Novel benzothiazinone derivatives and use thereof as antibacterial agents

FIELD: chemistry.

SUBSTANCE: invention describes novel benzothiazinone derivatives of formula (I) and their use as antibacterial agents in infectious diseases caused by bacteria, especially mycobacterium tuberculosis (TB) and leprosy, in which R1 and R2 independently denote NO2, CN, CONR7R8, COOR9 CHO, halogen, SO2NR7R8, OCF3, trifluromethyl; R3 and R4 independently denote H or methyl; R5 and R6 independently denote a straight or branched aliphatic radical having 1-8 members in the chain, or R5 and R6 together denote a divalent radical -(CR92)m- or R5 and R6 together denote a divalent radical: R7, R8 and R9 independently denote H or a straight or branched aliphatic radical having 1-7 members in the chain, or phenyl.

EFFECT: design of an efficient method of obtaining benzothiazinone derivatives, a pharmaceutical composition having anti-mycobacterial activity.

12 cl, 6 tbl, 12 ex

 

The present invention relates to new derivatives benzothiazine and their use as antibacterial agents in infectious diseases of mammals (humans and animals), caused by bacteria, especially for diseases such as tuberculosis (TB) and leprosy, caused by Mycobacterium.

Diazinon, their derivatives and their use as antibacterial agents, particularly against mycobacteria (TB), described, for example, in AR 242567 A1, AU 3704400 A1, CA 1322551 C1 or EP 0245901 B1.

As is known, globally there is an alarming increase in the incidence of tuberculosis caused by mycobacteria, have developed resistance to existing drugs (B.R.Bloom, J.L.Murray. Tuberculosis: commentary on a reemergent killer. Science 257, 1992, 1055-1064). Extremely dangerous is the spread of tuberculosis multidrug-resistant (MDR). These are bacilli resistant to at least to two of the most active drugs against tuberculosis, isoniazid and rifampicin, as well as resistant to streptomycin, pyrazinamide and ethambutol. The proportion of MDR-TB in some countries already exceeds 20%. Given the overall growth in the number of TB cases that annually causes about 3000000 deaths worldwide.

For the treatment of diseases such as TB or leprosy, there is an urgent need for new drugs is new mechanisms of action, especially to overcome drug resistance and to overcome the known major side effects of medications available.

The objective of the invention

The present invention is directed to new compounds with activity against mycobacteria, as potential new drugs for tuberculosis, designed to solve problems associated with stability and drug intolerance.

The solution of the technical problem

The goal was achieved by obtaining the compounds of formula I

or its salt,

where R1and R2independently from each other represent NO2, CN, CONR7R8, COOR9, SNO, halogen, SO2NR7R8, OCF3mono-, di - or trifluoromethyl;

R3and R4independently of one another represent H or methyl;

R5and R6independently from each other represent a linear or branched aliphatic radical having 1-8 members in the chain, or R5and R6together represent a bivalent radical -(CR92)m-, or R5and R6together represent a bivalent radical:

where m is 1-4;

R7, R8and R9independently represent H or a linear or branched aliphatic radical having 1-7 members in the chain, or phenyl.

In a preferred embodiment, the present invention relates to compounds of formula (I)selected from the group consisting of:

2-(4-R5-4-R6-piperidine-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one,

6-cyano-2-(4-R5-4-R6-piperidine-1-yl)-8-nitro-1,3-benzothiazin-4-one,

6-amido-2-(4-R5-4-R6-piperidine-1-yl)-8-nitro-1,3-benzothiazin-4-one,

2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-Rl-6-R2-1,3-benzothiazin-4-one,

2-(2-methyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-Rl-6-R2-1,3-benzothiazin-4-one,

2-[(2R)-2-methyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl]-8-Rl-6-R2-1,3-benzothiazin-4-one,

2-[(2S)-2-methyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl]-8-Rl-6-R2-l,3-benzothiazin-4-one,

2-(2,3-dimethyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-Rl-6-R2-1,3-benzothiazin-4-one,

2-(1,5-dioxa-9 azaspiro[5.5]undec-9-yl)-8-Rl-6-R2-1,3-benzothiazin-4-one,

where R1, R2, R5and R6have the values specified above.

More specifically, the present invention relates to at least one compound selected from the group consisting of:

2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one,

2-(7,12-dioxa-8 azaspiro[5.6]dodec-3-yl)-6,8-dinitro-1,3-benzothiazin-4-one,

2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-7-methyl-6,8-dinitro-1,3-benzothiazin-4-one,

2-(1,4-dioxa-8-AZ is Spiro[4.5]Dec-8-yl)-8-nitro-4-oxo-1,3-benzothiazin-6-carbonitrile,

2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-6,8-dinitro-1,3-benzothiazin-4-one,

2-(2-methyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-6,8-dinitro-1,3-benzothiazin-4-one,

2-(4,4-detoxificatin-1-yl)-6,8-dinitro-1,3-benzothiazin-4-one,

7-methyl-2-(2-methyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-6,8-dinitro-1,3-benzothiazin-4-one,

2-(2-methyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one,

2-(2,3-dimethyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one,

2-(1,5-dioxa-9 azaspiro[5,.5]undec-9-yl)-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one,

2-(1,5-dioxa-9 azaspiro[5.5]undec-9-yl)-8-nitro-4-oxo-1,3-benzothiazin-6-carbonitrile,

2-(2-methyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-nitro-4-oxo-1,3-benzothiazin-6-carbonitrile.

To obtain the target compounds, we have developed an original method for the synthesis of 1,3-benzothiazin-4-the use of derivatives dithiocarbamate as intermediate compounds (method A). The classical method for the synthesis of 1,3-benzothiazin-4-it is using thiocyanate salts (method) is also suitable. Both are illustrated in the diagram below.

Compounds of the present invention unexpectedly exhibit high antibacterial activity, especially against mycobacteria, with the value of the minimum inhibitory concentrations (MICS) in the range from 0.23 PG/ml to no more than 10 m is g/ml for the fast-growing mycobacteria, in the range of € 0.195-of 1.56 μg/ml for M. tuberculosis, including multidrug-resistant strains, defined in the classical way, and the value of the IPC 0,030 µg/ml for M. tuberculosis H37Rv, a specific method using the dye Alamar Blue. Compounds of the present invention unexpectedly exhibit a high selectivity with respect solely to the mycobacteria, which significantly reduces the likelihood of harmful side effects.

