DK145121B - ANALOGY PROCEDURE FOR PREPARATION OF 5 (6) - ((CYCLOPROPYLETHYL) -SULPHINYL) -BENZIMIDAZOL-2-METHYL CARBAMATE - Google Patents

Description

in 145121

The present invention relates to an analogous process for the preparation of 5 (6) -cyclopropylethylsulfinyl] benzimidazole-2-methylcarbamate, a novel benzimidazole carbamate which can be used in suitable formulations for the control of gastroenteritic lung ™ and hepatic helminthic parasites of domestic animals (cattle, sheep, pigs, etc.). The process is peculiar to that described in the characterizing part of the claim.

5 (6) -substituted benzimidazoles are well known in the literature and their anti-helminthic action is also well known (compare, for example, German Patent Application Nos. 2 029 637 and 2,164,690, French Patent Nos. 1,556,824 and 2,052,988 , U.S. Patent No. 1,455,728, cf. p. 5, U.S. Patent No. 3,010,968 and 3,915,986).

Some of these products are commercially available such as e.g. Albendazole, Oxybendazole and Perbendazole manufactured by Smith-Kline and French Laboratories, Phenbendazole manufactured by Hoechst Company, Oxphendazole, manufactured by Syntex Co., Cambendazole and Thiabendazole manufactured by Merck Company and finally Mebendazole manufactured by Janssen Co.

All of these compounds exhibit good activity against intestinal worms; however, they are only slightly or not at all effective against lung nematodes or hepatic triathematics.

It has now been found that the heretofore known benzimidazole carbamate, 5 (6) - [(cyclopropylethyl) sulfinyl] benzimidazole-2-methylcarbamate (CPSBC), of the general formula: 0-m-C00CE3

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2 145121 exhibits a greater anti-helminthic effect on specific bovine parasites than the benzimidazole carbamates already introduced in veterinary practice, and exhibits a significantly broader range of activity, also being effective against lung nematodes and hepatic trema. - spells that are otherwise difficult to combat with conventional anti-helminth agents. The invention therefore relates to an analogous method for the preparation of said compound, which is characterized by the characterizing part of the claim.

The compound of the present invention exhibits exceptional efficacy against the genera Ostertagia, Oesophagostomum, Trichostrongylus and other intestinal worms, and has also been shown to be active against Dictyo cauli, Metastrongyli, protostrongyli, the nematodes of the lung which are only responsible for infections, can be kept under control, in sheep, cattle and horses; and they are also effective against Fasciolae, such as Fasciola hepatica.

Preparation of the starting compounds for use in the process of the invention presents no particular difficulties. The compound can be prepared from 2-nitro-4-thiocyano-aniline through the following synthesis steps; wherein the last step illustrates the present process.

3 145121 NHo NHp NHp A-. jLra nr * »

KJ e, Ljr -> KJ

SCN SNa \ / x ηη2 m2 | ^ | -N02 NagSgO ^^ l-®2 M2 s_ch n i-NH-COOCH3 NH-COOCH3 KJ - ^^

b CO-O-OH

^ ά (> A] Q [^)> - nh-cooch3 ^ ° ^^ - 1Q] ^ nh_C00 <ckbc)

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The cyclopropylethyl chloride can be prepared from CCl ^ and ethylene according to subsequent reaction scheme ch2 = ch2 cci4 + ch2 = ch2-> cci3-ch2-ch2-ci ->

Zn, HCl in gaseous form -> ci-ch2 -ch2 - cci2 - ch2- ch2 - ci - * · tA ^ cl CPSBC has been found to be useful both for the purification of infested animals and for protection against infestation; it can be administered by any method known in veterinary science, e.g. orally in the form of balls.

4 145121 tablets, capsules or suspensions or it can be added directly to the feed.

It is compatible with many of the usual diluents or extenders, such as e.g. corn starch, lactose, sucrose, calcium phosphate, gelatin, stearic acid, agar, pectin etc.

As liquid carriers can be used peanut oil, olive oil etc.

