Spiro and dispiro 1,2,4-trioxolane antimalarials
AssigneeMedicines for Malaria Venture MMV International Centre Cointrin
InventorsJonathan L. Vennerstrom, Yuxiang Dong, Jacques Chollet, Hugues Matile
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Abstract
A means and method for treating malaria using a spiro or dispiro 1,2,4-trioxolane is described. The preferred 1,2,4-trioxolanes include a spiroadamantane group on one side of the trioxolane group, and a spirocyclohexyl or spiropiperidyl ring on the other side of the trioxolane group, whereby the spirocyclohexyl ring is preferably functionalized or substituted at the 4-position or a spiropiperidyl ring that is functionalized or substituted at the nitrogen atom. In comparison to artemisinin semisynthetic derivatives, the compounds of this invention are structurally simple, easy to synthesize, non-toxic, and potent against malarial parasites.
Claims34
A spiro or dispiro 1,2,4-trioxolane wherein the 1,2,4-trioxolane is selected from the group consisting of:
- adamantane-2-spiro-3′-1′,2′,4′-trioxaspiro[4.5]decane;
- adamantane-2-spiro-3′-8′-oxo-1′,2′,4′-trioxaspiro[4.5]decane;
- adamantane-2-spiro-3′-1′,2′,4′,9′,12′-pentaoxadispiro[4.2.4.2]tetradecane;
- adamantane-2-spiro-3′-11′,11′-dimethyl-1′,2′,4′,9′,13′-pentaoxadispiro[4.2.5.2]pentadecane;
- adamantane-2-spiro-3′-8′-ethoxycarbonyl-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane;
- adamantane-2-spiro-3′-8′-propyl-1′,2′,4′-trioxaspiro[4.5]decane;
- and adamantane-2-spiro-3′-8′-phenyl-1′,2′,4′-trioxaspiro[4.5]decane.
A pharmaceutical composition for prophylaxis and treatment of malaria comprising:
- a malaria prophylaxis or malaria treatment-effective amount of a spiro or dispiro 1,2,4-trioxolane, its prodrugs and optical isomers thereof, and a pharmaceutically acceptable carrier, said trioxolane being sterically hindered on at least one side of the trioxolane heterocycle.
Adamantane-2-spiro-3′-1′,2′,4′, 9′,12′-pentaoxadispiro[4.2.4.2]tetradecane.
Adamantane-2-spiro-3′-11′,11′-dimethyl-1′,2′,4′, 9′, 13′-pentaoxadispiro[4.2.5.2]pentadecane.
Adamantane-2-spiro-3′-8′-ethoxycarbonyl-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane.
Adamantane-2-spiro-3′-8′-propyl-1′,2′,4′-trioxaspiro[4.5]decane.
Adamantane-2-spiro-3′-8′-phenyl-1′,2′,4′-trioxaspiro[4.5]decane.
Adamantane-2-spiro-3′-5′,5′-diphenyl-1′,2′,4′-trioxolane.
Adamantane-2-spiro-3′-8′-(4′-fluorophenyl)-8′-methoxy-1′,2′,4′-trioxaspiro[4.5]decane.
Adamantane-2-spiro-3′-8′-carboxymethyl-1′,2′,4′-trioxaspiro[4.5]decane.
Adamantane-2-spiro-3′-1′,2′,4′-trioxa-8′-azaspiro[4.5]decane hydrochloride.
Adamantane-2-spiro-3′-8′-(2′-hydroxyethyl)-1′,2′,4′-trioxaspiro[4.5]decane.
A method of preventing or treating malaria comprising:
- administrating a malaria prevention or malaria treatment effective amount of a Spiro or dispiro 1,2,4-trioxolane in a pharmaceutically acceptable carrier, said trioxolane being sterically hindered on at least one side of the trioxolane heterocycle.
A method of manufacturing a composition for prophylaxis and treatment of malaria comprising:
- mixing a malaria prophylaxis or malaria treatment-effective amount of a spiro or dispiro 1,2,4-trioxolane, its prodrugs and optical isomers thereof, with a pharmaceutically acceptable carrier, said trioxolane being sterically hindered on at least one side of the trioxolane heterocycle.
A method of treating cancer comprising:
- administrating a cancer treatment effective amount of a spiro or dispiro 1,2,4-trioxolane in a pharmaceutically acceptable carrier, said trioxolane being sterically hindered on at least one side of the trioxolane heterocycle.
A method of prophylaxis or treatment of schistosomiasis comprising:
- administrating a schistosomiasis prophylaxis or treatment effective amount of a spiro or dispiro 1,2,4-trioxolane in a pharmaceutically acceptable carrier, said trioxolane being sterically hindered on at least one side of the trioxolane heterocycle.
Dependencies are inferred from the claim text.