2-substituted-1,2,4,5-tetrahydro-3h-pyrrolo[1,2-a][1,4]diazepin-3-ones. RU patent 2472795.

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, particularly to a new group pyrrolo[1,2-a][1,4]of benzodiazepines the General formula:

where R = hydrogen, linear or branched (With 1-4 )-alkyl; hydroxyalkyl containing alkyl chain with 2-3 With atoms; phenylalkyl containing alkyl chain with 1-2 With atoms, while the phenyl ring can be one or two metoxygroup.

The claimed compounds have expressed anxiolytic and antidepressant activity.

The results of numerous clinical studies show that certain forms of a mental pathology rather seldom isolated and often presented in the form of complex compositions in structure of various psychopathological syndromes. This fully applies to mental disorders neurotic level at which revealed a significant frequency of States with comorbid anxiety, affective and cognitive impairment [of Depression and comorbid disorders. Abisalovich (as amended), Moscow (1997)]. The treatment of such disorders is always a serious issue, due to the lack of use of specific drugs of different groups because of the complexity of "targets" of therapeutic effects [Tab, Chasunah, Vasily Bochkarev, Eshtaeva, Phenazepam: 25 years in medical practice, Moscow (2007), SS-277], and the possible risk of increased side effects of the drugs caused by the mechanisms of their interaction with combination therapy [Tab, Psihofarmakoterapia neurotic disorders, Moscow (1987), SS-268].

In addition, separately and used psychotropic drugs also have negative effects. So, reduction of anxiety with anxiolytics accompanied miorelaksantnoe, sedative and amnestic effects, particularly pronounced in the elderly. In addition, benzodiazepine anxiolytics (like other GABA-positive substance) can have negative effects on the immune system [V.Covelli, I.Munno, P.Decandia, et al. Acta Neurologica, 1991, 13, 418]. Reducing depression with antidepressants (including atypical) often leads to increased anxiety, development cardiotoxic and anticholinergic effects. Prolonged use of memory for the correction of frustration often leads to negative results and patients refuse treatment. In a joint introduction of pharmacological preparations of different classes (anxiolytics with antidepressants or nootropics, nootropics with antidepressants) are increasing their main effects, as a rule, accompanied by increased side effects [Tab, Psychother. malteria neurotic disorders, Moscow (1987), SS-268].

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

The connection I, their properties and how to obtain not described in literature. The closest prototype of the chemical structure is 7-methyl-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepam-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 the 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 (bul. invention №3, 1981); US Patent 5378846 (1995)]. Previously described connections are different from the claimed in structure and pharmacological properties.

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

Boiling solution 2,5-dimethoxy-2-(dimethoxymethyl)tetrahydrofuran (II) [Vpered, Rootrevoke, Ameliorarea, Aphrodyne, Segerberg, Apostolidou, Khim.-Pharm. Ukr., 1982, 16, 537] and 3-aminopropionic acid (III) in water for one hour will receive 3-(2-formyl-1H-pyrrol-1-yl)propionic acid (IV). Hydrogenation when a mixture of 3-(2-formyl-1H-pyrrol-1-yl)propionic acid (IV) and hydroxylamine in methanol for palladium catalyst get a mixture of amino acids (V and VI), which is then without separation eterificare 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), without which the selection is turned into a mixture of relevant 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepam-3-ones (Ia and AI), which is shared by chromatography column on aluminum oxide. Connection Ia is a light yellow powder, insoluble in water, soluble in alcohols. 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]diazepam-3-ones (IB-C) receive, as follows:

During the restoration aminating aldehidelor (IV) with primary amines by hydrogenation on palladium catalyst at atmospheric pressure receive amino acids (Ha-W), which are further eterificare effect of methanol thionyl chloride with subsequent alkalinization of potash. The resulting amino esters (X) without releasing next cyclist by boiling in o-xylene in the relevant 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepam-3-ones (IB-C). Connection IB-C are white or slightly yellow 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 spectra 1 N 2-substituted 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepam-3-ones are multiplets N 2 C(4)-group in the field 2.90-3.10 ppm, multiplets N 2(5)groups in the field 4.10-4.27 ppm, singlets (doublet for connection Ia) N 2(1)-group and three multiplet of pyrrole protons in the field of 5.85-6.65 ppm

