NL8200339A - Antiparasitic 2-benzimidazolylcarbanates prepn. - from substd. 1,2-diamino-benzenes and isothioureas - Google Patents

Abstract

2-Benzimidazolyl carbamates of formula (I): (where R is 1-4C alkyl; R1 is -SO2R2, -SOR2, -SCN, -SR2, -OR5 or M'(CH2)nMR7; M and M1 are O, S, SO or SO2; R7 is 1-4C alkyl or aryl; n = 1-4; R2 is 1-4C alkyl, 3-7C cycloalkyl, 3-6C alkenyl or alkynyl; aralkyl or aryl; R5 is lower alkenyl, lower alkynyl or aralkyl) possess broad-spectrum anthelmintic activity. They are also active as fungicides for plant treatment.

Description

V N.O.30577 - 1 - /

A process for the preparation or manufacture of anthelmintic active pharmaceutical preparations and fungicidal preparations and a process for the preparation of anthelmintic and fungicidal 2-alkoxy-

a

carbo-nylamino-benzimidazole derivatives.

_V ____ _ _ _

The present invention relates to a process for the preparation or manufacture of anthelmintically active pharmaceutical preparations in which a 2-alkoxycarbonylamino-benzimidazole derivative is formed in a form suitable for therapeutic use, and for the preparation of fungicidal preparations in which a 2- alkoxycarbonylamino-benzimidazole derivative mixes with a carrier.

Such a method is known. For example, U.S. Pat. No. 3,574,845 discloses anthelmintically active 2-10 alkoxycarbonylaminobenzimidazole derivatives which contain, in the benzene core, one or two alkyl, alkoxy, trifluoromethyl, amino, hydroxy, nitro, alkyl mercapto, alkylamino, may contain dialkylamino, cyano, acylamino, carboxyl, carbalkoxy, N-alkylcarbamoyl or N-dialkylcarbamoyl groups, or halogen atoms as substituents. Israeli patent 27 * 006 corresponding to this U.S. Patent shows that within the large group of imidazoyl-2-carbamic acid esters described therein, the 5 (6) -n-butylimidazolycarbamic acid methyl ester (Parbendazole) exhibits the best activity, while 5 (8) - alkoxy compounds also show good activity, although the methoxy compound has less activity than the butoxy and propoxy compounds. Torch discloses a fungicidal action of 2-alkoxycarbonylaminobenzimidazole derivatives which, in the benzene nucleus, contain 1, 2 or 3 halogen atoms, alkyl enzyme alkoxy groups and additionally a chlorine atom or a nitro, methyl or ethyl group in U.S. Pat. as substituents.

It has now been found that the new compounds of formula I of the formula sheet and salts thereof, in which formula R is an alkyl group of 1-4 carbon atoms and R is a radical -M 2 - (-) located at position 2 (5). CH2) nMR, where n is an integer of 1-4, M and M. each is -0-, -S- or -S (0) -2 and R is an optionally phenyl or halogen substituted alkyl group having 1 -4 carbon atoms or an optionally substituted phenyl group with halogen, methyl and / or methoxy, an excellent 8200339 “i ............. *" ...... "" '... ....... '' "..............

- 2 - f '- anthelmintic and fungicidal action.

The compounds of the invention and their non-toxic salts, which are formed with pharmaceutically acceptable inorganic or organic acids or bases, have a broad spectrum activity against mammalian and human parasites, ie both adult and immature parasitic forms, such as, for example, of genera Tricho stronglylus, Haemonchus, Ostertagia, Cooperia, Nematodirus and Stronglyoides and more in particular against, for example, Nemato sp iro i de s dubius., Hymeno-10 lepis nana, Syphacia obvelata and / or Aspiculuria tetraptera. In particular, the compounds appear to have high activity against various helminth infections of the intestinal tract of economically important animals, which is associated with low systemic toxicity of the host animal.

The compounds of the invention are also useful as fungicides, in particular as systemic fungicides for controlling fungal diseases in plants, which are of economic interest.

The anthelmintic activity of the compounds of formula 1 and their salts can be determined as follows.

Four young male Swiss-Webster mice (16-20 g) are artificially infected with 200 larvae of Nematospiroides dubius and Hymenolepis nana. as well as naturally infected with 15-40 larvae of Syphacia obvelata and Aspiculuris tetraptera. The drug is administered in a commercially available rat / mouse diet at the indicated doses from day 1 to day 18. Infection is accomplished on day 0. The animals are sacrificed on day 18 and the parasites left in the entire small intestine, the cecum and the colon are counted and 50 by species. The mean number of each parasite species in each treated group is compared to the mean number left in the control group. This comparison is expressed as a percentage reduction compared to the parasites in the control group.

In the following Table A, some representative representatives of the compounds of formula 1 are listed.

Table B lists the values found for compounds of formula 1 in the above test along with those of the corresponding 5 (6) -n-butyl compound (Parbendazole).

8200339 - 3 -

v Table A

-j 5 (6) -] ¾ 2-methoxycarbonylaminobenzimidazoles, which are numbered in Table B.

Number of the E Melting or decomposition compound point 1 ethylsulfinylethylthio 190 ° C (dec.) 2 methylthioethylsulfinyl 172 ° C (dec.) 3 ethylsulfinylethylsulfinyl 169 ° C (dec.)

4 phenylthioethylthio 210-212 ° C

Phenylsulfinylethylthio 186-188 ° C

6 3 ~ pheno2ypropylthio 196 ° G (dec.) 7 3 ° f -rioxypropyl snylphinyl 189 ° C (dec.) 8 p-chlorophenylthiomethylsulfinyl + p-chlorophenylsulfinylmethylthioH ^ 174 ° C (dec.) 15 9 phenoxybutylthio 189-191 ° C (dec.) 10 2- (phenylsulfinyl) ethoxy 230 ° C (dec.) 11 2- (phenylthio) ethoxy 210 ° G (dec.) 12 2- (benzyloxy) ethoxy 191 ° C (dec.) 13 2- ( p-methylbenzyloxy) ethoxy 210-212 ° C (dec.)

Methoxymethylthio see Yoorb. I

Methoylthiomethylthio see Yoorb. II

16 methylthiomethoxy see Yoorb.IX

Methoxymethoxy see Yoorb.YIII

18 methoxymethylsulfinyl see Yoorb.YII

19 methylsulfinylmethoxy see Yoorb.IX

Ethoxymethylsulfinyl see Yoorb.YI

21 2-phenoxyethoxy see Yoorb.X

22 2-ethoxyethylsulfinyl see Yoorb.XII

23 2-methoxyethylsulfinyl see Yoorb.XII

30 24 2-phenoxyethylthio -------- 25 methylsnifinylmethylthio -------- 26 2-phenoxyethylsulfinyl -------- x) mixture 8200339 - 4 - fc j »

". Table B

Anthelmintic effect of

H

5 (6) -E -2 Haethoxycarbonylaminobenzimidazoles.

