7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidin -5-yl]-(3r,5s)-3,5-dihydroxyhept-6-enoic acid crystalline salts, method for their preparing and pharmaceutical composition

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

SUBSTANCE: invention relates to (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(me-thylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dih-ydroxyhept-6-enoic acid crystalline salts wherein salt represents ammonium, methyl ammonium, ethyl ammonium, diethanol ammonium, tris-(hydroxymethyl)methyl ammonium, benzyl ammonium, 4-methoxybenzyl ammonium, lithium or magnesium salt possessing property of HMG CoA-reductase inhibitor. Also, invention relates to a pharmaceutical composition comprising crystalline salt in mixture with a pharmaceutically acceptable diluting agent or vehicle an to a method for preparing crystalline salt. Method involves addition of corresponding amine or a base to a solution of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(me-thylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-dihydro-xyhept-6-enoic acid in acetonitrile or ethyl acetate medium. The advantage of crystalline salts involves the possibility for enhancing purity and homogenicity of compounds, the possibility for re-crystallization and preparing the pure amorphous form and enhancing stability of the form.

EFFECT: improved preparing method.

15 cl, 9 dwg, 10 ex

 

The present invention relates to the derivatives of pyrimidine and more specifically to novel crystalline salts of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid formula

which are useful as inhibitors of the enzyme reductase 3-hydroxy-3-methylglutaryl-coenzyme A (HMG COA reductase) and as intermediates in the production of, for example, non-crystalline calcium salt of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid formula

The invention relates also to pharmaceutical compositions that include salt crystals, as well as to methods of production of crystalline salts. In addition, the invention relates to methods for treating medical conditions in which development involved HMG COA reductase, using a crystalline salts, such as hyperlipidemia, hypercholesterolemia and atherosclerosis, and to the use of crystalline salts in the production of medicines. In addition, the invention relates to the use of crystalline salts in the production of non-crystalline calcium salt of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-3R,5S) - for 3,5-dihydroxide-6-ene acid.

In European patent application, publication No. 521471 (hereinafter EP 521471) described amorphous powder form of the calcium salt of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl) amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, and sodium salt obtained here in the form of powdery crystals. These salts are inhibitors of HMG COA reductase, and the calcium salt is undergoing clinical trials.

Powder or amorphous form of compound intended for pharmaceutical use may cause production difficulties and, therefore, there is a need to identify alternative salts of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, which is crystalline. Such crystalline salt, as a rule, it is easier treated than amorphous forms and can have other advantageous properties, for example, with regard to their specific crystalline forms, and/or characteristics of their solubility, and/or nephroscopes, and/or characteristics of their stability, including properties, thermal stability and/or their ability to undergo oxidative degradation. In practice also face difficulty in obtaining pure amorphous calcium salt using techniques that op is pulling in EP 521471, due to the complexity of treatment prior sodium salt resulting from its physical form. Another feature of crystalline salts is that they can preferably be used as intermediate compounds for the production of non-crystalline calcium salt, in order to be able to allocate non-crystalline calcium salt with a level of purity and homogeneity, which are suitable for preparation of the drug to meet the required pharmaceutical requirements and farmstay.

Currently found new crystalline salts of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino] pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, form the basis of the present invention.

In accordance with the invention features a crystalline salt of compound (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, which salt is a salt of ammonia (NH4+), methylamine (CH3NH3+), ethylamine (CH3With2NH3+) diethanolamine [(NON2CH2)2NH2+], Tris(hydroxymethyl)methylamine [(NON2)3CH3+], benzylamine (C6H5CH2NH3 ), 4-methoxybenzylamine (4-CH3O-C6H5CH2NH3+), lithium (Li+), or magnesium (Mg2+).

Crystalline salts of this invention are described in the following examples. Independent aspects of the invention include:

(1) crystalline ammonium salt of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S)-3, 5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta= 12,9, 15,2, 18,0, 18,2, 18,5, 20,2, 22,4, 23,0, 24,0 and 27.2°;

(2) crystalline methylammonium salt (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta= 8,2, 12,3, 15,7, 16,5, 17,6, 18,7, 19,9, 21,0, 24,3 and 25.9°;

(3) crystalline ethylammonium salt (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta= 8,6, 15,9, 16,9, 18,4, 18,7, 19,7, 20,8, 23,3, 23,8 and 25.8°;

(4) crystalline diethanolammonium salt (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray which in wdtout characteristic peaks at 2-theta = 9,9, 11,4, 16,1, 18,0, 18,7, 19,0, 20,6, 22,9, 24,3 and 25.0°;

(5) crystalline Tris(hydroxymethyl)methylammonium salt (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino] pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta= 7,9, 8,5, 10,2, 16,7, 18,4, 19,3, 19,8, 20,2, 21,5 and 24.9°;

(6) crystal benzylammonium salt (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta= 6,1, 6,7, 16,8, 17,6, 18,1, 19,3, 21,1, 21,9, 23,0 and 26.8°;

(7) of crystalline 4-methoxybenzylamine salt (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]-pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta= 14,2, 15,1, 17,5, 18,8, 19,7, 20,1, 20,7, 21,5, 23,7 and 24.5°;

(8) crystalline lithium salt (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta= 10,2, 11,0, 16,4, 17,0, 19,8, 20,4, 20,9, 21,5 and 28.0°;

(9) crystalline magnesium salt of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-d is hydroxygen-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta= 11,5, 14,5, 16,3, 16,8, 18,0, 19,1, 19,8, 21,8, 22, 6 and 23.0°.

