CS261699B1 - 6-Amino-2-n-pentylthiobenzothiazole - Google Patents

Abstract

The subject of the solution is the hitherto unknown 6-amino-2-n-pentylthiobenzothiazole of the formula C-S N Ch?ch? which is prepared by alkylating the potassium salt of 6-amino-2-mercaptobenzothiazole with n-pentyl iodide in a mixture of dimethylformamide or dimethyl sulfoxide with water. The compound is antifungally effective against yeasts, including pathogenic ones, and inhibits the transformation of the yeast-like form of pathogenic dimorphic yeasts into the mycelial form. The compound can be used as an effective component of anti-yeast preparations (antifungals) or as an intermediate for further syntheses.

Description

The subject of the solution is the previously unknown 6-amino-2-n-pentylthiobenzothiazole of the formula

C-S

Ch?ch?

which is prepared by alkylation of the potassium salt of 6-amino-2-mercaptobenzothiazole with n-pentyl iodide in a mixture of dimethylformamide or dimethyl sulfoxide with water. The compound is antifungally active against yeasts, including pathogenic ones, and inhibits the transformation of the yeast-like form of pathogenic dimorphic yeasts into the mycelial form. The compound can be used as an active ingredient in anti-yeast preparations (antifungals) or as an intermediate for further syntheses.

2S1

The subject of the invention is 6-amino-2-n-pentylthiobenzothiazole. 2-alkylthio-6-aminobenzothiazoles have shown good antimycobacterial activity, especially against atypical strains of tuberculous mycobacteria [Sidóová, E., Odletová Z., Volná F. and Blockinger G., Chem.

Zvesti 33, 830 (1979), Sidóová E. and Odlerová Ž., Czechoslovak AO 189 212 (1978) J, however, due to difficult isolation, not all derivatives were isolated in the pure state.

It has now been discovered that a previously unknown compound of the formula

^CH Z ^Ch £ ^CH 2 ^Ch 3 is anti-yeast effective against Candida albicans, Saccharomyces cerevisiae, as well as against some pathogenic yeasts.

At the same time, a method of preparing the above-mentioned compound based on 6-amino-2-benzothiazolinethione (also known as 6-amino-2-mercaptobenzothiazole) was discovered by alkylating the potassium salt ^of 6-amino-2-mercaptobenzothiazole with n-pentyl iodide in a mixture of dimethylformamide with water or dimethylsulfoxide with water.

The following examples illustrate, but do not limit, the preparation and properties of the compounds of the invention.

Example 1

Preparation of 6-amino-2-n-pentylthiohenzothiazole

6-Amino-2-benzothiazolinethione (27.3 g, 0.15 mol) was dissolved in a solution of potassium hydroxide (9.9 g, 0.15 mol) in water (50 cm ³ ). Dimethylformamide (125 cm ³ ) was added to the reaction mixture with vigorous stirring and, as soon as a homogeneous solution was formed, n-pentyl iodide (29.7 g, 0.15 mol) was added to the reaction mixture in one portion. Vigorous stirring was continued for 30 minutes, then the mixture was poured onto ice (1,500 g) and allowed to stand. After filtration, the crude product was filtered off with suction and, while still wet, was triturated with several portions of petroleum ether (total 300 cm ³ ), the aqueous petroleum ether being decanted each time. The solid residue was dissolved in boiling acetone, water was added to the solution until the first slight turbidity and the mixture was decolorized with activated carbon. The filtrate, after cooling, was poured back onto ice (1,500 grams).

The yield of the product with a melting point of 33.5 to 36.5 ^° C was 30 g (79.4%).

The sample for analysis was purified by dissolving the substance in boiling ethanol, adding water to the solution until it became cloudy, and decolorizing the mixture with activated carbon. The filtrate, after cooling, was poured onto ice, with 50 g of ice per 1 g of sample being used. Pure 6-amino-2-n-pentylthiobenzothiazole with a melting point of 35 to 37 °C was obtained.

For:

C12H16N2S2 (252.40) calculated:

57.10% C, 6.39% H, 11.10% N,

25.41% with, found:

56.86% C, 6.31% H, 11.87% N,

25.10% S.

