IP Library › Patent Application 14567475

Patent Application

App. No. 14/567,475

Modulators of ATP-Binding Cassette Transporters

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Patent No.: US None
App. No.: 14/567,475

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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 (132)

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, —CH 2 OH, or R 4 and R 5 taken together form a fused pyrrolidine ring.

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 (R)—CH 2 CH(OH)CH 2 OH.

8 . 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

9 . 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 and R 5 taken together form a fused pyrrolidine ring.

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

11 . 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.

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 —CH 2 CH(OH)CH 2 OH.

13 . 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.

14 . 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.

15 . 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, —CH 2 OH, or R 4 and R 5 taken together form a fused pyrrolidine ring.

16 . The compound of claim 15 , 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.

17 . The compound of claim 15 , wherein R 5 is OH, —CH 2 OCH 2 CH(OH)CH 2 OH, or —CH 2 OH.

18 . The compound of claim 15 , wherein R s 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.

19 . A compound is selected from Table 1.

20 . A pharmaceutical composition comprising

(i) a compound according to claim 1 ; and

(ii) a pharmaceutically acceptable carrier.

21 . The composition of claim 20 , 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.

22 . A method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting said cell with a compound of formula II:

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, or R 4 and R 5 taken together form a fused pyrrolidine ring.

23 . The method of claim 22 , wherein the ABC transporter is CFTR.

24 . The method of claim 22 , wherein two R taken together form —OCF 2 O—, R 1 is H, and R 2 is F.

25 . The method of claim 22 , wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, and R 3 is H.

26 . The method of claim 22 , 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.

27 . The method of claim 22 , 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 .

28 . The method of claim 22 , 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.

29 . The method of claim 22 , 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.

30 . The method of claim 22 , 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.

31 . The method of claim 22 , 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.

32 . The method of claim 22 , wherein two R taken together form —OCH 2 O—, R 1 is H, and R 2 is F.

33 . The method of claim 22 , wherein two R taken together form —OCH 2 O—, R 1 is H, R 2 is F, and R 3 is H.

34 . The method of claim 22 , 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.

35 . The method of claim 22 , 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.

36 . The method of claim 22 , 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.

37 . The method of claim 22 , 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.

38 . The method of claim 37 , 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.

39 . The method of claim 37 , wherein R 5 is OH, —CH 2 OCH 2 CH(OH)CH 2 OH, or —CH 2 OH.

40 . The method of claim 37 , 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.

41 . The method of claim 22 , wherein the compound is selected from Table 1.

42 . A method of treating a condition, disease, or disorder in a patient implicated by ABC transporter activity, comprising the step of administering to said patient a compound having 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, or R 4 and R 5 taken together form a fused pyrrolidine ring.

43 . The method of claim 42 , wherein two R taken together form —OCF 2 O—, R 1 is H, and R 2 is F.

44 . The method of claim 42 , wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, and R 3 is H.

45 . The method of claim 42 , 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.

46 . The method of claim 42 , 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 .

47 . The method of claim 42 , 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.

48 . The method of claim 42 , 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.

49 . The method of claim 42 , 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.

50 . The method of claim 42 , 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.

51 . The method of claim 42 , wherein two R taken together form —OCH 2 O—, R 1 is H, and R 2 is F.

52 . The method of claim 42 , wherein two R taken together form —OCH 2 O—, R 1 is H, R 2 is F, and R 3 is H.

53 . The method of claim 42 , 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.

54 . The method of claim 42 , 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.

55 . The method of claim 42 , 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.

56 . The method of claim 42 , 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.

57 . The method of claim 56 , 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.

58 . The method of claim 56 , wherein R 5 is OH, —CH 2 OCH 2 CH(OH)CH 2 OH, or —CH 2 OH.

59 . The method of claim 56 , 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.

60 . The method of claim 42 , wherein the compound is selected from Table 1.

61 . The method according to claim 42 , wherein said condition, disease, or disorder is selected from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as 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, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (di), neurophyseal di, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, and Sjögren's disease.

62 . 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 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, 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.

63 . The kit according to claim 62 , 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.

64 . The kit of claim 62 , wherein the kit is used to measure the density of CFTR.

65 . The kit of claim 62 , wherein two R taken together form —OCF 2 O—, R 1 is H, and R 2 is F.

66 . The kit of claim 62 , wherein two R taken together form —OCF 2 O—, R 1 is H, R 2 is F, and

R 3 is H.

67 . The kit of claim 62 , 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.

68 . The kit of claim 62 , 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 .

69 . The kit of claim 62 , 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.

70 . The kit of claim 62 , 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.

71 . The kit of claim 62 , 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.

72 . The kit of claim 62 , 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.

73 . The kit of claim 62 , wherein two R taken together form —OCH 2 O—, R 1 is H, and R 2 is F.

74 . The kit of claim 62 , wherein two R taken together form —OCH 2 O—, R 1 is H, R 2 is F, and R 3 is H.

75 . The kit of claim 62 , 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.

76 . The kit of claim 62 , 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.

77 . The kit of claim 62 , 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.

78 . The kit of claim 62 , 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.

79 . The kit of claim 78 , 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.

80 . The kit of claim 78 , wherein R 5 is OH, —CH 2 OCH 2 CH(OH)CH 2 OH, or —CH 2 OH.

81 . The kit of claim 78 , 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.

82 . The kit of claim 62 , wherein the compound is selected from Table 1.