Patent GB-1113808-A (GB)
Title: Antifungal methods and compositions
IPC: C07D235/18
Filed: 1965-07-28
Abstract: Substituted benzimidazoles of the general formula <FORM:1113808/C2/1> wherein R is an aromatic radical, a 5-membered heterocyclic radical containing only one hetero atom, a 6-membered heterocyclic radical or a condensed ring heterocyclic radical; R1 is a hydrogen atom or a C1- 5 alkyl, C2- 5 alkenyl, aroyl, alkanoyl, aralkyl or aralkenyl radical; R5 is a hydrogen or halogen atom or a C1- 5 alkyl, amino, phenyl, phenoxy or C1- 5 alkoxyphenyl radical; and R6 is a hydrogen atom or a C1- 5 alkyl radical; and acid addition salts thereof; are employed as antifungal agents (see Divisions A2, A5 and B8).  The substituted benzimidazoles may be prepared by treating an appropriately substituted nitroaniline with a compound of formula R-B, where R is as defined above and B is carboxy, carboalkoxy or acyl halide, and then reducing the anilide thus obtained to convert the nitro group to an amino group and to cyclize the product.  The preparation, by this method, of the following compounds is described: 2 - (21 - furyl) - 5 - phenyl benzimidazole, 2 - (21 - thienyl) - 5 - phenyl benzimidazole, 2-(41-chloro - 21 - furyl) benzimidazole and 2 - (21-furyl)-5-fluor benzimidazole. Alternatively, the substituted benzimidazoles may be prepared by treating an o-phenylene diamine with an aldehyde R-CHO (where R is as defined above), oxidizing the product with a heavy metal salt and then removing heavy metal.  The preparation of 2 - (21 - pyrryl) - 5 - phenyl benzimidazole by this method is described.  A further method of preparing the substituted benzimidazoles consists in reacting an appropriately substituted o-phenylene diamine with a compound R-D (where R is as defined above and D is a carboxylic acid group or a derivative thereof) in the presence of polyphosphoric acid.  The preparation of 2-(31-coumarinyl benzimidazole, 2-(31-thiacoumarinyl) benzimidazole and 2-(41H-41-oxo - 31 - thiapyranyl) benzimidazole by this method is described. Further substituents may be introduced by reacting the substituted benzimidazole with an acyl, alkyl or aralkyl halide.  The preparation by this method, of the following compounds is described: the 1-benzoyl, 1-acetyl, 1-methyl and 1-benzyl derivatives of 2 - (41 - chloro - 21 - furyl) benzimidazole and 1 - benzoyl - (derivative of) 2 - (41 - chloro - 21-furyl)-5-phenyl benzimidazole.  In the preparation of 2 - (41 - chloro - 21 - furyl) benzimidazole by the acylation of o-nitroaniline, followed by reduction of the nitro group and cyclization of the product, the acylating agent employed is one obtained by refluxing 4-chloro-2-furoic acid with thionyl chloride. A scheme for the preparation of 4-chloro-2-furoic acid is described in which: (a) ethyl-2-furoate is chlorinated to yield ethyl-2,3,4,5-tetrachlorotetrahydrofuran-2-carboxylate, which is then pyrolysed, (b) a fraction of the pyrolysis products which comprises ethyl-3,5 (and 4,5)-dichloro-2-furoates is hydrolysed with methanolic KOH and worked up to yield 4,5-dichloro-2-furoic acid and (c) an acetic acid solution of 4,5-dichloro-2-furoic acid is dehalogenated by the action of zinc dust and HCl to yield 4-chloro-2-furoic acid. Reference has been directed by the Comptroller to Specification 977,073.ALSO:Substituted benzimidazoles of the general formula <FORM:1113808/A1-A3/1> wherein R is an aromatic radical, a 5-membered heterocyclic radical containing only one hetero-atom, a 6-membered heterocyclic radical or a condensed ring heterocyclic radical; R1 is a hydrogen atom or a C1-5 alkyl, C2-5 alkenyl, aroyl, alkanoyl, aralkyl or aralkenyl radical; R5 is a hydrogen or halogen atom or a C1-5 alkyl, amino, phenyl, phenoxy or C1-5 alboxyphenyl radical; and R6 is a hydrogen atom or a C1-5 alkyl radical; and acid additional salts thereof; are employed as antifungal agents for use with foods. Thus, the substituted benzimidazoles may be incorporated in cheese or bread dough or applied to citrus fruit. The substituted benzimidazoles are useful for food preservation where fungi of the Aspergillus and Penicillium species are known to attack doughs, cakes, breads, pastries, meats, cheese, fruits, vegetables, cereal, jams and jellies, brines, fish, poultry, fats and oils, juices, honey, syrup, condiments, alcoholic beverages, confections and other food products.  Reference has been directed by the Comptroller to Specification 977,073.ALSO:Substituted benzimidazoles of the general formula <FORM:1113808/A5-A6/1> wherein R is an aromatic radical, a 5-membered heterocyclic radical containing only one hetero-atom, a 6-membered heterocyclic radical or a condensed ring heterocyclic radical; R1 is a hydrogen atom or a C1-5 alkyl, C2-5 alkenyl, aroyl, alkanoyl, aralkyl or aralkenyl radical; R5 is a hydrogen or halogen atom or a C1-5 alkyl, amino, phenyl, phenoxy or C1-5 alkoxyphenyl radical; and R6 is a hydrogen atom or a C1-5 alkyl radical; and acid addition salts thereof; are employed as antifungal agents.  Acid addition salts mentioned are hydrohalides, sulphates, nitrates, phosphates, salts of aliphatic acids and salts of polycarboxylic acids.  The antifungal agents may be utilized as powders, granular materials, solutions, emulsions, suspensions, concentrates, emulsifiable concentrates or slurries.  They may be used to form fungicidally active compositions which may also include finely divided dry or liquid diluents, extenders, fillers, conditioners and excipients, including various clays, diatomaceous earth, talc, water, C1-6 alkanols, kerosene, benzene, toluene and other petroleum distillate fractions or mixtures of them.  The antifungal agents may also be used in the topical treatment of mycotic infection in human beings.  For this furpose, they may be formulated as powders, creams or ointments, which may also contain bactericides and/or antiseptics. Specific examples are given of ointments or creams containing 2 - phenyl benzimidazole, 2 - (3\sv-furyl) benzimidazole or 2 - (3\sv - isoquinolyl) benzimidazole.