DE2332343A1 - 2-CARBALCOXY-AMINO-BENZIMIDAZOL-5 (6) PHENYL ETHER, THEIR PRODUCTION AND USE IN AGENTS AGAINST HELMETS - Google Patents

Abstract

The novel anthelmintically active 2-carbalkoxy-amino-benzimidazole-5(6)-phenyl ethers and thioethers of the formula I <IMAGE> wherein R1 denotes alkyl having 1 to 4 carbon atoms, R2 and R3 independently of one another each denote hydrogen, hydroxyl, alkoxy having 1 to 4 carbon atoms, halogen, trifluoromethyl, alkyl having 1 to 4 carbon atoms or carbalkoxy having 1 to 4 carbon atoms in the alkoxy radical, R4 denotes hydrogen or chlorine and X denotes oxygen of sulphur, are prepared by reaction of appropriately substituted o-phenylenediamine derivatives with an appropriately substituted dithiomethyleneamino-formic acid ester. The compounds are valuable chemotherapeutics for the control of parasitic diseases in man and animals. They are particularly active against a large number of helminths, for example Haemonchus, Trichostrongylus, Ostertagia, Strongyloides, Cooperia, Chabertia, Oesophagostomum, Hyostrongylus, Ankylostoma, Askaris and Heterakis.

Description

FARBWERKS HOECHST AKTIENGESELLSCHAFT

Gle Master Lucius & Brüning 2332343

File number: P 23 32 343.5 HOE 73 / F 133

Date: 29th Api-il 1974 Dr. KM / Eh

Benzimidazole-5 (6) -phenyläther 2-carbalkoxy-aa! Ino ~ their Hers Tellun g and Verweij invention in agents against helminths

2 ~ Carbalkoxy-amino-benziraidazole derivativeG with alkyl or acyl residues in the 5 (6) ~ position are known as anthelmintics (P. Acfcor et al., Nature 215 , 321 (1967); DOS 2.029.637).

The invention relates to anthelmintically effective 2-carbalkoxy-amino-benziraidaaol-5 (6) -phenyl ether of formula (1)

C-NH-COOR ₁ (1),

in which R is alkyl with 1 to k carbon atoms, R ₂ and R ^ are each independently hydrogen, hydroxyl, alkoxy rait 1 to Ί

409883/1323 sad

C atoms, halogen, trifluoromethyl, alkyl with 1 to k C atoms or carbalkoxy with 1 to 4 C atoms in the alkoxy radical, R. denotes hydrogen or chlorine and X denotes oxygen or sulfur.

Particularly preferred are compounds of the formaldehyde (1) in which R. is methyl, R _0, R and R. are each hydrogen and X is oxygen or sulfur.

Possible alkyl gratings in the substituents R ₁ , R 1 and R 1 are: methyl, ethyl, propyl, isopropyl, butyl, secondary butyl and tertiary butyl. Suitable alkoxy groups in the substituents R ₀ and RJ are: methoxy, ethoxy, propoxy, isopropoxy and butoxy. As halogen atoms in the substituents R ₀

and R- come into consideration: fluorine, chlorine, bromine and iodine. As car alkoxy groups in the substituents. R ₀ and R ₀ come into consideration: carbomethoxy, carbethoxy, carbopropoxy or carbobutoxy.

The invention also relates to a process for the preparation of 2-carbalkoxy-amino-benzimidazole-5 (6) -phenyl ethers of the formula (I) ₁ -In which R ₁₁ R ₀ , R ₀ , R ·, and X are the above

i - λ j t

have bene meaning, which is characterized in that one o-phenylene-diamine derivative of the formula (5)

NH ₀

² (5),

in which R_, R, R. and X have the same meaning as in formula (1) have, with either a bis-alkyl or bis-arylthio-methylenamino-formic acid ester of formula (2)

C = NC-OR ₁ (2),

Il *

409883/1323

in. Which R. has the meaning given for formula (1) and R ₀ and R, either the same or different and an alkyl radical with 1 to k carbon atoms, an alkenyl radical with 3 to 5 carbon atoms, a cyclohexyl radical or a optionally substituted phenyl or phenyl. Benzyl radical of the formulas (3) or (k) ,

(3)

where X is independently a halogen atom, a methyl or nitro group, or in which R ₀ and R_ can also be connected to form a ring which contains 2 or 3 methylene groups, and in which η is the number 0, 1 or 2 means.

The course of the reaction is shown by the following reaction scheme:

^R 2 ^S

R ₃

C = NC-OR ₁

The bis-alkyl- or bis-arylthio-methylenamino-formic acid esters are obtained from the corresponding dithio-iminocarbonic acid esters by reaction with chloroformic acid esters according to US Pat. No. 3,562 accessible.

