Chroman-spirocyclic piperidine amides as modulators of ion channels

• US 10,385,070 B2
• Filed: 02/16/2012
• Issued: 08/20/2019
• Est. Priority Date: 02/18/2011
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Hadida-Ruah, Sara Sabina, Miller, Mark Thomas, Kallel, Edward Adam, Bear, Brian Richard, Arumugam, Vijayalaksmi, Deninno, Michael Paul, Zhou, Jinglan, Uy, Johnny, Frieman, Bryan A.
• Primary Examiner(s): Desai, Rita J
• Application Number:
  US13/398,184
• Publication Number:
  US 20120245136A1
• Time in Patent Office: 2,742 Days
• Field of Search: 546 17, 5142101, 514278, 544230, 544 70
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
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• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 : for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 491/107 : with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07D 491/20 : Spiro-condensed systems
• CPC Class Codes: C07D 495/10 : Spiro-condensed systems
• CPC Class Codes: C07D 498/08 : Bridged systems
• CPC Class Codes: C07D 519/00 : Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention relates to chroman spirocyclic piperidine amide derivatives useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein all W'"'"'s are CH.

3. The compound of claim 1, wherein R¹ is halo.

4. The compound of claim 1, wherein R¹ is F.

5. The compound of claim 1, wherein R² is C1-C6 alkoxy, OR⁷, or N(R⁷)₂.

6. The compound of claim 1, wherein R² is OCH₃, CH₂OCHF₂, CH₂OCH₃, OCH₂CH₃, CH₃, CH(CH₃)₂, OCH(CH₃)₂, CH₂OCH₂CH₃, CH(CH₃)OCH₃, CH₂SCH₃,

7. The compound of claim 1, wherein A is

8. The compound of claim 7, wherein R⁴ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, CHF₂, CF₃, OCHF₂, OCF₃, a straight chain (C1-C8)-R⁸, or branched or cyclic (C3-C8)-R⁸ wherein up to three CH₂ units of the straight chain (C1-C8)-R⁸ and branched or cyclic (C3-C8)-R⁸ may be replaced with O, CO, S, SO, SO₂, or NR⁷.

9. The compound of claim 7, wherein R⁴ is H, OCH₃, OCHF₂, OCF₃, F, CH₃, or CH₂OCH₃.

10. The compound of claim 7, wherein R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, CN, a straight chain (C1-C8)-R⁸, branched, or cyclic (C3-C8)-R⁸ wherein up to three CH₂ units of the straight chain (C1-C8)-R⁸ and branched or cyclic (C3-C8)-R⁸ may be replaced with O, CO, S, SO, SO₂, or NR⁷.

11. The compound of claim 7, wherein R⁵ is H, F, CH₃, OCH₃, CH₂OH, OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, or CN.

12. The compound of claim 7, wherein R⁶ is H, C1-C6 alkyl, C1-C6 alkoxy, SO₂R⁷, SO₂N(R⁷)₂, a straight chain (C1-C8)-R⁸, or branched or cyclic (C3-C8)-R⁸, wherein up to three CH₂ units of the straight chain (C1-C8)-R⁸ and branched or cyclic (C3-C8)-R⁸ may be replaced with O, S, SO, SO₂, or NR⁷.

13. The compound of claim 7, wherein R⁶ is H, OCH₃, OH, OCH(CH₃)₂,

14. The compound of claim 7, wherein

15. The compound of claim 1, wherein the compound has formula IA:

16. The compound of claim 15, wherein R¹ is halo.

17. The compound of claim 15, wherein R¹ is F.

18. The compound of claim 15, wherein R² is C1-C6 alkoxy, N(R⁷)₂, a straight chain or branched (C1-C8)-H wherein up to two CH₂ units are replaced with O, S, SO, SO₂ or NR⁷.

19. The compound of claim 15, wherein R² is OCH₃, CH₂OCH₃, OCH₂CH₃, CH₃, CH(CH₃)₂, OCH(CH₃)₂, CH₂OCH(CH₃)₂, CH₂OCHF₂, CH₂OCH₂CH₃, CH(CH₃)OCH₃,

20. The compound of claim 15, wherein R⁴ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR⁷, CHF₂, CF₃, OCHF₂, OCF₃, a straight chain (C1-C8)-R⁸, or branched or cyclic (C3-C8)-R⁸ wherein up to three CH₂ units of the straight chain (C1-C8)-R⁸ and branched or cyclic (C3-C8)-R⁸ may be replaced with O, S, SO, SO₂, or NR⁷.

21. The compound of claim 15, wherein R⁴ is H, OCH₃, OCHF₂, OCF₃, F, CH₃, or CH₃.

22. The compound of claim 15, wherein R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, CN, a straight chain (C1-C8)-R⁸, or branched or cyclic (C3-C8)-R⁸ wherein up to three CH₂ units of the straight chain (C1-C8)-R⁸ and branched or cyclic (C3-C8)-R⁸ may be replaced with O, S, SO, SO₂, or NR⁷.

23. The compound of claim 15, wherein R⁵ is H, CH₃, OCH₃, CH₂OH, F, OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, or CN.

24. The compound of claim 15, wherein R⁶ is H, C1-C6 alkyl, C1-C6 alkoxy, SO₂R⁷, SO₂N(R⁷)₂, a straight chain (C1-C8)-R⁸, or branched or cyclic (C3-C8)-R⁸, wherein up to three CH₂ units of the straight chain (C1-C8)-R⁸ and branched or cyclic (C3-C8)-R⁸ may be replaced with O, S, SO, SO₂, or NR⁷.

25. The compound of claim 15, wherein R⁶ is H, OH, OCH₃, OCH(CH₃)₂, OCH₂CH₂OH, OCH₂CH₂CH₂OH,

26. The compound of claim 15, wherein n is 1.

27. The compound of claim 15, wherein

41. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

42. A method of inhibiting a voltage-gated sodium ion channel in:

a patient;

or

a biological sample;

comprising administering to the patient, or contacting the biological sample, with the compound of claim 1.

43. The method of claim 42, wherein the voltage-gated sodium ion channel is NaV 1.7.

28. A compound having formula IB:

29. The compound of claim 28, wherein R² is C1-C6 alkoxy.

30. The compound of claim 28, wherein R² is OCH₃, OC₂H₅, or OCH(CH₃)₂.

31. The compound of claim 28, wherein R⁴ is H, C1-C6 alkyl, C1-C6 alkoxy.

32. The compound of claim 28, wherein R⁴ is H or OCHF₂.

33. The compound of claim 28, wherein R⁵ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, a straight chain (C1-C8)-R⁸, or branched or cyclic (C3-C8)-R⁸ wherein up to three CH₂ units of the straight chain (C1-C8)-R⁸ and branched or cyclic (C3-C8)-R⁸ may be replaced with O, S, SO, SO₂, or NR⁷.

34. The compound of claim 28, wherein R⁵ is H, CH₃ or OCH₃.

35. The compound of claim 28, wherein R⁶ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, a straight chain (C1-C8)-R⁸, or branched or cyclic (C3-C8)-R⁸ wherein up to three CH₂ units of the straight chain (C1-C8)-R⁸ and branched or cyclic (C3-C8)-R⁸ may be replaced with O, S, SO, SO₂, or NR⁷.

36. The compound of claim 28, wherein R⁶ is OCH(CH₃)₂.

37. The compound of claim 28, wherein n is 1.

38. The compound of claim 28, wherein o is 0.

39. The compound of claim 28, wherein

40. A compound selected from the following table: