2-substituted-1,2,4,5-tetrahydro-3h-pyrrolo[1,2-a][1,4]diazepin-3-ones

FIELD: chemistry.

SUBSTANCE: invention relates to biologically active compounds, specifically to a group of 2-substituted 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-ones of general formula where R denotes hydrogen, a straight or branched (C1-C4)-alkyl; a hydroxyalkyl having an alkyl chain with 2-3 C atoms; a phenylalkyl having an alkyl chain with 1-2 C atoms, wherein the phenyl ring can have one or two methoxy groups. The invention also relates to a method of producing said compounds.

EFFECT: novel compounds can be used in medicine as antidepressant and antianxiety agents.

6 cl, 3 tbl, 9 ex

 

The invention relates to the field of biologically active compounds, specifically to the new group pyrrolo[1,2-a][1,4]benzodiazepines of the General formula:

where R = hydrogen, linear or branched (C1-C4)-alkyl; hydroxyalkyl containing alkyl chain with 2 to 3 C-atoms; phenylalkyl containing alkyl chain with 1-2 C-atoms, the phenyl ring may contain one or two metoxygroup.

The claimed compounds have a pronounced anxiolytic and antidepressant activity.

The results of numerous clinical studies suggest that certain forms of mental pathology rather rarely isolated and are often presented in the form of a complex pattern in the structure of different psychopathological syndromes. This fully applies to mental disorders neurotic level, which revealed a significant frequency States with comorbid anxiety, affective and cognitive impairment [of Depression and comorbid disorders. Abimelech (as amended), Moscow (1997)]. The treatment of such disorders is always a serious problem, due to the lack of use of specific drugs of different groups because of the complexity of "targets" therapeutic effects [Now, Saunaka, VCB Carew, Ecelesia, Phenazepam: 25 years in medical practice, Moscow (2007), SS-277] and a possible risk of increased side effects of drugs, due to the mechanisms of their interaction with combination therapy [Now, Psychopharmacotherapy neurotic disorders, Moscow (1987), SS-268].

In addition, and separately used psychotropic drugs is also not devoid of negative effects. Thus, the reduction of anxiety with anxiety accompanied miorelaksantnoe, sedative and amnestic effects are particularly pronounced in the elderly. In addition, benzodiazepine anxiolytics (like other GABA-positive substances) can have a negative impact on the immune system [V.Covelli, I.Munno, P.Decandia, et al. Acta Neurologica, 1991, 13, 418]. The reduction of depression with antidepressants (including atypical) often leads to increased anxiety, development of cardiotoxic and anticholinergic effects. Prolonged use of nootropics for correction of frustration often leads to negative results and patients refuse treatment. When the joint introduction of pharmacological drugs of different classes (anxiolytics with antidepressants or nootropics, nootropics with antidepressants) amplification of their main effects, usually accompanied by increased by the full-time steps [Now, Psychother. macotherapy neurotic disorders, Moscow (1987), SS-268].

All of the above determines the relevance of search and study of medicinal substances with a broad spectrum of pharmacological activity, potentially promising as a means of therapy of these disorders.

The compounds I, their properties and the method of obtaining not described in literature. The closest prototype of the chemical structure of 7-methyl-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-one [.V.Butin, .A.Nevolina, V.A.Shcherbinin, M.G.Uchuskin, .V.Serdyuk, I.V.Trushkov, Synthesis, 2010, 17, 2969]. The closest prototype of pharmacological action are 2,6-substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine and their salts with ansioliticos activity [Patent USSR 798104, 1981 (bull. inventions No. 3, 1981); US Patent 5378846 (1995)]. The previously described compounds differ from the claimed structure and pharmacological properties.

Unsubstituted 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-one (1A) and methyl ester of 3-(2-{[3-oxo-4,5-dihydro-1H-pyrrolo[1,2-a][1,4]diazepin-2(3H)-yl]methyl}-1H-pyrrol-1-yl)propionic acid (AI) are obtained according to the following scheme:

When boiling solution of 2,5-dimethoxy-2-(dimethoxymethyl)tetrahydrofuran (II) [Vpered, Roostersa, Amicosante, Aphrodyne, Segerberg, Apostolidou, Chem.-Pharm. zhurn., 1982, 6, 537] and 3-aminopropionic acid (III) in water for hours to get 3-(2-formyl-1H-pyrrol-1-yl)propionic acid (IV). When the hydrogenation of a mixture of 3-(2-formyl-1H-pyrrol-1-yl)propionic acid (IV) and hydroxylamine in methanol at palladium catalyst to obtain a mixture of amino acids (V and VI), which is then without separation atrificial effect of methanol in the presence of thionyl chloride and subsequent alkalinization of potash. The result is a mixture of amino esters (VII and VIII), the selection is converted into a mixture of the corresponding 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-ones (Ia and AI), which is shared by chromatography on a column of aluminum oxide. Compound Ia is a light yellow powder, insoluble in water, soluble in alcohols. The connection AI is a yellow-orange oil, insoluble in water, soluble in alcohols.

2-Substituted 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-ones (IB-C) are obtained according to the following scheme:

During the restoration aminating allegedely (IV) with primary amines by hydrogenation on a palladium catalyst at atmospheric pressure get amino acids (A-W), which further etherification effect of methanol with thionyl chloride followed by alkalinization of potash. The resulting amino esters (X) without releasing next CEC shall isout by boiling in o-xylene in the corresponding 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-ones (IB-C). Compounds IB-C are white or slightly yellowish crystalline substance or yellow-orange oil, insoluble in water, soluble in alcohol.

The structure of the obtained substances confirmed by the data of elemental analysis and spectral data. So, in NMR spectra1H-2-substituted 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-ones are multiplets of H2C(4)-groups in the field 2.90-3.10 ppm, multiplet H2(5)groups in the field of 4.10-4.27 ppm, singlets (doublet for compounds Ia) H2(1)groups and three multiplet pyrrole protons in the field 5.85-6.65 ppm

Example 1: 2-methyl-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4|diazepin-3-one (IB, R=Me).

To a solution of 5.01 g (30 mmol) of 3-(2-formyl-1H-pyrrol-1-yl)propionic acid and 5.10 g (33 mmol) of 20%alcohol solution of methylamine in 80 ml of ethanol was added 0.4 g of palladium on coal (10% Pd)and the reaction mass was first made at atmospheric pressure until the absorption of theoretical amount of hydrogen. The catalyst was filtered, the filtrate was evaporated to dryness. The residue was dissolved in 50 ml of methanol. To the resulting solution at a temperature of -10°C was pinned 2.55 ml (35 mmol) of thionyl chloride for 5 minutes. The reaction mass was passed the day at room temperature and was evaporated to dryness. To the residue was added a solution of 8 g2CO3in 40 ml of water, and the product was extracted with 30+20+10 ml of chloro who Orme. The combined chloroform solutions were washed with 20 ml water was filtered through a paper filter and evaporated to dryness. The residue was dissolved in 30 ml of xylene, the resulting solution was boiled under reflux for 8 hours and evaporated to dryness. The residue was recrystallized from 15 ml of toluene. Received 2.81 g of the product in the form of light yellow needle crystals (yield 57%). TPL 108-110°C. Found (%): C, 66.05; H, 7.36; N, 17.34. C9H12N2O. Calculated (%): C, 65.83; H, 7.37; N, 17.06. An NMR spectrum1H (CDCl3, δ, ppm): 3.01 (m, 2H, H2(4)); 3.03 (s, 3H, Me); 4.21 (m, 2H, H2(5)); 4.43 (s, 2 H, H2(1)); 5.96 (m, 1H, HC(9)); 6.07 (m, 1H, HC(8)); 6.61 (m, 1 H, HC(7)).

Obtaining initial connection:

3-(2-formyl-1H-pyrrol-1-yl)propionic acid (IV).

The solution 17.82 g (0.2 mol) of 3-aminopropionic acid in 240 ml of water and 45.37 g (0.22 mol) of 2,5-dimethoxy-2-(dimethoxymethyl)of tetrahydrofuran was heated under reflux for one hour, evaporated to half volume and cooled to room temperature. The precipitated reaction product was filtered, washed with water and dried. Output 92.2%, red-brown crystals, TPL 98-99°C. Found (%): C, 57.64; H, 5.40; N, 8.49. C8H9NO3. Calculated (%): C, at 57.48; H, 5.43; N, 8.38. An NMR spectrum1H (DMSO, δ, ppm, J/Hz): 2.93 (t, 2H,CH2-CO2H,3J=6.5); 4.58 (t, 2H,N2-CH2-CO2H,3J=6.5); 6.15 (m, 1H, HC(4)); 6.95 m, 1H, HC(3)); 7.31 (m, 1H, HC(5)); 9.35 (s, 1H, SLEEP).

Example 2: 2-isobutyl-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a]|1,4]diazepin-3-one (Ie, R=i-Bu).

To a suspension of 4.49 g (20 mmol) 3-{2-[(isobutylamino)methyl]-1H-pyrrol-1-yl}propionic acid in 40 ml of methanol at a temperature of -10°C was pinned 1.82 ml (25 mmol) of thionyl chloride for 5 minutes. The reaction mass was passed the day at room temperature and was evaporated to dryness. To the residue was added a solution of 5 g of K2CO3in 20 ml of water, and the product was extracted with 20+20+5 ml of toluene. The combined toluene solutions were filtered through a paper filter, boiled under reflux for 10 hours, passed through a column of alumina, using as eluent toluene, and evaporated to dryness. The residue was distilled at 1.5 mm Hg (BP. 152-154°C). Received 2.60 g of the product as a pale yellow powder (yield 63%). TPL 57-59°C. Found (%): C, at 69.74; H, 8.66; N, 13.43. C9H12N2O. Calculated (%): C, 69.87; H, 8.79; N, 13.58. An NMR spectrum1H (CDCl3, δ, ppm,.J/Hz): 0.84 (d, 6N, Me 2, J=6.7); 1.91 (m, 1H, CHMe2); 3.02 (m, 2H, H2(4)); 3.26 (d, 2H,N2-Snme2,3J=7.6); 4.21 (m, 2H, H2C(5)); 4.42 (s, 2H, H2C(1)); 5.92 (m, 1H, HC(9)); 6.06 (m, 1H, HC(8)); 6.60 (m, 1H, HC(7)).

Obtaining initial connection:

3-{2-[(isobutylamino)methyl]-1H-pyrrol-1-yl}propionic acid (I, R=i-Bu).

To a solution of 5.01 g (30 mmol) of 3-(2-formyl-1H-pyrrol-1-yl)p is pianoboy acid and 2.41 g (33 mmol) of isobutylamine in 80 ml etiole was added 0.4 g of palladium on coal (10% Pd), and the reaction mass was first made at atmospheric pressure until the absorption of theoretical amount of hydrogen. The catalyst was filtered, the filtrate was evaporated to dryness. The residue was recrystallized from 75 ml of isopropanol. Got 5.22 g of the product as a yellow-pink powder (yield 78%). TPL 154-156°C. Found (%): C, at 64.29; H, 9.21; N, 12.37. C12H20N2O2. Calculated (%): C, at 64.26; H, 8.99; N, 12.49. An NMR spectrum1H (DMSO, δ, ppm, J/Hz): 0.91 (d, 6N, 2 Me,3J=6.7); 1.95 (m, 1H,NIU2); 2.49 (t, 2H,N2-CO2H,3J=5.3); 2.67 (d, 2H, NH-CH2-CH,3J=7.5); 3.96 (m, 4H, CH2- N2-CO2H-Pyrrol-CH2-NH); 6.01 (m, 1H, HC(3)); 6.09 (m, 1H, HC(4)); 6.83 (m, 1H, HC(5)).

Example 3: 2-(2-hydroxyethyl)-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-one (Iك, R=CH2CH2OH).

To a suspension of 4.25 g (20 mmol) 3-(2-{[(2-hydroxyethyl)amino]methyl}-1H-pyrrol-1-yl)propionic acid in 70 ml of methanol at a temperature of -10°C was pinned 1.82 ml (25 mmol) of thionyl chloride for 5 minutes. The reaction mass was passed the day at room temperature and was evaporated to dryness. To the residue was added a solution of 5 g of K2CO3in 20 ml of water, and the product was extracted with 20+10+5 ml of chloroform. The combined chloroform solutions were filtered through a paper filter and evaporated to dryness. The residue was dissolved in 30 ml of xylene, the solution was heated from the reverse was built in the ICOM for 14 hours and was evaporated to dryness. The residue was dissolved when heated in 15 ml of toluene and left for 1 day at 4°C. the precipitation was filtered. Received 3.19 g of the product as a white powder (yield 82%). TPL 111-113°C. Found (%): C, 61.62; H, 7.32; N, at 14.66. C10H14N2O2. Calculated (%): C, 61.84; H, 7.27; N, 14.42. Range of NMR 'H (CDCl3, δ, ppm, J/Hz): 2.25 (ush. s, 1H, HE); 3.05 (m, 2H, H2(4)); 3.62 (t, 2H,N2-CH2HE,3J=5.2); 3.74 (t, 2H,N2HE,3J=5.2); 4.22 (m, 2H, H2(5)); 4.53 (s, 2H, H2(1)); 5.96 (m, 1H, HC(9)); 6.08 (m, 1H, HC(8)); 6.62 (m, 1H, HC(7)).

Obtaining initial connection:

3-(2-{[(2-hydroxyethyl)amino]methyl}-1H-pyrrol-1-yl)propionic acid (IXC, R=CH2CH2OH).

To a solution of 5.01 g (30 mmol) of 3-(2-formyl-1H-pyrrol-1-yl)propionic acid and 2.02 g (33 mmol) of 2-ethanolamine in 70 ml of ethanol was added 0.4 g of palladium on coal (10% Pd)and the reaction mass was first made at atmospheric pressure until the absorption of theoretical amount of hydrogen. The catalyst was filtered, the filtrate was evaporated to ~20 ml and left for 1 day at 4°C. the precipitation was filtered. Got 5.35 g of the product as a white powder (yield 84%). TPL 158-160°C. Found (%): C, 56.51; H, 7.83; N, 13.33. C10H16N2O3. Calculated (%): C, 56.59; H, 7.60; N, 13.20. An NMR spectrum1H (DMSO, δ, ppm,3J/Hz): 2.79 (t, 2H,N2-CO2H,3J=5.5); 3.52-3.62 (m, 4H, CH2- N -HE); 3.98 (s, 2H, Pyrrol-CH2-NH); 4.00 (t, 2H, CH2-CH2-CO2H,3J=5.5); 5.96 (m, 1H, HC(3)); 6.00 (m, 1H, HC(4)); 6.81 (m, 1H, HC(5)).

Example 4: 2-(3-hydroxypropyl)-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-one (Ia, R=CH2CH2CH2OH).

To a suspension of 4.53 g (20 mmol) 3-(2-{[(3-hydroxypropyl)amino]methyl}-1H-pyrrol-1-yl)propionic acid in 70 ml of methanol at a temperature of -10°C was pinned 1.82 ml (25 mmol) of thionyl chloride for 5 minutes. The reaction mass was passed the day at room temperature and was evaporated to dryness. To the residue was added a solution of 5 g of K2CO3in 20 ml of water, and the product was extracted with 20+10+5 ml of chloroform. The combined chloroform solutions were filtered through a paper filter and evaporated to dryness. The residue was dissolved in 30 ml of xylene, the solution was boiled under reflux for 14 hours and was evaporated to dryness. The residue was dissolved in 5 ml of toluene and passed through a column of Al2O3using as eluent toluene. The eluate was evaporated to dryness, obtaining 3.62 g of the product as a pale yellow powder (yield 87%). TPL 37-39°C. Found (%): C, 63.30; H, 7.82; N, 13.46. C11H16N2O2. Calculated (%): C, 63.44; H, 7.74; N, 13.45. An NMR spectrum1H (CDCl3, δ, ppm, J/Hz): 1.68 (m, 2H,N2-CH2-HE); 2.59 (ush. s, 1H, HE); 3.05 (m, 2H, H2(4)); 3.38 (t, 2H,N2-(CH2)2HE,3=5.5); 3.60 (t, 2H, CH2-OH,3J=6.1); 4.23 (m, 2H, H2(5)); 4.43 (s, 2H, H2(1)); 5.95 (m, 1H, HC(9)); 6.07 (m, 1H, HC(8)); 6.61 (m, 1H, HC(7)).

Obtaining initial connection:

3-(2-{[(3-hydroxypropyl)amino]methyl}-1H-pyrrol-1-yl)propionic acid (Hg, R=CH2CH2CH2OH).

To a solution of 5.01 g (30 mmol) of 3-(2-formyl-1H-pyrrol-1-yl)propionic acid and 2.48 g (33 mmol) of 3-propanolamine in 70 ml of ethanol was added 0.4 g of palladium on coal (10% Pd)and the reaction mass was first made at atmospheric pressure until the absorption of theoretical amount of hydrogen. The catalyst was filtered, the filtrate was evaporated to ~20 ml and left for 1 day at 4°C. the precipitation was filtered. Obtained 5.6 g of the product as a white powder (yield 83%). TPL 164-166°C. Found (%): C, 58.49; H, 8.25; N, 12.30. C11H18N2O3. Calculated (%): C, 58.39; H, 8.02; N, 12.38. An NMR spectrum1H (DMSO, δ, ppm, J/Hz): 1.72 (m, 2H, CH2-CH2-HE); 2.49 (t, 2H, NH-CH2-CH2,3J=6.7); 2.82 (t, 2H, CH2-CO2H,2J=5.7); 3.48 (t, 2H,N2HE,3J=6.0); 4.00 (t, 2H,N2-CH2-CO2H,3J=5.7); 4.05 (s, 2H, Pyrrol-CH2-NH); 6.00 (m, 1H, HC(3)); 6.03 (m, 1H, HC(4)); 6.85 (m, 1H, HC(5)).

Example 5: 2-benzyl-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-one (Ie, R=CH2Ph).

To a suspension of 5.17 g (20 mmol) 3-{2-[(benzylamino)methyl]-1H-pyrrol-1-yl}propionic acid in 70 ml of methanol is at a temperature of -10°C was pinned 1.82 ml (25 mmol) of thionyl chloride for 5 minutes. The reaction mass was passed the day at room temperature and was evaporated to dryness. To the residue was added a solution of 5 g of K2CO3in 20 ml of water, and the product was extracted with 20+20+5 ml of toluene. The combined toluene solutions were filtered through a paper filter and evaporated to dryness. The residue was dissolved in 30 ml of xylene, the solution was boiled under reflux for 20 hours and evaporated to dryness. The residue was distilled at 1 mm Hg (BP. 204-206°C). Received 3.12 g of the product as a yellow oil (yield 65%). Found (percent): C, 75.08; H, 6.59; N, 11.80. C15H16N2O. Calculated (%): C, at 74.97; H, 6.71; N, 11.66. An NMR spectrum1H (CDCl3, δ, ppm): 3.10 (m, 2H, H2(4)); 4.27 (m, 2H, H2(5)); 4.34 (s, 2H,N2-Ph); 4.65 (s, 2H, H2(1)); 5.85 (m, 1H, HC(9)); 6.06 (m, 1H, HC(8)); 6.63 (m, 1H, HC(7)); 7.21-7.39 (m, 5H, Ph).

Obtaining initial connection:

3-{2-[(benzylamino)methyl]-1H-pyrrol-1-yl}propionic acid (GD, R=CH3RH).

To a solution of 5.01 g (30 mmol) of 3-(2-formyl-1H-pyrrol-1-yl)propionic acid and 3.54 g (33 mmol) of benzylamine in 80 ml of methanol and 40 ml of water was added 0.4 g of palladium on coal (10% Pd)and the reaction mass was first made at atmospheric pressure until the absorption of theoretical amount of hydrogen. The catalyst was filtered, the filtrate was evaporated to dryness. The residue was recrystallized from 60 ml of ethanol. Got 6.51 g of the product as a white powder (yield 84). TPL 174-175°C. Found (%): C, 69.79; H, 6.88; N, 10.67. C15H18N2O2. Calculated (%): C, at 69.74; H, 7.02; N, 10.84. An NMR spectrum1H (DMSO, δ, ppm, J/Hz): 2.62 (t, 2H,N2-CO2H,3J=5.3); 3.75, 3.79 (both, 2H, CH2-Ph, Pyrrol-CH2-NH); 4.06 (t, 2H,N2-CH2-CO2H,3J=5.3); 5.93 (m, 2H, HC(3), HC(4)); 6.76 (m, 1H, HC(5)); 7.26-7.45 (m, 5H, Ph).

