CA1122219A - Sulfur-containing benzimidazole derivatives, process for the preparation thereof and intermediates useful in production of the same - Google Patents
Sulfur-containing benzimidazole derivatives, process for the preparation thereof and intermediates useful in production of the sameInfo
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- CA1122219A CA1122219A CA000370240A CA370240A CA1122219A CA 1122219 A CA1122219 A CA 1122219A CA 000370240 A CA000370240 A CA 000370240A CA 370240 A CA370240 A CA 370240A CA 1122219 A CA1122219 A CA 1122219A
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Abstract
Abstract of the Disclosure The invention relates to compounds of formula VI
wherein R1 is hydrogen or a group of formula -COOR5 in which R5 is C1-4 alkyl; R2 is hydrogen, halogen, C1-6 alkyl, trifluoromethyl or a group of formula -OR3 in which R3 is C1-4 alkyl, aryl or aralkyl, and salts thereof.
The compounds are useful as intermediates in the preparation of novel compounds having useful anthelmintic properties.
wherein R1 is hydrogen or a group of formula -COOR5 in which R5 is C1-4 alkyl; R2 is hydrogen, halogen, C1-6 alkyl, trifluoromethyl or a group of formula -OR3 in which R3 is C1-4 alkyl, aryl or aralkyl, and salts thereof.
The compounds are useful as intermediates in the preparation of novel compounds having useful anthelmintic properties.
Description
11;~2Z19 This application is divided out of our Application Serial No.
303,127, filed on May 11, 1978, which relates to sulfur-containing benzimida-zole derivatives and to process for the preparation thereof. This applica-tion relates to intermediates useful in the production of the sulfur-containing benzimidazole compounds of Application Serial No. 303,127.
Most of the end-products which are the subject of Application Serial No. 303,127 (Formula I) are new compounds, never described in litera-ture. The compounds of the Formula I possess useful anthelmintic properties and may be used in human and veterinary therapy as anthelmin~ic agents.
In the Formula I
R2 ~ ~ NH R (I) the various symbols have the following definitions: R is hydrogen or a group of the Formula -COOR ; R is Cl 4 alkyl; R is hydrogen, halogen, Cl 6 alkyl, trifluoromethyl or a group of the Formula -oR3; R3 is Cl 4 alkyl, aryl or aralkyl; R stands for hydrogen, Cl 6 alkyl, C3 7 cycloalkyl, C3 6 alkenyl, C3 6 alkynyl, or an aryl or aralkyl gI OUp whereby the aryl ring of the aryl or aralkyl group may be optionally 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 combinations : j - 2 -ll~Z2~9 such as allcoxy, alkyithio e~c. - used in the specification relates to straight or branched chain saturated aliphatic hydrocarbon groups having 1-6, preferably 1-4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-amyl etc.). The term "halogeno atom" covers all the four halogens i.e. fluorine, chlorine, bromine and iodine. The C3 7 cycloallcyl group may be cyclobutyl, cyclopentyl and cyclohexyl preferably. The C3 6 all<enyl group may be straight or branched chained and is preferably allyl. The C~ 6 all<inyl group may be straight or branched chained and represents preferably propinyl. The term "aryl groupn - used either alone or in combinations such as aralkyl - represents a mono- or bicyclic aromatic ring te.9.
phenyl, naphthyl) which may optionally bear one or more of the conventional substituents of the aromatic rings (e.g.
halogeno atom, lower allcyl, lower alkoxy, lower alkylthio, carboxy, nitro, hydroxy, cyano, alkylsulphinyl, alkyl-sulfonyl, all<ylthio etc.).
Some representatives of the compounds of the Formula I
are disclosed in prior art as anthelmintic agents te.9.
US Patents No. 3.574,845, 3~915J986 and 3,956,499; German Federal Republic Patent No. 2,250,469 and French Patent No. 2,134,558).
It is Icnown that a certain compound-group of the Formula II
R9S ~ ~ NH _ CUo~5 (II~
(falling under the scope of the class of compounds of the 11;~2~9 Formula I, wherein R is Cl 4 allcyl, C3_7 cycloallcyl, C3 6 all<enyl, C3 6 all<inyl or benzyl) may be prepared by reacting an 1,2-diamino-all<ylthio-benzene derivative of the Formula III
~ NH2 (III) R9S ~ NH2 10 either with an 1,3-bis-(all<oxycarbonyl)-S-all<yl-isothio-urea of the Formula IV
~ C - SR (IV) (German Federal Republic Patent No. 2,363,351 - reaction scheme A) ~ NH2 R OOC-N ~ 5 (II) ~9 ~ NH2 R500C-NH /
or with a carballcoxy-cyanamide of the Formula V
NC - NH - CoOR5 (V) tUS Patents No. 3,915,986 and 3,956,499 - reaction scheme B).
t NC - NH - CoOR5 ~~~ (II) (III) (V) The above proced-ure~ ~uffer from the ~erioua drawba~k that the be~zimidazole carbamate ring system is formed by 1,2-diamino-4-alkylthio-benzene derivatives of the formula III which can be obtained by means Or a complicated multi-step synthe~is from relatively expensive st,~rting material~
(reaction scheme C) and D) )~
Reactio~ scheme C
~ acet~latiorl~ ~ nitratior~
~i NH-COCH3 ~ N0~ 0 20 Cl ~ ___N~-COCH3 Cl ~ ~ H-CoCHj By-product + R~,SH
~ N02 h~dr~l~si~ ~ N0 25R S ~-- E-COC~ R9B ~ NH
reduction ~ ~
~9r~H
Reaction scheme D~
~ 2 rhod inat in~ ~--iH
~C acetylatio-~ H-~OCH3 ~ - NH-CO~3 NCS ~ nitration ~ NCS ~ ~2 reduction ~ NH-~OcH~ h~drolysis.
alkylatlon R~S - ~ - NO~
~9S ~ ~ reductio~ ~ (III) The synthesis-route shown i~ reaction schema C) comprise~ the nitration of m-chloro-acetanilide which gives rise to the formation of two isomeric compounds.
~herefore the useful o-nitro-acetamido isomer required for the synthe,sis is av3ilable but with moderate yields /J. Or~. Chem. 12, 799 (1947)7. ~he further step of the reaction needs toxical mercaptanes of very bad odour (US, Patents No, ~.915.986 and 3.956.499). ~his reaction can be generally carried only with low yields ~J. Org. Chem.
42, 554 /1977/7. For the reasons stated above the compounds of the Formula III can be obtained in poor yi(~lds.
Reaction scheme D) provides the desired eompounds of 3o the Formula III with the aid of a seven-step synthesis by ll;~Z219 low yields [Ber. 59, 190 (1926); J. Chem. Soc. (1928) 1364].
It has been found that the compounds of the Formula I can be pre-pared by reducing the new benzimidazole-di-sulfides of the formula VI and if desired subjecting the thiophenol derivatives of the Formula I thus obtained (R is hydrogen = la) R2 ~ \ ~ NH-Rl (Ia) HS H
to selective substitution reaction on the sulfur atom. Thus the compounds of the Formula I are available in a simple manner by very good yields.
The invention of Application Serial No. 303,127 provides a process for the preparation of compounds of the Formula I and salts thereof which comprises subjecting a compound of the Formula VI
303,127, filed on May 11, 1978, which relates to sulfur-containing benzimida-zole derivatives and to process for the preparation thereof. This applica-tion relates to intermediates useful in the production of the sulfur-containing benzimidazole compounds of Application Serial No. 303,127.
Most of the end-products which are the subject of Application Serial No. 303,127 (Formula I) are new compounds, never described in litera-ture. The compounds of the Formula I possess useful anthelmintic properties and may be used in human and veterinary therapy as anthelmin~ic agents.
In the Formula I
R2 ~ ~ NH R (I) the various symbols have the following definitions: R is hydrogen or a group of the Formula -COOR ; R is Cl 4 alkyl; R is hydrogen, halogen, Cl 6 alkyl, trifluoromethyl or a group of the Formula -oR3; R3 is Cl 4 alkyl, aryl or aralkyl; R stands for hydrogen, Cl 6 alkyl, C3 7 cycloalkyl, C3 6 alkenyl, C3 6 alkynyl, or an aryl or aralkyl gI OUp whereby the aryl ring of the aryl or aralkyl group may be optionally 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 combinations : j - 2 -ll~Z2~9 such as allcoxy, alkyithio e~c. - used in the specification relates to straight or branched chain saturated aliphatic hydrocarbon groups having 1-6, preferably 1-4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-amyl etc.). The term "halogeno atom" covers all the four halogens i.e. fluorine, chlorine, bromine and iodine. The C3 7 cycloallcyl group may be cyclobutyl, cyclopentyl and cyclohexyl preferably. The C3 6 all<enyl group may be straight or branched chained and is preferably allyl. The C~ 6 all<inyl group may be straight or branched chained and represents preferably propinyl. The term "aryl groupn - used either alone or in combinations such as aralkyl - represents a mono- or bicyclic aromatic ring te.9.
phenyl, naphthyl) which may optionally bear one or more of the conventional substituents of the aromatic rings (e.g.
halogeno atom, lower allcyl, lower alkoxy, lower alkylthio, carboxy, nitro, hydroxy, cyano, alkylsulphinyl, alkyl-sulfonyl, all<ylthio etc.).
Some representatives of the compounds of the Formula I
are disclosed in prior art as anthelmintic agents te.9.
US Patents No. 3.574,845, 3~915J986 and 3,956,499; German Federal Republic Patent No. 2,250,469 and French Patent No. 2,134,558).
It is Icnown that a certain compound-group of the Formula II
R9S ~ ~ NH _ CUo~5 (II~
(falling under the scope of the class of compounds of the 11;~2~9 Formula I, wherein R is Cl 4 allcyl, C3_7 cycloallcyl, C3 6 all<enyl, C3 6 all<inyl or benzyl) may be prepared by reacting an 1,2-diamino-all<ylthio-benzene derivative of the Formula III
~ NH2 (III) R9S ~ NH2 10 either with an 1,3-bis-(all<oxycarbonyl)-S-all<yl-isothio-urea of the Formula IV
~ C - SR (IV) (German Federal Republic Patent No. 2,363,351 - reaction scheme A) ~ NH2 R OOC-N ~ 5 (II) ~9 ~ NH2 R500C-NH /
or with a carballcoxy-cyanamide of the Formula V
NC - NH - CoOR5 (V) tUS Patents No. 3,915,986 and 3,956,499 - reaction scheme B).
t NC - NH - CoOR5 ~~~ (II) (III) (V) The above proced-ure~ ~uffer from the ~erioua drawba~k that the be~zimidazole carbamate ring system is formed by 1,2-diamino-4-alkylthio-benzene derivatives of the formula III which can be obtained by means Or a complicated multi-step synthe~is from relatively expensive st,~rting material~
(reaction scheme C) and D) )~
Reactio~ scheme C
~ acet~latiorl~ ~ nitratior~
~i NH-COCH3 ~ N0~ 0 20 Cl ~ ___N~-COCH3 Cl ~ ~ H-CoCHj By-product + R~,SH
~ N02 h~dr~l~si~ ~ N0 25R S ~-- E-COC~ R9B ~ NH
reduction ~ ~
~9r~H
Reaction scheme D~
~ 2 rhod inat in~ ~--iH
~C acetylatio-~ H-~OCH3 ~ - NH-CO~3 NCS ~ nitration ~ NCS ~ ~2 reduction ~ NH-~OcH~ h~drolysis.
alkylatlon R~S - ~ - NO~
~9S ~ ~ reductio~ ~ (III) The synthesis-route shown i~ reaction schema C) comprise~ the nitration of m-chloro-acetanilide which gives rise to the formation of two isomeric compounds.
~herefore the useful o-nitro-acetamido isomer required for the synthe,sis is av3ilable but with moderate yields /J. Or~. Chem. 12, 799 (1947)7. ~he further step of the reaction needs toxical mercaptanes of very bad odour (US, Patents No, ~.915.986 and 3.956.499). ~his reaction can be generally carried only with low yields ~J. Org. Chem.
42, 554 /1977/7. For the reasons stated above the compounds of the Formula III can be obtained in poor yi(~lds.
Reaction scheme D) provides the desired eompounds of 3o the Formula III with the aid of a seven-step synthesis by ll;~Z219 low yields [Ber. 59, 190 (1926); J. Chem. Soc. (1928) 1364].
It has been found that the compounds of the Formula I can be pre-pared by reducing the new benzimidazole-di-sulfides of the formula VI and if desired subjecting the thiophenol derivatives of the Formula I thus obtained (R is hydrogen = la) R2 ~ \ ~ NH-Rl (Ia) HS H
to selective substitution reaction on the sulfur atom. Thus the compounds of the Formula I are available in a simple manner by very good yields.
The invention of Application Serial No. 303,127 provides a process for the preparation of compounds of the Formula I and salts thereof which comprises subjecting a compound of the Formula VI
2 ~ ~ NH-R 1 (Vl) H
~ 1 2 2 to reduction (wherein R and R are as stated above~ and if desired introduc-ing an R group being other than hydroge~ into the compound of the Formula I
thus formed (wherein R and R are as stated above and R4 is hydrogen) and if desired converting a compound of the Formula I thus obtained into its salt.
l ~
~ - 7 -2~9 According to a preferred embodiment of our process a compound of the Formula VI is reacted with a complex metal hydride such as lithium aluminium hydride, sodiumborohydride-aluminium chloride complex~ sodium borohydride or sodium-dihydro-bis-(2-methoxy-ethoxy)-aluminate in anhydrous medium. ~s reaction medium preferably organic solvents such as diall<yl ethers, cyclic ethers (eOgO tetrahydrofurane, dioxane), dimethylformamide, dimethylacetamide, hexamethyl-phosphoric triamide, diethylene-glycol dimethyl ether, lower alcohols etc.) may be usedO
Ylhen u~ing a sodium borohydride - alu~inium chloride complex, the reaction may be preferably carried out in tetra-hydrofurane or dioxane. In this case the reaction takes place at room ~emperature with 2-3 hours.
When using sodium borohydride the reaction may be carried out i~ adition to the above solvents also in the mixture of water and a lower all<anol in the presence of an allcali hydroxide. The thiophenol derivative of the formula Ia thus formed can either be isolated or directly con-verted into other compounds of the Formula I.
The disulfide bond of the compounds of the Formula VI
may also be reduced by means of alkali metals. The starting material of the Formula VI is suspended in an inert solvent (e.g. toluene, xylene) and admixed with pDwdered ?~ potassium or sodium at room temperature or under warmingO
2-4 equivalents of alkali metal are used for 1 equivalent of the compound of the Formula VIo If ~ equivalents of alkali are used, the dialkali salt of the compound of the Formula Ia is obtained. The reaction mixture is then acidified and the compound of the Formula Ia can be isolated if desiredO If 11;~2Z19 - 8a -only 2 equivalents of an acid (e.~. acetic acid) are added to the reaction mixture, the solution of the mono-allcali salt of the compound of the Formula Ia is formed which may be converted into o~her compounds of the Formula I directly, ll;~Z219 without isolation. The said reduction may be pre~erably accomplished in ~uid ammonia at a temperature between -20 C and -40 C. On evaporating the ammonia solvent the all<ali salt of the compounds of the Formula Ia is obtained as residue, which may be either 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 pyrosulfite. Sodium hydrogen sulfite and sodium dithionite proved ~o be particularly suitable for this purpose. When using the said reducing ayents 2-2.6 moles of all~ali hydroxide and 2-2.2 moles of the reducing agent are applied for 1 mole of a starting material of the Formula VIo Reduction may be preferably carried out in an alcoholic solution and/or dimethylformamide containing 10-30 ~ of water. The reaction is accomplished under heating at 50-80 C, preferably a~ the boiling point of the reaction mixture. The compounds of the Formula Ia formed are either isolated or directly converted into other compounds of the Formula I.
