Composition of 3-oxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salt in tabletted form, method for making thereof, and therapy

FIELD: medicine.

SUBSTANCE: as additional components, a new medicinal form contains stearic acid or its pharmaceutically acceptable salt, succinic acid or its pharmaceutically acceptable salt, microcrystalline cellulose, magnesium carbonate, starch and hydroxypropyl cellulose.

EFFECT: extended range of storage-stable preparations of 3-oxy-6-methyl-2-ethylpyridine as solid oral dosage forms without by-effects of existing preparations.

14 cl, 2 tbl

 

The invention relates to the field of medicine and pharmacy, more specifically, to the field of neuroscience, particularly to pharmaceutical compositions of 3-hydroxy-6-methyl-ethylpyridine or its pharmaceutically acceptable derivative, as well as to its preparation, to a method of treatment and to medical application.

3-hydroxy-6-methyl-2-ethylpyridine and its pharmaceutically acceptable derivatives, including 3-hydroxy-6-methyl-2-ethylpyridine hydrochloride (amoxi-pin) and 3-hydroxy-6-methyl-2-ethylpyridine succinate (Mexidol), belong to the group of drugs to treat diseases of the Central nervous system, neuroprotective agents, nootropic and anxiolytic. Have mnemo genotype, magnetobacteria, anxiolytic, stress-protective, antiamnesic action to improve the adaptation and emotional status, contribute to the restoration of memory and cognitive functions during aging, enhance compensatory activation of aerobic glycolysis, contribute to the restoration of mitochondrial redox processes in hypoxia, increase ATP synthesis and creatinephosphate; stabilize membrane structure and, in particular, the membrane structure of blood cells (erythrocytes), negate caused by hypoxia changes the physicochemical properties of the cell membranes of nerve tissue, which is beneficial to its metabolic and biosi thetic activity. Accelerates the evolution of intracerebral, including posttraumatic hemorrhage. Has a beneficial effect on the processes of mass transfer of oxygen in the brain in hypoxia, reducing the maximum respiration rate and increasing the stationary level of the syndrome in coronary insufficiency.

3-hydroxy-6-methyl-2-ethylpyridine and its pharmaceutically acceptable derivatives, including 3-hydroxy-6-methyl-2-ethylpyridine hydrochloride (emoxipin) and 3-hydroxy-6-methyl-2-ethylpyridine succinate (Mexidol), shown in chronic cerebral ischemia (dyscirculatory encephalopathy) I-III stage, vertebrobasilar insufficiency due to degenerative disc disease of the cervical spine, traumatic brain injury (recovery period), focal and diffuse traumatic brain injuries, post-traumatic encephalopathy (at the end of the course application of injection dosage forms of 3-hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salt), ischemic and hemorrhagic stroke in the late recovery period (at the end of the course the use of injectable dosage forms 3-hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salt), toxic encephalopathy of any Genesis (at the end of the course the use of injectable dosage forms 3 oaks is-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salt), diabetic discirculatory-metabolic encephalopathy, a degenerative-dystrophic lesions of the nervous system, polineiropatia various origins, exogenous-organic brain diseases due to the CNS, disorders of memory and intellectual insufficiency in the elderly, anxiety disorders with neurotic and neurosis-like States, emotional stress, anxiety or fear on the background of alcoholic intoxicatie, lung cognitive disorders of atherosclerotic Genesis, progressive Central involutional haritunians dystrophy, progressive myopic maculopathy and progressive glaucomatous optionaldata.

Most of the currently known from the prior art drugs 3-hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable derivatives represented by the solutions for injection or solution for intraocular injection of [1] (see list of sources at the end of the description)that it is not always convenient in clinical practice. This raises the need for new, technologically advanced and at the same time affordable solid oral forms emoxipin, suitable for use in the neurological clinic.

