JP3523887B2 - Condensed heterocyclic ketone derivative, production method thereof, intermediate and agent - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel fused heterocyclic ketone derivative and a salt thereof. The compounds of this invention are
It is useful as a medicine, more specifically as a cholinesterase inhibitor, especially as a therapeutic / preventive agent for senile dementia in senile dementia, Alzheimer's disease and the like.

[0002]

2. Description of the Related Art With the aging of society, various compounds having a treatment / preventive action for senile dementia have been proposed. Among them, physostigmine, a natural substance that is a cholinesterase inhibitor, has been found to have a therapeutic / preventive action on senile dementia (International Journal of Cli.
nical Pharmacology, Therapy and Toxicology, Vol.
29, No. 1, p. 23-37 (1991)). However, physostigmine has drawbacks such as short duration of action and strong toxicity. On the other hand, various heterocyclic compounds have been proposed as synthetic products (for example, EP-A
-0,378,207, JP-A-62-234065,
JP-A-64-79151 and JP-A-2-169569
JP-A No. 52-72829 and JP-A No. 55-9070 disclose an antidepressant having a chemical structure similar to that of the cholinesterase inhibitor described above. Or anxiolytics are listed.

More specifically, EP-A-0,378,207
In the formula

[Chemical 9] [In the formula, B is an optionally substituted saturated or unsaturated 5
~ 7-membered aza heterocyclic group, A is a bond or substituted with a hydrocarbon residue, oxo group or hydroxy group

[Chemical 10] R ₂ and R ₃ each independently represent a hydrogen atom or a hydrocarbon residue which may have a substituent (however, not simultaneously a hydrogen atom), or form a cyclic amino group with an adjacent nitrogen atom. And n is 0, 1 or 2, and p is 1 or 2] and its salts, specifically, the following compounds:

[Chemical 11] Etc. are described. Japanese Unexamined Patent Publication No. 62-234065 discloses a formula

[Chemical 12] [In the formula, R ¹ is substituted or unsubstituted benzene, pyridine, pyrazine, indole, anthraquinone, quinoline, substituted or unsubstituted phthalimide, homophthalimide, pyridinecarboxylic acid imide, pyridine-N-
Oxide, pyrazine dicarboxylic acid imide, naphthalene dicarboxylic acid imide, substituted or unsubstituted quinazolinedione, 1,8-naphthalimide, bicyclo [2.2.
2] Oct-5-ene-2,3-dicarboxylic acid imide,
It means a monovalent group derived from one selected from pyromeryl imide.

X is a group represented by the formula-(CH ₂ ) _m- (wherein m represents an integer of 0 to 7), a group represented by the formula --O (CH ₂ ) _n- , a group represented by the formula --S ( CH _{2) n} -, a group represented by the formula -NH (C
H _{2) n} -, a group represented by the formula _{-SO 2 NH (CH 2) n} - , a group represented by the formula _{-NH-CO- (CH 2) n} - , a group represented by the formula -NH (CH ₂₎ a group represented by _n- CO-, formula-COO (C
H _{2) n} -, a group represented by the formula _{-CH 2 NH (CH 2) n} - , a group represented by the formula _{^{-CO-NR 3 - (CH 2}} ) n - in the definition of group (X represented by this In the formulas above, n means an integer of 1 to 7, R ³ means a lower alkyl or benzyl group), a group represented by the formula —O—CH ₂ CH ₂ CH (CH ₃ ) —, a formula A group represented by —O—CH (CH ₃ ) CH ₂ CH ₂ —,
Formula -O-CH ₂ CH ₂ CH = group represented by, or formula -O-
It means a group represented by CH ₂ CH (OH) CH ₂ —.

[Chemical 13]

R ² is a hydrogen atom, a lower alkyl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted benzoyl group, a pyridyl group, a 2-hydroxyethyl group, a phenyl group.

[Chemical 14] And a pharmaceutically acceptable salt thereof, specifically, the following compounds

[Chemical 15] Etc. are described. In JP-A-64-79151 and JP-A-02-169569, the general formula

[Chemical 16] [Wherein, 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 which may be substituted with a phenyl group; indanyl, Indanonyl, indenyl, indenonyl, indandionyl, tetralonyl, benzperonyl, indanolyl, formula

[Chemical 17] (c) Monovalent group derived from cyclic amide compound, (d) lower alkyl group, or (e) formula R ¹ —CH═CH— (wherein
R ¹ means a hydrogen atom or a lower alkoxycarbonyl group).

[0006] 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 of the formula —CO—NR ⁴ — (C (R ² ) H) _n — (in the formula, R ⁴ means 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 represented by the formula —O A group represented by —CO—NH— (C (R ² ) H) _n —, a group represented by the formula —NH—CO— (C (R ² ) H) _n —, a formula —CH ₂ —CO—NH— A group represented by (C (R ² ) H) _n −,
Formula ^{-CO-NH- (C (R 2} ) H) n - , a group represented by the formula -C
(OH) H- (C (R 2) H) n - group (in the above equations represented by,
n means 0 or an integer of 1 to 10. R ² is the formula − (C
It means a hydrogen atom or a methyl group in such a form that the alkylene group represented by (R ² ) H) _n — has no substituent or has one or more methyl groups. ), The formula =
_{(CH-CH = CH) b} - (wherein, b is an integer of 1 to 3) represented by the formula _{= CH- (CH 2) c -} ( wherein,
c represents an integer of 0 or 1 to 9), a group of the formula = (CH-CH) _d = (in the formula, d means an integer of 0 or 1 to 5), Formula-CO-CH = CH-C
H ₂ -, a group represented by the formula _{-C O-CH 2 -C (OH} ) H-
A group represented by CH ₂ —, a formula —C (CH ₃ ) H—CO—NH
A group represented by —CH ₂ —, a formula —CH═CH—CO—NH
A group represented by — (CH ₂ ) ₂ —, a group represented by the formula —NH—, a group represented by the formula —O—, a group represented by the formula —S—, a dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group. means. T means a nitrogen atom or a carbon atom. Q means 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 which may be substituted with a phenyl group, a cinnamyl group which may be substituted with a phenyl group, a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, It means 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.

