DE2843008C2 - - Google Patents

Description

The present invention relates to that in the claims described objects.

The compound of the invention is used to combat im Gastrointestinal tract, lungs and liver of breeding animals (such as e.g. B. cattle, sheep, pigs) parasites occurring Suitable type of helminths.

5 (6) -substituted benzamidazoles are known in the literature; the same applies to their effect as antihelminthics (see e.g. GB-PS 14 28 933, 14 64 326 and 14 56 497).

All of these compounds show good activity against intestinal helminths; however, they are little or not effective at all against nematodes in the Lungs or trematodes in the liver.  

A new benzimidazole carbamate, 5 (6) - [(cyclopropylethyl) - sulphinyl] -benzimidazole-2-methylcarbamate (im hereinafter abbreviated as CPSBC) found what subject The present invention is and the formula

having; this compound has an antihelminthic effect against special parasites of cattle, which are larger is that of various benzimidazole carbamates which already used in veterinary practice; they has a much broader scope in that and is also opposed to lung nematodes and liver trematodes effective, which otherwise with conventional antihelminthics are difficult to attack.

The connection according to the invention shows, in addition to an extraordinary Effectiveness against the genera Ostertagia, Esophagostomun, Trichostrongylus and other intestinal Helminths, also effective against Dictyocauli, Metastrongyli, Protostrongyli, lung nematodes, which for Infections are responsible in sheep, cattle and horses are difficult to control; further is it also against Fasciolae, such as. B. Fasciola hepatica, effective.

The preparation of the compound according to the invention is of no use particular difficulties with it. The connection can starting from 2-nitro-4-thiocyano-aniline, according to the following Reaction stages are produced:  

The cyclopropylethyl chloride can from CCl₄ and ethylene after following reactions are obtained:

The CPSBC proved useful for both the liberation of the animals infested with parasites as well as for their protection before an infestation; it can be according to any of the veterinary Known methods are administered, for example orally, in the form of a pill, tablet, capsule or suspension, or it can go directly to the animal feed be mixed. The connection is compatible with many of the usual diluents or excipients, such as B. corn starch, lactose, sucrose, calcium phosphate, Gelatin, stearic acid, agar agar, or pectin.

For example, peanut or Olive oil can be used; this enables formulation to compositions which are known to the person skilled in the art.

The effectiveness of the compound according to the invention in comparison to the previously known, structurally related Connections were found in experiments with sheep, which preventively carefully from parasites by administration suitable doses of conventional antihelminthics and then in a controlled way with parasites of those to be tested Species have been infested. The infested animals were then divided into 2 groups, one with one single oral dose of the product under test in the form an aqueous suspension was treated while the other group was used as a control. 48 hours after Administration of the antihelminthic, the animals were sacrificed, and the parasites present in them were made using methods counted, which is usually in the helminthological Practice.

The results were expressed as a percentage of parasite release expressed according to the following rating scale:  

Parasite Relief Rating (%) 00-10 or irrelevant 111-25 226-60 361-90 491-100

Table 1

The results obtained show the surprisingly high effectiveness from CPSBC to everyone used in the tests Helminths, especially with regard to lung nematodes and trematodes - an effectiveness that is only partial finds an equivalent in oxyphendazole.  

The results demonstrate that the CPSBC at a single dose of 5 mg / kg the complete and simultaneous relief which enables sheep from nematodes, cestoids and trematodes, what so far with no alone used, previously known Reaching the product was possible.

In the following example is the preparation of 5 (6) - [(cyclopropylethyl) sulphinyl] benzimidazole-2-methyl carbamate by a process comprising reaction stages (I) - (VI) described in more detail.  

example Preparation of 5 (6) - [(Cyclopropylethyl) Sulphinyl] - benzimidazole-2-methyl carbamate

In an enamelled 5-liter autoclave, which is equipped with a suitable stirring system and a suitable heat regulation device was provided, 2.1 kg (11.5 mol) CCl₃-CH₂-CH₂Cl, 1 l CH₃CN, 20 g FeCl₂ · 4 H₂O, 22 g (C₂H₅) ₂- NH · HCl and 21 g of benzoin. After removing the air was at the autoclave ethylene with a pressure of a few Atmospheres. The temperature was then raised to 120 ° C and the whole was pressurized with ethylene Brought 35 atmospheres. These conditions then became Maintain 5½ hours by using the autoclave charged with ethylene depending on consumption. After filtering the mixture was fractionated from the suspended solids distilled, 1300 g of a fraction with the boiling point 80 to 82 ° C at 2 Torr were obtained, which made up 97%

duration.

Under the above conditions, the conversion was of the CCl₃CH₂CH₂Cl 65%, while the selectivity in terms of the desired product was 80%, which is one Yield of 52% corresponds.

