Selective anti-tuberculosis agents, representing 3-aminosubstituted 6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazines

FIELD: chemistry.

SUBSTANCE: invention represents 3-aminosubstituted 6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazines, which applied as anti-tuberculosis medications make it possible to increase activity and specificity of antimicrobacterial action, extend its spectrum (impact on atypical strains of mycobacteria) as well as reduce toxicity in comparison with analogues.

EFFECT: toxicity of claimed compounds is 10-20 times lower than toxicity of anti-tuberculosis medications applied in medicine.

5 tbl, 16 ex

 

The invention relates to asymmetric 3,6-disubstituted 1,2,4,5-tetrazine containing in position 6 tyrosinemia cycle 3,5-dimethylpyrazole group in position 3 is the residue of an aromatic or aliphatic amine. 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 agents described [Zhur.org.chem., 1999, 35, s; Abstracts of the Second International Symposium of Molecular Design and Synthesis of Supramolecular Architectures, Kazan, 2002, p.154], 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 ven the rata are its high toxicity and a variety of side effects when used. 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].

Methods for obtaining compounds As described. Substituted 3-(N-R1-amino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine General formula A receive interaction in acetonitrile 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine with the appropriate substituted amine [Zhur.org.chem., 2006, 42, No. 3, s-780].

The objective of the invention is the use of known substances as antimycobacterial agents with high specificity, while expanding the spectrum antimycobacterial actions.

The problem is solved by the fact that as anti-TB agents use asymmetric 3,6-disubstituted 1,2,4,5-tetrazine containing in position 3 residue substituted amine - 3-amino-substituted 6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine General formula A

where R1=amino group, a C1-C12-alkyl, 3-hydroxy-5-hydroxyphenyl, propyne-2-yl, ethylindole, Adam is until, aryl selected from a possibly substituted phenyl, hetaryl selected from indol-3-yl, quinoline-3-yl, pyridyl, with the substituted phenyl has a Deputy selected from the group comprising methyl, bromo, hydroxy group, and has pyridyl substituents selected from the group chlorine, methyl.

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

Structural features of the claimed compounds lead to increased specificity antimycobacterial actions and expand the range of validity - enhancing activity of these compounds against typical and atypical 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, practically non-toxic (table 2, 4, 5). Identified therapeutic effect of 3-(4-brompheniramine)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 9) in the treatment of experimental tuberculosis of mice.

The study antimycobacterial activity of the claimed compounds in the in vitro experiments carried out bacteriologically, using vertical diffusion on solid nutrient medium is e 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 study of the cytotoxicity of the claimed compounds is performed on cell culture MT-4 (human cell line T lymphocytes person). The toxicity of different concentrations of the compounds is determined by cell viability relative to control using the spectrophotometer at a wavelength of 540 nm, the data and build the dose-dependent curves and determine the concentration by 50% reduce cell viability compared to control (CD50).

The study of the acute toxicity of the inventive compounds is carried out by a standard method on white mice. Animals receive the drug per os in a 10% solution of starch. The study of therapeutic action of the compound (example 9) carry out on white laboratory mice weighing 18-23 g, infected intravenously into the tail vein at a dose of 0.5 mg two weeks of culture (strain H37R.V) in 0.5 ml of physiological solution. Treatment begin within a week after infection and conduct daily for 8 weeks. The study drug, including control isoniazid, given to mice at a dose of 10 mg/kg of body weight.

The optimal ratio of tuberculostatic activity - toxicity has 3-(2-(1H-indol-3-yl)ethylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine. This connection has the lowest toxicity in the investigated range. According to intragastric administration, according to GOST 12.1.007-76 and project classification OESD it belongs to the fourth class of low - hazard substances (L50>5000,0 mg/kg). According to the subcutaneous injection of this drug is on the border between III and IV class of hazard (L50=1949,8 (1183,09 - 3213,43) mg/kg (DL50for compounds IV class of danger in a subcutaneous exceed 2000,0 mg/kg).

