Selective antituberculosis agent representing 3-hydrazono-6-(3,5-dimethylpyrazol-1-yl)- 1,2,4,5-tetrazine and method for preparing it

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a selective antituberculosis agent representing 3-hydrazono-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine of general formula A

wherein R2 = hydrogen atom or methyl; R3 = methyl, aryl specified in optionally substituted phenyl, heteryl specified in furyl, pyridyl, 3-phenylallyl. The invention also refers to a method for preparing 3-hydrazono-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine with the use of microwave radiation; the given method is implemented with high speed and selectivity.

EFFECT: invention provides higher activity and specificity of antimycobacterial action.

2 cl, 3 tbl, 16 ex

 

The present invention relates to asymmetric 3,6-disubstituted 1,2,4,5-tetrazine, containing 6 position tyrosinemia cycle 3,5-dimethylpyrazole group, and in position 3 - residue substituted hydrazone, and the method of its production. These compounds can be used as anti-TB agents, primarily for the treatment of tuberculosis.

The structure and method of producing the compounds claimed as selective anti-TB agent as described [Zhur.org.chem., 2006, 42, No. 3, s-780; Heterocycles, 2003, 60 (12), PP.2653-2668}, but their activity against Mycobacterium tuberculosis is not known and is not described.

Similar to the above substances, the structure is the methyl ester of 2-N-[6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-aminopropionic acid of the formula (I), which shows little tuberculostatic activity against strains of Mycobacterium H37Rv, but for other members of this series of compounds characterized by the opposite effect - increasing growth of colonies of mycobacteria in their presence, associated with the release of amino acids [Chem. Pharm. journal, 39, No. 1, 2005, p.10-12].

Similar in purpose, isoniazid formula II, is a selective anti-TB drug, but the disadvantages of this drug are high the Kai toxicity and various side effects in the application. Isoniazid Allergy, affects the function of the gastrointestinal tract, have an adverse effect on the nervous system [Medmaravis. Medicines, 15th ed., Rev., Corr. and supplementary): RIA "New wave": the publisher Merenkov, 2007, s and Pharmacology and toxicology, 1987, 50, (4), p.87]. The broad distribution of isoniazid-resistant clinical strains of Mycobacterium tuberculosis (Antibiotics and chemotherapy, 2002, 47, No. 6, pp.28-30].

Describes how to obtain the claimed compounds by condensation of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine with aldehydes or ketones in methyl alcohol at room temperature in the presence of acid [Zhur.org.chem., 2006, 42, No. 3, s-780]. The resulting product is separated by filtration, washed and dried. The outputs are 70-91%. However, this method is characterized by the duration of the process (3 hours), which leads in some cases to the formation of by-products.

The objective of the invention is the use of known substances as antimycobacterial agents with high specificity, while expanding the spectrum antimycobacterial actions and the development of more effective ways of obtaining them.

The problem is solved in that the quality of anti-TB agent use asymmetric 3,6-disubstituted 1,2,4,5-tetrazine formula And containing the B3 position residue substituted hydrazone

where R2=a hydrogen atom or methyl; R3=methyl, 1-phenylpropan-1-yl, aryl, selected from a possibly substituted phenyl, hetaryl selected from Furie, pyridyl, with the substituted phenyl has 1-3 substituent selected from the group including bromine, chlorine, methoxy, nitro, hydroxy group, n=0,1,2.

To obtain the substituted 3-hydrazono-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine use a new microwave method comprising heating at a temperature of 55-60°With equimolar quantities of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine with the appropriate aryl-, getallimages, aliphatic or aromatic ketone in the environment of acetonitrile, and the reaction are under the influence of microwave radiation with a power of 200 watts. This method differs from the prototype greater selectivity of the process, thus reducing the reaction time to 15-20 minutes and increase yields of target products to 90-95%.

Unlike similar in structure and purpose, these compounds represent a 3,6-disubstituted 1,2,4,5-tetrazine containing hydrazone fragments, as well as additional heteroaromatic residues, the presence of tuberculostatic activity have not been obvious.

Structural features of the claimed substances lead to increased specificity antimycobacterial what about the actions and expansion of the spectrum - increased activity of these compounds against typical, atypical, and resistant strains of mycobacteria (table 1-3). Due to its specificity to M. they do not have an overwhelming effect in normal flora of the body.

