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

Patent metadata

Field	Value
Publication number	US-12059418-B2
Application number	US-202017115317-A
Country	US
Kind code	B2
Filing date	Dec 8, 2020
Priority date	Apr 12, 2011
Publication date	Aug 13, 2024
Grant date	Aug 13, 2024

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—R1—R2  (I),wherein Q, Y, R1, and R2 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, 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 piperidinyl 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; 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 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;
(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 (CH 2 O) 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 1 , wherein Q is

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

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

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

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

8. A pharmaceutical composition comprising (i) a compound of ISG-23 or a pharmaceutically acceptable salt thereof wherein ISG-23 comprises the structure of

and (ii) at least one other antimalarial compound.

Assignees

• Us Health

Inventors

• Desai Sanjay A

Classifications

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/4355

  the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/423

  condensed with carbocyclic rings · CPC title