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

The solution 5.01 g (30 mmol) 3-(2-formyl-1H-pyrrol-1-yl)propionic acid and 5.10 g (33 mmol) 20%alcohol solution methylamine in 80 ml of ethanol was added 0.4 grams of palladium on coal (10% Pd), and the reaction mass was first made at atmospheric pressure to absorb theoretical quantity of hydrogen. The catalyst was filtered and the filtrate was evaporated to dryness. The residue was dissolved in 50 ml of methanol. To the obtained solution at temperature-10C pinned 2.55 ml (35 mmol) of thionyl chloride in 5 minutes. The reaction mass was passed the day at room temperature and evaporated to dryness. The residue was added to the solution of 8 g TO 2, WITH 3 in 40 ml of water, and the product was extracted 30+20+10 ml of chloroform. United chloroform solutions washed 20 ml of water were filtered through a paper filter and evaporated to dryness. The residue was dissolved in 30 ml of xylene, the resulting solution was heated under reflux for 8 hours and were evaporated to dryness. The residue was recrystallized from 15 ml of toluene. Got 2.81 g of the product in the form of a light yellow needle-shaped crystals (exit 57%). TPL 108-110°N Found (%): S, 66.05; N, 7.36; N, 17.34. C 9 12 H N 2 O. Calculated (%): S, 65.83; N, 7.37; N, 17.06. An NMR spectrum 1 N (CDCl 3 , Delta that ppm): 3.01 (m 2N, N 2(4)); 3.03 (C, 3H, Me); 4.21 (m 2N, N 2(5)); 4.43 (s, 2 N, N 2(1)); 5.96 (m, 1H, NS(9)); 6.07 (m, 1H, NS(8)); 6.61 (m, 1 N, NS(7)).

Obtaining initial connection:

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

The solution 17.82 g (0.2 mol) 3-aminopropionic acid 240 ml of water and 45.37 g (0.22 mol) 2,5-dimethoxy-2-(dimethoxymethyl)tetrahydrofuran was heated under reflux for one hour, was evaporated to half of the volume and cooled to room temperature. Dropped the reaction product was filtered, washed with water and dried. Output 92.2%, red-brown crystals, TPL 98-99°N Found (%): S, 57.64; N, 5.40; N 8.49. C 8 H 9 NO 3 . Calculated (%): S, at 57.48; N, 5.43; N, 8.38. An NMR spectrum 1 H (DMSO, Delta that ppm, J/Hz): 2.93 (t, 2N, CH

2-CO 2 H, 3 J=6.5); 4.58 (t, 2N, N

2-CH 2 CO 2 H, 3 J=6.5); 6.15 (m, 1H, NS(4)); 6.95 (m, 1H, NS(3)); 7.31 (m, 1H, NS(5)); 9.35 (, 1H, SLEEP).

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

To 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 minus 10 Celsius pinned 1.82 ml (25 mmol) of thionyl chloride in 5 minutes. The reaction mass was passed the day at room temperature and evaporated to dryness. The remainder was added to a solution of 5 g K 2 CO 3 in 20 ml of water, and the product was extracted with 20+20+5 ml of toluene. United toluene solution was filtered through a paper filter, heated under reflux for 10 hours, passed through a column of alumina, using as eluent toluene, and was evaporated to dryness. The remainder were directed at 1.5 mm Hg (BP. 152-154 C). Got 2.60 g of the product in the form of a light yellow powder (exit 63%). TPL 57-59°N Found (%): S, at 69.74; N, 8.66; N, 13.43. C 9 12 H N 2 O. Calculated (%): S, 69.87; N, 8.79; N, 13.58. An NMR spectrum 1 N (CDCl 3 , Delta that MD,.J/Hz): 0.84 (d, 6N, 2 Me, J=6.7); 1.91 (m, 1H, C H Me 2 ); 3.02 (m 2N, N 2(4)); 3.26 (d, 2N, N

2-Snme 2 , 3 J=7.6); 4.21 (m 2N, C H 2(5)); 4.42 (C, 2H, H 2 C(1)); 5.92 (m, 1H, NS(9)); 6.06 (m, 1H, NS(8)); 6.60 (m, 1H, NS(7)).

