CA1117952A - Sulfur-containing benzimidazole derivatives, process for the preparation thereof and intermediates useful in production of the same - Google Patents

Abstract

Abstract This invention relates to a process for the preparation of 5(6)-thio-benzimidazole derivatives of the formula I and salts thereof (I) (wherein R1 is hydrogen or a group of the formula -COOR5; R5 is C1-4 alkyl;
R2 is hydrogen, halogen, C1-6 alkyl, trifluoromethyl or a group of the formula -OR3; R3 is C1-4 alkyl, aryl or aralkyl; R4 stands for hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-6 alkenyl, C3-6 alkynyl, or an aryl or aralkyl group whereby the aryl ring of the aryl or aralkyl group may be optionally substituted by one or more halogeno, C1-4 alkyl, nitro, hydroxy, C1-4 alkoxy, C1-4 alkylthio, carboxy or cyano substituent(s) or a group of the formula -S(O)n-R8 in which R8 is lower alkyl; n stands for 0, 1 or 2) which comprises subjecting a compound of the Formula VI

Description

~7~52 This invention relates to sulfur-containing benzimida-zole derivatives and a process for the preparation thereof. Our copending applications Serial Nos.3 70,~40 and ~7D~/which are divided out of this application relate to intermediates useful in the production of these benzimidazole derivatives.
Most of the end-products of the present invention (Formula I) are new compounds, never described in literature.
The compounds of the Formula I possess useful anthelmintic prop-erties and may be used in human and veterinary therapy as anthelmintic agents.
In the Formula I

R2 ~ N ~ (I) the various s~mbols have the following definitions:
Rl is hydrogen or a group of the Formula -CooR5;
R5 is Cl 4 alkyl;
R2 is hydrogen, halogen, Cl 6 alkyl, trifluoromethyl or a group of the Formula -OR ;
R3 is Cl 4 alkyl, aryl or aralkyl;
R4 stands for hydrogen, Cl 6alkyl, C3 7 cycloalkyl, C3 6 2Q alkenyl, C3 6 alkynyl, or an aryl or aralkyl yroup where-by the aryl ring of the aryl or aralkyl group may be op-tionally substituted by one or more halogeno, Cl_4 alkyl, nitro, hydroxy, Cl 4 alkoxy, Cl 4 alkylthio, carboxy, or cyano substituent(s) or a group of the Formula -S(O)n-R

in which R is lower alkyl;
n stands for 0, 1 or 2, The term "lower alkyl group" - alone or in combination

- 2 C
,,. I
... ..
., , .; ,.... .. ..

~795~:

such as alkoxy, allcylthio etc~ - used in the specifica~ion relates to straight or branched chain saturatecl aliphatic hydrocarbon ~roups having 1-6, preFerably 1-4 carbon atoms (e.y. methyl, ethyl, n~propyl, isopropyl, n-butyl, isobutyl, n-amyl etc.). The term "halogeno a~om" covers all the four halogens i.e. -Fluorine, chlorine, bromine and iodine. The C3 7 cycloallsyl group may be cyclobutyl, cyclopentyl and cyclohexyl preferably. The C3 6 allcenyl group may be straight or branched chained a~ is preferably allyl~ The C3 6 all<inyl group may be straight or branched chained and represents preferably propinyl~ The term "aryl group" - used ei~her alone or in combinations such as arallcyl - represents a mono- or bicyclic aromatic ring (e.gO phenyll, naphthyl) which may op~ionally bear one or more of the conventional ~ubstituen~s of the aromatic rin~s (e.g~ halogeno atom, lower alkyl, lower allcoxy~
lower alkylthio, carboxy, nitro, hydroxy, cyano, allsyl-sulphinyl, alkylsulfonyl, allcylthio etcO).
Some representatives of the compounds oF the Formula I are disclosed in prior art as anthelmintic agents (e.g. US Patents No~ 3~574~845~ 3~915~986 and

3~956~499;~ German Federal Republic Paten~ No. 2,250,469 and French Patent No. 2~134-~558~o It is known that a certain compound-group of the Formula II

R S ~ ~ ~ NH ~ W OR (II) ~falling undor the scope of the class of compounds of the ~"..

, ~79~

... , ~

Formula I, wherein R is C1_L~ alkyl, C3 7 cycloalkyl, - C3-6 alkenyl, C3 6 all<inyl or benzyl) may be prepared by reacting an 1,2~diamino-alkylthio-benzene derivative of the Formula III

~ NHz (III) ei~her with an lr3-bis-(allco~ycarbonyl)-S~alisyl-isothio-urea of the Formula IV

~500C - N~_ ~i~ C - SR5 (IV~
R OOC - NH

(German Federal Republic Patsnt No. 2,363,351 - reaction scheme A~ `

~ NH2 R5QoC-N~ C SR5- II ...
R9S ~ N~2 R OOC-NH /

or with a carbalkoxy-cyanamide of the Formula V
NC - NH - ~oR5 (V) (US Patents No~ 3/915,986 and 3,956~99 - reaction : :
scheme B).

j , .. ; .

795~

~-- NH2 ~ NC - NH - CoOR5~
R9S~__ NH2 (II) (III~ (V) The abovs procedures suf~er From ~he serious drawback that the benzimidazols carbama~s ring systsm is formed by using 1~2-diamino-L~-alkylthio-benzene deriva~ives of the Formula III which can be obtained by means of a complicated ~ultistsp synthesis From relatively sxpensive starting materials (reaction scheme C~ and Dl ).
Reaction schems C
~ Cl ~ N02 02N~
Cl ~ ~ NH-COCH l 3 Cl _ ~ NH-OOCH3 ~ ~ R9SH By-product 2 ~ ~1---- 2 ~9S ~NH-COCH3 R9S _ N~2 reduction ~ NH2(III ) R9S~ NH2 .....

. .

s~

Reac~ion sch~me D) ~ N~l2 0~_ NH2 CS~
ace tvla tion_ NH-COCH ~.~\
, 1 3 ~ ~--NH-COCH3 NCS--:~ I ~ NCS ~JL N02 reduction ~
~ N~l -COCH
alkylation l l 3 ~y~
R9$ ~ N02 ~ NH
S ~, N02 --~ (III) The synthesis-route shown in reaction scheme C) comprises the nitra~ion of m-chloro-acetanilide which gives rise to the Formation of two isomeric compounds.
There~oreJ ~he useful o-nitro-acetamido isomer required for the synthesis is available but with moderate yields ~-p. OrgO ChemO 12, 799 (19L~7)J. The further step of the reaction needs ~o~ical mercaptanes of very bad odour ~US. Patents No. 3,915t986 and 3,956,L~99J. This reaction can be generally carried only wi~h low yields r~. Org. Chem. L~2, 55~ /1977/]~ For ~he reasons sta~ed above the compounds of the Formula III can be ob~ained in poor yields.
Reaction scheme D) provides the desired compounds of the Formula III with the aid of a seven-step synthesis by ~7~
.
low yields Cser. 59, 190 /1926/D ~ Chem. Soc. /192~/
136~].
It has bsen Found that the compounds oF the Formula I can be prepared by reducin~ the new benzimidazole-di-sulfides oF the Formula VI and if desired subjecting thethiophenol derivatived of the Formula I thus obtained (R~ is hydro~en = Ia) R ~ ~ _ NH-Rl (Ia~

to selective substitution reaction on the sulFur atom.
Thus the compounds of ~he Formula I are available in a simple manner by very good yields.
According to the presen~ invention there is provided a process for the preparation of compounds of the Formula I and salts thereof which comprises subjecting a compound of the Formula VI

R2~N ~ . ;
_ _ S ~I~ N ~ NH~ ~ VI ) H
_ ~

to reduction (wherein Rl and R2 are as stated above~ and i~ desired introducing an R~ group being other than hydrogen into the compound of the Formula I ~hus formed (wherein Rl and R2 are as stated above and R~ is hydrogen~ and if desired converting a co~pound of the Formula I thus obtained into its salt.

.

~7~
, According to a preferred er~bodirnent of our process a ccmpound of the Forrnula VI is reacted with a complex metal hydride such as lithium aluminium hydride, sodiumborohydride-alurninium chloride complex, sodiumborohydride or sodiun~dihydro-bis-(2-methoxy-ethoxy)-alurninate in anhydrals mediurn and op-tionally in the presence of a Lewis Acid. Suitable Lewis Acids are alurniniurn chloride, boron trifluoride or titaniurn tetrachloride. As reaction medium preferably organic solvents such as diaIkyl ethers, cyclic ethers (e.g. tetra-hydrofurane, dioxane), dimethylform~mide, dimethylacetamide, he~nethylphos-phoric triam~de, diethylene-glycol dimethyl ether, lcwer alcohols etc.) may be used.
When using a sodium borohydride-aluminium chloride cc~plex, the re-action may ~e preferably carried out in tetrahydrofurane or dioxane. In this case the reaction takes place at room temperature within 2-3 hours.
When using sodiumborohydride the reaction may be carried out in addition to the above solvents also in the m~xture of water and a lower aIkan-ol in the presence of an aIkali hydroxide. me thiophenol derivative of the Forrnula Ia thus formed can either be isolated or directly converted into other con~x~.ds of the Formula I.
m e disulfide bond of the compour.ds of the Formula Vl may also be reduced by means of aIkali metals. The starting material of the Formula Vl is suspended in an inert solvent (e.g. toluene, xylene) and admuxed wi-th powdered potassium or sodium at room ternperature or under ~arming, suitably at a temp- ~
erature bet~een -40C and 130C. 2-4 equivalents of aIkali metal are used -for 1 equivalent of the compcwnd of the Formula VI. If 4 equivalents of aIk ali are used, the diaIkali salt of the ccmpound of the Fo~mula Ia is obtained.
me react~on mixture is then acidified and the compound of ~he Formula Ia can be isolated if desired. If only 2 equivalents of an acid (e.g. acetic acid) are added to the react~on mixture, the solution of the mono-aIkali salt of the compound of t~e Formula Ia is forrnRd which may be converted into other compounds of the Fo~mula I directly, .fr~
~,;' :

9~i~
_ 9 _ without isolationO The said reduction may be preferably accomplished in liquid ammonia at a temperature between -20 C and -~0 C. On evapora~ing the ammonia solvent the alkali salt oF the compounds of the Formula Ia is obtained as rasidue, which may be ei~her isolated or subjected to Further reactions~
The compounds of the Formula VI may also be reduced with sulfur-containing inorganic reducing agents such as sodium sulfide, sodium sulfite, sodium dithionite, sodium hydrogen sulfite or potassium pyrosulfiteO Sodium hydrogen sulfite and sodium dithionite proved to be particularly suitable for this purpose, When using the said reducing agents 2-2,6 moles of allcali hydroxide and 2-2.2 moles of ~he reducing agent are applied for 1 mole of a starting material of the formula VI. Reduction may be preFerably carried out in an alcoholic solution and/or dimethylformamide containing 10-30 ~ of water, The reaction is accomplished under hea~ing a~ 50-80 C, preferably at tha boiling point of the reaction mix~ureO
The compounds of the Formula Ia formed are either isolated or directly converted into ~thcr compounds of the Formula I.
~ s reducing agen~s organic sulFur compounds may be used as well (e.g, mercapto-ethanol or amino-imino-m~thane sulfinic acid)O The solution or suspension oF the starting material of the Formula VI in an or~anic solvent (eOg.
lower alkanol or dimethylformamide) is reacted with 1-3 equivalents of mercapto-ethanol at 20-80 C in the presence of a basical catalyst (eOg. triethylamine~. The compounds of the Formula Ia thus formed are either directly converted into an other compound of the Formula I or isolateda . . .