Example 6: 2-phenethyl-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-one (If, R=CH2CH2Ph).

To a suspension of 5.45 g (20 mmol) 3-{2-[(phenethylamine)methyl]-1H-pyrrol-1-yl}propionic acid in 70 ml of methanol at a temperature of -10°C was pinned 1.82 ml (25 mmol) of thionyl chloride for 5 minutes. The reaction mass was passed the day at room temperature and was evaporated to dryness. To the residue was added a solution of 5 g of K2CO3in 20 ml of water, and the product was extracted with 20+20+5 ml of toluene. The combined toluene solutions were filtered through a paper filter and evaporated to dryness. The residue was dissolved in 30 ml of xylene, the solution was boiled under reflux for 20 hours and evaporated to dryness. The residue was dissolved by heating in 12 ml of isopropanol and left for 1 day at 4°C. the precipitation was filtered. Got 3.61 g of the product as a pale pink powder (yield 71%). TPL 101-102°C. Found (%): C, 75.55; H, 6.98; N, 10.88. C16H18N2O. Calculated (%): C, 75.56; H, 7.13; N, 11.01. An NMR spectrum1N CDCl 3, δ, ppm, J/Hz): 2.83 (t, 2H, CH2Ph3J=7.3); 2.97 (m, 2H, H2(4)); 3.71 (t, 2H, CH2-CH2-Ph,3J=7.3); 4.10 (m, 2H, H2(5)); 4.34 (s, 2H, H2(1)); 5.92 (m, 1H, HC(9)); 6.08 (m, 1H, HC(8)); 6.60 (m, 1H, HC(7)); 7.05-7.29 (m, 5H, Ph).

Obtaining initial connection:

3-{2-1(phenethylamine)methyl]-1H-pyrrol-1-yl}propionic acid (IXe, R=CH2CH2Ph).

To a solution of 5.01 g (30 mmol) of 3-(2-formyl-1H-pyrrol-1-yl)propionic acid and 4.00 g (33 mmol) of phenethylamine in 100 ml of methanol was added 0.4 g of palladium on coal (10% Pd)and the reaction mass was first made at atmospheric pressure until the absorption of theoretical amount of hydrogen. The catalyst was filtered, the filtrate was left for 1 day at 4°C. the precipitation was filtered. Got 6.54 g of the product as a white powder (yield 80%). TPL 160-161°C. Found (%): C, 70.79; H, 7.72; N, 10.43. C16H20N2O2. Calculated (%): C, 70.56; H, 7.40; N, 10.29. An NMR spectrum1H (DMSO, δ, ppm, J/Hz): 2.72 (t, 2H,N2-CO2H,3J=5.3); 2.95 (m, 4H, CH2-CH2-Ph); 3.92 (t, 2H,N2-CH2-CO2H,3J=5.3); 3.99 (s, 2H, Pyrrol-CH2-NH); 6.03-6.11 (m, 2H, HC(3), HC(4)); 6.70 (m, 1H, HC(5)); 7.03-7.26 (m, 5H, Ph).

Example 7: 2-(3,4-dimethoxyphenethyl)-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-one (Z, R=CH2CH2Ph(OMe)2-3,4).

To a suspension of 6.65 g (20 mmol) 3-{2-[(phenethylamine)methyl]-1H-pyrrol-1-yl}propionate the acid in 70 ml of methanol at a temperature of -10°C was pinned 1.82 ml (25 mmol) of thionyl chloride for 5 minutes. The reaction mass was passed the day at room temperature and was evaporated to dryness. To the residue was added a solution of 5 g of K2CO3in 20 ml of water, and the product was extracted with 20+20+5 ml of toluene. The combined toluene solutions were filtered through a paper filter and evaporated to dryness. The residue was dissolved in 30 ml of xylene, the solution was boiled under reflux for 20 hours and evaporated to dryness. The residue was dissolved by heating in 12 ml of isopropanol and left for 1 day at 4°C. the precipitation was filtered. Received 4.65 g of the product as a pale yellow powder (yield 74%). TPL 115-116°C. Found (%): C, 68.78; H, 7.11; N, 8.82. C16H18N2O. Calculated (%): C, 68.77; H, 7.05; N, 8.91. An NMR spectrum1H (CDCl3, δ, ppm, J/Hz): 2.77 (t, 2H, CH2-Ph,3J=7.3); 2.97 (m, 2H, H2(4)); 3.69 (t, 2H, CH2-CH2-Ph,3J=7.3); 3.83, 3.84 (both, 3H, 2 OMe); 4.11 (m, 2H, H2(5)); 4.35 (s, 2H, H2C(1)); 5.90 (m, 1H, HC(9)); 6.07 (m, 1H, HC(8)); 6.58 (m, 1H, HC(7)); 6.60-6.77 (m, 3H, Ar).

Obtaining initial connection:

3-{2-[(3,4-dimethoxyphenethylamine)methyl]-1H-pyrrol-1-yl}propionic acid (Hi, R=CH2CH2Ph(OMe)2-3,4).

To a solution of 5.01 g (30 mmol) of 3-(2-formyl-1H-pyrrol-1-yl)propionic acid and 5.98 g (33 mmol) of 3,4-dimethoxyphenethylamine in 100 ml of methanol was added 0.4 g of palladium on coal (10% Pd)and the reaction mass was first made at atmospheric pressure is to the absorption of theoretical amount of hydrogen. The catalyst was filtered, the filtrate was left for 1 day at 4°C. the precipitation was filtered. Got 7.68 g of the product as a white powder (yield 77%). TPL 175-180°C. Found (%): C, 65.18; H, 7.15; N, 8.59. C18H24N2O4. Calculated (%): C, 65.04; H, 7.28; N, 8.43. An NMR spectrum1H (DMSO, δ, ppm, J/Hz): 2.73 (t, 2H,N2-CO2H,3J=5.2); 2.85-3.05 (m, 4H, CH2-CH2-Ph); 3.78, 3.81 (both, 3H, 2 OMe); 3.92-3.99 (m, 4H,N2-CH2-CO2H, Pyrrol-CH2-NH); 6.04 (m, 1H, HC(3)); 6.11 (m, 1H, HC(4)); 6.62-6.74 (m, 4H, HC(5), Ar).

Examples 8 and 9: 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4)diazepin-3-one (Ia) and methyl ester of 3-(2-{[3-oxo-4,5-dihydro-1H-pyrrolo[1,2-a][1,4]diazepin-2(3H)-yl]methyl}-1H-pyrrol-1-yl)propionic acid (S).

