Pharmaceutical composition comprising inhibitor of hmg-coa- reductase

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-methyl-[(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid as an active component or its pharmaceutically acceptable salt and inorganic salt with polyvalent cation also. Also, invention proposes a method for preparing the stabilized pharmaceutical composition. Invention provides preparing the stabilized pharmaceutical composition.

EFFECT: valuable medicinal properties of composition.

25 cl, 4 ex

 

The present invention relates to pharmaceutical compositions and, more specifically, to a pharmaceutical composition containing (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-envoy acid or its pharmaceutically acceptable salt (hereinafter referred to as "Agent"). In particular, sodium and calcium salts, especially calcium salts, i.e. the calcium salt of bis [(E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-ene acid (Formula I which is presented below).

The agent discovered as an inhibitor of 3-hydroxy-3-methylglutaryl COA reductase (HMG COA reductase) in the application for a European patent. Publication No. 0521471 and in Bioorganic and Medicinal Chemistry, (1997), 5(2), 437-444, and it is used to treat hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis.

The problem associated with the specified Agent, is that this substance is particularly sensitive to degradation under certain conditions. The main decomposition products are the corresponding (3R,5S) lactone (hereinafter referred to as the "lactone") and oxidation products (hereinafter "B2"), in which the hydroxy group adjacent to the carbon-carbon double bond is oxidized to ketone functional group. The existing potential for significant degradation Agent complicates aluchemie and manufacture of a pharmaceutical composition with an acceptable shelf life as a market product.

Pharmaceutical formulations of some salts of 7-substituted-3,5-dihydroxy-6-heptenophos acids, which are inhibitors of HMG COA reductase, are disclosed in UK Patent 2262229 and notes that they are susceptible to decomposition under the action of pH. Consider recipes require the presence of an alkaline environment (e.g., carbonate or bicarbonate), which can generate a pH of at least 8 in an aqueous solution or dispersion medium under consideration compositions.

However, the authors found that for the considered Agent is insufficient stability is improved only by regulating the pH of the formulation. Applicants have discovered that the stability of the Agent is increased by the selection of the inorganic salt, which is added to the composition, and which contains one or more polyvalent inorganic cations. Not limited to a particular theory, the applicant believes that the polyvalent inorganic cation stabilizes the structure of the Agent and makes it less sensitive to oxidation and/or lactonization.

Distinctive features of the invention are

(1) a Pharmaceutical composition comprising an Agent as an active ingredient and an inorganic salt with a polyvalent cation.

(2) the Use of inorganic salts with polyvalent cation as a stabilizing agent supplied with the tion of the composition, includes Agent.

Preferred distinctive features of the invention are the following:

(1) the Agent is present in the composition in amounts of more than 5 mg, preferably 10 mg Excluded compositions, in which the Agent is present in quantities of 1, 2, 5 and 10 mg. Preferred compositions are those in which the number of Agent is 20, 40 or 80 mg

(2) Stabilizing the connection is not synthetic hydrotalcite.

(3) the Pharmaceutical composition form in the form of tablets or powder.

Preferred pharmaceutical composition of the present invention is a tablet.

Polyvalent cation of the inorganic salt may be selected from the following elements: calcium, magnesium, zinc, aluminum and iron or mixtures thereof. Preferred polyvalent cations are calcium, aluminum and magnesium, or their mixture. Especially preferred polyvalent cations are aluminum and magnesium, or their mixture.

Protivoiadie inorganic salt may be selected from a phosphate, carbonate, silicate, oxide and metasilicate.

Preferred protivoanemi selected from carbonate, silicate, oxide and metasilicate. The most preferred protivoanemi selected from silicate, oxide or metasilicate.

Individual aspects of this and the finding include inorganic salt with a polyvalent cation, selected from any of the above, and protivoiadie also choose from any of the above.

Preferred inorganic salts intended for use in the present invention include: aluminum-magnesium metasilicate (Neusolin™, Fuji Chemical Industry Limited), dibasic or rejonowy calcium phosphate, rejonowy phosphate magnesium and rejonowy phosphate of aluminum. Especially preferred compounds are the aluminum-magnesium metasilicate and rejonowy calcium phosphate.

Also preferably, this composition had good fluidity to facilitate processing in a single dosage form intended for oral administration, e.g. tablets, as well as good characteristics concerning the disintegration and dissolution in the formation of tablets for oral administration, and such tablets may include various effective dose.

