Mono - or dicale 2-[[5-ethyl-3-[2'-(1h-tetrazol-5-yl) biphenyl-4-yl]methyl-1,3,4-thiadiazoline-2 - ilidene] aminocarbonyl]-1-cyclopentanecarboxylate, pharmaceutical composition and method for therapeutic treatment of hypertension

 

(57) Abstract:

The invention relates to novel potassium salts derived biphenylmethane - mono - or dicale 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4-thiadiazoline-2-ilidene] aminocarbonyl] -1-cyclopentanecarboxylate having hypotensive activity. 3 C. p. F.-ly, 3 tables.

This invention relates to new and potassium salts derived biphenylmethane possessing a strong antagonist activity of angiotensin II and hypotensive activity, and to pharmaceutical preparations containing these salts.

Angiotensin II is the active center of the system the renin-angiotensin and has strong vasoconstrictive action and stimulating effect on the synthesis and secretion of aldosterone in the cortical substance of the adrenal gland. It is also known that it is a substance that causes hypertension. I believe that his action is invoked by specific receptors on different target organs, such as the cortical substance of adrenal glands, the kidneys, the arterioles and peripheral sympathetic nerves.

Known examples of substances which exhibit hypotensive action by pharmacological inhibition system the renin-honesty of angiotensin II and renin inhibitors. As an antagonist of angiotensin II, not related to these substances, known saralasin ([Sar', Ala8] AG11), the peptide-type angiotensin II, and ones derivatives such as imidazole derivatives (patent application laid Japan NN 7103/1981 and 71074/1981 and laid out the publication in Japanese N 501020/1991), pyrazole derivatives (patent application laid Japan N 218371/1991) and derivatives aminoate (WO93/17681).

In clinical applications derived peptides, however, difficulties arise because of their short in vivo period of life, lack of effectiveness when administered orally and significant agonistic activity. Among the ones derived neither one has not yet been used clinically as a drug.

The purpose of this invention lies in the fact that a drug, which can be applied clinically, and which has the above-described activity.

With the goal of developing clinically superior drug in such circumstances, the authors of this invention have conducted extensive research. As a result, they found that the derived biphenylmethane represented by the following formula is an analytical tool for diseases, proceeding with circulatory disorders, heart diseases and cerebral apoplexy, and filed after the application under the PCT (PCT/JP93/01134).

< / BR>
where a represents a group

< / BR>
where R1represents a hydrogen atom, a lower alkyl group, lower cycloalkyl group, a substituted or unsubstituted phenyl group, substituted or unsubstituted aracelio group, substituted or unsubstituted acyl group, or amino acid residue; X represents an oxygen atom, a sulfur atom or the group =CH-, Y represents a nitrogen atom or a group =CR2-, Z represents an oxygen atom, a nitrogen atom or a group =CR3- and these Y and Z can not be heteroatoms at the same time, each of R2and R3represents a hydrogen atom, halogen atom, substituted or unsubstituted lower alkyl group, a protected or unprotected carboxyl group, a lower cycloalkyl group, lower alkenylphenol group, lower CNS group, a lower allylthiourea or aryl group, or R2and R3may form together with the adjacent carbon atoms substituted or unsubstituted benzene ring. B represents a cyano, protected or nesasio bond or single bond.

As a result of further study, the authors present invention have found that among the above derivative difenilmetana (1) mono - and Dikili 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl-1,3,4-thiadiazoline-2-ilidene] aminocarbonyl]-1-cyclopentanecarboxylate have a particularly strong activity of the antagonist of angiotensin II and hypotensive activity and also have very high bioavailability when administered orally, leading to completion of this invention.

This invention, therefore, offers a mono - or Pikalevo salt of 2-[[5-ethyl-3-[2'-(1H - tetrazol-5-yl)biphenyl-4-yl] methyl-1,3,4-thiadiazoline-2-ilide] aminocarbonyl]1-cyclo-pentanecarboxylic, represented by the following formula (2):

< / BR>
This invention also provides a pharmaceutical composition, which contains mono - or Pikalevo salt of the compounds (2) and a pharmaceutical carrier.

This invention also provides the use of a mono - or Pikalevo salt of the compound (2) as pharmaceuticals.

In addition, this invention also provides a method of treatment of diseases, flowing with blood circulation, which provides an introduction to the effective number of the ti salt relate to this invention, dikalova salt is particularly preferred.

