New substituted 2-cyanopyrrolidines

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to new (N-substitutes glycyl)-2-cyanopyrrolidines of formula I , wherein R is adamantly, substituted in 3- and/or 5-site with one or more substituents, selected from group including C1-C10-alkyl, OR1 (R1 is C1-C10-alkyl, C1-C8-alkanoyl, -CO-NR4R5, wherein R4 and R5 are independently from one another hydrogen, cyclohexyl, C1-C10-alkyl, phenyl optionally substituted with C1-C10-alkyl or C1-C10-alkoxy), in free form or in form of acid additive salt. Claimed compounds inhibit dipeptidyl-peptidase IV (DPP-IV) activity and useful in pharmaceutical composition for treatment of conditions mediated by DPP-IV, such as insulin-independent diabetes mellitus and obesity.

EFFECT: new pharmaceutical compounds inhibiting dipeptidyl-peptidase IV.

5 cl, 1 dwg, 4 tbl, 12 ex

 

The present invention relates to new inhibitors dipeptidylpeptidase IV (DPP-IV), effective in treating conditions mediated by DPP-IV.

In recent years it was found that DPP-IV causes inactivation glucoheptonate peptide-1 (GLP-1). Because GLP-1 is a major stimulator of insulin secretion, pancreatic gland and has a direct beneficial effect on the excretion of glucose, the inhibition GLP-1, apparently, is a promising approach to the treatment of conditions such as non-insulin dependent diabetes mellitus (NIDDM).

The known N-(N’-substituted glycyl)-2-cyanopyrrolidine that inhibit DPP-IV and are used for treating conditions mediated by DPP-IV (WO 98/19998).

The present invention relates to novel N-(substituted glycyl)-2-canberratimes formula I

where R denotes a substituted substituted; and

n is 0-3; in free form or in the form of an acid additive salt.

The compounds of formula I may exist in free form or in the form of an acid additive salt. Preferred are pharmaceutically acceptable (i.e. non-toxic physiologically acceptable) salts, but can also be applied to other salts, for example, when selecting or clearing the compounds of the present invention. Although predpochtitel the governmental acid additive salts are hydrochloride, can also be used salts methansulfonate, sulfuric, phosphoric, citric, lactic and acetic acids.

Compounds according to the invention can exist in the form of optically active isomers or diastereoisomers and can be separated and selected using conventional methods such as chromatography.

Listed below are definitions of various terms used in the description of the present invention. These definitions apply to terms used in the present description, individually or as part of a larger group, if in case not specified.

The term "alkyl" denotes a hydrocarbon group with a straight or branched chain having 1-10 carbon atoms, preferably 1-7 carbon atoms, most preferably 1-5 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, etc.

The concept of "alkanoyl" refers to alkyl-S(O)-.

The term "substituted substituted" means substituted, i.e. a 1 - or 2-substituted with one or more, for example, two substituent selected from the series comprising alkyl, -OR1or-NR2R3; where R1, R2and R3independently of one another denote hydrogen, alkyl, C1-C8alkanoyl, carbamyl or-CO-NR4R5; where R4and R5independently on the angle from one another denote alkyl, unsubstituted or substituted aryl, and where one of the radicals R4and R5additionally denotes hydrogen, or R4and R5together denote With2-C7alkylen.

The term "aryl" preferably denotes phenyl. Substituted phenyl preferably represents phenyl substituted by one or more, for example two, substituents selected from, for example, of a number, including alkyl, alkoxy, halogen and trifluoromethyl.

The term "alkoxy" means alkyl-O-.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

The concept of "alkylene" means the bridge represents a straight chain comprising 2 to 7 carbon atoms, preferably 3-6 carbon atoms, most preferably 5 carbon atoms.

A preferred group of compounds according to the invention consists of compounds of formula I where the substituents on Adamantine attached in position in front of the bridge or to the methylene adjacent to the position before the bridge. In the compounds of formula I, where glycyl-2-canberratimes fragment attached in position in front of the bridge, the substituent R’ in Adamantine preferably represents 3-hydroxy. In the compounds of formula I, where glycyl-2-canberratimes fragment attached to the methylene adjacent to the position in front of the bridge, the substituent R’ in Adamantine preferably of t is made by a 5-hydroxy.

The present invention preferably relates to a compound of formula (IA) or (IB)

where R’ represents hydroxy, C1-C7alkoxy, C1-C8-alkanoyloxy or R5R4N-CO-O-, where R4and R5independently of one another denote With1-C7alkyl or phenyl, which is unsubstituted or substituted by Deputy, selected from a range that includes With1-C7alkyl, C1-C7alkoxy, halogen and trifluoromethyl and R4additionally denotes hydrogen; or R4and R5together denote With3-C6alkylene; and R’ represents hydrogen; or R’ and R’ independently of one another denote With1-C7alkyl; in free form or in the form of a pharmaceutically acceptable acid additive salt.

Compounds according to the invention can be obtained, for example, in a way that provides a combination of reactive (2-cianergoline)carbonylmethyl derivative with an appropriately substituted amine; more specifically, to obtain the compounds of formula I of the method involves the interaction of the compounds of formula II

where Y represents a reactive group, preferably halogen, such as bromine, chlorine or iodine), the compound of formula III

where R has the above values, and recovering the resulting compound of formula I in free form or in the form of an acid additive salt.

The method according to the invention can be carried out in the usual way. For example, the compound of formula II is subjected to interaction with 1-3 equivalents, preferably 3 equivalents of a primary amine of the formula III. The reaction is usually carried out in the presence of an inert organic solvent, such as methylene chloride, or a simple cyclic ether, such as tetrahydrofuran. The temperature preferably is in the range from about 0 to about 35°C, preferably from about 0 to about 25°C.

Compounds according to the invention can be isolated from the reaction mixture and purified conventional method, for example by chromatography.