Number of the test organism 3? Ss ^ compound s) dose ** '(? Ó reduction) ppm Nd And So At

Comparison; R ^ = n.butyl (par-500 100 100 100 100 bendazole; IS 250 100 69 100 100 5,574,845 column 125 59 0 100 100 5, line 33) ~ 62.5 0 0 100 0 24 62, 5 0 0 100 100 31 00 100 100 1 125 0 0 100 100 62 0 0 100 100 25 125 95 ÏÖO ÏÖÖ ïöö 62 0 0 100 100 26 62 0 0 100 100 31 oo 100 100 8 125 0 0 90 100 62 o 0 39 100 2 125 50 0 100 100 62 0 0 100 100 3 62 0 0 100 100 4 125 75 o 100 100 62 00 100 100 5 62 0 0 100 100 6 125 o 100 100 100 62 0 77 100 100 7 125 75 100 100 100 62 o 100 100 100 31 o 72 100 100 16 0 0 97 100 9 Ï25 41 34 ÏÖÖ Ïöo 62 0 0 100 100 10 125 o 100 100 100 62 O 69 100 100 11 125 O 85 100 100 __62_O_75 100_100 8200339 * * - 5 -

Table B (continued) yyj yygp)

Hummer of dose 'Test organism compound x) ppm (% reduction) _M_Hn_, So_At_ 14 250 100 87 100 100 125 (2) 100 0 100 100 62.5 100 o 100 91 31 29 o 70 o 15 250 100 85 100 100 125 75 28 100 10a 62.5 0 0 100 100 16 125 (2) 97 92.5 100 100 62.5 (5) 83.3 14.3 100 100 31 (2) '58, 5 o 100 100 16 oo 95 34 17 250 100 o 100 100 125 94 0 100 84 62.5 (3) 93.3 0 92.7 64.3 31 (2) 55.5 0 53 0 16 (2) 40.5 o 18 .0 18 125 100 0 100 100 62.5 (3) 100 o 94.3 79.6 31 (2) 81 0 0 0 16 (2) 14.5 000 19 125 98 0 100 100 62.5 (2) 83.5 o 100 100 31 00 100 100 16 0 0 92 96 20 125 100 o 100 100 62.5 100 O 100 97

31 44 o 67 O

21 125 100 100 100 100 62.5 (2) 74 72.5 100 100 31 (3) 25.7 o 100 100 16 OO 98 100 ______ ___________ ____ · _____ 22 125 100 O 100 100 62.5 90 o 100 100 31 00 100 100 23 125 100 o 100 100 62.5 (2) 88 O 98.5 100 31 (3) 63 o 52.3 61 _16_O_O_O_52 x) Table A lists the compound numbers together with their names.

xx) The number in brackets indicates the number of tests, the average result of which is shown here.

8200339 - 6 - 'axis *) Nd = Nematosuiroides dubius

Hn = Hymenolepis nana So = Syphacia obvelata At = Asuiculuris tetrautera 5 According to the invention, the active substance defined in the first paragraph of this description uses an active compound of formula 1 or a salt thereof, in which formula ΊE is an alkyl group with 1-4 carbon atoms and E represent the above-defined residue -M-(CHO) -ME.

The term "alkyl group" as used in the description of the invention denotes straight or branched chain alkyl groups having 1 to 4 carbon atoms and thus includes primary, secondary and tertiary alkyl groups. Typical examples of these alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-15 butyl, isobutyl and tert-butyl groups. An alkyl group of the radical E may be optionally substituted with halogen or phenyl. The term "halogen atom" designates an iodine, bromine, chlorine or fluorine atom. The phenyl group can be optionally substituted with halogen, methyl or methoxy.

In addition to being anthelmintics and fungicides, some of the compounds of the invention are also useful as intermediates for the preparation of other compounds of the invention. For example, the 5 (6) sulfinyl compounds can be prepared from the corresponding 5 (6) thio compounds.

The term "non-toxic salts," as used in the description of the invention, refers to pharmaceutically acceptable salts of the compounds of the invention that do not adversely affect the fungicidal or anthelmintic properties of the base compound, such as the salts commonly used in the present field. These non-toxic salts include, for example, salts of inorganic acids, such as, for example, sulfuric acid, sulfonic acid, sulfamic acid, nitric acid, phosphoric acid, hydrochloric acid and the like, and salts of organic acids such as, for example, acetic acid, citric acid, lactic acid, palmitic acid, tartaric acid, tartaric acid, maleic acid, benzoic acid and the like.

The compositions are prepared in known manner, and may contain conventional auxiliaries and excipients as anti-fungal agents in plants.

40 Helminth-active pharmaceutical preparations may be mixtures of feedingstuffs or feed components with the active substance, 8200339-7. It is also possible to prepare and manufacture other preparations for oral administration, such as filled gelatin capsules, tablets, pills, suspensions, etc. In general, the active substance is mixed with a solid or liquid carrier. Examples of solid carriers are corn starch , terra alba, lactose, sucrose, calcium phosphate, gelatin, stearic acid, agar and pectin. Examples of suitable liquid carriers are arachis oil, sesame oil and water. The invention also relates to a process for the preparation of 2-alkoxycarbonylaminobrizimidazole derivatives with anthelmintic and fungicidal action, suitable for use in the above-mentioned method of preparing pharmaceutical and fungicidal preparations, characterized in that compounds of formula I and salts thereof as defined above are prepared in a manner known for the synthesis of analogous compounds.

Generally, the compounds of the invention may be prepared from benzene starting materials with nitro and amino or acylamino (e.g. acetamido) substituents at adjacent sites of the benzene core (e.g. at sites 1 and 2) and the desired radical R (or a residue which can be reacted to form the desired residue R) in position 4 or 5 of the benzene core (ie in the position which will later be position 5 or 6 in the benzimidazole compound to be prepared) . The nitro group is reduced to one amino group to give a benzene derivative having amino groups in positions 1 and 2. The diamino compound is then reacted with a 1,3-bis (alkoxycarbonyl) S-alkyl isothiourea, to obtain the corresponding benzimidazole 2-carbamate derivative substituted in position 5 (6).

