CS203790B1 - 2-r-6-r1-sulphonylbenzothiazoles - Google Patents

Description

The invention relates to the antibacterial, antiprotozoal and antifungal activity of 2-alkylsulfonylbenzothiazoles, 2-alkylsulfonyl-6-nitrobenzothiazoles and 2-arylalkyl- ^1- thionylbenzothiazoles and their preparation.

In the patent literature [Popoff I. Ch., Buchholz B., Miller H. J., U.S. Patent 3,519,630 (1960); Chetna. Abstr. 73, 76, 154 (1970);

Chetna. Abstr. 83, 73 468 (1975)] · discloses the preparation of a fungicidally and bactericidally active preparation comprising an inert carrier and the efficacy of the compound 2-alkyl (C1-Cn-branched saturated chain), cycloalkyl 5,6-halogen, NO 2, NHa, NHR N (R) z; R = alkyl) sulfonylbenzothiazole and various 6. Substituted-2-methylBulphonylbenzothiazoles [Agui H., Mitani T., Niakashita M., Murayama E., Okamura K., Nakagoime T., Komatsu T., Izawa A, Eda Y. , Ger. Offen. 2,449,544 (1975); Chem. Abstr. 83, 79 231 (1975)) in which bactericidal and inhibitory activity has been observed. In the other Gh synthesized 6-R1-2-R-sulfonylbenzothiazolocih described in the current literature [Kučerov V. F., Ž. Obšč. Chim. 19, 752 (1949); Hofmann A., Ber. 13, 11 (1880); Bedniagina N.P ,, Postovekij I.J., Z. Obšč. Chim. 30, 3193 (1960); Kuznecova E.A., Zuravlev S.V., Stepanova T.N., Z.Org. Chim. 1, 767 (1965); Svetlajeva V.M., Kuznecova E.A., tt

Žuravleiv S.V., Ž. Org. Chim. 34, 983 (1964) fails to pay attention to their antimicrobial activity.

We have found that the novel compounds of formula I synthesized by us

where

R = CH 2 Cl, R ¹ = H (I);

R = 1-C 3 H 7, R ¹ = H (II);

R = 1 -C 3 H 7, R ¹ = NO 2 (III);

R = CH 2 CH 2 CH, R ¹ = H (IV);

R = CH 2 CH 2 OH) CH 2 Cl, R ¹ = H (V);

R = CH 2 CH = CH 2, R ¹ = NO 2 (VI);

R = CH 2 CB (CH 3) 2, R 1 = NO 2 (VII);

R = CH 2 CH (C ₂ H ₅ ) (CH 2) 3 CH 3, R ¹ = NO ² (1H); R = CH ² C 6 H 6 Cl-a, R ¹ = H (1X);

R = CH 2 C 6 H 3 (Cl) 2-3.4, R 1 = H (X);

R = CH2CeH3 _(NO2) 2-2,4, R = H (XI);

R = Ctf ₄ - (O < O

203700

R1 = H. (XII);

R 1 = H (XIII);

R = (CH 2) 2 SO 2 C 6 H 4 Cl-4, R ¹ = H (XIV);

R =? CH 2 COOC 2 H 5, R ¹ = NOa (XV);

R = CH 2 COOCH 2 CH 2 Cl, R ¹ = Ή (XVI);

R = CH 2 COOCH 2 CH 2 Cl, R ¹ = NOa (XVII);

R = CH 2 COOCH 2 CH = CH 2, R ¹ = NOa (VIII); R = CH 2 COOCH (CH 3) 2 H 5, R ¹ = NO 2 (XIX);

R ¹ = 2θ2 [ΧΧ]

