SU1056616A1 - Iodomethylates of 3-aminoderivatives of 1,5-dihydropyridazino-(3,4-b) quinoxaline having antituberculosis activity in vitro - Google Patents

Abstract

Iodomethyls of 3-amino derivatives of 1,5-dihydropyrchdazino {s, 4-hJ quinoxaline of the general formula I Ri, J., 3® N CNe where R is CH5npH, Rj is CHj and 1C is -N N-CHj; fNH (CH2) eOHi or, Hj with Rji "R, H and 4 - H (L or with, Rj-Cl and Cz - NH cd have anti-tuberculosis activity in vitro. (35 55 New biologically active compounds are proposed, namely Iodomethylates of 3-amino derivatives 1, 5-dihydropyridazine 3,4-bj quinoxal of the general formula I tjfe-, o «i, H9 where, when Rt is H, RI is CH, and R, is -N (N-CHJ, 1 tcHj), oHj -NHnQ-CH ,, -n „About

Description

or R-ScNR with R Rj H and: R. - BN or CHj with Rj-Cl and R4-vi H showing anti-tuberculosis activity. These compounds can find npiHMenenie in medicine. The closest structural analogue of the compounds of general formula I is 1,5-dihydropyridazino / 3,4-bJ quinoxaline hydrochloride, which has a phenylhydrazine group, of formula 2, exhibiting a counter-Uberculosis activity in position 3 of the pyridazine ring. Hydrodist, isonicotinic acid (isoniazid) is widely used in medicine as an anti-tuberculosis drug. However, these compounds, which possess anti-tuberculosis activity against common tuberculosis microbes, do not act on atypical mycobacteria. The aim of the invention is to expand the arsenal of means of influencing a living organism. This goal is achieved by new iodomethyls of 3-amino derivatives 1,5-dihydropyridazinoGZ, 4-b | quinoxaline of general formula I as substances with anti-tuberculosis activity. The method of producing compounds of general formula 1 is based on the reaction of methyl 2-halopyridine methyl with amines known in the pyridine series. Compounds of general formula I are obtained by reacting iodomethyl with 1 64 tov 1-butyl-3-iodine-1 jS-flHrHflponHpHflaSHHo | 3,4-bJhinoxalines of general formula 3 / fI, F LF-CH. J T N where R, Rt and R have the indicated meanings, with an excess of the corresponding substituted amine in an organic solvent medium at the boil. the starting materials of general formula 3 are obtained in a known manner based on the reaction of the interaction of} -butyl-3-chloro-1, 5-dihydropyridazino f3,4-bj quinoxalic with an excess of iodide, methyl in anhydrous benzene. The compounds of the general formula 1 are crystalline, powdery substances of yellow or orange color, insoluble in water, soluble in polar organic solutions. J. Pr and measure 1. Preparation of iodometl-; lata 1-butyl-3- (1methylpiperazineSH1-. -4) -5.8 dimethyl-1,5-dihydropyridesine {3, 4-b} quinoxaline (compound IX Mixture 2.5 g (0.0046 mol) iodomethyl 5 -butyl-3-iodo-5. 8-dnmethyl-1, 3-dihydropyridazino 3,4-bj quinoxaline, 1.12 g (0.0122 mol) N-methyl-: piperazine and 50 ml of absolute eta-nola boil t 1 h. When the solution was cooled down to 0–2 ° C, the crystals were filtered to give 2.2 g (75.5%) of the desired product in the form of orange crystals with a melting point of 240–242 ° C (acetone / spray 1: 1) Found,%: C 51.77; H 6.51; I 24.74; N 16.58. Cn.HjjI N5 Calculated,%: C 51.96 {H 6.54, I 24.95J N 16.53 Examples 2-7. Under conditions similar to example. in I, the indicated Iodmethyl is obtained. Types of 3-amino derivatives of 1,5-dihydro-pyridazine 3, 4-b quinoxaline of the general formula 1 (compounds 2-7), the properties of 1 "1X are shown in Table 1.

ef

X

h y

here N

I I

W I I 91

I o

The structure of the compounds of general formula I is proved by spectral data and elemental analysis. The presence of the NH group in compounds 2-7 (see .1) is confirmed by the presence in the IR spectra of the absorption bands in the region of 3250-3280 cm. The UV spectra of these compounds are characterized by three absorption maxima at 252-258, 302-312 and 412-448 nm.

Testing anti-TB activity.

.

The study of the anti-tuberculosis activity of compounds of the general formula 1 was carried out .in vitro by the method of serial dilutions on Soton medium. These compounds were studied in comparison with a compound of formula 2 similar in structure and biological action, as well as with the known anti-tuberculosis drug Isoniazvd. Mycobacterium tuberculosis of strain H-37 and atypical mycobacterium of strain ATCC-607 were used as test cultures. Bacteriostatic activity of compounds of general formula 1 with respect to (strains H-37RV and ATCC-607)

or0, 12

2000678

y

0.05

As a result of the study, it was found that the bacteriostatic concentration of the compounds of general formula 1 with respect to the strain H-37Rv without blood seoric is 0.001-4 µg / ml and the most active (compounds 6 and 7 0.001 and 0.06 µg / ml, respectively. Activity 2 and isoniazid in the same conditions 0.12 and 0.05 µg / ml, respectively. In the presence of horse serum, the activity of the compounds of the general formula 1 is 0.25-4 µg / ml, and in the most active (5 and 6). 0 , 5-0.25 μg / ml, respectively, and for a compound of formula 2, 4 μg / ml.

The bacteriostaosic concentration of the compound of general formula 1 with respect to atypical mycobacteria is 0.06-4 µg / ml, and for the most active (compounds 4 and 6) it is 0.125 and 0.06 µg / ml, respectively. Isoniazvd against atypical bacteria is 11 ktimically inactive.

The results of biological tests of compounds of general formula 1 are presented in table. 2

Table 2

4.0 0.25 2.0 0.125 2.0

0.06-0.25 0.25

4.0

32.0

0.05 in vitro s mycobacte |) y tuberculosis.

91056616О

Thus, new compounds with known compounds in that

in the pyridazino z, 4-b Quinoxaline series, they exhibit a high tuberculous status; they have a high anti-tuberculosis activity not only against

In vivo in vitro and H-37Rv, HOHB ratios, they have an advantage over these primary mycocacteria (strain ATCC-607).

Claims (1)

<claim-text> <table border = "1"> <tbody> <tr> <td> mules 2 </ td> <td> 2000678 </ td> <td> 0.12 </ td> <td> 4.0 </ td> <td> - </ td> </ tr> <tr> <td> Drug </ td> <td> </ td> <td> </ td> <td> </ td> <td> </ td> </ tr> <tr> <td> drug </ td> <td> </ td> <td> </ td> <td> </ td> <td> </ td> </ tr> <tr> <td> "isoniazid" </ td> <td> </ td> <td> 0.05 </ td> <td> 0.05 </ td> <td> 32.0 </ td> </ tr> </ tbody> </ table> <claim-text> 9 1056616 ’θ </ claim-text> <claim-text> Thus, new compounds in the pyridazino series (3,4-b] quinoxaline have high anti-tuberculosis activity in the ίη νίϋτο experiments and have an advantage over these </ claim-text> <claim> known compounds in that <sub> (</ sub>) exhibit high tuberculosis activity not only against strain H-37Kch, but also against atypical mycobacteria (strain ATCC-607). </ claim-text>