DE2843008A1 - 5 (6) -ANGLE CLIP ON (CYCLOPROPYLETHYL) -SULPHINYL SQUARE CLAMP ON -BENZIMIDAZOLE-2-METHYLCARBAMATE, A METHOD FOR THE PRODUCTION THEREOF AND THE PHARMACEUTICAL COMPOSITION - Google Patents

Description

Our No. 22 O89 F / La

Montedison SpA
Milan / Italy

5 (6) - / X cyclopropylethyl) -sulphonyl / -benzimidazol-2-methy 1-carbamate, a process for its preparation, as well as pharmaceutical composition

The present invention relates to the subject matter described in the claims.

The compound of the invention is used to combat im Gastrointestinal, lung and liver of breeding animals (such as cattle, sheep, pigs) occurring parasites of Kind of helminth suitable.

5 (6) -substituted benzamidazoles are known in the literature; The same applies to their effect as antihelminthics (see e.g. DE-PAn 2 029 637 and 2 164 69Ο, FR-PSn 1 556 and 2,052,988 and U.S. Patents 3,010,968 and 3,915,986).

Some of these compounds have been commercialized (such as albendazole, oxybendazole and parbendazole, commercial products from Smith-Kline and French Lab., Phenbendazole from Hoechst AG, Oxphendazole from Syntex Co., Cambendazole and thiabendazole from Merck Co. and mebendazole from Janssen Co.).

All of these compounds show good efficacy against intestinal helminths; however, they are little or no effective against nematodes in the Lungs or trematodes in the liver.

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There has now been a new benzimidazole carbamate, the 5 {6) - £ (cyelopropylethyl) sulphinyl7-benzimidazole-2-ynethylcarbainate {in the

found

hereinafter abbreviated as CPSBC) /, which is the subject of the present invention and the formula

- NH-COOCH

having; this compound has an antihelminthic effect on specific cattle parasites which is greater than that of various benzinidazole carbamates which are already used in veterinary practice; it has a much broader range of action insofar as & ^{e is} also effective against lung nematodes and liver trematodes, which are otherwise difficult to attack with conventional antihelminthics.

The compound according to the invention shows, in addition to an extraordinary one Efficacy against the genera Ostertagia, Oesophagostomum, Trichostrongylus and other intestinal ones. Helminths, also an activity against Dictyocauli, Metastrongylij-Protost'rongyli, lung nematodes, which for Infections are responsible, which are difficult to control in sheep, cattle and horses; further is it also against Pasciolae, such as Fasciola hepatica, effective.

The preparation of the compound according to the invention does not present any particular difficulties. The connection can starting from 2-nitro-M-thiocyano-anilinj according to the following Reaction stages are produced:

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-H-

NH

NH.

NO

2 r v-No

NaBH. ^

SCN

NH

Cl. NH.

NO.

NH.

^N °

H.

KH ₂ f- ^CH 3 ■

C-NH-COOCH ^ y \ yS

NH-COOCH.

-NH-COOCH.

NH-COOCH

(CPSBC)

The cyclopropylethyl chloride can be made from CCl ^ and ethylene the following reactions can be obtained:

+ CH ₂ =

CH ₃ = CH-

Zn, HCl gas

_ri

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ras CPSBC was found to be useful for both the liberation of the animals infested by parasites and to protect them from infestation; it can be according to any of the on the veterinary Methods known in the art can be administered, for example orally, in the form of a pill, tablet, capsule or suspension, or it can be mixed directly with the animal feed. The compound is compatible with many of the common diluents or excipients, such as corn starch, lactose, sucrose, calcium phosphate, Gelatin, stearic acid, agar-agar, or pectin.

As a liquid vehicle, for example, peanut or Olive oil can be used; this enables formulation to form compositions known to those skilled in the art.

The effectiveness of the compound according to the invention in comparison to the previously known, structurally related compounds, it was determined in experiments with sheep, which carefully and preventively freed from parasites by administering suitable doses of conventional antihelminthics were then allowed to be infested with parasites of the species to be tested in a controlled manner. The infected animals were then divided into 2 groups, one of which with a single oral dose of the product to be tested in the form an aqueous suspension while the other group was used as a control. 48 hours after Administration of the antihelminthic, the animals were killed and the parasites present in them were removed according to methods counted which are commonly used in helminthological practice.