I. 2-Chloromethylsulfonylbenzothiazole, <

'II. 2-Izopropylsulfonylbenzotiazol,

III. 2-Isopropylsulfonyl-6-nitrobenzothiazoles,

IV. 2-PrOipargylsulíonylbenzotiazol,

G. 2- ^{(2-hydroxy-3-chlorophenyl:} lórpropylsulfonyl) benzothiazole,

VI. 2-Allyphenulfonyl-6-nitrobenz'thiazal, VII. 2-Ia-butylsulfonyl-6-nitrohenizole thiazole,

VIII. 2- (2-Etylhexylsulfonyl) -6-niitrobeaizotiazol,

IX. 2- (4-Chlórbenzyl'Sulfonyl) Beneo, thiazolyl ^and L,

X. 2- (3,4-Di ^; chlorobenzylisulfonyl) berizothiazole,

XI. 2- {2,4-DinitrObenzylsulfonyl) benzothiazole,

XII. 2- (l-Naftylmetylsulfonyl) benzothiazole,

XIII. 2,2'-Metyléndisulfonyldi'benzotiazol.

XIV. 2-2- (4-Chlorophenylsulfonyl) ethylsulfonylbenzothiazole,

XV. (6-Nitro-2-benzothiazolyleulfonyl) -acetic acid ethyl ester, ·

XVI. (2-Benzothiazolylsulfonyl) acetic acid, 6-chloroethyl ether,

XVII. (6-Nitro-2-benzothiazolylsulfonyl) acetic acid 2-chloroethyl ester,

XVIII. (6-Nitro-2-benzothiazolylsulfonyl) acetic acid allyl ester,

XIX. Check. (6-nitro-2-benzothiazolylsulfonyl) acetic acid buityl ester,

XX. (6-Nitro-2-benzothiazolylsulfonyl) acetic acid furyl ester is antibiacterial, antiprotozoal, and antifungal. At the same time, a process for the preparation of said compounds based on 2-alkylthiobenzothiazoles, 2-alkylthio-6-nitrobenzothiazoloiv and 2-arylalkylthiobenzothiazoles was prepared.

The following example explains in more detail the preparation of the compounds (I, II., -IV., V., XVI.) Of the invention which is prepared according to the basic procedure of Example 1. Scheme 1:.

^{R <} lgŮr ^s '% _Mn o'

EXAMPLE.

Preparation of Compound IV:

Dissolve 6,15 g (0,03 mol) of 2-propargylthiobenzothiazole in a three-necked flask in a mixture of 100 ml of acetone, 20 ml of water and 10 ml of acetic acid and add a saturated aqueous solution of 4,74 g (0,03 g) from the dropping funnel. mol) of potassium permanganate. After the temperature has stabilized at 50 ° C, the reaction mixture is stirred for a further 4 hours, filtered hot with manganese dioxide and washed with acetone. After cooled pastry 2-propargylsulphonylbenzothiazole Filter and crystallize from ethyl alcohol.

Another example explains in more detail the preparation of the compounds (III, VI-XV, XVII-XX) of the invention which hurt according to the basic procedure set forth in Example 2. Scheme 2:

Preparation of Compound X:

. Dissolve 9.78 g (0.03 mol) of 3,4-dichlorobenzylthiobenzothiazole in 150 ml of 98 to 99% acetic acid in a three-necked flask (500 mL) with mechanical stirrer and reflux condenser. After stabilizing the temperature at 40-45 ° C with constant stirring, add 21.7 in small portions from the dropping funnel. g (0.18 mol) of 28% hydrogen peroxide. The reaction mixture is then stirred for 3 to 4 hours at 55 to 65 ° C and, after cooling to room temperature, is poured onto crushed ice (400 to 600 grams). The isolated product is purified by charcoal and crystallized from tetrahydrofuran and ethyl alcohol (1: 3).

and

Elemental analysis results and physicochemical constant of synthesized compounds (I-XX); according to the invention are given in Table 1. ',