The above-described crystalline Tris(hydroxymethyl)methyl ammonium salt is particularly preferred crystalline salt, which has a particularly advantageous physical characteristics, for example, it has the best thermal properties, it nephroscopy and has favorable solubility profile.

X-ray diffraction spectra of the powder was measured by setting the sample crystalline salt on the plate holders of monocrystalline silicon Siemens (SSC) and the distribution of the sample in the form of a thin layer using the object-glass of the microscope. The sample was rotated at 30 revolutions per minute (to improve the statistical account) and was irradiated with x-rays generated by long copper tube operating at 40 kV and 40 mA with a wavelength of 1,5406 angstroms. Source calminian x-rays passed through the slit installation with automatic variable divergence at 20, and the reflected radiation is directed through a 2 mm anti-scattering slit and 0.2 mm detector slit. The sample was subjected to irradiation for 4 seconds with 2-theta increment of 0.02 degrees (continuous scan) in the range from 2 degrees to 40 degrees 2-theta if theta is ETA scanning. The duration was 2 hours 6 minutes and 40 seconds. The instrument was equipped with a scintillation counter as a detector. Control and data recording was carried out using Dell Optiplex 686 NT 4.0 Workstation operating software package Diffract+.

X-ray diffraction spectra of powders typical samples of the salts described above (1)to(9) below in the figures. It will be clear that the values of the 2-theta, a powder x-ray picture may slightly vary from one device to another, or from one sample to another, and, thus, the above values should not be interpreted as absolute.

Another aspect of the present invention includes methods of obtaining crystalline salts. The exact conditions under which the formation of crystalline salts can be determined empirically. Salt can be obtained by crystallization under controlled conditions. The ways found suitable, are described in the examples below, and they represent independent aspects of the invention. For example, the method of obtaining the above-described methylammonium salt (2) includes the addition of methylamine in a suitable solvent such as water or methanol, to the cold, preferably freshly prepared solution of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]-pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid in approaching the eat solvent, such as a solvent containing acetonitrile. In the case of other crystalline salts can be used cold, preferably freshly prepared solution heptenophos acid in a solvent containing, for example, acetonitrile or ethyl acetate, and the corresponding amine or base can be added in the presence or in the absence of solvent, depending on the nature of the specific amine or base. Usually after adding the amine or base mixture is stirred at a temperature of from ambient temperature to about 30°and the crystalline product produce by filtration (after concentration and/or cooling, if necessary). The solution of the original substance heptenophos acid in a suitable solvent can be obtained, as described in the examples hereinafter. Another aspect of the invention includes a crystalline salt of compound (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl-(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid that can be obtained by the method described in example 1, 2, 3, 4, 5, 6, 7, 8, or 9.

The use of salts according to the invention as inhibitors of HMG COA reductase can be demonstrated using standard tests and clinical studies, including the one described in EP 521471. Usually crystalline salt of the invention showing the value of the IC50for Inga is financing the activity of HMG COA reductase in rat liver microsomes, equal 9 to 16 nm.

The next aspect of the invention is a method of treating a painful condition that benefits from inhibition of HMG COA reductase, which includes the introduction of warm-blooded mammal an effective amount of a crystalline salt, described above. The invention relates also to the use of crystalline salts described above, in the manufacture of a medicinal product for use in a painful condition.

The compound of the invention can enter TemplateName animal, particularly a human, if necessary, for the treatment of diseases, the development of which involved the HMG COA reductase, in the form of conventional pharmaceutical compositions. Therefore, in the following aspect of the invention features a pharmaceutical composition comprising a crystalline salt, described above, in a mixture with a pharmaceutically acceptable diluent or carrier.

Such compositions can enter a default by painful condition, from which it is desirable to cure, for example, oral, topical, parenteral, buccal, nazalnam, vaginal or rectal introduction, or by inhalation. For these purposes, the crystalline salt can be represented in the form of tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, t the NGOs crushed powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) as a sterile solution in water or oil, or suspensions or sterile emulsions obtained are known in this field means. The preferred route of administration is oral. Crystalline salt will be introduced to people at a daily dose in the range, for example, described in EP 521471. These daily doses may be given in divided doses, if necessary, the exact amount of the salt crystal and the way of administration depend on the weight, age and sex of the patient treated, and the specific painful conditions, which are treated in accordance with well-known in this field rules.

According to the following characteristic of the invention features a method of obtaining a pharmaceutical composition containing the above-described crystalline salt as an active ingredient, which comprises mixing a crystalline salt with a pharmaceutically acceptable diluent or carrier.

In accordance with the following characteristic of the invention features the use of the above-described crystalline salt to obtain an amorphous calcium salt of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid. For this purpose, particularly climbed the and crystal methylammonium salt. The next element of the invention includes a method of obtaining amorphous calcium salt of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, comprising the sequential reaction of crystalline methylammonium salt with sodium hydroxide, then with water-soluble calcium salt such as calcium chloride, in aqueous conditions.

Hereinafter the present invention will be illustrated in the following non-limiting examples.