Obtaining initial connection:

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

The solution 5.01 g (30 mmol) 3-(2-formyl-1H-pyrrol-1-yl)propionic acid and 2.41 g (33 mmol) isobutylamine 80 ml atiola added 0.4 grams of palladium on coal (10% Pd), and the reaction mass was first made at atmospheric pressure to absorb theoretical quantity of hydrogen. The catalyst was filtered and the filtrate was evaporated to dryness. The residue was recrystallized from 75 ml of isopropanol. Got 5.22 g of the product in the form of yellow-pink powder (exit 78%). TPL 154-156°N Found (%): S, at 64.29; N, 9.21; N, 12.37. C 12 H 20 N 2 O 2 . Calculated (%): S, at 64.26; N, 8.99; N, 12.49. An NMR spectrum 1 N (DMSO, Delta that ppm, J/Hz): 0.91 (d, 6N, 2 Me, 3 J=6.7); 1.95 (m, 1H, N. IU 2 ); 2.49 (t, 2N, N

2-CO 2 H, 3 J=5.3); 2.67 (d, 2H, NH-C H

2-CH, 3 J=7.5); 3.96 (m, 4H, CH 2 s N

2-CO 2 H and Pyrrol-C H

2-NH); 6.01 (m, 1H, NS(3)); 6.09 (m, 1H, NS(4)); 6.83 (m, 1H, NS(5)).

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

To suspension of 4.25 g (20 mmol) 3-(2-{[(2-hydroxyethyl)amino]methyl}-1H-pyrrol-1-yl)propionic acid 70 ml of methanol at a temperature of minus 10 Celsius pinned 1.82 ml (25 mmol) of thionyl chloride in 5 minutes. The reaction mass was passed the day at room temperature and evaporated to dryness. The remainder was added to a solution of 5 g K 2 CO 3 in 20 ml of water, and the product was extracted with 20+10+5 ml of chloroform. United chloroform solution was filtered through a paper filter and evaporated to dryness. The residue was dissolved in 30 ml of xylene, the solution was heated under reflux for 14 hours and was evaporated to dryness. The residue was dissolved when heated in 15 ml of toluene and leave for 1 day at the 4th C. the formed sediment was filtered. Got 3.19 g of the product in the form of a white powder (exit 82%). TPL 111-113°N Found (%): S, 61.62; N, 7.32; N, at 14.66. C 10 14 N H 2 O 2 . Calculated (%): S, 61.84; N, 7.27; N, 14.42. An NMR spectrum 'N (CDCl 3 , Delta that ppm, J/Hz): 2.25 (ush. with, 1H, IT); 3.05 (m 2N, N 2(4)); 3.62 (t, 2N, N

2 CH 2 Oh, 3 J=5.2); 3.74 (t, 2N, N

2-HE, 3 J=5.2); 4.22 (m 2N, N 2(5)); 4.53 (2N, N 2(1)); 5.96 (m, 1H, NS(9)); 6.08 (m, 1H, NS(8)); 6.62 (m, 1H, NS(7)).

Obtaining initial connection:

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

The solution 5.01 g (30 mmol) 3-(2-formyl-1H-pyrrol-1-yl)propionic acid and 2.02 g (33 mmol) 2-ethanolamine 70 ml of ethanol was added 0.4 grams of palladium on coal (10% Pd), and the reaction mass was first made at atmospheric pressure to absorb theoretical quantity of hydrogen. The catalyst was filtered and the filtrate was evaporated to approximately 20 ml and leave for 1 day at the 4th C. the formed sediment was filtered. Got 5.35 g of the product in the form of a white powder (exit 84%). TPL 158-160°N Found (%): S, 56.51; N, 7.83; N, 13.33. C 10 16 N H 2 O 3 . Calculated (%): S, 56.59; N, 7.60; N, 13.20. An NMR spectrum 1 N (DMSO, Delta that ppm, 3 J/Hz): 2.79 (t, 2N, N

2-CO 2 H, 3 J=5.5); 3.52-3.62 (m, 4H, C H

2-ONE); 3.98 (C, 2H, Pyrrol-C H

2-NH); 4.00 (t, 2N, C H

2-CH 2 CO 2 H, 3 J=5.5); 5.96 (m, 1H, NS(3)); 6.00 (m, 1H, NS(4)); 6.81 (m, 1H, NS(5)).