In studying the antimiphrobic activity of 2-alkylsulfonylbenzothiazoles, 6-nitro-2-aralkylsulfonylbenzothiazoles and 2-arylalkylsulfonylbenzothiazoles, the methods used in the study of the biological effects of substances of a similar type were used. Efficacy on bacterial strains was studied by a modified, canvas diffusion test method [Foltinova P., Sutoris V., Bldckinger G., Ebrimger L., Acta Facult. Rer. Natural. Univ, Comenianae, Microbiol., IV, 97, 1976). Antimycobacterial and antifungal activity was followed by dilution method in appropriate culture medium [Foltinova P., Sutoris V., Bldckinger G., Ebringer L., Folia Microbiol. 23, 225, 1978). The effect on the proto-isolate strains of Tritrichomonas foetus and the epimastigous forms of Trypanosoma rose was examined in a liquid culture medium where we monitored the number of motile individuals [Foltínová P., Ebringer L., Jurášek A., Rybář A., Acta Facult. Rer. Natural. Univ. Comenianae, Microbiol., IV, 35, 1978). The results of microbial activity are shown in Tables 2 and 3. Significantly, the synthesized compounds are antimicrobial active. Particularly 6-nitro-2-alkylsulfonylbenzothiazoles and B-nitro-6-arylalkylsulfonylbenzothiazoles, which have good antibacterial, antifungal and antiprotozoal effects. The effect on omonrichomonas foetus is also interesting compared to the effect of reference metronidazole, which is effective at a concentration of 2 to 5 µg / ml. This group of substances is highly evaluated for its effect on epimastigotic forms of Trypanosoma cruzi. For some substances, we found a 100% lethal effect at an in vitro concentration of 0.8 <µg / ml. The active compounds according to the invention can be formulated into solutions, emulsions, suspensions, powders, pastes and ointments. The active compounds can be used in the form of a concentrate, solution, powder, paste and ointment. The content of active ingredient in the dosage form used may vary depending on the intended use. In general, the preparations may contain from 0.1 to 5% by weight, most preferably from 0.5 to 2% by weight of active ingredient.

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Synthesized compounds of the invention

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Table 2

Antibacterial and antiprotozoal activity of the synthesized compounds of the invention

Minimum inhibitory concentration (Og / ml)

Number Staiphylo- ooccu® aureus Bacillus subtilis Esdheri- chia coli Pseutdo- monash · aeruginosa and BCG ^and Mycobac- Tritricho- Trypa- inosoma cruzi Terium foriťuitum ixnonas řoetus' I 200 200 200 200 50 / 12.5 200/50 ' 12.5 50 II 200 200 200 200 200/50 800/20 50 200 III 3.1 3.1 3.1 12.5 12.5 / 3.1 50 / 12.5 3.1 0.8 IV 50 50 - 50 200 200/50 800/200 50 50 IN 200 200 200 200 200/50 800/200 200 200 VI 3.1 3.1 3.1 12.5 3.1 / 3.1 12.5 / 3.1 0.8 98 VII 3.1 3.1 3.1 12.5 12.5 / 3.1 50 / 12.5 3.1 3.1 VIII 50 50 . 50 50 50 / 12.5 200/50 12.5 3.1 IX 200 200 200 200 200/50 800/200 200 200 X 200 200 200 200 200/50 800/200 200 200 XI 200 200 200 200 200/50 800/200 200 - 200 XII 200 200 200 200 800/200 200 200 XIII 200 200 200 200 800/200. 200, · 200 XIV 200 200 200 200 800/200 - 200 200 XV 12.5 12.5 12.5 50 12.5 / 3.1 12.5 12.5 XVI 12.5 12.5 50 50 12.5 / 3.1 12.5 3.1 XVII 12.5 12.5 50 50 ' 12.5 / 3.1 12.5 3.1 XVIII 12.5 12.5 12.5 50 50 / 12.5 200/50 12.5 3,1- XIX 50 12.5 50 200 50 / 12.5 200/50 12.5 12.5 XX 12.5 12.5 12.5 50 12.5 / 31 200/50 12.5 3.1

^a = bactericidal / bacterlostatic conc.

\ Table 5 '

Antifungal activity of the synthesized compounds of the invention fungicidal / fungistitic conc. Ug / ml

Number Mlcrosporum ¹ Trlchophyton Epidermophyton Candida pseudogypseum rubrum floccosum (tropicaliis

I 50/5 50/5 50/5 50/5 II 500/50 500/50 500/50 500/50 III 50/5 50/5 50/5 50/5 IV 50 /> 5 50 /> 5 50 /> 5 50 /> 5 IN > 500/500, > 500/500 500 /> 50 500 /> 50 VI 50/5 50/5 5 / 0.5 5 / 0.5 VII 50/5 5 / 0.5 50/5 50/5 VIII 500/50 50 /> 5 50/5 500/50 IX 500/50 50 /> 5 500/50 500/50 X 500/50 50 /> 5 500/50 500/50 XI 500/50 50/5 500/50 500/50 XII 500 /> 50 500 /> 50 500 /> 50 500 /> 50 XIII 500/50 500/50 500/50 500 /> 50 XIV 500 /> 50 500 /> 50 500 /> 50 500 /> 50 XV 500/50 50/5 50/5 50/5 XVI > 500/500 > 500/500 > 500/500 > 500/500. XVII 500/50 500 /> 5 500/5 50/5 XVIII 50/5 50/5 50/5 50/5 XIX 50 /> 5 50 /> 5 50 /> 5 50 /> 5 XX 50 /> 5 50 /> 5 . 5Q /> 5 50 /> 5