The results were expressed as the percentage of parasite clearance using the following rating scale:

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valuation

O 1 2

3 H.

Parasite clearance (%

0-10 or irrelevant 11-25 26-60 61-90 91-100

Table I.

Efficacy of CPSBC in sheep compared to analogous antihelminthic benzimxdazoles i

Meaning- ν ~ .- · -Κ
in d. -PormeLt- dose NematedeH- der-Ltinge
Dyctyocau-
lus ? ^estoide: - Trematodes H (mg / kg) d ..., gastric
■ - intestines
Ostertagia
Oesofagostonum
'Tr ϊ castrorigylus 4th Moniez'ia Fasciola
-hepatica 5 ... ... 4 .._. 4®. 4th _ 4 2.5 . .4. ._. 3-4 _r - w ^s \ 5 . .4 ..;. 1 .3. 2 2.5 1 0 w ° \ 5 ®® 4th 0 0 S. 4th 2 2-3 2.5 2 4th _- - <0> so- 5 _ .. 4 4th 4th . 1" 2.5 4th 2 '- - (Ö) -co- 5 .. 0
I. 3-4 2.5 - ·. ~ 0 - I.
Il " W. 5 @ θ ® ® & '4 ΟΛ / ^ _(i) 4th - O FTXH ₂ -SO- 5 3 - Ä - O

(1) manufactured according to GB-PS 1,455,728;

(χ) at 1 mg / kg there is still complete effectiveness:

(x) (x) doses of 12.5 mg / kg are required for effectiveness; (x) (x) (x) 5 doses of 10 mg / kg each are required for effectiveness;

(x) (x) (x) (x) doses greater than 25 mg / kg are required; (x) (x) (x) (x) (x) doses of 20 mg / kg are required; (x) (x) (x) (x) (x) (x) doses of 60 mg / kg each are required .

The results obtained show the surprisingly high effectiveness of CPSBG to all helminths used in the tests, particularly with regard to lung nematodes and trematodes, - an effectiveness which is only partial finds a counterpart in oxyphendazole.

The results make it evident that the CPSBC is with a single dose of 5 mg / kg enables the complete and simultaneous liberation of the sheep from nematodes, cestoids and trematodes, what so far with none used alone, so far known Product was possible to achieve.

The following example describes in more detail the preparation of 5 (6) - Ck cyclopropylethyl) sulphiny17-benzimidazole-2-methylcarbamate by a process comprising reaction stages (I) - (VI).

example

Preparation of 5 (6) - / ~ (Cyclopropylethyl) -sulphinyl7- benzimidazole-2-methylcarbamate

Λ. CCl v / v

(I) Preparation of Cl ^{7 v} ^ ^X C1

Into an enamelled 5 l autoclave, which was provided with a suitable stirring system and a suitable heat regulation device, were 2.1 kg (11.5 mol) CCl ₃ -CH ₂ -CH ₂ Cl, 1 1 CH CN, 20 g FeCl ₂ . 4H ₂ O, 22 g of (C ₃ H) ₂ ~ NH.HCl and 21 g of benzoin. After removing the air, ethylene was applied to the autoclave at a pressure of a few atmospheres. Thereafter, the temperature was raised to 120 ° C and the whole was pressurized to 35 atmospheres with ethylene. These conditions were then maintained for 51/2 hours by charging the autoclave with ethylene as it was consumed. After the suspended solids had been filtered off, the mixture was fractionally distilled, 1,300 g of a fraction having a boiling point of 80 to 82 ° C. at 2 torr being obtained, which was 97 % off

CCl
Cr ^^ Cl consisted.

Under the conditions given above, the conversion of the CCl CH ₂ CH ₂ Cl was 65 %, while the selectivity for the desired product was 80 % , which corresponds to a yield of 52 % .

(II) Manufacture of

In a flask fitted with a reflux condenser, a bubble inlet tube, a stirrer and a thermometer, obtained 210 g (1 mol) of the compound

9Ö98T6 / 07 & 4

he ^ \ ei

1,000 ecm of ethanol and 325 g (5 mol) of zinc powder. This reaction mixture was then heated under reflux (the temperature of the external heating bath was 97 - 98 ° C), and then the bubbling of HCl into the reactor was started with a weak, constant flow of HCl was maintained; the reaction was determined by chromatographic Surveillance tracked and broken when the connection