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

To suspension 4.53 g (20 mmol) 3-(2-{[(3-hydroxypropyl)amino]methyl}-1H-pyrrol-1-yl)propionic acid 70 ml of methanol at a temperature of minus 10 Celsius pinned 1.82 ml (25 mmol) of thionyl chloride in 5 minutes. The reaction mass was passed the day at room temperature and evaporated to dryness. The remainder was added to a solution of 5 g K 2 CO 3 in 20 ml of water, and the product was extracted with 20+10+5 ml of chloroform. United chloroform solution was filtered through a paper filter and evaporated to dryness. The residue was dissolved in 30 ml of xylene, the solution was heated 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 Al 2 O 3 , using as eluent toluene. The eluate was evaporated to dryness, receiving 3.62 g of the product in the form of a light yellow powder (exit 87%). TPL 37-39°N Found (%): S, 63.30; N, 7.82; N, 13.46. C 11 16 N H 2 O 2 . Calculated (%): S, 63.44; N, 7.74; N 13.45. An NMR spectrum 1 N (CDCl 3 , Delta that ppm, J/Hz): 1.68 (m 2N, N

2 CH 2 Oh); 2.59 (ush. with, 1H, IT); 3.05 (m 2N, N 2(4)); 3.38 (t, 2N, N

2 -(CH 2 ) 2-HE, 3 J=5.5); 3.60 (t, 2N, C H

2-OH, 3 J=6.1); 4.23 (m 2N, N 2(5)); 4.43 (2N, N 2(1)); 5.95 (m, 1H, NS(9)); 6.07 (m, 1H, NS(8)); 6.61 (m, 1H, NS(7)).

Obtaining initial connection:

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

The solution 5.01 g (30 mmol) 3-(2-formyl-1H-pyrrol-1-yl)propionic acid and 2.48 g (33 mm) 3-propanolamine 70 ml of ethanol was added 0.4 grams of palladium on coal (10% Pd), and the reaction mass was first made at atmospheric pressure to absorb theoretical quantity of hydrogen. The catalyst was filtered and the filtrate was evaporated to approximately 20 ml and leave for 1 day at the 4th C. the formed sediment was filtered. Received 5.6 g of the product in the form of a white powder (exit 83%). TPL 164-166°N Found (%): S, 58.49; N, 8.25; N, 12.30. C 11 18 N H 2 O 3 . Calculated (%): S, 58.39; N, 8.02; N, 12.38. An NMR spectrum 1 N (DMSO, Delta that ppm, J/Hz): 1.72 (m 2N, C H

2-CH 2-ONE); 2.49 (t, 2N, NH-C H

2-CH 2 , 3 J=6.7); 2.82 (t, 2N, C H

2-CO 2 H 2 J=5.7); 3.48 (t, 2N, N

2-HE, 3 J=6.0); 4.00 (t, 2N, N

2-CH 2 CO 2 H, 3 J=5.7); 4.05 (C, 2H, Pyrrol-C H

2-NH); 6.00 (m, 1H, NS(3)); 6.03 (m, 1H, NS(4)); 6.85 (m, 1H, NS(5)).

