BE809234A - NEW PRODUCTS WITH ANTHELMINTHIC ACTIVITY - Google Patents

Description

       

  "New products with anthelmintic activity" <EMI ID = 1.1>

  
ques and, more particularly, new benzimidazole-2carbamates possessing anthelmintic activity and in which the benzene ring is substituted in position 5 (6).

  
Benzimidazole-2-carbamates with anthelmintic activity are already known which are unsubstituted or positively substituted.

  
 <EMI ID = 2.1>

  
described in the present application (see for example the patents

  
 <EMI ID = 3.1>

  
related fungicidal compounds are also known (see for example US Patents N [deg.] 2,933,504 and N [deg.] 3,010,968).

  
The new benzimidazole-2-carbamates substituted on the benzene ring, in accordance with the invention can be represented by the formula:

  

 <EMI ID = 4.1>


  
in which R is a lower alkyl radical of 1 to 4 atoms

  
 <EMI ID = 5.1> regardless

  

 <EMI ID = 6.1>


  
 <EMI ID = 7.1>

  
 <EMI ID = 8.1>

  
R <2> is a lower alkyl radical of 1 to 6 carbon atoms,

  
 <EMI ID = 9.1>

  
 <EMI ID = 10.1>

  
 <EMI ID = 11.1>

  
tution R is in position 5 (6).

  
The hydrogen atom on the nitrogen in position 1 can be replaced by substituents which do not exhibit the anthelmintic and / or antifungal properties of the base compound, in particular by the following substituents: N-alkylcarbamoyl, N, Ndialkylcarbamoyl, N -alkoxycarbonylcarbamoyl, cyano-, trichloromethylthio, alkylthio, phenylthio, nitrophenylthio, alkylsulfinyl, phenylsulfinyl, acyl, alkoxycarbonyl, benzoyl, alkoxycarbonylalkylcarbonyl, alkylthio, phenylthio, nitrophenylthio, alkylsulfinyl, phenylsulfinyl, acyl, alkoxycarbonyl, benzoyl, alkoxycarbonylalkylcarbonyl, alkyl, alkenyl, benzyl, hydroxyl, alkoxyalkoxycarbonyl, benzyl, alkoxyalkoxycarboxycarbonyl, hydroxyl, alkoxycarboxycarbonyl, benzyl, alkoxycarboxycarbonyl, alkoxycarbonyl, hydroxyl, alkoxycarboxycarbonyl, benzyl, hydroxyl, alkoxyalkoxycarbonyl

  
 <EMI ID = 12.1>

  
In the present description, as well as in the claims

  
 <EMI ID = 13.1>

  
 <EMI ID = 14.1>

  
carbon or 1 to 6 carbon atoms, so that the definition

  
 <EMI ID = 15.1>

  
 <EMI ID = 16.1>

  
etc. The term cycloalkyl denotes a cyclic hydrocarbon group containing from 3 to? carbon atoms, for example cyclo-

  
 <EMI ID = 17.1>

  
lower denotes an unsaturated hydrocarbon group containing

  
 <EMI ID = 18.1>

  
carbon, provided that this double bond is not on

  
 <EMI ID = 19.1>

  
lower alkynyl moiety denotes an unsaturated hydrocarbon radical containing from 3 to 6 carbon atoms and a single carbon-carbon triple bond, provided that this triple bond is not on the carbon atom and. Representative groups of this kind are, for example, 2-propynyl, 2-butynyl, 3-butynyl,

  
 <EMI ID = 20.1>

  
may be optionally substituted by one or more radicals such as, for example, the thiocyanato radical, an alkoxy radical such as methoxy, an aryl radical such as quophenyl, an aroyl radical such as benzoyl, a hydroxy group, a cycloalkyl radical, an atom d halogen or a cyano or nitro group. The term alkoxy denotes a group of formula RO- in which R is an alkyl radical as defined above. The most representative alkoxy groups are methoxy, ethoxy, t-butoxy, etc. The term halo denotes the atoms of iodine, bromine, chlorine and fluorine. The term aryl denotes an aromatic hydrocarbon group such as phenyl.

  
 <EMI ID = 21.1>

  
aroyl, for example benzyl or phenet. The term aroyl denotes a group of the formula R'C- in which R 'is an aryl radical.

  
0

  
The aryl or aralkyl groups may optionally carry one or more lower alkyl, alkoxy, halo, nitro, cyano, thiccyanato, isothiocyanato, trifluoromethyl, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl or acylamino substituents in which <EMI ID = 22.1> hydrogen atom or an alkyl radical of 1 to 6 carbon atoms. The terms “alkylthio”, alkylsulfinyl ”and“ alkylsulfonyl ”re

  
0

  
respectively present the groups RS-, RS- and RS-, R being

  
a lower alkyl radical of 1 to 6 carbon atoms. The term acyl denotes an acyl radical originating from carboxylic acids of 1 to 6 carbon atoms, such as acetyl. propionyl, butyryl, valeryl, isovaleryl, hexanoyl, etc.

  
The compounds according to the invention and their non-toxic salts prepared with pharmaceutically acceptable organic or mineral acids have a broad spectrum of activity against parasites in mammals, both adult parasites and parasites in embryonic form, such as for example organisms of the genera Trichostronglylus, Haemonchus,

  
 <EMI ID = 23.1>

  
precisely, against the organisms Nematosniroides dubius, Hymenolepis Nana, Syphacia Obvelata and / or Aspiculuris tetraptera. In particular, these compounds possess high activity against various helminthic infections of the intestinal tract of economically important animals, together with low systemic toxicity to the treated animal.

  
The compounds according to the invention are also antifungal agents, and are in particular effective as systemic fungicides intended for combating fungal diseases of plants of economic importance.

  
In addition to their indicated anthelmintic and antifungal properties, certain compounds according to the invention are also useful intermediates for preparing other compounds in accordance with

  
to invention. For example, the 5 (6) sulfinyl compounds can be prepared and used as raw materials for the preparation of the corresponding 5 (6) -sulfonyl compounds.

  
When the compound contains a basic fraction, the expression “non-toxic salts” used hereafter denotes the pharmaceutically acceptable salts of the compounds according to the invention which do not adversely affect the antifungal or anthelmintic properties of the basic compound, for example the various salts commonly used by specialists. Such non-toxic salts are, for example, salts of mineral acids such as

it

  
 <EMI ID = 24.1>

  
as, hydrochloric acid and the like or salts of organic acids such as acetic, citric, lactic, palmitic, tartaric, succinic, maleic, benzoic and the like. When the compound contains an acid moiety, the non-toxic salts are cationic salts, for example sodium, potassium, ammonium salts, etc.

  
The amount of the compound to be administered depends on the nature of the compound itself and the weight of the animal being treated. However, the daily dosage is generally between 5 and 100 mg per kg of weight of the animal treated. The active ingredient can be administered to the animal by mixing it with the animal's feed, for example with the usual feed mixture, or the active compound can be combined with a non-toxic carrier and thereby obtain an anthelmintic composition. The vehicle may be an orally ingestible container for the active ingredient, for example a gelatin capsule, or it may be an excipient of the type normally used in such drugs, for example March starch. , terra alba, lactose, sucrose, calcium phosphate, gelatin, stearic acid, agar-agar, pectin, etc.

   Among suitable liquid vehicles, there can be mentioned peanut oil, sesame oil and water.

  
Various dosage forms can be used in cases where it is not intended to mix the drug with the

  
 <EMI ID = 25.1>

  
be administered in tablets or capsules. If a liquid vehicle is used, the drug may be in the form of a capsule.

  
 <EMI ID = 26.1>

  
In general, the compounds according to the invention can be prepared.

  
 <EMI ID = 27.1>

  
pt amino to acylamine (for example acetamido) in adjacent positions on the benzene ring (for example in the positions

  
1 and 2), and the desired fragment R (or a fragment which can be made

  
 <EMI ID = 28.1>

  
 <EMI ID = 29.1>

  
The 5 or 6 position of the benzimidazole compound will come. must prepare). The nitro group is reduced to an amino group, not obtaining a benzene derivative having amino groups in petitions 1 and 2. The diamino compound is then reacted with

U)

  
 <EMI ID = 30.1> the corresponding derivative benzimidazole-2-carbamate substituted in 5 (6).

  
The functional moiety at position 4 or 5 of the starting benzene material may be, for example, the thiocyanato group which can be left unmodified in its position during formation of the remainder of the benzimidazole-2-carbamate or which can be converted. , by known reactions, into an alkylthio or arylthio group, the latter possibly being converted, in turn, also by known means, into an alkyl- or aryl-sulfinyl or sulfonyl group. The functional moiety at position 4 or 5 can also be chloro and in this case it can be reacted with a substituted or unsubstituted aryl-mercaptan to form the corresponding compound aryl-thio and the latter can be reacted, for example to forming an arylsulfonyl compound.

   In this regard, it should be indicated that the substances thiocyanato, chloro, etc.,
-that is used in the raw materials are compounds already described in the literature.

  
A sequence of reactions for carrying out the stages considered and especially intended for the preparation of 5 (6) alkylsulfinyl-, 5 (6) -alkylsulfonyl- and 5 (6) -thiocyanato-benzimidazole-2-carbamates is as follows:

  

 <EMI ID = 31.1>
 

  

 <EMI ID = 32.1>


  
in which Z, depending on the nature of the reagents and / or the reaction conditions, may represent R? -S-

  
0

  
 <EMI ID = 33.1>

  
&#65533;

  
0

  
cal lower alkyl of 1 to G carbon atoms.