~795~Z:

When using amino-imino-methane sulFinic acid as reducing agent, the solution or suspension oF the startiny material oF the formula VI in a mixture of aquaous alkali and alcohol or a dipolar apro~ic solvent (in ~ho :Latter case a phase-transmitting ca~alyst is also added e.g.
cetyl-pyridinium bromide and methyl-capryl-ammonium chloride etc.) is reacted with amino-imino-methane-sulfinic acid at 60-80 C in an inert atmosphere~
One may also proceed by carrying out reduction with glucoseO As solvent or diluent a mixture oF wa~er and lower alcohols or dimethylformamide may be used~
Reduction talces place at room temperature within 5-10 hours~ It is preferred to subject the aqueous alkaline -alcoholic suspension to strong stirring in the presence of a phase-transmitting catalyst. This may significantly shorten the reaction time.
The reduction of the disulfide bond of the starting materials of the formula VI may also be accomplished with metals in acidic medium. ~s mstal preferably zinc,~ tin, iron or aluminium may be used. One may proceed preferably by using salts of metals of varying valency in which the metal is in a lower oxidation stage Ce.g. stannou~
chloride, titanium(~II)chloride~ in acidic medium. The suitable pH value may be adjustéd by adding a diluted (0.1-2.5 N) inorganic acid such as hydrochloric acid or sulfuric acid. As reaction medium water and/or water-miscible organic solvents le.g. allcanols,~ glycols, di- -methylFormamide, dioxane, diethyleneglycol-dimethyl-ether, tetrahydrofurane, preferably lower alkanols~ may be used. The reaction may be preferably carried out at a ?~,~, .

,.: , . , . . ~

7~S2 temperature betweell 25 C and llO C, particularly a~ the boiling point o~ the reaction mixture~ According to a preFerred embodiment of ~he la~ter me~hod acetic acid is used which serves both as solven~ and for ths adjustment oF ~he pH-value.
Accordin~ to an other method a solu~ion of a compound of the formula VI in the mixture of a mineral acid and alkanol or în dimethylformamide is passed through zinc amalgamated in a ~ones-reductor, As mineral acid first of all hydrochloric acid and sulfuric acid may be used. The acid concentra~ion is preferably 0.1-2.5 No As solvent or diluent water-miscible lower alkanols (e.g. methanol/
ethanol or isopropanol~ may be used. The above method provides very mild reducing conditions and may be very quickly carried out at room temperature ~oo~
According to a preferred form of realisation of the above reducing methods one may work in an iner~
atmosphere particularly, under nitrogen. If the reaction is carried ou~ in heterogeneous system i~ is expedient to use a phase-transmitting catalyst.
The compounds of the Formula Ia thus obtained may be optionally converted into the thio ethers oF the Formula I - wherein R~ is other than hydrogen - by transforming the said compounds of the formula Ia into a compound of the Formula Ib ~ ~ .:
R9S ~ ~ N ~ NH-R rIb) H

by reacting with a compound of the Formula R9~Q-~ or into a J

.

s~
-compound of the Formula Ic 12 ~ R2_ ~ ~ NH-R (Ic) R ~ S - ~ N

by reacting with a compound of the Formula X;

R12 ~ ~ Q (x) or into a compound of the Formula Id R13 S ~ ~ NH-R (Id) by react~ng with a compound of the Formula XI;

~ N2Cl (XI) Rl 4 or into a compound of the Formula Id, wherein both R 3 and are hydrogen, with chloro-benzene or bromo-benzene, in which Formulae R9 is Cl_6 alkyl; C3_7 cycloalkyl, C3 6 alkenyl, C3 6 alkinyl or an aralkyl group which is unsubstituted or is sub-stituted by one or more halogenor Cl 4 alkyl, nitro, hydroxy, Cl 4 alkoxy, Cl 4 alkylthio, carboxy or cyano su~stituent(s) or a group of formula ~S(o)n-R3 in which R8 and n are as defined above;
Q is chlorine, bromine or iodine or a group of the ' ~7~5~

~ 13 Formula RlQ-So3 ;
R10 is a phenyl group op~ionally substituted in position ~ by a me~hyl group;
Rl and R12 are hydrogen, nitro, cyano, carboxylic group or a group of the Formula ~S(O)n-R8, R and n are as stated above;
R13 and R14 are hydrogen, halogen~ C1 ~ alkyl, hydro~y~
Cl_4 alkoxy or alkylthio.
The compound Ia is at first converted into its all<ali salt by dissolving or suspending in an organic solvent and adding an equivalent amount oF alkali hydroxide (sodium or potassium hydroxide). The solution of this alkali salt - or that of an alkali salt of a compound of the Formula Ia directly formed in the course of one of the 1~ reducing method`s~ discussed above - is reacted wi~h a compound of the Formula R9-Q (wherein R9 and Q are as stated above~. The reaction is carried ou~ at a temperature of 10 ~o 60C. As solvent or suspending mediu~ water-miscible organic solvent (e.g~ me~hanol, ethanol and/or dimethylFormamide, dimethylacetamide, or hexamethyl-phosphoric triamide~ may be used. Thus compounds of the formula Ib are obtained. -~
The thioethers of the Formula Ic may be prepared by reac~ing a compound of the Formula Ia with a compound of the Formula X. In this case the compound of the Formula Ia is first converted into its alkali salt as described above. The ~ction takes place at room temperature within some hours, The reactants are used in equimolar amount.
As reaction medium pre-Ferably water and/or lower alkanols or dimethylformamide may be used.

~`;

~ 7~S~:

_ lL~

The compounds of the Formula Id may be prepared by reac~ing the alkali sal~ o-F a compound o-F ~he Formula Ia -prepared as described above - with a compound of ~he Formula ~I. One may proceed preferably by pouring ~he solutlon.
of the diazonium sal~ of ~he Formula XI ~o the solution or suspension of an alkali sal~ of a compound of the Formula Ia in a lower alkanol or a mixture of water and a lower allcanol, or water, lower alkanol and dimethyl-formamide respectively under boiliny. The reaction mixture is diluted with water if necessary whereupon the compound of the Formula Id is recovered by filtra~ion or extraction.
The reaction may be optionally carriad out in the presence of powdered copper~
Compounds of the Formula Id - wherein both R13 and Rl~ are hydrogen - may also be prepared by reacting the alkali salt of a compound of the Formula Ia with chloro-benzene or bromo-benzene at 100-200 C in the presence o^f 0.1-2.5 equivalsnts of a heavy metal salt ~e.g. cuprous(I~-or cupric(II)-salt such as cupricrII~chloride or cupric(II)-bromide].
The conversion of the compounds of the formula Ia into thioethers of the Formula I ~R~ is other than - hydrogen) is carried out in inert atmosphere preferably under nitrogen. Reactions in heterogenous system are expediently carried out in the presence of a phase transmitting ca~alyst in order to shorten reaction time and to increase the yield. For this purpose both phosphonium and ammonium type phase transmittants may be readily applied which are generally used in chemistry, According to a furthar feature of our invention there : , .
- . -.

9~

aro provided nsw compounds of ~he Formula I and salts thereo~ (wherein ~1, R2 and R4 have the same meaning as stated above with the proviso ~hat R2 is o~har than hydrogen).
PreFerable sub-class of tho compounds of the Formula I are those derivatives wherein ~1 is -CooR5~ R5 is lower alkyl, pre-Ferably methyl; R is lower allcyl~ preferably methyl, ethyl or n-propyl; allyl, propinyl, benzyl or cyclo-hexyl and R2 is halogen preferably chlorine, bromine or ~luorine; lower alkoxy, preferably metho~y, lowsr alkyl, prsfsrably msthylg or tri~luoromsthyl.
Par~icularly preferable representatives of ~hs compounds o~ the Formula I are ~he following dorivativesO
5(6~-n-propylthio-6(5)-fluoro-benzimidazolyl-2-methyl--carbamate;
5(6)-n-propylthio-6(5)-chloro-benzimidazolyl-Z-msthyl--carbamate~
5(6)-benzyl~hio-6~5~-chloro-benzimidazolyl~2-methyl--carbamate~j 5(6~-allylthio-6(5~ chloro-benzimidazolyl-2-methyl--carbamateO
5(6)-propynyl-6t5~-chloro-benzimidazolyl-2-methyl--carbamatej~
5(6)-sthylthio-6(5)-chloro-bsnzimidazolyl-2-methyl--carbamate~
5~6)-cyclohexylthio-6(5)-chloro-benzimidazolyl-2-methyl- ;~;
-carbamate;
5(6)-n-propylthio-6~5~-bromo-benzimidazolyl-2-mqthyl--carbamate:~ :
5~6)-n-propylthio-6~5~-me~hyl-benzimidazolyl-2-methyl-i. ~, . .~

, ': ,, ;' . . ..

