Modulators for atp-binding cassette transporters

Patent metadata

Field	Value
Publication number	US-2016166540-A1
Application number	US-201614992132-A
Country	US
Kind code	A1
Filing date	Jan 11, 2016
Priority date	Nov 8, 2011
Publication date	Jun 16, 2016
Grant date	—

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

1 . A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:
Y is OH or NH; and
X is CO 2 J;
wherein J is H or C 1 -C 6 alkyl;

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; and
R 3 is H or C 1 -C 6 alkyl;

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

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

5 . The compound of claim 1 of formula I, wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, R 3 is CH 3 , X is CO 2 H, and Y is OH.

6 .- 9 . (canceled)

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

11 . (canceled)

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

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

14 . The composition of claim 13 , 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.

15 . A method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting the cell with a compound of claim 1 .

16 . The method of claim 15 , wherein the ABC transporter is CFTR.

17 . A method of treating a condition, disease, or disorder in a subject implicated by ABC transporter activity, comprising the step of administering to the subject a compound or composition of claim 1 .

18 . The method of claim 17 , wherein the condition, disease, or disorder is selected from cystic fibrosis, emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, diabetes mellitus, laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (di), neurophyseal di, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, polyglutamine neurological disorders, Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, myotonic dystrophy, spongiform encephalopathies, hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjögren's disease.

19 . The method of claim 18 , wherein the condition, disease, or disorder is selected from cystic fibrosis, emphysema, COPD, or dry-eye disease.

20 . (canceled)

21 . (canceled)

22 . A process for preparing a compound of formula Ia

comprising converting an ester of formula I-1 to a compound of formula Ia:

wherein independently for each occurrence:
R 2 is H or halo; and
R 4 is C 1 -C 6 alkyl or benzyl.

23 . The process of claim 22 , wherein R 2 is H or F, and R 4 is methyl, ethyl, isopropyl, butyl, or benzyl.

24 . The process of claim 23 , wherein R 2 is H or F, and R 4 is isopropyl or benzyl.

25 . The process of claim 22 , wherein converting comprises contacting the compound of formula I-1 with a base in the presence of a solvent.

26 . The process of claim 25 , wherein the base is an alkali or alkali metal hydroxide. In one embodiment, the base is NaOH or LiOH and the solvent is methanol or THF either of which may be admixed with water.

27 . A process for preparing a compound of formula Ia

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 as provided above 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 as provided above to give a compound of formula I-3

(c) contacting the compound of formula I-3 with an oxidant in the presence of a solvent as provided above to give compound of formula I-2;

and
(d) contacting the compound of formula I-2 with a base in the presence of a solvent as provided above to give a compound of formula Ia.

28 . The process of claim 27 , wherein R 2 is H or F.

29 . (canceled)

30 . (canceled)

31 . A compound which is:

wherein R 2 is H or F and R 4 is iPr or benzyl.

32 . The compound of claim 1 which is:

wherein R 2 is H or halo and R 4 is iPr or benzyl.

33 . The compound of claim 1 which is:

34 . The compound of claim 1 which is:

Assignees

• Vertex Pharma

Inventors

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

Classifications

• H10W20/081 Primary

  by forming openings in the dielectric parts · CPC title

• A61K31/404 Primary

  Indoles, e.g. pindolol · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title