In a flask equipped with a reflux condenser, a bubble inlet tube, a stirrer and thermometer, became 210 g (1 mole) of the compound

1000 cc of ethanol and 325 g (5 mol) of zinc powder. This reaction mixture was then heated under reflux (the temperature of the outdoor heating bath was 97-98 ° C), and then bubbling HCl into the Reactor started, with a weak, constant stream of HCl was maintained; the reaction was by chromatographic Surveillance pursued and canceled as the connection

seemed completely used up. The reaction mixture was then with 300 cc of a 5% aqueous Diluted hydrochloric acid to increase its fluidity; it was then with diethyl ether with removal of the aqueous Phase extracted. The organic phase became after drying concentrated, and the residue was under atmospheric pressure fractionated, a fraction with the boiling point 109-111 ° C was collected. In this way, 86 g the connection

obtained which according to the chromatographic Analysis was 98% pure; this corresponds to one molar yield of 80%, based on the compound

(III) Preparation of 4- [cyclopropylethylthio] -2-nitro-aniline

At room temperature, with moderate stirring, 51.2 mmol 2-nitro-4-thiocyananiline, dissolved in 25 cc dimethylformamide (DMF), with 54 mmol sodium borohydride, dissolved in 25 cc DMF, mixed. Then the temperature rose by itself to 30-35 ° C. The mixture was 1 hour at room temperature (15-20 ° C), after which 66 mmol

on such  Were added so that the temperature below 25 ° C. stayed. After the addition was complete, the mixture was 3 hours heated at 100 ° C. The reaction mass was then cooled and poured into water with vigorous stirring. Then was extracted with chloroform; the organic extracts were united, dried over Na₂SO, and the solvent was stripped under vacuum. The yield of the thus obtained Crude product was 85%; the product can be used directly for the following Synthesis can be used.

(IV) Preparation of 4- [cyclopropylethylthio] -2-ortho phenylenediamine

34.4 mmol of 4- [cyclopropylethylthio] -2-nitro-aniline were obtained in 340 cc of a mixture of methanol and 43 g of Na₂S₂O₄ containing Water suspended in a volume ratio of 1: 1.

The reaction mixture was then heated under reflux, the course of the reaction by thin layer chromatography was monitored. The implementation was within about 10 to 15 minutes completely. After the reduction was completed the methanol and part of the water are removed under vacuum, an oily suspension was obtained which was washed with chloroform was extracted. The organic extracts yielded Dry over anhydrous Na₂SO₄ and evaporate the solvent under vacuum in practically quantitative yield the raw diamine (a thick, intensely colored oil), which can be used directly for the subsequent synthesis stage can.

(V) Preparation of 5 (6) - [(cyclopropylethyl) thio] benzimidazole - 2-methyl carbamate

In 20 cc of a mixture of C₂H₅OH, H₂O and CH₃COOH in Ratio of 40: 40: 1, 16 mmol of 4- [cyclopropylethyl thio] ortho-phenylenediamine and 18 mmol 1,3-methoxycarbonylisourea  dispersed. The mixture was then 4 hours heated under reflux. Then the solid, which had formed in the reaction medium, filtered and then from a mixture of methanol and chloroform in the ratio 1: 1 recrystallized, the desired benzimidazole carbamate in a yield of 70% with a melting point of 187-189 ° C was obtained.

(VI) 5 (6) - [(cyclopropylethyl) sulphinyl] benzimidazole-2- methyl carbamate

In a mixture of 400 ccm CHCl₃, 100 ccm methanol and 2 cc of acetic acid was 2.39 mmol of that obtained in step (V) Resolved ester. The temperature was kept at 0 ° C and it 2.51 mmol of m-chloroperbenzoic acid were added. After 1 The hour was the reaction according to thin layer chromatography (Silica gel; eluent: mixture of 3 parts of CHCl₃, 2 parts CH₃COOC₂H₅ and 1 part CH₃OH) completely.

The organic solution was treated with 150 ml of a saturated aqueous Washed solution of NaHCO₃; the organic phase was dried over Na₂SO₄ and concentrated to dryness in vacuo.

The oily residue obtained was taken up in methanol; he then crystallized to deliver the Sulfoxide. The pure sulfoxide is recrystallized obtained from methanol in a yield of 85%; F. = 215 ° C.

Claims (3)

1. 5 (6) - [(Cyclopropylethyl) sulphinyl] benzimidazole-2-methylcarbamate of the formula 2. A process for the preparation of the compound according to claim 1, characterized in that in a conventional manner, the corresponding thio derivative of the formula oxidized with perbenzoic acid, peracetic acid, performic acid or hydrogen peroxide in inert solvents at 0 ° C. 3. Pharmaceutical composition for veterinary medicine, labeled by a content of the compound according to Claim 1 as an active ingredient.