CS257398B1 - 2-alkylthio-8 íormamidobenzotiazoly - Google Patents

Abstract

The solution concerns previously unknown 2- -alkylthio-6-formamidobenzothiazoles of the formula and a method for their preparation. The reaction is carried out by formylation of 2- alkylthio-6-aminobenzothiazoles with 85% formic acid at boiling. The new compounds are antimycobacterially active against tuberculous mycobacteria, especially against atypical strains of M. avium, M. fortuitum and M. kansasii; they can be used as an active ingredient in antimycobacterial preparations, or as an intermediate for further syntheses.

Description

257398 3

The present invention provides 2-alkylthio-6-formamide-benzothiazoles. 6-Acetylamino-2-alkylthiobenzothiazoles effective against typical atypical tuberculous mycobacteria [Sidó E. E. and Odler J., CS. AO 216 450 (1982)].

It has now been found that the hitherto unknown 2-alkylthio-6-formamidobenzothiazoles of the general formula wherein R is straight or branched alkyl, alkenyl, or cycloalkyl of 2 to 9 carbon atoms are antimycobacterial active against typical and atypical tuberculosis. mycobacteria. At the same time, a method for preparing said compounds based on 2-alkylthio-6-aminobenzothiazoles and resp. the hydrochlorides thereof, characterized in that the 2-alkylthio-6-aminobenzothiazole and / or the hydrochloride thereof are characterized by its hydrochloride reacts with 85% formic acid in a molar ratio of 1: 4 to 1: 12 to boil for 2 to 30 minutes. The following examples illustrate, but do not limit, the preparation and properties of the compounds of the invention. Example 1 Preparation of 2-ethylthio-6-formamidobenzothiazole 6-Amino-2-ethylthiobenzothiazole (6.3 g, 0.03 mol) was refluxed with 85% formic acid (7.5 cm 3, 9 g, 0.166 mol) for 10 minutes. After cooling to room temperature, the reaction mixture was poured onto ice (100 g) and made up to 200 cm 3 with water. The solid fraction of the liquid was separated by decantation and was recrystallized from ethanol-water 1: 1 using charcoal. Pure 2-ethylthio-6-formamidobenzothiazole was obtained with mp 89-91 ° C at 4.95 g (69.2%). 0 / o). For C10H10OS2 (238.33) calculated: 50.40% C, 4.23% H, 11.75% N, 26.91% S, found 50.70%. Example 2 Preparation of 6-formamido-2-n-propylthiobenzothiazole 6-Amino-2-n-propylthiobenzothiazole (6.75 g, 0.03 mol) was refluxed with 85% acid formate (7.5 cm 3, 9 g, 0.166 mol) over 10 minutes. After cooling to room temperature, the reaction mixture was poured onto ice (100 g) and made up to 200 cm 3 with water. The crude product was precipitated from the reaction mixture at a temperature of 7.3 g (96.4%), 60-67 ° C, recrystallized from a 1: 3 mixture of benzene-cyclohexane and charcoal. -formamido-2-n-propylthiobenzothiazole with mp 64-67 ° C. For C 11 H 12 N 2 OS 2 (252.36) calculated: 52.35% C, 4.79% H, 11.10% N, 25.41% S, found 52.31 ° C, 4.70% H, 11.16% N, 25.70% S. EXAMPLE 3 Preparation of 6-formamido-2-isopropylthiobenzo-thiazole Preparation according to Example 2 using 6-amino-2-isopropylthiobenzothiazole (6.75 g, 0.03 mol). The yield of the crude product, m.p. 92-95 ° C, was 97.1%. The material was recrystallized from ethanol-water 1: 1 using activated carbon. N-pure 6-formamido-2-isopropylthiobenzothiazole was obtained with mp 93-95 ° C. 41% S, found * 52.38% C, 4.76% II, 10.96% N, 25.16% S. EXAMPLE 4 Preparation of 2-allythio-6-formamidobenzothiazole The preparation was carried out according to Example 2 using 2-allylthio-6-formamidobenzothiazole (6.7 g, 0.03 mol). The yield of the crude product, m.p. 75-81 ° C, was 96.0. The material was recrystallized from ethanol-water 2: 1 using charcoal. Pure 2-allylthio-6-formamidobenzothiazole was obtained with m.p. 78.5-81.0 ° C in an amount of 5.95 g (79.2%). 257398 1

