BE666351A - - Google Patents

Description

       

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  New benzimidazoles
The present invention relates to new derivatives of benzimidazole which have been recognized to have particularly advantageous anti-parasitic properties due to their distribution over a very broad spectrum.



   The products of the invention have in common a heterocyclic subolution in position 2, the heterocyole being attached to the benzimidazole directly or through a hydrocarbon group which may bear a hydroxyl radical.



   The products of the invention correspond to one of the following general formulas:
 EMI1.1
 

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In this formula 1, R represents a carboxy (-COOH), sulfo (-SOH), halogenosulfonyl (-SO2X) or carbonhydrazide (-CO.NH.NH2) radical; R can also represent a sulfonamide (-SO2NH2 and SONH.R ') or sulfonamido (-NH.SO2R') radical in which R 'is an alkyl, alkenyl, aralkyl, aralkenyl, aryl or heterocyclic residue; this residue may have one or more of its hydrogen atoms replaced by one or more halogens and / or one or more hydroxy, alkoxy, mercaptan, alkylmercapto, nitro, carboxy, alkoxycarbonyl, amino, alkylamino and / or acylamino groups;

   R can also represent an alkoxycarbonyl radical; the R substituent is located in any position on the benzene ring of the benzimidazole, the 5 or 6 position being however the preferred position of the invention.



   R1 represents a hydrogen atom or an alkyl, 1-nyl, aralkyl, aralkenyl, aryl or heterocyclic residue; this roste may have one or more of its hydrogen atoms replaced by one or more halogens and / or one or more nitro, hydroxy, alkoxy, mercaptan, alkylmercapto, oarboxy, alkoxycarbonyl, amino, alkylamino and / or acylamino groups; it can be linked to the nitrogen atom of benzimidazole directly or through a CO or SO2 group.



   R2 represents a heterocycle with five elements including a sulfur atom and one or more nitrogen atoms linked by one of its carbon atoms directly to the benzimidazole or by the intermediary of a hydrocarbon group containing one to four atoms carbon in a straight or branched chain, saturated or having an ethylenic bond; the other carbon atom (s) of this heterocycle bear one or more hydrogen atoms and / or one or more amino, alkylamino, acylamino, nitro, hydroxy, alkoxy, carboxy and / or alkoxycarbonyl groups and / or one or more alkyl radicals , aralkyl and / or aryl; these residues can carry an alcohol, phenol or ether-oxide function.

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 EMI3.1
 



   In this formula 2, Rla represents one of the following substitutions; - a -CH2.CH2.SO2.O.R radical in which R can be an alkyl, aralkyl or aryl residue; this residue may have one or more of its hydrogen atoms replaced by one or more halogens and / or one or more nitro and / or alkoxycarbonyl groups; - a radical -SO2.R 'in which R' can be an alkyl, aralkyl, aryl or heterocyclic residue; this residue may have one or more of its hydrogen atoms replaced by one or more halogens and / or one or more nitro, hydroxy, alkoxy, mercaptan, alkylmercapto, carboxy, alkoxyarbonyl, amino, alkyllamino and / or groups. acylamino;

   - a hydrocarbon radical of two to twenty carbon atoms in a straight or branched chain, saturated or having an ethylenic bond and bearing, in any position, a carboxy (-COOH) or carbonhydrazide (-CO.NH.NH2) group or alkoxycarbonyl (-COOR ") in which R" represents an alkyl, alkenyl, aralkyl or aralkenyl residue; the radical is attached to the nitrogen atom of the benzimidazole directly or through a CO group; a saturated hydrocarbon radical containing three to six carbon atoms, in a straight or branched chain or in a closed cycle, and carrying two to five hydroxy groups;
 EMI3.2
 - a -CH 2- (CH-0-CH) -CH-OH radical in which n represents a Ril RE, any number which may, in particular, be zero and R "'a hydrogen atom or a methyl, ethyl or phenyl;

   - a furannosyl or pyrannosyl radical deriving, by loss of a .., hydroxy group, from an aldose or a ketose under one of their

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 two oxidic forms; the other hydroxy groups of the radical may be free or esterified with one or more organic acids;
R2 represents a substitution as defined for formula 1;
The benzene ring of benzimidazole carries one or more hydrogen atoms and / or one or more halogens and / or one or more nitro, hydroxy and / or mercaptan groups and / or one or more alkyl, alkenyl, aralkyl, aralkenyl and / or aryl connected to the nucleus directly or through a sulfur or oxygen atom.
 EMI4.1
 



   In this formula 3, Rlb represents a hydrogen atom or an alkyl, alkenyl, aralkyl, aralkenyl or aryl residue linked to the nitrogen atom of benzimidazole directly or through the intermediary of a CO group; the remainder may have one or more of its hydrogen atoms replaced by one or more halogens and / or one or more nitro, hydroxy, alkoxy, mercaptan, alkylmercapto, carboxy, alkoxycarbonyl, amino, alooylamino and / or acylamino groups;
R2a represents a thiazole heterocycle linked directly to benzimidazole through one of its carbon atoms in position 4 or 5; the carbon atom in position 2 of the thiazole carries a carboxy, alkoxycarbonyl or nitrile group;
The benzene ring of benzimidazole carries the substitutions indicated for formula 2;

   it can also carry any heterocyclic radical.
 EMI4.2
 

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   In this formula 4, Rlb represents a substitution as defined for formula 3;
R2 represents a substitution as defined for formula 1, the heterocycle being, however, necessarily linked to the benzimidazole through the hydrocarbon group.



   The benzene ring of benzimidazole carries the substitutions indicated for formula 2; can also carry any heterocyclic radical or a primary, secondary or tertiary amino group.
 EMI5.1
 



   In this formula 5, n can be between 0 and 3 inclusive;
Ra represents a hydrogen atom or an alkyl, alkenyl, aralkyl, aralkenyl or aryl residue; remainder may have one or more of its hydrogen atoms replaced by one or more halogens and / or one or more hydroxy, alkoxy and / or nitro groups;
R1c represents a hydrogen atom or an alkyl, alkenyl, aralkyl, aralkenyl or aryl residue which may have one or more of its hydrogen atoms replaced by one or more halogens and / or one or more hydroxy, nitro or alkoxy groups and / or alkylmercapto;
R2b represents a five-membered heterocycle 4 including a sulfur atom and one or more nitrogen atoms linked by one of its carbon atoms;

   this heterocycle bears, on its other carbon atom (s), one or more hydrogen atoms and / or one or more alkyl, alkenyl, aralkyl, aralkenyl and / or aryl and / or one or more hydroxy, alkoxy, nitro groups and / or alkylmercapto;
The benzene ring of benzimidazole carries one or more atoms

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 of hydrogen and / or one or more halogens and / or one or more hydroxy, nitro, carboxy and / or alkoxycarbonyl groups and / or one or more alkyl, alkenyl, aralkyl, araloenyl and / or aryl groups connected to the ring directly or by the intermediary of a sulfur or oxygen atom.
 EMI6.1
 



   In this formula 6, Rld and R3 may be the same or different and each represent an alkyl, alkenyl, aralkyl, aralkenyl or aryl residue which may have one or more of its hydrogen atoms replaced by one or halogens and / or one or hydroxy, nitro, alkoxy and / or alkylmercapto groups;
R2 represents a substitution as defined for formula 1;
X- represents an anion consisting of the residue of an inorganic or organic acid, of a phenol or of a mercaptan;
The benzene ring of benzimidazole carries the substitutions indicated for formula 2; it can also carry any heterocyclic radical.
 EMI6.2
 



   In this formula 7, Rle represents a hydrogen atom or an alkyl, alkenyl, aralkyl, aralkenyl, aryl or heterocyclic residue; this remainder can have one or more of its atoms

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 of hydrogen replaced by one or more halogens and / or one or more nitro, hydroxy, alkoxy, mercaptan, alkylmercapto, amino, alkyllamino, acylamino, carboxy and / or alkoxycarbonyl groups; it can be connected to the nitrogen atom of benzimidazole directly or through a CO or SO2 group;
R2c represents a thiazole heterocycle linked via its nitrogen atom to benzimidazole directly or via a hydrocarbon group containing one to four carbon atoms in the form of a straight or branched chain, saturated or having an ethylenic bond;

   the carbon atoms of the thiazole may bear one or more hydrogen atoms and / or one or more nitro, hydroxy, mercaptan, carboxy, alkoxycarbonyl and / or acylamino groups and / or one or more alkyl, alkenyl, aralkyl, aralkenyl and / or aryl linked directly or through the chemical of a sulfur or oxygen atom;
X- represents an anion consisting of the residue of an inorganic or organic acid, of a phenol or of a mercaptan;
The benzene ring of benzimidazole carries the substitutions indicated for formula 2.