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

To suspension 5.17 g (20 mmol) 3-{2-[(benzylamino)methyl]-1H-pyrrol-1-yl}propionic acid 70 ml of methanol at a temperature of minus 10 Celsius pinned 1.82 ml (25 mmol) of thionyl chloride in 5 minutes. The reaction mass was passed the day at room temperature and evaporated to dryness. The remainder was added to a solution of 5 g K 2 CO 3 in 20 ml of water, and the product was extracted with 20+20+5 ml of toluene. United toluene solution was filtered through a paper filter and evaporated to dryness. The residue was dissolved in 30 ml of xylene, the solution was heated under reflux for 20 hours and was evaporated to dryness. The remainder were directed at 1 mm Hg (BP. 204-206 C). Received 3.12 g of the product in the form of a yellow oil (exit 65%). Found (%): S, 75.08; N, 6.59; N 11.80. C 15 16 H N 2 O. Calculated (%): S, at 74.97; N, 6.71; N, 11.66. An NMR spectrum 1 N (CDCl 3 , Delta that ppm): 3.10 (m 2N, N 2(4)); 4.27 (m 2N, N 2(5)); 4.34 (2N, N

2-Ph); 4.65 (2N, N 2(1)); 5.85 (m, 1H, NS(9)); 6.06 (m, 1H, NS(8)); 6.63 (m, 1H, NS(7)); 7.21-7.39 (m, 5H, Ph).

Obtaining initial connection:

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

To suspension of 5.45 g (20 mmol) 3-{2-[(fenetylline)methyl]-1H-pyrrol-1-yl}propionic acid 70 ml of methanol at a temperature of minus 10 Celsius pinned 1.82 ml (25 mmol) of thionyl chloride in 5 minutes. The reaction mass was passed the day at room temperature and evaporated to dryness. The remainder was added to a solution of 5 g K 2 CO 3 in 20 ml of water, and the product was extracted with 20+20+5 ml of toluene. United toluene solution was filtered through a paper filter and evaporated to dryness. The residue was dissolved in 30 ml of xylene, the solution was heated under reflux for 20 hours and was evaporated to dryness. The residue was dissolved when heated under 12 ml isopropanol and leave for 1 day at the 4th C. the formed sediment was filtered. Got 3.61 g of the product in the form of light pink powder (exit 71%). TPL 101-102°N Found (%): S, 75.55; N, 6.98; N, 10.88. C 16 H 18 N 2 O. Calculated (%): S, 75.56; N, 7.13; N, 11.01. An NMR spectrum 1 N (CDCl 3 , Delta that ppm, J/Hz): 2.83 (t, 2N, C H

2 Ph, 3 J=7.3); 2.97 (m 2N, N 2(4)); 3.71 (t, 2N, C H

2-CH 2-Ph, 3 J=7.3); 4.10 (m 2N, N 2(5)); 4.34 (2N, N 2(1)); 5.92 (m, 1H, NS(9)); 6.08 (m, 1H, NS(8)); 6.60 (m, 1H, NS(7)); 7.05-7.29 (m, 5H, Ph).

Obtaining initial connection:

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

The solution 5.01 g (30 mmol) 3-(2-formyl-1H-pyrrol-1-yl)propionic acid and 4.00 g (33 mmol) phenethylamine in 100 ml of methanol were added 0.4 grams of palladium on coal (10% Pd), and the reaction mass was first made at atmospheric pressure to absorb theoretical quantity of hydrogen. The catalyst was filtered and the filtrate was left for 1 day at the 4th C. the formed sediment was filtered. Got 6.54 g of the product in the form of a white powder (exit 80%). TPL 160-161°N Found (%): S, 70.79; N, 7.72; N, 10.43. C 16 H 20 N 2 O 2 . Calculated (%): S, 70.56; N, 7.40; N 10.29. An NMR spectrum 1 N (DMSO, Delta that ppm, J/Hz): 2.72 (t, 2N, N

2-CO 2 H, 3 J=5.3); 2.95 (m, 4H, C H

2-Ph); 3.92 (t, 2N, N

2-CH 2 CO 2 H, 3 J=5.3); 3.99 (C, 2H, Pyrrol-C H

2-NH); 6.03-6.11 (m 2N, NS(3), NA(4)); 6.70 (m, 1H, NS(5)); 7.03-7.26 (m, 5H, Ph).

Example 7: 2-(3,4-dimethoxyphenyl)-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepam-3-one (Z, R=CH 2 CH 2 Ph(OMe) 2 -3,4).