Original products can also be obtained from a conventional method. The compounds of formula II can be obtained according to the following reaction scheme, which includes two stages:

Stage 1 includes the interaction of pyrrolidine formula IV with a small molar excess of gloucestershireguide, such as bromoacetamide or chlorocatechol, and a base such as potassium carbonate or triethylamine. The reaction is usually carried out in prisutstvie and an inert organic solvent, such as tetrahydrofuran or a chlorinated aliphatic hydrocarbon, such as methylene chloride, at temperatures from approximately 0° up to about 25°C, preferably at temperatures from approximately 0° up to about 15°C.

Stage 2 involves dehydration of the compounds of formula V obtained in stage 1, with 1-2 equivalents of anhydride triperoxonane acid (TFW). The dehydration is preferably carried out in the presence of an inert organic solvent, such as tetrahydrofuran or a chlorinated aliphatic hydrocarbon, such as methylene chloride, at a temperature of from about 0 to about 25°C, preferably at a temperature of from about 0 to about 15°C.

In the case where in the present description does not specifically describes the method of obtaining the compound used as the source of the product is known or can be obtained from known compounds in a known manner or analogously to known methods or analogously to the methods described in the example.

For example, a derivative of a primary amine of the formula III are known and can be obtained by the methods described in the literature, for example in Khim.-Farm. Zh., 20(7), 810-815 (1986).

Finally, the compounds according to the invention are given either in free form or in salt form,if present soleobrazutaya group.

Compounds according to the invention, having a basic group can be converted into an acid additive salt, especially in pharmaceutically acceptable acid salt additive. They can be formed, for example, with inorganic acids such as mineral acids, e.g. sulfuric acid, phosphate, or halogen acid, or with organic carboxylic acids. Preferred are the salts of hydrochloric acid.

Given the proximity of the compounds in free form and compounds in the form of their salts, it should be borne in mind that, when in the present description mentions the connection, it also refers to the corresponding salt, if it is possible or practical in certain conditions.

The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for crystallization.

Under the scope of the present invention also includes pharmaceutical compositions, for example compositions suitable for inhibiting DPP-IV, containing a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable acid additive salt.

In another embodiment, the invention relates to a method of inhibiting DPP-IV, etc usmatrivaya administration to a mammal, in need of such treatment, a therapeutically effective amount of the compounds of formula I or a therapeutically acceptable acid additive salt.

In another embodiment, the invention relates to a method of treating conditions, facilitated by inhibition of DPP-IV, involving the administration to a mammal in need of such treatment, a therapeutically effective amount of the compounds of formula I or a therapeutically acceptable acid additive salt.

The present invention also relates to the use of compounds of the present invention or its pharmaceutically acceptable salt, for example, for preparing a medicinal product intended for the prevention or treatment of diseases or conditions associated with elevated levels of DPP-IV.

As noted above, all compounds of formula I and their corresponding pharmaceutically acceptable acid salt additive can be used for inhibition of DPP-IV. The ability of compounds of the formula I and their corresponding pharmaceutically acceptable acid additive salts to inhibit DPP-IV can be demonstrated by analysis using the DPP-IV produced by the cell line of SASO-2, allowing to evaluate the ability of test compounds to inhibit the activity of DPP-IV from extracts of human cells karzi the ohms of the colon. The cell line of SASO-2 human carcinoma of the colon were obtained from the American type culture collection (American Type Culture Collection (ATCC, HTB 37). Differentiation of cells for the induction of expression of DPP-IV is carried out according to the method described in Reisher and others in the article entitled "Increased expression of intestinal cell line SASO-2", in Proc. Natl. Acad. Sci., vol. 90, str-5761 (1993). Cell extracts prepared from cells solubilizing in 10 mm Tris-HCl, 0.15 M NaCl, 0.04 to t.i.u. Aprotinin, 0.5% of nonidet-R40, pH 8.0, and centrifuged at 35000xg for 30 min at 4°With removal of cellular debris. The analysis is performed by adding 20 μg solubilizing protein, SASO-2, diluted in a final volume of 125 μl of buffer for analysis (25 mm Tris-Hcl pH 7.4, 140 mm NaCl, 10 mm KCl, 1% bovine serum albumin), wells tiralongo microplate. After incubation for 60 min at room temperature the reaction was initiated by adding 25 μl of 1 mm substrate (H-alanine-Proline-pNA; pNA denotes para-nitroaniline). The reaction is carried out at room temperature for 10 min, after which to terminate the reaction, add 19 ál of 25%glacial acetic acid. The test compounds are usually added in portions to 30 ml and the volume of buffer for analysis is reduced to 95 µl. The calibration curve for the free para-nitroaniline is obtained using 0-500 mm rest the ditch of free pNA buffer for analysis. The obtained dependence is linear and it is used for interpolation of the absorption of the substrate (catalytic activity in nolah decomposed substrate/min). The final concentration determined by measuring absorbance at 405 nm using a tablet reader for titration tablets type Molecular Devices UV Max.

The activity of test compounds as inhibitors of DPP-IV, expressed as IC50derived based dose-response, constructed by 8 points, using four-parameter logarithmic function.

We obtained the following values IC50listed in table 1.

