CS264967B1

CS264967B1 - 3-/2-alkylthio-6-benzolylaminomethyl/-6-brom-2-benzothialinones and process for preparing them

Info

Publication number: CS264967B1
Application number: CS875107A
Authority: CS
Inventors: Elena Rndr Csc Holbova; Eva Ing Csc Sidoova; Maria Doc Rndr Csc Zemanova; Irena Ing Csc Drobnicova
Original assignee: Holbova Elena; Sidoova Eva; Zemanova Maria; Irena Ing Csc Drobnicova
Priority date: 1987-07-06
Filing date: 1987-07-06
Publication date: 1989-09-12
Also published as: CS510787A1

Abstract

Boli připravené doteraz neznáme 3- -/2-alkyltio-6-benzotiazolylaminometyl/- -6-bróm-2-benzotiazolinony vzorca I, kde R znamená alkyl s 1 až 9 atómami uhlíka, cyklopentyl, alyl alebo benzyl. Syntéza uvedených zlúčenín sa uskutočňuje reakciou 6-bróm-3-hydroxymetyl-2-benzotiazolinónu s 2-alkyltio-6-aminobenzotiazolmi v metanole za varu. Zlúčeniny sú antialgálne, antifugálne a antiprotozoálne účinné.Until now unknown 3- - (2-alkylthio-6-benzothiazolylaminomethyl) - - 6-bromo-2-benzothiazolinones of formula I where R is alkyl of 1 to 9 carbon atoms; cyclopentyl, allyl or benzyl. Synthesis of said compounds is carried out by reaction 6-bromo-3-hydroxymethyl-2-benzothiazolinone with 2-alkylthio-6-aminobenzothiazoles in methanol for boiling. The compounds are antialgeal, antifungal and antiprotozoally effective.

Description

264967 2

The present invention relates to 3- (2-alkylthio-6-benzothiazolylaminomethyl) -6-bromo-2-benzothiazolinones. So far, 3- (2-alkylthio-6-benzothiazolylaminomethyl) -2-benzothiazolinothiones have been known as antimyobacterial [Holb, E. , Sidóová, E. and Odlerová, Ž., Chem · Zvěsti 30, 709 (1976)] and anti-viral active compounds [Rada, B., Holbová, E., Mikulášek, S., Sidóová, E. and Gvozdjaková, A., Acta Virol, 23, 203 (1979)].

Now, they have found that hitherto unknown compounds of the formula

wherein R is alkyl of 1 to 9 carbon atoms, cyclopentyl, allyl or benzyl, are antialgeal, antifungal and antiprotozoal. Simultaneously, a process for the preparation of said compounds was found by reacting 6-bromo-3-hydroxymethyl-2-benzothiazolinone of formula II.

and 2-alkylthio-6-aminobenzothiazoles of formula III H2N- //

C-S-R (III) 1 wherein R is as defined above for formula I [sidóová, E., Odlerová, Ž., Volná, F. and Blockínger, G., Chem. News 33, 830 (1979)], in methanol for 1 to 20 minutes.

The following examples further illustrate the compounds of the invention. but not limiting the preparation and properties of Example 1 Preparation of 6-bromo-3- (2-methylthio-6-benzothiazolylaminomethyl) -2-benzothiazolinone 6-amino-2-methylthiobenzothiazole (1.96 g, 0.01 mol) was mixed with 6 bromo-3-hydroxymethyl-2-benzothiazolinone (2.60 g, 0.01 mol) and methanol (30 cm 3) with stirring and heating on a water bath until a solution is formed. Thereafter, the heating is stopped and the solution is allowed to cool to ambient temperature with stirring while the reaction product crystallizes as a raw consistency. 3

During suction on a Buchner funnel, the product was washed (dropwise) with ethanol (15 cm). The crude product was obtained in 3.5 g (80%). The reaction product is recrystallized using 2.5 g of 150 cm 3 of acetone using charcoal and precipitating with water until the first constant cloudiness. The crystallized product is sucked off on a Buchner funnel, where it is dropped with ethanol. Pure 6-bromo-3- (2-methylthio-6-benzothiazolylaminomethyl) -2-benzothiazolinone was obtained with mp 174-176 ° C. 3 264967 N 9.58 S 21.94 Br 18.22 9.62 22.00 18.15

