Substituted 2-[2(3-oxomorpholin-4-yl)ethylthio]benzimidazoles, with anxiolytic activity

FIELD: chemistry.

SUBSTANCE: invention relates to substituted 2-[2-(3-oxomorpholin-4-yl)ethylthio]benzimidazoles of general formula: , where R1, R2, R3, R4, R5 are identical or different: H, lower alkyls or alkoxy groups.

EFFECT: obtaining new compounds with anxiolytic properties, which allows for their potential use in medicine for treating neuropsychic disorders.

2 cl, 4 tbl, 9 ex

 

The invention relates to the chemistry of biologically active compounds, namely hydrochloridum substituted 2-[2-(3-exmortis-4-yl)ethylthio]benzimidazole of General formula

where R1, R2, R3, R4, R5same or different: H, lower alkali or alkoxygroup.

The claimed compounds possess anxiolytic effect and may find application in medicine for the treatment of neuropsychiatric disorders.

In the literature, starting with 1958, describes a number of derivatives of 2-mercaptobenzimidazole containing substituents on atoms like sulfur and nitrogen, and a benzene ring, which possess a variety of biological activities: bacteriostatic, insecticidal, anthelmintic, anti-ulcer, anti-inflammatory and analgesic etc. (W. Knobloch et al., Arch.Pharmaz., 1958, 291, 113-118; S. Nakajima et al., Jap.pat. 10978, 1961; Hideg, K. et al., Brit.Pat. 1234058, 1971; Johnson C.A. et al., Med.Chem.Rec., 1992, 2(4), 247-255; Hasegawa N. et al., Jap.Pat. 7441198, 1974).

Domestic drug "Bemythyl" (2-ethylthiophenethylamine hydrobromide), described Bobkova YG (Awts of the USSR №1251374, 1986) and Neznamov, and others (Physiologically active substance, 1993, 25, 40-49) as antihypoxic drug and psychostimulant that has found application in medical practice as a means for the treatment of asthenic and astheno-depressive disorders.

In 1996, he was granted a patent of the Russian Federation No. 2061686 (priority 10.06.1994; publ. in bull. Fig. No. 16, 1996), which describes a large number of S-derivatives of 2-mercaptobenzimidazole with the end of the alkyl chain dialkylamino or nitrogen-containing heterocycle. These compounds showed selective anxiolytic properties. One of them, namely 2-(2-morpholinoethyl)-5-ethoxybenzothiazole the dihydrochloride called AFOBAZOLE, following extensive clinical trials were registered Pharmacological Committee, Ministry of health and the CF of the Russian Federation as a selective anxiolytic drug with an activating component. The effect of AFOBAZOLE is not accompanied gipnosedativnogo effects inherent in the benzodiazepines, it has no miorelaksantnoe properties, negative impact on the performance of memory and attention. Thanks to all these important qualities, providing a high therapeutic activity, this drug has been successfully used in medical practice in the treatment of anxiety and anxiety-asthenic disorders (Neznamov, and others, Exp.Clin.Pharm. 2001, Vol.64. No. 2. P 15-19). In the process of studying the pharmacokinetics and metabolism of AFOBAZOLE methods high-performance liquid chromatography and mass spectrometry have identified a number of metabolites of this drug, one of which was 2-[2-(3-exmortis-4-yl)ethylthio]-5-atosiban the imidazole. This fact initiated the decision to synthesize previously not known this connection, as well as a number of related compounds represented by the General formula I.

The claimed compound I was synthesized directly as hydrochloride by alkylation of 2-mercaptobenzimidazole corresponding 4-(2-chloroethyl)morpholine-3-areas (II) in absolute alcohol; a series of N-alkyl derivatives of I obtained by alkylation halide alkilani in dimethylformamide in the presence of sodium hydride corresponding unsubstituted products I.

Used as intermediate products derived morpholine-3-one (II) were obtained by alkylation of monosodium salts diethanolamine or substituted in dioxane corresponding ethyl esters of α-bromo(chloro)carboxylic acid, followed by cyclization of 4-(2-oxyethyl)morpholine-3-ones, further replacement of the hydroxyl group by chlorine reaction with chloride tiomila in chloroform.

The claimed compound I was synthesized according to the following scheme:

Experimental chemical part

Monitoring the progress of reactions and the purity of the obtained products was carried out using thin-layer chromatography on Silufol or ulufale.

The PMR spectra taken on the instrument Bruker AC 250", internal standard TMS.

Example 1. 4-(Chloroethyl)morpholine-3-one (IIA) (R 4=H).

Dissolve to 1.15 g (0.005 m) of metallic sodium in a 5.25 g (4,77 ml, 0.005 m) of fresh diethanolamine in 20 ml of absolute dioxane by heating, then cooling the reaction mixture to room temperature and slowly added 6,12 g (5.2 ml (0.005 m) ethyl ester of Chloroacetic acid, gradually bring the reaction mixture to a boil and boil for 1 hour. After cooling, is filtered emitted NaCl, washed many times with dioxane, dioxane is distilled off, the remaining oil - 4-(2-oxyethyl)morpholine-3-it is used without purification in the next stage.

To a solution of the oil (7 g) in 15 ml of chloroform is added gradually a solution of 24 g (15 ml; 0.2 m) chloride tiomila in 20 ml of chloroform at a temperature below 30°C, stirred for 1 hour, poured into ice water, washed with cold sodium bicarbonate solution, water, dried over Na2SO4the solvent is distilled off, the residue is distilled in vacuum, get 5,23 g (64%, counting on diethanolamin) IIA, BP. 144-6°C./10 mm. Found, %: Cl 21,50; N 8,32. C6H10ClNO2. Calculated, %: Cl 21,67; N 8,56. PMR-spectrum (CDCl3), δ, ppm:of 3.54 (2H, t, NCH2morpholine), 3,69, and to 3.73 (4H, two m, CH2CH2Cl)to 3.89 (2H, t, och2CH2morpholine), 4,17 (2H, s, och2WITH morpholine).