The prior art has developed a computer what their "Belmedpreparaty" and registered in the Republic of Belarus the preparation of 3-hydroxy-6-methyl-2-ethylpyridine hydrochloride (emoxipin) (tablet, 100 mg) [see: Emoxipin, tablets 0.1 g - Directory - RUE Belmedpreparaty. - Available on the Internet at the following address (WWW): http://www.belmedpreparaty.com/product/anot.php?anat_id=243 on 23.11.2007], which contains as excipients lactose, calcium stearate, and starch (quantitative composition of the drug is not disclosed).

As noted in the instructions to the drug, in its application may diarrhoeal disorders such as bloating, flatulence, dry mouth, diarrhea.

In connection with the foregoing, the challenge is to extend the range of solid oral dosage forms, preferably tablets) emoxipin, devoid of the disadvantages of the known drugs and is characterized by greater physical and chemical stability during storage. In addition, the current is increased efficiency containing emoxipin of the drug due to the inclusion in the composition of intracellular metabolites, such as succinic acid or its pharmaceutically acceptable derivatives (biological properties of succinic acid as an intracellular metabolite, see [Aigain. Oxidative stress and the use of antioxidants in neurology is Available on the Internet at the following address (WWW): http://pentadent.ru/pet/neurology_and_neurosurgery/s/6827.html on 23.11.2007].

In the prior art it is known [RF Patent for the invention №2065299, publ. 20.08.1996] nootropic and tra is qualitywise means, which is a tablet consisting of a core and a polymer shell containing 3-hydroxy-6-methyl-2-ethylpyridine and a carrier, wherein the core as excipients contains clay white, potato starch, calcium stearinovokisly, stearic acid, talc and methylcellulose in the following ratio, wt.:

3-hydroxy-6-methyl-2-ethylpyridine 16,7-41,6,

Clay white 16,7-33,3,

Potato starch 16,7-33,3,

Calcium stearinovokisly 0.3 to 0.5,

Stearic acid 0.3 to 0.5,

Talc 0,5-1,00,

The methylcellulose 0.3 to 0.5,

and the shell contains methylcellulose, tween 80, and titanium dioxide in the following ratio, wt.:

The methylcellulose 25,0-50,0,

Tween-80 8,3-25,0,

Titanium dioxide 8,3-25,0.

The coatings are significantly complicates the production technology of medicinal forms. Tablet core contains a high percentage of such excipients as starch from 16.7 to 33.3% and clay white from 16.7 to 33.3%. The combination of starch and clay white in the specified high content does not provide stable quality tablets, even at the stage of manufacturing the core tablets yellow.

Known from the prior art [RF Patent for the invention №2144822, publ. 27.01.2000] the composition of the capsule mass, containing 3-hydroxy-6-methyl-2-ethylpyridine succinate (Mexidol):

3-hydroxy-6-methyl-2-ethylpyridine succinate - 50,0,

Starch - 40,5-50,5,

Polyvinylpyrrolidone - 2,4-2,8,

Magnesium stearinovokisly - 0,9-1,2,

Talc - 0,9-1,1.

The contents of the capsules valium color.

As follows from the formulas of the invention, the starch content is almost equivalent to the content of 3-hydroxy-6-methyl-2-ethylpyridine. This structure does not provide the quality of capsule powder.

It is also known [RF Patent for the invention №2145855, publ. 27.02.2000] anxiolytic, protivoallergennoy and cerebroprotective means, characterized in that it contains as excipients potato starch, polyvinylpyrrolidone, magnesium stearinovokisly, microcrystalline cellulose and sugar of milk in the following ratio, wt.%:

3-hydroxy-6-methyl-2-ethylpyridine succinate - 30-60,

Potato starch - 17,0-35,

Polyvinylpyrrolidone - 2,5-3,5,

Microcrystalline cellulose - 7,7-12,2,

Milk sugar - 12,0-18,0.

This structure also does not provide a stable quality of the powder, the total sugar content of milk and starch from 29% to 53% leads to yellowing of the masses despite the introduction of microcrystalline cellulose.