The study antimycobacterial activity of the claimed compounds in the in vitro experiments carried out bacteriologically, using vertical diffusion in a dense nutrient medium of Levenshtein-Jensen or "New". In the test tube is seeded with the test microbe on the free edge to the bottom buried by 0.3 ml of each dilution. The tubes are placed in the device in an upright position and incubated at 37°C, the results account for 10-12 days.

Antibacterial activity of the claimed compounds is studied by the method of sowing the drug solution into the wells. In a Petri dish with a simple nutrient agar make the test microbe. In the hole located in the middle of the Petri dishes, contribute to 0.02 ml of the drug in the required concentrations. The results take into account after 24-hour incubation in an incubator at 37°C, the definition of the zone of growth inhibition of microorganisms on the edges of the hole.

The purity of the obtained compounds is controlled by TLC, the values of Rfdetermine, using records "Sorbfil" (Silica gel CTX-1A,UV) (Russia) or "Silufol UV" (Czechoslovakia). The structure of the compounds obtained a confirmation is ereaut elemental analysis data (C,H,N,O - the analyzer company Karlo Erba). IR spectra were recorded on FTIR spectrometer Spectrum One" firm "PerkinElmer" with consoles diffuse reflection (Diffuse Reflectance Sampling Accessory (DRA). The NMR spectra of1N compounds recorded in DMSO-d6on the instrument Bruker-400 operating frequency of 400 MHz, TMS as internal standard. The melting temperature determined by the heating table "Boetius". For microwave irradiation of the investigated reactions using microwave chemical reactor ProLabo (frequency 2.45 Hz, the radiation power of 200 watts).

Examples of specific performance.

Example 1

N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-utilitiesin

(Compound of formula A, where R2=N, R3=methyl)

A solution containing 10 mmol of acetic aldehyde and 10 mmol of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine in 5 ml of acetonitrile is subjected to microwave irradiation in a microwave chemical reactor ProLabo (frequency 2.45 Hz, the radiation power of 200 W at 55°C for 15-20 minutes (control by TLC). The solvent is evaporated, the residue is washed with acetonitrile and aliphatic alcohol and air-dried.

Output 90%. TPL 120°C. Calculated (%): C, at 46.54; H, 5.21; N, 48.25. C9H12N8.

Found (percent): C, 46.63; H, 5.20; N, 48.17.1H NMR (CDCl3), δ: 2.34 (3H, 3Pz-CH3); 2.58 (3H, 5Pz-CH3); 6.12 (1H, 4Pz-CH3 ); 2,13 D. (3H, SNSN3); to 7.68 (1H,=CH) (5,4); 9,86 s (1H, NH).

Example 2

N-Benzylidene-N'-[6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]hydrazine

(Compound of formula A, where R2=N, R3=phenyl)

Get analogously to example 17 from 1.0 mmol of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.0 mmol of benzaldehyde at 60°C for 15-20 minutes. Yield: 97%. TPL 202-204°C. Calculated (%): C, 57.13; H, 4.79; N, 38.07. With14H14N8. Found (percent): C, 57.24; H, 5.02; N, 37.86.1H NMR (Dl3), δ: 2.71 (3H, 3Pz-CH3); 2.61 (3H, 5Pz-CH3); 6.11 (1H, 4Pz-CH3); 7.34-7,43 m (3N, Narene); 7.74-7.80 m (2N, Narene); 8,17 (1H, N=CH); to 9.57 (1H, NH).

Example 3

N-[6-(3,5-Dimethylpyrazol-1-yl)-s-tetrazine-3-yl]-N'-(3,4-dimethoxybenzamide)-hydrazine

(Compound of formula A, where R2=N, R3=3,4-acid)

Get analogously to example 18 from 1.0 mmol of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.0 mmol of 3,4-dimethoxybenzaldehyde.

Yield 91%. TPL 199°N Calculated (%): C, 54.23; H, 5.12; N, 31.62. C16H18N8O2. Found (percent): C, 54.13; H, 5.21; N, 31.67. An NMR spectrum1H (DMSO; 100 MHz; δ, ppm): 2.25 (3H, 3Pz-CH3); 2.46 (3H, 5Pz-CH3) (J=0.6 Hz); 3.82 and 3.84 two (6N, ON3); 6.23 (1H, 4Pz-CH); 7.00-7.38 m (5H, HAr); 8.29 (1H, N=CH); 12.47 (1H, NH).

Example 4

N-(4-Methoxybenzylidene)-N'-[6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl hydrazine

(Compound of formula A, where R2=N, R3=4-methoxyphenyl)

Get analogously to example 18 from 1.0 mmol of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.0 mmol of 4-methoxybenzaldehyde.

