Substituted di(formulary)polyesters, or their coordination compounds, or their pharmaceutically acceptable salt additive, the method of production thereof and pharmaceutical composition based on them

 

(57) Abstract:

Describes the new substituted di(formulary)polyesters of General formula A, where AG - substituted phenylene or naftilan; Y is a hydrogen atom, a halogen or a methoxy group; an oxygen atom NN-R1group; R1- substituted phenyl, benzoyl, 2 -, or 4-nicotinoyl, n = an integer from 1 to 3; m = an integer from 1 to 4, or coordination compounds with cations of one-, two-, three -, or tetravalent metals or their salts, or their pharmaceutically acceptable salt additive compounds And in which R denotes-NNH-R1group, with organic and inorganic acids having antimycobacterial activity. Connections are antimycobacterial drugs with high specificity to the mycobacteria, high activity against atypical, typical, drug-resistant strains of mycobacteria, low toxicity. The claimed compounds can be used in practical medicine for the treatment of patients infected with sensitive and resistant, typical and atypical strains of mycobacteria. Describes also an effective way of obtaining the claimed compounds and pharmaceutical composition thereof. 3 S. and 7 C.p. f-crystals, 9 tab the ladies), specifically to di(formulary)polyesters, their hydrazones with substituted hydrazines, as well as to pharmaceutically acceptable additive salts and coordination compounds, and to methods for their preparation. Patented compounds can be used, primarily, as active principle, of pharmaceutical products for the treatment of patients with mycobacteriosis, including tuberculosis.

Known industrially produced oxyethylene surfactant type Triton-20, with an average anti-TB activity in experiments in vivo in the absence of activity in vitro [Nature, 1987, 29(10),2219.].

One of the widely used tools for the treatment of tuberculosis is ftivazid formula I [M. D. Mashkovsky, Medicines, T. II, Kharkov, Torgsin, 1998, p 334.], obtained by heating the raw materials (the hydrazide of isonicotinic acid and vanillin in the presence of alcohol, water and acid. The resulting product is separated by filtration, washed and dehydrated.

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The disadvantages ftivazide should be attributed to its lack of specificity with respect to the mycobacteria, as well as the rapid development of resistance of Mycobacterium tuberculosis to the action.

Known what digigami. For example, the known 1-(4-aminobenzoyl)-2-benzyliden with weak tuberculostatic activity and specificity (J. Ind. Chem. Soc. 1984, 61(8), S. 718-720).

The compound 1-(4-aminobenzoyl)-2-benzyliden get keeping alcohol solution of the initial reagents at 25oC for 24 hours. The yield of the target product is 87%.

The closest analogue of the claimed substances are 2-(allylthio)-6-(2-chlorobenzylamino)benzothiazole of the formula II [Patent Czechoslovakia N 239438, MKI C 07 D 277/64, 1987] and isonicotinic acid hydrazide (isoniazid) of formula III, which is the active beginning of a pharmaceutical composition intended for the treatment of patients with mycobacteriosis [M. D. Mashkovsky, Medicines, T. II, Kharkov, Torgsin, 1998, S. 332.].

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The compound of formula II has antimycobacterial activity, but its activity against typical mycobacteria low. Isoniazid formula III has a selective antimycobacterial action, however, the disadvantages of this drug is its low activity against atypical mycobacteria, as well as high toxicity and a variety of side effects when used. Isoniazid causes allergies, negative OTL the only means T. II, Kharkov, Torgsin, 1998, S. 332 and Pharmacology and toxicology, 1987, 50, (4), S. 87.]. The broad distribution of isoniazid-resistant clinical strains of mycobacteria.

The objective of the invention is the synthesis of antimycobacterial drugs with high specificity while reducing side effects when applying and expanding antimycobacterial activity: the effect of typical and atypical, sensitive and resistant strains of mycobacteria.

