JP3286056B2 - Tricyclic fused heterocyclic derivatives, their production and use - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medicament, more specifically, a cholinesterase inhibitor, particularly a therapeutic or prophylactic agent for senile dementia in senile dementia, Alzheimer's disease, etc., and a novel tricyclic condensation compound as an active ingredient thereof. The present invention relates to a heterocyclic derivative, a salt thereof and a production method.

[0002]

2. Description of the Related Art With the aging of society, various compounds having a therapeutic / preventive action for senile dementia have been proposed.
Among them, physostigmine, a natural product that is a cholinesterase inhibitor, has been found to have therapeutic and preventive effects on senile dementia (International Journal of Clinical
Pharmacology, Therapy and Toxicology, Vol. 29,
No. 1, p. 23-37 (1991) and the like). However, physostigmine has drawbacks such as a short duration of action and high toxicity. On the other hand, as synthetic products, various tricyclic fused ring compounds having a cholinesterase inhibitory action have been proposed (JP-A-2-169569, JP-A-4-1992).
234845, U.S. Pat. No. 5,106,856).
JP-A-2-169569 discloses a compound of the general formula

[0003]

Embedded image [In the formula, J is (a) a substituted or unsubstituted group shown below;
A phenyl group, a pyridyl group, a pyrazyl group, a quinolyl group, a cyclohexyl group, a quinoxalyl group or a furyl group, (b) a monovalent or divalent group selected from the following groups in which the phenyl group may be substituted; Indanonyl, indenyl, indenonyl, indanionyl, tetralonyl, benzperonyl, indanolyl, formula

Embedded image (c) a monovalent group derived from a cyclic amide compound, (d) a lower alkyl group, or (e) a formula R ¹ —CH 1CH— (wherein
R ¹ represents a hydrogen atom or a lower alkoxycarbonyl group).

[0004] B is the formula ^{- (C (R 2) H} ) n - , a group represented by the formula ^{-CO- (C (R 2) H} ) n - , a group represented by the formula -NR ² - (C
(R ² ) H) _n- (wherein R ² is a hydrogen atom, a lower alkyl group,
An acyl group, a lower alkylsulfonyl group, an optionally substituted phenyl group or a benzyl group), a group represented by the formula —CO—NR ⁴ — (C (R ² ) H) _n — ⁴ represents a hydrogen atom, a lower alkyl group or a phenyl group)
A group represented by the formula ^{-CH = CH- (C (R 2} ) H) n - , a group represented by the formula ^{-O-COO- (C (R 2} ) H) n - , a group of the formula -O ^{-CO-NH- (C (R 2} ) H) n - , a group represented by the formula ^{-NH-CO- (C (R 2} ) H) n - , a group represented by the formula -CH ₂ -CO-NH- A group represented by (C (R ² ) H) _n- ,
A group of the formula —CO—NH— (C (R ² ) H) _n —,
A group represented by (OH) H- (C (R ² ) H) _n- (in the above formula,
n means 0 or an integer of 1 to 10. R ² has the formula-(C
(R ² ) H) A hydrogen atom or a methyl group in such a manner that the alkylene group represented by _n- has no substituent or one or more methyl groups. ), Formula =
A group represented by (CH-CH = CH) _b- (where b represents an integer of 1 to 3), and a formula = CH- (CH ₂ ) _c- (wherein
c represents a group represented by 0 or an integer of 1 to 9); a group represented by the formula = (CH-CH) _d = (where d represents an integer of 0 or 1 to 5); Formula = CO-CH = CH-C
A group represented by H ₂ —, a formula of —CO—CH ₂ —C (OH) H—C
A group represented by H ₂ —, a formula of —C (CH ₃ ) H—CO—NH—C
A group represented by H ₂ —, a formula of —CH ＝ CH—CO—NH— (C
A group represented by H ₂ ) ₂ —, a group represented by the formula —NH—,
It means a group represented by O-, a group represented by the formula -S-, a dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group.

[0005] T means a nitrogen atom or a carbon atom. Q
Represents a nitrogen atom, a carbon atom or a group represented by the formula> N → O. K is a hydrogen atom, a substituted or unsubstituted phenyl group, an arylalkyl group optionally substituted with a phenyl group, a cinnamyl group optionally substituted with a phenyl group,
It means a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, an adamantanemethyl group, a furylmethyl group, a cycloalkyl group, a lower alkoxycarbonyl group or an acyl group. q means an integer of 1 to 3.

Embedded image A cyclic amine derivative represented by and a pharmacologically acceptable salt thereof are disclosed, and specifically as a tricyclic fused ring compound, the following compound

Embedded image Is described.

[0006] Japanese Patent Application Laid-Open No. Hei 4-234845 discloses a formula

Embedded image Wherein P is an N-substituted piperidino-1-yl (N-substituted piperazino-1-yl) methyl group, G is carbon or nitrogen, E is carbon, nitrogen, oxygen, sulfur; Is an aromatic ring such as benzene, pyridine and thiophene. And a pharmaceutical composition containing the compound as an active ingredient. A
Specific examples of the BD ring system include 1H-pyrrolo [1,2-
a] Indol-1-one, cyclopent [d] indol-3-one, cyclopent [b] (benzo [b] thieno) -1-one, 1H-pyrrolo [1,2-a] (6-
Azaindole) -1-one, pyrrolo [1,2-a]
The compound of the formula [I] having a ring system such as (thieno [2,3-b] pyrrole) -1-one has a cholinesterase inhibitory activity, and a pharmaceutical composition containing the same as an active ingredient can be used for dementia or Alzheimer's disease. It has been described to help enhance memory in patients with the disease. Specifically, compounds of the following formula and the like are described.

Embedded image

[0007] US Patent No. 5,106,856 describes the formula

Embedded image [In the formula, X represents a hydrogen atom, a hydroxyl group, a nitro group, a lower alkyl group or a lower alkoxy group, Y represents a hydrogen atom or a lower alkoxy group, or X and Y together form an OCH ₂ O group. ], Specifically, the following compounds and the like are described.

Embedded image However, JP-A-2-169569 and JP-A-4-234
No. 845 and US Pat. No. 5,106,856 include:
A compound in which an N-substituted piperidino-1-yl (methyl or ethyl) group is directly substituted on a heterocyclic ring or a non-aromatic carbocyclic ring in a tricyclic fused ring is disclosed. No disclosure or suggestion is made of a compound in which an N-substituted piperidino-1-yl (methyl or ethyl) group is bonded to a benzene ring via a carbonyl group.

JP-A-54-22333 discloses a compound represented by the formula R-CO-CHR ⁴ -R ⁷ wherein R is 2-dibenzothienyl or the like, R ⁴ is H or the like, and R ⁷ is-( CH ₂ ) _n -Z (n is 1, 2, 3 and Z is-
NR ¹ R ² (R ¹ , R ² : H, C _1-4 alkyl, which together represent C _4-7 alkylene, 3-oxapentamethylene), etc.] It is disclosed as a synthetic intermediate of a base thioether compound having an antifungal, antibacterial, anti-inflammatory effect and the like, but does not disclose any cholinesterase inhibitory action or action as a therapeutic or preventive drug for senile dementia.

Further, JP-A-59-167546 discloses the formula

Embedded image [Wherein Ar is

Embedded image (Z represents a direct bond, a —CH ₂ — group, a —CH ₂ CH ₂ — group, or a —O— group), and X represents an amino group —N
(R ¹¹ ) represents (R ¹² ), wherein R ¹¹ is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, the following groups: an OH group, an alkoxy group having 1 to 4 carbon atoms, a CN group or —COO
Represents an alkyl group having 2 to 4 carbon atoms substituted by one or more groups selected from (alkyl having 1 to 4 carbon atoms), or an alkenyl group having 3 to 5 carbon atoms, Cyclohexyl group, 7 carbon atoms
To 9 phenylalkyl groups, phenyl or Cl, 1 to 4 carbon atom alkyl groups, OH groups, 1 carbon atom
Represents a phenyl group substituted by 1 to 4 alkoxy groups or -COO (alkyl having 1 to 4 carbon atoms), or R ¹¹ and R ¹ together form a group -CH ₂ OC
H ₂ - the stands, R ¹² is either has one of the meanings given for R ^11, or -C 5 taken together with R ¹¹
To 7 alkylene group, or a -O- group, -S- group, or -N (R ¹⁴⁾ - is 3 -C interposed 7
Or R ¹² together with R ² represents an alkylene group having 1 to 8 carbon atoms, a phenylalkylene group having 7 to 10 carbon atoms or a carbon atom having 2 carbon atoms.
To 4 oxyalkylene or azaalkylene groups, wherein R ¹ and R ² each independently represent 1 carbon atom;
Or an alkyl group of from 8 to 8, etc.], specifically, a compound represented by the following formula and the like are described as the photocurable coloring composition.

Embedded image However, it does not disclose any cholinesterase inhibitory action or action as a drug for treating or preventing senile dementia.

[0010]

Today, when senile dementia increases, it has a stronger action than known compounds known to have a therapeutic / preventive action for senile dementia. There is a demand for the development of an excellent therapeutic and / or preventive agent for senile dementia with a long time and low toxicity.

[0011]

In view of such circumstances, the present inventors have conducted various studies on the biological activity and pharmacological action of a heterocyclic compound containing a novel compound, and have found that a tricyclic condensation of a specific chemical structure is possible. Heterocyclic derivatives have been found to have unexpectedly excellent therapeutic and preventive effects on senile dementia based on their unique chemical structure, and based on this, the present invention has been completed.

That is, the present invention provides the following equation (1).

Embedded image [In the formula, Ar is a tricyclic fused benzene ring group in which at least one heterocyclic ring is fused, may further have a substituent, n represents an integer of 2 to 10, and R ¹ represents hydrogen. A hydrocarbon group which may have an atom or a substituent, may be different in repeating n, and Y is a 4-piperidinyl group which may each have a substituent,
It represents a 1-piperazinyl group or a 4-benzyl-1-piperidinyl group. Or a salt thereof,

(2) Formula Ar-H (II) wherein Ar is as defined above. A compound represented by the formula:

Embedded image [In the formula, R ¹ , Y and n have the same meanings as described above, and Z ¹ represents a leaving group. A process for producing the compound according to the above (1), which comprises reacting the compound represented by the formula

Equation (3)

Embedded image Or a salt thereof and a compound of the formula Z ³ -Y ″ (V) [wherein Z ² and Z ³ are groups capable of reacting and leaving together, and Y ″ is a substituent The 1-piperazinyl or 4-benzyl-1-piperidinyl group which may be possessed, and other symbols are as defined above. With the formula

Embedded image [The symbols in the formula are as defined above. The method for producing a compound represented by the formula or a salt thereof,

Equation (4)

Embedded image [In the formula, n ′ represents an integer of 1 to 10, R ¹ may be different in repeating n ′, and Y ′ is an optionally substituted amino group or an optionally substituted nitrogen-containing saturated group. It represents a heterocyclic group, and other symbols have the same meanings as described above. And (5) a cholinesterase inhibitor as described in (4) above, which is used as a therapeutic / prophylactic agent for senile dementia. The compound (I) of the present invention or a salt thereof is substituted with a carbon atom of a benzene ring in a tricyclic fused benzene ring in which at least one heterocycle is fused.

Embedded image Is a novel compound having a chemical structural feature due to its binding, and exhibits an excellent therapeutic / prophylactic action for senile dementia based on this feature.

In the above formula, n represents an integer of 2 to 10, and n 'represents an integer of 1 to 10. In the above formula, R ¹ represents a hydrogen atom or a hydrocarbon group which may have a substituent, and may be different in repeating n and n ′. As the “hydrocarbon group” of the “hydrocarbon group which may have a substituent” represented by R ¹ , for example, a C _1-18 hydrocarbon group composed of a chain, a ring, or a combination thereof is used. Can be As such a chain hydrocarbon group, for example, a linear or branched C _1-11 alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert.
- butyl, n- pentyl, n- hexyl), straight-chain or branched C _2-6 alkenyl group (e.g., vinyl, allyl, 2-butenyl, etc.) and linear or branched C _{2 -6} alkynyl groups (eg, propargyl,
2-butynyl and the like are used. Examples of the cyclic hydrocarbon group include a C _3-7 monocyclic cycloalkyl group (eg, cyclobutyl, cyclopentyl, cyclohexyl, etc.) and a C _8-14 bridged cyclic saturated hydrocarbon group (eg, bicyclo [3.2.1. ] Oct-2-yl, bicyclo [3.3.
1] non-2-yl, adamantane-1-yl and the like),
A C _6-14 aryl group (eg, a phenyl group, a naphthyl group, etc.) is used.

Examples of the hydrocarbon group comprising a combination of a chain and a ring include C _7-18 aralkyl (for example, benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, α-naphthylmethyl, etc.). Phenyl-C _1-12 alkyl or naphthyl-C _1-8 alkyl, for example diphenyl-C _1-3 alkyl such as diphenylmethyl, diphenylethyl, etc., C _6-14 aryl-C _2-12 alkenyl (eg styryl) , Cinnamyl, 4-phenyl-2-butenyl, 4-
Phenyl-C _2-12 alkenyl such as phenyl-3-butenyl, etc., C _6-14 aryl-C _2-12 alkynyl (eg, phenylethynyl, 3-phenyl-2-propynyl, 3-phenyl-1- Phenyl-C such as propynyl
_2-12 alkynyl, etc., C _3-7 cycloalkyl-C _1-6 alkyl (for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl , Cyclohexylethyl, cycloheptylethyl, cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclopropylbutyl, cyclobutylbutyl, cyclopentylbutyl, cyclohexylbutyl, cycloheptylbutyl, cyclopropylpentyl, cyclobutyl Pentyl, cyclopentylpentyl, cyclohexylpentyl, cycloheptylpentyl, cyclopropylhexyl, cyclobutylhexyl , Cyclopentanol hexyl,
Cyclohexylhexyl, cycloheptylhexyl, etc.) are used.

Preferred examples of the "hydrocarbon group" represented by R ¹ include a linear or branched C _1-11 alkyl group, and more preferably a linear or branched C _1-7 alkyl group.
Alkyl groups (eg, methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl and the like or a C _7-18 aralkyl group, more preferably a C _7-10 aralkyl group (for example, benzyl, phenylethyl, And phenyl-C _1-4 alkyl such as phenylpropyl).
The “hydrocarbon group” represented by R ¹ may have a substituent, and as such a substituent, those generally used as a substituent of a hydrocarbon group can be appropriately used. Specifically, the above C _1-11 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 monocyclic cycloalkyl,
Examples of the substituent that the _8-14 bridged cyclic saturated hydrocarbon group may have include, for example, a halogen atom (for example, fluoro, chloro, bromo, iodo, etc.), a nitro group, a cyano group, a hydroxy group, a C _{1- 4} alkoxy groups (for example, methoxy,
Ethoxy, propyloxy, butyloxy, isopropyloxy, etc.), C _1-4 alkylthio groups (eg, methylthio, ethylthio, propylthio, etc.), amino groups,
A mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), for example, a heteroatom selected from nitrogen, oxygen and sulfur atoms in addition to one nitrogen atom 5 to 7 optionally having 1 to 3 atoms
Membered cyclic amino groups (eg, pyrrolidino, piperidino, morpholino, etc.), C _1-4 alkyl-carbonylamino groups (eg, acetylamino, propionylamino, butyrylamino, etc.), C _1-4 alkylsulfonylamino groups (eg, methylsulfonyl) Amino, ethylsulfonylamino, etc.), C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxyl group, C _1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, propyl carbonyl, etc.), a carbamoyl group, mono- or di-C _1-4 alkyl - carbamoyl group (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), C _1-6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl, 1 selected from etc.) Ropirusuruhoniru five used.

A C _6-14 aryl group represented by R ¹ ,
_7-18 aralkyl, C _6-14 aryl-C _2-12 alkenyl,
Examples of the substituent which the C _6-14 aryl-C _2-12 alkynyl and the C _3-7 cycloalkyl-C _1-6 alkyl group may have include, for example, a C _1-4 alkyl group (for example, methyl, Ethyl, propyl, butyl, etc.), halogen atoms (eg, fluoro, chloro, bromo, iodo, etc.), nitro group, cyano group, hydroxy group, C _1-4 alkoxy group (eg, methoxy, ethoxy, propyloxy, butyloxy, Isopropyloxy, etc.), C _1-4 alkylthio groups (eg, methylthio, ethylthio, propylthio,
Isopropylthio, butylthio, etc.), amino group, mono- or di-C _1-4 alkylamino group (for example, methylamino, ethylamino, propylamino, dimethylamino,
Diethylamino etc.), for example, a 5- to 7-membered cyclic amino group which may have 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to one nitrogen atom (for example, pyrrolidino, piperidino , Morpholino, etc.), C _1-4 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), aminocarbonyloxy group, mono- or di-C _1-4 alkylamino-carbonyloxy group (eg, methylamino Carbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.), C _1-4 alkylsulfonylamino group (for example, methylsulfonylamino,
Ethylsulfonylamino, propylsulfonylamino, etc.), C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl, etc.), carboxyl group, C _1-6 alkyl-carbonyl group (eg, methyl Carbonyl, ethylcarbonyl, butylcarbonyl, etc.), C _3-7 cycloalkyl-carbonyl (eg, cyclohexylcarbonyl), carbamoyl group, mono- or di-C _1-4 alkyl-carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, propyl) carbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.), C _1-6 alkyl sulfonyl Le group (e.g., methylsulfonyl, ethylsulfonyl, etc. propylsulfonyl) _3-7 cycloalkylsulfonyl (e.g., cyclopentylsulfonyl, cyclo hexyl sulfonyl), or 1-4 phenyl which may have a substituent, naphthyl, mono -
Or di-phenyl-C _1-3 alkyl (eg, benzyl, diphenylmethyl, etc.), phenoxy, benzoyl, phenoxycarbonyl, benzylcarbonyl, phenyl-C _1-4 alkyl-carbamoyl, phenylcarbamoyl, phenyl-C _1-4 alkyl- Carbonylamino, benzoylamino, phenyl-C _1-4 alkylsulfonyl, phenylsulfonyl, phenyl-C _1-4 alkylsulfinyl, phenyl-C _1-4 alkylsulfonylamino or phenylsulfonylamino group (each phenyl or naphthyl group) Examples of the substituent in the above include a C _1-4 alkyl group such as methyl, ethyl, propyl, butyl, and isopropyl, methoxy, ethoxy,
n- propyloxy, i- propyloxy, C _1-4 alkoxy group such as n- butyloxy, chlorine, bromine, halogen atoms such as iodo, hydroxy group, benzyloxy group, an amino group, the such as mono- or di C _{1 -4} alkylamino group, a nitro group, above such C _1-6 alkylcarbonyl group, benzoyl group is used. ) Is used. These C _6-14 aryl group, C _7-18 aralkyl, C _6-14 aryl-C _2-12 alkenyl, C _6-14 aryl-C _2-12 alkynyl, C _3-7 cycloalkyl-C
The number of substituents which may be substituted on the _1-6 alkyl group is 1 to
About five are suitable.