Example 2

Antifungal activity of the compound according to the invention (10 ^H mol.dm ^-3 ) compared to the activity of 2-mercaptobenzothiazole (2-MBT)

Substance ED50 (10” ^B mol. dm ^-3 ) C. albicans PnlO S. cerevisiae V3 Day 3 Day 4 Compound according to the invention 32 19 2-MBT 231 431

ED50 = concentration of a substance that inhibits yeast reproduction by 11% compared to the control.

To determine the anti-yeast activity, a liquid synthetic media with vitamins (5 cm ³ in test tubes) was used, static cultivation at 28 °C. Substances dissolved in dimethyl sulfoxide were dosed into the media, then the inoculum. Yeast growth was monitored turbidimetrically, and ED50 values were obtained from the constructed growth curves by mathematical-graphical calculation.

Example 3

The efficacy of the compound of the invention compared to the efficacy of 2-mercaptobenzothiazole (2-MBT) on the growth of pathogenic yeasts

Yeast EDso (10~ ^e mol. dm” ⁵ )

Deri subtract. Compound. according to the 2-MBT of the invention

a. CCY 4 153 243 a. 1164/84 4 183 352 a. 1158/86 3 23 220 No. 1292/86 5 >1,000 90 g. 1076/86 4 29 125 c. 1288/86 4 >1,000 72 p. 1264/86 4 157 402 year 1069/86 1 35 380 2 94 > 1,000 3 568 >1,000 4 556 >1,000 5 564 >1,000 year 1322/86 4 140 54

EDso — the concentration of a substance that inhibits yeast reproduction by exactly 50%, compared to the control,

C. a. = Candida albicans,

C. c. = Candida cilierrii,

Mr. C. = Candida guillermondii,

C. k. = Candida krusei,

C. p. = Candida parapsilosis,

C. r. = Candida robusta,

R. r. = Rhodotorula rubra.

Antifungal activity was determined in the same manner as described in Example 2.

Example 4

Efficacy of the compound according to the invention and 2-mercaptobenzothiazole (2-MBT) as inhibitors of the transformation of the yeast-like form of Candida albicans into the mycelial form

To determine the inhibitory efficacy on the transformation of the yeast form of Candida albicans into the mycelial form, a liquid medium with N-acetylglucosamine as an inducer of mycelial growth was used. The substances were dosed into the medium dissolved in dimethyl sulfoxide. Inoculation was performed exclusively with the yeast form, prepared by a special procedure. Cultivation was static at 37 °C for 48 hours. The growth of the mycelial and yeast forms was observed microscopically.

Yeast ID95( _Y _ _M) (mol. dm” ³ )

Compound according to the 2-MBT invention

C. a. Mon 10 4.10” ⁵ 1.10” ³

C. a. 1158/86 2.10” ⁴ >1.10” ³

C. a. — Candida albicans,

ID95(y_ _M ) = concentration of substance which reduces the amount of yeast mycelial form by 95 or 95%, relative to the control.

It is significant that the compound according to the invention has a new, previously unknown structure and its anti-yeast activity exceeds 2-mercaptobenzothiazole, the active ingredient of the established preparation Dermacld.

Furthermore, it is significant that the compound according to the invention has shown good activity against some pathogenic yeasts. Particularly significant is the fact that the activity (ED50) of the compound according to the invention against the pathogenic yeast Candida robusta 1069/86, isolated from feces, is stable after 3 days and does not change further with time. Furthermore, it is significant that the compound according to the invention inhibits the transformation of the yeast-like form of pathogenic dimorphic yeasts into the mycelial form, which is an important property of known antifungal agents.

The compound according to the invention can be used as an active ingredient in anti-yeast preparations (antifungals), either alone or in admixture with other substances, or as an intermediate for further syntheses.

Claims (2)

SUBJECT A 6-amino-2-n-pentylthiobenzothiazole of the formula OF THE INVENTION ^ C-S-CH ^ · CH ^ CH- ch $ 2. A process for the preparation of a compound according to claim 1, which comprises reacting the potassium salt of 6-amino-2-mercaptobenzothiazole with n-pentyl iodide in dimethylformamide-water or dimethylsulfoxide-water in a ratio of 2: 5 to 2: 3 at room temperature. for 10 to 60 minutes. Severogratia, n. p. Race 7, Most Price 2,40 KCs