H, 4.04; N, 11.19; S, 25.61. Found: C, 52.58; H, 3.89; % N, 25.35% S. EXAMPLE 5 Preparation of 2-n-butylthio-6-formamidobenzothiazole The preparation was carried out according to Example 2 using 6-amino-2-n-butylthiobenzothiazole (7.17 g, 0.03 mole). The yield of crude product, m.p. 56-59 ° C, was 7.3 g (91.3%). The material was recrystallized from ethanol-water to give a 2: 1 mixture using active bleach. Pure 2-n-butyl-thio-6-formamidobenzothiazole of m.p. 58-59 degrees Celsius was obtained.

For C12H14N2OS2 (266.39) calculated: 54.11% C, 5.30% H, 10.52% N, 24.07% Szistene: 54.11 ° / o C, 5.31% H, 10.36 % N, 23.89% Example 6 Preparation of 6-formamido-2-isobutylthiobenzothiazole The preparation was carried out according to Example 2 using 6-amino-2-isobutylthiobenzothiazole (7.15 g, 0.03 mol) ). The yield of the crude product, m.p. 81-83 ° C, was 7.8 g (97.5%). The material was recrystallized from ethanol-water 2: 1 using charcoal. Neat 6-formamido-2-isobutylthiobenzothiazole of tt 82-84 ° C was obtained. For C 12 H 4 N 2 OS 2 (266.39) calculated: 54.11% C 5.30% N, 10.52% N, 24.07% S, found: 54.01% C, 5.25% H, 10.53% N, 24.24% S. EXAMPLE 7 Preparation of 6-formamido-2-n-pentylthiobenzothiazole du 2 using 6-amino-2-n-pentylthiobenzothiazole (7.5 g, 0.03 mol). The yield of the crude product, m.p. 64-68 ° C, was 8.0 grams (95.2%). The material was recrystallized from ethanol-water 2: 1 using charcoal. Pure 6-formamido-2-n-pentylthiobenzothiazole of m.p. 66.5-68.0 degrees Celsius was obtained.

For C13H16N2OS2 (280.41) calculated: 55.68% C, 5.75% H, 9.99% N, 22.87% S, found: 55.38% C, 5.71% H, 9.76% N Example 8 Preparation of 6-formamido-2-isopentylthiobenzothiazole

6-Amino-2-isopentylthiobenzothiazole hydrochloride (2.9 g, 0.01 mol) was refluxed with 85% formic acid (5 cm 3, 3 g, 0.111 mol) for 20 minutes. After cooling to room temperature, the reaction mixture was quenched to ice (100 g) and made up to 250 cm 3 with water. The soaked greasy product solidified on standing for 48 hours at 5 ° C. A crude product having a melting point of 63-67 ° C of 2.7 g (96.4%) was obtained. The material was purified by dissolution in 25 cm 3 of ethyl acetate. Cyclohexane (75 cm 3) was added to the solution and treated with charcoal. After the addition of pentroleter to the first turbidity, the solution was crystallized at 5 ° C. The pure 6-formamido-2-isopentylthiobenzothiazole was obtained. mp 69-70.5 ° C.

For C13H16N2OS2 (280.41) calculated: 55.68% C, 5.75% H, 9.99% N, 22.87% S, found: C, 55.85; H, 5.87; EXAMPLE 9 Preparation of 2-cyclopentylthio-6-formamidobenzothiazole The preparation was carried out according to Example 2 using 6-amino-2-cyclopentylthio-benzothiazole (7.5 g, 0.03 mol). ). Yield of the urea product: mp 117.5-120.5 ° C was 7.9 g (94.9%). The material was recrystallized from ethanol-water 2: 1 using charcoal. Pure 2-cyclopentylthio-6-formamidobenzothiazole of m.p. 119.5-121.5 ° C was obtained.