Compounds of the present invention is not mutagenic at concentrations of 5 mg/ml in SOS-chromotest.

Compounds according to the present invention is therapeutically active in vivo in the mouse model of TB infection, surpassing the main anti-TB drug isoniazid, used as positive control. Survived 100% of mice. All animals in the control group died no later than 33 days.

The compound of the present invention (especially connection # 2 = example 1 in the examples of the invention) is not toxic by oral administration of dosages in the range of up to 2000 mg/kg, and represents a connection, well tolerated by the animals in the first and subsequent 24 hours after injection. Within 7 days of the research compound 2 did not cause any change in the General condition and behavior of the mice did not affect motor and reflex activity, activity cycles and tranquility, cleaning, need to change the consumption of food, no deaths of animals. LD50to connect 2 is >2000 mg/kg

Thus, the compounds of the present invention is suitable for treatment of TB and other infections caused by mycobacteria, in humans and animals.

Accordingly, the present invention relates to pharmaceutical compositions containing a compound of formula I.

The invention also relates to the compound of formula I for use in the treatment of bacterial infections in mammals. Preferred compounds of formula I for use in this method are compounds specifically listed above.

Preparations of the compounds of the present invention is produced by preparing dilute solutions or suspensions in pharmaceutically acceptable, aqueous, organic or aqueous-organic medium for local or parenteral administration by intravenous, subcutaneous or intramuscular injection or intranasal use; or are produced in the form of tablets, capsules or aqueous suspension with conventional excipients for oral administration or in the form of a suppository.

The compounds can be used in dosages of 0.001 to 1000 mg/kg of body weight.

The following examples in the following experimental part, serve to illustrate the invention, but should not be understood to is to restrict the invention.

The structure of the compounds of the present invention was determined by the method of synthesis and the data of elemental analysis, as well as by the method of nuclear magnetic resonance and/or mass spectrometry, and x-ray diffraction analysis.

Examples of carrying out the invention

Raw materials

Reagents and solvents were purchased from Lancaster Synthesis (Lancashire, England) or Aldrich (Sigma-Aldrich Company, St Louis, USA) and used in the synthesis without further purification. The melting temperature was determined in accordance with the BP procedure and not corrected (Electrothermal 9001, GB). If the results of the analysis indicated only by symbols of the elements, the experimentally found values were within ±0.3% from theoretically calculated values (Carlo-Erba 5500, Italy). NMR spectra were recorded on the instrument Varian Unity Plus 400 (USA). Chemical shifts for1H NMR are expressed in ppm, in the weak field relative to TMS (δ). Mass spectra were recorded on the device Finnigan SSQ-700 (USA) with direct input. The reactions and the purity of the compounds was monitored by TLC using aluminum plates Silicagel 60 F254(Merck Co, Germany).

Example 1

2-(1,4-Dioxa-8 azaspiro[4.5]Dec-8-yl)-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one, (compound 1)

Method A.

To 50 ml of stirred 25%aqueous ammonia solution was bury a solution of 5 g of 2-chloro-3-nitro-5-triptime is eventyrland (D.E Welch, R.R.Baron, B.A.Burton, J. Med. Chem. 12; 2; 1969; 299-303) in acetonitrile (10 ml) at -20°C. After 10 min was added 50 ml of ethyl acetate. The organic phase was separated, washed twice with water, dried over Na2SO4, was treated with activated charcoal, filtered and concentrated in vacuum. The crude product was purified by crystallization from ethanol. The yield of 2-chloro-3-nitro-5-(trifluoromethyl)benzamide was 92%. TPL 195-197°C (methanol). Calculated for C8H4ClFN2O3: C, 35,78; N, 1,50; N, 10,43

Found: C, 36,01; N, 1,53; N, accounted for 10.39

0.5 g of 2,2-chloro-3-nitro-5-(trifluoromethyl)benzamide was dissolved in 25 ml of ethanol. The reaction mixture was treated with 0.5 g dihydrate sodium salt of 1,4-dioxa-8 azaspiro[4.5]decane-8-dithiocarbonic acid (Z. Ge, R. Li, T. Cheng, Synth. Commun., 29, 18, 1999, 3191 - 3196) and left for 18 h at room temperature. Then the reaction mixture was poured into 50 ml of chilled water was filtered and the obtained yellow precipitate. Pure final product was obtained after two recrystallization from ethanol. 2-(Aminocarbonyl)-6-nitro-4-(trifluoromethyl)phenyl-1,4-dioxa-8 azaspiro[4.5]decane-8-carbolicious is a light yellow crystalline substance. The output of 0.47 GPL 138-140°C.

Calculated for C11H12N4O2S2: C, 42,57; N, Of 3.57; N, 9,31; S, 14,21

Found: C, 42,61; N, To 3.67; N, Which 9.22; S, 14,30

0.4 g of 2-(aminocarbonyl)-6-nitro-4-(trifluoromethyl)phenyl-1,4-dioxa-8 azaspiro[4.]decane-8-carbodiimide was dissolved in 25 ml of ethanol. The reaction mixture was treated with 0.32 g of Na2HPO4×12H2O and boiled for 6 hours Then the reaction mixture was cooled, light yellow precipitate was filtered and washed with 30 ml of methanol. Pure final product was obtained after two recrystallization from ethanol. 2 is a light yellow crystalline substance. The output of 0.47, TPL 211-212°C.

Rf(hexane-acetone; 2/1) - 0,35

MC:m/z 417(M+).

1H NMR (DMSO-d6) δ 8,83 and 8,77 (two 1H, two s, 2CH), 3,80 (8H, broadened s, N(CH2CH2)2C)2,02 (4H, broadened s, OCH2CH2O) ppm

Calculated for C16H14F3N3O5S: C, 46,04; N, To 3.38; N, 10,07; S, 7.68 per

Found: C, 45,94; N, 3,37; N, Of 10.09; S 7,76

Method C. this Method was exactly the same as the method described in J.Imrich, P.Kristian, Coll. Czech. Chem. Commun., 47, 1982. 3268-3282; D.Koscik, P.Kristian, J.Gonda, E.Dandarova, Coll. Czech. Chem. Commun., 48, 1983, 3315-3328; D.Koscik, P.Kristian, O.Forgac, Coll. Czech. Chem. Commun., 48, 1983, 3427-3432; Tngop, N. - J.E. Hess, Pat. US 3522247. The yield of 2-(1,4-dioxa-8-Aza-Spiro[4.5]Dec-8-yl)-8-nitro-6-trifluoromethyl)-1,3-benzo-thiazin-4-it amounted to 0.21, the combination according to spectroscopic data is identical to the compound obtained by method A.