The functional residue in position 4 or 5 of the benzene used as starting material can be, for example, the thiocyanato group, which will remain in place unchanged during the formation of the residue of the benzimidazole-2-carbamate or according to known reactions. can be converted into the group -S-iCHg ^ -MR, which in turn can be converted into the group -S (0) - (CHg) nMR according to known reactions. The functional moiety in position 4 or 5 may also be a chlorine atom, which can be reacted with a substituted alkyl mereaptan to obtain the corresponding -S- (CHg) MR ^ compound, which in turn can 8200339-8 - are converted to the snifinyl compound. In this regard, it should be noted that the thiocyanato and chlorine starting materials are compounds already described in the literature.

A synthesis which may serve to illustrate these steps is illustrated by the reaction scheme of Fig. 1 wherein the residue represents R-M-1GHg - and R, R, M and n have the above meanings.

Another synthesis is elucidated with reference to the A 2 reaction scheme of Fig. 2, in which E ^ represents the remainder E -Μ, - ζΟΗ ,,) - 2 * - n 10 and E, E, M and and n de have the above meaning.

A suitable starting material for the synthesis of Figure 1 is the 1-acetamido 2-nitro 4-thiocyanatobenzene (of the formula 2) which can be prepared according to the method of E. Challenger and A.T. Peters, J. Chem. Soc. 1364 (1928). Starting materials for the other 15 syntheses are for example 1-amino 2-nitro 4-khiocyanatobenzene, 2-amino 4-chloro 1-nitrobenzene, 2-acetamido 4-chlorophor 1-nitrobenzene, 1-acetamido 4-hydroxy 2 nitrobenzene and 1-amino 4-hydrosy-2-nitrobenzene.

The conversion of an acylamino group, for example an acetate-amido group, into an amino group, as illustrated for example by reaction steps I, V, YII and XY, can be carried out by the acylamino group-containing compound with a strong acid, such as hydrochloric acid, or treat a strong base, such as sodium hydroxide, potassium hydroxide, potassium carbonate, or sodium carbonate in aqueous methanol at about 20 ° C to about 100 ° C for about \ to about 24 hours.

The reduction of the nitro group to an amino group as illustrated by reaction steps VIII, XI and XYI can be carried out by various techniques. For example, the nitro-30 group can be catalytically reduced using hydrogen in the presence of a palladium / charcoal catalyst. This conversion is carried out in an inert solvent, such as methanol, from about 1 to about 2 hours at a temperature of about 0-35 ° C and generally at about room temperature. Other suitable inert solvents are ethyl acetate, acetic acid and ethanol.

According to another suitable reduction technique, the nitro compound is treated with iron powder and ferrous salt, such as ferrous sulfate or ferrous chloride, in aqueous methanol, refluxing the mixture under neutral conditions for about 1-6 hours under 8200339-9. Other suitable reaction mediums are acetic acid and concentrated hydrochloric acid, while other suitable metals can also be used, such as zinc. It is desirable to add the iron powder in portions (and thus not all of a sudden) and carefully control the reactants and reaction conditions to ensure, for example, that sulfinyl compounds are not reduced to the corresponding thio compounds. This technique is suitable for materials containing a phenylthio substituent.

According to a reduction technique suitable for use with thiocyanato or phenylthio compounds, these compounds are treated with stannous chloride in concentrated hydrochloric acid at a temperature within the range of about -20 ° C to about + 100 ° C, in the generally at room temperature, using a reaction period from about one to about 6 hours. An excess of stannous chloride should be used as the reactant, generally about 5 parts by weight per part by weight of the starting compound.

The reduction can also be carried out with sodium diethionite (sodium hydrosulfite) in alkaline aqueous methanol, by refluxing for 10 minutes to 6 hours.

The diamino compounds, such as, for example, the compounds of formulas 8, 14 and 19 are converted into the corresponding benzimidazole 2-carbamate compounds, for example according to reaction steps IX, XII and XVII, by the diamino compound with a 1,5-bis (alkoxycarbonyl) S-alkylisothiourea, for example 1.3-bis (methoxycarbonyl) S-methylisothiourea or 1,3-bis (ethoxycarbinyl) S-methylisothiourea, to react in an aqueous alcoholic medium, for example aqueous methanol or aqueous ethanol, at a temperature within the range of about room temperature to the temperature at which the reaction medium refluxes, with a reaction time of about one until about 6 hours is applied. The reaction medium is preferably acidified to a pH of about 4-6 with, for example, a vol-35 amount (e.g., 1-2 moles) of acetic acid. About 1-2 moles, generally about 1.1 moles, of the isothiourea reaction component is used per mole of the diamino compound.

The conversion of the thiocyanato group of the 1-acetamido 2-nitro 4 "phhiocyanatobenzene used as starting material to a 40 group -S-iCHg ^ -MR simultaneously with the conversion of the acetamido-8200339-10 group to one amino group, as indicated by reaction step IV, can be carried out by treating the thiocyanato compound (e.g. the compound of the formula 2) with a compound of the formula X-CCHg ^ ME, wherein X represents halogen, in dimethyl-5 formamide or an alcoholic medium such as methanol or ethanol, in the presence of a base, such as potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate. The conversion is carried out at a temperature from about 10 ° C to about 50 ° C, generally at about room temperature, over a period of from about 10 to about 12 hours, with a substantially molar ratio of the major reactants is used. The conversion is preferably carried out in isopropanol or dimethylformamide. Optionally, the thiocyanato group can be converted into a group -S- ^ CHg ^ -MR without changing the acetamido group 15, as illustrated by reaction step III, by the 1-acetamido 2-nitro 4- used as starting material Thioeyanatobenzene at room temperature for about 1 to about 2 hours with sodium borohydride in dimethylformamide, followed by treatment with the above-mentioned halide reaction components under the conditions described above. The same conditions are used in the conversion of the compound of formula 3 to the compound of formula 4 via step (11).

The conversion of an amino group to an acylamino group, for example an acetamido group, as illustrated by reaction step XIII, can conveniently be carried out by treatment with an acyl halide, for example acetyl chloride, or acetic anhydride in an inert organic reaction medium, which is suitable or is adapted to dissolve the compound to be treated. Suitable organic reaction environments are, for example, tetrahydrofuran in the presence of pyridine, acetone in the presence of a base, such as potassium hydroxide or potassium carbonate, or pyridine as such. Acetic anhydride can be used as an acylation reaction component and can moreover be used as a reaction medium. If the acetic anhydride is used in this way, it is present in a substantial excess, generally in an amount sufficient to dissolve the compound to be converted. The well-known Schotten-Baumann reaction can also be used for the above-described purpose. In this reaction, the compound to be treated is dissolved in an aqueous base, an excess of acetic anhydride is added and the precipitated product is collected by filtration. If acetic acid ash hydride is used in these conversions, it can be used in combination with an acidic catalyst, such as sulfuric acid or p-toluenesulfonic acid. These conversions are typically performed at a temperature of about -30 ° C to about room temperature over a period of about one hour to about 24 hours using a slight excess (about 1.5-2 moles) of the acylating agent.