For C16H12N3S3OBr (438.38) calculated% C 43.83 H 2.75%: 43.78 2.73 Example 2 Preparation of 6-bromo-3- (2-ethylthio-6-benzothiazolylaminomethyl) -2-benzothiazolinone 6- amino-2-ethylthiobenzothiazole (2.10 g, 0.01 mol) was mixed with 6-bromo-3-hydroxymethyl-2-3-benzothiazoline (2.60 g, 0.01 mol) and methanol (55 cm 2) ) with stirring and heating on a water bath until a solution is formed. The heating is then stopped and the solution is left to stand the next day. The crystallized white raw consistency is aspirated on a Buchner funnel, 3

where it is washed with methanol (20 cm). 3.5 g (77.7%) of theory are obtained. The material is recrystallized as described in Example 1. Melting point: 165-167 ° C

For C11H14N3S3OBr (452.41) calculated%: C 45.12 H 3.11 N 9.28 S 21.26 Br 17.66, found%: 44.99 2.95 9.32 20.80 17.68 Example 3 Preparation of 6-bromo-3- (2-propylthio-6-benzothiazolylaminomethyl) -2-benzothiazolinone 6-Amino-2-propylthiobenzothiazole (1.30 g, 0.005 mol) is mixed with 6-bromo-3-hydroxymethyl-2- benzothiazolinone (1.30 g, 0.005 mol) and methanol (20 cn) with stirring and heating in a water bath at the boiling point of methanol for 2 minutes. After cooling to ambient temperature, the 3 product of the reaction, which was washed with methanol (10 cm), crystallized after drying and recrystallized as described in Example 1. The crude product yield was 3.0 g (66%). 169-172 ° C.

For c 18 H 16 N 3 S 3 ° Br (466.43) calculated%: C 46.34 H 3.45 N 9.00 S 20.62 Br 17.13 found%: 46.23 3.43 8.90 20.19 17.22 Example 4 Preparation of 6-bromo-3- (2-isopropylthio-6-benzothiazolylaminomethyl) -2-benzothiazolinone 6-amino-2-isopropylthiobenzothiazole (2.20 g, 0.01 mol) was mixed with 6-bromo-3-hydroxymethyl- -2-benzothiazolinone (2.60 g, 0.01 mol) at boiling methanol for 2 minutes. Then the mixture was left to stand overnight at room temperature. Aspirate the crystallized product of the reaction and wash the filter with 3 ethanol. The yield of the crude product was 2.29 g, 52%). The product is crystallized from acetone (25 cm) by adding water to the filtrate after boiling with charcoal for the first constant haze, then ethyl acetate is added dropwise until a solution is formed. After addition of 3 cm @ 3 of acetone, the mixture is placed in a refrigerator for 3 days. The product is crystallized and the filter is washed with petroleum ether.

Melting point 168-170 ° C.

For C. "H, N, S, OBr (446.43) 18 16 3 3 calculated%: C 46.34 H 3.45 N 9.00 S 20.62 Br 17.13% detected: 46.77 3 EXAMPLE 5 Preparation of 3- (2-aliltio-6-benzothiazolylaminomethyl) -6-bromo-2-benzothiazolinone 6-amino-2-allylthiobenzothiazole (1.10 g, 0.005 mol) ) was mixed with 6-bromo-3-hydroxymethyl-2-benzothiazolinone (1.30 g, 0.005 mol) and methanol (20 cnr) with stirring and heating on a water bath to give a solution. After one minute, the reaction product crystallized from the solution, which was filtered on the filter after washing the reaction mixture and washed dropwise with methanol. The yield of the crude product was 4.0 g (87%). Crystallization as in Example 1 except for an amount of acetone that is 2.0 g of 125 cm 3.