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Claims (23)

SUBJECT We claim: A compound of formula I wherein R is chloromethyl, isopropyl, propargyl, 3-chloro-2-hydroxypropyl, allyl, isobutyl, 2-ethylhexyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, 2, 4-dinitrohenzyl, 1-naphthylmethyl, 2-benzotiazolylsulfonylmetyl, 2- (4-Chlorophenyl-phenylsulfonyl) ethyl, ethoxycarbonylmethyl, 2-chlóretoxykarbonylmetyl, allyloxycarbonylmethyl, sek.butoxykarbonylmetyl and furfuryloxykarbonylmetylskdpinu and ^R1 is hydrogen or nitro. 2. 2-Chloromethylsulfonylbenzothiazole. 3. 2-Isopropylsulfonylbenzothiazole. 4. 2-Isopropylsulfonyl-6-nitrobenisothiazole. 5. 2-Propargylsulfonylbenzothiazole. 6. 2- (2-Hydroxy-3-chloropropylsulfonyl) benzothiazole. 7. 2-AllylBulfonyl-6-nitrobenzothiazole. 8. 2-Isoibutylsulfonyl-6-nitrobenzothiazole. 9. 2- (2-Ethylhexylsulfonyl) -6-nitrobenzothiazole. 10. 2- (4-Chlorobenzylsulfonyl) benzothiazole. 11. 2- (3,4-Dichlorobenzylsulfonyl) henzothiazole. 12. 2- (2,4-Dinitrobenzylsulfonyl) benzothiazole. 13. 2- (1-Naphthylmethylsulfonyl) benzothiazole. 14. 2,2‘-Methylenedisulfonyldibenzothiazole. 15. 2-2- (4-Chlorophenylsulfionyl) ethylsulfonylbenzothiazole. 16. (6-Nitro-2-benzothiazolylsulfonyl) acetic acid ethyl ester. 17. (2-Benzothiazolylsulfonyl) acetic acid 2-chloroethyl ester, 18. 2- (Chloroethyl (6-nitro-2-benzothiazolylsulfonyl) acetic acid tester). (6-Nitro-2-benzothiazolylsulfonyl) acetic acid allyl ester. 20. · (6-Nitro-2-benzothiazolylsulfonyl) acetic acid, sec-butyl ester. 21. (6-Nitro-2-benzothiazolyl-sulfonyl) -acetic acid furfury j. 22. A process for the preparation of 2-R-sulfonylbenzothiazoles of the formula I according to claim 1, wherein R is chloromethyl, isopropyl, propargyl, 2-hydroxy-3-chloropropyl and 2-chloroethoxycarbonylmethyl, characterized in that equimolar amounts of 2- R-thiobenzothiazole, wherein R is as defined herein, potassium permanganate in acetone, acetic acid and water at 50-55 ° C for 4 hours, the product is isolated after removal of the manganese dioxide and subsequently purified. 2'3. A process for the preparation of the ZRG-R 1 -sulfonylbenzotlazoles of formula I according to item 1, wherein R is iso-propyl, allyl, isobutyl, 2-ethylhexyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, 2,4-dinitrobemzyl, 1-naphthylmethyl, 2'- metylénsulf onylbenzotiazol, 2- (4-Chlorophenyl-phenylsulfonyl) obese, ethoxycarbonylmethyl, 2-phlóretoxykarbonylmetyl, allyloxycarbonylmethyl, sek.butoxykarbonylmetyl, furfury.loxykarbonylmetyl and R ¹ is hydrogen or nitro, characterized in that by contacting equimolar amounts of 2-R 6-R ¹ -thiohenzothiazole, wherein R and R ¹ are as defined herein and 6 molar amounts of 28% hydrogen peroxide in 98 and 99% acetic acid at 55 to 60 ° C for 4 to 5 hours, wherein the product is isolated by pouring onto ice and subsequently purified.