Example 2. 2-Methyl-4-(2-chloroethyl)morpholine-3-one (IIB) (R4=Me).

Synthesized similarly to the previous of the 5.25 g (0.005 m) diethanolamine and 1.5 g (0.005 m) of metallic sodium, 9,05 g (0.005 m) ethyl ester of α-bromopropionic acid, followed by treatment of 24 g of chloride tiomila. Output IIB - 4.8 g (54%, counting on diethanolamin, BP. 142-4°C./10 mm. Found, %: N 7,70; Cl 19,80. C7H12ClNO2. Calculated, %: N 7.89; Cl 19,96. PMR-spectrum (CDCl3), δ, ppm: 1.42 (3H, d, CH3); 3.34 and 3.96 (1H, DDD and 1H, DDD CH2N morpholino), 3.6-3.83 (6N, m, CH2About morpholone, ClCH2CH2). 4.18 (3H, kV, SNSN3morpholine).

Example 3. 2-[2-(3-Exmortis-4-yl)ethylthio]-5-ethoxybenzothiazole hydrochloride (Ia) (R1=OEt, R2=R3=R4=R5=H).

A mixture of 0.49 g (0,0025 m) 2-mercapto-5-ethoxybenzothiazole and 0.49 g (0,003 m) 4-(2-chloroethyl)morpholine-3-one (IIA) in 10 ml of absolute ethanol is boiled for 1 hour, the solvent is distilled off, the residue is recrystallized from methanol-ether, obtain 0.71 g (80%) of compound Ia, TPL 178-82°C (with decomp.). Found, %: C 50,37; N 5,65; Cl 10,00; N 12,02; S 9.22. C15H20ClN3O3S. Calculated, %: 50,34; N 5,63; Cl To 9.91; N 11,74; S 8,96. PMR-spectrum (D2O), δ, ppm: 1.64 (3H, t, och2CH3), 3.72 (2H, t, CH2N morpholino), 3.82 (2H, t, CH2S), 3,98 (2H, t, CH2N), 4.05 (2H, t, och2CH2morpholine), 4.25 (2H, s, och2WITH morpholine), 4,35 (2H, q, CH2CH3), 7,30 (1H, d, 6-H), 7,35 (1H, USS, 4-H), 7,74 (1H, d, 7-H).

Treated with an aqueous solution of Ia with sodium bicarbonate, extracted with ethyl acetate, dried with sodium sulfate, evaporated dissolve Italy, get the base I in the form of oil. PMR-spectrum (CDCl3), δ, ppm: 1,4 (3H, t, CH3CH2O)3,30 (2H, t, CH2S)to 3.49 (2H, t, CH2N morpholino), 3,70 (2H, t, CH2CH2About morpholone), Android 4.04 (2H, q, och2CH3), is 4.21 (2H, s, och2WITH morpholine), at 6.84 (1H, Shostakovich, 6-H, J6,7=2,5 Hz, J4,6=8,5 Hz), 7,01 (1H, d, 4-H, J4,6=2,5 Hz), the 7.43 (1H, d, 7-H, J6,7=8,5 Hz).

Example 4. 2-(2-(3-Exmortis-4-yl)ethylthio]-5,6-dimethylbenzimidazole hydrochloride (IB) (R1=R2=Me, R3=R4=R5=H)

Synthesized similarly to the previous of 0.45 g (0,0025 m) 2-mercapto-5,6-dimethylbenzimidazole and 0.49 g (0,003 m) compounds IIA, in 10 ml of absolute alcohol. Output connection IB - 0.73 g (86%), TPL 236-8°C. Found, %: C 52,72; N 6,12; Cl 10,06; N 12,49; S 9.28 are. C15H20ClN3O2S. Calculated, %: C 52,70; N 5,90; Cl 10,37; N 12,29; S 9,38. PMR-spectrum (D2O), δ, ppm: 2,5 (6N, s, 2CH3); 3,68 (2H, t, CH2N morpholino), 3,76 (2H, t, CH2S)of 3.95 (2H, t, CH2N), Android 4.04 (2H, t, och2CH2morpholine), 4,22 (2H, s, och2WITH morpholine), 7,49 (2H, s, ArH).

Example 5. 2-[2-(2-Methyl-3-exmortis-4-yl)ethylthio]-5-ethoxybenzothiazole hydrochloride (IB) (R1=OEt, R2=R3=R5=H, R4=Me).

Synthesized similarly to the previous out of 0.58 g (0,003 m) 2-mercapto-5-ethoxybenzothiazole and 0.71 g (0.004 m) of chloride IIB in 15 ml of absolute alcohol. Output IB - 0.95 g (85%), TPL 86-8°C (sec.). Found, %: Cl 9,54; N 11,34; S 8,68. C 16H22ClN3O3S. Calculated, %: Cl At 9.53; N 11,30; S 8,62. PMR-spectrum (D2O), δ, ppm: 1,5 (3H, d, SNSN3morpholine), to 1.61 (3H, t, OCH2CH3), of 3.60 and 4,20 (1H, DDD and 1H, DDD CH2N morpholino), of 3.80-4.08 (6N, m, CH2CH2O morpholine, SCH2CH2N), a 4.3 (2H, q, OCH2CH3), 4,39 (1H, kV, SNSN3morpholine), 7,25 (1H, Shostakovich 6-H), 7,26 (1H, d, 4-H), A 7.62 (1H, d, 7-H).

Example 6. 2-[2-(2-Methyl-3-exmortis-4-yl)ethylthio]-5,6-dimethylbenzimidazole hydrochloride (Iك) (R1=R2=R4=Me, R3=R5=H).

