Compounds and methods for the treatment of malaria

Patent metadata

Field	Value
Publication number	US-11325913-B2
Application number	US-202016915660-A
Country	US
Kind code	B2
Filing date	Jun 29, 2020
Priority date	Nov 11, 2013
Publication date	May 10, 2022
Grant date	May 10, 2022

Abstract

Provided herein are compounds of the formula (I):as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of malaria.

First claim

What is claimed is:

1. A compound according to formula (I):

wherein the dotted line represents an optional double bond;
m is 0 or 1;
n is 0, 1, or 2;
A is CH or N;
X is absent or —C≡C—;
R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 6 -C 10 aryl, or C 2 -C 9 heteroaryl;
Y is C 1 -C 6 alkylene;
R 2 is C 1 -C 6 perfluoroalkyl, C 6 -C 10 aryl, C 6 -C 10 aryl C 1 -C 6 alkyl, or C 3 -C 10 carbocyclyl, wherein R 2 is not 2-methoxyphenyl;
Z is absent, C 1 -C 6 alkylene, or C 1 -C 6 heteroalkylene;
R 3 is hydrogen, hydroxyl, —OCH 2 C(O)OH, —NR 5 R 6 , —C(O)R 7 , or C 2 -C 9 heterocyclyl;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 and R 6 are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 acyl; and
R 7 is hydroxyl, C 1 -C 6 heteroalkyl, or C 2 -C 9 heterocyclyl;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein said compound has the structure:

3. The compound of claim 1 , wherein said compound has the structure:

4. The compound of claim 1 , wherein X is —C≡C—.

5. The compound of claim 1 , wherein R 1 is C 6 -C 10 aryl.

6. The compound of claim 1 , wherein R 2 is C 6 -C 10 aryl.

7. The compound of claim 1 , wherein Z is methylene.

8. The compound of claim 1 , wherein R 3 is hydroxyl, 4-methylpiperazyl, 4-hydroxy-4-methyl-piperidyl, 3-hydroxyl-3-methyl-azetidinyl, —OCH 2 C(O)OH, —NH 2 , morpholinyl, —NHC(O)CH 3 , —NHCH 3 , —N(CH 3 ) 2 , or —N(CH 3 )C(O)CH 3 .

9. The compound claim 1 , wherein Y is methylene.

10. The compound of claim 1 , wherein R 2 is substituted phenyl.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure:

wherein the dotted line represents an optional double bond;
m is 0 or 1;
n is 0, 1, or 2;
A is CH or N;
X is absent or —C≡C—;
R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 6 -C 10 aryl, or C 2 -C 9 heteroaryl;
Y is C 1 -C 6 alkylene;
R 2 is C 1 -C 6 perfluoroalkyl, C 6 -C 10 aryl, C 6 -C 10 aryl C 1 -C 6 alkyl, or C 3 -C 10 carbocyclyl, wherein R 2 is not 2-methoxyphenyl;
Z is absent, C 1 -C 6 alkylene, or C 1 -C 6 heteroalkylene;
R 3 is hydrogen, hydroxyl, —OCH 2 C(O)OH, —NR 5 R 6 , —C(O)R 7 , or C 2 -C 9 heterocyclyl;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 and R 6 are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 acyl; and
R 7 is hydroxyl, C 1 -C 6 heteroalkyl, or C 2 -C 9 heterocyclyl;
or a pharmaceutically acceptable salt thereof, and
a pharmaceutically acceptable excipient.

12. A method of preventing or treating malaria in a subject, comprising the step of administering to the subject an effective amount of a compound having the structure:

wherein the dotted line represents an optional double bond;
m is 0 or 1;
n is 0, 1, or 2;
A is CH or N;
X is absent or —C≡C—;
R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 6 -C 10 aryl, or C 2 -C 9 heteroaryl;
Y is C 1 -C 6 alkylene;
R 2 is C 1 -C 6 perfluoroalkyl, C 6 -C 10 aryl, C 6 -C 10 aryl C 1 -C 6 alkyl, or C 3 -C 10 carbocyclyl, wherein R 2 is not 2-methoxyphenyl;
Z is absent, C 1 -C 6 alkylene, or C 1 -C 6 heteroalkylene;
R 3 is hydrogen, hydroxyl, —NR 5 R 6 , —OCH 2 C(O)OH, —C(O)R 7 , or C 2 -C 9 heterocyclyl;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 and R 6 are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 acyl; and
R 7 is hydroxyl, C 1 -C 6 heteroalkyl, or C 2 -C 9 heterocyclyl;
or a pharmaceutically acceptable salt thereof.

13. The method of claim 12 , wherein said malaria is drug resistant malaria.

14. The method of claim 13 , wherein drug resistant malaria is resistant to chloroquine, quinine, prymethamine, sulfadoxine, mefloquine, artemether, lumefantrine, artesunate, amodiaquine, dihydroartemisinin, piperaquine, proguanil, doxycycline, clindamycin, artemisinin, atovaquone, or any combination thereof.

15. The method of claim 12 , wherein said malaria is liver stage malaria, blood stage malaria, or transmission stage malaria.

16. The method of claim 12 , wherein the liver of said subject is infected with a malaria-causing parasite and said treatment prevents spread of said infection from their liver.

17. The compound according to claim 1 , wherein R 2 is phenyl substituted with —CH 3 , —OCH 3 or halogen.

18. The compound according to claim 1 , wherein R 2 is phenyl substituted with halogen.

19. The compound according to claim 1 , wherein R 2 is not 3-methoxyphenyl or 4-methoxyphenyl.

20. The compound according to claim 1 , wherein R 1 is substituted phenyl.

Assignees

• Broad Inst Inc

Inventors

• Comer Eamon
• Kato Nobutaka
• Scherer Christina
• Bastien Jessica
• Duvall Jeremy
• Lewis Timothy
• Sayes Morgane
• Leighty Matthew
• Pu Jun
• Beaudoin Jennifer
• Braibant Bertrand
• Munoz Benito

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61P33/06

  Antimalarials · CPC title

• 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