Modulators of ATP-binding cassette transporters

Patent metadata

Field	Value
Publication number	US-9254291-B2
Application number	US-201213672538-A
Country	US
Kind code	B2
Filing date	Nov 8, 2012
Priority date	Nov 8, 2011
Publication date	Feb 9, 2016
Grant date	Feb 9, 2016

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.

First claim

We claim:

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 —OCH 2 O— or —OCF 2 O—;
R 1 is H or up to two C 1 -C 6 alkyl;
R 2 is H or halo;
R 3 is H or C 1 -C 6 alkyl; and
Y is O.

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

3. The compound of claim 1 of formula II, wherein two R taken together form OCF 2 O—, R 1 is H, R 2 is F, and R 3 is CH 3 .

4. The compound of claim 1 , having formula IIa:

or a pharmaceutically acceptable salt thereof, wherein:
R 2 is H or halo.

5. The compound of claim 4 , wherein R 2 is F.

6. The compound of claim 1 , wherein the compound is

7. The compound of claim 1 , wherein the compound is

8. A pharmaceutical composition comprising
(i) a compound according to claim 1 ; and
(ii) a pharmaceutically acceptable carrier.

9. A method of treating cystic fibrosis, emphysema, COPD, or dry-eye disease comprising the step of administering to the subject a compound of claim 1 .

10. A process for preparing a compound of formula IIa

wherein R 2 is H or halo, comprising:
(a) contacting the compound of formula I-5 with carbonyl diimidazole (CDI) in the presence of a solvent to give a compound of formula I-4;

 (b) contacting the compound of formula I-4 with an oxidant in the presence of a solvent to give a compound of formula I-3;

and
 (c) contacting the compound of formula I-3 with a base in the presence of a solvent to give a compound of formula IIa:

11. The process of claim 10 , wherein R 2 is H or F.

Assignees

• Vertex Pharma

Inventors

• Looker Adam
• Littler Benjamin Joseph
• Choudhury Anusuya
• Harrison Cristian
• Veluri Ravikanth
• Ryan Michael P
• Jiang Licong
• Luss-Lusis Eduard

Classifications

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P37/02

  Immunomodulators · CPC title