Plasmodial surface anion channel inhibitors for the treatment or prevention of malaria

Patent metadata

Field	Value
Publication number	US-9808458-B2
Application number	US-201615072902-A
Country	US
Kind code	B2
Filing date	Mar 17, 2016
Priority date	Apr 12, 2011
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

Abstract

The invention provides methods of treating or preventing malaria comprising administering to an animal an effective amount of a compound of formula I:

Q-Y—R 1 —R 2   (I),

wherein Q, Y, R 1 , and R 2 are as described herein. Methods of inhibiting a plasmodial surface anion channel of a parasite in an animal are also provided. The invention also provides pharmaceutical compositions comprising a compound represented by formula I in combination with any one or more compounds represented by formulas II, V, and VI. Use of the pharmaceutical compositions for treating or preventing malaria or for inhibiting a plasmodial surface anion channel in animals including humans are also provided. Also provided by the invention are clag3 amino acid sequences and related nucleic acids, vectors, host cells, populations of cells, antibodies, and pharmaceutical compositions.

First claim

The invention claimed is:

1. A method of treating malaria in an animal comprising administering an effective amount of a compound of formula (I) to the animal:
Q-Y—R 1 —R 2   (I),

wherein:
Q is a dioxo heterocyclyl ring fused to an aryl group, is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, mercapto, alkoxy, alkylthio, nitro, cyano, amino, alkyl, aryl, hydroxyalkyl, haloalkyl, cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, carboxy, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, ureido, and formyl;
Y is SO 2 ;
R 1 is piperazinyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, mercapto, alkoxy, alkylthio, nitro, cyano, amino, alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, carboxy, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, ureido, and formyl;
R 2 is aryloxyalkyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, mercapto, alkoxy, alkylthio, nitro, cyano, amino, alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, carboxy, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, ureido, and formyl;
or a pharmaceutically acceptable salt thereof.

2. A method of inhibiting a plasmodial surface anion channel of a parasite in an animal comprising administering an effective amount of a compound of formula (I) to the animal:
Q-Y—R 1 -R 2   (I),

wherein:
Q is a dioxo heterocyclyl ring fused to an aryl group, is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, mercapto, alkoxy, alkylthio, nitro, cyano, amino, alkyl, aryl, hydroxyalkyl, haloalkyl, cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, carboxy, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, ureido, and formyl;
Y is SO 2 ;
R 1 is piperazinyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, mercapto, alkoxy, alkylthio, nitro, cyano, amino, alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, carboxy, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, ureido, and formyl;
R 2 is aryloxyalkyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, mercapto, alkoxy, alkylthio, nitro, cyano, amino, alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, carboxy, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, ureido, and formyl;
or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 , wherein Q is dioxotetrahydroquinoxalinyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, mercapto, alkoxy, alkylthio, nitro, cyano, amino, alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, ureido, and formyl.

4. The method according to claim 1 , wherein R 1 is piperazinyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, mercapto, alkoxy, alkylthio, nitro, cyano, amino, alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, ureido, and formyl.

5. The method according to claim 1 , wherein R 2 is aryloxyalkyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, mercapto, alkoxy, alkylthio, nitro, cyano, amino, alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, ureido, and formyl.

6. The method according to claim 1 , wherein Q is:

7. The method according to claim 1 , wherein R 1 is:

8. The method according to claim 1 , wherein R 2 is:

9. The method according to claim 1 , wherein the compound is:

10. The method according to claim 1 , further comprising administering at least one other antimalarial compound to the animal.

11. The method according to claim 10 , wherein the at least one other antimalarial compound is
a compound of formula II:

wherein R 100 is hydrogen or alkyl and R 200 is arylalkyl, optionally substituted on the aryl with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; or R 200 is a group of formula (III):

wherein n=0 to 6;
or R 100 and R 200 together with the N to which they are attached form a heterocycle of formula IV:

wherein X is N or CH; and
Y 1 is aryl, alkylaryl, dialkylaryl, arylalkyl, alkoxyaryl, or heterocyclic, optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; and
R 3 -R 10 are hydrogen or alkyl;
or a pharmaceutically acceptable salt thereof.

12. The method according to claim 1 , wherein the animal is a human.

13. The method according to claim 1 , wherein the compound inhibits growth of P. falciparum Dd2.

14. The method according to claim 2 , wherein Q is dioxotetrahydroquinoxalinyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, mercapto, alkoxy, alkylthio, nitro, cyano, amino, alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, ureido, and formyl.

15. The method according to claim 2 , wherein R′ is piperazinyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, mercapto, alkoxy, alkylthio, nitro, cyano, amino, alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, ureido, and formyl.

16. The method according to claim 2 , wherein R 2 is aryloxyalkyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, mercapto, alkoxy, alkylthio, nitro, cyano, amino, alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, ureido, and formyl.

17. The method according to claim 2 , wherein Q is:

18. The method according to claim 2 , wh

Assignees

• Us Health

Inventors

• Desai Sanjay A

Classifications

• A61P33/06

  Antimalarials · CPC title

• C07D417/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K39/015

  Hemosporidia antigens, e.g. Plasmodium antigens · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/50

  Pyridazines; Hydrogenated pyridazines · CPC title