Isonicotinohydrazide exhibiting anti-tb activity

IPC classes for russian patent Isonicotinohydrazide exhibiting anti-tb activity (RU 2054002):

C07D213/24 - with substituted hydrocarbon radicals attached to ring carbon atoms

C07C249/16 - of hydrazones

A61K31/44 - Non-condensed pyridines; Hydrogenated derivatives thereof

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(57) Abstract:

Usage: as substances exhibiting anti-TB activity. The inventive product - isonicotinohydrazide General formula 1,
where R is H or Me, R₁-




table 1.

The invention relates to new biologically active compounds derived from the hydrazide of isonicotinic acid (isoniazid) isonicotinohydrazide unsaturated carbonyl compounds (retinoid and its analogues), having a high anti-TB activity, of the formula I a-g;
NC-N C =
From the known anti-TB drugs the most high bacteriostatic activity has isoniazid, he is in the last almost forty years, the main drug, especially in the treatment of new TB cases. However, during this period has accumulated and enough information about its toxicity and some side effects of its long-term use: violation of the nervous system, musculoskeletal system and others chemotherapeutic properties and indications for use do not significantly differ from isoniazid, but its less toxic synthetic the deposits on the chemical structure [1]
Despite the fact that all these drugs are highly effective, modern chemotherapy of tuberculosis is almost always complex. Research in the last years developed new areas in this field associated with the belief that one of the main reasons for the poor results of conservative treatment of this disease is a disorder of the immune system, which will require adequate immunotherapy aimed at the stimulation of protective forces of an organism and anti-infective resistance. On the other hand, it was found that most patients with pulmonary tuberculosis significantly activating the processes of free radical oxidation in bronchopulmonary space of lipid peroxidation in the blood of violation of systems and mechanisms antiradical protection of the body. Hence, given the role of free-radical reactions in the pathogenesis of tuberculosis, as well as the importance of reparative processes, is proposed [2-4] in the treatment of this disease to use in complex chemotherapy of various oxidants and immunokorrigiruyuschy drugs.

At the same time numerous publications last desyatiletiu), indicate that these compounds can be clearly attributed to means capable of stimulate immune defenses and play an important role in the correction of free-radical oxidation of cellular structures, the preservation of the antioxidant system of the organism.

The aim of the invention are surveys in a series of polyene isonicotinohydrazide with complex biological activity (TB, immunostabilizing and antioxidant) and reduced toxicity.

Declare new connection and I-g (N state. reg. 9623690-9623990) in contrast to the nearest analogues (saluted, ftivazide), contain the chemical combination of 2 biologically active centers-retinoid (or similar) and isoniazid and can be obtained by condensation of the latter with the corresponding unsaturated carbonyl compound according to the chemical scheme:
NCO-NH-NH₂+RCOR¹___ NH-N C
P R I m e R 1. Isonicotinohydrazide 3,7-dimethyl-9-(2',6',6'-trimethylcyclohex - sen-1'-yl-1')-2,4,6,8-nonadien-1-al (I, a).

14.4 g (0.05 g-mol) retinal dissolved in 100 ml of ethanol and add 6.85 g (0.05 g-mole) of the hydrazide of isonicotinic acid. The mixture is stirred in a stream of inert gas at 58-argibay 3-4 hours Loose orange precipitate is filtered off, dried in vacuum at room temperature. Gain of 19.1 g (94.5% of the technical product. After recrystallization from ethanol obtained 14.9 g of isonicotinohydrazide with so pl. 140-142^aboutC.

IR spectrum (cm^-1): 1650 (>C=0), 1640 (>C=N), 1510-1600 (>C=C<). UV range:_max396 nm (ethanol).

P R I m m e R 2. Isonicotinohydrazide 6-methyl-8-(2',6',6'-trimethylcyclohexen-1'-yl-1')-3,5,7-octadien-2-she (I b).