Known [RF Patent for the invention №2065299, publ. 20.08.1996] nootropic and anxiolytic pills, consisting of a nucleus containing 3-hydroxy-6-methyl-2-ethylpyridine succinate and accessories, and covers the core on kernou shell, the next time the kernel:

3-hydroxy-6-methyl-2-ethylpyridine succinate 16,7-41,6,

Clay white 16,7-33,3,

Potato starch 16,7-33,3,

Calcium stearinovokisly 0.3 to 0.5,

Stearic acid 0.3 to 0.5,

Talc 0,5-1,00,

The methylcellulose 0.3 to 0.5.

The shell contains methylcellulose, tween 80, and titanium dioxide in the following ratio, wt.%:

The methylcellulose 25,0-50,0,

Tween 80 8,3-25,0,

Titanium dioxide 8,3 25,0.

The coatings are significantly complicates the production technology of medicinal forms. Tablet core contains a high percentage of such excipients as starch from 16.7 to 33.3% and clay white from 16.7 to 33.3%. The combination of starch and clay white in the specified high content does not provide stable quality tablets, even at the stage of manufacturing the core tablets yellow.

Also known [RF Patent for the invention №2205640, publ. 10.06.2003] the pharmaceutical composition is proposed as a prototype of the invention, designed for tablets and contain the following components, wt%:

3-hydroxy-6-methyl-2-ethylpyridine succinate 50,0-60,0,

Succinic acid is 0.5 to 5.0,

Trilon B - 0,0-0,2,

Microcrystalline cellulose - 14,0-25,0,

Starch - 15,0-25,0,

The low-molecular polyvinylpyrrolidone - 4,0-6,0,

Sodium starch glycolate - 0,0-5,0,

Magnesium stearinovokisly - 0,8-1,0,

Talc - 0,0-1,0,

To the Lydon CL - 0,0-3,0.

Manufactured in accordance with the prototype tablets 3-hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salts are characterized by a shelf life of about 2 years, however, there is a need to broaden the range of stable long-term oral dosage forms (tablets) 3-hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salt.

The problem is solved by developing a new composition of solid dosage forms (tablets) 3-hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salt (hydrochloride or succinate), declare in accordance with the present invention, and the method of its production. Thus, in accordance with the present claimed invention solid dosage form containing an active component selected from 3-hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salts, stearic acid or its pharmaceutically acceptable salt and starch (preferably corn starch pregelatinized) as auxiliary components, characterized in that it further comprises succinic acid or its pharmaceutically acceptable salt (preferably sodium succinate or magnesium succinate), a derivative of cellulose and microcrystalline cellulose in the following ratio to the components, wt.%:

3-hydroxy-6-methyl-2-ethylpyridine

or its pharmaceutically acceptable salt (hydrochloride or succinate) - 20,0-30,0,

Derived cellulose - 2,0-5,0,

Succinic acid

or its pharmaceutically acceptable salt (preferably sodium succinate or magnesium succinate) - 15,0-25,0,

Starch - 10,0-15,0,

preferably, corn starch pregelatinized)

Stearic acid

or its pharmaceutically acceptable salt

(preferably magnesium stearate) of 0.5-1.0,

Magnesium carbonate 10,0-20,0,

Microcrystalline cellulose 14,0-20,0.

As a derivative of cellulose is preferably used cellulose ether, preferably, hydroxypropylcellulose, more preferably, hydroxypropylcellulose brand Klucel LF.

Included in the tablets of magnesium carbonate provides protection of the gastrointestinal mucosa from irritation of emoxipin.

On prepared in accordance with the present invention the tablet 3-hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salt (preferably, 3-hydroxy-6-methyl-2-ethylpyridine hydrochloride (emoxipin) or 3-hydroxy-6-methyl-2-ethylpyridine succinate) is applied enteric coating on the basis of methacrylic acid copolymer (commercially available under the trade name Acrylis®) in an amount of 5.0-10.0 wt.%, protecting the mucous W is lubochna-intestinal tract.

