CS209518B2 - Method of making the new derivatives of the benzimidazole - Google Patents

Description

(54, A method for producing novel benzimidazole derivatives

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 1 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, 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 in the meaning of R2, R3 and R4 in formula I as well as Y in formula Ib is preferably chlorine or bromine.

In the present disclosure, "helminths" means nematodes (nematodes), tapeworms (Cestoidea) 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 to such an extent that the sick animals die. In order to prevent, or at least to mitigate such damage, which may be of great magnitude in the event of epidemic worm infestation in cattle herds, there is an ongoing effort to prepare means to combat helminths, including their developmental stages.

209318

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

Thus, for example, benzimidazole derivatives for use in various fields are disclosed in British Patent Specification No. 1,344,548 and French Patent Specification No. 1,476,558, and therefrom, 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 characterized by a higher anthelmintic activity, in particular against trematodes (Trematoda), with particular emphasis on their effect on fluke (Fasciolidae), such as the liver fluk (Fasciola hepatica).

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

S (la.) 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 la.

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

S (Ibl 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 unoccupied, and m is 1 or 2; 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:

(I) wherein

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

The reaction is carried out at temperatures from 10 ^C to 150 C, preferably at 30-100 ° C in water or in organic solvents in the presence of a base.

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.

Suitable bases are, for example, alkali, tertiary amines or organic bases, such as pyridine.

The method used to produce the compounds of formula (I) for the process of the invention is analogous to that described in J. Chem. Soc. 1950, 1515-1519.

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 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

256.2 g of 4-chloro-5- (2 ', 4'-dichlorophenoxy) -1,2-phenylenediamine is added to a solution of 135.6 g of potassium hydroxide in 540 ml of absolute ethanol. 480.2 g of carbon disulfide are then added dropwise to the mixture while stirring at room temperature without external cooling for half an hour. This reaction is slightly exothermic. A brown precipitate formed during the second quarter of addition. The mixture was then heated to reflux and maintained at a bath temperature of 60 ° C for 6 hours and then stirred for an additional 15 hours at room temperature. The suspension is poured into 6 liters of ice water, the precipitate is filtered off, washed with about 3 liters of water and dried under vacuum at 0 ° C. The crude product is dissolved in 10 liters of hot acetone, the solution is clarified with charcoal, filtered through "Hyflosupercel", concentrated to 4 liters and then cooled to 0 ° C. The resulting precipitate was filtered off, washed with acetone and dried under vacuum at 40 ° C. There were obtained 266 g of 5-chloro-6- (2 ', 4'-dichlorophenoxy-2H-l, 3-dihydro-benzoimidazol-2-thione, m.p. 309-311 ^C, a yield of 91%.

The following compounds were prepared analogously to the above example:

TABLE 1

Whose

3 Cl 4 Cl IN/

288 to 290

267-268

318 to 320

288 to 290

286 to 288

283 to 285

Cl

281 to 282

Cl

268-270

209318

R3 melting point ° C

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

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

288 to 290

C.

R3

OF

Cl

23 Cl 0 _S - 24 Cl Cl O- 25 Cl 26 H 27 Mar: H ^f -O ~ ^s - 28 H O- 29 H 30 H CHj-θ-ο- 31 H O-o- 32 Cl Cl · 33 CH3O— ch $ 34 Cl CHs 0- ° - 35 Cl ch ₃ 36 Cl CH _h 37 Cl H ^ C CN 38 Cl

•. «Sfcí

1 · -4 melting temperature ° C

310 to 312

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

308 to 310

322 to 325

305 to 307

C.

R3

OF

Cl

Cl

Cl

Cl

CH3

CH3

CH3

CH3

and

CH3

CH3

CH3

CHs

melting point ° C

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

227-229 ° C

257 to 263

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

R3 OF melting point Cl Cl H 283 to 287 H CH _% CH, \ / d- ° - Cl CH, Cl CHa cn _{i s} - ^ - o- Cl ^CH 3 ^S ° ^ -O- 304 to 306 Cl Cl Cl Cl ^c in ^ Q ~ ° ' Cl Cl CHš ^^ - O- Cl Cl Ο ^ ΟΟ-ζ ^ -Ο- Cl Br 254 to 257 H 290 OH Cl o-thi- 275 to 276 Cl H tí- ° - 294 to 298 Cl CHs H 0- 267 to 275 ch ₃

C.