-j

The conversion of the thio group (s) into the substituent R into the corresponding sulfinyl group as illustrated by reaction steps VI, XIV and XIV 'is suitably carried out by treatment with a peracid, such as peracetic acid, perbenzoic acid, m chloroperbenzoic acid or perphthalic acid, in an inert solvent for the compound to be treated. Suitable solvents are, for example, dichloromethane and chloroform. If the compound to be treated is not soluble in the particular reaction medium desired to be used, an auxiliary solvent such as acetic acid or methanol is to be used in an amount sufficient to dissolve the compound to be treated. In particular, the conversion is carried out at a temperature from about -30 ° C to about room temperature over a period from about one hour to about 6 hours. Molar amounts are used to convert the thio group (s) to the corresponding sulfinyl group (s) and the reaction conditions are carefully controlled to ensure that the reaction proceeds no further than desired. Optionally, this conversion can be carried out by treatment with periodate in aqueous methand or aqueous acetonitrile at a temperature from about -20 ° C to about -50 ° C over a period from about 1 to about 12 hours.

If 2-amino 4-chloro-1-nitrobenzene (of the formula 12) or 2-acetamido-4-chloro-1-nitrobenzene is used as starting material, it can be converted into the corresponding R 1 -St 1 -CH 2 -S compound, such as is illustrated by reaction clap X, 35 by reacting it with the appropriate mercaptan, in an inert solvent, such as dimethylformamide, ethanol or methanol, in the presence of a suitable inorganic base, such as potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydroxide or sodium hydride. This conversion is usually carried out at a temperature from about 20 ° C to about 150 ° C (ie about 8200339 - 12 - the temperature at which the solvent material is refluxed) over a period of about one § Up to about 6 hours using a slight excess (1.5 -2 mol) of the meroaptan reaction component. Reaction step XVIII can be carried out as described for reaction step X, although this conversion is preferably carried out in dimethyl formalde using, for example, 2-acetamido 4- chloro 1-nitrobenzene (of the formula 21) as starting material.

Compounds having the substituent -0 (CHg) nMR in the .105 (6) position may be prepared by reacting 1-acetamido 4-hydroxy-2-nitrobenzene with an optionally phenyl-substituted haloalkylphenyl ether (such as 2-bromoethylphenyl ether) , an optionally substituted haloalkylalkyl sulfide (such as chloromethylmethyl sulfide), or an optionally substituted haloalkylalkyl ether (such as chloromethylmethyl ether), etc., and then carry out the other steps as necessary and in the manner described above to obtain * the desired compound . Compounds 2 with the substituent -SiCHg ^ MR ^ in position 5 (6) can be prepared by treating 1-acetamido 2-nitro 4-thiocyanatobenzene at room temperature with sodium borohydride in dimethylformamide for about 2 to about 2 hours, followed by treatment with an optionally substituted haloalkylalkylsulfide (such as chloromethylmethylsulfide), an optionally substituted haloalkylalkyl ether (such as chloromethylmethyl ether), an optionally substituted phenyl-substituted haloalkylphenyl sulfide (such as chloromethyl-p-chlorophenyl sulfide), as described above, etc., as described above, etc. to obtain the desired connection. The thio bridges in the substituents -M ^ CHg ^ MR ^ can be converted to the corresponding sulfinyl bridges according to the steps described above.

Examples of the compounds according to the invention, which correspond to the formula 1, include the following compounds: 5 (6) -methylthiomethylthio 2-methoxycarbonylaminobenzimidazole 5 (6) -methoxymethylthio 2-methoxycarbonylamino-benzimidazole [5] (6) -methoxymetho2ylamino-benzoyl-2-metho-3-benzoyl (6) -methylthiomethoxy 2-methoxycarbonylaminobenzimidazole 5 (6) -methoxymethylsulfinyl 2-methoxycarbonylaminobenzimidazole 5 (6) -methylsulfinylmethoxy 2-methoxycarbonylaminobenzimidazole.

These compounds are currently preferred, because they exhibit substantial activity against the above mentioned helminths.

Other representative compounds which are "within the scope of the invention include, for example: 5 (6) -trifluoromethylthiomethylthio-2-methoxycarb onylamino-benzimidazole 5 (6) -trichloromethylthiomethylthio-2-methoxycarbonylaminobenzimidazole 5 (6) -trifluoromethyl 2-methoxyoarbonylaminobenzimidazool 5 (6) 2--methoxyethylthio methoxycarbonylaminobenzimicLazool 10 5 (6) 2--methoxyethylsulfinyl methoxycarbonylaminobenzimidazooi 5 (6) -ethoxyethylthio 2-methoxycarbonylamino-benzimidazole-5 (6) -ethoxyethylsulfinyl 2-methoxycarbonylamino-benzimidazole-5 (6) 2-methoxycarbonylamino-5 -methoxyethoxy (6) -ethoxyethoxy 2-methoxycarbonylamino-15, 5 (6) -ethoxymethylthio 2-methoxycarbonylamino-benzimidazole-5 (6} ethoxymethylsulfinyl 2-methoxycarbonylamino-benzimidazole-5 (6) -methylthioethylthio 2-methoxycarbonylamino-benzimidazole-5 (6) -methylsulfinylethylthio 2-methoxycarbonylamino-benzimidazole-5 (6) -methylthioethoxy 2-methoxycarbonylaminobenzimidazole 5 (6) -methylsulfinyle thoxy 2-methoxycarbonylaminobenzimidazole? 5 (6) -methylsulfinylmethylthio 2-methoxycarbonylaminobenzimidazole; melting point 189 ° O (with decomposition) 5 (6) -phenoxyethoxy 2-methoxycarbonylaminobenzimidazole 5 (6) -phenoxyethylthio 2-methoxyoarbonylaminobenzimidazole; melting point 25 205 ° C (with decomposition) 5 (6) -phenoxyethylsulfiny1 2-methoxycarbonylamino and enzimi dazole; melting point 227 ° C (with decomposition) 5 (6) - (p-chlorophenylthiomethylthio) 2-methoxycarb onylamino benzimidazole; melting point 206-207 ° C (with decomposition) 5 (6) -phenylsulfinylmethyl-11hio-2-methoxyoarbonylamino-benzimazazol and the corresponding 2-ethoxycarbonylamino, 2-propoxycarbonyl-amino and 2-butoxycarbonylamino compounds.