Yield: 97%. TPL 196-197°C. Calculated (%): C, at 55.55; H, 4.97; N, 34.55. C15H16N8O.

Found (percent): C, 55.68; H, 4.99; N, 34.51.1H NMR (DMSO-d6), δ: 2.25 (3H, 3Pz-CH3); 2.46 (3H, 5Pz-CH3); 6.23 (1H, 4Pz-CH3); 6,98-7,09 d (2N, Narene) (9); 7,66-7,78 d (2N, Narene) (9); 8,31 (1H,=CH); 12,42 (1H, NH).

Example 5

N-(4-Nitrobenzylidene)-N'-[6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]hydrazine

(Compound of formula A, where R2=N, R3=4-nitrophenyl)

Get analogously to example 17 from 1.0 mmol of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.0 mmol of 4-nitrobenzaldehyde.

Yield: 94%. TPL 219-220°C. Calculated (%): C, 49.56; H, 3.86; N, at 37.15. With14H13N9About2.

Found (percent): C, at 49.68; H. 3.97; N, 37.08.1H NMR (DMSO-d6), δ: 2.26 (3H, 3Pz-CH3); 2.49 (3H, 5Pz-CH3) (J 0.6 Hz); 6.25 (1H, 4Pz-CH3); 7,98-8,07 m (2N, Narene.); 7,27-at 8.36 m (2H, CHarene.); to 8.45 (1H,=CH); 12,86 s (1H, NH).

Example 6

N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-(3,4,5-trimetoksi-benzylidene)-hydrazine

(Compound of formula A, where R2=N, R3=3,4,5-trimethoxyphenyl)

Get analogously to example 18 from 1.0 mmol, hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.0 mmol of 3,4,5-trimethoxybenzaldehyde.

The output of 95.5%, TPL 190°C. Calculated (%): C, 53.12; H, 5.24; N 29.15. C17H20N8O3.

Found (percent): C, 52.85; H, 5.11; N, 28.92. An NMR spectrum1H (DMSO-d6, δ): 2.25 (3H, 3Pz-CH3); 2.47 (3H, 5Pz-CH3); 3.72 (3H, p-och3); 3.86 (6N, 2m-och3); 6.23 (1H, 4Pz-CH); 7.08 (2H, HAr); 8.28 (1H,CH=N); 12.60 (1H, NH).

Example 7

N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-(4-hydroxy-3-methoxybenzylidene)-hydrazine

(Compound of formula A, where R2=N, R3=4-hydroxy-3-methoxyphenyl)

Get analogously to example 18 from 1.0 mmol of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.0 mmol of 4-hydroxy-3-methoxybenzaldehyde.

Yield 93%. TPL 230-231°C. Calculated (%): C, at 52.94; H, 4.74; N, 32.92. C15H16N8O2. Found (percent): C, 51.60; H, 5.03; N, 33.60. An NMR spectrum1H (DMSO; 100 MHz; δ, ppm): 2.24 (3H, 3Pz-CH3); 2.45 (3H, 5Pz-CH3); 6.22 (1H, 4Pz-CH); 6.82-6.90 m (1H, HAr); 7.10-7.20 m (1H, HAr); 7.35 USS (1H, HAr); 8.25 (1H, N=CH); 9.6 (1H, HE); 12.3 OSS (1H, NH).

Example 8

N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-(3-phenylalaline)-hydrazine

(Compound of formula A, where R2=N, R3=1 phenylpropen-1-yl)

Get analogously to example 17 from 1.0 mmol of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.0 mmol cinnamic aldehyde.

Yield 91%. TPL 193-195°C. Calculated (%): C, 59.99; H, 5.03; N, 34.98. C 16H16N8. Found (percent): C, 59.93; H, 5.07; N, 34.95. An NMR spectrum1H (DMSO-d6/CCl4; 400 MHz; δ, ppm): 2.24 (3H, 3Pz-CH3); 2.45 (3H, 5Pz-CH3); 6.22 (1H, 4Pz-CH); 7.08-7.13 m (2H, 2CH); 7.36-7.50 m (3N, NAr); 7.62-7.69 m (2N, NAr); 8.18 m (1H, CH-CHCH); 12.5 USS (1H, NH).

Example 9

N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-(furan-2-iletiler)-hydrazine

(Compound of formula A, where R2=N, R3=furan-2-yl)

Get analogously to example 17 from 1.0 mmol of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.0 mmol of shrilled.