As reducing agents organic sulfur compounds may be used as well ~e.g. mercapto-ethanol or amino-imino-methane sulfinic acid). The solution or suspension of the starting material of the formula VI in an organic solvent (e.g. lower all~anol or dimethylformamide) is reacted with 1-3 equivalents of mercapto-ethanol at 20-80 C in the presence of a basical catalyst (e.g. triethylamine). The compounds of the Formula Ia thus formed are either directly converted into an other compound of the Formula I or isolatedO
- 10 _ When using amino-imino-methane s~lfinic acid as reducing agent, the solution or suspension of the starting material of the formula VI in a mixture of aqueous alkali and alcohol or a dipolar aprotic solvent (in the la~er case a phase-transmitting catalyst 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 glucose. ~s solvent or diluent a mixture of water and lower alcohols or dimethylformamide may be used. Reduction takes 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 ca~yst. This may significantly ~horten thereaction time.
The reduction of the disulfide bond of the starting materials of the formula VI may also be accomplished with metals in acidic medium. As metal 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 r.g. stannous(II)-chloride, titani-um(III)chloride7in acidic medium. ~he suitable pH value may be adjusted 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 (e.g. alkanols, glycols, di-methylformamide, dioxane, diethyleneglycol-dimethyl-ether, tetrah~drofurane, preferabiy lower alkanols) may be used. The reactio~may be preferably carried out at a 11;~ 9 temperature between 25 C and 110 C, particularly at the boiling point of the reaction mixture. According to a preferred embodimen-t of the l~tter method acetic acid is used which serves bo-th ~s so],vent and for the adjustment of the pH-value.
According to an other method a solution of a co~lpo~ld Or the formula VI in the mixture of a mineral acid and alkanol or in dimethylformamide is passed through zinc amalgamated in a Jones-reductor~ ~s mineral acid first of all hydro-chloric acid and sulfuric acid may be used. The acidconcentration is prefera'bly 0.1-2.5 N. ~s solvent or diluent water-miscible lower alkanols (e~g. methanol, ethanol or isopropanol) may be used. ~he above m~thod provides very mild reducing-collditions and may be v~ry ' ' quic~ly carried out at room temperature too. -~ ccording to a preferred form of realisation of the above reducing methods one may work in an inert atmosphere particularly ~lder nitro~en. If the reaction is carried out in heterogeneous system it 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 R4 i5 other than hydrogen - by transforming the said compounds of the Formula Ia into a compound of the Formula Ib R96 ~ H_R1 (Ib) by reacting wlth a compound of the ~ormula R9~Q; or into a 1~ 9 compo~ d of tlle Formula Io 11 2 ~ ~ 1 (Ic) ~y reactin~r with a compound of the ~ormula X;
. ~12 ~ Q (X) or i~t a compound of the Formula Id ; ~ > ..~d_R1 (Id) b~- reacti~g with a compound of the Formula XI;
R13 N2Cl (~I) or into a compou~d of the Formula Id, wherein both R 3 and R14 are hydrogen, with chloro-benzene or bromG-benzene, in which Formulae R is C1-6 alkyl; C3_7 cycloalkyl, C3_6 alkenyl, C3 6 alkinyl or aralkyl;
Q is chlori~e, bromine or iodine or a group of the ll;~Z;~9 Formula R1 -S0 -;
~10 is a phenyl group optionally substituted in position ~ by a me~chyl group;
R11 ancl~12 are hydrogen, nitro, cyano, carboxylic group S or a group of ~he Formula -S(O)n-R8;
f~ and n are as stated above;
~13 and ~1~ are hydrogen, halogen, C1 4 all~yl, hydroxy, C1_4 all<oxy or allcylthioO
The compound Ia is at first converted into its alkali 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 all<ali salt - or that of an alkali salt of a compound of the Formula Ia directly formed in the course of one of the reducing methods discussed above - is reacted with a compound of the Formula R9-Q (wherein R and Q are as stated above). The reaction is carried out at a temperature of 10 to ~0 C. As solvent or suspending rnedium water-miscible organic solvents (e.~. methanol, ethanol and/or dimethylformamide, dimethy~acetamide, or hexamethylphosphoric triamide) may be usedO Thus compound of the formula Ib are obtained.
The thioethers of the Formula Ic may be prepared by reacting 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 all<ali salt as described above~ The reaction takes place at room temperature within some hours. The reactants are used in equimolar amount.
As reaction medium preferably water and/or lower alkanols ~0 or dimethylformamide may be used.
ii'~2~19 The compounds of the Formula Id may be prepared by reacting the alkali salt of a compound of the Formula Ia - prepared as described above -with a compound of the Formula XI. ~ne may proceed preferably by pouring the solution of the diazonium salt of the Formula XI to the solution or suspension of an alkali salt of a compound of the Formula Ia in a lower alkanol or a mixture of water and a lower alkanol, or water, lower alkanol and dimethylformamide respectively under boiling. The reaction mixture is diluted with water if necessary whereupon the compound of the Formula Id is recovered by filtration or extraction. The reaction may be optionally carried out in the presence of powdered copper.
Compounds of the Formula Id - wherein both R and R 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 100-200C in the presence of 0.1-2.5 equivalents of a heavy metal salt [e.g. cuprous(I)- or cupric(II)-salt such as cupric(II)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 atmos-phere preferably under nitrogen. Reactions in heterogenous system are expediently carried out in the presence of a phase transmitting catalyst 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 further feature of Application Serial No. 303,127 there ~ - 14 -~ 3~, ~` ~
li;~Z~9 r ~ 15 ~
are provided new compounds of the Formula I and salts thereof (wherein R1, R2 and R4 have the same meaning as stated above with the proviso that R2 is other than hydrogen).
Preferable sub-class of the compounds of the Formula I are those derivative~ wherein R1 i~ -CooR5; R5 is lower alkyl, preferably methyl; R4 is lower alkyl, preferably methyl, ethyl or n-propyl; allyl, propinyl, benzyl or cyclohexyl and R is halogen preferably chlorine, bromine or fluorine; lower alkoxy, preferably methoxy; lower alkyl, preferably methyl; or trifluoromethyl.
Particularly preferable repre~entatives of the com_ pounds of the Formula 1 are the following derivativess 5(6)-~-propylthio-6(5~-fluoro-benzimidazolyl-2-methyl--carbamate;
5(6)-n-propylthio-6(5)-chloro-benzimidazolyl-2-methyl--carbamate;
5(6)-benzylthio-6(5)-chloro-benzlmidazolyl-2-methyl--carbamate;
5(6) allylthio-6(5)-chloro-benzimidazolyl-2-methyl--carbamate;
5(6)-propynyl-6(5)-chloro-benzimidazolyl-2-methyl--carbamate;
5(6)-ethylthio-6~5)-chloro-benzimidazolyl-2-methyl-~
z~ . -carbamate;
5(6)-cyclohexylthio-655)-chloro-benzimidazolyl-2-methyl--carbamate;
5(6)-~-propylthio-6~5~-bromo-benzimidazolyl-2-methyl--carbamate;
3o ~(6)-n-propylthio-6(5)-methyl-benzimidazolyl-2-methyl--carbamate; 5(6)-n-propylthio-6(5)-methoxy-benzimidazolyl-2-methyl-carbamate;
5(6)-n-propylthio-6(5)-n-butyl-benzimidazolyl-2-methyl-carbamate; 5(6)-n-propylthio-6(5)-trifluoromethyl-benzimidazolyl-2-methyl-carbamate.
The compounds of the Formula I possess useful anthelmintic proper-ties and may be used in human and veterinary therapy as anthelmintic agent.
Thc new compounds of the Formula I and salts thereof are formulated with non-toxical animal veterinary or feed carrier to give a usual anthelmintic compo-sition. 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 capsule. It may also be a pharmaceutically 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.). As liquid carrier e.g.
peanut oil, olive oil, sesame oil and water may be used.
A wide variety of pharmaceutical and veterinary forms can be em-ployed. Thus if a solid carrier is used the composition can be tableted, Zi9 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 administra-tion ~e.g. solution, emulsion, suspension in water or an edible oil). The administration may also be carried out with such forms as bolus, tablet, drench, top dressing etc.
The anthelmintic compositions are made by conventional methods by admixing the active ingredient or a salt thereof with suitable inert solid or liquid carriers or diluents.
The salts of the compounds of the formula I are pharmaceutically 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 content may be administered at once or in more doses.
The starting materials of the formula VI and salts thereof are new compounds which are the subject of this application. Thus, this application relates to new compounds of the formula VI and salts thereof and a process for their preparation (wherein R , R5, R and R3 have the same meaning as stated above). 1'he compounds of the formula VI are useful as intermediates in the preparation of the anthelmintic compounds of the formula I while on the other hand they possess themselves fungicidal and anthelmintic properties and can be used in agriculture as fungicides and in pharmacy as anthelmintics.
~ - 17 -, ~.
i9 The preferred class of the compounds of the formula VI are those derivatives in which R is hydrogen or methoxycarbonyl and R is hydrogen, 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~ disulfide; bis-(2-amino-6-fluoro-benzimida-zole-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;
~ ., i9 bis-(2-methoxycarbonylamino-6-fluoro-benzimidazole-5-yl)-disulfide; bis-(2-methoxycarbonylamino-6-trifluoromethyl-benzimidazole-5-yl)-disulfide; bis-(2-methoxycarbonylamino-6-methoxy-benzimidazole-5-yl)-disulfide; bis-(2-methoxycarbonylamino-6-phenoxy-benzimidazole-5-yl)-disulfide; bis-(2-methoxy-carbonylamino-6-benzyloxy-benzimidazole-5-yl)-disulfide.
The compounds of the ~ormula VI may be prepared as follows:
(a) to prepare a compound of formula VI in which Rl is hydrogen, reacting a compound of formula VII
~ R2 ~ NHH2 ~ 2 VII
wherein R2 is as defined above, with cyanamide or bromocyane;
(b) to prepare a compound of formula VI in which R is a -CooR5 group in which R is as defined above, reacting a compound of formula VII
with a compound of formula XII
R OOCN=C-NH-COOR
~R5 XII
or of formula XIII
NC-NH-COOR XIII
wherein R is as defined above; or (c) to prepare a compound of formula VI in which R is a -COOR
group, reacting a compound of formula VI in which Rl is hydrogen with an agent for introducing a group -COOR into the compound of formula VI. The compound of formula VI can be converted into a salt or a compound of formula VI can be freed from a salt.
lliZZ2:~9 When process (c) is used, the preferred agent for introducing the group -COOR is a compound of formula XIV
X-COOR XIV
a compound of formula XV
(R 0)2CO XV
or a compound of formula XIII
NC-NH-COOR XIII.
According to one embodiment of method (a) a compound of the formula VII is reacted with cyanamide. The reaction is accomplished in the presence of a mineral acid (e.g. hydrochloric acid, sulfuric acid, phosphoric acid) in aqueous medium. Thereafter the reaction mixture is treated with an inor-ganic base (e.g. sodium or potassium hydroxide) or an alkali carbonate (e.g.
sodium or potassium carbonate) and the precipitated bis-(2-amino-benzimida-zolyl)-disulfide of the formula VIa ~ 5 ~ ~ ~ Vla) is isolated.
According to an other embodiment of method (a) a compound of the formula VII is reacted with bromocyane in a lower alkanol (e.g. methanol, ethanol, propanol, isopropanol, preferably in ethanol) at a temperature 9 f between 0 C and 40 C, prererably at 20 C. The reaction mixture is treated with an alkali (e.g. sodium or potassium hydroxide) or an allcali carbonate (e.g.. ~odium or potassium carbonate) to give a compound of the formula V~.
According to an embodiment of method b) of our process a compound of the Formula VII is reacted with an isothiourea derivative of the Formula XII. The process is preferably carried out by heating the 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 i8 preferably accomplished at a pH value of 3-6, particularly at an interval of 3.5-5. The pH is adJusted with an inorganic acid (e.g. hydrochloric acid, sulfuric acidl phosphoric acid) or an organic acid, e.g. formic acid, acetic acid, propionic acid etc. preferably acetic acid. The reaction temperature is preferably 50-100 C and one may work ad-v~ntageously at the boiling point of the reaction mixture.
Thus compounds of the Formula VIb ~ H-COOR5 ] ~VIb) are obtained.
According to an other embodiment of method b) a compound of the Formula VTI is reacted with a carbalkoxy-cyanamide of the formula XIII in a water-miscible organic solvent (e.g, methanol, ethanol, acetone, dio~ane, pyridine) or a . ~x~ .
mixture of water and an organic solvent. The reaction may be accomplished preferably at a temperature between 20C and the boiling point of the reac-tion mixture. Thus compounds of the Formula Vlb are obtained.
A compound of the Formula VIa may be converted into the correspond-ing compound of the lormula VIb by reacting with an agent capable for the introduction of a carbalkoxy group. Reaction is carried out preferably in a basical organic solvent (e.g. pyridine) at a temperature of 0-100C. As agent capable for the introduction of a carbalkoxy group agents generally used for this purpose (e.g. alkyl halogeno formiates of the Formula XIV) may be used.
The compounds of the Formula VIa may also be transformed into the corresponding compounds of the Formula VIb by reacting with a dialkyl carbon-ate of the Formula XV in the presence of an equimolar amount of an alkali alcoholate. As solvent preferably an alkanol may be used. One may proceed preferably by using as reaction medium an alcohol which corresponds to the R alkyl group of the alkali alcoholate. The reaction temperature amounts to 20~120C, preferably the boiling point of the alcohol solvent used.
It is evident for one skilled in the art that the compounds appear-ing in the examples may be designated in two manne~s depending on the fact whether thc numbering is started from the N-atom or the NH group. Thus bis-(2-methoxycarbonylamino-benzimidazole-5-yl)-disulfide can also be named as bis-(2-methoxycarbonylamino-ben7imidazole-6-yl~-disulfide.
The compounds of the Formula VII are useful on the one hand as intermediates in the preparation of anthelmintic agents of the Formula I
while on the other they possess valuable fungicidal and anthelmintic proper-ties and may be used as fungicides in agriculture and anthelmintics in pharmacy.
All of the compounds of the Formula VII are new except the deriva-tive in which R is hydrogen. In prior art a very complicated and circum-stantialseven-step synthesis is disclosed for the preparation of this compound in which aniline is rhodinated, the amino group is protected by introducing an acetyl group, the product is subjected to nitration and hydrolysis, where-upon the product obtained is converted into a disulfide, which is then cleaved into 2-amino-4-mercapto-aniline and finally a disulfide is formed [Ber. 59J
l90 (1926); J. Chem. Soc. 1928, 1364; Pharmazie 3J 151 (1948); Arzneimittel-forschung 2J 455 (1952)]. In view of the complicated steps and the low yield this process is unsuitable for industrial scale production. The compound of the Formula VIIJ wherein R is hydrogenJ was only known as a laboratory pro-duct 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 prepara-tion of various heterocyclic compoundsJ e.g. dibenzimidazolyl-disulfide deriv-atives. The following preparation of the compounds of the Formula ~II can be readily carried out on ~ - 23 -. ~.,.
ll;~ZZ:~9 industrial scale. Practically no by-produc~s are formed.
The compounds of ~he Formula VII may be prepared by heating a compound of the Formula XVI.
R2 ~ NH2 (XVI) NCS ~ NH2 ~he reaction may be carried out preferably by heating the starting material of the Formula XVI in a suitable solvent in the presence of a catalyst.
As solvent water or lower alkanols (e.g. methanol, ethanol, propanol) or a mixture of water and the above all<anols may be used. The catalyst may be an inorganic base (preferably sodium hydroxide, potassium hydroxide), an alkali carbonate (e.g. 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 place within 1-5 hours, preferably 3 hours.
According to an other embodiment of this process a compound of the Formula XVI is heated in the mixture of a lower all<anoic acid (e.g. acetic acid) and a tertiary amine (e.g. triethylamine, dimethylaniline, pyridine).
Particularly preferable class of compounds are those derivatives of the Formula VII wherein R2 is methyl, butyl, chlorine, bromine, fluorine, trifluoromethyl or -oR3 and R~ is methyl, benzyl or phenyl.
