Quinoline derivatives and uses thereof
View Patent ↗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 ).
1. An antimalarial compound having the formula:
wherein X 1 and X 2 are independently alkoxy, optionally substituted amino, halo, haloalkyl or hydroxy;
n is from 0 to 2;
m is from 0 to 4;
R 1 is H, alkyl, heteroalkyl, alkylamino, sulfonyl, haloalkyl, or carbonyl;
Y 1 represents N, CH, CH 2 CH or C(O)CH;
R 3 and R 4 are independently cycloalkyl, heterocyclyl, aryl, or heteroaryl;
L 1 is an ethyl or propyl chain; and
ring 1 is a five-, six-, or seven-membered heterocyclic ring.
2. An antimalarial compound having the formula
wherein R 3 and R 4 are independently cycloalkyl, heterocyclyl, aryl, or heteroaryl; and
L 1 is alkyl or heteroalkyl.
3. The compound of claim 2 , having the formula
4. An antimalarial compound having the formula
wherein R 3 and R 4 are independently cycloalkyl, heterocyclyl, aryl, or heteroaryl; and
L 1 is alkyl or heteroalkyl.
5. An antimalarial compound having the formula:
Q-L-G
wherein Q represents
X 1 and X 2 are independently alkoxy, optionally substituted amino, halo, haloalkyl or hydroxy;
n is from 0 to 2;
m is from 0 to 4;
R 1 is H, alkyl, heteroalkyl, alkylamino, sulfonyl, haloalkyl, or carbonyl;
L is L 1 or a hydrocarbon chain containing from 1 to 12 carbon atoms, optionally substituted, branched or both and optionally interrupted by one or more heteroatoms;
wherein G is
Y 1 represents N, CH, CH 2 CH or C(O)CH;
R 3 and R 4 are independently cycloalkyl, heterocyclyl, aryl, heteroaryl;
L 1 is alkyl or heteroalkyl;
ring 1 is a five-, six-, or seven-membered heterocyclic ring; and
wherein R 3 and R 4 together with Y 1 form a tricyclic ring system.
6. An antimalarial compound having the formula:
wherein G is
(X 1 ) m and (X 2 ) n are independently H, halo, haloalkyl, amino, hydroxyl, alkoxy, alkylamino, or arylamino;
m is 0 to 4;
n is 0 to 2;
R 1 is H, alkyl, heteroalkyl, alkylamino, haloalkyl, or alkylsulfonamide;
L 1 alkyl or heteroalkyl;
Y′ 1 is carbon;
R 3 and R 4 are independently aryl, or heteroaryl, or together with Y′ 1 form a tricyclic ring system; and
Ring 1 is a five- to six-membered heterocyclic ring.
7. The compound of claim 6 , wherein (X 1 ) m are independently H, chloro, or trifluoromethyl; and (X 2 ) n are H.
8. The compound of claim 7 , wherein m is 1 and (X 1 ) 1 is chloro at position C 7 .
9. The compound of claim 6 , wherein R 1 is H, alkyl having from 1 to 4 carbon atoms, or heteroalkyl having from 1 to 4 carbon atoms.
10. The compound of claim 9 , wherein R 1 is 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 .
11. The compound of claim 5 , wherein the tricyclic ring system comprises a central ring and two peripheral rings, having a formula selected from:
wherein Y 2 is N, NR 14 , 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; (X 4 ) q and (X 5 ) t are independently H, alkyl, halo, haloalkyl, alkoxy, amino, hydroxyl, alkylamino, cyano, or mercapto; q and t are independently 0 to 4 as valence requirements permit; R 14 is H, lower alkyl, or acyl; and each of peripheral rings can independently include at least one heteroatom at any position that valence requirements permit.
12. The compound of claim 11 , wherein q and t are independently 0 to 2; (X 4 ) q and (X 5 ) t are independently H, methyl, fluoro, chloro, trifluoromethyl, methoxy, or cyano; Y 2 is N or S; and R 13 is H or ═O.
13. The compound of claim 11 , wherein Y 1 is nitrogen; Y 2 is CH, CH 2 or S; R 13 is H or ═O; (X 4 ) q and (X 5 ) t are independently H, fluoro, chloro, trifluoromethyl, cyano, or alkoxy; and q and t are independently 0 to 2.
