Method of producing intermediate product for synthesis of dabigatran etexilate

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula which includes treating a diamine of formula in an aprotic solvent with an oxadiazole of formula , which, in the presence of a water-binding agent in a mixture with a tertiary amine, at temperature of 10-100°C and pressure of 1-6 bar, is converted to a compound of formula which, without separation, is then converted by hydrogenation and addition of para-toluene sulphonic acid and ammonia to an amidine of formula 1.

EFFECT: method enables to conduct synthesis without separating the intermediate product and replacing the solvent, avoids use of hot filtration and increases output of the product.

3 cl, 6 ex

 

The present invention relates to a method for obtaining compounds of formula 1

,

represent valuable intermediate product in the synthesis of pharmaceutical active substances - etexilate of dabigatran.

The level of technology

Etexilate of dabigatran known from the prior art and was first described in WO 98/37075. Methods of obtaining etexilate of dabigatran known, furthermore, from WO 2006/000353, as well as from the publication Hauel, etc. (Journ. Med. Chem, 45, 2002, s).

As described in WO 98/37075, as well as in WO 2006/000353, in the synthesis of etexilate of dabigatran a major role as an intermediate product is given to the compound of formula 1, namely: paratoluenesulfonyl N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide 1-methyl-2-[N-[4-lidinopril]aminomethyl]benzimidazole-5-icarbonell acid.

Along with these publications WO 98/37075 and WO 2006/000353 some aspects concerning the possible ways of obtaining etexilate of dabigatran also presented in WO 2007/071742 A1 and WO 2007/071743 A1.

In WO 98/37075 is proposed to obtain the substituted (4-(benzimidazole-2-ylmethylamino)benzamidine interaction of the corresponding substituted (4-benzoimidazol-2-ylmethylamino)benzonitrile with ammonia. However, this method from a technological point of view is associated with extremely high costs and leads to significant pollution Ki is lots want to dispose of.

According to WO 2006/000353 A1, WO 2007/071742 A1 and WO 2007/071743 A1 compound of formula 1 is obtained by synthesis of condensation products of formula 4 in accordance with the following scheme 1.

Scheme 1

According to known prior art methods, the compound of formula 4 is first allocated, and then hydronaut.

When carrying out the condensation reaction according to scheme 1 often is a by-product of formula 5

,

before the selection of the condensation product of the formula 4 are removed by complex and associated with high costs, filtering while hot.

In addition, subsequent reaction for obtaining the compounds of formula 1. requires replacement of solvents and in addition requires associated with substantial time and cost allocation and drying the intermediate product of formula 4. For these reasons, it can reduce the yield of the final product.

The present invention was based on the objective to develop a method of obtaining the compounds of formula 1, which would allow more efficient to synthesize this compound in an industrial scale and would avoid the above drawbacks.

Detailed description of the invention

The present invention relates to a method recip is of the compounds of formula 1

on an industrial scale, wherein the diamine of formula 2

interaction with oxadiazolones formula 3

turn in the compound of formula 4

,

without the allocation of turn by hydrogenation and add paratoluenesulfonyl and ammonia in amidin formula 1.

The initial compounds of formulas 2 and 3 can be obtained by the method described in WO 2006/000353.

When carrying out the proposed invention the reaction of compounds of formulas 2 and 3 is dissolved in an inert organic solvent and condense in the presence of water-bonding means. As the inert organic solvent is preferable to use an aprotic solvent. It can, for example, be selected from the group including aliphatic and aromatic, optionally halogenated hydrocarbons, ethers, amides and mixtures thereof. As the aprotic nonpolar solvents, it is preferable to use a branched or unbranched aliphatic C5-C8alkanes,4-C10cycloalkanes, aliphatic C1-C6halogenoalkane, aromatic With6-C10alkanes or a mixture thereof. Particularly preferable to use alkanes, such as pentane, hexane or g is PTEN, cycloalkanes, such as cyclohexane or methylcyclohexane, halogenoalkane, such as dichloromethane, aromatic alkanes, such as benzene, toluene or xylene, or a mixture thereof. For use as aprotic solvents suitable next polar ethers such as tetrahydrofuran (THF), methyltetrahydrofuran, dioxane, tert-butyl methyl ether or dimethoxyethane ether, amides, such as dimethylformamide, or lactams such as N-organic.