Mono - or dikalova salt of the compound (2), to which this invention relates may be in the form of various stereoisomers (CIS-form, TRANS-form). These stereoisomers are also included in this invention. The compounds of this invention may also be present in the form of solvated products, such as hydrates, which are also included in the invention.

Mono - or Pikalevo salt of the compound (2) can be obtained in various ways. Preferred is a method of obtaining specified below:

< / BR>
where R1represents a substituted or unsubstituted acyl group, and Z represents a halogen atom or sulfonyloxy.

Namely, 2-amino-5-ethyl-1,3,4-thiadiazole (3) is subjected to acylation to obtain compound (4). The compound (4) is condensed with compound (5) in the presence of a base, receiving the connection (6). Connection (6) then tetrazolium to obtain compound (7), which is then hydrolized to remove the acyl group, through which they receive a connection (8). Then the reaction of the compound (8) with compound (9) to obtain compound (2). Thus obtained compound (2) Prietenia can be obtained in this way. Compound (7) can also be obtained by reaction of the compound (4) with 4 - halogenmethyl-2-(1H-tetrazol-5-yl)biphenyl.

The above stages of the reaction will then be described respectively in detail.

Examples Alliluyeva agent suitable for the acylation of the compound (3) include acetic acid, triperoxonane acid or similar agents. The acylation can take place via any desired reaction, usually used for acylation of the amino group. Described, in particular, the acylation can be carried out by reaction of the compound (3) with acylchlorides or anhydride, which corresponds to the desired acyl group, in an aprotic polar solvent such as a halogenated hydrocarbon, for example methylene chloride, chloroform, carbon tetrachloride or chlorobenzene; aromatic hydrocarbons such as benzene or toluene: a simple ether, for example tetrahydrofuran or dioxane; acetonitrile or N,N-dimethylformamide, at temperatures from 0oC to room temperature in the presence or in the absence of a base, such as pyridine, picoline, N,N-dimethylaniline, N-methylmorpholine, dimethylamine, triethylamine, sodium carbonate or potassium carbonate at a temperature of from -70 to 100oC; or by the reaction of f is P>oC.

Examples of the base usable in the above condensation of compounds (4) and compound (5) include sodium hydride, lithium hydride, potassium carbonate, sodium carbonate, sodium alcoholate, tert-piperonyl potassium, caustic soda, sodium hydroxide, triethylamine and diisopropylethylamine. Here you can apply any solvent, if he have no effect on the reaction. Examples of suitable solvents include aprotic polar solvents such as N,N-dimethylformamide and dimethylsulfoxide, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme (1,2-dimethoxyethane) and diglyme (dimethyl esters diethylenglycol); halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; alcohols such as methanol, ethanol and propanol.

As a reaction accelerator can be added interphase catalyst. Examples of the phase transfer catalyst include Quaternary ammonium salts, such as chloride of Tetramethylammonium, chloride of tetraoctylammonium and tetrabutylammonium bromide; pyridinium salts such as chloride N-neopentyl-4-(N',N'-dimethylamino)-pyridinium and chloride N-(2-ethylhexyl)-4-(N', N'-dimethylamino)pyridinium; and Quaternary postname salt, for example bromine is the temperature from 30 to 150oC, preferably from 10 to 100oC. the reaction Time may usually be from 10 minutes to 24 hours, preferably from 1 to 10 hours

Especially preferred example of condensation is an example in which the metal salt of the compound (4) are obtained in an aprotic polar solvent such as N, N-dimethylformamide, when using sodium hydride or potassium carbonate as a base and the resulting salt of the metal is treated with compound (5) at temperatures from 0oC to room temperature.

Examples of the halogen atom represented by Z in the compound (5) include fluorine atom, chlorine atom, bromine atom, iodine atom etc., Illustrative examples of sulfonyloxy include alkylsulfonates, for example, methanesulfonate, econsultancy and triftormetilfullerenov, and arylsulfonate, for example, benzosulfimide and n-toluensulfonate

Tetraallylsilane compound (6) can be carried out in accordance with the known method (patent application laid Japan N 23868/1988), namely, the annexation of 1,3-dipolar ring to the compound (6) with the use of azide compounds of the metal, such as azide three-C1-C1-8-alkalolu, three-C1-C18the first connection metal to the compound (6) in a solvent, for example benzene or toluene, their reaction when heated and then the processing of the reaction product with hydrochloric acid or similar reagent.

The compound (5) can be obtained by a method known to date (lined patent application Japan N 23868/1988, 27362/1991 or 74369/1991; J. Org.Chem. 56, 2395-2400 (1991), or so forth).