Also, in accordance with the present invention, there is a method of manufacturing a solid dosage form emoxipin, characterized in that:

a) mixing 3-hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salt, preferably 3-hydroxy-6-methyl-2-ethylpyridine hydrochloride or 3-hydroxy-6-methyl-2-ethylpyridine succinate, magnesium carbonate;

b) adding to the mixture obtained succinic acid or its pharmaceutically acceptable salt (sodium succinate or magnesium succinate),

C) the mixture is stirred,

g) hydrate mixture solution hydroxypropylcellulose,

d) dried hydrated mass,

e) granularit,

W) optivault a mixture of succinic acid and stearic acid or its pharmaceutically acceptable salt,

C) tabletirujut obtaining biconvex tablets with a diameter of 10±0.3 mm average weight 400 mg ±5%,

and cause enteric coated.

Also, in accordance with the present invention, there is a method for the treatment and/or prevention of diseases of the nervous system, including the introduction of solid dosage forms emoxipin according to the invention and application of solid dosage forms emoxipin for the treatment and/or prevention of diseases of the nervous system.

The following example illustrates (without limitation of the scope of claims) most of predpochtitel the major embodiments of the invention, and also confirms the possibility of achieving the stated technical result.

3-hydroxy-6-methyl-2-ethylpyridine, or 3-hydroxy-6-methyl-2-ethylpyridine hydrochloride or 3-hydroxy-6-methyl-2-ethylpyridine succinate (active substance and all auxiliary components are used for formulations I, II, III in amounts according to Table 1) is mixed with magnesium carbonate, add succinic acid (or sodium succinate, and magnesium succinate), the resulting mixture is stirred, add the microcrystalline cellulose and pregelatinized corn starch, mix and hydrate solution hydroxypropylcellulose trademark Klucel LF. The wetted mass is dried, granularit and optivault a mixture of succinic acid and magnesium stearate; tabletirujut on press tablet press with getting biconvex tablets with a diameter of 10±0.3 mm, average weight of 400 mg ±5%.

On made in accordance with the present invention, biconvex tablets 3-hydroxy-6-methyl-2-ethylpyridine hydrochloride (compounds I, II and III) cause enteric coated, containing a copolymer of methacrylic acid Acrylis® and, if necessary, pigments such as titanium dioxide, iron oxide red, iron oxide yellow.

Get biconvex tablets with a diameter of 10±0.3 mm, average weight of 400 mg ±5%.

Table 1
Part IPart IIPart III
3-hydroxy-6-methyl-2-ethylpyridine hydrochloride mg110,0100,095,0
Hydroxypropylcellulose (Klucel LF), mg15,011,09,0
The succinic acid, mg60,068,075,0
Pregelatinized starch, mg55,050,060,0
Magnesium carbonate, mg72,080,083,0
Magnesium stearate or calcium stearate, mg3,03,54,0
Pulp microcrystallite., mg60,068,075,0
Acrylis mg28,0 34,030,0

Table 2
Part IV
3-hydroxy-6-methyl-2-ethylpyridine tartrate mg165,4
Hydroxypropylcellulose (Klucel LF), mg22,6
The succinic acid, mg90,2
Pregelatinized starch, mg82,7
Magnesium carbonate, mg108,3
Magnesium stearate or calcium stearate, mg4,5
Pulp microcrystallite., mg90,2
Acrylis mg42,1

3-hydroxy-6-methyl-2-ethylpyridine tartrate (active substance and all auxiliary components are used for composition IV in amounts according to Table 2) is mixed with magnesium carbonate, add succinic acid (or sodium succinate, and magnesium succinate), the resulting mixture is stirred, add the microcrystalline cellulose and starch to kurosky prezentatsionnyy, mix and hydrate solution hydroxypropylcellulose trademark Klucel LF. The wetted mass is dried, granularit and optivault a mixture of succinic acid and magnesium stearate; tabletirujut on press tablet press with getting biconvex tablets with a diameter of 10±0.3 mm, average weight of 400 mg ±5%.

On made in accordance with the present invention, biconvex tablets 3-hydroxy-6-methyl-2-ethylpyridine tartrate (part IV) cause enteric coated, containing a copolymer of methacrylic acid Acrylis® and, if necessary, pigments such as titanium dioxide, iron oxide red, iron oxide yellow.

Get biconvex tablets with a diameter of 10±0.3 mm, average weight of 400 mg ±5%.