   The salts formed between the compounds defined by formulas 1 to 5 inclusive and mineral acids, organic acids, phenols or mer-captans also belong to the invention. By way of nonlimiting examples of mineral acids, mention may be made of halhydric, sulfuric, phosphoric, boric, nitric and hexacyanoferric acids; as organic acids, there may also be cited, by way of nonlimiting examples, mono or polycarboxylic acids and mono or poly sulfonic acids; organic acids, phenols and mercaptans may have one or more additional functions represented, for example, by one or more halogens, and / or one or more hydroxy, nitro, amino, alkylamino, and / or acylamino groups.



   The salts formed between the compounds defined by formulas 1 to 5 inclusive also belong to the invention, in

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 which include a carboxylic or sulfonic group, and organic bases, ammonia or metals.



   Also belonging to the invention are products in which any metal is attached to a nitrogen atom of one of the above-defined benzimidazloes.



   By way of nonlimiting examples of metals which may be found in the salts or metal derivatives of the invention, there may be mentioned sodium, potassium, lithium, calcium, strontium, magnesium, aluminum. , iron, cobalt, nickel, copper, mercury, lead, silver, gold, zinc, manganese and cadmium; the metal may appear alone in the compound or, on the contrary, be linked on the other hand to another element or group of elements such as in the case, for example, of halogenomerouric or uranyl ions.



   The products of the invention are very effective antiparasitic agents against numerous harmful living organisms; their properties vary, of course, from one product to another depending on the substitutions but their activity generally allows the destruction of parasitic helminths such as, in particular, eels, ascarids, hookworms, trichinae and eustron- gylus responsible for diseases of the gastrointestinal tract, urinary tract or skin both in humans and in many animals such as horses, cattle and sheep.



   Products bearing, in position 1, a radical originating from a sugar or a polyol are particularly suitable for this application on account of their solubility allowing their more rapid penetration into biological fluids.



   The products of the invention are also very effective anti-fungal agents against numerous species of fungi responsible for diseases, in man or in animals, such as aspergillosis, trichophytia, microspotia, pityriasis. , epidermophytia and cryptococcosis.

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   The products of the invention are active against various pathogenic fungi of soil and plants such as, for example, species of the Fusarium, Pythium, Rhizoctonia, Alternaris, Erysiphé, Monilia, Colletotrichmm, Venturia, Cercospora, and Sclerotinia type,
Many saprophytes responsible for degradation of wood, leather, textiles, paints and other materials are effectively combated by the products of the invention.



   The appearance of fungi known as molds such as those which grow on bread, meat, fish, vegetables, cheese, fats, creams, jams, etc., is easily avoided by the use of products of the invention.



   Antibacterial properties have been noted in certain products of the invention and in particular in those carrying a sulfonamide function.



   Antiviral properties have also been observed in certain products of the invention and in particular among those belonging to formula 5.



   An advantageous advantage of the products of the invention lies in their very low toxicity.



   The invention aims to use the products in view. of the applications indicated above; they can be used singly or in pairs or more; they can also be used in the form of liquid, plastic or solid compositions.



   A composition may consist of one or more products of the invention, either alone or as a mixture with one or more inert products and / or one or more products having one or more activities similar or foreign to those which are the subject of 1 ' invention.



   A liquid composition can be, for example, a solution or a suspension or a dispersion in water or in any suitable liquid.

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   A solid composition can, for example, be presented in the form of powder, granules, tablets, agglomerates or doses containing one or other of these forms,
A plastic composition can, for example, be a solution or a suspension or a dispersion in a plastic body such as a more or less compact fat or a liquid of high viscosity so as to constitute, for example, a liniment, a liquid. ointment, cream, balm, ointment or plaster.



   The compositions can be used, for example, for sprinkling, watering, spreading, irrigating, washing, nebulizing, vaporizing or fumigating carried out manually or by motorized or non-powered instrument methods. In internal therapy, the compositions can be used in ingestion or in injections or according to any other mode of penetration.



   By way of nonlimiting examples, there may be mentioned compositions as follows; - a flour, a yeast, a sugar and / or a flavoring containing one or more products of the invention intended to prevent the formation of mold in bakery, pastry or biscuit products; such a composition allows the action of the yeast while being more effective against molds than known products such as propionates; it does not affect the aroma, the smell or the volume of the breads, cakes or cookies containing it.



  - A foaming agent containing one or more products of the invention, the whole constituting a shampoo product having anti-dandruff properties.



  - a lubricating oil containing a dispersing agent and one or more products of the invention, the whole constituting a basic product for the preparation of a stable emulsion intended for the lubrication of machines cutting or working metallic materials,

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 - A food, or a food premix, containing one or more products of the invention, the whole being intended for the feeding of domestic animals at the same time as for the prevention in the latter of helminthiases and mycoses.



  - A compound fertilizer or not containing one or more products of the invention intended for soil disinfection and for the treatment or protection of plants by systemic effect.



  a liquid containing a propellant, such as a fluorinated hydrocarbon, and one or more products of the invention, the whole allowing the creation of disinfectant aerosols.



  - A paint based on curable synthetic resins containing one or more products of the invention in order to provide it with fungicidal properties.



   The products of the invention can be prepared according to several methods described below:
1. By the action of the aromatic orthodiamines suitably substituted on the acids of general formula R.COOH in which R represents the desired radical in position 2 of the benzimidazole; it is also possible to use the anhydrides, amides, nitriles, esters or helogens corresponding to these acids.

   The reaction is preferably carried out in a liquid serving as a solvent or a carrier; is carried out, temperatures varying according to the products used but generally between 80 and 300 C; the reaction gives good yields under atmospheric pressure but can sometimes be improved by the use of a different pressure; catalysts such as, for example, hydrohalic, sulfuric, phosphoric, polyphosphoric or boric acids can be used to promote the reaction.



   2. By the action of suitably substituted aromatic orthodiamines on the aldehydes of general formula R. CHO in which R represents the desired radical in position 2 of the benzimidazole. This action is accompanied or followed by oxidation

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 by oxygen, atmospheric or not, or by oxygen carriers such as, for example, mercuric or cupric compounds.

   The reaction is preferably carried out in a solvent or a liquid carrier; the metal complexes formed between the compounds of the invention and the cations used can be treated so as to separate their constituents either by precipitation of an insoluble derivative of the cation, the benzimidazole remaining in solution, or by treatment with a more complexing agent. strong retaining the metal in soluble form at the time of precipitation of the compound of the invention.



   3. by reduction of the orthonitionilides formed by the condensation of the orthonitranilines suitably substituted with the acids of general formula R.COOH in which R represents the desired radical in position 2 of the benzimidazole. The reduction can be carried out by oxygen acceptors such as certain metals such as, for example, tin, zinc, cadmium or iron, such as reducing metal salts such as, for example, those of tin II , iron II or titanium III, or, alternatively, as nascent hydrogen and / or in the presence of hydrogenation catalysts. As suitable catalysts, there may be cited by way of example, nickel prepared according to Raney, divided platinum and other metals of the same family or their oxides.



   4. By halogenation of an N-arylcarbonamidine in which the aryl radical is suitably substituted and in which also the carbon atom of the carbonamidine radical is linked to the desired radical at the 2-position of the benzimidazole. Secondly, dehalogenation is caused by the action of a base and this results in cyclization such that the carbon atom of the carbonamidine radical becomes that occupying position 2 of the benzimidazole formed.

   The N-arylcarbonamidines can be used in the free state or, preferably, in the state of salts with a strong mineral acid; in the latter case, the halogenation can

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 be easily achieved by using an alkaline hypohalogenite; the reaction is preferably carried out in a solvent or in a liquid carrier; ambient temperature and atmospheric pressure are generally suitable, but different temperatures and pressures can sometimes help improve efficiency.



  As bases suitable for dehalogenation, there may be mentioned, for example, alkali hydroxides and carbonates.



   The N-arylcarbonamidines used in the present method of preparation are obtained by the action of aromatic amines and / or their salts on the compounds having a nitrile group, in place of the desired arylcarbonamidine group, the reaction being carried out by presence of a catalyst such as, for example, an arylsulfonic acid or an aluminum or zinc halide.