  
A reaction sequence especially useful for preparing

  
 <EMI ID = 34.1>

  
 <EMI ID = 35.1>

  

 <EMI ID = 36.1>


  
in which R <2> is as defined above, in particular the

  
 <EMI ID = 37.1>

  
 <EMI ID = 38.1>

  
 <EMI ID = 39.1>

  
 <EMI ID = 40.1>

  
benzene (i.e. compound A) which can be prepared by the method described by F. Challenger and A.T. Peters, J. Chem. Soc.
1364 (1928). The starting materials for the other reaction sequences can be, for example, 1-amino-2-nitro-4-thiocyana-

  
 <EMI ID = 41.1> <EMI ID = 42.1>

  
into an amino group (see steps 1, 6 and 14) can be done by

  
 <EMI ID = 43.1>

  
strong acid such as hydrochloric acid or a strong base such as sodium or potassium hydroxide or carbonate in

  
 <EMI ID = 44.1>

  
0.25 to 24 hours. The choice of a strong acid or a strong base depends on the substituent in position 4 or 5 on the benzene ring;

  
 <EMI ID = 45.1>

  
use a strong acid if it is desired to retain this substituent. In general, for the other substituents indicated, a

  
strong base; however, the material required for a substituent

  
or a given compound can be determined by routine tests or will result from the nature and chemical stability of the compound considered.

  
The reduction of the nitro group to an amino group (stages 2, 7, 10 and '15) can be carried out by a wide variety of techniques; we

  
can, for example, catalytically reduce the nitro group by using hydrogen over a palladium-charcoal catalyst. This reaction is carried out in an inert solvent such as methanol, at a temperature of about 0 to 35 [deg.] C, generally around room temperature, for a period of 0.5 to

  
2 hours. Other suitable inert solvents are ethyl acetate, acetic acid and ethanol. This technique is especially suitable for compounds containing an arylsulfinyl or arylsulfonyl substituent in position 4 or 5 of the benzene ring.

  
Another suitable technique is to treat the compound containing the nitro group with powdered iron and a ferrous salt such as sulphate or ferrous chloride, in aqueous methanol under reflux, under neutral conditions, for a period of time.

  
 <EMI ID = 46.1>

  
 <EMI ID = 47.1>

  
tré and, among the other metals, there may be mentioned zinc. he

  
 <EMI ID = 48.1>

  
(not all at once) and carefully monitor reagents and operating conditions to ensure that sulfinyl compounds are not reduced to thio compounds

  
 <EMI ID = 49.1>

  
 <EMI ID = 50.1>

  
A suitable reduction technique for thiocyanato or arylthio substituted compounds is to treat these compounds.

  
 <EMI ID = 51.1>

  
 <EMI ID = 52.1>

  
biante, for about 0.5 to 6 hours. An excess of stannous chloride, generally about 5 parts by weight, per unit weight of the starting material should be used.

  
The reduction can also be carried out using di-

  
 <EMI ID = 53.1>

  
than aqueous under reflux for a period of 10 minutes to 6 hours.

  
 <EMI ID = 54.1>

  
 <EMI ID = 55.1>

  
reaction steps 3, 8, 11 and 16, consisting in reacting the diamino compound with a 1,3-bis (alkoxycarbonyl) -S-alkyl-isothiourea, for example 1,3-bis (methoxycarbonyl) -S- methyl - isothiourea or 1,3-bis (ethoxycarbonyl) -S-methyl-isothiourea in an aqueous alcoholic medium, for example methanol or aqueous ethanol, at a temperature between about room temperature and reflux temperature of the reaction medium, for about 0.5 to 6 hours. It is preferred to acidify the reaction medium to a pH of about 4 to 6 using a sufficient amount (eg 1 to 2 moles) of acetic acid. We use nor-

  
 <EMI ID = 56.1>

  
of isothiourea per mole of the diamino compound.

  
The thiocyanato group of 1-acetamido-2-nitro-4-thiocyanatobenzene (raw material) can be converted into

  
an alkylthio or arylthio group, simultaneously with the conversion of the acetamido group to an amino group, as can be seen by

  
Step 4 ', by treating the thiocyanato compound (e.g. compound A) with an alkyl cycloalkyl or activated aryl halide, in an alcoholic medium or dimethylformamide' e.g. in methanol or ethanol, in the presence of a base such as sodium or potassium hydroxide or carbonate. The reaction is carried out at a temperature of about 10 to 50 [deg.] C, most often around room temperature, for about 0.25 to 12 hours, using essentially molar ratios of the main reactants. When the hydrocarbon radical of the halide is different from that of the alcoholic reaction medium, it is preferred to carry out the reaction in isopro-

  
b <EMI ID = 57.1>

  
the thiocyanato group to an alkylthio or arylthio group without change; in the acetamido group (see stage 4 above) in

  
 <EMI ID = 58.1>

  
at room temperature with sodium borohydride in dimethylformamide for about 0.25 to 2 hours, then treating with one of the halides indicated under the conditions previously described.

  
The conversion of an amino group to an acylamino group, for example acetamido (see steps 4 "and 12), can conveniently be done by treatment with an acyl halide such as acetyl chloride or acetic anhydride, in an inert organic reaction medium capable of dissolving the current compound

  
treatment or which can be adjusted to make it capable of dissolving said compound. For example, the organic reaction media which can be used are tetrahydrofuran in the presence of pyridine, acetone in the presence of a base such as potassium hydroxide or carbonate, or pyridine alone. Acetic anhydride can be used as an acylation reagent and also as a reaction medium. When used in this dual capacity, acetic anhydride should be present in a large excess, usually in an amount sufficient to dissolve the compound being reacted. The well-known Schotten-Baumann reaction can also be used for the same purpose. In

  
 <EMI ID = 59.1>

  
in an aqueous base, an excess of acetic anhydride is added and the precipitated product is collected by filtration. When acetic anhydride is used in such a reaction, it can be em-

  
 <EMI ID = 60.1>

  
sulfuric or p-toluenesulfonic. Normally we do these

  
 <EMI ID = 61.1>

  
room temperature for about 0.25 to 24 hours with a slight excess (about 1.5 to 2 moles) of the acylating agent.

  
 <EMI ID = 62.1>

  
corresponding finyl or sulfonyl, or the conversion of the sulfinyl group to a sulfonyl group (see steps 5, 13 and 13 ') is conveniently carried out by treatment with a peracid such as peracetic, perbenzoic, m-chloro-perbenzoic or perphthalic acid, in a solvent inert to the compound being treated.

  
 <EMI ID = 63.1>

  
lene or chloroform. If the compound being processed is not soluble in the reaction medium desired to be used, a co-solvent such as acetic acid or methanol should be incorporated in an amount sufficient to dissolve the compound being processed. treatment. Normally, the reaction is carried out at a temperature between about -30 [deg.] C and room temperature for about 0.5 to 6 hours. If it is desired to convert the alkylthio or arylthio group to the corresponding sulfinyl group, molar proportions are used and the operating conditions are carefully monitored to ensure that the reaction does not proceed.

  
 <EMI ID = 64.1>

  
the alkylthio or arylthio group into the corresponding sulphonyl group or converting the sulfinyl group into sulphonyl, an excess of the peracid, for example 2 moles of the peracid per mole of the compound being treated, is used and it is unnecessary to monitor the operating conditions so carefully. Such conversions can optionally be carried out by treatment with a periodate in aqueous methanol or aqueous acetonitrile at a temperature of about -20 to 50 [deg.] C and for a period of time of about 0.5 to. 12 hours.

  
When 2-amino-4-chloro-

  
 <EMI ID = 65.1>

  
chloro-1-nitrobenzene, it can be converted to the corresponding substituted or unsubstituted 4-phenylthio compound (see reaction 9) by reaction with a suitable aryl-mercaptan such as phenyl-

  
 <EMI ID = 66.1>

  
mercaptan, in an inert solvent such as dimethylformamide, ethanol or methanol and in the presence of a suitable inorganic base such as sodium or potassium hydroxide, sodium or potassium carbunate, or hydride of sodium. We perform

  
 <EMI ID = 67.1>

  
150 [deg.] C (i.e. up to the reflux temperature of the solvent) for about 0.5 to 6 hours and using a slight excess (1.5 to 2 moles) of the mercaptan. For reaction stage 17,

  
 <EMI ID = 68.1> <EMI ID = 69.1>

  
chlorine with a metal arylsulfinate, for example sodium benzenesulfinate. This displacement is normally carried out in an inert polar organic solvent such as dimethylformamide, acetone, or dimethylsulfoxide, at one. temperature between room temperature and the reflux temperature of the solvent used, for a period of about 0.5 to 6 hours and essentially using a molar ratio between the raw material and the metal sulfinate.

  
 <EMI ID = 70.1>

  
 <EMI ID = 71.1>

  
laughing (such as 1-bromo-propyne-2), an aralkyl halide
(such as benzyl bromide), a haloalkyl aryl ether
(such as 2-bromethyl phenyl ether, haloalkyl alkyl sulfide (such as chloromethyl methyl sulfide) or haloalkyl alkyl ether (such as chloromethyl methyl ether), etc, then performing the others necessary steps which have been previously described to arrive at the desired compound Compounds carrying a substituent <EMI ID = 72.1> hours can be prepared, followed by treatment with an alkyl haloalkyl sulfide.
(eg, methyl chloromethyl sulfide), alkyl haloalkyl ether (such as methyl chloromethyl ether), aryl haloalkyl sulfide (such as p-

  
 <EMI ID = 73.1>

  
into sulfinylic and / or sulphonylic bridges corresponding to the stages described above.