Example 1

To a solution of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl-(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5 - dihydroxide-6-ene acid (obtained as described below) was added with stirring a solution of methylamine in methanol (1.4 ml 40% solution) at -5°C. the Mixture was stirred at 30°C for 90 minutes, and then cooled to 3°C. the Crystalline product was collected by filtration, washed with acetonitrile and dried in vacuum at 40°receiving (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ENOAT methylamine (3,85 g; output 87,9%) as white crystals. (The same crystalline salt was obtained with 40% solution of methylamine in water (1.1 ml).) X-ray diffraction spectra of the powder (XRD) of a typical sample of the crystalline methylammonium salt is shown in figure 2. esati the most prominent peaks in the XRD occur at about 2-theta = 8,2, 12,3, 15,7, 16,5, 17,6, 18,7, 19,9, 21,0, 24,3 and 25.9°.

Used in example 1, a solution of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid in acetonitrile was prepared as follows:

(1) a mixture of methyl 2-amino-4-(4-forfinal)-6-isopropyl-pyrimidine-5-carboxylate (19,0 g) (described in Japanese patent application No. 06-256318), tert-pentoxide, niobium sodium (22, 95mm g) and dimethoxyethane (190 ml) was stirred for 30 minutes at 25°C. Stir the mixture was cooled to -10°and was added dropwise methanesulfonanilide (8,4 ml), maintaining the temperature of the mixture at -5°C. After 20 minutes was added dimethylsulfate (8.1 ml), and gave the mixture to warm to 25°C. the Mixture was stirred for one hour at 25°and the solution was added tert-pentoxide, niobium sodium (1,91 g) dimethoxyethane (10 ml). The mixture was stirred for one hour at 25°C. was Added a solution of sodium chloride (13.3 g) in water (133 ml) and the mixture was stirred for 10 minutes at 25°C. the Mixture was allowed to stand for 15 minutes and the lower aqueous phase was separated and discarded. To the remaining mixture was added water (38 ml) and the mixture was stirred for 30 minutes at 25°C. thereafter, the mixture was heated for a complete solution. The mixture was slowly cooled to 25°C for one hour. The mixture was cooled to 0°C, stirred for one hour and collected by filtration suspended the solid substance. The solid is washed with cold (0° (C) a solution of 50:50 water/dimethoxyethane (20 ml). The solid was dried in vacuum at 60°receiving methyl 4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-carboxylate (compound A; 19,35 g); NMR1H (270 MHz, CDCl3): of 7.69 (m, 2H), 7,14 (m, 2H), 3,71, 3,60, 3, 51 (HS, N), 3,20 (m, 1H), 1,32 (d, 6N)

(2) stir the mixture compound A (12.0 g) in toluene (55 ml) was cooled to -10°and added hydride diisobutylaluminum (50 ml, 1.5 M solution in toluene) for two hours, keeping the temperature below 0°C. After the addition the mixture was stirred for 30 minutes at 0°C. To the mixture was added methanol (0,64 ml), maintaining the temperature at 0°C. After this mixture for two hours was added to a stirred mixture of concentrated hydrochloric acid (23,3 ml), water (40,5 ml) and acetonitrile (24 ml) at 40°maintaining the temperature of the mixture at 40°C. After the addition the mixture was stirred at 40°C for an additional 30 minutes and then purged with nitrogen to remove any isobutane). The mixture was cooled to 20°and allowed to stand for 20 minutes. The organic phase was separated and washed with a mixture of concentrated hydrochloric acid (0.7 ml) and water (30 ml). To the organic phase was added acetonitrile (24 ml) and the mixture was washed with sodium bicarbonate solution (0,038 g) in water (120 ml).

The PR is onicescu phase was heated up to 40° With, and then from 40 to 80°using purging with nitrogen. The mixture was concentrated by distillation at atmospheric pressure, collecting 54 ml of distillate. To the concentrated solution was added acetonitrile (24 ml) was added under stirring trichromacy phosphorus (1.2 ml), maintaining the temperature of the mixture at 20°C. After the addition the mixture was stirred at 20°C for 30 minutes. The mixture was added to water (36 ml) for 30 minutes, maintaining the temperature at 20°C. the Mixture was stirred for 5 minutes and separated the organic phase. The organic phase is washed with sodium bicarbonate solution (0,027 g) in water (36 ml)and then water (36 ml). The organic phase was distilled under reduced pressure until collected 29 ml of distillate. The mixture was cooled to 60°and added ethyldiphenylphosphine (7,47 ml). The mixture was stirred at 60°C for 3 hours, then boiled. Was added toluene (40 ml) and cooled the mixture to 0°C for 2 hours. The product was collected by filtration, washed with cold toluene (10 ml) and dried in vacuum at 50°receiving diphenyl[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino] pyrimidine-5-ylmethyl]phosphine oxide (compound; 14,66 g); NMR1H (CDCl3, 270 MHz): 7, 42 [m, 10H, P(C6N5)2], 7,12 [m, 2H, Ar-H], 6,92 [m, 2H, Ar-H], 3,92 [d, 2H,N2R],3,51 346 [HS, 6N, NCN3SO2N3], 3, 43 [hept., 1H, CH(CH3/sub> )2], 1,25 [d, 6N, CH(CH3)2]