14. An antimalarial compound having the formula:
wherein m is 1; (X 1 ) m is chloro at position C 7 ; (X 2 ) n are each H; R 1 and is H, alkyl, or heteroalkyl; L 1 is alkyl or heteroalkyl; ring 1 is a five-, six-, or seven-membered heterocyclic ring; Y′ 1 is carbon; and R 3 and R 4 are independently aryl, or heteroaryl, or together with Y′ 1 form a tricyclic ring system.
15. The compound of claim 14 , wherein R 3 and R 4 independently have the formula:
where (X 3 ) s are independently H, halo, haloalkyl, amino, hydroxyl, alkylamino, cyano, alkoxy, sulfonamide, mercapto, or keto; s is 0 to 4; Y 2 is CH, S or N; and L 3 is alkyl, heteroalkyl, —N—, —O—, or —S—.
16. The compound of claim 15 , wherein s is 1 to 2; (X 3 ), are independently H, fluoro, chloro, trifluoromethyl, methoxy, mercapto, or keto.
17. The compound of claim 15 , wherein Y 2 is nitrogen.
18. The compound of claim 15 , wherein L 3 is methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, —N—, or —O—.
19. The compound of claim 15 , wherein s is 1 to 2; (X 3 ) s are independently 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—.
20. The compound of claim 6 , wherein Y′ 1 , R 3 , and R 4 form a tricyclic ring system having a formula selected from:
wherein Y 2 is NR 14 , O, S, CH, or CH 2 ; 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; (X 4 ) q and (X 5 ) t are independently H, alkyl, halo, haloalkyl, alkoxy, amino, hydroxyl, alkylamino, cyano, or mercapto; q and t are independently 0 to 4 as valence requirements permit; R 14 is H, lower alkyl or acyl and each peripheral ring can independently include at least one heteroatom at any position that valence requirements permit.
21. The compound of claim 20 , wherein Y 2 is CH, CH 2 , or NR 14 ; R 13 is H or ═O; (X 4 ) q and (X 5 ) t are independently H, fluoro, chloro, trifluoromethyl, cyano, or alkoxy; and q and t are independently 0 to 2.
22. The compound of claim 21 , wherein the compound is selected from
23. The compound of claim 19 , wherein R 1 is H.
24. An antimalarial compound having the formula:
Q-L-G
wherein Q represents
wherein X 1 is halo, m is from 0 to 4, n=0, R 1 is H, L is a hydrocarbon chain containing from 1 to 12 carbon atoms, and G is
wherein Y 1 is CH, R 3 and R 4 independently are heteroaryl, and Ring 1 is a six-membered heterocyclic ring.
25. The compound of claim 5 , having a formula selected from
26. The compound of claim 6 , having a formula selected from
27. The compound of claim 2 , wherein L 1 is from 1 to 12 atoms in length, and each position of L 1 is independently methylene, difluoromethylene, dichloromethylene, di(methylamino), —NH—, or —O—.
28. The compound of claim 4 , wherein L 1 is from 1 to 12 atoms in length, and each position of L 1 is independently methylene, difluoromethylene, dichloromethylene, di(methylamino), —NH—, or —O—.
29. The compound of claim 5 , wherein L 1 is from 1 to 12 atoms in length, and each position of L 1 is independently methylene, difluoromethylene, dichloromethylene, di(methylamino), —NH—, or —O—.
30. The compound of claim 6 , wherein L 1 is from 1 to 12 atoms in length, and each position of L 1 is independently methylene, difluoromethylene, dichloromethylene, di(methylamino), —NH—, or —O—.
31. The compound of claim 14 , wherein L 1 is from 1 to 12 atoms in length, and each position of L 1 is independently methylene, difluoromethylene, dichloromethylene, di(methylamino), —NH—, or —O—.
32. The compound of claim 1 , wherein m is 1; (X 1 ) m is chloro at position C 7 ; n=0; and R 1 is 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 .
33. The compound of claim 2 , wherein the chloro is at position C 7 , L 1 is from 1 to 12 atoms in length, and each position of L 1 is independently methylene, difluoromethylene, dichloromethylene), di(methylamino), —NH—, or —O—.
34. The compound of claim 5 , wherein m is 1; (X 1 ) m is chloro at position C 7 ; n=0; R 1 is 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 ; and L 1 is from 1 to 12 atoms in length, and each position of L 1 is methylene, difluoromethylene, dichloromethylene), di(methylamino), —NH—, or —O—.
