SK278149B6 - 2-alkylthio-6-(4-benzenesulfonamidosalicylidenamino) benzothiazoles - Google Patents

Abstract

There was prepared the 2-alkylthio-6-(4-benzenesulfoamido- -salicylidenamino) benzothiazoles of general formula I, where alkyl means direct or branched saturated chain and 1 to 9 carbon atoms, cyclopentyl, alkyl or benzyl. Synthesis of these compounds is realized by reaction of 4-benzenesulfonamidosalicylaldehyde with 2-alkylthio-6-aminobenzothiazoles in ethanol by boiling point. Compounds are antihelminthic effective.

Description

2-Alkylthio-6- (4-benzenesulfoamidosalicylidenamino) benzothiazoles of formula (I) are prepared wherein alkyl is a straight or branched saturated chain of 1 to 9 carbon atoms, cyclopentyl, allyl, or benzyl. alkylthio-6-aminobenzothiazoles in ethanol at boiling The compounds are anthelmintically active.

I

Technical field

The invention relates to 2-alkylthio-6- (4-benzenesulfonamidosalicylidenamino) benzothiazoles.

BACKGROUND OF THE INVENTION

To date, 2-isopentylthio-6-salicylidenaminobenzothiazole has been shown to exhibit anti-helminthic activity 10 against the Hymenolepis nana model helminth (Sidóová E. and Danik J., CS 271547) and salicylidenamino-2-benzothiazolinethi thion (anti-helminthic tinth). Sidóová E. and Dančk J..CS276317). 15

Example 2

Preparation of 6- (4-benzenesulfonamidosalicylidenamino) -2-ethylthiobenzothiazole.

6-Amino-2-ethylthiobenzothiazole (2.1 g, 0.01 mol) in ethanol (20 cm ³ ) and 4-benzenesulfonamidosalicylaldehyde (2.75 g, 0.01 mol) in ethanol (50 cm ³ ) were heated together to boiling for 2 minutes, then decolourised with charcoal. A clear yellow crystalline solid with m.p. 207 DEG-208 DEG C. at 2.85 g (60.7%). The substance did not require further purification. M = 469.61.

For C 22 H 19 N 3 O 3 S 3 C

Calculated%: 56.27 Found%: 56.19

H NS

4.08 8.9520.48

4.07 8.7920.53

Example 3

SUMMARY OF THE INVENTION

We have now found that compounds of formula 20

Preparation of 6- (4-benzenesulfonamidosalicylidenamino) -2-n-propylthiobenzothiazole.

The preparation was carried out according to Example 1, except that 6-amino-2-n-propylthiobenzothiazole (1.15 g, 0.005 mol) was used. The product with m.p. t. 163.0 ° C at 1.85 g (76.5%), which did not require further purification. M = 483.63.

where R is alkyl of 1 to 9 carbon atoms, cycloalkyl, alkenyl or arylaalkyl are antihelmintically effective.

At the same time, a process for the preparation of said compounds of the formula by reaction was found

4-benzénsulfonamidosalicylaldehydu

with 2-alkylthio-6-aminobenzothiazoles of general formula

ΠΙ

For C 23 H 21 N 3 O 3 S 3 C

Calculated%: 57.12

Found%: 57.14

H NS

4.38 8.6919.89

4.41 8.5319.83

Example 4

Preparation of 6- (4-benzenesulfonamidosalicylidenamino) -2-isopropylthiobenzothiazole.

The preparation was carried out according to Example 1, except that 6-amino-2-isopropylbenzothiazole (1.15 g, 0.005 mol) was used. The product with m.p. t. 183.5 to 185.0'C in 1.6 g (66.2%), which did not require further purification. M = 483.63.

For C 23 H 21 N 3 O 3 S 3

C

Calculated%: 57.12

Found%: 57.20

H NS

4.38 8.6919.89

4,47, 8,6619,77 wherein R is as defined for Formula I (Sidó R., Odler W., Free F. and Bläckinger G., Chem. Reports 33, 830 (1979)) in ethanol at boiling.

DETAILED DESCRIPTION OF THE INVENTION

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

Example 1

Preparation of 6- (4-benzenesulfonamidosalicylidenamino) -2-methylthiobenzothiazole.

