➤ Get the DrugPatentWatch Daily Briefing

Get Daily Updates on Generic Entry, Litigation, Biosimilars, and more …

Serving leading biopharmaceutical companies globally:

Dow
Moodys
Medtronic
Johnson and Johnson
Harvard Business School
Express Scripts

Last Updated: October 23, 2020

DrugPatentWatch Database Preview

Claims for Patent: 8,623,905

➤ Get the DrugPatentWatch Daily Briefing
» See Plans and Pricing

« Back to Dashboard

Summary for Patent: 8,623,905
Title:Modulators of ATP-binding cassette transporters
Abstract: 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.
Inventor(s): Ruah; Sara S. Hadida (La Jolla, CA), Grootenhuis; Peter D. J. (San Diego, CA), van Goor; Fredrick F. (San Diego, CA), Zhou; Jinglan (San Diego, CA), Bear; Brian (Oceanside, CA), Miller; Mark T. (San Diego, CA), McCartney; Jason (Cardiff by the Sea, CA), Numa; Mehdi Michel Djamel (San Diego, CA)
Assignee: Vertex Pharmaceuticals Incorporated (Cambridge, MA)
Application Number:12/767,472
Patent Claims: 1. A compound of formula II: ##STR00848## or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence: R is H, OH, OCH.sub.3 or two R taken together form --CH.sub.2CH.sub.2CH.sub.2--, --OCH.sub.2O-- or --OCF.sub.2O--; R.sub.1 is H or up to two C1-C6 alkyl; R.sub.2 is H or F; R.sub.3 is H or CN; R.sub.4 is H, --CH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, or --CH.sub.2CH.sub.2OH; and R.sub.5 is H, OH, --CH.sub.2OCH.sub.2CH(OH)CH.sub.2OH, or --CH.sub.2OH.

2. The compound of claim 1, wherein two R taken together form --OCF.sub.2O--, R.sub.1 is H, and R.sub.2 is F.

3. The compound of claim 1, wherein two R taken together form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, and R.sub.3 is H.

4. The compound of claim 1, wherein two R taken together form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is H.

5. The compound of claim 1, wherein two R taken together form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is --CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3.

6. The compound of claim 1, wherein two R taken together form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is --CH.sub.2CH(OH)CH.sub.2OH.

7. The compound of claim 1, wherein two R taken together form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is (S)--CH.sub.2CH(OH)CH.sub.2OH.

8. The compound of claim 1, wherein two R taken together form --OCH.sub.2O--, R.sub.1 is H, and R.sub.2 is F.

9. The compound of claim 1, wherein two R taken together form --OCH.sub.2O--, R.sub.1 is H, R.sub.2 is F, and R.sub.3 is H.

10. The compound of claim 1, wherein two R taken together form --OCH.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is --CH.sub.2CH(OH)CH.sub.2OH.

11. The compound of claim 1, wherein two R taken together form --OCH.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is (R)--CH.sub.2CH(OH)CH.sub.2OH.

12. The compound of claim 1, wherein two R taken together form --OCH.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is (S)--CH.sub.2CH(OH)CH.sub.2OH.

13. The compound of claim 1, having formula IIa: ##STR00849## or a pharmaceutically acceptable salt thereof, wherein: R.sub.4 is H, --CH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, or --CH.sub.2CH.sub.2OH; and R.sub.5 is H, OH, --CH.sub.2OCH.sub.2CH(OH)CH.sub.2OH, or --CH.sub.2OH.

14. The compound of claim 13, wherein R.sub.4 is (R)--CH.sub.2CH(OH)CH.sub.2OH, (S)--CH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, or --CH.sub.2CH.sub.2OH.

15. The compound of claim 13, wherein R.sub.5 is OH, --CH.sub.2OCH.sub.2CH(OH)CH.sub.2OH, or --CH.sub.2OH.

16. The compound of claim 13, wherein R.sub.4 is (R)--CH.sub.2CH(OH)CH.sub.2OH, (S)--CH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, or --CH.sub.2CH.sub.2OH; and R.sub.5 is OH, --CH.sub.2OCH.sub.2CH(OH)CH.sub.2OH, or --CH.sub.2OH.

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: ##STR00850## wherein independently for each occurrence: R is H, OH, OCH.sub.3 or two R taken together form --CH.sub.2C.sub.2CH.sub.2--, --OCH.sub.2O-- or --OCF.sub.2O--; R.sub.1 is H or up to two C1-C6 alkyl; R.sub.2 is H or F; R.sub.3 is H or CN; R.sub.4 is H, --CH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, or --CH.sub.2CH.sub.2OH; and R.sub.5 is H, OH, --CH.sub.2OCH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2OH, or R.sub.4 and R.sub.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.sub.2O--, R.sub.1 is H, and R.sub.2 is F.

23. The kit of claim 19, wherein two R taken together form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, and R.sub.3 is H.

24. The kit of claim 19, wherein two R taken together form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is H.

25. The kit of claim 19, wherein two R taken together form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is --CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3.

26. The kit of claim 19, wherein two R taken together form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is --CH.sub.2CH(OH)CH.sub.2OH.

27. The kit of claim 19, wherein two R taken together form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is (R)--CH.sub.2CH(OH)CH.sub.2OH.

28. The kit of claim 19, wherein two R taken together form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is (S)--CH.sub.2CH(OH)CH.sub.2OH.

29. The kit of claim 1, wherein two R taken together form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 and R.sub.5 taken together form a fused pyrrolidine ring.