As examples of bis-alkyl or bis-arylthio-methyleneaminoformic acid esters may be mentioned: the bis-raothylthio-methylenamino-formic acid methyl ester, the bis-methylthio-methylenamino-formic acid ethyl ester, the bis-methylthio-methylenamino-formic acid propyl ester, the bis-methylthio-methylene

409883/1323

amino-formic acid-isopropyl ester, the bis-methylthio-methylenamino-anie-iron acid re-butyl ester, the ice methylthio-methyleneaminoformic acid sec-butyl ester, the bis-butylthio-methyleneaminoformic acid methyl ester, the methylthio-butylthio-methylenamino-formic acid methyl ester, the allylthio-cyclohexylthioraethyleneamino-formic acid methyl ester, the methylthio-phenylthio-methyienamino-formic acid methyl ester, the methylthio- (3 ι ^ -dichlor-benzyl-thio) -raethyleneamino-amßisensäure-t -ethylester or the methylthio- (2-chloro-4-methylthio) -niethylenaminoformic acid methyl ester.

When carrying out the method according to the invention expediently 1 mole of the o-phenylenediamine derivative of the formula (5) with 1 mole of the bis-alkyl- or bis-arylthio-niethylenaminoformic acid ester in an inert solvent such as tetrahydrofuran, dioxane, Isopropyläthcr odei- chloroform at increased Temperature, expediently the boiling point of the solvent used.

According to the process of the invention, the bis-alkyl- or arylthio-methylenamino-formic acid ester can also only be prepared from the hydrochloride of the imino-dithiocarbonic acid ester in the reaction vessel by adding a chloroformic acid ester.

In this case, an acid acceptor must be present, which can be an organic or inorganic base such as sodium hydroxide, sodium bicarbonate or triethylamine. Polar and non-polar solvents such as ether, acetone, dioxane, V / water, dimethylformamide, benzene or cyclohexane are suitable as the reaction stage, where ι
lets rise.

hexane, the temperature advantageously not exceeding 20 ° C

The o-phenylenediamine derivative (5) used as starting material is made according to the following reaction scheme by reducing a corresponding «anvinonilrodiplieiiylätherr. of the formula (6) obtained, in which R, R, R. and X have the same meaning v; io in formula (1) have, never reduction can, for example - by Hydriorori. in

409883/1323 "dormin".

Presence of Ranay nickel in a solvent such as methanol or dimethylformamide at a temperature between 20 and 60 ° C or by treating with reducing agents, e.g. a solution of tin-2-chloride in glacial acetic acid mixed with hydrogen chloride gas is saturated, can be carried out; in this case, the tin double salt of o-phenylenediamine is used first (5) isolated, which is broken down by treatment with concentrated sodium hydroxide solution. The diamine released in this way becomes expediently taken up in a water-immiscible organic solvent.

XH + Cl

(7)

(6)

(6)

- X

(5)

Dio amino-nitro-diphenyl ethers (6) are in turn produced by the reaction of a phenol of the formula (7) in which R ₃ , R and X

409883/1323

have the same meaning as in formula (1), with 5-chloro-2-nitroanilir »or - insofar as these are compounds of the formula (6) in which R _; Chlorine means - obtained with 4,5-dichloro-2-nitroaniline, expediently in dimethylformamide in the presence of alkaline reacting agents such as potassium carbonate, at temperatures between 80 ° C. and the boiling point of the solvent used, for a period of half an hour to 5 hours. Isolation takes place by diluting the reaction mixture with water and filtering off the precipitate which has precipitated out.

If in one of the amino-nitro-diphenyl ethers (6) R ₁ or R 0 denotes hydroxyl, compounds of the formula (6) in which R ₀ or R denotes a methoxy group are used and these are treated with ether-splitting agents, for example with concentrated hydrobromic acid.

The 2-carbalkoxy-amino-ben2iinidazol-5 (6) -phenyl ethers according to of the invention are valuable chemotherapeutic agents and are suitable for combating parasitic diseases in humans and animal.

They are particularly effective against a large number of helminths, e.g. Haemonchus, Trichostrongylus, Ostertagia,

409883/1323

Strongyloidos, Coopcria, Chabertia, Oesophagostoinum, Hyostrongylus, Ankylostoma, Askaris and Heteiakis. Bosonders the effectiveness against gastrointestinal strongyles is pronounced, which mainly attack ruminants. The infestation of the animals by these parasites results too great economic damage, which is why the connections according to the invention in particular in veterinary drugs Find use.

The active ingredients are combined with suitable pharmaceutical Oral or subcutaneous solvents or animal substances applied, one or the other depending on the circumstances Application form is preferred.

