Modulators of ATP-binding cassette transporters

• US 10,022,352 B2
• Filed: 03/23/2016
• Issued: 07/17/2018
• Est. Priority Date: 04/07/2006
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Hadida Ruah, Sara Sabina, Grootenhuis, Peter Diederik Jan, Van Goor, Fredrick F., Zhou, Jinglan, Bear, Brian Richard, Miller, Mark Thomas, McCartney, Jason, Numa, Mehdi Michel Djamel
• Primary Examiner(s): Jackson, Shawquia
• Application Number:
  US15/078,800
• Publication Number:
  US 20160271105A1
• Time in Patent Office: 846 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/4192 1,2,3-Triazoles
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: G01N 2333/705 : Assays involving receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: G01N 2800/382 : Cystic fibrosis
• CPC Class Codes: G01N 33/5035 : on sub-cellular localization
• CPC Class Codes: G01N 33/6893 : related to diseases not provided for elsewhere

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 (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.

Claims

1. A method of treating cystic fibrosis in a patient in need thereof, comprising administering to said patient an effective amount of a pharmaceutical composition comprising compound (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound A)

2. The method of claim 1, wherein the pharmaceutical composition further comprises a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator.

3. The method of claim 2, wherein the cystic fibrosis transmembrane conductance regulator (CFTR) potentiator is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

4. The method of claim 1, wherein the patient possesses a cystic fibrosis transmembrane conductance regulator (CFTR) with a Δ

F508 mutation on both alleles.

5. The method of claim 1, wherein the pharmaceutical composition is in solid dosage form.

6. A method of treating cystic fibrosis in a patient in need thereof, comprising the step of administering to said patient an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable salt of compound (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound A)

7. The method of claim 6, wherein the pharmaceutical composition further comprises a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator.

8. The method of claim 7, wherein the cystic fibrosis transmembrane conductance regulator (CFTR) potentiator is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

9. The method of claim 6, wherein the patient possesses a cystic fibrosis transmembrane conductance regulator (CFTR) with a Δ

F508 mutation on both alleles.

10. The method of claim 6, wherein the pharmaceutical composition is in solid dosage form.

11. A solid dosage form comprising (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound A).

12. The solid dosage form of claim 11, which is a tablet.

13. The solid dosage form of claim 11, further comprising at least one excipient chosen from fillers, lubricants, opacifying agents, and buffering agents.

14. The solid dosage form of claim 12, wherein the tablet further comprises a film coat.

19. The solid dosage form of claim 12, further comprising at least one excipient chosen from fillers, lubricants, opacifying agents, and buffering agents.

15. A solid dosage form comprising a pharmaceutically acceptable salt of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound A).

16. The solid dosage form of claim 15, which is a tablet.

17. The solid dosage form of claim 15, further comprising at least one excipient chosen from fillers, lubricants, opacifying agents, and buffering agents.

18. The solid dosage form of claim 16, wherein the tablet further comprises a film coat.

20. The solid dosage form of claim 16, further comprising at least one excipient chosen from fillers, lubricants, opacifying agents, and buffering agents.