30. The kit of claim 19, wherein two R taken together form --OCH.sub.2O--, R.sub.1 is H, and R.sub.2 is F.

31. The kit of claim 19, wherein two R taken together form --OCH.sub.2O--, R.sub.1 is H, R.sub.2 is F, and R.sub.3 is H.

32. The kit of claim 19, wherein two R taken together form --OCH.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is --CH.sub.2CH(OH)CH.sub.2OH.

33. The kit of claim 19, wherein two R taken together form --OCH.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is (R)--CH.sub.2CH(OH)CH.sub.2OH.

34. The kit of claim 19, wherein two R taken together form --OCH.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is (S)--CH.sub.2CH(OH)CH.sub.2OH.

35. The kit of claim 19, wherein the compound is represented by formula IIa: ##STR00851## or a pharmaceutically acceptable salt thereof, wherein: R.sub.4 is H, --CH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, or --CH.sub.2CH.sub.2OH; and R.sub.5 is H, OH, --CH.sub.2OCH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2OH, or R.sub.4 and R.sub.5 taken together form a fused pyrrolidine ring.

36. The kit of claim 35, wherein R.sub.4 is (R)--CH.sub.2CH(OH)CH.sub.2OH, (S)--CH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, or --CH.sub.2CH.sub.2OH.

37. The kit of claim 35, wherein R.sub.5 is OH, --CH.sub.2OCH.sub.2CH(OH)CH.sub.2OH, or --CH.sub.2OH.

38. The kit of claim 35, wherein R.sub.4 is (R)--CH.sub.2CH(OH)CH.sub.2OH, (S)--CH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, or --CH.sub.2CH.sub.2OH; and R.sub.5 is OH, --CH.sub.2OCH.sub.2CH(OH)CH.sub.2OH, or --CH.sub.2OH.

39. The kit of claim 19, wherein the compound is selected from: ##STR00852## ##STR00853## ##STR00854## .

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: ##STR00855## or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence: R is H, OH, OCH.sub.3 or two R taken together form --CH.sub.2CH.sub.2CH.sub.2--, --OCH.sub.2O-- or --OCF.sub.2O--; R.sub.1 is H or up to two C1-C6 alkyl; R.sub.2 is H or F; R.sub.3 is H or CN; R.sub.4 is H, --CH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, or --CH.sub.2CH.sub.2OH; and R.sub.5 is H, OH, --CH.sub.2OCH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2OH; (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.sub.2O--, R.sub.1 is H, and R.sub.2 is F.

43. The compound of claim 41, wherein two R taken together in the compound of formula II form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, and R.sub.3 is H.

44. The composition of claim 41, wherein two R taken together in the compound of formula II form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is H.

45. The composition of claim 41, wherein two R taken together in the compound of formula II form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is --CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3.

46. The composition of claim 41, wherein two R taken together in the compound of formula II form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is --CH.sub.2CH(OH)CH.sub.2OH.

47. The composition of claim 41, wherein two R taken together in the compound of formula II form --OCF.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is (S)--CH.sub.2CH(OH)CH.sub.2OH.

48. The composition of claim 41, wherein two R taken together in the compound of formula II form --OCH.sub.2O--, R.sub.1 is H, and R.sub.2 is F.

49. The composition of claim 41, wherein two R taken together in the compound of formula II form --OCH.sub.2O--, R.sub.1 is H, R.sub.2 is F, and R.sub.3 is H.

50. The composition of claim 41, wherein two R taken together in the compound of formula II form --OCH.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is --CH.sub.2CH(OH)CH.sub.2OH.

51. The composition of claim 41, wherein two R taken together in the compound of formula II form --OCH.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is (R)--CH.sub.2CH(OH)CH.sub.2OH.

52. The composition of claim 41, wherein two R taken together in the compound of formula II form --OCH.sub.2O--, R.sub.1 is H, R.sub.2 is F, R.sub.3 is H, and R.sub.4 is (S)--CH.sub.2CH(OH)CH.sub.2OH.

53. The composition of claim 41, wherein the compound of formula II is a compound having formula IIa: ##STR00856## or a pharmaceutically acceptable salt thereof, wherein: R.sub.4 is H, --CH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, or --CH.sub.2CH.sub.2OH; and R.sub.5 is H, OH, --CH.sub.2OCH.sub.2CH(OH)CH.sub.2OH, or --CH.sub.2OH.

54. The composition of claim 53, wherein R.sub.4 is (R)--CH.sub.2CH(OH)CH.sub.2OH, (S)--CH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, or --CH.sub.2CH.sub.2OH in the compound of formula IIa.

55. The composition of claim 53, wherein R.sub.5 is OH, --CH.sub.2OCH.sub.2CH(OH)CH.sub.2OH, or --CH.sub.2OH in the compound of formula IIa.

56. The composition of claim 53, wherein R.sub.4 is (R)--CH.sub.2CH(OH)CH.sub.2OH, (S)--CH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, or --CH.sub.2CH.sub.2OH; and R.sub.5 is OH, --CH.sub.2OCH.sub.2CH(OH)CH.sub.2OH, or --CH.sub.2OH in the compound of formula IIa.

57. A compound selected from: ##STR00857## ##STR00858## ##STR00859##

Make Better Decisions: Try a trial or see plans & pricing

Serving leading biopharmaceutical companies globally:

Medtronic
Colorcon
Mallinckrodt
Baxter
Dow
Moodys

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.