Yield 92%. TPL 188-189°C. Calculated (%): C, 50.70; H, 4.25; N, 39.42. C12H12N8O Found (%): C, 50.86; H, 4.20; N, at 39.34. An NMR spectrum1H (DMSO; 400 MHz; δ, ppm): 2.27 (3H, 3Pz-CH3); 2.50 (3H, 5Pz-CH3); 6.13 (1H, 4Pr-CH); 6.56-6.58 m (1H, HAr); 6.87 in d (1H, HAr) (J=3.4 Hz); 6.87 (1H, HAr) (J=3,4 Hz); 7.73 (1H, HAr) (J=1.6 Hz); 8.20 (1H, N=CH); 12.46 c (1H, NH)

Example 10

N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-pyridin-4-iletiler-hydrazine

(Compound of formula A, where R2=N, R3=pyridine-4-yl)

Get analogously to example 17 from 1.0 mmol of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.0 mmol of 4-pyridinylmethyl.

The output of 91.7%. TPL 224°C. Calculated (%): C, at 52.87; H, 4.44; N, 42.69. With13H13N9. Found (%): C; H, 4.57; N, 42.90. An NMR spectrum1H (CDCl ; 100 MHz; δ, ppm): 2.40 (3H, 3Pz-CH3); 2.66 (3H, 5Pz-CH3) (J=0.8 Hz); 6.16 (1H, 4PzCH); 7.67 (2H, N.Ar); 8.10 (1H, CH=N); 8.75 d (2N, NAr); 9.52 (1H, NH)

Example 11

N-[6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-pyridine-3-ylmethylene-hydrazine

(Compound of formula A, where R2=N, R3=pyridine-3-yl)

Get analogously to example 17 from 1.0 mmol of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.0 mmol of 4-pyridinylmethyl.

Yield: 94.3%. TPL 232°C. Calculated (%): C, at 52.87; H, 4.44; N, 42.69. C13H13N9.

Found (percent): C, 52.85; H, 4.26; N, 42.96.1H NMR (DMSO-d6/CCl4), δ): 2.28 (3H, 3Pz-CH3); 2.52 (3H, 5Pz-CH3); 6.14 (1H, 4Pz-CH3); 7,34-7,50 m (1H, H5); 8,15-8,27 and 8,51-8,59 both m (1H, Harene); 8,d (1H, H6) (1,6); of 8.37 (1H,=CH); 12,63 s (1H, NH).

Example 12

N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-(isopropylidene)-hydrazine

(Compound of formula A, where R2=methyl, R3=methyl)

Get analogously to example 18 from 1.0 mmol of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.0 mmol of acetone.

Output 90%. TPL 121°C. Calculated (%): C, at 48.77; H, 5.73; N, 45.50. C10H14N8. Found (percent): C, 48.71; H, 5.69; N, 45.30. An NMR spectrum1N (Dl3; 400 MHz; δ, ppm): 2.21 2.08 and both with (3H, 2CH3); 2.36 (3H, 3Pz-CH3); 2.59 (3H, 5Pz-CH3); 6.12 (1H, 4Pz-CH); at 8.62 c (1H, NH).

p> Example 13

N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-(1-phenylethylene-hydrazine

(Compound of formula A, where R2=methyl, R3=phenyl)

Get analogously to example 18 from 1.0 mmol of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.0 mmol of acetophenone.

The output of 95.7%. TPL 175-177°C. Calculated (%): C, 58.42; H, 5.23; N, 36.35. C15H16N8. Found (percent): C, 58.61; H, 5.34; N, at 36.42. An NMR spectrum1H (Dl3, δ, ppm, J/Hz): 8.97 (USS, 1H, -NH-N=); 6.13 (s, 1H, H(4) in pyrazoline); 2.62, 2.46, 2.37 (all, N, SN3), 7.85-7.35 (m, 5H, Ar).

Example 14

N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-[1-(4-bromophenyl)-ethylidene] hydrazine

(Compound of formula A, where R2=methyl, R3=4-bromophenyl)

Get analogously to example 18 from 1.0 mmol of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.0 mmol of 4-bromoacetophenone.

Yield 96%. TPL 189-191°C. Calculated (%): C, 46.52; H, 3.90; N, 28.94. 79.2.

C15H15BrN8. Found (percent): C, at 46.45; H, 3.80; N, 28.95; NMR Spectrum1H (Dl3, δ, ppm, J/Hz): 8.97 (USS, 1H, -NH-N=); 6.14 (s, 1H, H(4) in pyrazoline); 7.76-7.54 (m, 4H, Ar); 2.63, 2.40, 2.38 (all, N, SN3).

