Guanidines and biguanides

Certain aromatic guanidines (and biguanides) are known to cause a reflex fall of blood pressure and heart rate by an action on receptors in the heart [288]. However, there have been no reports of arylguanidines exhibiting activity at sympathetic nerve endings. o-Bromophenylguanidine (LXXIV) does not affect cat nictitating membranes [239]. 

Biguanides, which are even stronger bases, open new perspectives but they require special preparations. Novel syntheses of poly-N-alkylated biguanides have been devised from carbodiimides, and recent examples of catalyses with soluble and immobilised guanidines and biguanides are presented with emphasis on the transesterification of triglycerides from vegetable oils. 

A short review of the uses of polymeric and immobilised guanidines and biguanides is given along with recent results on the preparation and properties of biguanides. 

Table 1 Comparative efficiencies of soluble and immobilised guanidines and biguanides in the transesterification of rapeseed oil with methanola.

Long-chain alkylamines and the corresponding ammonium salts can also be characterized as cationic surface agents they exhibit considerable antimicrobial activity if the alkyl chain consists of 12-15 carbon atoms. This is also valid for aliphatic diamines, guanidines and biguanides (Section 16.2). 

The guanidines and biguanides exhibiting antimicrobial activity derive from guanidine and guanylguanidine = biguanide respectively. These are alkaline substances, stabilized by resonance they form salts with acids. 

GUANIDINES AND BIGUANIDES 18.3.2. Bis(guanidinooctyl)amine triacetate C24H53N7O6... 

A recent new synthesis of biguanide, affording 50—60% yields of product, utilises the reaction between 0-adkylisoureas and equimolar proportions of guanidine and its hydrochloride in ethanol (612). Small amounts of melamine and cycuioguanidine are formed as by-products. 

Under the influence of desulphurising agents, guanidines and thioureas combine to form biguanides (XIX), albeit in low yields (722, 575). In their re-examination of this reaction. Curd, Rose et al. (24, 57, 754) synthesised 1,5-disubstituted biguanides however, the yields did not... 

The formation of a biguanide as a by-product in a condensation of a cyanamide and amine (225) (which would normally be expected to yield a guanidine) and as main product in the reaction of glucosamine and cyanamide (437) has been noted. In the former example, the small amount of biguanide probably arose by further reaction of the primary guanidine (which formed the main product) with C5 namide. In the second example the biguanide may be the result of the interaction of the amine and intermediate cyanoguanidine. 

The acid hydrolysis of biguanides under a variety of conditions 5uelds chiefly amidinoureas the subject has been reviewed by Ray (531). The reaction proceeds slowly under very mild conditions at room temperature thus, Paludrine, when stored in 2N hydrochloric add slowly deposits N-p-chlorophenyl-N -isopropylamidinourea hydrochloride (140). That this product was not the isomeric N-isopropyl-N -p-chlorophenyl-amidinourea was verified by its rmequivocal s3uithesis from isopropyl-guanidine and p-chlorophenyl isocyanate (140) ... 

The filtrate contains guanidine nitrate along with a small amount of ammonium nitrate and very small amounts of dicyano-diamide and biguanide nitrate (Note 6). The solution is concentrated to about 1 1. and the guanidine nitrate which crystallizes on cooling is filtered off. A second crop is obtained by... 

Figure 2 Cross-conjugated 4 and fully-conjugated biguanides 5. 2 SOLUBLE GUANIDINES AND POLYGUANIDINES...

These biguanide-supported catalysts are far more reactive and more stable than the previously described guanidines.,7b This confirms the higher basicity of biguanides vs. guanidines and that their immobilisation induces only a very limited decrease in reactivity 90% instead of 94% yield after 30 mn reaction time. 

Oral antidiabetes drugs are of two kinds sulphon-amide derivatives (sulphonylureas) and guanidine derivatives (biguanides). They are used by 30% of all diabetics. Unlike insulin they are not essential for life. 

Lowering of blood glucose by the infusion of guanidine [89], biguanides and two linked guanidine moieties has proved to be useful for the treatment of diabetes meUims. Three compounds became available for diabetes therapy, phenformin (51), buformin (52) and metformin (53) (Figure 10.12). Phenformin (51) was withdrawn due to lactic acidosis [90]. Metformin (53), a less lipophilic biguanide, was recently approved for use in the USA after 20 years of use in Europe [91]. 

Guanidine and guanylguanidine (biguanide) are bases which are stabilized by resonance. They exhibit strong alkaline reaction in aqueous media and form salts with acids. Alkyl derivatives dispose of distinctive antimicrobial efficacy. 

More than a third part of all the described principal syntheses of pyrimidines bearing fluorinated alkyl at C-4 atom commences from fluorinated p-dicarbonyl compounds 699. The chemistry of these bis-electrophiles was reviewed recently [411, 412] therefore, their preparation is not discussed herein. This synthesis of pyrimidines is fairly general (Table 34) it allows for introducing aliphatic, alicyclic and aromatic p-diketones (Entries 1-10), p-ketoesters (Entries 11-16), and cyclic P-ketoamides (Entry 17). Presence of some functional groups, such as additional ester moiety (Entry 15), is more or less tolerated, whereas increasing steric hindrance results in lowered yields of the products (Entry 10). A scope of conunon NCN binucleophiles include amidines (Entries 1, 11, 12, 17), (thio)urea and its derivatives (Entries 2-4), guanidines (Entries 5,16) and biguanides (Entry 6). Electron-rich amino heterocycles e.g. aminoazoles and even 2,6-diaminopyridine) are excellent NCN binucleophiles for the principal synthesis of fused pyrimidine derivatives (Entries 7-10, 13-15). 

Uses. Dicyandiamide is used as a raw material for the manufacture of several chemicals, such as guanamines, biguanide and guanidine salts, and various resias. Siace 1975, it has also been used ia the manufacture of potassium or sodium dicyanamide which are used as iasecticides and ia chemotherapy. Melamine has extensive appHcations ia the resia and plastic iadustry guanamines are used as copolymers (qv) ia many resia compositions. Guanidine phosphate [1763-07-1] is employed as a fire retardant ia appHcations where water solubiHty is not a drawback. 

Benzoguanamine has been prepared by the reaction of dicyandiamide with benzonitrile in a sealed tube at 220-230°,2 with an excess of benzonitrile in the presence of piperidine and potassium carbonate,3 with benzonitrile in a solvent in the presence of a basic catalyst,4 and with benzamidine hydrochloride at elevated temperatures.5 It has also been prepared from the reaction of biguanide acetate with benzamidine hydrochloride,5 or of bigua-nide sulfate with benzoyl chloride in an alkaline medium,7 and by the distillation of guanidine benzoate.5... 

Later workers (489) have postulated the existence of intermediate biguanide in the interaction of cyanoguanidine and ammonium nitrate in liquid ammonia (at relatively high temperatures). The reaction is thus thought to adopt the same reaction path as that of the analogous fusion, but positive evidence for this view is difficult to obtain, because of the rapidity with which all postulated intermediates are onverted into guanidine salts. 

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