The efficacy of the compound prepared according to the present invention in comparison with previously known compounds has been determined by experiments on sheep which had previously been thoroughly liberated from infection by administration of appropriate doses of conventional anti-helminthic products and subsequently infested under control of parasites belonging to the species to be investigated.

The infected animals were then divided into two groups, one of which was treated with a single dose of the product to be tested, in the form of an aqueous suspension administered orally, while the other group was used as a control group. Forty-eight hours after the administration of the anti-helminthic product, the animals were slaughtered and the parasites present in them were counted according to the usual method of helminthology.

The results were expressed as percent disinfection using the following scale:

Scale step% disinfection 0 0-10, or meaningless 1 11-25 2 26-60 3 61-90 4 91-100 5 145121

Table I

The effectiveness of CPSBS on sheep compared to analogue anti-helminthic benzimidazoles.

Nature of R Nematodes Cestoidei Trematodes in the joint estrogen- in the lungs Moniezia Fasciola - τν, οΐβ terric Djrctyo hepatica

Ostertagia caulus T (6) T ^ WH-CO ^ Wkg Oesophagostomum

Tricbstrongylus ^ 5 4 4 4 4 2.5 4 4®

VvA 5 4 3-4. 3 2 2.5 1 1 vV ° v 5 ®® 0 O 0 ^ y ~ S- 5 4 4 2-3 φφ® 2.5 2 2 ØSO- 5 4 4 4 1 2.5 4 4 <Q-CO- 5 2 3-4 2.5 - 0 - w 5 ® <g) ® (g) ® 0 Ø @ (x) ® @ <x) p / nA 5 4 4 0 2 -r-CHg-SO- ^ 5 3 - o (1) Prepared According to British Patent Specification No. 1,455,728 φ at 1 mg / kg, total efficiency still exists.

φφ doses of 12.5 mg / kg are required to achieve efficacy 5 doses of 10 mg / kg are required.

φφφφ doses greater than 25 mg / kg are required.

φφφφφ doses of 20 mg / kg are required.

φφφφφφ doses of 60 mg / kg are required.

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These results show the very high degree of efficacy associated with CPSBC in all of the worm species studied, in particular with respect to lung nematodes, as well as trematodes, an efficiency which is only partially similar to oxiphendazole.

The data presented further shows that CPSBC administered at a single dose of 5 mg / kg allows total and simultaneous disinfection in sheep of nematodes, cestoids and trematodes, which has heretofore been impossible to achieve with any known product used alone.

For better illustration of the present invention, some examples of the synthesis of 5 (6) - [(cyclopropylethyl) sulfinyl] benzimidazole-2-methylcarbamate are given below, Examples I-V illustrating the preparation of the starting materials and Example V of the process of the invention.

EXAMPLE I

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Preparation of C3 / * V 2-n // xC1 In an enamelled 5 liter autoclave equipped with appropriate stirring system and heat control, 2.1 kg (11.5 moles) of CC13-CH2-CH2-C1 were placed in 1 liter of Cft 2 CN, 20 g of FeCl 2, 4 H 2 O, 22 g (C 2 H 3) 2 NH, HCl and 21 g of benzoin. The air was then removed and the autoclave was put under a few atmospheres of ethylene pressure. Then the temperature was increased to 120 ° C and additional ethylene was added to give a pressure of 35 atm. The indicated reaction conditions were maintained for 5.5 hours by addition of ethylene as the consumption progressed. After filtering off the solid particles in suspension, the mixture was fractionated by distillation to give 1300 g of a boiling point 80-82 ° C fraction at 2 mmHg.

CCI

which consisted of 97%

Under the above reaction conditions, the conversion of CC13CH2CH2C1 was 65%, while the selectivity with respect to the desired product was 80%, which corresponds to a total yield of 52%.