Melting point: 180-183 ° C

For C18H14N3S3OBr (464.42) calculated: C 46.54 H 3.03 N 9.04 S 20.71 Br 17.20 Found%: 46.53 2.95 8.98 20.52 16.80 Example 6 Preparation 6-bromo-3- (2-n-butylthio-6-benzothiazolylaminomethyl) -2-benzothiazolinone 6-amino-2-n-butylthiobenzothiazole (1.2 g, 0.005 mol) was mixed with 6-bromo-3-hydroxymethyl- 2-3-benzothiazolinone (1.3 g, 0.005 mol) and methanol (20 cm) with stirring and heating on a water bath to give a solution. After one minute, the reaction product crystallized from the solution, which was filtered off with suction on a Buchner funnel after cooling to room temperature, and the filter was washed dropwise with methanol (10 cm 3). After drying, the crude product weighed 1.8 g (77%).

the product was recrystallized from acetone (130 cm) from which it was hot precipitated with cold water. Melting point: 167-169 ° C

For C18H18N3S3OBr (480.46) calculated%: C 47.49 H 3.77 N 8.74 S 20.02 Br 16.63Heared%: 47.67 3.74 8.75 20.10 16.70 Example 7 Preparation 6-bromo-3- (2-n-pentylthio-6-benzothiazolylaminomethyl) -2-benzothiazolinone 6-amino-2-n-pentylthiobenzothiazole (1.25 g, 0.005 mol) is mixed with 6-bromo-3-hydroxymethyl- With 3 -2-benzothiazolinone (1.3 g, 0.005 mol) and methanol (20 cm) with stirring and heating in a water bath until a solution is formed. After 10 minutes, stop the heating and let the mixture stand for the next day. Wash the crystalline product with methanol (10 cm). The crude product weighed 3 2.0 g (81%). Recrystallized from acetone (70 cm).

Melting point: 145-148 ° C

For C20H20N3S3OBr (494.49) calculated%: C 48.57 H 4.07 N 8.49 S 19.45 Br 16.16Heared%: 48.71 3.99 8.48 19.03 15.62 Example 8 Preparation 6-bromo-3- (2-cyclopentylthio-6-benzothiazolylaminomethyl) -2-benzothiazolinone 6-amino-2-cyclopentylthiobenzothiazole (2.5 g, 0.01 mol) is mixed with 6-bromo-3-hydroxy-3 methyl -2-benzothiazolinone (2.6 g, 0.01 mol) and methanol (25 cm) with stirring and heating of 5 264967 in a water bath until a solution is formed. The heating is then stopped and the mixture is allowed to stand for 24 hours at room temperature. Then petroleum ether (20 cm), acetone (10 cm) and water 3 (5 cm) are poured into the mixture. The mixture was stored in a refrigerator at -22 ° C for 24 hours. The crystallized white sheet is filtered off with suction and washed on the filter with petroleum ether (10 cm 3). Yield 2.3 g (48%).

Melting point: 149-152 ° C

For C2QH18N3S3OBr (492.48) calculated%: C 48.77 H 3.68 N 8.53 S 19.52 Br 16.22Heared%: 49.37 3.67 8.53 19.50 15.98

Example9. Preparation of 6-bromo-3- (2-n-hexylthio-6-benzothiazolylaminomethyl) -2-benzothiazoline 6-amino-2-n-ethylthiobenzothiazole (2.6 g, 0.01 mol) was mixed with 6-bromo-2 -hydroxymethyl-2-3-benzothiazolinone (2.6 g, 0.01 mol) and methanol (30 cm) with stirring and heating on a water bath until a solution is formed. The heating is then stopped and the mixture is left to stand the next day. The crystallized material is filtered off with suction and washed on the filter with methanol (10 cm). The yield of the crude product was 4.1 g (82%). Melting point: 135-137 ° C after crystallization and acetone 2: 1.

For C21H22N3S3OBr (508.51) calculated%: C 49.59 H, 4.35 N 8.26 S 18.91 Br 15.71 detected%: 49.70 4.40 8.23 18.74 15.36 Example 10 Preparation of 6-bromo-3- (2-n-heptylthio-6-benzothiazolylaminomethyl) -2-benzothiazolinone 6-amino-2-n-heptylthiobenzothiazole (1.3 g, 0.005 mol) was mixed with 6-bromo-3-hydroxymethyl 22-benzothiazolinone (1.4 g, 0.005 mol) and methanol (20 cm) with stirring and heating with an aqueous bath to form a solution. After 15 minutes of reflux, the heating is stopped and the mixture is left to stand at room temperature for 48 hours. The reaction product is filtered off with suction and washed with methanol on the filter. The yield of the crude product was 2.0 g (80%). It was recrystallized from acetone-water 1: 1. Melting point: 132-135 ° C.