For diallylamine (removal of the protective group) of the compound (7) can be applied in any desired well-known reaction. For example, the removal of the protective group may be carried out by reaction of the compound (7) in aqueous alkaline solution, for example aqueous sodium hydroxide solution, aqueous solution sodium hydroxide or aqueous sodium carbonate solution, or the acid solution, for example hydrochloric acid or acetic acid, at a temperature of from room temperature to 100oC, with the use of a solvent miscible with water, such as ethanol, methanol, tetrahydrofuran or N,N-dimethylformamide, or without solvent.

The reaction between the compound (8) and compound (9) can be carried out in an aprotic polar solvent such as a halogenated hydrocarbon, for example methylene chloride, chloroform, carbon tetrachloride or chlorobenzene, aromatic hydrocarbons such as benzene or toluene, about theC to room temperature in the presence or in the absence of a base, such as pyridine, picoline, N,N-dimethylaniline, N-methylmorpholine, dimethylamine, triethylamine, sodium carbonate or potassium carbonate, at temperatures from -70 to 100oC.

In the specified method of obtaining, when tetrazol-5-ilen group has a protective group, if necessary, the protective group can be removed.

For the above removal of the protective group, it is desirable to remove the protective group, the reaction of the compound in a water-containing alcohol or simply ether, for example dioxane or tetrahydrofuran, which contains hydrochloric acid, acetic acid or a similar acid, at room temperature or so for about 1-10 hours

Thus obtained compound (2) can be transformed into its mono - or Pikalevo salt by a method known per se in this area. In particular, it is only necessary to dissolve the compound (2) in caustic soda solution and then precipitated as a salt. Preferably used as a solution of caustic potash solution caustic potash in water, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, acetone and similar solvents used in a quantity which is m solution of sodium hydroxide. The temperature of dissolution can be determined between room temperature and the desired temperature of the heating, which depends on the connection (2). In addition, you can select the desired method of deposition of salt, because some of the salts are precipitated when the solution just leave, but some of the salts are not deposited until then, until it is to some extent removed the solvent.

Thus obtained mono - or Pikalevo salt of the compound (2), if necessary, can be cleaned by a method known per se in this area, for example by dissolving the salt in one or more solvents selected from water, methanol, ethanol, n-propyl alcohol, isopropyl alcohol or acetone, followed by recrystallization from a solution.

When mono - and Pikalevo salt of the compound (2) which relate to this invention are used as therapeutic agents for diseases associated with the circulatory, you can enter them in a composition together with a pharmaceutically acceptable carrier for parenteral administration, for example injection or rectal administration, or for oral administration in solid or liquid form.

The composition of this invention for organizmy water, non-aqueous solutions, suspensions or emulsions. Examples of suitable nonaqueous carriers, diluents, solvents and excipients include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable organic esters, for example etiloleat. These preparations can contain one or more auxiliary tools, such as antiseptics, moisturizers, emulsifiers and dispersing agents. These ready-made formulation can be sterilized, for example, by filtration through a bacterial filter or mixing immediately before use with sterilizing means in the form does not contain pathogenic microorganisms solid composition, dissolved in sterilized water or one of the other environments that can be sterilized and to be injected.

Examples of solid preparations for oral administration include capsules, tablets, pills, powders, granules, etc. In the manufacture of these solid preparations of the compounds in accordance with this invention are usually mixed with at least one inert filler, such as sucrose, lactose or starch. In the manufacture of drugs in the usual way they can also enter the AK stearate. In the case of capsules, tablets and pills can also enter the buffer. Tablets and pills may be coated intersolubility shell.

Illustrative liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluent, usually used by experts of this field, for example water. Besides such inert diluent in liquid preparations can also add one or more auxiliary tools, such as humectants, emulsifiers, suspendresume tools, sweeteners, conditioners and fragrances. Preferred preparations for rectal administration, which contain fillers, for example cocoa butter or a suppository wax, in addition to the compounds of this invention.

Dose mono - or Pikalevo salt of the compound (2) in accordance with the present invention depends on the properties of the compound that is administered, method of administration, the desired time of treatment and other factors. It usually ranges from about 0.1 mg/kg to 100 mg/kg / day, particularly preferably about 0.5-50 mg/kg per day. If desired, this daily dose can be administered in the form of 2-4 servings.

This izaberete is their no way limited to these examples or by these examples.

Example 1 synthesis.

1) Synthesis of 2-triptoreline-5-ethyl-1,3,4-thiadiazole.