Preparation instructions

175 S of S-methylisothiouronium sulfate in 1 liter of water are cooled to a temperature of 0 ° C, followed by the addition of 162.5% methyl chloroformate, followed by the addition of a solution of 25 g of potassium hydroxide in 750 ml of water at a temperature of 0-5 ° 0. The crude product is extracted with benzene, the benzene extract is dried and evaporated and the residue is recrystallized from methanol. The 1,3-bis (methoxycarbonyl) S-methyl isothiourea is obtained in this way.

Similarly, by replacing the methyl chloroformate with ethyl chloroformate, propyl chloroformate and butyl 5 chloroformate, the 1,3-bis (ethoxycarbonyl) S-methylisothio urea, 1,3-bis (propoxycarbonyl) S-methylthothiourea, and the 1-3-bis (butoxycarbonyl) ) -S-methylisothiourea.

Example I ......

2.37-1-acetamido-2-nitro-4-thiocyanatoben-10-zene in 10 ml of dimethylformamide is treated under a nitrogen atmosphere at a temperature of 20 to 25 ° C with 0.38 g of sodium borohydride. After 1 hour, 1.6 ml of chloromethyl methyl ether are added, after which the mixture is kept at a temperature of 20 to 30 ° C for a further 3 hours. Water is then added and the product is filtered off. Recrystallization from cyclohexane gives the 1-acetamido 2-nitro 4-methoxymethylthiobenzene.

1.4 g of 1-acetamido 2-nitro 4-methoxymethylthio-benzene with 3 nil of a 5 M sodium hydroxide solution and 6 ml of methanol are treated on a steam bath for about 15 minutes. The mixture is stripped in vacuo and the residue is extracted with chloroform. The dried extracts are evaporated to give the 1-amino 2-nitro 4-methoxymethylthiobenzene in the form of a red crystalline solid.

1.3 g of 1-amino 2-nitro 4-methoxymethylthio-25-benzene in 80 ml of methanol and 20 ml of water are treated under a nitrogen atmosphere with 0.7-ferrous sulfate and 2.8 g of iron (added in two amounts) for 4 reflux for hours. The mixture is filtered and stripped in vacuo, after which the residue is recrystallized from eyclohexane. The 1,2-diamino-4-methoxymethylthiobenzene is thus obtained.

A mixture of 0.85 g of 1,2-diamino 4-methoxymethylthio-benzene and 1.0 g of 1,3-bis (methoxycarbonyl) S-methylisothiourea in 25 ml of ethanol and 25 ml of water is treated with reflux under 0.7 ml of acetic acid . After 4 hours, the mixture is cooled and filtered to yield the 5 (6) -methoxymethylthio 2-methoxycarbonylaminobenzimidazole, which can be recrystallized from methanol / chloroform (mp 200-201.5 ° C). The yield of the last step is about 75, the overall yield is also about 75%. 8200339-15. By replacing the chloromethyl methyl ether with the chloropropyl methyl ether, the 1,2-diamino 4 ** diethoxypropylthiobenzene and 5 (6) -methoxy-propylthio 2-methoxycarbonylaminobenzimidazole (melting point 5 171> 5-174 ° C) are obtained in a similar manner. -bis (methoxycarbonyl) S-methylisothiourea can be replaced by 1,3-bis (ethoxyearbonyl) S-methylisothiourea, 1,3-bis (propoxycarbonyl) S-methylisothiourea or 1,3-bis (butoxy-carbonyl) S-methylisothiourea in the same way the corresponding 5 (é) -alkoxyalkylthio 2-alkoxycarbonylaminobenz-10 imidazole compounds, wherein voorstellen represents an ethyl, propyl or butyl group.

Example II

5.85 of 1-amino 2-nitro-4-thiocyanatobenzene in 20 ml of dimethylformamide are treated under nitrogen at a temperature of 15 to 25 ° C with 1.14 g of sodium borohydride. After 1 hour, 10 ml of methylthiomethyl chloride are added, the mixture is stirred overnight, diluted with water and extracted with chloroform. The dried chloroform solution is passed through a silica gel column and then evaporated to dryness leaving the 1-amino-2-nitro-4-methylthiomethylthiobenzene as a red solid.

Then 2.5 8 1-amino 2-nitro 4-methyl-thiomethylthiobenzene in 1/10 ml of methanol and 40 ml of water are treated with 1.25 g of ferrous sulfate and 5 iron powder (which iron powder is added in two parts 25) for 5 hours refluxing. The mixture is filtered and stripped and the residual oily 1,2-diamino 4-methylthiomethylthiobenzene extracted with chloroform, washed, dried and isolated. by evaporating the solvent.

A mixture of 1.8 g of 1,2-diamino 4-methylthiomethylthiobenzene, 1.9 8 l of 3-bis (methoxycarbonyl) S-methyl isothiourea and 0.8 ml of acetic acid in 20 ml of ethanol and 20 ml of water is Refluxed for 5 hours, cooled and filtered. The product, the 5 (6) -methylthiomethylthio 2-methoxycarbonylaminobenzimi-35 dazole, is purified by recrystallization from methanol / chloroform (mp 208-210.5 ° C). Overall yield 20%

By replacing the methylthiomethyl chloride with ethylthiomethyl chloride or ethylthioethyl chloride, 5 (6) -methylthioethylthio-2-methoxycarbonylamino-40 benzimidazole (melting point 209 ° C, decomposition) and 8200339-16 - are likewise obtained. 5 (6) -ethylthioethylthio 2-methoxy carbonyl aminobenzimidazone (melting point 297 ° C, decomposition). By reacting the 1,2-diamino 4-alkylthioalkylthiobenzenes prepared in this way with 1,3-bis (ethoxycarbonyl) S-methylisothiourea, 1,3-bis (propoxy-carbonyl) S-methylisothiourea or 1,3-bis (butoxycarbonyl) S-methyl- isothiourea instead of with the 1,3-bis (methoxycarbonyl) S-methyl isothiourea, the corresponding 5 (6) -alkylthioalkylthio-2-alkoxycarbonylaminobenzimidazole compounds are obtained in which R represents the ethyl, propyl or butyl group.