Example 2

2-(2-Methyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one, (compound 2)

Obtained according to the method described in Example 1. Light yellow crystalline substance. Yield 54%. TPL 192-3°C

Rf(hexane-acetone; 2/1) - 0,30.

MC: m/z 431 (M+).

1H NMR (DMSO-d6) δ 8,81 and 8,77 (two 1H, two s, 2CH), 4,24 (1H, m, CH), 4,11 (1H, m, CH), 4,06 (4H, broadened s, N(CH2)2), 3,47 (1H, t, CH), with 3.27 (1H, s, CH), of 1.80 (4H, broadened d, C(CH2)2), of 1.23 (3H, d, CH3) ppm

Calculated for C17H16N3O5S: C, 47,33; N, 3,74; N, 9,74; S, 7,43

Found: C, 47,36; N, Of 3.80; N, 9,87; S, 7,51

Example 3

2-(1,4-Dioxa-8 azaspiro[4.5]Dec-8-yl)-6,8-dinitro-1,3-benzothiazin-4-one, (compound 4)

Obtained according to the method described in Example 1 using 2-hydroxy-3,5-dinitrobenzoic acid as the starting material. Light yellow crystalline substance. Yield 43%. TPL 271-3°C (EtOH/DMF).

Rf(hexane-acetone; 2/1) - 0,25.

MC: m/z 394 (M+).

1H NMR (DMSO-d6) δ 9,15 and 9,12 (two 1H, two s, 2CH), 3,86 (8H, broadened s, N(CH2CH2)2C)of 2.97 (4H, broadened s, OCH2CH2O) ppm

Calculated for C15H14N4O7S: C, 45,68; N, To 3.58; N, 14,21; S, 8,13

Found: C, 45,34; N, Of 3.56; N, 14,30; S 7,98

Example 4

2-(2-Methyl-1,4-dioxa-8 azaspiro[4.5]decyl)-6,8-dinitro-1,3-benzothiazin-4-one, (compound 4)

Obtained according to the method described in Example 1 using 2-hydroxy-3,5-dinitrobenzoic acid as the starting material. A yellow crystalline substance. Yield 57%. TPL 139-142°C (EtOH/DMF).

Rf(hexane-acetone; 2/1) -0,50.

MC: m/z 408 (M+).

1H NMR (DMSO-d6) δ and the remaining 9.08 9,11 (two 1H, two s, 2CH), TO 4.23 (1H, m, CH), 4,10 (1H, m, CH), 4,06 (4H, broadened s, N(HC2)2), of 3.43 (1H, t, CH), with 3.27 (1H, s, CH), of 1.80 (4H, broadened d, C(CH2)2), of 1.20 (3H, d, CH3) ppm

Calculated for C16H16N4O7S: C, 47,06; N, Of 3.95; N, 13,72; S, a 7.85

Found: C, 46,87; N, 3,91; N, 13,57; S, 7,83

Example 5

2-(2,3-Dimethyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one, (compound 5)

Obtained according to the method described in Example 1 using 2-hydroxy-3-nitro-5-triftorperasin acid as the starting material. Light yellow crystalline substance. Yield 58%. TPL 205-207°C (EtOH/DMF).

Rf(hexane-acetone; 2/1) is 0.55.

MC: m/z 44522 (M+).

1H NMR (DMSO-d6) δ 8,82 and 8,77 (two 1H, two s, 2CH), 3,86 (4H, broadened s, N(CH2)2), 3,45-of 3.53 (2H, m, 2CH), IS 2.41 (4H, broadened d, C(CH2)2), 1,13-1,17 (6N, m, 2CH3) ppm

Calculated for C18H18F3N3O5S: C, 48,54; N, 4,07; N, 9,43; S, 7,20

Found: C, 48,66; N, 4,12; N, To 9.32; S, 7,46

Example 6

2-(4,4-Detoxificatin-1-yl)-6,8-dinitro-1,3-benzothiazin-4-one, (compound 6)

Obtained according to the method described in Example 1, using as starting material 2-hydroxy-3,5-dinitrobenzoic acid. A yellow crystalline substance. Yield 32%. TPL 179-181°C (i-D).

R f(hexane-acetone; 2/1) - 0,30.

MC: m/z 424(M+).

1H NMR (DMSO-d6) δ and the remaining 9.08 9,11 (two 1H, two s, 2CH), 3,60-TO 3.67 (4H, m, N(CH2)2) 2,11-of 2.08 (4H, m, (CH2)2), 3,47 and 3.57 (two 2H, kV, 2OCH2), 1,16 (6N, t, 2CH3), ppm

Calculated for C17H20N4O7S: C, 48,11; N, Of 4.75; N, 13,20; S, 7,56

Found: C, 48,12; N, To 4.73; N, 13,41; S, to 7.67

Example 7

2-(7,12-Dioxa-3-azaspiro[5.6]dodec-3-yl)-6,8-dinitro-1,3-benzothiazin-4-one, (compound 7)

Obtained according to the method described in Example 1, using as starting material 2-hydroxy-3,5-dinitrobenzoic acid. A yellow crystalline substance. Yield 51%. TPL 193-195°C (i-D/DMF).

Rf(hexane-acetone; 2/1) - 0,45.

MC: m/z 422(M+).

1H NMR (DMSO-d6) δ 8,97 and 9,16 (two 1H, two s, 2CH), 3,57-3,74 (8H, m, SN2), 1,93 to 2.35 (8H, m, SN2) ppm

Calculated for C17H18H4O7S: C, 48,34; N, 4,30; N, 13,26; S, 7,56

Found: C, 48,21; N, 4,43; N, 13,30; S, 7,66

Example 8

2-(1,4-Dioxa-8 azaspiro[4.5]Dec-8-yl)-7-methyl-6,8-dinitro-1,3-benzothiazin-4-one, (compound 8)

Obtained according to the method described in Example 1, using as starting material 2-hydroxy-4-methyl-3,5-dinitrobenzoic acid. A yellow crystalline substance. Yield 51%. TPL 207-210°C (i-D/DMF).