To a suspension of 200 g of 2-amino-5-ethyl-1,3,4-thiadiazole in 3 l of toluene was added to 260 ml of triethylamine at room temperature, then added 265 ml triperoxonane anhydride under cooling with ice. The mixture was stirred 1 h at room temperature. In the reaction mixture was added water and the precipitated crystals were separated by filtration. To the filtrate was added ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuum, obtaining 237,5 (68%) of the title compound.

2) Synthesis of 4-methyl bromide-2'-cyanobiphenyl.

In 110 ml of carbon tetrachloride was added to 10.5 g of 4 - methyl-2'-cyanobiphenyl, 9,79 g of N-bromosuccinimide and 120 mg of 2,2'-azobisisobutyronitrile. The resulting mixture was boiled under reflux for 2 hours, the Insoluble material was removed by filtration under heating. The filtrate was cooled when standing. Precipitated crystals were separated by filtration, resulting in a received 6.6 g (44%) of the title compound.

3) Synthesis of 2-triptorelin-5-ethyl-3-(2'-cyanobiphenyl-4-yl)-methyl-1,3,4-thiadiazoline.

In the suspension of 124.1 g of sodium hydride (55% in oil) in 1.5 liters of N,N-di is. After the evolution of hydrogen in the reaction mixture was added dropwise a solution of 643,6 g of 4-methyl bromide-2'-cyanobiphenyl obtained in (2), in 3 l of N,N-dimethylformamide. The reaction mixture was stirred 1 h at room temperature and then was stirred 5 h at 80oC. the Solvent is evaporated in vacuo and to the residue was added water and ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporation of the solvent in vacuo the residue was purified by chromatography on a column of silica gel (eluent:a mixture of n-hexane and ethyl acetate 3:1) to give crude (raw) crystals. These crystals have recrystallize from ethanol, getting 490,8 g (50%) of the title compound.

4) Synthesis of 2-triptorelin-5-ethyl-3-(2'-cyanobiphenyl-4-yl)-methyl-1,3,4-thiadiazoline.

In 18 l of N,N-dimethylformamide was added 2.44 kg (10,8 mol) 2-triptoreline-5-ethyl-1,3,4-thiadiazole and 2,80 kg (10,3 mol) 4-methyl bromide-2'-cyanobiphenyl, then added 894 g (6.5 mol) of anhydrous potassium carbonate and 60 g of potassium iodide. The reaction mixture was stirred for 41 h at room temperature. Insoluble material was removed by filtration and the filtrate was concentrated in vacuum. To the residue was added 45 l of water and 18 l of ethyl acetate. The organic layer is Precipitated crystals were separated by filtration and washed successively with ethanol and diisopropyl ether. Crystals (purity: 95,8%) was recrystallized from 5 l of ethanol, getting 2,70 kg crystals (purity, 94%). These crystals (purity, 94%) was purified column chromatography on silica gel (10 kg of silica gel, eluent: a mixture of n-hexane and ethyl acetate, 3: 1 - 2:1), getting 2,64 kg (purity: 99%) of the title compound. All the filtrates were combined and the solvent evaporated. The residue was dissolved in 3 liters of hot ethanol and the solution was added activated charcoal. The mixture was stirred for 30 min at 80oC and filtered through celite. The filtrate was left overnight at room temperature. Precipitated crystals were separated by filtration. The crystals were treated again activated carbon, as described above, whereby received 562 g (purity: 98%) of the title compound. The filtrate is evaporated and the residue was purified column chromatography on silica gel (4 kg of silica gel, eluent: a mixture of n-hexane and ethyl acetate, 5:1), receiving 371 g of the title compound. Just received 3.57 g of the title compound.

Properties: colorless crystals in the form of prisms.

Melting point: 106-107oC.

1H NMR spectrum ( M. D., CDCl3): 7,43-7,79 (8H, m), the ceiling of 5.60 (2H, s), 2,95 (2H, K) of 1.39 (3H, t).

5) Synthesis of 2-triptorelin-5-ethyl-3- [2'-(1H-tet-cyanobiphenyl-4-yl)methyl-1,3,4-thiadiazoline, obtained in (4), and 485,5 azide trimacinolone. The mixture was boiled under reflux for 40 h In the reaction mixture were added 200 ml of concentrated hydrochloric acid and then stirred for 10 minutes, the Reaction mixture was extracted with 5 l of ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed in vacuum, obtaining the title compound, which was not purified for use in the next stage.