The problem is solved in that, as antimycobacterial drugs use of substituted di(formulary)polyesters of General formula (IV), and their pharmaceutically acceptable additive salts of General formula (V), and coordination compounds of General formula (VI).

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where Ar is a substituted phenylene or naftilan; Y = hydrogen atom, halogen or methoxy group; R = oxygen atom) NNH-R1group; R1- substituted phenyl, benzoyl, 2 -, or 4-nicotinoyl, n = an integer from 1 to 3; m = an integer from 1 to 4;

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where Ar is a substituted phenylene or naftilan; R1= substituted phenyl, benzoyl or 2 - or 4-nicotinoyl; Y = hydrogen atom, halogen or methoxy group, n = an integer from 1 to 3; m = an integer from 1 to 4; In - EN the config phenylene or naftilan, R is an oxygen atom or-N-NH-R1group, R1- substituted phenyl, benzoyl, 2 -, or 4-nicotinoyl, Y is a hydrogen atom, a halogen or methoxy group. Me - cation of one-, two-, three -, or tetravalent metal. An anion of a mineral acid, n, and h is an integer from 1 to 3, m is an integer from 1 to 4, k -1,2 or 3

As cations of metals Me can be used cation of Li, Na, K, Cu, Co, Ni; Fe or Zr.

The method of obtaining the group of compounds of the formula (IV) is to obtain di(formulary)polyester of General formula

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the reaction of alkylation of substituted aromatic aldehyde dichloro - or diethylsilane the glycol by heating and mixing of the reagents in the formamide of the formula C3H7NO (DMF) in the presence of alkali in an inert gas environment. The obtained di(formulary)the polyester is dissolved in an organic solvent, and conducting condensation reaction with an aqueous solution of the substituted hydrazine of General

The reaction is carried out at heating using the promoting effects, obtaining the compounds of formula (IV). The promoting effect provide ultrasound or weak organic or inorganic acid, for example acetic acid (CH3COOH), coal (H2CO3) and others as the-C6alkyl. The target product is separated by filtration and/or purified, for example by washing, crystallization, and other known methods.

The compounds of formula (V) obtained by condensation reaction of pre-dissolved in an organic solvent di(formulary)polyester and an aqueous solution of the substituted hydrazine of formula (VII) using the promoting effects when heated with obtaining the compounds of formula (V). The promoting effects of exercise by ultrasound and/or conduct the reaction in the presence of a strong organic or inorganic acid. As the organic solvent used DMF or alcohol (VIII). As a strong acid using hydrochloric (HCl), sulfuric(H2SO4), phosphorous (H3PO4), lemon (C6H8O7) wine (C4H6O6) and other known acids. The target product is separated by filtration and/or purified, for example by washing, crystallization, and other known methods.

The compounds of formula (VI) is obtained by condensation reaction of pre-dissolved in an organic solvent di(formulary)polyester and an aqueous solution of the substituted hydrazine (VII) using promoterwise what travelcom or carry out the reaction in an environment of weak organic or inorganic acid, for example, acetic acid. The resulting hydrazones (IV) in the form of the base is separated by filtration, and/or cleaned, for example by washing, crystallization, and other known methods. Coordination compounds obtained by mixing equimolar amounts of the compound (IV) and a metal salt in a medium of an organic solvent by heating or sonochemical impact. As the organic solvent used DMF or alcohol (VIII).

The pharmaceutical composition was prepared by mixing the pharmaceutically acceptable excipient and an effective amount of compounds of formula IV, V or VI. As filler can be used any known for these purposes, solid, liquid or plastic substance.

Synthesis and use as antimycobacterial drugs substituted di(formulary)polyethers, their pharmaceutically acceptable additive salts and coordination compounds are connected by a single inventive concept.

