Uchikawa O, Fukatsu K, Suno M, Aono T, Doi T
Pharmaceutical Research Laboratories I, Takeda Chemical Industries, Ltd., Osaka, Japan.
Chem Pharm Bull (Tokyo). 1996 Nov;44(11):2070-7. doi: 10.1248/cpb.44.2070.
For the development of novel antioxidants having therapeutic utility, a new series of condensed 4- and 5-aminothiazole derivatives has been synthesized using simple methods. Condensed 4-aminothiazoles were prepared by the reaction of alpha-bromolactams with thioamides in ethanol and 5-aminothiazole derivatives were obtained by the treatment of 3-(acylamino)lactams with a thiating agent such as phosphorous pentasulfide and Lawesson's reagent in pyridine. In vitro assay of the condensed 5-aminothiazole derivatives showed them to be potent inhibitors of lipid peroxidation. In order to evaluate these compounds in an in vivo system, we devised a simple and reproducible method in which the inhibition of characteristic behaviors induced by spinal injection of FeCl2 was expressed numerically. Compounds having strong in vitro activity protected the central nervous system form injury caused by iron-dependent lipid peroxidation. The results suggest that the in vivo assay developed in this study should be useful as a screening method for antioxidants and also that condensed 5-aminothiazole derivatives are promising candidates for the treatment of traumatic and ischemic injury of the central nervous system.
为了开发具有治疗效用的新型抗氧化剂，已采用简单方法合成了一系列新的稠合4-和5-氨基噻唑衍生物。稠合4-氨基噻唑是通过α-溴代内酰胺与硫代酰胺在乙醇中反应制备的，而5-氨基噻唑衍生物是通过用硫代试剂如五硫化二磷和劳森试剂在吡啶中处理3-（酰氨基）内酰胺获得的。对稠合5-氨基噻唑衍生物的体外测定表明它们是脂质过氧化的有效抑制剂。为了在体内系统中评估这些化合物，我们设计了一种简单且可重复的方法，其中通过数值表达对脊髓注射FeCl2诱导的特征行为的抑制作用。具有强体外活性的化合物可保护中枢神经系统免受铁依赖性脂质过氧化引起的损伤。结果表明，本研究中开发的体内测定法应可作为抗氧化剂的筛选方法，并且稠合5-氨基噻唑衍生物有望成为治疗中枢神经系统创伤和缺血性损伤的候选药物。