Table 1
ConnectionSASO-2, DPP-IV (nm)
example 13,5±1,5
example 48

The ability of compounds of the formula I, and their corresponding pharmaceutically acceptable acid additive salts to inhibit DPP-IV can also be demonstrated by measuring the effects of test compounds on the activity of DPP-IV in the plasma of humans and rats using a modified version of the method of analysis described Kubota and others in the article entitled "Involvement of dipeptidylpeptidase IV in an in vivo immune response" in Clin. Exp. Immunol, volume 89, str-197 (1992). In General, the anal which C is as follows: 5 μl of plasma added to wells of 96-well flat-bottomed titration microplate (firm Falcon), then add 5 ál of 80 mm MgCl2in the buffer for incubation (25 mm HEPES, 140 mm NaCl, 1% BSA with purity, suitable for RIA, 7,8). After incubation for 60 min at room temperature the reaction initiated by adding 10 μl of buffer for incubation, containing 0.1 mm of substrate (H-glycine-Proline-AMC; AMC denotes 7-amino-4-methylcoumarin). The tablets covered with aluminum foil (or kept in the dark) and incubated at room temperature for 20 minutes After the reaction for 20 min measure fluorescence using fluorimetry type CytoFluor 2350 (wavelength excitation 380 nm, the wavelength of emission of 460 nm; the position of the sensitivity control 4). The test compounds are usually added in portions of 2 ml and the volume of buffer for analysis is reduced to 13 ál. The dependence of fluorescence on the concentration of free AMC is obtained using 0-50 mm solutions AMS in the buffer for analysis. The obtained dependence is linear and it is used for interpolation of the absorption of the substrate (catalytic activity in nolah decomposed substrate/min). As in the previous analysis, the activity of the test compounds as inhibitors of DPP-IV, expressed as IC50derived based dose-response, constructed by 8 points, using the four-parameter logarithmically.

We obtained the following values IC50in table 2.

Table 2
ConnectionDPP-IV in human plasma (nm)DPP-IV plasma of rats (nm)
example 12,7±0,12,3±0,1
example 8612

Taking into account the ability of the compounds of formula I, and their corresponding pharmaceutically acceptable acid additive salts to inhibit DPP-IV can be applied to treat conditions, facilitated by inhibition of DPP-IV. Based on the above results, as well as on the basis of literature data, we should expect that in this description of the connections can be used to treat conditions such as non-insulin-dependent diabetes mellitus, arthritis, obesity, complications associated with transplantation of allograft and sensitive to the action of calcitonin osteoporosis. In addition, based on the role glucagonomas peptides such as GLP-1 and GLP-2) and their relation to inhibition of DPP-IV, it is expected that presented in the present description, the compounds can be used, for example, to produce a sedative or anxiolytic action, or to reduce the catabolic changes the response after surgery and hormonal reactions to stress, or to reduce mortality and alleviate painful conditions after myocardial infarction, or for the treatment of conditions associated with the above actions, which may be mediated by elevated levels of GLP-1 and/or GLP-2.

More specifically, the compounds of formula I and their corresponding pharmaceutically acceptable acid salt additive, for example, increase immediate insulin response after oral glucose and, therefore, can be used for treatment of non-insulin-dependent diabetes mellitus. The ability of compounds of the formula I and their corresponding pharmaceutically acceptable acid additive salts to enhance immediate insulin response during oral glucose can be measured in experiments on resistant to the action of insulin rats according to the following method.

Male rats Sprague-Dawley, which contain within 2-3 weeks on a diet with a high content of fat (saturated fat = 57% of calories), on the day of testing forced to starve for approximately 2 h, the animals are divided into groups of 8-10 individuals in each and administered orally to 10 mcmole/kg test compound is carboxymethyl cellulose (CMC). After 30 min after administration of test compounds directly into the stomach of the test animals administered by oral bolus containing 1 g/kg glucose. Sample is blood, received at different points in time using a catheter from the jugular vein, is subjected to the analysis with respect to the concentrations of glucose and immunoreactive insulin (IRI) and the activity of DPP-IV in the plasma. The levels of insulin in the plasma is analyzed by the method of radioimmune assay (RIA), based on the use of a double antibody, using specific Anticriminal insulin antibodies obtained from the company Linco Research (St. Louis, Missouri). RIA has a lower detection limit of 0.5 MCED./ml and variation within a single analysis and between individual analyses less than 5%. Data is expressed as the percent increase relative to the average value for control animals. After oral administration each of the tested compounds enhances immediate insulin response, resulting in improved glucose tolerance resistant to the action of insulin test animals. The following results, shown in table 3.

Table 3
ConnectionThe increased insulin response at the dose of 10 mcmole/kg
example 164%

The exact dose of the compounds of formula I and their corresponding pharmaceutically acceptable acid additive salts, which should be used for the treatment is of ostani, facilitated by inhibition of DPP-IV, depends on several factors, including the host (patient), the nature and severity of the condition to be treated, the route of administration, and specific applicable connection. In General, however, the state, facilitated by inhibition of DPP-IV, can be effectively treated, if the compound of formula I or a corresponding pharmaceutically acceptable acid additive salt is introduced enterline, for example oral, or parenteral, e.g. intravenous, preferably orally, in a daily dose of 0.002-5, preferably of 0.02-2.5 mg/kg body weight or, for most larger primates, a daily dose of 0.1 to 250, preferably 1-100 mg Normal dose for oral administration is 0.01-0.75 mg/kg, and it can be administered 1-3 times a day. As a rule, first enter a small dose and then gradually increase the dose until then, until the optimal dose for the patient to be treated. The upper dose limit is a limit, defined side effects, and it can be determined empirically for a patient to be treated.

The compounds of formula I and their corresponding pharmaceutically acceptable acid salt additive can be combined with one or more pharmaceutically acceptable carriers and optionally with one or more other usual the pharmaceutical adjuvants, and they can be entered enterline, for example, orally in the form of tablets, capsules, capleton, etc. or parenterally, for example intravenously, in the form of sterile injectable solutions or suspensions. Compositions for enteral and parenteral injection can be prepared using conventional methods.

The compounds of formula I and their corresponding pharmaceutically acceptable acid salt additive can be introduced into pharmaceutical compositions for enteral and parenteral administration containing a quantity of an active agent effective for treating conditions, facilitated by inhibition of DPP-IV, for example, in compositions which are standard dosage form, and, for example, in compositions which contain a pharmaceutically acceptable carrier.

The compounds of formula I (including compounds described each option formula, and compounds described in the examples) can be entered in the form of pure enantiomers (for example, >98%, preferably >99%) or together with R-enantiomer, for example, in racemic form. The above dose ranges based on the number of compounds of the formula I (except for the amount of R-enantiomer).

The following examples describe representative compounds falling under the scope of the present invention, and the method of their synthesis. However, the Dol is but to be clear, what examples are given only for illustration purpose.