To determine the effect of the compounds according to the invention, chemotherapeutic investigations were carried out on sheep lambs weighing approximately 30 kg which had been experimentally infected with larvae of the Haemonclius coiitortus or Trichostrpngj'ljUa cplubrifoi ^ mis. The test animals were kept in tiled boxes that were thoroughly cleaned every day. After the prepatency period (time between infection and sexual maturity of the parasites with the beginning of excretion of eggs or larvae), the number of eggs per gram of feces was determined using the modified Mc> lastei method according to Wetzol (Tierärztliche Umschau ^, 209-210 (1951)). Immediately thereafter, the sheep were treated (generally h up to 8 animals px'o active ingredient, but at least 2). A suspension of 2.5 or 5 mg / kg body weight in 10 ml of a 1% igon TyJose suspension was administered to the animals pororally, and in one case also subcutaneously. On the 7th day of the treatment, the number of feces per gram of feces was again determined using the method given above

409883/1323

BATHROOM 0RK3INAL

t and ij.ue percentage Abi ι. ah in ο compared to the
Auegangsvex-t errechnot before dor treatment.

The table below shows the effect determined using the experimental method described above .
new substances according to the invention presented and compared with two known compounds of similar stimulus;
this is parbfndazole (previously P. Actor et al., Nature ^, 321 (1967); D. Ross, Veterinary Record
82: 731 (1968); I). R. Johns et al., Australian Veterinarian Journal ^, Ί6θ (1969)) and mebendazole (DOS 2,029,637).

The investigated new active ingredients o according to the invention
were designated as follows:

A = 5 ~ Phen o> r. j - ben; i: i.mld £ iz ο 1 - 2- methyl-carbamin at
13 = 5- ('l "chloro-p] ienoxy) -beiizimidazol ~ 2-ine th3 ^r l ~ cax ^s bcimiiiat C = 5""(3 ~ Clilor-pli.enoxy)" benaiiiiidazol-2-iHO tbyl-carbaminate D - 5- (2-Clilor-p] ienoxy) -benzini; ldazol-2-inethj'l-carbanjiiiat 3D = 5- (3-I ^v Iot ⁿ oxy-- pberio ^ -y) -benzimidazol-2 ~ niet ] iyl carbamate

The known active ingredients were designated as followsJ

Compare 1 = parbendazole
Compare 2 = mebondazole

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T a b e .1. J

Active ingredient Dο.s. cur. min.
in mg / kg application Effect in $ A. 2.5 perorally 100 " B. 5.0 perorally 9h C. 2.5 perorally 100 D. 5.0 perorally 96 E. 2.5 perorally 100 F. 2.5 pororal 100 P. 2.5 subcutaneous 100 See 1 15.0 perorally 100 '' See 2 10.0 perorally 76-100

As the table shows, the new carbaininates are in accordance with Compounds known to the invention have a similar structure superior to curativa due to the lower dose.

\
j

The dose tolerata maxima of the process products is both peroral and subcutaneous administration more than 3200 mg / kg body weight.

- 10 -

409883/1323

The active ingredients of the formula I are depending on the situation administered in doses between 0.5 and 50 mg per kg of body weight for 1 to 14 days.

For oral administration, tablets, coated tablets, capsules, powders, granulates or pastes come into consideration, which the active ingredients together with customary auxiliaries and carriers such as
Contain starch, cellulose powder, talc, magnesium stearate, sugar, gelatine, calcium carbonate, finely divided silica, carboxymethyl cellulose or similar substances.

Solutions can be considered for parenteral administration,
e.g. oily solutions made using sesame oil,
Castor oil or synthetic triglycerides, optionally with an addition of tocopherol as an antioxidant and / or using surface-active substances such as sorbitan fatty acid esters. In addition, aqueous suspensions can be used which are prepared using ethoxylated sorbitan fatty acid esters, optionally with the addition of thickeners such as polyethylene glycol or carboxymethyl cellulose.

The concentrations of the active substances according to the invention in the Preparations made therewith are preferably between 2 and 20 percent by weight for use as veterinary medicinal products; For use as human medicinal products, the concentrations of the active ingredients are preferably between 20 and 80 percent by weight.

4098 ^ 3/1323

- Ii -

Example 1;
5 ~ Phe r) ox y-benzimidazole-2-methyl-carba! Ninate

17.9 g of methyl bis-methylthio-methyleneaminoatneisate are added to 20.1 g of 3, ^ - diamino-diphenyl ether in 200 ml of tetrahydrofuran and reflux the mixture for a few hours. It is allowed to cool and the precipitated 5-phenoxy-benzimidaxol is sucked 2-methyl-carbaminate. After recrystallization from glacial acetic acid / methanol, the melting point is 248 with decomposition.