   N-arylcarbonamidines can also be prepared by the action of metal arylamides, such as those formed, for example, with alkali metals, on compounds having a nitrile group in place of the desired arylcarbonamidine group, or by the action aromatic amines and / or their salts on compounds having a functional group representing a carboxylic ester in place of the desired carbonamidine group.



   5. By the action of compounds possessing carbon, sulfur and nitrogen atoms in vici- nal positions such as thioamides, thiocyanates, thiocarbamates and thioxamates on suitably substituted benzimidazoles bearing, in position 2, one of the four following radicals:

   (a) -CH2-CO-CHX-R '(b) -CH2-CHX-CO-R "(c) -CO-CHX-R' (d) -CHX-CO-R" in which X is halogen such as chlorine, bromine or iodine and R ′ and R ″ alkyl, aralkyl or aryl radicals, R ′ may also be a hydrogen atom. The reaction is carried out, from

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 preferably, in a solvent or in an aqueous or non-aqueous liquid support; the temperature of the reaction can be equal to the ambient temperature but it can also, according to the case, be lower or higher; atmospheric pressure is generally suitable but the use of a different pressure can sometimes be advantageous.

   Good stirring facilitates and activates the reaction. The introduction of a base, preferably weak, acting as an acid acceptor, facilitates the formation of the thiazolic ring; this acceptor can constitute all or part of the solvent or support and can also be introduced only at the end of the reaction. The thioamide derivatives used as starting material can be replaced by a mixture containing the corresponding amide derivative and a sulfur carrier such as, for example, phosphorus pentasulfide.

   The present method of preparation makes it possible in particular to prepare in a new way already known products; these products do not form part of the invention, but the latter nonetheless relates to their manufacture according to the present mode; products correspond to general formula 3 in which the thiazole bears on its carbon atom in position 2, that is to say between the sulfur and nitrogen atoms, a hydrogen atom, an alkyl, nlkenyl or aralkyl residue, aralkenyl or aryl or a hydroxy, amino or alkylamino group.



   In the present method of preparation, it is possible to obtain products carboxylated on the carbon atom located in position 2 of the thiazole; their decarboxylation can be obtained by simple heating of the carboxylic acid; the latter can be prepared by saponification of the corresponding alkoxycarbonyl compound; sometimes decarboxylation takes place even at room temperature.



   6. The products of the invention bearing an alpha hydroxy group on the substituent at position 2 can be prepared according to mode 1 or by the action of mixed magnesium halides of general formula R2b- (CH2) n-MgX, in which X is halogen and n and R2b are as defined for formula 5, on the

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 suitably substituted 2-acylbenzimidazoles; the reaction is carried out in a suitable solvent or liquid carrier such as, for example, ether oxides or oxygen heterocycles; the operation is protected from the oxygen in the air; At the end of the reaction, the complex formed is hydrolyzed using, preferably, an extended acid.



   7. The compounds of the invention having, in position 1, a hydrocarbon-based substituent can generally be obtained by starting from N-substituted aromatic orthodiamines according to modes 1 and 2, N-substituted orthonitranilines according to mode 3, N-arylcarbonamidines N- substituted following modo 4 or benzimidazoles already substituted in position 1 according to modes 5 and 6.

   These compounds can also be prepared from benzidazoles whose 1 position is oceupée by a hydrogen atom or, preferably, from their metal derivatives, that is to say bearing, in position 1, an alkali metal, a silver atom or a halogen-mercuric group; it suffices to treat these products with the halogen compound corresponding to the hydrocarbon residue to be fixed; one can also use another strong acid ester such as, for example, a sulfate.

   The present method of preparation is applicable to compounds which must have, in position 1, an alkyl, alkenyl, aralkyl or aralkenyl residue which may or may not bear substituents other than hydrogen; the present mode is also applicable for fixing a furanosyl or pyrr, nnosyl radical; a halide is preferably used, the hydroxy groups of which are esterified with an organic acid such as, for example, acetic acid or benzoic acid; the hydroxy groups can then be released by saponification using, for example, ammonia.



   8. The products of the invention bearing, in position 1, an acyl residue can be obtained according to mode 5 from benzimidazoles already acylated in position 1 or by the action of anhydrides or acid halides on the benzimidazoles

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 suitably substituted bearing, in position 1, a hydrogen atom; the reaction is preferably carried out in an inert liquid serving as a solvent or a carrier and in the presence of an acid acceptor such as a base; this acceptor can constitute all or part of the solvent or support. We can also operate on a metal derivative as in mode 7.



   9. The products of the invention bearing, in position 1, an organic sulfonyl residue can be obtained according to method 5 from benzimidazoles already sulfonylated in position 1 or by the action of organic sulfonyl halides of general formula R.SO2X , wherein X represents halogen and R.SO2- the desired radical in position 1, on suitably substituted benzimidazoles bearing, in position 1, a hydrogen atom; the reaction is carried out as in mode 8; one can also operate on a metal derivative as in mode 7. The products having, on the benzene nucleus of the benzimidazole, a sulphonamido radical are prepared in a similar manner starting from the corresponding aminobenzimidazoles.



   10. The products of the invention bearing, in position 1, a -CH2.CH2.SO2.OR radical as defined in formula 2 are prepared by the action of ethylene sulfonic esters of general formula CH2 = CH- SO2-0-R on benzimidazoles having the desired substitutions and, in position 1, a hydrogen atom; the operation is preferably carried out in an inert liquid used as a solvent or a support such as alcohols and hydrocarbons, for example; the reaction will generally take place at atmospheric pressure and room temperature, but it may be useful to employ different pressures and temperatures in order to improve yields and / or reduce the duration of the reaction. surgery.



   11. The products of the invention bearing, in position 1, a
 EMI16.1
 radical -CH- (H-0-Cin-H-OH you that it is defined in R "1 R" '

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 Formula 2 are prepared according to Mode 7 using the suitable glycol monohalohydrins or monohalides of the products known as polyethylene glycolt polypropylene glycol and polybutylene glycol; they can also be prepared by the action, on the benzimidazoles bearing the desired substituents and a hydrogen atom in position 1, of the epoxides below:

   - oxirane, known as ethylene oxide, - 2-methyl oxirane, known as propylene oxide, - 2-ethyl oxirane, known as butylene oxide , - 2-phenyloxirane, known under the name of styrene oxide.



   The operation is carried out, or not, in an inert liquid serving as a solvent or support such as, for example, water or hydroarbides; it is possible to operate at atmospheric pressure or at a higher pressure, the latter often being necessary because of the temperature of the reaction; the temperature to be applied may vary according to the products but is generally between 70 and 200 C; the presence of a quantity of water, large or small, is desirable and promotes the reaction. the number of molecules of epoxide condensed on a molecule of benzimidazole depends on the proportion of the reagents used,
12.

   Quaternary benzimidazoliums corresponding to formula 6 can be prepared by adding the desired radical in position 3 to the corresponding non-quaternary benzimidazoles; this addition can be carried out by treatment with an alkylating agent such as esters of strong acids; the operation already takes place cold and can be carried out without solvent or support, but it is preferably carried out hot and in an inert liquid. The compounds obtained contain the anion corresponding to the acid residue of the ester used. By treating a benzimidazole having a hydrogen atom in position 1 or its metal derivative, compounds can be obtained containing two identical radicals in positions 1 and 3.

   Excess should be avoided

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 of alkylating agent, quaternization on a nitrogen atom belonging to the sulfur-containing heterocycle which may occur, creating by-products which are difficult to separate,
The anion of a compound of the invention prepared in accordance with the present procedure can be replaced by another using the displacement properties of insoluble salts or volatile acids which may form; for example, when a compound of the invention possesses a hydrohalic anion, this can be replaced by another anion by reacting with the compound the silver salt corresponding to this new anion.

   Benzimidazolium carbonates can thus be prepared using silver carbonate; from these new compounds the other salts of the invention are easily reached by the action of an acid which displaces carbon dioxide. Benzimidazolium sulphates can, in an analogous manner, lead to neutral salts by the action of barium salts. The replacement of one anion by another can, moreover, be carried out by passing over a suitable ion exchange resin.