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 obtained compounds is confirmed by elemental analysis data (C, H, N, O - analyzer company Karlo Erba). IR spectra were recorded on FTIR spectrometer Spectrum One" firm "PerkinElmer" using prefixes of diffusing the reflection (Diffuse Reflectance Sampling Accessory (DRA). The NMR spectra of1H 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

3 Hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine

(Compound of formula A, where R1=amino group)

1.0 Mmol 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine suspended in 10 ml of acetonitrile and stirring, 1.1 mmol hydrazine hydrate.

The reaction mixture was placed in a porcelain Cup, the solvent is evaporated, the residue is recrystallized from aliphatic alcohol, air-dried. Yield 91%, TPL 153-154°C (CH3CN). C7H10N8. Calculated (%): C, at 40.77; H, 4.89; N, 54.34. Found (percent): C, at 40.77; H, 4.98; N, at 54.24.1H NMR (CDCl3), δ): 2.37 (s, 3H, 3Pz-CH3); 2.58 (s, 3H, 5Pz-CH3); 6.13 (s, 1H, 4Pz-CH); 4.18 (USS, 2H, NH2); 7.16 (USS 1H, NH).

Example 2

3-Methylamino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine

(Compound of formula A, where R1=methyl)

Get analogously to example 1 from 1.0 mmol of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.1 mmol of methylamine.

Output 90%. TPL 194-195°C. Wyche the Leno, (%): C, 46.83; H, 5.37; N, 47.80. C8H11N7.

Found (percent): C, 47.16; H, 5.32; N, 48.13. An NMR spectrum1H (CDCl3, δ, ppm, J/Hz): 6.18 (s, 1H, 4Pz-CH); 8.71 (m, 1H, -NH-CH3), 2.23, 2.38 (both s, 6N, 2CH3Pz); 3.01 (d, 3H, J=4.9).

Example 3

3 Undecillion-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine

(Compound of formula A, where R1=undecyl)

Get analogously to example 1 from 1.0 mmol of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.1 mmol of undecillion.

Output (%): 91.4. TPL 57-58°C. Calculated (%): C, 62.57; H, 9.05; N 28.38. C18H31N7. Found (percent): C, 62.63; H, 9.20; N 28.59. An NMR spectrumlH (CDCl3, δ, ppm, J/Hz): 6.10 (s, 1H, 4Pz-CH); 5.80 (t, 1H, -NH-CH2-), 2.56, 2.35 (both s, 6N, 2CH3Pz); 3.62 (q, 2H, -NH-CH2--), 1.76-1.69 (m, 2H, -NH-(CH2)9CH2CH3); 1.42-1.27 (m, N, -NH-CH2-(CH2)8-C2H5); 0.88 (t, 3H, -NH-(CH2)10CH3J=7,0 Hz).

Example 4

3-Dodecyl-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine

(Compound of formula A, where R1=dodecyl)

Get analogously to example 1 from 1.0 mmol of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.1 mmol of dodecylamine.

Yield 94%. TPL 71-72°C. Calculated (%): C at 63.47; H, 9.25; N 27.27. C19H33N7. Found (percent): C, 63.45; H, 9.13; N 27.32. An NMR spectrum1H (CDCl3, δ, ppm, J/Hz): 6.10 (s, 1H, 4Pz-CH); 5.79 (t, 1H, -NH-CH2-), 2.56, 2.35 (both s, 6N, 2CH3Pz); 3.62 (q, 2H, -NH-CH2the -), 1.76-1.69 (m, 2H, -NH-(CH2)10CH2CH3); 1.43-1.26 (m, N, -NH-CH2-(CH2)9-C2H5); 0.88 (t, 3H, -NH-(CH2)11CH3. J=7,0 Hz).

Example 5

2-{2-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-ylamino]ethoxy}ethanol

(Compound of formula A, where R1=3-hydroxy-5-hydroxyphenyl)

Get analogously to example 1 from 1.0 mmol of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.1 mmol of 3-hydroxy-5-hydroxy-heptylamine.

Yield 95%. TPL 88-89°C. Calculated (%): C, 47.30; H, 6.14; N 35.11. C11H17N7O2. Found (%): C at 47.27; H 6.22; N 34.91. An NMR spectrum1H (DMCO, δ, ppm, J/Hz): 8.83 (USS, 1H, -NH-); 6.19 (s, 1H, 4Pz-CH); 4.62 (USS, 1H, -OH), 2.38, 2.22 (both s, 6N, 2CH3Pz); 3.67-3.65; 3.51-3.46 (both m, 8H, -(CH2)2-O-(CH2)2).