EXAMPLE II

Preparation of In a flask equipped with a reflux condenser, plug-in tube, stir barrel and a thermometer was placed 210 g of 1 N N 5 SCl (1 mole), 1000 cm 2 of ethanol and 325 g (5 mole) of zinc powder. This reaction mixture was then heated at reflux (the external hot bath temperature was 97 0 - 98 ° C) and then bubbling of gaseous HCl was started through the reaction vessel while maintaining a low uniform flow rate; the reaction was followed by chromatographic control, and it was discontinued, the yarns seemed to be totally converted. The reaction mixture was then diluted with 300 cm 3 of 5% aqueous HCl to make it thinner and then extracted with diethyl ether and the aqueous phase removed. The organic phase was evaporated after drying and the residue was fractionated at atmospheric pressure, collecting a fraction of b.p. 10S-111 ° C. Thus 86 g were obtained, which by chromatographic analysis was found to be 98% pure, which corresponds to a molar yield of 80% relative to Cl

EXAMPLE III

Preparation of 4-cyclopropylethylthio] -2-nitroaniline.

At room temperature, with gentle stirring, 51.2 mM 2-nitro-4-thiocyanoaniline dissolved in 25 cm 3 of dimethylformamide (EMF) and 54 mM sodium borohydride dissolved in 25 cm 3 of IMF were mixed.

Then the temperature rose to 30-35 ° C by itself.

The mixture was kept under stirring for 1 (one) hour at room temperature (15-20 ° C), after which 66 mM was added, the addition being regulated so as to maintain the temperature below 25 ° C. After the addition was complete, the mixture was heated to 100 ° C for 3 hours. The reaction mass was then cooled and poured into water with vigorous stirring. Then extraction with chloroform; the organic extracts were combined, dried on Na 2 SO 4 and the solvent removed under vacuum. The yield of the crude product thus formed was 85% and the product can be used immediately for the subsequent synthesis.

EXAMPLE IV

Preparation of 4-Cyclonronylethyl-thiol-o-nhenylenediamine 34.4 mM 4- [cyclopropylethyl-thio] -2-nitroaniline was suspended in 340 cm of a mixture of methanol and water in a volume ratio of 1: 1 containing 43 g. ^ 2820 ^.,

The reaction mixture was then heated at reflux, the reaction being monitored by thin layer chromatography. The reaction was complete for 10-15 minutes. After the reaction was complete, methanol and part of the water were removed under vacuum to form an oily suspension which was extracted with chloroform.

The organic extracts, after drying over anhydrous NagSO ^ and evaporation under vacuum of the solvent with practically quantitative yield, yielded the crude diamine (a viscous, very vigorously colored oil) which can be used directly for the subsequent synthesis step.

EXAMPLE V

Preparation of 5 (6) -Γ (cyclonropylethyl) -thiolbenzimidazole-2-methylcarbamate. 1 20 cm 3 of a mixture of C ^OH / H₂ / CH₂COOH (40: 40: 1) was dispersed 16 mM 4 - [(cyclopropylethyl) thio] o-phenylenediamine and 18 mM 1.3 isothiourea.

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The mixture was then refluxed for 4 hours.

The solid thus formed in the reaction mixture was filtered off and then recrystallized from methanol and chloroform (1: 1) to give the desired benzimidazole carbamate (yield = 70%; mp = 187 ° -189 ° C).

EXAMPLE VI

Preparation of 5 (6) -r (cyclopropylethyl) sulfinyl 3 benzimidazole-2-methylcarbamate.

In a mixture of CHCl 3 (400 cm 2), methanol (100 cm 3) and vinegar

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acid (2 cnr) was dissolved 2.39 mM of the ester formed in the above Example V. The temperature was maintained at 0 ° C and 2.51 mM m-chloroperbenzoic acid was added. After 1 hour, the reaction was completed as shown by thin layer chromatography (silica gel - elution solution: mixture of CHCl 3 parts, CH 2 COOC 2 parts, CH 2 OH 1 part).

The organic solution was washed with 150 ml of a saturated aqueous solution of sodium bicarbonate; the organic phase was dried over sodium sulfate and evaporated to dryness under vacuum.

The oily residue thus formed was dissolved in methanol. The crystallized precipitate from there led to the sulfoxide. After recrystallization from methanol, the pure sulfoxide was obtained (m.p. 215 ° C, yield 85%).