As connecting water means you can use hygroscopic salts, inorganic or organic acids, respectively, their anhydrides, anhydrides of inorganic or organic acids, anhydrides alkanephosphonic acid, molecular sieves or derivatives of urea. Preferred however 1,1'-carbonyldiimidazole and alkanephosphonic anhydrides, and the most preferred alkanephosphonic anhydrides. Among the latter are of particular importance according to the invention is given papapostolou anhydride (PFA, 2,4,6-trioxide 2,4,6-tripropyl-[1,3,5,2,4,6]trioxatridecane). According to the invention when using alkanephosphonic anhydrides, it is preferable to add an organic base, particularly preferably a tertiary amine, most preferably diisopropylethylamine.

Per mole of the used link the formula 2 above inert organic solvent preferably used in quantities of from 0.5 to 2.5 l, particularly preferably from 1.0 to 2.0 l, most preferably from 1.3 to 1.5 liters used per mole of the compounds of formula 2 compound of formula 3 is preferably further used in stoichiometric quantities. Especially preferable to use the compound of formula 3 in a small excess. Per mole of the used compounds of formula 2 compound of formula 3 is used in an amount of from 1.0 to 2.0 moles, especially preferably from 1.0 to 1.5 mol, most preferably from 1.1 to 1.3 mole.

Compounds of formulas 2 and 3 are dissolved in the above inert organic solvent at a temperature in the range from 10 to 50°C., preferably from 20 to 40°C., particularly preferably from 25 to 35°Statem at a constant temperature according to a particularly preferred variant of the invention, the type of tertiary amine. Per mole of the used compounds of formula 2 tertiary amine is preferably used in at least stoichiometric amounts. Particularly preferably, however, use of the tertiary amine in significant excess. In accordance with this used per mole of the compounds of formula 2 tertiary amine is used in amounts of from 1.5 to 5.0 moles, especially preferably from 2.0 to 4.0 moles, most preferably from 2.3 to 2.7 mole.

After adding a tertiary amine and then at a temperature ol doctitle in the range from 10 to 40°C, particularly preferably from 20 to 30°C, dispense alkanephosphonic anhydride, preferably above the APF. Per mole of the used connection 2 alkanephosphonic anhydride is preferably used in at least stoichiometric amounts. Particularly preferable to use alkanephosphonic anhydride in a small excess. Per mole of the used compounds of formula 2 alkanephosphonic anhydride is preferably used in an amount of from 1.0 to 2.0 moles, especially preferably from 1.0 to 1.7 mol, most preferably from 1.1 to 1.4 mol. Preferably used according to the invention the APF is advisable to add in diluted form. In one of the preferred options the APF for adding dissolved in the used inert organic solvent. Particularly preferable to add the APF in the form of 30-60% (wt.%), most preferably in the form of a 50%solution in tetrahydrofuran or ethyl acetate.

Upon completion of the addition the APF, the mixture is stirred at constant temperature for about 0.25 to 4 hours After that add a weak organic acid in a quantity in terms of the applied amount of the compounds of formula 2 is preferably at least 0.5 equivalent. Under such a weak organic acid in a preferred embodiment, podrazumevao the Xia citric or acetic acid. This acid, however, can also be used in excess. In accordance with this used per mole of the compounds of formula 2 mentioned acid is used in amounts of from 0.5 to 4.0 equivalents, more preferably from 1.0 to 3 equivalents, particularly preferably from 1.0 to 2.0 equivalents. If necessary, the reaction mixture can be diluted one of the aforementioned inert organic solvent, preferably the same solvent. For dilution of the mixture solvent is preferably added in amounts up to 50%, particularly preferably in the range from 10 to 30%, from the previously used his number.

After addition of acid, and an optional dilution of the reaction mixture is then at an elevated temperature and optionally elevated pressure conducting a condensation reaction to obtain compounds of formula 4. The temperature thus according to the invention is preferably maintained above 50°C, more preferably in the range from 60 to 100°C., particularly preferably from 65 to 85°C. When using a solvent, which is already in full swing in the specified temperature range, the pressure is increased to a level that despite the lower the boiling point of the solvent, the reaction can be conducted at the same temperature. The pressure at which carry out the reaction, prepact the positive set at the level of 1-3 bar.