In the above formula, Ar is a group having a bond at the carbon atom of the benzene ring of the tricyclic fused benzene ring in which at least one heterocyclic ring is fused, and may have a substituent. As described above, the compound of the present invention has a benzene ring in a tricyclic fused benzene ring in which at least one heterocycle is fused, and

Embedded image Has a unique chemical structural feature at the point where it is bonded to the group represented by, and exhibits an excellent cholinesterase inhibitory action based on this feature, so that the tricyclic fused benzene ring group represented by Ar The substituent is not particularly limited. Ar is represented by the formula

Embedded image [In the formula, ring A is a benzene ring which may further have a substituent, and ring B and ring C are a heterocyclic ring which may have a substituent, and the other has a substituent. Represents a 5- to 8-membered ring which may contain a hetero atom. ] Is used.

The benzene ring represented by the ring A has the formula

Embedded image May be further substituted in addition to being substituted with a group represented by the following _formula . Examples of such a substituent include a C _6-14 aryl group of the above R ¹ , C _7-18 aralkyl,
_6-14 aryl-C _2-12 alkenyl, C _6-14 aryl-C
_The substituents described for _2-12 alkynyl and C _3-7 cycloalkyl-C _1-6 alkyl group are used, and the number is preferably 1 to 3. Preferred substituents which the benzene ring may further have include, for example, halogen atoms such as fluoro and chloro, halogeno-C _1-3 alkyl such as trifluoromethyl, and C _1-3 such as methyl. Examples thereof include an alkyl group, a C _1-3 alkoxy group such as methoxy, and a hydroxy group. Particularly preferred are one or two halogens such as fluoro.

The "heterocycle" in the "heterocycle optionally having substituent (s)" represented by ring B or ring C includes
For example, a 4- to 14-membered ring, preferably a 5- to 9-membered ring is used. As the hetero atom, for example, 1 to 3 atoms selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like are used. Specifically, for example, pyridine, pyrazine, pyrimidine, imidazole, furan, thiophene, pyrrolidine, piperidine, hexamethyleneimine,
Tetrahydrofuran, piperazine, morpholine, thiomorpholine and the like are used. In particular, 5 containing one heteroatom or two identical or different heteroatoms
To a 9-membered non-aromatic heterocycle (eg, pyrrolidine,
Piperidine, hexamethyleneimine, tetrahydrofuran, piperazine, morpholine, thiomorpholine and the like). In particular, for example, a non-aromatic heterocyclic ring containing one hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and one nitrogen atom and one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom Non-aromatic heterocycles containing atoms are frequently used.

As the "5- to 8-membered ring optionally containing a hetero atom" represented by the ring B or C, a 5- to 8-membered heterocyclic ring or carbocyclic ring is used, which may have a substituent. . The 5- to 8-membered carbon ring may be a benzene ring or a saturated or unsaturated ring, for example, benzene, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptane. Diene or the like is used. Further, when the ring B or C has a hetero atom in the ring, that is, in the case of a hetero ring, 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom or a sulfur atom are used. The ring B or C may be aromatic or non-aromatic, and examples of aromatic heterocycles include pyridine, furan, and thiophene. As the non-aromatic heterocyclic ring, a non-aromatic heterocyclic ring represented by ring B or ring C is preferable.

That is, as Ar

Embedded image For example, carbazole, 1,2,3,4,4a, 9a-hexahydrocarbazole, 9,10-dihydroacridine, 1,2,3,4-tetrahydroacridine, 11-dihydro-5H-dibenz [b, f] azepine, 5,6,7,12-tetrahydrodibenz [b, g] azocine, 6,11-dihydro-5H-
Dibenz [b, e] azepine, 6,7-dihydro-5H-dibenz [c, e] azepine, 5,6,11,12-tetrahydrodibenz [b, f] azocin, dibenzofuran, 9H-
Xanthene, 10,11-dihydrodibenz [b, f] oxepin, 6,11-dihydrodibenz [b, e] oxepin, 6,7-dihydro-5H-dibenz [b, g] oxocin, dibenzothiophene, 9H -Thioxanthene, 1
0,11-dihydrodibenzo [b, f] thiepine, 6,11
-Dihydrodibenzo [b, e] thiepin, 6,7-dihydro-5H-dibenzo [b, g] thiocin, 10H-phenothiazine, 10H-phenoxazine, 5,10-dihydrophenazine, 10,11-dibenzo [b, f] [1,4] thiazepine, 10,11-dihydrodibenz [b, f] [1,
4] oxazepine, 2,3,5,6,11,11a-hexahydro-1H-pyrrolo [2,1-b] [3] benzazepine, 10,11-dihydro-5H-dibenzo [b, e]
[1,4] diazepine, 5,11-dihydrodibenz [b,
e] [1,4] oxazepine, 5,11-dihydrodibenzo [b, f] [1,4] thiazepine, 10,11-dihydro-5H-dibenzo [b, e] [1,4] diazepine, 1, Two,
3,3a, 8,8a-Hexahydropyrrolo [2,3-b]
Such as indole, or

[0025]

Embedded image A tricyclic fused benzene ring represented by, for example, 1H, 3H-
Naphtho [1,8-cd] [1,2] oxazine, naphtho [1,8-de] -1,3-oxazine, naphtho [1,8-d
e] -1,2-oxazine, 1,2,2a, 3,4,5-hexahydrobenz [cd] indole, 2,3,3a, 4,5,
6-hexahydro-1H-benzo [de] quinoline, 4H
-Pyrrolo [3,2,1-ij] quinoline, 1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1-ij] quinoline,
5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinoline, 1H, 5H-benzo [ij] quinolidine, azepino [3,2,1-hi] indole, 1,2,4,5, 6,7-hexahydroazepino [3,2,1-hi] indole, 1H
-Pyrido [3,2,1-jk] [1] benzazepine, 5,
6,7,8-tetrahydro-1H-pyrido [3,2,1-j
k] [1] benzazepine, 1,2,5,6,7,8-hexahydro-1H-pyrido [3,2,1-jk] [1] benzazepine, 2,3-dihydro-1H-benz [de] Isoquinoline, 1,2,3,4,4a, 5,6,7-octahydronaphtho [1,8-bc] azepine, 2,3,5,6,7,8-hexahydro-1H-pyrido [3, 2,1-jk] [1] benzazepine or the like or formula

Embedded image A tricyclic fused benzene ring represented by, for example, 1,2,3,
5,6,7-hexahydrobenzo [1,2-b: 4.5-
b ′] dipyrrole, 1,2,3,5,6,7-hexahydrocyclopent [f] indole, or a compound of the formula

Embedded image A tricyclic fused benzene ring represented by, for example, 1,2,3,6,
7,8-hexahydrocyclopent [e] indole,
A group having a bond at the benzene ring such as 2,3,4,7,8,9-hexahydro-1H-cyclopenta [f] quinoline is preferable. Especially

Embedded image A group formed by removing one hydrogen atom from the benzene ring of the tricyclic fused benzene ring represented by

Ring B and ring C may have a substituent, and the substituent may be substituted on any carbon atom of ring B and ring C. Examples of the substituent include a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), a nitro group, a cyano group, an oxo group, a hydroxy group,
A C _1-4 alkoxy group (eg, methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.), a C _1-4 alkylthio group (eg, methylthio, ethylthio, propylthio, etc.), an amino group, mono- or di-C _1-4 An alkylamino group (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), for example, one or more heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon and one nitrogen atom; 5 to 7 which may have 3
Membered cyclic amino groups (eg, pyrrolidino, piperidino, morpholino, thiomorpholino, etc.), C _1-4 alkyl-carbonylamino groups (eg, acetylamino, propionylamino, butyrylamino, etc.), C _1-4 alkylsulfonylamino groups (eg, , Methylsulfonylamino,
Ethylsulfonylamino, C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxyl group, C _1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, propylcarbonyl) Carbamoyl group, mono- or di-C _1-4 alkyl-
One to five members selected from a carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, etc.) and a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.) are used. Among them, C _1-6 such as oxo group and methyl
Alkyl groups and the like are preferred. As ring B or ring C,
(1) a benzene ring optionally substituted with C _1-6 alkyl (eg, methyl, etc.) and / or C _1-6 alkyl-carbonyl (eg, acetyl, etc.); 1 or 2 selected from an oxygen atom, a nitrogen atom, and a sulfur atom such as a saturated carbocycle or (3) a 5- to 8-membered nitrogen-containing saturated heterocycle (eg, pyrrolidine and the like).
Preferred are 5- to 8-membered saturated heterocycles containing two heteroatoms.

When the rings B and C have a nitrogen atom in the ring, they may have a substituent on the nitrogen atom. That is, the ring B and the ring C each have> NR
⁶ [R ⁶ represents a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group which may have a substituent. ]
May be provided. As the optionally substituted hydrocarbon group represented by R ^{6, for example} , the optionally substituted hydrocarbon group described for R ¹ may be used as it is, and among them, for example, a halogen atom ( For example, Flor,
A C _1-7 alkyl group (eg, methyl, ethyl, n-propyl, etc.) which may be substituted with a nitro group, a C _1-4 alkoxy group (eg, methoxy, ethoxy, etc.), a hydroxy group, etc. ) Or a C _7-10 aralkyl group (eg, phenylmethyl, phenylethyl, etc.)
Are preferred. In particular, an unsubstituted benzyl group is frequently used.

Y 'represents an amino group which may be substituted or a nitrogen-containing saturated heterocyclic group which may have a substituent. As the “optionally substituted amino group” represented by Y ′, for example,

Embedded image [In the formula, R ² ′ and R ³ ′ are the same or different and each represent a hydrogen atom, a hydrocarbon group which may have a substituent, or an acyl group which may have a substituent. And the like are used. As the optionally substituted hydrocarbon group represented by R ² ′ and R ³ ′, for example, the optionally substituted hydrocarbon group described above for R ¹ can be used. Preferred examples of the optionally substituted hydrocarbon group represented by R ² ′ and R ³ ′ include, for example, a halogen atom (eg, fluor, chloro, etc.),
_1-3 alkoxy groups (for example, methoxy, ethoxy, etc.), _{1-3 of} which may be substituted with hydroxy groups, for example, linear or branched C _1-11 alkyl groups, more preferably linear Alternatively, a branched C _1-7 alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-
Pentyl, n-hexyl, etc.) or a C _7-18 aralkyl group (eg, phenyl-C _1-12 such as phenylmethyl, phenylethyl, phenylpropyl, phenylhexyl).
Naphthyl-C _1-8 such as alkyl and α-naphthylmethyl
Alkyl and the like, and more preferably a _C7-10 aralkyl group (for example, phenylmethyl, phenylethyl, phenylpropyl and the like) and the like.

The “acyl group” of the “optionally substituted acyl group” represented by R ⁶ , R ² ′ and R ³ ′ includes, for example, acyl carboxylate (eg, formyl,
C _2-8 alkylcarbonyl or phenylcarbonyl such as acetyl, propionyl, butyryl, benzoyl and the like; acyl sulfonate group (for example, C _1-7 such as methanesulfonyl, ethanesulfonyl, propanesulfonyl, benzenesulfonyl and p-toluenesulfonyl) Alkylsulfonyl or phenylsulfonyl, etc.), phosphonic acid acyl group (for example, methanephosphonyl, ethanephosphonyl, propanephosphonyl, benzenephosphonyl,
C _1-7 alkylphosphonyl or phenylphosphonyl such as p-toluenephosphonyl, and substituted oxycarbonyl group (for example, C1-7 such as methyloxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, etc.)
_2-8 alkyloxycarbonyl or _C7-8 aralkyloxy-carbonyl) is used. Above all, C _2-8
Alkyloxycarbonyl is preferred. Examples of the substituent which the acyl group may have include a halogen atom (for example, fluoro, chloro, bromo, iodo, etc.), a nitro group, a hydroxy group, an amino group, a mono- or di-C _1-6.
An alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.) and a C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, etc.) are used, and these substituents are 1 to 3
, Preferably one or two. R ² 'and R
Preferred examples of ³ ′ include, for example, linear or branched C _1-7
Alkyl groups (eg, methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl, etc.) or a _C7-10 aralkyl group (e.g., benzyl, phenylethyl, phenylpropyl, etc.), especially methyl. And C _1-3 alkyl such as phenylethyl, and C _7-10 aralkyl such as phenylmethyl.

In the "nitrogen-containing saturated heterocyclic group optionally having substituent (s)" represented by Y ', the "nitrogen-containing saturated heterocyclic group" includes, in addition to a carbon atom and one nitrogen atom, Examples thereof include a 5- to 9-membered nitrogen-containing saturated heterocyclic group which may contain 1 to 3 hetero atoms such as an atom, an oxygen atom and a sulfur atom. These nitrogen-containing saturated heterocyclic groups may be groups having a bond at a ring-forming nitrogen atom or groups having a bond at a ring-forming carbon atom. As the group having a bond at the ring-constituting nitrogen atom, for example,

Embedded image (Q ¹ ring nitrogen atom in addition to carbon atoms and one nitrogen atom,
And a 5- to 9-membered nitrogen-containing saturated heterocyclic group which may contain 1 or 2 hetero atoms selected from an oxygen atom and a sulfur atom). More specifically, for example,

Embedded image Are often used. Examples of the group having a bond at a ring-constituting carbon atom include, for example,

[0031]

Embedded image (Q ² ring nitrogen atom in addition to carbon atoms and one nitrogen atom,
And a 5- to 9-membered nitrogen-containing saturated heterocyclic group which may contain 1 or 2 hetero atoms selected from an oxygen atom and a sulfur atom). More specifically, for example,

Embedded image Are often used. Y is a 4-piperidinyl group, a 1-piperazinyl group or a 4-benzyl-1-piperidinyl group which may have a substituent,

Embedded image (R represents H or a substituent.).

The above "nitrogen-containing saturated heterocyclic group" or "4
As the substituent which R may have and the substituent which R may have, for example, a hydrocarbon group which may have a substituent described for R ¹ above, The acyl group which may have a substituent described in R ² ′ and R ³ ′, a halogen atom (for example, fluoro,
Chloro, bromo, iodo, etc.), nitro, cyano,
Oxo group, hydroxy group, C _1-4 alkoxy group (eg, methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.), C _1-4 alkylthio group (eg, methylthio, ethylthio, propylthio, isopropylthio, etc.), amino Group, mono- or di-C
_1-4 alkylamino groups (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), a carbon atom and one nitrogen atom and one heteroatom such as a nitrogen atom, an oxygen atom and a sulfur atom.
And a 5- to 7-membered cyclic amino group optionally containing 3 to 3 (eg, pyrrolidino, piperidino, morpholino,
Thiomorpholino, etc.), C _1-4 alkyl - carbonyl amino group (e.g., acetylamino, propionylamino, butyrylamino, etc.), C _1-4 alkylsulfonyl group (e.g., methylsulfonylamino, ethylsulfonylamino, etc.), C _{1 -4} alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), phenyl-C _1-4 alkyl-oxycarbonyl (eg, benzyloxycarbonyl, etc.), carboxyl group, C _1-6 alkyl-carbonyl group (E.g., methylcarbonyl, ethylcarbonyl, propylcarbonyl, etc.), a benzoyl group which may have a substituent (here, the substituent is
For example, C _1-4 alkyl such as methyl, ethyl, etc., halogen such as fluoro, chloro, bromo, etc., C _1-4 alkoxy such as methoxy, ethoxy, etc., mono- or di-C _1-, such as methylamino, dimethylamino, etc. ₄ alkylamino, such as piperidino, morpholino, etc.
And 1 to 3 members selected from a 7-membered cyclic amino group, nitro, hydroxy and the like are used.
Fluorobenzoyl, 3,4-dimethoxybenzoyl, etc.), carbamoyl group, mono- or di-C _1-4 alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, etc.), C _1-6 alkylsulfonyl group (eg, methylsulfonyl) , Ethylsulfonyl, propylsulfonyl, etc.). Among such substituents, a hydrocarbon group which may have a substituent described above for R ¹ is preferable,
For example, linear or branched, which may be substituted with a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), a nitro group, a C _1-4 alkoxy group (eg, methoxy, ethoxy, etc.), a hydroxy group, etc. C _1-11 alkyl group, more preferably linear or branched C _1-11 alkyl group
_{A 1-7} alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, etc.), a C _7-18 aralkyl group (eg, phenylmethyl, Phenyl-C _1-12 alkyl such as phenylethyl, phenylpropyl, phenylhexyl and the like, and naphthyl-C _1-8 alkyl such as α-naphthylmethyl, and more preferably a C _7-10 aralkyl group (eg, phenylmethyl, Ethyl, phenylpropyl and the like, or a diphenyl-C _1-3 alkyl group (for example, diphenylmethyl and the like) are frequently used. The substitution position is on a carbon atom of the nitrogen-containing saturated heterocyclic ring or (and)
It may be on a nitrogen atom.

