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

Patent metadata

Field	Value
Publication number	US-10869865-B2
Application number	US-201916292722-A
Country	US
Kind code	B2
Filing date	Mar 5, 2019
Priority date	Apr 12, 2011
Publication date	Dec 22, 2020
Grant date	Dec 22, 2020

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 pharmaceutical composition comprising:
i) a compound of formula (I):
Q-Y—R 1 —R 2   (I),

wherein:
Q is a heterocyclic amido group linked to a heterocyclic group, which 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 divalent 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 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; and
ii) at least one other antimalarial compound.

2. The pharmaceutical composition of claim 1 , wherein the at least one other antimalarial compound is selected from the group consisting of:
a) a compound of formula II:

wherein R 200 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;
(b) a compound of formula V:

wherein
Z is a group having one or more 4-7 membered rings, wherein at least one of the rings has at least one heteroatom selected from the group consisting of O, S, and N; and when two or more 4-7 membered rings are present, the rings may be fused or unfused; wherein the rings are optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl;
R a is hydrogen, alkyl, or alkoxy;
L is a bond, alkyl, alkoxy, (CH 2 )r, or (CH2O) s , wherein r and s are independently 1 to 6;
Q 1 is a heterocyclic group, an aryl group, or an heterocyclyl aryl group, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; and

when L is alkyl or alkoxy, Q 1 is absent;
or a pharmaceutically acceptable salt thereof; and
(c) a compound of formula VI:

wherein R 11 and R 12 are independently hydrogen, alkyl, cycloalkyl, or aryl which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halo, hydroxy, nitro, cyano, amino, alkylamino, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl;
R 13 - R 15 are independently selected from the group consisting of alkyl, halo, alkoxy, hydroxy, nitro, cyano, amino, alkylamino, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl;

or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 2 , wherein the compound of formula (II) is:

4. The pharmaceutical composition of claim 2 , wherein the compound of formula (VI) is:

5. The pharmaceutical composition of claim 1 , wherein Q is pyridazinyl heterocyclyl, 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 pharmaceutical composition of 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.

7. The pharmaceutical composition of claim 1 , wherein R 2 is aryl, 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.

8. The pharmaceutical composition of claim 1 , wherein Q is

9. The pharmaceutical composition of claim 1 , wherein R 1 is

10. The pharmaceutical composition of claim 1 , wherein R 2 is selected from the group consisting of:

11. The pharmaceutical composition of claim 1 , wherein the compound of formula (I) is:

Assignees

• Us Health

Inventors

• Desai Sanjay A

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• A61K31/433 Primary

  Thidiazoles · CPC title

• A61K31/554

  having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem · CPC title

• A61K31/498 Primary

  Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine · CPC title

• C07K16/205

  Plasmodium · CPC title