To suspension of 6.65 g (20 mmol) 3-{2-[(fenetylline)methyl]-1H-pyrrol-1-yl}propionic acid 70 ml of methanol at a temperature of minus 10 Celsius pinned 1.82 ml (25 mmol) of thionyl chloride in 5 minutes. The reaction mass was passed the day at room temperature and evaporated to dryness. The remainder was added to a solution of 5 g K 2 CO 3 in 20 ml of water, and the product was extracted with 20+20+5 ml of toluene. United toluene solution was filtered through a paper filter and evaporated to dryness. The residue was dissolved in 30 ml of xylene, the solution was heated under reflux for 20 hours and was evaporated to dryness. The residue was dissolved when heated under 12 ml isopropanol and leave for 1 day at the 4th C. the formed sediment was filtered. Got 4.65 g of the product in the form of a light yellow powder (exit 74%). TPL 115-116°N Found (%): S, 68.78; N, 7.11; N, 8.82. C 16 H 18 N 2 O. Calculated (%): S, 68.77; N, 7.05; N, 8.91. An NMR spectrum 1 N (CDCl 3 , Delta that ppm, J/Hz): 2.77 (t, 2N, C H

2-Ph, 3 J=7.3); 2.97 (m 2N, N 2(4)); 3.69 (t, 2N, C H

2-CH 2-Ph, 3 J=7.3); 3.83, 3.84 (both with, 3H, 2 OMe); 4.11 (m 2N, N 2(5)); 4.35 (2N, C H 2(1)); 5.90 (m, 1H, NS(9)); 6.07 (m, 1H, NS(8)); 6.58 (m, 1H, NS(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=CH 2 CH 2 Ph(OMe) 2 -3,4).

The solution 5.01 g (30 mmol) 3-(2-formyl-1H-pyrrol-1-yl)propionic acid and 5.98 grams (33 mmol) 3,4-dimethoxyphenethylamine in 100 ml of methanol were added 0.4 grams of palladium on coal (10% Pd), and the reaction mass was first made at atmospheric pressure to absorb theoretical quantity of hydrogen. The catalyst was filtered and the filtrate was left for 1 day at the 4th C. the formed sediment was filtered. Got 7.68 g of the product in the form of a white powder (exit 77%). TPL 175-180°N Found (%): S, 65.18; N, 7.15; N, 8.59. C 18 H 24 N 2 O 4 . Calculated (%): S, 65.04; N, 7.28; N, 8.43. An NMR spectrum 1 N (DMSO, Delta that ppm, J/Hz): 2.73 (t, 2N, N

2-CO 2 H, 3 J=5.2); 2.85-3.05 (m, 4H, C H

2-Ph); 3.78, 3.81 (both with, 3H, 2 OMe); 3.92-3.99 (m, 4H, H

2-CH 2 CO 2 H, Pyrrol-C H

2-NH); 6.04 (m, 1H, NS(3)); 6.11 (m, 1H, NS(4)); 6.62-6.74 (m, 4H, NS(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 3-(2-{[3-oxo-4,5-dihydro-1H-pyrrole[1,2-a][1,4]diazepam-2(3H)-yl]methyl}-1H-pyrrol-1-yl)propionic acid (AI).

The solution 5.01 g (30 mmol) 3-(2-formyl-1H-pyrrol-1-yl)propionic acid (IV) and 4.95 g 50%solution of hydroxylamine in water (75 mmol) in 70 ml of methanol and 20 ml of water was added 0.5 grams of palladium on coal (10% Pd)y and the reaction mass was first made at atmospheric pressure to absorb theoretical quantity of hydrogen. The catalyst was filtered and the filtrate was evaporated to dryness. The residue was added 70 ml of methanol. To the obtained suspension at a temperature of minus 10 Celsius pinned 2.85 ml (39 mmol) of thionyl chloride in 5 minutes. The reaction mass was passed the day at room temperature and evaporated to dryness. The residue was added solution 10 g K 2 CO 3 in 40 ml of water, and the product was extracted 30+20+10 ml of chloroform. United chloroform solutions washed 20 ml of water were filtered through a paper filter and evaporated to dryness. The residue was dissolved in 30 ml of xylene, the solution was heated under reflux for 10 hours and was evaporated to dryness. The remainder was chromatographically on a column with aluminum oxide, using as eluent the chloroform. After a full cut output from R f =0.44 column washed with a mixture of methanol and chloroform in the ratio 1:2 until the shut faction with R f =0.22. The first fraction (R f =0.44) was evaporated to dryness, receiving 2.71 g methyl ester 3-(2-{[3-oxo-4,5-dihydro-1H-pyrrole[1,2-a][1,4]diazepam-2(3H)-yl]methyl}-1H-pyrrol-1-yl)propionic acid (AI) in the form of orange oil (exit 57%). Found (%): S, 64.61; N, 6.55; N 13.45. C 17 21 N H 3 O 3 . Calculated (%): S, 64.74; N, 6.71; N, 13.32. An NMR spectrum 1 N (CDCl 3 , Delta that ppm, J/Hz): 2.48 (t, 2N, N