The course of the reaction is controlled by conventional methods, for example, by means of thin layer chromatography or liquid chromatography high resolution (IHVR). Upon completion of the reaction, the reaction mixture is slowly cooled, preferably to a temperature in the range from 10 to 50°C., particularly preferably to a temperature of about 20-30°C.

Next, to the reaction mixture without further processing to add an appropriate catalyst for the hydrogenation. For use as hydrogenation catalysts generally suitable transition metals, such as Nickel, platinum or palladium or their salts or oxides. Preferably Raney Nickel, platinum oxide and palladium on an inert carrier, especially palladium on charcoal (Pd/C). In one preferred options use water-wetted 10%Pd/C. used per mole of the compounds of formula 2 such a catalyst is preferably used in an amount of from 2 to 35 g, more preferably from about 4 to 25 g, especially preferably from about 8 to 18, After adding the catalyst hydrogenation add water. The added amount of water is determined principally by the total number of used inert organic solvent. Water is preferably added in an amount that ranges from 50 to 100% (vol./vol.), W is preferably from 70 to 90% (vol./vol.), all the used amount of the solvent.

After adding water, the reaction mixture is heated to a temperature in the range from 30 to 70°C., particularly preferably to a temperature of about 40-60°C., and with stirring hydronaut when the hydrogen pressure 2-6 bar, preferably 3-5 bar.

Upon completion of the reaction the catalyst is filtered off, the filtrate is optionally diluted with water in an amount of from about 5 to 30% from its previously used amount and at a temperature in the range from 10 to 60°C., particularly preferably from 20 to 40°C., mixed with paratoluenesulfonyl. Paratoluenesulfonyl can be added in the form of a solid substance, optionally in the form of its monohydrate or in aqueous solution. Per mole of the used compounds of formula 2 paratoluenesulfonyl preferably used in at least stoichiometric amounts. Particularly preferable to use paratoluenesulfonyl in a small excess. Per mole of the used compounds of formula 2 paratoluenesulfonyl preferably used in an amount of from 1.0 to 2.0 moles, more preferably from 1.0 to 1.7 mol, particularly preferably from 1.0 to 1.4 mol, especially from 1.1 to 1.3 mole.

After that add the ammonia, which is used either in gaseous form or in the form of aqueous solutions. According to the invention, AMIA is preferably used in the form of aqueous solutions, especially preferably in the form of an aqueous solution containing ammonia (NH4OH) about 25% (wt./wt). Add ammonia, for example, at a temperature in the range from 30 to 65°C. used per mole of the compounds of formula 2 ammonia at this stage is preferably added in an amount of from 2 to 20 moles, especially preferably from 6 to 16 moles, most preferably from about 9 to 13 moles.

In the process of adding ammonia compound of formula 1 starts yet to crystallize. The reaction mixture is cooled to a temperature in the range from 0 to 40°C, particularly preferably from about 15 to 25°C, after which the compound of formula 1 is filtered and washed with water or acetone. If you need to stock solution for further bicrystalline the compounds of formula 1 can re-add the ammonia. In this case, per mole of the used compounds of formula 2, the ammonia is preferably added in an amount of from 1 to 10 moles, especially preferably from 2 to 8 moles, most preferably from 3 to 5 moles.

With the invention it has been unexpectedly found that by adding ammonia compound of formula 1 is almost completely precipitated from the reaction mixture. Due to that known from the prior art methods provide a number of advantages, some of which more detail is discussed below. One such advantage is the significant increase in the yield of the compounds of formula 1. In addition, when receiving the intermediate compounds of formula 4 eliminates the need for filtering in a hot state, which under certain conditions is required to remove the polluting compounds of formula 5. Furthermore, the reduced consumption is necessary for carrying out the invention a method of solvents and reagents, which greatly simplifies the synthesis primarily on an industrial scale. Another advantage is that unlike the prior art, there is no need associated with a high expenditure of time allocation and drying the intermediate product.