[Chemical 18]

[Chemical 19] Etc. are described.

JP-A-52-72829 discloses a general formula used especially for treating diseases caused by dysfunction of serotonergic system.

[Chemical 20] [In the formula, R represents a hydrogen atom, an alkyl group containing 1 to 4 carbon atoms or an alkyl moiety having 1 or 2 carbon atoms.
Represents an aralkyl group contained therein, X is a hydrogen atom or a halogen atom, an alkyl, alkoxy, or alkylthio group in which each group can have 1 to 4 carbon atoms, trifluoromethyl, nitro, hydroxy or substituted. Represents an unsubstituted amino group or an amino group substituted with one or two alkyl groups or an acyl or alkylsulfonyl group, and A represents a group —CO— or a group —CH.
_2- and n is 0, 1 or 2, and a pharmaceutical composition containing a pharmaceutically acceptable salt thereof is disclosed in JP-A-55-90.
No. 70 has the general formula

[Chemical 21] [Wherein R is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an aralkyl group in which the alkyl group has 1 to 2 carbon atoms, X is a hydrogen atom or a halogen atom,
Alkyl group, alkoxy group or alkyl group has 1 carbon atom
An alkylthio group having 4 to 4, A is —CO— or —CH ₂ —, and n is 1 or 2. ] And a pharmaceutically active compound having an affinity for the receptor of ³ H-diazepam.
Furthermore, WO 91/03243 describes the general formula used as an antipsychotic drug.

[Chemical formula 22] [In the formula, m represents 0 to 3, n represents 0 to 3,
m and n never show 0, p is 0 to 3,
X is O, S, SO, SO ₂ , NR ⁶ , CR ⁷ R ⁸ , CO or CHOH, and R ¹ , R ³ and R ⁷ are each a hydrogen atom, C _1-5 alkyl, halogen, NR ¹⁰ R ¹¹ , OH, C
OOH, C _2-6 carboalkoxy, CN, Ar, C _1-5 alkoxy or C _1-5 alkylthio is shown, and R ² , R ⁴ and R ⁸ are each a hydrogen atom, C _1-5 alkyl, C _2-6 Carboalkoxy, CN, C _1-5 alkoxy or Ar ¹ is shown, and when X is O, S, SO, SO ₂ or NR ⁶ , R ¹ ,
R ² , R ³ and R ⁴ are not C _1-5 alkoxy, C _1-5 alkylthio, NR ¹⁰ R ¹¹ or OH, and R ⁵ is a hydrogen atom, alkyl, halogen, OH or alkenyl,
⁶ is a hydrogen atom, C _1-5 alkyl or Ar ¹ , and Ar and Ar ¹ are naphthyl, pyridyl, pyrimidyl, indolyl, quinolinyl, isoquinolinyl or phenyl group, and these groups are C _1-3 alkyl, C _{1 -3} alkoxy, 1 to C _1-3 haloalkyl having 3-7 halogen _{atoms, SH, S (O) t} -C 1-3 alkyl (t is 1, 2 or 3), C _2-6 dialkylamino, halogen, C _1-3 alkylamino, NH ₂ , CN, NO ₂ , SO ₃ H, tetrazole, COOH, C _2-6 carboalkoxy, CON
H ₂ , SO ₂ NO ₂ , COR ⁹ , CONR ¹² R ¹³ , SO ₂ N
It may be substituted with R ¹² R ¹³ , Ar ² , OAr ² or SAr ² . Ar ² is naphthyl or phenyl group, these groups being substituted with C _1-3 alkyl, 1 to C _1-3 haloalkyl having 3-7 halogen atoms, C _1-3 alkoxy, halogen or C _1-3 alkylthio May be.
R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ each represent a hydrogen atom, C _1-5 alkyl or phenyl, and R ¹⁰ and R ¹¹
_Are both C _3-6 alkylene chains, R ¹² and R ¹³ are both C _3-6
An alkylene chain may be formed. a or b represents a double bond or a single bond, and neither of them represents a double bond. ] Or a pharmacologically acceptable salt thereof is described.

On the other hand, various oxygen-containing or sulfur-containing condensed heterocyclic ketone derivatives have been synthesized, and their biological activities and pharmacological actions have been reported. However, no report has been made on the cholinesterase inhibitory action or the action as a therapeutic / preventive agent for senile dementia. Specifically, Chem. Abstr., 107 , 1903.
32h (1987) includes the general formula

[Chemical formula 23] [Wherein R = Ac, COEt, COPr, COCHMe ₂ ,
CO (CH ₂ ) ₂ Cl, CO (CH ₂ ) ₃ Cl, COCH ₂ NMe ₂ ,
CO (CH ₂ ) ₂ NMe ₂ , CO (CH ₂ ) ₃ NMe ₂ , and their salts or R = COCH = CHPh, X = CH ₂ ,
Alternatively, the compound represented by 0, n = 1, 2 or 3] has an anti-inflammatory effect. chemical·
Chem. Abstr., 89 , 36594y
(1978) has the general formula

[Chemical formula 24] It is described that the compound represented by the formula: R ¹ = H, Me; n = 2,3 has a convulsive action, an arterial blood pressure lowering action, and a local anesthetic action.