~z~9 Particularly preferred representatives of the compounds of the Formula VII are the following compounds:
2,2'-dimethyl-4,4',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 Patent Application Serial No. 370,241, which is also divided out of our Application Serial No. 303,127, filed May 11, 1978 provide com-pounds of the formula XVII
NCS ~ R21 (XVII) salts thereof and a process for the preparation of the same.
In the compounds of the Formula XVII R l stands for hydrogen or amino; and if R is hydrogen, then R22 is amino and if R represents amino, then R stands for hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy, aryloxy or aralkoxy.
The compounds of the Formula XVII and salts thereof are prepared by reacting a compound of the Formula XVIII
. '`~,r~ ~ 25 -lliZ'~Z~ ~
~ 6 NH~, R21 (XVIII) (wherein K21 and R are as stated above) with an agent capable of introducing a thiocyanato (SCN) group in anhydrous medium and if desired converting a compound of 1~ the Formula XVII into its salt or setting free the same from its salt.
The compounds of the Formula XVII are useful inter-mediates which may be used in the preparation of biologically active compounds~ particularly pharmaceuticals and products for application in agriculture such as pesticides, e.g, fungicides.
One of the compounds of the Formula XVII - the 1,2-diamino-4-thiocyenato-ben~ene - has been described as intermediate without di3closing its physical constants (Hungarian laid open patent application Serial No. SI-1367).
According to the known process 1-amino-2-nitro-4-thio-cyanato3-benzene (~. Chem. Soc. 1928, 1364 - a compound which i8 ~ery difficulty available on indu~trial scale - is reduced with stannous (II)chloride at -40 C.
(Reaction scheme E) 22:~9 NH NHAC
C ~ 1. N1145CN I Br2 ~ cc. HN03 2- AC2/ ~J cc. H2S04 SCN
NHAc NH2 SCN SCN
SnC12 ~ NH2 cc. HCl SCN
It is known [J. Gen. Chem. (USSR), 3, 183 (1933); C.A. 28, 1677 (1934)] that 1,3-diamino-benzene may be rhodinated (thiocyanated) with the aid of N,N-dichloro-urea and ammonium rhodanide (ammonium thiocyanate) in aqueous acetic acid. The authors stated however that this method does not lead to the desired result when diamino-benzene derivatives sensible against oxidation (such as p-phenylene-diamine) are used. A recently published summarizing monography about rhodinating was silent in teaching the rhodina-tion of such diamino-benzene derivatives [Die Pharmazie 32, 195 (1977)].
It has been found surprisingly that the diamino-thiocyanato benzene derivatives of the Formula XVII may be prepared by excellent yields from the compounds of the ~ ~ - 27 -ll;~Z~:~9 Formula XVIII by direct rhodination in moderately acidic anhydrous medium.
According to the process of the present invention as rhodinating agent preferably compounds of the Formula XIX
~4 - SCN (XIX) may be used (wherein R4 is a metal atom, preferably an all<ali metal atom, alkaline earth metal atom or a heavy metal atom or an ammonium ion) in the presence or in the absence of an oxidizing agent - depending on the definition of R4.
These rhodinating agents provide under the reaction conditions used the desired compounds of the Formula XVII in a simple manner, by excellent yields and in high purity.
One may proceed preferably by preparing in advance the active rhodinating agent and adding the same to the solution of the starting material of the Formula XVIII. The active rhodinating agent may also be prepared by reacting a compound of the Formula XIX with an oxidizing agent. In this reaction both inorganic and organic oxidizing agents may be usedO Frorn the oxidizing agents e.g. organic N-halogeno compounds, such as Chloramine-T, N-bromo-succinimide, N,N~-dichloro-urea;peroxides e.g. hydrogen peroxide;
all<ali hypochlorites, alkali bromates, alkali iodates;
ions of heavy metals of suitable oxidation grade e.g~
ions of lead, manganese and chromium: furtheron sil~er 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 il;~;~Z:~9 _ ~ 9 _ of heavy metals however ~his embodiment of the process is less preferableO
According to a particularly preferable emdodiment of our process the oxidizing a~ent or a solution thereof is added at a suitable rate to the solution of a compound of the Formula XVIII and a rhodanide of the Formula XIX
wherein R~ is ammonium, sodium or potassium ion, preferably ammonium ion. 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.g. dimethylformamide, dimethylsulfoxide, hexa-methylphosphoric triamide, lower fatty acids, esters of alcohols formed acetic acid or formic acid and all<anols having 1-4 carbon atoms. It is preferred t~ use methanol or ethanol in which most organic rhodanides are easily soluble. Methanol proved to give the best results. In the case of the preparation of compounds of the Formula XVII wherein R 1 is amino and R22 is all<yl, all<oxy, aryloxy or arall<oxy, 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)O One may proceed particularly preferably by using methanol or ethanol as solvent and adding 25 0-2 moles of acetic acid - related to the diamino-benzene derivative of the Formula XVIII - to the reaction mixtureO
The reaction temperature depends on the solvent and the reactants used and is from about -20 C to about +200C.
The process may be particularly advantageously accomplished by reacting a compound of the Formula XVIII in a mixture of - 30 _ methanol and acetic acid at a temperature between -10C and +25C with a rhodinatin~ ayent 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 sl<illed in the art that the numbering of the substituents may be started from either amlno group. Thus 1,2-diamino-4-chloro-5-thiocyanato-benzene may be designated as 1~2-diamino-4-thiocyanato-5-chloro-benzene as well.
The compounds of the Formula XVII are new and also belong to the scope of our invention, with the provi~o that if R2~ i8 amino then R22 is other than hydrogen.
Preferred representatives of the compounds of the formula XVII are the following derivatives:
1~-diamino-4-methyl-5-thiocyanato-benzene;
1,4-diami~o-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-thiocyanato-benzene;
1,2-diamino-4-trifluoro-ethyl-5-thiocyanato -benzene 1,2-diamino-4-methoxy-5-thiocyanato-benzeneS
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 .
ll;~Z'~:~9 (wherein Rl, R2, R3, and R4 and R5 are as stated above) may be thus prepared from the diamino-benzene derivatives of the Formula XVIII by the following reaction series: reacting a compound of the Formula XVIII (wherein R is amino and R stands for hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy, aryloxy or aralkoxy) with an agent capable of introducing a thiocyanato-group (SCN); thereafter heating the compound of the Formula XVI
thus formed (wherein R has the same meaning as stated in claim l); there-after reacting the compound of the Formula VII thus formed (wherein R has the same meaning as stated in claim l)(with cyanamide, bromo cyane or a compound of the Formula XII or XIII (wherein R5 is as stated in claim 1) and if desired reacting a compound of the Formula VI thus formed (wherein R is as stated in claim l; 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 R is as stated above and Rl is a group of the Formula -COOR, in which formula R is as stated above);
and thereafter subjecting a compound of the Formula VI to reduction (wherein R and R are as stated in claim 1) and if desired introducing an R4 group being other than hydrogen into a compound of the Formula I thus formed (wherein R and R are as stated above and R4 is hydrogen) and if desired convertin~ a compound of the Formula I thus obtained into its salt.
Acccording to a particularly preferred aspect of the invention of Application Serial No. 303,127 there is provided a new process for the prepar-ation of 5 (6) -n-propylthio-benzimidazolyl-2-methyl-~ . 3 1 carbamate (a well-known anthelmintic agent - a compound of the Formula I
wherein R is methoxycarbonyl; R2 is hydrogen and R4 is n-propyl) which com-prises reacting o-phenylene-diamine with an agent capable of introducing a thiocyanato group (SCN); heating the compound of the Formula (XVI) thus obtained (wherein R is hydrogen); reacting the compound of the Formula VII
thus obtained (wherein R is hydrogen) with cyanamide, bromocyane or a com-pound 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 Formula XIV or XV (wherein R5 is methyl); reducing the compound of the Formula VI thus obtained (wherein R is hydrogen; Rl is -COOR and R5 is methyl) and reacting the compound of the Formula I thus obtained (in which R and R are hydrogen; R is -COOR and R5 is hydrogen) with a propylating agent.
Further details of the present invention and the inventions of copending Applications Serial Nos. 303,127 and 370,241 are to be found in the Examples without limiting the scope of our invention to the Examples.
~ - 32 -.~,~
.
E~ample 1 10.3 9 of o-~h~nylene diamine and 1~.2 9 o~ ammonium rho(~artide ar~ di~solved in a mixture o~ 80 ml of n-ethyl alcohol and lO ml of acetic acid and to the mixture cooled at a temperature of 10 C a solution of 6.5 ml of bromine in 20 ml of melhyl alcohol is added while stirring in 30 60 minute~ and the temperature is maintained at 10 C while stirriny until the reaction is finished (5 to 30 minutes).
The fin~l point of the reaction is determined by thinlayer c~romatographic analysis (Layer: Polyram Sil. G., Macherey Nagel Co.: Development with: benzene-ethylacetate-methyl alcoholic ammonium solution 8:1:1. Developer : Iodine)O
The reaction finished the mixture is poured into water and the acid is neutralized by adding a 20 % ammonium hydroxide solution, pH value 7-7.5. The precipitated crystfllline 1,2-diamino-4-thio-cyanato-benzene is filtered.
Weight: 13.2 9 (yield 80 %). Melting point 123 C
(recrystallized from benzene).
Example 2 10.8 g of phenylene diamine and 50 9 of potassium rhodanide are dissolved in1100 ml of methyl alcohol and to the solution at a temperature of 10 C a solùtion of 7.0 ml of bromine in 30 ml of methyl alcohol is added while stirring vigorously in 30-60 minutes. The final point of the reaction is determined by the method set forth in Example 1.
After pouring the mixture into water and ad~usting the pH value1 the product is isolated by extraction with chloroform. After drying and evaporating the solvent 13.5 9 of 1,2-diamino-4-thiocyanato-benzene are~obtained.
Mp. 123 C (from benzene).
2~9 - ;~4 _ Example 3 15.9 9 of brom!ne are added dropwise while stirring into a solution of ;-0 9 of potassium rhodanide in 100 ml of methyl alcohol at a temperature of -10C. The obtained yellowish birhodane solution is added to a solution of 10.8 g of o-ph~nylene diamine in 40 ml of a mixture from acetic acid-methyl alcohol 1:1, while stirring at a temperature of 5-10 C. Processing the reaction mixture as set forth in Example 1 the 1,2-diamino-4-thiocyanato-benzene is obtained~ melting at 123 C.
Example 4 rO a solution of 14.2 g of 4(5)-chloro-o-phenylene diamine and 38 9 of ammonium rhodanide in 120 ml of methyl alc~hol 5 ml of acetic acid are added, whereafter a solution of 7.2 ml of bromine in 20 ml of methyl alcohol is added at a temperature of 15-17 C in 30-60 minutes.
The mixture is diluted with water and after adjustlng the pH value to 8, 1,2-diamino-4-chloro-5-thiocyanato-~ benzene i9 obtained, melting at 108-110 C.
Example 5 To a solution of 13.8 g of 4(5)-methoxy-o-phenylene diamine and 38 g of ammonium rhodanide in 80 ml of methyl alcohol and 15 ml of acetic acid a solution of 6.5 ml of bromine in 20 ml of methyl alcohol is added dropwise within 40-6Q minutes at 8 temperature of 5-10 C. Processing the reaction mixture as set forth in Example 1 the 1,2-diamino-4-methoxy-5-thiocyanato-benzene is obbined.
Mp.: 112-114 C.
Example 6 21.4 g of 4(5)-benzyloxy-o-phenylene diamine and 50 g ll;ZZ2~9 of potassium rhodanide are dissolved in a mixture of 100 ml of methyl alcohol and 20 ml of acetic acid and to the solution obtained a solution of 605 ml of bromine in 30 ml of methyl alcohol is added at a temperature of 5-10 C
in 30-60 minutes. Processing the mixture as set forth in Example 1 the 1,2-diamino-3-benzyloxy-4-thiocyanato-benzene is obtained.
Example 7 To a solution of 1008 g of p-phenylene-diamine and 38 g of ammonium rhodanide 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 stirring at a temperature of 8-10 C, Processing the reaction mixture as set forth in Example 1 the 1,4-diamino-2-thiocyanato-benzene is obtained.
Example 8 In an analogous-manner to the process described in Example 1 to 3, the following compounds are prepared:
1,2-diamino-4-methyl-5-thiocyanato-benzene, mp.: 117 C, 1,2-diamino-4-chloro-5-thiocyanato-benzene; mp.: 108-110 C;
1,2-diamino-4-bromo-5-thiocyanato-benzene, mp.: 9g-100 C;
1,2-diamino-4-fluoro-5-thiocyanato-benzene, mp.: 104-1oB C;
1,2-diamino-4-trifluoromethyl-5-thiocyanato-benzene, mp.:
154-1~6 C;
1,2-diamino-4-n-butyl-5-thiocyanato-benzene, mp.: 109-11 C.
Example 9 22.0 9 of 1,2-diamino-4-thiocyanato-benzene are dissolved in 100 ml. of methyl alcohol and to the solution 100 ml~ of a 25 ~ ammonium hydroxide solution and 1000 ml of water are added. The mixture is l<ept at a temperature ll'~Z2~9 of 80-85 C for 3-4 hours. The final point of the reaction is deterrnined by thinlayer chroma~ographic analysis.
(Layer: Macherey-Nagel Polygram Sil. G. Development with: benzene-ethylacetate - a 1() ~ alcoholic ammonium 5 solution 8 :1 :1. Developer: Iodine ~f U.4~).
The reaction finished, the mixture is cooled, let to stand overnight in a refrigerator and the precipitated product is filtered, washed with water and dried. 16,1 9 of 3,3~,4,4~-tetraamino-diphenyl-disulfide are obtained (Yield 87 ,0), melting point: 161-162 C.
Example 10_ 16.5 9 of 1 ,2-diamino-4-thiocyanato-benzene are dissolved in 20 ml of acetic acid and after addin~ 4 9 of pyridine catalyst the reaction mixture is boiled. The final point of the reaction i5 determined by thinlayer chromatographic analysis (see Example 1). The mixture is poured on 200 9 of ice-water, whereafter is made alkaline by adding a 4 N sodium hydroxide solution (pH value 7.5-8).
After standing for a half hour the product is filtered~
washed with water and dried. 11.1 g (yield 81 ~) of 3,31,4,4~_ tetraamino-diphenyl-disulfide are obtained. Mp. 161-162 C.
Example 11 One proceeds in the same way as in Examples 9 or 10, with the difference, that instead of 1 ,2-diamino-4-thiocyanato-benzene an equivalent amount of a compound of the ~eneral formula XVI is used, wherein R2 represents a methyl-, butyl-, bromine-, chlorine-, fluorine-, trifluoromethyl-, methoxy-, phenoxy- or benzyloxy group .
By this way the following compounds of the general formula VII are prepared:
2,2'-dimethyl-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.:174-175C;
2,2'-dibutyl-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 205-207C;
2,2'-dibromo-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 179-180C;
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.: 172-173C;
2,2'-di(trifluoromethyl)-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 194-196C;
2,2'-dimethoxy-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 190-192C;
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), where-after 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 50 ml of water and 4.2 g of cyanamide are added. ~he mixture is cooled to 10C and 9.4 g of chloro-formic acid methyl ester ,~
ll^~ZZi9
~ 1 2 2 to reduction (wherein R and R are as stated above~ and if desired introduc-ing an R group being other than hydroge~ into the compound of the Formula I
thus formed (wherein R and R are as stated above and R4 is hydrogen) and if desired converting a compound of the Formula I thus obtained into its salt.
l ~
~ - 7 -2~9 According to a preferred embodiment of our process a compound of the Formula VI is reacted with a complex metal hydride such as lithium aluminium hydride, sodiumborohydride-aluminium chloride complex~ sodium borohydride or sodium-dihydro-bis-(2-methoxy-ethoxy)-aluminate in anhydrous medium. ~s reaction medium preferably organic solvents such as diall<yl ethers, cyclic ethers (eOgO tetrahydrofurane, dioxane), dimethylformamide, dimethylacetamide, hexamethyl-phosphoric triamide, diethylene-glycol dimethyl ether, lower alcohols etc.) may be usedO
Ylhen u~ing a sodium borohydride - alu~inium chloride complex, the reaction may be preferably carried out in tetra-hydrofurane or dioxane. In this case the reaction takes place at room ~emperature with 2-3 hours.
