Method for preparing stable pharmaceutical compositions in omeprazole-containing tablet formulation and pharmaceutical composition prepared by this method

FIELD: chemical-pharmaceutical industry and technology, pharmacy.

SUBSTANCE: omeprazole is a strong anti-ulcer agent that is absorbed in intestine preferably but it unstable in acid medium. Some methods for preparing stable pharmaceutical compositions and solution of two main problems of effect on their stability, pH and moisture, have been studied. Invention describes a method for preparing pharmaceutical composition as tablet formulation comprising omeprazole, sodium alginate and basic amino acid and involving following steps: (a) preliminary modification of external morphology of basic amino acid by wetting and the following drying up to the water content in the total amount less 0.75 wt.-% of amino acid mass; (b) incorporation of basic amino acid to preliminary prepared granulate comprising omeprazole and sodium alginate with the low moisture content; (c) incorporation of other excipients up to preparing granulate; (d) grinding granulate from step (c) up to preparing uniform granulometric composite; (e) incorporation of lubricating agent, carrying out the tableting process and applying enterosoluble coating on tablets made. Such method is simpler as compared with known ones and provides preparing compositions with improved indices of extrusion. The content of sodium alginate can up to 15 wt.-% of tablet mass, preferably, from 8 to 12 wt.-%. Basic amino acid can represent L-arginine, L-lysine or L-histidine. Pharmaceutical compositions prepared by this method comprise omeprazole in concentrations 10-40 mg per a tablet.

EFFECT: improved preparing method.

6 cl, 4 ex

 

Description

The present invention relates to a method for producing stable tablet of omeprazole and its salts, have good pharmaceutical properties and stability. The invention also relates to pharmaceutical compositions of the tablets obtained in this way.

Omeprazole is a strong antiulcer agent, which, preferably, is absorbed in the intestine and reduces the secretion of acid in the stomach by selective inhibition of the enzyme P+/K+ATPase located in the intercellular canaliculi parietally cells (LANCET-Nov.27, 1982, pp.1123-1124).

Omeprazole is unstable in an acidic environment (Pilbrant and Cederberg, Scand. J. Gastroenterology (1985), 20 (Suppl. 108), pp.113-120), (Per Lindberg et al., J. Med. Chem. (1986), 29, pp.1327-1329). The half life in water and at pH 7 is less than 10 minutes, being equal to about 14 hours at pH about 7.

Investigated a number of options with the aim of obtaining a stable pharmaceutical compositions. The main task is to solve two main problems (pH and moisture), activating the stability of omeprazole.

For example, in the United Kingdom patent GB No. 218969 (1987) describes receiving oral formulations of omeprazole, characterized by the presence of the core formed by the active ingredient (omeprazole)with alkaline properties, and applied on the core coverage of one or more protective the layers, soluble in water, and having the outer layer Intercollege coverage. Method and obtained for him the products showed a suitable resistance to gastric juice and the good stability of the contained active element (omeprazole) in the gastric juice, as well as during storage for a long time.

In U.S. patent 4786505 (1988) describes receiving oral compositions containing omeprazole, characterized by the presence in the heart of alkaline compounds together with the active ingredient. On the specified core are coated with a sublayer formed by a water-soluble substance or the substance is rapidly decomposed in the presence of water, and outdoor Intercollege layer.

In U.S. patent 5690960 (1977) also describes a method of obtaining a stable oral form, characterized by the presence of a magnesium salt of omeprazole in the core, which is applied to two layers, one of which is able to decompose in aqueous medium, and the second layer is intersolubility.

In U.S. patent 5232706 (1993) describes the receiving core with two layers of coating. The first layer is formed of soluble excipients and compounds like essential amino acids, and the second layer is intersolubility floor. Both layers are intended to protect the omeprazole from exposure to acidic environment and moisture.

The above methods or other methods described in the patent literature, although allow you to obtain suitable pharmaceutical agents (tablets/capsules)demonstrate a number of practical disadvantages, such as described below.

1. Obtaining pharmaceutical mixture for oral administration (tablets or capsules) requires the implementation of several stages:

a) receiving core or granules with the active ingredient or its salt, and in some cases specified in the core include base materials;

b) coating the core with the formation of the underlayer, easily degradable in the aquatic environment, for example, in the fluidized bed;

c) applying onto the pellet or core Intercollege coating and drying;

d) finally, implement, respectively, tabletting or encapsulation.

2. Each process for its implementation requires the use of various equipment, such as, for example, mixer, installation of fluidized bed, tabletiruemye or encapsulating machine, or other equipment.