   13. The quaternary thiazoliums corresponding to formula 7 can be prepared by condensation of the thiazole or of its suitably substituted derivatives with the benzimidazoles having in position 2 a halogen or a halogenated hydrocarbon radical. The condensation is more or less easy depending on the compounds present; sometimes the reaction can take place in the cold, but more often it is necessary to heat; it is possible to use a pressure other than atmospheric pressure, but the latter is generally suitable; it is preferable to operate in a solvent or inert liquid support such as, for example, hydrocarbons, alcohols, ethers or nitriles.

   The compounds thus prepared contain as anion.l'halogen which was in position 2 or on the chain occupying this position; this anion can be replaced by another in the same way as was said in mode 12.

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     14, The products of the invention having, on the nucleus of the benzimidazole, a sulfonamide radical, are obtained either direct. tement according to modes 1, 2, 3 or 5 starting from products already possessing the sulfonamide radical, either by the action of ammonia or of a suitable amine on the benzimidazoles of the invention bearing a radical halosulfonyl.



   15. The products of the invention bearing a carbonhydrazide radical are obtained by the action of hydrazine on the corresponding carboxylic esters; the reaction is preferably carried out in a liquid serving as a solvent or a carrier; this liquid can be inert such as, for example, water, hydrocarbons, alcohols or ether-oxides or be an excess of hydrazine. It is generally preferable to operate at a temperature higher than ambient, such as, for example, that of the reflux of the solvent or support, but the invention does not reject the use of ambient temperature or of a temperature lower than that. this ; atmospheric pressure is generally adequate, but a higher pressure can be artificially created in order to facilitate and / or accelerate the reaction.

   The hydrazine can be replaced by its salts used in the presence of a strong alkali in a calculated amount.



   16. The products of the invention having an ester function can be obtained, in particular, from the corresponding acids and suitable alcohols by known esterification means such as those using dehydration, azeotropic or not, in the presence or not of d a catalyst such as, for example, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, boron fluoride or the halides of mineral acids; The alcohols can also react with the halides of the acids of the invention prepared separately by the action of a suitable halogenating agent such as, for example, the halides of phosphorus or thionyl.



   17. The salts in which the anion comes from a compound of the invention are obtained by the action of the bases on the acids

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 of the invention; it is also possible to use salts of weak acids which are easily displaced, such as, for example, carbonates. Saponification of the esters of the invention also leads to salts of the same category,
18. The salts in which the cation originates from a compound of the invention are obtained by the action of organic or mineral acids, phenols or mercaptans on the free bases of the invention; can switch from one salt to another in the same way as was said in mode 12.



   19. The free carboxylic acids of the invention can be obtained in particular by the action of strong acids in an amount calculated on the salts in which the anion originates from a compound of the invention.



   20. The free bases of the invention can be obtained in particular by the action of strong bases in an amount calculated on the salts in which the cation originates from a compound of the invention.



   21. The products of the invention in which a metal is linked to a nitrogen atom are obtained by the action of oxides, hydroxides, alkoxides, salts or other metal compounds on the benzimidazoles having the desired substituents; the alkali derivatives are preferably formed in anhydrous medium using. 'for example, methoxides, ethoxides, hydrides or amides; the non-alkaline derivatives can be obtained not only from benzimidazoles but also from their alkaline derivatives; the reaction is carried out in water or in another aqueous or non-aqueous solvent, chosen so as, for example, to allow precipitation of the derivative formed.



   Some examples of preparation are given below; these examples are purely illustrative and in no way limit the invention.
 EMI20.1
 



  1. Thiazolylw4) ¯2-N = hCnl-acet.midine 9.3 grams (0.1 mol) are treated with good stirring.

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 of aniline and 12.4 grams of (4-thiazolyl) acetonitrile in 50 milliliters of trichloroethane per 13.3 grams (0.1 mole) of anhydrous powdered aluminum chloride; the temperature rises by itself and reaches around 70 C; when the temperature no longer rises, the mixture is gently heated to obtain a reflux which is maintained for one hour, the mixture is cooled to room temperature and 150 milliliters of 5M sodium hydroxide solution are added while stirring; it is left to stand and then the aqueous layer is removed; the orgauque layer is washed with cold water and dried over potassium carbonate; the trichloroethane is removed by distillation under reduced pressure.



  2. (Thiazolyl-4) methy1-2 benzimidazole
21.8 grams (0.1 mol) of (thiazolyl-4) -2 N-phenyl acetamidine in solution in a mixture containing 125 milliliters of methanol and 100 milliliters of hydrochloric acid are treated at room temperature and with good stirring. normal, with a solution containing 0.1 mole of sodium hypochlorite in about 50 milliliters of water; after ten minutes, a saturated aqueous solution containing 12.7 grams (0.12 mol) of sodium carbonate is added; maintain stirring and reflux for thirty minutes; the product formed is cooled and separated by filtration.



  3. (Thiazoly1-4) methyl1-2 benzimidazole
25.3 grams (0.1 mole) of (3-bromoacetonyl) -2 benzimidazole are treated with good stirring per 6.7 grams (0.11 mole) of thioformamide and 6 grams of fine powdered chalk of ouis 250 milliliters of ethanol while maintaining the temperature in the vicinity of 10 ° C. for one hour; the temperature is gradually raised to reach 3540 C in two hours; this is maintained for one hour and then brought to a gentle boil for 15 minutes; the boiling solution is filtered then the alcohol is removed by distillation under reduced pressure.

   It can be recrystallized from ethyl acetate.

 <Desc / Clms Page number 22>

 
 EMI22.1
  , (Amino-2 thiazolrl4mëthyl-.2 benzim.dazole
25.3 grams (0.1 mole) of (3-bromo-aoetonyl) -2 benzimidazole are treated, with good stirring for three hours, per 8.4 grams (0.11 mole) of thiourea in 160 milliliters of water and 40 grams of crushed ice; during the third hour, the temperature is raised between 20 and 25 0; at the end of the reaction, 30 milliliters of 4M ammonia are added and, after fifteen minutes of stirring, the product formed is separated by filtration,
 EMI22.2
 5.

   (Ethoxxetrbonxl ^ 2 thizoll.) Mthrl- ^ benzimidazo.e
Treated, with good stirring for two hours at 40.0, 25.3 grams (0.1 mole) of (3-bromoacetionyl) -2 benzimidazole with 14.4 grams (0.11 mole) of ethyl thioxamate and 6 grams of fine powdered chalk in 250 milliliters of ethanol; the temperature is then raised to obtain, after one hour, a slight reflux which is maintained for two hours; it is filtered boiling to remove the mineral salts and then the alcohol is removed by distillation under reduced pressure. It can be recrystallized from dioxanno.
 EMI22.3
 



  6 ¯ (Thirtzol1-4) meth 1-2 bnzimidazole
28.7 grams (0.1 mole) of (2-ethoxycarbonyl-4-thiazolyl) methyl-2-benzimidazole are treated in a boiling water bath for one hour with 10 grams of caustic soda in 250 milli-liters of n-amyl alcohol. ; it is cooled to room temperature then slowly added n-amyl alcohol saturated with hydrochloric gas in an amount corresponding to that of sodium hydroxide used plus a slight excess; half the total volume of n-amyl alcohol is distilled under normal pressure and then neutralized between pH 6 and 7; ripples until dry under reduced pressure; the residue is taken up in boiling ethyl acetate and the sodium chloride is removed by filtration; the deoarboxylated product crystallizes on cooling.
 EMI22.4
 



  1¯E: !! r2 ± ±:! ¯iËh! 21!: 11h!: G¯! ± h! 2! 2: 22- We operate as in example 6 but using 45.7 grams-

 <Desc / Clms Page number 23>

 mes (0.1 mol) of p-nitrobenzyl-1 (3-bromo-acetonyl) -2 dichloro-5,6 benzimidazole.
 EMI23.1
 



  8. (Thiazol 1-4) -2 carbox-5 benzimidazole
18.2 grams (0.1 mole) of 4-amino-3-nitro benzoic acid in 100 milliliters of anhydrous pyridine are treated with 14.8 grams (0.1 mole) of (4-thiazolyl) carbonyl chloride. overnight at room temperature then precipitates the nitranilide formed by adding water; the nitranilide is separated by filtration and introduced into 200 milliliters of acetic acid and 60 milliliters of 6M hydrochloric acid; 70 grams of powdered zinc are added a little bit with stirring; all of the metal seems to have reacted, it is brought to a gentle boil for 20 minutes, cooled and neutralized to pH 4 using 10 Bé ammonia. The product for @@ is then separated by filtration.
 EMI23.2
 



  9. (Thiazol 1-4) -2 methox carbon 1-5 benzimidazole
The procedure is as in Example 8 but using 19.6 grams (0.1 mole) of 4-amino-3-methyl-3-nitro benzoate.
 EMI23.3
 



  10. (Ethox carbon 1-3 ro xl) -1 (Thiazol 1-4) -2 benzimidazole 20.1 grams (0.1 mol) of (thiazolyl-4) -2 benzimidazole are treated with 5.4 grams of methoxide sodium in 200 milliliters of absolute methanol then add 250 grams of N, N-dimethylformamide; the methanol is removed by distillation under a vacuum of a few mm / Hg; the distillation is stopped when the internal temperature of the residue reaches 50 ° C; the atmospheric pressure is reestablished by means of nitrogen and 15.1 grams (0.1 mol) of ethyl 4-chlorobutyrate are introduced with good stirring; the temperature is maintained at 50 ° C. for one hour after the end of the introduction, then the alkali halide is removed by filtration;

   almost all of the dimethylformamide is removed by distillation under reduced pressure and the cooled residue is added with 200 milliliters of cold water; the product is collected by spinning.