Cl ' ^N C1 seemed to be completely consumed. The reaction mixture was then diluted with 300 ecm of a 5% aqueous hydrochloric acid in order to increase its flowability; it was then extracted with diethyl ether to remove the aqueous phase. After drying, the organic phase was concentrated and the residue was fractionated under atmospheric pressure, a fraction having a boiling point of 109 - Hl C being collected. In this way, 86 g of the compound were obtained

^ obtained which was found to be 98 % pure according to chromatographic analysis; this corresponds to a molar yield of 80 %, based on the compound ^CC1

(III) Preparation of ^ - / Cyclopropylethyl-thio 7-2-nitroaniline

At room temperature, 51.2 mmol of 2-nitro- ⁱ l-thiocyanate-aniline, dissolved in 25 ecm of dimethylformamide (DMF) ^{, were mixed with 5 1} * mmol of sodium borohydride, dissolved in 25 ecm of DMF, with moderate stirring. Then the temperature rose by itself to 30-35 ° C. The mixture was stirred for 1 hour at room temperature (15-20 ^P C), after which 66 mmol / \ yCl on such

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• ~ ίο "■

Were added in a manner that the temperature remained below 25 ° C. After the addition had ended, the mixture was heated at 100 ° C. for 3 hours. The reaction mass was then cooled and poured into water / water with vigorous stirring. It was then extracted with chloroform; the organic extracts were combined, dried over NapSO ^, and the solvent was removed in vacuo. The yield of the crude product thus obtained was 85 %; the product can be used directly for the subsequent synthesis.

(IV) Production of ⁱ J- £ Cyclopropylethyl-thio_7-orthophenylen_jiiamine

There were 3 ¹ 1/2 mmol of iJ- £ cyclopropylethyl-thio-7-2-nitro-aniline in 3 * »0 ecm of a mixture of methanol and 13 g of Na ^ S ^ Oj, containing water in a volume ratio of 1: 1 suspended .

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

(V) Preparation of 5 (6) -ZT (cyclopropylethyl) -thiq7-benzimidazole-2-methyl_, carbamate

In 20 ecm of a mixture of CpH ₁ -OH, HpO and CH, COOH in a ratio of ¹ IOr ¹ IO :! 16 mmol of kL ( cyclopropylethyl) -thio / -ortho-phenylenediamine and 18 mmol of 1,3-methoxycarbonyl-

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isourea dispersed. The mixture was then refluxed for 4 hours. Thereafter, the solid which had formed in the reaction medium was filtered and then recrystallized from a mixture of methanol and chloroform in a ratio of 1: 1, whereby the desired benzimidazole carbamate was obtained in a yield of 70 % with a melting point of 187-189 ° C .

(VI) 5 (6) - £ (Cy clcrpropy lethy 1) -sulphinyl_7-benzimidazole-2-methylcarbamate

2.39 mmol of the ester obtained in stage (V) were dissolved in a mixture of HOC- ecm CHCl .., 100 ecm methanol and 2 ecm acetic acid. The temperature was kept at 0 ° C. and 2.51 mmol of m-chloroperbenzoic acid were added. After 1 hour, the reaction was complete according to thin layer chromatography (silica gel; eluent: mixture of 3 parts of CHCl, 2 parts of CH ₃ COOC ₂ H ₅ and 1 part of CH ₃ OH).

aqueous The organic solution was washed with 150 ml of a saturated solution of NaHCO; the organic phase was over Na ₂ SO ₁ . dried and concentrated to dryness in vacuo.

The oily residue obtained in this way was taken up in methanol; it then crystallized to yield the sulfoxide. The pure sulfoxide is obtained in a yield of 85 % on recrystallization from methanol; M.p. = 215 ° C.

For: Montedison /. P. A. Milan / / Italy

Y-

Dr. H. J.ΐ / olf f lawyer

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... COPY

Claims (2)

28A3008 BEIT, WOLFF & BSIL REC HTPAMWAi.TE FKAfJKFURT AM MAIN 80 claims: 1. 5 (6) -C ( cyclopropylethyl) sulphinyl7-benzimidazole-2-methylcarbaraate of the formula SO NH-COOCH. 2. Process for the preparation of the compound according to claim 1, characterized in that the corresponding Thio derivative of the formula ίοΥ V ΐ I W j V-NH - COCH with perbenzoic acid, peracetic acid, performic acid or hydrogen peroxide in inert solvents at 0 C oxidized. 3 * Pharmaceutical composition for veterinary medicine, labeled by containing the compound according to claim 1 as an active ingredient. 909816/0754