Synthesized similarly by the above method of 0.45 g (0,0025 m) 2-mercapto-5,6-dimethylbenzimidazole and of 0.53 g (0,003 m) compounds IIB in 10 ml of absolute alcohol. Output connections Iك - 0,78 g (87%), TPL 194-6°C (with decomp.). Found, %: C 53,83; N 6.35mm; Cl 10,02; N Of $ 11.97. C16H22ClN3O2S. Calculated, %: C 54,00; N 6,23; Cl 9,96; N 11,81. PMR-spectrum (D2O), δ, ppm: of 1.46 (3H, d, SNSN3morpholine), 2,5 (6N, s, 2CH3), 3,59, and 4,18 (1H, DDD and 1H, DDD CH2N morpholino), 3,75-4.00 points (6N, m, CH2CH2About morpholone, SCH2CH2N)4,30 (1H, kV, SNSN3morpholine), and 7.5 (2H, s, ArH).

Example 7. 2-[2-(3-Exmortis-4-yl)ethylthio]benzimidazole hydrochloride (Ia) (R1=R2=R3=R4=R5=H)

Synthesized similarly to the previous of 0.45 g (0,003 m) 2-mercaptobenzimidazole and 0.65 g (0,004 m) compounds IIA in 15 ml of absolute alcohol. The output of the compounds Ia - 0.6 g (80%), TPL 182-4°C (with decomp.). Naydenov, %: 49,52; N 4,96; N 13,2; Cl 11,05. Calculated, %: C 49,76; N 5,14; N 13,39; Cl 11,30. PMR-spectrum (D2O), δ, ppm: 3,74 (2H, t, CH2N morpholino), 3.82 (2H, t, CH2S), 4.00 (2H, t, CH2N). 4.08 (2H, t, och2CH2morpholine), 4.22 (2H, s, och2WITH morpholine); 7.72-7.76 (3H, m, 4N-6N), 7.8 (1H, Shostakovich, 7-H).

Example 8. 1,5,6-Trimethyl-2-(2-(3-exmortis-4-yl)ethylthio]benzimidazole hydrochloride (Ie) (R1=R2=R3=Me, R4=R5=H).

To 7 ml of absolute dimethylformamide was added 0.12 g (0.03 m) of 60% sodium hydride in 30 minutes under stirring was added a solution of compound IB in 5 ml of abs DMF. The mixture is stirred for 1 hour, add 1 ml (0,23 g, 0.016 m) of methyl iodide, stirred for 0.5 hours. The reaction mixture was poured into water, extracted with chloroform, the extract is dried with magnesium sulfate, the solvent is distilled off, the residue is dissolved in absolute ether, filtered and treated with an ethereal solution of hydrogen chloride. The precipitation is filtered off, recrystallized from methanol-ether, obtain 0.3 g (83%) of compound Ie, TPL 132-4°C (with decomp.). Found, %: Cl There Is A 10.03; N 12,00; S A 9.25. C16H22C1N3O2S. Calculated, %: Cl 9,96; N 11,81; S 9,01. PMR-spectrum (D2O), δ, ppm: 2,59 and 2,61 (3H, s, 3H, s, 2CH3), 3,70 (2H, t, CH2N morpholino), 3,82 (2H, t, CH2S)of 3.97 (2H, t, CH2N), of 4.00 (3H, s, NCH3), 4,10 (2H, t, och2CH2morpholine), 4,25 (2H, d, OCH2 CO morpholine), 7,65 (6N, s, ArH)

Example 9. 1,5,6-Trimethyl-2-[2-(2-methyl-3-exmortis-4-yl)ethyl-thio]benzimidazole hydrochloride (If) (R1=R2=R3=R4=Me, R5=H).

Synthesized similarly to the previous of 0.36 g (0.001 m) connection Iك, 0.12 g (0.03 m) of 60% sodium hydride and 0.1 ml (0,016 m) of methyl iodide in absolute dimethylformamide. Output connections If - 0.32 g (86%), TPL 124-6°C (with decomp.). Found, %: Cl 9,25; N Of 11.15; S 8.63. C17H24ClN3O2S. Calculated, %: Cl 9.58; N 11,36; S 8,67. PMR-spectrum (D2O), δ, ppm: is 1.51 (3H, d, SNSN3morpholine), 2,54, and to 2.55 (3H, and 3H, s, 2CH3), 2,60 and 4,20 (1H, DDD and 1H, DDD CH2N morpholino), 3.75 to 4,05 (6N, m, CH2CH2O morpholine, SCH2CH2N), of 4.00 (3H, s, NCH3), 4,30 (1H, kV, SNSN3morpholine), a 7.62 (2H, s, ArH).

The results of the pharmacological study of the compounds

1. The effect of compounds I-series behavior of small laboratory animals in open-field test (Archer J. Tests for emotionality in rats and mice: a review. // Anim. Behav. - 1973. - 21. - 205-235).

There were used small laboratory animals-males weighing 20-22 g and 180-200 g, which were kept in the laboratory animal facility for 6 animals in a cage on a standard diet with free access to water for at least 10 days before the start of the experiment at regular 12-hour light regime. All experiments were performed between 9:00-13:00.

After 30 min after intraperitoneal (WB) administration of the compounds at a dose of 1.0 mg/kg animal is first placed for 1 min in a dark chamber, and then on one of the peripheral squares OP, which is a white circular arena with a diameter of 200 cm with white boards. Arena evenly lit 4 bulbs of 100 watts each, spaced at a height of 100 cm above the surface of the field, separated by 3 concentric circles, which in turn defeated by the radii of the sector so that the floor consists of 16 identical peripheral and 8 of the Central segments. The observation was carried out for 5 minutes Recorded the following parameters:

- the number of intersections of the peripheral segments of IT (ICP);

- the number of crossings of the Central segments and visits to the center (CDA);

- the number of stevani on his hind legs (VA);

- emotionality was determined by the number of defecations in the testing process (EM);

- General locomotor activity (ODA) was estimated as the sum of PDA, CDA and VA.