Example 6

3-N(t-Butylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine

(Compound of formula A, where R1=t-butyl)

Get analogously to example 1 from 1.0 mmol of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.1 mmol of t-butylamine.

Yield 93%. TPL 127°C. Calculated, %: C, 53.42, H 6.93, N 39.65. C11H17N7. Found (percent): C, 53.18, H 6.50, N 39.83. An NMR spectrum1H (400 MHz, CDCl3, δ, ppm, J/Hz): 6.09 (s, 1H at C(4) pyrazolyl), 5.85 (USS, 1H, NH), 2.57, 2.35, 1.56 (all, 15 NM, SN3).

Example 7

3-(Adamantane-1-ylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine

(Compound of formula A, where R1=substituted)

Get the analogously to example 1 from 1.0 mmol of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.1 mmol of adamantylamine.

Yield 92%. TPL 162-164°C. Calculated (%): C, 62.77; H, 7.08; N 30.15. C17H24N8. Found (percent): C, 62.69; H, 7.12; N 30.21.1H NMR (CDCl3), δ): 8.48 (USS, 1H, NH); 6.17 (s, 1H, 4Pz-CH); 2.05-2.08 (m, N, substituted), 2.21, 2.40 (both s, 6N, 2CH3).

Example 8

3-N-(2-Hydroxyphenylazo)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine

(Compound of formula A, where R1=2-hydroxyphenyl)

Get analogously to example 1 from 1.0 mmol of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.1 mmol of 2-hydroxyanisole.

Yield 94%. TPL 218-218,5°C. Calculated (%): C, 55.12, H 4.59, N 34.63. C13H13N7O Found (%): C, 55.23, H 4.50, N 34.43. An NMR spectrum1H (400 MHz, CDCl3, δ, ppm, J/Hz): 8.16-8.12, 7.07-6.95 (both m, 5H, OH, Ar) 6.14 (s, 1H at C(4) pyrazolyl), 2.62, 2.38 (both s, 6N, 2CH3when C(3) and C(5) pyrazolyl).

Example 9

3-(4-Brompheniramine)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine

(Compound of formula A, where R1=4-bromophenyl)

Get analogously to example 1 from 1.0 mmol of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.1 mmol of 4-bromo-3-aminobenzene.

The output of 95.3%. TPL 215-216°C. Calculated (%): C, 45.09; H, 3.47; N 28.56. d3H12BrN7. Found (%): C at 45.21; H, 3.56; N at 28.58. An NMR spectrum1H (CDC13, δ, ppm, J/Hz): 6.23 (s, 1H, 4Pz-CH); 11.14 (s, 1H, -NH-Ar), 2.25, 2.47 (both s, 6N, 2CH3Pz); 7.59, 7.74 (both d, 2H, J=6.8).

Example 10

3-(Indol-3-yl-ethylamino)-6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine

(Compound of formula A, where R1=2-(indol-yl)ethyl)

Get analogously to example 1 from 1.0 mmol of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.1 mmol of indole-3-yl-ethylamine.

Yield 92%. TPL 197-198°C. Calculated (%): C, 61.09, H 5.67, N 33.64. C17H17N8. Found (percent): C, 61.08, H 5.39, N 33.53. An NMR spectrum1H (400 MHz; CDCl3; δ, ppm): 8.93 (t, 1H, NH); 6.18 (s, 1H at C(4) pyrazolyl); 3.07 (t, 2H, CH2); 3.75 (K, 2H, CH2); 2.23, 2.38 (both s, 6N, 2CH3); 6.97-7.02, 7.05-7.09 (both m, 2H, 2CH); 7.25, 7.35, 7.59 (all d, 3H, CH 3); 10.86 (s, 1H, NH).

Example 11

3-(6-Methylpyridin-2-yl-amino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine

(Compound of formula A, where R1=6-methylpyridin-2-yl)

Get analogously to example 1 from 1.0 mmol of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.1 mmol of 2-amino-6-methylpyridine.