Above and below the following abbreviations are used:

Asónacetic acid
DIPEAN,N-diisopropylethylamine
EtOActhe ethyl acetate
Pd/Cpalladium on charcoal
The APFpapapostolou anhydride
PTSCparatoluenesulfonyl
CTroom temperature
THFtetrahydrofuran

In the following examples is explained in more detail one possible implementation of the present invention in the synthesis method. These examples serve only to illustrate the invention and do not limit its scope.

Example 1

24,20 g of compound of formula 2 and 19,95 g of compound of formula 3 is almost completely dissolved in 100 ml of THF at a temperature about 30°C. Then, at this temperature, add 24,92 g DIPEA. After that, when CT metered 57,89 g of a 50%aqueous solution of the APF in THF and stirred for about 2 hours After adding 13,44 g of citric acid and 20 ml of THF and then at a temperature of about 90°C under the pressure of conducting a condensation reaction with obtaining unmarked intermediate compounds of formula 4. Upon completion of the reaction, the reaction mixture was cooled to CT and mixed with 1,21 g moistened with water and 10%Pd/C and 100 ml of water. Then the suspension is heated to about 50°C and hydronaut in an atmosphere of hydrogen at a pressure of about 4 bar). Then Pd/C is filtered off and washed with 25 ml of water. After adding 25 ml of water the reaction mixture at a temperature of about 50°C is mixed with 20,40 g of a 65%aqueous solution PTSC and 60 ml of 25%aqueous ammonia solution. Thus begins a loss tosilata in the sediment. is th is cooled to CT, the product of formula 1 is filtered off and washed with water. Drying is carried out at 60°C or at a temperature up to 95°C under vacuum.

Output: 41,4 g (87,2%).

Purity: above 99%, determined by peak area at GHUR-the chromatogram.

Example 2

24,20 g of compound of formula 2 and 19,95 g of compound of formula 3 is almost completely dissolved in 87 ml of THF at RT. Then, at this temperature, add 24,92 g DIPEA. After that, when CT metered 57,89 g of a 50%aqueous solution of the APF in THF, washed with 13 ml of THF and stirred for about 2 hours After adding 6,72 g of citric acid and 20 ml of THF and then at a temperature of about 90°C under the pressure of conducting a condensation reaction with obtaining unmarked intermediate compounds of formula 4. Upon completion of the reaction, the reaction mixture was cooled to CT and mixed with 1.24 g moistened with water and 10%Pd/C and 60 ml of water. Then the suspension is heated to about 50°C and hydronaut in an atmosphere of hydrogen at a pressure of about 4 bar). Then Pd/C is filtered off and washed with 50 ml of a mixture of THF and water (in the ratio 7:3). After adding 20 ml of a mixture of THF and water (in the ratio 7:3) the reaction mixture at a temperature of about 50°C is mixed with 39,93 g hard PTSC and 60 ml of 25%aqueous ammonia solution. Thus begins a loss tosilata in the sediment. It is cooled to CT, the product of formula 1 is filtered off and washed with water. Drying is carried out at 40°C or at t is mperature up to 95°C under vacuum.

Output: 42.2 g (88,9%).

Purity: above 99%, determined by peak area at GHUR-the chromatogram.

Example 3

24,20 g of compound of formula 2 and 19,95 g of compound of formula 3 is almost completely dissolved in 87 ml of THF at RT. Then, at this temperature, add 24,92 g DIPEA. After that, when CT metered 57,89 g of a 50%aqueous solution of the APF in EtO, washed with 13 ml of THF and stirred for about 2 hours After adding 6,72 g of citric acid and 20 ml of THF and then at a temperature of about 90°C under the pressure of conducting a condensation reaction with obtaining unmarked intermediate product, representing okamiden connection BIBR 1048. Upon completion of the reaction, the reaction mixture was cooled to CT and mixed with 1,21 g moistened with water and 10%Pd/C and 75 ml of water. Then the suspension is heated to about 50°C and hydronaut in an atmosphere of hydrogen at a pressure of about 4 bar). Then Pd/C is filtered off and washed with 50 ml of a mixture of THF and water (1:1 ratio). After adding 25 ml of THF and 10 ml of water the reaction mixture at a temperature of about 50°C is mixed with 39,93 g hard PTSC and 60 ml of 25%aqueous ammonia solution. Thus begins a loss tosilata in the sediment. It is cooled to CT, the product of formula 1 is filtered off and washed with water. Drying is carried out at 40°C or at a temperature up to 95°C under vacuum.