Pharmaceutical Journal, 97 , 540 (1977),
General formula

[Chemical 25] [Wherein R ¹ = H, Me; R ² = H, Cl, Me; R ³ = H,
F, Me, OMe, Cl; n = 1, 2, 3; Z = O, O
H, H (above compound I) or R ² = H, Cl; R ^{4
_{= H, Me; NR 5 2}} = NMe 2, morpholino, compounds represented by piperidino (or compound II)] have been described to have an antidepressant action. EP-163,537 includes the general formula

[Chemical formula 26] [Wherein R = 4-cycloalkylphenyl, 3,4-methylenedioxyphenyl, 2,3-dihydro-5-benzofuranyl; R ¹ = alkyl, cycloalkyl, cyclopentylmethyl; R ² = substituted and unsubstituted Pyrrolidino, piperidino, hexahydro-1H-azepine-1
-Yl, octahydro-1-azocinyl] is described as having a muscle relaxant action. Chemical Abstracts (Chem. Abstr.), 91 , 211
631y (1979) has the following formula

[Chemical 27] It is described that a compound represented by the formula: R = H, Me is synthesized as an derivative of the alkaloid cytisine and has an anticholinergic effect.

As the nitrogen-containing condensed heterocyclic ketone derivative, Helvetica Chimic (Helvetica Chimic)
a Acta), 51 , 1616 (1968), formula (A) and formula
(B)

[Chemical 28] The compound represented by the formula (C)

[Chemical 29] It is described as a synthetic intermediate such as alkanolamine, which is a sympathetic nervous system agonist.

[0011]

However, in the present day where the senile dementia increases, it has a stronger action than the known compounds known to have the treatment / preventive action for senile dementia. It is desired to develop an excellent therapeutic / preventive agent for senile dementia with a long duration of action and weak toxicity.

[0012]

Means for Solving the Problems As a result of various studies, the present inventors succeeded in creating a novel compound having a condensed heterocyclic group having a unique chemical structure, and unexpectedly showed excellent inhibition of cholinesterase. It has activity and monoamine reuptake inhibitory activity, and it was found that it is useful as an excellent therapeutic / preventive agent for senile dementia,
The present invention has been completed based on these. Specifically, formula (1)

[Chemical 30] [In the formula, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group which may have a substituent, and the A ring may further have a substituent. Represents a benzene ring, n represents an integer of 1 to 10, R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a hydrocarbon group which may have a substituent, or R ³ and R ³ R ⁴ may form a heterocyclic group which may have a substituent together with the adjacent nitrogen atom, R ² may be different from each other in repeating n, and k is an integer of 0 to 3. , M represents an integer of 1 to 8. However, when k = 0 and m = 2, n> 1. ] A condensed heterocyclic ketone derivative represented by the following or a salt thereof, (2) formula

[Chemical 31] [In the formula, Y represents a leaving group, and R ¹ , A ring, R ² , n, k and m have the same meanings as described above. ] The compound or its salt represented by these, and a formula

[Chemical 32] [In the formula, R ³ and R ⁴ have the same meanings as described above. ] The compound which reacts with the compound or its salt represented by [I]
Alternatively, a method for producing the salt, formula (3)

[Chemical 33] [In the formula, R ⁵ represents a hydrogen atom or a hydrocarbon group which may have a substituent, and R ¹ , the A ring, k and m have the same meanings as described above. ] The compound or its salt represented by these,
Wherein R ⁶ -CHO [V] [wherein, R ⁶ represents a hydrogen atom or an optionally substituted hydrocarbon group. ] The compound represented by

[Chemical 34] [In the formula, R ³ and R ⁴ have the same meanings as described above. ] The compound consisting of reacting with the compound or its salt represented by

[Chemical 35] [In the formula, each symbol has the same meaning as described above. ] The manufacturing method of the compound or its salt represented by these, (4) Formula

[Chemical 36] [In the formula, Y, R ¹ , A ring, R ² , n, k and m have the same meanings as described above. ] The compound or its salt represented by these,
Equation (5)

[Chemical 37] [In the formula, X ¹ represents R ¹ -N <(R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group which may have a substituent), an oxygen atom or Represents a sulfur atom, ring A represents a benzene ring which may further have a substituent, n represents an integer of 1 to 10, and R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom or a substituent. Represents a hydrocarbon group which may have a group, or R ³ and R ⁴
May form a heterocyclic group which may have a substituent together with an adjacent nitrogen atom, R ^{2 s} may be different from each other in the repetition of n, k is an integer of 0 to 3 and m is Represents an integer of 1 to 8. ] A cholinesterase inhibitor characterized by containing a fused heterocyclic ketone derivative represented by the following or a salt thereof, and (6) treatment of senile dementia containing compound [VII] or a salt thereof
Regarding preventive agents.