Yield 93%. TPL 164-165°C. Calculated (%): C, 55.32, H 4.96, N 39.72. C13H14N8. Found (percent): C, 55.35, H 4.98, N 39.69. An NMR spectrum1H (400 MHz; CDCl3; δ, ppm): 11.21 (USS,1H, NH); 6.15 (s, 1H, 4Pz-CH); 7.63, (K, 1H, pyridine); 7.96 (d, 1H, pyridine); 8.20 (t, 1H, pyridine), 2.27, 2.33, 2.52 (all, S, 3CH3).

Example 12

3-(Pyridine-2-ylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine

(Compound of formula A, where R1=pyridine-2-yl)

Get analogously to example 1 from 1.0 mmol of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.1 mmol of 2-aminopyridine.

Output 90%. TPL 248°C. Calculated (%): C, 53.73, H 4.48, N 41.79. C12H12N8. Found (percent): C, 53.79, H 4.51, N at 41.56. the range of NMR 1H (400 MHz; CDCl3; δ, ppm): 11.35 (USS,1H, NH); 6.20 (s, 1H, 4Pz-CH); 7.10-7.14, 7.83-7.86, 8.02-8.04, 8.37-8.39 (all m, 4H, pyridine) 2.27, 2.48 (both s, 6N, 2CH3).

Example 13

3-(4-methylpyridin-2-ylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine

(Compound of formula A, where R1=4-methylpyridin-2-yl)

Get analogously to example 1 from 1.0 mmol of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.1 mmol of 2-amino-4-methylpyridine.

Yield 92%. TPL 245°C. Calculated (%): C, 55.32, H 4.96, N 39.72. C13H14N8. Found (percent): C, 55.47, H 4.83, N 40.00. An NMR spectrum1H (400 MHz; CDCl3; δ, ppm): 11.28 (USS,1H, NH); 6.24 (s, 1H, 4Pz-CH); 6.98-7.00, 7.83-7.85, 8.25-8.26 (all m, 3H, pyridine) 2.24, 2.36, 2.49 (all, S, 3CH3).

Example 14

3-(5-chloropyridin-2-ylamino-)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine

(Compound of formula A, where R1=5-chloropyridin-2-yl)

Get analogously to example 1 from 1.0 mmol of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.1 mmol of 2-amino-5-chloropyridine.

Output 90%. TPL 260°C. Calculated (%): C, 47.60, H 3.64, N 37.02. C12H11ClN8. Found (percent): C, 47.79, H 3.66, N 37.01. An NMR spectrum1H (400 MHz; CDCl3; δ, ppm): 11.68 (USS,1H, NH); 6.26 (s, 1H, 4Pz-CH); 7.63, (K, 1H, pyridine); 7.96 (d, 1H, pyridine); 8.20 (t, 1H, pyridine), 2.26; 2.50 (both s, 6N, 2CH3); 8.00, 8.06, 8.45 (all, 3H, pyridine).

Example 15

3-(Quinoline-3-ylamino)-3-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine

(Compound of formula A,where Ri=quinoline-3-yl)

Get analogously to example 1 from 1.0 mmol of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.1 mmol of 3-aminoquinoline.

The output of 92.5%. TPL 240-242°C. Calculated (%): C, 60.38, H 4.40, N at 35.22. C14H10N8. Found (percent): C, 60.40, H 4.32, N at 35.31. An NMR spectrum1H (400 MHz; CDCl3; δ, ppm): 11.50 (USS,1H, NH); 6.16 (s, 1H, 4Pz-CH); 7.53-7.63 (m, 2H, chinoline); 7.90-7.91 (2N, chinoline); 8.78; 9.12 (both d, 2H, chinoline), 2.29, 2.56 (both s, 6N, 2CH3).

Example 16

[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]prop-2-ynylamine

(Compound of formula A, where R1=prop-2-inyl)

Get analogously to example 1 from 1.0 mmol of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine and 1.1 mmol of propargylamine.

