CS262597B1 - 5,6-bis/3-alkoxycarbonyl-1-1-2-thioureido/-benzimidazoles - Google Patents

Abstract

The present invention relates to 5,6-bis (3-alkoxycarbonyl-2-thioureido) benzimidazoles general of Formula I NHCSNHCOOR2 NHCSNHCOOR2 H (I) wherein R is an alkyl group of 1 to 3 atoms carbon and R 2 is methyl or ethyl. These new substances have not yet been reported anthelmintic activity against model Hymenolepis nana.

Description

The invention relates to 5,6-bis (3-alkoxycarbonyl-2-thioureido) benzimidazoles of the general formula I wherein R ¹

R

NHCSNHCOOR ²

NHCSNHCOOR ²

H is C 1 -C 3 alkyl and is methyl or ethyl.

These novel substances, which have not yet been described, exhibit useful anthelmintic activity, in particular against the model helminth of Hymenolepis nana.

The compounds of the formula I according to the invention can be prepared by reaction of the known 5,6-diamino-2-methylbenzimidazole or imidazole (Ficken GE, Fry DJ: J. Chem. Soc. 1963, 736) and methoxycarbonyl isothiocyanate or ethoxycarbonyl isothiocyanate in acetone at 20 to 40 ° C.

Methoxycarbonyl isothiocyanate or ethoxycarbonyl isothiocyanate was obtained by reacting potassium thiocyanate with methyl or ethyl chloroformate in boiling acetone.

Evaluation of anthelmintic activity against model helminth Hymenolepis nana:

The tests were performed on male H strain mice weighing 10-13 g in groups of 6 each. Two of the three control groups were invaded, untreated, the third invaded, treated with the standard niclosamic piperazine salt - against which the efficacy of the substances was compared.

Invasion was performed by probing orally with 500 mature Hymenolepis nana eggs in a volume of 0.25 ml / mouse. Compounds of formula I were administered orally by gavage at 150 mg.kg ^-2 body weight (w / w) as a homogenate in Dorfman's reagent on days 13 and 14 after oral invasion by gavage. Mice were sacrificed on day 3 post-application and, after total colonic tapeworm count at complete helmintological dissection of the small intestine of mice, the anthelmintic efficacy was determined by the Steward indirect activity method. The standard was also applied on days 13 and 14 after invasion at a dose of 150 mg.kg ^-1 . wt., which, calculated as niclosamide, means a dose of 4.48.10 ^-4 mol.kg ^-1 bw. hm.

The anthelmintic activity of the compounds of formula I against the model helminth of Hymenolepis nana, expressed as a percentage by the Steward indirect activity method, is shown below.

Fabric according to an exemplary embodiment Dose mol.kg ^-1 b. hm. Efficacy in 8 indirect method activities 1 3,50.10 ^-4 80 2 3,53.10 ^-4 95 3 3,50.10 ^-4 100 ALIGN! 4 3,35.10 ^-4 100 ALIGN! 5 3,53.10 ^-4 96 6 3,31.10 ^-4 100 ALIGN!

The process for preparing the compounds of the invention is simple and provides the desired products in satisfactory yields. Further details are given in the following examples. The examples given are merely illustrative and not limiting.

Example 1

2-Methyl-5,6-bis (3-methoxycarbonyl-2-thioureido) benzimidazole

To a solution of 14.6 g (0.15 mol) of potassium thiocyanate in 150 ml of acetone was added 14.1 g (0.15 mol) of methyl chloroformate and the mixture was refluxed for 1 h.

After cooling to 20 ° C, the precipitated potassium chloride was aspirated and 8.1 g (0.05 mol) of 2-methyl-5,6-diaminobenzimidazole was added with stirring. After stirring for 5 h, the product was filtered off with suction and the product recrystallized from methanol. Afforded 14.48 g (67.6%) of material melting at 174-175 ° C, composed of CO ^ H ^ ^ Ngo .CH ₃ OH.

Example 2

2-methyl-5,6-bis (3-ethoxycarbonyl-2-thioureido) benzimidazole

As described in Example 1, from 14.6 g (0.15 mol) of potassium thiocyanate, 16.27 g (0.15 mol) of ethyl chloroformate and 8.1 g (0.05 mol) of 2-methyl-5, 6-Diaminobenzimide azole prepared crude material which was recrystallized from ethanol. 13.37 g (63%) of a substance melting at 188-189 ° C with a composition of ^C 16 ^H 20 ^N 6 ° 4 ^S 2

Example 3

2-ethyl-5,6-bis (3-methoxycarbonyl-2-thioureido) benzimidazole

As described in Example 1, from 14.6 g (0.15 mol) of potassium thiocyanate, 14.1 g (0.15 mol) of methyl chloroformate and 8.81 g (0.05 mol) of 2-ethyl-5, 6-Diaminobenzimidazole was prepared as a crude material which was recrystallized from methanol. Afforded 7.21 g (33.7%) of material melting at 171.5 to 173 ° C of the composition C ₁₅ H _g N ₆ O ₄ S ₂ .H ₂ O.

Example 4

2-ethyl-5,6-bis (3-ethoxycarbonyl-2-thioureido) benzimidazole

As described in Example 1, from 14.6 g (0.15 mol) of potassium thiocyanate, 16.27 g (0.15 mol) of ethyl chloroformate and 8.81 g (0.05 mol) of 2-ethyl-5, 6-Diaminobenzimidazole was prepared as a crude material which was recrystallized from aqueous methanol. Afforded 10.6 g (47.4 ») of material melting at 148-150 ° C of the composition C ₁₇ H ₂₂ S ₂ Ngo ₄ .l / 2 HJO.

Example 5

2-Propyl-5,6-bis (3-methoxycarbonyl-2-thioureido) benzimidazole

As described in Example 1, from 14.6 g (0.15 mol) of potassium thiocyanate, 14.1 g (0.15 mol) of methyl chloroformate and 9.51 g (0.05 mol) of 2-propyl-5, 6-Diaminobenzimidazole was prepared as a crude material which was recrystallized from methanol. 8.97 g (42.3%) of m.p.

Example 6

2-propyl-5,6-bie (3-ethoxycarbonyl-2-thioureido) benzimidazole

As described in Example 1, from 14.6 g (0.15 mol) of potassium thiocyanate, 16.27 g (0.15 mol) of ethyl chloroformate and 9.51 g (0.05 mol) of 2-propyl-5, 6-Diaminobenzimidazole was prepared as a crude material which was recrystallized from ethanol. Yield: 12.01 g (53.1%), m.p. 189-190 ° C.

5,6-bis (3-alkoxycarbonyl-2-thioureidobenzimidazoles of formula I (I)),

Claims (1)

OBJECT OF THE INVENTION rW NHCSNHCOOR · ⁴ . NI 'SNHCOOR ² ' N AND H Wherein R is C 1 -C 3 alkyl and R is methyl or ethyl;