To a solution of 5.01 g (30 mmol) of 3-(2-formyl-1H-pyrrol-1-yl)propionic acid (IV) and 4.95 g of a 50%aqueous solution of hydroxylamine in water (75 mmol) in 70 ml of methanol and 20 ml of water was added 0.5 g of palladium on coal (10% Pd)and y reaction mass was first made at atmospheric pressure until the absorption of theoretical amount of hydrogen. The catalyst was filtered, the filtrate was evaporated to dryness. To the residue was added 70 ml of methanol. To the resulting suspension at a temperature of -10°C was pinned 2.85 ml (39 mmol) of thionyl chloride for 5 minutes. The reaction mass was passed the day at room temperature and was evaporated to dryness. To the residue was added a solution of 10 g Ksub> 2CO3in 40 ml of water, and the product was extracted with 30+20+10 ml of chloroform. The combined chloroform solutions were washed with 20 ml water was filtered through a paper filter and evaporated to dryness. The residue was dissolved in 30 ml of xylene, the solution was boiled under reflux for 10 hours and evaporated to dryness. The residue was chromatographically on a column of alumina using chloroform as eluent. After full recovery fraction Rf=0.44 column was washed with a mixture of methanol and chloroform in a ratio of 1:2 up to full output fraction with Rf=0.22. The first fraction (Rf=0.44) was evaporated to dryness, obtaining 2.71 g of methyl ester of 3-(2-{[3-oxo-4,5-dihydro-1H-pyrrolo[1,2-a][1,4]diazepin-2(3H)-yl]methyl}-1H-pyrrol-1-yl)propionic acid (AI) as an orange oil (yield 57%). Found (percent): C, 64.61; H, 6.55; N, 13.45. C17H21N3O3. Calculated (%): C, 64.74; H, 6.71; N, 13.32. An NMR spectrum1H (CDCl3, δ, ppm, J/Hz): 2.48 (t, 2H,N2-CO2Me,3J=6.9); 3.07 (m, 2H, H2(4)); 3.65 (s, 3H, OMe); 4.05 (t, 2H,N2-CH2-CO2Me,3J=6.9); 4.25 (m, 2H, H2(5)); 4.34 (s, 2H, Pyrrole-CH2); 4.60 (s, 2H, H2(1)); 5.76 (m, 1H, Hpyrr'(3)); 6.03 (m, 1H, Hpyrr'(4)); 6.08 (m, 1H, HC(9)); 6.13 (m, 1H, HC(8)); 6.59 (m, 1H, Hpyrr'(5)); 6.65 (m, 1H, HC(7)). The second fraction (Rf=0.22) was also evaporated to dryness, the residue was recrystallized from isopropanol, the floor is tea 0.84 g of 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-one (Ia) as a yellow powder (yield 19%). TPL 115-117°C. Found (%): C, 63.83; H, 6.80; N, 18.79. C8H10N2O. Calculated (%): C, 63.98; H, 6.71; N, 18.65. An NMR spectrum1H (CDCl3, δ, ppm, J/Hz): 2.90 (m, 2H, H2(4)); 4.21 (m, 2H, H2(5)); 4.34 (d, 2 H, H2With(1),3J=5.4); 5.96 (m, 1H, HC(9)); 6.06 (m, 1H, HC(8)); 6.62 (m, 1H, HC(7)); 6.80 (ush. s, 1H, NH).

Pharmacological study of the proposed connection.

The study of the antidepressant activity of the compounds.

The antidepressant activity of the compounds was studied using the model of forced swimming in rats test despair [Andreeva N. guidelines for the study of the antidepressant activity of drugs, substances. Manual on experimental (preclinical) study of new pharmacological substances. - Second edition, revised and expanded. / CH. edit Ruhara, Moscow (2005), s-252] according to the methods Porsolt et al. [R.D.Porsolt, G.Anton, N.Blavet, M.Jalfre, Eur. J. Pharmacol., 1978, 47, 379] and Nomura et al. [S.Nomura, J.Shimizu, M.Kinjo, H.Kametani, T.Nakazawa, Eur. J. Pharmacol., 1982, 83, 171]. Investigations were carried out on outbred rats male age 2-2 .5 months and weighing 220-250 g

To evaluate the antidepressant effect of the compounds according to the method of Nomura et al. in the test, forced swimming in rats in a vessel with water and a freely rotating wheels was used four-channel installation, developed in the Institute of pharmacology them. You RAMS [Gemmological, Tauramena, Alizarine and, The experimental. and the wedge. Pharmacol., 1994, 57, 3]. The unit is a vessel of size 64×30×42 cm, divided into 4 equal compartments. The compartments are wheel width 11 cm with 12 blades with a width of 2 cm, the outer diameter of the wheels 10 see the edges of each wheel fortified magnets, and over the wheels - the switches that are activated each time the magnet passes under them. So there is an automatic check of rotation of the wheels, which is an objective measure of the activity of animals. The vessel was filled with water with a temperature of 25°C until the middle of the wheels. Rats were placed in each compartment muzzle from the wheel and record the number of revolutions of the wheels for 10 min with Electromechanical meters.

The effect of each compound was studied on 8 animals, substances suspended using tween-80 and was administered intraperitoneally in doses: Ia - 1.1 mg/kg; IB - 1,15 mg/kg; IB of 1.45 mg/kg; Iك - 1.4 mg/kg; Ia - 1.5 mg/kg; If the 1.8 - mg/kg, and Z - 2.2 mg/kg over 40 min before the experiment. The comparison was carried out with the antidepressant amitriptyline.

When the statistical processing of the obtained results to calculate the average speed for each group and standard deviations, significance of differences between groups was determined using analysis of variance, included in the statistical software package Statistica 6,0 (MathSoft, USA).

Found that when using compounds IB, Iك, Ia Is If the number of revolutions of the wheels was significantly increased compared with the control group (table 1). The maximum effect greater than the effect of amitriptyline, noted in connection Iك and If.

The investigated substances showed high efficiency of test and forced swimming in rats by the method of Porsolt et al. Evaluation of the effect of the compounds was performed in comparison with amitriptyline.

40 minutes after injection, animals were placed in a container of water with a diameter of 40 cm and a depth of 60 cm, so that the rat could not escape from the vessel, neither find it as a support. In this situation, the animal is forced to make active swimming movements to get out, or hang in the water and make minor rowing motions to maintain the snout above the water surface. Water temperature was maintained at 25°C. the State of immobilization was evaluated visually by determining its duration within 10 min of observation.

Statistical processing of data was performed by calculating the average duration Immobilise and their standard deviations for each group of animals. Differences between groups were determined using analysis of variance (Statistica, MathSoft, USA).

It is established that the compounds IB, Ia, and If Z significantly reduced the immobility time of rats compared with the control group (table 2).

The study of the anxiolytic activity of the compounds.