Statistical processing of data was performed using non-parametric analysis for the independent variables (U-Mann-Whitney test).

It is established that one of the studied compounds activating (anxiolytic) effects possessed by the compounds Ia and IB, after the introduction which animals increased total physical activity (ODA) through the intersection of the peripheral and Central segments, the last statistically significant (table 1).

2. The effect of the compounds of series I n the behavior of small laboratory animals to test elevated plus maze (Pellow, S., Chopin P., S. Pile, Briley M. Validation of open: closed arm entries in elevated plas-maze as a nuasure of anxiety in the rat // Neurosci. Meth J., No. 14, p.149-167 (1985)).

There were used small laboratory animals-males weighing 20-22 g and 180-200 g, which were kept in the laboratory animal facility for 6 animals in a cage on a standard diet with free access to water for at least 10 days before the start of the experiment at regular 12-hour light regime. All experiments were performed between 9:00 to 13:00.

For evaluation of the anxiolytic effects of substances was used elevated plus maze (PCL) and the methodology for the assessment of animal behavior according to Pellow et al. (1985). The labyrinth represents the crossed strips of size 50×10 cm Two opposite compartments have vertical walls with a height of 40 see the Maze is elevated from the floor by 50 see the place of intersection of the planes is the Central platform 10×10 cm in 30 min after intraperitoneal (/b) introduction of compounds Ia-Iك, Ie, If the dose of 1.0 mg/kg animal was placed on the Central area of the tail to the open sleeve. Recorded the time spent by the animal in the open, closed sleeves and on the Central platform, and the number of entries in open and closed sleeves. The total observation time for each animal was 5 minutes. As a criterion anxiolytic actions used measure of the time proveden the th in open sleeve installation. The number of intersections of a Central platform (total number of visits in dark and light sleeves maze) was used to assess the effect of compounds on locomotor activity in laboratory animals.

It is established that the compounds Ia, IB, Iك, Ie and If caused a statistically significant increase in the experimental animals stay in the open arms of the maze by reducing the stay in closed sleeves that clearly indicates the presence of anxiolytic activity (table 2).

3. The effect of compound Ia on the behavior of mice of Balb/c under conditions of emotional stress in open-field test (Sberezheny, Air / Influence of psychotropic drugs on the behavior of inbred mice in the open field / bull. Expir. The honey. - 1979. - C, No. 7, ñ.38-40).

To study anxiolytic action and dose-response relationships of compounds Ia method was used to measure locomotor activity in open field test. About the presence of anxiolytic action was tried to identify the activating effect on locomotor activity in animals with a "passive" type ESR (line Balb/c).

At work, we have used mice male Balb/c weighing 20-22 g (kennel "Pillar"). Animals were kept in the laboratory animal facility in cells of 10 animals each, for at least two weeks prior to the Ala of the experiment, on a standard diet with free access to water during the normal 12-hour light regime. All experiments were performed in the period from 9.00 to 13.00.

30 minutes after intraperitoneal administration of the compounds 1A, the animal was kept in the dark for 1 minute and then placed in one of the peripheral squares "open field", which is a white circular arena with a diameter of 1 meter with white sides of a height of 50 cm arena evenly lit 4 bulbs of 75 watts each, spaced at a height of 1 m above the ground surface. The arena is evenly divided by 4 concentric circles, which in turn defeated by the radii of the sector so that the peripheral circumference consists of 16 identical curvilinear squares. Observation of the animal made within 3 minutes, separately recorded the number of crossed squares in the periphery and in the Central regions, and the number of racks. The total number of crossed squares together with the number of racks meant as a General activity.

Statistical processing of the obtained results was performed using one-factor analysis of variance and nonparametric statistics for the independent variables (U-Mann-Whitney test).

In conditions of emotional stress in open-field test intraperitoneal injection is soedineniya Ia in doses of 0.1; of 0.5; 1.0; 5.0 and 10.0 mg/kg find the significant dose-dependent increase in peripheral, Central and total motor activity of mice of Balb/c compared to the control in the dose range of 0.1-5.0 mg/kg Maximum increase in total YES identified using the drug in doses of 0.5 and 1.0 mg/kg (table 3).

Thus, compound Ia in a wide range of doses of intraperitoneal way of introduction has a pronounced anxiolytic effect in mice Balb/C. This activation was due to increased peripheral and Central motor activity, which is typical for compounds with anxiolytic action.

The dose range of the compounds Ia in which he exhibits pharmacological activity, coincides with analogous pharmacological effect of Afobazole intraperitoneal injection of the used strains of mice.

4. The effect of compound Ia on the behavior of mice of Balb/c in the test, the elevated plus maze"

(Pellow S.E., Johnston A.L., File S.E. - J. Pharm.Pharmacol. - 1987, - v.37 - pp.917-928).

Method the elevated cross maze (PC), proposed by the famous psychopharmacologia S. File, generally accepted at the present time to evaluate the anxiolytic actions (File S.E. - J. Pharm. PharmacoL, 1984, 36, pp.837-840). The essence of the method consists in the analysis of the ratio of the fear responses of animals in an unfamiliar space is e and the height with one hand and exploratory activity in a new environment on the other.

Installing the PCL were the two intersecting at right angles (cross) horizontal paths (corridors) 22×5 cm, raised to a height of 60 cm, one of which was secured at the opposite ends of the vertical opaque walls with a height of 15 cm (dark or "protected" sleeve). The Central area of 5×5 cm (center PC), on which the animal was placed in the beginning of the experiment, gave the opportunity for the animal to move in the dark, or bright sleeves maze - depending on the prevalence of anxiety (fear of heights, open space) or research activity (that's what led the animal out of the "protected" arms). Lighting standard. The observation time was 5 minutes after pre-incubation of the animal in a darkened space of 1 minute.

