CS209520B2 - Method of making the new benzimidazole derivatives - Google Patents

Description

The present invention relates to a process for the preparation of novel benzimidazole derivatives with anthelmintic activity. These compounds are used as active ingredients in nematode control agents, particularly fluke in domestic and commercial animals.

The novel compounds correspond to the general formula I

in which

R2 and R4 are each independently hydrogen or halogen,

R3 is hydrogen, halogen, methyl or methoxy,

X is oxygen or sulfur,

Y is halogen, (C1 -C4) alkyl, (C1 -C4) alkoxy, (carbon, methylthio, methylsulfonyl, trifluoromethyl, nitro, hydroxy, cyano or acetyl), m is 0, 1, 2 or 3 and wherein when m is greater than 1, the meanings of Y may be the same or different, including possible tautomeric compounds of formula I.

Halogen for R2, R3 and Rd in formula I as well as Y in formula Ib is preferably chlorine or bromine.

In the present disclosure, "helminths" means nematodes (Nematodaj, tapeworms (Cestoideaj and flukes) (Trematodaj parasitic in the gastrointestinal tract or other organs).

Of the endoparasites occurring in warm-blooded animals, helminths are particularly harmful. Animals infected with these parasites not only grow more slowly and exhibit a markedly reduced performance, but in part cause these parasites so severe damage that the sick animals die. In order to prevent, or at least mitigate such damage, which may be of great magnitude in the event of epidemic worm infestation in cattle herds, there is ongoing efforts to prepare means to combat helminths, including their developmental stages.

Although a number of substances with anthel209520 are known to be effective, these active substances do not satisfactorily meet the requirements imposed on them, since, for example, they do not have sufficient activity or are therapeutically effective at tolerable doses in each case. side effects such as intoxication.

Thus, for example, they are disclosed in British Patent Specification No. 1,344,548 and in French Patent Specification. 1,476,558 benzimidazole derivatives for use in a variety of areas, and therefrom in general form for use against helminths.

It has now been proposed to use the inventive benzimidazole derivatives of the formula I for combating helminths.

The benzimidazole derivatives of the formula I are characterized by a higher anthelmintic activity, in particular against trematodes (Trematoda), with particular emphasis on their effect on fluke (Fasciolidae j, such as, for example, the liver fluk) (Fasciola hepatica).

Of the compounds of formula (I), the following compounds of formula (Ia) are preferred in terms of activity

in which

R3 is hydrogen, chlorine or methyl,

X is oxygen or sulfur,

Y is halogen, methyl, methoxy, methylthio, methylsulfonyl, cyano or acetyl, m is 0, 1 or 2, and when m is greater than 1, the meanings of Y may be the same or different, including possible tautomeric compounds of formula Ia.

In addition, the compounds of the following Formula (Ib) exhibit favorable therapeutic efficacy

R 3 is hydrogen, chlorine or methyl;

Y is halogen preferably chloro or bromo or methyl, provided that in the phenyl moiety bonded via an oxygen atom, the 2-position must always be occupied by a substituent corresponding to the meanings of Y and the 6-position is always unoccupied; when m is greater than 1, the meanings of Y are the same or different, including possible tautomeric compounds of formula Ib.

The novel compounds of formula I are prepared according to the invention as follows:

R.

(Yj, rn

© © + C, H _and OC-SM.

NH 3, ¹ S (ID (Y)),

(I) wherein

R 2, R 3, R 6, X, Y and m are as defined in formula I, and m is an alkali metal.

The reaction is carried out at temperatures of from 20 to 20 ° C

150 ° C, preferably at 50 to 100 ° C, in water or in organic solvents.

Suitable organic solvents are, for example, alcohols, such as methanol, ethanol or propyl alcohols, or hydrocarbons, such as benzene or toluene, or chlorinated hydrocarbons, such as chlorobenzene or methylene chloride.

9 5 20

The method used for the process of the invention to produce compounds of formula I ss is an analogous procedure to that described in Org. Syntheses Coli., Vol. IV, 569–570.

The starting materials used to produce the compounds of the formula I produced according to the invention are partly known. Thus, some of the compounds of formula II are described in Swiss Patent Specification No. 462,847. The starting materials can be prepared by known methods.

Example

Preparation of 5-chloro-6- (2 ‘, 3‘-dichlorophenoxy) -2H-1,3-dihydrobenzimidazole-2-thione

Dissolve 304 g of 4-chloro-5- (2 ‘, 3‘-dichlorophenoxy) -1,2-phenylenediamine in 1000 ml of ethanol, then add a solution of 180 g of potassium methylxanthogenate in 150 ml of water. The brown mixture was stirred under heating and reflux for 5 hours, filtered hot over activated carbon and then poured into 6 liters of water. A yellow flocculent precipitate formed and the mixture was adjusted to pH 5 by the addition of 530 mL of 2 N hydrochloric acid while the precipitate turned white. After stirring for half an hour, the precipitate is filtered off, suspended in water, filtered again, washed with water and dried at 60 DEG C./20 mbar. 290 to 300 g of 5-chloro-6 (2 ‘, 3‘-dichlorophenoxy) -2H-1,3-dihydrobenzimidazole-2-thione, m.p. 305-307 ° C (yield 85%), are obtained.