Anxiolytic activity of the compounds IB, Iك, and If Z studied the Ali test a conflict situation based on the collision drinking and defensive motivation [Voronina T.A., Seredenin S.B. guidelines for the study of anxiolytic (anxiolytic) actions of pharmacological substances. Manual on experimental (preclinical) study of new pharmacological substances. -Second edition, revised and expanded. / CH. edit Ruhara, Moscow (2005), SS-262]. Investigations were carried out on outbred rats male age 2-2 .5 months and weighing 220-250 g

Previously, animals were deprived of water and succulent feed for 24 h, and then developed the skill of taking water from the trough, placing the rat in the chamber, where she found the drinking water and began to drink. The camera has a size of 275×275×450 mm, the electrode floor and drinking water (vessel with a nipple on the wall), located at a height of 5 cm from the floor. To conduct a conflict situation used four-chamber installation, developed in the Institute of pharmacology them. You RAMS [Gemmological, Tauramena, Experimental. and wedge Pharmacol., 1995, 58, 54].

The next day training-development of the skill of taking water from the troughs. The training lasted for 5 min, allowed to develop skill takes water in rats and not allow animals to drink before experience, i.e. to keep drinking motivation. The next day the rat was placed in a cell for 10 min and after 10 seconds on the Ala drinking at the trough and the floor of the chamber electrode was applied current of 0.25 mA, so every draw water became punishable. In order to meet drinking motivation, the rat must overcome the feeling of fear of punishment. The punishment takes the water for 10 minutes spent in the chamber is a measure of entries status. Tranquilizers eliminate the anxiety and fear and increase the number of punishable takes water.

Anxiolytic effect of the compounds were investigated in doses: IB - 1,15 mg/kg, Iك - 1.4 mg/kg, If - 1.8 mg/kg, and Z - 2.2 mg/kg Effect of compounds in each dose studied for 6 animals. Substances suspended using tween-80 and was administered intraperitoneally for 40 min before the experiment. As the comparison drug used medazepama at a dose of 10 mg/kg

When aggregated to calculate the average number punishable takes water for each group and their standard deviations. Differences between groups were determined using analysis of variance (Statistica, MathSoft, USA).

It is established that the anxiolytic effects of compounds IB and Z significantly exceed the effect of the control group in the test conflicts. These compounds exhibit maximum anxiolytic effect greater than the effect medazepama (table 3).

Conclusion

The researches have revealed a pronounced anti-depressive effect of compounds IB, Iك, Ia and If. This effect is most active compounds Gravesham effect of amitriptyline.

It is established that the compounds IB and Z are anxiolytic effect greater than the effect medazepama.

Table 1
Antidepressant effect of compounds in the test, forced swimming in rats according to the method S.Nomura
GroupDose, mg/kgThe number of revolutions of the wheels
Control-88,30±21,10
Ia1,1069,13±29,83
IB1.15120,00±27,69*
IB1,45by 87.63±57,38
1,40172,41±7,62*
Ia1.50119,49±22,49*
If1,80124,20±22,92*
Z2,20100,00±70,41
Amitriptyline 10,00117,64±16,71*
Note: * - the difference with the control group significantly at P<0,05.

Table 2
The antidepressant activity of the compounds in the test forced swim by the method of Porsolt
GroupDose, mg/kgThe time of immobility (s)
Control-462,40±29,40
Ia1,10419,53±68,41
IB1,15352,47±48,31*
1,40420,66±24,41
Ia1,50380,84±15,93*
If1,80319,79±92,69*
Z2,20294,00±74,72*
Amitriptyline10,00 308,91±69,86*
Note: * - the difference with the control group significantly at P<0,05.

Table 3
Anxiolytic activity of the compounds in the test conflicts
GroupDose, mg/kgThe punishment takes the water
Control-614,60±112,84
IB1,15885,05±84,34*
1,40348,42±186,53
If1,80404,50±286,80
Z2,201049,60±215,43*
The medazepama10,00782,49±69,84*
Note: * - the difference with the control group significantly at P<0,05.

1. 2-Substituted-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-ones of General formula

where R is hydrogen, linear or branched (C1-C4)-alkyl; hydroxyalkyl containing alkyl chain with 2 to 3 C-atoms; phenylalkyl containing alkyl chain with 1-2 C-atoms, the phenyl ring may contain one or two metoxygroup.

2. 2-Methyl-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-one, has antidepressant and anxiolytic action.

3. 2-(2-Hydroxyethyl)-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin - 3-one having the antidepressant effect.

4. 2-(3,4-Dimethoxyphenethyl)-1,2,4,5-tetrahydro-3H-pyrrolo[1,2 - a][1,4]diazepin-3-one, possessing anxiolytic effect.

5. The method of obtaining the compounds described in claim 1, including the interaction of 2,5-dimethoxy-2-(dimethoxymethyl)tetrahydrofuran 3 - aminopropionic acid and subsequent reduction of the mixture of generated allegedely and primary amines (or hydroxylamine), esterification of the resulting amino acid and subsequent cyclization of the resulting compounds.

6. The use of compounds according to claims 1 to 4 as antidepressant and anxiolytics.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: compound is a pyrrolidine derivative having a fragment of a sterically hindered phenol, having general formula: where R1 denotes H, Me, Et; R2 denotes Me, Et, i-Pr, i-Bu; Ar denotes Ph, 2-HalPh, 3-HalPh, 4-HalPh, (where Hal denotes F, Cl, Br, I), 2,6-diMePh, 2,3,5,6-tetraFPh, 2-MeOPh, 3-MeOPh, 4-MeOPh, (naphthalen-1-yl), (naphthalen-2-yl), 2-NO2PH, 3-NO2Ph, 4-NO2Ph. The compounds are obtained by mixing a solution of azomethine of formula: where values of R1, R2 are given above, with N-substituted malemide in air and reaction thereof is induced by catalytic amounts of N-tert-butoxycarbonyl derivatives of alpha-amino acids (glycine, alanine, phenylalanine), followed by concentration of the organic phase at low pressure, and cleaning the residue by chromatography on silica gel using CHCl3/MeOH as the eluent.

EFFECT: prolonged antioxidant activity.

2 cl, 2 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 3-aroyl-2-arylhydrazonopyrrolo[1,2-a]quinozaline-1,4(2H,5H)-diones of formula:

Ar=Ph, R=Me, R1=H (a); Ar=4-MeC6H4 R=Me, R1=H (b); Ar=Ph, R=H, R1=COOH (c).

EFFECT: there are produced new compounds possessing analgesic activity that makes them being suggested to be used in medicine as drugs with the analgesic properties.

1 cl, 3 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel, highly crystalline mono(benzenesulphonic acid)besylate salts and polymorphs of the compound of formula (I): , a pharmaceutical composition containing said compounds, methods of producing the salts and use thereof as medicinal agents, particularly for sedative or hypnotic, anxiolytic, muscle relaxation or anticonvulsant purposes.

EFFECT: improved method.