2-CO 2 Me, 3 J=6.9); 3.07 (m 2N, N 2(4)); 3.65 (C, 3H, OMe); 4.05 (t, 2N, N

2-CH 2 CO 2 Me, 3 J=6.9); 4.25 (m 2N, N 2(5)); 4.34 (C, 2H, Pyrrole-C H

2 ); 4.60 (2N, N 2(1)); 5.76 (m, 1H, H pyrr' (3)); 6.03 (m, 1H, H pyrr' (4)); 6.08 (m, 1H, NS(9)); 6.13 (m, 1H, NS(8)); 6.59 (m, 1H, H pyrr' (5)); 6.65 (m, 1H, NS(7)). The second fraction (R f =0.22) also were evaporated to dryness, the residue was recrystallized from isopropanol, receiving 0.84 g 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepam-3-one (Ia) in the form of a yellow powder (exit 19%). TPL 115-117°N Found (%): S, 63.83; N, 6.80; N, 18.79. C 8 H 10 N 2 O. Calculated (%): S, 63.98; N, 6.71; N, 18.65. An NMR spectrum 1 N (CDCl 3 , Delta that ppm, J/Hz): 2.90 (m 2N, N 2(4)); 4.21 (m 2N, N 2(5)); 4.34 (l, 2 N, N 2(1), 3 J=5.4); 5.96 (m, 1H, NS(9)); 6.06 (m, 1H, NS(8)); 6.62 (m, 1H, NS(7)); 6.80 (ush. with, 1H, NH).

Pharmacological study of the claimed compounds.

The study of the antidepressive activity of compounds.

Antidepressive activity of the compounds were studied by the model of forced swimming in rats test of despair [Andreeva N I Methodical instructions for study antidepressant activity, pharmacological substances. Guide to experimental (pre-clinical) studies of new pharmacological substances. - Second edition, revised and supplemented. / CH. Ed. Rugalev, Moscow (2005), s-252] on techniques 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]. The studies were performed on white mongrel rats-males age of 2-2,5 months and a lot of 220-250,

To estimate effect of antidepressant compounds method Nomura et al. in the test of forced swimming in rats in a jar with water and freely rotating wheels was used four-channel installation, developed in the Institute of pharmacology them. You RAMS [Gemmologischen, Tagaranna, Allmineral, Experimental. and the wedge. Pharmacol., 1994, 57, 3]. The installation is a vessel the size of 64 x 30 x 42 cm, divided into 4 equal compartment. In the compartments are wheel width of 11 cm with 12 blades 2 cm wide, the external diameter of the wheels 10 see At the edges of each wheel fortified magnet, and over the wheels - the switches that works every time, when the magnet passes under them. So there is an automatic check of rotation of the wheels, which is an objective measure of activity of animals. The vessel is filled with water with a temperature of 25 C to mid-wheels. Rats were placed in each compartment muzzle from the wheel and record the speed of the wheels for 10 minutes with the help of Electromechanical meters.

The effect of each of the compounds were studied in 8 animals, suspended substances with the twin-80 and was injected intraperitoneally: Ia - 1,1 mg/kg; IB - 1,15 mg/kg; In 1,45 - mg/kg; Iك - 1.4 mg/kg; Ia - 1.5 mg/kg; If 1,8 - mg/kg and IP - 2.2 mg/kg for 40 minutes before experience. The comparison was carried out with antidepressant amitriptyline.