 <Desc / Clms Page number 24>

 
 EMI24.1
 éé ± ¯ (µ ± j ± µzgµ ± bozé = ¯, j ± h ± zQQ = µ¯ (jjoµµ $ gzé = ±) gf ± gzo = g benzimidazole
21.5 grams (0.1 mole) of (thiazolyl-4) methyl-2-benzimidazole in 500 milliliters of benzene are treated with 2.4 grams (0.1 mole) of sodium hydride for two hours at 50 C then added little by little a solution containing 16.5 grams (0.1 mol) of monoethyl succinate monochloride in 100 milliliters of benzene; maintained at 50 C for one hour, cooled and washed several times with an aqueous bicarbonate solution; the benzene is removed by distillation under reduced pressure.
 EMI24.2
 



  Q2. (Carboxz-3 hò ± zl [-1¯ (tgiaõlzJ-4) -g Éenzggµµzoe 31.6 grams (0.1 mole) of (3-ethoxycarbonyl propyl) -1 (thiazolyl-4) -2 benzimidazole are treated with 100 milliliters of 1.5M soda in alcohol in a water bath for one hour; then cool and add a quantity of hydrochloric acid M corresponding exactly to the quantity of soda used; add another 200 milliliters of cold water and separates the product by filtration.
 EMI24.3
 



  13 ¯rSel, from (carboxy = 1-undecyl) ¯1- (thiazoll =) benzimidazole morhdlirie
40 grams (0.1 mole) of (carboxy-l undecyl) -1 (thiazolyl-4) -2 benzimidazole in boiling saturated alcoholic solution are treated with 8.7 grams (0.1 mole) of morpholine; is removed by distillation under reduced pressure.



   The acid used is obtained by saponification of (methoxycarbonyl-1 undecyl) -l (thiazolyl-4) -2 benzimidazole, itself obtained by operating as in Example 10 or 11 but using 29.3 grams ( 0.1 mol) of methyl 2-bromo laurate.
 EMI24.4
 ijf, ¯ (ggfiõ) z = ± 1 = g¯gzµ ± µ ± gf9jmzé = µ¯É ± ± ìmidµ ± ±) j We treat 6 grammEd (0.12 mol) of hydrazine hydrate in 200 milliliters of methanol at reflux with 27.3 grams (0.1 mol) of (thiazolyl-4) -2 ethoxycarbony1-5 benzimidazole added little by little; reflux is maintained for two hours after the end of

 <Desc / Clms Page number 25>

 the bill; cooled to 10 ° C. then separated the hydrazide formed by draining,
 EMI25.1
 15.

   (H drazinoform 1-2 entne- 0 1) -1 L (thiazol 1-4 -2 ethyl-2-benzimidazole
The procedure is as in Example 14 but using 38.3 grams (0.1 mol) of (2-ethoxycarbonyl penten-4 oyl) -1 (thiazoly1 -4) -2 ethyl @ -2 benzimidazole.
 EMI25.2
 



  16. (Thiazol 1-q.) Mcth 1-2 (thiazol 1- °) -5 benzimidazole
14.4 grams (0.1 mole) of (thiazolyl-4) acetic acid and 19.2 grams (0.1 mole) of (thiazolyl-4) -4 diaminobenzene are treated in 250 grams of polyphosphoric acid for one hour at 120 ° C. then the temperature is gradually increased so as to reach 180 ° C. in two hours; maintain this temperature for two hours and break the hot mixture onto 500 grams of brayed ice; stirred until the liquid has become homogeneous and then neutralized to pH 7 using a sodium hydroxide solution; the product formed precipitates and is drained.
 EMI25.3
 



  170. IIxdroxy = 1- (thiazo11w4) ¯2wethxl -2 benzimidazole
2.5 grams of magnesium are reacted with 17.8 grams (0.1 mule) of 4-bromomethyl thiazole in 50 milliliters of tetrahydrofuran and then 14.6 grams (0.1 mole) of 2-formylbenzimidazole in 75 milliliters are added. tetrahydrofuran; one heated in a boiling water bath for two hours; a stream of dry nitrogen is maintained in the reaction medium throughout the operation; it is cooled and then poured into approximately 250 milliliters of normal sulfuric acid, still operating under nitrogen; stirred for ten minutes then neutralized between pH 6 and 7 with ammonia; the product formed is separated by filtration.
 EMI25.4
 



  ) 8f.¯ (ghiazoo) = µlhzdj ± xzmfthzl = g¯É ± nµimiãzgjf
10.8 grams (0.1 mol) of orthophenylenediamine are treated per 14 grams (0.1 mol) of α-cyano α-4-hydroxymethyl-thiazole in 100 milliliters of 6M hydrochloric acid at the boiling point for two o'clock; the product formed is precipitated, after

 <Desc / Clms Page number 26>

 cooling, by adding ammonia to a pH between 6 and 7, then it is separated by draining.
 EMI26.1
 



  19. (Thiazol 14) -2 benzimidazole-aulfonamide-5
11.4 grams (0.1 mole) of 4-formyl thiazole and 18.7 grams (0.1 mole) of 3,4-diamino-benzenesulfonamide are treated in 200 milliliters of ethanol for gentle hours then added little to little 22 grams (011 mole) of copper acetate monohydrate dissolved in 200 milliliters of water; then reflux for one hour and leave to cool; cupric complex of the compound formed is destroyed by a stream of hydrogen sulfide sent into the medium subjected to vigorous stirring; reflux door and boiling filter to remove copper sulphide;

   the product formed is isolated by distillation under reduced pressure from the solvent and is then washed several times with slightly ammoniacal water.
 EMI26.2
 



  20. (Thiazo.xl4) methZ = 2 aminō5 benzimidazole
18.3 grams (0.1 mole) of 2,4-dinitroaniline in solution in 100 milliliters of anhydrous pyridine are treated with 16.2 grams (0.1 mole) of (14-thiazolyl) acetyl chloride overnight. at room temperature then precipitates, by addition of water, the dinitranilide formed; filtered off and the precipitate introduced into 150 milliliters of ethanol and 50 milliliters of concentrated hydrochloric acid; it is treated with hydrogen, at a pressure in the region of 3 bars, and in the presence of 2 grams of catalyst containing 5% palladium on alumina; the hydrogenation is carried out with good stirring and is stopped when the hydrogen absorption reaches 0.6 mol, that is to say 1.2 grams;

   the pressure is brought back to atmospheric value and the reaction medium is brought to the boil for four hours to complete the reaction; the major part of the alcohol is removed by distillation then the cooled residue is neutralized by means of ammonia; it is filtered and the residue is dried in an oven under reduced pressure and then subjected to an extraction with boiling dioxane;

   