(3) a mixture of compounds (19,17 g) and THF (tetrahydrofuran) (227 ml) a short while was heated to 40°C to obtain a clear solution, then created an inert atmosphere consistent application of vacuum and nitrogen (5 cycles). The mixture was immersed in a bath containing acetone/CO2, cooling the contents to -75°C. Within 10 minutes from a dropping funnel with a balanced pressure to the reaction mixture was added bis (trimethylsilyl) amide, sodium (or 37.4 ml of 1.0 M solution in THF), keeping the temperature below -74°and receiving a red solution of the anion. In the mixture through an addition funnel were poured THF (10 ml) and the mixture was stirred for 1 hour at -76°receiving a red suspension. To this suspension over 20 minutes portions was added from a dropping funnel with a balanced pressure of tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl] acetate (which can be obtained as described in European patent 0319847) (80 ml ˜13,5% weight/weight solution in toluene), keeping the temperature below -73°C. the mixture through an addition funnel poured into toluene (20 ml) and the mixture was stirred for 15 minutes at -76°C. the Cooling bath was lowered and given a suspension to warm to 10°C for 1.5 hours. Added glacial acetic acid (3,21 g) in water (15 g) with one that has led to increasing tempera is URS to 18° With and dissolution of all solids, and the mixture was stirred for another five minutes.

The mixture was concentrated by distillation at atmospheric pressure (shirt at 110° (C) to a temperature of 94°collecting in General 274 ml of distillate. The concentrated mixture was cooled to 40°With added water (40 ml) and gave stir for 5 minutes the mixture rest for 15 minutes. The lower aqueous phase was discarded. Was added sodium bicarbonate (2,99 g) in water (40 ml) and gave stir for 5 minutes the mixture rest for 15 minutes. The lower aqueous phase was discarded. Was added water (30 ml) and gave stir for 5 minutes the mixture rest for 15 minutes. The lower aqueous phase was discarded.

The organic phase was transferred into a distillation apparatus with toluene (20 ml) and was concentrated by distillation at atmospheric pressure (shirt 125-130° (C) to a temperature of 116°collecting 85 ml of distillate. Have connected the vacuum (400-500 mbar) and collected more of 16.5 ml of distillate to a temperature of 111°C. were Removed by vacuum and gave the concentrated mixture to cool to 80°C. was Added a warm Meon (140 ml, 50° (C) with rapid stirring and was given the boot by yourself to cool down to 20°C for 30 minutes, during which the deposited solid. The suspension was further cooled to 2°C for 30 minutes, then solid prophetic the STV was collected by filtration on a glass filter and was pressed to possible dry condition. The solid is washed with cold Meon (60 ml, 2°) and again pressed to possible dry condition, and then was transferred to a vacuum oven and dried overnight (50°C, 200 mbar)to give compound C. Compound C (5.0 g) in acetonitrile (70 ml) was heated to 40°and added 0.01 M hydrochloric acid (19 ml). The reaction mixture was heated to 40°C for 5 hours. Was added 1.0 M sodium hydroxide (9.5 ml) at 25°ipermediali the reaction mixture for one hour. Was added sodium chloride and cooled the mixture to -5°C. was Added 1.0 M hydrochloric acid to bring the pH of the mixture to a pH of 3.4 to 4.0. The aqueous phase was separated and the organic phase was diluted with acetonitrile (15 ml), then dried over anhydrous magnesium sulfate. Added acetonitrile (20 ml)to give a solution of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl-(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid in acetonitrile.

Example 2

(E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl) amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ENOAT methylamine (10 g) was added to acetonitrile (125 ml) and water (5 ml). The mixture was cooled to 5°and brought the pH to 3.7 1 M hydrochloric acid in a saturated salt solution (19 ml). The aqueous phase was separated and the resulting solution was dried over anhydrous magnesium sulfate. Added Tris(hydroxymethyl)-and Inomata (2,48 g) and gave the solution to warm to ambient temperature and was stirred for 2 hours. The crystalline product was isolated by filtration at ambient temperature and dried at 30°in vacuum, obtaining crystalline (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl-(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ENOAT Tris(hydroxymethyl)methylamine in the form of white crystals. X-ray diffraction spectra of a powder of a typical sample of the crystalline Tris(hydroxymethyl)-methylammonium salt represented on figure 5. Ten most prominent peaks in XRD are present at about 2-theta= 7,9, 8,5, 10,2, 16,7, 18,4, 19,3, 19,8, 20,2, 21,5 and 24.9°.

Example 3

(E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl) amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ENOAT methylamine (10 g) was added to ethyl acetate (125 ml) and water (30 ml). The mixture was cooled to 5°and added 2 M hydrochloric acid (9.5 ml) to obtain a two-phase solution. The aqueous phase was separated and the organic phase washed with water (30 ml) and dried over anhydrous magnesium sulfate. Solution was added diethanolamine (3.1 ml) in ethyl acetate (5 ml) and gave the solution to warm to ambient temperature. The product was isolated by filtration at a temperature of from 0 to 5°C and dried at 30°C in vacuum, obtaining (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ENOAT of diethanolamine in the form of a white crystal of the century X-ray diffraction spectra of a powder of a typical sample of the crystalline salt of diethanolamine presented on figure 4. Ten most prominent peaks in XRD are present at about 2-theta= 9,9, 11,4, 16,1, 18,0, 18,7, 19,0, 20,6, 22,9, 24,3 and 25.0°.