7~

-carbamate;
5(6)-n-propylthio-6(5)-methoxy-benzimidazolyl-2-mcthyl--carbamate;
5(6~-n-propylthio-6(53-n-bu~yl-benzimidazolyl-2-methyl--carbamatep 5~6)-n-propyl~hio-6(5)-triFluoromethyl-benzimidazolyl-2--methyl-carbamate.
According to a still further feature of the present invention there are provided anthelmintic compositions comprising as active ingredient a compound of the Formula I (wherein Rl, R2 and R~ are as stated above with the prov,iso that R2 is other than hydrogen) or a salt ~hereof in admixture with suitable inert non-toxic solid or liquid carriers or diluents.
The compounds of the Formula I possess useful anthelmintic properties and may be used in human and veterinary therapy as anthelmintic agen~. The new compounds of the Formula I and salts thereof are formulated with non-toxical animal veterinary or feed carrier to give a usual anthelmintic composition. The carrier may be a standard animal feed composition based on a Feed carrier or an orally ingestible container for the active ingredient for example a hard or soft gelatine capsule4 It may also be a pharmaceu~ically acceptable diluent or excipient of the kind normally used in the production of medicaments (e.g. starch~ lactose, sucrose, calcium phosphate, gelatine, talcum, magnesium stearate, dextrin, agar etc~3f As liquid carrier e.g. peanut oil, olive oil, sesame oil and water may be used.
A wide varie~y of pharmaceutical and veterinary forms

4~ ~A~
~L~7~

can be employed. Thus if a solid carrier is used the composition can be tableted, placed in a hard gelatine capsule, compounded in a salt block, as a powder for drench or gavage use, whole feed or other conventional formulations. The compositions are often finished in forms suitable for oral administration (e.g. solu-tion, emulsionl suspension in water or an edible oil). The ad-ministration may also be carried out with such forms as bolus, tablet, drench, top dressing, etc..
The anthelmintic compositions of the present invention are made by conventional methods by admixing the active ingred-ient or a salt thereof with suitable inert solid or liquid carriers or diluents.
The salts of the compounds of the formula I are pharm-aceutically acceptable salts.
The dosage of the active ingredient may vary between wide ranges depending on various factors ~e.g. seriousness of the infection, condition and weight of the host etc.) and may be generally between about 0.5 mg/kg and 150 mg/kg, preferably 2-20 mg/kg of body weight/dose. The daily active ingredient ~0 content may be administered at once or in more doses.
TRe starting materials of the formula VI and salts there-of are ne~ compounds and are the subject of our copendiny D application Serial No. 3~ , mentioned a~ove. According to that application, there are provided new compounds of the form-ula VI and salts thereof and a process for their preparation ~where~n Rl, R5, R2 and R3 have the same meaning as stated above~. The compounds of the formula VI are useful as inter-mediates ir. the preparation of tne anthelmintic compounds of the formula I while on the other hand they possess ~7~5~ `

themselves fungicidal and anthelmintic properties and can be used in agri-culture as fungicides and in pharmacy as anthelmintics.
The preferred class of the compounds of the formula VI are those derivatives in which Rl is hydrogen or methoxycarbonyl and R2 is llydrogen, chlorine, bromine, fluorine, trifluoromethyl, methyl, butyl or -oR3 wherein R is methyl, phenyl or benzyl.
Particularly useful intermediates of the formula VI are the follow-ing derivatives: bis-(2-amino-benzimidazole-5-yl)-disulfide; bis-(2-amino-6-methyl-benzimidazole-5-yl)-disulfide; bis-(2-amino-6-butyl-benzimidazole-

5-yl)-disulfide, bis-(2-amino-6-bromo-benzimidazole-5-yl)-disulfide; bis-(2-amino-6-chloro-benzimidazole-5-yl)-disulfide; bis-~2-amino-6-fluoro-benzimidazole-5-yl)-disulfide; bis-~2-amino-6-trifluoromethyl-benzimidazole-5-yl)-disulfide; bis-~2-amino-6-methoxy-benzimidazole-5-yl)-disulfide; bis-(2-amino-6-phenyloxy-benzimidazole-5-yl)-disulfide; bis-(2-amino-6-benzyloxy-benzimidazole-5-yl)-disulfide; bis-(2-methoxycarbonylamino-benzimidazole-5-yl)-disulfide; bis-(2-methoxycarbonylamino-6-methyl-benzimidazole-5-yl)-disulfide; bis-(2-methoxycarbonylamino-6-butyl-benzimidazole-5-yl)-disulfide;
bis-(2-methoxycarbonylamino-6-bromo-benzimidazole-5-yl)-disulfide; bis-(2-methoxycarbonylamino-6-chloro-benzimidazole-5-yl)-disulfide;

~L7~5~

bis-(2-methoxycarbonylamino-6_Fluoro-benzirnidazole-5vl)--disulfide 9 bis-(2-methoxycarbonylamino-6-~rifluorome~hyl-benzimidazole--5-yl~-disulfide;
bis-(2-me~ho~ycarbonylamino-6-methoxy-benzimidazole~5-yl)-~disulfide~
bis-(2 methoxycarbonylamlno-6-phenoxy-benzimidazole 5-yl)--disulfide;
bis-~2-me~hoxycarbonylamino-6-benzyloxy-benzimidazole-5--yl~-disulfide.
The cornpounds of the Formula VI may be prepared as follows:
a) for ~he preparation of compounds of the Formula VI, wherein Rl is hydrogen, reac~ing a compound of the Formula VII _ ._ R2 ~ NH2 (VII~
-- S~NH2 . _ 2 (wherein R2 has the same meanin~ as stated above~ with cyanamide or bromo cyane~ or b~ for ~he prepara~ion of compounds of ~he formula VI, wherein Rl is a group of the Formula ~CooR5 and R5 is as stated above, reacting a compound of the Formula VII with a compound of the Formula XII
R500CN - C - NH - CoOR5 SR (XII) or NC - NH COOR (XIII) .

.
. . ~ : . ., ;, ,.

- 2~ -(in which formulae R5 is as stated above) or reac~ing a compound of the Formula VI, wherein R1 is hydrogen, Nith an agen~ suitable for the in~roduction of the group of the formula -CooR5~ such as a compound of the Formula XIV
X - COOR (XIV) or XV
(R50~2 co (XV~
~wharein R5 is as sta~ed above and X is halogen~
and if desired converting a compound of the Formula V,~
thus obtained into its sal~ or setting free the same from its salt.
According ~o one embodiment of method a) a compound of the Formula VII is raacted with cyanamide. The reaction is accomplished in the presence of a ~ineral acid (e.gO hydrochloric acidJ sulfuric acid, phosphoric acid) in aqueous medium~ Thereafter the reaction mixture is treated wi~h an inorganic base ~e.g. sodium or p~tassium hydroxide~ or an allcali carbonate (e.g. sodium ;~
or potassium carbonate) and ~he precipitated bis-(2-amino-benzimidazolyl)-disulfide of the Formula VXa t ~NH2 ¦ ( is isolated.
According to an other embodiment of method a) a compound oF the Formula VII is reacted wi~h bromo cyane in a lower alkanol (e.g, me~hanol,' ethanol,' propanol?
isopropanol`,' preferably in ethanol~ at a temperature ~7~3!S~

between 0 C and ~0 C, preFerably at 20 C, The reaction mixture is treated With an alkali le.g. sodiurn or po~assium hydroxide) or an alkali carbonate (e,g. sodium or potassium carbonats~ to give a compound of ~he ~ormula VIa, Accordin~ to an embodiment of method b) of our process a compound of the Formula VII is reacted with an iso-thiourea derivative of ~he Formula XII. The process is preferably carried out by heatiny ~he components in a protic solvent in the presence of an acid. As reaction medium, water, or organic solvents or a mixture of water and an organic solvent (e~g. water-ethanol mixture) may be used.
The reaction i5 preferably accomplished at a pH value of 3-5, particularly a~ an interval of 3.5-5. The p~l is adjusted with an inorganic acid (e.g~ hydrochloric acid, sulfuric acid, pho~phoric acid~ or an organic ~acid, e.g.
formic acid~, acetic acid,~ propionic acid etc. preferably acetic acid. The reaction temperature is prefsrably 50-100 C and one may worlc advantageously at the boiling point of the reaction mixture. Thus compound of the Formula VIb ~ ~ NH-Coo~5 l (VIb~

are obtained.
According to an other embodiment of method b) a compound of the Formula Y~I is reacted with a carbalkoxy-cyanamide of the formula XIII in a water~miscible organic solvent 3~ (e.g. methanol, ethanol, acetone, dioxaneJI pyridine) or a \~2~' 7~5~

mixture of wa~er and an organic solvent. The reaction may be accomplished pre-ferably at a temperature be~ween 20 C
and the boiling point of tbe reac~ion mixture. Thus compounds of ~he Formula VIb are ob~ainsd.
A compound of ~he Formula VIa may be convertsd inta ~he corresponding compound of the Formula VIb by reacting with an agent capable for the introduction of a carbalkoxy group. Reaction is carried ou~ preferably in a basical organic solvent (e.g. pyridine) at a temperature of O-100C.
As agent capable For the introduc~ion of a carbalkoxy yroup agents generally used for this purpose (e~g. allcyl halogeno formiates of the Formula XIV~ may be used~
The compounds of the Formula VIa may also be trans~
formed into the corresponding compounds of the Formula VIb by reacting with a dialkyl carbonate of ~he Formula XV in the presence of an equimolar amount of an alkali alcoholate.
As solven~ preferably an alkanol may be used. One may proceed preferably by using as reaction medium an alcohol which corresponds to the R5 alkyl group of the alkali alcoholate. The reaction temperature amounts to 20-120 C, preFerably the boiling point of ~he alcohol solvent used.
It is evident For one skilled in the art that the compounds appearing in the Examples may be designated in two manners depending on the Fact whether the numbering is started ~rom the N-atom or the NH group. Thus bis--(2-methoxycarbonylamino-benzimidazole~5~yl)-disulfide can also be named as bis-~2~methoxycarbonylamino-benzimida~ole-6-yl~ disulFide.
According to a further feature o~ the present invention there are provided compounds of the Formula VII and salts .

, . . , . : . .