Output: 43,1 g (90,8%).

Purity: above 99%, determined by size, the peak at GHUR-the chromatogram.

Example 4

24,20 g of compound of formula 2 and 19,95 g of compound of formula 3 is almost completely dissolved in 87 ml of THF at RT. Then, at this temperature, add 24,92 g DIPEA. After that, when CT metered 57,89 g of a 50%aqueous solution of the APF in tO, washed with 13 ml of THF and stirred for about 2 hours After adding 4,20 g Asón and 20 ml of THF and then at a temperature of about 90°C under the pressure of conducting a condensation reaction with obtaining unmarked intermediate compounds of formula 4. Upon completion of the reaction, the reaction mixture was cooled to CT and mixed with 1.25 g of hydrated water 10%Pd/C and 60 ml of water. Then the suspension is heated to about 50°C and hydronaut in an atmosphere of hydrogen at a pressure of about 4 bar). Then Pd/C is filtered off and washed with 50 ml of a mixture of THF and water (in the ratio 7:3). After adding 20 ml of a mixture of THF and water (in the ratio 7:3) the reaction mixture at a temperature of about 50°C is mixed with 39,93 g hard PTSC and 60 ml of 25%aqueous ammonia solution. Thus begins a loss tosilata in the sediment. It is cooled to CT, the product of formula 1 is filtered off and washed with water. Drying is carried out at 45°C or at a temperature up to 95°C under vacuum.

Output: of 36.4 g (76.7 percent).

Purity: above 99%, determined by peak area at GHUR-the chromatogram.

Example 5

24,20 g of compound of formula 2 and 19,95 g of compound of formula 3 is almost completely Rast is oraut in 86 ml of THF at a temperature about 30°C. Then, at this temperature, add 24,92 g DIPEA. After that, when CT metered 57,89 g of a 50%aqueous solution of the APF in THF and stirred for about 2 hours After the addition of 10.50 g of L-tartaric acid and 20 ml of THF and then at a temperature of about 90°C under the pressure of conducting a condensation reaction with obtaining unmarked intermediate compounds of formula 4. Upon completion of the reaction, the reaction mixture was cooled to CT and mixed with 1,21 g moistened with water and 10%Pd/C and 100 ml of water. Then the suspension is heated to about 50°C and hydronaut in an atmosphere of hydrogen at a pressure of about 4 bar). Then Pd/C is filtered off and washed with 30 ml of water. After adding 20 ml of water the reaction mixture at a temperature of about 50°C is mixed with 22,25 g of a 65%aqueous solution PTSC and 60 ml of 25%aqueous ammonia solution. Thus begins a loss tosilata in the sediment. It is cooled to CT, the product of formula 1 is filtered off and washed with water. Drying is carried out at 90°C or at a temperature up to 95°C under vacuum.

Output: 39,3 g (82,8%).

Purity: above 99%, determined by peak area at GHUR-the chromatogram.

Example 6

24,20 g of compound of formula 2 and 19,95 g of compound of formula 3 is almost completely dissolved in 100 ml of THF at a temperature about 30°C. Then, at this temperature, add 23,07 g DIPEA. Then at 25°C. dispense 57,89 g of a 50%aqueous solution of the APF in THF and stirred during about 30 minutes After adding 20,17 g of citric acid and 20 ml of THF and then at a temperature of about 75°C. under the pressure of conducting a condensation reaction with obtaining unmarked intermediate compounds of formula 4. Upon completion of the reaction, the reaction mixture was cooled to CT and mixed with 1,21 g moistened with water and 10%Pd/C and 100 ml of water. Then the suspension is heated to about 50°C and hydronaut in an atmosphere of hydrogen at a pressure of about 4 bar). Then Pd/C is filtered off and washed with 30 ml of water. After adding 20 ml of water the reaction mixture at a temperature of 28-38°C is mixed with 22,25 g of a 65%aqueous solution PTSC. Then at a temperature in the range from 38°C to a temperature distillation (64-65°C) dose of 60 ml of 25%aqueous ammonia solution. Thus begins a loss tosilata in the sediment. It is cooled to CT and add 20 ml of 25%aqueous ammonia solution. The product of formula 1 is filtered off and washed with water. Drying is carried out at 60°C or at a temperature up to 95°C under vacuum.