Rf(hexane-acetone; 2/1) - 0,30.

MC: m/z 408(M+).

1H NMR (DMSO-d6) δ 8,77 (1H, s, CH), 3,86(8H widened with, N(CH2CH2)2C)of 2.97 (4H, broadened s, OCH2CH2O), and 2.79 (3H, CH3) ppm

Calculated for C16H16H4O7S: C, 47,06; N, Of 3.95; N, 13,72; S, a 7.85

Found: C, 47,12; N, 4,01; N, 13,69; S 7,94

Example 9

2-(1,4-Dioxa-8 azaspiro[4.5]Dec-8-yl)-8-nitro-4-oxo-1,3-benzothiazin-6-carbonitrile, (compound 9)

To a stirred solution of 5 g (19 mmol) of 2-hydroxy-5-iodobenzoic acid in 50 ml of DMF was added in small portions 2.5 g (22 mmol) of dry CuCN (I). The reaction mixture was heated for 5 h, was added 100 ml of water and 50 ml of ethyl acetate. Then, with good ventilation caution was added concentrated hydrochloric acid until the pH is not reached ~ 3. The organic phase was separated, washed twice with water, dried over Na2SO4, was treated with activated charcoal, filtered and concentrated in vacuum. The crude product was purified by crystallization from water. Output 5-cyano-2-hydroxybenzoic acid was 71%. According to the method described in Example 1. Yield 44%. TPL 217 to 220°C (EtOH/DMF).

Rf(hexane-acetone; 2/1) - 0,50.

MC: m/z 374(M+).

1H NMR (DMSO-d6) δ total of 8.74 and 8,67 (two 1H, two s, 2CH), 3,41 (8H, broadened s, N(CH2CH2)2C)of 2.93 (4H, broadened s, OCH2CH2O) ppm

Calculated for C16H14N4O5S: C, 51,33; N, Of 3.77; N, 14,97; S, 8,57

Found: C, 51,30; N, Of 3.84; N, 14,89; S, 8,62

Example 10

2-(2-Methyl-1,4-dioc the a-8 azaspiro[4.5]Dec-8-yl)-8-nitro-4-oxo-1,3-benzothiazin-6-carbonitrile, (compound 10)

Obtained by the method described in Example 9. A yellow crystalline substance. The output is 34%. TPL 251-253°C (EtOH/DMF).

Rf(hexane-acetone; 2/1) - 0,40.

MS: m/z 388 (M+).

1H NMR (DMSO-d6) δ 8,73 and 8,61 (two 1H, two s, 2CH), TO 4.23 (1H, m, CH), 4,11 (1H, m, CH), 4,07 (4H, extended with N(CH2)2), 3,51 (1H, t, CH), with 3.27 (1H, s, CH), is 1.81 (4H, broadened d, C(CH2)2), to 1.22 (3H, d CH3) ppm

Calculated for C17H16N4O5S: C, 52,57; N, 4,15; N, 14,43; S, compared to 8.26

Found: C, 52,42; N, 4,08; N, 14,50; S, 8,27

Example 11

2-(1,5-Dioxa-9 azaspiro[5.5]undec-9-yl)-8-nitro-4-oxo-1,3-benzothiazin-6-carbonitrile, (compound 11)

Obtained by the method described in Example 9. A yellow crystalline substance. Yield 40%. TPL 230-232°C (EtOH/DMF).

Rf(hexane-acetone; 2/1) to 0.15.

MS: m/z 388 (M+).

1H NMR (DMSO-d6) 6 a total of 8.74 and 8,61 (two 1H, two s, 2CH), 3,29-3,65 (6N, m, SN2), of 2.38 (4H, broadened s, 2CH2), 1,82-of 1.93 (4H, m, 20%) ppm

Calculated for C17H16N4O5S: C, 52,57; N, 4,15; N, 14,43; S, compared to 8.26

Found: C, 52,52; N, 4,11; N, 14,59; S, 8,13

Example 12

Determination of in vitro inhibitory activity against mycobacteria for compounds of the present invention.

Antibacterial activity of the considered compounds against Mycobacterium smegmatis SG 987, M. aureum SB66, M. vaccae IMET 1010670 and M.fortuitum In was tested by determining the minimum is talauma concentrations (MICS) method microrasbora in broth Mueller-Hinton (Difco) according to NCCLS guidelines [National Committee for Clinical Laboratory Standards: Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; 5thEd.; Villanova, Ed.; Approved standard Document M7-A5. NCCLS, (2000)].

Activity against M. tuberculosis H37Rv tested the following method to determine minimum inhibitory concentrations (MICS) and minimum bactericidal concentrations (MBC).

The strains were sown on solid medium of Löwenstein-Jensen medium. After 21 days, the grown culture was used to prepare suspensions for planting, having a concentration of 5×108microbial cells/ml to 0.2 ml of this suspension were planted in test tubes with 2 ml of a liquid medium Shkolnikova containing the appropriate concentrations of these compounds from 100,0 to 0.195 mg/ml After 14 days of incubation at 37°C, the tubes with liquid medium were centrifuged for 15 min at 3000 rpm/min After removal of the supernatant, the sediment resuspendable in 0.8 ml sterile 0,9%NaCl solution. 0.1 ml of this suspension were taken for preparation of smears, which were then stained according to the method of ZIL-Nielsen. The remaining precipitate was sown in volumes of 0.2 ml in three test tubes with solid environment Löwenstein-Jensen medium containing no drug, to determine the minimum bactericidal concentration (MBC). The results were summarized after 21-28 days of cultivation at 37°C. the Control were tubes with cultures of test strains not exposed to processing of the investigated substances.

Minimum bactericidal concentrations of drugs (BC) believed to the ncentratio drugs completely inhibiting the growth of bacteria on solid medium. Bacteriostatic effect (IPC) was characterized by the presence of smears only isolated mycobacteria and a strong decrease in the number of colonies grown on solid medium, in comparison with the control samples.