~7~5~

~hereof and a process for the prepara~ion of the same.
The compounds of the Formula VI~ are useFul on ~he one hand as intermediates in the preparation of anthelmin~ic agents of ~he Formula I while on the othsr they possess valuable fungicidal and anthelmintic properties and may be used as fungicides in agruculture and anthelmintics in pharmacy.
All of the compounds of the Formula VII are new except the derivative in which R2 is hydrogen, In prior art a very complicated and circumstantial seven-step synthesis is disclosed for ~he preparation of this compound in which aniline is rhodinated, tha amino group is protected by introducing an acetyl group, ~he product is subjected to nitration and hydrolysis, whereupon the product ob~ained is converted into a disulfide, which i5 than cleaned into 2-amino-4-mercapto-aniline and finally a disulfide is formed ~Ber. 59, 190 (1926)1;~ a. Chem. Soc. 1928, 136 Pharmazie 3, 151 ~l9~8); Arzneimi~telforschung 2, 455 ~lg52)J. In view of the complicatsd steps and the low yield this process is unsuitable for industrial scale production~ The compound of the Formula VII, wherein R2 is hydrogen, was only Icnown as a labora~ory product of theoretical interest.
It has been -Found that the compounds of the Formula VII are valuable intermediates in the preparation of biologically active derivatives by further reactions of the active amino groups. Thus they are suitable for the pre-paration of various heterocyclic compounds, eOg. dibenz-imidazolyl-disulfide derivatives~ The following preparation 3~ oF the compounds oF the Formula VII can be readily carried ~7~5;2 ou~ on industrial scale. Practically no by-products are formed.
The compounds of the Formula XII may be prepared by heating a compound of the Formula XVIo p~2 ~ N~2 (XVI~
NCS- ~ ~ NH2 The reaction may be carried out preferably by heating the star~ing ma~erial of the Formula XVI in a suitable solvent in the presence of a ca~alyst.
As solvent water or lower alkanols ~e,g. methanol, e~hanol, propanol) or a mixture of water and the above allcanols may be used. The catalyst may be an inorganic base ~preferably sodium hydroxide/ potassium hydroxide~r an alkali carbonate (e.gO sodium carbonate~,~ potassium carbonate~
or - preferably - ammonium hydroxide.
One may proceed particularly preferably by heating a compound of the Formula XVI with a 3,5 ~ aqueous ammonium hydroxide solution. The reaction temperature is preferably 20-100 C~, advantageously 80 C. The reaction , .
takes plaoe within 1-5 hours/ preferably 3 hours.
According to an other embodiment of this process a compound of the Formula XVI is heatsd in the mixture of a lower alkanoic acid (e.g. acetic acid~ and a tertiary amine (eOg. triethylamino, dimethylaniline, pyridine 9 ~ :
Particularly preferable class of compounds are those derivatives of the Formula VII wherein R2 is me~hyl, butyl, chlorine, bromine, fluorine, trifluoromethyl or -OR and R3 is methyll benzyl or phenyl~

"
. ;.

.:

~7~5~

Particularly preferred representatives of the compounds of the Formula ~II are the following compounds:
2,2'-dimethyl-~,4',5~5'-tetraamino-diphenyl-disulfide;
2,2'-dibutyl-4,4',5,5'-tetraamino~diphenyl-disulfide;
2,2'-dibromo-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2'-dichloro-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2'-difluoro-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2'-di-(trifluoromethyl)-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2'-dimethoxy-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2'-diphenoxy-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2'-di-(benzyloxy)-4,4',5,5'-tetraamino-diphenyl-disulfide.
Our copending application Serial No. ~ /, mentioned above relates to compounds of the formula XVII

I

~R21 ~ .
NCS ~ (XVII) salts thereof and a process for the preparation of the same.
In the compounds of the Yormula XVII R stands for hydrogen or amino; and if R21 is hydrogen, then R22 is amino and if R21 represents amino, then R22 stands for hydrogen, halo-gen, trifluoromethyl, lower alkyl, lower alkoxy, aryloxy or ~i~
aralkoxy.
The compounds of the Formula XVII and salts thereof areprepared by reacting a compound of the Formula XVIII

~ .

~6 ~

N~12 - R21 (XVIII) ~22 ~wherein R21 and R~Z are as stated above) with an agent capable of introduciny a thio~yanato (SCN~ group in anhydrous medium and if desired converting a compound oF
the Formula XVII into its salt or setting free ~he same from i~s sal~.
The compounds of ~he Formula XVII are useful intarmediates which may be used in the preparation of bio logically active compounds, particularly pharmaceuticals and products for application in agr~culture such as pesticides, eOgO fungicides~ :`
One of the compounds of the Formula XVII - the 1,2-diamino-~-thiocyanato-benzene - has been described as intermediate without disclosing its physical constan~s ZO (t-tungarian laid open paten~ application Serial No.
SI-l367~. According to the known process 1-amino-2-nitro- ;
Lt-thiocyanato-benzene (~, Chem. Soc. ,1928,,i 136L~ ~ a :
compounds which is available with difficulty on inttustrial scale - is reduced with stannous(II)chloride at -~O C
(Reaction scheme E), 5~2 N~12 IlH~c ~ ~c~
2. Ac20/ ~ ccO ~l2S0 SCN
NHAc NH2 d~r N0 2 ~ N 2 10 ~ ~ ~

~H2 SnC12 ~ N~2 -~o C
SCN
It is known ~. GenO ChemO (USSR), 3, 133 (1933):~
C. A. 28~ 1677 ~193~)3 tha~ 1l3-diamino-benzene may be rhodinated with the aid of N,Nt-dichloro-urea and ammonium rhodanide in aqueous acetic acid. The authors stated however that this method does not lead to the desired resul~ when diamino-benzene derivativos sensible against oxidation tsuch as p-phenylene-diamine~ are used.
A recently published summarizing monography about rhodinating was silent in teaching the rhodination of such diamino-ben~ene derivatives ~Die Pharmazie 32~: 195 (1977~
It has been found surprisingly that the diamino-thio-cyanato benzene derivatives of the Formula XVII may be prepared by excellent yields from the compounds of ~he L7~5~

Formula XVIII by direct rhodination in moderately acidic anhy-drous medium.
As rhodinating ayent preferably compounds of the Formula XIX

R - SCN (XIX) may be used (wherein R4 is a metal atom, preferably an alkali metal atom, alkaline earth metal atom or a heavy metal atom or an ammonium ion) in the presence or in the absence of an oxidiz-ing agent - depending on the definition of R4. These rhodinat-ing agents provide under the reaction conditions used the de-sired compounds of the Formula XVII in a simple manner, by ex-cellent yields and in high purity.
One may proceed preferably ~y preparing in advance the active rhodinating agent and adding the same to the solution of tHe starting material of the Formula XVIII. The active rhodin-ating agent may also be prepared by reacting a compound of the Formula XIX with an oxidizing agent. In this reaction both in-organic and organic oxidizing agents may be used. From the oxidizing agents e.g. organic N-halogeno compounds, such as ~0 Chloramine-T, N-bromo-succinimide, N,N'-dichloro-urea; perox-ides e.g. hydrogen peroxides; alkali hypocHlorites, alkali bromates, alkali iodates; ions of heavy metals of suitable -oxidation grade e~g. ions of lead, manganese and chromium:
further onsilver oxide and elementary halogens such as chlorine and bromine may be used.

One may also proceed by adding the above oxidizing agent at a suitable rate to the solution of the compounds of the Formulae XVIII and XIX. In the case of rhodanides ,, ~17~%
_ z9 ~

of heavy metals howsver this embodiment of the process is less preferable~
According to a particularly preFera'ole embodiment of our process the oxidizing agent or a solu~ion ~hereof is.
added at a sui~able rate to the solution oF a compound of the Formula XVIII and a rhodanide of the Formula XXX
wherein R~ is ammoniumt sodium or potassium ion, preFerably ammonium ionO One may use preferably an elementary halogen, particularly bromine or chlorine.
As reaction medium organic solvents may be used in which the components are readily soluble such as dipolar aprotic solvents (e~gO dimethylformamide, dimethylsulfoxide, hexame~hylphosphoric triamide~ lower fatty acids, esters of alcohols formed acetic acid or formic acid and alkanols having 1-4 carbon atoms. It is preferred to use methanol or ethanol in which most organic rhodanides are easily soluble. Methanol proved to give ~he best results~ In the case of the preparation of compounds of the Formula XVII whersin ~ is amino and R 2 is alkyl, alkoxy, aryloxy or aralkoxy, the reaction is carried out under the addition of an acid. For this purpose organic acids may be very advantageously used which act also as solvent (e.g.
acetic acid or formic acid). One may proceed par~icularly preferably by using methanol or e~hanol as solvent and adding 0 2 moles of acetic acid - related to the diamino-benzene derivati~e of the Formula XVIII- to the reac~on mixture.
The reaction temperature depends on the solvent and the reactants used and is from about -20C to about ~200Co -The process may be particularly advantageously aox~pli~
by reacting a compound of ~he formula XVIII in a mixture of . . . , ~