Example 15

N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-[1-(4-methoxyphenyl)-ethylidene] hydrazine

(Compound of formula A, where R2=methyl, R3=4-methoxyphenyl)

Get analogously to example 18 from 1.0 mmol of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine is 1.0 mmol of 4-methoxyacetophenone.

Output 90%. TPL 152-153°C. Calculated (%): C, 56.79; H, 5.36; N, 33.12. C16H18N8O Found (%): C, 56.66; H, 5.25; N, 32.92; NMR Spectrum1N (Dl3, δ, ppm, J/Hz): 8.98 (USS, 1H, -NH-N=); 6.12 (s, 1H, H(4) in pyrazoline); 3.84 (s, 3H, och3); 2.61, 2.39, 2.36 (all, N, SN3), 7.80-7.31 (m, 4H, Ar).

Example 16

N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-[1-(4-chlorophenyl)-ethylidene] hydrazine

(Compound of formula A, where R2=methyl, R3=4-chlorophenyl)

Get analogously to example 18 from 1.0 mmol of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.0 mmol of 4-chloroacetophenone.

Yield 97%. TPL 182-184°C. Calculated (%): C, 52.55; H, 4.41; N, 32.69. C15H15ClN8. Found (percent): C, 52.29; H, 4.33; N, 32.55; NMR Spectrum1N (Dl3, δ, ppm, J/Hz): 8.96 (USS, 1H, -NH-N=); 6.14 (s, 1H, H(4) in pyrazoline); 7.87-7.34 (m, 4H, Ar); 2.63, 2.40, 2.38 (all, N, SN3).

As can be seen from tables 1-3 of the claimed compounds show high specificity against mycobacteria, as well as high activity against typical, atypical, and resistant strains of mycobacteria.

Table 1
Antibacterial activity of the claimed compounds in vitro
Connection
E. coliKlebsiella pneumoniaeStreptococcus groupS. aureusPseudomon as aeruginosa
N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-pyridin-4-yl-methylidene-hydrazine (example 10)>100>100>100>100>100
N-(4-Methoxybenzylidene)-N'-[6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]hydrazine (example 4)>100>100>100>100>100

Table 2
Tuberculostatic activity of the claimed compounds in relation to typical and atypical mycobacterial strains, MIC, mcg/ml
The structural formulaH37RvM.Fortuitium
Isoniazid (II) - analog0.03250
Methyl ester of 2-N-[6-(3,5-is emailparts-1-yl)-1,2,4,5-tetrazine-3-yl]-aminopropionic acid (II) similar 1.25Not defined
N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-(3,4-dimethoxybenzamide)-hydrazine (example 3)0.150.15
N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-(3-phenylalaline)-hydrazine (example 8)0.310.31
N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-(isopropylidene)-hydrazine (example 12)0.150.15
N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-(4-hydroxy-3-methoxybenzylidene)-hydrazine (example 7)0.150.15
N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-(furan-2-iletiler)-hydrazine (example 9)1.51.25
N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-pyridin-4-iletiler-hydrazine (example 10)6.25Not defined

Table 3
Tuberculostatics the activity of the claimed compounds against M. Tuberculosis isoniazid-resistant clinical strains of Mycobacterium
Connection nameMIC, mcg/ml
Isoniazid (II) - analog<100
N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-(4-0.15
hydroxy-3-methoxybenzylidene)-hydrazine (example 7)
N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-N'-pyridin-4-iletiler-hydrazine (example 10)25.0

Thus, the claimed compounds with characteristics superior counterparts in structure and action and can be used in practical medicine for the treatment of patients infected with both typical and atypical mycobacteria.

1. Selective anti-TB agent representing a 3-hydrazono-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine General formula And

where R2=a hydrogen atom or methyl; R3=methyl, aryl, selected from a possibly substituted phenyl, hetaryl selected from Furie, pyridyl, 3-phenylaline, with the substituted phenyl has 1-3 substituent selected from the group including bromine, chlorine, methoxy, nitro, hydroxy group, n=0, 1,2.