Example 1

(S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-zanperrion

A. 1-Aminoadamantana-3-ol:

Can be used synthesis method described in Khim.-Farm. Zh., 20(7), 810-15 (1986), with minor modifications.

Towards transparent and colorless chilled on ice mixture containing 96%concentrated sulfuric acid (210 ml; 3,943 mmole) and ± 5%nitric acid (21,0 ml; 217,0 mmol), with vigorous stirring, in small portions over 30 min to 21.0 g (112,0 mmol) of the hydrochloride of 1-adamantylamine (99%). When you are finished adding hydrochloride adamantylamine starts weak bubbling and the reaction is slightly exothermic. In the process of separation bubbles the yellow solution is stirred at the temperature of ice water for approximately 2 h and then at room temperature for 30 hours Then this transparent reaction mixture was a light yellow color was poured onto 100 g of ice and the resulting solution becomes transparent and becomes blue-green color.

The solution is placed in a bath of ice water and stirred for 30 minutes then in small portions over 45 min add approximately 550 g of KOH (purity 89%) (a total of 8.74 mol). During this addition the reaction becomes ectothermy eskay; the temperature reaches 80°and releases a significant amount of brown gaseous NO2. After the addition, the reaction mixture thickens with the formation of white solids (representing both product and salt). Then the resulting white paste was poured onto a bed of celite in a Buechner funnel and washed with 1.2 l of CH2CL2. Then CH2CL2layer is extracted from the aqueous layer and dried over PA2SO4. After that, the solution is filtered and concentrated (rotary vacuum pump)to give 1-aminoadamantana-3-ol in the form of a solid white color.

B. 1-Chloroacetyl-2-zanperrion

To a solution containing 20,0 g (180,0 mmol) chloracetamide and 97 g (0,70 mole) of potassium carbonate in 150 ml of tetrahydrofuran, is added dropwise with mechanical stirring for 45 min the solution containing 20,0 g (180,0 mmol) of L-prolinamide in 500 ml of tetrahydrofuran. Then this reaction mixture was mechanically stirred for 2 h at room temperature. After that the reaction mixture is filtered, removing the potassium salts, and the filtrate dried over Na2SO4. Then Na2SO4remove the filter and to this colorless filtrate is added in one portion triperoxonane anhydride (25,0 ml, 0,180 mol). After that, the reaction mixture is stirred using a magnetic mesh is key for 1 h at room temperature and the resulting clear solution yellow-orange concentrate on a rotary evaporator. Excess triperoxonane anhydride is removed by addition of ethyl acetate to the concentrated oil and re-concentration on a rotary evaporator. This purification procedure was repeated three times.

The resulting oil is distributed between ethyl acetate and water. Then the product is extracted with ethyl acetate and then the aqueous layer was washed twice with ethyl acetate. Then the combined organic layers are successively washed with water and with brine, dried over magnesium sulfate, filtered and concentrated, obtaining 1-chloroacetyl-2-zanperrion in a solid yellow color.

C. (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-zanperrion

For the heterogeneous solution specified in the section header And connections (1-aminoadamantana-3-ol) (5,80 g, to 34.7 mmole) in CH2Cl2(68,0 ml) is added 9.6 g (69 mmol) of K2CO3. Then this heterogeneous mixture is cooled in a bath of ice water, and within 30 minutes added dropwise a solution containing 3.0 g (17 mmol) specified in the section title B compound (1-chloroacetyl-2-cianergoline)dissolved in 25,0 ml of CH2CL2. The resulting mixture is stirred for 2 h at 0°and for 6 days at room temperature. Then the reaction mixture was concentrated, getting pasty yellow product, which is purified on silica gel with POM is using a system for rapid chromatography type SIMS/Biotage Flash, using as eluent a 7%solution of methanol in methylene chloride, getting mentioned in the title compound in free base form in the form of a crystalline solid, white (tPL138-140°,13C-NMR (part./million)=119,59).

Examples 2-12

The following compounds get similar to the method described in example 1 (first stage), see table 4.

All final products in the form of hydrochloride get by passing gaseous Hcl through a 0.1 molar solution of the free base in tetrahydrofuran until then, until the solution becomes pronouncedly acid, and then removing the solvent (rotary vacuum pump).

Aminoadamantane source products are known from the literature or can be obtained in the following way:

Obtain 3,5-dimethyl-1-adamantylamine described in J. Med. Chem, 25, 1, 51-56, 1982.

Obtain 3-ethyl-1-adamantylamine described in J. Med. Chem, 25, 1, 51-56, 1982.

3-Methoxy-1-adamantylamine can be obtained as follows.

To a cooled with ice water) suspension of potassium hydride (0,680 g; 5,95 mmole) in 15.0 ml of tetrahydrofuran under stirring is added dropwise within 30 min the mixture of 1-aminoadamantana-3-ol (1,00 g; 5,95 mmol who) and 15.0 ml of tetrahydrofuran. Then the resulting mixture is stirred for another 30 min and then added dropwise over 1 min add logmean (0,370 ml; 5,95 mmole). Then the resulting opaque reaction mixture is white stirred at room temperature for 18 hours then the mixture is diluted with 50 ml methylene chloride and filtered to remove inorganic impurities. Then the filtrate is concentrated and purified on silica gel using devices like SIMS/Biotage, using as eluent a mixture containing 19% methanol and 1% ammonium hydroxide in methylene chloride, resulting in a gain of 3-methoxy-1-adamantylamine in the form of an opaque oil.

Synthesis of 3-[[(tert-butylamino)carbonyl]oxy]-1-aminoadamantana:

To a mixture containing 1-aminoadamantana-3-ol (5,00 g; 30.0 mmol) and potassium carbonate (6.20 g; 45 mmol) in 150 ml of tetrahydrofuran, is added dropwise within 10 min benzylchloride (4,70 g of 33.0 mmole). The mixture is then stirred at room temperature for 2 h and then distributed between ethyl acetate and water. Then the product is extracted with ethyl acetate and the aqueous layer was washed twice with ethyl acetate (100 ml). Then the combined organic layers are successively washed with 100 ml of 2 N. aqueous sodium hydroxide solution, water and saline solution, dried over sodium sulfate, filtered and concentrated (rotary vacuum us is) getting 1-benzylcarbamoyl-3-ol in the form of a solid white color with a yield of 85%.