~7~5~

methanol and acetic acid at a temperature between -10C and +25C with a rhodinating agent formed from ammonium rhodanide and elementary bromine or chlorine.
The above novel process opens a new way in the synthesis of sulfur-containing diamino-benzene derivatives. The process is very simple, the starting materials are cheap and easily available in great quantities too and the desired diamino-thiocyanato benzene derivatives are obtained in one step with excellent yields.
It is evident for one skilled in the art that the numbering of the substituents may be started from either amino group. Thus 1,2-diamino-4-chloro-5-thiocyanato-benæene may be designated as 1,2-diamino-4-thiocyanato-5-chloro-benzene as well.
The compounds of the Formula XVII are new and belong to the scope of our copending application Serial No. 370,241, with the proviso that if R 1 is amino then R is other than hydrogen.
Preferred representatives of the compounds of the formula XVII are the following derivatives: 1,2-diamino-4-methyl-5-thiocyanato-benzene; 1,4-diamino-2-thiocyanato-benzene; 1,2-diamino-4-chloro-5-thiocyanato-benzene;
1,2-diamino-4-bromo-5-thiocyanato-benzene; 1,2-diamino-4-fluoro-5-thio-cyanato-benzene; 1,2-diamino-4-trifluoro-ethyl-5-thiocyanato-benzene, 1,2-diamino-4-methoxy-5-thiocyanato-benzene; 1,2-diamino-4-phenoxy-5-thiocyanato-benzene; 1,2-diamino-4-benzyloxy-5-thiocyanato-benzene; 1,2-diamino-4-n- -butyl-5-thiocyanato-benzene.
The compounds of the Formula I and salts thereof 7~S~
_ 31 -(wherein Rlr R2, R3 and l~ and R5 are as s~ated abovc) may be thus prepared From the diamino-benzene dcrivatives of the formula XVIII by the following reac~ion seriasO
reacting a compound o-f the Formula XVIII (wherein R21 is amino and ~22 stands For hydrogen, halogen, trifluoro-methyl, lower alkyl, lower alkoxy, aryloxy or aralkoxy) wi~h an agent capable of in~roducing a thiocyanato-group (SCN)p thereafter hea~ing the compound oF ~he Formula XVI thus formed (wherein R2 has the same meaning as stated in Claim 1)p thereafter reacting the compound of the Formula VII thus formed (wherein R2 has ~he same meaning as stated in Claim 1) (with cyanamide, bromo cyane or a compound oF
the Formula XII or XII (wherein R5 is as stated in Claim 1) and if desired reacting a compound of the Formula VI thus formed (wherein R2 is as stated in Claim 1p Rl is hydrogen) with a compound of the Formula XIV or XV (wherein R5 is as stated above and X is halogen) to give a compound .:
of the Formula VI wherein R2 is as stated above and Rl is a group of the formula -CooR5, in which formula R5 is as stated above):~
and thereafter sub;ecting a compound of the Formula VI to reduction (wherein Rl and R2 are as stated in Claim 13 and if desired introclucing an R~ group being other ~han hydrogen into a compound of the Formula I thus formed (wherein Rl and R2 are as stated above and R~ is hydrogen~
and if desired converting a compound oF the ~ormula I thus ~:
obtained into its salt.
AccordincJ to a particularly pre-Ferred asp~ct of the present invention there i~ provided a new proc~ss For the 30 preparation of 5~6)-n-propylt~io-benzimicdazolyl-2-methyl- `

~' :

carbamate (a well-known anthelmintic agent - a compound of the Formula I wherein Rl is methoxycarbonyl; R2 is hydrogen and R4 is n-propyl) which comprises reac-ting o-phenylene-diamine with an agent capable of introducing a thiocyanato group (SCN);
heating the compound of the Formula (XVI) thus obtained (where-in R is hydrogen); reacting the compound of the Formula VII
thus obtained (wherein R2 is hydrogen) with cyanamide, bromo-cyane or a compound of the Formula XII or XIII (wherein R is methyl) - whereby if cyanamide or bromo cyane is used, the product thus obtained is reacted with a compound of the Eormula XIV or XV (wherein R5 is methyl); reducing the compound of the Formula VI thus obtained (wherein R2 is hydrogen; R is -CooR5 and R5 is methyl) and reacting the compound of the Formula I thus obtained (in which R2 and R4 are hydrogen;
is -CooR5 and R5 is hydrogen) with a propylating agent.
Further details of the present invention and the inventions of our copending applications Serial Nos. 3~ R
D and 3~o,~ ~1 are to ~e found in the Examples without limiting the scope of our invention to the Examples.

t , `:
:
~ ~ .

~L7~5~

~ 33 -~e~
lO~8 g of o-phenylene diamine and ].802 g Of ammonium rhodanide are dissolve~ in a mixture of ~0 ml oF methyl alcohol and lO ml of acetic acid and to the mix~ure cooled at a temperature of lO C a solution oF 6.5 ml o-F bromine in 20 ml oF me~hyl alcohol is addecl while stirring in 30-60 minutes and the temperature is maintained at lO C while stirring until the reaction is Finished (5 to 30 minutes).
The Final point of the reaction is determined by thinlayer chromatographic analysis tLayer: Polyram Silo G., Macherey Nagel Co.~0 Development with: benzene-ethylacetate-methyl alcoholic ammonium solution 8~l:l. Developer Iodine~.
The reaction finished the mixture is poured into water and the acid is neutralized by adding a 20 y~ ammonium hydroxide solution, pH value 7-7~5. The precipitated crystalline l,~-diamino-L~-~hio-cyanato-benzene is filtered.
Weight: 13,2 g (yield 80 ~), Melting point 123 C
(recrys~alli~d from benzene).
Exam~le 2 10.8 ~ of phenylene diamine and 50g oF potassium rhodanide are dissolved in llO0 ml of methyl alcohol and to the solution at a temperature of lO C a solu~ion of 7.0 ml of bromine in 30 ml oF me~hyl alcohol is added while stirring vigorously in ~0-60 minutes, The final point o-F
25 the reaction is determined by the method set forth in Example 1. AFter pouring the mixture into watar and adjusting the pH value, ~he product is isolatcd by extraction with chloroform. After drying and evapora~ing the solvent 13.5 g of l/2-diamino-4-thiocyanato-benzene 30 are obtained. Mp. 123 C (from benzene).

7~S2 - 3~ -Exam~ 3 15.9 g oF bromine are added dropwise while s~irring into a solu~ion of 20 g oF potassium rhodanide in 100 ml of methyl alcohol at a ~emperature of -10C. The obtained yellowish birhodane solution is added to a solution of 1008 g o~ o-phenylene diamine in L~O ml oF a mixture From acetic acid-me~hyl alcohol l.:l~ while stirring at a temperature of 5~10 C. Processing ~he reaction mixture as set forth in Example 1 the 1,2-diamino-L~-thiocyanato-benzene is obtained, meltiny at 123 C.

To a solution of 1~.2 g oF 4(5)-chloro-o-phenylene diamine and 38 9 of ammonium rhodanide in 120 ml of me~hyl alcohol 5 ml of acetic acid are added~` wherea~ter a :
solution of 702 ml of bromine in 20 ml of me~hyl alcohol i~ added at a temperature of 15-17 C in 30-60 minutesO
The mixture is diluted with water and after adjusting ~he pH value to 3, 1,2-diamino-L~-chloro-5-thiocyanato-benzene is obtained, melting at 108-llO C.
.~o a solution of 13.8 g~of L~(5)-methoxy-ophenylene diamine and 38 g of ammonium rhodanide in 80 ml of methyl alcohol and 15 ml of ace~ic acid a solution of 6.S ml of bromine in 20 ml o~ me~hyl alcohol is added dropwise within 40-60 minutes a~ a temperature of 5-10 C~
Proc0ssing the reaction mixture as se~ forth i.n }xample 1 the 1,2-diamino-4-methoxy-5-thiocyanato-benzene is obtainedc Mpo: 112 llL~ C~
~, .
21.~ g of ~(5)-benzyloxy-o-phenylene diamin~ and 50 g .... .

of potassium rhodanide are dissolved in a mixture of 100 ml of me~hyl alcohol and 20 ml oF acetic acid and to ~he solution obtained a solution of 6~5 ml of bromine in 30 ml o~ msthyl alcohol i~ added at a temperature of 5-10 C
in 30-60 minutes. Processing the mixture as se~ forth in Example 1 the 1,2-diamino-3-benzyloxy-4-~hiocyanato-benzene is obtained, Example 7 To a solution of 10,8 g of p-phenylene-diamine and 38 g of ammonium rhodanida in 100 ml of methyl alcohol and 15 ml of acetic acid a solution of 6.5 ml of bromine in 25 ml of methyl alcohol is added while stirriny at a tempera~ure of 8-10 C. Processing the reaction mixture as set forth in Exampls 1 the 1,L~-diamino-2~thiocyanato-henzene 16 is obtained.
~e~
In an analogous manner ~o thc process described in Example 1 to 3, the following compounds are preparad:
1,2-diamino-~-methyl-5-thiocyanato-benzene, mp.: 117 C, 1,2-diamino-~-chloro-S-chiocyanato-benzene~ mp.l 108-1~10C~
1,2-diamino-L~-bromo-6-thiocyanato-benzene, mp.i 99-100 C
lJ2-diamino-L~-fluoro-5-thiocyanato-benzene~ mp~- 104~106C~
1,2-diamino-~-trifluoromethyl-5-thiocyanato-benzene, mp,:
154 156 ~;
1,2-diamino-~-n-butyl-5-thiocyanato~benzen~ mp~ 109-110C.
Example 9 22,0 ~ of 1,2-diaminow4-thiocyanato-benzene are dissolved in lOO ml. of methyl alcohol and ~o the solution 100 ml. of a 2~ % ammonium h~droxide solution and 1000 ml of water are added. The mixture is kept at a temperature ... .

, , o-f 80-85 C for 3 L~ hOUrSb The final point oF ~he reac~ion is determined by thinlayer chroma~ographic analysis.
~Layer- Macherey-Nagel Polygrarn Sil. Go Development with: Benzene-ethylacetate - a 10 ,' alcoholic a~monium solution 8:1:1. Developer- Iodine ~f O~L~8~o The reaction finished, the mix~ure i5 cool~d, le~ to stand overnight in a reFrigerator and the precipitated product is fil~ered, washed with water and dried, 1601 9 of 3,3'34,~'-tetraamino-diphenyl-disulfide are obtained ~ield 87 ,~, melting point. 161-162 CO
:
16~5 g of 192-diamino-~-thiocyanato~benzene are dissolved in 20 ml of ace~ic acid and after adding 4 g of pyridine catalyst the reaction mix~ure is boiled. The final point of the reaction is determined by ~hinlayer chromato-graphic analysis (see Example 1~o The mixture is poured on 200 9 of ice-water, whereafter is made alkaline by adding a ~ N sodium hydroxide solution (pH ~alue 7.5~8~.
After standing for a half hour the product is filtered washed with water and driedO 11.1 g (yield 81 ~) of 3,3'~
tetraamino-diphenyl-disulfide are obtainedO Mp~ 161~162 C.