The following compounds were prepared analogously to the above example:

TABLE 1

H

Cl

Cl

Cl

Cl

Cl

Cl

and

a-in Vo

Cl

288 to 290

267-268

318 to 320

288 to 290

286 to 288

233 to 285

Number

Melting point ° C

Κ ₃

OF

281 to 282

268-270

290-292

257 to 259

306 to 308

296 to 298

300 to 302

335 to 337

300 to 303

305 to 307

301 to 303

325 to 327

325 to 327

Cl

Cl

Cl

H

H

H

H

H

H

Cl

CH3OC1

Cl

289-291

293 to 295

259 to 262

285 to 286

239 to 240

283 to 284

289-290

245 to 247

317 to 318

308 to 311

300 to 301

288 to 289

Cl h ₅ c

CH _and A Vo308-310

Cl

322 to 325

R3

Cl

Cl

Cl

Cl

Cl

CH3

CH3 ch ₃

CH3

OCK

oCHa

CH3

CH3 _ct and ϋ> - ° ci

00Cl

CH _and CH,

Cl oCl s-

Cl

CH3

O- ⁵ · och ₃

Cl <5 Melting point ° C

305 to 307

305 to 308

275 to 276

300 to 301

286 to 288

303 to 304

279 to 280

303 to 304

310 to 312

253 to 255

310 to 312

331 to 332

258 to 260

232 to 235

227 to 229

H

Number

Rs

I-I

Cl

CHs

Cl

Cl

H

Cl

252 to 255

272-275

275 to 279

236 to 240

265 to 270

205 to 208

245 to 248

268-271

260 to 270

Melting point ° C

Number r ₃

OF

Cl Cl 67 H Q ° - CWj CM 68 H & - cl ch ₃ 69 Cl 70 CH3 CH _i so _l - ^ - o- 71 Cl a ^ soi ^ -o- and 72 Cl ^w d ^so iO ⁰ ' Cl 73 Cl CH 2 O - ^ - O- Ct, 74 Cl Cl 75 Cl CH £ o - ^ - y-o- Ct 76 Br ct ^ -c 77 H OH 78 Cl Cl 79 H 0 - »- Cl cu ₃ 80 H 0-

283 to 287

304 to 306

254 to 257

290

275 to 276

294 to 298

267 to 275

Number R3

CH30—

CHsO—

C2H5O—

C4H9O—

Br

11-C4H9 — O— ·

Number

Cl

Cl T sTABLE 2 Compound

Melting point ° C

200 to 207

298 to 302

305 to 307

257 to 259

250 to 253

255

276 to 280

Melting point ° C

334 to 336

350 to 355

291-294

The anthelmintic activity of the benzimidazole derivatives of the formula I is demonstrated by the following experiment:

Experiment on rats infected with fluke (Fasciola hepaticaj)

White laboratory rats are infected with Fasciola hepaticaj. After the expiration period, 3 infected rats are treated with the appropriate active compound, which is administered as a suspension by gavage, once a day for three consecutive days. are tested at doses of 300, 100, 30 and 10 mg / kg body weight Two weeks after the administration of the active substance, the animals are sacrificed and necropsied.

The evaluation is performed after necropsy of the test animals by comparing the number of parasites remaining in the bile ducts with untreated but in the same way and simultaneously infected control animals.

At therapeutically effective doses, the composition is tolerated by rats without side effects.

TABLE 3

Minimum dose of active substance at 100% action against liver fluke

Compound No. Dose in mg / kg of Example 1/2 3 x 10 (T1) 3 x 300 (T1) 3 x 10 (T1j 3 x 100 (T1) 3 x 30 (T1j 3 x 10 (T1) 3 x 300 (Tlj 3 x 10 (Tlj 3 x 30 (TI)) 3 x 30 (TI) 3 x 100 (TI) 3 x 10 (Tlj 3 x 30)

Toxicity values (acute):

Example compound 1/2:

LD50 rat, oral: 3105 mg / kg

LD50 rat, dermal: > 3000 mg / kg

LD 50 rabbit, orally:> 6000 mg / kg.

Explanatory notes to the table:

* at lower dose the compound was not tested.

The active ingredients produced according to the invention are used to combat parasitic helminths in domestic and commercial animals such as cattle, sheep, goats, cats and dogs. The active compounds can be administered to the animals both in a single dose and repeatedly, with the individual dose being preferably between 0.5 and 100 mg per kg of body weight, depending on the species. By prolonged application, in many cases a better effect is achieved or a lower total dose may be sufficient. The active compounds or mixtures in which the active compounds are present can also be added to the feed or beverage. The finished feed contains the compounds of formula I preferably in a concentration of 0.005 to 0.1% by weight.