To prepare the 3i ^ ~ diamino-diphenyl ether used as the starting material, 172.5 g of 5 "chloro-2-nitro-aniline in 500 ml of dimethylformamide with 9 ^ g of phenol in the presence of 150 g of anhydrous potassium carbonate are refluxed for four hours . heats After cooling, it is diluted with 1000 ml of water, sucks the precipitated 3-amino ^/ i-nitro-diphonyläther from and purifying it by recrystallization from isopropanol, yield: 110 g, melting point: 142 ⁰ C.

IO3 g of the 3-amino-4-nitro ~ diphenyl ether thus obtained hydrogenated in 800 ml of dimethylformamide with Raney nickel under 100 at pressure at room temperature, the catalyst is filtered off and the solution evaporated in vacuo. The 3,4-diaminodiphenyl ether formed is available as a dark, syrupy masso, the one without further purification as above is used in the reaction.

Example 2:

5 "phenoxy-benzimidazole-2-methyl-carbaminate

To a cooled solution of 1917 g of imino-dithiocarbonic acid methyl ester hydrochloride and 12.5 g of methyl chloroformate in 50 ml of water are added dropwise to 10% sodium hydroxide solution, the temperature Should not exceed 10 C. As soon as the pH has adjusted to 7.5, 20.1 g of 3,4-diamino-diphenyl ether are added in 5% glacial acetic acid and heat the mixture for 2 hours Stir at reflux. It is allowed to cool and the 5-phenoxy-benzimidazole-2-methyl-carbaininate formed is filtered off with suction from the properties of the reaction product described in Example 1

/ 12

Procedure. 409393 / ^ 23

Examples 3 - 31 ^

The following connections are made in the same way:

3) From 3-amino ~ 'l-nitx ^ o-4-chloro-diphenylaether vom Melting point 135 C above the 3 j 4-diamino ~ 4'-chloro

\ diplieny.1 ether the 5 - (^ ~ dJ.or ~ phenoxy) -benziniidazol-2-methyl-carbaminate with a melting point of 197 C.

4) From 3-Amxno-4-nitro-3 '-cblor-diplienylae from melting point 114 C via the 3>' f-diamino-3 ^f -clilordiph.enylaetb.er the 5 ~ (3-chloro-phenoxy) -benzimidazol-2 ~ meth3'l-carbaminate vom Selimelzpixnkt 230 C.

5) From 3 ~ amino-4-n: Ltro-2 ^! -clilor-dxpl'ienylaethei * from the melting point 161 ° C via the 3, ^ f-diamino-2'-chlorodiphenyl ether the 5 ~ (2 "^> ChloT ^> -phenoxy) ~ benz: imiclas5ol · -2-metbyl-carbciininat from the melting point 200 "C.

6) from 3 ~ ^{Amino-'l-nitro-2-liter,} 5 '~ ^r dlchlor-dipheri3 laetber from

Melting point: 14O ° G on the 3, ^ - diamino ~ 2 ^t, 5'-dichloro ~ '■ diphenyl the 5 ~ (^, 5 "Diclilor-phenox3 ^r) -benzlmid- \ azol-2-methyl-carbamate of melting point 244 C.

7) From 3-amino ~ 4 ~ nitro-3 '> 5 ^f -diclilor-diplienylaether of melting point 162 ° C via the 3,4-diamino-3', 5 '~

ι dichloro-diphenyl ether the 5 ~ (3 »5-dichloro-phenoxy) - '■ benzimidazole-2-methyl-carbaininate with a melting point of 226 ° C.

8) _; 3 ~ Ainiiio-4-nitro-4'-bromo-diphen3 ^r laether of melting point 129 C over the 3 "4-Diamino ~ 4'-bromo-diphenyl ether, the 5 - (^ - I3rom-phenoxy) benzimidazole-2- Raetliylcarbaininat of melting point 248 C.

-12-

I 409883/1323

BATHROOM LOCAL GINAL

-13-

S) From 3-Amiiio-4-nitro-3 ^! -bx'oin - diphenylaetIier from S <point 127 C · when · the 3 "4-Diaiaiiio-3 ^t -barom-diphenyl ether, the 5- (3-Bi-oni-ph.enoxy) -benziniidazol ~ 2-methylcarbaminat from Schiselzpunkt 232 C.

From 3-amino-4 ~ nitro-2 ^I -bromo-diphenylaether of melting point 152 ° C via the 3 ^ -diamino-2 ^! -Bromodiphenyl ether the 5 - "{2-bromo-phenoxy) -benziHiidazol-2-iHethylcarbaminat with a melting point of 211 C.