Yield 94%. TPL 182°C. Calculated (%): C, 52.39; H, 4.84; N 42.77. C10H11N7. Found (percent): C, 52.55; H, 4.90; N 42.77.1H NMR (DMSO-d6), δ: 2.23 (3H, 3Pz-CH3); 2.41 (3H, 5Pz-CH3) (J 0.7 Hz); 6.20 (1H, 4Pz-CH3); 3,22 t (1H, CH) (2,5); 4,28 DD (2H, CH2) (2,5); 9,19 t (1H, NH) (5,8).

Tuberculostatic activity (minimum inhibitory concentration) and the toxicity of these compounds compared to its closest analogues are given in table 1.

Table 1
Tuberculostatic activity in in vitro experiments (strain H37Rνand toxicity of the claimed soybean is ineni (mice) in comparison with analogues
ConnectionMinimum inhibitory concentration (MIC)ug/mlLD50mg/kg
Isoniazid (II) - analog0.03200
Methyl ester of 2-N-[6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]-aminopropionic acid (II) similar1.25not defined
3-(Adamantane-1-ylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 7)0.37>2500
3-(Indol-3-yl-ethylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 10)0.37>5000
3-(4-Brompheniramine)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 9)0.152500

Table 2
Antibacterial activity of the claimed compounds in vitro
ConnectionMIC, mcg/ml
Klebsiella pneumoniaeStreptococcus group CS.aureusPseudomon as aeruginosa
3-(6-Methylpyridin-2-ylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 11)>100>100>100>100>100
[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]prop-2-ynylamine (example 16)>100>100>100>100>100

Table 3
Tuberculostatic activity of the claimed compounds in relation to typical and atypical mycobacterial strains, MIC, mcg/ml
The structural formulaH37M.Fortuitium
Isoniazid (II) - analog0.03250
3 Hydrazino-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 1)1.2 1.25
3-(4-Brompheniramine)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 9)0.150.15
3-(Adamantane-1-ylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 7)0.37not defined
3-(Indol-3-yl-ethylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 10)0.37not defined
2-{2-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-ylamino]ethoxy} ethanol (example 5)6.25not defined
3-Dodecyl-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 4)6.25not defined
3-(Pyridine-2-ylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 12)12.5not defined

Table 4
Study of acute toxicity of the inventive compounds on mice (per os)
Structural form is and Tuberculostatic activity, ug/mlAcute toxicity (mg/kg
Isoniazid (II) - analog0.03200
3-(Indol-3-yl-ethylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 10)0.37>5000
3-(Adamantane-1-ylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 7)0.37>2500
3-(4-Brompheniramine)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 9)0.151200

Table 5
The cytotoxicity of the claimed compounds
ConnectionCytotoxicity, CD50µg/ml
3-(Adamantane-1-ylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 7)30
3-(Indol-3-yl-ethylamino)-6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 10)28.5
17.5
3-(4-Methylpyridin-2-ylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 13)16
6-(5-Chloropyridin-2-ylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (example 14)18.5
[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazine-3-yl]prop-2-ynylamine (example 16)3.1

Thus, the claimed compounds in their characteristics (high specificity for mycobacteria, high activity against typical and atypical strains of mycobacteria, low toxicity) than counterparts in structure and action. These compounds can be used in practical medicine for the treatment of patients infected with both typical and atypical mycobacteria.

Selective anti-TB agents representing 3-amino-substituted 6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine General formula A

where R1=amino group, a C1-C12-alkyl, 3-hydroxy-5-hydroxyphenyl, propyne-2-yl, ethylindole, substituted, aryl that is selected from a possibly substituted phenyl, hetaryl selected from indol-3-yl, 3-chinoline, pyridyl, with the substituted phenyl has a Deputy selected from the group comprising methyl, bromine, is hydroxy group and has pyridyl substituents selected from the group chlorine, methyl.



 

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SUBSTANCE: invention provides macrocyclic metal complexes, preparation thereof, and application thereof to form conjugates with biomolecules. Such conjugates are appropriate for use as contrast substances in NMR diagnostics and for use in radiotherapy.

EFFECT: enhanced relaxation ability and possibility to control it due to special ligands attached to macrocycles.