Quantitatively assessed the following parameters: the time spent in open and closed arms of the maze (in seconds), the time on the Central platform of the maze, the number of transitions in open and closed sleeves.

Statistical processing of the obtained results was performed using one-factor analysis of variance and nonparametric statistics for the independent variables (U-Mann-Whitney test).

In accordance with the specifications for laboratory mice behaviour fear reaction is determined by what trillenium animals to be in the closed arms of the maze, the decrease in motor activity. Search activity determines the stay of animals in open sleeves, increased motor activity.

At work, we have used mice male Balb/c with genetically determined expressed a fear reaction mass 20-22,

Compound Ia, introduced intraperitoneally 30 minutes prior to the experiment in doses of 0.1; 0.5 and 1.0 mg/kg, activated behavior of mice Balb/c mice (table 4), increasing significantly the time spent in open arms, reducing the time spent in closed arms compared with the control. Thus, in the test PC it is shown that compound Ia exerts a significant anxiolytic effect in the dose range of 0.1-1.0 mg/kg

13,3±2,8
Table 1
The effect of compounds I-series behavior of small laboratory animals in open-field test
GroupnODEPDACDAVAEm
Control636,0±4,922,5±3,90,2±0,20,7±0,5
Ia8of 116.8±14.6 Toto 106.0±11,49,8±4,00,8±0,60,4±0,2
IB632,0±2,719,3±2,41,5±0,911,2±3,12,5±0,9
IB655,3±8,533,8±3,54,7±2,216,8±5,22,7±0,8
636,8±13,223,5±8,22,3±1,211,0±4,01,3±0,6
S640,8±7,331,3±4,91,7±1,77,8±1,72,2±0,5
If643,2±9,629,5±5,82,7±1, 11,0±3,91,8±0,4
Note that n is the number of observations; data are presented as M±m, where M is the arithmetic mean; m - error of the arithmetic mean; - statistically significant differences compared to the group Control (p<0,01), according to U-test Mann-Whitney.

Table 2
The effect of compounds I-series behavior of small laboratory animals to test the elevated plus maze"
GroupnTime, t (sec)The number of transitions
In the centerIn open sleevesIn closed sleevesIn the centerIn open sleevesIn closed sleeves
Control3220,9±3,019,1±4,2260,0±6,42,1±0,41,4±0,3Ia1046,6±9,4for 77.2±29,2176,2±28,43,7±0,73,2±0,71,5±0,3
IB1633,0±5,746,4±18,6220,8±17,5 To2,9±0,61,7±0,53,4±0,7
IB1619,6±4,811,9±4,2268,5±6,41,6±0,40,7±0,22,6±0,5
1626,3±4,073,6±20,3200,1±20,03.3V±0,63,1±0,94,4±0,7
S1630,6±6,864,6±23,8204,8±23,13,1±0,91,9±0,53.3V±0,9
If1638,3±4,427,8±8,4233,9±11,53,7±0,71,6±0,44,3±0,7
Note that n is the number of observations; data are presented as M±m, where M is the arithmetic mean; m - error of the arithmetic mean; - statistically significant differences compared to the group Control (p<0,05), according to U-test Mann-Whitney.

Table 3
The effect of the compound la on the behavior of mice Balb/c mice in the open-field test
DosenODEPDACDACenterVertDef
Control924,0±5,922,7±6,11,3±0,60,0±0,00,0±0,01,0±0,4
0.1 mg/kg 1044,8±5,642,4±5,2 To2,1±1,00,0±0,00,3±0,20,8±0,4
0.5 mg/kg1352,0±4.2 K51,4±4,10,5±0,30,0±0,00,1±0,10,3±0,2
1.0 mg/kg8of 116.8±14.6 Toto 106.0±11,49,8±4,00,3±0,30,8±0,60,4±0,2
5.0 mg/kg827,6±5,126,9±4,80,8±0,80,0±0,00,0±0,00,9±0,3
10.0 mg/kg846,9±10,544,3±9,52,1±1,40,1±0,10,4±0,41,6±0,5
Note, n - colorability; data are presented as M±m, where M is the arithmetic mean; m - error of the arithmetic mean; - statistically significant differences compared to the group Control (p<0,01), according to U-test Mann-Whitney.

Table 4
The effect of compound Ia on the behavior of mice of Balb/c test elevated plus maze
MedicationnTime, t (sec)The number of transitionsThe number of bowel movements
In the centerIn open sleevesIn closed sleevesIn open sleevesIn closed sleeves
Control1527,4±1,911,7±2,5258,3±3,39,1±0,68,0±0,60,6±0,2
0.1 mg/kg1038,1±5,5 49,7±9,1212,2±6,29,4±0,97,8±0,40,7±0,3
0.5 mg/kg1036,4±5,765,1±8,4199,5±5,97,0±0,57,2±0,60,3±0,2
1.0 mg/kg1042,8±4,749,2±5,7208,0±5.0 To9,2±0,77,9±0,51,1±0,3
Note that n is the number of observations; data are presented as M±m, where M is the arithmetic mean; m - error of the arithmetic mean; - statistically significant differences compared to the group Control (p<0,01), according to U-test Mann-Whitney.

1. Substituted 2-[2-(3-exmortis-4-yl)ethylthio]benzimidazole of General formula

where R1, R2, R3, R4, R5same or different: H, lower alkali or alkoxygroup possessing anxiolytic effect.

2. The compound according to claim 1, where R1=OEt, R2=R3=R4=R5=H.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of the formula and other compounds listed in cl. 1 of invention claim, and pharmaceutical composition based on them, as well as method of mGluR5 receptor activity inhibition involving claimed compounds.

EFFECT: application in treatment and prevention of diseases mediated by mGluR5 receptor activity.