3. As a rule, because of the instability easy gidrolizuyushchie medicines and availability of the substrate hydrophilic water-soluble coating upon receipt to make a quick drying and further to regulate the humidity.

4. Pravilnogibochnomu each stage as in the case of capsules, and in the case of tablets, requires a significantly longer period of time than the time required for industrial production of such pharmaceutical forms, but with other active ingredients.

In the patent of Korea KR 115254 (1997), corresponding to the publication of the application 95-15059 (1995), describes the use of basic amino acids to stabilize the omeprazole. Some of them are L-arginine, L-lysine, its calcium salt, hydroxylysine and histidine, in the 15-25-fold molar excess, and get a steady drugs, bypassing the intermediate coating prior to the outer intersolubility layer. This method has important advantages over the methods described in the patent literature and above, allowing, as indicated, to obtain tablets of omeprazole with adequate stability when performing fewer operations and the use of less hardware than the already described procedure.

However, the receipt is not simple due to the crystalline nature of the amino acids. In addition, these tablets usually have unfavorable characteristics in terms of hardness and fragility.

Thus, there is still a need for pharmaceutical compositions containing omeprazole, with increased stability relative to the pH and the logs, not connected with the above-mentioned inconveniences (the complexity of the production and use of complex equipment, high cost of production), and also allows you to get farmacevticheskie compositions with improved properties pressuemosti.

The objective of this invention is to provide a simple, rapid and economical method of producing pharmaceutical compositions containing omeprazole.

Another objective of this invention is to provide a method of producing pharmaceutical compositions in the form of tablets containing omeprazole, resistant to pH and moisture, and storage conditions.

Another objective of this invention is to provide a method of producing pharmaceutical compositions in the form of tablets containing omeprazole and amino acids having good properties pressuemosti.

Finally, another objective of this invention is to provide pharmaceutical compositions in the form of tablets containing omeprazole, possessing good properties of pressuemosti, sustainable approach. the pH and moisture, and storage conditions.

These objectives are achieved by the method of the present invention. Unexpectedly showed the possibility of obtaining pharmaceutical compositions in the form of tablets containing omeprazole or its salts and basic amino acid in crystallic the Russian form, selected from the group of L-arginine, L-lysine and L-histidine; such compositions have good stability of omeprazole in relation to pH and moisture and also satisfactory characteristics pressuemosti that was achieved by wetting and drying of the basic amino acid to the residual water of less than 0.75% and the subsequent addition of sodium alginate.

The method of this invention includes two different essential stage.

The first stage represents the external morphological modification of the particles amino acids to obtain tablets without violating its crystalline form by wetting and drying of the particles. Unexpectedly, it was found that this modification is achieved by a simple stage, consisting in the inclusion of water in the total number of less than 0.75 wt.% from amino acids.

Another stage is the addition of sodium alginate with low thickening ability and low water content. Thus, only by including one excipient introduce several features that contribute to the stabilization of omeprazole.

Brief description of figures

Figures 1(a) and 1(B) are pictures of images of particles of L-arginine before and after treatment, obtained by electron microscopy.

Figure 2 shows the spectra of x-ray diffraction pattern of L-arginine without processing andafter treatment by wetting and drying.

The present invention relates to a method for producing a stable pharmaceutical compositions in the form of tablets containing omeprazole, sodium alginate and a basic amino acid selected from the group of L-arginine, L-lysine and L-histidine, which includes stages:

a) pre-modification of the surface morphology of the primary amino acids by wetting and drying to a residual water in the total number of less than 0.75 wt.% by weight of the amino acids;

b) activate the main amino acids in a pre-obtained granules containing omeprazole and sodium alginate with low moisture content;

c) inclusion of other excipients to obtain a granulate;

d) grinding the granules from step (C) until a homogeneous particle size distribution; and

e) include lubricants, process tabletting and coating Intercollege coating on the obtained tablets.

In industry there is a General demand for active pharmaceutical compounds and excipients, which are processed in ways that give products with adequate properties with which you can easily work on an industrial scale, and which have good stability during storage. These characteristics make pharmaceutical compounds and excipients suitable for the pharmacist the economic agents. In order to obtain a composition useful and important to not only active substance, but also all the components of the composition were obtained and are presented in the most appropriate form.

That's why unexpectedly discovered that by subjecting the basic amino acids the process of wetting and drying to a residual water in the amount of less than 0.75 wt.% by weight of the amino acids, receive partial modification of the surface morphology of the crystals of the basic amino acids without violating its crystalline state.