  
In each of the stages described above and in those which will be described below, the respective intermediates

  
They are preferably separated from the reaction mixture and are purified before their use as a starting material in a later stage. For the separation and purification, any suitable techniques can be employed. For example, the separation can be done by filtration, extraction or evaporation while the purification can be done * 'by crystallization, or by thin layer or column chromatography. For each given stage, the optimal separation and isolation processes can be determined by routine testing, as will be obvious to those skilled in the art.

  
Compounds given according to the invention can be prepared by choosing an appropriate starting material (for example one of those which have been described above) and then the reaction stage (s) necessary to achieve the desired compound. Anyone skilled in the art will be able to deduce from the present description the methods for preparing particular compounds, in accordance with the invention, not described here in detail.

  
As examples of compounds according to the invention, represented by the structural formula above, the following compounds can be indicated:

  
 <EMI ID = 74.1>

  
5 (6) -methylthiomethylthio-2-carbomethoxyaminobenzimidazole;

  
5 (6) -methoxymethylthio-2-carbomethoxyaminobenzimidazole;

  
5 (6) -methoxymethoxy-2-carbomethoxyaminobenzimidazole;

  
 <EMI ID = 75.1>

  
benzimidazole;

  
5 (6) - (prop-2-en-1-ylthio) -2-carbomethoxyaminobenzimidazole;

  
5 (6) - (prop-2-en-1-ylsulfinyl) -2-carboEethoxyaminobenzimidazole;

  
 <EMI ID = 76.1>

  
midazole.

  
These compounds are currently preferred because of their

  
 <EMI ID = 77.1> Other compounds that are also compliant include the following:

  
5 (6) -n-hexylsulfinyl-2-carbomethoxyaminobenzimidazole;

  
5 (6) -methylsulfonyl-2-carbomethoxyaminobenzimidazole;

  
 <EMI ID = 78.1>

  
5 (6) -n-hexylsulfonyl-2-carbomethoxyaminobenzimidazole;

  
5 (6) -phenylsulfonyl-2-carbomethoxyaminobenzimidazole;

  
 <EMI ID = 79.1>

  
dazole;

  
5 (6) -cyanomethylsulfinyl-2-carbomethoxyaminobenzimidazole .;

  
5 (6) -phenethylthio-2-carbomethoxyaminobenzimidazole; - 5 (6) -phenethylsulfinyl-2-carbomethoxyaminobenzimidazole;

  
 <EMI ID = 80.1>

  
15

  
 <EMI ID = 81.1>

  
zole;

  
5 (6) - (beta-hydroxyphenethylthio) -2-carbomethoxyaminobenzimidazole;

  
 <EMI ID = 82.1>

  
zole;

  
5 (6) - (2-cyanoethylsuliinyl) -2-rarbomethoxyaminobenzimidazole;

  
 <EMI ID = 83.1> <EMI ID = 84.1>

  
5 (6) -thiocyanato -? - phenylsulfinyl-2-carbomethoxy-aminobenzimidazole;

  
and the corresponding compounds 2-carbethoxynmino-, 2-carbopropoxyamino- and 2-carbobutoxyaminu-

  
The following examples serve to specify the implementation,

  
and carrying out the invention without in any way limiting its scope. PREPARATION

  
 <EMI ID = 85.1>

  
 <EMI ID = 86.1>

  
of methyl, then a solution of, 250 g of potassium hydroxide in 750 ml of water at a temperature of 0 to 5 [deg.] C. The crude product is extracted with benzene, the benzene layer is dried and evaporated, then the residue is recrystallized from methanol to give 1,3-bis (methoxycarbonyl) -Smethyl-. isothiourea.

  
Similarly, using ethyl chloroformate,

  
propyl or butyl instead of methyl chloroformate, the 1,3-bis (ethoxycarbonyl) -S-methyl-iso-

  
 <EMI ID = 87.1>

  
EXAMPLE 1

  
2 g of 1-amino-2-nitro-4-thiocyanatobenzene are mixed with

  
6 ml of concentrated HCl and the mixture is cooled to approximately -40 [deg.] C.

  
A solution of 12 g of standard chloride is added dropwise.

  
 <EMI ID = 88.1>

  
slowly to room temperature. After 15 to 20 minutes at a temperature of 15 to 20 [deg.] C, the product is separated by filtration and washed with 12 ml of hexanormal hydrochloric acid. The treatment with 25 ml of a saturated solution of potassium bicarbonate

  
 <EMI ID = 89.1>

  
Recrystallization from benzene makes it possible to obtain? 1,2- <EMI ID = 90.1>

  
 <EMI ID = 91.1>

  
tick. The mixture is refluxed for 90 minutes, then cooled and filtered. The solid material is recrystallized from a mixture of methanol and chloroform and one obtains

  
 <EMI ID = 92.1>

  
Analogously, using

  
1,3-bis (ethoxycarbonyl) -S-methyl-isothiourea,

  
1,3-bis (propoxycarbonyl) -S-methyl-: sothiourea, and 1,3-bis (butoxycarbonyl) -S-methyl-isothiourea instead

  
 <EMI ID = 93.1>

  
5 (6) -thiocyanato-2-carbethoxyaminobenzimidazole, 5 (6) -thiocyanato-2-carbopropoxyaminobenzimidazole, and 5 (6) -thiocyanato-2-carbobutoxyaminobenzimidazole, respectively.

EXAMPLE 2

  
 <EMI ID = 94.1>

  
in 70 ml of n-propyl alcohol containing 4.8 g of potassium hydroxide with 2.6 g of n-propyl bromide. The mixture was stirred for 16 hours at 15-20 [deg.] C, then poured into water, extracted with chloroform, the dried extracts were purified in vacuo and the residual red oil dissolved in 25 ml. acetic anhydride. A few drops of sulfuric acid are added, the mixture is left to stand for 1 hour at 20-25 [deg.] C, sodium acetate is added, the solvent is removed in vacuo, the residue is treated with water and the crude product is filtered off. Recrystallization from methanol gives 1-ketamido-2nitro-4-n-propylthiobenzene.

   (This same intermediate can also be obtained directly by alkylation of 1-acetamido-2-nitro4-thiocyanato-benzene with n-propyl bromide in dimethylformamide in the presence of sodium borohydride).

  
3.81 g of 1-acetamido-2-nitro-4-n-propylthiobenzene in 35 ml of chloroform are treated at a temperature of -20 to -15 [deg.] C with a solution of 3.0 g of acid. 40% peracetic in 3 ml of methanol. The mixture is allowed to warm to 20 [deg.] C and stirred for 4 hours at a temperature of 15 to 25 [deg.] C, then washed with sodium bisulfite and sodium bicarbonate in solution.

  
Removal of the chloroform leaves a gum which is treated on a steam bath with 15 ml of pentanormal sodium hydroxide for 1 hour. The mixture is cooled, extracted with chloroform, separated and the solvent removed. We recrystallize the re-

  
 <EMI ID = 95.1>

  
4-n-propyl-sulfonylbenzene.

  
1.14 g of the mentioned product are subjected to hydrogenation.

  
 <EMI ID = 96.1>

  
atmosphere and in the presence of 1 g of 5% palladium on carbon, until the absorption of the theoretical quantity of hydro-

  
 <EMI ID = 97.1>

  
 <EMI ID = 98.1>

  
carbonyl) -S-methyl-isothiourea and 0.3 ml of acetic acid in a boiling mixture of 10 ml of ethanol and 10 ml of water. After 3 hours, the mixture is cooled, filtered and recrystallized.

  
 <EMI ID = 99.1>

  
ethanol.

  
Analogously, using methyl or ethyl iodide, isopropyl, butyl, isobutyl, pentyl, hexyl, cyclopropyl, cyclopentyl or cyclohexyl bromide.

  
 <EMI ID = 100.1>

  
corresponding dazoles and 5 (6) -cycloalkylsulfonyl-2-benzimidazoles and in particular:

  
 <EMI ID = 101.1>

  
 <EMI ID = 102.1>

  
corresponding carbalkoxyaminobenzimidazoles in which R is

  
the methyl, ethyl, propyl or butyl radical.

  
&#65533;

  
 <EMI ID = 103.1>

  
5 g of 1-acetamido-2-nitro-4-thiocyanatobenzene are added

  
and 1.7 ml of methyl iodide to a solution of 4.8 g of hydroxy-

  
of potassium in 70 ml of ethanol. The mixture is left for 16 hours at room temperature, then diluted with

  
water and the 1-amino-2-nitro-4-methylthiobenzene is collected by filtration.

  
A few drops of concentrated sulfuric acid are added to 3.7 g of the latter product in 37 ml of acetic anhydride, the mixture is left at room temperature for 1 to 2 hours, treated with a slight excess of sodium acetate. and we evaporate, then

  
 <EMI ID = 107.1>

  
 <EMI ID = 104.1>

  
 <EMI ID = 105.1>

  
4.0 g of the latter product in 40 ml of chloroform is treated with 12 ml of 40% peracetic acid at room temperature. The mixture is left to stand for 90 minutes, then filtered, washed with methanol and 1-acetamido-4- is obtained.