One proseeds in the same way as in Examples 9 or 10, with the difference, that ins~ead of 1,2-diamino~ hio-cyanate~benzen~ an;aquivalent amount of a compound of the general Formula XVI is used, wherein R2 represan~s a methyl-, butyl-, bromins~, chlorine-, fluorine--~j trifluoromethyl-, methoxy-, phenoxy- or benzyloxy groupe By this way the following compounds of the general formula V~I are prepared:

' , ,, s~

2,2'-dimethyl-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 174-175 C;
2,2'-dibutyl-4~4',5,5'-tetraamino-diphenyl-disulfide, mp.: 205-207 C;
2,2'-dibromo-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 179-180 C;
2,2'-dichloro-4,4',5,5'-tetraamino-diphenyl-disulfide; mp.: 182-183 C;
2,2'-difluoro-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 172-173 C;
2,2'-di(trifluoromethyl)-4,4',5,5~-tetraamino-diphenyl-disulfide, mp.: 194-196 C;
2,2'-dimethoxy-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 190-192 C;
2,2'-diphenoxy-4,4',5,5'-tetraamino-diphenyl-disulfide, 2,2'-di-benzyloxy-4,4',5,5'-tetraamino-diphenyl-disulfide.
Example 12 2.78 g of 3,3',4,4'-tetraamino-diphenyl-disulfide and 6.0 g of S-methyl-N,N'-bis(methoxycarbonyl)-isothiourea-diurethane are dissolved in 100 ml of a 50 vol% alcohol and 1 ml of acetic acid is added, the mixture is boiled until the methyl mercaptane evolution ceases (about 3 hours), whereafter the precipitated bis-(2-methoxycarbonyl-benzimidazole-5-yl)-disulfide is filtered, washed and dried. 4.2 g of the product are obtained (95%), melting point 328C ~decomposition).
Example 13 `~
8.8 g of sodium hydroxide are dissolved in S0 ml of water and 4.2 g of cyanamide are added. The mixture is cooled to 10C and 9.4 g of chloro-formic acid methyl ester e~f~

~7~5~

are added dropwise in 30-L~5 minu~esO The mixture is stirred for a further half hour, ~hen adcled to a solu~ion o-f 13.9 g of 3,3'~L~,L~'-tetraamino-diphenyl~disulfide in 200 ml oF
a 75 vol~,~ alcohol. The reaction mixture is boiled and the pH value is main~ained between 3_L~ by addng sorne concentrated hydrochloric acid at intervalsO Af~er boiling for 90 minutes the mixture is cooled to room temperature and ~he precipitated product is isolated by filtration~
l9oQ 9 of ~he bis(2~methoxycarbonylamino-benzimidazole-5-yl~-disulfide are obtained. Melting pointO 325C (decomposition~.
Examples lL~ to 2 One proceeds according to the process of the Examples 12 to 13 by using the Following o-phenylene diamine derivatives-2,2'-dimethyl-L~,L~',5~5~-tetraamino-diphenyl-disulfide, 2,2'-dibuthyl-L~ ',5,5'-tetraamino-diphenyl-disulfida, 2,2'-dibromo~ 'J5,51-tetraamino-diphenyl-disulfide, 2,2'-dichloro-~,4~',5,-5'-tetraamino-diphenyl-disulfide, 2,2'-difluoro-L~,L~',5,5'-tetraamino-diphenyl-disulfide, 2,2'-di(trifluoromethyl)-4 ,L~ ~ ~ 5,5'-te~raamino-diphenyl--disul~ide~, . ;
2,2'-dimethoxy-4,L~',`5,5'-tetraamino-diphenyl-disulFide, 2,2'-diphanoxy-L~;~',5,~5'-te~raamino-diphenyl-disulfide, 2,2'-dibenzyloxy-L~ 5~5'-tetraamino-diphenyl disulfide, This way the following products were obtainedO
bis(2-methoxycarbonyl-amino-6-methyl-benzimidazole-5-yl)~
-bisulfide~, .mp~ 305-10 C, bis(2-methoxycarbonyl-amino-6-butyl~benzimidazole- 5-yl)--disulfide, mp,.- 295-8 C:"`
bis~2-methoxycarbonyl-amino-6-bromo-henzirnidazole-5-yl~
-disulfide, mp.: 310C (d).
.

- 39 _ bis(2-me~ho~ycarbonyl-amino-6-chloro-benzimiclazole-5~yl~
~ disulfide, mp. 305~10 C (d), bis(2-me~hoxycarbonyl-amino-6--fluoro-benzimidazole-5 yl)--disulfide, mp. 285-8 C.
bis(2-me~hoxycarbonyl-amino-6-trifluoromethyl-benzimidazole--5-yl~-disulfide~ mp.~ above 3~0 C.
bis(2-methoxycarbonyl-amino-6-methoxy benzimidazole-5-yl~--disulFide~ mp~: 297-300 C (b~.
bis(2-methoxycarbonyl-amino-6-phenoxy-benzimidazole-5-yl)~
-disulFide.
bis(2-methoxycarbonyl-amino-6-benzyloxy-benzimidazole-5-yl)--disulfida.
ExamPle 23 2,78 9 of 3,3'lL~4'-tetraamino-diphenyl-disulfide are dissolved in 70 ml of alcohol and to the solution 2.12 g of bromocyane dissolved in 10 ml alcohol are added. The mixture is allowed to stand overnight, whereafter the alcohol is distilled off and the residue is dissolvedin water and made alkaline with sodium hydroxide. 3~0 9 (90 %) of the bis(2-amino-benzimidazole-5-y~-disulfide are obtained, melting at 245 C by decomposition.
~!:
2.78 g of 3J3',L~ tetraamino-diphenyl disulfide are dissolved in 1.7 ml of a 37 % hydrochloric acid and a solution of 0092 9 of cyanamide in 1 mI of wa~er is added dropwise. The reaction mixture is Icep~ For 60 minutes at a temparature oF 100 C~ 0.9 9 oF sodium hydroxide are added in the form of a L~0% solution, until the ammonia evolution has ceased the mixture is heated at a temperature of 100 Cc AFter cooling the bist2-amino-benzimidazole-5-yl~disulfide is S ~

. ~ . .

s~
- /~o -precipita~edO Weigh~: 2.70 g (~1 5'), Mel~ing point:
2~5 ~C ~decomposition).

One proceeds according to ~he process of the Examples 23 or 2L~, using the following o-phenylene-diamine deriva~ives:
2,2'-dimethyl-4,4' J 5,5'-~e~raamino-~iphenyl-disulfide, 2,2 t -dibut~yl-~ ',5,5'-tetraamino-diphenyl~disulFide D
2,2'-dibromo-~,,41,5,5'-tetraamino-diphenyl-disulFide~
2,2'-dichloro-4,l~',5,5'-tetraamino-diphenyl-disulfide~ -2,21-diFluoro-L~,~',5,5~-tetraamino-diphenyl-disulfide;
2,2'-di(trilfuoromethyl~-~,4',6,5'-tetraamino-diphenyl--disul-Fide, 2,2'-dimethoxy-~,4',5,5t-te~raamino-diphenyl-disul~idelp 2,2'-diphenoxy~ ',5,5'-tetraamino diphenyl-disulfide.
2,2'-diphenyloxy-~,L~ ,5'-tetraamino-diphenyl-disulfide~
This was the following products are obtainedO
bis52-amino-6-methyl-benzimidazole-5-yl)-disulfide, bis(2-amino~6-but~yl-benzimidazole-5-yl)-disulfidsi7 bis~2-amino-6-bromo-benzimidazole-5~yl)-dislllfide bis(2-amino-6-chloro~benzimidazole-5-yl)-disulFide~
bis~2-amino-6-fluoro-benzimidazole-5-yl)-disulfide;~
bis(2-amino-6-trifluoromethyl benzimidazole-5-yl)~
-disulfide~ :
bis~2-amino-6-methoxy-benzimidazole-5-yl)-disulfide~-bis(2-amino~6-phenoxy-benzimidazole-5-yl)-disulFide~;
bis(2-amino-6-benzyloxy-benzimidazole~5-yl)-disulfide.
~ `:
3~32 g oF bis(2-amino-benzimidazole~5-yl)-disulFide are dissolved in 300 ml oF pyridine and 2.0 9 chloro-~, ~ ~"7~52 formic acid methyles~er are add~d while cooling. The mixture is allowed to s~and overni~h~, whereaF-ter it is heated on a hot water-bath for 90-120 minu~os~ The pyridine i5 distilled of in vacuo and water is poured on tha residue and ~he precipitated crys~als are FilteredJ washad and dried. 3.~ 9 of the bis(2-me~hoxy-carbonyl-amino-benzimidazole-5-yl)-disulfide are ob~ainedO Yield 78 %.
Melting poin~o 3z5 C (decomposi~ion)O

3.32 g of bis~(2-amino-benzimidazole-5-yl)-disulfide are dissolved in 30 ml of methyl alcohol and to ~he solution 1.80 ~ dimethyl carbonate and 00~6 g oF metallic sodium dissolved in 30 ml o-F methyl alcohol are addedO The mixture is boiled for 1 hourO Thereafter the reaction 15 mixturs is acidifiod with acetic acid ~pH value between ,' 5.5-6) and ~he precipi~ated bis(2-methoxycarbonyl-amino-benzimidazole-5-yl)-disulfide is filtered off, Weight:
4.1 9 (92.5 ,~'~. Melting point 325 C (decomposition), Example_36 to L~
One proceeds according the the process of Examples 3~ or 35 using tha followin~ bis(2-amino-benzimidazole-5 yl)-disulfide derivativesO
bis[2-amino-6-methyl~benzimidazole-5-yl)-disulfide;' bis~2-amino-6-buthyl-benzimidazole-5-yl)-disulfide bis~2-amino-6-bromo-benzimidazole-5-yl)-disulFide~
bis52-amino-6-chloro-benzimidazole-5-yl3~disulfide bis52-,amino-6-fluoro-benzimidazole-5-yl)--disulfide'~-bis(2-amino-6-trifluoromethyl benzimidazole-5-yl) disulfidep bis(2-amino-6-methoxy-benzimidazole-5-yl)-disulfide~

bis(2-amino~6-phenoxy-benzimidazols 5-yl)-disulfide~

_, , .. . .