In contrast to the known analogues in pharmaceutical action of the claimed compounds represents a new class of compounds and their derivatives, used for the treatment of mycobacteriosis. Antimycobacterial activity stated the compounds may be due to the fact, they contain polyester fragment of a certain length, which gives them the ability to migrate through lipophilic membranes of neutral molecules and charged particles, in particular of metal cations (table.2) and, apparently, provide enhanced permeability of the inventive compounds through the cell membrane of the pathogen.

These features of the structure and behavior lead to the broadening of the spectrum antimycobacterial activity: effects on drug-resistant mycobacteria (table.3,4), the action of typical and atypical mycobacteria (table. 5), as well as increasing the specificity of the claimed compounds (table. 6,7). Due to its specificity to the mycobacteria of the claimed compounds do not have an overwhelming effect in normal flora of the body, practically non-toxic (table. 8), have a high therapeutic effect in the treatment of experimental animals (table.9).

The method is as follows.

Di(formulary)polyesters of the formula

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receive by dissolving in DMF substituted aromatic aldehyde and alkali at 60-70oC added within half an hour of a solution of dichloro - or detailsusing glycol in DMF and subsequent heating poludnie, purify by crystallization or chromatography on a column filled with alumina.

The hydrazones di(formulary)polyesters obtained by mixing at 40-45oC solutions of di(formulary)polyester in DMF and substituted hydrazine of the formula VII in a dilute weak, for example, acetic acid, stirring for 5 minutes, keeping at room temperature, followed by filtration, washing and crystallization.

The hydrazones di(formulary)polyesters also receive ultrasonic treatment suspensions di(formulary)polyester and substituted hydrazine of formula VII in an alcohol solution for 3-5 minutes, followed by filtration and washing of the target product with alcohol.

The compounds of formula V is produced by mixing at 45-50oC solutions of di(formulary)polyester in DMF and hydrazine of the formula VII in a dilute aqueous solution of a strong inorganic or organic acids, for example hydrochloric, obtained by stirring the reaction mixture for 25 min, maintaining at room temperature for 1 hour, followed by filtering and presidenial of alcohol diethyl ether.

The compounds of formula V also receive ultrasonic treatment the acid in alcohol, followed by filtration and washing of the target product with alcohol.

The compounds of formula VI obtained by heating equimolar amounts of hydrazone and metal salt in DMF at 140-145oC for 10 min, remove the solvent in vacuo, followed by washing and crystallization of the desired product.

The compounds of formula VI also receive ultrasonic treatment for 10 min equimolar amounts of hydrazone salt and one-, two-, three -, or tetravalent metal in alcohol, followed by filtration and washing of the target product with alcohol.

The use of non-solutions, and suspensions initial reagents allows to reduce the consumption of solvents, replace toxic or expensive solvents. In addition, the use of ultrasonic influence is characterized by a significant increase in the selectivity of the process, resulting in increased output of the target product until quantitative.

The purity of the obtained compounds was monitored by TLC. Values of Rfthe claimed compounds was determined using records "Sorbfil" (Silica gel CTX-1A,UV) (Russia) or "Silufol UV" (Czechoslovakia). The structure and the structure of new compounds proved by data of elemental analysis (C,H,N,O-analyzer company Karlo Erba), IR (Specord UV-.751R) and TMR-SPEKOL disperser brand UZDN-2T with a frequency of 22 kHz. Camiontransport.ro properties of the claimed compounds was studied by the standard technique, which consists in the study of cation transfer from one aqueous phase to another aqueous phase through the layer of non-polar organic solvent.

Examples of specific performance.