When using sodium borohydride the reaction may be carried out i~ adition to the above solvents also in the mixture of water and a lower all<anol in the presence of an allcali hydroxide. The thiophenol derivative of the formula Ia thus formed can either be isolated or directly con-verted into other compounds of the Formula I.
The disulfide bond of the compounds of the Formula VI
may also be reduced by means of alkali metals. The starting material of the Formula VI is suspended in an inert solvent (e.g. toluene, xylene) and admixed with pDwdered ?~ potassium or sodium at room temperature or under warmingO
2-4 equivalents of alkali metal are used for 1 equivalent of the compound of the Formula VIo If ~ equivalents of alkali are used, the dialkali salt of the compound of the Formula Ia is obtained. The reaction mixture is then acidified and the compound of the Formula Ia can be isolated if desiredO If 11;~2Z19 - 8a -only 2 equivalents of an acid (e.~. acetic acid) are added to the reaction mixture, the solution of the mono-allcali salt of the compound of the Formula Ia is formed which may be converted into o~her compounds of the Formula I directly, ll;~Z219 without isolation. The said reduction may be pre~erably accomplished in ~uid ammonia at a temperature between -20 C and -40 C. On evaporating the ammonia solvent the all<ali salt of the compounds of the Formula Ia is obtained as residue, which may be either 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 pyrosulfite. Sodium hydrogen sulfite and sodium dithionite proved ~o be particularly suitable for this purpose. When using the said reducing ayents 2-2.6 moles of all~ali hydroxide and 2-2.2 moles of the reducing agent are applied for 1 mole of a starting material of the Formula VIo Reduction may be preferably carried out in an alcoholic solution and/or dimethylformamide containing 10-30 ~ of water. The reaction is accomplished under heating at 50-80 C, preferably a~ the boiling point of the reaction mixture. The compounds of the Formula Ia formed are either isolated or directly converted into other compounds of the Formula I.
As reducing agents organic sulfur compounds may be used as well ~e.g. mercapto-ethanol or amino-imino-methane sulfinic acid). The solution or suspension of the starting material of the formula VI in an organic solvent (e.g. lower all~anol or dimethylformamide) is reacted with 1-3 equivalents of mercapto-ethanol at 20-80 C in the presence of a basical catalyst (e.g. triethylamine). The compounds of the Formula Ia thus formed are either directly converted into an other compound of the Formula I or isolatedO
- 10 _ When using amino-imino-methane s~lfinic acid as reducing agent, the solution or suspension of the starting material of the formula VI in a mixture of aqueous alkali and alcohol or a dipolar aprotic solvent (in the la~er case a phase-transmitting catalyst 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 glucose. ~s solvent or diluent a mixture of water and lower alcohols or dimethylformamide may be used. Reduction takes 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 ca~yst. This may significantly ~horten thereaction time.
The reduction of the disulfide bond of the starting materials of the formula VI may also be accomplished with metals in acidic medium. As metal 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 r.g. stannous(II)-chloride, titani-um(III)chloride7in acidic medium. ~he suitable pH value may be adjusted 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 (e.g. alkanols, glycols, di-methylformamide, dioxane, diethyleneglycol-dimethyl-ether, tetrah~drofurane, preferabiy lower alkanols) may be used. The reactio~may be preferably carried out at a 11;~ 9 temperature between 25 C and 110 C, particularly at the boiling point of the reaction mixture. According to a preferred embodimen-t of the l~tter method acetic acid is used which serves bo-th ~s so],vent and for the adjustment of the pH-value.
According to an other method a solution of a co~lpo~ld Or the formula VI in the mixture of a mineral acid and alkanol or in dimethylformamide is passed through zinc amalgamated in a Jones-reductor~ ~s mineral acid first of all hydro-chloric acid and sulfuric acid may be used. The acidconcentration is prefera'bly 0.1-2.5 N. ~s solvent or diluent water-miscible lower alkanols (e~g. methanol, ethanol or isopropanol) may be used. ~he above m~thod provides very mild reducing-collditions and may be v~ry ' ' quic~ly carried out at room temperature too. -~ ccording to a preferred form of realisation of the above reducing methods one may work in an inert atmosphere particularly ~lder nitro~en. If the reaction is carried out in heterogeneous system it 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 R4 i5 other than hydrogen - by transforming the said compounds of the Formula Ia into a compound of the Formula Ib R96 ~ H_R1 (Ib) by reacting wlth a compound of the ~ormula R9~Q; or into a 1~ 9 compo~ d of tlle Formula Io 11 2 ~ ~ 1 (Ic) ~y reactin~r with a compound of the ~ormula X;
. ~12 ~ Q (X) or i~t a compound of the Formula Id ; ~ > ..~d_R1 (Id) b~- reacti~g with a compound of the Formula XI;
R13 N2Cl (~I) or into a compou~d of the Formula Id, wherein both R 3 and R14 are hydrogen, with chloro-benzene or bromG-benzene, in which Formulae R is C1-6 alkyl; C3_7 cycloalkyl, C3_6 alkenyl, C3 6 alkinyl or aralkyl;
Q is chlori~e, bromine or iodine or a group of the ll;~Z;~9 Formula R1 -S0 -;
~10 is a phenyl group optionally substituted in position ~ by a me~chyl group;
R11 ancl~12 are hydrogen, nitro, cyano, carboxylic group S or a group of ~he Formula -S(O)n-R8;
f~ and n are as stated above;
~13 and ~1~ are hydrogen, halogen, C1 4 all~yl, hydroxy, C1_4 all<oxy or allcylthioO
The compound Ia is at first converted into its alkali 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 all<ali salt - or that of an alkali salt of a compound of the Formula Ia directly formed in the course of one of the reducing methods discussed above - is reacted with a compound of the Formula R9-Q (wherein R and Q are as stated above). The reaction is carried out at a temperature of 10 to ~0 C. As solvent or suspending rnedium water-miscible organic solvents (e.~. methanol, ethanol and/or dimethylformamide, dimethy~acetamide, or hexamethylphosphoric triamide) may be usedO Thus compound of the formula Ib are obtained.
The thioethers of the Formula Ic may be prepared by reacting 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 all<ali salt as described above~ The reaction takes place at room temperature within some hours. The reactants are used in equimolar amount.
As reaction medium preferably water and/or lower alkanols ~0 or dimethylformamide may be used.
ii'~2~19 The compounds of the Formula Id may be prepared by reacting the alkali salt of a compound of the Formula Ia - prepared as described above -with a compound of the Formula XI. ~ne may proceed preferably by pouring the solution of the diazonium salt of the Formula XI to the solution or suspension of an alkali salt of a compound of the Formula Ia in a lower alkanol or a mixture of water and a lower alkanol, or water, lower alkanol and dimethylformamide respectively under boiling. The reaction mixture is diluted with water if necessary whereupon the compound of the Formula Id is recovered by filtration or extraction. The reaction may be optionally carried out in the presence of powdered copper.
Compounds of the Formula Id - wherein both R and R 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 100-200C in the presence of 0.1-2.5 equivalents of a heavy metal salt [e.g. cuprous(I)- or cupric(II)-salt such as cupric(II)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 atmos-phere preferably under nitrogen. Reactions in heterogenous system are expediently carried out in the presence of a phase transmitting catalyst 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 further feature of Application Serial No. 303,127 there ~ - 14 -~ 3~, ~` ~
li;~Z~9 r ~ 15 ~
are provided new compounds of the Formula I and salts thereof (wherein R1, R2 and R4 have the same meaning as stated above with the proviso that R2 is other than hydrogen).
Preferable sub-class of the compounds of the Formula I are those derivative~ wherein R1 i~ -CooR5; R5 is lower alkyl, preferably methyl; R4 is lower alkyl, preferably methyl, ethyl or n-propyl; allyl, propinyl, benzyl or cyclohexyl and R is halogen preferably chlorine, bromine or fluorine; lower alkoxy, preferably methoxy; lower alkyl, preferably methyl; or trifluoromethyl.
Particularly preferable repre~entatives of the com_ pounds of the Formula 1 are the following derivativess 5(6)-~-propylthio-6(5~-fluoro-benzimidazolyl-2-methyl--carbamate;
5(6)-n-propylthio-6(5)-chloro-benzimidazolyl-2-methyl--carbamate;
5(6)-benzylthio-6(5)-chloro-benzlmidazolyl-2-methyl--carbamate;
5(6) allylthio-6(5)-chloro-benzimidazolyl-2-methyl--carbamate;
5(6)-propynyl-6(5)-chloro-benzimidazolyl-2-methyl--carbamate;
5(6)-ethylthio-6~5)-chloro-benzimidazolyl-2-methyl-~
z~ . -carbamate;
5(6)-cyclohexylthio-655)-chloro-benzimidazolyl-2-methyl--carbamate;
5(6)-~-propylthio-6~5~-bromo-benzimidazolyl-2-methyl--carbamate;
3o ~(6)-n-propylthio-6(5)-methyl-benzimidazolyl-2-methyl--carbamate; 5(6)-n-propylthio-6(5)-methoxy-benzimidazolyl-2-methyl-carbamate;
5(6)-n-propylthio-6(5)-n-butyl-benzimidazolyl-2-methyl-carbamate; 5(6)-n-propylthio-6(5)-trifluoromethyl-benzimidazolyl-2-methyl-carbamate.
The compounds of the Formula I possess useful anthelmintic proper-ties and may be used in human and veterinary therapy as anthelmintic agent.
Thc new compounds of the Formula I and salts thereof are formulated with non-toxical animal veterinary or feed carrier to give a usual anthelmintic compo-sition. 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 capsule. It may also be a pharmaceutically 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.). As liquid carrier e.g.
peanut oil, olive oil, sesame oil and water may be used.
A wide variety of pharmaceutical and veterinary forms can be em-ployed. Thus if a solid carrier is used the composition can be tableted, Zi9 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 administra-tion ~e.g. solution, emulsion, suspension in water or an edible oil). The administration may also be carried out with such forms as bolus, tablet, drench, top dressing etc.
The anthelmintic compositions are made by conventional methods by admixing the active ingredient or a salt thereof with suitable inert solid or liquid carriers or diluents.
The salts of the compounds of the formula I are pharmaceutically 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 content may be administered at once or in more doses.
The starting materials of the formula VI and salts thereof are new compounds which are the subject of this application. Thus, this application relates to new compounds of the formula VI and salts thereof and a process for their preparation (wherein R , R5, R and R3 have the same meaning as stated above). 1'he compounds of the formula VI are useful as intermediates in the preparation of the anthelmintic compounds of the formula I while on the other hand they possess themselves fungicidal and anthelmintic properties and can be used in agriculture as fungicides and in pharmacy as anthelmintics.
~ - 17 -, ~.
i9 The preferred class of the compounds of the formula VI are those derivatives in which R is hydrogen or methoxycarbonyl and R is hydrogen, 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~ disulfide; bis-(2-amino-6-fluoro-benzimida-zole-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;
~ ., i9 bis-(2-methoxycarbonylamino-6-fluoro-benzimidazole-5-yl)-disulfide; bis-(2-methoxycarbonylamino-6-trifluoromethyl-benzimidazole-5-yl)-disulfide; bis-(2-methoxycarbonylamino-6-methoxy-benzimidazole-5-yl)-disulfide; bis-(2-methoxycarbonylamino-6-phenoxy-benzimidazole-5-yl)-disulfide; bis-(2-methoxy-carbonylamino-6-benzyloxy-benzimidazole-5-yl)-disulfide.
The compounds of the ~ormula VI may be prepared as follows:
(a) to prepare a compound of formula VI in which Rl is hydrogen, reacting a compound of formula VII
~ R2 ~ NHH2 ~ 2 VII
wherein R2 is as defined above, with cyanamide or bromocyane;
(b) to prepare a compound of formula VI in which R is a -CooR5 group in which R is as defined above, reacting a compound of formula VII
with a compound of formula XII
R OOCN=C-NH-COOR
~R5 XII
or of formula XIII
NC-NH-COOR XIII
wherein R is as defined above; or (c) to prepare a compound of formula VI in which R is a -COOR
group, reacting a compound of formula VI in which Rl is hydrogen with an agent for introducing a group -COOR into the compound of formula VI. The compound of formula VI can be converted into a salt or a compound of formula VI can be freed from a salt.
lliZZ2:~9 When process (c) is used, the preferred agent for introducing the group -COOR is a compound of formula XIV
X-COOR XIV
a compound of formula XV
(R 0)2CO XV
or a compound of formula XIII
NC-NH-COOR XIII.
According to one embodiment of method (a) a compound of the formula VII is reacted with cyanamide. The reaction is accomplished in the presence of a mineral acid (e.g. hydrochloric acid, sulfuric acid, phosphoric acid) in aqueous medium. Thereafter the reaction mixture is treated with an inor-ganic base (e.g. sodium or potassium hydroxide) or an alkali carbonate (e.g.
sodium or potassium carbonate) and the precipitated bis-(2-amino-benzimida-zolyl)-disulfide of the formula VIa ~ 5 ~ ~ ~ Vla) is isolated.
According to an other embodiment of method (a) a compound of the formula VII is reacted with bromocyane in a lower alkanol (e.g. methanol, ethanol, propanol, isopropanol, preferably in ethanol) at a temperature 9 f between 0 C and 40 C, prererably at 20 C. The reaction mixture is treated with an alkali (e.g. sodium or potassium hydroxide) or an allcali carbonate (e.g.. ~odium or potassium carbonate) to give a compound of the formula V~.
According to an embodiment of method b) of our process a compound of the Formula VII is reacted with an isothiourea derivative of the Formula XII. The process is preferably carried out by heating the 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 i8 preferably accomplished at a pH value of 3-6, particularly at an interval of 3.5-5. The pH is adJusted with an inorganic acid (e.g. hydrochloric acid, sulfuric acidl phosphoric acid) or an organic acid, e.g. formic acid, acetic acid, propionic acid etc. preferably acetic acid. The reaction temperature is preferably 50-100 C and one may work ad-v~ntageously at the boiling point of the reaction mixture.
Thus compounds of the Formula VIb ~ H-COOR5 ] ~VIb) are obtained.
According to an other embodiment of method b) a compound of the Formula VTI is reacted with a carbalkoxy-cyanamide of the formula XIII in a water-miscible organic solvent (e.g, methanol, ethanol, acetone, dio~ane, pyridine) or a . ~x~ .
mixture of water and an organic solvent. The reaction may be accomplished preferably at a temperature between 20C and the boiling point of the reac-tion mixture. Thus compounds of the Formula Vlb are obtained.
A compound of the Formula VIa may be converted into the correspond-ing compound of the lormula VIb by reacting with an agent capable for the introduction of a carbalkoxy group. Reaction is carried out preferably in a basical organic solvent (e.g. pyridine) at a temperature of 0-100C. As agent capable for the introduction of a carbalkoxy group agents generally used for this purpose (e.g. alkyl halogeno formiates of the Formula XIV) may be used.
The compounds of the Formula VIa may also be transformed into the corresponding compounds of the Formula VIb by reacting with a dialkyl carbon-ate of the Formula XV in the presence of an equimolar amount of an alkali alcoholate. As solvent preferably an alkanol may be used. One may proceed preferably by using as reaction medium an alcohol which corresponds to the R alkyl group of the alkali alcoholate. The reaction temperature amounts to 20~120C, preferably the boiling point of the alcohol solvent used.