To a transparent solution containing 1-benzylcarbamoyl-3-ol (1,00 g, 3.32 mmole) and tert-utilizationa (380 μl, 3.32 mmole) in 30 ml of methylene chloride, added with a syringe trimethylsilane (20,0 ál, to 0.17 mmole). Then this reaction mixture is stirred at room temperature for 18 h, concentrated (rotary evaporator) and purified on silica gel using devices like SIMS/Biotage, using as eluent 20%ethyl acetate in hexane, resulting in a gain of 3-[[(tributylamine)carbonyl]oxy]-1-benzylcarbamoyl in a solid white color with a quantitative yield.

To a mixture containing 3-[[(tributylamine) carbonyl] oxy]-1-benzylcarbamoyl (1.50 g, of 3.75 mmole) and 10%palladium on coal (400 mg) in ethanol (150 ml) in a vessel Parra for hydrogenation of 1 liter, add hydrogen at a pressure of 50 psi). Then this opaque mixture of black color shaken for 24 hours then the reaction mixture was filtered through celite to remove the palladium catalyst and concentrated (rotary vacuum pump)to give 3-[[(tert-butylamino)carbonyl]oxy]-1-aminoadamantana in the form of a clear oil with 99%yield.

The synthesis of 4-[[[(methoxyphenyl)amino]carbonyl]oxy]-1-Aminadab is ntana almost corresponds to the synthesis of 3-[[(tert-butylamino)carbonyl]oxy]-1-aminoadamantana except on the second stage tert-utilitzant replace an equivalent amount of 4-methoxyphenylalanine, in the solvent used 1,2-dichloroethane instead of methylene chloride and the reaction mixture is stirred at 50°within 18 hours of the End of the intermediate amine obtained as oil.

The synthesis of 3-[[(phenylamino)carbonyl]oxy]-1-aminoadamantana almost corresponds to the synthesis of 3-[[(tert-butylamino)carbonyl]oxy]-1-aminoadamantana except that in the second stage tert-utilitzant replace an equivalent number of phenylisocyanate, in the solvent used 1,2-dichloroethane instead of methylene chloride and the reaction mixture is stirred at 50°within 18 hours of the End of the intermediate amine obtained as oil.

The synthesis of 2-aminoadamantana-5-ol corresponds to the synthesis process described in example 1, except that as the original product instead of 1-aminoadamantana use 2-aminoadamantana.

The process of synthesis of the nucleophile 3-acetoxy-1-aminoadamantana almost corresponds to the synthesis of 3-[[(tert-butylamino)carbonyl]oxy]-1-aminoadamantana except that the standard acylation of 1-benzylcarbamoyl-3-ol is carried out with the use of 1,2 EQ. acetylchloride, 3.0 EQ. pyridine, 0.1 EQ. 4-dimethylaminopyridine and 1,2-dichloroethane,all components are mixed at room temperature for 24 hours The final amine obtained as a thick oil.

The synthesis of 3-[[[(aminobutiramida)amino]carbonyl]oxy]-1-aminoadamantana almost corresponds to the synthesis of 3-[[(tert-butylamino)carbonyl]oxy]-1-aminoadamantana except that in the second stage tert-utilitzant replace an equivalent number of diisopropylcarbodiimide, in the solvent used 1,2-dichloroethane instead of methylene chloride and the reaction mixture stirred at 85°within 18 hours of the End of the intermediate amine get in a solid gray color.

The synthesis of 3-[[[(cyclohexyl)amino]carbonyl]oxy]-1-aminoadamantana almost corresponds to the synthesis of 3-[[(tert-butylamino)carbonyl]oxy]-1-aminoadamantana except that in the second stage tert-utilitzant replace an equivalent number cyclohexylsulfamate, in the solvent used 1,2-dichloroethane instead of methylene chloride and the reaction mixture is stirred at 50°within 18 hours of the End of the intermediate amine obtained as a thick transparent oil.

The synthesis of 3-ethoxy-1-adamantylamine (clear oil) corresponds to the process of synthesis of 3-methoxy-1-adamantylamine except that instead of iodomethane use Iodate (1.3 EQ.).

Example song:

Tablets, each of which aderito 50 mg of active substance, for example, (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cianergoline, can be prepared as follows:

Composition (for 10,000 tablets):

Active substance 500.0 g

Lactose 500.0 g

Potato starch 352,0 g

Gelatin 8.0 g

Talc 60,0

Magnesium stearate 10.0 g

Silicon dioxide (fine) 20,0 g

Ethanol q.s.

The active substance is mixed with the lactose and 292 g of potato starch and the mixture is moistened with the alcohol solution of gelatin and granularit by sifting through a sieve. After drying, add the remaining potato starch, talc, magnesium stearate and highly dispersed silicon dioxide and the mixture is pressed with reception of tablets, each of which has a mass 145,0 mg and contains 50.0 mg of active ingredient, optionally, the tablets can be coated with notches for breaking with the aim of more accurate control of the dose.

1. N-(Substituted glycyl)-2-cyanopyrrolidine formula I

where R denotes substituted, substituted in position 3 and/or in position 5 one or two substituents selected from the series comprising (C1-C10)alkyl or-OR1where R1denotes hydrogen, (C1-C10)alkyl, (C1-C8alkanoyl) or-CO-NR4R5where R4and R5independently of one another denote the (C 1-C10)alkyl, phenyl, which is unsubstituted or substituted by Deputy, selected from the series comprising (C1-C10)alkyl and (C1-C10)alkoxy, and where one of the radicals R4and R5additionally denotes hydrogen or one of R4and R5additionally denotes hydrogen and the other denotes cyclohexyl; and

n is 0;

in free form or in the form of an acid additive salt.