4 cl, 18 dwg, 1009 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula I, in which R1 represents hydrogen or a group, which forms a biologically labile ester, R2 represents hydrogen, C1-C4-alkyl or C1-C4-hydroxyalkyl, and R3 represents C1-C4-alkyl; C1-C4-alkoxy-C1-C4-alkyl; C1-C4-hydroxyalkyl, which is optionally substituted with a second hydroxy group and all hydroxy groups of which are optionally esterified with C2-C4-alkanoyl or amino-acid residue; (C0-C4-alkyl)2amino-C1-C6-alkyl; C3-C7-cycloalkyl; C3-C7-cycloalkyl-C1-C4-alkyl; phenyl-C1-C4-alkyl, the phenyl group of which is optionally substituted 1-2 times with C1-C4-alkyl, C1-C4-alkoxy group and/or halogen; naphthyl-C1-C4-alkyl; C3-C6-oxoalkyl; phenylcarbonylmethyl, the phenyl group of which is optionally substituted 1-2 times with C1-C4-alkyl, C1-C4-alkoxy group and/or halogen, or 2-oxoazepanyl, or R2 and R3 together represent C4-C7-alkylene, methylene groups of which are optionally substituted 1-2 times with carbonyl, nitrogen, oxygen and/or sulphur and/or optionally substituted once with a hydroxy group, which is optionally esterified with C2-C4-alkanoyl or amino-acid residue; C1-C4-alkyl; C1-C4-hydroxyalkyl, the hydroxy group of which is optionally esterified with C2-C4-alkanoyl or amino-acid residue; phenyl or benzyl, and R4 represents hydrogen or a group, which forms a biologically labile ester, where R1 and R4 groups are independently chosen from C1-C4-alkyl; C1-C4-alkoxy-C1-C4-alkoxy-C1-C4-alkyl; C3-C7-cycloalkyl; C3-C7-cycloalkyl-C1-C4-alkyl; N,N-di-(C0-C4-alkyl)amino-C1-C6-alkyl; phenyl or phenyl-C1-C4-alkyl, optionally substituted 1 or 2 times in the phenyl ring with halogen, C1-C4-alkyl or C1-C4-alkoxy group or C1-C4-alkylene chain, bonded with two neighbouring carbon atoms; dioxolanylmethyl, optionally substituted in the dioxolane ring with C1-C4-alkyl; C1-C6-alkanoyloxy-C1-C4-alkyl, optionally substituted in the oxy-C1-C4-alkyl group with C1-C4-alkyl; 1-[[(C1-C4-alkyl)carbonyl]oxy]C1-C4-alkyl esters; 1-[[(C4-C7 cycloalkyloxy)carbonyl]oxy]C1-C4-alkyl esters, 2-oxo-1,3-dioxolan-4-yl-C1-C4-alkyl esters, which optionally contain a double bond in the dioxolane ring; 2-oxo-1,3-dioxolan-4-ylmethyl; and to physiologically compatible salts of acids with formula I and/or to physiologically compatible acid-additive salts of formula I compounds. The invention also relates to a pharmaceutical composition, to use of formula I compounds in paragraph 1, to a method of obtaining formula I compounds, as well as to compounds with general formula II.

EFFECT: obtaining new biologically active compounds, with inhibitory activity towards neutral endopeptidase, endothelin converting enzyme and soluble human endopeptidase.

20 cl, 80 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: described are derivatives of 1,3,4-oxadiazol-2-on of formula (I) , where ARYL represents phenyl; Z represents -O(CH2)n- and n represents independent integer number from 1 to 5; X represents S; R1 represents C1-6alkyl; R2 represents phenyl, substituted with C1-6perfluoralkyl; or its pharmaceutically acceptable salt; based on it pharmaceutical composition; and method of disease treatment, where disease can be modulated by activity of PPAR-delta binding.

EFFECT: obtaining compounds which possess agonistic or antagonistic activity.

7 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I: or its pharmacologically acceptable salts, where n equals 1, 2 or 3; and values of R1, R2, R3, R4, R3', R10, R11 are given in i.1 of formula.

EFFECT: compounds I have ability to inhibit release and/or synthesis of β-amyloid peptide, which allows to apply them in pharmaceutical composition.

25 cl, 3 dwg, 5 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new coumarin derivatives and their carboxamides, with general formula (I) , where R3 is chosen from a group consisting of H, carboxyl, alkyloxycarbonyl, 5'-(phenyloxadiazol-2')-yl, 5'-(pyridyl-4"-oxadiazol-2')-yl, , CONHR9, where R9 is chosen from a group consisting of fatty acids C2-C8, benzoxamido, isonicotinamido, unsubstituted, or mono-, or polysubstituted phenyl, in which the substitute can be hydroxy, C1-C8-alkoxy, CF3, carboxyl, alkyloxycarbonyl, OCH2CO2H, NO2, halogen, SO3H, SO2NHR11, where R11 is chosen from a group consisting of hydrogen, amidino, 2"-thizolyl, 3"-(511-methylisooxazolyl), 2"-pyrimidinyl, 2"-(4",6"-dimethylpyrimidinyl), 4"-(5",6"-dimethoxypyrimidinyl); R4 is chosen from a group consisting of hydrogen, CONHR10, where R10 is chosen from a group consisting of C2-C8 fatty acids, unsubstituted phenyl; R5 is chosen from a group consisting of H, C1-C4 alkyl; R6 is chosen from a group consisting of H, C1-C12-alkyl, halogen, NO2, CONHR13, where R13 is substituted phenyl; R7 is chosen from a group consisting of H, hydroxyl, C1-C4alkyl or alkoxyl, carboxyalkyleneoxyl, OCH2CONHR14, where R14 is chosen from a group consisting of unsubstituted, mono-, or polysubstituted phenyl, in which the substitute can be hydroxyl, OCH3, CF3, CO2H, CO2C2H5, NO2; R8 is chosen from a group consisting of H, C1-C4-alkyl or alkoxyl, NO2; under the condition that, when R3, R5 and R6 are H, and R7 is OH, R4 and R7 are not groups, chosen from H, C1-C6-alkyl or C1-C6-alkoxy. The invention also relates to pharmaceutical compositions based on formula I compounds and their use as medicinal preparations for protecting kidneys, for curing hypertonia, cardio-cerebrovascular diseases, non-achrestic diabetes, tumours, precancerous diseases and oedema.

