying process implementation in the two-sectional dryer. At the first stage apple refuses with moisture content equal to 65…70% are subjected to drying in a pulse vibrofluidised layer with atmospheric pressure superheated steam with a temperature equal to 130…135°C at a rate of 1.5…2 m/sec till moisture content is equal to 45…50%. The product layer is brought into a vibrofluidised state for 3 sec every 60 sec with an air distributor plate having oscillation amplitude and frequency equal to 5…7 mm and 10…12.5 Hz respectively. At the second stage apple refuses are dried in a pseudofluidised layer with superheated steam with decreased pressure equal to 0.02…0.04 MPa and temperature equal to 80…100°C at a rate of 1.0…1.5 m/sec till the final moisture content is equal to 8…10%. The exhaust superheated steam from the first dryer section, with a temperature equal to 105…110°C, is divided into two flows. One flow is supplied into an atmospheric pressure steam superheater for superheating up to a temperature equal to 130…135°C with heating steam by way of recuperative heat exchange and then is returned into the first section with a recirculation loop formation. The other steam flow in the amount generated in the product drying process at the first stage is supplied into a decreased pressure steam superheater where steam condensation takes place while condensation heat is used for superheating decreased pressure steam up to a temperature equal to 80…100°C due to recuperative heat exchange. The exhaust superheated steam from the second section of the dryer (having a decreased pressure and temperature equal to 65…80°C) is divided into two flows; one of them is supplied by a blower into the decreased pressure steam superheater for superheating up to 80…100°C and then is returned into the second section with a recirculation loop formation. The other seam flow in an amount generated in the apple refuses drying process at the second stage is supplied through the separating wall of the condenser into the condenser where steam condensation and atmospheric air preliminary heating up to a temperature equal to 45…50°C take place. The produced heating steam condensate with a temperature equal to 125…130°C from the atmospheric pressure steam superheater and exhaust atmospheric pressure superheated steam condensate with a temperature equal to 100…105°C from the decreased pressure steam superheater are supplied through the separating wall of the calorifier into the calorifier for final heating of atmospheric air up to a temperature equal to 65…70°C. Produced dry apple refuses are milled into particles sized 1 mm, fractionated; the sieve overtail is supplied for additional milling while the sieve undersize is mixed with choline chloride water solution preliminarily heated up to 35…40°C at a ratio of 2:3. Then the produced mixture with moisture content equal to 47…50% is supplied into the drier where the mixture is dried in the fluidised layer, till the final moisture content is equal to 10%, with atmospheric air heated up to 65…70°C at airflow rate in the drier operation chamber equal to 0.8…1.0 m/sec. The exhaust atmospheric air with a temperature equal to 40…45°C is supplied at first from the drier for purification into the purifier cyclone and then - into the heater for heating the initial choline chloride solution before supplying it into the mixer. Then the finely dispersed choline chloride fraction produced after purification is combined with a flow of the ready powdered choline chloride released from the dryer and is supplied for cooling.

EFFECT: invention allows to produce powdered choline chloride with high quality and high nutritional value and ensure vitamin B4 preservation in the ready product and enhance energy efficiency of the ready product production method.

1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing biologically active pluripotential compounds - 2-methyl-4-halogen-phenoxyacetates of tris-(2-hydroxyethyl)-ammonium of general formula given below referred to as chlorocresacin and bromocresacin respectively, by reacting 4-halogen-substituted 2-methyl-phenoxyacetic acid, where the halogen is chlorine or bromine, with triethanolamine. 4-halogen-substituted 2-methyl-phenoxyacetic acid is obtained via chlorination with sulphuryl chloride, where catalyst used is aluminium powder in an ester solution and bromation is carried out using elementary bromine in a glacial acetic acid medium. The obtained compounds have proven to be highly efficient biologically active substances with unique physiological action, for example as biostimulators or adaptogen. The method is characterised by replacement of chlorine gas with sulphuryl chloride which is more suitable for use in preparations. .

EFFECT: method enables to obtain desired products with high degree of purity.

2 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel salt clusters of ammonium salt and mineral salt with dibasic acid anions of formula (I) which are resistant and stable during storage and can be used for pain relief in case of inflammation of nerve fibres. In formula (I) • x moles of mineral salt R1, R2, R3 and R4, together with the nitrogen atom in the cluster are derivatives from bases, as components of the active substance, wherein the bases of the active substance are procaine, substituted procaines, adrenalin, tetracaine, lidocaine, bupivacaine, pontocaine, propoxycaine, octacaine, mepivacaine, prilocaine, dibucaine, isocaine, marcaine, etidocaine, piridocaine, eucaine, butacaine, cocaine, articaine, N,N-diethylaminoethanol, N,N-dimethylaminoethanol, N-ethyl-N-methylaminoethanol or N,N-diethylaminopropagyl with free or protected alcohol groups, which can be esterified into esters or converted to ethers, Y denotes CO32-, corresponding HY- = HCO3-, and x=0.5-30 denotes the number of molecules of the mineral salt for formation of the cluster.

EFFECT: invention also relates to a method of producing said clusters, a product for medical and pharmaceutical purposes and a pain relief method.

7 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: method involves reacting triethanol ammonium salts of o-cresoxyacetic and p-chloro-o-cresoxyacetic acid with the corresponding metal salt in alcohol or aqueous medium preferably at room temperature for 1-48 hours. The three-component complexes are extracted through solvent distillation with subsequent washing of the formed powder with ether and drying in a vacuum. The said complexes can be used as a base for making medicinal drugs.

