4-substituted piperidine compound
The present invention provides a novel compound having an excellent acetylcholinesterase inhibitory effect. That is, it provides a compound represented by formula: (wherein R 1 and R 2 represent substituents), a pharmacologically acceptable salt thereof or hydrates thereof.
1. A compound represented by the formula:
a pharmacologically acceptable salt thereof or hydrates thereof, wherein in the formula, R 1 represents the formula:
wherein:
(R 3 )s are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxyalkoxy group, a halogeno C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a cyano C 1-6 alkyl group, an amino C 1-6 alkyl group, a halogeno C 1-6 alkoxy group, a hydroxy C 1-6 alkoxy group, a cyano C 1-6 alkoxy group, a lower acyl group, nitro group, an optionally substituted amino group, an optionally substituted carbamoyl group, mercapto group or a C 1-6 thioalkoxy group;
R 5 represents a halogen atom (provided that fluorine is excluded), hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, cyano group, a halogeno C 1-6 alkyl group, a cyano C 1-6 alkyl group, an amino C 1-6 alkyl group, nitro group, an azido group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted carboxyl group, mercapto group or a C 1-6 thioalkoxy group;
m is 0 or an integer from 1 to 6; and
n is an integer from 1 to 4; and
R 2 represents a C 3-8 cycloalkylmethyl, a 2,2-(alkylenedioxy)ethyl or a group represented by the formula:
wherein:
the ring A represents a benzene ring or a heterocyclic ring;
(R 6 )s are the same as or different from each other and each represents hydrogen, a halogen atom, hydroxyl group, nitrile group, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxyalkoxy group, an aryloxy group, an aralkyloxy group, a halogeno C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a cyano C 1-6 alkyl group, a halogeno C 1-6 alkoxy group, a hydroxy C 1-6 alkoxy group, a cyano C 1-6 alkoxy group, a lower acyl group, nitro group, an optionally substituted amino group, an optionally substituted amide group, mercapto group or a C 1-6 thioalkoxy group, and
two of the R 6 may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; and
q is 0 or an integer from 1 to 5.
2. The compound according to claim 1 , a pharmacologically acceptable salt thereof or hydrates thereof, wherein R 1 is represented by the formula:
in which R 3a and R 3b are the same as or different from each other and each represents a C 1-6 alkoxy group;
R 5 represents a halogen atom (provided that fluorine is excluded), hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, cyano group, a halogeno C 1-6 alkyl group, a cyano C 1-6 alkyl group, an amino C 1-6 alkyl group, nitro group, an azido group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted carboxyl group, mercapto group or a C 1-6 thioalkoxy group; and
m is 0 or an integer from 1 to 6.
3. The compound according to claim 2 , a pharmacologically acceptable salt thereof or hydrates thereof, wherein R 3a and R 3b are methoxy groups.
4. A compound represented by the formula:
a pharmacologically acceptable salt thereof or hydrates thereof,
wherein in the formula, R 1 represents the formula:
wherein:
(R 3 )s are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxyalkoxy group, a halogeno C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a cyano C 1-6 alkyl group, an amino C 1-6 alkyl group, a halogeno C 1-6 alkoxy group, a hydroxy C 1-6 alkoxy group, a cyano C 1-6 alkoxy group, a lower acyl group, nitro group, an optionally substituted amino group, an optionally substituted carbamoyl group, mercapto group or a C 1-6 thioalkoxy group;
R 5 is chlorine or bromine;
m is 0 or an integer from 1 to 6; and
n is an integer from 1 to 4; and
R 2 represents a C 3-8 cycloalkylmethyl, a 2,2-(alkylenedioxy)ethyl or a group represented by the formula:
wherein:
the ring A represents a benzene ring or a heterocyclic ring;
(R 6 )s are the same as or different from each other and each represents hydrogen, a halogen atom, hydroxyl group, nitrile group, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxyalkoxy group, an aryloxy group, an aralkyloxy group, a halogeno C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a cyano C 1-6 alkyl group, a halogeno C 1-6 alkoxy group, a hydroxy C 1-6 alkoxy group, a cyano C 1-6 alkoxy group, a lower acyl group, nitro group, an optionally substituted amino group, an optionally substituted amide group, mercapto group or a C 1-6 thioalkoxy group, and
two of the R 6 may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; and
q is 0 or an integer from 1 to 5.
5. The compound according to claim 1 , a pharmacologically acceptable salt thereof or hydrates thereof, wherein m is 1.
6. The compound according to claim 1 , a pharmacologically acceptable salt thereof or hydrates thereof, wherein R 2 is a group represented by the formula:
wherein:
the ring A represents a benzene ring or a heterocyclic ring;
(R 6 )s are the same as or different from each other and each represents hydrogen, a halogen atom, hydroxyl group, nitrile group, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxyalkoxy group, an aryloxy group, an aralkyloxy group, a halogeno C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a cyano C 1-6 alkyl group, a halogeno C 1-6 alkoxy group, a hydroxy C 1-6 alkoxy group, a cyano C 1-6 alkoxy group, a lower acyl group, nitro group, an optionally substituted amino group, an optionally substituted amide group, mercapto group or a C 1-6 thioalkoxy group, and
two of the R 6 may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; and
q is 0 or an integer from 1 to 5.