From 3-amino-4-nitro-4 ^f -methyl-diphenyl ether with a melting point of 128 C over the 3? 4-Dianiino-4'-methyldijihenylaether 5- (4-methyl-phenoxy) -benzimidazole-2-methyl-carbaminate with a melting point of 251 C.

Of 3 ~ amino-4-niti "o-3 '-methyl-dxphonyJ.aether of melting point 110 ° C over the 3,4-diamino-3 ^f -methyldiphenylaether 5- (3-Mcthyl ~ phenoxy) -benzimidaüol-2 ~ methyl carbaminate with a melting point of 228 C.

3-Ainino-4-nitro-2 '-methyl-diphenylae tliei' of melting point 137 ° C over the 3 _s 4-diamino-2 * -mneth) ^ ldiphenylaether the 5- (2-methyl-phenoxy) -benzimidazole- 2-methyl-carbaminate with a melting point of 216 ° C.

From 3-amino-4-nitro ~ 4 ^I -t-Butyl-diphenyl ether of melting point Sh C over the 3,4-diamino-H-Mjert butyldiphenylaether-3- (4-tert-butyl _r phenoxy) -benza.midazol -2-ynethyl carbaminate with a melting point of 250 C.

3-Araino-4 ~ nitro ~ 2 ^f out, 4'-dimethyl-diphenyl ether of melting point 116 ° C for the ^{3,4-diamino-2-liter,} 4 ^l -dimethyldiphenylaother the 5 ~ "(2, 4-dimethyl ~ plienoxy ) ~ benzimide "azole-2 ~ methyl-carbamiriate melting point 239 C.

-13

409883/1323 **

From 3 ~ Ainino - 4 ~ nitro-2 · -chlor - '+ ^! -methyl diphenyl ether with a melting point of 15 ° C above the 3? '+ -Diamino-2' -chlor-4-methyl-diphenyl ether 5 ~ (2-chloro-4-methylphenoxy) -benzim: Ldazol ~ 2 -niethyJ -carbaminat of melting point 209 ° C.

From 3-amino-'i-nitro-2 '«chloro-6 ^! -nie thyl-diph.eiiylaeth.er with a melting point of 164 C above a? the 3>'l ~ ßiamiiio-2' -chloro-6'-methyl-diijhenylaether the 5 ~ (2 'chloro-6-motlryljjhenoxy) ~ benzimidazol-2 ~ m' ~ othyl carbamate of melting point 300 ° C.

IS) From 3 ~ -Amlno-4 - nitro-3 '-chlor -' + '-methyl-diphenylaethei " from the melting point> 139 ° C via the 3, 4-diamiiio-3'-chloro-4'-methyl-diphenylaothei ^ the 5 ~ (3-chloro-4-methylphenoxy) -benzimida.zol-2-thethyl-carbaminate with a melting point of 236 ° C.

From 3 ~ Amino-4 ~ nitro-3'-chloro-6'-never ethyl-dihenyl ether with a melting point of 14 ° C via the 3 "4-diarnino-3'-chloro-6 ¹ -methyl-diplienyl ether the 5th - (3-ChIor-6-methylphenoxy) -benzimidazol-2-methyl-carbaminate from the enamel

; point 218 ° C.

j From 3 - Ä.miiio-4-niti ^< o-3 '-chlox -' + ¹ -cax ^ boaethoxy-diphenyl-ether with a melting point of 13 ^ C via the 3 j4-diamino-3 '-chlor - '+' - carboaethoxy-diphenylaether 5- (3-chloro-4-carboaethoxy-phenox3 ^) - benzimidaz oil-2-methyl-carbaminate with a melting point of 19'l C.

From 3-amino-4-n: ltro-4'-chloro ~ 2 ^f -methyl-diphenyl ether with a melting point of 142 ° C via the 3,4-diamino-4'-chloro! 2 ^l -methyl-diphenylaetliei * the 5- (4-chloro-2-methyl-

ί -14-

BAD 409883/1323

; phenoxy) -bGnzimidazol ~ 2-mctliyl - carbaminate from Sclimelz-ί point 230 ° C.

22) From 3-Aiflino-4-nitro-4 * -chior-3'-methyl-diphenylaether of melting point 135 C via the 3> ^ -Diamino - ** ¹ -chlor-3 * -mothyl-diphenylae ther the 5 ""(^" - Clilor-3 ~ ynethylphenoxy) ~ benzimidazole ~ 2-methyl-carbamate with a melting point of 253 ° C.,

23) From 3-ainino-4-nitro-4'-chloro-3 ', 5 ^! -dimethyl-dipheiiylaether of melting point 158 C over the 3 _} ^ -Diamino-4 "-chlor-3 ', 5'-dimethyl-diphenylaether the 5- (A-Chior-3, 5-dä methyl-phenoxy) -benziiiiidazol- 2-methyl-carbaniiriate from melting point 239 C.