Output: 42,4 g (89.3 per cent).

Purity: above 99%, determined by peak area at GHUR-the chromatogram.

1. The method of obtaining the compounds of formula 1

characterized in that the diamine of formula 2

process in an aprotic solvent chosen from the group comprising tetrahydrofuran (THF), methyltetrahydrofuran, diox is h, tert-butyl methyl ether, dimethoxyethane ether, dimethylformamide and N-methylpyrrolidone, oxadiazolones formula 3

which in the presence of water-bonding tool, which is chosen from the group comprising 1,1'-carbonyldiimidazole and anhydride papapostolou acid, in a mixture with a tertiary amine, at a temperature of from 10 to 100°C and a pressure of from 1 to 6 bar, is converted into a compound of formula 4

then without releasing transformed by hydrogenation and add paratoluenesulfonyl and ammonia in amidin formula 1.

2. The method according to claim 1, characterized in that the reaction between the compounds of formulas 2 and 3 to obtain the intermediate compounds of formula 4 is carried out in tetrahydrofurane (THF).

3. The method according to claim 1 or 2, characterized in that the water-bonding tool is an anhydride papapostolou acid in a mixture with diisopropylethylamine.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel fungicidally active 5-fluoropyrimidines of general formula I. In compounds of formula , R1 is -N(R3)R4; R2 is -OR21; R3 is: H; C1-C6-alkyl, optionally substituted with 1-3 groups R5; C2-C6-alkenyl, optionally substituted with 1-3 groups R5; a 5- or 6-member heteroaromatic cycle, selected from a group consisting of furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl; wherein each heteroaromatic cycle is optionally substituted with 1-3 R29 groups; 3H-isobenzofuran-1-oyl; -C(=O)R6; -C(=S)R6; -C(=S)NHR8; -(=O)N(R8)R10; -OR7; -P(O)(OR15)2; -S(O)2R8;-SR8; -Si(R8)3; -N(R9)R10; -(CHR24)mOR29 or -C(=NR16)SR16; where m equals an integer from 1 to 3; R4 is: H; C1-C6-alkyl, optionally substituted with 1-3 R5 groups; or -C(=O)R6; alternatively, R3 and R4 together can form: a 5- or 6-member saturated or unsaturated cycle containing 1-2 heteroatoms selected from N and O, where each cycle can be optionally substituted with 1-3 R11 groups; =C(R12)N(R13)R14 or =C(R15)OR15. The rest of the radicals are given in the claim.

EFFECT: obtaining novel fungicidally active 5-fluoropyrimidines of general formula I.

4 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to using an oxadiazolyl compound of the formula I

,

wherein R1 and R2 mean hydrogen; X means a methylene group; Y represents an oxygen atom; n represents an integer of 0, 1, 2 or 3, and m represents an integer of 0 or 1; R3 means a group of N-oxide pyridine according to the formula B which is attached as shown by an unmarked bond: ,

wherein R4, R5, R6 and R7 are the same or different and mean hydrogen, lower alkyl, halogen, haloalkyl, trifluoromethyl; the term "alkyl" means carbon chains, unbranched or branched, containing one to six carbon atoms; the term "halogen" means fluorine, chlorine, bromine or iodine; or its pharmacologically acceptable salt for preparing a drug for preventing or treating diseases related to the central and peripheral nervous system, wherein the above drug is administered according to a dosage regimen characterised by a dosage rate within approximately twice a day to approximately once every two days.

EFFECT: optimising the dosage regimen.

84 cl, 3 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to form A of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl-)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, where said form A is characterised by peak at approximately 7.9 degree, peak at approximately 11.9 degree, peak at approximately 14.4 degree and peak at approximately 15.8 degree in powder X-ray. Invention also relates to pharmaceutical composition and set based on said form A, application of form A, method of CFTR modulation.