Example 4

(E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl) amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ENOAT methylamine (10 g) was added to ethyl acetate (125 ml). The mixture was cooled to 5°and added 1 M hydrochloric acid in a saturated saline solution (20 ml), then added water (30 ml) to obtain a two-phase solution. The aqueous phase was separated and the organic phase washed with water (30 ml) and dried over anhydrous magnesium sulfate. Was added aqueous ammonia (1.7 ml), then ethyl acetate (80 ml) and concentrated solution in vacuum and razbavlyali with ethyl acetate (60 ml). The mixture was stirred at a temperature of from 0 to 5°C for 90 minutes and provided the product by filtration and dried at 30°C in vacuum, obtaining (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino] pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ENOAT ammonium in the form of white crystals. X-ray diffraction spectra of a powder of a typical sample of crystalline ammonium salts represented on figure 1. Ten most prominent peaks in XRD are present at about 2-theta= 12,9, 15,2, 18,0, 18,2, 18,5, 20,2, 22,4, 23,0, 24,0 and 27.2°.

p> Example 5

(E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl) amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ENOAT methylamine (10 g) was added to ethyl acetate (125 ml) and water (30 ml). The mixture was cooled to 5°and added 2 M hydrochloric acid (9.5 ml) to obtain a two-phase solution. The aqueous phase was separated and the organic phase washed with water (30 ml) and dried over anhydrous magnesium sulfate. Added monohydrate of lithium hydroxide (0.9 g) and water (3 ml) and concentrate the solution in vacuo, then was diluted with ethyl acetate (100 ml). The product was isolated by filtration at a temperature of from 0 to 5°and dried at 30°in vacuum, obtaining (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)-amino] pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ENOAT lithium (8,23 g) as white crystals. Rentgendifraktsionnye powder typical sample of crystalline lithium salts represented on figure 8. Ten most prominent peaks in XRD are present at about 2-theta= 10,2, 11,0, 16,4, 17,0, 19,3, 19,8, 20,4, 20,9, 21,5 and 28.0°.

Example 6

A solution of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methyl-sulfonyl)amino]pyrimidine-5-yl]-(3R,53)for 3,5-dihydroxide-6-enoate sodium in aqueous acetonitrile (11 ml)containing sodium chloride (1.4 g), cooled to -5°and brought the pH to values from 3.4 to 4 1 M hydrochloric acid. The aqueous phase was separated and the organic phase is filtered through anhydrous magnesium sulfate. To the organic phase was added acetonitrile (14 ml) was added aqueous ethylamine (0,21 ml). The solution was heated to 30°C and held at this temperature for 90 minutes. The product was isolated by filtration at 0°and dried at 35°in vacuum, obtaining (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ENOAT of ethylamine (0.7 g) as white crystals. X-ray diffraction spectra of a powder of a typical sample of the crystalline salt of ethylamine presented on figure 3. Ten most prominent peaks in XRD are present at about 2-theta= 8,6, 15,9, 16,9, 18,4, 18,7, 19,7, 20,8, 23,3, 23,8 and 25.8°.

Example 7

A solution of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-enoate sodium in aqueous acetonitrile (40 ml) was cooled to -5°and added 1 M hydrochloric acid (9.5 ml), stereodownload sodium (7,1 g), to bring the pH to 3.8. The aqueous phase was separated, and the organic phase was added acetonitrile (70 ml). Added benzylamine (1,4 ml) and the solution was heated to 30°C and held at this temperature for 90 minutes. The product was isolated by filtration at 0°and dried at 35°in vacuum, obtaining (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino] pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ENOAT of benzylamine (4.4 g) as white to the of itallow. X-ray diffraction spectra of a powder of a typical sample of the crystalline salt of benzylamine presented in figure 6. Ten most prominent peaks in XRD are present at about 2-theta= 6,1, 6,7, 16,8, 17,6, 18,1, 19,3, 21,1, 21,9, 23,0 and 26.8°.

Example 8

A solution of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl (methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-enoate sodium in aqueous acetonitrile (11 ml)containing sodium chloride (1.4 g), cooled to -5°and brought the pH to values from 3.4 to 4 1 M hydrochloric acid. The aqueous phase was separated and the organic phase was filtered through anhydrous magnesium sulfate. To the organic phase was added acetonitrile (14 ml) was added 4-methoxybenzylamine (0,34 ml). The solution was heated to 30°C and held at this temperature for 60 minutes. The product was isolated by filtration at 0°and dried in vacuum at ambient temperature, obtaining (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ENOAT 4-methoxybenzylamine (0.65 g) as white crystals. Rentgendifraktsionnye powder typical sample of the crystalline salt of 4-methoxybenzylamine presented in figure 7. Ten most prominent peaks in XRD are present at about 2-theta= 14,2, 15,1, 17,5, 18,8, 19,7, 20,1, 20,7, 21,5, 23,7 and 24.5°.

A solution of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[ethyl(methyl-sulfonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-enoate sodium in aqueous acetonitrile, used in examples 6, 7 and 8, was prepared as follows.

Connection (obtained in example 1, part (3)) (5.0 g) in acetonitrile (35 ml) was heated to 40°and added 0.02 M hydrochloric acid (9.5 ml). The reaction mixture was heated to 40°C for 4 hours. Was added 1.0 M sodium hydroxide (9.5 ml) at 25°and the mixture was stirred for 60 minutes, getting solution of sodium salt in aqueous acetonitrile.