2. The method of obtaining selective anti-TB agent according to claim 1, including the interaction of equimolar amounts of 3-hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and aryl-, getallimages, aliphatic or aromatic ketone when heated in the organic solvent, wherein the process is conducted under the influence of microwave radiation with a power of 200 W at a temperature of 55-60°C for 15-20 min, and as the organic solvent used acetonitrile.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of producing 1,3-diazido-2-nitro-2-azapropane (DANP), which is one of the most powerful liquid expolosives. The disclosed method involves nitration of the initial substance, chlorination of the nitration products and subsequent azidation of the obtained reaction mass in a water-acetone medium with sodium azide, where the initial substance used is urea, which is nitrated with a mixture of sulphuric acid and nitric acid, taken in weight ratio 40-60:60-40; the nitrated mass is diluted with water and extracted with ethyl acetate or the nitrated mass is cooled to temperature ranging from minus 15°C to minus 10°C; the obtained precipitate is filtered and dissolved in ethyl acetate, where the product of nitration of urea in ethyl acetate is mixed with aqueous formalin solution in molar ratio 1:4 (urea:formaldehyde), where the obtained reaction mass undergoes treatment with acetic anhydride, followed by treatment with hydrogen chloride or thionyl chloride.

EFFECT: high technological effectiveness and safety of the process, implementation of which enables to obtain an end product which does not require further purification.

1 cl, 4 ex, 1 tbl

FIELD: molecular biology, bioorganic chemistry.

SUBSTANCE: method for preparing DNA-chip involves modifying a polymer surface comprising electrophilic groups with compound of the formula: H2N-X-Si(OR)3 wherein X means propyl; R means ethyl in gaseous phase, and with a solution of compound of the formula: Y-X-Si(OR)3 wherein Y means a functional group; X means propyl; R means ethyl or methyl. Then oligonucleotide is immobilized on the modified surface of a polymer by the covalent route. Use of the invention provides decreasing the cost and enhancing effectiveness of modification of backing in production of DNA-chips.

EFFECT: improved preparing method.

11 cl, 10 dwg, 2 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and deals with combined pharmaceutical composition, which possesses anti-tuberculosis action. Composition is made in form of solid drug form, which contains combination of levofloxacin, protionamide, pyrazinamide, ethambutol hydrochloride and pyridoxine hydrochloride ad active ingredient, and pharmaceutically acceptable auxiliary substances.

EFFECT: composition is characterised by high therapeutic activity.

10 cl, 2 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a method for increasing streptomycin activity on streptomycin-resistant tuberculosis mycobacteria consisting in the fact that streptomycin detoxification and polymerisation are conducted at first in 0.15±0.05% glutaric aldehyde at 38±40°C for 2-3 days, and then in 0.1% aethonium or 0.1% alkyldimethylbenzene ammonium chloride or 0.1% Biopague D at 38-40°C for 2-3 days at 100-150 mg/ml of the antibiotic.

EFFECT: invention provides higher efficacy and lower toxicity of the antibiotics.

3 ex

FIELD: medicine.

SUBSTANCE: invention concerns a method for screening in vitro of potential drugs for treating tuberculosis by deranged arabinogalactan biosynthesis wherein said method involves the stage of contacting a cell culture Mycobacterium tuberculosis, overexpressing protein ensuring the transformation of decaprenyl-P-ribose into decaprenyl-P-arabinose, and which can be coded by rv3790 gene or its homologues, or an artificial open reading frame, an expression product which is identical to Rv3790 protein, or it is its homologue with a potential drug; it is followed by evaluating an inhibition percentage caused by the potential drug relative to controlling in the analytic test.

EFFECT: invention provides identification of the new drugs.

25 cl, 2 dwg, 9 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the use of a live mycobacterium of the complex M. tuberculosis wherein a zmpl gene function is inactivated for making a drug, pharmaceutical compositions prepared of such mycobacteria, as well as a method for prevention and/or treatment of diseases or conditions involved in antigen and/or immunogen expression in the mycobacterium. The mycobacterium used according to the invention may contains a genetic material coding an antigen and/or immunogen exogenic or xenogenic for the mycobacterium.

EFFECT: invention provides the live mycobacterium based drug with improved immunogenicity and protection effectiveness.

12 cl, 4 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine and concerns a therpaeutic composition of antituberculous preparations with a phospholipid transport system consisting of fatty acid salt, herbal phosphatidylcholine (73-94%), maltose and an antituberculous agent specified in rifamycin, protionamide, rifabutin and rifapentine, and method for preparing it.

EFFECT: composition possess higher antitubeculous activity.

3 cl, 3 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to dimephosphone nicotinoylhydrazone of formula (I) which may be used in medicine and veterinary science: I.

EFFECT: what is presented is a new compound showing high anti-tuberculosis activity and low toxicity.

2 cl, 1 ex, 3 dwg, 3 tbl

FIELD: medicine.