EFFECT: enhanced effectiveness of the composition and treatment method.

17 cl, 6 tbl, 51 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to 3-phenylpropionic acid derivatives of formula (I) as ligand of peroxisome proliferator-activated gamma-receptor (PPARγ), to their pharmaceutically acceptable salts, as well as to their application, treatment method and based on them pharmaceutical composition. Compounds can be applied for treatment and prevention of diseases mediated by peroxisome proliferator-activated gamma-receptor (PPARγ), for instance type 2 diabetes, insulin-resistance, metabolic syndrome, complications resulting from or connected with diabetes, cardio-vascular dysfunctions, atherosclerosis, obesity, cognition disturbances and lipid metabolism derangements. In general formula (I): W represents COOH or -COO-C1 - C4-alkyl group; Y represents NH; Z represents S or O; X represents O; R1 - R8 each independently represents hydrogen atom or halogen atom; A represents mono-, bi- or tri-cyclic 5-13-member heteroaryl with 1 or 2 heteroatoms selected from N, S or O, aryl, selected from phenyl and naphtyl, or -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, where heteroaryl is optionally substituted with 1-3 substituents, independently selected from group, consisting of C1-C4-alkyl, CN, phenyl halogen and phenyl, optionally substituted with 1-3 substituents, independently selected from C1-C4alkoxy, halogen and ethylenedioxy-group; and n represents integer number from 0 to 3 including; and their pharmaceutically acceptable salts.

EFFECT: increased efficiency of composition and treatment method.

20 cl, 14 dwg, 10 ex

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical and medical industry. Common valerian roots and rhizomes are extracted in 70% ethyl alcohol with following filtration of the extract from herbal raw material. Extraction is aided with ultrasonic waves of frequency 30 kHz and intensity 365-370 Wt/cm2 during 18-20 minutes at temperature 25-27°C at the relation of herbal raw material to 70% ethyl alcohol as 1:10.

EFFECT: invention allows improving yield and reducing preparation time of the product.

2 cl, 1 dwg, 1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medical products and concerns applications of a film for internal application containing triprolidine or its salt, or hydrate, as an active component of the remedy for awakening vigorous after sleeping. There is also disclosed method for treatment or prevention of sluggishness or somnolence in awakening after sleeping, the method that makes it possible for an individual to wake up vigorous after sleeping and the method ensuring falling asleep of an individual.

EFFECT: invention aims at development of the agent that makes it possible for an individual to wake up vigorous after sleeping.

19 cl, 5 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and medicine, namely to an oral gindarine tranquiliser. There is offered composition for capsule containing as an active substance, gindarine in the form of gindarine hydrochloride, and an adjuvant chemically inert to the active substance and physiologically acceptable or number of adjuvants enabling prolonged release of gindarine hydrochloride. The composition represents granules, or mixed powders, or mixed granules and powder, or liquid, or soft form. As adjuvants, the composition contains an excipient, alone or combined with a disintegrant, or an antifriction substance, or a binding substance, or mixture thereof. The composition representing the liquid form - suspension, or the soft form - gel, as adjuvant contains a liquid base, alone or mixed with a thickener or a preservative, or mixture thereof.

EFFECT: according to the invention the composition is characterised by prolonged release of gindarine from oral dosage capsular form.

10 cl, 18 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and pharmacology and presents a pharmaceutical composition based on alpha-lipoic acid as an aqueous solution for injections, for treatment and/or prevention of a disease chosen from group including alcoholic and/or diabetic polyneuropathy, coronary atherosclerosis, hyperlipidemia, hyperlipoproteinemia, mild and moderate viral hepatitis type A, hepatic cirrhosis, heavy metal salts poisoning, intoxications of various aetiologies, differing that it contains ethylenediamine, propylene glycol, solubiliser presented with plasdone, water for injection or 0.9% NaCI solution for injection in a certain relation components in the composition.

EFFECT: invention provides improved stability and absence of sediment in the solution, as well as extended range of products.

5 cl, 1 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to neurology, and can be used in treatment of the patients with diskogenic radiculopathy of lumbosacral spine. That is ensured by intravenous drop infusion of the mixed medicinal preparations containing 2.4% aminophylline 5-10 ml, dexamethasone 8-16 mg per 100 ml of 0.9% sodium chloride brine at rate 30-35 drops per minute during 4-5 days. Upon termination of the infusion, lasix 20-40 mg is added to the mixture. Then 30 minutes after introduction of the mixture, manual therapy follows as postisometric relaxation of posterior muscles of thigh. Starting from the 2-3 day of introduction of the mixture, postisometric relaxation is combined with mobilisation and manipulations within lumbosacral spine.

EFFECT: method allows improving clinical effectiveness in such patients owing to integrated effect on various links of pathogenesis.

2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention concerns new biologically active compound peptide possessing protective action against Alzheimer's disease of formula Glu-Trp-Asp-Leu-Val-Gly-Ile-Pro-Gly-Lys-Arg-Ser-Glu-Arg-Phe-Tyr-Glu-Cys-Cys-Lys-Glu.

EFFECT: can be used to produce a preparation for immunoprophylaxis of Alzheimer's diseases.

