Bicyclic heterocyclic compound
View Patent ↗The invention provides a compound for the treatment or prophylaxis of pathology involving SNS, specifically diseases such as neuropathic pain, nociceptive pain, dysuria, multiple sclerosis and the like. The compound is represented by formula (1) or a pharmaceutically acceptable salt thereof wherein R 1 is a hydrogen atom or the like, L is a single bond, —O— or the like, R 2 is a phenyl group or the like, X is a carbon atom or a nitrogen atom, and R 3 , R 4 , R 5a , R 5b , R 6 and R 7 are each independently a substituted or unsubstituted alkyl group or the like:
1. A compound represented by formula (1):
wherein
R 1 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a haloalkoxy group having 1 to 6 carbon atoms (R 1 can substitute the benzene ring or pyridine ring at any substitutable position thereon),
L is a single bond, —O— or —CH 2 O— (L can substitute the benzene ring or pyridine ring at any substitutable position thereon),
R 2 is a substituted or unsubstituted 6- to 10-membered aryl group, or a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic group,
X is a carbon atom or a nitrogen atom,
R 3 is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered cycloalkenyl group, a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group,
R 4 is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted 3- to 8-membered cycloalkyl group,
R 5a and R 5b are each independently a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or R 4 and R 5a are optionally bonded to form, together with the nitrogen atom that R 4 is bonded to, a 4- to 8-membered saturated nitrogen-containing aliphatic heterocycle (in this case, R 5b is a hydrogen atom),
R 6 and R 7 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered cycloalkenyl group, a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, a substituted or unsubstituted 6- to 10-membered aryl group, or a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic group, or R 6 and R 7 are optionally bonded to form, together with the nitrogen atom that they are bond to, a substituted or unsubstituted 4- to 8-membered saturated nitrogen-containing aliphatic heterocycle, or a substituted or unsubstituted 5- to 10-membered unsaturated nitrogen-containing aliphatic heterocycle (the saturated or unsaturated nitrogen-containing aliphatic heterocycle contains 0 to 2 oxygen atoms, 0 to 2 sulfur atoms and 1 to 3 nitrogen atoms),
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , which is represented by formula (2):
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , which is represented by formula (3):
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein R 2 is a substituted or unsubstituted phenyl group, or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein R 3 is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein R 6 and R 7 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, or R 6 and R 7 are optionally bonded to form, together with the nitrogen atom that they are bond to, a substituted or unsubstituted 4- to 8-membered saturated nitrogen-containing aliphatic heterocycle, or a substituted or unsubstituted 5- to 10-membered unsaturated nitrogen-containing aliphatic heterocycle (the saturated or unsaturated nitrogen-containing aliphatic heterocycle contains 0 to 2 oxygen atoms, 0 to 2 sulfur atoms and 1 to 3 nitrogen atoms), or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , wherein R 4 is a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , wherein R 5a and R 5b are each independently a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein X is a carbon atom, or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , wherein R 1 is a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , wherein L is a single bond, or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , wherein L is —O—, or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 , wherein L is —CH 2 O—, or a pharmaceutically acceptable salt thereof.
14. N 2 -{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}glycinamide,
N 2 -{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-2-methylalaninamide,
N 2 -{[1-cyclopropyl-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,
N 2 -{[1-cyclobutyl-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,
N 2 -{[6-(4-chlorophenoxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,
N 2 -{[6-(4-fluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,
N 2 -{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,
N 2 -{[6-(4-fluorophenoxy)-1-(3-methoxypropyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,
N 2 -{[6-(2-chloro-4-fluorophenoxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,
N 2 -{[1-ethyl-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,
N 2 -{[6-(2,4-difluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,
N 2 -{[1-(2-ethoxyethyl)-5-fluoro-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,
N 2 -{[1-ethyl-5-fluoro-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,
N 2 -{[1-(3-methoxypropyl)-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,
N 2 -{[6-(4-methylphenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,
N 2 -{[5-chloro-1-(2-ethoxyethyl)-6-(4-fluorophenyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or
N 2 -{[5-chloro-6-(3,4-difluorophenyl)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. A method for the treatment of neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis in a patient, which method comprises administering an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need of treatment of neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis, thereby providing treatment of neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis in the patient.
17. The method of claim 16 , wherein the neuropathic pain is selected from neuralgia after lumbar operation, diabetic neuropathy, neuralgia after herpes zoster, reflex sympathetic dystrophy, phantom limb pain, spinal cord injury, late stage carcinomatous pain, and prolonged postoperative pain.
18. N 2 -{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-2-methylalaninamide, or a pharmaceutically acceptable salt thereof.
19. N 2 -{[6-(2-chloro-4-fluorophenoxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
20. N 2 -{[1-ethyl-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
21. N 2 -{[1-(3-methoxypropyl)-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
22. N 2 -{[6-(4-methylphenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising the compound of claim 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
24. The pharmaceutical composition of claim 23 , wherein the compound is N 2 -{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-2-methylalaninamide, or a pharmaceutically acceptable salt thereof.
25. The pharmaceutical composition of claim 23 , wherein the compound is N 2 -{[6-(2-chloro-4-fluorophenoxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
26. The pharmaceutical composition of claim 23 , wherein the compound is N 2 -{[1-ethyl-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
27. The pharmaceutical composition of claim 23 , wherein the compound is N 2 -{[1-(3-methoxypropyl)-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
28. The pharmaceutical composition of claim 23 , wherein the compound is N 2 -{[6-(4-methylphenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
29. A method for the treatment of neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis in a patient, which method comprises administering an effective amount of the compound of claim 14 or a pharmaceutically acceptable salt thereof to a patient in need of treatment of neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis, thereby providing treatment of neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis in the patient.
30. The method of claim 29 , wherein the compound is N 2 -{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-2-methylalaninamide, or a pharmaceutically acceptable salt thereof.
31. The method of claim 29 , wherein the compound is N 2 -{[6-(2-chloro-4-fluorophenoxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
32. The method of claim 29 , wherein the compound is N 2 -{[1-ethyl-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
33. The method of claim 29 , wherein the compound is N 2 -{[1-(3-methoxypropyl)-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
34. The method of claim 29 , wherein the compound is N 2 -{[6-(4-methylphenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
35. The method of claim 29 , wherein the neuropathic pain is selected from neuralgia after lumbar operation, diabetic neuropathy, neuralgia after herpes zoster, reflex sympathetic dystrophy, phantom limb pain, spinal cord injury, late stage carcinomatous pain, and prolonged postoperative pain.
36. The method of claim 24 , wherein the compound is N 2 -{[1-(2-ethoxyethyl)-6-(4-fluorophenoxy)-1H-benzimidazol-2-yl]methyl}-2-methylalaninamide, or a pharmaceutically acceptable salt thereof.
37. The method of claim 35 , wherein the compound is N 2 -{[6-(2-chloro-4-fluorophenoxy)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
38. The method of claim 35 , wherein the compound is N 2 -{[1-ethyl-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
39. The method of claim 35 , wherein the compound is N 2 -{[1-(3-methoxypropyl)-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
40. The method of claim 35 , wherein the compound is N 2 -{[6-(4-methylphenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.