The ratio of inorganic salt and an Agent in the pharmaceutical composition is in the range of 1:80-50:1 wt., for example, 1:50-50:1 wt., up to 1:10-10:1 wt., and more preferably 1:5-10:1 wt.

Preferably, the pharmaceutical composition of the present invention formed into an oral dosage form, such as tablets. According to an additional aspect of the present invention VK is uchet pharmaceutical composition, containing Agent, inorganic salt with a polyvalent cation and one or more fillers, binding agents, disintegrators or lubricating agents. Another aspect of the present invention relates to a pharmaceutical composition for oral administration comprising an Agent, one or more fillers, one or more binders, one or more disintegrators, one or more lubricating agents, and inorganic salt with a polyvalent cation.

Suitable fillers include, for example, lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g. microcrystalline cellulose, cellulose, calcium sulphate, xylitol and lactic.

Suitable binding agents include, for example, polyvinylpyrrolidone, lactose, starches, modified starches, sugar, Arabian gum, tragakant, guar gum, pectin, binder based on waxes, microcrystalline cellulose, methylcellulose, carboxymethyl cellulose, hypromellose, hydroxyethylcellulose, hydroxypropylcellulose, copolyvidone, gelatin and sodium alginate.

Suitable disintegrators include, for example, croscarmellose sodium, crosspovidone, polyvinylpyrrolidone, matrikamantra, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose and hydroxypropylcellulose.

Suitable lubricating agents include, for example, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, Carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycols and sodium fumarate.

Additional conventional excipients that can be added to the composition include preservatives, stabilizers, antioxidants, conditioned-based flowable oxide of silicon, antiadhesive, or glidant.

Other suitable fillers, binders, disintegrators, lubricants and additional excipients that may be used are described in Handbook of Pharmaceutical Excipients, 2ndEdition, American Pharmaceutical Association; theory and practice of industrial pharmacy, 2ndEdition, Lachman, Leon, 1976; Pharmaceutical dosage forms: Tablets Volume 1, 2ndedition, Lieberman, A. Hebert, et al, 1989; Modern pharmaceutics, Banker, Gilbert and Rhodes, Christopher T, 1979; and Remington's Pharmaceutical Sciences, 15thEdition, 1975.

Typically, the Agent is present in an amount in the range of 1-50%, for example, 1-25%, or 1-20%, and preferably 5-18 wt.%.

Typically, inorganic salt, such as rejonowy calcium phosphate, is present in an amount of 1-25%, for example, 1-20%, or 5-18 wt.%.

Typically, one or more filler present in the composition in an amount of 30-90 wt.%.

Usually one or more binding agent is present in an amount of 2-90 wt.%.

As a rule, one and the and more disintegrators are present in amounts of 2-10%, especially, 4-6 wt.%.

It should be borne in mind that the specific excipient can serve as a bonding agent and filler or binding agent, filler and disintegrator. Usually, the total amount of filler, a coupling agent and the cage is, for example, 70-90% by weight of the composition.

Typically, the composition contains one or more lubricants in an amount of 0.5 to 3%, especially, 1-2 wt.%.

The pharmaceutical composition of the present invention may be obtained using standard techniques and production methods generally known in the art, for example, by dry mixing of the components. For example, the Agent and the inorganic salt with a polyvalent cation, one or more fillers, one or more binders and one or more of the disintegrator, and additional excipients, if desired, are mixed with each other. The components of the mixture before mixing, or the mixture can be passed through the holes of the sieve, for example, sieves with apertures of 400-700 microns. Lubricant, which can also be passed through a sieve, then add to the mixture, and stirring is continued until a homogeneous mixture. Then the obtained mixture is pressed into tablets. On the other hand, you can use the technique of wet granulation. So the example The agent and the inorganic salt with a polyvalent cation, one or more fillers, one or more binders and part of the cage, as well as other excipients, if desired, are mixed with each other, for example, using a granulator, and the resulting powder was granularit in the presence of a small amount of purified water. The granulate is dried and passed through a mill. The remaining quantity of the cage and the lubricant is added to the ground granulate and after stirring the resulting homogeneous mixture is pressed into tablets. It should be borne in mind that various modifications of the method of dry mixing and wet granulation, including the order of addition of components and their screening and mixing before pressing into tablets, can be carried out in accordance with principles known in the art.

