Cyclic sulfonamides as sodium channel blockers

• US 9,714,252 B2
• Filed: 12/18/2013
• Issued: 07/25/2017
• Est. Priority Date: 12/20/2012
• Status: Active Grant

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Youngman, Mark Andrew
• Primary Examiner(s): DESAI, RITA J
• Application Number:
  US14/653,471
• Publication Number:
  US 20150336974A1
• Time in Patent Office: 1,315 Days
• Field of Search: 546 15, 514359
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 491/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/107 with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: G01N 2500/02 Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
• CPC Class Codes: G01N 33/60 involving radioactive labelled substances
• CPC Class Codes: G01N 33/6872 Intracellular protein regulatory factors and their receptors, e.g. including ion channels

Abstract

The present disclosure provides cyclic sulfonamides of Formula (I), and the pharmaceutically acceptable salts and solvates thereof, wherein R¹, R², R^3a, R^3b, and n are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of sodium channels. For example, compounds of the present disclosure are useful for treating pain.

Claims

1. A compound having Formula I:

2. The compound of claim 1, wherein R^3a and R^3b are hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1, wherein n is 1, or a pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 1, wherein n is 2, or a pharmaceutically acceptable salt or solvate thereof.

5. The compound of claim 1, wherein R¹ is optionally substituted 2-thiazolyl, or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of claim 1, wherein:

R² is;

7. The compound of claim 6, wherein R² is:

8. The compound of claim 1, wherein:

R² is;

9. The compound of claim 8, wherein R^5a is optionally substituted phenyl, or a pharmaceutically acceptable salt or solvate thereof.

10. The compound of claim 1, wherein R² is:

11. The compound of claim 10, wherein R^6a, R^6b, R^6c, and R^6d are each hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

12. The compound of claim 1 selected from the group consisting of:

5-(2-(pyridazin-4-yl)-4-(trifluoromethyl)phenoxy)-2-(thiazol-2-yl)-2,3-dihydrobenzo-[d]isothiazole 1,1-dioxide;

5-([1,1′

-biphenyl]-2-yloxy)-2-(thiazol-2-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide;

5-(4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)-2-(thiazol-2-yl)-2,3-dihydrobenzo-[d]isothiazole 1,1-dioxide;

5-(3H-spiro[isobenzofuran-1,4′

-piperidin]-1′

-yl)-2-(thiazol-2-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide;

6-(3H-spiro[isobenzofuran-1,4′

-piperidin]-1′

-yl)-2-(thiazol-2-yl)-3,4-dihydro-2H -benzo[e][1,2]thiazine 1,1-dioxide;

6-([1,1′

-biphenyl]-2-yloxy)-2-(thiazol-2-yl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide; and

2-(thiazol-2-yl)-6-(4-(4-(trifluoromethyl)phenoxy)phenyl)-3,4-dihydro-2H -benzo[e][1,2]thiazine 1,1-dioxide,

or a pharmaceutically acceptable salt or solvate thereof.

13. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

14. A method of treating pain in a mammal, comprising administering an effective amount of a compound as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need of such treatment.

15. The method of claim 14, wherein said method is for preemptive or palliative treatment of pain.

16. The method of claim 14, wherein said pain is selected from the group consisting of chronic pain, inflammatory pain, neuropathic pain, acute pain, and surgical pain.

17. A method of modulating Na_v1.7 sodium channels in a mammal, comprising administering to the mammal a modulating-effective amount of at least one compound as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

18. The compound as claimed in claim 1, wherein said compound is ³H, ¹¹C, or ¹⁴C radiolabeled, or a pharmaceutically acceptable salt or solvate thereof.

19. The compound as claimed in claim 8, wherein R^5a is optionally substituted heteroaryl, or a pharmaceutically acceptable salt or solvate thereof.

20. A method of modulating sodium channels in vitro, comprising administering to a cell a modulating-effective amount of a compound as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

21. The method of claim 20, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, blocks Na_v1.7 sodium channels in the cell.