"4-benzyl-1" represented by Y
-Piperidinyl group "may have, for example, a C _6-14 aryl group represented by R ¹ above,
_7-18 aralkyl, C _6-14 aryl-C _2-12 alkenyl,
The same substituents as the substituents that the C _6-14 aryl-C _2-12 alkynyl and C _3-7 cycloalkyl-C _1-6 alkyl group may have are used. Y ′ contained in the compound (I ′) or a salt thereof of the present invention may be a 4-piperidinyl group, a 1-piperazinyl group or a 4-piperidinyl group, each of which may have a substituent.
Compound (I) or a salt thereof, which represents a benzyl-1-piperidinyl group and n 'represents an integer of 2 to 10, is a novel compound and has a more excellent cholinesterase inhibitory action. In the above formula, R ¹ is preferably, for example, a hydrogen atom. The benzene ring represented by ring A is preferably unsubstituted. As Ar, for example,

Embedded image (R ⁶ has the same meaning as described above). R ⁶ is substituted with one or two selected from (1) hydrogen atom, (2) halogen (eg, fluoro, chloro, etc.), nitro, C _1-4 alkoxy (eg, methoxy, ethoxy, etc.) and hydroxy. _{Optionally a} C _1-6 alkyl (eg,
Methyl, ethyl, etc.), phenyl-C _1-4 alkyl (eg, benzyl, etc.), C _1-6 alkyl-carbonyl (eg, acetyl, etc.), benzoyl, C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxy) Carbonyl) or mono- or di-C _1-4 alkyl-
A carbamoyl group, (3) formyl or (4) carbamoyl is preferable, and among them, a hydrogen atom, a formyl group or a methyl group is particularly preferable.

As Y ′, for example, a group (VII) (particularly,
One of R ² ′ and R ³ ′ is a linear or branched C _1-7 alkyl group (for example, methyl, ethyl, n-propyl, i-
Propyl, n-butyl, i-butyl, tert-butyl, n
-Pentyl, n-hexyl, etc.) and the other is a C _7-10 aralkyl group (eg, phenylmethyl, phenylethyl, phenylpropyl, etc.), or pyrrolidine substituted with an optionally substituted benzyl group, etc. Piperidine, piperazine, morpholine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 2,3,4,5-tetrahydro-1H-1-benzazepine, 2,3,4, 5-tetrahydro-1H-2-
Benzazepine, 2,3,4,5-tetrahydro-1H-
3-Benzazepine and the like are preferred. Particularly, pyrrolidine, piperidine, piperazine, morpholine and the like substituted with a substituted or unsubstituted benzyl group are preferable. Preferred substituents for the benzyl group include halogen such as fluoro and chloro, C _1-4 alkyl such as methyl and ethyl, C _1-4 alkoxy such as methoxy, hydroxy, nitro and amino. For Y, the formula

Embedded image [Wherein, R ′ represents (1) C _1-6 alkyl (eg, methyl, ethyl, etc.), halogen (eg, fluoro, chloro, etc.),
Nitro, cyano, amino, mono- or di-C _1-6 alkylamino (eg, methylamino, etc.), hydroxy, C
_1-6 alkoxy (eg, methoxy, ethoxy, etc.), phenyl-C _1-4 alkoxy (eg, benzyl, etc.) and C
_1-4 alkylenedioxy (eg, methylenedioxy, etc.)
Benzyl optionally substituted by one or two selected from the group consisting of: (2) cyclohexyl, (3) phenyl, (4)
Formyl, (5) C _1-6 alkyl-carbonyl (eg, acetyl, etc.), (6) benzoyl or (7) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, etc.)
And R ″ and R ′ ″ each represent C _1-6 alkyl (eg, methyl, ethyl, etc.), halogen (eg, fluoro, chloro, etc.), nitro, cyano, amino, mono- or di-C
_1-6 alkylamino (eg, methylamino, etc.), hydroxy, C _1-6 alkoxy (eg, methoxy, ethoxy, etc.), phenyl-C _1-4 alkoxy (eg, benzyl, etc.) or C _1-4 alkylenedioxy (Eg, methylenedioxy, etc.). ] Is preferable. In particular, Y is preferably 4-piperidinyl or 1-piperazinyl substituted with a substituted or unsubstituted benzyl group, or 4-substituted or unsubstituted 4-benzyl-1-piperidinyl. As the substituent of the benzyl group,
Preferred are halogen such as fluoro and chloro, C _1-4 alkyl such as methyl and ethyl, C _1-4 alkoxy such as methoxy, hydroxy, nitro and amino. Particularly, Y is preferably a 1-benzyl-4-piperidinyl group, a 4-benzyl-1-piperazinyl group or a 4-benzyl-1-piperidinyl group. n and n ′ are preferably an integer of 2 to 6. More specifically, the following compounds belonging to compounds (I) and (I ′) and salts thereof are preferable.

[0035]

[Table 1]

[0036]

[Table 2]

[0037]

[Table 3]

[0038]

[Table 4]

[0039]

[Table 5]

[0040]

[Table 6]

[0041]

[Table 7]

[0042]

[Table 8]

[0043]

[Table 9]

[0044]

[Table 10]

[0045]

[Table 11]

[0046]

[Table 12]

[0047]

[Table 13]

[0048]

[Table 14]

[0049]

[Table 15]

[0050]

[Table 16]

[0051]

[Table 17]

[0052]

[Table 18]

[0053]

[Table 19]

[0054]

[Table 20]

[0055]

[Table 21]

[0056]

[Table 22]

[0057]

[Table 23]

[0058]

[Table 24]

[0059]

[Table 25]

[0060]

[Table 26]

[0061]

[Table 27]

[0062]

[Table 28]

[0063]

[Table 29]

[0064]

[Table 30]

[0065]

[Table 31]

[0066]

[Table 32]

[0067]

[Table 33]

[0068]

[Table 34]

[0069]

[Table 35]

[0070]

[Table 36]

[0071]

[Table 37]

[0072]

[Table 38]

[0073]

[Table 39]

[0074]

[Table 40]

[0075]

[Table 41]

[0076]

[Table 42]

[0077]

[Table 43]

[0078]

[Table 44]

[0079]

[Table 45]

[0080]

[Table 46]

[0081]

[Table 47]

[0082]

[Table 48]

[0083]

[Table 49]

[0084]

[Table 50]

[0085]

[Table 51] In the table, Ac represents an acetyl group, Et represents an ethyl group, and Ph represents a phenyl group.

As the salt of compound (I ') of the present invention, a physiologically acceptable acid addition salt is particularly preferable. Examples of such salts include salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) and organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, Salts with tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) are used. Further, the compound (I ') of the present invention is-
When it has an acidic group such as COOH, compound (I ′)
May form a salt with an inorganic base (eg, sodium, potassium, calcium, magnesium, ammonia) or an organic base (eg, triethylamine), and such salts are also included in the object of the present invention.

Next, a method for producing the compound (I ′) of the present invention or a salt thereof will be described. The following description of the production method applies not only to the compound (I ′) itself, but also to the above-mentioned salts thereof, but is simply abbreviated as the compound (I ′) in the following description. Formula Ar-H (II) [The symbols in the formula are as defined above. A compound represented by the formula:

Embedded image [In the formula, Z ¹ represents a leaving group, and other symbols have the same meanings as described above. Compound (I ') can be produced by reacting the compound represented by the formula (I) or a salt thereof.
Examples of the leaving group represented by Z ¹ include a halogen atom (eg, chloro, bromo, iodo), C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy,
Ethanesulfonyloxy), C _6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy) and the like are used. Particularly, for example, a halogen atom (for example, chloro or the like) is preferable.
Compound (II) or a salt thereof can be produced by a method known per se or a method analogous thereto. For example, Journal of Chemical Society (J. Chem. Soc.), 1381 (1949), Canadian Journal of Chemistry (Can. J. Chem.), 42 , 2
904 (1964), Journal of Organic Chemistry (J. Org. Chem.), 28 , 3058 (1963), Journal of American Chemical Society (J. A.
m. Chem. Soc.), 76 , 3194 (1954), 87 , 1397 (1965), 8
8 , 4061 (1966), JP-A-49-41539, and the like, or a method analogous thereto. Compound (III) or a salt thereof can be produced by a method known per se or a method analogous thereto. For example, Chemical Pharmaceutical Bulletin (Chem. Pharm. Bull.) 34 , 3747-3761 (198
6), it can be produced according to the method described in EP-A-0,378,207 and the like.

The salts of the compounds (II) and (III) of the present invention include, for example, salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) and organic acids (eg, acetic acid, formic acid) , Propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid,
A salt with methanesulfonic acid or benzenesulfonic acid) is used. Further, the compounds (II) and (III) of the present invention
Has an acidic group such as —COOH, the compounds (II) and (III) can be an inorganic base (eg, an alkali metal such as sodium, potassium, calcium, magnesium or an alkaline earth metal, ammonia, etc.) or Organic bases (for example, tri-C such as triethylamine)
_{With 1-3} alkylamines). The reaction of compound (III) or a salt thereof with compound (II) or a salt thereof is carried out, for example, by reacting compound (III) or a salt thereof with compound (II) or a salt thereof without using a solvent, or as necessary. The reaction can be carried out in a solvent. As the solvent, any solvent which can be generally used for a chemical reaction may be used as long as the reaction is not hindered. For example, a hydrocarbon solvent (for example, pentane,
Hexane, benzene, toluene, nitrobenzene, etc.), halogenated hydrocarbon solvents (eg, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc.), ether solvents (eg, ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane) And organic solvents such as nitroalkane (eg, nitromethane, propionitrile, etc.), carbon disulfide and the like. Particularly, dichloromethane, 1,2-dichloroethane, nitrobenzene, carbon disulfide and the like are preferable. The amount of the solvent used is the same as that of compound (III) or a salt thereof.
Usually 0.5 to 100 ml, preferably 5 to 100 mmol,
~ 20 ml. The reaction temperature is usually −30 ° C. to 150 ° C.
Degree, preferably about 20 ° C to 100 ° C. The reaction time is generally 0.5 to 72 hours, preferably 1 to 16 hours.

Examples of the Lewis acid used in this reaction include aluminum chloride, aluminum bromide, zinc chloride, titanium chloride, tin (IV) chloride, boron trifluoride, iron (II) chloride, and iron (III) chloride. ), Antimony pentachloride (V), bismuth (III) chloride, mercury (II) chloride, hydrogen fluoride, sulfuric acid, polyphosphoric acid, etc., with aluminum chloride being preferred. The amount of the Lewis acid to be used is generally 1 to 10 mol, preferably 2 to 10 mol, per 1 mol of compound (III) or a salt thereof. The amount of compound (II) or a salt thereof to be used is generally about 1-20 mol, preferably about 1-5 mol, per 1 mol of compound (III) or a salt thereof. In the above reaction, compound (III)
Or a group in a salt thereof

Embedded image Is introduced into the compound (II) or a salt thereof at any of the substitutable positions on the ring A. For example, the skeleton of the compound (II) or a salt thereof has 1,2,2a, 3, 4,5
In the case of hexahydrobenz [cd] indole (where ring A is unsubstituted), it is mainly introduced at the 6-position. However, compounds introduced at other positions (positions 7 and 8) can also be generated and separated.

Also, for example, the formula

Embedded image [Each symbol in the formula is as defined above. And a salt thereof, and a compound represented by the formula Z ³ -Y ″ (V) wherein each symbol is as defined above, or a salt thereof.

Embedded image [Each symbol in the formula is as defined above. Or a salt thereof.

Z ² and Z ³ represent groups capable of reacting and leaving together. Examples of the leaving group represented by Z ² include a halogen atom (eg, chloro, bromo, iodo, etc.), C _1-6
Alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, etc.), C _6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.) are used. Among them, a halogen atom is preferable. More specifically, as Z ² , a halogen atom such as chloro or bromo is preferable. As the leaving group represented by Z ³ , for example, a hydrogen atom, a trialkylsilyl group (eg, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, etc.) or a metal atom (eg, sodium, potassium, lithium, etc.) is used. Can be
Among them, for example, a hydrogen atom is frequently used. Compound (VI)
As the salt of, those similar to the salt of compound (I ') are used. Examples of the salts of compounds (IV) and (V) include salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) and organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid) , Maleic acid, succinic acid, tartar, citric, cider, oxalic, benzoic, methanesulfonic,
A salt with benzenesulfonic acid) is used. Further, when the compounds (IV) and (V) of the present invention have an acidic group such as —COOH, the compounds (IV) and (V)
Inorganic bases (eg, alkali or alkaline earth metals such as sodium, potassium, calcium, magnesium, etc., ammonia) or organic bases (eg, tri-C _1-3 alkylamines, such as triethylamine)
And a salt may be formed.

The amount of compound (V) or a salt thereof to be used in this reaction is usually 1.0 to 50.0 times, preferably 1.0 to 10 times, per 1 mol of compound (IV) or a salt thereof. 0
It is twice the mole. This reaction is carried out under cooling or heating (0 ° C to 1 ° C).
20 ° C.). The reaction time is usually 1
0 minutes to 48 hours, preferably 2 to 16 hours. This reaction can be carried out without using a solvent, but the reaction can be carried out in a solvent if necessary. As such a solvent, any solvent may be used as long as it does not inhibit the progress of this reaction. For example, lower alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, t-butanol, dioxane, ether, Ethers such as tetrahydrofuran, toluene,
Aromatic hydrocarbons such as benzene and xylene, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, amides such as dimethylformamide, dimethylacetamide and hexamethylphosphonotriamide;
Esters such as ethyl acetate and butyl acetate are used. The amount of the solvent used is the same as that of compound (IV-a) or a salt thereof.
It is usually 0.5 to 100 ml, preferably 5 to 20 ml, based on mmol. This reaction can be carried out in the presence of a base, if necessary. Examples of the base used include inorganic bases such as sodium carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride and the like, pyridine, 4-dimethylaminopyridine, triethylamine and the like. Organic bases. The amount of the base to be used is generally equimolar to excess, preferably 1.0 to 5.0 moles, relative to compound (V) or a salt thereof.

Further, this reaction may be promoted in the presence of an iodide compound (eg, sodium iodide, potassium iodide, lithium iodide) if desired. In such a case, the amount of the iodide compound to be used is generally 1 to 5 molar equivalents, preferably 1.0 equivalent, relative to compound (IV) or a salt thereof.
0 to 1.5 times the molar amount. The starting compound (IV) or a salt thereof is, for example, a compound represented by the formula: Ar-H (II) wherein each symbol is as defined above. A compound represented by the formula:

Embedded image [In the formula, Z ⁴ represents a leaving group, and the other symbols have the same meanings as described above. And a compound represented by the following formula: Examples of the leaving group represented by Z ⁴ include a halogen atom (eg, chloro, bromo, iodo, etc.), C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, etc.), C _6-10 aryl Sulfonyloxy (for example, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.) and the like are used. Particularly, for example, a halogen atom (for example, chloro or the like) is preferable.

Compound (VIII) can be produced by a method known per se or a method analogous thereto. The reaction of compound (II) or a salt thereof with compound (VIII)
The reaction can be carried out under the same conditions as in the reaction of compound (II) or a salt thereof with compound (III) or a salt thereof. In the above reaction, the group in compound (VIII)

Embedded image Is introduced into the compound (II) or a salt thereof at any of the substitutable positions on the ring A. For example, the skeleton of the compound (II) or a salt thereof has 1,2,2a, 3, 4,5
-Hexahydro [cd] indole (however, ring A is unsubstituted)
In the case of, it is mainly introduced in the sixth place. However, compounds introduced at other positions (positions 7 and 8) can also be formed and separated. The compound (IV) or a salt thereof thus obtained can be isolated and purified by a known means such as concentration, liquid conversion, phase transfer, solvent extraction, fractionation, distillation, crystallization, recrystallization, chromatography and the like. However, the reaction mixture may be used as a raw material in the next step without isolation. Starting compound (V) or a salt thereof can be produced by a method known per se or a method analogous thereto.

In the compound (I '), when n is 2, Y
Is a 1-piperazinyl group or a 4-benzyl-1-piperidinyl group, that is, a compound of the formula

Embedded image [Wherein, R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a hydrocarbon group which may have a substituent, and other symbols have the same meanings as described above. A compound represented by the formula:

Embedded image [Each symbol in the formula is as defined above. And a salt thereof, and a compound represented by the formula: R ⁵ —CHO (XI) wherein R ⁵ is as defined above. A compound represented by] the formula Z ³ -Y "(V) [wherein each symbol can also be prepared by reacting a compound or a salt thereof.] Of the same meaning as defined above .

Examples of the optionally substituted hydrocarbon group represented by R ⁴ and R ⁵ include, for example, the optionally substituted hydrocarbon group represented by R ¹ . As the salt of compound (IX), those similar to the salts of compound (I ') are used. As the salt of the compound (X), for example, a salt with an inorganic acid (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) or an organic acid (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, Salts with succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) are used. Further, when the compound (X) of the present invention has an acidic group such as —COOH, the compound (X) may be an inorganic base (for example, an alkali metal or an alkaline earth metal such as sodium, potassium, calcium, or magnesium). , Ammonia) or organic bases (eg, tri-C _1-3 alkylamines such as triethylamine).

This reaction can be carried out in the same manner as in the Mannich reaction method described in, for example, Organic Reaction, Vol. 1, p. 303-341. Specifically, for example, compound (XI) and compound (V) or a salt thereof are generally used in an amount of 0.9 to 10 equivalents, preferably 1.0 to 3.0 equivalents per equivalent of compound (X) or a salt thereof. It can be produced by reacting an equivalent amount. This reaction can be carried out usually at room temperature or under heating (10 to 150 ° C.), but is particularly preferably carried out at 80 to 120 ° C. The reaction time is generally 1 to 48 hours, preferably 2 to 24 hours. This reaction can be usually performed without a solvent or using a solvent. As the solvent, any solvent generally used for a Mannich reaction can be used as long as the reaction is not hindered. For example, alcohol solvents such as ethanol are frequently used. The amount of the solvent to be used is generally 0.5-200 ml, preferably 5-40 ml, per 1 mmol of compound (X) or a salt thereof. Further, this reaction can be carried out in the presence of an inorganic acid such as hydrochloric acid, if desired. The acid is used in a catalytic amount (0.001 to 0.05 equivalent relative to 1 equivalent of compound (X)) relative to compound [IV] or a salt thereof. However, when the compound (V) or (X) used in the reaction does not form a salt, it is preferable to use an excess amount of acid used for forming a salt with these compounds. Compound (X) or a salt thereof is prepared by combining compound (II) or a salt thereof with a compound of the formula Z ⁵ —CO—CH ₂ —R ⁴ (XII) (wherein Z ⁵ represents a leaving group, and other symbols are as defined above. Can be produced by reacting a compound represented by the following formula: This reaction can be carried out, for example, under the same conditions as in the reaction of compound (II) or a salt thereof with compound (VIII). Compound (XI) is
It can be produced by a method known per se or a method analogous thereto.