Example 1

1,2-Bis(2-formyl-5-chlorophenoxy)-ethane

To a solution of 19.6 g (0,14 m) 5-chlorosalicylic aldehyde in 200 ml of DMF was added 5,6 (0,14 m) NaOH and heated at a temperature of 60-70oC in a stream of argon until complete dissolution of alkali. Then 6,93 g (0,07 m) dichloride in 50 ml of DMF was added within half an hour. Then the temperature was raised up to 110-120oC and kept stirring at this temperature for 15 hours. After cooling the reaction mass was filtered and planted 500 ml of water. The precipitation was filtered, washed with water. Was purified by crystallization from a mixture of DMF: ethanol:water with coal and alumina. Dried at a temperature of 100-120oC. Rf= 0,75 (ethanol), so pl. 82-84oC, Yield=75%

Calculated for C16H12O4Cl2M M 339

C=56,64 H=3,54 Cl=20,94

Found

C=56,45 H=3,43 Cl=20,53

IR spectrum, cm-1: 1685 (C=O), 1250, 1040(C-O-C).

The PMR spectrum, M. D.: 10,22(s,2H,H-C=O); 7,78-7,34(m,6H,C6H4),4,59(s,4H, OCH2). the alicelove aldehyde and 1.00 g (0.05 m) dichlorodifluoro ether. Was purified by paracrystalline from methanol. Rf= 0,78 (ethanol), so pl. 197oC, Yield=77%

Calculated for C22H26O5M M 370

C=71,35 H=7,03

Found:

C=71,28 H-7,10

IR spectrum , cm-1: 1680 (C=O), 1255, 1145, 1080, 1040(C-O-C)

The PMR spectrum, M. D.: 12,08 (s,2H,H-C=O); 8,21-6,94 (m,8H,aromatic protons); 4,13 is-3.45 (m,8H,OCH2); to 1.76(s,8H,CH2)

Example 3

1,5-Bis(2-isonicotinohydrazide)-3-oxapentane

To a solution of 0.94 g (0,003 m) 1,5-bis(2-formylphenoxy)-3 - oxapentane in 30 ml of DMF was added a solution of 0.83 g (0,006 m) of the hydrazide of isonicotinic acid in 30 ml of 20% CH3COOH at 45-50oC and vigorously stirred at this temperature for 5 minutes, the precipitation was filtered, washed with water. Was purified by crystallization from a mixture of DMF:ethanol. Rf= 0,29 (acetone), so pl. 230 - 232oC, Yield=79%

Calculated for C30H28N6O5M M 552

C=65.22 PER H=5,07 N=15,30

Found:

C=65,28 H=4,92 N=15,59

IR spectrum , cm-1: 3200 (NH), 1679 (C=N), 1655 (C=O), 1555 (NH), 1245, 1150, 1115, 1080 (C-O-C).

The PMR spectrum ,M. D.: 12,09 (c,2H,HN-C=0); 8,81 (c,2H,H-C=N); 8,75? 7.04 baby mortality (m,16H,aromatic protons); 3,72-4,30 (m,8H,OCH2).

Example 4

1,5-Bis(2-isonicotinohydrazide)-3-oxapentane

Suspension of 0.94 g (0,003 m) 1,5-bis(formalparameters using device UZDN-2T (22 kHz) within 3-5 minutes (control by TLC), then the precipitate was filtered and purified by washing with ethanol, dried in vacuum. Rf=0,29 (acetone), so pl. 230-232oC, Yield=95%

Calculated for C30H28N6O5M M 552

C=65.22 PER H=5,07 N=15,30

Found:

C=65,35 H=5,22 N=15,47

IR spectrum, cm-1: 3200 (NH), 1679 (C=N), 1655 (C=O), 1555 (NH), 1245, 1150, 1115, 1080 (C-O-C).

The PMR spectrum, M. D.: 12,09 (c,2H,HN-C=O); 8,81 (c,2H,H-C=N); 8,75? 7.04 baby mortality (m,16H, aromatic protons); 3,72-4,30 (m,8H,OCH2).

Example 5

1,8-Bis[2(nicotinereplacement-2)]-3,6-dioxaoctyl

Was obtained analogously to example 3 from 1,37 g (0,003 m) 1,8 - bis[2(formindex-2)] -3,6-dioxaoctyl and 0,83 g (0,006 m) nicotinic acid hydrazide. Rf= 0,03 (acetone), so pl. 82-84oC, Yield=78%

Calculated for C40H36N6O6M M 696

C=68,97 H=5,17 N=12,07

Found:

C=68,70 H-A 5.25 N=12,00.