SUBSTANCE: for the purpose of producing a probiotic preparation, a biomass of the symbiontic strain Corynebacterium diphtheriae tox No. 2 of Federal State Institution L.A. Tarasevich State Institution of Standardization and Control is cultured in a liquid nutrient medium; microbial cells are deposited by centrifugation, washed to precipitate whole cells by centrifugation; the cells are suspended in a sodium chloride solution. Then, the cells are disintegrated at temperature 25-30°C for 15 min at frequency 20 kHz and amplitude 14 mcm; the desintegrant is centrifugated at 5000 g; and the remained whole cells are removed. The prepared precipitation is centrifugated at 14000 g for 20 min. to produce precipitated corpuscular antigens of cell walls of lipopeptidopolysaccharide corynebacteria which is resuspended and disintegrated at temperature 25-30°C for 5 min. at frequency 20 kHz and amplitude 14 mcm. Then the preparation is diluted to the concentration of 225-275 mcg/ml, sterilised and lyophilised.

EFFECT: use of the invention enables producing the safe and effective preparation of corpuscular antigens providing creating specific and non-specific immunity to tuberculosis.

2 cl, 2 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, and concerns a combined therapeutic agent possessing antituberculous action. The agent is presented in a solid dosage form which contains a combination of paraaminosalicylic acid and a zinc-containing compound as an active principle, and pharmaceutically acceptable excipients. The zinc-containing compound is specified in zinc picolinate, zinc citrate, zinc acetate, zinc glycerate, zinc monomethionine, zinc aspartate, zinc hyaluronate, zinc gluconate, zinc bisvinylimidazole diacetate, zinc oxide.

EFFECT: composition is characterised by high efficacy.

8 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to phthisiology, and may be used for treating tuberculosis complicated by intolerance to chemotherapy. That is ensured by prescribing the product "Cedar Proteins" 15.0 g of powder dissolved in boiled water 150.0-200.0 ml once a day 1.5-2 h after breakfast for 21 days with underlying standard anti-tuberculosis chemotherapy.

EFFECT: use of the given method of treating provides improving tolerance to the anti-tuberculosis therapy and reducing the symptoms of tuberculous intoxication.

1 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to phthisio-orthopedics and can be used for treatment of progressing tuberculosis of hip joint. For this purpose first pre-operation anti-tuberculosis therapy is performed by 4 medications in usual dosages during 30 days. After that performed is sanitising operation on hip joint in volume of necrotomy of destruction foci, plasty of joint defects, application of apparatus constructions. Then, after 8-12 month course of anti-tuberculosis treatment by 4 medications in case of absence of signs of activity of specific inflammatory process in joint, confirmed by clinical, radiation and laboratory methods, total arthroplasty is performed. After that, one more course of intensive anti-tuberculosis treatment during 4-6 months is performed.

EFFECT: method ensures increase of efficiency of surgical treatment of progressing tuberculosis of hip joint due to radical sanitisation of specific focus in joint affected by tuberculosis and creation of optimal conditions for functionally directed operation of arthroplasty, thus considerably improve patient's life quality in early time.

5 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics and medicine and deals with application of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydroimidaso[4,5-c]quinilin-1-yl)phenyl]propionitryl or 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidaso[4,5-c]quinoline-2-on or its tautomer, pharmaceutically acceptable salt, hydrate or solvate for obtaining medication, intended for treatment of disease, connected with change or impairment of mTOR kinase regulation, selected from group, including glioma, disease transplant-against-host, for instance, after bone marrow transplantation, restenosis, tuberous sclerosis, lymphangioleimyomatosis, pigment retinitis, autoimmune diseases, including encephalomyelitis, insulin-dependent diabetes mellitus, dermatomyositis, rheumatoid diseases, steroid-resistant acute lymphoblastic leukemia, fibrous diseases, pulmonary hypertension, immunomodulation, Von Hippel-Lindau syndrome, Carney syndrome, familial adenomatous polyposis, juvenile polyposis syndrome, Birt-Hogg-Duke syndrome, familial hypertrophic cardiomyopathy, Wolff-Parkinson-White syndrome, neurodegenerative disorders, wet and dry macular degeneration, muscle dystrophy (atrophy, cachexia) and myopathies, such as Danone disease, bacterial and viral infections, including military tuberculosis, group A streptococcus, virus of type I herpes simplex, HIV-infection, neurofibromatosis, including type 1 neurofibromatosis, Peutz-Jeghers syndrome, or any their combinations.

EFFECT: invention ensures high efficiency.