In each of the above reactions, when the starting compound has an amino group, a carboxyl group, a hydroxyl group or the like as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. The target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group include C _1-6 which may have a substituent.
Alkyl-carbonyl (eg, formyl, acetyl,
Ethylcarbonyl, etc.), benzoyl, C _1-6 alkyl-oxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl (eg, phenoxycarbonyl, etc.), C _7-15 aralkyloxy-carbonyl (eg, benzyloxy Carbonyl, fluorenyloxycarbonyl, etc.), trityl, phthaloyl and the like. Examples of these substituents include halogen atom (e.g., fluoro, chloro, bromo, iodo, etc.), C _1-6 alkyl - carbonyl (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl and the like), and nitro groups, The number of substituents is about 1 to 3. Examples of the carboxyl-protecting group include, for example, optionally substituted C _1-6 alkyl (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.), phenyl, Trityl, silyl and the like are used. These substituents include a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), C _1-6 alkyl-carbonyl (eg, formyl, methylcarbonyl, ethylcarbonyl,
Butylcarbonyl) and a nitro group, and the number of substituents is about 1 to 3.

Examples of the protecting group for the hydroxyl group include C _1-6 alkyl which may have a substituent (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.) Phenyl, C _7-10 aralkyl (eg, benzyl etc.), C _1-6 alkylcarbonyl (eg, formyl, acetyl, ethyl carbonyl etc.), phenyloxycarbonyl (eg, phenoxycarbonyl etc.), C _7-10 aralkyl- Carbonyl (eg, benzyloxycarbonyl), pyranyl, furanyl, silyl, and the like are used. These substituents include a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), C _1-6 alkyl, phenyl, C _7-10
Aralkyl, nitro group, etc. are used, and the number of substituents is 1
Or about four. As the method for removing the protecting group, a method known per se or a method analogous thereto is used.For example, an acid, a base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, A method of treating with palladium acetate or the like is used.

When the thus obtained compound (I ′), (VI) or (IX) or a salt thereof has an acylamino group which may have a substituent, the compound is subjected to a deacylation reaction to obtain a primary or secondary compound. It can be a compound having a secondary amino group or a salt thereof. Compound (I ′), (VI) or (IX) having an acylamino group which may have a substituent used as a raw material compound or a salt thereof is
It may be isolated and purified by known means such as concentration, liquid conversion, phase transfer, solvent extraction, fractionation, distillation, crystallization, recrystallization, chromatography, etc. It may be provided as a raw material. That is, the compound (I ′), (VI) or (IX) or a salt thereof having an acylamino group which may have a substituent is
For example, acids such as mineral acids (eg, nitric acid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid) or alkali metal hydroxides (eg, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide). In an aqueous solution of a base, the temperature is generally maintained at 10 ° to 150 ° C, preferably 50 ° to 100 ° C. The amount of the acid or base to be used is generally 1 to 100 equivalents, preferably 1 equivalent, relative to compound (XII) or a salt thereof.
４０40 equivalents. The strength of the acid and the base is usually about 0.1 to 10 normal, preferably 2 to 10 normal.
The reaction time depends on the reaction temperature, but is usually about 1 hour to 24 hours, preferably about 2 hours to 10 hours.

The thus-obtained compound (I '), (VI) or (IX) having a primary or secondary amino group or a salt thereof may have a substituent on the primary or secondary amino group. By introducing a hydrocarbon group, it is possible to produce a compound (I ′), (VI) or (IX) or a salt thereof in which an amino group is substituted with a hydrocarbon group which may have a substituent. . The compound (I '), (VI) or (IX) having a primary or secondary amino group or a salt thereof used as a raw material compound can be obtained by a known method such as concentration, liquid conversion, phase transfer, solvent extraction, and fractionation. It can be used after isolation and purification by distillation, crystallization, recrystallization, chromatography and the like, but may be used as a raw material as it is without isolation. That is, a compound (I ′), (VI) or (IX) having a primary or secondary amino group or a salt thereof and a compound represented by the formula R ⁷ -Z ³ (XIII) wherein R ⁷ has a substituent And Z ³ represents a leaving group. Compound (I ′), (VI) or (IX) in which the amino group is also substituted by a hydrocarbon group which may have a substituent by reaction with the compound represented by the formula
Alternatively, a salt thereof can be produced. As the optionally substituted hydrocarbon group represented by R ^{7, for example} , the optionally substituted hydrocarbon groups described for R ² , R ³ and R ⁶ can be used.

The leaving group represented by Z ³ includes, for example, a halogen atom (eg, chloro, bromo, iodo),
Examples include _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy), C _6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy) and the like.
Particularly, for example, a halogen atom (for example, chloro or the like) is preferable. The above reaction is carried out with or without a solvent and, if necessary, in the presence of a base. Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, and sodium hydride, and pyridine, 4-dimethylaminopyridine, triethylamine and the like. Organic bases are used. When a solvent is used, examples of the solvent include lower alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol and t-butanol, ethers such as dioxane, ether and tetrahydrofuran, and aromatic compounds such as toluene, benzene and xylene. Reaction progress such as aromatic hydrocarbons, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, amides such as dimethylformamide, dimethylacetamide and hexamethylphosphonotriamide, and esters such as ethyl acetate and butyl acetate Solvents that do not interfere with This reaction is carried out under cooling (about 0 ° C. to 10 ° C.), at room temperature (about 10 ° C. to 40 ° C.) or under heating (about 40 ° C. to
0 ° C.), and the reaction time is generally from 10 minutes to
48 hours, preferably 2 to 16 hours. The amount of the compound (XIII) used is preferably 0.3 to 5.0 times the amount of the compound (I '), (VI) or (IX) having a primary or secondary amino group or a salt thereof. Is a mole. When a base is used, the amount of the base used is usually the compound (I ′), (VI) or (I) having a primary or secondary amino group.
X) or about an equimolar amount to an excess amount based on the salt thereof,
Preferably, it is used in a molar amount of 1.1 to 5 times.

The reaction is further carried out, if desired, with an iodide compound,
For example, the reaction may be promoted in the presence of sodium iodide, potassium iodide, lithium iodide and the like. When the reaction is carried out in the presence of these iodine compounds, the amount used is generally 1 to 5 molar equivalents, preferably 1.1 to 1.5 molar equivalents, relative to compound (XI). Compound (XIII)
Can be produced by a method known per se or a method analogous thereto.

The compound (I) or a salt thereof, which is a novel compound, can be produced in the same manner as the method used for producing the compound (I ') or a salt thereof. The compound (I) or compound (I ') thus obtained can be converted to a free form or another salt according to a conventional method when a free form is formed. Can also. Compound (I) or compound (I ') obtained
Alternatively, the salt thereof can be isolated and purified by known means as described above. The compound (I) or (I ′) or a salt thereof includes stereoisomers based on the presence of an asymmetric carbon atom. These are also known by the above-mentioned means or by fractional recrystallization, optically active columns. Can be isolated and purified by a means such as chromatography. The compound (I) or (I ′) or a salt thereof of the present invention acts on the central nervous system of mammals, has a strong cholinesterase inhibitory activity, and has various amnestic inducing effects in humans or animals (eg, mice). It shows an excellent anti-amnesic effect. Further, the compound (I) or (I ′) of the present invention or a salt thereof has a monoamine (eg, norepinephrine or serotonin) reuptake inhibitory activity, and has an excellent antidepressant effect in humans or animals. The action of The compound (I) or (I ′) or a salt thereof of the present invention has an excellent effect of separating the action on the central nervous system and the action on the peripheral nerve compared with physostigmine, and has an effect such as an antiamnestic effect and an antidepressant effect. At the indicated doses, peripheral nerve effects such as convulsions, salivation, and diarrhea are absent or very slight, have a long duration of action, low toxicity, and are remarkably effective when administered orally. The acute toxicity (LD ₅₀ ) of the compound (I) or (I ′) or a salt thereof of the present invention is 100 mg / kg or more. Therefore, the compound of the present invention is useful as a drug for improving brain function in mammals including humans.

The useful target names of the compounds of the present invention include, for example, senile dementia, Alzheimer's disease, Huntington's disease, hyperkinetic disease, mania and the like. Can be used for treatment. The compounds of this invention can be formulated orally with pharmaceutically acceptable carriers or excipients and administered orally or parenterally to mammals, including humans. The dosage form of the preparation may be any of an oral preparation (eg, powder, tablet, granule, capsule) and a parenteral preparation (eg, suppository, injection). These preparations can be prepared by a method known per se. The dose varies depending on the type of the target disease, symptoms, etc., but in general, for an adult (body weight 70 kg), in the case of oral administration, about 0.01 mg to 50 mg, preferably 0.1 to 30 mg per day, More preferably, it is 0.5 to 10 mg.

[0106]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Formulation Examples, and Experimental Examples, but the present invention is not limited thereto. Elution in column chromatography in Experimental Examples and Reference Examples was performed under observation by TLC (Thin Layer Chromatography, thin layer chromatography) unless otherwise specified. In the TLC observation, Merck was used as a TLC plate.
A solvent used as an elution solvent in column chromatography was used as a developing solvent for 60F ₂₅₄ manufactured by the company, and a UV detector was adopted as a detection method. Also, the phenomenon of spraying a 48% HBr onto a spot on a TLC plate, heating and hydrolyzing, spraying a ninhydrin reagent and heating again to change from red to reddish purple is also used as a detection method. The eluted fractions containing the product were identified and collected. Unless otherwise specified, silica gel for columns is Kieselgel 6 manufactured by Merck.
0 (70-230 mesh) was used. "Normal temperature"
Alternatively, “room temperature” usually means about 5 ° C. to 40 ° C., and “normal pressure” means around one atmosphere. Also,
Unless otherwise specified,% indicates weight percentage and C ₄ H ₄ O ₄ indicates fumaric acid.

Reference Example 1 1-Formyl-1,2,2a, 3,4,5-hexahydrobenz [cd] indole

Embedded image (1) 1-benzoyl-1,2,2a, 3,4,5-hexahydrobenz [cd] indol-5-one 5.0 g, potassium hydroxide 2.7 g, hydrazine-hydrate 2 ml, and ethylene The mixture of 20 ml of glycol was heated at 120 ° C. for 2 hours and further at 190 ° C. for 3 hours. After cooling, water was added and the product was extracted with dichloromethane. After the extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure.
The obtained residue is subjected to silica gel column chromatography (developing solvent: dichloromethane-ethyl acetate = 10: 1).
(v / v)), and 1.9 g of 1,2,2a, 3,4,5-hexahydrobenz [cd] indole was melted at a melting point of 58-5.
Obtained as colorless crystals at 9 ° C. Elemental analysis calculated as C ₁₁ H ₁₃ N Calculated: C, 82.97; H, 8.23; N,
8.80 experimental: C, 83.02; H, 8.18; N,
8.80 (2) 6 ml of acetic anhydride was added dropwise to 18 ml of formic acid, and the mixture was stirred at room temperature for 20 minutes. A solution of 1.6 g of 1,2,2a, 3,4,5-hexahydrobenz [cd] indole obtained in (1) in 2 ml of dichloromethane was added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted with dichloromethane. After the extract was washed with a 5% aqueous sodium hydroxide solution and then with water, the solvent was distilled off under reduced pressure. The obtained crystals were recrystallized from dichloromethane-ether to give the title compound having a melting point of 93-.
Obtained as colorless crystals at 94 ° C. Elemental analysis calculated as C ₁₂ H ₁₃ NO Calculated: C, 76.98; H, 7.00; N,
7.48 Found: C, 76.94; H, 7.01; N,
7.52

Reference Example 2 3-chloro- (1-formyl-1,2,2a, 3,4,5-
Hexahydrobenz [cd] indol-6-yl) -1
-Propanone

Embedded image 1-formyl-1,2,2a, 3,4,5- obtained in Reference Example 1
1.4 g of aluminum chloride was added little by little to 10 ml of a solution of 0.8 g of hexahydrobenz [cd] indole and 0.55 g of 3-chloropropionic chloride in 1,2-dichloroethane, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into ice water, and the product was extracted with dichloromethane. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate-dichloromethane = 1).
0: 3: 1 (v / v)) to give 0.7 g of the title compound.
Was obtained as colorless crystals having a melting point of 82-85 ° C. Elemental analysis: C ₁₅ H ₁₆ ClNO ₂ Calculated: C, 64.87; H, 5.81; N,
5.04 Experimental: C, 64.98; H, 5.84; N,
4.99

Reference Example 3 3-chloro-1- (benzofuran-2-yl) -1-propanone

Embedded image By performing the same operation as in Reference Example 2 using dibenzofuran and 3-chloropropionic chloride, the title compound was obtained as colorless crystals having a melting point of 116 to 118 ° C. Elemental analysis: C ₁₅ H ₁₁ ClO ₂ Calculated: C, 69.64; H, 4.29 Experimental: C, 69.80; H, 4.25

Reference Example 4 3-chloro-1- (2-oxo-1,2,2a, 3,4,5
-Hexahydrobenz [cd] indol-6-yl)-
1-propanone

Embedded image 2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) -one and 3-chloropropionic chloride were used to carry out the same operation as in Reference Example 2 to give the title compound having a melting point of 175-178. C. as colorless needles. Elemental analysis: C ₁₄ H ₁₄ ClNO ₂ Calculated: C, 63.76; H, 5.35; N,
5.31, experimental: C, 63.58; H, 5.29; N,
5.33

Reference Example 5 3-chloro-1- (3-carbazolyl) -1-propanone

Embedded image To a nitromethane solution (90 ml) of 5.0 g of carbazole and 4.2 g of 3-chloropropionyl chloride was added 4.8 g of aluminum chloride little by little, and the mixture was stirred at 45 ° C for 1 hour. The reaction solution was poured into 100 ml of ice water, and the organic layer was separated.
After washing with 50 ml of a saturated aqueous solution of sodium hydrogen carbonate and 50 ml of pure water and drying over anhydrous sodium sulfate, the solvent was distilled off to obtain a crystalline residue. The residue was collected by filtration, and the crystals were dried under reduced pressure to give 4.8 g of the title compound as pale red crystals having a melting point of 148-151 ° C. Elemental analysis: C ₁₅ H ₁₂ ClNO Calculated: C, 69.91; H, 4.69; N,
5.43 experimental: C, 69.82; H, 4.76; N,
5.44

Reference Example 6 The same operation as in Reference Example 2 was carried out using a known tricyclic fused heterocycle and 3-chloropropionic acid chloride to obtain
The compounds shown in [Table 52] were obtained.

[Table 52]

Reference Example 7 3- (1-methoxycarbonyl-4-piperidinyl) propionic acid

Embedded image 99.63 g of 3- (1-acetyl-4-piperidinyl) propionic acid was suspended in 208 ml of concentrated hydrochloric acid and stirred under reflux for 6 hours. The solution was concentrated under reduced pressure to a half volume and left at 0 ° C. overnight. The precipitated crystals are collected by filtration, washed with cold ethanol,
Drying gave 77.9 g of 3- (4-piperidinyl) propion hydrochloride. 77.5 g of the obtained crystals were dissolved in 360 ml of dichloromethane and 400 ml of a 3N aqueous sodium hydroxide solution, and 34 ml of methyl chlorocarbonate was added dropwise at 0 ° C.
After stirring at room temperature for 5 hours, the aqueous layer was adjusted to pH 8 with a 50% aqueous sodium hydroxide solution. The organic layer was separated, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from isopropyl ether-hexane to give the title compound 7
6.5 g were obtained as colorless crystals, mp 88-90 ° C. Elemental analysis: C ₁₀ H ₁₇ NO ₄ Calculated: C, 55.80; H, 7.96; N,
6.51 Found: C, 55.69; H, 8.01; N,
6.47

Reference Example 8 8- (4-chlorobutyryl) -1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1-ij] quinolin-4-one

Embedded image 1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1
-Ij] Quinolin-4-one (5 g) and 4-chlorobutyryl chloride (4.15 g) were subjected to the same operation as in Reference Example 2 to give the title compound (6.4 g) having a melting point of 130-13.
Obtained as colorless needles at 1 ° C. Elemental analysis: C ₁₅ H ₁₆ ClNO ₂ Calculated: C, 64.87; H, 5.81; N,
5.04 Experimental: C, 64.71; H, 5.88; N,
4.99

Example 1 1- (1-Formyl-1,2,2a, 3,4,5-hexahydrobenz [cd] indol-6-yl) -3- [1-
(Phenylmethyl) piperazin-4-yl] -1-propanone

Embedded image 3-chloro- (1-formyl-1,2,2) obtained in Reference Example 2
a, 3,4,5-hexahydrobenz [cd] indole-
6-yl) -1-propanone (0.65 g), 0.42 g of potassium carbonate and 20 ml of dichloromethane were added to a suspension of 1-.
5 ml of a methanol solution of 0.41 g of (phenylmethyl) piperazine was added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the residue obtained by evaporating the solvent under reduced pressure, and the product was extracted with dichloromethane. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained oil was purified by silica gel column chromatography (eluent: ethyl acetate-methanol = 10: 1 (v / v)) to give 0.6 g of the title compound as a colorless oil. Elemental analysis: calculated as C ₂₆ H ₃₁ N ₃ O ₂ Calculated: C, 74.79; H, 7.48; N,
10.06 experimental: C, 74.59; H, 7.52; N,
10.03