1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with formula I: , where D is O; E is CH2 or O; n equals 1 or 2, and R1 is chosen from hydrogen, halogen or substituted or unsubstituted 5- or 6-member aromatic or heteroaromatic ring with 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom, or is chosen from substituted or unsubstituted 8-, 9- or 10-member condensed heteroaromatic ring system with 0 or 1 nitrogen atom, 0 or 1 oxygen atom, where the said aromatic or heteroaromatic rings or ring systems, when they are substituted, have substitutes which are chosen from -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, halogen, -CF3, -S(O)mR2, where m equals 0, 1 or 2, -NR2R3, -NR2C(O)R3 or -C(O)NR2R3; R2 and R3 are in each case independently chosen from hydrogen, -C1-C4alkyl, -C3-C6cycloalkyl, aryl; or its stereoisomers, enantiomers or pharmaceutically acceptable salts; under the condition that the given compound is not 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydroisoindol-1-one. The invention also relates to compounds with formulae II or III, to a pharmaceutical composition, as well as to use of compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds with activity towards alpha 7 nicotinic acetylcholine receptors (α7 nAChRs).

8 cl, 72 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to a tetrazole compound with general formula I , where X3 and X4 are independently N and C, where one of X3 and X4 is certainly C; P is phenyl; m equals 1 or 2, where if m equals 1, R1 is bonded to P through a carbon atom on ring P in the meta-position of ring P relative the point at which P is bonded to X3, and if m equals 2, R1 is bonded to P through a carbon atom on ring P in positions 2 and 5 of ring P; R1 is halogen, C1-6alkyl, OC1-6alkyl or cyano group; X1 is C2-3alkyl, C2-3alkenyl, NR3, O, S, CR3R4, SO, SO2; X2 is a bond, CR3R4, O, S, NR3, SO, SO2; R3 and R4 are independently chosen from a group which consists of hydrogen, hydroxy, C1-6alkyl; Q is triazolyl, piperazinyl, or triazole or imidazole ring, condensed with a 6- or 7-member heterocyclic ring with one or two N atoms as heteroatoms; R is C1-6alkyl, C3-6cycloalkyl, pyridinyl, which can be substituted with a nitro, cyano, halogen or OC1-4alkyl group; phenyl, which can be substituted with a halogen, C1-4alkyl, OC1-4alkyl group; (CO)OC1-4alkyl; pyrimidinyl, which can be substituted with a OC1-4alkyl group; p equals 0, 1 or 2, or pharmaceutically acceptable salt or hydrate thereof.

EFFECT: invention also relates to method of inhibiting activity of mGluR5 receptors.

11 cl, 44 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds of formula I: , where m ranges from 0 to 3, n ranges from 1 to 3, p is 0, Ar is phenyl, possibly substituted with C1-C6-alkyl, cycloalkyl, hydroxyalkyl, halogen, hydroxyl or cyano group, X is -O-,R1 and R2 each is independently hydrogen, C1-6alkyl or C1-6alkoxy-C1-6alkyl or hydroxy-C1-6alkyl, or one of R1 and R2 is hydrogen or C1-6 alkyl, and the other is C1-6alkylcarbonyl, C3-C8 cycloalkyl, aryl-C1-6alkyl or hydroxyl, or R1 and R2 together with the nitrogen atom to which they are bonded can form a three- to seven-member ring, which can possibly contain an additional N heteroatom, or R1 and R2 together with the nitrogen atom to which they are bonded can form a guanidyl group, amidinyl group, carbamyl group or urea group, each R3 is independently C1-6alkyl, R4 and R5 each is independently hydrogen or C1-6alkyl; or their pharmaceutically acceptable salts, as well as pharmaceutical compositions containing these compounds.

EFFECT: invention can selectively modulate 5-HT receptors, including 5-HT6 and 5-HT2A receptors.

17 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: described are new derivatives of 1,2,4-triazole with general formula or , their pharmaceutically acceptable salts, where R1 is H, C1-6alkyl, CONH2 or COOH; R2 is H; R3 is H, halogen or O-C1-4 perfluoroalkyl; R4 is H or halogen; one of the radicals R5, R6, R7 is H; the other is H or halogen, and the third is O-C1-6 alkyl, halogen, O-C0-4alkyl C1-4perfluoroalkyl, O-C2-6alkenyl, phenyl, possibly substituted with 1 to 3 substitutes, chosen from halogen, CN, CF3, pyrazole, -ORa, where Ra is CF3, NRaRb, where Ra and Rb are C1-4alkyl, a group with formula C(O)-ORa, where Ra is C1-4alkyl, or a group with formula - O-C1-4alkylphenyl, where phenyl can be substituted with 1 to 3 halogens; a pharmaceutical composition containing said compounds.

EFFECT: use of new compounds for treating and preventing chronic and neuropathic pain.

39 cl, 72 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (I): , where each of R1, R2, R3 and R4 is independently selected out of hydrogen, hydroxy, and -NHCHO, or R1 and R2 together are selected out of -NHC(=O)CH=CH- and -CH=CHC(=O)NH-; R1 can also be -CH2OH; one of R5 and R6 is -[X-C1-6alkylenyl]n-NR10R11 or C1-6alkylenyl-NR12R13, and the other of R5 and R6 is selected out of hydrogen, C1-4alkoxy and C1-4alkyl, where C1-4alkylis optionally substituted by halogen, where each X is -O-; each of R10, R11, R12 and R13 is independently hydrogen or C1-4alkyl; or R10 and R11 together with nitrogen atom linking them, or R10 together with nitrogen atom linking it and carbon atom from neighbour C1-6alkylenyl form heterocyclic or heteroaryl ring with 5 to 7 atoms in ring and optionally with additional heteroatom selected out of oxygen and nitrogen, where nitrogen atom is optionally substituted by -S(O)2-C1-4alkyl; and n is 1 or 2; and each of R7, R8 and R9 is independently hydrogen; and pharmaceutically acceptable salt or solvate or stereoisomer of claimed compounds. Also invention claims application and pharmaceutical composition based on the compounds and having agonistic effect on β2 adrenergetic receptor.

EFFECT: obtaining novel compounds for application in therapy of asthma or chronic obstructive lung disease.

25 cl, 1 tbl, 6 dwg, 17 ex

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