2. The compound according to claim 1 of formula (IA) or (IB)

where R’ represents hydroxy, C1-C7alkoxy, C1-C8-alkanoyloxy or R5R4N-CO-O-, where R4and R5independently of one another denote With1-C7alkyl or phenyl, which is unsubstituted or substituted by Deputy, selected from a range that includes the C1-C7alkyl and C1-C7alkoxy, and where R4additionally denotes hydrogen or one of R4and R5additionally denotes hydrogen and the other denotes cyclohexyl, and R’ represents hydrogen; or R’ and R’ independently of one another denote With1-C7alkyl;

in free form or in the form of a pharmaceutically acceptable acid additive salt.

3. The compound of formula I according to claim 1, selected from the group including

(S)-1-[[(3,5-dimethyl-1-substituted)amino]-acetyl]-2-zanperrion;

(S)-1-[[(3-ethyl-1-substituted)amino]acetyl]-2-zanperrion;

(S)-1-[[(3-methoxy-1-substituted)amino]acetyl]-2-zanperrion;

(S)-1-[[[3-[[(tert-butylamino)carbonyl]oxy]-1-substituted]amino]acetyl]-2-zanperrion;

(S)-1-[[[3-[[[(4-methoxyphenyl)amino]carbonyl]oxy]-1-substituted]amino]acetyl]-2-zanperrion;

(S)-1-[[[(3-[[(phenylamino)carbonyl]oxy]-1-substituted]amino]acetyl]-2-zanperrion;

(S)-1-[[(5-hydroxy-2-substituted)amino]-acetyl]-2-zanperrion;

(S)-1-[[(3-atomic charges of-1-substituted)amino]acetyl]-2-zanperrion

(S)-1-[[[3-[[[(diisopropyl)amino]carbonyl]oxy]-1-substituted]amino]acetyl]-2-zanperrion;

(S)-1-[[[3-[[[(cyclohexyl)amino]carbonyl]oxy]-1-substituted]amino]acetyl]-2-zanperrion; and

(S)-1-[[(3-ethoxy-1-substituted)amino]acetyl]-2-zanperrion;

or in each case its pharmaceutically acceptable acid additive salt.

4. The compound according to claim 1, which represents the (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-zanperrion or its pharmaceutically acceptable acid additive salt.

5. The pharmaceutical composition intended for treating conditions mediated by DPP-IV, such as non-insulin-dependent diabetes mellitus and obesity, containing a compound according to claim 1 freely in the form or in the form of its pharmaceutically acceptable acid additive salts in combination with at least one pharmaceutically acceptable carrier or diluent.



 

Same patents:

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to a derivative of D-Proline General formula

< / BR>
or

< / BR>
where R is SH, benzyl or phenyl, optionally substituted by a hydroxy-group or a lower alkoxygroup, or a group of the formula

< / BR>
R1is hydrogen or halogen; X represents -(CH2)n-; -CH(R2)(CH2)n-; -CH2O(CH2)n-; CH2NH-; benzyl, -C(R2)=CH-; CH2CH (OH)- or thiazol-2,5-diyl; Y represents-S -; (CH2)n; -O-; -NH-; -N (R2)-; -CH=CH-; -NHC(O)NH-; -N(R2)C(O)N(R2)-; -N[CH2WITH6H3(OCH3)2]-; -N(CH2WITH6H5)-; -N(CH2WITH6H5)C(O)N(CH2WITH6H5)-; -N(alkoxyalkyl)-; -N(cyclooctylmethyl)-; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl or diphenylene; 1,2-phenylene; 1,3-phenylene or 1,4-phenylene, where phenylenebis group optionally substituted by 1-4 substituents selected from the group comprising halogen, lower alkyl, lower alkoxygroup, the hydroxy-group, carboxypropyl, -COO-lower thiazolyl, 2-oxo[1,2,3,5] oxadiazolyl, 5-thioxo[1,2,4]oxadiazolyl and 5-tert-butylsulfonyl[1,2,4] oxadiazolyl; X' represents -(CH2)n-; (CH2)nCH(R2)-; -(CH2)nOCH2-; -NHCH2-; benzyl, -CH= C(R2)-; -CH(OH)CH2or thiazol-2,5-diyl; R2denotes lower alkyl, lower alkoxygroup or benzyl and n = 0-3, their pharmaceutically acceptable salts, mono - and diesters, except (R)-1-[(R)- and (R)-1-[(S)-3-mercapto-2-methylpropionyl] pyrrolidin-2-carboxylic acid; medicinal product with amyloidoses activity, and the method of obtaining these derivatives

The invention relates to nitrate ACE-inhibitor of formula I or II, where Y is phenyl, X is C(RIIIRIV, RIII, RIV, RVand RVI- hydrogen containing stoichiometric amount of nitric acid

The invention relates to a new derived neurotrophic N-glyoxal-propyl ether of the formula 1

< / BR>
where R1means1-C5alkyl linear or branched chain, possibly substituted C3-C6cycloalkyl,3- WITH5- WITH6-cycloalkyl, or AG1where Ar1selected from the group consisting of 2-tanila, 2-furanyl, 2-thiazolyl or phenyl; X is oxygen; Y represents oxygen or NR2where R2is hydrogen; Z means WITH2-C6alkyl or alkenyl with a linear or branched chain, which is substituted by one or more than one position AG2or3-C6cycloalkyl, where AG2selected from the group consisting of phenyl, 2-, 3 - or 4-pyridyl, phenyl, substituted methylenedioxy, and phenyl, having one to three substituents, which independently represent a chlorine or1-C4alkoxy, or pharmaceutically acceptable salts or hydrates