Example 9

To a stirred solution of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl-(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-enoate methylamine (15 g) in water (106 ml) was added a 1.0 M solution of sodium hydroxide (26,3 ml) at ambient temperature. Within 20 minutes the solution was added magnesium sulfate (4.3 g) in water (26 ml) and was precipitated solid. The solid is collected by filtration, washed with water (20 ml) and dried in vacuum at 40°With (7.7). A mixture of a solid (5.8 g) and water (50 ml) was heated to 38°and was diluted with water (35 ml). The mixture was stirred at ambient temperature for 4 hours and then left to stand for 66 hours. Solid-liberalitarian after dilution with water (30 ml). The product was dried at 35°in vacuum, obtaining (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ENOAT magnesium (4.68 g) in the form of b is smaller crystals. X-ray diffraction spectra of a powder of a typical sample of the crystalline salts of magnesium are presented in figure 9. Ten most prominent peaks in XRD are present at about 2-theta= 11,5, 14,5, 16,3, 16,8, 18,0, 19,1, 19,8, 21,8, 22,6 and 23.0°.

Example 10

To stir the mixture of salt, methylamine obtained in example 1 (6.0 g)in degassed water (30 ml) was added sodium hydroxide (8% aqueous solution, mass/mass; 5,44 ml) at 20°and the mixture was stirred for one hour. The mixture was filtered and concentrated under reduced pressure at 40°until then, until he had 24 ml of distillate. Was added water (24 ml) and again concentrated mixture under reduced pressure at 40°until then, until he had 24 ml of distillate. Was added water (30 ml) was added dropwise a solution of dihydrate of calcium chloride (1,03 g) in water (6 ml) at 20°C. the Mixture was stirred for 45 minutes and filtered the obtained solid substance. The solid is washed with water (36 ml) and dried in vacuum at 40°receiving non-crystalline calcium salt of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid.

1. Crystalline salt of the compound (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, which salt is an ammonium salt, METI the ammonium, ethylamine, diethanolamine, Tris(hydroxymethyl)methylamine, benzyl ammonium, 4-methoxybenzylamine, lithium or magnesium.

2. The crystalline salt according to claim 1, which is a crystalline ammonium salt of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta=12,9, 15,2, 18,0, 18,2, 18,5, 20,2, 22,4, 23,0, 24,0 and 27.2°obtained at the copper source radiation with wavelength 1,5406Å.

3. The crystalline salt according to claim 1, which is a crystalline methylammonium salt (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta=8,2, 12,3, 15,7, 16,5, 17,6, 18,7, 19,9, 21,0, 24,3 and 25.9°obtained at the copper source radiation with wavelength 1,5406Å.

4. The crystalline salt according to claim 1, which is a crystalline ethylammonium salt (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta=8,6, 15,9, 16,9, 18,4, 18,7, 19,7, 20,8, 23,3, 23,8 and 25.8°obtained at the copper source radiation from donovani 1,5406Å .

5. The crystalline salt according to claim 1, which is a crystalline diethanolammonium salt (E)-7-[4-{4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta=9,9, 11,4, 16,1, 18,0, 18,7, 19,0, 20,6, 22,9, 24,3 and 25.0°obtained at the copper source radiation with wavelength 1,5406Å.

6. The crystalline salt according to claim 1, which is a crystalline Tris(hydroxymethyl)methylammonium salt (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]-pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta=7,9, 8,5, 10,2, 16,7, 18,4, 19,3, 19,8, 20,2, 21,5 and 24.9°obtained by copper radiation source with a wavelength of 1,5406Å.

7. The crystalline salt according to claim 1, which is a crystalline benzylammonium salt (E}-7-[4-[4-forfinal}-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta=6,1, 6,7, 16,8, 17,6, 18,1, 19,3, 21,1, 21,9, 23,0 and 26.8°obtained at the copper source radiation with wavelength 1,5406Å.

8. The crystalline salt according to claim 1, which is crystallises the th 4-methoxybenzylamine salt (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta=14,2, 15,1, 17,5, 18,8, 19,7, 20,1, 20,7, 21,5, 23,7 and 24.5°obtained on a copper radiation source with a wavelength of 1,5406Å.

9. The crystalline salt according to claim 1, which is a crystalline lithium salt (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta=10,2, 11,0, 16,4, 17,0, 19,3, 19,8, 20,4, 20,9, 21,5 and 28.0°obtained at the copper source radiation with wavelength 1,5406Å.

10. The crystalline salt according to claim 1, which is a crystalline magnesium salt of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid, in powder x-ray showing characteristic peaks at 2-theta=11,5, 14,5, 16,3, 16,8, 18,0, 19,1, 19,8, 21,8, 22,6 and 23.0°obtained at the copper source radiation with wavelength 1,5406Å.

11. The crystalline salt according to any one of claims 1 to 10, is used to obtain an amorphous calcium salt of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid.

12. The crystalline salt according to claim 11, where the crystalline salt used is a salt matrimonio p.3.

13. The crystalline salt according to any one of claims 1 to 10 to obtain the drug.

14. Pharmaceutical composition having the properties of an inhibitor of HMG CoA reductase containing a crystalline salt according to any one of claims 1 to 10 in a mixture with a pharmaceutically acceptable diluent or carrier.

