pyrimidinones and ferric-chloride

An efficient and practical protocol has been developed to synthesize dihydropyrimidinones and dihydropyrimidinethiones through FeCl₃∙6H₂O/TMSBr-catalyzed three-component cyclocondensation under microwave irradiation. This approach features high yields, broad substrate scope, short reaction time, mild reaction conditions, operational simplicity and easy work-up, thus affording a versatile method for the synthesis of dihydropyrimidinones and dihydropyrimidinethiones.

Topics: Catalysis; Chemistry Techniques, Synthetic; Chlorides; Ferric Compounds; Magnetic Resonance Spectroscopy; Microwaves; Molecular Structure; Pyridines; Pyrimidinones; Thiones; Trimethylsilyl Compounds

Polysubstituted 3-arylaminoacrylate and tetrahydropyrimidin-2-one derivatives could be selectively produced from the one-pot domino reaction of arylamines, methyl propiolate, aromatic aldehydes, and urea in ethanol in the presence of FeCl3 as catalyst. Under similar reactions secondary amines such as morpholine and piperidine predominately afford tetrahydropyrimidin-2-one derivatives in good yields.

Topics: Aldehydes; Alkynes; Amines; Catalysis; Chemistry Techniques, Synthetic; Chlorides; Ferric Compounds; Propionates; Pyrimidinones; Urea

Treatment of myocardial infarction within the first 1 to 2 hours with a thrombolytic agent, percutaneous coronary intervention, or an αIIbβ3 antagonist decreases mortality and the later development of heart failure. We previously reported on a novel small molecule αIIbβ3 antagonist, RUC-2, that has a unique mechanism of action. We have now developed a more potent and more soluble congener of RUC-2, RUC-4, designed to be easily administered intramuscularly by autoinjector to facilitate its use in the prehospital setting. Here, we report the properties of RUC-4 and the antiplatelet and antithrombotic effects of RUC-2 and RUC-4 in animal models.. RUC-4 was ≈ 20% more potent than RUC-2 in inhibiting human ADP-induced platelet aggregation and much more soluble in aqueous solutions (60-80 mg/mL). It shared RUC-2's specificity for αIIbβ3 versus αVβ3, did not prime the receptor to bind fibrinogen, or induce changes in β3 identified by a conformation-specific monoclonal antibody. Both RUC-2 and RUC-4 prevented FeCl3-induced thrombotic occlusion of the carotid artery in mice and decreased microvascular thrombi in response to laser injury produced by human platelets infused into transgenic mice containing a mutated von Willebrand factor that reacts with human but not mouse platelets. Intramuscular injection of RUC-4 in nonhuman primates at 1.9 and 3.85 mg/kg led to complete inhibition of platelet aggregation within 15 minutes, with dose-dependent return of platelet aggregation after 4.5 to 24 hours.. RUC-4 has favorable biochemical, pharmacokinetic, pharmacodynamic, antithrombotic, and solubility properties as a prehospital therapy of myocardial infarction, but the possibility of increased bleeding with therapeutic doses remains to be evaluated.

Topics: Animals; Binding Sites; Blood Platelets; Carotid Stenosis; Chlorides; Disease Models, Animal; Emergency Medical Services; Ferric Compounds; Fibrinolytic Agents; Humans; Macaca fascicularis; Male; Mice; Mice, Transgenic; Molecular Dynamics Simulation; Myocardial Infarction; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Protein Binding; Protein Conformation; Pyrimidinones; Solubility; Thiadiazoles; Thrombosis; von Willebrand Factor