9 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to pharmaceutical composition for local application, which possesses antibacterial properties.

EFFECT: invention represents pharmaceutical stable semi-hard compositions for local application, which contain from 0.2 to 5 wt % of desfluoroquinolone compound, suitable for ointment or cream production.

24 cl, 5 ex, 15 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein m is equal to 0, 1, 2; n is equal to 0, 1, 2, 3; each p, s, t is equal to 0 or 1; X represents CHR8 wherein R8 represents hydrogen; represents -CR9=C<, and then a dash line represents a bond, R9 independently represents hydrogen or C1-6-alkyl, or wherein R9 together with one of R2 or R20 forms a direct bond; R1 represents hydrogen; R2 and R20 are specified in: halogen, cyano, polyhalogen-C1-6-alkyl, C1-6-alkyl, morpholinyl, C1-6-alkyloxy with any of said groups is optionally and independently substituted by hydroxy, NR21R22 wherein R21 and R22 are independently specified in hydrogen, C1-6-alkylcarbonyl; or R2 and R20 together with a phenyl cycle whereto attached form a naphthaline group; or one of R2 or R20 have the values specified above, and the other of R2 or R20 together with R9 form a direct bond; R3 represents hydrogen; R4 and R5 independently represent hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6-alkenyl or C1-6-alkyloxy; or R6 represents hydrogen; when p is equal to 1, then R7 represents hydrogen; Z represents one of the radicals presented in the patent claim. Also, the invention refers to a based pharmaceutical composition, using the compounds of formula (I) for producing the drug preparation for treating the disorders medicated by p53-MDM2 interaction for treating cancer, and to methods for producing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) as p53-MDM2 interaction inhibitors.

13 cl, 5 tbl, 31 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly gastroenterology, and may be applied in treating secondary lactase deficiency. For this purpose, with underlying diet and drug-induced therapy, bifiform 1 tablet 2-3 times a day and No-spa 1-2 tablets 3 times a day are additionally administered. The therapeutic course makes 14 days.

EFFECT: method enables higher clinical effectiveness in secondary lactase deficiency.

3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to neurology, restorative medicine, and can be applied in treatment of consequences of infantile cerebral paralysis. For this purpose reflex low temperature impact on nerve plexuses of peripheral artery is performed. Said impact is performed first in lower third of forearm, and after three months in first interdigital space of foot. Cryoapplicator with diameter 2 mm is installed on exposed peripheral artery and double cryogenic impact with duration 10 seconds is performed at temperature minus 186°C. In the period between low temperature impacts complex drug therapy is carried out: in the first two weeks administered are detralex in dose 1 capsule 2 times per day, nicospan in dose 1 tablet 3 times; in the second two weeks grandaxin in dose 0.05 in the morning; spasgan in dose 1 tablet in the afternoon; atarax in dose 1/2 tablet before going to bed.

EFFECT: method ensures definite consistency, which makes it possible to compensate vegetative dystonia syndrome, normalise neuromuscular transmission, reduce muscle spasticity, optimise motor functions of upper and lower extremities and, therefore, improve coordination of movements and supportability of lower extremities.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely addictology, psychiatry and combustiology and may be used for anaesthesia in desomorphin addicted patients suffering thermal burns. After admission to hospital, the burns are localised with describing the aethiology, the comorbidity, the psychological and social characterisation of the patient. If observing the flame-caused injuries, and if the thermal injury localisation and severity are different from the circumstances described by the patient; if chemical burning smell and fly ash are seen, while the burns are found to be localised on face, neck, front and/or back trunk, hands, forearms; and in case of airway burn, signs of lymphangitis, phlebitis and thrombophlebitis, no criticism with persistent mental disturbances; if the patient is unemployed or does not study, desomorphine addiction is diagnosed. During a period of septic toxaemia, dressing procedures required a local anaesthetic to be used, while narcotic analgesics are introduced after the dressing procedures to be gradually replaced by non-narcotic analgesics.

EFFECT: improved anaesthesia.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, namely a stable pharmaceutical composition of a water-soluble salt of vinorelbine. The composition contains approximately 56 wt % of a diluent, approximately 2.5 wt % of a binding agent, approximately 5 wt % of a disintegrant, approximately 0.25 wt % of a flow agent and approximately 0.5 wt % of a lubrication agent. The water-soluble salt of vinorelbine is preferentially vinorelbine ditartrate.

EFFECT: pharmaceutical composition is preferentially presented in the form of a gelatine capsule or a tablet.

5 cl, 6 ex, 12 tbl

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