Modulators of ATP-binding cassette transporters
Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFFR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.
1. A compound of formula II:
or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:
R is H, OH, OCH 3 or two R taken together form —CH 2 CH 2 CH 2 —, —OCH 2 O— or —OCF 2 O—;
R 1 is H or up to two C1-C6 alkyl;
R 2 is H or F;
R 3 is H or CN;
R 4 is H, —CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 , or —CH 2 CH 2 OH; and
R 5 is H, OH, —CH 2 OCH 2 CH(OH)CH 2 OH, or —CH 2 OH.
2. The compound of claim 1 , wherein two R taken together form —OCF 2 O—, R 1 is H, and R 2 is F.
3. The compound of claim 1 , wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, and R 3 is H.
4. The compound of claim 1 , wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is H.
5. The compound of claim 1 , wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is —CH 2 CH 2 N + (CH 3 ) 3 .
6. The compound of claim 1 , wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is —CH 2 CH(OH)CH 2 OH.
7. The compound of claim 1 , wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is (S)—CH 2 CH(OH)CH 2 OH.
8. The compound of claim 1 , wherein two R taken together form —OCH 2 O—, R 1 is H, and R 2 is F.
9. The compound of claim 1 , wherein two R taken together form —OCH 2 O—, R 1 is H, R 2 is F, and R 3 is H.
10. The compound of claim 1 , wherein two R taken together form —OCH 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is —CH 2 CH(OH)CH 2 OH.
11. The compound of claim 1 , wherein two R taken together form —OCH 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is (R)—CH 2 CH(OH)CH 2 OH.
12. The compound of claim 1 , wherein two R taken together form —OCH 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is (S)—CH 2 CH(OH)CH 2 OH.
13. The compound of claim 1 , having formula IIa:
or a pharmaceutically acceptable salt thereof, wherein:
R 4 is H, —CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 , or —CH 2 CH 2 OH; and
R 5 is H, OH, —CH 2 OCH 2 CH(OH)CH 2 OH, or —CH 2 OH.
14. The compound of claim 13 , wherein R 4 is (R)—CH 2 CH(OH)CH 2 OH, (S)—CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 , or —CH 2 CH 2 OH.
15. The compound of claim 13 , wherein R 5 is OH, —CH 2 OCH 2 CH(OH)CH 2 OH, or —CH 2 OH.
16. The compound of claim 13 , wherein R 4 is (R)—CH 2 CH(OH)CH 2 OH, (S)—CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 , or —CH 2 CH 2 OH; and R 5 is OH, —CH 2 OCH 2 CH(OH)CH 2 OH, or —CH 2 OH.
17. A pharmaceutical composition comprising
(i) a compound according to claim 1 ; and
(ii) a pharmaceutically acceptable carrier.
18. The composition of claim 17 , further comprising an additional agent selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, CFTR corrector, CFTR potentiator, or a nutritional agent.
19. A kit for use in measuring the activity of a ABC transporter or a fragment thereof in a biological sample in vitro or in vivo, comprising:
(i) a first composition comprising a compound of formula II:
wherein independently for each occurrence:
R is H, OH, OCH 3 or two R taken together form —CH 2 C 2 CH 2 —, —OCH 2 O— or —OCF 2 O—;
R 1 is H or up to two C1-C6 alkyl;
R 2 is H or F;
R 3 is H or CN;
R 4 is H, —CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 , or —CH 2 CH 2 OH; and
R 5 is H, OH, —CH 2 OCH 2 CH(OH)CH 2 OH, —CH 2 OH, or R 4 and R 5 taken together form a fused pyrrolidine ring; and
(ii) instructions for:
a) contacting the composition with the biological sample;
b) measuring activity of said ABC transporter or a fragment thereof.
20. The kit according to claim 19 , further comprising instructions for
a) contacting an additional composition with the biological sample;
b) measuring the activity of said ABC transporter or a fragment thereof in the presence of said additional compound, and
c) comparing the activity of the ABC transporter in the presence of the additional compound with the density of the ABC transporter in the presence of said first composition.
21. The kit of claim 19 , wherein the kit is used to measure the density of CFTR.
22. The kit of claim 19 , wherein two R taken together form —OCF 2 O—, R 1 is H, and R 2 is F.
23. The kit of claim 19 , wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, and R 3 is H.
24. The kit of claim 19 , wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is H.
25. The kit of claim 19 , wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is —CH 2 CH 2 N + (CH 3 ) 3 .
26. The kit of claim 19 , wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is —CH 2 CH(OH)CH 2 OH.
27. The kit of claim 19 , wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is (R)—CH 2 CH(OH)CH 2 OH.
28. The kit of claim 19 , wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is (S)—CH 2 CH(OH)CH 2 OH.
29. The kit of claim 1 , wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 and R 5 taken together form a fused pyrrolidine ring.