This can easily be seen in figures 1(a) and 1(B). Procedure wetting allows to achieve surface modification in the structure of basic amino acids by erosion, which leads to increased porosity and deformation of particles.

However, although there are superficial changes, the crystal structure of amino acids does not change significantly, which can be seen in the spectra of x-ray diffraction obtained before and after treatment by wetting and drying (figure 2). As can be seen in figure 2, the spectrum does not change significantly, which indicates that the crystal structure remains the same after the particles are subjected to the specified process. Therefore, modification of the particles is only superficial, and only increase Aristotle and surface deformation.

It should be noted that this modification is achieved by obtaining particles of amino acids with the final residual moisture of less than 0.75 wt.% by weight of the amino acids.

This process of wetting can be accomplished by spraying or fluidized bed.

In the technique is known, and is also indicated in the literature that "no substance is not less compression than a fully crystalline material" (Ralph Shangraw F., Pharmaceutical Dosage Forms, pgs 225, Editorial Marcel Dekker); and, as mentioned earlier, it is important that all components in the composition was in the most favorable condition. For this reason, without going into theory, it is believed that this structural change in the surface morphology of the particles used amino acids leads to the acquisition of morphological characteristics that are more appropriate to obtain tablets containing omeprazole, with the desired compressibility.

Another distinctive stage of the method of this invention involves the addition of sodium alginate with low thickening ability and low water content. Alginic acid and its sodium salt are linear copolymers β(1-4)-D-mannurone acid and α-L-guluronic acid. They may have different morphology and different molecular mass. The molecular weight can range from 20000 to 200000. Such feature is specific give each of them special properties.

The addition of sodium alginate in the tablets obtained according to the method of the present invention includes several features, some of which contribute to the stabilization of omeprazole. These include the functions listed below.

1. Dewatering activity due to their ability to bind water or moisture. It is well known and described in the literature (Handbook of Pharmaceutical Excipients (1994), pp.428-429)that the sodium alginate is poorly soluble in water, but easily attaches water, forming a gel and removes moisture or water from the environment. Sodium alginate has an almost neutral pH. A 1%solution pH is about 7.2. It is stable at pH 4 to 10, but he easily captures a proton from the medium into alginic acid at pH 4.

In the case of formation of alginic acid because of its insolubility reduced availability of free protons in the environment. In addition, alginic acid, resulting in such conditions, also contributes to dehydration environment because of its ability to absorb water in an amount equivalent to 200-300 own mass (Handbook of Pharmaceutical Excipients (1994), pp.10-11).

2. Binding and destructive activity. Upon receipt of the tablets sodium alginate can be used as a binder, as well as substances that contribute to the decomposition (Sakr A.M., Elsabbagh H.M., Shalaby A.N., Effect of the technique of incorporating sodium alginate on its binding and/or disintegating effectiveness in sulphathiazole tablets, Pharm. Ind. (1978); 40(10); 1080-1086). At concentrations above 2% due to the ability to absorb water it acts as a substance that promotes the decomposition (Esezobo S., Disintegrants: effects of interacting variables on the tensile strengths and disintegration times of sulphaguanidine tablets. Int. J. Pharmaceutics (1989); 56:207-211). At concentrations up to 10%, typically use in tablets, dissolving emitting bubbles, as well as to change the speed of release of the active components (Klaudianos S., Alginate sustained-action tablets, Dtsch Apoth Zig (1978); 118:683-684).

It is found experimentally that at reception of tablets and omeprazole preferably, when using sodium alginate was observed the conditions specified below.

A. The content of sodium alginate should be less than 15%, preferably from 8 to 12%. If the percentage content of sodium alginate above, getting the pills becomes complicated and may affect the release of omeprazole due to gel formation. Higher concentrations (20-50%) are used for obtaining tablets with controlled release.

b. The moisture content in the sodium alginate should be less than 2%. The literature describes alginates suitable for pharmaceutical use, containing up to 15% of water, determined by the mass loss during drying. It is shown that such alginates are not suitable for the method of the present invention, because of the disadvantages associated with sustainability. Maxim is Ino acceptable water content, which gives satisfactory experimental results in the method of this invention, correspond to a value of less than 2%. Pre-vacuum drying at 70°commercial alginates makes readily available alginate with a suitable moisture content.

Other properties of importance, which must satisfy the sodium alginate in the method of this invention, are listed below.

C. the Molecular weight of sodium alginate should be low.

d. Preferably, the particle morphology should represent the granules.

that is, He must have the ability to form aqueous solutions (at a content of 1%) low viscosity (20-100 centipoise).