R3

Mp ° C

CH3O—

CH3O—

C2H5O—

C4H9O—

Br n-C4H9-O-No.

ci a

0Cl ci.

TABLE 2 Compound

H

WITH

200 to 207

298 to 302

305 to 307

257 to 259

250 to 253

255

276 DEG-280 DEG

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 hepatica)

White laboratory rats are infected with fluke (Fasciola hepatica). After the pre-retention period, 3 infected rats are treated with the appropriate active ingredient, which is applied as a suspension by gavage, once a day on three consecutive days per experiment. The active substances are tested at doses of 300, 100, 30 and 10 mg / kg body weight. Two weeks after application of the active compound, 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 ingredient at 100% anti-fluff effect liver compound No dose in mg / kg of Example 1/2 3 x 10 (T 1) 3 x 300 (T 1) 3 x 10 (T 1) 3 x 100 (T 1) 3x30 (TI) 3x10 (TI) 3x30 (TI) 3x10 (TI) 3x30 (TI) 3x30 (TI) 3x30 (TI) 3x10 (TI) 3x30

Toxicity values (acute):

Example 1/2 compound:

LD50 rat, oral: 3105 mg / kg

LD50 rat, dermally:> 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 for combating parasitic belminths in domestic and productive 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 administration, 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 abonasally 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 active substances, additives, vitamins, antibiotics, chemotherapeutics or other pesticides, in particular bacteriostatics, fungistatics, coccidiostats or hormonal preparations, substances with anabolic action or other substances which favorably affect the quality of meat 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, Ascaridol, 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, Nidanthel, Parbendazole, Parvex, phenothiazine, piperazine, polymethylenpipervinine, Pyrantel, Pyretel, Pyretel, Shell 1808, Stilbazium, Tetramisol, Thenium, Thiabendazole, Thymolan, Vermella, Mebendazole, Oxybendazole, Fenbendazole, Albendazole, Oxfendazole;

Anti-tapeworm agents: for example Acranil, Arecoline, Atebrin, Bithionol, Bithionol sulfoxide, Bunamldin, Cestondin, Cambehdazole, dibutyltin dilaurate, dichlorophen, dioctyltin dichloride, dioctyltin laurate, filixic acid, Hexachloresophene, Mepantloresophene, Mepantloresophene, Mepantloresophene, Mepantloresophene, Mepantloresophene, Mepantloresphene, Mepantloresin,

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

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%.

They can be further added to these mixtures

Claims (4)

печет i. A process for the preparation of the novel benzimidazole derivatives of the general formula I by means of stabilizing additives and / or non-ionic, anionic and cationic substances which provide, for example, better wettability (s) as well as dispersibility (dispersants). Example Water-dispersible powder mixture: 25 parts by weight of the active compound of the formula I are mixed intimately with a blender 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 warm suspension in water. A compound of formula (I), characterized in that the compound of formula (II): wherein: R2 and Rd are each independently hydrogen or halogen, R3 is hydrogen, halogen, methyl or methoxy, X is oxygen or sulfur, Y is halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, methylthio, methylsulfonyl, trifluoromethyl, nitro, hydroxy, cyano or acetyl; and m is 0, 1, 2 or 3, wherein v is 0, 1, 2 or 3; when m is greater than 1, the meanings of Y may be the same or different, including possible tautomeric compounds in which R 2, R 3, R 4, Y, X and m are as defined in formula I, reacted with carbon disulfide at temperatures from 10 to 150 ° C in water or in an organic solvent in the presence of a base. 2. The process of Claim 1 wherein the reaction is carried out at a temperature of 30 to 100 ° C. 3. The process according to claim 1, wherein the organic solvents used are alcohols, hydrocarbons or chlorinated hydrocarbons. 4. Process according to claim 1, characterized in that the bases used are alkali, tertiary amines or organic bases.