30. The kit of claim 19 , wherein two R taken together form —OCH 2 O—, R 1 is H, and R 2 is F.
31. The kit of claim 19 , wherein two R taken together form —OCH 2 O—, R 1 is H, R 2 is F, and R 3 is H.
32. The kit of claim 19 , wherein two R taken together form —OCH 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is —CH 2 CH(OH)CH 2 OH.
33. The kit of claim 19 , wherein two R taken together form —OCH 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is (R)—CH 2 CH(OH)CH 2 OH.
34. The kit of claim 19 , wherein two R taken together form —OCH 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is (S)—CH 2 CH(OH)CH 2 OH.
35. The kit of claim 19 , wherein the compound is represented by formula IIa:
or a pharmaceutically acceptable salt thereof, wherein:
R 4 is H, —CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 , or —CH 2 CH 2 OH; and
R 5 is H, OH, —CH 2 OCH 2 CH(OH)CH 2 OH, —CH 2 OH, or R 4 and R 5 taken together form a fused pyrrolidine ring.
36. The kit of claim 35 , wherein R 4 is (R)—CH 2 CH(OH)CH 2 OH, (S)—CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 , or —CH 2 CH 2 OH.
37. The kit of claim 35 , wherein R 5 is OH, —CH 2 OCH 2 CH(OH)CH 2 OH, or —CH 2 OH.
38. The kit of claim 35 , wherein R 4 is (R)—CH 2 CH(OH)CH 2 OH, (S)—CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 , or —CH 2 CH 2 OH; and R 5 is OH, —CH 2 OCH 2 CH(OH)CH 2 OH, or —CH 2 OH.
39. The kit of claim 19 , wherein the compound is selected from:
.
40. The composition of claim 18 , wherein the additional agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
41. A pharmaceutical composition comprising:
a compound of formula II:
or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:
R is H, OH, OCH 3 or two R taken together form —CH 2 CH 2 CH 2 —, —OCH 2 O— or —OCF 2 O—;
R 1 is H or up to two C1-C6 alkyl;
R 2 is H or F;
R 3 is H or CN;
R 4 is H, —CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 , or —CH 2 CH 2 OH; and
R 5 is H, OH, —CH 2 OCH 2 CH(OH)CH 2 OH, —CH 2 OH;
(ii) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide; and
(iii) a pharmaceutically acceptable carrier.
42. The composition of claim 41 , wherein two R taken together in the compound of formula II form —OCF 2 O—, R 1 is H, and R 2 is F.
43. The compound of claim 41 , wherein two R taken together in the compound of formula II form —OCF 2 O—, R 1 is H, R 2 is F, and R 3 is H.
44. The composition of claim 41 , wherein two R taken together in the compound of formula II form —OCF 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is H.
45. The composition of claim 41 , wherein two R taken together in the compound of formula II form —OCF 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is —CH 2 CH 2 N + (CH 3 ) 3 .
46. The composition of claim 41 , wherein two R taken together in the compound of formula II form —OCF 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is —CH 2 CH(OH)CH 2 OH.
47. The composition of claim 41 , wherein two R taken together in the compound of formula II form —OCF 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is (S)—CH 2 CH(OH)CH 2 OH.
48. The composition of claim 41 , wherein two R taken together in the compound of formula II form —OCH 2 O—, R 1 is H, and R 2 is F.
49. The composition of claim 41 , wherein two R taken together in the compound of formula II form —OCH 2 O—, R 1 is H, R 2 is F, and R 3 is H.
50. The composition of claim 41 , wherein two R taken together in the compound of formula II form —OCH 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is —CH 2 CH(OH)CH 2 OH.
51. The composition of claim 41 , wherein two R taken together in the compound of formula II form —OCH 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is (R)—CH 2 CH(OH)CH 2 OH.
52. The composition of claim 41 , wherein two R taken together in the compound of formula II form —OCH 2 O—, R 1 is H, R 2 is F, R 3 is H, and R 4 is (S)—CH 2 CH(OH)CH 2 OH.
53. The composition of claim 41 , wherein the compound of formula II is a compound having formula IIa:
or a pharmaceutically acceptable salt thereof, wherein:
R 4 is H, —CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 , or —CH 2 CH 2 OH; and
R 5 is H, OH, —CH 2 OCH 2 CH(OH)CH 2 OH, or —CH 2 OH.
54. The composition of claim 53 , wherein R 4 is (R)—CH 2 CH(OH)CH 2 OH, (S)—CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 , or —CH 2 CH 2 OH in the compound of formula IIa.
55. The composition of claim 53 , wherein R 5 is OH, —CH 2 OCH 2 CH(OH)CH 2 OH, or —CH 2 OH in the compound of formula IIa.
56. The composition of claim 53 , wherein R 4 is (R)—CH 2 CH(OH)CH 2 OH, (S)—CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 , or —CH 2 CH 2 OH; and R 5 is OH, —CH 2 OCH 2 CH(OH)CH 2 OH, or —CH 2 OH in the compound of formula IIa.
57. A compound selected from: