Chemistry and Structure-Activity Relationships of Biguanides
In 1878–1879, Rathke obtained a new compound in very low yield via a condensation reaction of thiourea and phosphorus trichloride (which are cyanamide generators) with guanidine.
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Chemistry and Structure-Activity Relationships of Biguanides E. PRUGNARD and M. NOEL
A. Introduction I. The First Known Synthesis In 1878-1879, RATHKE obtained a new compound in very low yield via a condensation reaction of thiourea and phosphorus trichloride (which are cyanamide generators) with guanidine.
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He decided to name this new compound "biguanide", considering that it could be Iikened to the result of a condensation between two molecules of guanidine with ammonia elimination. Subsequently, RATHKE noticed that the resuIting new product reacted with a copper sulfate solution to give pink crystals of the copper-biguanide complex, which was then converted into the sulfate (HERTH 1880). The synthesis was rapidly improved by using a condensation reaction of cyanoguanidine with an ammoniacal solution of cupric sulfate at 110°C in a sealed tube. The resulting complex was subsequently treated to give the sulfate. A few years later, it was shown that biguanides can be prepared by treating cyanoguanidine with ammonium chloride in boiling ethanol (SMOLKA and FRIEDREICH 1888). Finally, it was found that biguanides can be obtained by direct fusion of ammonium chloride with cyanoguanidine at 195°C for a few minutes (BAMBERGER and DIECKMANN 1892). It is noteworthy that, in all cases, the purification was effected by using the intermediate copper complex and the sulfate. A century later, this complexation reaction is still used in the synthesis of substituted biguanides to demonstrate the presence of biguanide (PATEREAU 1965, unpublished resuIts). This is a very suitable and easy to use method for detecting the presence of biguanide derivatives. J. Kuhlmann et al. (eds.), Oral Antidiabetics © Springer-Verlag Berlin Heidelberg 1996
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In 1951, OXLEY and SHORT improved the re action by the use of ammonium benzene sulfonate instead of ammonium chloride. Nevertheless, the yield never exceeded 30%. Concurrently, the same procedures have been followed for the synthesis of N-substituted biguanides, but relatively few compounds have been synthesized. In 1946 Chemical Abstracts mentioned only about 100 molecules which still had not found any application.
11. The Golden Age By contrast, the decade which followed World War 11 saw a very great deal of productive research, with the discoveries of: paludrine, an effective antimalarial drug (1947), antidiabetic biguanides (1958-1959) and chlorhexidine, a topical antibacterial and disinfectant (1956). In addition, the anticarcinogenic effect of some biguanides was established. Other compounds revealed an antitubercular or antiviral activity. On the other hand, biguanides are known to be starting materials for a variety of triazines and heterocyclic compounds of medical value. As KURZER (1955) said, "Although investigations on biguanides have been diverse, much remains to be done."
111. Nomenclature Since 1972, the nomenclature usually employed by Chemical Abstracts has been: "imidodicarbonimidic diamide". Nevertheless, for practical reasons and in con
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