For c22H24N3S3OBr (522.54) calculated%: C 50.56 H 4.62 N 8.04 S 18.41 Br 15.29 detected%: 50.65 4.64 7.92 17.98 15.01 Example 11 Preparation 6-bromo-3- (2-n-octylthio-6-benzothiazolylaminomethyl) -2-benzothiazolinone 6-amino-2-n-octylthiobenzothiazole (1.4 g, 0.005 mol) is mixed with 6-bromo-3-hydroxymethyl- . With 3 -2-benzothiazolone (1.3 g, 0.005 mol) and methanol (20 cm) with stirring and heating with an aqueous bath until a solution is formed. After 18 minutes of methanol reflux, the heating was stopped for 48 hours. During this time, the reaction product crystallized in the form of semolina. The yield of crude product was 1.37 g (52%). After crystallization from acetone (50 cm) and precipitation of the hot solution with cold water, the product was obtained as shiny flakes.

Melting point: 130-132 ° C. 264967 6

For C23H26N3S3OBr (536.56) calculated% C 51.45 H 4.88 found%: 51.04 4.91 N 7.83 S 17.927.74 17.54

Br 14.89. 14.71 Example 12 Preparation of 6-bromo-3- (2-n-nonylthio-6-benzothiazolylaminomethyl) -2-benzothiazolinone 6-amino-2-n-nonylthiobenzothiazole (1.5 g, 0.005 mol) was mixed with 6- bromo-3-hydroxymethyl- < 3 > -2-benzothiazolinone (1.3 g, 0.005 mol) and methanol (20 cm) with stirring and heating with an aqueous bath to form a solution. After 20 minutes of methanol reflux, heating is stopped and the solution is allowed to crystallize at room temperature for 48 hours. The crystallized product is sucked off on a Buchner funnel and washed with methanol (10 cm) dropwise during suction. The crude product was obtained in 1.3 g (50%). The material was recrystallized using acetone

3 'S (75 cm) at reflux, boiling with activated carbon and precipitating with cold water into the first permanent heat. Melting point: 129-131 ° C.

For C24H28N3S3OBr / 550.59) calculated%: C 52.35 H 5.12 N 7.63 S 17.47 Br 14.51prepared%: 52.04 5.15 7.47 17.13 14.73 P r. k 1 ad 13 Preparation of 3- (2-benzylthio-6-benzothiazolylaminomethyl) -6-bromo-2-benzothiazolinone 6-Amino-2-benzylthiobenzothiazole (1.35 g, 0.005 mol) was mixed with 6-bromo-3-hydroxymethyl -2-3-benzothiazolinone (1.3 g, 0.05 mol) and methanol (20 cm) with stirring and heating on a water bath to give a solution. After 20 minutes, the methanol reflux was removed and the solution was allowed to crystallize at room temperature for 48 hours. The crystallized product is sucked on a Buchner funnel and washed with methylene (10 cm) during suction. Obtained the sasur product at 2.0 g (80%). The material was recrystallized from acetone (80 cm < -1 > L and precipitated with water. Melting point: 152-155 [deg.] C.

For c22H16N3S3OBr (514.47) calculated%: C 51.35 H 3.13 N 8.16 S 18.69 Br 15.53 found%: 51.65 3.07 8.15 18.48 14.96 Example 14

Antialgeal and antiprotozoal activity of the compounds of the invention

Chlorella vulgaris Euglena gracilis Example MIC /10"6.mol.dm_3/ MIC /10-6.mol.dm~3/ 10 days 21 days 7 days 10 days 1 <40 200 1,000 1,000 2 <40,200 1 000 1 000 3 <40 <40 1 000 1 000 4 <40 200 1 000 1 000 5 <40 <40 1 000 1 000 6 <40 <40 1 000 1 000 9 <40 <40 200 200 11 1 000> 1 000 1,000 1,000 7 26,467

The sub-example compound ChlorellaMIC / 10'6. vulgarismol.dm-3 / Euglena gracilis MIC /10"6.ιηοΙ.άπΓ3/ 10 days 21 days 7 days 10 days 12>1,000> 1,000 1,000 1,000 13 <40,200 1,000 1,000 2-MBT 200,200 1,000 1,000 MIC = minimal inhibitory concentration, meaning the lowest test concentration that completely inhibits growth.

Test corrections: 1,000; 200 and 40.10 mol.dm 3.

The solvent DMSO (dimethylsulfoxide) used, whose concentration in the cultivation stages did not exceed 1%.