To spectrum , cm-1: 3245 (NH), 1683 (C=N), 1652 (C=O), 1560 (NH), 1242, 1140, 1080, 1059 (C-O-C).

The PMR spectrum , M. D.: 12,08 (c,2H,HN-C=O); 9,14 (c,2H,H-C=N); to 7.59-7,20 (m,20H, aromatic protons); 4,33-of 3.85 (m,12H,OCH2).

Example 6

1,2-Bis(2-methoxy-4-benzoylisothiocyanate)-ethane

Was obtained analogously to example 4 from 0,99 g (0,003 m) 1,2-bis(2 - methoxy-4 - formylphenoxy)-ethane and 0.82 g (0,006 m) benzoic acid hydrazide in 20 ml of 50% mean

C=68,84 H=5,30 N=9,89

Found:

C=67,65 H=5,66 N=OF 10.25

IR spectrum , cm-1: 3240 (NH), 1690 (C=N), 1650 (C=O), 1560 (NH), 1285, 1080 (C-O-C).

The PMR spectrum ,M. D.: 11,75 (c,2H,HN-C=O); 8,39 (c,2H,H-C=N); of 7.90-7,17 (m,16H, aromatic protons); 4,39 (s,4H,OCH2); a 3.83 (s,6H,OCH3).

Example 7

1,2-Bis(5-chloro-2-isonicotinohydrazide)ethane

Was obtained analogously to example 4 from 1,02 g (0,003 m) 1,2-bis(5-chloro-2-formylphenoxy)-ethane and 0,83 g (0,006 m) of the hydrazide of isonicotinic acid in 20 ml of isopropanol. Rf= 0,43 (acetone), so pl. 65-267oC, Yield=94%

Calculated for C28H22N6O4Cl2M M 577

C=58,23 H=3,81 N=14,56

Found:

C=58,99 H=TO 3.58 N=14,44

IR spectrum , cm-1: 3260 (NH), 1670 (C=N), 1650 (C=O), 1555 (NH), 1265, 1065 (C-O-C).

The PMR spectrum, M. D.: 12,13 (c,2H,HN-C=O); 8,76 (c,2H,H-C=N); 8,71-7,02 (m,14H, aromatic protons); of 4.49 (s,4H,OCH2).

Example 8

1,11-Bis(2-isonicotinohydrazide)-3,6,9-trioxadecyl

Was obtained analogously to example 4 from 1,21 g (0,003 m) 1,11-bis(2-formylphenoxy)-3,6,9-trioxadecyl and 0,83 g (0,006 m) of the hydrazide of isonicotinic acid. Rf= 0,17 (acetone), so pl. 68 - 70oC, Yield=98%

Calculated for C34H40N6O8M M 658

C=62,01 H=5,78 N=12,77

Found:

C=62,12 H=5,66 N=12,58

IR SPE is 7,00-7,83 (m,16H, aromatic protons); 4,22 of 3.56 (m,16H,OCH2).

Example 9

1,5-Bis(2-phenylhydrazones)-3-oxapentane

Was obtained analogously to example 3 from 2,88 g (0.02 m) of phenylhydrazine hydrochloride and 2.86 g (0.01 m)of 1,5-bis(2-formylphenoxy)-3 - oxapentane. Rf= 0,33 (acetone), so pl. 169-170oC, Yield 84%

Calculated for C30H28N4O3M M 494

C=72,89 H=6,07 N=11,34

Found:

C=72,46 H=5,97 N=11,09

IR spectrum, cm-1: 3330 (NH), 1685(C=N), 1565 (NH), 1256, 1160, 1116, 1050(C-O-C).

