Benzimidazole compounds and medical uses thereof

Patent metadata

Field	Value
Publication number	US-9688670-B2
Application number	US-201615395338-A
Country	US
Kind code	B2
Filing date	Dec 30, 2016
Priority date	Sep 11, 2015
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

Abstract

The present invention provides a medicament for treating a disease involving Nav 1.7 such as neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria, and multiple sclerosis, which comprises a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein R 1a , R 1b , R 1c and R 1d are hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, or the like, provided that at least one of R 1a , R 1b , R 1c and R 1d is C 6-10 aryl, C 6-10 aryloxy, or the like, R 2 and R 3 are hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, or the like, R 4 is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, or the like, m is 1, 2 or 3, L is CR 7 R 8 , and R 7 and R 8 are hydrogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, or the like.

First claim

The invention claimed is:

1. A compound selected from the group of compounds consisting of:
a) 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol;
b) 1-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol;
c) 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol;
d) 2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol;
e) 3-({6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol;
f) 4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylbutan-2-ol;
g) cis-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)cyclohexanol;
h) 3-({6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol;
i) 3-({5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol; and
j) (3 S)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol;
or a pharmaceutically acceptable salt of the compound of a)-j).

2. The compound of claim 1 wherein the compound is 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein the compound is 1-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein the compound is 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein the compound is 2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein the compound is 3-({6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 wherein the compound is 4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylbutan-2-ol, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 wherein the compound is cis-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)cyclohexanol, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 wherein the compound is 3-({6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 wherein the compound is 3-({5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 wherein the compound is (3S)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol, or a pharmaceutically acceptable salt thereof.

12. A method for treating neuropathic pain, which comprises administering a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a mammal in need thereof.

13. The method of claim 12 wherein the compound is 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol, or a pharmaceutically acceptable salt thereof.

14. The method of claim 12 wherein the compound is 1-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol, or a pharmaceutically acceptable salt thereof.

15. The method of claim 12 wherein the compound is 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof.

16. The method of claim 12 wherein the compound is 2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol, or a pharmaceutically acceptable salt thereof.

17. The method of claim 12 wherein the compound is 3-({6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol, or a pharmaceutically acceptable salt thereof.

18. The method of claim 12 wherein the compound is 4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylbutan-2-ol, or a pharmaceutically acceptable salt thereof.

19. The method of claim 12 wherein the compound is cis-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)cyclohexanol, or a pharmaceutically acceptable salt thereof.

20. The method of claim 12 wherein the compound is 3-({6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol, or a pharmaceutically acceptable salt thereof.

21. The method of claim 12 wherein the compound is 3-({5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol, or a pharmaceutically acceptable salt thereof.

22. The method of claim 12 wherein the compound is (3S)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol, or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive agent.

Assignees

• Sumitomo Dainippon Pharma Co Ltd

Inventors

• Komiya Masafumi
• Iwamoto Kohei
• Kanai Toshio
• Mizushima Shingo
• Adachi Keiji
• Urashima Kuniko

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• A61P13/00 Primary

  Drugs for disorders of the urinary system · CPC title

• C07D403/12

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

• C07D235/06

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2 · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title