It is evident for one skilled in the art that the compounds appear-ing in the examples may be designated in two manne~s depending on the fact whether thc numbering is started from the N-atom or the NH group. Thus bis-(2-methoxycarbonylamino-benzimidazole-5-yl)-disulfide can also be named as bis-(2-methoxycarbonylamino-ben7imidazole-6-yl~-disulfide.
The compounds of the Formula VII are useful on the one hand as intermediates in the preparation of anthelmintic agents of the Formula I
while on the other they possess valuable fungicidal and anthelmintic proper-ties and may be used as fungicides in agriculture and anthelmintics in pharmacy.
All of the compounds of the Formula VII are new except the deriva-tive in which R is hydrogen. In prior art a very complicated and circum-stantialseven-step synthesis is disclosed for the preparation of this compound in which aniline is rhodinated, the amino group is protected by introducing an acetyl group, the product is subjected to nitration and hydrolysis, where-upon the product obtained is converted into a disulfide, which is then cleaved into 2-amino-4-mercapto-aniline and finally a disulfide is formed [Ber. 59J
l90 (1926); J. Chem. Soc. 1928, 1364; Pharmazie 3J 151 (1948); Arzneimittel-forschung 2J 455 (1952)]. In view of the complicated steps and the low yield this process is unsuitable for industrial scale production. The compound of the Formula VIIJ wherein R is hydrogenJ was only known as a laboratory pro-duct 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 prepara-tion of various heterocyclic compoundsJ e.g. dibenzimidazolyl-disulfide deriv-atives. The following preparation of the compounds of the Formula ~II can be readily carried out on ~ - 23 -. ~.,.
ll;~ZZ:~9 industrial scale. Practically no by-produc~s are formed.
The compounds of ~he Formula VII may be prepared by heating a compound of the Formula XVI.
R2 ~ NH2 (XVI) NCS ~ NH2 ~he reaction may be carried out preferably by heating the starting material of the Formula XVI in a suitable solvent in the presence of a catalyst.
As solvent water or lower alkanols (e.g. methanol, ethanol, propanol) or a mixture of water and the above all<anols may be used. The catalyst may be an inorganic base (preferably sodium hydroxide, potassium hydroxide), an alkali carbonate (e.g. 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 place within 1-5 hours, preferably 3 hours.
According to an other embodiment of this process a compound of the Formula XVI is heated in the mixture of a lower all<anoic acid (e.g. acetic acid) and a tertiary amine (e.g. triethylamine, dimethylaniline, pyridine).
Particularly preferable class of compounds are those derivatives of the Formula VII wherein R2 is methyl, butyl, chlorine, bromine, fluorine, trifluoromethyl or -oR3 and R~ is methyl, benzyl or phenyl.
~z~9 Particularly preferred representatives of the compounds of the Formula VII are the following compounds:
2,2'-dimethyl-4,4',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 Patent Application Serial No. 370,241, which is also divided out of our Application Serial No. 303,127, filed May 11, 1978 provide com-pounds of the formula XVII
NCS ~ R21 (XVII) salts thereof and a process for the preparation of the same.
In the compounds of the Formula XVII R l stands for hydrogen or amino; and if R is hydrogen, then R22 is amino and if R represents amino, then R stands for hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy, aryloxy or aralkoxy.
The compounds of the Formula XVII and salts thereof are prepared by reacting a compound of the Formula XVIII
. '`~,r~ ~ 25 -lliZ'~Z~ ~
~ 6 NH~, R21 (XVIII) (wherein K21 and R are as stated above) with an agent capable of introducing a thiocyanato (SCN) group in anhydrous medium and if desired converting a compound of 1~ the Formula XVII into its salt or setting free the same from its salt.
The compounds of the Formula XVII are useful inter-mediates which may be used in the preparation of biologically active compounds~ particularly pharmaceuticals and products for application in agriculture such as pesticides, e.g, fungicides.
One of the compounds of the Formula XVII - the 1,2-diamino-4-thiocyenato-ben~ene - has been described as intermediate without di3closing its physical constants (Hungarian laid open patent application Serial No. SI-1367).
According to the known process 1-amino-2-nitro-4-thio-cyanato3-benzene (~. Chem. Soc. 1928, 1364 - a compound which i8 ~ery difficulty available on indu~trial scale - is reduced with stannous (II)chloride at -40 C.
(Reaction scheme E) 22:~9 NH NHAC
C ~ 1. N1145CN I Br2 ~ cc. HN03 2- AC2/ ~J cc. H2S04 SCN
NHAc NH2 SCN SCN
SnC12 ~ NH2 cc. HCl SCN
It is known [J. Gen. Chem. (USSR), 3, 183 (1933); C.A. 28, 1677 (1934)] that 1,3-diamino-benzene may be rhodinated (thiocyanated) with the aid of N,N-dichloro-urea and ammonium rhodanide (ammonium thiocyanate) in aqueous acetic acid. The authors stated however that this method does not lead to the desired result when diamino-benzene derivatives sensible against oxidation (such as p-phenylene-diamine) are used. A recently published summarizing monography about rhodinating was silent in teaching the rhodina-tion of such diamino-benzene derivatives [Die Pharmazie 32, 195 (1977)].
It has been found surprisingly that the diamino-thiocyanato benzene derivatives of the Formula XVII may be prepared by excellent yields from the compounds of the ~ ~ - 27 -ll;~Z~:~9 Formula XVIII by direct rhodination in moderately acidic anhydrous medium.
According to the process of the present invention as rhodinating agent preferably compounds of the Formula XIX
~4 - SCN (XIX) may be used (wherein R4 is a metal atom, preferably an all<ali metal atom, alkaline earth metal atom or a heavy metal atom or an ammonium ion) in the presence or in the absence of an oxidizing agent - depending on the definition of R4.
These rhodinating agents provide under the reaction conditions used the desired compounds of the Formula XVII in a simple manner, by excellent yields and in high purity.
One may proceed preferably by preparing in advance the active rhodinating agent and adding the same to the solution of the starting material of the Formula XVIII. The active rhodinating agent may also be prepared by reacting a compound of the Formula XIX with an oxidizing agent. In this reaction both inorganic and organic oxidizing agents may be usedO Frorn the oxidizing agents e.g. organic N-halogeno compounds, such as Chloramine-T, N-bromo-succinimide, N,N~-dichloro-urea;peroxides e.g. hydrogen peroxide;
all<ali hypochlorites, alkali bromates, alkali iodates;
ions of heavy metals of suitable oxidation grade e.g~
ions of lead, manganese and chromium: furtheron sil~er 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 il;~;~Z:~9 _ ~ 9 _ of heavy metals however ~his embodiment of the process is less preferableO
According to a particularly preferable emdodiment of our process the oxidizing a~ent or a solution thereof is added at a suitable rate to the solution of a compound of the Formula XVIII and a rhodanide of the Formula XIX
wherein R~ is ammonium, sodium or potassium ion, preferably ammonium ion. 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.g. dimethylformamide, dimethylsulfoxide, hexa-methylphosphoric triamide, lower fatty acids, esters of alcohols formed acetic acid or formic acid and all<anols having 1-4 carbon atoms. It is preferred t~ use methanol or ethanol in which most organic rhodanides are easily soluble. Methanol proved to give the best results. In the case of the preparation of compounds of the Formula XVII wherein R 1 is amino and R22 is all<yl, all<oxy, aryloxy or arall<oxy, 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)O One may proceed particularly preferably by using methanol or ethanol as solvent and adding 25 0-2 moles of acetic acid - related to the diamino-benzene derivative of the Formula XVIII - to the reaction mixtureO
The reaction temperature depends on the solvent and the reactants used and is from about -20 C to about +200C.
The process may be particularly advantageously accomplished by reacting a compound of the Formula XVIII in a mixture of - 30 _ methanol and acetic acid at a temperature between -10C and +25C with a rhodinatin~ ayent 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 sl<illed in the art that the numbering of the substituents may be started from either amlno group. Thus 1,2-diamino-4-chloro-5-thiocyanato-benzene may be designated as 1~2-diamino-4-thiocyanato-5-chloro-benzene as well.
The compounds of the Formula XVII are new and also belong to the scope of our invention, with the provi~o that if R2~ i8 amino then R22 is other than hydrogen.
Preferred representatives of the compounds of the formula XVII are the following derivatives:
1~-diamino-4-methyl-5-thiocyanato-benzene;
1,4-diami~o-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-thiocyanato-benzene;
1,2-diamino-4-trifluoro-ethyl-5-thiocyanato -benzene 1,2-diamino-4-methoxy-5-thiocyanato-benzeneS
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 .
ll;~Z'~:~9 (wherein Rl, R2, R3, and R4 and R5 are as stated above) may be thus prepared from the diamino-benzene derivatives of the Formula XVIII by the following reaction series: reacting a compound of the Formula XVIII (wherein R is amino and R stands for hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy, aryloxy or aralkoxy) with an agent capable of introducing a thiocyanato-group (SCN); thereafter heating the compound of the Formula XVI
thus formed (wherein R has the same meaning as stated in claim l); there-after reacting the compound of the Formula VII thus formed (wherein R has the same meaning as stated in claim l)(with cyanamide, bromo cyane or a compound of the Formula XII or XIII (wherein R5 is as stated in claim 1) and if desired reacting a compound of the Formula VI thus formed (wherein R is as stated in claim l; 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 R is as stated above and Rl is a group of the Formula -COOR, in which formula R is as stated above);
and thereafter subjecting a compound of the Formula VI to reduction (wherein R and R are as stated in claim 1) and if desired introducing an R4 group being other than hydrogen into a compound of the Formula I thus formed (wherein R and R are as stated above and R4 is hydrogen) and if desired convertin~ a compound of the Formula I thus obtained into its salt.
Acccording to a particularly preferred aspect of the invention of Application Serial No. 303,127 there is provided a new process for the prepar-ation of 5 (6) -n-propylthio-benzimidazolyl-2-methyl-~ . 3 1 carbamate (a well-known anthelmintic agent - a compound of the Formula I
wherein R is methoxycarbonyl; R2 is hydrogen and R4 is n-propyl) which com-prises reacting o-phenylene-diamine with an agent capable of introducing a thiocyanato group (SCN); heating the compound of the Formula (XVI) thus obtained (wherein R is hydrogen); reacting the compound of the Formula VII
thus obtained (wherein R is hydrogen) with cyanamide, bromocyane or a com-pound 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 Formula XIV or XV (wherein R5 is methyl); reducing the compound of the Formula VI thus obtained (wherein R is hydrogen; Rl is -COOR and R5 is methyl) and reacting the compound of the Formula I thus obtained (in which R and R are hydrogen; R is -COOR and R5 is hydrogen) with a propylating agent.
Further details of the present invention and the inventions of copending Applications Serial Nos. 303,127 and 370,241 are to be found in the Examples without limiting the scope of our invention to the Examples.
~ - 32 -.~,~
.
E~ample 1 10.3 9 of o-~h~nylene diamine and 1~.2 9 o~ ammonium rho(~artide ar~ di~solved in a mixture o~ 80 ml of n-ethyl alcohol and lO ml of acetic acid and to the mixture cooled at a temperature of 10 C a solution of 6.5 ml of bromine in 20 ml of melhyl alcohol is added while stirring in 30 60 minute~ and the temperature is maintained at 10 C while stirriny until the reaction is finished (5 to 30 minutes).
The fin~l point of the reaction is determined by thinlayer c~romatographic analysis (Layer: Polyram Sil. G., Macherey Nagel Co.: Development with: benzene-ethylacetate-methyl alcoholic ammonium solution 8:1:1. Developer : Iodine)O
The reaction finished the mixture is poured into water and the acid is neutralized by adding a 20 % ammonium hydroxide solution, pH value 7-7.5. The precipitated crystfllline 1,2-diamino-4-thio-cyanato-benzene is filtered.
Weight: 13.2 9 (yield 80 %). Melting point 123 C
(recrystallized from benzene).
Example 2 10.8 g of phenylene diamine and 50 9 of potassium rhodanide are dissolved in1100 ml of methyl alcohol and to the solution at a temperature of 10 C a solùtion of 7.0 ml of bromine in 30 ml of methyl alcohol is added while stirring vigorously in 30-60 minutes. The final point of the reaction is determined by the method set forth in Example 1.
After pouring the mixture into water and ad~usting the pH value1 the product is isolated by extraction with chloroform. After drying and evaporating the solvent 13.5 9 of 1,2-diamino-4-thiocyanato-benzene are~obtained.
Mp. 123 C (from benzene).
2~9 - ;~4 _ Example 3 15.9 9 of brom!ne are added dropwise while stirring into a solution of ;-0 9 of potassium rhodanide in 100 ml of methyl alcohol at a temperature of -10C. The obtained yellowish birhodane solution is added to a solution of 10.8 g of o-ph~nylene diamine in 40 ml of a mixture from acetic acid-methyl alcohol 1:1, while stirring at a temperature of 5-10 C. Processing the reaction mixture as set forth in Example 1 the 1,2-diamino-4-thiocyanato-benzene is obtained~ melting at 123 C.
Example 4 rO a solution of 14.2 g of 4(5)-chloro-o-phenylene diamine and 38 9 of ammonium rhodanide in 120 ml of methyl alc~hol 5 ml of acetic acid are added, whereafter a solution of 7.2 ml of bromine in 20 ml of methyl alcohol is added at a temperature of 15-17 C in 30-60 minutes.
The mixture is diluted with water and after adjustlng the pH value to 8, 1,2-diamino-4-chloro-5-thiocyanato-~ benzene i9 obtained, melting at 108-110 C.
Example 5 To a solution of 13.8 g of 4(5)-methoxy-o-phenylene diamine and 38 g of ammonium rhodanide in 80 ml of methyl alcohol and 15 ml of acetic acid a solution of 6.5 ml of bromine in 20 ml of methyl alcohol is added dropwise within 40-6Q minutes at 8 temperature of 5-10 C. Processing the reaction mixture as set forth in Example 1 the 1,2-diamino-4-methoxy-5-thiocyanato-benzene is obbined.
Mp.: 112-114 C.
Example 6 21.4 g of 4(5)-benzyloxy-o-phenylene diamine and 50 g ll;ZZ2~9 of potassium rhodanide are dissolved in a mixture of 100 ml of methyl alcohol and 20 ml of acetic acid and to the solution obtained a solution of 605 ml of bromine in 30 ml of methyl alcohol is added at a temperature of 5-10 C
in 30-60 minutes. Processing the mixture as set forth in Example 1 the 1,2-diamino-3-benzyloxy-4-thiocyanato-benzene is obtained.
Example 7 To a solution of 1008 g of p-phenylene-diamine and 38 g of ammonium rhodanide 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 stirring at a temperature of 8-10 C, Processing the reaction mixture as set forth in Example 1 the 1,4-diamino-2-thiocyanato-benzene is obtained.
Example 8 In an analogous-manner to the process described in Example 1 to 3, the following compounds are prepared:
1,2-diamino-4-methyl-5-thiocyanato-benzene, mp.: 117 C, 1,2-diamino-4-chloro-5-thiocyanato-benzene; mp.: 108-110 C;
1,2-diamino-4-bromo-5-thiocyanato-benzene, mp.: 9g-100 C;
1,2-diamino-4-fluoro-5-thiocyanato-benzene, mp.: 104-1oB C;
1,2-diamino-4-trifluoromethyl-5-thiocyanato-benzene, mp.:
154-1~6 C;
1,2-diamino-4-n-butyl-5-thiocyanato-benzene, mp.: 109-11 C.
Example 9 22.0 9 of 1,2-diamino-4-thiocyanato-benzene are dissolved in 100 ml. of methyl alcohol and to the solution 100 ml~ of a 25 ~ ammonium hydroxide solution and 1000 ml of water are added. The mixture is l<ept at a temperature ll'~Z2~9 of 80-85 C for 3-4 hours. The final point of the reaction is deterrnined by thinlayer chroma~ographic analysis.
(Layer: Macherey-Nagel Polygram Sil. G. Development with: benzene-ethylacetate - a 1() ~ alcoholic ammonium 5 solution 8 :1 :1. Developer: Iodine ~f U.4~).