The PMR spectrum, M. D.: 10,36 (c,2H,NH); 8,21 (c,2H6H-C=N); 6,72-7,81 (m, 18H, aromatic protons); 3,96-4,24 (m,8H,OCH2).

Example 10

1,5-Bis(2-methoxy-4-nicotinereplacement)-3 - oxapentane trisulfate

A solution of 0.94 g (0,003 m) 1,5-bis(2 - formylphenoxy)-3-oxapentane in 30 ml DMF and 0,83 g (0,006 m) nicotinic acid hydrazide in 30 ml of 20% sulfuric acid was combined with 45-50oC, stirred for 20 minutes, and then kept at room temperature for 1 hour, filtered. Purified product planting from methanol-ether. Was dried in vacuum, so pl. 185 - 186oC, Yield=72%

Calculated for C30H28N6O53H2SO4M M 748

C=48,13 H=4,28 N=11,23 S=8,56

Found

C=48,08 H=WITH 4.64 N=11,36 S=A 9.09

IR spectrum, cm-1: 2700-2650, 2100, 1670 (C=NRath

A suspension of 0.14 g (is 0.0002 m) 1,8-bis[2- (nicotinereplacement-2)] -3,6-dioxaoctyl and 0,077 g (of 0.0004 m) citric acid was subjected to ultrasound for 3 minutes, then cooled and filtered. Purified the product by washing with ethanol. Was dried in vacuum, so pl. 145-146oC, Yield=92%

Calculated for C46H46N6O14M M 906

C=60,93 H=5,07 N=9,27

Found

C=60,83 H=4,71 N=9,20

IR spectrum , cm-1: 2650-2500, 1950, 1665 (C=N+H); 1249, 1111, 1083, 1043 (C-O-C), 1580 (COO-)

Example 12

[1,5-Bis(2-methoxy-4-formylphenoxy)-3,6-dioxaoctyl] potassium (1) isothiocyanate

The solution 0,074 g (is 0.0002 m) 1,2-bis(2 - methoxy-4-formylphenoxy)-ethane and 0.02 g (is 0.0002 m KSCN in 20 ml of DMF was heated for 10 minutes, drove the solvent in vacuo, the residue was purified by recrystallization from ethanol. Was dried in vacuum,so pl. 135oC, Yield=68%

Calculated for C21H22NSK M M 471

C=53,48 H=4,67 N=2,97

Found

C=53,58 N=4,78 N=3,01

IR spectrum , cm-1: 1690 (C=O), 1265, 1150, 1070, 1050 (C-O-C)

Example 13

[1,8-Bis(3-nicotinereplacement)-3,6-dioxaoctyl] Nickel(II)

0.6 g (0.005 m) of 1,8-Bis(3-nicotinereplacement)-3,6-dioxaoctyl and 0.36 (0.01 m) Ni(NO3)2were placed in 15 ml of methanol was dropped into the flask emitter ultra is amywali hot methanol and dried in vacuum, so pl. above 250oC, Yield=90%

Calculated for C32H32N6O6Ni M M 655

C=58,63 H=4,89 N=12,82

Found

C=58,77 H=5,30 N=12,36

IR spectrum , cm-1: 3450, 3180 (NH), 1680 (C=N), 1650 (C=O), 1265, 1140, 1100, 1050 (C-O-C).

Example 14

[1,5-Bis(2-methoxy-4-nicotinereplacement)-3 - oxapentane] iron(III)

Was obtained analogously to example 13 from 0.5 g (0,0008 m) 1,5-bis(2-methoxy-4-nicotinereplacement)- 3-oxapentane and 0.26 g (0,0016 m) FeCl3so pl. above 250oC,

Yield=91%

Calculated for C34H34N4O7Fe M M 665,8

C=61,28 H=5,11 N=TO 8.41

Found

C=61,61 H=LOWER THAN THE 5.37 N=8,66

IR spectrum , cm-1: 3460, 3200 (NH), 1685 (C=N), 1655 (C=O), 1266, 1145, 1190, 1055 (C-O-C)

Example 15

Farmcampsite based on 1,8-bis(2-isonicotinohydrazide)-3,6-dioxaoctyl to study therapeutic effect

21 mg of the drug was ground in a mortar and gradually added in small portions 3 ml of 1% starch solution to obtain a homogeneous suspension. The resulting composition is used for treatment of Guinea pigs by daily injection of 1 ml of the resulting suspension in a few days. The data in the table. 9.