Chlorella3 vulgaris was used to determine the arctal activity of the compounds of the invention and was cultured on Chodata foot (20 cm) in the presence of test substances in culture broth, at 20 ° C, for 21 days under constant illumination. The resulting concentration of the compounds according to the invention and the reference sample of 2-benzothiazolinone (other name 2-mercapto-benzothiazole, 2-MBT) was 1000.10 µmol / m 3 (concentration 1), 200.10-mole-dm-3 (concentration 2) and 40.10 ® mol-dm 3 (concentration 3). At the indicated time, the increase in greenery was evaluated visually. Dimethylsulfoxide was used as solvent. To determine the anti-protozoal efficacy of the compounds of the present invention, Euglena gracilis was used on the liquid hydrolyzate with the added substances, at 20 ° C under continuous illumination for 10 days. Example 15

The anti-yeast activity of the compounds of the invention (10 ® mole.dm 3) compared to 2-MBT activity

A compound of the sub-example

Candida albicans

Saccharomyces cerevisiae

ED 50

ED 100

ED 50

ED 100 1,240,850 370,910 2,850> 1,000,900. > 1 000 3 430> 1 000 870> 1 000 4 500> 1 000 350> 1 000 5 •> 1 000> 1 000> 1 000> 1 000 6 500> 1 000 500> 1 000 7 250> 1 000 18 32 8 910> 1 000 90 320 9 40 470 15 54 10 81> 1 000 18 320 11 52 780 140> 1 000 12 320> 1 000> 1 000> 1 000 13 78 210 100 200 2-MBT 360 1 000 520 > 1 000 ED50, EDjqq = the concentration of the substance that inhibits yeast multiplication to 50% resp. 100% over control; > = even the concentration indicated is not sufficient.

To determine the anti-yeast activity, a liquid synthetic pod with vitamins, static culture, temperature of 28 ° C was used. The substances dissolved in dimethyl sulfoxide were dosed to pfid, then inoculum. Yeast proliferation was monitored turbidimetrically, and EDj-θ and Εϋ ^ θθ values were obtained from the set of 264967 8 growth curves. Tietose in Candida albicans refers to day 6 of culture, Saccharomyces cerevisiae to day 4, when controls reached maximum increase. Example 16

The activity of the compounds of the invention against filamentous microscopic fungi is compared to that of 2-MBT

A compound of the sub-example

MIC / 10 ® mol.dm

Asprgillus Penicillium Rhizopus Alternaria niger cyclopium oryzae alternata 10 11 12 13

2-MBT 1 1 000 1 000 200 200 2 1 000 1 000 1 000 1 000 1 000 1 000 40 2 1 000 1 000 1 000 1 1 000 200 200 200 2 1 000 200 200 200 1 1 000 200 , 200 200 2> 1 000 1 000> 1 000 200 1 1 000 1 000 1 000 200 2> 1 000 1 000> 1 000 200 1 1 000 200 200 200 2> 1 000 1 000> 1 000 200 1 1 000 200 1 000 40 2> 1 000> 1 000> 1 000 200 1 1 000 200 200 200 2> 1 000 1 000>] 000 1 000 1> 1 000 1 000 1 000 200 2> 1 000 1 000> 1 000 200 1 1,000 1,000 1,000 40 2>1,000>1,000> 1,000 200 1> 1,000 200 200 200 2>1,000>1,000> 1,000,000 1>1,000> 1,000 1,000 1,000 1,000 2>1,000>1,000> 1,000 1,000 1>1,000> 1,000 200 200 2>1,000>1,000> 1,000 200 1> 1,000 1,000> 1,000,000 2> 1,000 1,000> 1 000 1,000

Claims

3- (2-alkylthio-6-benzothiaosolylaminomethyl) -6-bromo-2-benzothiazolinones of the general formula I wherein R represents alkyl of 1 to 9 carbon atoms, cyclopentyl, allyl or benzyl.

2. A process for the preparation of the compounds according to claim 1, which comprises reacting 6-bromo-3-hydroxymethyl-2-benzothiazolinone of the formula II.

Br - X = X ^with c = o (II) with 2-alkylthio-6-aminobenzothiazoles of formula III h ₂ n (III) wherein R is as defined in point 1, in methanol, boiling for 1 to 20 minutes.