The compound [I] or a salt thereof of the present invention is such that the hetero atom (oxygen, sulfur or nitrogen) -containing heterocycle condensed with the benzene ring A is a saturated ring, and the benzene ring A
Substituted for carbon atom of

[Chemical 38] Is a novel compound having a chemical structure characteristic in that it is bonded to the compound, and based on this characteristic, it exhibits an excellent therapeutic / preventive action for senile dementia. In the above formula, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group which may have a substituent. R ² represents a hydrogen atom or a hydrocarbon group which may have a substituent, R 2
² may be different in each repeating n. R ³ and R ⁴ each represent a hydrogen atom or a hydrocarbon group which may have a substituent, or R ³ and R ⁴ represent a heterocyclic group which may have a substituent with an adjacent nitrogen atom. You may form. R ⁵ and R ⁶ each represent a hydrogen atom or a hydrocarbon group which may have a substituent.
Examples of the "hydrocarbon group" of the "hydrocarbon group which may have a substituent" represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ include, for example, a chain or cyclic group, or A C _1-18 hydrocarbon group composed of a combination thereof is used. Examples of such a chain hydrocarbon group include 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, etc.), linear or branched C _2-4 alkenyl group (eg, vinyl, allyl, 2-butenyl, etc.) and linear or branched C _2-4 alkynyl group (eg, propargyl, 2-butynyl, etc.) and the like are used. Examples of the cyclic hydrocarbon group include a C _3-7 monocyclic cycloalkyl group (eg, cyclobutyl, cyclopentyl, cyclohexyl, etc.), 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, etc.), C _6-14 aryl group (eg, phenyl group, naphthyl group, etc.) and the like are used. The hydrocarbon group composed of a combination of chain and ring is, for example, C _7-18
Aralkyl (eg phenylmethyl, phenylethyl,
Phenyl-C _1-12 alkyl such as phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, α-naphthylmethyl or naphthyl-C _1-8 alkyl, such as di-phenyl-C _1-3 such as diphenylmethyl, diphenylethyl. Alkyl, etc., C _6-14 aryl-C _2-12 alkenyl (eg styryl, cinnamyl, 4
-Phenyl-2-butenyl, phenyl-C _2-12 alkenyl such as 4-phenyl-3-butenyl), C _6-14 aryl-C _2-12 alkynyl (eg phenylethynyl, 3-phenyl-2) -Propynyl, 3-phenyl-1
-Phenyl-C _2-12 alkynyl such as propynyl), C _3-7 cycloalkyl-C _1-6 alkyl (eg,
Cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylethyl,
Cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclopropylbutyl, cyclobutylbutyl, cyclopentylbutyl, cyclohexylbutyl, cycloheptylbutyl, cyclopropylpentyl, Cyclobutylpentyl, cyclopentylpentyl, cyclohexylpentyl, cycloheptylpentyl, cyclopropylhexyl, cyclobutylhexyl, cyclopentylhexyl, cyclohexylhexyl, cycloheptylhexyl, etc.) are used.

The "hydrocarbon group" of the "hydrocarbon group which may have a substituent" represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is, for example, a straight chain group. Or branched C
_1-11 alkyl group, preferably 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.) or C _7-18
Aralkyl groups, preferably C _7-10 aralkyl groups (eg, phenyl-C _1-4 alkyl such as phenylmethyl, phenylethyl, phenylpropyl, etc.) and the like are frequently used. The hydrocarbon group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ may have a substituent, and such a substituent is generally used as a substituent of a hydrocarbon group. What is mentioned can be used suitably. Specifically, the above-mentioned C _1-11 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-7 monocyclic cycloalkyl, C _8-14 bridged cyclic saturated hydrocarbon group has Examples of the substituent include halogen atom (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 group (eg, methylthio, ethylthio, propylthio, etc.), amino group, mono- or di-C
_1-4 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), 5- to 7-membered cyclic amino group (eg, pyrrolidino, piperidino, morpholino, etc.), C _1-4 alkyl-carbonyl Amino group (eg, acetylamino, propionylamino, butyrylamino, etc.), C _1-4 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C _1-4 alkoxy-carbonyl group (eg, methoxycarboamino) Nyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxyl group, C _1-6 alkyl-carbonyl group (eg,
Methylcarbonyl, ethylcarbonyl, etc. profile pills carbonyl), a carbamoyl group, mono- or di-C _1-4 alkyl - Cal Bamoiru group (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), C _{1 -6} alkylsulfonyl group (e.g., methyl Sulfonyl, ethylsulfonyl, propylsulfonyl etc.), C _1-4 alkylenedioxy (eg methylenedioxy etc.) and C _1-4 alkyl (eg methyl, ethyl etc.) etc. A 5- or 6-membered heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen or a condensed ring group thereof (for example, pyridyl, pyridinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, naphthyridinyl, thiazolyl, benzothiazolyl) , Benzoxazolyl Furyl, furanyl, thiophenyl, etc.) to 1 selected from such five is used.