Example 2 1- (1,2,2a, 3,4,5-hexahydrobenz [c
d] Indol-6-yl) -3- [1- (phenylmethyl) piperazin-4-yl] -1-propanone trihydrochloride

Embedded image 1- (1-formyl-1,2,2a, 3,
4,5-hexahydrobenz [cd] indol-6-yl) -3- [1- (phenylmethyl) piperazine-4-
[Il] -1-propanone 0.4m methanol solution 10m
To this was added 10 ml of 3N hydrochloric acid, and the mixture was stirred at room temperature for 30 minutes. After methanol was distilled off under reduced pressure, a 10% aqueous sodium hydroxide solution was added to adjust the pH of the solution to about 10, and the product was extracted with dichloromethane. After the extract was dried over anhydrous sodium sulfate, 0.8 ml of 4N methanolic hydrochloric acid was added. The solid obtained by evaporating the solvent under reduced pressure was crystallized from methanol-ether to obtain 0.46 g of the title compound.
Was obtained as colorless crystals having a melting point of 207 to 211 ° C. (decomposition). Elemental analysis calculated as C ₂₅ H ₃₁ N ₃ O.3HCl Calculated: C, 60.18; H, 6.87; N,
8.42 experimental: C, 59.98; H, 7.01; N,
8.22

Example 3 3- (1-acetylpiperidin-4-yl) -1- (1
-Formyl-1,2,2a, 3,4,5-hexahydrobenz [cd] indol-6-yl) -1-propanone

Embedded image 1-formyl-1,2,2a, 3,4,5- obtained in Reference Example 1
0.8 g of hexahydrobenz [cd] indole and 3-
To a solution of 1.2 g of (1-acetylpiperidin-4-yl) propionyl chloride in 10 ml of 1,2-dichloroethane,
2.0 g of aluminum chloride was added little by little, and the mixture was refluxed for 2 hours. The reaction solution was poured into ice water, and the product was extracted with dichloromethane. After drying the extract over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-methanol = 20: 1 (v / v)) to obtain 1.0 g of the title compound as a viscous oil. Calculated elemental analysis _{C 22 H 28 N 2 O 3} : C, 71.71; H, 7.66; N,
7.60 experimental: C, 71.47; H, 7.58; N,
7.57

Example 4 1- (1,2,2a, 3,4,5-hexahydrobenz [c
d] Indol-6-yl) -3- [1- (phenylmethyl) piperidin-4-yl] -1-propanone dihydrochloride

Embedded image 3- (1-Acetylpiperidin-4-yl) -1- (1-formyl-1,2,2a, 3,4,5-hexahydrobenz [cd] indol-6-yl) obtained in Example 3. -1-
A mixture of 0.4 g of propanone and 10 ml of concentrated hydrochloric acid was heated under reflux for 8 hours. The residue obtained by evaporating the concentrated hydrochloric acid under reduced pressure was dissolved in water, and the pH was adjusted to about 11 by adding a 10% aqueous sodium hydroxide solution. After the product was extracted with dichloromethane and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained oil was dissolved in 10 ml of ethanol, 0.2 g of potassium carbonate was added, and 2 ml of an ethanol solution of 0.17 g of benzyl bromide was added dropwise. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the product was extracted with dichloromethane.
The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained oil is subjected to silica gel column chromatography (developing solvent: dichloromethane-ethyl acetate =
Purification by 2: 1 (v / v)) afforded the free base of the title compound as a colorless oil. To the obtained oil was added 0.6 ml of 4N methanolic hydrochloric acid, and the solvent was distilled off to obtain 0.36 g of the title compound as an amorphous powder. Elemental analysis: calculated as C ₂₆ H ₃₂ N ₂ O.2HCl Calculated: C, 67.67; H, 7.43; N,
6.07 Experimental: C, 67.43; H, 7.44; N,
6.02

Example 5 1- (Dibenzofuran-2-yl) -3- [1- (phenylmethyl) piperazin-4-yl] -1-propanone

Embedded image 3-chloro-1- (dibenzofuran-2) obtained in Reference Example 3
By performing the same operation as in Example 1 using-(yl) -1-propanone and 1- (phenylmethyl) piperazine, the title compound was obtained as colorless crystals having a melting point of 135 to 136 ° C. Elemental analysis: calculated as C ₂₆ H ₂₆ N ₂ O ₂ Calculated: C, 78.36; H, 6.58; N,
7.03 Experimental: C, 78.21; H, 6.60; N,
6.99

Example 6 1- [1- (phenylmethyl) -1,2,2a, 3,4,5
-Hexahydrobenz [cd] indol-6-yl]-
3- [1- (phenylmethyl) piperidin-4-yl]
-1-propanone fumarate

Embedded image 1- (1,2,2a, 3,4,5-hexahydrobenz [c
d] Indol-6-yl) -3- [1- (phenylmethyl) piperidin-4-yl] -1-propanone 0.5
0.23 g of potassium carbonate was added to 10 ml of an ethanol solution of g, and 2 ml of an ethanol solution of 0.22 g of benzyl bromide was further added dropwise. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the product was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was purified by silica gel column chromatography (developing solvent: ethyl acetate-methanol = 40: 1 (v / v)) to give 0.47 g of the free base of the title compound, melting point 143-14.
Obtained as colorless crystals at 6 ° C. Elemental analysis: calculated as C ₃₃ H ₃₈ N ₂ O: C, 82.80; H, 8.00; N,
5.85 experimental: C, 82.71; H, 8.02; N,
5.74 Fumaric acid 1 was added to 5 ml of dichloromethane solution of the obtained crystals.
A solution of 14 mg in 5 ml of methanol was added, and the solvent was distilled off under reduced pressure to obtain 0.53 g of the title compound.
Obtained as colorless crystals at 166 ° C. Elemental analysis _{C 33 H 38 N 2 O ·} C 4 H 4 O 4 · 1 / 2H 2 O
Calculated: C, 73.61; H, 7.18; N,
4.64 experimental: C, 73.43; H, 7.04; N,
4.71

Example 7 In the same manner as in Example 6, the compounds shown in [Table 53] were obtained.

[Table 53]

Example 8 1- (1-Acetyl-1,2,2a, 3,4,5-hexahydrobenz [cd] indol-6-yl] -3- [1-
(Phenylmethyl) piperidin-4-yl] -1-propanone fumarate

Embedded image 1- (1,2,2a, 3,4,5-hexahydrobenz [c
d] Indol-6-yl) -3- [1- (phenylmethyl) piperidin-4-yl] -1-propanone 0.5
0.14 g of acetic anhydride was added to 10 ml of a dichloromethane solution of the above, and the mixture was stirred at room temperature for 30 minutes. 20 ml of a 5% aqueous sodium hydroxide solution was added to the reaction solution, and the product was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-methanol = 20: 1 (v / v)) to obtain 0.48 g of a free base of the title compound as a colorless powder. To 5 ml of a dichloromethane solution of the obtained powder was added 5 ml of a methanol solution of 0.13 g of fumaric acid, and the solvent was distilled off under reduced pressure to obtain 0.54 g of the title compound as colorless crystals having a melting point of 173-175 ° C. Elemental analysis: C ₂₈ H ₃₄ N ₂ O ₂ · C ₄ H ₄ O ₄ Calculated: C, 70.31; H, 7.01; N,
5.12 Experimental: C, 70.11; H, 7.16; N,
5.13

Example 9 1- (2-oxo-2a, 3,4,5-tetrahydro-1
H-benz [cd] indol-6-yl] -3- [4-
(Phenylmethyl) piperazin-1-yl] -1-propanone dihydrochloride

Embedded image The same operation as in Example 1 was performed using the compound obtained in Reference Example 4 to obtain a free base of the title compound.
The obtained free base was converted into the dihydrochloride by the method described in Example 2 to give the title compound having a melting point of 185-188.
As colorless crystals. Elemental analysis: C ₂₅ H ₂₉ N ₃ O ₂ .2HCl Calculated: C, 63.02; H, 6.56; N,
8.82 experimental: C, 62.88; H, 6.57; N,
8.75

Example 10 1- (3-Carbazolyl) -3- (4-benzylpiperazin-1-yl) -1-propanone dihydrochloride

Embedded image 2.1 g of 3-chloro-1- (3-carbazolyl) -1-propanone obtained in Reference Example 5 was added to 50 ml of dichloromethane.
, 1.7 g of potassium carbonate and 4.4 g of 1-benzylpiperazine were added, and the mixture was stirred at room temperature for 4 hours. 30m pure water
The organic layer was separated, washed with 50 ml of pure water and dried over anhydrous sodium sulfate. The crystals obtained by evaporating the solvent were dried under reduced pressure to give 3.0 g of the title compound as free colorless crystals having a melting point of 124 to 126 ° C. 3.0 g of the obtained free compound was dissolved in methanol, and 4.0 ml of 4N methanolic hydrochloric acid was added. The solid obtained by evaporating the solvent under reduced pressure was washed with methanol to obtain 2.8 g of the title compound as pale red crystals having a melting point of 206 to 208 ° C. Elemental analysis: C ₂₆ H ₂₇ N ₃ O.2HCl.1 / 2H ₂ O Calculated: C, 65.13; H, 6.31; N,
8.76 experimental: C, 65.13; H, 6.23; N,
8.72

Example 11 1- (3-carbazolyl) -3- (1-acetylpiperidin-4-yl) -1-propanone

Embedded image 9.3 g of aluminum chloride was added little by little to 90 ml of a nitromethane solution of 5.0 g of carbazole and 7.2 g of 3- (1-acetylpiperidin-4-yl) propionyl chloride, and the mixture was stirred at 70 ° C. for 11 hours. 100 ml of ice water
The organic layer was separated, washed with 50 ml of a saturated aqueous solution of sodium hydrogencarbonate and 50 ml of pure water, dried over anhydrous sodium sulfate and evaporated to obtain an oily residue. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol = 20: 1 (v / v)) to give 2.6 g of the title compound as a pale yellow powder. Elemental analysis: calculated as C ₂₂ H ₂₄ N ₂ O ₂ Calculated: C, 75.83; H, 6.94; N,
8.04 Found: C, 75.77; H, 6.98; N,
7.96

Example 12 1- (3-carbazolyl) -3- (4-piperidinyl)
-1-propanone

Embedded image 1- (3-carbazolyl) -3- (1) obtained in Example 11
-Acetylpiperidin-4-yl) -1-propanone (2.1 g) in concentrated hydrochloric acid was stirred under reflux for 19 hours. The solvent was distilled off to obtain a crystalline residue. Part of the residue (about 0.25
g) The crystals were collected by filtration and the crystals were dried under reduced pressure to obtain 0.24 g of the monohydrochloride of the title compound as pale blue crystals having a melting point of 243-247 ° C (decomposition). Elemental analysis _{C 20 H 22 N 2 O ·} HCl · 1 / 2H 2 O Calculated: C, 68.27; H, 6.87 ; N,
7.96 experimental: C, 68.56; H, 6.60; N,
7.99 The remaining residue is dissolved in pure water (20 ml), and 10% aqueous sodium hydroxide solution (10 ml) and dichloromethane (20 ml) are added.
The organic layer was separated, washed with 30 ml of pure water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting crystals were dried under reduced pressure to obtain 1.2 g of the title compound as pale yellow crystals having a melting point of 206-209 ° C. As obtained. Elemental analysis: calculated as C ₂₀ H ₂₂ N ₂ O: C, 78.40; H, 7.24; N,
9.14 experimental: C, 78.35; H, 7.31; N,
9.08

Example 13 1- (3-Carbazolyl) -3- [1- (phenylmethyl) piperidin-4-yl] -1-propanone hydrochloride

Embedded image 0.7 g of N, N of 1- (3-carbazolyl) -3- (piperidin-4-yl) -1-propanone obtained in Example 12
-Dimethylformamide-dichloromethane (3/1 (v
/ V)) 0.41 g of potassium carbonate was added to the mixed solution, and 1
After stirring at 5 ° C for 15 minutes, a solution of 0.37 g of benzyl bromide in 3 ml of dichloromethane was added dropwise, and the mixture was stirred at room temperature for 2.5 hours. After the solvent was distilled off, 30 ml of pure water and 30 ml of dichloromethane were added, the organic layer was separated, washed with 50 ml of pure water and dried over anhydrous sodium sulfate. The crystals obtained by distilling off the solvent were dried under reduced pressure to obtain 0.69 of the free base form of the title compound.
g were obtained as colorless crystals with a melting point of 155-158 ° C. 0.55 g of the obtained free base was dissolved in methanol and 4N
0.5 ml of methanolic hydrochloric acid was added, and the solvent was distilled off under reduced pressure. The obtained solid was washed with ethanol to give the title compound (0.5).
2 g were obtained as pale blue crystals with a melting point of 206-208 ° C. Elemental analysis _{C 27 H 28 N 2 O ·} HCl · 1 / 2H 2 O Calculated: C, 73.37; H, 6.84 ; N,
6.34 experimental values: C, 73.46; H, 6.77; N,
6.46

Example 14 3- (1-acetylpiperidin-4-yl) -1-
(1,2,2a, 3,4,5-hexahydrobenz [cd] indol-6-yl) -1-propanone

Embedded image 1) 1-formyl-1,2,2a, 3,4,5-hexahydrobenz [cd] indole (compound of Reference Example 1) 17 g
By performing the same operation as in Example 3 using
(1-acetylpiperidin-4-yl) -1- (1-formyl-1,2,2a, 3,4,5-hexahydrobenz [c
d] 20 g of indol-6-yl) -1-propanone were obtained. 2) 150 ml of a methanol solution of 20 g of the compound obtained in 1)
And a mixed solution of 150 ml of 10% hydrochloric acid were stirred at room temperature for 30 minutes. After the methanol was distilled off under reduced pressure, the pH of the solution was adjusted to about 10 using a 10% aqueous sodium hydroxide solution,
The product was extracted with dichloromethane. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 17 g of crude crystals of the title compound. Further, recrystallization from dichloromethane-ether gave 9.8 g of colorless crystals having a melting point of 167-169 ° C. Elemental analysis: C ₂₁ H ₂₈ N ₂ O ₂ Calculated: C, 74.08; H, 8.29; N,
8.23 experimental values: C, 73.79; H, 8.33; N,
8.12

Example 15 1- (1-Ethyl-1,2,2a, 3,4,5-hexahydrobenz [cd] indol-6-yl) -3- [1- (phenylmethyl) piperidine-4 -Yl] -1-propanone fumarate

Embedded image 1) 3- (1-acetylpiperidine- obtained in Example 14
4-yl) -1- (1,2,2a, 3,4,5-hexahydrobenz [cd] indol-6-yl) -1-propanone 1.0 g, ethyl iodide 2.3 g and potassium carbonate 0 .5
10 ml of a 3 g ethanol suspension was stirred at 60-70 ° C for 12 hours. Water was added to the residue obtained by evaporating the solvent under reduced pressure, and the product was extracted with dichloromethane. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) to give 3- (1-acetylpiperidin-4-yl) -1- (1-ethyl-1,
0.82 g of 2,2a, 3,4,5-hexahydrobenz [cd] indol-6-yl) -1-propanone was obtained as a colorless oil. Elemental analysis: calculated as C ₂₃ H ₃₂ N ₂ O ₂ Calculated: C, 74.96; H, 8.75; N,
7.60 experimental: C, 74.88; H, 8.74; N,
7.62 2) Using 0.75 g of the compound obtained in 1), the same operation as in Example 4 was performed to obtain 0.65 g of the free base of the title compound. 5 ml of a methanol solution of 0.18 g of fumaric acid was added to 5 ml of a dichloromethane solution of 0.65 g of the obtained free base, and the solvent was distilled off under reduced pressure. 68 g were obtained as colorless crystals with a melting point of 177-178 ° C. Elemental analysis _{C 28 H 36 N 2 O ·} C 4 H 4 O 4 · 3 / 2H 2 O
Calculated: C, 68.67; H, 7.74; N,
5.01 experimental: C, 69.05; H, 7.50; N,
5.26

Example 16 Using the compound obtained in Example 14, the same operation as in Example 15 was performed to obtain the compound shown in [Table 54].

[Table 54]

Example 17 By using the compound obtained in Reference Example 6 and performing the same operation as in Example 1, the compounds shown in [Table 55] and [Table 56] were obtained.

[Table 55]

[Table 56]

Example 18 1- (2-oxo-1H-benz [cd] indole-6
-Yl) -3- [4- (phenylmethyl) piperazine-
1-yl] -1-propanone dihydrochloride

Embedded image 1) Benz [cd] indole-2 (1H) -one 7.5
g and 6.2 g of 3-chloropropionic acid chloride, and the same operation as in Reference Example 2 was carried out.
1- (2-oxo-1H-benz [cd] indole-6
4.8) about a 1: 1 mixture of -yl) -1-propanone and unreacted benz [cd] indol-2 (1H) -one.
g was obtained. 2) 0.68 g of 1-benzylpiperazine and 0.34 g of potassium carbonate were added to a mixed solution (2 ml / 20 ml) of 1.0 g of the mixture obtained in 1) in dimethylformamide-dichloromethane.
Was added and stirred at room temperature for 1 hour. Water was added to the residue obtained by evaporating the solvent under reduced pressure, and the product was extracted with dichloromethane. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue is subjected to silica gel column chromatography [developing solvent: ethyl acetate-methanol = 1.
0: 1 (V / V)] to obtain a fraction containing the target compound. The solvent was distilled off under reduced pressure to obtain 0.52 g of a free base of the title compound as a colorless powder having a melting point of 208 to 210 ° C. The obtained free base was converted into a dihydrochloride by the method described in Example 2 to obtain 0.51 g of the title compound as colorless crystals having a melting point of 166 to 170 ° C. Elemental analysis: C ₂₅ H ₂₅ N ₃ O ₂ .2HCl.3 / 2H ₂ O Calculated: C, 60.12; H, 6.05; N,
8.41 experimental: C, 60.17; H, 6.25; N,
8.19

Example 19 In the same manner as in Example 18, the compounds shown in [Table 57] were obtained.