The reaction finished, the mixture is cooled, let to stand overnight in a refrigerator and the precipitated product is filtered, washed with water and dried. 16,1 9 of 3,3~,4,4~-tetraamino-diphenyl-disulfide are obtained (Yield 87 ,0), melting point: 161-162 C.
Example 10_ 16.5 9 of 1 ,2-diamino-4-thiocyanato-benzene are dissolved in 20 ml of acetic acid and after addin~ 4 9 of pyridine catalyst the reaction mixture is boiled. The final point of the reaction i5 determined by thinlayer chromatographic analysis (see Example 1). The mixture is poured on 200 9 of ice-water, whereafter is made alkaline by adding a 4 N sodium hydroxide solution (pH value 7.5-8).
After standing for a half hour the product is filtered~
washed with water and dried. 11.1 g (yield 81 ~) of 3,31,4,4~_ tetraamino-diphenyl-disulfide are obtained. Mp. 161-162 C.
Example 11 One proceeds in the same way as in Examples 9 or 10, with the difference, that instead of 1 ,2-diamino-4-thiocyanato-benzene an equivalent amount of a compound of the ~eneral formula XVI is used, wherein R2 represents a methyl-, butyl-, bromine-, chlorine-, fluorine-, trifluoromethyl-, methoxy-, phenoxy- or benzyloxy group .
By this way the following compounds of the general formula VII are prepared:
2,2'-dimethyl-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.:174-175C;
2,2'-dibutyl-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 205-207C;
2,2'-dibromo-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 179-180C;
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.: 172-173C;
2,2'-di(trifluoromethyl)-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 194-196C;
2,2'-dimethoxy-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 190-192C;
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), where-after 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 50 ml of water and 4.2 g of cyanamide are added. ~he mixture is cooled to 10C and 9.4 g of chloro-formic acid methyl ester ,~
ll^~ZZi9
3~3 _ are added dropwise in 3G-45 minutes. The mixture is stirred for a further half hour, then added to a solution of 13.9 ~ of 3,3',4,4~-tetraamino-diphenyl-disulfide in 200 ml of a 75 vol~O alcohol. ~rhe reaction mixture is boiled and the p~l value is maintained between 3-4 by adding some concentrated hydrochlor ic acid at intervals. ~f~er boiling for 90 minutes the mixture is cooled to room temperature and the precipitated product is isolated by Filtration.
19,0 9 of the bis(2-methoxycarbonylamino-benzimidazole-5-yl)-disulfide are obtained. I~elting point: 325C(decomposition).
Exarnples 14 to 22 One proceeds according to the process of the Examples 12 to 13 by using the following o-phenylene diamine derivatives:
2,2'-dimethyl-4,4',5,5'-tetraamino-diphenyl-disulfide, 2,2'-dibutyl-4,4',5,5'-tetraamino-diphenyl-disulfide, 2,2',dibromo-4,4t,5,5'-tetraamino-diphenyl-disulfide,, 2,2'-dichloro-4,4',5,5'-tetraamino-diphenyl-disulfide, 2,2'-difluoro-~,4',5,5l-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'-dibenzyloxy-4,4',5,5'-tetraamino-diphenyl-disulfide, This way the following products were obtained:
bis(2-methoxycarbonyl-amino--6-methyl-benzimidazole-5-yl)--disulfide, mp~: 305-10 C;
bis(2-methoxycarbonyl-amino-6-butyl-benzimidazole-5-yl) -disulfide, mp.: 295-8 C;
bis(2 methoxycarbonyl-amino-6-bromo-benzimidazole-5-yl)--disulfide, mp.: 310 C (d).
1~ 9 bis(2-me~hoxycarbonyl-amino-6-chloro-benzimidazole-5-yl)--disulfide, mp. 305-10~(d).
bis(2-methoxycarbonyl-amino-6-fluoro-benzimidazole-5-yl)--disulfide, mp. 285 8C.
bis(2-methoxycarbonyl amino-6-trifluorolnethyl-benzimidazole--5-yl)-disulfide, mp: above 340 C.
bi~(2-methoxycarbonyl-amino-6-methoxy-benzimidazole-5-yl)--disulfide, Mp.: 29~-300~(b).
bis(2-methoxycarbonyl-amino-6-phenoxy-benzimidazole-5-yl)--disulfide bis~2-methoxycarbonyl-amino-6-benzyloxy-benzimidazole~5-yl)--disulfide.
Example 23 .
2~78 9 of 3,3',4,4'-tetraamino-diphenyl-disulfide are dissolved in 70 ml of alcohol and to the solution 2.12 9 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 dissolved in water and made alkaline with sodium hydroxide. 3.0 g (90 %) of the bis(2-a~ino-benzimidazole-5-yl-disulfide are obtained, melting at 245 C by decomposition.
Example 24 2.78 g of 3,3',4,4'-tetraamino-diphenyl-disulfide are dissolved in 1.7 ml. of a 37 % hydrochloric acid and a solution ~5 of 0.92 9 of cyanamide in 1 ml of water is added dropwise.
The reaction mixture is kept for 60 minutes at a temperature of 100 C. 0.9 9 of sodium hydroxide are added in the form of a 40 % solution, until the ammonia evolution has ceased the mixture is heated at a temperature of 100 C. After cooling the bis(2-amino-benzimidazole-5-yl)-disulfide is ll;ZZ~:l9 precipitated. Wei.ght: 2.70 3 (81 ~). ~lelting point:
245 C (decomposition).
Examples 25 ~o 33 One proceeds according to the process of the Examples 23 or 2~, using the following o-phenylene-diamine derivatives:
2,2~-dimethyl-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2~-dibuthyl-4,4',5,5S-tetraamino-diphenyl-disulfide;
2,2J-dibromo-4,41,5,5~-tetraamino-diphenyl-disulfide;
2,2'-diLhloro-4,4l,5,5'-tetraamino-diphenyl-disulfide;
2,2~-difluoro-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2~-di(trifluoromethyl)-~ ,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~-diphenyloxy-4,4',5,5~-tetraamino-diphenyl-disulfide~.
This was the following products are obtained:
bis(2-amino-6-methyl-benzimidazole-5-yl)-disulfide;
bis(2-amino-6-buthyl-benzimidazole-5-yl)-disulfide;
2~ 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)-di-sulfide;
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.
Example 34 3.32 ~ of bis(2-amino-benzimidazole-5-yl)-disulfide are dissolved in 300 ml of pyridine and 2.0 g chloro-llZZ2:~9 formic acid methylester are added while cooling. The mixture is allowed to stand overni~ht, whereafter it is heated on a hot water-bath for 90-120 minutes. The pyridine is distilled of in vacuo and water is poured on the residue 5 and the precipitated crystals are filtered t washed and dried.
3.4 9 of the bist2-methoxy-carbonyl-amino-benzimidazole-6-yl)disulfide are obtained. Yield 78 ~6. Melting point:
325 C tdecomposition).
Example 35 3.32 9 of bis(2-amino-benzimidazole-5-yl)-disulfide are dissolved in 3b rnl of methyl alcohol and to the solution 1.80 g dimethyl carbonate and 0.46 9 of metallic sodium dissolved in 30 ml of methyl alcohol are added. The mixture is boiled for 1 hour. Thereafter the reaction mixture is acidified with acetic acid ~pH value between 5.5-6) and the precipitated bis(2-methoxycarbonyl-amino-benzimidazole-5-yl)-disulfide is filtered off. Weight:
19,0 9 of the bis(2-methoxycarbonylamino-benzimidazole-5-yl)-disulfide are obtained. I~elting point: 325C(decomposition).
Exarnples 14 to 22 One proceeds according to the process of the Examples 12 to 13 by using the following o-phenylene diamine derivatives:
2,2'-dimethyl-4,4',5,5'-tetraamino-diphenyl-disulfide, 2,2'-dibutyl-4,4',5,5'-tetraamino-diphenyl-disulfide, 2,2',dibromo-4,4t,5,5'-tetraamino-diphenyl-disulfide,, 2,2'-dichloro-4,4',5,5'-tetraamino-diphenyl-disulfide, 2,2'-difluoro-~,4',5,5l-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'-dibenzyloxy-4,4',5,5'-tetraamino-diphenyl-disulfide, This way the following products were obtained:
bis(2-methoxycarbonyl-amino--6-methyl-benzimidazole-5-yl)--disulfide, mp~: 305-10 C;
bis(2-methoxycarbonyl-amino-6-butyl-benzimidazole-5-yl) -disulfide, mp.: 295-8 C;
bis(2 methoxycarbonyl-amino-6-bromo-benzimidazole-5-yl)--disulfide, mp.: 310 C (d).
1~ 9 bis(2-me~hoxycarbonyl-amino-6-chloro-benzimidazole-5-yl)--disulfide, mp. 305-10~(d).
bis(2-methoxycarbonyl-amino-6-fluoro-benzimidazole-5-yl)--disulfide, mp. 285 8C.
bis(2-methoxycarbonyl amino-6-trifluorolnethyl-benzimidazole--5-yl)-disulfide, mp: above 340 C.
bi~(2-methoxycarbonyl-amino-6-methoxy-benzimidazole-5-yl)--disulfide, Mp.: 29~-300~(b).
bis(2-methoxycarbonyl-amino-6-phenoxy-benzimidazole-5-yl)--disulfide bis~2-methoxycarbonyl-amino-6-benzyloxy-benzimidazole~5-yl)--disulfide.
Example 23 .
2~78 9 of 3,3',4,4'-tetraamino-diphenyl-disulfide are dissolved in 70 ml of alcohol and to the solution 2.12 9 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 dissolved in water and made alkaline with sodium hydroxide. 3.0 g (90 %) of the bis(2-a~ino-benzimidazole-5-yl-disulfide are obtained, melting at 245 C by decomposition.
Example 24 2.78 g of 3,3',4,4'-tetraamino-diphenyl-disulfide are dissolved in 1.7 ml. of a 37 % hydrochloric acid and a solution ~5 of 0.92 9 of cyanamide in 1 ml of water is added dropwise.
The reaction mixture is kept for 60 minutes at a temperature of 100 C. 0.9 9 of sodium hydroxide are added in the form of a 40 % solution, until the ammonia evolution has ceased the mixture is heated at a temperature of 100 C. After cooling the bis(2-amino-benzimidazole-5-yl)-disulfide is ll;ZZ~:l9 precipitated. Wei.ght: 2.70 3 (81 ~). ~lelting point:
245 C (decomposition).
Examples 25 ~o 33 One proceeds according to the process of the Examples 23 or 2~, using the following o-phenylene-diamine derivatives:
2,2~-dimethyl-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2~-dibuthyl-4,4',5,5S-tetraamino-diphenyl-disulfide;
2,2J-dibromo-4,41,5,5~-tetraamino-diphenyl-disulfide;
2,2'-diLhloro-4,4l,5,5'-tetraamino-diphenyl-disulfide;
2,2~-difluoro-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2~-di(trifluoromethyl)-~ ,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~-diphenyloxy-4,4',5,5~-tetraamino-diphenyl-disulfide~.
This was the following products are obtained:
bis(2-amino-6-methyl-benzimidazole-5-yl)-disulfide;
bis(2-amino-6-buthyl-benzimidazole-5-yl)-disulfide;
2~ 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)-di-sulfide;
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.
Example 34 3.32 ~ of bis(2-amino-benzimidazole-5-yl)-disulfide are dissolved in 300 ml of pyridine and 2.0 g chloro-llZZ2:~9 formic acid methylester are added while cooling. The mixture is allowed to stand overni~ht, whereafter it is heated on a hot water-bath for 90-120 minutes. The pyridine is distilled of in vacuo and water is poured on the residue 5 and the precipitated crystals are filtered t washed and dried.
3.4 9 of the bist2-methoxy-carbonyl-amino-benzimidazole-6-yl)disulfide are obtained. Yield 78 ~6. Melting point:
325 C tdecomposition).
Example 35 3.32 9 of bis(2-amino-benzimidazole-5-yl)-disulfide are dissolved in 3b rnl of methyl alcohol and to the solution 1.80 g dimethyl carbonate and 0.46 9 of metallic sodium dissolved in 30 ml of methyl alcohol are added. The mixture is boiled for 1 hour. Thereafter the reaction mixture is acidified with acetic acid ~pH value between 5.5-6) and the precipitated bis(2-methoxycarbonyl-amino-benzimidazole-5-yl)-disulfide is filtered off. Weight:
4.1 g (92.5 %). Melting point 325 C (decomposition).
Example 36 to A4 One proceeds according to the process of Examples 34 or 35 using the following bis(2-amino-benzimidazole-5-yl)-disulfide derivatives:
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;
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~
ll'ZZ219 bis(2-amino-6-benzyloxy-benzimidazole-5-yl~-disulfidep This way the following products were obtained:
bis(2-methoxycarbonyl-amino-6-methyl-benzimidazole-5-yl)-disulfide;
bis(2-methoxycarbonyl-amino-6-buthyl-benzimidazole-5-yl)-disulfide;
bis(2-methoxycarbonyl-amino-6-bromo-benzimidazole-5-yl)-disulfide;
bis(2-methoxycarbonyl-amino-6-chloro-benzimidazole-5-yl)-disulfide;bis(2-methoxycarbonyl-amino-6-fluoro-benzimidazole-5-yl)-disulfide;
bis(2-methoxycarbonyl-amino-6-trilfuoromethyl-benzimidazole-
Example 36 to A4 One proceeds according to the process of Examples 34 or 35 using the following bis(2-amino-benzimidazole-5-yl)-disulfide derivatives:
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;
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~
ll'ZZ219 bis(2-amino-6-benzyloxy-benzimidazole-5-yl~-disulfidep This way the following products were obtained:
bis(2-methoxycarbonyl-amino-6-methyl-benzimidazole-5-yl)-disulfide;
bis(2-methoxycarbonyl-amino-6-buthyl-benzimidazole-5-yl)-disulfide;
bis(2-methoxycarbonyl-amino-6-bromo-benzimidazole-5-yl)-disulfide;
bis(2-methoxycarbonyl-amino-6-chloro-benzimidazole-5-yl)-disulfide;bis(2-methoxycarbonyl-amino-6-fluoro-benzimidazole-5-yl)-disulfide;
bis(2-methoxycarbonyl-amino-6-trilfuoromethyl-benzimidazole-
5-yl)-disulfide;
bis(2-methoxycarbonyl-amino-6-methoxy-benzimidazole-5-yl) disulfide;
bis(2-methoxycarbonyl-amino-6-phenoxy-benzimidazole-5-yl)-disulfide;
bls~2-methoxycarbanyl-amino-6-benzyloxy-benzimidazole-5-yl)-disulfide~
Example 45 44.4 g of 2-(methoxycarbonyl-amino)-benzimidazole-5(6)-yl-disulfide are dissolved in 800 ml of hexamethyl-phosphoric acid triam~'de 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 C0 After addition of the first parts of .the reducing agent the faint yellowish colour of the solution becomes bronnO
After 2 hours a solution of 24.6 g of propylbromide ~0 in 600 ml of anhydrous alcohol is added and the reaction llZZ219 mixture is stirred in a nitrogen atmosphere for further 3 hours at room temperature. Thereafter the mixture is diluted with 1 lit. of water and the precipitated product is filtered, washed with water and recrystallized from n-propanol. 40.7 g (77 ~) of the 5(6)-propylthio-benzimidazolyl-2-methyl-carbamate are obtained. Melting point: 214-215 C.
Example 46 4.4 g of 2-~methoxycarbonyl-amino~-benzimidazole-5(6)-yl-disulfide are dissolved in 60 ml of hot dimethylformamide, whereafter the solution is cooled to room temperature and in a nitrogen atmosphere, while stirring vigorously 0.8 g of sodium borohydride are added in portions in 30 minutes.