12 cl, 2 tbl, 91 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes perfluoroalkyl-containing complexes with polar residues of the general formula (I):

wherein R means a polar residue; G means a trifunctional residue, a perfluorinated carbon chain; K means a metal complex; Z means a linker group. Proposed complexes can be used for intravenous lymphography, tumor diagnosis and for visualization of infarctions and necrosis. Also, invention describes a method for synthesis of these complexes.

EFFECT: valuable medicinal properties of complexes.

16 cl, 1 tbl, 26 ex

The invention relates to biochemistry, in particular to the use of bromo derivatives known betterin-1,3-dioxide of the General formula I

< / BR>
where R1and R2different and mean hydrogen or Br,

as irreversible inhibitors of H, K-adenosinetriphosphatase (N,K-Atraz)

FIELD: medicine.

SUBSTANCE: in an intensive phase of the therapeutic course, a conventional anti-tuberculosis therapy is added with the oral preparation Thiotriazoline 100 mg 2 times a day daily for 45 days. Besides, pulmonary administration of the preparation Hixozide 350 mg dissolved in 10 ml of water for injection every second day in the number of 20 procedures is added.

EFFECT: infiltrate resolution, cavity closure and abacillation with no hepatotoxic reaction ensured by creating high concentrations of drug preparations directly in the lesion and increased activity of the immune system.

2 ex, 3 tbl

FIELD: biotechnologies.

SUBSTANCE: invention refers to a number of bicyclic nitroimidazole-replaced phenyloxazolydinones of the following structural formula (I):

,

containing nitroimidazole circle, or to its pharmaceutically acceptable salt; where R1 represents hydrogen, (C1-C6)alkyl or aryl; n is equal to 0, 1 or 2; X1 and X2 independently represent H, CF3, CI, OCF3 or F; G represents -OH, triazole or -NHCOR2; R2 represents (C1-C6)alkyl, cycloalkyl or aryl; and L represents a bond or a linker group chosen from any combination 2-3 of the following groups: 1) (C1-C6)alkylene, 2) (C3-C8)cycloalkylene, 3) arylene, arylene-replaced CN, ore arylene-replaced F, 4) group chosen from the group consisting of

,

where R10 represents H, CF3, hydroxyl, amino, alkyl, alkylamino, alkoxy or aryl, and R13 represents H, hydroxyl, amino, alkyl, alkyl amino, alkoxy or aryl, or R13 in combination with nitroimidazole circle can form spiral-shaped structure, 5) -C(=O)-, 6) -O-, 7) -S(O)n-, in which n is equal to 0.1 or 2, 8) -N(R3)-, 9) -C(R4)=C(R5)-, R3 represents hydrogen, (C1-C6) alkyl or aryl, and R4 and R5 represent hydrogen, (C1-C6) alkyl or aryl, or R4 and R5 can be combined together so that they can form a bond. Besides, the invention refers to pharmaceutical composition for treatment of bacterial infection based on compounds of formula I, as well as to a bacterial infection treatment method.

EFFECT: invention describes new compounds that have antibacterial activity against a line of wild type and stable lines of pathogenic microorganisms, and as a result, are suitable for prevention, control and treatment of a number of human and mammal bacterial infections caused by these pathogenic microorganisms such as bacillus Kochii.

15 cl, 93 ex, 1 tbl, 22 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to dialkyl(2-methyl-4-oxopent-2-yl) phosphine oxide pyridinoyl hydrazones (Ia-c) for treating tuberculosis, which can be used in medicine and veterinary: la Py-4-Py, R=Et; Ib Py=4-Py, R=Pr; 1c Py=3-Py, R=Et.

EFFECT: novel efficient antituberculous preparations with low toxicity, which do not exhibit neurotoxic activity.

2 cl, 3 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to oral antituberculous agents. The given agent is presented in the form of an enteric-coated granule and contains: sodium para-aminosalicylate - 500 to 900 mg; isoniaside 19 to 26 mg; hydrogenated vegetable oil - 1.1-1.5 mg; crospovidone - 22-31 mg; sodium disulphite - 4-12 mg; methylcellulose - 11-19 mg with a granule density varying within 0.9 to 1.05 g/ml, a enteric coating thickness making 0.2-0.3 mm, a particle size of isoniaside falling within the range that is 2-3 higher than that of sodium para-aminosalicylate, while a particle size of crospovidone is 2-3 times higher than those of sodium para-aminosalicylate and sodium disulphite. All particles of the active ingredients are uniformly distributed throughout the granule.