The shelf life of the tablets produced in accordance with the present invention (formulations I-IV, table 1, 2), when determining the method of accelerated aging corresponded with the period of storage under natural conditions for about 3 years (unlike tablets in accordance with the prototype, the retention of which was about 2 years old).

1. Solid dosage form intended for the treatment and/or prevention of diseases of the Central nervous system, characterized in that it contains an active ingredient selected from 3-hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salts, and as an auxiliary is komponentov - stearic acid or its pharmaceutically acceptable salt, succinic acid or its pharmaceutically acceptable salt, microcrystalline cellulose, magnesium carbonate, starch, hydroxypropylcellulose in the following ratio, wt.%:

3-Hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically
acceptable salt20,0-30,0
Hydroxypropylcellulose2,0-5,0
Succinic acid or its pharmaceutically acceptable
Sol15,0-25,0
Starch10,0-15,0
Stearic acid or its pharmaceutically acceptable
salt (preferably magnesium stearate)0,5-1,0
Magnesium carbonate10,0-20,0
Microcrystalline cellulose14,0-20,0

2. Solid dosage form according to claim 1, characterized in that hydroxypropylcellulose represent hydroxypropylcellulose brand Klucel LF.

3. Solid dosage form according to claim 1, characterized in that the pharmaceutically acceptable salt of succinic acid is a sodium or magnesium succinate succinate.

4. Solid dosage form according to claim 1, characterized in that the starch is a pregelatinized corn starch.

5. Solid dosage form according to claim 1, characterized in that the pharmaceutically acceptable salt of stearic acid is a magnesium stearate.

6. Solid dosage form according to claim 1, characterized in that it further contains enteric-soluble coating on the basis of a copolymer of methacrylic acid in the amount of 5.0-10.0 wt.%.

7. Solid dosage form according to claim 6, characterized in that the methacrylic acid copolymer is Acrylis®.

8. Solid dosage form according to claim 1, characterized in that it is a tablet.

9. Solid dosage form according to any one of claims 1 to 8, characterized in that the pharmaceutically acceptable salt of 3-hydroxy-6-methyl-2-ethylpyridine is a 3-hydroxy-6-methyl-2-ethylpyridine hydrochloride or 3-hydroxy-6-methyl-2-ethylpyridine succinate.

10. A method of manufacturing a solid dosage form according to any one of claims 1 to 9, characterized in that:
a) mixing 3-hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salt with magnesium carbonate;
b) add the amount to the resulting mixture, succinic acid, or sodium succinate, and magnesium succinate;
C) the mixture is stirred;
g) add microcrystalline cellulose;
d) add starch;
e) hydrate mixture solution hydroxypropylcellulose;
g) dry wet weight;
C) granularit dried weight;
and optivault a mixture of succinic acid and stearic acid or its pharmaceutically acceptable salt;
K) tabletirujut obtaining biconvex tablets with a diameter of 10±0.3 mm average weight 400 mg ±5%;
l) causing enteric-soluble coating.

11. The method according to item 12, wherein the enteric-soluble coating is performed based on the polymer Acrylis®.

12. The method according to item 12, wherein the pharmaceutically acceptable salt of 3-hydroxy-6-methyl-2-ethylpyridine is a 3-hydroxy-6-methyl-2-ethylpyridine succinate or hydrochloride.

13. The method of treatment and/or prevention of diseases of the Central nervous system of a mammal selected from the group comprising chronic cerebral ischemia (dyscirculatory encephalopathy) I-III stage, vertebrobasilar insufficiency due to degenerative disc disease of the cervical spine, traumatic brain injury during the rehabilitation period, focal and diffuse traumatic brain injury, post-traumatic encephalopathy (at the end of the course the use of the surveillance injectable dosage forms 3-hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salt), ischemic and hemorrhagic stroke in the late recovery period (at the end of the course the use of injectable dosage forms 3-hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salt), toxic encephalopathy of any Genesis (at the end of the course the use of injectable dosage forms 3-hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salt), diabetic discirculatory-metabolic encephalopathy, a degenerative-dystrophic lesions of the nervous system, polyneuropathy of various origins, exogenous-organic diseases of the brain due to the CNS, disorders of memory and intellectual failure in the elderly anxiety disorders with neurotic and neurosis-like States, emotional tension, anxiety or fear in the face of alcoholic intoxication, mild cognitive disorder of atherosclerotic Genesis, progressive Central involutional haritunians dystrophy, progressive the myopic maculopathy and progressive glaucomatous optionaldata, wherein the orally administered dosage form 3-hydroxy-6-methyl-2-ethylpyridine or its pharmaceutically acceptable salt according to any one of claims 1 to 9.