Next, the tablets can be coated, for example, by a method of sputtering film-forming compositions are water-based. This coating may contain, for example, lactose, hypromellose, triacetin, titanium dioxide and iron oxides. The combination of ingredients of the coating are commercially available products, for example, those described in the following examples. Consider coating can be, for example, 0.5-10% Almassy composition for tableting, especially, 1-6%, preferably 2-3%. Coatings containing iron oxides, are particularly preferred because they reduce the rate of formation of products of photodegradation of the Agent.

In accordance with the above distinguishing feature of the invention is a pharmaceutical composition containing the Agent, and this composition has a light coating of oxide of iron.

Another aspect of the present invention relates to a method for producing a stable pharmaceutical composition, which consists in mixing the Agent with an inorganic salt with a polyvalent cation. Another aspect of the present invention relates to a method for producing a stable pharmaceutical composition, which consists in the introduction to pharmaceutical composition comprising the Agent, inorganic salt with a polyvalent cation.

Example 1

Agent2,50 mg
Rejonowy calcium phosphate20.0 mg
Microcrystalline cellulose47.0 mg
The lactose monohydrate47.0 mg
Matrikamantra3,00 mg
Butoxycarbonyl hydroxytrol0.05 mg
The magnesium stearate is 1.00 mg

Agent, microcrystalline cellulose, lactose monohydrate, matrikamantra, rejonowy calcium phosphate and butoxycarbonyl hydroxytrol mixed with each other within 10 minutes. Magnesium stearate was passed through a sieve with holes # 40 mesh (425 μm) was added to the mixture, after which the stirring was continued for three minutes. The resulting homogeneous mixture was pressed into tablets.

These tablets were stored at 70°C/80% relative humidity for one week. A week later, it was found that the mixture contains only 0,11% wt./wt. the oxidation product B2 and only 0,50% wt./wt. the lactone.

Example 2

Agent2,50 mg
Povidone2,50 mg
Rejonowy calcium phosphate20.0 mg
Microcrystalline cellulose47.0 mg
Mannitol47.0 mg
Matrikamantra3,00 mg
Butoxycarbonyl hydroxytrol0.05 mg
Magnesium stearate1.00 mg

Agent, povidone, mannitol, microcrystalline cellulose, butoxycarbonyl hydroxytoluene, rejonowy calcium phosphate and nutricell icost (in the above amounts) was stirred for 5-60 minutes. Magnesium stearate was passed through sieve #40 mesh (425 μm) was added to the mixture, after which the stirring was continued for three minutes. The resulting homogeneous mixture was pressed into tablets. In pressed tablets were coated by spraying a mixture of hydroxypropylmethylcellulose, polyethylene glycol 400, titanium dioxide and iron oxide (manufactured under the brand Spectrablend™ Warner-Jenkinson) and water in the tank for coating. Gain at the expense of the coating was 1-6%, preferably 2-3% wt./wt.

Tablets were stored at 70°/a relative humidity of 80% within one week. A week later it was established that formed just 0.06% of wt./wt. the oxidation product B2 and only 2,22% wt./wt. the lactone.

Example 3

Agent2,60 mg
Crosspovidone3.75 mg
Rejonowy calcium phosphateto 5.66 mg
Microcrystalline cellulose15,5 mg
The lactose monohydrate46,5 mg
Magnesium stearate0,94 mg

Agent and crosspovidone were mixed with each other for 5 minutes and the resulting mixture was passed through a sieve with openings of 400-700 microns. Then through a sieve missed a small the amount of microcrystalline cellulose. The sifted material for 10 minutes, mixed with other ingredients, excluding the lubricant. Magnesium stearate was passed through # 40 mesh (425 μm) sieve and added to the mixture, after which the stirring was continued for another 3 minutes. The resulting homogeneous mixture was pressed into tablets. On the compressed tablets were coated by spraying upon the surface a mixture of lactose monohydrate, hydroxypropylmethylcellulose, triacetin and iron oxide (manufactured by use, as Opadry IITM), as well as the water in the tank for coating. The gain due to the coating was 1-6% wt./wt., preferably, 2-3% wt./wt.

The obtained tablets were stored at 70°C/80% relative humidity during the week. After a specified period of time, there was a formation of only 0.19% wt./wt. the oxidation product B2 and only 2,71% wt./wt. the lactone.

