Various 1,2-isothiazolidine-1,1-dioxide (gamma-sultam) derivatives containing an antioxidant moiety, 2,6-di-tert-butylphenol substituent, were prepared. Some compounds, which have a lower alkyl group at the 2-position of the gamma-sultam skeleton, showed potent inhibitory effects on both cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LO), as well as production of interleukin (IL)-1 in in vitro assays. They also proved to be effective in several animal arthritic models without any ulcerogenic activities. Among these compounds, (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1, 2-isothiazolidine-1,1-dioxide (S-2474) was selected as an antiarthritic drug candidate and is now under clinical trials. The structure-activity relationships (SAR) examined and some pharmacological evaluations are described.

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SUMMARYThe TK-5803 strain of an agent which induces chicken anaemia was propagated and titrated in cultures of the MDCC-MSB1 cell line. When the isolates (tentatively designated MSBI-TK-5803 strain) from the original material were inoculated into 1-day-old susceptible chicks, they showed a severe pathogenicity, inducing anaemia with aplasia of the bone marrow and atrophy of the lymphoid organs. On density gradient separation, the peak of their infectivity titre appeared at a density of 1.35 to 1.36 g/cm 3 and numerous virus particles were demonstrated in the same fraction. The agent was resistant to heating for 30 min at 60°C and 50% chloroform for 15 min at 4°C, and passed through a 25 nm membrane filter, but it was completely inactivated after heating for 30 min at 70°C or more. The purified virus particles were spherical or hexagonal in shape and 19.1 ± 0.2 nm in diameter.

A synthetic study was made on the active metabolite of cyclophosphamide. Ozonolysis of O-(3 butenyl)-N,N-bis(2-chloroethyl)phosphorodiamidate, prepared by reaction of POC13 with 3-buten-1-ol followed by treatment with N,N-bis(2-chloroethyl)amine (nor mustard) and NH3, afforded 2-[bis(2-chloroethyl)amino]-4-hydroperoxytetrahydro-2H-1, 3,2-oxazaphosphorine 2-oxide (4-hydroperoxycyclophosphamide). Deoxygenation of 4-hydroperoxycyclophosphamide by triphenylphosphine yielded 4-hydroxycyclophosphamide in a pure crystalline state. These products exhibited high cytostatic activity in both in vitro and in vivo experiments. The results give confirmatory evidence for the hypothesis that C4-hydroxylation on the 1,3,2-oxazaphosphorinane ring of cyclophosphamide is necessary for its activation.

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