Brickner S J, Hutchinson D K, Barbachyn M R, Manninen P R, Ulanowicz D A, Garmon S A, Grega K C, Hendges S K, Toops D S, Ford C W, Zurenko G E
Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001, USA.
J Med Chem. 1996 Feb 2;39(3):673-9. doi: 10.1021/jm9509556.
Bacterial resistance development has become a very serious clinical problem for many classes of antibiotics. The 3-aryl-2-oxazolidinones are a relatively new class of synthetic antibacterial agents, having a new mechanism of action which involves very early inhibition of bacterial protein synthesis. We have prepared two potent, synthetic oxazolidinones, U-100592 and U-100766, which are currently in clinical development for the treatment of serious multidrug-resistant Gram-positive bacterial infections caused by strains of staphylococci, streptococci, and enterococci. The in vitro and in vivo (po and iv) activities of U-100592 and U-100766 against representative strains are similar to those of vancomycin. U-100592 and U-100766 demonstrate potent in vitro activity against Mycobacterium tuberculosis. A novel and practical asymmetric synthesis of (5S)-(acetamidomethyl)-2-oxazolidinones has been developed and is employed for the synthesis of U-100592 and U-100766. This involves the reaction of N-lithioarylcarbamates with (R)-glycidyl butyrate, resulting in excellent yields and high enantiomeric purity of the intermediate (R)-5-(hydroxymethyl)-2-oxazolidinones.
细菌耐药性的发展已成为许多类抗生素面临的一个非常严重的临床问题。3-芳基-2-恶唑烷酮是一类相对较新的合成抗菌剂，具有一种新的作用机制，涉及对细菌蛋白质合成的极早期抑制。我们制备了两种高效的合成恶唑烷酮，U-100592和U-100766，它们目前正处于临床开发阶段，用于治疗由葡萄球菌、链球菌和肠球菌菌株引起的严重多重耐药革兰氏阳性细菌感染。U-100592和U-100766对代表性菌株的体外和体内（口服和静脉注射）活性与万古霉素相似。U-100592和U-100766对结核分枝杆菌表现出强大的体外活性。一种新颖且实用的(5S)-(乙酰氨基甲基)-2-恶唑烷酮的不对称合成方法已被开发出来，并用于合成U-100592和U-100766。这涉及N-锂代芳基氨基甲酸酯与(R)-缩水甘油丁酸酯的反应，从而得到高产率和高对映体纯度的中间体(R)-5-(羟甲基)-2-恶唑烷酮。
