Monomeric trioxane amide sulfur compounds

Patent metadata

Field	Value
Publication number	US-9493480-B2
Application number	US-201214111991-A
Country	US
Kind code	B2
Filing date	Apr 16, 2012
Priority date	Apr 15, 2011
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

Anilide derivatives of the natural trioxane artemisinin were prepared and evaluated for antimalarial efficacy in Plasmodium berghei -infected mice. Selected anilides derivatives administered orally as one single-digit dose combined with mefloquine hydrochloride were completely curative, i.e., all 5 of the mice in the particular treatment group had no detectable parasitemia on day 30 post infection, gained as much weight by day 30 post infection as the control mice (no infection), and behaved normally.

First claim

That which is claimed:

1. A compound of formula (I):

wherein:
m is an integer selected from the group consisting of 0, 1, 2, and 3;
n is an integer selected from the group consisting of 0, 1, 2, 3, and 4;
q is an integer selected from the group consisting of 1, 2, 3, 4, and 5;
R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl;
each occurrence of R 2 is independently selected from the group consisting of hydroxyl, mercapto, nitro, halogen, unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl, —SR 3 , —S(O 2 )R 3 , —S(O)R 3 , wherein R 3 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl;
provided that if one occurrence of R 2 is halogen, then at least one occurrence of R 2 must be —SR 3 , —S(O 2 )R 3 , —S(O)R 3 ;
or an enantiomer, diastereomer, racemate or pharmaceutically acceptable salt, prodrug, or solvate thereof.

2. The compound of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

3. A pharmaceutical composition comprising a compound of formula (I) of claim 1 .

4. A method for preventing, controlling or treating a plasmodia parasite infection in a subject in need of such treatment, comprising administering to the subject a therapeutically-effective amount of a compound of formula (I):

wherein:
m is an integer selected from the group consisting of 0, 1, 2, and 3;
n is an integer selected from the group consisting of 0, 1, 2, 3, and 4;
q is an integer selected from the group consisting of 1, 2, 3, 4, and 5;
R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl;
each occurrence of R 2 is independently selected from the group consisting of hydroxyl, mercapto, nitro, halogen, unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl, —SR 3 , —S(O 2 )R 3 , —S(O)R 3 , wherein R 3 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl;
provided that if one occurrence of R 2 is halogen, then at least one occurrence of R 2 must be —SR 3 , —S(O 2 )R 3 , —S(O)R 3 ;
or an enantiomer, diastereomer, racemate or pharmaceutically acceptable salt, prodrug, or solvate thereof.

5. The method of claim 4 , wherein the plasmodia parasite infection is selected from the group consisting of Plasmodium falciparum, Plasmodium vivax, and Plasmodium berghei.

6. The method of claim 4 , further comprising administering to the subject a quinoline anti-malarial drug concurrently or sequentially with the compound of formula (I).

7. The method of claim 6 , wherein the quinoline anti-malarial drug is selected from the group consisting of chloroquine, quinine, mefloquine, and primaquine, or a pharmaceutically acceptable salt thereof.

8. A compound selected from the group consisting of:

9. A method for preventing, controlling or treating a plasmodia parasite infection in a subject in need of such treatment, comprising administering to the subject a therapeutically-effective amount of a compound of claim 8 .

Assignees

• Posner Gary H
• Slack Rachel D
• Univ Johns Hopkins

Inventors

• Posner Gary H
• Slack Rachel D

Classifications

• A61P33/06

  Antimalarials · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/357

  having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel · CPC title

• A61K31/537

  spiro-condensed or forming part of bridged ring systems · CPC title

• C07D493/08

  Bridged systems · CPC title