6-Amino-2-methylthiobenzothiazole (1.0 g, 0.005 mol) in ethanol (12 cm ³ ) and 4-benzenesulfonamidosalicylaldehyde (1.4 g, 0.005 mol) in ethanol (12 cm ³ ) were heated together to boil for 3 hours. minutes and the reaction mixture was decolourised with charcoal. An orange crystalline solid having a melting point of 225.0 to 256.0 ° C in the filtrate after cooling to 5 ° C was precipitated.

amount of 1.3 g (54.9%). The substance did not require next cleaning. M = 455.58. For C 21 H 17 N 3 O 3 S 3 From c C H N WITH ol> Calculated%: 55.36 3.76 922 21,11 Found%: 55.16 3.73 9.14 20.82

Example 5

Preparation of 2-allythio-6- (4-benzenesulfonamosalicylidenamino) benzothiazole.

The preparation was carried out according to Example 1, except that 2-allythio-6-aminobenzothiazole (1.1 g, 0.05 mol) was used. The product with m.p. t. 168.0 to 170.0'C in 1.4 g (58.1%), which did not require further purification. M = 481.62.

For C 23 H 19 N 3 O 3 S 3 C

Calculated%: 57.35

Found%: 57.15

H NS

3.98 8.7219.97

3.91 8.6619.68

Example 6

Preparation of 6- (4-benzenesulfonamidosalicylidenamino) -2-n-butylthiobenzothiazole.

The preparation was carried out according to Example 1 except that 6-amino-2-n-butylthiobenzothiazole (1.2 g, 0.005 mol) was used. The product with 1.1. 162.5 to 163.5'C at 1.55 g (62.3%), which did not require further purification. M = 497.66.

For C 24 H 23 N 3 O 3 S 3 C

Calculated%: 57.92 Found%: 57.84

H NS

4.66 8.4419.33

4.63 8.4419.26

SK 278149 BE

Example 7

Example 12

Preparation 6- (4-Benzenesulfonamidosalicylidenamino) -2-n-pentylthiobenzothiazole.

The preparation was carried out according to Example 1, except that 6-amino-2-n-pentylthiobenzothiazole (1.25 g, 0.005 mol) was used. The product with 1.1. 161.0-163.0 ° C in an amount of 1.5 g (58.6%) which did not require further purification. M = 511.69.

For C 25 H 23 N 3 O 3 S 3

C

Calculated%: 58.68 Found%: 58.80

H NS

4.92 8.2118.80

4.99 8.2418.70

Example 8 Preparation of 6- (4-benzenesulfonamidosalicylidenamino) -2-15-cyclopentylthiobenzothiazole.

The preparation was carried out according to Example 1, except that 6-amino-2-cyclopentylthiobenzothiazole (1.25 g, 0.005 mol) was used. The product with m.p. t. 180.5-182.5 ° C in an amount of 1.3 g (51.0%) which did not require 20

further cleaning. M = 509.67. For C 25 H 23 N 3 O 3 S 3 C H N WITH Calculated%: 58.91 4.55 8.24 18.87 Found%: 58.92 4.68 8.11 18.65

Example 9

Preparation of 6- (4-Benzenesulfonamidosalicylidenamino) 2-hexylthiobenzothiazole.

The preparation was carried out according to Example 1, except for 30 except that 6-amino-2-hexylthiobenzothiazole (1.35 g, 0.005 mol) was used. The product with m.p. t. 141.5-163.0 ° C at an amount of 1.65 g (62.8%), which was not required

further cleaning. M = 525.72. For C 26 H 27 N 3 O 3 S 3 35 C H N WITH Calculated%: 59.40 5.18 7.99 18,30 Found%: 59.08 8.18 7.84 18.40

Example 10

Preparation of 6- (4-benzenesulfonamidosalicylidenamino) -2-heptylthiobenzothiazole.

The preparation was carried out according to Example 1, except that 6-amino-2-heptylthiobenzothiazole (1.4 g, 0.005 mol) was used. The product with m.p. t. 154.0-155.5 ° C at 1.6 g (59.3%), which did not require further purification. M = 539.74.

For C 27 H 29 N 3 O 3 S 3 C

Calculated%: 60.08

Found%: 59.84

H NS

5.42 7.7917.82

5.47 7.7717.90

Example 11

Preparation of 6- (4-Benzenesulfonamidosalicylidenamino) -2-n-nonylthiobenzothiazole. 55

The preparation was carried out according to Example 1, except that 6-amino-2-n-nonylthiobenzothiazole (1.55 g, 0.005 mol) was used. t. 142.0-143.5 ° C at an amount of 1.45 g (51.1%) which it did not require

further cleaning. M = 567.80. 60 For C29H33N3O3S3 C H N WITH Calculated%: 61.35 5.86 7.40 16.94 Found%: 61.44 5.91 7.33 16.78

Preparation of 6- (4-Benzenesulfonamidosalicylidenamino) -2-benzylthiobenzothiazole.