The results are presented in Tables 1 and 2.

Example 13

In vivo inhibitory activity of the compounds of the present invention against Mycobacterium tuberculosis in the mouse model of TB

To determine the chemotherapeutic efficacy, the authors used mice of BALB/c experimental hematogenous disseminated tuberculosis. Mice were obtained from the Central Nursery of Laboratory Animals of the Russian Academy of Medical Sciences. In this study, the authors included mice after quarantine, with a standard weight (20-25 g) and male. Mice infected 2 weeks virulent culture of Mycobacterium tuberculosis H37Rv via intravenous injection (tail vein) mycobacterial suspension at a dose of 5×106CFU (colony forming units) in 0.5 ml of saline. All the experimental animals were divided into groups depending on the applied treatments (table 3). Doses of the test drugs were chosen on the basis of the letter the business data and results of previous studies.

Table 3
Group # ConnectionDosage (mg/kg)The number of animals in group
321210
422510
5Isoniazid (INH)2510
6Without treatment10

Treatment was started the next day after infection. Medication is administered orally in the form of a suspension in a mixture of carboxymethyl cellulose/water with a small amount of PEG-400.

Chemotherapy was carried out daily 6 times a week (except Sunday).

Animals were euthanized ether anesthesia. To determine the effectiveness of each regimen, the authors recorded the macroscopic changes in parenchymatous organs of mice, the growth of mycobacteria from pathological material on solid medium, and bakteriostaticheski the index organs. The authors conducted qualitative and quantitative analysis of microscopic changes in the liver, spleen and lungs and to calculate the index lesion (using a four-point scale).

Macroscopic determine the effectiveness of each treatment was expressed in the performance index, calculated by the formula:

Microbiological study included culture to determine SOME parenchymatous organs. For this purpose, the authors have homogenital right lung separately and spleen with 6%sulfuric acid, centrifuged, washed with water and brine. The resulting material (about 0.5 ml) was diluted to 1.0 ml of saline solution and was homogenital. This suspension (0.5 ml) of the studied organs were diluted in 100 and 1000 times salt solution and distributed on a solid medium Finn-2. Cultures were incubated at 37°C for 1 month and monitored on a weekly basis starting from the 10th day. After 28 days was calculated CFU.

Data macroscopic and microbiological studies of parenchymatous organs of mice that died during the experiment were also taken into account in the overall assessment of the results of the experiment are presented in Tables 4-6.

Table 4
Indexes defeat org is new in mice and the efficacy of the treatment
GroupMedicationDosage (mg/kg)The index lesionThe performance index (%)
3Connection 2122,144.7
4Connection 2251,078
5INH, Isoniazid251,270,5
6Control-the 3.8-

Table 5
The results of the microbiological examination of the right lung and spleen of experimental mice (42 days after sowing environment culture)
GroupConnectionDosage (mg/kg)Right is egcoa
Culture without dilution CFU
Spleen
Culture without dilution CFU
3212~60~60
4225-35~35
5INH, Isoniazid25~40~40
6Control->120 (total height)>120 (total height)

All animals from the control group died no later than 33 days.

1. The compound of the formula I

or its salt,
where R1and R2independently from each other represent NO2, CN, CONR7R8, COOR9, SNO, halogen, SO2NR7R8, OCF3or trifluoromethyl;
R3and R4independently of one another represent H or methyl;
R5and R6independently from each other represent a linear is or branched aliphatic radical, having 1 to 8 members in the chain, or R5and R6together represent a bivalent radical -(CR92)m-where m is 1-4, or R5and R6together represent a bivalent radical:

R7, R8and R9independently represent H or a linear or branched aliphatic radical having 1-7 members in the chain, or phenyl.

2. The compound of formula (I) according to claim 1, in which R1represents NO2, R2is a CF3, R3and R4are H, and R5and R6have the meanings indicated in claim 1.

3. The compound of formula (I) according to claim 1, in which R1represents NO2, R2represents CN, R3and R4are H, and R5and R6have the meanings indicated in claim 1.

4. The compound of formula (I) according to claim 1, in which R1and R2represents NO2, R3and R4are H, and R5and R6have the meanings indicated in claim 1.

5. The compound of formula (I) according to claim 1, in which R5and R6independently of one another represent C1-8alkyl.

6. The compound of formula (I) according to claim 1, selected from the group consisting of the following compounds:
2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one,
2-(7,12-dioxa-8-azaspiro,6]dodec-3-yl)-6,8-dinitro-1,3-benzothiazin-4-one,
2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-7-methyl-6,8-dinitro-1,3-benzothiazin-4-one,
2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-nitro-4-oxo-1,3-benzothiazin-6-carbonitrile,
2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-6,8-dinitro-1,3-benzothiazin-4-one,
2-(2-methyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-6,8-dinitro-1,3-benzothiazin-4-one,
2-(4,4-detoxificatin-1-yl)-6,8-dinitro-1,3-benzothiazin-4-one,
7-methyl-2-(2-methyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-6,8-dinitro-1,3-benzothiazin-4-one,
2-(2-methyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one,
2-(2,3-dimethyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one,
2-(1,5-dioxa-9 azaspiro[5.5]undec-9-yl)-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one,
2-(1,5-dioxa-9 azaspiro[5.5]undec-9-yl)-8-nitro-4-oxo-1,3-benzothiazin-6-carbonitrile,
2-(2-methyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-nitro-4-oxo-1,3-benzothiazin-6-carbonitrile.

7. 2-(2-methyl-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one.

8. The use of the compounds of formula (I) or its salt according to any one of the preceding paragraphs for the preparation of a pharmaceutical composition having activity against mycobacteria.

9. The use of compounds according to any one of claims 1 to 7 for the preparation of medicinal products for therapeutic or prophylactic treatment of tuberculosis infection or infection of leprosy in mammals.

10. farmacevticheskaja composition, possessing activity against mycobacteria, comprising the compound according to any one of claims 1 to 7.

11. The compound according to any one of claims 1 to 7 for use in a method of therapeutic or prophylactic treatment of tuberculosis infection or infection of leprosy in mammals.

12. The method of obtaining the compounds of formula (I), including the stage of processing the compounds of formula:

where the substituents R1, R2, R5and R6such as defined in claim 1, and the substituents R3and R4represent hydrogen, H2O/EtOH to obtain the compounds of formula (I).



