The present invention provides a heterocyclic compound represented by the general formula (1): The compound of the present invention has a wide treatment spectrum for mental disorders including central nervous system disorders, no side effects and high safety.
##STR00001##
|
##STR00176##
[wherein ring Q represented by
##STR00177##
represents —NH—CH2—, —N═CH—, —CH2—NH— or —CH═N—; and
the carbon-carbon bond
between the 3-position and 4-position of the heterocyclic skeleton containing Z and Y represents a single bond or a double bond);
the ring Q may have at least one substituent selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, an aryl group, an aryl lower alkyl group, an aryl lower alkoxy group, an arylcarbonyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cycloalkyl group, a cycloalkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thienyl group, a saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 nitrogen atoms-substituted lower alkyl group and an oxo group;
R2 represents a hydrogen atom or a lower alkyl group; and
A represents —O-A1- (wherein A1 represents an alkylene group which may be substituted with a hydroxy group (wherein one oxygen atom may replace a carbon of the alkylene chain) or a lower alkenylene group) or a lower alkylene group;
provided that when A represents a lower alkylene group, the ring Q represents a bicyclic group selected from the group consisting of:
##STR00178##
(wherein the carbon-carbon-bond
represents a single bond or a double bond)] or a salt thereof.
##STR00184##
[wherein ring Q represented by
##STR00185##
represents —NH—CH2—, —N═CH—, —CH2—NH— or —CH═N; and
the carbon-carbon bond
between the 3-position and 4-position of the heterocyclic skeleton containing Z and Y represents a single bond or a double bond);
the ring Q may have at least one substituent selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, an aryl group, an aryl lower alkyl group, an aryl lower alkoxy group, an arylcarbonyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cycloalkyl group, a cycloalkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thienyl group, a saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 nitrogen atoms-substituted lower alkyl group and an oxo group;
R2 represents a hydrogen atom or a lower alkyl group; and
A represents —O-A1- (wherein A1 represents an alkylene group which may be substituted with a hydroxy group (wherein one oxygen atom may replace a carbon of the alkylene chain) or a lower alkenylene group) or a lower alkylene group;
provided that when A represents a lower alkylene group, the ring Q represents a bicyclic group selected from the group consisting of:
##STR00186##
(wherein the carbon-carbon bond
represents a single bond or a double bond)] or a salt thereof,
characterized by comprising a reaction of a compound represented by the formula:
##STR00187##
(wherein the ring Q and A are the same as defined above, and X1 represents a halogen atom or a group which causes a substitution reaction the same as in a halogen atom) or a salt thereof with a compound represented by the formula:
##STR00188##
(wherein R2 is the same as defined above) or a salt thereof.
2. The heterocyclic compound of the formula (I) according to
##STR00179##
(wherein the carbon-carbon bond
between the 3-position and 4-position of the bicyclic heterocyclic skeleton represents a single bond or a double bond);
the ring Q may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, a phenyl group, a phenyl lower alkyl group, a naphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyl lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, a cyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a caroboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thienyl group and a saturated 5- to 6-membered heteromonocyclic group containing 1 to 2 nitrogen atoms-substituted lower alkyl group; and
A represents —O-A1- (wherein A1 represents a C1-C6 alkylene group which may be substituted with a hydroxy group (wherein one oxygen atom may replace a carbon of the alkylene chain)), or a salt thereof.
3. The heterocyclic compound of the formula (1) according to
##STR00180##
the ring Q may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, a phenyl group, a phenyl lower alkyl group, a naphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyl lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, a cyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a phenyl group, a thienyl group and a pyrrolidinyl lower alkyl group; and
A represents —O-A1- (wherein A1 represents a C1-C6 alkylene group which may be substituted with a hydroxy group (wherein one oxygen atom may replace a carbon of the alkylene chain)), or a salt thereof.
4. The heterocyclic compound of the formula (1) according to
##STR00181##
(the ring Q may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, a phenyl group, a phenyl lower alkyl group, a naphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyl lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, a cyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thienyl group and a pyrrolidinyl lower alkyl group) or a salt thereof.
5. The heterocyclic compound of the formula (1) according to
##STR00182##
(wherein the carbon-carbon bond
between the 3-position and 4-position of the bicyclic heterocyclic skeleton represents a single bond or a double bond);
the ring Q may have 1 to 3 substituents thereon selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, a phenyl group, a phenyl lower alkyl group, a naphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyl lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, a cyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thienyl group, a pyrrolidinyl lower alkyl group and an oxo group; and
A represents a lower alkylene group, or a salt thereof.