  
 <EMI ID = 106.1>

  
4 g of the latter product are treated on a steam bath for 1 hour with 40 ml of concentrated HCl, the mixture is cooled and diluted with water. The

  
2 g of the latter product in 200 ml of methanol is treated with hydrogen under a pressure of 4 atmospheres in the presence of a Raney nickel catalyst. The catalyst is removed by filtration, the filtrate is concentrated and the 1,2-diumino-

  
 <EMI ID = 108.1>

  
of chloroform to thereby obtain 5 (6) -icethylsulfonyl-2-carbomethoxyaminobenzimidazole (m.p. about 270 [deg.] C, dec.).

  
Analogously, by using ethyl iodide, butyl, pentyl, d: hexyl, cyclopentyl or cyclohexyl bromide in place of nethyl iodide, the 1,2-diamino-4-alkylthiobenzenes are prepared. , 1,2-diaminocycloalkylthiobcnzènes,

  
 <EMI ID = 109.1> <EMI ID = 110.1>

  
isothiourea, 1,3-bis-propoxycarbonyl-S-methyl-isothiourea or 1,3-bis-butoxycarbonyl-S-methyl-isothiourea instead of 1,3-

  
 <EMI ID = 111.1>

  
which R represents the ethyl, propyl or butyl radical.

  
Example 4 5.85 g of 1-amino-2-nitro-4-thiocyana- are treated under nitrogen

  
 <EMI ID = 112.1>

  
 <EMI ID = 113.1>

  
for 1 hour at 15-20 [deg.] C, then treated with 5 ml of propargyl bromide at 20-25 [deg.] C. After another 3 hours, water is added, the crude product is extracted with chloroform, the dried chloroform solution is passed through a column of silica gel to remove a small amount of the polar substance. and from the eluate, pure 1 amino-2-nitro-4- (prop-2-yn-1-ylthio) benzene is obtained.

  
4.8 g of the latter product is treated in 14 ml of concentrated HCl with a solution of 24 g of stannous chloride in 14

  
 <EMI ID = 114.1>

  
neutralize the mixture with saturated potassium bicarbonate solution and chloroform is added. We filter, we separate the

  
 <EMI ID = 115.1>

  
diamino-4- (prop-2-yn-1-ylthio) benzene.

  
 <EMI ID = 116.1>

  
 <EMI ID = 117.1>

  
isothiourea and 1.5 ml of acetic acid, under reflux, for 3 hours. The mixture is cooled and the mixture is isolated by filtration.

  
 <EMI ID = 118.1>

  
can recrystallize from a mixture of methanol and chloroform.

  
 <EMI ID = 119.1>

  
in a mixture of 75 ml of acetic acid and 75 ml of chloroforma

  
A solution of 1.02 g of m-chloroperbenzoic acid is added

  
 <EMI ID = 120.1>

  
let the mixture warm up slowly to 20 [deg.] C and let stand for 5 hours. The solvents are removed in vacuo and the residue treated with a solution of sodium bicarbonate. The 5 (6) - (prop-2-yn-1-ylsulfinyl) -2-carbomethoxyaminobenzimidazole is filtered off and can be recrystallized from a mixture of methanol and chloroform.

  
Analogously, using 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 2-hexenyl, 2-butynyl, 3-butynyl, 2-pentynyl or 2-hexynyl or instead of propargyl bromide, 5 (6) -alkenylthio-, 5 (6) -alkynylthio-, 5 (6) -alkenylsulfinyl-, and 5 (6) -alkynyl- are prepared.

  
 <EMI ID = 121.1>

  
dazole, and 5 (6) - (prop-2-en-1-ylsulfinyl) -2-carbonethoxyaminobenzimidazole.

  
Analogously, using 1,2-dianino-4-alkenyl-

  
 <EMI ID = 122.1>

  
 <EMI ID = 123.1>

  
1,3-bis-propoxycarbonyl-S-methyl-isothiourea or 1,3-bis-butoxycarbonyl-S-methyl-isothiourea instead of 1,3-bis-methoxycarbonyl-S-methyl-isothiourea, the 5 are prepared. (6) -alkenylthio-, 5 (6) al 'ynylthio-, 5 (6) -alkenylsulfinyl or 5 (5) -alkynylsulfinyl-2carbalcoxyaminobenzimidazoles corresponding in which R is the ethyl, propyl or butyl radical.

  
EXAMPLE 5

  
The 5 (6) -alkenylthio-2-carbalkoxyaminobenzimidazoles and 5 (6) -alkynylthio-2-carbalkoxyaminobenzimidazoles of Example 4 are treated with 2 moles of a peracid (for example m-chloroperbenzoic or peracetic acid) per mole of starting material according to the process described in the third paragraph of Example 3 or the fourth paragraph of Example 4 (but for a longer time) and thus obtained 5 (6) -alkenyl-sulfonyl-2-

  
 <EMI ID = 124.1>

EXAMPLE 6

  
1.0 g of 1-acetamido-2-nitro-4-benzylthiobenzene prepared as in Example 9 is treated with 2 ml of pentanormal sodium hydroxide and 6 ml of methanol on a steam bath for 15

  
 <EMI ID = 125.1> <EMI ID = 126.1>

  
0.9 g of the latter product is treated in 5 ml of concentrated HCl with 4.5 g of stannous chloride for a very short time on a steam bath. The mixture is cooled, the liquid is decanted from the gum which is then washed with 5. ml of cold hexanormal HCl. Treatment of the gum with a solution of given potassium bicarbonate, 1,2-diamino-4-benzylthiobenzene

  
 <EMI ID = 127.1>

  
by recrystallization from cyclohexane. Analogously, by the method of the third paragraph of Example 4, 5 (6) -benzylt-io-2-carbomethoxyaminobenzimidazole is prepared.

  
Analogously, using p-chlorobenzyl, p-methylbenzyl and p-methoxybenzyl bromide instead of benzyl bromide (as in Example 9), the 1,2-diamino-

  
 <EMI ID = 128.1>

  
gir the 1,2-diamino- (4-substituted benzylthio) -benzenes thus prepared with 1,3-bis-ethoxycarbonyl-S-methyl-isothiourea, 1,3-bis-prcpoxycarbonyl-S-methyl isothiourea, or 1,3-bis-butoxycarbonyl-S-methyl-isothiourea instead of 1,3-bis-methoxycarbonyl-S-methyl-isothiourea, the 5 (6) - (benzylthio-

  
 <EMI ID = 129.1>

  
ethyl, propyl, or butyl radical.

  
EXAMPLE 7

  
 <EMI ID = 130.1>

  
ne in 10 ml of dimethylformamide under nitrogen with 0.38 g of sodium borohydride at 20-25 [deg.] C. After one hour, 2.4 ml of benzyl bromide are added, the mixture is left losing 2 hours.

  
 <EMI ID = 131.1>

  
ne, recrystallized from methanol and 1-acetamido-2-nitro-4-benzylthiobenzene is obtained.

  
 <EMI ID = 132.1>

  
 <EMI ID = 133.1>

  
 <EMI ID = 134.1>

  
slowly to room temperature, left to stand for

  
6 hours, washed with sodium bisulfite solution and

  
 <EMI ID = 135.1>

  
cristollizes the residue from methanol to thereby obtain 1-acet & midG-2-nitro-4-benzylsulfinylbenzene.

  
 <EMI ID = 136.1>

I &#65533;

  
 <EMI ID = 137.1>

  
 <EMI ID = 138.1>

  
 <EMI ID = 139.1>

  
ferrous material under reflux for 4 hours, filtered, the filtrate is concentrated in vacuo, the residue is extracted with chloroform and isolated by evaporation. The residue is recrystallized from a mixture of methylene chloride and benzene to obtain

  
 <EMI ID = 140.1>

  
rea, 0.15 if acetic acid in 20 ml of ethanol and 20 ml of water,

  
 <EMI ID = 141.1>

  
 <EMI ID = 142.1>

  
benzimidazole (F.F.224.5-226 [deg.] C).

  
Analogously, using p-chlorobenzy- bromide

  
 <EMI ID = 143.1>

  
of benzyl, the 1,2-diamino-4- (benzylsulfinyl- substituted) benzenes and 5 (6) - (benzylsulfinyl-substituted) -2-carbomethoxy- are prepared.

  
 <EMI ID = 144.1>

  
S-methylisothiourea instead of 1,3-bis (methoxycarbonyl) -Smethyl-isothiourea, we obtain 5 (6) - (substituted benzylsulfinyl)
-2- carbalkoxy-anino-benzimidazoles corresponding in which

  
R is ethyl, propyl or b &#65533; tyl.

  
 <EMI ID = 145.1>

  
ple 6 with an excess of peracetic acid under the conditions indicated in the second paragraph of Example 7 but for a longer period, and thus obtained 5 (6) -benzyl-sulfonyl-2-

  
 <EMI ID = 146.1>

AT

  
 <EMI ID = 147.1>

  
EXAMPLE 9 ............. 5 g of 2-amino-4-ohloro-1-nitrobenzene are added to a so-

  
 <EMI ID = 148.1>

  
 <EMI ID = 149.1>

  
nol in 20 ml of dimethylformamide and with a rinse with 10 ml of dimethylformamide. The mixture was stirred under nitrogen for 3 hours at 20-30 [deg.] C, then diluted with water, the product washed.

  
 <EMI ID = 150.1>

  
of methanol and 2-amino-4-phenylthio-1-nitrobenzene is obtained,

  
6.0 g of the latter product is dissolved in 80 ml of acetic anhydride and treated with a few drops of sulfuric acid. The mixture is left to stand for 2 hours at 20-30 [deg.] C, then a little sodium acetate is added, the solvent is removed in vacuo, the residue is treated with water and filtered. , it is recrystallized from methanol and 2-acetamido-4- is obtained

  
 <EMI ID = 151.1>

  
posed in. reacting 2-acetamido-4-chloro-1-nitrobenzene with sodium phenyl-mercaptide essentially as described in connection with the free amine.