The invention relates to N-(N'-substituted glycyl)-2-cyanopyrrolidine formula I, where R denotes: a)1R1aN (CH2)m-, where R1means pyridinoline or pyrimidinyl fragment, optional one - or disubstituted independently of one another by halogen, trifluoromethyl, cyano - or nitro-group; R1adenotes hydrogen or C1-C8alkyl, m is equal to 2,3, b)3-C12cycloalkyl, optional one-deputizing in position 1 WITH1-C3hydroxyalkyl,) R2(CH2)n- where either R2denotes phenyl, optional one-, two - or tizamidine selected independently of each1-C4alkoxygroup, halogen or phenylthiourea, optional one-deputizing in the phenyl ring with hydroxymethyl; or denotes a C1-C8alkyl, [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8the alkyl, pyridinoline or nattily fragment, or cyclohexenyl, or substituted and n is 1-3, or R2denotes fenoxaprop; and n is 2; d) (R3)2CH(CH2)2-, where each R3independently represents phenyl; d) R4(CH2)p-, where R4ebony in position 1 WITH1-C3hydroxyalkyl, W) R5that means indanyl piperidinyl fragment, optionally substituted benzyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8by alkyl, substituted or1-C8alkyl, optionally one or mnogozalny independently from each other hydroxy-group, hydroxymethyl or phenyl, optional one - or disubstituted independently selected from each other WITH1-C4the alkyl, C1-C4alkoxygroup or halogen, in free form or in the form of an acid additive salt

The invention relates to new derivatives carbapenem formula I, where R1and R2may be the same or different, and each represents a modifiable group that can be hydrolyzed in the body, selected from 1-alkanoyloxy, 1-alkoxycarbonylmethyl, 5-methyl-1,3-dioxolan-2-he-4-ylmethyl; R3and R4may be the same or different and each represents lower alkyl, or R3and R4together with the adjacent nitrogen atom form a cyclic amino; or pharmaceutically acceptable salts

The invention relates to new derivatives of 1-methylcarbamate General formula (I) described in the claims

The invention relates to inhibitors of processes mediated by the action of DP-IV, which are characterized by the General formula:

A-B (Groups I and II) or

< / BR>
where is a

< / BR>
n = 1 or 2; m = 0, 1, or 2; NH or NR, where R = lower alkyl(C-C);

A is attached to Y;

-Y = -N, -CH, or C (when-CO group, A substituted group CH= CF,=),

R=H, CN, CHO, B(OH)2CC-R7or CH=N-R8;

R7=H, F, lower alkyl(C1-C6), CN, NO2OR9, CO2R9or COR9;

R8=Ph, HE, OR9, OCOR9or OBn;

R9= lower alkyl (C1-C6); and either oneor bothmay be missing

FIELD: medicine.

SUBSTANCE: the present innovation deals with insulin preparations applied in therapy of diabetes mellitus. This innovation could be applied in medicinal industry for insulin manufacturing. To obtain insulin one should apply reindeer's pancreas to be homogenized in solution of hydrochloric acid ethanol followed by extraction with subsequent clarification of solution and obtaining the supernatant which then should undergo ion-exchange chromatography and isoelectric deposition by obtaining insulin. The latter should be purified due to high-performance reversed-phase liquid chromatography. Insulin obtained is competitive for the bond with insulin receptor at concentration of above 100 ng/ml due to causing high increase of receptor binding, moreover, it has higher hydrophoby against standard insulins, thus, it has certain differences in the structure of its molecule.

EFFECT: higher efficiency of insulin manufacturing.

2 cl, 2 dwg, 2 ex

FIELD: organic chemistry, medicine.

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

EFFECT: new compound useful in medicine.

5 cl, 10 tbl, 10 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a form with reduced size of particles of the compound (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid described by the formula (I)

or its pharmaceutically acceptable salt or any solvate. Above said compound is useful in treatment of metabolic disorders, such as insulin resistance syndrome determined as reduced sensitivity to insulin effect. Also, invention relates to pharmaceutical compositions containing form with reduced size of particles of this compound or its pharmaceutically acceptable salt or their solvate as an active component, and to methods for preparing form with reduced size of particles of this compound or its pharmaceutically acceptable salt.

EFFECT: improved preparing methods, valuable medicinal properties of compound.

12 cl, 5 ex

FIELD: medicine, cardiology, endocrinology.

SUBSTANCE: invention proposes applying false flax plant oil as a hypoglycemic agent and agent that exerts the normalizing effect on lipid fraction of alpha-lipoproteins (high density lipoproteins; HDLP) and used in treatment of cardiovascular and endocrine diseases, and a method for it applying. This agent is known early as an antioxidant and a hypolipidemic preparation. Detection of new properties allows expanding application of this agent in clinics for treatment of patients with heart ischemic disease, stenocardia, hypertension and diabetes mellitus. The preparation reduces risk for development of atherosclerosis and allows significant reducing doses of basic drugs.

EFFECT: valuable medicinal properties of agent, enhanced effectiveness of treatment.

4 cl, 6 ex

FIELD: organic chemistry, biochemistry, medicine, endocrinology.

SUBSTANCE: invention relates to a trans-olefinic activator of glucokinase representing compound taken among the group consisting of olefinic amide of the formula (I): wherein R1 and R2 mean independently of one another hydrogen, halogen atom, nitro-group, perfluoro-(lower)-alkyl, (lower)-alkylsulfonyl or (lower)-alkylsulfonylmethyl; R means -(CH2)m-R3 or lower alkyl comprising from 2 to 4 carbon atoms; R3 means cycloalkyl comprising from 3 to 8 carbon atoms; R4 means the group: or unsubstituted, or monosubstituted five- or six-membered heteroaromatic ring linked by ring carbon atom with indicated amino-group wherein this five- or six-membered heteroaromatic ring comprises from 1 to 2 heteroatoms taken among the group consisting of sulfur or nitrogen atom wherein one heteroatom being as nitrogen atom is arranged near with binding ring carbon atom, and wherein indicated monosubstituted heteroaromatic ring is substituted at ring carbon atom not adjacent with mentioned binding carbon atom with a substitute taken among the group consisting of halogen atom and group of the formula: m = 0 or 1; n = 0, 1, 2, 3 or 4; R7 means hydrogen atom or lower alkyl; Δ means trans-configuration relatively to a double bond; or its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition, method for prophylactic or therapeutic treatment of diabetes mellitus of type II and to methods for preparing compounds of the formula (I). Invention provides preparing activators of glucokinase that enhance insulin secretion in treatment of diabetes mellitus of type II.

