The Synthesis of New Antimalarial Drugs Derivatives of Benzothiopyrans, Derivatives of Menoctone.
Annual rept. no. 2 (Final) 1 Jan 70-1 Jul 71,
LITTLE (ARTHUR D) INC CAMBRIDGE MASS
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The purpose of the work performed was to prepare analogs and derivatives of the compounds N,N-dimethyl-N-6-chloro-2-phenyl-4H-1-benzothiopyran-4- ylidene-1,3-propanediamine hydrochloride WR 95214 and to prepare derivatives of the naphthoquinone antimalarial menoctone 3-8-cyclohexyloctyl -2-hydroxy-1,4-naphthoquinone that might retain the antimalarial potency of menoctone but achieve an enhanced distribution and metabolism in vivo. The compound 3-8-cyclohexyloctyl-1-4-dimethoxy-2-naphthol was of particular interest. In the report the synthesis of 43 target benzothiopyrans and 23 intermediates is described. Of the 43 target compounds evaluated as antimalarials 9 were active, 10 were curative, and 24 were inactive in a mouse screen at dose levels of 160-640 mgkg. A few general conclusions were reached relevant to structure-activity relationships in this series. A 4-step synthesis of 3-8-cyclohexyloctyl-1,4-dimethoxy-2-naphthol from menoctone was developed and samples of 3 intermediates and the target compound were submitted for evaluation. In addition, a water-soluble derivative of menoctone was prepared by esterification of the phenolic group with 4-diethylaminobutyric acid hydrochloride. Author
- Organic Chemistry