  
 <EMI ID = 152.1>

  
ne in 77 ml of chloroform and treated at a temperature of
-20 to -15 [deg.] C with a solution of 5.0 g of 40% peracetic acid in 10 ml of methanol. The mixture is allowed to come back slowly <EMI ID = 153.1>

  
reaction with sodium bisulfite solution, then with sodium bicarbonate solution, dried and evaporated. We

  
 <EMI ID = 154.1>

  
nitrobenzene with 20 ml of heptanormal sodium hydroxide and 40 ml of methanol at 20-25 [deg.] C for 1 hour. Water is added and a substantially pure 2-amino-4-phenylsulfinyl-1-nitrobenzene is filtered off which can be recrystallized from benzene.

  
5.4 g of the latter compound are hydrogenated under a pressure of 1 atmosphere in 500 ml of methanol in the presence of 5 g of 5% palladium on carbon, until the theoretical amount of hydrogen has been absorbed. The catalyst is removed by filtration and the filtrate is purified in vacuo. The residue is recrystallized from

  
 <EMI ID = 155.1>

  
We. treated under reflux rendering a mixture of 5.5 g for 4 hours

K

  
 <EMI ID = 156.1>

  
so pure that it is washed with methanol. It is possible to recrystallize from a mixture of methanol and chloroform (m.p. 253 [deg.] C dec.).

  
 <EMI ID = 157.1>

  
 <EMI ID = 158.1>

  
respondants in which R is the ethyl, propyl or butyl radical.

  
Analogously, using naphth-2-yl-mercaptido

  
Instead of sodium phenylmercaptide, 5 (6) -naphth-2-ylsulfinyl-2-carbomethoxyaminobenzimidazole is prepared.

EXAMPLE 10

  
Stirred for 16 hours at room temperature and then poured into water a mixture of 2.5 g of 2-amino-4-chloro1-nitrobenzene, 3.6 g of p-thiocresol and 4.2 g of carbonate. of potassium in 20 ml of dimethylformamide. The crude product is recrystallized from methanol and 2-amino-4- (pmethylphenylthio) -1-nitrobenzene is obtained.

  
 <EMI ID = 159.1>

  
 <EMI ID = 160.1>

  
on a steam bath for 1 hour. The mixture is cooled, treated with an excess of potassium bicarbonate, extracted with chloroform, the chloroform is evaporated and the 1,2- is obtained.

  
 <EMI ID = 161.1>

  
and 0.75 ml of acetic acid in 50 ml of water and 50 ml of ethanol.

  
 <EMI ID = 162.1>

  
mixture of methanol and chloroform to thereby obtain 2- (carbomethoxyamino) -5 (6) - (p-methylphenylthio) -benzimidazole.

  
1.88 g of the latter product are dissolved in a mixture of

  
 <EMI ID = 163.1>

  
solution of 1.22 g of m-chloroperbenzoic acid in 20 ml of

  
 <EMI ID = 164.1> <EMI ID = 165.1> hours, the solvent was removed in vacuo at 20-30 [deg.] C and the residue treated with sodium bicarbonate solution. The product is filtered and recrystallized from a mixture of methanol and chloroform to thereby obtain 5 (6) -p-methylphenylsulfinyl-2-

  
 <EMI ID = 166.1>

  
tively.

  
Analogously, using one of the 1,2diamino compounds prepared in this example and using 1,3-bisethoxycarbonyl-S-methyl-isothiourea, 1,3-bis-propoxycarbonyl-

  
 <EMI ID = 167.1>

  
isothiourea instead of 1,3-bis-methoxycarbonyl-S-methyl-iso-

  
 <EMI ID = 168.1> in which R is ethyl, propyl or butyl.

EXAMPLE 11

  
 <EMI ID = 169.1>

  
4-chloro-1-nitrobenzene and 5.0 g of sodium benzine sulfonate in 20 ml of dimethylformamide. Cool, dilute with water and filter to thereby obtain 2-amino-1-nitro-4-phenylsulfonylbenzene.

  
1.9 g of the latter compound are treated in methanol with hydrogen under a pressure of 4 atmospheres and in the presence

  
 <EMI ID = 170.1>

  
catalyst and the filtrate is purified in vacuo. The recrystallisa-

  
 <EMI ID = 171.1>

  
0.75 g of the latter is treated under reflux for 4 hours.

  
 <EMI ID = 172.1>

  
and 0.2 ml of acetic acid in 10 ml of ethanol and 10 ml of water. The product is filtered, recrystallized from a mixture of methanol and chloroform and the 5 (6) -phenyl-dulfonyl- is obtained.

  
 <EMI ID = 173.1>

  
î <EMI ID = 174.1>

  
respondants in which R is the ethyl, propyl or butyl radical.

EXAMPLE 12

  
We treat 5 (6) - (phenylthio-p-substituted) -2-carbalkoxy-

  
 <EMI ID = 175.1>

  
zoles of Example 10.

EXAMPLE 13

  
Treated under reflux for 16 hours in acetone

  
 <EMI ID = 176.1>

  
5.13 g of benzyl bromide and 4.2 g of anhydrous potassium carbonate, evaporated to dryness, the excess of benzyl bromide is removed in vacuo, water is added, extracted with dichlo-

  
 <EMI ID = 177.1>

  
benzene.

  
The product thus obtained is treated with sodium hydroxide in methanol, heated on a steam bath for about fifteen minutes until the reaction is complete, diluted with water and treated with water. dichloromethane for obtaining

  
 <EMI ID = 178.1>

  
2.44 g of the latter product are stirred in 100 ml of metha-

  
 <EMI ID = 179.1>

  
ambient erasure. 2 hours later, the mixture is poured into an excess of ammonium hydroxide solution, the residue is extracted with

  
 <EMI ID = 180.1>

  
gnesium, filtered again, evaporated to dryness and

  
 <EMI ID = 181.1>

IQ

  
 <EMI ID = 182.1>

  
Similarly, using p-chlorobenzyl, p-methylbenzyl, and p-methoxybenzyl bromide in place of benzyl bromide, 192-diamino-4- (substituted benzyloxy) -benzenes and 2- corresponding carbomethoxyamino-5 (6) - (benzyloxy-substituted) -benzimidazoles. By reacting the 1,2diamino-4- (benzyloxy-substituted) -benzenes thus prepared with

  
1,3-bis-ethoxycarbonyl-S-methyl-isothiourea, 1,3-bis-propoxy-carbonyl-S-methyl-isothiourea, or 1,3-bis-butoxycarbonylS-methyl-isothiourea instead of 1 , 3-bis-methoxycarbonyl-S-

  
 <EMI ID = 183.1>

  
ethyl, propyl or butyl.

EXAMPLE 14

  
1-Acetamido-4-hydroxy-2-nitrobenzene is treated with

  
 <EMI ID = 184.1>

  
ditions set forth in Example 13 (or similar conditions) to form the 5 (6) -alkenyloxy-2-carbalkoxy-benzimidazoles cor-

  
 <EMI ID = 185.1>

  
correspondents.

  
EXAMPLE 15

  
 <EMI ID = 186.1>

  
benzene in 10 ml of dimethylformamide at a temperature of 20-
25 [deg.] C under nitrogen with 0.38 g of sodium borohydride. After one hour, 1.6 ml of chloromethyl methyl ether was added and the mixture was kept at 20-30 [deg.] C for a further 3 hours. Water is added and the product is filtered. Recrystallization

  
 <EMI ID = 187.1>

  
methylthiobenzene.

  
1.4 g of the latter product is treated with 3 ml of pentanormal sodium hydroxide and 6 ml of methanol on a steam bath for about 15 minutes. Purify in vacuo and extract the residue with chloroform. The dried extracts are evaporated off and

  
 <EMI ID = 188.1>

  
of a red crystalline material,

  
1.3 g of the latter compound are treated in 80 ml of metha-

  
 <EMI ID = 189.1>

  
with 0.7 g of ferrous sulphate and 2.8 g of iron (introduced in two

  
 <EMI ID = 190.1>

  
vacuum and recrystallize the residue from cyclohexane. On <EMI ID = 191.1>

  
Treated under reflux with 0.7 ml of acetic acid 0.85 g of 1,2-diamino-4-methoxymethylthiobenzene and 1.0 g of 1,3-bis

  
 <EMI ID = 192.1>

  
25 ml of water. After 4 hours, the mixture is cooled and filtered to obtain 5 (6) -methoxymethylthio-2-carbomethoxyamino-benzimidazole, which can be recrystallized from a mixture of methanol and chloroform (PF 200-201.5 [deg .]VS).

  
Analogously, using chlor- methyl ether

  
 <EMI ID = 193.1>

  
propyl ether or chloromethyl butyl ether,

  
 <EMI ID = 194.1>

  
diamino-4-alkoxy-alkylthiobenzenes and 5 (6) -alkoxy-alkylthio-2carbomethoxy-amino-benzimidazoles corresponding. In an ana-

  
 <EMI ID = 195.1>

  
methoxycarbonyl-S-methyl-isothiourea, the corresponding 5 (6) -alkoxyalkylthio-2-carbalkoxyaminobenzimidazoles are prepared in which R is the ethyl, propyl or butyl radical.