24) From 3-Ajnino-4-nltro ~ 3 '' 5 '-bis-trifluoromethyl-luoirniGthyl dipheiiylaether of melting point 129 C over the 3J4 ~ diamino-3', 5 '-bis-trifluoromethyl-diphenyl ether 5- (3, 5-bistr! Fluorine thy! -Phenoxy) -benzimidazole-2-meth3 ^r l-cai * bamJnat

^! with a melting point of 238 C.

.

25) From 3-amino ~ 4 ~ ialtro-J | ' -methoxy-diphenyl ether of melting point 169 C via the 3 '4-diamino-4 ^J -methoxydiphenylaether the 5 ~ (k-methoxy-phenoxy) ~ ben2; imidazol ~

, 2-methyl-carbamina.t from melting point 2h6 C.

26): From 3-Ajniiio-4 ~ nitro-3 ^! -methoxy-diphenyl from Sclimolzpunkt 128 ° C over the 3,4-ϋχΒΐηχηο ~ 3 x -methoxydiphenylaether 5- (3-M ^e thoxy-phenoxy) -benxisnidazol ~ 2-methyl-carbamate from Sclxmelzpunkt 203 C.

27) From 3-amino-4-nitro-2 ^l -methoxy-diphenylaether from the melting point I3O ⁰ C over the 3, 4-diamino-2 "-methoxy-

- 1 D

409883/1323

diphenyl ether 5- (2 ~ methoxy-phenoxy) -benzimidazole-2-methyl-carbaminate with a melting point of 212 ° C.

28. From 3-Amino - ^ - nitro-4'-propoxy-diphenyl ether (oily) over the 3ί4-diamino-4-propoxy-diphenyl ether, the 5 ~ (^ - pfopoxyphenoxy) -benzimidazole-2-methyl-carbatainate with a melting point of 218 ° C.

29. From 3-amino-4-nitro- ^/ i'-isopropoxy-diphenyl ether (oily) via the 314-diamino-4 ^f -isopropoxy-diphenyl ether the 5 - (^ - isopropoxy-phenoxy) -benzimidazole-2-methylcarbaminate from Melting point 208 ° C.

30. From 3-amino-4-nitro- ^/ i'-butoxy-diphenyl ether (oily) via the 31 ^ -diamino- ^ '- butoxy-diphenyl ether the 5- (4-butoxyphenoxy) -benziraidazole-2-methyl-carbaminate with a melting point of 210 ° C.

31. From 3-amino-4-nitro- ^z l ^f -iso-butoxy-diphenyl ether (oily) via the 3,4-diamino- ^ '- iso-butoxy-diphenyl ether 5- (4-iso-butoxy-phenoxy ) -benziniidazol-2-methyl-carbamate of melting point 198 ⁰ C.

Example 32: g-Phenoxy-benzimidazole ^ -butyl-carbaminate

The procedure is analogous to Example 1, using the bis-methylthiomethyleneamino formic acid-e-methyl ester by 22.1 g of bis-methylthiomethyleneaminoformic acid butyl ester replaced and so the 5-phenoxy-benzimidazole-2-butyl-carbaminate from the melting point 188 ° C.

Example 33:

J? -Ph onG xy-6-chloro-benziPlidazo l. -2-mGthyl-carbam i 11 at

Proceed as in Example 1, using the 3, ^ -Dia: i3xno-di ~ phenyl & ther by 23.6 g of 3, 't-diauino-o-chloro-dipheiiylether

409883/1323 ^{/ 1?}

replaced. The 5-phenoxy-6-chloro-benzimidazole-2-methyl-carbaminate is obtained in this way with a melting point of 27O C.

To prepare the 3 ^ - diamino-6-chloro-diphenyl ether used as the starting material, 20.7 g of t, 5-dichloro-2-nitro-aniline in 150 ml of dimethylformamide with 9.4 g of phenol in the presence of 1 g of anhydrous Potassium carbonate refluxed for 6 hours. After cooling, 150 ml of water are added, the mixture is stirred for a further 3 hours and the crude product is filtered off with suction. After Umkristallxsieren from glacial acetic acid / methanol gives 3 ~ Ainino-4-nitro-6-chloro-diphenyl ether of melting point 131 · ^O C.

41.5 g of the 3 ~ araino-'i-nitro-6-chloro-diphenyl ether obtained in this way are in 300 ml of dimethylformamide with Raney nickel Hydrogenated at normal pressure and 40 ° C. The filtrate from the catalyst is concentrated in vacuo. The remaining brown viscous mass of 31 ^ -Diamino-6-chloro-diphenylether is used without further purification for the reaction according to paragraph 1.