The stirring and introduction of nitrogen is continued for further 90 minutes, whereafter 2.5 g of propylbromide dissolved in 50 ml of alcohol are added to the reacti~
mixture. The mixture is stirred for further 3 hours at room temperature and is diluted with 120 ml of water. The precipitated product is filtered, washed thoroughly with water and dried. 4.9 9 of the 5t6)-propylthio-benzimidazolyl-2-methyl-carbamate are obtained. Yield: 92.5 56- melting point 208-211 C. After recrystallization from n-propanol the product ~nelts at 215 C.
Example _7 One proceeds according to Examples ~5 or 46, but t;~nstead of n-propylbromide) allylbromide, propargylbromide, benzylchloride, 4-nitro-fluorobenzene and 2,4-dinitro-chloro-benzene are used. This way the following compounds are obtained: -5~6)-allylthio-benzimidazolyl-2-methylcarbamate;
~; t llZZZ~9 5(6)-propin-2-ylthio-benzimidazolyl-2-methylcarbamate;
5(6)-benzylthio-benzimidazolyl-2-methylcarbamate;
5(6)-(4-nitrophenylthio)-benzimidazolyl-2-methylcarbamate;
5(6~-(2,4-dinitrophenylthio)-benzimidazolyl-2-methylcarbamate.
Example 48 4.4 g of 2-(methoxycarbonyl-amino)-benzimidazol-5(6)-yl-disulfide are suspended in 30 ml. of methyl alcohol and a solution of 1.12 g of potassium hydroxide in 15 ml of methyl alcohol is added. To the solution thus obtained, while continuously stirring, in a nitrogen atmosphere 2~5 9 of propylbromide, thereafter 0.6 of sodium borohydride are added in 30 minutes at a temperature of 25 C in portionsO
The mixture is stirred for further 3 hours, whereafter is diluted with 50 ml of water. After standing the precipitated product is filtered, washed and dried, 3 9 (57 ~) of the crude 5(6)-propylthio-benzimidazolyl-2-methyl-carbamate are obtained. Melting point after recrystallisation from n-propanol is214-215 C. The product obtained is identic with that obtained in Examples 45 and 46.
~!e~:~
4.4 9 of 2-(methoxycarbonyl-amino)-benzimidazol-5(6)-yl-disulfide are suspended in 30 ml of methyl alcohol, and a hot solution of 1.12 9 of potassium hydroxide in 15 ml of methyl alc~hol is added in nitrogen atmosphere. To the sol~tion obtained oO8 9 of sodium borohydride are added at room temperature in 30-40 minutes. After stirring for 30 minutes 1.2 mI of acetic acid, then a solution of 2.5 9 propylbromide in 1~ ml of methyl alcohol is added to the reaction mixture. Stirring is continued for further 2 30 hours. Thereafter the mixture is diluted with 50 ml of 1 1 2Z2~9 water, and after standing for a while the precipitated product is filtered, washed and driedO 3.9 g of the 5(6)-propylthio-benzimidazolyl-2-methylcaroamate is obtained.
Ivlelting point 211-Z13 C, yield 53 ~.
Example 50 2.2 0 of 2-(methoxycarbonyl-amino)-benzimidazol-5(6)-yl-disulfide are suspended in 20 ml of alcohol and 1.2 ml of triethylamine, then 008 g of 2-mercapto-ethanol are added. The reaction mixture is stirred for 5 hours. There-after a solution of o.56 g of potassium hydroxide in 10 ml of anhydrous alcohol and 1.3 9 of propylbromide are added O
Stirring is continued for fu~ther 2-3 hours at room temperature. Finally the mixture is diluted with 30 ml of water and the precipitated product is filtered, washed and dried. 1.~ 9 (53 ~) of the 5(6)-propylthio-benzimidazolyl-2-methylcarbamate are obtained. Melting point: 211-213 C.
Example 51 4.4 g of 2-(methoxycarbonyl-amino)-benzimidazol-5(6)-yl-disulfide are suspended in 100 ml of hot alcohol and to the suspension a solution of 1.12 g potassium hydroxide in 15 ml of water is added, then a solution of 12 g of crystalline sodium sulfide in '15 ml of water is added in portions in a nitrogen atmosphere, in 30-45 minutes. There-after a phenyl-diazonium-chloride solution prepared from 1.9 g of aniline and buffered with sodium acetate is added to the hot reaction mixture in 10-15 minutes. ~ vigorous foaming begins, which ceases 15-20 minutes after dosage.
The pH value of the mixture is adjusted to 6.5 and the precipitated product is filtered, washed and dried. 3.3 g -` ~ llZ2Zi9 qfj _ (60 %) of the 5(6)-phenylthio-benzimidazolyl-2-methy carbamate are obtained. Melting point: 243 C (de-composing).
Ex_~ple 52 2~2 g of 2-(methoxycarbonyl-amino)-benlzimidazol-5(6)-yl-disulfide are dissolved in 60 ml of hot acetic acid and in a nitrogen atmosphere 0.8 g of zinc dust is added in portions. After complete dissolving of thez zinc the reactlon mixture is evaporated to dryness in vacuo and is stirred in nitrogen atmosphere for 1 hour with an alcohdic potassium hydroxide solution. The reaction mixture is filtered and to the alcoholic solution 1.3 9 of propylbromlde are added. The reaction mixture is let to stand for 2 hours at room temperature, whereafter it ~s diluted with water and the precipitated product is filtered, washed and dried.
1.8 9 (68 %) of the S(6)-propylthio-benzimidazolyl-2-meth~l-carbamste are obtained, melting at 211-214 C.
Example ~3 2.2 9 of Z-(methoxycarbonyl-amino)-benzimidazol-5(6)-yl-di9ulfide sre dissolved in 40 ml of alcohol containing 0.6 g of potassium hydroxide and to the hot ~olution a solution of ~.0 g of glucose in 15 ml of weter is added ln 60 minutes. The reaction mixture i9 boiled vigorou81y for further 45 minutes, whereafter it i5 ~iltered by a pressure-filter ~n a nitrogen atmosphere. The alcoholic solutionls cooled to room temperature and 1.3 g of propylbromide are added. ~fter 3 hours the reaction mixture is diluted with water, the precipitated product is filtered, washed and dried. 1.6 g (60 %) of the St6)-propylthio-benzimidazolyl-2-methylcarbamate are obtained. Melting point: 210-2~3 C.
f 11222~9 Example 54 2.2 g of 2-(methoxycarbonyl-arl1ino)-benzimida2ol-5(6)-yl-disulfide are suspended in ethyl alcohol containing 1.6 g of potassium hydroxide and 2 9 of amino-imino-methane-sulfinic acid and 1 drop of an alcoholic cet~y-pyridinium-bromide solution (or hexadecyl-tributyl-phosphonium-chloride are added. The reaction mixture is boiled in nitrogen at-mosphere for 2-3 hours, ~hereafter it is cooled ~ room temperature and 1.3 9 of propylbromide are added. After 3 hours the reaction mixture is diluted with 40 ml of water and the pH value is adjusted to 6, the precipitated product is filtered, washed and dried. 2.1 ~ (79 %) of the 5(6)-propylthio-benzlm~dazolyl-2-methylcarbamate are obtained.
Melting point: 210-212 C.
Examples 55 to 66 In an analogous manner to Examples 45 to 54 by usin~
the following starting materials the following compounds of the Formula I are prepared (R1 is always methoxycarbonyl):
Ex~le_ _ _ _R2 R4 Mp C
56 fluorine n-propyl 252-Z53 56 chlorine n-propyl 266-269 57 chlorine benzyl 234-236 68 chlorine allyl 203-205 59 chlorine propinyl 305-307 chlorine ethyl 237-238 61 chlorine cyclohexyl 294-295 62 bromine n-propyl 191-193 63 methyl n-propyl 230-232 (d) 64 methoxy n-propyl 296-298 butyl n-propyl 202-204 66 _ trifluoro~ethyl n-propyl 252
bis(2-methoxycarbonyl-amino-6-methoxy-benzimidazole-5-yl) disulfide;
bis(2-methoxycarbonyl-amino-6-phenoxy-benzimidazole-5-yl)-disulfide;
bls~2-methoxycarbanyl-amino-6-benzyloxy-benzimidazole-5-yl)-disulfide~
Example 45 44.4 g of 2-(methoxycarbonyl-amino)-benzimidazole-5(6)-yl-disulfide are dissolved in 800 ml of hexamethyl-phosphoric acid triam~'de 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 C0 After addition of the first parts of .the reducing agent the faint yellowish colour of the solution becomes bronnO
After 2 hours a solution of 24.6 g of propylbromide ~0 in 600 ml of anhydrous alcohol is added and the reaction llZZ219 mixture is stirred in a nitrogen atmosphere for further 3 hours at room temperature. Thereafter the mixture is diluted with 1 lit. of water and the precipitated product is filtered, washed with water and recrystallized from n-propanol. 40.7 g (77 ~) of the 5(6)-propylthio-benzimidazolyl-2-methyl-carbamate are obtained. Melting point: 214-215 C.
Example 46 4.4 g of 2-~methoxycarbonyl-amino~-benzimidazole-5(6)-yl-disulfide are dissolved in 60 ml of hot dimethylformamide, whereafter the solution is cooled to room temperature and in a nitrogen atmosphere, while stirring vigorously 0.8 g of sodium borohydride are added in portions in 30 minutes.
The stirring and introduction of nitrogen is continued for further 90 minutes, whereafter 2.5 g of propylbromide dissolved in 50 ml of alcohol are added to the reacti~
mixture. The mixture is stirred for further 3 hours at room temperature and is diluted with 120 ml of water. The precipitated product is filtered, washed thoroughly with water and dried. 4.9 9 of the 5t6)-propylthio-benzimidazolyl-2-methyl-carbamate are obtained. Yield: 92.5 56- melting point 208-211 C. After recrystallization from n-propanol the product ~nelts at 215 C.
Example _7 One proceeds according to Examples ~5 or 46, but t;~nstead of n-propylbromide) allylbromide, propargylbromide, benzylchloride, 4-nitro-fluorobenzene and 2,4-dinitro-chloro-benzene are used. This way the following compounds are obtained: -5~6)-allylthio-benzimidazolyl-2-methylcarbamate;
~; t llZZZ~9 5(6)-propin-2-ylthio-benzimidazolyl-2-methylcarbamate;
5(6)-benzylthio-benzimidazolyl-2-methylcarbamate;
5(6)-(4-nitrophenylthio)-benzimidazolyl-2-methylcarbamate;
5(6~-(2,4-dinitrophenylthio)-benzimidazolyl-2-methylcarbamate.
Example 48 4.4 g of 2-(methoxycarbonyl-amino)-benzimidazol-5(6)-yl-disulfide are suspended in 30 ml. of methyl alcohol and a solution of 1.12 g of potassium hydroxide in 15 ml of methyl alcohol is added. To the solution thus obtained, while continuously stirring, in a nitrogen atmosphere 2~5 9 of propylbromide, thereafter 0.6 of sodium borohydride are added in 30 minutes at a temperature of 25 C in portionsO
The mixture is stirred for further 3 hours, whereafter is diluted with 50 ml of water. After standing the precipitated product is filtered, washed and dried, 3 9 (57 ~) of the crude 5(6)-propylthio-benzimidazolyl-2-methyl-carbamate are obtained. Melting point after recrystallisation from n-propanol is214-215 C. The product obtained is identic with that obtained in Examples 45 and 46.
~!e~:~
4.4 9 of 2-(methoxycarbonyl-amino)-benzimidazol-5(6)-yl-disulfide are suspended in 30 ml of methyl alcohol, and a hot solution of 1.12 9 of potassium hydroxide in 15 ml of methyl alc~hol is added in nitrogen atmosphere. To the sol~tion obtained oO8 9 of sodium borohydride are added at room temperature in 30-40 minutes. After stirring for 30 minutes 1.2 mI of acetic acid, then a solution of 2.5 9 propylbromide in 1~ ml of methyl alcohol is added to the reaction mixture. Stirring is continued for further 2 30 hours. Thereafter the mixture is diluted with 50 ml of 1 1 2Z2~9 water, and after standing for a while the precipitated product is filtered, washed and driedO 3.9 g of the 5(6)-propylthio-benzimidazolyl-2-methylcaroamate is obtained.
Ivlelting point 211-Z13 C, yield 53 ~.
Example 50 2.2 0 of 2-(methoxycarbonyl-amino)-benzimidazol-5(6)-yl-disulfide are suspended in 20 ml of alcohol and 1.2 ml of triethylamine, then 008 g of 2-mercapto-ethanol are added. The reaction mixture is stirred for 5 hours. There-after a solution of o.56 g of potassium hydroxide in 10 ml of anhydrous alcohol and 1.3 9 of propylbromide are added O
Stirring is continued for fu~ther 2-3 hours at room temperature. Finally the mixture is diluted with 30 ml of water and the precipitated product is filtered, washed and dried. 1.~ 9 (53 ~) of the 5(6)-propylthio-benzimidazolyl-2-methylcarbamate are obtained. Melting point: 211-213 C.
Example 51 4.4 g of 2-(methoxycarbonyl-amino)-benzimidazol-5(6)-yl-disulfide are suspended in 100 ml of hot alcohol and to the suspension a solution of 1.12 g potassium hydroxide in 15 ml of water is added, then a solution of 12 g of crystalline sodium sulfide in '15 ml of water is added in portions in a nitrogen atmosphere, in 30-45 minutes. There-after a phenyl-diazonium-chloride solution prepared from 1.9 g of aniline and buffered with sodium acetate is added to the hot reaction mixture in 10-15 minutes. ~ vigorous foaming begins, which ceases 15-20 minutes after dosage.
The pH value of the mixture is adjusted to 6.5 and the precipitated product is filtered, washed and dried. 3.3 g -` ~ llZ2Zi9 qfj _ (60 %) of the 5(6)-phenylthio-benzimidazolyl-2-methy carbamate are obtained. Melting point: 243 C (de-composing).
Ex_~ple 52 2~2 g of 2-(methoxycarbonyl-amino)-benlzimidazol-5(6)-yl-disulfide are dissolved in 60 ml of hot acetic acid and in a nitrogen atmosphere 0.8 g of zinc dust is added in portions. After complete dissolving of thez zinc the reactlon mixture is evaporated to dryness in vacuo and is stirred in nitrogen atmosphere for 1 hour with an alcohdic potassium hydroxide solution. The reaction mixture is filtered and to the alcoholic solution 1.3 9 of propylbromlde are added. The reaction mixture is let to stand for 2 hours at room temperature, whereafter it ~s diluted with water and the precipitated product is filtered, washed and dried.
1.8 9 (68 %) of the S(6)-propylthio-benzimidazolyl-2-meth~l-carbamste are obtained, melting at 211-214 C.
Example ~3 2.2 9 of Z-(methoxycarbonyl-amino)-benzimidazol-5(6)-yl-di9ulfide sre dissolved in 40 ml of alcohol containing 0.6 g of potassium hydroxide and to the hot ~olution a solution of ~.0 g of glucose in 15 ml of weter is added ln 60 minutes. The reaction mixture i9 boiled vigorou81y for further 45 minutes, whereafter it i5 ~iltered by a pressure-filter ~n a nitrogen atmosphere. The alcoholic solutionls cooled to room temperature and 1.3 g of propylbromide are added. ~fter 3 hours the reaction mixture is diluted with water, the precipitated product is filtered, washed and dried. 1.6 g (60 %) of the St6)-propylthio-benzimidazolyl-2-methylcarbamate are obtained. Melting point: 210-2~3 C.
f 11222~9 Example 54 2.2 g of 2-(methoxycarbonyl-arl1ino)-benzimida2ol-5(6)-yl-disulfide are suspended in ethyl alcohol containing 1.6 g of potassium hydroxide and 2 9 of amino-imino-methane-sulfinic acid and 1 drop of an alcoholic cet~y-pyridinium-bromide solution (or hexadecyl-tributyl-phosphonium-chloride are added. The reaction mixture is boiled in nitrogen at-mosphere for 2-3 hours, ~hereafter it is cooled ~ room temperature and 1.3 9 of propylbromide are added. After 3 hours the reaction mixture is diluted with 40 ml of water and the pH value is adjusted to 6, the precipitated product is filtered, washed and dried. 2.1 ~ (79 %) of the 5(6)-propylthio-benzlm~dazolyl-2-methylcarbamate are obtained.