For C13H14N2OS2 (278.40) calculated: 56.09% C, 5.07% N, 10.06% S, 23.03% S, found: 56.39% C, 5.07%. Example 10 Preparation of 6-formamido-2-n-hexylthiobenzothiazole The preparation was carried out according to Example 2 using 6-amino-2-n-hexylthiobenzothiazole ( 8.0 g, 0.03 mole). The yield of crude product was m.p. 9-71 ° C, was 8.3 g (94.3%). The material was recrystallized from ethanol-water 2: 1 using charcoal. Pure 6-formamido-2-n-hexylthiobenzothiazole of m.p. 70-71 ° C was obtained in 6.7 g (76.1%).

For C14H18N2OS2 (294.44) calculated: 57.11% C, 6.16% H, 9.51% N, 21.78% S, found ηθ * 57.11 ° / o C, 6.16% H N, 21.86%. EXAMPLE 11 Preparation of 6-formamido-2-n-heptylthiobenzothiazole The preparation was carried out according to Example 2 using 6-amino-2-n-heptylthiobenzothiazole. (8.4 g, 0.03 mol). The yield of the crude product, m.p. 66-70 ° C, was 9.0 grams (97.3%). The material was recrystallized from ethanol-water 3: 1 using charcoal. Pure 6-formamido-2-n-heptylthiobenzothiazole of m.p. 68-70 degrees Celsius was obtained.

% C, 58.41;% H, 6.54; N, 9.08; S, 20.79. Found: C, 58.10; H, 6.56; 8.81% N, 20.74% S. EXAMPLE 12 Preparation of 6-Formamido-2-n-octyl-thiobenzothiazole-Preparation was carried out according to Example 2 using 6-amino-2-n-octyl-thiobenzothiazole (8). , 85 g, 0.03 mole). The yield of the crude product, m.p. 68.0-69.5 ° C, was 9.6 g (99.2%). Recrystallized from ethanol-water 5: 1 using charcoal. Neat 6-formamido-2-n-octylthiobenzothiazole of m.p. 68.5-70.5 degrees Celsius was obtained.

For C16H22N2OS2 (322.49) calculated: 59.59% C, 6.88% H, 8.69% S, 19.88% S, found: 59.35% C, 7.01% H, 8.46 % N, 19.72%. EXAMPLE 13 Preparation of 6-formamido-2-n-nonylthiobenzothiazole The preparation was carried out according to Example 2 using 6-amino-2-n-nonylthiobenzothiazole (9.25 g, 0.03 mole). The yield of the crude product, m.p. 72-74 ° C, was 9.45 g (93.6%). Recrystallized from ethanol-water 5: 1 using charcoal. It obtained pure 6-formamido-2 n-nonylthiobenzothiazole of m.p. 72.5-74.5 degrees Celsius.

For C17H24N3OS2 (336.52) calculated: 60.67% C, 7.19% H, 8.32% N, 19.06% S, found 60.53 ° / o C, 7.43% H, 8 N, 18.88% S. Example 14

Antimycobacterial Activity of Compounds of the Invention Compared to Effect of Known Antituberculotics

The antimycobacterial activity against tuberculous mycobacteria was monitored by flowing under the dilution test of dimethylsulphide. As the solvent, dimethylsulfoxide was used. The final concentration of the substances at 0.5, 1, 5, 10, 25, 50 and 100, wg. cm'3.

Claims (2)

SUBJECT We claim: 1. 2-Alkylthio-6-formamidobenzothiazoles of general formula -alkylthio-6-aminobenzothiazole of general formula ncq-nb H.N where R is straight or branched / alkyl, alkenyl, or cycloalkyl of 2 to 9 carbon atoms. 2. A process for the preparation of the compounds according to claim 1, which comprises reacting 2 or its hydrochloride, where R is as in 1, with 85% formic acid in a molar ratio of 1: 4 to 1: 12 at boiling for 2 to 30 minutes.