;, , . . ................... " ,. . ~ . , ", , 7~52 _ L~2 -bis(2-amino-6-benzyloxy-benzimidazole-5~yl)-disulfide.
This way L-hC following products were ob~ained-bist2-me~lloxycarbonyl-amino-6-me~hy:L-benzimidazolo-6-yl~--disulfide;
bis(2-rne.hoxycarbon~/1-amino-6-buthyl-benzimidazole-5~yl)--disulfidet bis(2-methoxycarbonyl-amino-6-bromo-benzimidazole-5-yl)--disulfide~
bis(2-methoxycarbonyl-amino-6-chloro-benzimidazole-5-yl)--disulfide;
bis(2-me~hoxycarbonyl-amino-6-fluoro-benzimidazola-5-yl)--disulfide D
bis(2-methoxycarbonyl-amino-6-trifluoromethyl-benzimidazole--5-yl)-disulfidep bis(2-methoxycarbonyl amino-6-metho~y-benzimidazole-5-yl)--disulfide:;
bisl2-methoxycarbonyl-amino-6-phenoxy-benzimidazole-5-yl)--disulFide~
bist2-methoxycarbonyl-amino-6-benzyloxy-benzimidazole-5--yl)-disulfideO
Example_l~5 ~ .4 g of 2-(methoxycarbonyl-amino)-benzimidazole-5(6)-yl-disulfide are dissolved in 800 ml of hexamethyl-phosphoric flcid triamide and while stirring vigorously, in a nitrogen atmosphere 8 g of sodium borohydride are added in 60-90 minutes at a temperature of 20-25 C. Af-~er addition of the ~irst parts o~ the reducing agent the Faint yellowish colour of the solu~ion becomes brownO
Aftsr 2 hour~ a solu~ion of 2406 g of propylbromide in 600 ml of anhydrous alcohol is added and the reaction .
.. . . ~ ~ .... ..

79~
~ Llr3 _ mixture is ~irred in a nitro3en a~mosphere for further 3 hours a~ room temperatur~. Thereafter the mixture is dilu~ed wi~h 1 lit, of water and the precipitated product is filtered, washed with wa~er ancl recrystallized frorn

6 n-propanol. L~0.7 ~ (77%) of the 5(6) propylthio-benzimidazolyl-2-methyl-carbamate are obtained, Me1ting point. 21L~-215 C.

~.~ g of 2-(methoxycarbonyl-amino)-benzimidazole-5~6)-yl-disulfide are dissolved in 60 ml of ho~ dimethylforrnaT~id~
whereaf,ter the solu-tion is cooled to room temperature and in a nitroyen atmosphere, while stirring vigorously 0,8 g of sodium borohydride are added in portions in 30 minutesO
The stirring and introduction o~ nitrogen is continued for further 90 minutes, whereafter 2.5 g of propylbromide dissolved in 50 ml of alcohol are added to the reaction mixture, The mixture i5 stirred for furthar 3 hours at room temperature and is diluted with 120 ml of water, The precipitated product is filtered, washed thoroughly with water and dried~ ~.9 g o~ the 5(6)-propylthio-benz-imidazolyl-2-methyl-carbamate are obtained, Yield 92,5~, melting point 208-211C. ~fter recrystallization from n-propanol the product melts at 215 C.
xample ~7 2~ One proceeds according to Examples 45 or ~6, but (instead of n-propylbromide) allylbromide,~ proparyyl~
bromide, benzylchloride, 4-nitro-fluoroben~ene and 2,~-dinitro-chlorobenzene are used, This way the following compounds are obtained-5(6)-allylthio-benzimidazolyl-2-methylcarbamate;

- ~rL~ -5~6)-propin-2~yl-~hio-benzimidazolylw2-mechylcarbamate;
5(6)-benzylthio-benzimidazolyl-2-methylcarbamate D
5~6)-~4-nitrophenylthio)-benzimidazolyl-2-methylcarbamate;
5(6)-(Z,~-dinitrophenylthio)-benzimiclaZOlyl-2-me thylcarbama~i Example ~8 ~.~ g of 2-(methoxycarbonyl-amirlo~-benzimidazol-5(6)-yl-disulfide are suspended in 30 ml, o-F me~hyl alcohol and a solution of 1.12 g of potassium hydroxide in 15 ml of me~hyl alcohol is added. To ~he solution thus obtained, while con~inuously stirring, in a nitrogen atmosphere 2.5 g of propylbromide) ~hereafter 0.6 g of sodium borohydride are added in 30 minutes at a temperature of 25C in portionsO
The mixture is stirred for further 3 hoursJ whereafter is diluted with 50 ml. of water. After standing the precipitated product is Fil~ered, washed and dried. 3 9 ~57 ~j of the crude 5t6)-propyl~hio-banzimidazolyl-2-methylcarhamate are ob~ained. Melting point after recrystallization from n-propanol is 21~-215 0, The product ob~ained is identic with that obtained in Examples ~5 and 460 ~
4.~ g of 2-(methoxycarbonyl-amino)-benzimidazol-5(6)-yl-disulfide are suspended in 30 ml of methyl alcoholt and a hot solution of 1.12 9 of potassium hydroxide in 15 ml of methyl alcohol is added in nitrogen atmosphere. To ~he solution obtained 0.8 9 of sodium borohydride are added at room temperature in 30-l~0 minutes. AFter sti~ring For 30 minutes 1.2 ml of acetic acid, then a solution oF 2.5 g propylbromide in 10 ml of methyl alcohol is added to the reaction mixtur~0 Stirring is continued for further 2 hours. Thereafter the mixture is diluted with ~0 ml of ~' , ,~ ;" -.
,,, ~:, : ".

_ L~5 _ wa~er, and a-Fter standing For a while thc precipi~atcd product is Fil~ered, washed and driecl. 3.9 g of ~he 5(6~-propyl~hio-benzimidazolyl-2-me~hylcarbamate ie obtained, ~leltin~ point 211-213 C, yield 53 ,'.
2.2 g of 2-(methoxycarbonyl-amino~-benzimidazol-5~6~-yl-disulfide are suspended in 20 ml of alcohol and 1.2 ml of ~rie~hylamine7 then 0.~ g of 2-mercapto-e~hanol are added. The reaction mixture is s~irred for 5 hours~ There-after a solution of 0.56 9 of potassium hydroxide in 10 ml oF anhydrous alcohol and 1.3 9 oF propylbromide are addedO
Stirring is con~inued for further 2-3 hours at room ~emperature, Finally the mixture is diluted with 30 ml of water and the precipitated product is fil~ered~ washed and dried. 1.4 9 ~53 ~) oF the 5(6~-propylthio-benzimidazolyl-2-methylcarbamate are obtained. Melting poin~0 211-213 C, ~, , 4,L~ g oF 2-(me~hoxycarbonyl-amino~-benzimidazol-5(6~-yl-disulfide are suspended in 100 ml of hot alcohol and to ~he suspension a solution of 1.12 9 potassium hydroxide in 15 ml of water is added, then a solution of 12 ~ of crystalline sodiurn sulfide in 15 ml of water is added in portions in a nitrogen atmosphere, in 30-L~5 minutes~ There-after a phenyl-diazonium-chloride solution prepared from 1.9 9 of aniline and buffered with sodium acetate is added to the hot reaction mixture in 10-15 minutes. A vigorous foaming begins, whlch ceases I5-20 minutes after dosage.
The pH value of the mi~turz is adjusted to 6.5 and the precipitated produc~ is filtered, washed and dried. 3,3 g ,~

- ~6 -(60 ~) of the 5(6)-phenyl~hio-benzimidazolyl~2-methyl-carbamate are obtained 7 Meltirlg pointO 243 C (de-composing).
Example 52 2~2 y oF 2-(methoxycarbonyl-amino)-benzimidazol-5(6 yl-disulfide are dissolved in 60 ml of hotace~ic acid and in a nitroyen atmosphere 0.8 y of zinc dust is addad in portions. After complate dissolving of the zinc the reaction mix~ure is evapora~ed to dryness in vacuo and is stirred in nitrogen atmosphere for 1 hour with an alcoholic potassium hydroxide solution. The reaction mi~ure is filtered and to the alcoholic solu~ion 1.3 y of propyl-bromide are added. The reaction mixture is let to stand for 2 hours at room tempera~ure, whereaFter it is diluted wi~h water and the precipitated product is filtered, washed and dried. 1.8 9 (68 %) of the 5(6~-propylthio-benzimidazolyl-2-methylcarbamate are obtained~ melting at 211-21~ C.
~, .
2.2 9 of 2-(methoxycarbonyl-amino)-benzimidazol-5(6)--yl-disulfide are dissolved in 40 ml of alcohol containing 0.6 9 oF potassium hydroxide and to the hot solution a solution of 1,0 9 of glucose in 15 ml of wat~r is added in 60 minutes. The reaction mixture is boiled uigorously for further ~5 minutes, whereafter it is Filt~red by a pressure-filter in a nitrogen atmosphere~ The alcoholic solution is cooled to room temperature and 1~3 y of propylbromide are addedO After 3 hours the reaction mixture is diluted with water,- the precipita~ed product is filtered,- washed and dried. 1.6 9 (60 %~ of the 5(6~-propylthio-benzimidazolyl-2-methylcarbamate are obtained~ Melting point, 210-213 C.

P..

Lr~5~5~
- ~7 -' ~
-2.2 9 of 2-(methoxycarbonyl-amino)-benzimidazol-5(6)~
yl-disulfide are suspended in ethyl alcohol con~aining 1.6 9 of potassium hydroxide and 2 g of amino-imino-methane-sulfinic acid and 1 drop of an alcoholic cetyl-pyridinium-bromide solution (or hexadecyl-tributyl-phosphonium-chloride are added~ The reaction mixture is boiled in ni~rogen atmosphere for 2~3 hoursJ whereafter it is coolad ~o room temperature and 1.3 g of propylbromide are added. AFter 3 hours the r~action mixture is dilu~ed with ~0 ml of water and the pH value is adjusted to 6, the precipi~ated product is filteredl washed and dried. 2~1 g (79 %~ of ~he 5~6)-propylthio-benzimida~olyl~2-methylcarbamate are obtained~
~lelting point~ 210-212 C.
Examples 55 to 66 In an analogous-manner to Examples L~5 to 54 by using the following starting materials the following compounds of the Formula I are prepared ~Rl is always methoxycarbonyl)~

fluorine n-propyl 252-253 56 chlorine n-propyl 266-269 57 chlorine ben~yl 234-23~
58 chlorine allyl 203-205 59 chlorine propinyl 305-307 chlorine ethyl 237-238 61 chlorine cyclohexyl 29L~295 62 bromine n-propyl 191-193 63 methyl n-propyl 230~232 td) 64 methoxy n-propyl 296~298 butyl n-propyl 202-204 .