 <Desc / Clms Page number 27>

 the residue then mainly constitutes the catalyst while the product has gone into solution and is isolated by distillation of the solvent under reduced pressure.
 EMI27.1
 gj ± ¯Né ± hz) = ¯ (tjiazoly) = 4) = 2¯g = j ± lyµc = ju ± ± jg ± g = j¯bQµ ± ± fgfl #
23 grams (0.1 mole) of 1-methyl (4-thiazolyl) -2 aminobenzimidazole are treated in 100 milliliters of anhydrous pyridine per 21 grams (0.11 mole) of 80 p-toluene-sulfonyl chloride. C for two hours;

   the pyridine is removed by distillation under reduced pressure and the residue is washed several times with a bicarbonate aqueous solution.
 EMI27.2
 ggf¯gracétzlrîb ± fuànnosgl = 1¯ (thµzglzl- ± 1-2¯geozimiµjõl ±
20.1 grams (0.1 mol) of (thiazolyl-4) -2 benzidazole in 250 milliliters of absolute ethanol are treated with 6.8 grams (0.1 mol) of sodium ethoxide in a manner to form the soda derivative; a solution containing 27.2 grams (0.1 mol) of mercuric chloride in 200 milliliters of 50% aqueous alcohol is then added, the mixture is heated to 80 ° C. for 30 minutes while stirring, cooled and the chloromercuric compound separated by filtration;

     compound is suspended in 1500 milliliters of xylene; the alcohol transported by the compound is removed by distillation of 300 milliliters of xylene under normal pressure; refluxed and introduced little bit 31 grams (0.1 mol) of triacetyl-2,3,5 D-ribofuranosyl chloride; reflux is maintained for six hours then the xylene is removed by distillation under reduced pressure; the residue is introduced into 200 milliliters of 30% aqueous potassium iodide solution; extracted twice with 500 milliliters of boiling chloroform;

   the chloroform solution is dried over anhydrous magnesium sulfate and the chloroform is removed by distillation under reduced pressure.
 EMI27.3
 g¯ !! ± 1l! g! ± 2El! 2l! =! ¯i1h! 2l!: il! hl!: g benzimidazole
A solution containing 17 grams (0.1 mol) of silver nitrate in 100 milliliters of water is treated with sufficient

 <Desc / Clms Page number 28>

 ammonia to redissolve the precipitate formed; a saturated alcoholic solution containing 21.5 grams (0.1 mol) of (4-thiazolyl) 2-methylbenzimidazole is added; the whole is concentrated to 75 milliliters by distillation under reduced pressure, allowed to cool and the compound formed is separated by filtration.

   This compound is suspended in 1500 milliliters of xylene and the aqueous alcohol transported by the compound is distilled off from 300 milliliters of xylene under normal pressure; is refluxed and introduced little by little 42.6 grams (0.1 mol) of tetraacetylglucopyrannosyl bromide; reflux is maintained for six hours then the xylene is removed by distillation under reduced pressure; the residue is introduced into 200 milliliters of M aqueous solution of sodium thiosulfate; entered with twice 500 milliliters of boiling chloroform;

   the chloroform solution is dried over anhydrous magnesium sulfate and the chloroform is removed by distillation under reduced pressure.
 EMI28.1
 g4 ± ¯Régg ± µrgsz) = 1¯ (tgiµzo) z-4) gf ± jz = g¯bjµmµjµè
Is treated, with stirring at 0 C for 24 hours, 47.7 grams (0.1 mol) of triacetylribofurannosyl-1 (thiazolyl-4) methyl-2 benzimidazole with 1500 milliliters of mehanol saturated with anhydrous ammonia at 0 C; the methanol is then removed by distillation under reduced pressure and the product is recrystallized from absolute ethanol.
 EMI28.2
 



  25. Copper (Thiazol 1-4) meth 1¯2 bepzimidazolate
250 milliliters of absolute ethanol are treated with 2.3 grams of sodium; when the metal has disappeared, 21.5 grams (0.1 mol) of (thiazolyl-4) methyl-2 bonzimidazole are added and refluxed; 10 grams (0.05 mole) of crystallized cupric acetate in solution in 150 milliliters of alcohol are introduced; the whole is concentrated to 75 milliliters, 100 milliliters of cold water are added and the compound formed is separated by filtration.
 EMI28.3
 



  26. Calcium (Thiazol 1-4) -2 benzimidazole-sulfonate5 28.1 grams (0.1 mole) of (thiazoly1-4) -2 acid are introduced

 <Desc / Clms Page number 29>

   benzimida.zole-sulfonique-5 and 7.4 grams (0.1 mole) of calcium hydroxide in 200 milliliters of water and boil for a few minutes; the boiling mixture is vaporized in a container where a vacuum is maintained; the compound formed is collected in the form of a very fine white powder.
 EMI29.1
 gzīh = J ± él = µuònz = 1¯ (± gg ± ± gozé = 41rg¯erzgmgµ ± ± ± ± g
38.5 grams (0.1 mol) of p-toluene-sulfonyl-1-chloroacetyl-2 bonzimidazolee are treated with 9.2 grams (0.11 molu) of sodium bicarbonate and 6.7 grams (0.11 mol) thioformamide in 250 milliliters of ethanol;

   it is maintained at around 20 ° C. for one hour with good stirring and then the temperature is gradually raised to reach 40 ° C. in two hours; hold for one hour then bring to a gentle boil for 15 minutes; the alcohol is distilled off under reduced pressure and the residue is washed several times with ice water to remove mineral salts.
 EMI29.2
 gµ ± ¯ (± hµloxzsµ) ± '± nz) = g¯µ ± jzl [= ¯ (± g [µ ± ±) z = ± 1 = g¯ ± ljj ± µ ± ±) ±
18.4 grams (0.1 mol) of ethylene phenyl sulfonate in 50 milliliters of methanol are treated at 30 ° C. with good stirring with 20.1 grams (0.1 mol) of (thiazolyl-4) - 2 benzimidazole suspended in 100 milliliters of methanol; the suspension is introduced in about 30 minutes;

   then gently heated so as to obtain, after one hour, a slight reflux which is maintained for one hour; removes methanol by distillation under reduced pressure.
 EMI29.3
 



  29. (H drox -2 Eth 1) -1 (thiazolyl -.) - 2 benzimidazole
We treat, 170/180 C for 4 hours in a small autoclave, with good agitation, 20.1 grams (0.1 mol) of (thiazolyl-4) -2 benzimi.azole in 250 milliliters of xylene and 0 , 5 milliliters of water per 4.4 grams (0.1 mole) of ethylene oxide; after reaction, it is cooled and brought back to atmospheric pressure;

   the xylene is removed by distillation under reduced pressure,

 <Desc / Clms Page number 30>

 
 EMI30.1
 300. f (gµ ± gz) = ± 1 = g¯ ± +/−−−− [± ± ± ± ± ± -1¯7jfµµf ± gz ± µQf = g ± z ± g
The procedure is as in Example 29 but using 26.4 grams (0.6 mol) of ethylene oxide,
 EMI30.2
 Q ± ¯Br ± g ± ± ¯µf¯µggg ± y ± =) z¯ (± jQµj ± z ± = ±) = ± ¯ ± f ± µgtlgµµjgoxg
20.1 grams (0.1 mol) of (thi-zoly1-4) -2 benzimidazole are treated with a solution of 9.6 grams (0.1 mol) of sodium butoxide in 250 milliliters of n-butanol; 38.6 grams (0.2 mol) of 1-bromo-octane are added and gradually brought to the boil, which is maintained for two hours; the sodium bromide is removed by filtration of the boiling liquid and then, after cooling the filtrate, the compound formed is separated by suction.



  320. Benzimidazolium bromide
25.7 grams (0.1 mole) of propyl-1 (4-thiazolyl) methyl-2-benzimidazole are treated at reflux for five hours and are dissolved in 300 milliliters of n-butanol per 22.1 grams (0.1 mole) bromo-1 decane; after cooling, the compound formed is separated by suction.
 EMI30.3
 



  33. Ro sulphate 1-1 Dec 1-3 (thiazol 1) -methr.-2 benzimidazolium
95.6 grams (0.2 mol) of propyl-1-decyl-3 (thiazoly1-4) methyl-2-benzimidazolium bromide in saturated solution in boiling water are treated with a saturated solution, also boiling, containing 31.2 grams (0.1 mole) of silver sulfate. The silver chloride is removed by filtration of the boiling solution; after cooling the filtrate, the compound formed is separated by suction.
 EMI30.4
 



  34. Roxl carbonate = 1¯déerl¯3 (thiazolx, -4) 2-methylbenzimidazolium
The procedure is as in Example 33 but using a freshly prepared suspension containing 27.6 grams (0.1 mole) of silver carbonate.