The preparation was carried out according to Example 1, except that 6-amino-2-benzylthiobenzothiazole (1.35 g, 0.005 mol) was used. The product with m.p. t. 199.5 - 201.5 ° C at 2.2 g (82.8%), which did not require further purification. M = 531.68.

For C 27 H 21 N 3 O 3 S 3 C

Calculated%: 60.99

Found%: 60.88

H NS

3.98 7,9018,09

3.99 7,7817,79

Example 13

The anthelmintic activity of the compounds of the invention against a model helminth of Nippostrongylus brasiliensis.

The anthelmintic efficacy was determined in male rats 4-6 weeks of age and weighed 120-140 g. The test group consisted of 6 rats each. Two groups were control invaded, untreated, one group treated with the standard Levamisol preparation and another group treated with the compound of the invention. Invasion was performed with fresh larvae of Nippostrongylus brasiliensis ΠΙ. invasive stage of 500 larvae per rat. The first application was performed in 3. day after invasion (day 4 of experiment), second application on day 6 after invasion. The dose was 2 times as much as 150 mg.kg ^{-1 of the} live mass. The application was carried out without a hunger strike. The substances were suspended in Dorfman's reagent and applied by weight in a volume of 0.65 to 12 cm ³ . The rats in the untreated control groups were treated per se with Dorfman's reagent alone. Dung corpological examination was performed on day 6 after invasion (day 7 of the experiment) before the second administration of test substance or Dorfman's reagent in control groups. The trial was terminated by hunger strike on day 7 after invasion and killing of rats on day 8 after invasion (day 9 of the experiment). Efficacy was evaluated by performing a helminthologic autopsy on the first two thirds of the small intestine. The efficiency was expressed as a percentage by the indirect activity method according to Steward.

Súltanla · wtfXs borehole · * 0UiM »c <A Miawti suntert 1 ? * E, 3 3 W 0 »4th 4 b 7 9 55.2 U 38.5 U 33.6 in 25.6

(The above helminth is considered to be remarkably effective above 20%).

Example 14

The anthelmintic activity of the compound of Example 12 against a model helminth of Hymenolepis nana var. fratema (Stiles 1908).

The anthelmintic activity was determined in male NMRI mice of 12-15 g body weight. The number of mice per group consisted of 6 pieces each. Two groups were invaded, untreated, one treated with a standard preparation (piperazine salt of niclosamide) and another group treated with the compound of Example 12. Invasion was performed with a standard amount of mature Hymenolepis nana per os eggs. The compound of Example 12 was administered on days 17 and 18 after invasion of eggs dissolved in Dorfman 5 reagent at a dose of 150 mg.kg ^{-1 of} live matter. Mice in the control untreated groups were treated consistently with Darfman's reagent. After starvation on day 20 after egg invasion, the experiment was terminated on day 21 by killing the mouse and dissecting the small intestine by helminthology. 10 Whole tapeworms (Hymenolepis nana) with head were counted.

Example 12 showed activity equivalent to 59.0% of the niclosamide piperazine salt. 15

Significantly, the compounds exhibited activity against the model helminth of Nippostrongylus brasiliensis, which represents up to 89.0% of the efficacy of the Levamisol standard for the compound of Example 3 (remarkable activity above 20%) and that the compound of Example 20 exhibited activity against the model helminth. Helminth Hymenolepis nana, which represents 59.0% of the potency of the standard niclosamide piperazine salt (the potency is remarkable above 50%).

The compounds of the invention may be used as an active ingredient of anthelmintic preparations alone or in admixture with other substances, or as an intermediate for further syntheses.

Claims (3)

2-Alkylthio-6- (4-benzenesulfonamidosalicylidenamino) benzothiazoles of the general formula wherein R represents alkyl of 1 to 9 carbon atoms, cycloalkyl, alkenyl or aralkyl. 2. A process for the preparation of the compounds according to claim 1, which is reacted 4-Benzenesulfonamidosalicylaldehyde of formula II with 2-alkylthio-6-aminobenzothiazoles of general formula Wherein R is as defined in claim 1, in ethanol at boiling.