Orally active, antimalarial, anticancer, artemisinin-derived trioxane dimers

US7417156B2 · kind B2 · utility

Assignee

• THE JOHNS HOPKINS UNIVERSITY · US

Inventors

• Gary H. Posner · Baltimore, US
• Theresa A. Shapiro · Towson, US
• Surojit Sur · Gaithersburg, US
• Tanzina Labonte · Cambridge, US
• Kristina Borstnik · State College, US
• Ik-Hyeon Paik · Needham, US
• Andrew J. McRiner · Melrose, US

Key dates

• Filing date: Sep 26, 2003
• Grant date: Aug 26, 2008
• Expiry date: Sep 26, 2023

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07D493/18
• WIPO field: Organic fine chemistry
• WIPO sector: Chemistry

Abstract

In only two steps and in 65% overall yield, natural trioxane artemisinin (I) was converted on gram scale into C-10-carba trioxane dimer (3). This new, very stable dimer was then transformed easily in one additional step into four different dimers (4-7). Alcohol and diol dimers (4 and 5) and ketone dimer (7) are 10 times more antimalarially potent in vitro than artemisinin (I), and alcohol and diol dimers (4 and 5) are strongly inhibitory but not cytotoxic toward several human cancer cell lines. Water-soluble carboxylic acid derivatives (8a-10c and 12) were easily prepared from dimers (4-6); they are thermally stable even at 60° C. for 24 hours, are more orally efficacious as antimalarials than either artelinic acid or sodium artesunate, and have potent and selective anticancer activities. Further derivitization of the alcohol dimers (4 and 17), diol dimer (5) and ketone (7) has produced a number of analogs also antimalarially active in vitro at sub-nanomolar concentrations (most notably: pyridine N-oxides (13, 15, 18, 23, 24 and 25), phosphoric acid triesters (26 and 27), sulfonamide (40) and cyclic carbonate (41)). In addition, dimers (13 and 19) are more efficacious (when adminis…