 <Desc / Clms Page number 31>

 
 EMI31.1
 ± µīa = g ± ìlgjgigg ± ¯µēgrggzl-¯dfcz = ± ¯ (ìɵ ± zQ = ±) ijftzo = g benzimidazolium
Is added to the boiling solution of 1-propyl-decyl-3 (thiazolyl-4) methyl-2-benzimidazolium carbonate, prepared as in Example 34, a saturated solution containing 30.6 grams (0.2 mole) of acid. α-bromopropionic; after cooling, the compound formed is separated by draining.
 EMI31.2
 



  ¯ ± 2r¯ ± ¯! 22 !!:! L¯i! H !! 2!:! LgL¯!: 11: g benzimidazolium
The procedure is as in Example 31 but using 20.2 grams (0.1 mol) of (thiadiazol-1,2,3 yl-4) -2 benzimidazole.
 EMI31.3
 1-Qh! 2 ±! ± ¯ ± ¯i2 ±! 2! L!: Gl = ¯! H! 2 !!
15.3 grams (0.1 mole) of 2-chlorobenzimidazole are treated per 8.5 grams (0.1 mole) of thiazole in 250 milliliters of n-amyl alcohol under reflux and with stirring; the temperature of the limit point of reflux in the condenser increases as the disappearance of the thiazole is measured to reach that of the n-amyl alcohol (138 C) when the reaction is terminated; then leave to cool to room temperature and separate the product by spinning.
 EMI31.4
 éjs¯ez ± mgls¯siivantg¯ié) ytènt¯éi ± µ¯µ¯gjfgµ ± µ ± eg¯µ agi1Qgf¯auµ¯ ± ± nzimdazoles¯ ± trglge ± j¯à¯éāg ± ± ± nt ± ¯gy ± ± g ± 38.

   (Thiazoly1-4) -2 benzimidazole
19.5 grams (0.1 mol) of 2-chloroacetylbenzimidazole are treated with good stirring with 6 grams of fine powdered chalk and 6.7 grams (0.11 mol) of thioformamide in 250 milliliters of ethanol in maintaining the temperature in the neighborhood of 10 C for one hour; the temperature is gradually raised to reach 35/40 C in two hours; this is maintained for one hour then brought to a gentle boil for 15 minutes; the alcohol is then distilled off under reduced pressure; the residue is taken up in boiling ethyl acetate and the boiling solution is filtered; after cooling the filtrate, the product is

 <Desc / Clms Page number 32>

 isolated by spinning.



  39. (Methyl1-4 thiazoly1-5) -2 benzimidazole
The procedure is as in Example 38 but using 25.3 grams (0.1 mole) of (1-bromoacetonyl) -2 benzimidazole.
 EMI32.1
 1Q¯i! Hl: g¯! H! 2l = 11 = g¯ ± !! 2 ±
The procedure is as in Example 38 but using 8.2 grams (0.11 mole) of thioacetamide)
BEVENDICATIONS The invention relates to: 1, As new products, benzimidazoles having the following substitutions; - in position 1, a hydrogen atom or an alkyl, alk-
 EMI32.2
 nyle, aralcolet aralet "nyle, .artlc.ou * beta-cyclic; this residue may have one or more of its hydrogen atoms replaced by one or more halogens and / or one or more groups nitro, hydroxy, alkoxy, mercaptan, alcoylmercapto, carboxy, alkoxycarbonyl, amino, alkyllamino and / or acylamino;

   it can be connected to the nitrogen atom of benzimidazole directly or through a CO or SO2 group.



  - in position 2, a five-membered heterocycle including a sulfur atom and one or more nitrogen atoms linked by one of its carbon atoms directly to the benzimidazole or by the intermediary of a hydrocarbon group containing a with four carbon atoms in a straight or branched chain, saturated or having an ethylenic bond; the other carbon atom (s) of this heterocycle carry one or more hydrogen atoms and / or one or more amino, alkylamino, acylamino, nitro) hydroxy, alkoxy, carboxy and / or alkoxycarbonyl groups and / or one or more alkyl radicals , aralkyl and / or aryl; these residues can carry an alcohol, phenol or ether-oxide function.

** ATTENTION ** end of DESC field can contain start of CLMS **.


    

Claims (1)