Example III

6 g of 1-acetamido 4-hydroxy 2-nitrobenzene are added to 200 ml of acetone containing 25 g of potassium carbonate and 6 ml of chloromethylmethylsulfide. The mixture is refluxed for 4 hours and filtered. After evaporation of the acetone, the 1-a-15 ceetamido 4-methylthiomethoxy 2-ni, trobenzene remains as a gummy material. This is purified by column chromatography.

5 µl of 8 1-acetamido 4-methylthiomethoxy-2-nitrobenzene are added to a mixture of 12 ml of a 5 N NaOH solution and 60 ml of methanol, and the mixture is heated on a steam bath for 15 minutes. The mixture is poured into 500 ml of water and extracted with dichloromethane. The dichloromethane phase is separated, dried over sodium sulfate and evaporated to leave the 1-amino 4-methylthiomethoxy 2-nitrobenzene as a gummy material. This gummy material is dissolved in a mixture of 5 ml of acetic acid and 95 ml of methanol. 8 g of iron powder are added and the mixture is refluxed for 2 hours. The methanol and acetic acid are evaporated and the residue is extracted with 200 ml of hot tetrahydrofuran. This solution is filtered and the tetrahydrofuran is evaporated, yielding the 1,2-diamino 4-methylthiomethoxybenzene in the form of a gummy material. This is purified by column chromatography.

4 l of 1,2-diamino 4-methylthiomethoxybenzene, 1,3-bis (ethoxycarbonyl) S-methylthiothiourea and 1 g of acetic acid are dissolved in 50 ml of ethanol and 50 ml of water and the solution is boiled under reflux for 3 hours. The mixture is cooled and the 5 (6) -methylthiomethoxy-2-methoxyearbonylaminobenzimida sole is filtered off and washed with methanol. Recrystallization can be carried out from methanol / chloroform. Melting point 8200159-17, 215-217 ° C, with decomposition.

Similarly replace the chlorine thyme thy1 sulfide with chloroethylmethylsulfide 5 (6) -methylthioethoxy-2-methoxycarbonylbenzimidazod, mp 214-217 ° C, prepared under decomposition.

Example IV

1-Acetamido 4-hydroxy 2-nitrobenzene is treated with chloroethyl ethyl ether under the conditions described in Example III (or similar or analogous conditions) to give 5 (6) - (2-ethoxyethoxy) -2-methoxycarbonylaminobenzimidazole (melting point 206- 208 ° C, with decomposition).

Example V

Mén dissolves 2.4 to 100 percent sodium hydride in 120 ml of 2-methoxyethanol and adds 12 g of 2-nitro 5-chloroaniline. The mixture is refluxed for 4 hours, cooled and poured into water. The 2-nitro 5- (2-methoxyethoxy) aniline is collected by filtration.

A mixture of 11 g of 2-nitro-5- (2-methoxyethoxy) aniline, 220 ml of methanol, 40 ml of water, 40 g of sodium carbonate and 60 g of sodium hydrosulfite is refluxed for 15 minutes. The solution is concentrated, diluted with water and extracted with chloroform. After evaporation of the chloroform, the 1,2-diamino 4- (2-methoxyethoxy) benzene remains as an oil, which has sufficient purity for the next step.

A mixture of 1.8 g of 1,2-diamino 4- (2-methoxyethoxy) benzene, 2.2 g of 1,3-bis (methoxycarbonyl) S-methyl isothiourea and 0.8 ml of acetic acid is added in 20 ml of ethanol and 20 ml of water refluxed for 4 hours. The cooled mixture is filtered to give the 5 (6) - (2-methoxyethoxy) 2-methoxy-50-carbonylaminobenzimidazole, which can be recrystallized from methanol / chloroform. Melting point 213-215 ° C.

Example VI

A mixture of 5 2 2-nitro 5-chloroaniline and 7.5 natrium sodium sulfide monohydrate is refluxed in 25 ml ethanol and 25 ml water for 1 hour, diluted with water to a total volume of about 150 ml and filtered to remove a small amount of an insoluble contamination. The filtrate is treated with 2.5 ml of acetic acid and the 2-nitro-8200339 (- - 18 - 5-mereaptoaniline is filtered off.

A solution of 3.4 g of 2-nitro 5-mercaptoaniline in 20 ml of dimethylformamide is treated with 0.5 g of 100% sodium hydride, after which 2.2 g of chloromethyl ethyl ether are added to the solution. After 30 minutes at a temperature of 20-25 ° C, the solution is diluted with water and extracted with chloroform. Removal of the chloroform leaves 2-nitro 5- (ethoxymethylthio) aniline as an oil.

The above-described oil is treated for 15 minutes in a boiling mixture of 50 ml of methanol, 50 ml of water, 12 g of sodium carbonate and 12 of sodium hydrosulfite. The mixture is concentrated, diluted with water and extracted thoroughly with chiroform. After evaporation of the chloroform, 1,2-diamino-4-ethoxymethylthio-benzene remains in the form of an oil.

A mixture of 2.6 g of the oil obtained as described above, 2.6 g of 1,3-bis (methoxycarbonyl) S-methylisothiourea and 1 ml of acetic acid is treated with 40 ml of 50% ethanol in water by stirring for 4 hours under to reflux. The cooled mixture is filtered to give the 5 (6) -ethoxy-20-methylthio-2-methoxycarbonylaminobenzimidazole, which can be recrystallized from methanol / chloroform. Melting point 199-201 ° C.

0.84 g of 5 (6) -ethoxymethylthio 2-methoxycarbonylamino-benzimidazole are dissolved in a mixture of 50 ml of chloroform and 10 ml of acetic acid. The solution is treated with a solution of 0.62 g of m-chloroperbenzoic acid in 15 ml of chloroform at a temperature of -30 to -20 ° C, and the temperature of the reaction mixture is allowed to slowly rise to room temperature. After 15 hours, the solvent is removed in vacuo and the residue is treated with a dilute potassium bicarbonate solution. The crude 5 (6) -30 ethoxymethylsulfinyl 2-methoxycarbonylaminobenzimidazole is filtered off and recrystallized from methanol / chloroform.

Melting point 200 ° C, with decomposition.

Example VII

A solution of 2.37 g of 1-acetamido 2-nitro 4-thiocyanato-35 benzene in 10 ml of dimethylformamide is treated with 0.38 g of sodium borohydride under a nitrogen atmosphere at a temperature of 20 to 30 ° C. After 1 hour, 1.6 ml of chloromethyl-methyl ether are added at a temperature of 20-30 ° C, after which the mixture is diluted with water after 3 hours and filtered 8200339-19. is becoming. The crude 1-acetamido 2-nitro 4-methoxyme thy 11 hiobenze and is recrystallized from cyclohexane.