  
 <EMI ID = 196.1>

  
 <EMI ID = 197.1>

  
g of sodium borohydride. After 1 hour, 10 ml of methyl-thiomethyl chloride was added and stirred for 16 hours, diluted with water and extracted with chloroform. The dried chloroform solution is passed through a column of silica gel and evaporated to dryness, which leaves, in the form of a

  
 <EMI ID = 198.1>

  
thiobenzene.

  
2.5 g of the latter product are treated in 160: nl of methanol and 40 ml of water, under reflux, for 5 hours, with 1.25 g of ferrous sulfate and 5 g of iron powder (the latter being added in two portions). The mixture is filtered, stripped and the oily residue of 1,2-diamino- extracted with chloroform.

  
 <EMI ID = 199.1>

  
evaporation of the solvent.

  
 <EMI ID = 200.1>

  
 <EMI ID = 201.1> <EMI ID = 202.1> the product by recrystallization from a mixture of methanol and chloroform, this product being 5 (6) -methylthiomethyl- '

  
 <EMI ID = 203.1>

  
Similarly, using ethylthiomethyl, propylthiomethyl, butylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, ethylthioethyl or ethylthiopropyl chloride instead of methylthiomethyl chloride.

  
 <EMI ID = 204.1>

  
5 (6) -alkylthioalkylthio-2-carbomethoxyaminobenzimidazoled corresponding. By reacting 1,2-diamino-4-alkylthioalkylthio-

  
 <EMI ID = 205.1>

  
bis-methoxycarbonyl-S-methyl-isothiourea, the corresponding 5 (6) alkylthioalkylthio-2-carbalkoxyaminobenzimidnzoles are obtained, in which R is the ethyl, propyl or butyl radical.

EXAMPLE 17

  
 <EMI ID = 206.1>

  
200 ml of acetone containing 25 g of potassium carbonate and 6 ml of methyl chloromethyl sulfide. The mixture is heated under reflux for 4 hours, filtered, the acetone evaporated and the mixture

  
 <EMI ID = 207.1>

  
2-thiomethoxy-nitrobenzene which is purified by column chromatography.

  
 <EMI ID = 208.1>

  
of pentanormal NaOH and 60 ml of methanol, the mixture is heated for 15 minutes on a steam bath, the mixture is poured into 500 ml of water,

  
 <EMI ID = 209.1>

  
methylene chloride, dried over sodium sulfate, evaporated

  
 <EMI ID = 210.1>

  
 <EMI ID = 211.1>

  
mixture of 5 ml of acetic acid and 95 ml of methanol, 8 g of iron powder are added, the mixture is heated under reflux for 2 hours, the methanol and acetic acid are evaporated and the residue is extracted

  
 <EMI ID = 212.1>

  
 <EMI ID = 213.1>

  
 <EMI ID = 214.1>

  
For 3 hours, the mixture is cooled, filtered off

  
 <EMI ID = 215.1>

  
 <EMI ID = 216.1>

  
ge of methanol and chloroform.

  
Analogously, using chlorethyl sulfide

  
 <EMI ID = 217.1>

  
instead of chloromethylmethyl sulfide, 1,2diamino-4-alkylthioalkoxybenzenes and 5 (6) -alkylthioalkoxy-2- are prepared

  
 <EMI ID = 218.1>

  
isothiourea, the corresponding 5 (6) -alkylthioalkoxy-2-carbalkoxyaninobenzimidazoles are prepared in which R is the ethyl, propyl or butyl radical.

EXAMPLE 18

  
 <EMI ID = 219.1>

  
chloromethyl, chlorethyl, chloropropyl or chlorobutyl methyl ether or with chloromethyl ethyl, propyl or butyl ether or chloroethyl ethyl or propyl ether, under similar or analogous conditions

  
 <EMI ID = 220.1>

  
Corresponding 5 (6) -alkoxyalkoxy-2-carbalkoxyaminobenzimidazoles

  
 <EMI ID = 221.1>

  
 <EMI ID = 222.1>

  
2.4 g of 100% sodium hydride are dissolved in 120 ml of

  
 <EMI ID = 223.1>

  
treated under reflux for 4 hours, cooled and poured into water. The 2-nitro-5- (2-methoxy-

  
 <EMI ID = 224.1>

  
A mixture of 11 g of the latter product, 220 ml of methanol, 460 ml of water, 40 g of sodium carbonate and 60 g of sodium hydrosulphite is treated under reflux for 15 minutes. The solution is concentrated, diluted with water, extracted with chloroform, the chloroform is evaporated and thus obtained 1,2-diamino-

  
 <EMI ID = 225.1> <EMI ID = 226.1>

  
 <EMI ID = 227.1>

  
ml of water. The cooled mixture is filtered, thus obtaining 5 (6) -

  
 <EMI ID = 228.1>

  
recrystallize from a mixture of methanol and chloroform.

  
EXAMPLE 20

  
A mixture of 5 g of 2-nitro-5-chloraniline and 7.5 g of sodium sulfide monohydrate in 25 ml of ethanol and 25 ml of water is treated under reflux for 1 hour, diluted with water. to a total of about 150 ml, filtered to remove the small amount of insoluble impurities, the filtrate was treated with 2.5 ml of acetic acid and the 2-nitro-5-mercaptoaniline was filtered off.

  
A solution of 3.4 g of the latter product is treated in

  
20 ml of DMF with 0.% 100% sodium hydride and add

  
the solution of 2,2% of chloromethyl ethyl ether is left for 30 minutes at a temperature of 20 to 25 [deg.] C, diluted with water and extracted with chloroform. Removal of chloroform leaves 2-nitro-5- (ethoxymethylthio) aniline as an oil.

  
This 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 g of sodium hydrosulphite. We concentrate the mixture,

  
diluted with water, carefully extracted with chloroform, evaporated chloroform and obtained 1,2-diamino-4- <EMI ID = 229.1>

  
 <EMI ID = 230.1>

  
res. The cooled mixture is filtered and thus obtained 5 (6) ethoxymethylthio-2-carbomethoxy-aminobenzimidazole which can be recrystallized from a mixture of methanol and chloroform.

  
 <EMI ID = 231.1>

  
50 ml of chloroform and 10 ml of acetic acid. The solution is treated at a temperature of -30 to -20 [deg.] 0 with a solution of 0.62 g of m-chloroperbenzoic acid in 15 ml of chloroform, then allowed to warm slowly to room temperature. .

  
 <EMI ID = 232.1>

  
crude and recrystallized from a mixture of methanol and chloroform.

EXAMPLE 21

  
A solution of 2.37 g of 1-acetamido-2-nitro-4iocyanatobenzene in 10 ml of DMF under nitrogen is treated at a temperature

  
 <EMI ID = 233.1>

  
hour, 1.6 ml of 20- chloromethyl methyl ether are added.

  
 <EMI ID = 234.1>

  
and recrystallizing, from cyclohexane, crude 1-acetamido-2nitro-4-methoxymethylthiobenzene.

  
1.4 g of the latter product in 6 ml of methanol is treated with 3 ml of a pentanormal aqueous solution of sodium hydroxide and treated under reflux for 15 minutes. We eliminate the

  
 <EMI ID = 235.1>

  
with chloroform, the latter is evaporated and the 2-

  
 <EMI ID = 236.1>

  
1.4gde this aniline is treated in a mixture under reflux of 80 ml of methanol and 20 ml of water with 1.4 g of iron powder and 0.7 g of ferrous sulfate. After 2 hours, another 1.4 g of iron are added, wait for one or two hours, the mixture is filtered, the filtrate is concentrated in vacuo and recrystallized from

  
 <EMI ID = 237.1>

  
1.7 g of the latter product are treated in 50 ml of 50% aqueous ethanol under reflux, with 2.0 g of 1,3-bis- (methoxycarbonyl) S-methylisothiourea and 0.7 ml of acetic acid. for 4. hours. The mixture is cooled and the 5 (6) -methoxymethylthio-2-carbomethoxyaminobenzimidazole is separated by filtration, which can be recrystallized from a mixture of methanol and chloroform.

  
0.53 g of the latter compound is dissolved in a mixture of
50 ml of chloroform and 50 ml of acetic acid at -15 [deg.] C. A solution of 0.41 g of m-chloroperbenzoic acid in chloroform here is added at a temperature of -15 to -10 [deg.] C, then the mixture is allowed to warm up to 20-25 [deg. .] C, left for 10 hours at this temperature, the solvent is removed in vacuo and

  
the residue is carefully treated with a dilute solution of bi-

  
 <EMI ID = 238.1>

  
 <EMI ID = 239.1> <EMI ID = 240.1>

  
methoxyaminobenzimidazole).

  
EXAMPLE 22

  
 <EMI ID = 241.1>

  
of 4-hydroxy-4-nitroacetanilide, 17 g of potassium carbonate and 4 g of chloromethyl methyl ether in 50 ml of acetone under nitrogen, the hot mixture is diluted with 200 ml of hot acetone, filtered, the solvent evaporates and the 2-

  
 <EMI ID = 242.1>

  
4.5 g of this oil are heated for 30 minutes with 10 ml of a pentanormal solution of sodium hydroxide and 60 ml of methanol, cooled, diluted with water and separated by

  
 <EMI ID = 243.1>

  
It is subjected to hydrogenation under ambient conditions

  
 <EMI ID = 244.1>

  
5% dié and 120 ml of methanol. Once the absorption of the hydro-

  
 <EMI ID = 245.1>

  
 <EMI ID = 246.1>

  
3.0 g of the latter product is treated in 15 ml of ethanol,
15 ml of water and 0.5 ml of acetic acid with 3.0 g of 1,3-bis (methoxycarbonyl) -S-methylisothiourea under reflux for 4 hours, the mixture is cooled, filtered and the product recrystallized. in a mixture of methanol and chloroform to thus obtain

  
 <EMI ID = 247.1>

  
EXAMPLE 23

  
 <EMI ID = 248.1>

  
 <EMI ID = 249.1>

  
potassium carbonate, 5 g of chlorodimethyl sulfide in
200 ml of acetone, the hot mixture is diluted with 300 ml of hot acetone, filtered, the solvent evaporated and the oil obtained is chromatographed on silica gel using chloroform as eluent. Pure 2-nitro-4-methylthiomethoxyacetanilide is obtained from the eluate.