Example 3 * t - 36:

The following process products are produced analogously to Example 33:

409883/1323

34) From 3 ~ * Amiiio - ^ - nitro-6-cl ") loi '- ^' ~ chlor-diph.enylfietb.er from the melting point 210 ° C via the 3> ^ t-diamino ~ 6 ~ chloro-'l ^f -chlor'-diph.onylaether the 5 ~ (4 ~ chlorophenoxy) ö-chloro-benzimidazole ^ -methyl- ~ carbamin.at from the melting point 305 ° C.

) From 3-Άηι1ηο-J | --nxtro-6-ch.lor-3 '-chlor-diphenylae tilter

; from the end point 120 C through the 3 , ^ -diainino-o-chlox '* 3' -chior ~ d: Li) honylae ther the 5 ~ (3 ~ C) alox ^> plienox3i-) 6-chloro-acid: Lmidazole-2 -inethyl carbaniinate with a melting point of 263 ° C.

36) From 3-Aiiiino - 4-nitro-6-chloro-2 ^I -chlor-diphenylaetlier voiii melting point I67 C over the 3> ^ - Dia.mino ~ 6-chloro-2 -chloro-diphenylaether dp.η 5 '(2-chlorophenoxy) -6-chloro-benzImidazo1-2-mothyl-carbamate of melting \ point 238 ⁰ C.

Example · 37?

- ( k— ITydr oxy-p heno xy) -boiiziini d uz ο 1 - 2 -m e tliyl carbaiiii na t

The procedure is analogous to Example 1, using the 3,4-diaminodiphenyl ether through 21.7 g of 3,4-diamino-4'-hydroxy-diphenyl ether replaced. 5- (4-Hydroxyphenoxy) -benzimidazole-2-methyl-carbaminate is obtained in this way with a melting point of 238 C.

BAD ORfGINAL 409883/1323

To the division of de; s as an exit ?; materially used 3> ^! * ~ Diamino- ^ -hydroxy-dipbanylacthßrs Substituting 117 g Ί-hydroxyanisole in ^ 00 ml of dimethylformamide with 163 g of 5 ~ chloro-2-ni1; ro · - anllin to h hours at reflux in the presence of I32 g anhydrous potassium carbonate. After cooling down, it is diluted with 100 ml of water, the crude product is filtered off with suction, and after recrystallization from methyl glycol I5I S 3 ~ Aniino ~ ^ ln.itro · - ^ l'-mothoxy-diphenyl ether with a melting point of 16 $) '' C «

100 g of the 3-A.mlno ~ k ~ nltvo ~ k ^l -met.] Ioxy ~ di] i] ieny.L-ether obtained in this way are heated to the boil for 1 hour with 1 liter of hydrogenated biohydric acid. A clear lostmft is created,
from which a precipitate separates out after a short time. Egg'
is sucked off after cooling off from a mixture of
250 ml of ethanol and I3O ml of water recrystallized, with 60 {; des 3-Amino - ^ - nitro- ^ l'-hydroxy-diphcnj'laGtliors vom
Melting point 196 C can be obtained.

60 g of the nitro compound thus obtained are diluted in 100 ml
Dimethylformamide with Raney nickel at 50 atmospheres
Hydrogenated under pressure and at room temperature. The Filtx-at Λί-ird is suctioned off by the catalyst and evaporated in vacuo. The crude 3>-diamino-A '-hydroxy-diplionyl ether is used without
further purification further implemented.

Examples 38 and 30;

The following process products were carried out analogously to Example 37 manufactured:

38. From 3-A.iuino ~ 'l-n: i tro-3' -inothox3'-diphonyl aotlior vom

SchnioJ zpunJvt 128 C over 3 ~ Am.ino -'- i-n j tx ^ o-3 '-hydroxy-

-Ά0-

U 0 9 8 8 3/1 _{3 2 3 ^ 0 RK31NAL}

diphenyl ether (oily) and the 3 _t 4-diamino-3-hydroxy-diphenyl ether 5- (3-hydroxyphenoxy) -benzimidazole-2-methylcarbaminate with a melting point of 197 C.

39 · From 3-amino-4-nitro-2 ^f -methoxy-diphenyl ether with a melting point of 130 ° C. via 3-amino-4-nitro-2 ^l -hydroxy-diphenyl ether with a melting point of 134 ° C. and the 3-tert-diamino-2 ¹ -hydroxydiphenyläther 5- (2-hydroxy-phenoxy) -benzimidazole-2-methyl-carbamate of melting point 223 C.