The substituent which the C _6-14 aryl group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ may have is, for example, a C _1-4 alkyl group ( (Eg, methyl, ethyl, propyl, butyl, etc.), halogen atom (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 group (eg, methylthio, ethylthio, propylthio)
O, isopropylthio, butylthio, etc.), amino group,
Mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), 5- to 7-membered cyclic amino group (eg, pyrrolidino, piperidino, morpholino, etc.), C _{1- 4} alkyl-carbonylamino groups (for example,
Acetylamino, propionylamino, butyrylamino etc.), C _7-18 aralkyloxy group (eg phenylmethoxy, phenylethoxy etc.), aminocarbonyloxy group, mono or di C _1-4 alkylamino-carbonyloxy group (eg methyl Aminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.), C _1-4 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, etc.), C _1-4 alkoxy- Carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl, etc.), carboxyl group, C _1-6 alkyl-carbon group
Nyl group (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), C _3-7 cycloalkyl-
Carbonyl (eg cyclohexylcarbonyl
Etc.), carbamoyl group, mono- or di-C _1-4 alkyl-
Carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.), C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.), C _{3- 7} cycloalkylsulfonyl (eg, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.), C _1-4 alkylenedioxy (eg, methylenedioxy, etc.), or phenyl optionally having 1-4 substituents, naphthyl , Mono- or di-phenyl-C _1-3 alkyl (eg benzyl, diphenylmethyl etc.), phenoxy, benzoyl, phenoxycarbonyl, benzylcarbonyl, phenyl-C _1-4 alkyl-
Carbamoyl (eg, phenylmethylcarbonyl, etc.), phenylcarbamoyl, phenyl-C _1-4 alkylcarbonylamino (eg, phenylmethylcarbonylamino, etc.), benzoylamino, phenyl-C
_1-4 alkylsulfonyl (eg phenylmethylsulfur
(Phenyl etc.), phenylsulfonyl, phenyl-C _1-4
Alkylsulfinyl (eg, phenylmethylsulfinyl, etc.), Phenyl-C _1-4 alkylsulfonylamino (eg, phenylmethylsulfonylamino, etc.)
Or a phenylsulfonylamino group (as a substituent which each group may have, for example, a C _1-4 alkyl group such as methyl, ethyl, propyl, butyl, isopropyl, methoxy, ethoxy, n-propyloxy,
a C _1-4 alkoxy group such as i-propyloxy and n-butyloxy, a halogen atom such as chloro, bromo and iodo, a hydroxyl group, a benzyloxy group, an amino group, a mono- or di-C _1-4 alkylamino group as described above, A nitro group, a C _1-6 alkyl-carbonyl group as described above, a benzoyl group and the like are used. ) And the like are used. These C
_6-14 The number of the substituents which may be substituted on the aryl group is appropriately about 1 to 5. R ¹ , R ² , R ³ , R ⁴ , R ⁵
And 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 _1-6 alkyl group represented by R ⁶ As the substituent which may be possessed, for example, the same substituents as the substituent which may be possessed by the above-mentioned C _6-14 aryl group and the like are used. Even if these C _7-18 aralkyl, C _6-14 aryl-C _2-12 alkenyl, C _6-14 aryl-C _2-12 alkynyl and C _3-7 cycloalkyl-C _1-6 alkyl groups have The number of good substituents is suitably about 1 to 5.

Further, R ³ and R ⁴ together with the adjacent nitrogen atom may form a heterocyclic group which may have a substituent.
As the "heterocyclic group" of the "heterocyclic group optionally having substituent (s)", for example, in addition to the carbon atom and one nitrogen atom, for example, a hetero atom such as nitrogen, oxygen or sulfur atom is 1
A heterocyclic group which may contain 3 to 3 is used,
Particularly, a 3- to 13-membered heterocyclic group is often used. Specifically, for example, saturated monocyclic, non-conjugated unsaturated monocyclic, unsaturated monocyclic, polycyclic and bridged cyclic heterocyclic groups are used. Examples of the saturated monocyclic heterocyclic group include pyrrolidinyl, piperidinyl, hexamethyleneiminyl, heptamethyleneiminyl, oxazolidinyl, morpholinyl, thiazolidinyl, thiomorpholinyl, imidazolidinyl,
A 5- to 9-membered saturated monocyclic heterocyclic group such as piperazinyl and homopiperazinyl is used. Examples of the non-conjugated unsaturated monocyclic or unsaturated monocyclic heterocyclic group include pyrrolyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyrroyl. Zinyl, 2-
A 5- to 9-membered non-conjugated unsaturated monocyclic or unsaturated monocyclic heterocyclic group such as oxazolidonyl, 2-thiazolidonyl, imidazolyl, pyrazolyl, 1,4,5,6-tetrahydropyrimidinyl is used. Examples of the polycyclic heterocyclic group include 2,3-dihydro-1H-indolyl, 1,
2,3,4-tetrahydroquinolinyl, 2,3,4,5-tetrahydro-1H-1-benzazepinyl, 2,3-dihydro-1H-isoindolyl, 1,2,3,4-tetrahydroisoquinolinyl 2,3,4,5-tetrahydro-
1H-2-benzazepinyl, 2,3,4,5-tetrahydro-1H-3-benzazepinyl, 1,2,3,4,5
6-hexahydro-1-benzazocinyl, 1,2,3,
4,5,6-hexahydro-2-benzazocinyl, 1,
2,3,4,5,6-hexahydro-3-benzazocinyl, 2,3,4,5,6,7-hexahydro-1H-1-benzazonyl, 2,3,4,5,6,7-hexahydro- 1
H-2-benzazonyl, 2,3,4,5,6,7-hexahydro-1H-3-benzazonyl, 2,3,4,5
6,7-Hexahydro-1H-4-benzazonyl, β
-Carbolinyl, phenoxazinyl, phenothiazinyl, indolyl, 3H-3-benzazepinyl, 3,4
-Dihydroquinolinyl, benzimidazolyl, 1,4-
Polycyclic heterocyclic groups such as benzodiazepinyl are used. Examples of the bridged cyclic heterocyclic group include 1,8-diazaspiro [4.5] decanyl, 2,8-diazaspiro [4.
5] decanyl, 1,3,8-triazaspiro [4.5] decanyl, 1,5,9-triazaspiro [5.5] undecanyl, 1-oxa-3,9-diazaspiro [5.5] undecanyl, 7- Azabicyclo [2.2.1] heptanyl,
A bridged cyclic heterocyclic group such as 8-azabicyclo [3.2.1] octanyl and 9-azabicyclo [3.3.1] nonanyl is used. Examples of the “heterocyclic group” of the “heterocyclic group optionally having a substituent” which R ³ and R ⁴ may form together with the adjacent nitrogen atom include, for example, the saturated monocyclic heterocyclic group described above, A polycyclic heterocyclic group or a bridged cyclic heterocyclic group is preferable. Specifically, for example, pyrrolidinyl, piperidinyl,
Piperazinyl, morpholinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 2,3,4,5-tetrahydro-1H-1-benzazepinyl, 2,3 , 4,5-Tetrahydro-1H-2
-Benzazepinyl, 2,3,4,5-tetrahydro-1
H-3-benzazepinyl, 1,3,8-triazaspiro [4,5] decanyl and the like are preferable, and particularly pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,
2,3,4-Tetrahydroquinolinyl is often used.