1.4 g of 1-acetamido-2-nitro-4-methoxymethylthio-benzene in 6 ml of methanol are treated with 3 ml of a 5 M sodium hydroxide-5 aqueous solution by boiling under reflux for 15 minutes. The solvent is removed in vacuo and the residue is diluted with water and extracted with chloroform. Evaporation of the chloroform gives 2-nitro 4-methoxymethyl-thioaniline in the form of reddish crystals.

1.4 g of the aniline compound described above are treated in a refluxing mixture of 80 ml of methanol and 20 ml of water with 1.4 g of iron powder and 0.7 of ferrous sulfate. After 2 hours, 1.4 g of iron are added. After a further 1 to 2 hours, the mixture is filtered and the filtrate is concentrated in vacuo. The 1,2-diamino 4-methoxymethylthiobenzene obtained as residue is recrystallized from cyclohexane.

1.7 g of 1,2-diamino 4-methoxymethylthiobenzene with 2.0 g of 1,3-bis (methoxycarbonyl) S-methylisothiourea and 0.7 ml of acetic acid are treated under reflux for 4 hours in 50 ml of 50% aqueous ethanol. to cook. The mixture is cooled and the 5 (6) -methoxymethylthio 2-methoxycarbonylaminobenzimida sole is filtered off. The product can be recrystallized fromomethanol / chloroform. Melting point 200-201.5 C, with decomposition.

0.53 van of the benzimidazole obtained as described above is dissolved in a mixture of 50 ml of chloroform and 50 ml of acetic acid at a temperature of -15 ° C. A solution of 0.41 m-chloroperbenzoic acid in 10 ml of chloroform is added at a temperature of -15 to -10 ° C, after which the temperature of the mixture is allowed to rise to 20-25 ° C * Ha over 10 hours. at a temperature of 20 to 25 ° C, the solvent is removed in vacuo and the residue is carefully treated with a dilute sodium bicarbonate solution (to a pH of about 7). The crude product is filtered off and recrystallized from methanol / chloroform and then the 5 (6) -methoxymethylsulfinyl 2-methoxycarbonylamino-benzimidazole. Melting point 300 ° 0; mass spectrum: m / c = 283 (m +) $ base peak = 45

Example VIII

A mixture of 4 8 4-Hydroxy 6-nitroacetanilide, 17 g ka- S 2 0 0 3 3 9 - 20 ->

a

lium carbonate and 4 g of chloromethyl methyl ether, are refluxed in 50 ml of acetone under a nitrogen atmosphere for 4 hours. The hot mixture is diluted with 200 ml of hot acetone and then filtered. The solvent is evaporated to yield the 4-methoxymethoxyacetanilide in the form of a crude oil.

4.5 S of 2-nitro 4-methoxymethoxyacetanilide are heated for half an hour with 10 ml of a 5% sodium hydroxide solution and 60 ml of methanol. The solution is then cooled and with water.

10 and the 2-nitro 4-methoxymethoxyaniline is filtered off.

A mixture of 3> 5 g of 2-nitro 4-methoxymethoxyaniline, 1 g of 5% palladium on charcoal as a catalyst and 120 ml of methanol is hydrogenated under ambient conditions. After the hydrogen absorption is complete, the mixture is filtered, and the 1,2-diamino 4-methoxymethoxybenzene is obtained by evaporation of the solvent.

3.0 g of 1,2-diamino 4-methoxymethoxybenzene in 15 ml of ethanol, 15 ml of water and 0.5 ml of acetic acid are treated with 3> 0 g of 1,3-bis (methoxycarbonyl) S-methylisothiourea by refluxing for 2 hours under 2 ° C. Cook. The mixture is cooled and filtered and the product is recrystallized from methanol / chloroform to give the 5 (6) -methoxymethoxy-2-methoxycarbonyl-aminobenzimidazole; mp 216-218 ° C, with decomposition.

Example IX

A mixture of 6 g of 4-hydroxy 6-nitroacetanilide, 25 g of potassium carbonate and 5 g of chlorodimethyl sulfide in 200 ml of acetone is refluxed under a nitrogen atmosphere for 4 hours. The hot mixture is diluted with 3 ml of hot acetone and filtered. The solvent is evaporated and the oil obtained is chromatographed on silica gel, using chloroform as the eluent. The pure 2-nitro 4-methylthio-methoxyacetanilide is obtained from the eluate.

5 µg of 2-nitro 4-methylthiomethoxyacetanilide is treated with 12 ml of a 5% sodium hydroxide solution and 60 ml of methanol and the solution is heated for half an hour. The solution is cooled, diluted with water and extracted with chloroform. The chloroform solution is dried over sodium sulfate and evaporated to give the 2-nitro 4-methylthiomethoxyaniline.

4 5 g of 2-nitro 4-methylthiomethoxyaniline are treated in C 2003 39 ί - 21 - "95 ml of methanol and 5 ml of acetic acid with 8 g of iron powder and the mixture is refluxed for 4 hours. The hot solution is filtered and the solvent is evaporated. The residue is treated with hot tetrahydrofuran. The the mixture is filtered and the solvent is evaporated, yielding the 1,2-diamino 4-methylthiomethoxybenzene.

3/9 ë 1,2-diamino 4-methylthiomethoxybenzene in 25 ml of ethanol, 25 ml of water and 0.6 ml of acetic acid are treated with 5 µg of 1®3 “bis (methoxycarbonyl) S-methylisothiourea by refluxing for 4 hours. Cook. The mixture is cooled and filtered, and the product is recrystallized from tetrahydrofuran to give the 5 (6) -methylthiomethoxy-2-methybonycarbonyl aminobenzimidazole. Melting point 215-217 ° C, with decomposition.

The benzimidazole is oxidized in the manner described in Example YII with m-chloroperbenzoic acid to give 5 (6) -methylsulfinylmethoxy-2-methoxycarbonylaminobenzimidazole. Melting point 208-210 ° C.

Yoorbeeld X

A mixture of 2.5-4-hydroxy-6-nitroacetanilide, 2.1 g of 2-bromoethyl ethyl ether and 3-6 g of potassium carbonate in 25 ml of dimethylformamide is heated at 110 ° C under nitrogen for 16 hours. The mixture is cooled and diluted with water, after which the 4- (2-ethoxyethoxy) 2-nitroacetanilide is isolated by filtration.