- in any position on the benzene nucleus of the benzimidazole and preferably in position 5 or 6, a carboxy, sulfo, halogenosulfonyl, oarbonhydrazide, alkoxycarbonyl radical, or one of <Desc / Clms Page number 33> radicals -SO2.NH2, -SO2.NH.R 'or -NH.SO2.R' in which R 'represents an alkyl, alkenyl, aralkyl, aralkenyl, aryl or heterocyclic residue which may have one or more hydrogens replaced by a or halogens and / or one or more hydroxy, alkoxy, mercaptan, alkylmercapto, nitro, carboxy, alkoxycarbonyl, amino, alkyllamino and / or acylamino groups, 2. As new products, bcnzimidazoles having the following substitutions: - in position 1, one of the radicals below: - a -CH2.CH2.SO2.OR radical in which R can be an alkyl, aralkyl or aryl residue , possibly having one or more hydrogen atoms replaced by one or more halogens and / or one or more nitro and / or alkoxycarbonyl groups; - a radical -SO2.R 'in leq @@ l R' can be an alkyl, aralkyl, aryl or heterocyclic residue which may have one or more hydrogen atoms replaced by one or more halogens and / or one or more nitro groups, hydroxy, alkoxy, mercaptan, alkylmercapto, carboxy, alkoxycarbonyl, amino, alkylamino and / or acylamino, a hydrocarbon radical of 2 to 20 carbon atoms in a straight chain or branched, saturated or possessing an ethylenic bond and bearing in any position, a group - carboxy, carbonhydrazide or -COOR "in which R" represents an alkyl, alkenyl, aralkyl or aralkenyl residue; the hydrocarbon radical is linked to the benzimidazole directly or via a CO group. - a saturated hydrocarbon radical containing three% six carbon atoms, in a straight or branched chain or in a closed cycle, and bearing 2 to 5 hydroxy groups. EMI33.1 - a -CH2- (CH-O-CH2) nCH-OH radical in which n represents an R '"R" j any number which may be zero and R "' a hydrogen atom or a methylo, ethyl or phenyl residue. - a furannosyl or pyrannosyl radical deriving, by loss of a hydroxy group, from an aldose or a ketose under one of <Desc / Clms Page number 34> their two oxidic forms; the other hydroxy groups of the radioal may be free or esterified with one or more organic acids; - in position 2, a substitution as defined in 1; - in any position on the benzene ring of the benzimidazole, one or more hydrogen atoms and / or one or more halogens and / or one or more nitro, hydroxy and / or mercaptan groups and / or one or more alkyl or alkenyl radicals, aralkyl, aralkenyl and / or aryl connected to the nucleus directly or via a sulfur or oxygen atom. 3. As new products, benzimidazoles possessing the following substitutions: - in position 1, a hydrogen atom or an alkyl, alkenyl, aralkyl, aralkenyl or aryl residue linked to the nitrogen atom of the benzimidazole directly or by the intermediary of a CO group; the remainder may have one or more of its hydrogen atoms replaced by one or more halogens and / or one or more nitro, hydroxy, alkoxy, meroap @ an, alkyl mercaptb, carboxy, alkoxycarbonyl, amino, alkyllamino and / or groups acylamino; - in position 2, a thiazole heterocycle linked directly to the benzimidazole by one of its carbon atoms in position 4 or 5; the carbon atom in position 2 of the thiazole carries a car .. boxy, alkoxycarbonyl or nitrile group; - in any position on the benzene nucleus of bonzimidazole, the substitutions defined in 2 or, again, any heterocyclic radical. 4. As new products, benzimidazoles possessing the following substitutions: - in position 1, a substitution as defined in 3. - in position 2, a substitution as defined in 1, the heterocycle being, however, necessarily linked to the benzimidazole pax through the hydrocarbon group. -in any position on the benzene ring of benzimidazole, <Desc / Clms Page number 35> the substitutions defined in 2 or, alternatively, a heterocyclic radical Any or a primary, secondary or tertiary amino group. 5, As new products, the benzimidazoles having the following substitutions; . - in position 1, a hydrogen atom or an alkyl, aloenyl, aralkyl, aralkenyl or aryl residue; remainder may have one or more of its hydrogen atoms replaced by one or more halogens and / or one or more hydroxy, nitro, alkoxy and / or alkyl-mercapto groups; - in position 2, a hydrocarbon radical containing one to four carbon atoms in a saturated straight chain carrying in alpha a hydroxy group and, optionally, an alkyl, alkenyl, aralkyl, aralkenyl or aryl residue which can have one or more of its atoms. hydrogen replaced by one or more halogens and / or one or more hydroxy, alkoxy and / or nitro groups; the hydrocarbon-based group necessarily carries, at the end of the chain, a heterocycle with five elements including a sulfur atom and one or more nitrogen atoms linked to the chain by one of its carbon atoms; its other carbon atom (s) bear one or more hydrogen atoms and / or one or more alkyl, alkenyl, aralkyl, aralkenyl and / or aryl and / or one or more hydroxy, alkoxy, nitro or alkylmercapto; - in any position on the benzene ring of the benzimidazole, one or more hydrogen atoms and / or one or more halogens and / or one or more hydroxy, carboxy or alkoxycarbonyl groups and / or one or more alkyl, alkenyl or aralkyl groups, aralkenyl and / or aryl linked to the benzimidazole directly or through a sulfur or oxygen atom. 6. As new products, the exiting benzimidazoliums bearing the following substitutions; - in position 1, a residue as defined in 5; - in position 2, a substitution as defined in 1; <Desc / Clms Page number 36> - in position 3, a remainder as defined in 5 for lq position 1; - in any position on the benzene nucleus of the benzimidazole, the substitutions defined in 2 or, alternatively, any heterocyclic radical; - as anion, the remainder of a mineral or organic acid, of a phenol or of a mercaptan. 7. As new products, benzimidazoles bearing the following substitutions: - in position 1, a hydrogen atom or an alkyl, aloinyl, aralkyl, aralkenyl, aryl or heterocyclic residue; this residue may have one or more of its hydrogen atoms replaced by one or more halogens and / or one or more nitro, hydroxy, alkoxy, mercaptan, alcoylmercapto, amino, alcoylamino, acylamino, groups. carboxy and / or alkoxycarbonyl; it can be linked to the benzimidazole directly or via a CO or SO2 group, - in position 2, a thiazole heterocycle linked via its nitrogen atom to the benzimidazole directly or via a hydrocarbon group containing a , four carbon atoms in the form of a straight or branched chain, saturated or having an ethylenic bond; thiazole carbon atoms may carry one or more hydrogen atoms and / or one or more nitro, hydroxy, mercaptan, carboxy, alkoxycarbonyl and / or acylamino groups and / or one or more alkyl, alkenyl, aralkyl, aralkenyl, and / or aryl linked directly or through a sulfur or oxygen atom; - in any position on the benzene nucleus of benzimidazole, the substitutions defined in 2. - as anion, the remainder of a mineral or organic acid, of a phenol or of a mercaptnn. 8. As new products, the salts formed between the products defined in 1, 2, 3, 4 and 5 and mineral acids, organic acids, phenols or mercaptans. <Desc / Clms Page number 37> 9. As new products, the salts formed between the products defined in 1, 2, 3, 4 and 5, in which there is a carboxylic or sulphonic acid function, and the organic bases, ammonia. Or metals. 10. As new products, the compounds described above further carrying any metal attached to one of the nitrogen atoms. 11. The use of the suedefined products as agents for the control of helminths, parasitic fungi of wood, plants, man, animals, food and various materials, harmful bacteria and pathogenic viruses. 12. Liquid, plastic or solid compositions intended for the above applications and containing one or more products of the invention, 13, The manufacture of products by the action of aromatic orthodiamines suitably substituted on the carboxylic acids containing the desired radical in position 2 of benzimidazole or on the corresponding anhydrides, amides, nitriles, esters or halides. 14, The manufacture of products as stated in 13, the operation being catalyzed by a mineral acid, 15. The production of the products by the action of aromatic orthodiamines suitably substituted on the carbonalddhides containing the desired radical in position 2 of the benzimidazole, the reaction being accompanied or followed by oxidation by oxygen, atmospheric or not, or by a oxygen carrier. 16. The manufacture of the products by the reduction of the orthonitra- nilides formed by condensation of the orthonitranilines suitably substituted with the carboxylic acids containing the desired radical in position 2 of the benzimidazole, the reduction being carried out with hydrogen, in the presence or absence of d 'a catalytic converter, or by an oxygen acceptor. 17. The manufacture of products by halogenation of N-arylcar- <Desc / Clms Page number 38> bonamidines in which the aryl radical is suitably substituted and in which the carbon atom of the car- radical. bonamidine is linked to the desired radical in position 2 of the benzimidazole, the halogenation being followed by dehalogenation by means of a base or a basic salt. 18. The manufacture of the products by the action of compounds possessing vicinal sulfur, carbon and nitrogen atoms on the benzimidazoles bearing, in position 2, a hydrocarbon radical possessing a 00 group close to a halogenated carbon $ the operation being carried out in the presence or absence of an acid acceptor. 19, The manufacture of the products by the decarboxylation of the products of the invention having a carboxyl radical in position 2 of the thiazole ring, the decarboxylation being carried out by heating or not. 20. The production according to 18 and 19 of the foreign products 4 of the invention consisting of benzimidazoles having the following substitutions: - in position 1, a substitution as defined in 3; - in position 2, a thiazole heterocycle attached directly to the benzimidazole by one of the thiazole carbon in position 4 or 5, the other carbon atom carrying a hydrogen atom or an alkyl, aryl or aralkyl residue; the carbon atom in the 2-position of the thiazole forms a hydrogen atom or a hydrocarbon residue or a hydroxy, amino or alkylamino group. - in any position of the benzene nucleus of the benzimidazole, the substitutions defined in 2. 21. The manufacture of products by the action of strong acid esters on benzimidazoles having the desired substitutions and, in position 1, a hydrogen atom or a metal. 22. The production of the products by the action of anhydrides or halides of oarboxylic acids on the benzimidazoles having the desired substitutions and, in position 1, a hydrogen atom or a metal. <Desc / Clms Page number 39> 23. The production of the products by the action of organic sulfonyl halides on benzimidazoles having the desired substitutions and, in position 1, a hydrogen atom or a metal. 24. The manufacture of the products as described in 21 when the ester used is the halide derived from a furannose or a pyrannose by replacement of a hydroxy group by a halogen, the other OH groups possibly being esterified with an acid organic. 25. The manufacture of products as stated in 21 when the ester used is a polyethylene glycol, polypropylene glycol or polybutylene glycol monohalide. 26. The production of the products by the action of organic sulfonyl halides on benzimidazoles having the desired ingredients and a primary or secondary amino group. 27. The production of the products by the action of ethylene sulfonic esters on suitably substituted benzimidazoles having a hydrogen atom in position 1. 28. The manufacture of products by the action of 1,2-epoxides derived from ethylene, propylene, butylene or styrene on suitably substituted benzimidazoles having a hydrogen atom in position 1. 29. The production of quaternary benzimidazoliums by the action of strong acid esters on suitably substituted benzimidazoles or on their alkali derivatives. 30 . The manufacture of quaternary benzimidazoliums by displacing an anion by means of a salt whose cation can form an insoluble compound with the anion to be displaced or by means of an acid when the anion to be displaced can give a compound volatile. 31. The manufacture of the products in 7 by the action of a suitable thiazole on a suitably substituted benzimidazole having a halogen or a halogenated hydrocarbon radical in position 2. 32. The manufacture of the products described in 7 by displacement <Desc / Clms Page number 40> of an anion as stated in 30. 33. The manufacture of sulfonamide products by the action of ammonia or of a suitable amine on the benzimidazoles suitably substituted and bearing a halogenosulfonyl radical. 34. The manufacture of products bearing a hydrazide function by the action of hydrazine on the carboxylic esters of the invention. 35. The manufacture of products bearing an ester function by esterification of the carboxylic acids of the invention. 36. The manufacture of salts by the action of strong bases on the esters of the invention. 37. The manufacture of salts by the action of bases or basic salts on the carboxylic or sulphonic acids of the invention, 38, the manufacture of salts by the action of organic or mineral acids, phenols or mercaptans on the products of the invention. invention in the form of free bases. 39. The production of the free carboxylic acids of the invention by the action of strong acids in a quantity calculated on the salts in which the anion is obtained from a compound of the invention, 40. The production of free bases by the action of strong bases on the salts in which the cation is obtained from a compound of the invention. 41. The manufacture of products in which a metal is linked to a nitrogen atom by the action of oxides; hydroxides, alkoxides, salts and other metal compounds on suitably substituted benzimidazoles, or on their alkaline derivatives when it is a question of obtaining non-alkaline derivatives.