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12 cl, 3 dwg, 2 tbl, 3 ex

FIELD: chemistry.

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

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

22 cl, 1 tbl, 128 ex

FIELD: chemistry.

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

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

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to piperidine compounds of formula and their pharmaceutically acceptable salts, based on them pharmaceutical composition, treatment method with therein application and therein application for treatment of gastrointestinal diseases. In formula (I) m represents integer number 1 or 2; n represents integer number from 0 to 2, A is selected from phenyl group and benzimidazole group, where phenyl group is substituted with one or more groups, independently selected from C1-C6 linear or branched alkyl group, C1-C6 linear or branched alkoxygroup, aminogroup and halogen, and benzimidazole group is substituted with one or more groups, independently selected from C1-C6 linear or branched alkyl group, C1-C6 linear or branched alkoxygroup, C3-C7 cyclic alkyl group, aminogroup, halogen and oxogroup; X represents hydroxyl or OCONR1R2, where R1 and R2 are independently selected from hydrogen and C1-C6 linear or branched alkyl group, or R1 and R2 form 5-7-membered heterocyclic ring or 3,5-dimethylpiperidine ring, together with nitrogen atom, to which they are attached, and B is selected from phenyl group, phenoxygroup, thienyl group and naphthyl group, where phenyl group, phenoxygroup, thienyl group or naphthyl group is substituted with one or more groups, independently selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, phenyl, C1-C6 linear or branched alkyl group and C1-C6 linear or branched alkoxygroup.

EFFECT: obtaining novel compounds.

25 cl, 3 tbl, 163 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound, which contains pyridine ring, represented by formula (1) , where R0 represents C1-6alkoxygroup, C1-6alkoxy-C1-6alkoxygroup, C1-6alkoxy-C1-6alkyl group, 1,3-dioxan-2-yl-C1-6alkyl group or group CR01C(=NOR02) (where each of R01 and R02 independently represents C1-6alkyl group), R1 represents C1-2 alkoxycarbonyl group, acetyl group or benzoyl group, which can be substituted with nitrogroup, X represents halogen atom, and n represents quantity of X substituents and equals integer number from 0 to 3, and when n equals 2 or more, X substituents can be similar or different from each other, which can be synthesised in industrially profitable way and used as intermediate compound for obtaining tetrazolyloxime derivatives which demonstrate fungicidal activity.

EFFECT: industrially profitable methods of obtaining tetrazolyloxime derivatives are described.

10 cl, 3 tbl, 13 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

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

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

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

SUBSTANCE: invention proposes two variants of the improved method for preparing anti-ulcerous therapeutic agents of the formula (I): wherein radicals R1-R6 have values given in cl. 1 and cl. 2 of the invention claim. Method involves interaction of corresponding sulfides with m-chloroperoxybenzoic acid in acetone or a mixture acetone/water as a solvent. According to the first variant pH value of the reaction mixture is increased to the value above 7 after the reaction interaction and solvent is removed and crystals of compound of the formula (I) are separated. According to the second variant the interaction is carried out at pH ≥ 7.0 followed by addition of water if necessary and compound of the formula (I) crystals are separated. Invention is directed for preparing omeprazole or pantoprazole preferably. Invention provides preparing the end products of high purity and with high yield.

EFFECT: improved preparing method.

9 cl, 3 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new compound: N-[2-hydroxy-3(1-piperidinyl)-propoxy]-pyridine-1-oxyde-3-carboxyimidoyl chloride, stereoisomers thereof acid additional salts useful in treatment of pathological insulin resistance.

EFFECT: new compound useful in medicine.

5 cl, 10 tbl, 10 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new heterocyclic compounds corresponding to general formulas: (I) , (II) , (Ia) and (Ib) wherein substitutes have values given in the description. Such compounds are reversible inhibitors of cathepsins S, K, F, L and B. Also, invention relates to a method for preparing these compounds, pharmaceutical composition eliciting inhibitory activity with respect to cysteine proteases and to a method for modulation of autoimmune diseases, treatment of Alzheimer's disease and osteoporosis.

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

42 cl, 106 ex

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