Quinoline derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-9493420-B2
Application number	US-201313951340-A
Country	US
Kind code	B2
Filing date	Jul 25, 2013
Priority date	Feb 17, 2005
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

This disclosure provides a new class of compounds referred to as “reversed chloroquines” (RCQs), which are highly effective against CQ R and CQ S malaria parasites. RCQs are hybrid molecules, which include an antimalarial quinoline analog (such as chloroquine) moiety and a CQ R reversal moiety. Exemplary RCQ chemical structures are provided. Also provided are pharmaceutical compositions including the disclosed RCQ compounds, and methods of using such compounds and compositions for the treatment of malaria and inhibition of CQ R or CQ S Plasmodium sp. (such as P. falciparum ).

First claim

We claim:

1. An antimalarial compound having the formula

wherein X 1 and X 2 are independently halo, haloalkyl, amino, hydroxyl, alkoxy, alkylamino, or arylamino;
m is from 0 to 4;
n is from 0 to 2;
R 1 is H, alkyl, heteroalkyl, alkylamino, sulfonyl, haloalkyl, carbonyl, or alkylsulfonamide;
L 1 is from 1 to 12 atoms in length, and each position is independently methylene, difluoromethylene, dichloromethylene, —NH—, or —O—; and
G is a CQ R reversal moiety having the structure

wherein R 2 is H, alkyl, heteroalkyl, alkylamino, haloalkyl, alkylsulfonamide, amide, alkylamide, cyano, cyanoalkyl, furyl, alkylfuran, or —CONH 2 ;
L 2 is from 1 to 12 atoms in length, and each position is independently methylene, difluoromethylene, dichloromethylene, —NH—, or —O—;
Y 1 is N, NH + , CH, CH 2 CH, or C(O)CH; and
R 3 and R 4 are independently cycloalkyl, heterocyclyl, aryl, heteroaryl, or

where each X 3 is independently H, halo, haloalkyl, amino, hydroxyl, alkylamino, cyano, alkoxy, sulfonamide, mercapto, or keto, s is 0 to 4, Y 2 is C H , S or N, and L 3 is alkyl, methoxy, ethoxy, methylamino, ethylamino, —N—, —O—, or —S—, or R 3 and R 4 together with Y 1 form a tricyclic ring system having a formula selected from:

wherein Y 2 is N, O, CH, CH 2 or S;
R 13 is H, alkyl, heteroalkyl, ═O, amino, amine, amide, sulfonamide, halo, cyano, hydroxy, mercapto, haloalkyl, alkoxy, alkylthio, thioalkoxy, arylalkyl, heteroaryl, alkylamino, dialkylamino, or alkylsulfano;
q and t are independently 0 to 4 as valence requirements permit;
each X 4 and X 5 independently is H, alkyl, halo, haloalkyl, alkoxy, amino, hydroxyl, alkylamino, cyano, or mercapto; and
each peripheral ring can independently include at least one heteroatom at any position that valence requirements permit.

2. The compound of claim 1 , wherein Y 1 is N.

3. The compound of claim 1 , wherein L 2 is from 2 to 6 atoms in length.

4. The compound of claim 1 , wherein m is 1 or 2, n is 0 or 1, and each X 1 and X 2 independently is H, chloro, fluoro, or trifluoromethyl.

5. The compound of claim 1 , wherein each X 1 independently is H, chloro, or trifluoromethyl, and n is 0.

6. The compound of claim 5 , wherein m is 1 and (X 1 ) m is chloro at position C 7 .

7. The compound of claim 1 , wherein R 1 and R 2 are independently H, alkyl having from 1 to 4 carbon atoms, or heteroalkyl having from 1 to 4 carbon atoms.

8. The compound of claim 7 , wherein R 1 and R 2 are independently H, methyl, trifluoromethyl, —CH 2 CH 2 CF 3 , —CH 2 CF 3 , —CH 2 CH 2 NH 2 , —CH 2 NH 2 , —CH 2 CH 2 C(O)NH 2 , or —CH 2 C(O)NH 2 .