[Table 57]

Example 20 1- (1,2,2a, 3,4,5-hexahydrobenz [cd] indol-6-yl) -3- [1-
The compound shown in [Table 58] was obtained by performing the same operation as in Example 8 using (phenylmethyl) piperidin-4-yl] -1-propanone.

[Table 58]

Example 21 8- [3- (4-Formyl-1-piperazinyl) -1-
Oxopropyl] -5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-2 (1H) -one

Embedded image Reference Example 6 8- (3-chloropropionyl) -5,6-dihydro-4H-pyrrolo [3,2,1-i of Compound No. 2
j] Example 1 was prepared using 13.8 g of quinolin-2 (1H) -one and 7.8 g of 1-piperazinecarboxaldehyde.
By performing the same operation as in 11.0 g of the title compound,
Was obtained as a colorless powder having a melting point of 143-147 ° C. Elemental analysis: C ₁₉ H ₂₃ N ₃ O ₃ Calculated: C, 66.84; H, 6.79; N,
12.31 experimental: C, 66.69; H, 6.79; N,
12.07

Example 22 8- [3- (1-Piperazinyl) -1-oxopropyl] -5,6-dihydro-4H-pyrrolo [3,2,1-i
j] Quinoline-2 (1H) -one

Embedded image 8- [3- (4-Formyl-1-piperazinyl) -1-oxopropyl] -5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-2 (1H) obtained in Example 21 )
10-ml concentrated hydrochloric acid in a solution of 9.0 g of -one in 30 ml of methanol
Was added and stirred at room temperature for 14 hours. The aqueous solution obtained by distilling off methanol under reduced pressure was washed with ethyl acetate, and the pH of the solution was adjusted to about 11 by adding an aqueous solution of sodium hydroxide, followed by extraction with dichloromethane. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 6.3 g of the title compound as a colorless amorphous powder. Elemental analysis: C ₁₈ H ₂₃ N ₃ O ₂ Calculated: C, 68.98; H, 7.40; N,
13.41 experimental: C, 69.02; H, 7.38; N,
13.25

Example 23 8- [3- [4-[(2-methylphenyl) methyl]-
1-piperazinyl] -1-oxopropyl] -5,6-
Dihydro-4H-pyrrolo [3,2,1-ij] quinoline-2
(1H) -one dihydrochloride

Embedded image 8- [3- (1-Piperazinyl) -1 obtained in Example 22
-Oxopropyl] -5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-2 (1H) -one 0.34
g and 0.19 g of 2-methylbenzyl bromide in 10 ml of dichloromethane were stirred at room temperature for 6 hours. The residue obtained by evaporating the solvent was dissolved in a 10% aqueous hydrochloric acid solution, and washed with ethyl acetate. An aqueous solution of sodium hydroxide was added to the aqueous layer to adjust the pH of the solution to about 11, followed by extraction with dichloromethane. After the extract is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the residue obtained is subjected to silica gel column chromatography (developing solvent: ethyl acetate-methanol =
Purification by 10: 1 (V / V)) provided 0.32 g of the free base of the title compound as an anhydrous oil. To this oil was added 0.5 ml of 4N methanolic hydrochloric acid, and the solvent was distilled off to give 0.34 g of the title compound, melting point 205-20.
Obtained as colorless crystals at 8 ° C. Elemental analysis: C ₂₆ H ₃₁ N ₃ O ₂ .2HCl.H ₂ O Calculated: C, 61.41; H, 6.94; N,
8.26 Experimental: C, 61.64; H, 6.76; N,
8.25

Example 24 8- [3- (4-Formyl-1-piperazinyl) -1-
Oxopropyl] -1,2,5,6-tetrahydro-4H
-Pyrrolo [3,2,1-ij] quinolin-4-one

Embedded image Reference Example 6 8- (3-chloropropionyl) -1,2,5,6-tetrahydro-4H-pyrrolo [3,
2,1-ij] quinolin-4-one (20.0 g) and 1-piperazinecarboxaldehyde (11.4 g) were subjected to the same operation as in Example 1 to give the title compound (20.4).
g were obtained as a colorless powder. Elemental analysis: C ₁₈ H ₂₃ N ₃ O ₂ Calculated: C, 66.84; H, 6.79; N,
12.31 experimental: C, 66.79; H, 6.58; N,
12.05

Example 25 8- [3- (1-Piperazinyl) -1-oxopropyl] -1,2,5,6-tetrahydro-4H-pyrrolo [3,
2,1-ij] quinolin-4-one

Embedded image 8- [3- (4-Formyl-1-piperazinyl) -1-oxopropyl] -1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1-ij] quinoline obtained in Example 24 −
The same operation as in Example 22 was performed using 20 g of 4-one to obtain 14.0 g of the title compound as a colorless powder. Elemental analysis: C ₁₈ H ₂₃ N ₃ O ₂ Calculated: C, 68.98; H, 7.40; N,
13.41 experimental values: C, 68.69; H, 7.29; N,
13.27

Example 26 8- [3- (1-Methoxycarbonyl-4-piperidinyl) -1-oxopropyl] -1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1-ij] Quinolin-4-one

Embedded image 65.6 g of 3- (1-methoxycarbonyl-4-piperidinyl) propionic acid obtained in Reference Example 7 was added to thionyl chloride 1
It was added in small portions to 09 ml at 0-5 ° C. The resulting solution is
After stirring at −5 ° C. for a further 20 minutes, thionyl chloride was distilled off under reduced pressure. The obtained residue and 1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1-ij] quinoline-4-
The same operation as in Reference Example 2 was carried out using 43.3 g of ON to give 34.0 g of the title compound, melting point 139-14.
Obtained as colorless crystals at 0 ° C. Elemental analysis: C ₂₁ H ₂₆ N ₂ O ₄ Calculated: C, 68.09; H, 7.07; N,
7.56 Found: C, 68.21; H, 7.01; N,
7.29

Example 27 8- [3- (4-Piperidinyl) -1-oxopropyl] -1,2,5,6-tetrahydro-4H-pyrrolo [3,
2,1-ij] quinolin-4-one

Embedded image 8- [3- (1-Methoxycarbonyl-4-piperidinyl) -1-oxopropyl] -1,2, obtained in Example 26
5,6-tetrahydro-4H-pyrrolo [3,2,1-ij]
34.0 g of quinolin-4-one was dissolved in 200 ml of methanol and 400 ml of concentrated hydrochloric acid, and the mixture was stirred under reflux for 16 hours. After cooling, methanol was distilled off under reduced pressure, and the residue was adjusted to pH 8 to 9 with a 50% aqueous sodium hydroxide solution. After extracting twice with 500 ml of dichloromethane, the extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diethyl ether-ethyl acetate to give 28.3 g of the title compound.
Was obtained as colorless crystals having a melting point of 114-116 ° C. Elemental analysis: C ₁₉ H ₂₄ N ₂ O ₂ Calculated: C, 73.05; H, 7.74; N,
8.97 experimental: C, 73.21; H, 7.65; N,
8.99

Example 28 8- [3- (1-Methoxycarbonyl-4-piperidinyl) -1-oxopropyl] -5,6-dihydro-4H
-Pyrrolo [3,2,1-ij] quinolin-2 (1H) -one

Embedded image 3- (1-methoxycarbonyl-4-piperidinyl) propionic acid obtained in Reference Example 7 and a known 5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-2 (1H)
The title compound was obtained as colorless crystals having a melting point of 140 to 141 ° C by performing the same operation as in Example 26 using -on. Elemental analysis: C ₂₁ H ₂₆ N ₂ O ₄ Calculated: C, 68.09; H, 7.07; N,
7.56 Found: C, 68.00; H, 7.12; N,
7.73

Example 29 8- [3- (4-Piperidinyl) -1-oxopropyl] -5,6-dihydro-4H-pyrrolo [3,2,1-i
j] Quinoline-2 (1H) -one

Embedded image 8- [3- (1-Methoxycarbonyl-4-piperidinyl) -1-oxopropyl] -5,6 obtained in Example 28
-Dihydro-4H-pyrrolo [3,2,1-ij] quinoline-
The title compound was obtained as a colorless oil by performing the same operation as in Example 27 using 2 (1H) -one. Elemental analysis: C ₁₉ H ₂₄ N ₂ O ₂ Calculated: C, 73.05; H, 7.74; N,
8.97 experimental: C, 73.10; H, 7.58; N,
8.73

Example 30 Using the compound obtained in Example 22 or 25,
By performing the same operation as in Example 23, [Table 59]
To [Table 64], [Table 68] and [Table 69] were obtained (method A). In addition, compounds shown in [Table 63] to [Table 70] were obtained by performing the same operation as in Example 13 using the compound obtained in Example 27 or Example 29 (Method B).

[0145]

[Table 59]

[0146]

[Table 60]

[0147]

[Table 61]

[0148]

[Table 62]

[0149]

[Table 63]

[0150]

[Table 64]

[0151]

[Table 65]

[0152]

[Table 66]

[0153]

[Table 67]

[0154]

[Table 68]

[0155]

[Table 69]

[0156]

[Table 70]

Example 31 By using the compound obtained in Reference Example 6 or Reference Example 8 and performing the same operation as in Example 1, the compounds shown in [Table 71] and [Table 72] were obtained.

[0158]

[Table 71]

[0159]

[Table 72]

Example 32 By using the compound obtained in Example 17 and performing the same operation as in Example 2, the compounds shown in [Table 73] were obtained.

[Table 73]

Example 33 1- (6,7-Dihydro-5H-dibenz [c, e] azepin-3-yl) -3- [4- (phenylmethyl) -1
-Piperidinyl] -1-propanone dihydrochloride

Embedded image Example 31 Example 2 was repeated using the compound of Compound No. 11.
The title compound was obtained as an amorphous powder by performing the same operation as in. Elemental analysis: C ₂₉ H ₃₂ N ₂ O.2HCl.2H ₂ O Calculated: C, 65.28; H, 7.18; N, 5.25 Experimental: C, 65.22; H, 7.08; N, 5.08

Example 34 Using the compound obtained in Example 32 or 33,
The compounds shown in [Table 74] and [Table 75] were obtained by performing the same operations as in Example 6 (Method A) or Example 8 (Method B).

[Table 74]

[Table 75]

Example 35 1- (10-acetyl-10,11-dihydrodibenz [b, f] [1,4] oxazepin-2-yl) -3- [1-
(Phenylmethyl) -4-piperidinyl] -1-propanone hydrochloride

Embedded image The title compound was obtained as a colorless amorphous powder by performing the same operation as in Example 3 using a known 10-acetyl-10,11-dihydrodibenz [b, f] [1,4] oxazepine. . Elemental analysis value: C ₃₀ H ₃₂ N ₂ O ₃ .HCl Calculated value: C, 71.35; H, 6.59; N, 5.55 Experimental value: C, 71.21; H, 6.63; N, 5.50

Example 36 1- (10,11-Dihydrodibenz [b, f] [1,4] oxazepin-2-yl) -3- [1- (phenylmethyl) -4-piperidinyl] -1- Propanone dihydrochloride

Embedded image 1- (10-acetyl-10,11- obtained in Example 35
Same as Example 12 using dihydrodibenz [b, f] [1,4] oxazepin-2-yl) -3- [1- (phenylmethyl) -4-piperidinyl] -1-propanone hydrochloride By operating the title compound, the melting point of 144-
Obtained as colorless crystals at 147 ° C. (decomposition). Elemental analysis: C ₂₈ H ₃₀ N ₂ O ₂ .2HCl 3 / 2H ₂ O Calculated: C, 63.88; H, 6.70; N, 5.32 Experimental: C, 63.98; H, 6.48; N, 5.44

Example 37 Using a known compound, the same procedures as in Example 6 were carried out to obtain the compounds shown in [Table 76].

[Table 76]

Formulation Example 1 (1) 1- (1,2,2a, 3,4,5-hexahydrobenz [cd] indol-6-yl) -3- [1- (phenylmethyl) piperidin-4- Il] -1-propanone 2
Hydrochloride (compound of Example 4) 1 g (2) Lactose 197 g (3) Corn starch 50 g (4) Magnesium stearate 2 g (1) 1 g, (2) 197 g and 20 g of corn starch are mixed, and 15 g of corn starch are mixed. Granulated with a paste made from water and 25 ml of water, to which 15 g of corn starch and 2 g of (4) are added and the mixture is compressed on a compression tablet machine to a diameter containing 0.5 mg of (1) per tablet. 2,000 3 mm tablets were produced.

Formulation Example 2 (1) 1- (1,2,2a, 3,4,5-hexahydrobenz [cd] indol-6-yl) -3- [1- (phenylmethyl) piperidin-4- Il] -1-propanone 2
Hydrochloride (compound of Example 4) 2 g (2) Lactose 197 g (3) Corn starch 50 g (4) Magnesium stearate 2 g (1) 2 g, (2) 197 g and 20 g of corn starch are mixed, and 15 g of corn starch are mixed. Granules with a paste made from water and 25 ml of water, 15 g of corn starch and 2 g of (4) are added and the mixture is compressed on a compression tablet machine to a diameter containing 1.0 mg of (1) per tablet. 2,000 3 mm tablets were produced.

Experimental Example 1 The cholinesterase inhibitory effect of the compound of the present invention was examined using (acetyl- [ ³ H])-acetylcholine. That is, as cholinesterase source, using the S ₁ fraction of male Wistar rat cerebral cortex homogenate as a substrate (acetyl ^[3 H]) - acetylcholine, also adding the compound of the present invention as an object, after the incubation for 30 minutes The reaction was stopped, a toluene-based scintillator was added, and the mixture was shaken. [ ³ H] -acetic acid purified by the reaction was transferred to a toluene layer, and counted by a liquid scintillation counter to determine the cholinesterase inhibitory activity. The cholinesterase inhibitory activity of the test compound was represented by a 50% inhibitory concentration (IC ₅₀ ). The cholinesterase inhibitory activity of physostigmine was also measured by the same method. Table 7 shows the obtained results.
7].

[0169]

[Table 77] Compound Acetylcholinesterase (Example No.) Inhibitory activity IC ₅₀ (μM) ４40.0918 16 -1 0.154 17-1 0.0030 17-2 0.0076 17-3 0.0172 17-4 0.0095 17-5 0.0454 17-6 0.0151 17-7 0.0330 17-8 0.0470 17-9 0.0240 17-10 0.0968 20-1 0.182 23 0.0614 30-1 0.0287 30-3 0.0109 30-4 0.0430 30-10 0.0189 30 -11 0.0169 30-12 0.0239 30-13 0.1297 30-16 0.0058 30-18 0.0249 30-19 0.0119 30-21 0.0036 30-22 0.0062 30- 24 0.0015 30-25 0.000098 30-26 0.0044 30-27 0.188 30-29 0.0293 30-32 0.0911 30-34 0.0005 30-35 0.0679 30-38 0 0.00018 30-39 0.00050 30-40 0.0000092 30-41 0.00000430-42 0.00004 30-43 0.000065 30-44 0.0599 30-45 0.00000304 30-46 0.00000200 30-47 0.0195 30-48 0.0171 30-52 0.00036 30-53 0.0254 30-54 0.0609 30-56 0.0183 30-58 0.00012 30-59 0.00112 30- 60 0.000078 30-61 0.0156 31-4 0.188 32-1 0.0024 32 2 0.155 32-3 0.0590 34-1 0.0393 34-2 0.0200 34-3 0.171 34-5 0.0316 37-2 0.184 37-4 0.136 37-5 50 0.081 physostigmine 0.220 よ り [Table 77] shows that the compound of the present invention is superior to physostigmine in acetylcholinesterase. It turns out that it has inhibitory activity.

[0170] The monoamine reuptake inhibitory effect Experimental Example 2] The Compound ^[3 H] - norepinephrine (NE) and ^[3 H] - were studied using Serotonin (5-HT). That is, the brain was excised from male JCl: Wistar rats (9-13 weeks old), and the cerebral cortex and the hippocampus were collected. About 10-15 times the volume of ice-cooled 0.32M sucr
Homogenize (Potter type, 5 strokes) with ose,
The supernatant obtained by centrifugation at 1,000 × g for 10 minutes was further centrifuged at 20,000 × g for 20 minutes to obtain a precipitate (P ₂ ). This was added to a Krebs-Ringer bicarbonate (KRB) solution (KRB: 116 mM NaCl, 4.8 mM KCl, 1.3 mM).
M CaCl ₂ , 1.2 mM MgSO ₄ , 1.2 mM NaH ₂ PO
₄ , 25 mM NaHCO ₃ , 0.1 mM EDTA-2Na,
11.1 mM D-glucose, 0.11 mM L-ascorbic ac
id, 0.01 mM pargyline-HCl; 95% O ₂ /5%
(Aerated with CO ₂ ) and aliquots were used for the assay. Test compound (DMSO solution 100 times the final concentration)
After mixing 10 μl and 900 μl of the P ₂ suspension and preincubating at 37 ° C. for 5 minutes, [ ³ H] -NE (final 1)
1 nM) or [ ³ H] -5-HT (final 10 nM) 1
After adding 00 μl, the mixture was incubated at 37 ° C. for 5 minutes.
4 ml of ice-cold KRB was added to the assay tube and immediately filtered under reduced pressure on a Whatman CF / B filter, and the filter was further washed twice with 4 ml of KRB. The filter was transferred to a mini vial, 4 ml of scintillator was added, and the measurement was performed using a liquid scintillation counter. Imipramine was used as a control. All test compounds were at final concentrations of 10 ^-8 , 10 ^-7 , 10 ^-6 , 10 ^-5 M
4 points were tested. The results obtained are shown in [Table 78].

