Compositions and methods for treating malaria

Patent metadata

Field	Value
Publication number	US-12370183-B2
Application number	US-202117798391-A
Country	US
Kind code	B2
Filing date	Feb 16, 2021
Priority date	Feb 18, 2020
Publication date	Jul 29, 2025
Grant date	Jul 29, 2025

Abstract

Disclosed are methods of treating malaria with tetrahydrobenzonaphtyridine carboxanilide (TBN) derivatives and related pyrrolinones and hydrolysis products thereof. These compounds are active against Plasmodium falciparum strains that are resistant to multiple drugs currently on the market. The present invention further relates to novel compounds and pharmaceutical compositions comprising such compounds.

First claim

What is claimed:

1. A compound represented by the structure of formula (I):

or a derivative of compound (I) selected from the group consisting of:
(a) an iminium form of compound (I) represented by the structure of formula (I-a):

(b) a compound represented by the structure of formula (I-b):

(c) a compound represented by the structure of formula (I-c):

wherein
A is absent, or an unsubstituted or substituted cycloalkyl, aryl, ferrocenyl, heterocycloalkyl or heteroaryl group;
R 1 is selected from the group consisting of alkyl, cycloalkyl, aryl, ferrocenyl, heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, heterocycloalkylaryl, heteroarylalkyl, each of which is unsubstituted or substituted with at least one R 3 ;
R 2 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, aminoalkyl, sulfonylalkyl, alkenyl, cycloalkyl, aryl, ferrocenyl, heterocycloalkyl, heteroaryl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, alkyloxyalkyl, aryloxyalkyl, heteroalkyloxyalkyl, heterocycloalkyloxyalkyl, —SO 2 R b , —(CRR′) m C(O)R a , —(CRR′) m C(O)OR a , and —(CRR′) m C(O)NRR′;
R 3 is independently at each occurrence selected from the group consisting of halogen, CN, hydroxy, alkyloxy, aryloxy, cycloalkyloxy, heterocycloalkyloxy, heteroaryloxy —SO 2 R b , NRR′ and —NHC(═O)R;
R a , R and R′ are each independently H or alkyl;
R b is H, alkyl or NRR′;
m is 0, 1, 2, 3, 4, 5 or 6;
and enantiomers, diastereomers, polymorphs, salts, solvates and deuterated analogues thereof.

2. The compound according to claim 1 , which is represented by the structure of formula (I).

3. The compound according to claim 1 , wherein ring A is absent, or an unsubstituted or substituted cyclohexyl, phenyl or pyridyl.

4. The compound according to claim 3 , wherein ring A is a phenyl which is unsubstituted or substituted with a halogen.

5. The compound according to claim 1 , wherein R 1 is an unsubstituted or substituted phenyl, benzyl, alkyl, cycloalkyl or heterocycloalkyl.

6. The compound according to claim 1 , wherein R 1 is an unsubstituted or substituted phenyl represented by the structure:

wherein R 3 is as defined in claim 1 , and n is selected from the group consisting of 1, 2, 3, 4 and 5.

7. The compound according to claim 6 , wherein R 3 is selected from the group consisting of halogen, alkyloxy and cyano, and n is 1 or 2.

8. The compound according to claim 6 , wherein R 3 is selected from the group consisting chloro, fluoro, bromo, methoxy, cyano and hexahydrofurofuranyloxy.

9. The compound according to claim 1 , wherein R 2 is selected from the group consisting of H, an unsubstituted or substituted benzyl, phenethyl, piperazinyl, pyridinylalkyl, pyrimidinylalkyl, thiazolylalkyl, pyrazolylalkyl, imidazolylalkyl, triazolylalkyl, allyl, alkyl, carbomethoxyalkyl, cyclopropylalkyl, ethoxyalkyl, tetrahydropyranyloxylalkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, N,N-dimethylcarboxamidoalkyl, —C(═O)—CH 2 OR a wherein R a is alkyl, phthalimidealkyl, aminoalkyl, N,N-dimethylaminoalkyl, sulfonylalkyl and carboxyalkyl.

10. The compound according to claim 9 , wherein R 2 is selected from the group consisting of an unsubstituted or substituted benzyl, phenethyl and alkyl.

11. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable excipient.

12. A method of treating or inhibiting malaria, or reducing the symptoms of malaria, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) (I-a), (I-b) or (I-c) according to claim 1 , or a pharmaceutical composition comprising such compound.

13. A method of treating or inhibiting malaria, or reducing the symptoms of malaria, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound represented by the structure of formula (II), or a pharmaceutical composition comprising such compound

wherein
A is absent, or an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl or heteroaryl group;
R 1 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, heterocycloalkylaryl, heteroarylalkyl, each of which is unsubstituted or substituted with at least one R 3 ;
R 2 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, aminoalkyl, sulfonylalkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, alkyloxyalkyl, aryloxyalkyl, heteroalkyloxyalkyl, heterocycloalkyloxyalkyl, —SO 2 R b , —(CRR′) m C(O)R a , —(CRR′) m C(O)OR a , and —(CRR′) m C(O)NRR′;
R 3 is independently at each occurrence selected from the group consisting of halogen, CN, hydroxy, alkyloxy, aryloxy, cycloalkyloxy, heterocycloalkyloxy, heteroaryloxy —SO 2 R b , NRR′ and —NHC(═O)R;
R a , R and R′ are each independently H or alkyl;
R b is H, alkyl or NRR′;
m is 0, 1, 2, 3, 4, 5 or 6;

and enantiomers, diastereomers, polymorphs, salts, solvates and deuterated analogues thereof.

14. The method according to claim 13 , wherein ring A is a phenyl which is unsubstituted or substituted with a halogen.

15. The method according to claim 13 , wherein R 1 is an unsubstituted or substituted phenyl represented by the structure:

wherein R 3 is as defined in claim 1 , and n is selected from the group consisting of 1, 2, 3, 4 and 5.

16. The method according to claim 15 , wherein R 3 is selected from the group consisting of halogen, alkyloxy and cyano, and n is 1 or 2.

17. The method according to claim 15 , wherein R 3 is selected from the group consisting chloro, fluoro, bromo, methoxy, cyano and hexahydrofurofuranyloxy.

18. The method according to claim 13 , wherein R 2 is selected from the group consisting of an unsubstituted or substituted benzyl, phenethyl and alkyl.

19. A process for preparing a compound represented by the structure of formula (I), or enantiomers, diastereomers, polymorphs, salts, solvates and deuterated analogues thereof

the process comprising the step of reacting a compound of formula (II) with an oxidizing agent

wherein in the compounds of formula (I) or (II)
A is absent, or an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl or heteroaryl group;
R 1 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, heterocycloalkylaryl, hetero

Assignees

• Univ Rutgers
• Univ Kentucky Res Found

Inventors

• Knapp Spencer
• Barrows Robert D
• Guy R Kiplin
• Hammill Jared
• Davis Christopher

Classifications

• 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

• A61K31/122

  having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin · CPC title

• A61K31/045

  Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates · CPC title

• A61K31/085

  having an ether linkage to aromatic ring nuclear carbon · CPC title