Melting point: 210-212 C.
Examples 55 to 66 In an analogous manner to Examples 45 to 54 by usin~
the following starting materials the following compounds of the Formula I are prepared (R1 is always methoxycarbonyl):
Ex~le_ _ _ _R2 R4 Mp C
56 fluorine n-propyl 252-Z53 56 chlorine n-propyl 266-269 57 chlorine benzyl 234-236 68 chlorine allyl 203-205 59 chlorine propinyl 305-307 chlorine ethyl 237-238 61 chlorine cyclohexyl 294-295 62 bromine n-propyl 191-193 63 methyl n-propyl 230-232 (d) 64 methoxy n-propyl 296-298 butyl n-propyl 202-204 66 _ trifluoro~ethyl n-propyl 252
Claims (59)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of formula VI
VI
wherein R1 is hydrogen or a group of formula -COOR5 in which R5 is C1-4 alkyl; R2 is hydrogen, halogen, C1-6 alkyl, trifluoro-methyl or a group of formula -OR3 in which R3 is C1-4 alkyl, aryl or aralkyl; or a salt thereof, which process comprises:
(a) to prepare a compound of formula VI in which R1 is hydrogen, reacting a compound of formula VII
VII
wherein R2 is as defined above, with cyanamide or bromocyane;
(b) to prepare a compound of formula VI in which R1 is a -COOR5 group in which R5 is as defined above, reacting a compound of formula VII with a compound of formula XII
XII
or of formula XIII
wherein R5 is as defined above; or (c) to prepare a compound of formula VI in which R1 is a -COOR5 group, reacting a compound of formula VI in which R1 is hydrogen with an agent for introducing a group -COOR5 into the compound of formula VI
and, if required, converting a compound of formula VI into a salt or freeing a compound of formula VI from a salt.
VI
wherein R1 is hydrogen or a group of formula -COOR5 in which R5 is C1-4 alkyl; R2 is hydrogen, halogen, C1-6 alkyl, trifluoro-methyl or a group of formula -OR3 in which R3 is C1-4 alkyl, aryl or aralkyl; or a salt thereof, which process comprises:
(a) to prepare a compound of formula VI in which R1 is hydrogen, reacting a compound of formula VII
VII
wherein R2 is as defined above, with cyanamide or bromocyane;
(b) to prepare a compound of formula VI in which R1 is a -COOR5 group in which R5 is as defined above, reacting a compound of formula VII with a compound of formula XII
XII
or of formula XIII
wherein R5 is as defined above; or (c) to prepare a compound of formula VI in which R1 is a -COOR5 group, reacting a compound of formula VI in which R1 is hydrogen with an agent for introducing a group -COOR5 into the compound of formula VI
and, if required, converting a compound of formula VI into a salt or freeing a compound of formula VI from a salt.
2. A process according to claim 1 wherein process (c) is used and the starting material of formula VI in which R1 is hydrogen is obtained by process (a).
3. A process according to claim 1 or 2 wherein process (c) is used and the agent for introducing the group -COOR5 is a compound of formula XIV
a compound of formula XV
(R5O)2CO XV
or a compound of formula VIII
a compound of formula XV
(R5O)2CO XV
or a compound of formula VIII
4. A process according to claim 1 or 2 wherein process (c) is used and the compound of formula VI in which R1 is hydrogen is reacted with a compound of formula XIV in the presence of an organic solvent.
5. A process according to claim 1 or 2 wherein process (c) is used and the compound of formula VI in which R1 is hydrogen is reacted with a compound of formula XIV in the presence of pyridine at a temperature in the range of from 0 to 100°C or in a lower alkanol at a temperature in the range of from 0 to 40°C.
6. A process according to claim 1 or 2 wherein process (c) is used and the compound of formula VI in which R1 is hydrogen is reacted with a dialkyl carbonate of formula XV in the presence of an alkali alcoholate and an alcohol containing the same alkyl group as is present in the dialkyl carbonate, and the reaction is carried out at a temperature in the range of from 20 to 120°C.
7. A process according to claim 1 or 2 wherein process (c) is used and the compound of formula VI in which R1 is hydrogen is reacted with a compound of formula XIV in the presence of pyridine at a temperature in the range of from 0 to 100°C
or in a lower alkanol at a temperature in the range of from 0 to 40°C and the reaction is carried out at the boiling point of the alcohol.
or in a lower alkanol at a temperature in the range of from 0 to 40°C and the reaction is carried out at the boiling point of the alcohol.
8. A process according to claim 1 wherein process (a) is used and the compound of formula VII is reacted with cyanamide in an aqueous medium in the presence of a mineral acid and the product is isolated by treating the reaction mixture with an inorganic base.
9. A process according to claim 1 wherein process (a) is used and the compound of formula VII is reacted with bromocyane in a lower alkanol and the product is isolated by treating the reaction mixture with an inorganic base.
10. A process according to claim 8 or 9 wherein the inorganic base is sodium or potassium hydroxide or sodium or potassium carbonate.
11. A process according to claim 1 wherein process (b) is used and a compound of formula VII is reacted with a compound of formula XII in the presence of water or an organic solvent or a mixture of water and an organic solvent.
12. A process according to claim 11 wherein the reaction is carried out in aqueous ethanol at a pH in the range of from 3 to 6 and in the presence of acetic acid.
13. A process according to claim 1 wherein process (b) is used and a compound of formula VII is reacted with a compound of formula XII in the presence of water or a water miscible organic solvent or a mixture thereof, at a temperature between 20°C and the reflux temperature of the reaction mixture.
14. A process according to claim 1 wherein R2 is hydrogen and R5 is methyl.
15. A process according to claim 1 wherein R1 is hydrogen or methoxycarbonyl and R2 is hydrogen, chlorine, bromine, fluorine, trifluoromethyl, methyl, butyl or -OR3 wherein R3 is methyl, phenyl or benzyl.
16. Compounds of formula VI as defined in claim 1 and salts thereof when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.
17. A process according to claim 1 wherein R1 and R2 are both hydrogen.
18. A process according to claim 1 wherein the starting material of formula VII is obtained by heating a compound of formula XVI
XVI
wherein R2 is as defined in claim 1.
XVI
wherein R2 is as defined in claim 1.
19. A process for preparing bis-(2-amino-benzimidazol-5-yl)-disulfide which comprises reacting 3,3',4,4'-tetraamino-diphenyl-disulfide with bromocyane or cyanamide.
20. The compound bis-(2-amino-benzimidazol-5-yl)-disulfide when prepared by a process according to claim 19 or an obvious chemical equivalent thereof.
21. A process according to claim 1 or 2 wherein process (c) is used and the agent for introducing the group -COOR5 is a compound of formula V
formed in situ by reaction between cyanamide and a chloroformic acid ester of formula ClCOOR5 in the presence of sodium hydroxide.
formed in situ by reaction between cyanamide and a chloroformic acid ester of formula ClCOOR5 in the presence of sodium hydroxide.
22. A process according to claim 1 wherein R1 is a methoxycarbonyl group.
23. A process according to claim 22 wherein R2 is a methyl group.
24. A process according to claim 22 wherein R2 is a butyl group.
25. A process according to claim 22 wherein R2 is a bromine atom.
26. A process according to claim 22 wherein R2 is a chlorine atom.
27. A process according to claim 22 wherein R2 is a fluorine atom.
28. A process according to claim 22 wherein R2 is a trifluoromethyl group.
29. A process according to claim 22 wherein R2 is a methoxy group.
30. A process for preparing bis(2-methoxycarbonyl-amino-6-methyl-benz-imidazole-5-yl)-disulfide which comprises reacting 2,2'-dimethyl-4,4',5,5'-tetraamino-diphenyl-disulfide with S-methyl-isothiourea diurethane.
31. A process for preparing bis(2-methoxycarbonyl-amino-6-methyl-benz-imidazole-5-yl)-disulfide which comprises reacting 2,2'-dimethyl-4,4',5,5'-tetraamino-diphenyl-disulfide with the product formed by reaction between cyanamide, chloroformic acid methyl ester and sodium hydroxide.
32. The compound bis(2-methoxycarbonyl-amino-6-methyl-benzimidazole-5-yl)-disulfide when prepared by a process according to claim 30 or 31 or an obvious chemical equivalent thereof.
33. A process for preparing bis(2-methoxycarbonyl-amino-6-butyl-benz-imidazole-5-yl)-disulfide which comprises reacting 2,2'-dibutyl-4,4',5,5'-tetraamino-diphenyl-disulfide with S-methyl-isothiourea diurethane.
34. A process for preparing bis(2-methoxycarbonyl-amino-6-butyl-benzimidazole-5-yl)-disulfide which comprises reacting 2,2'-dibutyl-4,4',5,5'-tetraamino-diphenyl-disulfide with the product formed by reaction between cyanamide, chloroformic acid methyl ester and sodium hydroxide.
35. The compound bis(2-methoxycarbonyl-amino-6-butyl-benzimidazole-5-yl)-disulfide when prepared by a process according to claim 33 or 34 or an obvious chemical equivalent thereof.
36. A process for preparing bis(2-methoxycarbonyl-amino-6-bromo-benzimidazole-5-yl)-disulfide which comprises reacting 2,2'-dibromo-4,4',5,5'-tetraamino-diphenyl-disulfide with S-methyl-isothiourea diurethane.
37. A process for preparing bis(2-methoxycarbonyl-amino-6-bromo-benzimidazole-5-yl)-disulfide which comprises reacting 2,2'-dibromo-4,4',5,5'-tetraamino-diphenyl-disulfide with the product formed by reaction between cyanamide, chloroformic acid methyl ester and sodium hydroxide.
38. The compound bis(2-methoxycarbonyl-amino-6-bromo-benzimidazole-5-yl)-disulfide when prepared by a process according to claim 36 or 37 or an obvious chemical equivalent thereof.
39. A process for preparing bis(2-methoxycarbonyl-amino-6-chloro-benzimidazole-5-yl)-disulfide which comprises reacting 2,2'-dichloro-4,4',5, 5'-tetraamino-diphenyl-disulfide with S-methyl-isothiourea diurethane.
40. A process for preparing bis(2-methoxycarbonyl-amino-6-chloro-benzimidazole-5-yl)-disulfide which comprises reacting 2,2'-dichloro-4,4',5, 5'-tetraamino-diphenyl-disulfide with the product formed by reaction between cyanamide, chloroformic acid methyl ester and sodium hydroxide.
41. The compound bis(2-methoxycarbonyl-amino-6-chloro-benzimidazole-5-yl)-disulfide when prepared by a process according to claim 39 or 40 or an obvious chemical equivalent thereof.
42. A process for preparing bis(2-methoxycarbonyl-amino-6-fluoro-benzimidazole-5-yl)-disulfide which comprises reacting 2,2'-difluoro-4,4',5, 5'-tetraamino-diphenyl-disulfide with S-methyl-isothiourea diurethane.
43. A process for preparing bis-2-methoxycarbonyl-amino-6-fluoro-benzimidazole-5-yl)-disulfide which comprises reacting 2,2'-difluoro-4,4',5, 5'-tetraamino-diphenyl-disulfide with the product formed by reaction between cyanamide, chloroformic acid methyl ester and sodium hydroxide.
44. The compound bis(2-methoxycarbonyl-amino-6-fluoro-benzimidazole-5-yl)-disulfide when prepared by a process according to claim 42 or 43 or an obvious chemical equivalent thereof.
45. A process for preparing bis(2-methoxycarbonyl-amino-6-trifluoro-methyl-benzimidazole-5-yl)-disulfide which comprises reacting 2,2'-di-(fluoromethyl)-4,4',5,5'-tetraamino-diphenyl-disulfide with S-methyl-isothiourea diurethane.
46. A process for preparing bis(2-methoxycarbonyl-amino-6-trifluoro-methyl-benzimidazole-5-yl)-disulfide which comprises reacting 2,2'-di-(fluoromethyl)-4,4',5,5'-tetraamino-diphenyl-disulfide with the product formed by reaction between cyanamide, chloroformic acid methyl ester and sodium hydroxide.
47. The compound bis(2-methoxycarbonyl-amino-6-trifluoromethyl-benzimidazole-5-yl)-disulfide when prepared by a process according to claim 45 or 46 or an obvious chemical equivalent thereof.
48. A process for preparing bis(2-methoxycarbonyl-amino-6-methoxy-benzimidazole-5-yl)-disulfide which comprises reacting 2,2'-dimethoxy-4,4',5, 5'-tetraamino-diphenyl-disulfide with S-methyl-isothiourea diurethane.
49. A process for preparing bis(2-methoxycarbonyl-amino-6-methoxy-benzimidazole-5-yl)-disulfide which comprises reacting 2,2'-dimethoxy-4,4',5, 5'-tetraamino-diphenyl-disulfide with the product formed by reaction between cyanamide, chloroformic acid methyl ester and sodium hydroxide.
50. The compound bis(2-methoxycarbonyl-amino-6-methoxy-benzimidazole-5-yl)-disulfide when prepared by a process according to claim 48 or 49 or an obvious chemical equivalent thereof.
51. A process according to claim 1 wherein process (a) is used and the starting material of formula VII is obtained by condensing two molecules of a compound of formula XVI
or a salt thereof and, if required, freeing the compound of formula VII from its salt.
or a salt thereof and, if required, freeing the compound of formula VII from its salt.
52. A process according to claim 51 wherein the reaction is carried out in the presence of a catalyst.
53. A process according to claim 51 wherein the reaction is carried out in the presence of water or a lower alkanol as solvent.
54. A process according to claim 51 wherein the reaction is carried out in the presence of an alkali metal hydroxide or carbonate or ammonium hydroxide.
55. A process according to claim 51 wherein the reaction is carried out in the presence of a lower carboxylic acid and a tertiary amine.
56. A process according to claim 55 wherein the lower carboxylic acid is acetic acid.
57. A process according to claim 51 wherein the reaction is carried out in the presence of a 3-5% aqueous ammonium hydroxide solution.
58. A process according to claim 51, 52 or 53 wherein the reaction is carried out at a temperature in the range of from 20° to 100°C.
59. A process according to claim 51, 52 or 53 wherein in the compound of formula XVI R2 is hydrogen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000370240A CA1122219A (en) | 1977-05-11 | 1981-02-05 | Sulfur-containing benzimidazole derivatives, process for the preparation thereof and intermediates useful in production of the same |
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU77CI1736A HU176937B (en) | 1977-05-11 | 1977-05-11 | Process for producing diamino-thiocyanato-benzene derivatives |
| HUCI-1736 | 1977-05-11 | ||
| HUCI001738 HU177416B (en) | 1977-05-16 | 1977-05-16 | Process for preparing benzimidazolyl-disulphides |
| HUCI-1738 | 1977-05-16 | ||
| HUCI-1759 | 1977-07-29 | ||
| HUCI001759 HU177418B (en) | 1977-07-29 | 1977-07-29 | Process for preparing benzimidazole derivatives containing sulphur |
| CA000303127A CA1117952A (en) | 1978-05-11 | 1978-05-11 | Sulfur-containing benzimidazole derivatives, process for the preparation thereof and intermediates useful in production of the same |
| CA000370240A CA1122219A (en) | 1977-05-11 | 1981-02-05 | Sulfur-containing benzimidazole derivatives, process for the preparation thereof and intermediates useful in production of the same |
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| Publication Number | Publication Date |
|---|---|
| CA1122219A true CA1122219A (en) | 1982-04-20 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000370240A Expired CA1122219A (en) | 1977-05-11 | 1981-02-05 | Sulfur-containing benzimidazole derivatives, process for the preparation thereof and intermediates useful in production of the same |
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| Country | Link |
|---|---|
| CA (1) | CA1122219A (en) |
-
1981
- 1981-02-05 CA CA000370240A patent/CA1122219A/en not_active Expired
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