7. The compound according to claim 6 , a pharmacologically acceptable salt thereof or hydrates thereof, wherein the ring A is a benzene ring.
8. A compound represented by the formula:
a pharmacologically acceptable salt thereof or hydrates thereof, wherein in the formula, R 1 represents the formula:
wherein:
(R 3 )s are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxyalkoxy group, a halogeno C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a cyano C 1-6 alkyl group, an amino C 1-6 alkyl group, a halogeno C 1-6 alkoxy group, a hydroxy C 1-6 alkoxy group, a cyano C 1-6 alkoxy group, a lower acyl group, nitro group, an optionally substituted amino group, an optionally substituted carbamoyl group, mercapto group or a C 1-6 thioalkoxy group;
R 5 represents a halogen atom (provided that fluorine is excluded), hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, cyano group, a halogeno C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a cyano C 1-6 alkyl group, an amino C 1-6 alkyl group, nitro group, an azido group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted carboxyl group, mercapto group or a C 1-6 thioalkoxy group;
m is 0 or an integer from 1 to 6; and
n is an integer from 1 to 4; and
R 2 represents a C 3-8 cycloalkylmethyl, a 2,2-(alkylenedioxy)ethyl or a group represented by the formula:
wherein the ring A is a pyridine ring;
(R 6 )s are the same as or different from each other and each represents hydrogen, a halogen atom, hydroxyl group, nitrile group, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxyalkoxy group, an aryloxy group, an aralkyloxy group, a halogeno C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a cyano C 1-6 alkyl group, a halogeno C 1-6 alkoxy group, a hydroxy C 1-6 alkoxy group, a cyano C 1-6 alkoxy group, a lower acyl group, nitro group, an optionally substituted amino group, an optionally substituted amide group, mercapto group or a C 1-6 thioalkoxy group, and two of the R 6 may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; and
q is 0 or an integer from 1 to 5.
9. The compound according to claim 6 , a pharmacologically acceptable salt thereof or hydrates thereof, wherein q is an integer of 1 or 2.
10. The compound according to claim 1 , a pharmacologically acceptable salt thereof or hydrates thereof, which is selected from the group consisting of:
1-benzyl-4-[(5,6-dimethoxy-2-chloro-1-indanon)-1-yl]methylpiperidine,
1-benzyl-4-[(5,6-dimethoxy-2-bromo-1-indanon)-2-yl]methylpiperidine,
1-benzyl-4-[(5,6-dimethoxy-2-iodo-1-indanon)-2-yl]methylpiperidine,
1-benzyl-4-[(5,6-dimethoxy-2-hydroxy-1-indanon)-2-yl]methylpiperidine,
1-benzyl-4-[(5,6-dimethoxy-2-methyl-1-indanon)-2-yl]methylpiperidine,
1-benzyl-4-[(5,6-dimethoxy-2-ethyl-1-indanon)-2-yl]methylpiperidine,
1-benzyl-4-[(5,6-dimethoxy-2-azido-1-indanon)-2-yl]methylpiperidine,
1-benzyl-4-[(5,6-dimethoxy-2-amino-1-indanon)-2-yl]methylpiperidine,
1-benzyl-4-[(5,6-dimethoxy-2-methylamino-1-indanon)-2-yl]methylpiperidine,
1-benzyl-4-[(5,6-dimethoxy-2-dimethylamino-1-indanon)-2-yl]methylpiperidine, and
1-benzyl-4-[(5,6-dimethoxy-2-acetamide-1-indanon)-2-yl]methylpiperidine.
11. The compound according to claim 1 , the pharmacologically acceptable salt thereof or hydrates thereof, wherein R 5 in the formula represents a halogen atom (provided that fluorine is excluded), hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, cyano group, a halogeno C 1-6 alkyl group, a cyano C 1-6 alkyl group, an amino C 1-6 alkyl group, nitro group, an azido group, an optionally substituted amino group, an optionally substituted carbamoyl group, mercapto group or a C 1-6 thioalkoxy group.
12. A pharmaceutical composition comprising the compound according to claim 1 , a pharmacologically acceptable salt thereof or hydrates thereof; and
a pharmacologically acceptable carrier.
13. A method of treating Alzheimer-type senile dementia, said method comprising administering a pharmacologically effective amount of the compound according to claim 1 , a pharmacologically acceptable salt thereof or hydrates thereof to a patient in need thereof.
14. A method of treating cerebrovascular dementia, said method comprising administering a pharmacologically effective amount of the compound according to claim 1 , a pharmacologically acceptable salt thereof or hydrates thereof to a patient in need thereof.