Studies on the New Antiarthritic Drug Candidate S-2474
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Accession number;03A0318148
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| Title;Studies on the New Antiarthritic Drug Candidate S-2474 |
| Author;
INAGAKI MASANAO
(Shionogi & Co., Ltd, JPN)
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Journal Title;Journal of the Pharmaceutical Society of Japan
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Journal Code:F0508A
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ISSN:0031-6903
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VOL.123;NO.5;PAGE.323-330(2003)
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| Figure&Table&Reference;FIG.3, TBL.4, REF.25 |
| Pub. Country;Japan |
| Language;Japanese |
| Abstract;Various 1,2-isothiazolidine-1,1-dioxide (.GAMMA.-sultam) derivatives containing an antioxidant moiety, 2,6-di-tert-butylphenol substituent, were prepared. Some compounds that 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-1 (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. The structure-activity relationships examined and some pharmacological evaluations are described. Furthermore, we have developed an efficient and E-selective synthesis of S-2474, in which .ALPHA.-methoxy-p-quinone methide is used as a key intermediate. .ALPHA.-Methoxy-p-quinone methide was revealed to be equivalent to a p-hydroxy-protected benzaldehyde. It reacts smoothly with .ALPHA.-sulfonyl carbanion to give 1,6-addition intermediates, which can be further processed to provide S-2474 directly in the presence of a base. This procedure gives S-2474 as an almost single isomer on the benzylidene double bond in excellent yield and thus is a very practical method adaptable to large-scale synthesis. The detailed mechanistic aspects are studied and discussed. (author abst.) |
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