Example 16

[1,8-Bis(3-isonicotinohydrazide is on and 0.80 g (0.005 m) CuCl2were placed in 15 ml of methanol was dropped into the flask emitter ultrasonic disperser, and included the unit for 10 minutes. After cooling, the precipitated precipitate, which was filtered, washed with hot methanol and dried in vacuum,so pl. above 250oC, Yield=97%

Calculated for C32H32N6O8SCu M M 915

C=50,83 H=4,24 N=11,12

Found:

C=50,30 H=4,15 N=10,99

IR spectrum, cm-1: 1628 (C=N), 1600 (C=O), 1580 (NH), 1268, 1120, 1060, 1035 (C-O-C).

Example 17

[1,2-Bis(2-benzoylisothiocyanate)-ethane] cobalt (II)

2,53 g (0.005 m) of 1,2-bis(2-benzoylisothiocyanate)-ethane and 0,89 g (0.005 m) Co(CH3COOH)2were placed in 15 ml of methanol was dropped into the flask emitter ultrasonic disperser, and included the unit for 10 minutes. After cooling, the precipitated precipitate, which was filtered, washed with hot methanol and dried in vacuum,so pl. above 250oC, Yield=89%

Calculated for C32H34N4O4Co M M 563

C=63,94 H=4,24 N=9,95

Found

C=63,75 H=OR 4.31 N=10,33

IR spectrum , cm-1: 1625 (C=N), 1600 (C=O), 1585 (NH), 1265, 1025 (C-O-C).

Example 18

[1,5-Bis(2-isonicotinohydrazide)-3-oxapentane] zirconium (IV) disulfate

2.76 g (0.005 m) of 1,5 - bis(2-isonicotinohydrazide) -3-ekspertov (5 min). The solvent is kept in vacuum, the residue was washed with ethanol and dried in vacuum. So pl. above 250oC, Yield =95%

Calculated for C30H28N6O13S2Zr M M 835,2

C=43,10 H=3,35 N= 10,06

Found

C=43,40 H=3,05 N=OF 10.25

IR spectrum, cm-1: 1630 (C=N), 1610 (C=O), 1590 (NH), 1260, 1120, 1080, 1040 (C-O-C).

The study antimycobacterial activity of the claimed compounds in experiments conducted in vitro bacteriological, 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 in 0.3 ml of each dilution. The tubes were placed in a thermostat in a vertical position, and incubated at 37oC, the results were taken into account for 10-12 days. The inventive preparations showed high antimycobacterial activity, especially in relation to atypical mycobacterial strains (table. 5), as well as strains of mycobacteria resistant to the main anti-TB drugs (table. 3,4).

Antibacterial activity of the claimed compounds was studied by the method of sowing the drug solution into the wells. In a Petri dish with a simple nutrient agar was made the test microbe. In the hole located in the middle of the Cup Peter thermostat at 37oC, determination of the zone of growth inhibition of microorganisms on the edges of the hole.

The study of therapeutic action of the claimed compounds was carried out in Guinea pigs, average weight of 350 g, infected subcutaneously in the region of the right groin 0.001 mg/ml of culture (strain H37Rv). Treatment was started 2 weeks after infection and spent 5 times a week for 60 days. The drug was given to Guinea pigs at a dose of 21 mg/kg, control group of pigs received isoniazid in equivalent dose. The results are shown in table.9. The table shows that the studied animals that received 1,8-bis(2-isonicotinohydrazide)-3,6-dioxaoctyl differed significantly in weight compared to control animals. There were differences in the weight of bodies. All control animals tuberculous lesions were located mainly in the introduction. After the end of treatment in animals treated with isoniazid or declare the drug, tuberculosis changes it is not revealed as bacteriologically and morphologically.