The compositions may be administered in the form of solutions, emulsions, suspensions, powders, tablets, boluses or capsules orally or abomasally to animals. For example, conventional solid carriers such as kaolin, talc, bentonite, table salt, calcium phosphate, cottonseed meal or non-reactive liquids, such as oils and others, which are harmless to the organism, are suitable for the preparation of these dosage forms. If the physical and toxicological properties of the solutions or emulsions allow, the active substances can also be administered to animals, for example, by subcutaneous injection. Furthermore, it is also possible to administer the active compounds to animals in the form of salt or molasses blocks.

When anthelmintic compositions are used in the form of feed concentrates, they serve as carriers, for example, hay, nuclear feed, feed grain or protein concentrates. Such feedingstuffs may contain, in addition to the active substances, additives, vitamins, antibiotics, chemotherapeutics or other pesticides, in particular bacteriostats, fungistatics, coccidiostats or even hormonal preparations, substances with anabolic action or other substances which favorably affect the meat quality of slaughter animals or another way. They can also be combined with other anthelmintics to extend their effect and adapt to the circumstances.

Such as:

Nematocidal agents: for example Alcopar, Ascarldol, Banminth II, Bephenium, Cambendazole, Coumaphos, Cyanine, diethylcarbamazine, DDVP, 1,4-di (D-glyconyl) piperazine, dithiazanine, Dow ET / 57 Dowco 132, Gainex, Hexachlorophen, Hexachlorophen, Hexachlorophen, Jonit, Levamisol, methylene violet, 1-methyl-1-tridecylpiperazinium-4-carboxylic acid ethyl ester, Methyridine, Neguvon, Nematodine, Nemural, Nidanthsl, Parbendazole, Parvex, phenothiazine, piperazine, polymethylenpiperazin, Pyranteline, Pyranteline, Pyranteline, Pyranteline, Pyranteline, Pyranteline Shell 1808, Stllbazium, Tetramisol, Thenium, Thiabendazole, Thymolan, Vermella, Mebendazole, Oxybendazole, Fenbendazole, Albendazole, Oxfendazole;

Anti-tapeworm agents: for example Acran11, Arecoline, Atebrin, Bithionol, Bithionol sulfoxide, Bunamidine, Cestondin, Cambendazole, dibutyltin dilaurate, dlchlorophen, dioctyltin dichloride, dioctyltin laurate, filixic acid, Hexachloresophene, Nexantloresophene, Mepantloresophene, Mepantloresophene, Mepantloresophene, Mepantloresophene, Mepanthlorophen,

The anthelmintic compositions are prepared in a manner known per se by thoroughly mixing and grinding the active compounds of the formula I with suitable carriers, optionally with the addition of dispersants or solvents inert to the active compounds.

The active substances may be present and applied in the following processing forms:

Solid forms of processing:

Granules, coated granules, impregnated granules and homogeneous granules.

Water-dispersed concentrates of the active substance (wettable powders J.

Liquid forms of processing:

Solutions, pastes, emulsions, in particular drenches.

The carrier particle size is up to about 0.1 mm for the dust and wettable powder and 0.01 to 0.5 mm for the granulate.

The concentration in the solid forms is 0.5 to 80%, in the liquid forms 0.5 to 50%.

In addition, stabilizing additives and / or non-ionic, anionic and cationic substances can be added to these mixtures which provide, for example, better wettability (wetting agents) as well as dispersibility (dispersants).

Example

Water-dispersible powder mixture:

parts by weight of the active compound of the formula I are intimately mixed in a mixing device with

7.5 parts by weight of an absorbent support material, for example silicic acid;

59.4 parts by weight of a carrier, for example kaolin and

0.5 part by weight of oleic acid;

5.3 parts by weight of octylphenyl polyglycol ether; and

2.3 parts by weight of the stearylbenzimidazole derivative.

This mixture is ground to a particle size of 5 to 15 µm in a pin mill or jet mill. The wettable powder thus obtained provides a good suspension in water.

Claims (3)

A process for the preparation of novel benzimidazole derivatives of the general formula I wherein: R 2 and R 4 are each independently hydrogen or halogen, R3 is hydrogen, halogen, methyl or methoxy, X is oxygen or sulfur, Y is halogen, C1-C4alkyl, C1-C4alkoxy, methylthio, methylsulfonyl, trifluoromethyl, nitro, hydroxy, cyano or acetyl; and m is 0, 1, 2 or 3, wherein: when m is greater than 1, the meanings of Y may be the same or different, including possible tautomeric compounds of formula I, characterized in that the compound of formula II OF THE INVENTION in which R 2, R 3, R a, Y, X and m are as defined in formula I, reacted with a compound of formula C2H5O — C — S © M © II p where M is an alkali metal, at temperatures from 20 ° to 150 ° C in water or in an organic solvent. 2. The process of claim 1 wherein the reaction is carried out at a temperature of from about 50 ° C to about 100 ° C. 3. The process according to claim 1, wherein the organic solvents are alcohols, hydrocarbons or chlorinated hydrocarbons.