CS209519B2 - 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

R 2 and R 4 are each independently hydrogen or halogen,

R3 is hydrogen, halogen, methyl or methoxy,

X is oxygen or sulfur,

Y represents halogen, alkyl having up to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, raetyltioskupinu, metyisulfonylovou group, trifluoromethyl sku2 group, a nitro group, hydroxy group, cyano ^Nu or acetyl, 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.

Halogen in the meaning of R @ 2, R @ 3 and R @ 6 in formula I as well as Y in formula Ib is preferably chlorine or bromine.

In the present disclosure, "helminths" means nematodes (Nematoda), tapeworms (Cestoideaj and flukes (Trematoda) 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, damage to worms in cattle herds in the event of epidemic outbreaks of worms, there is an ongoing effort to prepare means to combat helminths, including their developmental stages, in cattle farming.

Although a number of substances with an antelminaric activity are known, these active substances do not satisfactorily satisfy the requirements imposed on them, since, for example, these active substances do not have sufficient efficacy or therapeutically in each case at tolerable doses. Effective doses cause undesirable side effects such as intoxication.

Thus, for example, benzimidazole derivatives for use in various fields are disclosed in British Patent No. 1,344,548 and French Patent No. 1,476,558, and thereafter, in general form, the possibility of 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 distinguished by a higher antelmintic activity, in particular against trematodes (Trematoda), with particular emphasis on their action against fasciolidae, 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

H

H Hal 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

in which

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 vacant; When m and m are 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:

(I) wherein

R 2, R 3, R 4, X, Y and m are as defined in Formula I.

The reaction is carried out at temperatures of from 0 to 120 ° C, preferably at 20 to 80 ° C, in water or in organic solvents which are inert to the reactants.

Suitable inert organic solvents are, for example, ethers, such as dioxane or tetrahydrofuran, or hydrocarbons, such as benzene or toluene, or chlorinated hydrocarbons, such as chlorobenzene or chloroform.

The method used in the process of the invention to produce compounds of formula I is analogous to that described in Chem. Ber. 20 (1887), 228-232.

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 ‘, 4‘-dichlorophenoxy) -2H-1,3-dihydrobenzimidazole-2-thione

23.4 g of 4-chloro-5- (2 ', 4'-dichlorophenoxy) -1,2-phenylenediamine dihydrochloride are suspended in 60 ml of dioxane. To this suspension, a solution of 9 g of thiophosgene in 100 ml of dioxane was added dropwise with stirring over 20 minutes. The temperature rises from 20 ° to 34 ° C, slowly suspending the suspension. After 15 minutes, the solution was heated to 70 ° C, stirred at this temperature for 3 hours and then evaporated to dryness. The residue is taken up in 300 ml of 2N sodium hydroxide solution and extracted twice with 200 ml of chloroform. The aqueous phase is acidified with concentrated hydrochloric acid to pH 1, the precipitate formed is filtered off and washed with water until the effluent wash water is neutral.

The crude product was dissolved in hot dioxane, treated with activated carbon, filtered, diluted with hot water and then cooled. After filtration and drying in vacuo, 18 g of 5-chloro-6- (2 ‘, 4‘-dichlorophenoxy) -2H-1,3-dihydrobenzimidazole-2-thione, m.p. 309 DEG-311 DEG C., is obtained in 74% yield.

The following compounds were prepared analogously to the above example:

TABLE 1

H

Number R3 Z

Melting point ° C

CH3

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

268-270

290-293

288 to 290

267-268

318 to 320

288 to 290

286 to 288

283 to 285

281 to 282

268-270

290-292

Melting point ° C

Z57 to 259

306 to 303

296 to 298

300 to 302

335 to 337

300 to 303

305 to 307

301 to 303

325 to 327

325 to 327

288 to 290

310 to 312

289-291

293 to 295

Number

Melting point ° C

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

308 to 310

322 to 325

305 to 307

305 to 308

275 to 276

300 to 301

286 to 288

Number

Rs

OF

Melting point ° C

CH3

CH3

CH3

CH3

CH3

CH3

CH3

CH3

H

H

H

H

H

Whose.