35. The compound of claim 6 , wherein m is 1; (X 1 ) m is chloro at position C 7 ; n=0; R 1 is 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 ; and L 1 is from 1 to 12 atoms in length, and each position of L 1 is methylene, difluoromethylene, dichloromethylene), di(methylamino), —NH—, or —O—.
36. The compound of claim 14 , wherein R 1 is 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 ; and L 1 is from 1 to 12 atoms in length, and each position of L 1 is methylene, difluoromethylene, dichloromethylene), di(methylamino), —NH—, or —O—.
37. The compound of claim 24 , wherein m is 1; (X 1 ) m is chloro at position C 7 ; and n=0.
38. The compound of claim 1 , wherein R 3 and R 4 are different.
39. The compound of claim 2 , wherein R 3 and R 4 are different.
40. The compound of claim 4 , wherein R 3 and R 4 are different.
41. The compound of claim 5 , wherein R 3 and R 4 are different.
42. The compound of claim 6 , wherein R 3 and R 4 are different.
43. The compound of claim 14 , wherein R 3 and R 4 are different.
44. The compound of claim 24 , wherein R 3 and R 4 are different.
45. A pharmaceutical composition, the composition comprising a therapeutically effective amount of the compound of claim 1 ; and a pharmaceutically acceptable carrier.
46. The pharmaceutical composition of claim 45 further comprising at least one additional antimalarial therapeutic agent.
47. The pharmaceutical composition of claim 46 , wherein the at least one additional antimalarial therapeutic agent is artesunate, mefloquine, sulfadoxine, or pyrimethamine, or combinations thereof.
48. A pharmaceutical composition, the composition comprising a therapeutically effective amount of the compound of claim 2 ; and a pharmaceutically acceptable carrier.
49. The pharmaceutical composition of claim 48 further comprising at least one additional antimalarial therapeutic agent.
50. The pharmaceutical composition of claim 49 , wherein the at least one additional antimalarial therapeutic agent is artesunate, mefloquine, sulfadoxine, or pyrimethamine, or combinations thereof.
51. A pharmaceutical composition, the composition comprising a therapeutically effective amount of the compound of claim 4 ; and a pharmaceutically acceptable carrier.
52. The pharmaceutical composition of claim 51 further comprising at least one additional antimalarial therapeutic agent.
53. The pharmaceutical composition of claim 52 , wherein the at least one additional antimalarial therapeutic agent is artesunate, mefloquine, sulfadoxine, or pyrimethamine, or combinations thereof.
54. A pharmaceutical composition, the composition comprising a therapeutically effective amount of the compound of claim 5 ; and a pharmaceutically acceptable carrier.
55. The pharmaceutical composition of claim 54 further comprising at least one additional antimalarial therapeutic agent.
56. The pharmaceutical composition of claim 55 , wherein the at least one additional antimalarial therapeutic agent is artesunate, mefloquine, sulfadoxine, or pyrimethamine, or combinations thereof.
57. A pharmaceutical composition, the composition comprising a therapeutically effective amount of the compound of claim 6 ; and a pharmaceutically acceptable carrier.
58. The pharmaceutical composition of claim 57 further comprising at least one additional antimalarial therapeutic agent.
59. The pharmaceutical composition of claim 58 , wherein the at least one additional antimalarial therapeutic agent is artesunate, mefloquine, sulfadoxine, or pyrimethamine, or combinations thereof.
60. A pharmaceutical composition, the composition comprising a therapeutically effective amount of the compound of claim 14 ; and a pharmaceutically acceptable carrier.
61. The pharmaceutical composition of claim 60 further comprising at least one additional antimalarial therapeutic agent.
62. The pharmaceutical composition of claim 61 , wherein the at least one additional antimalarial therapeutic agent is artesunate, mefloquine, sulfadoxine, or pyrimethamine, or combinations thereof.
63. A pharmaceutical composition, the composition comprising a therapeutically effective amount of the compound of claim 24 ; and a pharmaceutically acceptable carrier.
64. The pharmaceutical composition of claim 63 further comprising at least one additional antimalarial therapeutic agent.
65. The pharmaceutical composition of claim 64 , wherein the at least one additional antimalarial therapeutic agent is artesunate, mefloquine, sulfadoxine, or pyrimethamine, or combinations thereof.