EFFECT: reducing the toxic effect of para-aminosalicylate on the human body.

14 ex, 1 tbl

FIELD: biotechnologies.

SUBSTANCE: method is proposed to treat experimental pulmonary tuberculosis in mice using transplantation of stem cells by introduction of a suspension of stem cells resistant to tuberculosis with "k" genotype in the area H-2E into a caudal vein once a week.

EFFECT: method improvement.

3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, namely to pharmaceutical compositions and pharmaceutical kits for treating bacterial infections, and a new method for treating the diseases associated with bacterial infections, including tuberculosis. A pharmaceutical composition containing Rifalazil as rifamycin and Cycloferon as an interferon inducer in pharmacologically effective doses. The invention also concerns a pharmaceutical kit for treating the diseases caused by bacterial infections. The kit comprises rifamycin in pharmaceutically effective doses in the form of tablets, capsules or injections. Cycloferon is presented in the form of tablets, capsules or injections; instructions for administering the ingredients of the same pharmaceutical kit are also provided.

EFFECT: preparing the pharmaceutical compositions and pharmaceutical kits for treating bacterial infections, and presenting the new method of treating the diseases associated with bacterial infections, including tuberculosis.

4 cl, 2 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical engineering, and concerns a combined antituberculous remedy containing isonicotinic acid hydrazide (isoniaside) and 2-benzylbenzimidazole (dibazol), and a polymer carrier that is an interpolymer complex of poly(meth)acrylic acid and polyethylene glycol, as well as a method for preparing it.

EFFECT: antituberculous remedy according to the invention has bacteriostatic and bactericidal action on tuberculosis mycobacteria; it provides the continuous maintainance of the active substance concentration at the therapeutically effective level; it causes no considerable blood variations; it is 2,5 times less toxic than isoniaside, and 10 times more active than isoniaside.

7 cl, 1 dwg, 11 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: invention refers to veterinary science. Using ORF-2 PCV-2 protein for preparing an immunogenic composition applicable for relieving concurrent infections caused by one or more viral (e.g. PRRS), bacterial and/or fungal pathogens (e.g. Actinobacillus pleuropneumoniae, Haemophilus parasuis, Mycoplasma hyrhinis, Mycoplasma hyopneumoniae, Pasteurella multocida, Salmonella spp., or Strepococcus suis) different from PCV2 in pigs or pig herds with a percent of the concurrent infections in relation to one or more infections are reduced by more than 10% as compared to an unvaccinated reference group.

EFFECT: relieving the concurrent infections caused by one or more viral (eg PRRS), bacterial and/or fungal pathogens.

8 cl, 2 tbl, 1 ex, 11 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely phthisiology, and concerns treating tuberculous exudative pleuritis. That is ensured by carrying out the standard anti-tuberculosis therapy including pleural punctures with exudate aspiration. In addition, from the first day, the therapeutic course includes administering Wobenzym 2 tablets 3 times a day 30 minutes before meals daily. Also, percutaneous electric nerve stimulation of the points V 13 (Fei Shu), T 14 (Da Juy), J 19 (Pzy Gun), V 17 (Ge Shu), V 18 (Gan Shu), R 27 (Shu Fu), R 26 (Yui Jun), GT 4 (He Gu) for 1 minute on each point, in the comfortable power mode at pulse frequency 77 Hz is performed once a day for 20 days. On the 21st day, the percutaneous electric nerve stimulation is completed, while administering Wobenzym is continued in the same dosage for 10 days.

EFFECT: method provides higher effectiveness and reduced length of treating tuberculous exudative pleuritis ensured by faster cessation of exudation, prevented development of pleural adhesions and exudate block, as well as reduced rate of developing hepatotoxic adverse responses to the anti-TB drugs.