The "substituent" of the "heterocyclic group optionally having substituent (s)" which R ³ and R ⁴ may form together with the adjacent nitrogen atom is, for example, R ¹ , R ² , R ³ , R ⁴ ,
The hydrocarbon group which may have a substituent described for R ⁵ and R ⁶ , a halogen atom (for example, fluoro, chloro, bromo, iodo, etc.), a nitro group, a cyano group, a 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 A group (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), C _1-4
Alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), C
_1-4 alkyl-sulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C
_1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxyl group, formyl group, C _1-6 alkyl-
Carbonyl group (eg, methylcarbonyl, ethylcarbonyl, propylcarbonyl, etc.), C _1-4 alkyl-carbonyloxy group (eg, acetyloxy, ethylcarbonyloxy, etc.), ω-oxo-ω- (tetrahydrobenzazepinyl) C _1-6 alkyl group (for example, 1-oxo-1- (tetrahydrobenzazepinyl) methyl, 2-oxo-2- (tetrahydrobenzazepinyl) ethyl, 3-oxo-3- (tetrahydrobenzazepi) (Nyl) propyl, etc.), a benzoyl group which may have a substituent (wherein the substituent is
For example, C _1-4 alkyl such as methyl and ethyl, halogen such as fluoro, chloro and bromo, C _1-4 alkoxy such as methoxy and ethoxy, mono- or di-C ₁ such as methylamino and dimethylamino. _-4 alkylamino, eg 5 such as piperidino, morpholino
To 7-membered cyclic amino group, 1 to 3 selected from nitro, hydroxy, etc. are used, and specific examples thereof include benzoyl, 4-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.), oxo group, saturated heterocyclic group ( For example pyridyl, pyridinyl, pyrazinyl,
1 to 5 selected from pyrimidinyl, quinolinyl, isoquinolinyl, naphthyridinyl, benzothiazolyl, benzoxazolyl, furanyl, thiophenyl, etc.)
Individually, preferably 1 or 2 is used. Above all,
Formyl, C _1-4 alkyl-carbonyloxy group (eg, acetyloxy, etc.), hydroxy group, oxo group,
Pyridinyl group, benzoyl group which may have a substituent (for example, benzoyl group which may be substituted with halogen such as fluoro, chloro and bromo), ω-oxo-ω- (tetrahydrobenzazepinyl) C _1-6 alkyl groups (eg 1-oxo-1- (tetrahydrobenzazepinyl) methyl, 2-oxo-2- (tetrahydrobenzazepinyl) ethyl, 3-oxo-3- (tetrahydrobenzazepi) Nyl) propyl, etc.), R ¹ above,
The hydrocarbon group which may have a substituent as described for R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is preferable. put it here,
Examples of the hydrocarbon group which may have a substituent described in R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ include halogen (eg, fluoro, chloro, bromo, etc.), hydroxy group , C _1-4 alkylenedioxy (eg methylenedioxy) and pyridinyl and the like, which may be substituted with 1 to 3 linear or branched C _1-11 alkyl group (especially Linear or branched C _1-7
Alkyl groups such as methyl, ethyl, n-propyl, i
-Propyl, i-butyl, n-butyl, tert-butyl,
n-pentyl, n-hexyl etc.), heterocycle-C _1-3 alkyl group (eg thiazolylmethyl, furanylmethyl etc.), or C _7-18 aralkyl group (eg phenylmethyl, phenylethyl, phenylpropyl, phenylhexyl etc.) Phenyl-C _1-12 alkyl, naphthyl-C _1-8 alkyl such as α-naphthylmethyl, diphenyl-C _1-8 alkyl such as diphenylmethyl, etc., especially C
_7-10 aralkyl groups such as phenylmethyl, phenylethyl, phenylpropyl, etc. are commonly used.

