Patent GB-388374-A (GB)
Title: Process for the manufacture of therapeutically active complex metal compounds
Filed: 1931-08-19
Abstract: Complex heavy metal compounds are prepared in the known manner from benz- or naphth-imidazoles which contain at least one salt-forming group, starting materials which are dyestuffs or contain a mercapto group in the imidazole ring being excluded. The products, which are water-soluble, are useful therapeutically.  Examples of salt-forming groups are acid groups such as sulphonic acid, carboxylic acid, aminomethane-sulphonic acid, arsinic acid and the glycine residue, and basic groups such as aminoalkyl and amino-cycloalkyl groups and heterocyclic residues such as pyridyl, piperidyl and quinolyl; the basic residues may be connected with the imidazole directly or by means of oxygen, sulphur or nitrogen.  The preparation may be carried out by treating imidazoles containing the salt-forming group with heavy metal oxides or hydroxides, metal acids or salts or double salts and precipitating the product with a water-miscible organic liquid such as methyl or ethyl alcohol or acetone; or by converting imidazoles not containing salt-forming groups into the complex metal compounds and then introducing an acid or basic group; or by using materials which do not contain the imidazole ring and causing ring formation to take place before or after treatment with a heavy metal compound; or by forming the imidazole ring in heavy metal compounds simultaneously with the introduction of salt-forming groups. According to the examples, (1) gold benzimidazole-5-sulphonic acid is obtained by treating benzimidazole-5-sulphonic acid, prepared by sulphonating benzimidazole, with potassium aurichloride; the copper, silver, and mercury compounds are similarly prepared using cupric chloride, freshly-precipitated silver oxide and mercuric chloride respectively; (2) treatment of benzimidazole-5-carboxylic acid with gold chloride gives the gold compound; (3) gold benzimidazole-5-hydroxyacetic acid is obtained by reacting potassium aurichloride with benzimidazole-5-hydroxyacetic acid, which is prepared by reducing 3-nitro-4-amino-1-methoxy-benzene, condensing the 3-amino compound with formic acid, demethylating the resulting 5-methoxy - benzimidazole and treating it with chloracetic acid; (4) benzimidazole-5-aminoacetic acid, prepared by the action of chloracetic acid on 5-aminobenzimidazole, is converted into its gold compound by means of potassium aurichloride; (5) the gold compound of benzimidazole-5-acetic acid is prepared by means of potassium aurichloride; the starting material is obtained from p-aminophenylacetic acid by introducing a second amino group in the m-position by acetylation, nitration, deacetylation and reduction, followed by imidazole formation with formic acid; (6) benzimidazole-5-arsinic acid, which results from the treatment of 3 : 4-diaminophenylarsinic acid with formic acid, is converted into its silver salt with silver nitrate and into its gold compound by means of potassium aurichloride; (7) copper benzimidazole-5-sulphonic acid is prepared by heating the copper salt of 3 : 4-diaminobenzene-sulphonic acid with formic acid; (8) 3 : 4-diaminophenoxybenzene is condensed with o -diethylaminobutyric acid ester and the resulting 2 - diethylaminopropyl-5-phenoxybenzimidazole converted into its silver compound with silver nitrate; (9) the copper compound of benzimidazole-5-carboxylic acid ethyl ester is heated with dilute hydrochloric acid to give the corresponding free acid; treatment of the same starting material with diethylaminoethanol yields the copper compound of benzimidazole-5-carboxylic acid-diethylaminoethanol ester; (10) copper benzimidazole-5-sulphonic acid is prepared by heating either 3 : 4-diaminobenzene-sulphonic acid with copper formate and formic acid or benzimidazole with copper sulphate and concentrated sulphuric acid; (11) o-phenylenediamine is condensed with o -diethylaminobutyric acid ethyl ester in the presence of copper sulphate, forming the copper compound of 2-diethylaminopropylbenzimidazole; (12) 2- (2<1> - methyl - 4<1> - quinolyl)- benzimidazole is prepared by heating o-phenylenediamine with 2-methyl-4-quinolinecarboxylic acid ethyl ester and transformed into its silver salt using silver nitrate; (13) the silver compound is obtained by reacting silver nitrate with 5-w-diethylaminoethoxybenzimidazole, prepared by alkylation of 5-hydroxybenzimidazole by means of diethylaminoethyl chloride; (14) benzimidazole-sulphocarboxylic acid, formed on sulphonation of benzimidazole-5-carboxylic acid, is converted into its gold compound by means of auric chloride; in similar manner, the gold compounds of 1 : 2-naphthimidazole-5-sulphonic acid, obtained from 1 : 2-naphthylenediamine-5-sulphonic acid by means of formic acid, and of benzimidazole-5-stibinic acid, prepared from 5-aminobenzimidazole with diazotization and treatment with antimony trioxide, are obtained.