15,48 g (0.06 g-mol) of the ketone WITH₁₈dissolved in 70 ml of ethanol and add by 8.22 g (0.06 g-mole) of the hydrazide of isonicotinic acid, and then poured 1.5 ml of acetic acid. The mixture is stirred at a temperature of 58-60^aboutC in an atmosphere of inert gas until the complete disappearance of the ketone (TLC control). After completion of the reaction (2.5-3 hours) the mass is cooled down to 9-10^aboutC. the precipitation is filtered off and dried in vacuum. Get 20,61 g (91%) of orange crystalline substance. After recrystallization from ethanol so pl. 167-168^aboutC.

IR spectrum (cm^-1): 1673 (>=0), 1660 (>C=N), 1520-1630 (>C=C<). UV range:_max366 nm (ethanol).

Like I hydrazone b the compounds I and g

Isonicotinohydrazide 2-methyl-4-(2', 6',6'-trimethyltin is 95 (>C=C<). UV spectrum:_max293 nm (ethanol).

Isonicotinohydrazide 4-(2', 6',6'-trimethylcyclohexen-1'-yl-1')-3-butene-2-she (I g), so pl. 172-173^aboutC.

IR spectrum (cm^-1): 1653 (>C=O), 1646 (>C=N), 1520-1633 (>C=C<). UV range:_max315 nm (ethanol).

New connections are well crystallized substances with a clear melting point, easily soluble in conventional organic solvents, soluble in water.

Chemotherapeutic efficacy of new compounds was determined in experiments in vivo in 2 species of laboratory animals in two stages depending on the applied dose after you determine the bacteriostatic activity of drugs in vitro against Mycobacterium tuberculosis:
Phase I of the Guinea pig dose of 20 mg/kg weight of the animal;
Stage II mouse strain CBA dose of 10 mg/kg weight of the animal.

Just used 60 Guinea pigs and 60 mice of CBA. Animals were divided into 6 groups of 10 Guinea pigs and 60 mice each: 1-4 experienced receiving the drugs I and-g, respectively; 5 control group treated with the drug isoniazid and 6-untreated control animals.

Infection of Guinea pigs was conducted in the groin area at a dose of 0.025 mg / 0.5 ml suspension fesimg in 0.2 ml suspension of physiological solution also strain Erdman. Treatment of Guinea pigs was launched on the 10th day after infection and was conducted within 90 days daily, except Saturday and Sunday. Treatment of mice was carried out under the same scheme within 30 days. After this period, animals were scored using ether anesthesia. Parenchymatous organs were studied by microbiological methods. To this end the homogenate lung, liver and spleen was treated with 3% sulfuric acid and seeded on thick egg Lowenstein-Jensen medium, Popescu, Finn-P. Crops were placed in a thermostat at 37^aboutWith and reviewed daily for 3 months. From sludge treated material was prepared smears that were stained luminescently method for the Battle. Macroscopic index of treatment effectiveness was evaluated by A. I. Lagunovoi. Data for the study of chemotherapeutic efficacy of new drugs in the table.

Guinea pigs treated with the new drug I and d to the time of slaughter were alive. Control (untreated, treated with isoniazid) and treated with drugs I a and b fell earlier treatment.

All the synthesized compounds exhibit chemotherapeutic activity in the treatment of tuberculosis in op the structure of the performance index. Isonicotinohydrazide I and d show chemotherapeutic activity in excess of the effectiveness of isoniazid in the treatment of both Guinea pigs and mice of CBA doses of 20 mg/kg and 10 mg/kg, despite reduced 2.3-2.4 times in comparison with isoniazid, the content molar fraction isoniazide link. Recalculation of experimental data in the form of specific efficiency (the ratio of the performance index to the mole fraction of isoniazide link in each of the preparations) shows that all the synthesized compounds are on the same level in their chemotherapeutic activity, which in all cases is higher than that of isoniazid, several times.

Data microscopy of smears internal organs of experimental Guinea pigs and mice, as well as the study of seed confirm the results of macroscopic studies.

Isonicotinohydrazide General formula

where R is H or Me,

exhibiting anti-TB activity.