  
5.7 of the latter product is treated with 12 ml of a pentanormal solution of sodium hydroxide and 60 ml of methanol, the solution is heated for 30 minutes, cooled, diluted with water, extracted with chloroform, the chloroform solution is dried over sodium sulfate and evaporated to obtain

  
 <EMI ID = 250.1>

K

  
 <EMI ID = 251.1>

  
 <EMI ID = 252.1>

  
mixing under reflux for 4 hours, the hot solution is filtered, the solvent is evaporated, the residue is treated with hot tetrahydrofuran, it is filtered, the solvent is evaporated off and the residue is obtained.

  
 <EMI ID = 253.1>

  
3.9 g of the latter product are treated in 25 ml of ethanol,
25 ml of water and 0.6 ml of acetic acid with 5.0 g of 1,3-bis-
(methoxycarbonyl) -S-methylisothiourea under reflux for 4 hours it is cooled, filtered, recrystallized from tetrahydro-

  
 <EMI ID = 254.1>

  
aminobenzimidazole.

EXAMPLE 24

  
A mixture of 2.5 g of 4-hydroxy-6-nitroacetalinide, 2.1 g of ethyl ether is heated to 110 [deg.] C under nitrogen for 16 hours.

  
 <EMI ID = 255.1>

  
4- (2-ethoxyethoxy) -2-nitroacetalinide by filtration.

  
2.3 g of the latter product are heated for 30 minutes

  
 <EMI ID = 256.1>

  
30 ml of methanol, cooled, diluted with water and isolated pa &#65533; filtration 4- (2-cthoxyethoxy) -2-nitroaniline.

  
A mixture of 1.8 g of the latter product and 0.3 g of a 5% palladium on charcoal catalyst in 200 ml of methanol is hydrogenated under ambient conditions. Once the absorption of hydrogen is complete, it is filtered and

  
 <EMI ID = 257.1>

  
The mixture is cooled, filtered, recrystallized from a mixture of methanol and chloroform and 5 (6) - (2ethoxy-ethoxy) -2-carbomethoxyaninoben7.imidazole is obtained.

  
 <EMI ID = 258.1>

  
r <EMI ID = 259.1> <EMI ID = 260.1>

  
one hour then treated with 5 g of 2-bromethy- ethyl ether

  
 <EMI ID = 261.1>

  
it is diluted with water, the product is extracted with chloroform and, after drying the chloroform solution with sodium sulfate, by evaporation of the solution, 1-amino-2- is obtained.

  
 <EMI ID = 262.1>

  
 <EMI ID = 263.1>

  
nol and 50 ml of water with 16 ml of sodium dithionite and 14 g of sodium carbonate under nitrogen, at reflux. Heating is continued for 30 minutes, then the methanol is evaporated off, diluted with

  
100 ml of water and extracted with chloroform. The chloroform solution is dried over sodium sulphate and obtained by evaporation.

  
 <EMI ID = 264.1>

  
born.

  
 <EMI ID = 265.1>

  
 <EMI ID = 266.1>

  
 <EMI ID = 267.1>

  
shot of a mixture of methanol and chloroform and the

  
 <EMI ID = 268.1>

  
 <EMI ID = 269.1>

  
ture not exceeding 30 [deg.] C. Stirred at a temperature of 15 to 20 [deg.]

  
 <EMI ID = 270.1>

  
2-bromethane at a temperature of 20-25 [deg.] C. Heated at 100 [deg.] C for 3 hours, cooled, diluted with water, the mixture is extracted with chloroform, the chloroform solution is dried over sodium sulfate, the solution is evaporated and the mixture is obtained. 2nitro-4- (2,2,2-trifluoroethylthio) -aniline.

  
 <EMI ID = 271.1>

  
 <EMI ID = 272.1>

  
iron under reflux. After 2 hours, another 1.25 g of

  
 <EMI ID = 273.1>

  
 <EMI ID = 274.1> <EMI ID = 275.1>

  
3.4 g of the latter product are treated in 17 ml of ethanol.
17 ml of water, and 1 ml of acetic acid with 3.5 g of 1,3-bis- (methoxycarbonyl) -S-methylisothiourea under reflux for 4 hours. The mixture was cooled, filtered, and the product recrystallized from a mixture of methanol and chloroform to thereby obtain 5 (6) - (2,2,2-trifluoroethylthio) -2-carbomethoxyaminobenzimidazole.

  
 <EMI ID = 276.1>

  
form / 120 ml of methanol and 2 ml of acetic acid with 0.75 g of a-

  
 <EMI ID = 277.1>

  
te for one hour, then extracted with saturated sodium bicarbonate solution and with water, the solution is dried over sodium sulfate and evaporated. Recrystallization from methanol makes it possible to obtain 5 (6) - (2,2,2-trifluorethylsulfinyl) -2-carbomethoxyaminobenzimidazole. Analogously, using 5 (6) -methylthiomethoxy-2-carbomethoxyaminobenzimi-

  
 <EMI ID = 278.1>

EXAMPLE 27

  
1.8 g of 5 (6) -2- (2-ethoxyethylthio) -2-carbomethoxyaminobenzimidazole of Example 25 in 200 ml of chloroform and 1 ml of acetic acid are treated with 1.55 g of a 30% solution. peracetic acid in acetic acid at 15 [deg.] C. We shake for

  
 <EMI ID = 279.1>

  
ethyl and the solid is collected by filtrate. Recrystallization from a mixture of methanol and chloroform makes it possible to obtain 5 (6) - (2-ethoxyethylsulfonyl) -2-carbOEethoxyaminobenzimidazole.

  
 <EMI ID = 280.1>

  
EXAMPLE 8

  
5 g of 1-amino-2-nitro-4-thiocyanatobonzene are heated in

  
 <EMI ID = 281.1>

  
sodium in 20 ml of dimethylformaside at a temperature not

  
 <EMI ID = 282.1>

  
fluoropropane, heated to 100 [deg.] C for 4 hours, re <EMI ID = 283.1>

  
the chloroform is evaporated off and a red oil is obtained. Chromatography on silica gel makes it possible to obtain 2-nitro-4- (2,2,

  
 <EMI ID = 284.1>

  
 <EMI ID = 285.1>

  
 <EMI ID = 286.1>

  
calinized with ammonium hydroxide, extracted with chloroform, the chloroform solution is filtered, dried over sodium sulphate, evaporated and the 1,2-diamino-4- (2,2,3, 3tetrafluoropropylthio) -benzene.

  
3.5 g of the latter product are treated in 20 ml of ethanol,
-20 ml of water and 0.8 ml of acetic acid with 4.5 g of 1,3-bis- <EMI ID = 287.1>

  
2-carbomethoxyamino-benzimidazole.

  
10 g of the latter product is treated in 10 ml of acetic acid at 20 ° C. with 0.8 g of a 30% solution of peracetic acid in acetic acid, the solution is stirred for 30 minutes, we dilute &#65533; with 150 ml of water, the mixture is filtered, the solid material is recrystallized from methanol and 5 (6) - (2,2,

  
 <EMI ID = 288.1>

  
EXAMPLE 29

  
In a similar way to that of example 28, we use (a)

  
 <EMI ID = 289.1>

  
with the iron powder described in Example 23 (with 100 ml of methanol, 10 ml of acetic acid and 10 g of iron powder) and (c) 4.1

  
 <EMI ID = 290.1>

  
pentafluoropropylsulfonyl) -2-carbomethoxyaminobenzinidazole.

EXAMPLE 30

  
A mixture of 6.0 kg of 1-amino-2-nitro-4-chloro-

  
 <EMI ID = 291.1>

  
under nitrogen, with 4.0 kg of thiophenol. Stir for 2 hours, cool, dilute with 140 liters of ice-water, stir for 1 hour and filter off 1-amino-2-nitro-5-.

  
 <EMI ID = 292.1>

  
 <EMI ID = 293.1>

  
methanol and 30 liters of water, under nitrogen and naked reflux with 8.0 kg of sodium dithionito and 2.0 kg of sodium carbonate. The mixture is heated for 2 hours, the methanol is removed by distillation, the mixture is cooled, the mixture is extracted with dichloromethane, the solution is filtered, dried over sodium sulfate and isolated by

  
 <EMI ID = 294.1>

  
3.25 kg of the latter product is treated in 45 liters of ethanol, 45 liters of water and 2 liters of acetic acid with 4.3 kg

  
 <EMI ID = 295.1>

  
 <EMI ID = 296.1>

  
acetic acid with 2.70 kg of a solution of peracetic acid at

  
 <EMI ID = 297.1>

  
with 300 liters of water and the 5 (6) -phenyl- is isolated by filtration

  
 <EMI ID = 298.1>

EXAMPLE 31

  
A powder is prepared for forming an animal feed having the following composition:

  

 <EMI ID = 299.1>


  
A drink is prepared by mixing approximately 24 g of this product

  
 <EMI ID = 300.1>

  
desired ty of the mixture thus formed, which depends in particular on the size of the animal and the frequency of administration.

