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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.

A series of 2,3-dihydro-5-benzofuranamines (5-aminocoumarans) were developed for the treatment of traumatic and ischemic central nervous system (CNS) injury. Compounds within this class were extremely effective inhibitors of lipid peroxidation in vitro and antagonized excitatory behavior coupled with peroxidative injury induced by spinal intrathecal injection of FeCl2 (mouse-FeCl2-it assay) in vivo. Selected compounds were tested for antagonistic activity on methamphetamine (MAP)-induced hypermotility resulting from dopamine release in the mouse brain. Among the compounds synthesized, compound 26n (2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl) methyl]-5-benzofuranamine) exhibited potent effects in these assays (inhibition of lipid peroxidation, IC50 = 0.07 microM; mouse-FeCl2-it assay, ID50 = 10.4 mg/ kg, po; MAP-induced hypermotility, 98% inhibition, 10 mg/kg, ip). The S-(+)-form of compound 26n dihydrochloride (TAK-218), which has 30 times more potent antagonistic activity on MAP-induced hypermotility than the R-(-)-form, improved more significantly the survival rate in the cerebral ischemia model (rat, 1-3 mg/kg, ip) during the period of 1-14 days after ischemia and decreased functional disorders in the traumatic brain injury model (rat, 0.1-1 mg/kg, ip) 3-14 days after injury. These results imply a role for dopamine in deterioration of CNS function after ischemic and traumatic injury. TAK-218 is a promising compound for the treatment of stroke and CNS trauma and is now under clinical investigation.

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Crystal structures have been determined of methyl trans-1 -hydroxy-6-nitro-3-oxobicyclo[4.4.0]decane-2-carboxylate (19), cis-3-methyl-6-nitro-2-oxabicyclo[4.4.O]decan-1-01 (2), cis-7-hydroxy-1 -nitrobicyclo[5.4.0]undecan%one (13), and the medium-ring compounds 2-acetyl-4-nitrocyclooctanone (9), methyl 5-nitro-2-oxocyclooctanecarboxylate (4), 2-acetyl-4-nitrocyclononanone (ll), 2-acetyl-4-nitrocyclodecanone (15), benzyl 5-nitro-2,1 l-dioxocycloundecanecarboxylate (24), methyl 5-nitro-2,12-dioxocyclododecanecarboxylate (21), and 8-nitro-11 -oxo-13-tridecanolide (7), which are intermediates, side products, or end products of the 'Zip' ring-enlargement reaction. The conformations of most of the medium-ring compounds are very similar to equal-sized ring compounds previously determined by other authors. ~ ~In the past, a new method for ring enlargement by the so-called 'Zip' reaction was developed by which a number of new polyaminolactams were synthesized starting from lactams [ 11. The same reaction principle was followed to convert carbocyclic compounds 2,Part of the thesis of K. K. ') Postdoctoral fellow 1980182.