The "acyl group" of the "acyl group optionally having a substituent" represented by R ¹ is, for example, a carboxylate acyl group (for example, formyl, C such as acetyl, propionyl, butyryl, benzoyl and the like). _1-8 alkyl-
Carbonyl or C _6-14 aryl-carbonyl etc.),
Sulfonyl acyl group (eg, C _1-7 alkylsulfonyl such as methanesulfonyl, ethanesulfonyl, propanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, etc., or C _6-14 arylsulfonyl), phosphonate acyl group (eg, methanephosphon) cycloalkenyl, Etanhosuhoniru, propane phosphonyl, etc. C _1-7 alkylphosphonyl or C _6-14 aryl phosphonyl such as benzene phosphonyl), substituted oxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyl C _1-8 alkoxycarbonyl such as oxycarbonyl or C _7-18 aralkyloxy-carbonyl etc., a heterocyclic carbonyl group (wherein the heterocycle has 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen) 5 or A 6-membered ring is preferable, as the heterocyclic carbonyl group, for example, pyridylcarbonyl, pyrrolylcarbonyl, quinolylcarbonyl, etc., carbamoyl group, mono- or di-C _1-4 alkyl-carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, etc.) ) And the like are used. Among them, the above-mentioned C _1-8 alkyl-carbonyl, C _1-8 alkoxycarbonyl and the like are preferable. Examples of the substituent which these acyl groups may have include a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), an amino group, a mono- or di-
C _1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, hexylamino, dimethylamino, diethylamino, etc.), C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, etc.) and the like. 1-3 are used, preferably 1-2. The benzene ring represented by ring A has the formula

[Chemical Formula 39] In addition to being substituted by, it may further have a substituent, and examples of such a substituent include, for example, R ¹ , R ² and
The substituents and the like mentioned for the C _6-14 aryl group of R ³ , R ⁴ , R ⁵ and R ⁶ are used, and the number thereof is 1 to 3. Preferred examples of the substituent which the benzene ring may further have include, for example, halogen such as fluoro and chloro, and halogeno-C such as trifluoromethyl.
_Examples include C _1-3 alkyl such as _1-3 alkyl and methyl, and C _1-3 alkoxy such as methoxy. Especially for example fluoro
Are preferred. n represents an integer of 1 to 10. However, when k = 0 and m = 2, n> 1. As n,
An integer of 2 to 10 is preferable, and an integer of 2 to 8 is particularly preferable. k represents an integer of 0 to 3. m is 1 to 8
Indicates an integer. That is, the ring

[Chemical 40] Can form a 4- to 14-membered ring.

X ¹ represents R ¹ -N <(R ¹ has the same meaning as described above), an oxygen atom or a sulfur atom. R ¹ is (i) a hydrogen atom, or (ii) a C _1-11 chain hydrocarbon group which may have a substituent described in the above “hydrocarbon group which may have a substituent”. (For example, methyl, ethyl, n
Straight-chain or branched C _1-11 alkyl group such as -propyl, i-propyl, i-butyl, n-butyl, etc., straight-chain or branched C _2-4 such as vinyl, aryl, 2-butenyl, etc.
Alkenyl group, straight-chain or branched C _2-4 alkynyl group such as propargyl, 2-butynyl, etc., among them, C _1-4 alkyl group optionally substituted by hydroxy group, C, etc.
_2-4 alkenyl group and the like are preferable), (iii) C _7-18 aralkyl group which may have a substituent described in the above-mentioned "hydrocarbon group which may have a substituent" (eg phenyl) Methyl, (4-methoxyphenyl) methyl, phenylethyl, phenylpropyl, α-naphthylmethyl, etc., among them C _1-4 alkyl (methyl, ethyl, etc.), halogen,
Phenyl optionally substituted with 1 to 3 selected from nitro, cyano, hydroxy, C _1-4 alkoxy (methoxy, ethoxy, etc.) and phenyl-C _1-3 alkoxy (phenylmethoxy, phenylethoxy, etc.) -C
_1-3 alkyl group etc.), (iv) formyl group,
(V) C _1-4 alkyl-carbonyl (eg acetyl, propionyl, butyryl etc.), (vi) C _6-14 aryl-carbonyl (eg benzoyl etc.), (vii) C
_1-4 alkoxy-carbonyl (eg methoxycarbonyl, ethoxycarbonyl etc.), (viii) heterocyclic carbonyl (eg pyridylcarbonyl etc.), (ix) carbamoyl, (x) mono- or di-C _1-4 alkyl- Carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.) and the like are preferable. Among them, as R ¹ ,
Hydrogen atom; linear or branched C _1-4 alkyl group (eg, methyl, ethyl, n-propyl, i-propyl,
i-butyl, n-butyl); may be substituted with 1 to 3 selected from C _1-4 alkyl, halogen, nitro, cyano, hydroxy, C _1-4 alkoxy and phenyl-C _1-3 alkoxy. Good phenyl-C _1-3 alkyl groups (eg phenylmethyl, (4-methoxyphenyl) methyl, phenylethyl, phenylpropyl etc.); C _1-4 alkyl-carbonyls (eg acetyl, propionyl, butyryl); C _{6 -14} aryl-carbonyl (for example, benzoyl); C _1-4 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl) and the like are often used, and particularly hydrogen atom, C _1-4 alkyl group (for example, methyl, ethyl). , Propyl, i-propyl, i-butyl etc.), C _1-4 alkyl-carbonyl (eg acetyl etc.), 1 C Phenyl-C _1-3 alkyl optionally substituted with _1-4 alkoxy (for example, phenylmethyl, (4-methoxyphenyl) methyl, phenylethyl, etc.) and the like are commonly used, among others,
C _1-4 alkyl group such as i-butyl or one C _1-4
Phenyl-C _1-3 alkyl optionally substituted by alkoxy (eg methoxy) (eg phenylmethyl, (4-methoxyphenyl) methyl, phenylethyl etc.) and the like are most preferred as R ¹ .