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new a compound of formula I or formula II, or to its pharmaceutically acceptable salts, I II, where X is S; R1 is H or C1-C6alkyl; R2 is NR5R6; R3 is aryl, substituted with a halogen; R4 is H; R5 is H; R6 is H; R7 is CH2NR8R9 where R8 is H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl), heterocycle(C2-C6alkenyl), hydroxyl(C1-C6alkyl), hydroxyl(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbamoyl(C1-C6alkyl); where the above mentioned aryl is an aromatic ring and is not substituted or substituted with one to three substituting groups, each of which, independently from the others, is chosen from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, trifluoromethoxy, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy), R9 is H, C1-C10alkyl, heterocycle(C1-C6alkyl) or heterocycle(C2-C6alkenyl); where the above mentioned heterocycle represents a 5-member saturated monocyclic ring system, consisting of carbon atoms, as well as heteroatoms, chosen from a group comprising N, O, and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes NO2, aryl(C1-C6alkyl), arylsulphonyl; or R8 and R9 together with nitrogen, to which they are bonded, form a heterocycle, which represents a 5 - 7-member saturated monocyclic ring system, consisting of carbon atoms, as well as one to three heteroatoms, chosen from a group comprising N, O and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes C1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6-alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidin-2-yl; and m equals 0. The invention also relates to a pharmaceutical composition, as well as to use of formula I or formula II compounds.

EFFECT: obtaining new biologically active compounds, with inhibitory properties towards casein kinase 1ε.

32 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds -(Z)-1'-R-6',6'-dimethyl-3-(phenyl(arylamino)methylene)-6',7'-dihydro-3H-spiro[furane-2,3'-indol]-2',4,4',5(1'H,5'H)-tetraons of formula: , where Ar=phenyl, n-methoxyphenyl, n-tollyl; R=allyl, benzyl, phenyl, n-tollyl, n-methoxyphenyl, α-naphtyl, as well as to method of their obtaining, which consists in the following: isopropyl 2-(1-aryl-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-yl)-2-oxoacetates are subjected to interaction with N-substituted 3-amino-5,5-dimethylcyclohex-2-enons in medium of inert aprotonic solvent with further separation of target products. Process is carried out at temperature 20-22°C. As solvent, absolute chloroform is used.

EFFECT: obtaining compounds possessing analgesic activity.

4 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds, and more specifically to 5-formyl-substituted indoline spirobenzopyrans with general formula 1 where R1, R2 - Alk or c-Alk; R3 -CHO or NO2 group (electron-acceptor substitute), with photochromic properties. The invention also relates to the method of producing 5-formyl substituted derivatives of indoline spirobenzopyrans with formula 1. Spirobenzopyrans, which have electron-acceptor substitutes in the pyran part of the molecule, are subjected to direct selective formylation in position 5 in a trifluoroacetic acid medium with urotropine (hexamethylenetetramine) at boiling point of the mixture in an inert atmosphere for 1-1.5 hours. The obtained 5-formyl-substituted spirobenzopyrans are photochromic compounds are photochromic and can be used for making new photochromic materials (recording devices or information storage; photo-switching activity of biological objects and polymer matrices, complex formation; information security media, maps, special document protection equipment) or as advanced initial compounds for further synthesis of a large number of new photochromic objects.

EFFECT: wider field of application of the compounds.

2 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula: , where R is -(CH2)n-A, where A: where each of B and C independently represent phenyl or phenyl substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl) and -NO2; or n equals an integer from 0 to 3; n1 equals an integer from 1 to 3; n2 equals an integer from 0 to 4; n3 equals an integer from 0 to 3; n4 equals an integer from 0 to 2; X1 is chosen from a chemical bond -S-, -S(O)2-, -NH-, -NHC(O)- and -C=C-, R1 is chosen from C1-C6alkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, tetrahydropyranyl, CN, -N(C1-C6alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphtyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolydinyl, thiomopholinyl, tetrazolyl, benzoxazolyl, imidazolidine-2-thionyl, 7,7-dimethylbicyclo[2.2.1]heptane-2-onyl, benzo[1.2.5]oxadiazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl and pyrrolyl, each of which can be optionally substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, pyridyl, 2-methylazolyl, morpholino, 1-chloro-2-methylpropyl, phenyl, (optionally substituted with one or more halogens), benzyloxy, and , X2 selected from -O-, -CH2-, -S-, -SO-, -SO2-, -NH- and , R2 represents a ring group, chosen from a phenyl or thienyl group. Each ring group is substituted with a group with formula -(CH2)n4-CO2H; and besides that, the ring group can optionally be substituted with 1 or 2 extra substitutes, independently chosen from halogen, - C1-C6alkyl and -C1-C6alkoxy; R3 is chosen from H, halogen and -NO2; R4 is chosen from H, halogen and morpholino; or its salt form, used in pharmaceuticals. The invention also relates to pharmaceutical compositions, to methods of treatment, and to compounds with formula (A).

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on them, which have inhibiting effect on cytosolic phospholipase A2.

45 cl, 300 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to new compounds with formula I, their pharmaceutical salts and to complex esters. The invented compounds have inhibiting propertied towards catepsin K and can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved, for example, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumorous diseases. In general formula I R represents H, R13 represents (inferior)alkyl, C3-C10cylcloalkyl or C3-C10cycloalkyl(inferior)alkyl, each of which is independently optionally substituted with a halogen atom, hydroxyl, CN, NO2 or optionally mono- or di(inferior)alkyl substituted amino group; and R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(inferior)alkyl-W-, C3-C10cycloalkyl, C3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl -W-. Substitutes of the indicated values of radicals are shown in the formula of invention. The invention also relates to methods of obtaining the compounds.

EFFECT: obtaining pyrrolopyrimidines with inhibiting properties towards catepsin K, which can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved.

