Benzenesulfonamide compounds and their use as therapeutic agents

Patent metadata

Field	Value
Publication number	US-11299490-B2
Application number	US-202016940696-A
Country	US
Kind code	B2
Filing date	Jul 28, 2020
Priority date	May 20, 2016
Publication date	Apr 12, 2022
Grant date	Apr 12, 2022

Abstract

This invention is directed to benzenesulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy.

First claim

What is claimed is:

1. A method of treating a disease or a condition associated with aberrant Nav1.6 activity in a patient, wherein the disease or condition is epilepsy or epileptic seizure disorder, comprising administering to the patient a therapeutically effective amount of a compound of the following formula:

wherein:
R 1 is an optionally substituted phenyl or optionally substituted pyridyl;
R 2 is an optionally substituted thiazolyl, an optionally substituted thiadiazolyl, an optionally substituted isothiazolyl, or an optionally substituted pyridinyl;
R 3 is —O— or —N(R 13 )—;
R 4 , R 5 , and R 13 are each independently selected from hydrogen, alkyl, and haloalkyl;
each R 6 is independently selected from hydrogen, halo, alkyl, and haloalkyl;
R 7 is halo;
each R 8 is independently selected from hydrogen, alkyl, and haloalkyl;
m is 1 or 2; and
n is 1 or 2;
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt or solvate thereof.

2. The method of claim 1 , wherein the disease or condition is epilepsy.

3. The method of claim 1 , wherein the disease or condition is epileptic seizure disorder.

4. The method of claim 1 , wherein the disease or condition is SCN8A developmental and epileptic encephalopathy (SCN8A-DEE).

5. The method of claim 1 , wherein the patient has a SCN8A mutation.

6. The method of claim 1 , wherein:
R 1 is phenyl or pyridyl, each optionally substituted with halo or alkyl;
R 2 is thiazolyl, thiadiazolyl, isothiazolyl, or pyridinyl, each optionally substituted with halo or alkyl;
R 3 is —O— or —N(R 13 )—;
R 4 and R 5 are each hydrogen;
R 13 is hydrogen, alkyl, or haloalkyl;
each R 6 is independently selected from hydrogen, halo, alkyl, and haloalkyl;
R 7 is halo;
R 8 is hydrogen;
m is 1; and
n is 1 or 2;
as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt or solvate thereof.

7. The method of claim 1 , wherein the compound is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:

8. The method of claim 1 , wherein the compound is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:

or a pharmaceutically acceptable salt or solvate thereof.

9. The method of claim 1 , wherein the compound is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:

10. The method of claim 1 , wherein the compound is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:

or a pharmaceutically acceptable salt or solvate thereof.

11. The method of claim 1 , wherein the compound is (S)-2,6-difluoro-3-methyl-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:

12. The method of claim 1 , wherein the compound is (S)-2,6-difluoro-3-methyl-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:

or a pharmaceutically acceptable salt or solvate thereof.

13. The method of claim 1 , wherein the compound is (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:

14. The method of claim 1 , wherein the compound is (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:

or a pharmaceutically acceptable salt or solvate thereof.

15. The method of claim 1 , wherein the compound is (S)-3-chloro-2,6-difluoro-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:

16. The method of claim 1 , wherein the compound is (S)-3-chloro-2,6-difluoro-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide, represented by the formula:

or a pharmaceutically acceptable salt or solvate thereof.

17. The method of claim 1 , wherein the compound is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isothiazol-3-yl)-5-methylbenzenesulfonamide, represented by the formula:

18. The compound of claim 1 , wherein the compound is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isothiazol-3-yl)-5-methylbenzenesulfonamide, represented by the formula:

or a pharmaceutically acceptable salt or solvate thereof.

19. The method of claim 1 , wherein the compound is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)-3-methylbenzenesulfonamide, represented by the formula:

20. The method of claim 1 , wherein the compound is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)-3-methylbenzenesulfonamide, represented by the formula:

or a pharmaceutically acceptable salt or solvate thereof.

21. The method of claim 1 , wherein the compound is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-3-methylbenzenesulfonamide, represented by the formula:

22. The method of claim 1 , wherein the compound is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-3-methylbenzenesulfonamide, represented by the formula:

or a pharmaceutically acceptable salt or solvate thereof.

23. The method of claim 1 , wherein the compound

Assignees

• Xenon Pharmaceuticals Inc

Inventors

• Andrez Jean-Christophe
• Burford Kristen Nicole
• Chowdhury Sultan
• Cohen Charles Jay
• Dehnhardt Christoph Martin
• Devita Robert Joseph
• Empfield James Roy
• Focken Thilo
• Grimwood Michael Edward
• Hasan Syed Abid
• Johnson Jr James Philip
• Zenova Alla Yurevna

Classifications

• C07D493/10

  Spiro-condensed systems · CPC title

• C07D451/06 Primary

  Oxygen atoms · CPC title

• C07D403/12

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

• C07D285/08

  1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles · CPC title

• C07D277/52

  to sulfur atoms, e.g. sulfonamides · CPC title