[0171]

[Table 78] Monoamine uptake inhibitory activity IC ₅₀ (μM) Compound --─────────────────── (Example number) NE 5-HT ────── ────────────────────────── 2 0.420 0.594 4 0.347 0.601 19-1 0.328 1.67 23 2.43 0.0668 30-1 4.6 0.0956 30-6 5.96 0.0863 30-8 0.643 0.0607 30-19 2.82 0.066 30-21 1.54 0.05. 0882 30-22 0.795 0.0601 30-25 1.31 0.01117 30-27 0.559 0.0798 30-28 2.81 0.0615 30-36 7.48 0.0468 31-16 .183 0.0463 31-2 0.0738 0.00879 31-4 0.16 0.0207 3 1-11 0.515 0.0694 34-4 0.456 0.969 34-6.481 0.0806 34-8 0.197 0.363 imipramine 1.12 0.063よ り From Table 78, the compound of the present invention shows excellent monoamine equivalent to imipramine which is a control drug It turns out that it has an uptake inhibitory activity.

[0172]

The compound of the present invention has excellent cholinesterase inhibitory activity and monoamine uptake inhibitory activity, and is useful as a therapeutic or preventive drug for senile dementia.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/4545 A61K 31/4545 31/473 31/473 31/4745 31/4745 31/496 31/496 31/506 31/506 31/5377 31/5377 31/55 31/55 31/551 31/551 A61P 25/28 A61P 25/28 43/00 43/00 C07D 209/86 C07D 209/86 209/92 209/92 209/94 209 / 94 211/32 211/32 211/46 211/46 221/14 221/14 221/16 221/16 223/18 223/18 223/20 223/20 223/22 223/22 265/38 265/38 267/20 267/20 279/20 279/20 279/22 279/22 307/91 307/91 311/82 311/82 313/14 313/14 319/08 319/08 327/08 327/08 337 / 14 337/14 401/12 401/12 401/14 401/14 403/12 403/12 405/06 405/06 405/12 405/12 405/14 405/14 409/06 409/06 409/12 409 / 12 411/06 411/06 413/06 413/06 417/06 417/06 417/12 417/12 471/06 471/06 487/04 137 487/04 137 150 150 150 487/06 487/06 491 / 113 491/113 (31) Priority Claim number Japanese Patent Application No. 5-299827 (32) priority date 1993 November 30 (1993.11.30) (33) Priority Country Japan (JP) (58) investigated the field (Int.Cl. ⁷ , DB name) C07D 401/06 C07D 209/86 C07D 209/92 C07D 209/94 C07D 211/32 C07D 211/46 C07D 221/14 C07D 221/16 C07D 223/18 C07D 223/20 C07D 223/22 C07D 265 / 38 C07D 267/20 C07D 279/20 C07D 279/22 C07D 307/91 C07D 311/82 C07D 313/14 C07D 319/08 C07D 327/08 C07D 337/14 C07D 401/12 C07D 401/14 C07D 403/12 C07D 405/06 C07D 405/12 C07D 405/14 C07D 409/06 C07D 409/12 C07D 411/06 C07D 413/06 C07D 417/06 C07D 417/12 C07D 471/06 C07D 487/04 C07D 487/06 C07D 491 / 113 CA (STN) REGISTRY (STN)

Claims (25)