Ex iel kO; 5-phenylthio-benzimidazole ~ 2-raethyl-carbaminate

The procedure is analogous to Example 1 _t, replacing the 3, ^ - diaminodiphenyl ether with 21.7 S 3i ^ -diaminodiphenyl thioether. After recrystallization from glacial acetic acid / methanol, 5-phenylthio-benzimidazole-2-methyl-carbaminate with a melting point of 233 ° C. is obtained.

To represent the 3, ^ - diamino used as the starting material Diphenyl thioethers are 22 g of thiophenol in 100 ml of dimethylformamide with 3 ^ i6 g of 5-chloro-2-nitro-aniline in the presence of 30 g of anhydrous potassium carbonate were refluxed for 6 hours. After cooling, 100 ml of water are added and that Sucked off raw product. After recrystallization from isopropanol, 38 g of 3-amino-4-nitro-diphenylthioether are obtained with a melting point of 112 C.

38 g of the 3-amino-4-nitro-diphenylthioether obtained in this way are placed in a solution which is obtained by dissolving 180 g Stannous chloride containing water of crystallization in 200 ml of glacial acetic acid and saturation with gaseous hydrogen chloride at room temperature was obtained. After a short time a precipitate separates out. The solvent is distilled off in vacuo and the mixture is added the residue with ice and excess concentrated sodium hydroxide solution. The oil that separates out is taken up in Xther. After the ether has evaporated, the 3,4-diamino

4098 8 3/1323

diphenyl thioether as an oil that can be used without further purification veitervex * is working.

Examples 4i to k $ i

g-Phenoxy-benzirflida2ol-2-methyl-carbaffiinate

man

The procedure is analogous to Example 1, with / instead of bismethyl methyl thio-methylene-amino-formate

41. 26.3 g of bis-butylthio-methylGnamino-formic acid methyl ester

k2, 27.3 g of allyl thi ο-cyclohexyl thio-inethyleneamino formic acid methyl ester

43 · 24.1 g of methylthio-phenylthio-methyleneamino-ameisensätiremethylester

44. 32.5 g of methylthio- (3,4-dichlorobenzylthio) -methyleneaminoformic acid methyl ester

45. 29.0 g of methylthio- (2-chloro-4-methylthio) -methylene amino formic acid methyl ester

used and in each case _: the 5-phenoxy-benziraidazol-2-iaethylcarbaminat, which is identical in its properties to the process product from Example 1.

/ 22

409883/1323

Claims (3)

Patent claims: 1 /, 2-carbalkoxy ~ amino-benzimidazole-5 (6) -phenyl ether of the formula (i) C-NH-COOR. (D, in R. alkyl with 1 to h carbon atoms, R ₀ and R each independently of one another hydrogen, hydroxyl, alkoxy with 1 to 4 carbon atoms, halogen, trifluoromethyl, alkyl with 1 to k carbon atoms or carbalkoxy with 1 to 4 carbon atoms in the alkoxy radical, R. denotes hydrogen or chlorine and X denotes oxygen or sulfur. 2. Process for the preparation of 2-carbalkoxy-amino-benziraidazole-5 (6) -phenyl ethers of formula (1) C-NH-COOR. (D, in which R _{1 is} alkyl with 1 to ¹ carbon atoms, R ₀ and R are each independently hydrogen, hydroxyl, alkoxy with 1 to k carbon atoms, halogen, trifluoromethyl, alkyl with 1 to 4 carbon atoms or carbalkoxy with 1 to k denotes carbon atoms in the alkoxy radical, R, hydrogen odor chlorine and X denotes oxygen or Schv.'efel, characterized in that an o-phenylene diamine derivative cter formula (5) / 23 409883/1323 ORIGINAL INSPECTED (5) in which R ₂ , R-, R. and X have the same meaning as in formula (1), with a bis-alkyl- or -arylthio-methylenaraino-araeic acid ester of formula (2) C = NC-OR ₁ (2) ti ■ * · 0 in which 'R _{1 has} the meaning given for the formula (1) and R ₀ and R- are either identical or different and an alkyl radical with 1 to k carbon atoms, an alkenyl radical with 3 to 5 carbon atoms, a cyclohexyl radical or mean an aryl or benzyl radical of the formulas (3) or (4), (3) where X is independently a halogen atom, a methyl or nitro group and η can assume the value 0, 1 or 2. R ₀ and R can also be connected to form a ring *. j
which contains 2 or 3 methylene groups. 3. Means for combating worms, characterized in that that there is a 2-carbalkoxy-aminobenzimidazole ~ 5 (6) -phenyl ether of the formula (1) in claim i in mixture with one 409883/1323 HOK 7 ^ / P 1C-3 Contains pharmaceutically usual carrier. k. Use of a substance according to formula (1) in claim 1 for combating worms. 409883/1323