6. The heterocyclic compound of the formula (1) according to
##STR00183##
(wherein the carbon-carbon bond
between the 3-position and 4-position of the bicyclic heterocyclic skeleton represents a single bond or a double bond);
the ring Q may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, a phenyl group, a phenyl lower alkyl group, a naphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyl lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, a cyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thienyl group and a pyrrolidinyl lower alkyl group, or a salt thereof.
7. The heterocyclic compound of the formula (1) according to
(1) 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one,
(2) 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1H-quinolin-2-one,
(3) 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-1H-quinolin-2-one,
(4) 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one,
(5) 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1-methyl-3,4-dihydro-1H-quinolin-2-one and
(6) 6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-1H-quinolin-2-one;
or a salt thereof.
8. The heterocyclic compound of the formula (1) according to
(1) 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-isoquinolin-1-one
(2) 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one,
(3) 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one,
(4) 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-2H-isoquinoline-1-one,
(5) 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2H-isoquinolin-1-one and
(6) 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-2H-isoquinolin-1-one;
or a salt thereof.
0. 10. The heterocyclic compound according to claim 3, wherein Q may have 1 substituent, which is a lower alkyl group, R2 represents a hydrogen, and A1 represents a C1-C6 alkylene group (wherein one oxygen atom may replace a carbon of the alkylene chain).
0. 11. The heterocyclic compound according to claim 4, wherein Q may have 1 substituent, which is a lower alkyl group, R2 represents a hydrogen, and A1 represents a C1-C6 alkylene group.
0. 12. The heterocyclic compound according to claim 7, which is 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof.
0. 13. The heterocyclic compound according to claim 12, which is 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one.
0. 14. The process according to claim 9, wherein the process produces 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof.
0. 15. The process according to claim 14, wherein the process produces 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one.
|
|||||||||||||||||||
The results are shown in the next Table 24.
TABLE 24
Serotonin uptake inhibitory ratio
Test compound
(%)(300 nM)
Compound of Example 1
92.4
Compound of Example 2
78.8
Compound of Example 3
84.8
Compound of Example 4
91.0
Compound of Example 5
89.1
Compound of Example 6
91.3
Compound of Example 7
91.0
Compound of Example 8
95.0
Compound of Example 9
97.3
Compound of Example 10
92.6
Compound of Example 11
92.5
Compound of Example 13
77.0
Compound of Example 14
85.2
Compound of Example 15
87.2
Compound of Example 16
86.7
Compound of Example 17
86.3
Compound of Example 18
91.1
Compound of Example 19
86.3
Compound of Example 20
92.8
Compound of Example 21
81.4
Compound of Example 22
90.8
Compound of Example 23
95.5
Compound of Example 24
97.5
Compound of Example 25
91.9
Compound of Example 26
92.0
Compound of Example 27
94.0
Compound of Example 28
95.3
Compound of Example 30
95.8
Compound of Example 31
96.3
Compound of Example 32
96.9
Compound of Example 33
94.3
Compound of Example 34
94.2
Compound of Example 35
93.4
Compound of Example 36
97.4
Compound of Example 37
97.7
Compound of Example 38
96.7
Compound of Example 39
99.2
Compound of Example 40
91.6
Compound of Example 41
95.1
Compound of Example 64
73.0
Compound of Example 65
72.9
Compound of Example 66
74.1
Compound of Example 67
93.9
Compound of Example 68
95.7
Compound of Example 69
96.3
100 g of a compound of the present invention, 40 g of Avicel (trade name, product of Asahi Chemical Industry Co., Ltd.), 30 g of corn starch and 2 g of magnesium stearate was mixed and polished and tableted with a pestle for glycocalyx R10 mm.
The obtained tablet was coated with a film using a film coating agent made up of 10 g of TC-5 (trade name, product of Shin-Etsu Chemical Co., Ltd., hydroxypropyl methylcellulose), 3 g of polyethylene glycol 6000, 40 g of castor oil and an appropriate amount of ethanol to produce a film coated tablet of the above composition.
Shimizu, Satoshi, Yamashita, Hiroshi, Kuroda, Hideaki, Ito, Nobuaki, Miyamura, Shin, Oshima, Kunio, Matsubara, Jun, Takahashi, Haruka, Tanaka, Tatsuyoshi, Taira, Shinichi, Oshiro, Yasuo
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