EFFECT: valuable medicinal properties of compounds.

25 cl, 29 ex

FIELD: pharmaceutical agents, in particular glyburide containing composition.

SUBSTANCE: claimed composition contains 5-chloro-N-[2-[4-[[(cyclohexylamino) carbonyl]amino]sulfonyl]ethyl]-2-methoxybenzamide, known under generic name as glyburide, and has the next grain-size classification (%): undersize of 3-11 mum - 25; undersize of 6-23 mum - 50 %, and undersize of 15-46 mum - 75 %. Such grain-size classification affords the ability to increase glyburide dissolution rate and provide reproducible biological availability of glyburide.

EFFECT: pharmaceutical composition useful for treatment of II- type diabetes.

11 cl, 2 tbl, 6 ex

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

The invention relates to new derivatives and analogs 3-arylpropionic acid having the General formula (I), and their stereo and optical isomers and racemates, as well as their pharmaceutically acceptable salts, wherein in the formula And is located in the meta - or para-position and represents a

where: R represents hydrogen;

-ORawhere Rarepresents hydrogen, alkyl, phenyl or alkylphenyl;

-NRaRbwhere Raand Rbare the same or different and represent hydrogen, alkyl, phenyl, alkylphenyl, cyano;

R1represents alkyl, cyano;

-ORewhere Rerepresents alkyl, phenyl or alkylphenyl;

-O-(CH2]m-ORfwhere Rfrepresents alkyl, and m is an integer of 1-2;

-SRdwhere Rdrepresents an alkyl or phenyl;

-SO2ORawhere Rarepresents alkyl, phenyl or alkylphenyl;

-COORdwhere Rdrepresents alkyl;

R2represents hydrogen or alkyl;

R3and R4

D is situated in the ortho-, meta - or para-position and represents a

-OSO2Rdwhere Rdrepresents alkyl, phenyl or alkylphenyl;

-OCONRfRawhere Rfand Rarepresent hydrogen, alkyl, phenyl or alkylphenyl;

-NRcCOORdwhere Rcrepresents hydrogen or alkyl and Rdrepresents alkyl, phenyl or alkylphenyl;

-NRcCORawhere Rcrepresents hydrogen or alkyl, and Rarepresents hydrogen, alkyl, phenyl or alkylphenyl;

-NRcRdwhere Rcand Rdrepresent hydrogen, alkyl, phenyl or alkylphenyl;

-NRcSO2Rdwhere Rcrepresents hydrogen or alkyl, and Rdrepresents alkyl, phenyl or alkylphenyl;

-NRcCONRaRkwhere Rcrepresents hydrogen, Raand Rkare the same or different and each represents hydrogen, alkyl, phenyl or alkylphenyl;

-NRcCSNRaRkwhere Rcrepresents hydrogen, Raand Rkare the same or different and each represents hydrogen, phenyl иLASS="ptx">-SRcwhere Rcrepresents alkyl, phenyl or alkylphenyl;

-SO2ORawhere Rarepresents alkyl, phenyl or alkylphenyl;

-CN;

-CONRcRawhere Rcrepresents hydrogen or alkyl, and Rarepresents hydrogen or alkyl;

D’ is located in the meta-position and represents-ORfwhere Rfrepresents alkyl; or is located in the ortho-, meta - or para-position and represents hydrogen;

D’ is located in the ortho - or para-position and represents-NO2, -ORfwhere Rfrepresents alkyl; or is located in the ortho-, meta - or para-position and represents hydrogen;

where specified, the alkyl means a straight or branched alkyl group having from 1 to 6 carbon atoms, or cyclic alkyl having from 3 to 6 carbon atoms, with the specified alkyl may be substituted by one or more than one group of alkyl, alkoxy, halogen or phenyl; where the specified phenyl may be substituted by one or more than one group of alkyl, alkoxy, nitro, thiol, or halogen; the invention also relates to a method of their production, pharmaceutical preparations containing them, the Sabbath.

The invention relates to organic chemistry, in particular to the compounds representing amide of the formula I:

in which * denotes an asymmetric carbon atom; R1and R2independently from each other represent a hydrogen atom or halogen, amino, hydroxyamino-, nitro-, cyano-, sulfamidihappo, (ness.)alkyl, -OR5, -C(O)OR5, PERFLUORO(ness.)alkyl, (ness.)alkylthio, PERFLUORO(ness.)alkylthio, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkylsulfonyl or (ness.)alkylsulfonyl; R3denotes cycloalkyl containing from 3 to 7 carbon atoms, or (ness.)alkyl containing from 2 to 4 carbon atoms; R4means (O)other40or unsubstituted or monosubstituted five - or six-membered heteroaromatic ring bound ring carbon atom of the amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur atoms, oxygen, and nitrogen, with one heteroatom is a nitrogen atom, which is adjacent to the connecting ring carbon atom; this is monosubstituted heteroaromatic ring monogamist on the ring angle is found (ness.)alkyl, halo-, nitro-, cyano, -(CH2)n-OR6, -(CH2)n-C(O)OR7, -(CH2)n-C(O)OTHER6, -C(O)-C(O)OR8and -(CH2)n-OTHER6or its pharmaceutically acceptable salts

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to nootropic, cerebroprotective medicinal agents as tablets. Tablet of a medicinal agent comprises thiotriazoline and piracetam as active components and accessory components used for formation of core and applying an envelope on it. Invention provides elevating rate and power of a medicinal agent effect on the brain blood supply, expanding spectrum of its pharmacological effect and excludes negative adverse effects.

EFFECT: improved and valuable medicinal properties of agent.

6 tbl

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