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

257 to 263

252 to 255

272-275

Number R3

OF

Cl

CH3

Cl

Cl

H

Cl

CH3

Melting point ° C

275 to 279

236 to 240

265 to 270

205 to 208

245 to 248

268-271

260 to 270

283 to 287

Number R3 OF Melting point 71 Cl ^{CH 2 SO 3} -O-Cl 304 to 306 72 Cl Cl 73 Cl CH 2 O ct / 74 Cl Cl 75 Cl Cl 76 Br target- ^ zy-o- 254 to 257 77 H CW ₃ SO ₂ -O- _O -OH 290 78 Cl Cl - ^^ - O- Cl 275 to 276

294 to 298

Cl cw,

4 ° _CW

267 to 275

Q ₀ CRCH _d ) ₃

82 CH3O— 0-O- 83 CHsO— About ^the - 84 C2H5O— Q ₀ - Cl 85 CdHaO— Ci- ^ ~

Cl Cl

200 to 207

298 to 302

305 to 307

257 to 259

250 to 253

Ί

n-C4H9O

276 to 280

Number

TABLE 2 Compound

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 ·% effect against liver fluke

Compound No. Dose in mg / kg

Example 1/2 3 X 10 6 (TI) 3 x 300 13 (TI) 3 x 10 14 (TI) 3 x 100 17 (TI) 3 x 30 18 (TI) 3 x 10 19 (TI) 3 x 300 20 (TI) 3 x 10 21 (TI) 3 x 30 22 (TI) 3 x 30 28 (TI) 3 x 100 45 (TI) 3 x 10 46 (TI) 3 x 30

Toxicity values (acute):

Example compound 1/2:

LD 60 rat, oral: 3105 mg / kg

LD 50 rat, dermal:> 3000 mg / kg

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

Explanatory 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 so permit, the active compounds 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 agents are used in the form of feed concentrates, they serve as carriers, for example, hay, nuclear feed, fodder 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: e.g. Alcopar, Ascaridol, Banminth II, Bephenium, Cambendazole, Coumaphos, Cyanine, diethylcarbamazine, DDVP, 1,4-di (D-glyconyl) piperazine, diphiazanine, Dow ET / 57 Dowco 132,

Gainex, Hexachlorophen, Hexylresorcin, Jonit, Lexamisol, methylene violet, 1-methyl-1-tridecylpiperazinium-4-carboxylic acid ethyl ester, Methylridine, Neguvon, Nematodine, Nemural, Nidanthel, Parbendazole, Parvex, Phenothiazine, Piperothiazine, Piperothiazine, Piperothiazine, Piperothiazine , Rametin, Ronnel, Santoin Shell 1808, Stilbazium, Tetramisol, Thenium, Thiabendazole, Thymolan, Vermella, Mebendazole, Oxybendazole, Fenbendazole, Albendazole, Oxfendazole.

Anti-tapeworms: for example

Acranil, Arecoline, Atehrin, Bithionol, Bithionol sulfoxide, Bunamidine, Cestondin, Cambendazole, dibutyltin laurate, dichlorophen, dioctyltin dichloride, dioctyltin laurate, filixic acid, Hexachlorophen, Mepaesin, Nidanthel, Nidanthel, Nidanthel, Nidanthel.

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 dispersing agents 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-dispersible concentrates of the active substance (wettable powders).

Liquid forms of processing:

Solutions, pastes, emulsions, in particular drenchee suspensions. 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 (s) 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 and 5.3 parts by weight of octylphenyl polyglycol ether; and

209513

2.3 parts by weight of a stearylbenzimidazole derivative.

This mixture is pinned or ground

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: in the case where m is greater than 1, the meanings of the symbol Y may be the same or different, in a jet mill it is ground to particles of 5 to 15 μΐη. The wettable powder thus obtained provides a good suspension in water. The invention includes possible tautomeric compounds of formula (I), characterized in that the compound is: R 2, R 3, R a, Y, X and m are as defined in formula I, reacted with thiophosgene at temperatures from 0 ° to 120 ° C in water or in a solvent inert to the reactants. 2. The process according to claim 1, wherein the reaction is carried out at a temperature of 20 ° ^C to 80 ^° C. 3. The process according to claim 1, wherein ether, hydrocarbons or chlorinated hydrocarbons are used as inert organic solvents.