Subsequently, 2.3 g of 4- (2-ethoxyethoxy) 2-nitroacetanilide are heated for half an hour with 5 ml of a 5H sodium hydroxide solution and 30 ml of methanol. The mixture is cooled and diluted with water, after which the 4- (2-ethoxyethoxy) -2-nitroaniline is isolated by filtration.

A mixture of 1.8 g of 4- (2-ethoxyethoxy) 2-nitroaniline and 0.3 g of 5-percent palladium on charcoal as a catalyst and 200 ml of methanol is hydrogenated under ambient conditions. After the hydrogen absorption is complete, the mixture is filtered and the 1,2-diamino 4- (2-ethoxyethoxy) benzene is isolated from the filtrate by evaporation.

1.6 g of 1,2-diamino 4- (2-ethoxyethoxy) benzene in 12 ml of ethanol, 12 ml of water and 0.3 ml of acetic acid are treated with 2 g of 1,3-bis (methoxycarbonyl) S-methylisothiourea for 4 hours under 0200339 A- * - 22 - to reflux. The mixture is cooled and filtered, and the product is recrystallized from methanol / chloroform to give the 5 (6) - (2-ethoxyethoxy) 2-methoxycarbonyl-aminobenzimidazole. Melting point 206-208 ° C, with decomposition; 5 total yield 65%

Similarly, using 2-bromoethylphenyl ether, the 5 (6) - (2-phenoxyethoxy) 2-methoxycarbonylamino-benzimidazole is prepared. Melting point 221-225 ° C, with decomposition; yield 50%. The hydrochloride melts at 184 ° C.

Example XI

6 g of 1-amino 2-nitro 4-thiocyanatobenzene in 20 ml of dimethylformamide are treated under a nitrogen atmosphere with T178 sodium borohydride in 10 ml of dimethylformamide at a temperature not exceeding 30 ° C. The mixture is stirred at a temperature of 15 to 20 ° C for 1 hour and then treated with 5 8 2-bromoethyl ethyl ether at a temperature of 20 to 25 ° C. The mixture is heated at a temperature of 100 ° C for 2 hours, then cooled and diluted with water. The product is extracted with chloroform and the chloroform solution is dried over sodium sulphate, after which the 1-amino 2-nitro 4- (2-ethoxyethylthio) benzene is obtained by evaporation of the solution.

6.4 g of 1-amino 2-nitro 4- (2-ethoxyethylthio) -benzene in 100 ml of methanol and 50 ml of water are treated with 16 ml of sodium dithionite and 14 g of sodium carbonate by refluxing under a nitrogen atmosphere. Heating is continued for half an hour and the methanol is evaporated from the mixture.

The mixture is diluted with 100 ml of water and extracted with chloroform. The chloroform solution is dried over sodium sulfate and the 1,2-diamino 4- (2-ethoxyethylthio) benzene is obtained by evaporation of the solution.

4 »8 8 1« 2-diamlno 4_ (2-ethoxyethylthio) benzene in 25 ml ethanol, 25 ml water and 1 ml acetic acid are treated with 7 »5 8 1« 3-bis- (methoxycarbonyl) -S-methyl isothiourea by Reflux for 4 hours. The mixture is cooled and filtered, and the product is recrystallized from methanol / chloroform to give the 5 (6) - (2-ethoxyethylthio) 2-methoxycarbonyl-aminobenzimidazole. Melting point 185-188 ° C, with decomposition.

Likewise, using the 2-bromoethyl methyl ether, the corresponding 5 (6) - (2-methoxyethyl-.00339, -23 - ► thio) 2-methoxycarbonylaminobenzimidazole is obtained. Melting point 181 ° C, with decomposition.

Example XII

1.8 g of 5 (6) - (2-ethoxyethylthio) 2-methoxycar-5-bonylaminobenzimidazole obtained according to the procedure of Example XI are treated in 200 ml of chloroform and 1 ml of acetic acid with 1.55 g of 30% peracetic acid in acetic acid solution at a temperature of 15 ° 0. The solution is stirred for one hour and then evaporated. The residue is triturated with diethyl ether and the solid material is filtered off. The 5 (6) - (2-ethoxyethylsulfinyl) 2-methoxycarbonylaminobenzimidazole is obtained by recrystallization from methanol / chloroform. Melting point 1-7-170 ° C, with decomposition. Yield Λ / 60%,

Similarly, using the 5 (6) -15 (2-methoxyethylthio) 2-methoxycarbonylaminobenzimidazole prepared according to the procedure of Example XI, the 5 (6) - (2-methoxyethylsulfinyl) 2-methoxycarbonylaminobenzimidazole is prepared . Melting point 197 ° 200 ° C, with decomposition? yield / v 70%

Example XIII

A soaking powder is prepared with the following composition: 5 (6) - [2- (phenoxyethoxy)] 2-methoxycarbonylaminobenzimidazole 30% "Carbowax" 6000 40% "Myrj" 52 (polyoxyl (40) stearate); 25 ( a product of Atlas Chemical Co.) 30%

A soaking liquid is prepared by mixing 25 g of this powder with 1 liter of water, after which an appropriate amount thereof (depending inter alia on the weight of the animal and the frequency of administration) is administered to the animal to be treated.

- conclusions - 8200339

Claims (3)

A process for the preparation or manufacture of anthelmintically active pharmaceutical preparations, in which a 2-alkoxy-carbonylaminobenzimidazole derivative is brought into a form suitable for therapeutic use, and for the preparation of fungicidal preparations, wherein a 2-alkoxycarbonylaminobenzimidazole derivative is mixed with a carrier, characterized in that the active substance used is a compound of the formula 1 or a salt thereof, in which formula n is an integer with value i of 1-4, R an alkyl group with 1-4 carbon atoms and R represents the remainder 10 -M ^ (CH2) nMR ^, where M and each are -0-, -S- or -S (0) - and R ^ e, and optionally phenyl or halo-substituted alkyl of 1-4 carbon atoms or an optionally substituted phenyl group with halogen, methyl and / or methoxy. 2. A process for the preparation of anthelmintic and fungicidally active 2-alkoxycarbonylaminobenzimidazole derivatives suitable for use in the process according to claim 1, characterized in that compounds of formula 1 and salts thereof as defined in claim 1 are prepared for the synthesis of analog compounds in a known manner. 20 The process according to claim 2, characterized in that a 1,2-diamino 5 (6) -R-benzene is reacted with a 1,3-bis- (alkoxycarbonyl) -S-alkylisothiourea and optionally a compound obtained with formula 1, wherein in R at least one of the symbols represents M and a sulfur atom. 8200339