4 cl, 59 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): their using (variants) for preparing a drug used in treatment of diseases modulation of activity of chemokine receptors is useful, and to a pharmaceutical composition modulating chemokine receptors and comprising abovementioned compound. In compound of the formula (I) m = 0 or 1; R1 means halogen atom; X, Y and Z represent independently a bond, -CH2- or -O-, or X and Y form in common -CH=C(CH3)- or -C(CH3)=CH- under condition that only one radical among X, Y and Z can represents a bond, and under condition that X and Y both don't represent -O- simultaneously; n = 0, 1 or 2; R2 represents halogen atom, or (C1-C6)-alkyl; q = 0 or 1; R3 represents -NHC(O)R10, -C(O)NR11R12 or -COOR12a; each radical among R4, R5, R6, R7 and R8 represents independently hydrogen atom (H) or (C1-C6)-alkyl; t = 0, 1 or 2; R9 represents halogen atom, -OH, -COOH, (C1-C6)-alkoxy group, (C1-C6)-alkoxycarbonyl; R10 represents group (C1-C6)-alkyl, (C3-C6)-cycloalkyl, or R10 represents -NR14R15; each R11 and R12 represents independently (1) H; (2) 3-6-membered saturated cycloalkyl or phenyl or 5-membered unsaturated heterocyclyl comprising from 1 to 4 heteroatoms N wherein indicated cycloalkyl, phenyl and heterocyclyl are substituted possibly with one or two substitutes chosen from -OH, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl; (3) (C1-C6)-alkyl substituted possibly at least with one substitute chosen from halogen atom, -OH, -COOH, (C1-C6)-alkylcarbonylamino group, phenyl, 5-membered unsaturated heterocyclyl comprising oxygen atom (O), or from 1 to 2 N atoms, bicycloheptyl wherein this phenyl, heterocyclyl or bicycloheptyl is substituted possibly at least with one substitute chosen from halogen atom, -OH, =O, or (4) (C1-C6)-alkylsulfonyl, or R11 and R12 in common with N atoms to which they are bound form 5-membered unsaturated heterocyclyl comprising one N atom or 5-6-membered heterocyclyl comprising from 1 to 2 heteroatoms, such as S, O and N, or 5-6-membered saturated heterocyclyl, ortho-condensed with benzene ring and comprising one N atom and wherein indicated heterocyclic systems are substituted possibly with one or two substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-hyroxyalkyl, (C1-C6)-halogenalkyl, (C1-C6)-alkylamino, di-(C1-C6)-alkylamino group, phenyl, halogenphenyl and hydroxydiphenylmethyl; R12a represents H or (C1-C6)-alkyl; each radical among R14 and R15 represents independently H or (C1-C6)-alkylsulfonyl, or R14 and R15 in common with N atom to which they are bound form 5-membered saturated heterocyclyl comprising one N atom and substituted possibly with one -OH, or its pharmaceutically acceptable salt or solvate. Also, invention relates to a method (variants) for synthesis of compound of the formula (I) according to one of the following method: by one variant, compound of the formula (II): is subjected for interaction with compound of the formula (III): by other variant, compound of the formula (IV): is subjected for interaction with compound of the formula (V): by other variant, compound of the formula (VI): wherein R3 represents -NHC(O)R10 and L1 represents a leaving group is subjected for interaction with L1C(O)R10; by other variant, compound of the formula (VIII): wherein R3 represents -C(O)NR11R12 and L2 represents a leaving group is subjected for interaction with compound of the formula (IX) given in the invention description. Also, invention relates to an intermediate compound of the formula (IIA): (wherein R1a is chosen from F, Cl, -CH3 and -CF3; s = 1 or 2; q = 0 or 1; w = 0 or 1; R2a represents F, and when q and s = 1 and w = 0 then R1a can't represent chlorine atom), and to a method for synthesis of compound of the formula (IIA) (wherein s = 1) and wherein compound of the formula (XX): is subjected for interaction with compound of the formula (XXII): (wherein R20 represent a protective group) before formation of compound of the formula (XXIV): followed by carrying out the cyclization reaction and removing the protective group R20.

EFFECT: improved methods of synthesis.

25 cl, 236 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein (a) each R1 is chosen independently from hydrogen atom and alkoxy-group; (b) R2 represents hydrogen atom; (c) each R3 and R4 is chosen independently of one another from hydrogen atom, alkyl, alkynyl, heteroalkyl group, aryl; or R3 and R4 in common with nitrogen atom bound with them form heteroaryl or heterocycloaryl substitute optionally substituted with one or more hydroxo-group, carboxyl group, keto-, thioketo-, phenyl group, alkyl, heteroalkyl group, heteroaryl, heterocycloalkyl, spirocycloalkyl and their combinations; (d) each R5 and R6 represents hydrogen atom; or optical isomers, diastereomers and enantiomers represented by above given formula, and their pharmaceutically acceptable salts also. Also, invention describes using compound of the formula (I) for preparing a pharmaceutical composition possessing antibacterial activity and antibacterial pharmaceutical composition containing the safety and effective amount of compound of the formula (I) and a pharmaceutically acceptable carrier. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable properties of compounds and pharmaceutical composition.

7 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (XXI) where values of R1, Y, Ra and Rb are given in subparagraphs 1 and 2 of the formula of invention, as phosphatidylinositol-3-kinase inhibitors, a pharmaceutical composition based on said compounds and their use.

EFFECT: compounds can be used for treating and preventing diseases mediated by phosphatidylinositol-3-kinase.

5 cl, 5 tbl, 146 ex

FIELD: medicine.

SUBSTANCE: there is described thiomorpholine compound presented by formula (I) wherein the ring A represents benzene ring; the ring B represents benzene ring; R1 represents hydrogen atom, R2 represents C1-6-alkyl group; R3a and R3b are identical or different, each representing hydrogen atom or C1-6-alkyl group, and n represents an integer equal to 2, or its pharmaceutically acceptable salt. There is also described method for making the compound of formula (1), a pharmaceutical composition and application of the compound of formula (1) for making a medical product used for treatment and prevention of the disease chosen from inflammation, allergic diseases, pain, migraine, neuralgia, itch, cough, central nervous system diseases, alimentary organ diseases, nausea, vomiting and urological disorders.

EFFECT: compounds exhibits affinity to neurokinine-1 receptor.

6 cl, 4 tbl, 16 ex

Gsk-3 inhibitors // 2379300

FIELD: medicine.