  
 <EMI ID = 301.1>

  
 <EMI ID = 302.1>

  
stirred at a temperature of 15 to 20 [deg.] C for 1 hour, treated

  
 <EMI ID = 303.1>

  
heat the mixture at 100 [deg.] C for 3 hours, cooled, diluted with water, extracted with chloroform, dried over sodium sulfate, the solution evaporated and the 1- is obtained.

  
 <EMI ID = 304.1>

  
 <EMI ID = 305.1> .0 <EMI ID = 306.1>

  
under reflux. After 2 hours, 1.25 g of ferrous sulfate is added

  
 <EMI ID = 307.1>

  
 <EMI ID = 308.1>

  
1.9 g of the latter compound are treated in 10 ml of ethanol,

  
 <EMI ID = 309.1>

  
 <EMI ID = 310.1>

  
mixture of methanol and chloroform to obtain 5 (6) - (2cyanoethylthio) -2-carbomethoxyaminobenzimidazolù.

  
1.2 g of the latter product is treated in 400 ml of chloroform, 100 ml of methanol and 2 ml of acetic acid with 0.85 g

  
 <EMI ID = 311.1>

  
the solution for 1 hour, it is extracted with a salt solution.

  
 <EMI ID = 312.1>

  
chloroformed over sodium sulfate, evaporated, recrystallized from methanol and 5 (6) - (2-cyano-ethyl-

  
 <EMI ID = 313.1>

EXAMPLE 33

  
4.4 g of 1-amino-2-nitro-4-thiocyanatobenzene are treated in 10 ml of dimethylformamide, nitrogen bran, with 0.85 g of boro-

  
 <EMI ID = 314.1>

  
 <EMI ID = 315.1>

  
 <EMI ID = 316.1>

  
from 20 to 25 [deg.] C, the mixture is treated for 16 hours at room temperature and poured into water. Filtration and recrystallization from methanol make it possible to obtain 1-amino-2-

  
 <EMI ID = 317.1>

  
4.1 g of the latter product are treated in 60 ml of metha-

  
 <EMI ID = 318.1>

  
iron powder under reflux. After 2 hours, 1.25 g of ferrous sulfate and 3.3 g of iron powder are added, heating is continued for 4 hours, then the mixture is poured into 600 ml of hot tetrahydrofuran, filtered, evaporated, the filtrate and we ob-

  
 <EMI ID = 319.1>

  
 <EMI ID = 320.1>

  
17 ml of water and 1 ml of acetic acid with 3.5 S of 1,3-bis- (metho-

  
 <EMI ID = 321.1>

  
a <EMI ID = 322.1>

  
 <EMI ID = 323.1>

  
form, 120 ml of methanol and 2 ml of acetic acid with 0.75 g of 85% m-chloroperbenzoic acid at a temperature of 0 [deg.] C. The solution is stirred for 1 hour, then extracted with saturated sodium bicarbonate solution and with water, the chloroform solution is dried over sodium sulphate, evaporated, and again.

  
 <EMI ID = 324.1>

  
sulfinyl-2-carbomethoxyaminobenzimidazcle.

EXAMPLE 34

  
A mixture of 5 g of 2-nitro-5-chloraniline and 7s5 g of sodium sulfide monohydrate in 25 ml of ethanol and 25 ml of water is treated under reflux for 1 hour, diluted with water. to a total volume of about 150 ml, filter to remove a small amount of impurities / insoluble, the filtrate is treated with 2.5 ml of acetic acid and the 2nitro-5-mercapto is filtered off. aniline.

  
 <EMI ID = 325.1>

  
20 ml of DMF with 0.5 g of 1CO% sodium hydride and 2.2 g of chloromethyl thiocyanave are added to the solution. After 30 minutes at a temperature of 20-25 [deg.] C, the solution is diluted with water, extracted with chloroform, the latter is removed and thus obtained 1-amino-2-nitro- 5- (thiocyanatomethyltbio) benzene.

  
This compound 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 g of sodium hydrosulfite. The mixture is concentrated, diluted with water, carefully extracted with chloroform, the latter evaporated to give 1,2-diamino-4- (thiocyanatomethylthio) -benzene.

  
A mixture of 2.6 g of the latter compound, 2.6%, is treated.

  
 <EMI ID = 326.1>

  
acetic with 40 ml of a 50% aqueous ethanol solution under reflux for 4 hours, the cooled mixture is filtered and obtained.

  
 <EMI ID = 327.1>

  
dazole which can be recrystallized from a mixture of methanol and chloroform.

  
 <EMI ID = 328.1>

  
50 ml of chloroform and 10 ml of acetic acid, the solution is treated at a temperature of -30 to -20 [deg.] C with a solution of 0.62

  
 <EMI ID = 329.1>

  
allowed to return slowly to room temperature, wait 15 hours, remove the solvent in vacuo and treat the residue with a dilute solution of potassium bicarbonate. The 5 (6) -thiocyanato-methylsulfinyl-2-carbomethoxy- is separated by filtration.

  
 <EMI ID = 330.1>

  
of methanol and chloroform.

  
In some of the above examples, specific sequences of reactions have been applied, in a general sense, to the preparation of other similar or related compounds. It should be noted, however, that for each compound which

  
 <EMI ID = 331.1>

  
may be necessary or desirable to use solvents, reaction media, recrystallization media, reaction times or temperatures, etc., other than those indicated in connection with the sequence under consideration. In addition, the sequence or manner of preparing certain compounds will depend on the availability of the necessary starting materials and the ease with which they can be prepared, as well as on the reactivity of these materials. All these modifications are perfectly within the reach of those skilled in the art and can be easily deduced.

  
 <EMI ID = 332.1>

  
Furthermore, it goes without saying that various modifications can be made to the embodiments which have been described, relating to the processes and the materials, without departing for this from the scope of the invention.

  
 <EMI ID = 333.1>

  
1. An anthelmintic and antifungal compound, characterized in that it is represented by the formula:

  

 <EMI ID = 334.1>


  
 <EMI ID = 335.1>

  
 <EMI ID = 336.1> &#65533;

  
0, S, S or S, R 'is a lower alkyl radical of 1 to 4 ato-

  
 <EMI ID = 337.1>

  
 <EMI ID = 338.1>

  
 <EMI ID = 339.1>

  
cycloalkyl of 3 to 7 carbon atoms, lower alkenyl or lower alkynyl of 3 to 6 carbon atoms, aralkyl or aryl and R5 is a lower alkenyl, lower alkynyl or aralkyl radical, the substitution R being in position 5 (6); or by a salt

  
 <EMI ID = 340.1>


    

Claims (1)

2. A compound according to claim 1, wherein R is methyl. 3. A compound according to claim 1, in which the lower alkyl, lower alkenyl or lower alkynyl radical <EMI ID = 341.1> Lower nyl (substituent R) carries one or more substituents which are alkoxy, aryl, thiocyanato, aroyl, hydroxycycloalkyl, halo, cyano or nitro radicals. 4. A compound according to claim 1, in which the aralkyl radical (substituent R <2> or R5) or the aryl radical (substituent <EMI ID = 342.1> caux lower alkyl, alkoxy, halo, hitro, cyano, thiocyanato, <EMI ID = 343.1> <EMI ID = 344.1> 1 to 6 carbon atoms. <EMI ID = 345.1> characterized in that it is chosen from the following compounds: 5 (6) -methylsulfinyl-2-carbomethoxyaminobenzimidazole; 5 (6) -ethylsulfinyl-2-carbomethoxyaminobenzimidazole; <EMI ID = 346.1> 5 (6) -n-butylsulfinyl-2-carbomethoxyaminobenzimidazole; 5 (6) -phenylsulfinyl-2-carbomethoxyaminobenzimidazole; <EMI ID = 347.1> zole; 5 (6) - (prop-2-yn-1-ylsulfinyl) -2-carbomethoxyaminobenzimidr "101st; <EMI ID = 348.1> the. 6. Compound according to claim 1, characterized in that the hydrogen atom on the nitrogen atom in position 1 is replaced. <EMI ID = 349.1> minthics and / or antifungals of said compound. 7. Composition for the fight against helminths in mammals, characterized in that it comprises an excipient not <EMI ID = 350.1> effective ethics of a compound as defined in any one of sells' .allons 1 to 6. 8. Process for the preparation of a compound as defined in claim 1, characterized in that it consists in carrying out <EMI ID = 351.1> <EMI ID = 352.1> (alkoxycarbonyl) -S-alkylisothiourea to thereby obtain a compound of formula for a sulfinyl and / or sulfonyl derivative of such a compound. <EMI ID = 353.1> of formula I with a substituent which does not disturb the anthelmintic and / or antifungal properties of said compound. 9. The method of claim 8, characterized in that the reaction of 1,2-diamino-thiobenzène. carrying a substituent R in position 4 (5) which can carry other substituents with the <EMI ID = 354.1> holding the thio-2-carbalkoxyaminobenzimidazole substituted in 5 (6), after which said compound is oxidized to obtain sulfinyl- and / <EMI ID = 355.1> corresponding. <EMI ID = 356.1> that one operates according to the sequence shown schematically on pages 5 and 6 of the preceding description, or an equivalent sequence. 11. The method of claim 8, characterized in that one operates according to the sequence shown schematically on page 7 of the above description, or an equivalent sequence.