15. A method of obtaining a crystalline salt according to any one of claim 2 to 9, including the addition of an appropriate amine or base to a solution of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid in acetonitrile or ethyl acetate.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

The invention relates to new derivatives of 4-phenylpyrimidine and their pharmaceutically acceptable acid additive salts, which possess the properties of receptor antagonists neirokinina(NK-1), and can be used to treat diseases, oposredstvovanii NK-1 receptor, for example, headache, Alzheimer's disease, multiple sclerosis, cardiovascular changes, oedema, chronic inflammatory diseases and so on

The invention relates to organic chemistry, in particular to the compounds representing amide of the formula I:

in which * denotes an asymmetric carbon atom; R1and R2independently from each other represent a hydrogen atom or halogen, amino, hydroxyamino-, nitro-, cyano-, sulfamidihappo, (ness.)alkyl, -OR5, -C(O)OR5, PERFLUORO(ness.)alkyl, (ness.)alkylthio, PERFLUORO(ness.)alkylthio, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkylsulfonyl or (ness.)alkylsulfonyl; R3denotes cycloalkyl containing from 3 to 7 carbon atoms, or (ness.)alkyl containing from 2 to 4 carbon atoms; R4means (O)other40or unsubstituted or monosubstituted five - or six-membered heteroaromatic ring bound ring carbon atom of the amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur atoms, oxygen, and nitrogen, with one heteroatom is a nitrogen atom, which is adjacent to the connecting ring carbon atom; this is monosubstituted heteroaromatic ring monogamist on the ring angle is found (ness.)alkyl, halo-, nitro-, cyano, -(CH2)n-OR6, -(CH2)n-C(O)OR7, -(CH2)n-C(O)OTHER6, -C(O)-C(O)OR8and -(CH2)n-OTHER6or its pharmaceutically acceptable salts

The invention relates to a new crystalline hydrated form of the calcium salt of bis[(E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]-pyrimidine-5-yl](3R,5S)-3,5-dihydroxide-6-ene acid] of the formula I:

having a powder x-rays with characteristic peaks at values of angle 2-theta (2)=4,92; 11,50; 6,93; 9,35; 23,12 and 18,76for the manufacture of a medicinal product having the properties of an inhibitor of HMG-COA-reductase

The invention relates to arylpiperazines General formula I

< / BR>
where is phenyl, pyridyl or pyrimidyl; each R3- H, halogen, NO2, СООR, where R is H, C1-6alkyl, CN, CF3WITH1-6alkyl, -S - C1-6alkyl, -SO-Cl - C1-6alkyl, -SO2-Cl-C1-6alkyl, C1-6alkoxy and up to10aryloxy, n= 1, 2, or 3; R is a direct bond; And - piperazinil, X1and X2IS N; Y IS-SO2-; Z IS - N(OH)-CHO; Q - CH2-; R1- H, C1-6alkyl, C5-7cycloalkyl until10aryl, until10heteroaryl until1-2aralkyl or until12heteroallyl, R4- H, C1-6alkyl, and others; R2- H, C1-6alkyl, or together with R1- carbocyclic or heterocyclic Spiro 5-, 6 - or 7-membered ring containing at least one heteroatom selected from N, O or S, and the group Q can be associated either with R1or R2with the formation of 5,- 6 - or 7-membered alkyl or heteroalkyl ring that includes one or more O, S or N

The invention relates to new derivatives of phenylsulfonylacetate General formula (I), which are herbicide and regulating plant growth properties and can find application in agriculture

The invention relates to new substituted aminomethanesulfonic General formula (I) possessing a highly effective herbicide action, as well as the way they are received, herbicide tool based on these intermediate compounds of General formula (II)

The invention relates to new derivatives of arylpiperazines General formula I, where X Is O or S1- C1-C4alkoxy, CF3, R2- C1-C6alkyl, saturated WITH3-C6cycloalkyl; heteroseksualci of 3-6 ring atoms, heteroatom of which is O, S or N, optionally N-substituted WITH1-C6by alkyl; phenyl, optionally substituted by F, Cl, Br, NH2CH3CF3or OCH3; 5-6-membered heteroaryl, the heteroatom of which is O, S or N, possibly substituted, or condensed heteroaromatic system containing 9 atoms

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

SUBSTANCE: invention relates to new substituted derivatives of norbornylamine with exo-configuration of nitrogen atom and endo-anellated 5-6-membered cycles of the formula (I) and with exo-configuration of nitrogen atom and exo-anellated 5-6-membered cycles of the formula (Ia) , and their pharmaceutically acceptable salts or trifluoroacetates also. In compounds of the formula (I) or (Ia) A means (C1-C4)-alkylene; S1 means optionally (C1-C4)-alkyl; S2 means (C1-C4)-alkyl or hydrogen atom (H) being if S1 and S2 mean alkyl then X in the group [-N+(S1S2)-X-] corresponds to pharmacologically acceptable anion or trifluoroacetate; B means saturated or unsaturated carbon 5- or 6-membered cycle; R1, R2, R3, R4 and R5 have values given in the description. Also, invention relates to a method for preparing these compounds and to a medicinal agent. These compounds can be used for preparing medicinal agents useful for treatment or prophylaxis in breathing impulse disturbance, in particular, in breathing disturbance caused by sleep, transient breathing stop during sleep, snore, for treatment or prophylaxis of acute and chronic renal diseases, in particular, acute and chronic renal insufficiency and, disturbance in intestine, gallbladder, ischemic states of peripheral and central nervous system disturbances, severe attacks and others symptoms. Compounds are inhibitors of sodium-proton exchange, show effect on serum lipoprotein and therefore they can be used in prophylaxis and regression of atherosclerotic alterations.

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

21 cl, 70 ex

FIELD: medicine.