Among commercial sodium alginates, without limitation, satisfactory, as shown, is the so-called MANUCOL LB (available from KELCO company ALGINATOS).

One of the advantages obtained in the method of the present invention with the addition of sodium alginate, due to the properties of alginate, described earlier, is that it reduces the number of required components to stabilize the omeprazole is indicated in the patent literature.

Furthermore, the addition of sodium alginate reduces the number of operations and amount of equipment used in industrial production of tablets and omeprazole.

Stages of drying as sodium alginate, and processed the th of L-arginine are considered critical due to the fact, they can affect the stability of omeprazole. Found that optimum final residual humidity in the drying should be less than 2% of sodium alginate and less than 0.75% for L-arginine.

Each tablet obtained in accordance with the method of the present invention in the examples, below, shows adequate compressibility, excellent stability and a suitable pharmaceutical characteristics.

Hereinafter the invention is explained in the above examples, but is not limited to them.

Example 1

Coated tablets with 20 mg of omeprazole

Composition to obtain 10,000 tablets.

Omeprazole200 g
Sodium alginate250 g
L-Arginine1750
Sodium lauryl sulfate powder40 g
Copolyvidone150 g
Magnesium stearate15 g
Talc110 g
Microcrystalline cellulose485 g

250 g of sodium Alginate dried in vacuum at 70°to obtain a residual moisture content of less than 2%. At the same time, 1750 g of L-arginine moisten by sprinkling 4300 ml of distilled water and dried to a residual moisture content of not more than 0.75% (Drying Balance Metler LJ 16 Moisture Analyzer).

Both substances separately sieved and mixed with omeprazole, magnesium stearate and talc in amounts specified in part I. the resulting mixture is pressed (teletrauma machine of rotary type Piccola) and crushed (conical mill with sieve Quadro Comil) to achieve the proper particle size distribution.

Then the obtained granulate is mixed with specified amounts of lauryl sodium, copolyvidone and microcrystalline cellulose. The mixture is pressed into tablets weighing 300 mg (rotary teletrauma machine Piccola).

The obtained tablets are covered with a suspension obtained from 360 g of a mixture of polivinilatsetatftalat, talc, stearic acid, titanium dioxide and triethylcitrate (mixture type Opadry Enteric YP 6-7005 White)dispersed in 2000 g of a mixture of ethanol:water (14:3), to confirm gastroresistant tablets.

Gastrorresistente determined according to the method specified in USP 24.

Example 2

Composition to obtain 10,000 tablets.

Omeprazole200 g
Sodium alginate500 g
L-Arginine2000
Sodium lauryl sulfate powder40 g
The hypromellose250 g
Magnesium stearate75 g
Talc120 g
Lactose anhydride.1815

500 g of sodium Alginate dried in vacuum at 70°to obtain a residual moisture content of less than 2%. At the same time, 2000 g of L-arginine is humidified by spraying or fluidized bed 5000 ml of distilled water and dried to obtain a residual moisture content of not more than 0.75% (Drying Balance Mettler LJ 16 Moisture Analyzer).

Both substances separately sieved and mixed with 200 g of omeprazole, 25 g of magnesium stearate and 120 g of talc. The resulting mixture is pressed (teletrauma machine of rotary type Piccola) and crushed (conical mill with sieve Quadro Comil) to achieve the proper particle size distribution.

Then the obtained granulate is mixed with specified amounts of lauryl sodium, hydroxypropylmethylcellulose, lactose anhydride and the rest of the amount of magnesium stearate. The mixture is pressed into tablets weighing 500 mg (teletrauma machine of rotary type Piccola).

The obtained tablets are coated with a suspension obtained from 360 g of a mixture of polivinilatsetatftalat, talc, stearic acid, titanium dioxide and triethylcitrate (mixture type Opadry Enteric YP 6-7005 White)dispersed in 2040 g of a mixture of ethanol:water (14:3), to confirm gastroresistant tablets.

Gastrorresistente determined according to the method specified in USP 24./p>

Example 3

Coated tablets 40 mg omeprazole

Composition to obtain 10,000 tablets

Omeprazole400 g
Sodium alginate250 g
L-Arginine1750
Sodium lauryl sulfate powder40 g
Copolyvidone150 g
Magnesium stearate15 g
Talc110 g
Microcrystalline cellulose285 g

250 g of sodium Alginate dried in vacuum at 70°to obtain a residual moisture content of less than 2%. At the same time, 1750 g of L-arginine is humidified by spraying or fluidized bed 4300 ml of distilled water and dried to obtain a residual moisture content of not more than 0.75% (Drying Balance Mettler LJ 16 Moisture Analyzer).

