NOVEL BICYCLIC HETEROCYCLIC COMPOUND
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 method of inhibiting SNS in a patient, which comprises administering an effective amount of 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 O-5 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, to the patient, whereupon SNS is inhibited in the patient.
2 . The method of claim 1 , wherein the compound is represented by formula (2):
wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 6b , R 6 , R 7 , L and X are as defined in claim 1 , or a pharmaceutically acceptable salt thereof.
3 . The method of claim 1 , wherein the compound is represented by formula (3):
wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6 , R 7 , L and X are as defined in claim 1 , or a pharmaceutically acceptable salt thereof.
4 . The method of claim 1 , wherein R 2 is a substituted or unsubstituted phenyl group, or a pharmaceutically acceptable salt thereof.
5 . The method 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 method 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 method 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 method 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 method of claim 1 , wherein X is a carbon atom, or a pharmaceutically acceptable salt thereof.
10 . The method of claim 1 , wherein R 1 is a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof.
11 . The method of claim 1 , wherein L is a single bond, or a pharmaceutically acceptable salt thereof.
12 . The method of claim 1 , wherein L is —O—, or a pharmaceutically acceptable salt thereof.
13 . The method of claim 1 , wherein L is —CH 2 O—, or a pharmaceutically acceptable salt thereof.
14 . The method of claim 1 , wherein the compound is selected from
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, and
N 2 -{[5-chloro-6-(3,4-difluorophenyl)-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl}-L-alaninamide,
and a pharmaceutically acceptable salt thereof.
15 . The method of claim 1 , 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.
16 . The method of claim 1 , 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.
17 . The method of claim 1 , wherein the compound is N 2 -{[1-ethyl-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide, or a pharmaceutically acceptable salt thereof.
18 . The method of claim 1 , 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.
19 . The method of claim 1 , 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.