32 cl, 36 dwg, 22 tbl, 10 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel tricyclic derivative of chemical formula 1 or pharmaceutically acceptable salts thereof: formula 1, where Y1, Y2 and Y3 independently denote H, C1-C10 alkyl with a straight or branched chain, hydroxy, C1-C10 alkoxy, -CCOR1, -NR2R3 or -A-B; A denotes -O-, -CH2-, -CH(CH3)-, -CH-N- or -CONH-; B denotes -(CH2)n1-Z, -(CH2)n2-NR2R3 or -(CH2)n3-OR1; Z denotes C5-C20 aryl, unsubstituted or substituted with R5 and selectively R6, C3-C10 cycloalkyl, unsubstituted or substituted with R5 and selectively R6, C1-C20 heterocyclic compound, unsubstituted or substituted with R5 and selectively R6; R1 denotes H or C1-C10 alkyl with a straight or branched chain; R2 and R3 independently denote H, C1-C10 alkyl with a straight or branched chain or -(CH2)n4R7; R5 denotes H, C1-C10 alkyl with a straight or branched chain, C5-C20 aryl or C1-C20 heterocyclic compound; R6 denotes H or C1-C10 alkyl with a straight or branched chain; R7 denotes -NR8R9, -COOR1, -OR1, -CF3, -CN, halogen or Z; R8 and R9 independently denote H or C1-C10 alkyl with a straight or branched chain; n1-n4 respectively denote an integer from 0 to 15; Y denotes H or C1-C10 alkyl with a straight or branched chain. The invention also relates to methods of producing a compound of formula 1, compositions containing the described compound and with effective inhibiting activity on poly(ADP-ribose)polymerase (PARP).

EFFECT: obtaining and describing novel compounds which can be suitable for preventing or treating diseases caused by excess PARP activity, especially neuropathic pain, neurodegenerative diseases, cardiovascular diseases, diabetic neuropathy, inflammatory diseases, osteoporosis and cancer.

23 cl, 123 ex, 7 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula possessing action on a BH4 sensitive condition.

EFFECT: invention refers to a pharmaceutical composition containing said compound to applying the compound for preparing a drug for treating the BH4 sensitive condition, such as a vascular disease, a psychoneurological disease, hyperphenylalaninemia.

12 cl, 31 dwg, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel derivatives of hexahydro pyrazino [2,1-c][1,2,4]triazine of general formula (III) (values of radicals are given in invention formula), their pharmaceutically acceptable salts and application of said compounds for obtaining medication for treatment and prevention of acute myeloid leukemia.

EFFECT: obtaining medication for treatment and prevention of acute myeloid leukemia

3 cl, 3 ex, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted tetrahydropyrrolopyrazines of general formula I, wherein R1, R2 and R3 in each case independently mean hydrogen or groups R1 and R2 or R2 and R3 form a common cycle ; R4 and R5 in each case independently mean H; R6 means branched or unbranched saturated, unsubstituted C1-6-alkyl, or unsubstituted heteroaryl wherein heteroaryl is a 5- or 6-member aromatic residue containing 1 heteroatom specified in a group consisting of N, O and S, or means phenyl wherein phenyl is unsubstituted or single-substituted or double-substituted by 1 or 2 substitutes which in each case are independently specified in a group consisting of F, Cl, Br, I, CF3, C1-6-alkyl, O-C1-6-alkyl, and , or means unsubstituted phenyl attached through C1-3-alkyl chain; R4a, R5a and R6a in each case independently mean H; R7 means (CH2)tC(=O)R8, wherein t is equal to 1, (C=O)(CH2)mNR11R12, wherein m is equal to 1 or 2, C(=O)(CH2)n(C=O)R8, wherein n is equal to 1, 2 or 3, (CH2)sNHC(=O)R8, wherein s is equal to 1 or 2; R8 means NR9R10 or saturated, branched or unbranched, unsubstituted C1-6-alkyl; wherein R9 and R10 in each case independently mean H, saturated, branched or unbranched, unsubstituted C1-6-alkyl, or unsubstituted or saturated C3-8-cycloalkyl, or phenyl, or phenyl attached through C1-3-alkyl wherein the alkyl chain is saturated, branched or unbranched, and wherein phenyl in each case is unsaturated or single or double saturated by 1 or 2 substitutes which independently specified in a group consisting of F, Cl, Br, I, CF3, C1-6-alkyl, O-C1-6-alkyl, pyridyl, and , or unsubstituted heteroaryl attached through C1-3-alkyl wherein heteroaryl is a 5-member aromatic residue 1 heteroatom of which are specified in a group consisting of O and S, wherein the alkyl chain is saturated, branched or unbranched, or heterocyclyl, or heterocyclyl attached through C1-3-alkyl wherein the alkyl chain is saturated, branched or unbranched, and wherein heterocyclyl in each case is saturated, unsubstituted or single substituted by benzyl, and heterocyclyl contains cycloalkyl containing 5 to 6 atoms in a cycle wherein 1 or 2 carbon atoms are substituted by 1 or 2 heteroatoms which are specified in a group consisting of N; or both groups R9 and R10 mean (CH2)3-6, CH2CH2OCH2CH2 or CH2CH2NR14CH2CH2; wherein R14 means phenyl or phenyl attached through C1-3-alkyl wherein phenyl in each case is unsaturated or single substituted by a substitute whih is specified in a group consisting of F, Cl, Br, I, O-C1-6-alkyl, and , or R14 means C(=O)R13; wherein R13 means saturated and unbranched C1-6-alkyl or means phenyl condensed with heteroaryl wherein heteroaryl is a 6-member aromatic residue 1 heteroatom of which is specified in a group consisting of N; R11 and R12 in each case independently mean H, saturated, branched or unbranched C1-6-alkyl, or unsubstituted, saturated C3-8-cycloalkyl, C(=O)R20 or S(=O)2R13; wherein R20 means NR21NR22, or R20 means saturated, branched or unbranched C1-6-alkyl, or means saturated C3-8-cycloalkyl, unsubstituted or single substituted by phenyl, or means unsaturated heteroaryl wherein heteroaryl is a 5-member aromatic residue 1 heteroatom of which is specified in a group consisting of O, or means phenyl wherein phenyl is unsubstituted or single substituted by C1-6-alkyl or means phenyl attached through C1-6-alkyl which is unsubstituted or single substituted by a substitute specified in a group consisting of F, Cl, Br, I and CF3, wherein the alkyl chain is saturated or unsaturated, branched or unbranched; wherein R21 and R22 in each case independently mean H or saturated, branched or unbranched, unsubstituted C1-6-alkyl; in the form of bases and salts of physiologically acceptable acids. The invention also refers to methods for preparing them, to drug preparations for treating disorders or diseases related with at least partially KCNQ2/3 K+ canals containing such compounds.

EFFECT: there are prepared new compounds and based drug preparations which can find application in medicine for managing pain, epilepsy, migraine, panic conditions and urinary incontinence.