Both substances separately sieved and mixed with omeprazole, magnesium stearate and talc in amounts specified in the composition. The resulting mixture is pressed (teletrauma machine of rotary type Piccola) and crushed (conical mill with sieve Quadro Comil) to achieve the proper particle size distribution.

Then the obtained granulate is mixed with specified amounts of lauryl sodium, copolyvidone and microcrystalline cellulose. CME is pressed into tablets weighing 300 mg (teletrauma machine of rotary type Piccola).

The obtained tablets are coated with a suspension obtained from 360 g of a mixture of polivinilatsetatftalat, talc, stearic acid, titanium dioxide and triethylcitrate (mixture type Opadry Enteric YP 6-7005 White)dispersed in 2000 g of a mixture of ethanol:water (14:3), to confirm gastroresistant tablets.

Gastrorresistente determined according to the method specified in USP 24.

Example 4

Coated tablets with 20 mg of omeprazole in the form of minimarathon

Composition to obtain 10,000 tablets

Omeprazole (minimarathon)200 g
Sodium alginate250 g
L-Arginine1750
Sodium lauryl sulfate powder40 g
Copolyvidone150 g
Magnesium stearate15 g
Talc110 g
Microcrystalline cellulose485 g

250 g of sodium Alginate dried in vacuum at 70°to obtain a residual moisture content of less than 2%. At the same time, 1750 g of L-arginine is humidified by spraying or fluidized bed 4300 ml of distilled water and dried to obtain a residual moisture content of not more than 0.75% (Drying Balance Mettler LJ 16 Moisture Analyzer).

Both substances separately prosey is up and mixed with omeprazole, the stearate and talc in amounts specified in the composition. The resulting mixture is pressed (teletrauma machine of rotary type Piccola) and crushed (conical mill with sieve Quadro Comil) to achieve the proper particle size distribution.

Then the obtained granulate is mixed with specified amounts of lauryl sodium, copolyvidone and microcrystalline cellulose. The mixture is pressed into tablets weighing 300 mg (teletrauma machine of rotary type Piccola).

The obtained tablets are coated with a suspension obtained from 360 g of a mixture of polivinilatsetatftalat, talc, stearic acid, titanium dioxide and triethylcitrate (mixture type Opadry Enteric YP 6-7005 White)dispersed in 2000 g of a mixture of ethanol:water (14:3), to confirm gastroresistant tablets.

Gastrorresistente determined according to the method specified in USP 24.

1. A method of obtaining a stable pharmaceutical compositions in the form of tablets containing omeprazole and basic amino acid, characterized in that add the sodium alginate and the method includes the following stages: a) pre-modification of the surface morphology of the primary amino acids by wetting and drying to a residual water in the total number of less than 0.75 wt.% by weight of the amino acids; (b) the inclusion of basic amino acids in the pre-receive the hydrated granules, containing omeprazole and sodium alginate with moisture content less than or equal to 2%; (c) the inclusion of other excipients to obtain a granulate; (d) milling the granulate from step e) to obtain a homogeneous particle size distribution; (e) the inclusion of the lubricant, the process of tabletting and coating the obtained tablets Intercollege coverage.

2. The method according to claim 1, characterized in that the content of sodium alginate is 15 wt.% by weight of the tablet, preferably 8-12 wt.%.

3. The method according to claim 1 or 2, characterized in that the sodium alginate has a low molecular weight on the morphology of the particles are preferably granules, the moisture content of 1-2%.

4. The method according to claim 1, wherein the basic amino acid is an L-arginine, L-lysine or L-histidine.

5. Pharmaceutical composition in the form of tablets obtained by the method according to claim 1, characterized in that it contains omeprazole in concentrations of 1-40 mg per pill.

6. The pharmaceutical composition obtained by the method according to claim 1, characterized in that it contains minimarathon or salt of omeprazole and an alkaline metals in amounts equivalent to the amount of omeprazole 10-40 mg per pill.



 

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10 cl, 1 tbl, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 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, 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

The invention relates to the field of medicine for a stimulator of expression of MAG (myelin-associated glycoprotein) containing the compound of formula (I):

The connection is suitable for the treatment of diseases, representing hypomyelination, demyelinization or demyelination

The invention relates to medicine, in particular to pharmaceutical compositions containing the blocker of calcium and pharmacologically acceptable alkaline material, which is added in an amount such that the aqueous solution or dispersion solution of a specified pharmaceutical compositions containing a blocker of calcium, would have a pH of at least 8

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

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