# US 10,869,865 B2 · Plasmodial surface anion channel inhibitors for the treatment or prevention of malaria

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- Number: US 10,869,865 B2
- Document ID: US10869865B2
- Status: Granted
- Kind: B2
- Application number: 16/292,722
- Filed: 2019-03-05
- Published: 2019-06-20
- Granted: 2020-12-22
- Earliest claimed: 2011-04-12
- Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Serv
- Applicants: The United States of America, as represented by the Secretary, Department of Health and Human Services
- Inventors: Sanjay A. Desai
- Web page: https://patentgrep.com/patent/US10869865B2

## CPC

- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/42: Oxazoles
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/423: condensed with carbocyclic rings
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/433: Thidiazoles
- A61K 31/4355: the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/4741: condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/498: Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
- A61K 31/50: Pyridazines; Hydrogenated pyridazines
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/554: having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
- A61K 39/015: Hemosporidia antigens, e.g. Plasmodium antigens
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 33/06: Antimalarials
- C07D 239/84: Nitrogen atoms
- C07D 241/44: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D 263/57: Aryl or substituted aryl radicals
- C07D 277/54: Nitrogen and either oxygen or sulfur atoms
- C07D 281/16: [b, f]-condensed
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 498/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- C07K 14/445: Plasmodium
- C07K 16/205: {Plasmodium}
- C07K 2319/21: containing a His-tag
- C07K 2319/43: containing a FLAG-tag
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## 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.

## Claims

### Claim 1

A pharmaceutical composition comprising:
i) a compound of formula (I):
Q-Y—R1—R2 (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 SO2;
R1 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;
R2 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.

### Claim 2 (depends on 1)

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 R200 is hydrogen or alkyl and R200 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 R200 is a group of formula (III):
wherein n=0 to 6;
or R100 and R200 together with the N to which they are attached form a heterocycle of formula IV:
wherein X is N or CH; and
Y1 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
R3-R10 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;
Ra is hydrogen, alkyl, or alkoxy;
L is a bond, alkyl, alkoxy, (CH2)r, or (CH2O)s, wherein r and s are independently 1 to 6;
Q1 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, Q1 is absent;
or a pharmaceutically acceptable salt thereof; and
(c) a compound of formula VI:
wherein R11 and R12 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;
R13- R15 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.

### Claim 3 (depends on 2)

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

### Claim 4 (depends on 2)

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

### Claim 5 (depends on 1)

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.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein R1 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.

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, wherein R2 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.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, wherein Q is

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1, wherein R1 is

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1, wherein R2 is selected from the group consisting of:

### Claim 11 (depends on 1)

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