14. The method according to item 13, wherein melicope the surrounding is the man.



 

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34 cl, 24 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) and their pharmaceutically acceptable salts which have PDE9A inhibition properties. In formula (I) R1 represents alkyl with 1-8 carbon atoms or cycloalkyl with 5-6 carbon atoms which, if necessary, can have up to three substitutes independently selected from: alkyl with 1-6 carbon atoms, hydroxy, halogen and trifluoromethyl, where the alkyl with 1-6 carbon atoms, if necessary, can be substituted with 1-3 substitutes independently selected from halogen and trifluoromethyl, R2 represents phenyl or aromatic mono- or bicyclic heteroaryl with 5-10 atoms in the ring and up to 5 heteroatoms selected from: sulphur, oxygen and/or nitrogen, where phenyl is substituted with 1-3 substitutes, and the heteroaryl, if necessary, can be substituted with 1-3 substitutes in each case independently selected from: alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, hydroxyl and halogen.

EFFECT: compounds can be used for preparing medicinal agents for enhancing perception, ability to concentrate, learning capability and memory enhancement.

9 cl, 1 dwg, 2 tbl, 78 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine-condensed derivatives of formula , where n is selected from 0, 1, 2, 3 and 4, Z1 is selected from N, C(O) and CR3, where R3 represents hydrogen, Z2 is selected from N and CR4, where R4 is selected from hydrogen and halogen, where the bond between Z1 and Z2 is selected from a single bond and a double bond, R1 is selected from C1-C4alkyl and C1-C4alkoxy, R2 is selected from NR5C(O)R6, C(O)NR5R6 and NR5R6, where R5 represents hydrogen, and R6 is selected from hydrogen, C1-C4alkyl and phenyl, where phenyl as R6 is optionally substituted with 1-2 radicals independently selected from a group comprising halogen(C1-C4)alkyl, heteroaryl(C0-C4)alkyl and heterocycloalkyl(C0-C4)alkyl, where any heteroaryl or heterocycloalkyl substitute R6 can be optionally substituted with a substitute independently selected from C1-C4alkyl and heterocycloalkyl, where the said heteroaryl and heterocyclyl represent a saturated or unsaturated 5-6-member ring containing 1 or 2 N atoms as a heteroatom, and to their pharmaceutically acceptable salts, hydrates, solvates and isomers. The invention also relates to a pharmaceutical composition base on a formula I compound and to use of formula I compound for preparing a medicinal agent which can be used for treating diseases or disorders associated with anomalous or disrupted kinase activity, primarily diseases or disorders related to anomalous activation of kinase Ab1, Bcr-Ab1, BMX, BTK, CHK2, c-RAF, CSK, c-SRC, Fes, FGFR3, Flt3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRβ, PKA, PKBα, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and TrkB.

EFFECT: novel compounds have useful biological properties.

7 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to crystalline form of B (3-cyano-1N-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl] methanone hydrochloride, as well as to synthesis method thereof by passing HCl gas through a solution of (3-cyano-1N-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl] methanone, separating the formed residue from the reaction mixture and drying.

EFFECT: end product can be used in medicine as a medicinal agent which has antagonistic effect on 5-HT2A receptor.

4 cl, 4 dwg, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to crystalline form of B (3-cyano-1N-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl] methanone hydrochloride, as well as to synthesis method thereof by passing HCl gas through a solution of (3-cyano-1N-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl] methanone, separating the formed residue from the reaction mixture and drying.

