81- 81-2 Warfarin

It is important not to confuse the properties of tautomerism and resonance. They are quite different effects and the differences between them are summarised in Table 3.1. Although the enol form of warfarin is present to 

Resonance forms of a druga Tautomeric forms of a drucf  

Differ only in position of electrons Differ in position of atoms (usually 

Each canonical form contributes to a hydrogen) single Each form exists in equilibrium 

Represented by a double-headed arrow — . Represented by an equilibrium arrow  

Other historical examples for the validity of this approach are the antitussive and constipating morphine analogs [51]. 

Another example was the discovery, that the anticoagulant warfarin is also a weak inhibitor of a viral enzyme that is important in the life cycle of HIV. Warfarin was used as the lead compound in the development of an anti-HIV drug called tipranavir. 

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I6I C. Warfarin baits need contain only 0 025% active principle, and rats are killed after ingesting about 5 doses the bait can be left down and the risk of acute toxicity to man or domestic animals is not serious. In common with other coumarin derivatives, warfarin reduces the clotting power of blood and death is caused by haemorrhages initiated by any slight injury. Warfarin is a vitamin K antagonist, and large oral doses of the vitamin can be given as an antidote. 

Pharmacogenetics the responses to dmgs may be significantiy different according to heritable factors that can modulate pharmacodynamic or pharmacogenetic factors (118). Atypical cholinesterase occurs in about 1 in 2000 Caucasians and is associated with a markedly reduced sensitivity to hydrolysis of the muscle-relaxant cholinesterase. Similarly, the reduced sensitivity to the anticoagulant warfarin is associated with a reduced receptor affinity. 

In contrast to heparin, the coumarinic acid anticoagulants are inactive in vitw ]6k.e heparin they are active in vivo. The phenylindanedione-type compounds (7) (36) and warfarin (2) produce their in vivo inhibitory effect on the coagulation system by competitively antagonizing the normal activity of vitamin (8) (37—44). 

Hydroxycoumarin [1076-38-6] can be synthesized by cyclization of acetyl methyl salicylate. It is a coumatin metaboHte occurring in spoiled hay. Derivatives of 4-hydroxycoumarin such as dicoumarol [66-76-2] warfarin [81-81-2] cyclocoumarol [518-20-7] ethylbis—coumaracetate [548-00-5] and bis-4-hydroxycoumarin [25892-93-7] are synthetic blood anticoagulants (see Blood, coagulants and anticoagulants). 

Warfarin [81-81-2] (6) is prepared by the Michael condensation of benzyHdene acetone with 4-hydroxycoumarin (86). It is used as a rodenticide (see Poisons, commercial) and in anticoagulant therapy. 

Wadsworth-Emmons reactions crown ethers and, 7, 759 Warfarin... 

Zineb Rodenticides Sodium Fluoroacetate Strychnine Thallium Sulphate Warfarin 5200 0.05 SK 0.15 0.1 as Tl, SK 0.1... 

VM and P naphtha Warfarin Welding fumes (total particulate) (NOC) F (0.8 pm MCEF) 720 1500 G... 

The isoprene-derived molecule whose structure is shown here is known alternately as Coumarin and warfarin. By the former name, it is a widely prescribed anticoagulant. By the latter name, it is a component of rodent poisons. How can the same chemical species be used for such disparate purposes The key to both uses lies in its ability to act as an antagonist of vitamin K in the body. 

Coumarin/warfarin, given at a typical dosage of 4 to 5 mg/day, prevents the deleterious formation in the bloodstream of small blood clots and thus reduces the risk of heart attacks and strokes for individuals whose arteries contain sclerotic plaques. Taken in much larger doses, as for example in rodent poisons, Coumarin/warfarin can cause massive hemorrhages and death. 

Further work in this area showed that only one of the cou-marin rings was needed for biologic activity. Condensation of the hydroxyacetophenone, 4, with diethyl carbonate affords 4-hydroxycoumarin (2). The reaction may involve the 3-ketoester (5) cyclization of this would afford 2. Alternately, the reagent may first give the 0-acyl derivative cyclization as above will give the same product. Michael condensation of the coumarin with benzalacetone (6) affords the anticoagulant warfarin (named after its place of origin Wisconsin Alumni Research Foundation,... 

WARF) (7). The same reaction with p-nitrobenzalacetone (8) affords acenocoumarole (9). It might be mentioned in passing that one of the largest uses of warfarin is in fact as a rat poison animals that ingest the drug in large amounts simply bleed to death. 

It should be noted that the process is akin to that for Warfarin except that 4-nitrobenzal-acetone replaces benzalacetone as a raw material. 

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