2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely phthisiology, and concerns treating the patients suffering pulmonary tuberculosis. For this purpose anti-tuberculosis treatment according to the standard regimens is prescribed. Two months after the beginning of the therapeutic course, the same is added with subcutaneous injections at the level of an angle of scapula; what is injected is a mixture of equal portions of venous autoblood and 0.25% novocaine, once a day, in the fasted state, according to the schedule: on the 1st day - 1.0 ml, on the 4th day - 2.0 ml, on the 8th day - 3.0 ml, on the 11th day - 4.0 ml, on the 15th, 18th and 22nd days - 5.0 ml; If observing a unilateral lesion, the injections are administered on the side of the lesion; while a bilateral lesion requires the injections to be administered one by one on both sides.

EFFECT: method provides infiltrate dispersion, cavity closures and abacillation ensured by an anti-inflammatory and immunomodulatory effect of the autohemotherapy, as well as body reparation activation.

2 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and concerns an antitumour preparation containing a combination of (1) a combined therapeutic agent S-1, (2) at least one ingredient specified in a group consisting of folinic acid and its pharmaceutically acceptable salts, and (3) cis-oxalate(1R,2R-diaminocyclohexane)platinum(II); a kit for treating cancer in a mammal comprising a combination of the pharmaceutical compositions for treating cancer in the mammal; a method of treating cancer involving administration of the above combination into the mammal.

EFFECT: group of inventions provides the synergetic effect in treating tumour.

20 cl, 1 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a topical preparation for contaminated wound healing. The above preparation contains lidocaine hydrochloride 0.1-0.2%, thrombolysin 30-36%, metronidazole 0.25-0.5%, clindamycin 0.3-0.45%, rifampicine 0.45-0.6%, olive oil 10%, sea buckthorn oil 1.5-2.0%, starch 5.1% and silver water.

EFFECT: invention promotes reducing contaminated wound complications, provides the advance of antibacterial active substances through intertissue spaces to the deep tissues with faster pathogenic flora inhibition in a wide range.

2 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel biologically active 2,6-dimethylanilide of N-cyclohexylpyrrolidine-2-carboxylic acid, having surface, infiltration and conduction anaesthesia activity, considerably better than bupivacaine and ropivacaine with the same or less toxicity.

EFFECT: improved compounds.

2 tbl

FIELD: biotechnologies.

SUBSTANCE: new alicyclic derivatives are described from N,N'-substitute 3,7-diazabicyclo[3.3.1]nonanes of general formula 1

,

where E is carbonyl group; R1 is H, C1-C6 alkyl, C1-C10alkoxy; R2 is fragments of structural formulas (1.1a), (1.3a) or (1.4a), representing biheterocyclic relevant 5-member nuclei, containing N and/or S as heteroatoms, connected to each other by -CH2-(possibly substituted with alkyl), -C(=O)-, -NH-,-NH-CH2-(possibly substituted with alkyl); other R3 - R4 independently mean H, C1-C6 alkyl, C1-C10alkoxy.

EFFECT: compounds have pharmacological activity and may be used for treatment of Alzheimer's disease, Parkinson's disease and other neurodegenerative pathologies.

8 cl, 7 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to analogues of benzoquinone-containing ansamycins of formulae

and ,

in which radicals and symbols assume values given in the claim, and use thereof to treat and modulate proliferation-associated disorders such as cancer. The present invention describes a method of producing analogues of benzoquinone-containing ansamycins according to which benzoquinone is reduced to hydroquinone and bonded through reaction with a suitable acid.

EFFECT: high solubility and air stability of the obtained ammonium hydroquinone ansamycin analogue.

181 cl, 70 dwg, 38 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a composition of a rapamycin analogue for immunomodulation and antiproliferation that involves a crystalline form of the rapamycin analogue having at least one of the following structures: and a pharmaceutically acceptable carrier. What is also described a method for preparing the crystalline form of the rapamycin analogue.

EFFECT: what is described is a new form of rapamycin, which can be used in the therapeutic treatment.

38 cl, 30 ex, 11 tbl, 21 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to physiology and space medicine. The method for prevention of skeletal muscle atrophy after functional unloading involves administering 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) which increases an amount of muscle heat shock proteins and further reduces a level µ-calpain.

EFFECT: invention enabling managing the negative effects of hypokinesia or gravity unloading through the enhanced inhibition key signalling pathways initiating atrophy.

9 dwg

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

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