6) Synthesis of hydrochloride of 2-imino-5-ethyl-3-[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl-1,3,4-thiadiazoline.

In a mixture of 4 l of tetrahydrofuran and 200 ml of water and 2-triptorelin-5-ethyl-3-2'-(1H-tetrazol-5-yl)biphenyl-4-yl methyl-1,3,4-thiadiazoline obtained in (5), added 94,4 g of sodium hydroxide and the mixture is boiled under reflux for 7 hours, the Reaction mixture was concentrated in vacuum. To the residue was added water and ethyl acetate. The aqueous layer was separated and acidified with hydrochloric acid. Precipitated crystals were separated by filtration and received 168 g of the title compound. From the ethyl acetate layer was besieging the crystals were separated by filtration, whereby received an additional 80 g of the title compound.

Properties: colorless powder.

The fact is) 5,43 (2H, C) 2,89 (2H, K) to 1.22 (3H, t).

7) Synthesis of 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4 - yl] methyl-1,3,4-thiadiazoline-2-ilidene]aminocarbonyl]-1 - cyclopentanecarboxylic acid.

In 2 ml of N,N-dimethylformamide was added 200 mg of the hydrochloride of 5-ethyl-2-imino-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl] methyl-1,3,4-thiadiazoline and 76 mg anhydride 1,2-cyclo-pentadecanol acid. The reaction mixture was stirred 2 h at room temperature and poured into water. Precipitated crystals were separated by filtration, washed with water and ethanol and then dried, whereby was obtained 170 mg of the title compound.

Properties: colorless crystals.

Melting point: 234-235oC.

1H NMR spectrum ( M. D., CDCl3+ CD3OD): 7,76 (1H, d), 7,35-7,65 (MN, m), 7,29 (2H, d), 7,11 (2H, d), 5,52 (2H, s), 3,03 (4H, t), to 2.94 (2H, K), 1,89 (2H, m) of 1.39 (3H, t).

Example 1.

Synthesis of 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-1,3,4-thiadiazoline-2-ilidene] aminocarbonyl] - 1-cyclopentanecarboxylate of dicale (compound A).

In a mixture of 400 ml of 0.1 N solution (alcohol) sodium hydroxide and 600 ml of ethanol was added 10 g of 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl - 4-yl] methyl-1,3,4-thiadiazoline-2-ilidene] aminocarbonyl]-1 - cyclopentanecarboxylic acid. After kakaka solution volume has not been reduced to just about 200 ml. Precipitated crystals were separated by filtration, washed with ethanol and then dried in vacuum, whereby was obtained 11 g of the title compound.

Melting point: > 280oC.

IR-spectrum (KBr), cm-11642-(COOK), 1570(=N-CO-).

1H NMR spectrum ( M. D., D2O): 7,51-7,62 (MN, m), 7,37-7,39 (1H, m), 7,31 (2H, d),? 7.04 baby mortality (2H, d), 5,49(2H, s), 2,66 - of 2.86 (6H, m), 1,95-2,00 (2H, m) of 1.23 (3H, t)

Example 2 Synthesis of 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl-biphenyl-4-yl]methyl-1,3,4-thiadiazoline-2-ilidene] aminocarbonyl] -1 - cyclopentanecarboxylate of monogalia (compound B).

In a mixture of 8.3 ml of 0.05 N solution (alcohol) sodium hydroxide and 50 ml of ethanol was added 206 mg of 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1, 3,4-thiadiazoline-2-ilidene] aminocarbonyl] -1 - cyclopentanecarboxylic acid. After the mixture was completely dissolved by heating on a water bath, the solvent is evaporated in vacuum. To the residue was added ethanol. Precipitated portion was separated by filtration and dried in vacuum, whereby received 180 mg of the title compound.

IR-spectrum (KBr): 1680 (-COOH), 1570(=N-CO-).

Test 1.

Hypotensive effect in rats with renal hypertension (invasive).

Each of the rats with renal hypertension received is of NNI diameter: 0,4318 mm) during anaesthesia. The hypotensive effect was studied using rats, the mean blood pressure which was raised to 150 mm Hg or higher for 4-8 weeks after the compression of the renal artery. One day before testing in the femoral artery of each of the rats with renal hypertension inserted a cannula for blood pressure measurement. Rats were given plenty (ad libitum) feed and water immediately before testing. Inserted thus the cannula was connected with a sensor of blood pressure and mean blood pressure were recorded on a polygraph. After the blood pressure has become stable, each of the rats orally was administered 0.3 mg/kg of the test compound, which is suspended in 0.5% carboxymethylcellulose. In accordance with the equation given in table. 1, the degree of lowering blood pressure (%) was calculated from the values of blood pressure before and after administration of the test compounds. The results are given in table. 1.