Example 4

Agent2,50 mg
Povidone2,50 mg
Rejonowy calcium phosphate20.0 mg
Microcrystalline celluloseto 34.5 mg
The lactose monohydrate34,0 mg
Matrikamantra6,00 mg
Magnesium stearate1.00 mg
Butoxycarbonyl hydroxytrol0.05 mg

Part trehosnovnogo calcium phosphate and butoxyethanol of hydroxytoluene was mixed for 30 seconds in the sack. Agent, povidone, the remaining number trehosnovnogo of phosphatate calcium, microcrystalline cellulose, lactose monohydrate, the mixture rejonowy calcium phosphate/butoxycarbonyl hydroxytoluene and part of nachrichtentechnische was mixed for 30 seconds in the granulator. A powder mixture was granulated in the presence of purified water for 1 minute at a speed of adding mg/tablet/minute. The granulate was dried in a fluidized bed dryer at 50°up until loss on drying not reached a value of less than 2% wt./wt. The dried granulate was passed through a mill (for example, Comil™). Milled granulate and the remaining number of nachrichtentechnische was stirred for 5 minutes. Magnesium stearate was passed through # 40 mesh (425 μm) sieve and added to the mixture, after which the stirring was continued for three minutes. The resulting mixture was pressed into tablets.

The obtained tablets were stored at 70°C/80% relative humidity for one week. After the specified time has formed only a 0.23% wt./wt. the oxidation product B2 and only to 0.28 wt./wt. the lactone.

1. Pharmaceutical composition containing as active ingredient an inhibitor of HMG COA reductase, which is an (E)-7[4(4 forfinal)-6-isopropyl-2-methyl - (methylsulphonyl)amino pyrimidine-yl-(3R,5S) - for 3,5-dihydroxide-6-envoy acid or its pharmaceutically acceptable salt and inorganic salt with a polyvalent cation, provided that:

(i) inorganic salt is not synthetic hydrotalcite and

(ii) protivoiadie inorganic salt is phosphate.

2. Pharmaceutical tablet comprising as active ingredient an inhibitor of HMG COA reductase, which is an (E)-7-[4-(4-forfinal)-6-isopropyl-2-methyl - (methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-envoy acid or its pharmaceutically acceptable salt and inorganic salt with a polyvalent cation, provided that protivoiadie inorganic salt is phosphate.

3. The pharmaceutical composition according to claim 1, in which the cation of the inorganic salt is selected from calcium, magnesium, zinc, aluminum and iron.

4. The pharmaceutical composition according to claim 1 or 3, in which protivoiadie inorganic salt selected from carbonate, silicate, oxide and metasilicate.

5. The pharmaceutical composition according to claim 1 or 3, in which protivoiadie inorganic salt selected from a specification of the same, oxide or metasilicate.

6. The pharmaceutical composition according to claim 1, in which the inorganic salt is metasilicate aluminum-magnesium.

7. The pharmaceutical composition according to claim 1, which represents a pill or powder.

8. The pharmaceutical composition according to claim 1, in which there are more than 5 mg of the active ingredient.

9. The pharmaceutical composition according to any one of claims 1, 3 or 6 to 8, in which there are more than 10 mg of the active ingredient.

10. The pharmaceutical composition according to any one of claims 1, 3 or 6 to 8, in which the ratio between the inorganic salt and the active ingredient has a value in the range of 1:80-50:1 by weight.

11. The pharmaceutical composition according to any one of claims 1, 3 or 6 to 8, further comprising one or more fillers, binders, disintegrators or lubricants.

12. The pharmaceutical composition according to any one of claims 1, 3 or 6 to 8, in which the active ingredient is present in an amount of 1-50% by weight of the composition.

13. The pharmaceutical composition according to any one of claims 1, 3 or 6 to 8, in which the inorganic salt is present in an amount of 1-50% by weight of the composition.

14. The pharmaceutical composition according to claim 11, in which the filler is present in an amount of 30-90% by weight of the composition.

15. The pharmaceutical composition according to claim 11, in which the binder is present in an amount of 2-90% by weight of the s composition.

16. The pharmaceutical composition according to claim 11, in which the cage is present in the amount of 2-10% by weight of the composition.

17. The pharmaceutical composition according to claim 11, in which the lubricating substance is present in quantities of 0.5-3% by weight of the composition.