(57) [Claims] (1) Formula (1) Wherein Ar is of the formula : (Wherein ring A may further have a substituent.
Ring, and one of the ring B and the ring C may have a substituent.
A good heterocyclic ring, the other of which may have a substituent,
And represents a 5- to 8-membered ring which may contain a B atom. )so
Represents a condensed tricyclic benzene ring group, n represents an integer of 2 to 10, and R ¹ represents a hydrogen atom or a hydrocarbon group which may have a substituent, and is different in repeating n. And Y represents a 4-piperidinyl group, a 1-piperazinyl group or a 4-benzyl-1-piperidinyl group, each of which may have a substituent. Or a salt thereof. 2. The ring A is (1) C _1-4 Alkyl group, (2)
Halogen atom, (3) nitro group, (4) cyano group,
(5) hydroxy group, (6) C _1-4 An alkoxy group,
(7) C _1-4 Alkylthio group, (8) amino group, (9)
Mono or Di C _1-4 Alkylamino group, (10) one
From nitrogen, oxygen and sulfur atoms other than nitrogen atom
Optionally having 1 to 3 heteroatoms selected
Or a 7-membered cyclic amino group, (11) C _1-4 Alkyl-ka
Rubonylamino group, (12) aminocarbonyloxy
Group, (13) mono or di C _1-4 Alkylamino-cal
Bonyloxy group, (14) C _1-4 Alkylsulfonylua
Mino group, (15) C _1-4 An alkoxy-carbonyl group,
(16) carboxyl group, (17) C _1-6 Alkyl-ka
Rubonyl group, ( 18) C _3-7 Cycloalkyl-carboni
(19) carbamoyl group, (20) mono- or di-C
_1-4 Alkyl-carbamoyl group, (21) C _1-6 Alkyl
Sulfonyl group, (22) C _3-7 Cycloalkylsulfoni
(23) having 1 to 4 substituents
Phenyl, naphthyl, mono- or di-phenyl
-C _1-3 Alkyl, phenoxy, benzoyl, phenoxy
Cicarbonyl, benzylcarbonyl, phenyl-C _1-4
Alkyl-carbamoyl, phenylcarbamoyl,
Nil-C _1-4 Alkyl-carbonylamino, benzoyl
Amino, phenyl-C _1-4 Alkylsulfonyl, phenyl
Rusulfonyl, phenyl-C _1-4 Alkylsulfini
Phenyl-C _1-4 Alkylsulfonylamino or
Phenylsulfonylamino group (each phenyl or
Is naphthyl, C _1-4 Alkyl group, C _1-4 An alkoxy group,
Halogen atom, hydroxy group, benzyloxy group,
No group, mono or di C _1-4 Alkylamino group, nitro
Group, C _1-6 Alkylcarbonyl and benzoyl groups
May have 1 to 4 substituents selected from
May have 1 to 3 substituents selected from
With a benzene ring, One of the rings B and C has a halogen on the ring-constituting carbon atom.
Atom, nitro group, cyano group, oxo group, hydroxy group,
C _1-4 Alkoxy group, C _1-4 Alkylthio group, amino group,
Mono or Di C _1-4 Alkylamino group, one carbon atom
Other than nitrogen, nitrogen, oxygen and sulfur
May have 1 to 3 heteroatoms selected from
5- to 7-membered cyclic amino group, C _1-4 Alkyl-carboni
Ruamino group, C _1-4 Alkylsulfonylamino group, C _1-4
Alkoxy-carbonyl group, carboxyl group, C _1-6 A
Alkyl-carbonyl, carbamoyl, mono- or di-
C _1-4 Alkyl-carbamoyl group and C _1-6 Alkyls
Having 1 to 5 substituents selected from a rufonyl group
Selected from nitrogen, oxygen and sulfur
4 to 1 containing 1 to 3 hetero atoms
A 4-membered heterocyclic ring, the other of which is a halogen atom on a ring-constituting carbon atom.
, Nitro, cyano, oxo, hydroxy, C
_1-4 Alkoxy group, C _1-4 Alkylthio group, amino group,
No or Di C _1-4 An alkylamino group, with one carbon atom
From nitrogen, oxygen and sulfur atoms other than nitrogen atom
Optionally having 1 to 3 heteroatoms selected
Or a 7-membered cyclic amino group, C _1-4 Alkyl-carbonyl
Amino group, C _1-4 Alkylsulfonyl Amino group, C _1-4 A
Lucoxy-carbonyl group, carboxyl group, C _1-6 Al
Kill-carbonyl group, carbamoyl group, mono- or di-C
_1-4 Alkyl-carbamoyl group and C _1-6 Alkylsul
1 to 5 substituents selected from a honyl group
Nitrogen, oxygen and sulfur atoms that may be present
5 containing 1 to 3 heteroatoms selected from
An 8-membered heterocyclic ring or a 5- to 8-membered carbocyclic ring,
When the ring has a nitrogen atom in the ring and the C ring, the nitrogen
(1) halogen atom, nitro group, cyano group,
Droxy group, C _1-4 Alkoxy group, C _1-4 Alkylthio
Group, amino group, mono- or di-C _1-4 Alkylamino group,
In addition to one nitrogen atom, nitrogen atom, oxygen atom and sulfur atom
Having 1 to 3 heteroatoms selected from
Good 5- to 7-membered cyclic amino group, C _1-4 Alkyl-cal
Bonylamino group, C _1-4 Alkylsulfonylamino group,
C _1-4 Alkoxy-carbonyl group, carboxyl group, C
_1-6 Alkyl-carbonyl, carbamoyl, mono-
Or C _1-4 Alkyl-carbamoyl group and C _1-6 Al
1 to 5 substituents selected from killsulfonyl groups
Each may have, C _1-11 Alkyl, C _2-6 A
Lucenyl, C _2-6 Alkynyl, C _3-7 Monocyclic cycloalkyl
Or C _3-14 A bridged cyclic saturated hydrocarbon group, (2) (i) C
_1-4 Alkyl group, (ii) halogen atom, (iii) nitro
Group, (iv) cyano group, (v) hydroxy group, (vi) C
_1-4 Alkoxy group, (vii) C _1-4 Alkylthio group, (vii
i) amino group, (ix) mono or di C _1-4 Alkylamino
Group, (x) a nitrogen atom, an oxygen atom,
1 to 3 heteroatoms selected from sulfur and sulfur
Optionally a 5- to 7-membered cyclic amino group, (xi) C
_1-4 Alkyl-carbonylamino group, (xii) aminocar
A bonyloxy group, (xiii) mono- or di-C _1-4 Alkyl
Amino-carbonyloxy group, (xiv) C _1-4 Alkyls
Rufonylamino group, (xv) C _1-4 Alkoxy-carboni
Group, (xvi) carboxyl group, (xvii) C _1-6 Alkyl
-Carbonyl group, (xviii) C _3-7 Cycloalkyl-cal
Bonyl, (xix) carbamoyl, (xx) mono or di
C _1-4 Alkyl-carbamoyl group, (xxi) C _1-6 Archi
Rusulfonyl group, (xxii) C _3-7 Cycloalkyl sulfo
And (xxiii) having 1 to 4 substituents
Phenyl, naphthyl, mono- or di-phenyl
Le-C _1-3 Alkyl, phenoxy, benzoyl, pheno
Xycarbonyl, benzylcarbo Nil, phenyl-C
_1-4 Alkyl-carbamoyl, phenylcarbamoyl,
Phenyl-C _1-4 Alkyl-carbonylamino, benzo
Ilamino, phenyl-C _1-4 Alkylsulfonyl,
Phenylsulfonyl, phenyl-C _1-4 Alkylsulfi
Nil, phenyl-C _1-4 Alkylsulfonylamino or
Is a phenylsulfonylamino group (each phenyl or
Or naphthyl is C _1-4 Alkyl group, C _1-4 Alkoxy
Group, halogen atom, hydroxy group, benzyloxy group,
Amino group, mono or di C _1-4 Alkylamino group, nitro
B group, C _1-6 Alkylcarbonyl group and benzoyl group
May have 1 to 4 substituents selected from
I) each having 1 to 5 substituents selected from
May be, C _6-14 Aryl, C _7-18 Aralkyl, C
_6-14 Aryl-C _2-12 Alkenyl, C _6-14 Aryl-C
_2-12 Alkynyl or C _3-7 Cycloalkyl-C _1-6 Al
Kill group, or (3) halogen atom, nitro group, hydro
Xy, amino, mono- or di-C _1-6 Alkylam
No group and C _1-4 1 to 3 selected from alkoxy groups
C, each of which may have _2-8 Archi
Lecarbonyl, C _1-7 Alkylsulfonyl, phenyls
Ruphonyl, C _1-7 Alkylphosphonyl, phenylphospho
Nil, C _2-8 Alkyloxycarbonyl or C _7-18 A
May have an aralkyloxy-carbonyl group, R ¹ Is (1) hydrogen atom, (2) halogen atom, nitro
Group, cyano group, hydroxy group, C _1-4 Alkoxy group, C
_1-4 Alkylthio group, amino group, mono- or di-C _1-4 Al
Killamino group, nitrogen atom other than one nitrogen atom, oxygen atom
1 to 3 heteroatoms selected from
A 5- to 7-membered cyclic amino group which may have _1-4
Alkyl-carbonylamino group, C _1-4 Alkylsulfo
Nylamino group, C _1-4 Alkoxy-carbonyl group, cal
Boxyl group, C _1-6 Alkyl-carbonyl group, carbamo
Il group, mono or di C _1-4 Alkyl-carbamoyl group
And C _1-6 No one selected from alkylsulfonyl groups
And C may have 5 substituents. _1-11 A
Luquil, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-7 single
Ring cycloalkyl or C _8-14 Bridged cyclic saturated hydrocarbon
Group, or (3) (i) C _1-4 Alkyl group, (ii) halo
Gen atom, (iii) nitro group, (iv) cyano group, (v)
A hydroxy group, (vi) C _1-4 Alkoxy group, (vii) C
_1-4 Alkylthio group, (vii i) amino group, (ix) mono-
Or C _1-4 Alkylamino group, (x) one nitrogen atom
Other than nitrogen, oxygen and sulfur
5 to 7 optionally having 1 to 3 hetero atoms
Membered amino group, (xi) C _1-4 Alkyl-carbonyla
Amino group, (xii) aminocarbonyloxy group, (xiii)
Mono or Di C _1-4 Alkylamino-carbonyloxy
Group, (xiv) C _1-4 Alkylsulfonylamino group, (xv)
C _1-4 Alkoxy-carbonyl group, (xvi) carboxyl
Group, (xvii) C _1-6 Alkyl-carbonyl group, (xviii)
C _3-7 Cycloalkyl-carbonyl, (xix) carbamoy
Group, (xx) mono or di C _1-4 Alkyl-carbamoy
Group, (xxi) C _1-6 Alkylsulfonyl group, (xxii) C
_3-7 Cycloalkylsulfonyl and (xxiii) 1 to
Phenyl, naphthyl, which may have 4 substituents;
Mono- or di-phenyl-C _1-3 Alkyl, phenoki
Si, benzoyl, phenoxycarbonyl, benzylcar
Bonyl, phenyl-C _1-4 Alkyl-carbamoyl,
Phenylcarbamoyl, phenyl-C _1-4 Alkyl-cal
Bonylamino, benzoylamino, phenyl-C _1-4 A
Rukylsulfonyl, phenylsulfonyl, phenyl-C
_1-4 Alkylsulfinyl, phenyl-C _1-4 Alkyls
A ruphonylamino or phenylsulfonylamino group (that
Each phenyl or naphthyl is C _1-4 Alkyl
Group, C _1-4 Alkoxy group, halogen atom, hydroxy
Group, benzyloxy group, amino group, mono- or di-C _1-4
Alkylamino group, nitro group, C _1-6 Alkyl carboni
1 to 4 positions selected from
1 to 5 selected from
Each of which may have a substituent, _6-14 Aryl,
C _7-18 Aralkyl, C _6-14 Aryl-C _2-12 Alkene
Le, C _6-14 Aryl-C _2-12 Alkynyl or C _3-7 Shi
Chloroalkyl-C _1-6 With an alkyl group, Y is (1) (i) a halogen atom, a nitro group, a cyano group,
Hydroxy group, C _1-4 Alkoxy group, C _1-4 Alkylthio
Group, amino group, mono- or di-C _1-4 Alkylamino group,
In addition to one nitrogen atom, nitrogen atom, oxygen atom and sulfur atom
Having 1 to 3 heteroatoms selected from
Good 5- to 7-membered cyclic amino group, C _1-4 Alkyl-cal
Bonylamino group, C _1-4 Alkylsulfonylamino group,
C _1-4 Alkoxy-carbonyl group, carboxyl group, C
_1-6 Alkyl-carbonyl group, carba Moyl group, mono
Or C _1-4 Alkyl-carbamoyl group and C _1-6 Al
1 to 5 substituents selected from killsulfonyl groups
Each may have, C _1-11 Alkyl, C _2-6 A
Lucenyl, C _2-6 Alkynyl, C _3-7 Monocyclic cycloalkyl
Or C _8-14 A bridged cyclic saturated hydrocarbon group, (ii) (a) C
_1-4 Alkyl group, (b) halogen atom, (c) nitro
Group, (d) cyano group, (e) hydroxy group, (f) C
_1-4 Alkoxy group, (g) C _1-4 Alkylthio group, (h)
An amino group, (i) mono- or di-C _1-4 Alkylamino
Group, (j) a nitrogen atom, an oxygen atom,
1 to 3 heteroatoms selected from sulfur and sulfur
Optionally a 5- to 7-membered cyclic amino group, (k) C
_1-4 Alkyl-carbonylamino group, (l) aminocar
Bonyloxy group, (m) mono or di C _1-4 Alkyria
Mino-carbonyloxy group, (n) C _1-4 Alkylsul
Honylamino group, (o) C _1-4 Alkoxy-carbonyl
Group, (p) carboxyl group, (q) C _1-6 Alkyl-ka
Rubonyl group, (r) C _3-7 Cycloalkyl-carboni
, A (s) carbamoyl group, (t) a mono- or di-C _1-4
Alkyl-carbamoyl group, (u) C _1-6 Alkylsul
Honyl group, (v) C _3-7 Cycloalkylsulfonyl and
And (w) a group optionally having 1 to 4 substituents.
Nil, naphthyl, mono- or di-phenyl-C _1-3 A
Lucyl, phenoxy, benzoyl, phenoxycarboni
, Benzylcarbonyl, phenyl-C _1-4 Alkyl-
Carbamoyl, phenylcarbamoyl, phenyl-C
_1-4 Alkyl-carbonylamino, benzoylamino,
Phenyl-C _1-4 Alkylsulfonyl, phenylsulfo
Nil, phenyl-C _1-4 Alkylsulfinyl, phenyl
Le-C _1-4 Alkylsulfonylamino or phenyls
A rufonylamino group (each phenyl or naphthyl
Is C _1-4 Alkyl group, C _1-4 Alkoxy group, halogen source
, Hydroxy, benzyloxy, amino, mono
Or di C _1-4 Alkylamino group, nitro group, C _1-6 Al
One selected from a carbonyl group and a benzoyl group.
(Which may have four substituents)
C may have from 5 to 5 substituents,
_6-14 Aryl, C _7-18 Aralkyl, C _6-14 Aryl-C
_2-12 Alkenyl, C _6-14 Aryl-C _2-12 Alkynil
Or C _3-7 Cycloalkyl-C _1-6 An alkyl group, (iii)
Halogen atom, nitro group, hydroxy group, amino group,
No- or di-C _1-6 Alkylamino group, C _1-4 A Lucoxy
Each having from 1 to 3 substituents selected from
May be, C _2-8 Alkylcarbonyl, C _1-7 Alkyl
Sulfonyl, phenylsulfonyl, C _1-7 Alkylphos
Honyl, phenylphosphonyl, C _2-8 Alkyloxyca
Rubonyl or C _7-8 Aralkyloxy-carbonyl
Group, (iv) halogen atom, (v) nitro group, (vi) shea
(Vii) oxo group, (viii) hydroxy group, (i
x) C _1-4 Alkoxy group, (x) C _1-4 Alkylthio group,
(Xi) amino groups, (xii) mono- or di-C _1-4 Archi
A amino group, (xiii) a carbon atom and one nitrogen atom,
Hetero selected from nitrogen, oxygen and sulfur
5- to 7-membered ring optionally having 1 to 3 atoms
Amino group, (xiv) C _1-4 Alkyl-carbonylamino
Group, C _1-4 Alkylsulfonylamino group, (xv) C _1-4 A
Alkoxy-carbonyl group, (xvi) phenyl-C _1-4 Al
Kill-oxycarbonyl, (xvii) carboxyl group,
(Xviii) C _1-6 Alkyl-carbonyl group, (xix) C _1-4
Alkyl, halogen, C _1-4 Alkoxy, mono- or
Di-C _1-4 Alkylamino, 5- to 7-membered cyclic amino
1 to 3 selected from groups, nitro and hydroxy
A benzoyl group optionally having a substituent of (xx)
Bamoyl group, (xxi) mono or di C _1-4 Alkyl carba
Moyl group and (xxii) C _1-6 An alkylsulfonyl group
Each having from 1 to 5 substituents selected from
A 4-piperidinyl or 1-piperazinyl group,
Or (2) (i) C _1-4 Alkyl group, (ii) halogen
Atom, (iii) nitro group, (iv) cyano group, (v) hydrid
Roxy group, (vi) C _1-4 Alkoxy group, (vii) C _1-4 A
Alkylthio group, (viii) amino group, (ix) mono or di
C _1-4 Alkylamino group, (x) other than one nitrogen atom
Hetero selected from nitrogen, oxygen and sulfur
5- to 7-membered ring optionally having 1 to 3 atoms
Amino group, (xi) C _1-4 Alkyl-carbonylamino
Group, (xii) aminocarbonyloxy group, (xiii) mono
Or di C _1-4 Alkylamino-carbonyloxy group,
(Xiv) C _1-4 Alkylsulfonylamino group, (xv) C
_1-4 Alkoxy-carbonyl group, (xvi) carboxyl
Group, (xvii) C _1-6 Alkyl-carbonyl group, (xviii)
C _3-7 Cycloalkyl-carbonyl, (xix) carbamoy
Group, (xx) mono or di C _1-4 Alkyl-carbamoy
Group, (xxi) C _1-6 Alkylsulfonyl group, (xxii) C
_3-7 Cycloalkylsulfonyl and (xxiii) 1 to
4 pieces Optionally substituted phenyl, naphthyl,
Mono- or di-phenyl-C _1-3 Alkyl, phenoki
Si, benzoyl, phenoxycarbonyl, benzylcar
Bonyl, phenyl-C _1-4 Alkyl-carbamoyl,
Phenylcarbamoyl, phenyl-C _1-4 Alkyl-cal
Bonylamino, benzoylamino, phenyl-C _1-4 A
Rukylsulfonyl, phenylsulfonyl, phenyl-C
_1-4 Alkylsulfinyl, phenyl-C _1-4 Alkyls
A ruphonylamino or phenylsulfonylamino group (that
Each phenyl or naphthyl is C _1-4 Alkyl
Group, C _1-4 Alkoxy group, halogen atom, hydroxy
Group, benzyloxy group, amino group, mono- or di-C _1-4
Alkylamino group, nitro group, C _1-6 Alkyl carboni
1 to 4 positions selected from
1 to 5 selected from
4-benzyl-1- each optionally having a substituent
The compound according to claim 1, which is a piperidinyl group. (3) each of which Y may have a substituent;
The compound according to claim 1, which is a -piperidinyl group or a 1-piperazinyl group. In wherein A ring is a benzene ring, B ring in 5- to 7-membered nitrogen-containing heterocyclic 5 which may have a substituent, according to claim 1 wherein C ring is 5- to 7-membered saturated carbocyclic ring Compound. 5. A ring wherein the ring A is a benzene ring which may be substituted by one or two halogen atoms, and the ring B contains one or two oxygen, nitrogen and sulfur as hetero atoms other than carbon. An 8-membered heterocyclic ring, which may have C _1-6 alkyl and / or oxo on the carbon, and (1) one or more selected from halogen, nitro, C _1-4 alkoxy and hydroxy on the nitrogen; 2 in which may be substituted with C _1-6 alkyl, phenyl -C _1-4 alkyl, C _1-6 alkyl - carbonyl, benzoyl, C _1-6 alkoxy -
It may have a carbonyl, mono- or di-C _1-4 alkyl-carbamoyl group, (2) formyl group or (3) carbamoyl group, and the C ring is (1) a 5- to 7-membered saturated carbocycle, ( 2) C _1-6 alkyl and / or by a 5- or may be 7-membered nitrogen-containing saturated heterocyclic ring or substituted with oxo (3) the compound according to claim 1 wherein is benzene ring. 6. A ring is a benzene ring, B ring is a 5- or 6-membered nitrogen-containing saturated heterocyclic ring optionally having C _1-6 alkyl and / or oxo on a ring-constituting carbon, and C ring is cyclohexane ring or 5 to the compound of claim 1 wherein the 7-membered nitrogen-containing saturated heterocyclic ring. 7. Ar is a compound of the formula (Wherein, R ⁶ is a hydrogen atom, a carbon which may have a substituent,
Represents a hydride group or an optionally substituted acyl group.
The other symbols have the same meanings as described above. )
The compound according to claim 1, which is a group. 8. R ⁶ Is (1) hydrogen atom, (2) halogen
Atom, nitro group, cyano group, hydroxy group, C _1-4 Al
Coxy group, C _1-4 Alkylthio group, amino group, mono or
Is Di C _1-4 Alkylamino group, nitrogen atom other than one nitrogen atom
Heteroatoms selected from elemental, oxygen and sulfur atoms
5- to 7-membered ring which may have 1 to 3
Mino group, C _1-4 Alkyl-carbonylamino group, C _1-4 A
Rukylsulfonylamino group, C _1-4 Alkoxy-carbo
Nyl group, carboxyl group, C _1-6 Alkyl-carbonyl
Group, carbamoyl group, mono- or di-C _1-4 Alkyl-ka
Rubamoyl group and C _1-6 Select from alkylsulfonyl groups
Each of which may have 1 to 5 substituents
Yes, C _1-11 Alkyl, C _2-6 Alkenyl, C _2-6 Alkini
Le, C _3-7 Monocyclic cycloalkyl or C _3-14 Bridged cyclic
Japanese hydrocarbon group, (3) (i) C _1-4 An alkyl group, (ii)
A halogen atom, (iii) a nitro group, (iv) a cyano group,
(V) hydroxy group, (vi) C _1-4 An alkoxy group, (vi
i) C _1-4 Alkylthio group, (viii) amino group, (ix)
No or Di C _1-4 Alkylamino group, (x) one nitrogen
Other than atoms, selected from nitrogen, oxygen and sulfur
Heteroatoms 5 that may have 1 to 3
7-membered cyclic amino group, (xi) C _1-4 Alkyl-carboni
Amino group, (xii) aminocarbonyloxy group, (xii
i) mono or di C _1-4 Alkylamino-carbonyloxy
Si group, (xiv) C _1-4 Alkylsulfonylamino group, (x
v) C _1-4 Alkoxy-carbonyl group, (xvi) carboxy
A sil group, (xvii) C _1-6 An alkyl-carbonyl group, (xvi
ii) C _3-7 Cycloalkyl-carbonyl, (xix) carba
Moyl group, (xx) mono or di C _1-4 Alkyl-carba
Moyl group, (xxi) C _1-6 Alkylsulfonyl group, (xxi
i) C _3-7 Cycloalkylsulfonyl and (xxiii) 1
Phenyl, naph, optionally having 4 to 4 substituents
Chill, mono- or di-phenyl-C _1-3 Alkyl,
Phenoxy, benzoyl, phenoxycarbonyl, benzyl
Carbonyl, phenyl-C _1-4 Alkyl-carbamoy
Phenylcarbamoyl, phenyl-C _1-4 Alkyl
-Carbonylamino, benzoylamino, phenyl-C
_1-4 Alkylsulfonyl, phenylsulfonyl, phenyl
Le-C _1-4 Alkylsulfinyl, phenyl-C _1-4 Al
Killsulfonylamino or phenylsulfonylamino
Group (each phenyl or naphthyl is C _1-4 Al
Kill group, C _1-4 Alkoxy group, halogen atom, hydroxy
C, benzyloxy, amino, mono or di C
_1-4 Alkylamino group, nitro group, C _1-6 Alkyl carb
1 to 4 groups selected from a nyl group and a benzoyl group
1 to 5 selected from (which may have a substituent)
Each of which may have a substituent of _6-14 Ally
Le, C _7-18 Aralkyl, C _6-14 Aryl-C _2-12 Arche
Nil, C _6-14 Aryl-C _2-12 Alkynyl or C _3-7
Cycloalkyl-C _1-6 Alkyl group, or (4) halo
Gen atom, nitro group, hydroxy group, amino group, mono-
Or di-C _1-6 Alkylamino group and C _1-4 Alkoxy
Each having from 1 to 3 substituents selected from
May be, C _2-8 Alkylcarbonyl, C _1-7 Alkyl
Sulfonyl, phenylsulfonyl, C _1-7 Alkylphos
Honyl, phenylphosphonyl, C _2-8 Alkyloxyca
Rubonyl or C _7-18 Aralkyloxy-carbonyl group
The compound according to claim 7, which is 9. R ⁶ Is (1) a hydrogen atom, (2) a halogen,
Nitro, C _1-4 Selected from alkoxy and hydroxy
Each of which may be substituted with one or two substituents.
C _1-6 Alkyl, phenyl-C _1-4 Alkyl, C _1-6 A
Alkyl-carbonyl , Benzoyl, C _1-6 Alkoxy-
Carbonyl or mono- or di-C _1-4 Alkyl-ka
Rubamoyl group, (3) formyl or (4) carbamoy
The compound of claim 7, which is 10. The compound according to claim 1, wherein Ar is 1,2,2a, 3,4,5-hexahydrobenz [cd] indol-6-yl. 11. Ar is 1-formyl-1,2,2a,
3,4,5-hexahydrobenz [cd] indole-6
The compound according to claim 1, which is -yl. 12. The compound according to claim 1, wherein Ar is 5,6-dihydro-2 (1H) -oxo-4H-pyrrolo [3,2,1-ij] quinolin-8-yl. 13. Ar is 4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1-ij] quinoline-8.
The compound according to claim 1, which is -yl. 14. Ar is 1,2,4,5,6,7-hexahydro-2-oxoazepino [3,2,1-hi] indole-
The compound according to claim 1, which is 9-yl. 15. Ar is 2,3,6,7-tetrahydro-5.
-Oxo-1H, 5H-benzo [ij] quinolidine-9-
The compound of claim 1 which is yl. 16. The method according to claim 1, wherein n is an integer of 2 to 6.
A compound as described. 17. The compound according to claim ¹ , wherein R ¹ is a hydrogen atom. 18. Y is a compound of the formula Wherein R ′ is (1) C _1-6 alkyl, halogen, nitro, cyano, amino, mono- or di-C _1-6 alkylamino, hydroxy, C _1-6 alkoxy, phenyl-C
Benzyl optionally substituted with one or two selected from _1-4 alkoxy and C _1-4 alkylenedioxy,
(2) cyclohexyl, (3) phenyl, (4) formyl, (5) C _1-6 alkyl - carbonyl, (6) benzo <br/> yl, (7) C _1-6 alkoxy - carbonyl or
(8) R ″ and R ″ ″ each represent a hydrogen atom
Child, C _1-6 alkyl, halogen, nitro, cyano, amino, mono- - or di -C _1-6 alkylamino, hydroxy, C _1-6 alkoxy, phenyl -C _1-4 alkoxy or C _1-4 alkylenedioxy Indicates oxy. The compound according to claim 1, which is a group represented by the formula: 19. The compound according to claim 1, wherein Y is 1-benzyl-4-piperidinyl, 4-benzyl-1-piperazinyl or 4-benzyl-1-piperidinyl. 20. 8- [3- [4-[(3-methylphenyl) methyl] -1-piperazinyl] -1-oxopropyl] -1,2,5,6-tetrahydro-4H-pyrrolo [3,
2,1-ij] quinolin-4-one or a salt thereof, 8-
[3- [4-[(3-chlorophenyl) methyl] -1-
Piperazinyl] -1-oxopropyl] -1,2,5,6
-Tetrahydro-4H-pyrrolo [3,2,1-ij] quinolin-4-one or a salt thereof, 8- [3- [4-[(2-
Methylphenyl) methyl] -1-piperazinyl] -1-
Oxopropyl] -5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-2 (1H) -one or a salt thereof, 8- [3- [4-[(3-chlorophenyl) methyl] -1-piperazinyl] -1-oxopropyl]-
5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-2 (1H) -one or a salt thereof, 8- [3- [1
-(Phenylmethyl) -4-piperidinyl] -1-oxopropyl] -1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1-ij] quinolin-4-one or a salt thereof, 8- [3- [1-[(4-methylphenyl) methyl] -4-piperidinyl] -1-oxopropyl]-
1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1
-Ij] quinolin-4-one or a salt thereof, 8- [3-
[1-[(3-methoxyphenyl) methyl] -4-piperidinyl] -1-oxopropyl] -1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1-ij] quinoline-
4-one or a salt thereof, 8- [3- [1-[(2,4-
Dimethylphenyl) methyl] -4-piperidinyl] -1
-Oxopropyl] -1,2,5,6-tetrahydro-4
H-pyrrolo [3,2,1-ij] quinolin-4-one or a salt thereof, 8- [3- [1-[(2,5-dimethylphenyl) methyl] -4-piperidinyl] -1-oxopropyl ] -1,2,5,6-tetrahydro-4H-pyrrolo [3,
2,1-ij] quinolin-4-one or a salt thereof, 8-
[3- [1-[(4-chlorophenyl) methyl] -4-
Piperidinyl] -1-oxopropyl] -1,2,5,6
-Tetrahydro-4H-pyrrolo [3,2,1-ij] quinolin-4-one or a salt thereof, 8- [3- [1-[(4-
Nitrophenyl) methyl] -4-piperidinyl] -1-
Oxopropyl] -1,2,5,6-tetrahydro-4H
-Pyrrolo [3,2,1-ij] quinolin-4-one or a salt thereof, 8- [3- [1- (phenylmethyl) -4-piperidinyl] -1-oxopropyl] -5,6-dihydro- 4H-pyrrolo [3,2,1-ij] quinoline-2 (1H)
-One or a salt thereof, 8- [3- [1- (3-methoxyphenyl) methyl] -4-piperidinyl] -1-oxopropyl] -5,6-dihydro-4H-pyrrolo [3,2,
1-ij] quinolin-2 (1H) -one or a salt thereof, 8
-[3- [4- (Phenylmethyl) -1-piperidinyl] -1-oxopropyl] -1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1-ij] quinolin-4-one Or a salt thereof, 8- [3- [4- (phenylmethyl)
-1-piperidinyl] -1-oxopropyl] -5,6
-Dihydro-4H-pyrrolo [3,2,1-ij] quinoline-
2 (1H) -one or a salt thereof, 1- (1,2,2a, 3,
4,5-hexahydrobenz [cd] indol-6-yl) -3- [1- (phenylmethyl) piperidin-4-
Yl] -1-propanone or a salt thereof, 1- (1-methyl-1,2,2a, 3,4,5-hexahydrobenz [cd]
Indole-6-yl) -3- [1- (phenylmethyl) piperidin-4-yl] -1-propanone or a salt thereof or 1- [2- (phenylmethyl) -2,3-dihydro-1H-benz [ de] isoquinolin-6-yl]
-3- [1 (phenylmethyl) -4-piperidinyl]-
The compound according to claim 1, which is 1-propanone or a salt thereof. 21. 8- [3- [1-[(3-fluorophene)
Nyl) methyl] -4-piperidinyl] -1-oxopro
Pill] -1,2,5,6-tetrahydro-4H-pyrrolo
[3,2,1-ij] quinolin-4-one or a salt thereof
A compound according to claim 1, wherein 22. A compound of the formula Ar-H (II) wherein Ar is as defined in claim 1. And a salt thereof, and a compound represented by the formula: [Wherein R ¹ , Y and n have the same meanings as in claim 1,
Z ¹ represents a leaving group. And a salt thereof. 23. A compound of the formula Or a salt thereof and a compound of the formula Z ³ -Y ″ (V) [wherein Z ² and Z ³ are groups capable of reacting and leaving together, and Y ″ is a substituent The 1-piperazinyl or 4-benzyl-1-piperidinyl group which may be possessed, and other symbols are as defined in claim 1. With the formula: [The symbols in the formula are as defined above. ] Or a salt thereof. 24. The formula: [In the formula, n ′ represents an integer of 1 to 10, R ¹ may be different in repeating n ′, and Y ′ is an optionally substituted amino group or an optionally substituted nitrogen-containing saturated group. It represents a heterocyclic group, and other symbols have the same meanings as in claim 1. ] Or a salt thereof, which is a cholinesterase inhibitor. 25. The cholinesterase inhibitor according to claim 24, which is used as a therapeutic / prophylactic agent for senile dementia.