EFFECT: design of a method of preparing complexes of o-cresoxy- and p-chloro-o-cresoxyacetic acid, triethanolamine and metals having formula n[R(o-CH3)-C6H3-OCH2COO-•N+H(CH2CH2OH)3]•MXm, where R = H, p-Cl; M = Mg, Ca, Mn, Co, Ni, Cu, Zn, Rh, Ag; X = CI, NO3, CH3COO; n = 1, 2; m = 1-3.

2 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: phosphoric and/or hypophosphorus acid and a basic compound are added to triethanolamine, where the basic compound is selected from a hydroxide of alkali metals, a hydroxide of alkali-earth metals and [R1R2R3(2-hydroxyethyl)ammonium]hydroxide, where R1, R2 and R3 independently denote an alkyl having 1-30 carbon atoms, or hydroxyalkyl having 2-10 carbon atoms. If a hydroxide of alkali metals is used as the basic compound, molar ratio of acid (acids): hydroxide ranges from 1:0.1 to 1:1, and if hydroxide of alkali-earth metals is used as the basic compound, molar ratio of acid (acids): hydroxide ranges from 1:0.05 to 1:0.5. Phosphoric and/or hypophosphorus acid and the basic compound are added before and/or during distillation of triethanolamine. The invention also relates to triethanolamine containing 0.01-2 wt % (in terms of pure triethanolamine) phosphoric and/or hypophosphorus acid and the corresponding hydroxide.

EFFECT: stability of improved chromaticity of triethanolamine during storage and increased output during distillation of the triethanolamine.

15 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel soluble pharmaceutical salts formed from salt-forming active compound of the general formula (I) or (II) and sugar substitute that can be used in preparing medicinal agents useful in pain and enuresis treatment. Salt-forming active substance represents a salt-forming compound among 1-phenyl-3-dimethylaminopropane compounds of the general formula (I) wherein X means -OH, F, Cl, H or group -OCOR6; R1 represents (C1-C4)-alkyl group; R2 represents H or (C1-C4)-alkyl group; R3 represents H or (C1-C4)-alkyl group with a direct chain, or R2 and R3 form in common (C4-C7)-cycloalkyl group and if R5 means H then R4 represents group O-Z in meta-position wherein Z means H,(C1-C3)-alkyl, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl), -CONH-C6H4-(C1-C3-alkyl), -CO-C6H4-R7 wherein R7 represents -OCO-C1-C3-alkyl in ortho-position or group -CH2N(R8)2 in meta- or para-position and wherein R8 means (C1-C4)-alkyl or 4-morpholino-group, either R4 represents S-(C1-C3)-alkyl in meta-position, meta-Cl, meta-F, group -CR9R10R11 in meta-position wherein R9, R10 and R11 mean H or F, group -OH in ortho-position, O-(C2-C3)-alkyl in ortho-position, para-F or group -CR9R10R11 in para-position wherein R9, R10 and R11 mean H or F, or if R5 means Cl, F, group -OH or O-C1-C3-alkyl in para-position then R4 means Cl, F, group -OH or O-(C1-C3)-alkyl in meta-position, or R4 and R5 form in common group 3,4-OCH=CH- or OCH=CHO-; R6 means (C1-C3)-alkyl, or salt-forming active substance represents a salt-forming compound among 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula (II) wherein R1' represents H, -OH, Cl or F; R2' and R3' have similar or different values and represent H, (C1-C4)-alkyl, benzyl, -CF3, -OH, -OCH2-C6H5, O-(C1-C4)-alkyl, Cl or F under condition that at least one among radicals R2' either R3' means H; R4' represents H, -CH3, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl, -CO-NH-C6H4-(C1-C3)-alkyl, -CO-C6H4-R5', CO-(C1-C5)-alkyl), -CO-CHR6'-NHR7' or unsubstituted either substituted pyridyl, thienyl, thiazolyl or phenyl group; R5' represents -OC(O)-(C1-C3)-alkyl in ortho-position or -CH2N(R8')2 in meta- or para-position and wherein R8' means (C1-C4)-alkyl, or both radicals R8' in common with nitrogen atom (N) form 4-morpholino-group, and R6' and R7' have similar or different values and represent H or (C1-C6)-alkyl under condition that if both radicals R2' and R3' represent H then R4' doesn't mean -CH3 when R1' represents additionally H, -OH or Cl, either R4' doesn't mean H when R1' represents additionally -OH. Also, invention relates to a medicinal agent based on indicated salts.

EFFECT: valuable medicinal properties of salts and drug.

14 cl, 1 tbl, 8 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to preparing biologically active compounds used in agriculture and animal husbandry. Tris-(2-hydroxyethyl)-ammonium-o-cresoxyacetate is prepared by interaction of triethanolamine with o-cresozyacetic acid in the solvent medium under conditions of three-stage temperature effect. At the first stage the process is carried out at the solvent boiling point, at the second stage at temperatures 81-85°C, and at the three stage at temperatures 73-77°C. The process is carried out in the vertical device fitted with three heating zones and rotor with control number of revolution and consisting of shaft with movable vanes. Invention provides simplified method due to diminishing number of the process stages.

EFFECT: improved preparing method.

2 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining N,N-substituted 3-aminopropan-1-ols by: a) interaction of the secondary aliphatic amine with acrolein at a temperature from -50 to 100°C and pressure from 0.01 to 300 bars and b) interaction of the obtained at the stage a) reaction mixture with hydrogen and ammonia in the presence of a hydration catalyst under pressure from 1 to 400 bars. The molar ratio of the secondary aliphatic amine to acrolein at the stage a) constitutes 1:1 to 8:1, a temperature at the stage b) is in the interval from 20 to 40°C and the molar ratio of ammonia used at the stage b) to acrolein used at the stage a) constitutes from 1:1 to 10:1.

EFFECT: method makes it possible to obtain the target product with high selectivity.

13 cl, 6 ex

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