Warfarin anticoagulants formation

Halland N, Hansen T, Jprgensen KA (2003) Organocatalytic Asymmetric Michael Reaction of Cyclic 1,3-DicarbonyI Compounds and a,(3-Unsaturated Ketones - A Highly Atom-Economic Catalytic One-Step Formation of Optically Active Warfarin Anticoagulant. Angew Chem Int Ed 42 4955... 

Halland N, Hansen T, Jprgensen KA. Organocatalytic asymmetric Michael reaction of cyclic 1,3-dicarbonyl compounds and a, (3-unsaturated ketones - a highly atom-economic catalytic one-step formation of optically active warfarin anticoagulant. Angew. Chem. Int. Ed. 2003 42 (40) 4955-4957. 

Anticoagulant drugs include heparin and warfarin (Coumadin ) —agents used to prevent deep vein thrombosis. They are also used to prevent formation of emboli due to atrial fibrillation, valvular heart disease, and other cardiac disorders. Heparin, which is not absorbed by the gastrointestinal tract, is available only by injection its effect is immediate. 

The enantioselective reduction of unsaturated alcohol derivatives has been applied to the synthesis of several biologically active compounds (Scheme 24.12). Warfarin (123, R=H) is an important anticoagulant that is normally prescribed as the racemate, despite the enantiomers having dissimilar pharmacological profiles. One of the earliest reported uses of DuPhos was in the development of a chiral switch for this bioactive molecule, facilitating the preparation of (R)- and (S)-warfarin [184]. Although attempted reduction of the parent hydroxycoumarin 122 (R=H) led to formation of an unreactive cyclic hemiketal, hydrogenation of the sodium salt proceeded smoothly with Rh-Et-DuPhos in 86-89% ee. 

Anticoagnlants, medications that block the formation of clots, have also been used. These work by preventing clots from forming around the atherosclerotic plaques that would further block blood flow. A variety of anticoagulants including warfarin (Coumadin), pentoxifylline (Trental), and aspirin have been used. 

Coumarins are competitive inhibitors of vitamin K, which is required for the formation in the liver of the amino acid, gamma-carboxyglutamic acid. This is necessary for the synthesis of prothrombin and factors VII, IX and X (Figure 17.1). After starting treatment the anticoagulant effect is delayed until the concentration of normal coagulation factors falls (36-72 h). The effects can be reversed by vitamin K (slow maximum effect only after 3-6 h) or by whole blood or plasma (fast). Gut bacteria synthesise vitamin K and thus are an important source of this vitamin. Consequently, antibiotics can cause excessive prolongation of the prothrombin time in patients otherwise adequately controlled on warfarin. 

Warfarin (Fig. 10-22c) is a synthetic compound that inhibits the formation of active prothrombin. It is particularly poisonous to rats, causing death by internal bleeding. Ironically, this potent rodenticide is also an invaluable anticoagulant drug for treating humans at risk for excessive blood clotting, such as surgical patients and those with coronary thrombosis. ... 

Finally, aspirin has also been used to prevent thrombus formation in peripheral veins (deep vein thrombosis [DVT]), and aspirin is sometimes used as an adjunct or alternative to anticoagulants (heparin, warfarin) that are routinely used to treat DVTs.8 Aspirin can likewise be administered to prevent thromboembolism following surgical procedures such as coronary artery bypass, arterial grafts, endarterectomy, and valve replacement 45,78 By preventing platelet-induced thrombogenesis, aspirin helps maintain patency and prevent reocclusion of vessels following these procedures. 

Normal hemostasis is a balance between excessive and inadequate blood clotting. Overactive blood clotting is harmful because of the tendency for thrombus formation and occlusion of arteries and veins. Vessels may become directly blocked by the thrombus, or a portion of the thrombus may break off and create an embolism that lodges elsewhere in the vascular system. The tendency for excessive thrombus formation in the venous system is usually treated with anticoagulant drugs such as heparin and warfarin. Platelet inhibitors such as aspirin help prevent arterial thrombogenesis. Thrombolytic drugs (streptokinase, t-PA) that facilitate the dissolution of harmful clots may successfully reopen... 

Maupas, B. Letellier, S. Guyon, E. Determination of the formation constant for the inclusion complex of methyl-P-cyclodextrin with anticoagulant drugs warfarin and 8-chlorowarfarin in aqueous solution. J. Inclusion Phenom. Mol. Recognit. Chem. 1996,23 (4), 259-267. 

Warfarin and Phenoharhital. Phenobarbital, by causing enzyme induction, can increase the rate of metabolism of warfarin. The result of this interaction is a decreased response to the anticoagulant and an increased risk of thrombus formation if the interaction is not recognized. 

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