The study of the acute toxicity was performed according to standard methods on white mice. The animals received the drug per os in a 0.5% solution of starch within 5 days. Values Kaya toxicity, high specificity for mycobacteria, high activity against atypical, typical, drug-resistant strains of mycobacteria, including Mycobacterium strains resistant to isoniazid) than counterparts in structure and action. New connections can be used in practical medicine for the treatment of patients infected with sensitive and resistant, typical and atypical strains of mycobacteria.

1. Substituted di(formulary)polyesters of General formula

< / BR>
where AG - substituted phenylene or naftilan;

Y is a hydrogen atom, a halogen or methoxy group;

R is an oxygen atom, NNH-R1-group;

R1- substituted phenyl, benzoyl, 2 -, or 4-nicotinoyl;

n is an integer from 1 to 3;

m is an integer from 1 to 4;

or their coordination compounds with cations of one-, two-, three -, or tetravalent metals or their salts, or their pharmaceutically acceptable salt additive compounds And in which R denotes-NNH-R1group, with organic and inorganic acids having antimycobacterial activity.

2. Pharmaceutically acceptable salt additive compounds on p. 1 of General formula

< / BR>
where - AG - substituted phenylene or a methoxy group;

n is an integer from 1 to 3;

m is an integer from 1 to 4;

In - anion mineral, alkyl - or arylcarbamoyl acid;

x, q and R are integers from 1 to 3.

3. Coordination compounds on p. 1 of General formula

< / BR>
where AG - substituted phenylene or naftilan;

R is an oxygen atom or-N-NH-R1-group;

R1- substituted phenyl, benzoyl, 2 -, or 4-nicotinoyl;

Y is a hydrogen atom, a halogen or methoxy group;

Me - cation of one-, two-, three -, or tetravalent metal;

An anion of a mineral acid;

n and h is an integer from 1 to 3;

m is an integer from 1 to 4;

k = l, 2, 3, or 4.

4. Connection on p. 3 that as the cation of the metal Me contain a cation of Li, Na, K, Cu, Co, Ni, Fe, or Zr.

5. The method of obtaining compounds on p. 1, wherein the substituted aromatic aldehyde is subjected to alkylation dichloro - or diethylsilane the glycols in the presence of alkali in the medium of organic solvent by heating, the resulting di(formulary)the polyester is subjected to the condensation reaction with an aqueous solution of hydrazine of General formula

R1NHNH2,

where R1- substituted phenyl, benzoyl or 2 - or 4-nicotinoyl,

in the environment of organic restore or transfer it in a coordination compound or pharmaceutically acceptable additive salt.

6. The method according to p. 5, characterized in that the organic solvent used dimethylformamide or alcohol.

7. The method according to PP. 5 and 6, characterized in that the promoting effects of using ultrasound or weak organic or inorganic acid.

8. The method according to PP. 5 and 6, characterized in that compounds of the formula under item 2 is obtained using as the promoting influence of ultrasound and/or the reaction is carried out in the presence of a strong organic or inorganic acid.

9. The method according to PP. 5 and 7, characterized in that compounds of the formula under item 3 is produced by interaction of equimolar amounts of compounds of formula a and a metal salt in a medium of an organic solvent by heating or exposure to ultrasound.

10. Pharmaceutical composition having antimycobacterial activity, containing the active principle and a pharmaceutically acceptable excipient, characterized in that the active agent it contains a substituted di(formulary)polyesters under item 1, or salt additive, or coordination compounds with cations of one-, two-, three -, or tetravalent metals or their salts in an effective amount.

 

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< / BR>
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< / BR>
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