EFFECT: end product can be used in medicine as a medicinal agent which has antagonistic effect on 5-HT2A receptor.

4 cl, 4 dwg, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol-substituted ether derivatives of formula (I) to their pharmaceutically acceptable salts and to esters which are capable of bonding with LXR-alpha and/or LXR-beta, as well as to pharmaceutical compositions based on said compounds. In formula (I) R1 is hydrogen, lower alkyl or halogen, one of groups R2 and R3 is hydrogen, lower alkyl or halogen, and the second of groups R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6. Values of R4, R5, R6 m and n are given in the formula of invention.

EFFECT: novel compounds have useful biological properties.

22 cl, 4 dwg, 102 ex

FIELD: medicine.

SUBSTANCE: for prevention and treatment of diseases of cardiovascular and/or nervous system, arterial hypertension claimed is original composition of ethylmethylhydroxypyridine succinate, succinic acid and ethylenediaminetetraacetic acid disodium salt in form of solution for injections, which additionally contains pyridoxin or its pharmaceutically acceptable salt and povidon.

EFFECT: high stability, convenience in application and high therapeutic efficiency in prevention and treatment of diseases of cardiovascular and nervous system and arterial hypertension.

14 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: described are novel compounds with general formula , their stereoisomers and pharmaceutically acceptable salts or solvates, where the dashed line can represent a double bond (together with the present single bond); R represents phenyl or benzodioxolyl, each of which can be substituted; R1, R3 and R4 independently represent hydrogen or C1-C6alkyl; R5 represents C1-C6alkyl; R7 represents hydrogen; R12 represents R3 or -C(O)R2, where R2 represents C1-C4 alkyl; D and G represent -CH2 - or -CH- when they are bonded to each other by a double bond; m equals 1; a pharmaceutical composition containing said compounds, and use of the novel compounds in treating conditions mediated by corticotropin-releasing factor (CRF).

EFFECT: increased effectiveness of compounds.

11 cl, 13 ex, 11 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to benzothiazole derivatives with general formula and and their pharmaceutically acceptable acid-addition salts as adenosine receptor ligands and to a pharmaceutical preparation based on said compounds. The compounds can be used for treating and preventing diseases mediated by adenosine A2A receptors, for example Alzheimer's disease, certain depressive conditions, toxicomania and Parkinson's disease. In general formulae (IA) and (IB) R1, R2 independently represent lower alkyl or -(CH2)m-O-lower alkyl, or together with the N atom to which they are bonded form a 5-6-member heterocyclic ring which optionally contains 1 additional oxygen atom; R3 represents hydrogen or lower alkyl; R4 represents lower alkyl; hetaryl represents 3H-imidazole-2,4-diiyl or 1H-pyrazole-1,4-diiyl; n equals 1 or 2 and m equals 1 or 2.

EFFECT: more effective treatment.

12 cl, 36 ex

FIELD: chemistry.

SUBSTANCE: novel compound is N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or its pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with CFTR activity modulation properties.

2 cl, 485 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: there are described oral dosage forms of risedronate containing safe and effective amount of a pharmaceutical composition containing risedronate, a chelating agent and an agent for effective delayed release of risedronate and the chelating agent in small intestine. The pharmaceutical composition is directly released in a small intestine of a mammal with ensuring pharmaceutically effective absorption of bisphosphonate together with or without food or drinks. Present invention essentially reduces interaction between risedronate and food or drinks which leads to that the active component of bisphosphonate becomes inaccessible to absorption. Thus, the final oral dosage form can be taken with and without food. Further, present invention covers delivery of risedronate and the chelating agent in a small intestine, essentially reducing irritation of upper gastrointestinal tract associated with bisphosphonate therapy. These advantages simplify previous, complicated regimens and can lead to more complete observance of the bisphosphonate therapy regimen.

EFFECT: present invention essentially reduces interaction between risedronate and food or drinks which leads to that the active component of bisphosphonate becomes inaccessible to absorption.

23 cl, 12 ex

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