CS276651B6 - 6-Ftalimidometylamino-2-methylthiobenzothiazole - Google Patents

Abstract

The previously unknown 6-phthalimidonethylamino-2-methylthiobenzothiazole was prepared. The synthesis of the above compound is carried out by the reaction of phthalimide with an equivalent amount of formaldehyde and 6-amino-2-methylthiobenzothiazole in ethanol under boiling conditions. The compound is anthelmintic active against the model helminths Nippostrongylus brasiliensis, Hymenolepis nana and -Trichocephalus muris.

Description

The present invention provides 6-phthalimidomethylamino-2-methylthiobenzothiazole

Until now, 2-alkylthio-6- (bicyclo [2.2.1] hept-5-ene-2,3-dicarboxyimidomethylamino) benzothiazoles have been known, of which the n-propyl and sec-butyl derivative have shown low antimycobacterial activity (Sidóová, E., Odletová, L. and Blockinger, G. ·, Chem. Zvěsti 33, 542 (1979)).

We have now found that a hitherto unknown compound of the formula.

is anthelmintically effective against model helminths Nippostrongylus brasiliensis, Hymenolepis nana and Trichlocephalus muris.

At the same time, a process for the preparation of said compound based on phthalimide, formaldehyde and 6-amino-2-methylthiobenzothiazole has been found, characterized in that equivalent amounts of said starting materials are reacted together in boiling ethanol.

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

Example 1

Preparation of 6-phthalimidomethylamino-2-methylthiobenzothiazole

Phthalimide (7.35 g, 0.05 mol) was dissolved in ethanol (200 cm ³ ). 38% Formaldehyde (40 cm ³ , 0.05 mol) was added to the solution and the mixture was brought to a boil. After dissolving the solid, 6-amino-2-methylthiobenzothiazole (9.8 g, 0.05 mol) was added to the solution, and the reaction mixture was refluxed for 30 minutes. After cooling, the mixture was precipitated by the gradual addition of small portions of cold water to give 6-phthalimidomethylamino-2-methylthiobenzothiazole (m.p. 184-185 ° C) in an amount of 16.1 g (90.6%). The fabric did not require further cleaning. Mh = 355.44 For ^c i7 ^H i3 ^M j ° 2 ^S 2 calculated%: C 57.45 H 3.69 N 11.82 S 18.04 found ^? s: 57.16 3.62 11.59 17.92

Example 2

The anthelmintic activity of the compound of the invention against the model helmint Nippostrongylus brasiliensis

Anthelmintic efficacy was determined in male rats aged 4 to 6 weeks and weighing 120 to 140 g. The experimental group always consisted of 6 rats. 2 groups were control-invaded, untreated, one group treated with a standard levamisole preparation and the other group received a compound of the invention. The invasion was performed with fresh larvae of Nippostrongylus brasiliensis ΙΠ. invasive stage of 500 larvae per rat. The first application was performed on day 3 after invasion (day 4 of the experiment), the second application on day 6 after invasion. The dose size was 2 times and 150 mg kg ^-1 live weight. The application was performed without a previous hunger strike. The substances were suspended in Dorfman's reagent and applied by weight in a volume of 0.65 to 12 cm ³ . Rats in the control untreated groups were orally administered Dorfman's reagent alone. Corpological examination of faeces was performed on day 6 after invasion (day 7 of the experiment) before the second application of test substance or Dorfman's reagent in control groups. The experiment was terminated by fasting on day 7 after invasion and by killing rats on day 8 after invasion (day 9 of the experiment). Efficacy was evaluated by performing a helminth autopsy on the first two-thirds of the small intestine. The effectiveness of the treatment was expressed as a percentage, by the method of indirect activity according to Staward.

CS 276651 B 6 2

The compound of the invention showed an activity which corresponds to 32.0% of the activity of the standard (levamisole). (For this helmint, účinnost efficacy ’above 20’ is considered to be remarkable).

Example 3

The anthelmintic activity of the compound of the invention against the model helminth Hynienolepis nana var. Fraterna (Stiles, 1900)

The anthelmintic activity was determined in male NMRT mice with a live weight of 12 to 15 g. The number of mice in the group was always 6. 2 groups were control-invaded, untreated, one group treated with a standard preparation (piperazine salt of niclosamide) and the other group received a compound of the invention. The invasion was performed with a standard amount of mature Hynienolepis nana eggs by gavage. The compound of the invention was applied on days 17 and 18 after egg invasion, dissolved in Dorfman's reagent at a dose of 150 mg kg / l of live weight. Mice in control untreated groups were treated with Oorfman's reagent in the same manner. After fasting on day 20 after egg invasion, the experiment was terminated on day 21 by killing the mice and helmintological autopsy of the small intestine. Whole bandages (Hynienolepis nana) with head were counted.

The compound according to the invention showed an activity which corresponds to the 48.0% activity of the piperazine salt of niclosamide (in said model helmint it is considered to be a remarkable activity ’above 50%),

Example 4

Anthelmintic activity ’of the compound according to the invention against the model helminth Trichpcephalus muris - method of culturing Trichocephalus muris eggs in white mice (according to Keeling, 1963)

Anthelmintic efficacy ’was determined in a manner similar to that described in Examples 2 and 3. The patent period was 40 to 56 days. An invasive dose for one mouse was 200 eggs orally. The compound of the present invention exhibited 65 'activity (said helmint is considered to have a remarkable activity above 60%).

Eggs were obtained from the faeces of experimentally invaded mice by the sedimentation-flotation method according to Brez (1963). After centrifugation at the solution-layered water interface, a ring was formed in which the eggs were concentrated by flotation. This was carefully pipetted off, transferred to a 50 cnP beaker and made up to water. The suspension was allowed to settle for 30 minutes. The egg washing was repeated 3 more times. After the last wash, the sedimented eggs were transferred to 4 cm diameter petri dishes and layered with water to 2 to 3 mm. The eggs were cultured in a thermostat at 28 ° C. During the cultivation, the eggs were aerated with a pipette every day, once a week the steamed water was supplemented with fresh water to a height of 2 to 3 mm. After 4 weeks the eggs reached invasiveness (larvae developed in the eggs).

Significantly, the hitherto unknown compound of the new structure has shown activity against model helminths of Nippostrongylus brasiliensis, Trichocephalus muris and, to a lesser extent, against Hynienolepis nana.

Claims (2)

i. CS 276651 Β 6 PATENT APPLICATIONS 1. 6-Phthalimidomethylanino-2-methylthiobenzothiazole Formula 2. Process for the preparation of a compound according to claim 1, characterized in that it is reacted with phthalimides with formaldehyde and with 6-amino-2-methylthiobenzothiazole in ethanol at boiling point.