18. The pharmaceutical composition according to any one of claims 1, 3 or 6 to 8, in which the active ingredient is a 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.

19. The use of inorganic salts with polyvalent cation to stabilize the inhibitor of HMG COA reductase, which represents (E)-7-[4-(4-forfinal)-6-isopropyl-2-methyl - (methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-envoy acid or its pharmaceutically acceptable salt, provided that:

(i) inorganic salt is not synthetic hydrotalcite and

(ii) protivoiadie inorganic salt is phosphate.

20. The application of claim 19, in which protivoiadie inorganic salt selected from carbonate, silicate, oxide and metasilicate.

21. The application of claim 19, in which protivoiadie inorganic salt selected from silicate, oxide or metasilicate.

22. The application of claim 19, in which the inorganic salt with the polyvalent cation is metasilicate aluminum-magnesium.

23. Pic is b obtain a stabilized pharmaceutical composition, including the introduction of inorganic salts with polyvalent cation, a pharmaceutical composition comprising an inhibitor of HMG COA reductase, which represents (E)-7-[4-(4-forfinal)-6-isopropyl-2-methyl - (methylsulphonyl)amino]pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-envoy acid or its pharmaceutically acceptable salt, provided that:

(i) inorganic salt is not synthetic hydrotalcite and

(ii) protivoiadie inorganic salt is phosphate.

24. The method according to item 23, in which protivoiadie inorganic salt selected from silicate, oxide or metasilicate.

25. The method according to item 23, in which the inorganic salt with the polyvalent cation is metasilicate aluminum-magnesium.



 

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9 cl, 6 tbl, 8 ex

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

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

FIELD: medicine, narcology.

SUBSTANCE: invention relates to hepatoprotective and anti-encephalopathic agent used for reducing alcoholic intoxication. Invention comprises components based on succinic, fumaric, glutamic acids and, additionally, at least one vitamin of B group. Agent can comprise additionally vegetable extracts or their mixture, L-carnitine, glycine, L-arginine, taurine and/or their mixture, methylsulfonylmethane, dihydroquercitin, dimethylsulfoxide or their mixture, nicotinamide or nicotinic acid or their mixture, energy source and sweetening agent. Also, invention proposes a method for reducing alcoholic intoxication, prophylaxis and removing withdrawal syndrome, liver protection, among them, in non-alcoholic intoxication and protection against encephalopathy. Invention provides described effects without qualifying medical control.

EFFECT: valuable medicinal properties of agent.

16 cl, 3 tbl

FIELD: organic chemistry, medicine, pharmacy, pharmacotherapy.

SUBSTANCE: method involves administration in mammal the effective dose of 6-hydroxy-8-[4[4-(2-pyrimidinyl)piperazinyl]butyl]-8-azaspiro[4,5]-7,9-dione or its pharmaceutically acceptable salt of acid addition or its hydrate. Method expands arsenal of medicinal agents used for suppression of fear sensation.

EFFECT: valuable properties of agent.

3 tbl, 6 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: method involves applying eradicative anti-helicobacterial therapy comprising Omeprazol administration at a dose of 20 mg twice a day and Ximedone at a dose of 500 mg twice a day in 12 days long course.

EFFECT: enhanced effectiveness of eradication; reduced adverse side effects risk.

FIELD: medicine.

SUBSTANCE: method involves administering typical neuroleptics according to titration scheme and tricyclic antidepressants. Neuroleptics are applied according to titration scheme in the morning and tricyclic antidepressants are introduced as intravenous drop-by-drop infusion in the evening in combination with per os application of atypic neuroleptic risperidon. After having given 12-14 intravenous infusions, strategic supporting risperidon psychopharmacotherapy in combination with tricyclic antidepressants during 4-6 months.

EFFECT: enhanced effectiveness in overcoming pharmacological resistance; accelerated schizo-affective syndrome relief.

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing 1,3-oxathiolan nucleosides or a method for preparing derivatives of 1,3-oxathiolanyl-5-one that involve effective methods for formation of 1,3-oxathiolan ring followed by condensation of 1,3-oxathiolan with pyrimidine or purine base. Using indicated methods these compounds can be synthesized as separate enantiomers with high selectivity.

EFFECT: improved preparing methods.

27 cl, 3 dwg, 16 ex

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

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