17 cl, 2 tbl, 91 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to fluorinated compounds of formula , where: D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more halogen atoms; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: halogen, C1-C10 alkyl; E denotes aryl which can be substituted with one or more fluoro-substitutes or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more fluoro-substitutes, and where Q denotes O; m denotes a number from 1 to 2; under the condition that: R3 is a fluoro-substitute, or group E includes a fluoro-substitute, or group Z includes a fluoro-substitute, with the condition that E does not denote 4-fluorophenyl or a compound of formula , where D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more of the following substitutes: chlorine, bromine, iodine; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: chlorine, bromine, iodine, C1-C10 alkyl; E denotes aryl which can be substituted with one or more chlorine, bromine or iodine atoms, and/or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more substitutes selected from chlorine, bromine, iodine or hydroxy, where Q denotes O, wherein when E denotes phenyl, E does not contain, as a substitute, iodine which is directly bonded to it at position 4; m denotes a number from 1 to 2; wherein at least one of Z, E and R3 includes iodine; under the condition that E does not denote 4-iodophenyl and under the condition that said compound is not a compound of formula (Ia), defined in the following table:

The invention also relates to a pharmaceutical composition based on the compound of formula (I) or (Ia), a diagnosis method, a method of treating said disorders, based on use of the compound of formula (I) or (Ia), and use of the compound of formula (I) or (Ia).

EFFECT: obtaining novel compounds useful in treating disorders in mammals, characterised by anomalous density of peripheral benzodiazepine receptors.

24 cl, 13 dwg, 9 tbl, 23 ex

FIELD: medicine.

SUBSTANCE: invention refers to an agent for activation of lipoprotein lipase containing a benzene derivative of general formula (1) which is used for preventing and treating hyperlipidemia and obesity. The invention also refers to the benzene derivatives of general formula (1a).

EFFECT: composition improvement.

8 cl, 6 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to pharmaceutics and medicine and concerns the use of compounds of formula (I) their pharmaceutically acceptable salts and solvates for treating depression and related disorders, Parkinson's disease, drug addiction, morphine tolerance and morphine dependence.

EFFECT: development of the preparation for treating depression and related disorders, Parkinson's disease, drug addiction, morphine tolerance and morphine dependence.

7 cl, 5 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 2-substituted-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-ones and 2-substituted-2,3,5,6-tetrahydrooxazolo[3,2-a]pyrimidin-7-ones of formula (I): where p, n, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are described in the description. These compounds are modulators of metabotropic glutamate receptors (mGluR), particularly the mGluR2 receptor. Compounds in the present invention are therefore suitable for use as pharmaceutical agents, especially in treating and(or) preventing various disorders of the central nervous system (CNS), including, among others, acute and chronic neurodegenerative disorders, psychosis, convulsions, anxiety, depression, migraine, pain, sleep disorder and emesis.

EFFECT: improved method.

14 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel amino compound of formula: where X is S or O; R1 and R2 independently denote H or C1-4alkyl, or R1 and R2 together with the nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring; and n equals 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound as an active ingredient, and use of the amino compound or pharmaceutically acceptable salt thereof to produce a drug for treating depression.

EFFECT: improved method.

8 cl, 4 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an agent possessing normothymic activity and containing 0.65-1.95 wt % of potassium chloride, 0.007-0.021 wt % of magnesium sulphate, 0.0028-0.0084 wt % of zinc sulphate, 0.00065-0.00195 wt % of rubidium chloride and water.

EFFECT: invention provides normalisation of the CNS function ensured by normothymic activity.

2 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula possessing action on a BH4 sensitive condition.

EFFECT: invention refers to a pharmaceutical composition containing said compound to applying the compound for preparing a drug for treating the BH4 sensitive condition, such as a vascular disease, a psychoneurological disease, hyperphenylalaninemia.

12 cl, 31 dwg, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of cycloalkylamines, possessing inhibiting activity with respect to, at least, one monoamine transporter, selected from group, consisting of serotonin transporter, dopamine transporter and norepinephrine transporter. In formula (IV): n equals 1; s equals 1; Y and Z each independently represents halogen; X represents OR5; where R5 stands for H or non-substituted C1-C10alkyl; A represents H, non-substituted C1-C10alkyl or halogen; R1 and R2 each independently represents H; R3 and R4 each independently represents H or on-substituted C1-C10alkyl.

EFFECT: invention relates to pharmaceutical composition, containing said compounds and to method of treatment or prevention of neurological disorder or eating disorder, mediated by activity of monoamine transporter, selected from group, consisting of serotonin transporter, dopamine transporter and norepinephrine transporter, such as depression, neurodegenerative disease, abuse with psychoactive substances, fibromyalgia, pain, sleep disorder, syndrome of attention-deficit disorder, syndrome of attention-deficit disorder with hyperactivity, restless legs syndrome, schizophrenia, anxiety, obsessive-compulsive disorder, panic disorder, post-traumatic stress, premenstrual dysphoria.

35 cl, 6 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to a composition inhibiting norepinephrine and/or serotonin transporters containing (-) - [ (5-[3-methylaminoprop -(E)-ylidene] - 10, 11 -dihydro- 5H- dibenzo [a,d] cyclohepten-10-ol] in an enantiomeric residue about 90%, and its use for pain management.

EFFECT: higher clinical effectiveness.

12 cl, 21 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to neurology, therapy, family medicine, and can be used for selection of tactics for treatment of tension headache. For this purpose level of peripheral heart vegetative balance is determined in patient by analysis of index of sympathetic-parasympathetic relationship (LF/HF) in spectral analysis of cardiac rhythm. If LF/HF index increases higher than 2.0 conv. units, psychotropic drugs are introduced into therapy for relief of anxiety and/or depression.

EFFECT: method ensures possibility to stratify patients, requiring introduction of psychotropic drugs, thus making it possible to optimise treatment and increase its efficiency due to account of individual peculiarities of heart vegetative balance.

3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to specific compounds of 1-substituted 3,4-tetrahydroisoquinoline derivative. Invention also relates to pharmaceutical composition based on claimed compounds, to blocker of N-type Ca2+- channel based on claimed compounds, to application of claimed compounds, as well as to method of prevention or treatment of some pathologic conditions.

EFFECT: obtained are novel 3,4-tetrahydroisoquinoline derivatives, having substituent in 1-position and possessing blocking action on N-type Ca2+- channels.

15 cl, 129 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula , where A, Q, R1, R2, R3, R4, R5' are represented in i.1 of the formula, as well as to its hydrates, solvates and pharmaceutically acceptable salts, Also described are application of said compound and pharmaceutical composition, including such compound, for treatment of disease condition in mammals, which is sensitive to action of antagonists of vasopressin V1a, V1b or V2 receptors.

EFFECT: increase efficiency of compound application.

20 cl, 13 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to specific compounds of 1-substituted 3,4-tetrahydroisoquinoline derivative. Invention also relates to pharmaceutical composition based on claimed compounds, to blocker of N-type Ca2+- channel based on claimed compounds, to application of claimed compounds, as well as to method of prevention or treatment of some pathologic conditions.

EFFECT: obtained are novel 3,4-tetrahydroisoquinoline derivatives, having substituent in 1-position and possessing blocking action on N-type Ca2+- channels.

15 cl, 129 tbl, 17 ex

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