SUBSTANCE: invention concerns GSK-3 inhibitors of general formula (I), method for making thereof and based pharmaceutical compositions which can be used in medicine: formula I, where R1 means an organic group containing at least 8 atoms, chosen of C or O, including aromatic ring of phenyl, naphthyl or methylene dioxypjenyl, which is not bound directly with N through -C(O)- or oxygen; Ra, Rb, Rz, R3, R4, R5 and R6 represent hydrogen.

EFFECT: production of new biologically active compounds for treatment of GSK-3 mediated diseases.

28 cl, 13 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzyloxy-derivatives of general formula (I) , where R1 is a halogen; R2 is a 5-member heteroaryl group containing 2 or 3 heteroatoms selected from a group consisting of N, O or S, which can be substituted with R3, where R3 is a lower alkyl or -C(O)R; R is -NR'R" or lower alkoxy; R'/R" independently represent H; as well as to their pharmaceutically acceptable salts. Formula I compounds inhibit monoamine oxidase B.

EFFECT: compounds can be used for preparing a medicinal agent.

5 cl, 15 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of aryl and heteroarylpiperidinecarboxylates, of formula (I): , where: type means integer numbers from 1 to 3, such that m+n is integer number from 2 to 5; p means integer number from 1 to 7; A means simple connection or is selected from one or several groups X, Y; X means -CH2-; Y means C2-alkynilene group; R1 means group R5, substituted with one or several groups R6 and/or R7; R2 means H, F, OH; R3 means H; R4 means H, C1-6-alkyl; R5 means group selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, chinolynyl, tetrahydrochinolinyl, isochinolinyl, tetrahydroisochinolinyl, indolyl, indolinyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzizoxazolyl, benzothiazolyl, benzithiazolyl, benzotriazolyl, benzoxadiazolyl, pyrrolopyridinyl; R6 means halogen, CN, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, OH, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, or cycle selected from pyrrolidine and piperidine cycle, besides this cycle is unnecessarily substituted with C1-6-alkyl group; R7 means phenyl group, besides group or groups R7 may be substituted with one or several groups R6, identical or differing from each other, selected from halogen, C1-6-alkyl and C1-6-fluoroalkyl, C1-6-alkoxy, in the form of pharmaceutically acceptable base or acid-additive salt.

EFFECT: compounds are applicable as inhibitors of FAAH ferment.

10 cl, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives (indole-3-yl)heterocyclic compounds of formula 1: , where: A represents 5-member aromatic heterocyclic ring, where X1, X2 and X3 are independently selected from N, O, S, CR; R means H, (C1-4)alkyl; or R, when it is available in X2 or X3, may form 5-8-member ring together with R3; R1 means 5-8-member saturated carbocyclic ring, which unnecessarily contains heteroatom O; R2 means H; or R2 is connected to R7 with creation of 6-member ring, which unnecessarily contains heteroatom O, or where mentioned heteroatom is connected to position 7 of indole ring; R3 and R4 independently mean H, (C1-6)alkyl, which is unnecessarily substituted with OH, (C1-4)alkyloxy; or R3 together with R4 and N, with which they are connected, creates 4-8-member ring, which unnecessarily contains additional heteroatom, selected from O and S, and unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy or (C1-4)alkyloxy-(C1-4)alkyl; or R3 together with R5 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; or R3 together with R, when present in X2 or X3, creates 5-8-member ring; R5 means H; or R5 together with R3 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; R5' means H; R6 means one substituent selected from H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; R7 means H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; or R7 is connected to R2 with creation of 6-member ring, which unnecessarily contains additional heteroatom O, and where heteroatom is connected to position 7 of indole ring; or its pharmaceutically acceptable salt. Compounds of formula I display activity of agonists to cannabinoid receptor CB1.

EFFECT: possibility to use them for treatment of pains of various nature.

10 cl, 1 tbl, 42 ex

FIELD: medicine.

SUBSTANCE: invention is related to new heterocyclic compounds of common formula (I), and also their pharmaceutically acceptable salts, hydrates and/or solvates, possessing properties of human neutrophil elastase. In common formula (I) , A means phenyl or pyridyl cycle, R1 and R3 each means atom of hydrogen, R2 means atom of fluorine, chlorine, bromine, nitro group or cyano group, R4 means cyano group, alkyl carbonyl group with number of carbon atoms in alkyl residue from one to four, or alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, besides alkoxycarbonyk group with number of carbon items in alkoxyl residue from one to four, may be substituted with substituent, which is selected from the group that includes hydroxyl group, alkoxygroup with number of carbon atoms from one to four, alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, mono- or dialkylaminogroup, with number of carbon atoms in each of alkyl residues from one to four, 5-6-member heteroaryl group, which contains from 1 to 4 heteroatoms in heteroaryl ring, selected from nitrogen, oxygen or sulfur, possibly susbstituted with alkyl group, which contains from 1 to 4 atoms of carbon and possibly condensed with benzene ring, and 5-8 member heterocyclyl group, which contains from 1 to 3 heteroatoms from group of nitrogen, oxygen or sulfur, or SO, SO2 possibly substituted with ketogroup, R5 means methyl group, R6 means atom of hydrogen, alkyl group with number of carbon atoms from one to four, mono- or dialkylaminocarbonyl group with number of carbon atoms in each of alkyl residues from one to four, etc., Y1, Y2, Y3, Y4 and Y5 each means CH-group. Invention is also related to pharmaceutical composition.

EFFECT: possibility of application for treatment of chronic obstructive lung diseases, acute coronary syndrome, acute myocardial infarction and progressing cardiac decompensation.

8 cl, 1 dwg, 111 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: medicine.

SUBSTANCE: invention belongs to microbiology and biotechnology, notably to tuberculosis anatoxin manufacture for specific prevention of tuberculosis. Tuberculosis anatoxin is made by detoxication of tuberculosis exo- and endotoxins with two detoxifiers - 0.2% formalin solution during 7-9 days at 42-45 C° and 0.5% aethonium solution during 7-9 days at 42-45 C°. Then tuberculosis anatoxin is sorbed on 1-3 mg/ml of aluminium hydroxide, concentration of inactivated toxic allergens is doubled by decantation of 50±5% of supernatant.

EFFECT: usage of anatoxin manufactured by this method gives vaccinated animals immunity to induced by virulent tuberculosis mycobacterium infection due to immune reorganisation of organism; animals acquire moderate sensibility to tuberculin.

4 ex

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