Isonicotinohydrazide exhibiting anti-tb activity

 

(57) Abstract:

Usage: as substances exhibiting anti-TB activity. The inventive product - isonicotinohydrazide General formula 1,

where R is H or Me, R1-

< / BR>
< / BR>
< / BR>
< / BR>
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. 140-142aboutC.

IR spectrum (cm-1): 1650 (>C=0), 1640 (>C=N), 1510-1600 (>C=C<).<P> 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 58-60aboutC 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 9-10aboutC. the precipitation is filtered off and dried in vacuum. Get 20,61 g (91%) of orange crystalline substance. After recrystallization from ethanol so pl. 167-168aboutC.

IR spectrum (cm-1): 1673 (>=0), 1660 (>C=N), 1520-1630 (>C=C<).<P> 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<).<P> UV spectrum:max293 nm (ethanol).

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

IR spectrum (cm-1): 1653 (>C=O), 1646 (>C=N), 1520-1633 (>C=C<).<P> 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 37aboutWith 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

< / BR>
where R is H or Me,

< / BR>
exhibiting anti-TB activity.

 

Same patents:

The invention relates to medicine

The invention relates to medicine, specifically to radioprotectors

The invention relates to chemical compounds with valuable properties, in particular derivatives of 2,3-dihydropyrano[2,3-b] pyridine of General formula

< / BR>
(I) where a lower alkylene;

R is a hydrogen atom or a group

A< / BR>
or their salts

The invention relates to new compounds 1,2,5,6-tetrahydropyridine number of General formula

(I) where Z is oxygen or sulfur;

R is hydrogen or C1-3-alkyl; when Z stands for oxygen, R1is a halogen, amino group, acetylamino or-O-R2where R2is4-6-alkyl or C6-quinil; Z, meaning sulfur, R1is halogen, C1-8-alkyl, C6-alkenyl straight chain, cyclopropylmethyl, benzyloxypropionic, morpholino-, 4-methylpiperidino - or 4-hexylamino or a group-O-R2where R2linear or branched C3-6alkenyl,3-6-quinil, cyclopropylmethyl, -R3-O-R4or-R3-O-R4-O-R5where each of R3, R4and R5means1-4-alkyl, or R1represents a group S-R2where R2linear C2-8-alkyl, or their pharmaceutically acceptable salts

The invention relates to new azetidinone derived isothiazol-pyridone: 2,3,4,9-tetrahydroindazole[5,4-b]China - in-3,4-dione, 2,3,4,9-tetrahydrothieno [5,4-b] [1,8]-naphthiridine-3,4-dione, 1,2,8,9-tetrahydro-7H-isothiazol-[4',5',5,6]pyrido [1,2,3-de]benzoxazine-7,8-dione and its salts

The invention relates to benzothiazole derivative that is highly effective as a medicinal product, namely, benzothiazole derivative, useful as a preventive and therapeutic agent for diseases in which the function of suppressing the production of leukotrienes and thromboxanes are effective

FIELD: medicine, endocrinology, pharmacology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical combined composition used for treatment or prophylaxis of hypertension in patients suffering with diabetes mellitus. The composition comprises AT1-antagonist valsartan or its pharmaceutically acceptable salt and calcium channel blocking agent or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier. The composition elicits synergistic effect and expanded spectrum effect.

EFFECT: improved and valuable medicinal properties of composition.

10 cl, 3 tbl

FIELD: medicine, toxicology.

SUBSTANCE: invention proposes applying 15% aqueous solution of 1-methyl-5-[2'-(benzyldimethylammonio)ethyl]carbamoyl pyridinium-2-aldoxime dichloride that exceeds the 15% solution of dipiroxime (TMB-4, trimedoxime bromide) used in native medicinal practice by the curative effectiveness. Invention can be used in urgent treatment of acute poisoning with organophosphorus poisonous substances eliciting neuroparalytic effect.

EFFECT: enhanced effectiveness, valuable medicinal properties of agent.

3 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 1 tbl, 30 ex

FIELD: chemistry of metalloorganic compounds, medicine, oncology.

SUBSTANCE: invention relates to derivatives of platinum tetrachloride and to a method for their preparing also. Invention proposes compounds of the formula PtCl4 x 2 Li wherein Li represents N-(2-nitroxyethyl)nicotinamide or N-(2-nitroxyethyl)isonicotinamide, or nicotine hydroxamic acid, or isonicotine hydroxamic acid. Also, invention proposes a method for preparing these compounds that involves interaction of pyridine carboxylic acid nitroxyethylamides or hydroxamic acids, or their hydrochlorides with potassium hexachloroplatinate followed by isolation of the end product. Invention provides synthesis of the unknown early chelate platinum compounds that are physiologically active substances and can be used in medicinal practice instead cisplatin as effective anti-metastatic medicinal agents with low toxicity.

EFFECT: improved preparing method, enhanced and valuable medicinal properties of compounds.

2 cl, 3 ex

FIELD: chemistry of metalloorganic compounds, medicine, oncology.