SUBSTANCE: means has lipid fraction obtained from Berryteuthis Magister Comandor squid liver containing 10% of polyunsaturated fatty acids and 50% of alkyl-diacylglycerides showing marked lipid-correcting and immunomodulating properties.

EFFECT: enhanced effectiveness in treating lipid metabolism disorders and immunity system disorders.

4 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: medicine, hepatology.

SUBSTANCE: at achieving alkaline phosphatase of 580 U and more one should introduce ursodesoxycholic acid at the dosage of 15-20 mg/kg and orlistate at the dosage of 90-100 mg twice or thrice daily for patients with steatohepatitis. According to normalization of clinical and biochemical values of blood analyses it is possible to conclude upon successfulness of therapy performed. The method provides clinic-laboratory remission of the disease.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition for oral administration in treatment or prophylaxis of obesity or hyperlipidemia. The composition comprises orlistat and at least one ester of fatty acids and polyols. Melting point of fatty acid ester exceeds the body temperature and polyol is taken among group including glycerol, sugars, derivatives of sugars and their mixtures. Also, invention relates to a method for preparing above described composition and to a method for treatment or prophylaxis of obesity. Invention enhances effectiveness and activity of orlistat by reducing variability of effectiveness and/or activity of orlistat between patients and frequency and severity of adverse effects.

EFFECT: improved and valuable pharmaceutical properties of compositions.

24 cl, 1 tbl, 10 ex

FIELD: pharmaceutical chemistry, in particular crystal form of pravastatine sodium salt.

SUBSTANCE: invention relates to new crystal form of pravastatine sodium salt known under chemical name of 1,2,6,7,8,8a-hexahydro-b,d,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobubutoxy)-haphtaleneheptane acid monosodium salt, obtained by a) preparation of solution containing pravastatine and sodium cations in lower aliphatic C1-C4-alcohol; b) addition ethylacetate to said solution; c) cooling of obtained alcohol/ethylacetate mixture; and d) crystallization. Characteristics of new crystal form of pravastatine sodium salt such as crystallogram and melting point (170-1740C) also are disclosed. The subject invention also pertains to method for pravastatine production as well as pharmaceutical composition containing the same. Pravastatine, its derivatives and analogs are well-known HMG-CoA reductase inhibitors and are useful as anticholesterenemic agents in treatment of hypercholesterenemia and hyperlypemia.

EFFECT: crystal form of pravastatine sodium salt and pharmaceutical composition with improved therapeutic action.

29 cl, 5 ex, 4 dwg

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compositions eliciting an antilipidemic effect and comprising inhibitor of bile acid transport in jejunum of the general formula (I): and inhibitor of HMG-CoA-reductase. Also, invention relates to a method for carrying out the combined therapy.

EFFECT: improved treatment method, valuable medicinal properties of compositions.

15 cl, 9 tbl, 1401 ex

FIELD: medicine, cardiology, endocrinology.

SUBSTANCE: invention proposes applying false flax plant oil as a hypoglycemic agent and agent that exerts the normalizing effect on lipid fraction of alpha-lipoproteins (high density lipoproteins; HDLP) and used in treatment of cardiovascular and endocrine diseases, and a method for it applying. This agent is known early as an antioxidant and a hypolipidemic preparation. Detection of new properties allows expanding application of this agent in clinics for treatment of patients with heart ischemic disease, stenocardia, hypertension and diabetes mellitus. The preparation reduces risk for development of atherosclerosis and allows significant reducing doses of basic drugs.

EFFECT: valuable medicinal properties of agent, enhanced effectiveness of treatment.

4 cl, 6 ex

FIELD: medicine, pharmacology, biochemistry, pharmacy.

SUBSTANCE: invention relates to preparations reducing blood cholesterol level. Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin and their derivatives and analogs known as inhibitors of HMG-CoA-reductase are used as anti-hypercholesterolemic agents. Above mentioned active substances can be destabilized as result of effect of environment and their destruction can be accelerated in interaction with other pharmaceutical agents, such as excipients, binding agents, lubricating agents, substances promoting to slipping and disintegrating agents. Therefore, pharmaceutical components and a method for preparing a pharmaceutical preparation must be taken thoroughly to avoid above said undesirable interactions and reactions. Invention relates to inhibitor of HMG-CoA-reductase that stabilized by formation of a homogenous composition with buffer substance or an alkalinizing substance. This homogenous composition is used as an active substance in pharmaceutical preparation used for treatment of hypercholesterolemia and hyperlipidemia. Invention enhances the enhancement of stability and homogeneity of the preparation.

EFFECT: improved and valuable pharmaceutical properties of composition.

23 cl, 2 tbl, 3 dwg, 11 ex

FIELD: organic chemistry of heterocyclic compounds, biochemistry, pharmacy.

SUBSTANCE: invention describes alkylamino-substituted bicyclic nitrogen-containing heterocycles of the general formula (I):

wherein n = 1; R1 means (C1-C6)-alkyl; R2 means halogen atom; R3 means (C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkylsulfonyl-(C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, dihydroxy-(C1-C6)-alkyl, N-heterocyclyl-(C1-C6)-alkyl or (C1-C6-alkylene)-C(O)R31 wherein R31 means hydroxy- or (C1-C6)-alkoxy-group, and its pharmaceutically acceptable salts. New compounds are inhibitors of protein kinase p38 and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

8 cl, 13 ex

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