Test 2.

The inhibitory activity of the test compounds orally administered to the rats with normal blood pressure, but blood pressure which is deliberately increased by angiotensin II (intravenous injection of 0.1 mg/kg) (invasive).

For about the g) under anesthesia inserted a cannula for measuring blood pressure and other cannula to the solution of angiotensin II (AII) in physiological solution (intravenous infusion of 0.1 mcg/kg), respectively. Rats were given plenty (ad libitum) feed and water immediately before testing. On the day of the first test indicated a cannula inserted into an artery connected to the sensor blood pressure and mean blood pressure were recorded on a polygraph. Each of the rats to increase the pressure of intravenously injected with a solution of AII in physiological solution. The reaction pressure increase was repeated several times. After it was confirmed that the reaction became stable, orally was administered to the rat 1.0 mg/kg of the test compound, which is suspended in 0.5% carboxymethylcellulose. In accordance with the equation given in table. 2, the degree of inhibition (%) high blood pressure was calculated from the increase in blood pressure before and after administration of the test compounds. The results are given in table.2.

Test 3.

Measurement of the bioavailability of the test compound in rats.

Male SD rats aged 6 weeks (5 rats per group) were kept hungry during the night. Then each rat was administered 3 mg/kg of the test compound intravenously after dilution in saline and oral after suspension in 0.5% carboxy who Yali by centrifugation. The test compound in the plasma were determined by liquid chromatography and high resolution on the basis of this determined area with the concentration (AUC) for intravenous and oral administration, respectively. Bioavailability (BA) of the test compound in rats was calculated in accordance with the equation given in table.3. The test results are given in table.3.

As is evident from the results table. 1,2,3, mono - or dikalova salt of the compound (2) in comparison with compound (2) and its sodium salt has a strong activity of the antagonist of angiotensin II and a strong hypotensive effect and has a high bioavailability when administered orally.

Mono - or dikalova salt derived biphenylmethane in accordance with this invention has a strong activity of the antagonist of angiotensin II and high bioavailability compared with the free derivatives biphenylmethane or their salts, other than potassium salts of derivatives biphenylmethane, so it is not only useful as a therapeutic agent for diseases associated with the circulatory disorders such as hypertension, heart disease and cerebrolysinum tool for clinical use.

1. Mono-or dicale 2-[[5-ethyl-3-[2'-(1H-tetrazol-5 - yl)biphenyl-4-yl] methyl-1,3,4-thiadiazoline-2-ilidene]aminocarbonyl]-1-cyclopentanecarboxylate.

2. Pharmaceutical composition having anti-hypertensive activity, characterized in that it contains mono-or dicale 2-[[5-ethyl-3[2'-(1H-tetrazol-5-yl)biphenyl-4-yl] methyl-1,3,4-thiadiazoline-2-ilidene] aminocarbonyl] -1-cyclopentanecarboxylate and a pharmaceutically acceptable carrier.

3. The method of therapeutic treatment of hypertension, including the appointment of an effective amount of a mono - or dicale 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl] methyl,3,4 - thiadiazole-2-ilidene]aminocarbonyl]-1-cyclopentanecarboxylate.

 

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< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

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EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine, endocrinology, pharmacology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical combined composition used for treatment or prophylaxis of hypertension in patients suffering with diabetes mellitus. The composition comprises AT1-antagonist valsartan or its pharmaceutically acceptable salt and calcium channel blocking agent or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier. The composition elicits synergistic effect and expanded spectrum effect.

EFFECT: improved and valuable medicinal properties of composition.

10 cl, 3 tbl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention proposes the composition comprising xenon as NMDA-antagonist and alpha-2-adrenergic agonist used for treatment of tetanus or narcotics (alcohol) withdrawal syndrome, states with chronic pain syndrome. Also, invention relates to the anesthetic composition comprising xenon and alpha-2-adrenergic agonist and to a method for anesthesia. The synergistic interaction of xenon as NMDA-antagonist and alpha-2-adrenergic agonist provides reducing the dose and to maintain the prolonged effectiveness by prevention for arising the drug habitation to the claimed preparation.

EFFECT: valuable medicinal properties of composition.

9 cl, 6 dwg, 6 ex

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