9. The compound of claim 1 , wherein:
m is 1 and (X 1 ) m is chloro at position C 7 ;
n is 0; and
R 1 and R 2 are independently H, methyl, trifluoromethyl, —CH 2 CH 2 CF 3 , —CH 2 CF 3 , —CH 2 CH 2 NH 2 , —CH 2 NH 2 , —CH 2 CH 2 C(O)NH 2 , or —CH 2 C(O)NH 2 .

10. The compound of claim 1 , wherein:
R 1 and R 2 are independently H, alkyl, or heteroalkyl;
Y 1 is CH or N; and
R 3 and R 4 are independently aryl, or heteroaryl, or together with Y 1 form a tricyclic ring system.

11. The compound of claim 1 , wherein:
R 1 and R 2 are independently H, alkyl, or heteroalkyl;
Y 1 is CH or N; and
R 3 and R 4 independently have the formula:

where each X 3 independently is H, halo, haloalkyl, amino, hydroxyl, alkylamino, cyano, alkoxy, sulfonamide, mercapto, or keto, s is 0 to 4, and Y 2 is CH or N.

12. The compound of claim 11 , wherein:
R 1 is H;
s is 1;
X 3 is H, fluoro, chloro, trifluoromethyl, or hydroxyl; and
L 3 is methyl or ethyl.

13. The compound of claim 11 , wherein Y 2 is nitrogen.

14. The compound of claim 11 , wherein L 3 is methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, —N—, or —O—.

15. The compound of claim 11 , wherein:
s is 1 or 2;
each X 3 independently is H, fluoro, chloro, trifluoromethyl, methoxy, mercapto, or keto;
Y 2 is nitrogen; and
L 3 is methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, —N—, or —O—.

16. The compound of claim 11 , wherein R 3 and R 4 are the same.

17. The compound of claim 11 , wherein R 3 and R 4 are different.

18. The compound of claim 1 , having the formula

wherein Ar 1 and Ar 2 are independently selected aryl groups.

19. The compound of claim 18 , having the formula

20. The compound of claim 18 , having the formula

21. The compound of claim 1 , wherein R 3 and R 4 together with Y 1 form a tricyclic ring system wherein:
q and t are independently 0 to 2;
each X 4 and X 5 independently is H, methyl, fluoro, chloro, trifluoromethyl, methoxy, or cyano;
Y 2 is N or S; and
R 13 is H or ═O.

22. The compound of claim 1 , wherein R 3 and R 4 together with Y 1 form a tricyclic ring system wherein:
Y 1 is nitrogen;
Y 2 is CH, CH 2 or S;
R 13 is H or ═O;
q and t are independently 0 to 2; and
each X 4 and X 5 independently is H, fluoro, chloro, trifluoromethyl, cyano, or alkoxy.

23. A compound, having a formula selected from

24. A pharmaceutical composition, the composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.

25. The pharmaceutical composition of claim 24 , further comprising at least one additional medicinal or pharmaceutical agent.

26. The pharmaceutical composition of claim 25 , wherein the additional medicinal or pharmaceutical agent is an antimalarial therapeutic agent.

27. The pharmaceutical composition of claim 25 , wherein the at least one additional medicinal or pharmaceutical agent is selected from the group consisting of artesunate, mefloquine, sulfadoxine, pyrimethamine, and combinations thereof.

28. A pharmaceutical composition, the composition comprising a therapeutically effective amount of the compound of claim 23 and a pharmaceutically acceptable carrier.

29. The pharmaceutical composition of claim 28 , furt

Assignees

• Peyton David H
• Burgess Steven
• Univ Portland State

Inventors

• Peyton David H
• Burgess Steven

Classifications

• A61P33/06

  Antimalarials · CPC title

• C07D215/44

  with aryl radicals attached to said nitrogen atoms · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title