~,, -

Claims (41)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Process for the preparation of 5(6)-thio-benzimidazole compounds of formula I and pharmaceutically acceptable salts thereof (I) wherein R1 is hydrogen or a group of the formula -COOR5; R5 is C1-4 alkyl;
R2 is hydrogen, halogen, C1-6 alkyl, trifluoromethyl or a group of the formula -OR3; R3 is C1-4 alkyl, aryl or aralkyl; R4 stands for hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-6 alkenyl, C3-6 alkynyl, or an aryl or aralkyl group in which the aryl ring of the aryl or aralkyl group is un-substituted or is substituted by one or more halogeno, C1-4 alkyl, nitro, hydroxy, C1-4 alkoxy, C1-4 alkylthio, carboxy or cyano substituent(s) or a group of the formula -S(O)n-R8 in which R8 is lower alkyl; n stands for 0, 1 or 2 which comprises subjecting a compound of formula VI

(VI) wherein R1 and R2 are as defined above, to reduction to form a compound of formula Ia (Ia) and, if a compound of formula Ib is required (Ib) wherein R9 is C1-6 alkyl, C3-7 cycloalkyl, C3-6 alkenyl, C3-6 alkynyl or an aralkyl group which is unsubstituted or is substituted by one or more halo-geno, C1-4 alkyl, nitro, hydroxy, C1-4 alkoxy, C1-4 alkylthio, carboxy or cyano substituent(s) or a group of formula -S(O)n-R8 in which R8 and n are as defined above, reacting the compound of formula Ia above with a compound of formula R9-Q wherein R9 is as defined above and Q is chlorine, bromine or iodine or a group of formula R10-SO3- wherein R10 is a phenyl group which is unsubstituted or substituted in the 4-position by a methyl group;
or, if a compound of formula Ic is required (Ic) wherein R1 and R2 are as defined above and R11 and R12 are hydrogen, nitro, cyano, carboxyl or a group of formula -S(O)n-R8 in which R and n are as de-fined above, reacting the compound of formula Ia above with a compound of formula X

(X) wherein R11, R12 and Q are as defined above;
or, if a compound of formula Id is required (Id) wherein R1 and R2 are as defined above and R13 and R14 are hydrogen, halogen, C1-4 alkyl, hydroxy, C1-4 alkoxy or alkylthio, reacting the compound of formula Ia above with a compound of formula XI

(XI) wherein R13 and R14 are as defined above;
or, if a compound of formula I in which R4 is an unsubstituted phenyl group is required, reacting the compound of formula Ia with chloro-benzene or bromobenzene, and, if required, converting the product of formula I into a pharmaceutically acceptable salt.

2. A process according to claim 1 wherein the reduction of the com-pound of formula VI is carried out by means of a complex metal hydride select-ed from the group consisting of lithium aluminium hydride, sodium borohydride a sodium dihydro-bis-(2-methoxy-ethoxy)-aluminate in an anhydrous medium at 0 to 30°C; by means of an alkali metal; by means of an alkali sulfide, alkali sulfite, alkali hydrogen sulfite or alkali dithionate in alkaline medium or amino-imino-methane-sulfinic acid or mercapto-ethanol in the presence of a base; by means of glucose in an alkaline medium; by means of zinc, tin, iron or aluminium in the presence of an inorganic or organic acid; or by means of stannous(II)chloride or titanium(III)chloride in hydrochloric acid.

3. A process according to claim 2 wherein the reduction is carried out with sodium borohydride in an aqueous alcoholic medium and in the presence of a base.

4. A process according to claim 2 wherein the reduction is carried out with a complex metal hydride in the presence of a Lewis acid.

5. A process according to claim 4 wherein the Lewis acid is aluminium chloride, boron trifluoride or titanium tetrachloride.

6. A process according to claim 2 wherein the reduction is carried out with sodium or potassium at a temperature between -40°C and 130°C and in the presence of an inert solvent.

7. A process according to claim 1 which comprises reducing 2-(methoxy-carbonylamino)-benzimidazole-5(6)-yl-disulfide and reacting the 5(6)-mercapto-benzimidazolyl-2-methylcarbamate obtained with a propylating agent.

8. A process according to claim 7 wherein the propylating agent is an n-propyl halide.

9. A process according to claim 7 wherein the propylating agent is n-propyl bromide.

10. A process according to claim 1 wherein R1, R2 and R4 are as defined in claim 1, with the proviso that when R2 is hydrogen R4 is other than C1-4 alkyl, C3-7 cycloalkyl, C3-6 alkenyl, C3-6 alkynyl or benzyl.

11. A compound of formula I

(I) wherein R1, R2 and R4 are as defined in claim 10, when prepared by a process according to claim 10 or an obvious chemical equivalent thereof.

12. A process according to claim 1 wherein R1 is -COOR5, R4 is lower alkyl, allyl, propynyl, benzyl or cyclohexyl and R2 is halogen, lower alkoxy, lower alkyl or trifluoromethyl.

13. A process according to claim 12 wherein R5 is methyl, R4 is methyl, ethyl or n-propyl, and R2 is chlorine, bromine, fluorine, methoxy or methyl.

14. A process according to claim 1 wherein R1 is methoxycarbonyl.

15. A process according to claim 14 wherein R2 is fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl or butyl and R4 is n-propyl, benzyl, allyl, propynyl, ethyl or cyclohexyl.

16. A process according to claim 14 wherein R2 is fluorine and R4 is n-propyl.

17. A process according to claim 14 wherein R2 is chlorine and R4 is n-propyl.

18. A process according to claim 14 wherein R2 is chlorine and R4 is benzyl.

19. A process according to claim 14 wherein R2 is chlorine and R4 is allyl.

20. A process according to claim 14 wherein R2 is chlorine and R4 is propynyl.

21. A process according to claim 14 wherein R2 is chlorine and R4 is ethyl.

22. A process according to claim 14 wherein R2 is chlorine and R4 is cyclohexyl.

23. A process according to claim 14 wherein R2 is bromine and R4 is n-propyl.

24. A process according to claim 14 wherein R2 is methyl and R4 is n-propyl.

25. A process according to claim 14 wherein R2 is methoxy and R4 is n-propyl.

26. A process according to claim 14 wherein R2 is butyl and R4 is n-propyl.

27. A process according to claim 14 wherein R2 is trifluoromethyl and R4 is n-propyl.

28. A compound of formula I as defined in claim 1 wherein R1 is methoxycarbonyl, R2 is fluorine and R4 is n-propyl when prepared by a process according to claim 16 or an obvious chemical equivalent thereof.

29. A compound of formula I as defined in claim 1 wherein R1 is methoxycarbonyl, R2 is chlorine and R4 is n-propyl when prepared by a process according to claim 17 or an obvious chemical equivalent thereof.

30. A compound of formula I as defined in claim 1 wherein R1 is methoxycarbonyl, R2 is chlorine and R4 is benzyl when prepared by a process according to claim 18 or an obvious chemical equivalent thereof.

31. A compound of formula I as defined in claim 1 wherein R1 is methoxycarbonyl, R2 is chlorine and R4 is allyl when prepared by a process according to claim 19 or an obvious chemical equivalent thereof.

32. A compound of formula I as defined in claim 1 wherein R1 is methoxycarbonyl, R2 is chlorine and R4 is propynyl when prepared by a process according to claim 20 or an obvious chemical equivalent thereof.

33. A compound of formula I as defined in claim 1 wherein R1 is methoxycarbonyl, R2 is chlorine and R4 is ethyl when prepared by a process ac-cording to claim 21 or an obvious chemical equivalent thereof.

34. A compound of formula I as defined in claim 1 wherein R1 is methoxycarbonyl, R2 is chlorine and R4 is cyclohexyl when prepared by a pro-cess according to claim 22 or an obvious chemical equivalent thereof.

35. A compound of formula I as defined in claim 1 wherein R1 is methoxycarbonyl, R2 is bromine and R4 is n-propyl when prepared by a process according to claim 23 or an obvious chemical equivalent thereof.

36. A compound of formula I as defined in claim 1 wherein R1 is methoxycarbonyl, R2 is methyl and R4 is n-propyl when prepared by a process according to claim 24 or an obvious chemical equivalent thereof.

37. A compound of formula I as defined in claim 1 wherein R1 is methoxycarbonyl, R2 is methoxy and R4 is n-propyl when prepared by a process according to claim 25 or an obvious chemical equivalent thereof.

38. A compound of formula I as defined in claim 1 wherein R1 is methoxycarbonyl, R2 is butyl and R4 is n-propyl when prepared by a process according to claim 26 or an obvious chemical equivalent thereof.

39. A compound of formula I as defined in claim 1 wherein R1 is methoxycarbonyl, R2 is trifluoromethyl and R4 is n-propyl when prepared by a process according to claim 27 or an obvious chemical equivalent thereof.

40. A process according to claim 1 wherein the compound of formula VI
is obtained by a process which comprises reacting a compound of formula XVIII

XVIII

wherein R21 stands for hydrogen or amino; and if R21 is hydrogen then R22 is amino and if R21 represents amino then R22 stands for hydrogen, halogen trifluoromethyl, lower alkyl, lower alkoxy, aryloxy or aralkoxy, with dirhodane, chlororhodane, ammonium thiocyanate or an alkali metal thio-cyanate in the presence of an oxidizing agent and in an anhydrous medium, to obtain a compound of formula XVII

XVII

wherein R21 and R22 are as defined above, heating the compound of formula XVII to convert it to a compound of formula VII

VII

wherein R2 is as defined in claim 1, and, to obtain a compound of formula VI
in which R1 is hydrogen, reacting the obtained compound of formula VII with cyanamide or bromocyane, or, to obtain a compound of formula VI in which is a group of formula -COOR5 wherein R5 is as defined in claim 1, reacting the compound of formula VII with a compound of formula XII

XII

or with a compound of formula XIII

or, to obtain a compound of formula VI in which R1 is a group of formula -COOR5, reacting the compound of formula VI in which R1 is hydrogen with a compound of formula XIV

wherein X is halogen, or with a compound of formula XV
(R5O)2CO XV

41. A process according to claim 40 wherein R1 is methoxycarbonyl, R2 is hydrogen and R4 is n-propyl.