SUBSTANCE: invention relates to derivatives of platinum tetrachloride and to a method for their preparing also. Invention proposes compounds of the formula PtCl4 x 2 Li wherein Li represents N-(2-nitroxyethyl)nicotinamide or N-(2-nitroxyethyl)isonicotinamide, or nicotine hydroxamic acid, or isonicotine hydroxamic acid. Also, invention proposes a method for preparing these compounds that involves interaction of pyridine carboxylic acid nitroxyethylamides or hydroxamic acids, or their hydrochlorides with potassium hexachloroplatinate followed by isolation of the end product. Invention provides synthesis of the unknown early chelate platinum compounds that are physiologically active substances and can be used in medicinal practice instead cisplatin as effective anti-metastatic medicinal agents with low toxicity.

EFFECT: improved preparing method, enhanced and valuable medicinal properties of compounds.

2 cl, 3 ex

FIELD: organic chemistry, biochemistry, medicine, endocrinology.

SUBSTANCE: invention relates to a trans-olefinic activator of glucokinase representing compound taken among the group consisting of olefinic amide of the formula (I): wherein R1 and R2 mean independently of one another hydrogen, halogen atom, nitro-group, perfluoro-(lower)-alkyl, (lower)-alkylsulfonyl or (lower)-alkylsulfonylmethyl; R means -(CH2)m-R3 or lower alkyl comprising from 2 to 4 carbon atoms; R3 means cycloalkyl comprising from 3 to 8 carbon atoms; R4 means the group: or unsubstituted, or monosubstituted five- or six-membered heteroaromatic ring linked by ring carbon atom with indicated amino-group wherein this five- or six-membered heteroaromatic ring comprises from 1 to 2 heteroatoms taken among the group consisting of sulfur or nitrogen atom wherein one heteroatom being as nitrogen atom is arranged near with binding ring carbon atom, and wherein indicated monosubstituted heteroaromatic ring is substituted at ring carbon atom not adjacent with mentioned binding carbon atom with a substitute taken among the group consisting of halogen atom and group of the formula: m = 0 or 1; n = 0, 1, 2, 3 or 4; R7 means hydrogen atom or lower alkyl; Δ means trans-configuration relatively to a double bond; or its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition, method for prophylactic or therapeutic treatment of diabetes mellitus of type II and to methods for preparing compounds of the formula (I). Invention provides preparing activators of glucokinase that enhance insulin secretion in treatment of diabetes mellitus of type II.

EFFECT: valuable medicinal properties of compounds.

25 cl, 29 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein X means group of the formula (X-1) wherein R15 means halogen atom, (lower)-alkyl and perfluoro-(lower)-alkyl; R16 means hydrogen, halogen atom and (lower)-alkyl; or X means group of the formula (X-2) wherein Het means 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms as nitrogen (N) atom; R15 and R16 have values indicated above for (X-1); R30 means hydrogen atom or (lower)-alkyl; p means a whole number from 0 to 1; or X means group of the formula (X-3) wherein R18 means aryl; R19 means unsubstituted arylalkyl or heteroarylalkyl representing 6-membered heteroaromatic ring comprising nitrogen (N) atom as a heteroatom; R20 means unsubstituted (lower)-alkanoyl; Y means group of the formula (Y-1) wherein R22 and R23 mean independently from one another hydrogen atom, (lower)-alkyl, halogen atom or perfluoro-(lower)-alkyl and at least one of radicals R22 and R23 doesn't mean hydrogen atom; R24 means hydrogen atom; or Y means group of the (Y-3) wherein R25 means group of the formula: R26-(CH2)e- wherein R26 means (lower)-alkoxy-group, (lower)-alkylthio-group, (lower)-alkylsulfonyl; or R26 means group of the formula: -NR28R29 wherein R28 means hydrogen atom; R29 means (lower)-alkanoyl or (lower)-alkylaminocarbonyl; Q means -(CH2)f- wherein e means a whole number from 0 to 4; f means a whole number from 1 to 3; a bond denoted as a dotted line can be hydrogenated optionally; and to its pharmaceutically acceptable salts and esters. Also, invention proposes a pharmaceutical composition designated for treatment or prophylaxis of rheumatic arthritis, cerebrospinal sclerosis, intestine inflammatory disease and asthma and containing compound of the formula (I) or its pharmaceutically acceptable salt or ester in combination with a compatible pharmaceutical carrier. Invention proposes derivatives of thioamide inhibiting interaction between α4-comprising integrins and VCAM-1.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 1 tbl, 86 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a ketazine compound of formula (1) from a ketone compound of formula (2), ammonia and an oxidising agent, where a solution containing a ketone compound of formula (2) and ammonia is brought into contact with aqueous solution of sodium hypochlorite or hydrogen peroxide in a tubular reactor, having flow channel width between 2 and 10000 mcm where R1 and R2 are identical or different and each denotes a C1-6 alkyl group, or R1 and R2 are bonded to form a C2-7alkylene group with a straight chain where R1 and R2 are as described above and each of the liquids is in laminar flow state.

EFFECT: obtaining ketazine compounds with high output and with inhibition of by-products.

4 cl, 1 tbl, 2 ex, 2 dwg

Up!