The aggregation of the results obtained to calculate the average speed for each group and standard deviation, the significance of differences between groups were determined using variance analysis, which is part of the statistical software package Statistica 6.0 For (MathSoft, USA).

It is established that when using compounds IB, Iك, Ia and If the speed of the wheels was significantly increased compared with the control group (table 1). The maximum effect, exceeding the effect of amitriptyline, noted in connection Iك and If.

The investigated substance showed high efficiency test and forced swimming in rats by the method Porsolt et al. The effect of the compounds were carried out in comparison with amitriptyline.

The next day training-development of the skill of taking water from the trough. The training lasted for 5 min, which allowed to develop a skill takes water in rats and do not give the animals to drink before the experience, i.e. to keep drinking motivation. The next day the rat was placed in a cell for 10 minutes and 10 seconds after the start drinking at drinkers and electrode floor of the cell was filed current to 0.25 mA, so that each take the water was punishable. In order to meet drinking motivation, the rat must overcome the feeling of fear of punishment. Among the punishable takes water for 10 minutes spent in the camera is a measure entries status. Tranquilizers eliminate the feeling of anxiety and fear and increase the number punishable takes water.

Anxiolytic effect of the compounds investigated in doses: IB - 1,15 mg/kg, Iك - 1.4 mg/kg, If - 1.8 mg/kg and IP - 2.2 mg/kg Effect connections in each dose studied for 6 animals. Substances suspended use of the twin-80 and was administered intraperitoneally for 40 minutes before experience. As the comparison drug used medzepama in the 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 anxiolytic effects connections IB and Z significantly exceed the effect of the control group in the test conflict situation. These compounds exhibit maximum anxiolytic effect, exceeding the effect of the medzepama (table 3).

Conclusion

The researches have revealed a pronounced antidepressant effect connections IB, Iك, Ia and If. This effect is most active connection Iك than the effect of amitriptyline.

It is established, that connection IB and Z are anxiolytic effect, exceeding the effect medzepama.

Antidepressant effect of compounds in the test of forced swimming in rats by the method S.Nomura

Dose, mg/kg

The speed of the wheels

88,30±21,10

69,13±29,83

120,00±27,69*

by 87.63±57,38

172,41±7,62*

119,49±22,49*

124,20±22,92*

100,00±70,41

Amitriptyline

117,64±16,71*

Note: * - the difference with the control group significantly at P<0.05.

Antidepressant effect of compounds in the test of forced swimming technique Porsolt

Dose, mg/kg

Time of stillness, (C)

462,40±29,40

419,53±68,41

352,47±48,31*

420,66±24,41

380,84±15,93*

319,79±92,69*

294,00±74,72*

Amitriptyline

308,91±69,86*

Note: * - the difference with the control group significantly at P<0.05.

Anxiolytic effects connections in the test conflict situation

Dose, mg/kg

Among the punishable takes water

614,60±112,84

885,05±84,34*

348,42±186,53

404,50±286,80

1049,60±215,43*

The medzepama

782,49±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]diazepam-3-ons General formula

where R - hydrogen, linear or branched (With 1-4 )-alkyl; hydroxyalkyl containing alkyl chain with 2-3 With atoms; phenylalkyl containing alkyl chain with 1-2 With atoms, while the phenyl ring can be one or two metoxygroup.

2. 2-Methyl-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepam-3-one, with antidepressant and anxiolytic effects.

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

4. 2-(3,4-Dimethoxyphenyl)-1,2,4,5-tetrahydro-3H-pyrrolo[1,2 - a][1,4]diazepam-3-one with anksioliticski action.

5. The method of obtaining the compounds described in claim 1, comprising the interaction 2,5-dimethoxy-2-(dimethoxymethyl)tetragidrofurane with 3 - aminopropionic acid with subsequent restoration of the mixture generated aldehidelor and primary amines (or of hydroxylamine), esterification the resulting amino acids and followed by cyclization of produced substances.

6. The use of connections according to claims 1 to 4 as antidepressant and anxiolytic funds.