R ² , R ⁵ and R ⁶ are hydrogen atoms,
A straight-chain or branched C _1-3 alkyl group (eg, methyl, ethyl, n-propyl, i-propyl), phenyl and the like are preferable, and a hydrogen atom is particularly frequently used. One of R ³ and R ⁴ is a hydrogen atom or a linear or branched C _1-4 alkyl group (eg, methyl, ethyl,
n-propyl, i-propyl, n-butyl), the other being linear or branched C _1-4 alkyl group, phenyl-C
_{The case of a 1-3} alkyl group (for example, phenylmethyl, phenylethyl, phenylpropyl) or a naphthyl-C _1-3 alkyl group (for example, α-naphthylmethyl) is preferable. Further, as R ³ and R ⁴ , each is a linear or branched C _1-4 which may be substituted with one hydroxy.
Alkyl groups (eg methyl, ethyl, 2-hydroxyethyl etc.) or phenyl-C _1-3 alkyl groups optionally substituted with 1 to 3 halogens (eg phenylmethyl, phenylethyl, 2-chloro-). (Phenylmethyl etc.) is also preferable. Also, R ³ and R ⁴
Is also preferable when it forms a heterocyclic group which may have a substituent together with the adjacent nitrogen atom, and particularly as the substituent, (i) formyl, (ii) C _1-4 alkyl-carbonyl group (for example, Acetyl), (iii) hydroxy group, (iv) oxo group, (v) pyridyl group, (vi) optionally substituted benzoyl group (for example, 1 to 3 fluoro, chloro, bromo, etc.) And optionally a halogen-substituted benzoyl group, and (vii) a linear or branched C _1-7 alkyl group which may have a substituent (for example, 1 to 3 hydroxy groups). Or substituted with a 5- or 6-membered heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen such as pyridyl, furyl, thiazol-4-yl, 2-methylthiazol-4-yl, etc. Even Methyl, ethyl, n-
Propyl, i-propyl, n-butyl, tert-butyl,
n-pentyl, n-hexyl, etc., (viii) optionally substituted phenyl (eg, halogen such as fluoro, chloro, bromo, hydroxy group, C _1-4 alkylenedioxy such as methylenedioxy) , Phenyl optionally substituted with 1 to 3 selected from C _1-4 alkoxy such as methoxy), (ix) optionally substituted C _7-18 aralkyl group (eg fluoro) Phenylmethyl optionally substituted with 1 to 3 selected from halogen such as chloro, bromo, hydroxy group, C _1-4 alkylenedioxy such as methylenedioxy, C _1-4 alkoxy such as methoxy, etc. , phenylethyl, phenylpropyl, naphthyl -C _1-8 alkyl or diphenyl such as phenyl -C _1-12 alkyl, alpha-naphthylmethyl, such as phenyl hexyl Diphenyl -C _1-8 alkyl such Rumechiru), (x) ω- oxo -ω
-(Tetrahydrobenzazepinyl) C _1-6 alkyl (eg 1-oxo-1- (tetrahydrobenzazepinyl) methyl, 2-oxo-2- (tetrahydrobenzazepinyl) ethyl, 3-oxo- 3- (tetrahydrobenzazepinyl) propyl, etc.) as 1 or 2
Optionally (preferably 1) pyrrolidinyl,
Piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, 1,2,3,4-tetrahydroquinolinyl, 1,
2,3,4-tetrahydroisoquinolinyl, 2,3,4,5
-Tetrahydro-1H-1-benzazepinyl, 2,3,
4,5-Tetrahitoro-1H-2-benzazeponyl, 2,3,4,5-tetrahydro-1H-3-benzazepinyl, 1,3,8-triazaspiro [4.5] decanyl and the like, particularly pyrrolidinyl, piperidinyl, piperazinyl, Morpholinyl, 1,
2,3,4-tetrahydroquinolinyl and the like are preferable.
R ³ and R ⁴ together with the adjacent nitrogen atom are 4-
(Phenylmethyl) -piperazin-1-yl or 4-
Most preferred is the formation of [(2-methylthiazol-4-yl) methyl] -piperazin-1-yl.

The benzene ring represented by ring A is preferably unsubstituted. k and m are the sum of k and m (k + m)
Is an integer from 2 to 6, that is,

[Chemical 41] Preferably forms a 5- to 9-membered ring. Further, as a combination of k and m, when k is 0, m is 2, 3, 4 or 5, and when k is 1, m is 1, 2 or
Alternatively, 3 is preferable, and when k is 2, m is preferably 2. Ie

[Chemical 42] Examples of the nitrogen-containing condensed heterocycle represented by are 2,3-dihydro-1H-indole, 1,2,3,4-tetrahydroquinoline, 2,3,4,5-tetrahydro-1H-1-benzazepine, 2 , 3-Dihydro-1H-isoindole, 1,2,3,4-tetrahydroisoquinoline, 2,3,
4,5-tetrahydro-1H-2-benzazepine, 2,
3,4,5-tetrahydro-1H-3-benzazepine,
1,2,3,4,5,6-hexahydro-1-benzazocine, 1,2,3,4,5,6-hexahydro-2-benzazocine, 1,2,3,4,5,6-hexahydro- 3-benzazocine, 2,3,4,5,6,7-hexahydro-1H
-1-benzazonin, 2,3,4,5,6,7-hexahydro-1H-2-benzazonin, 2,3,4,5,6,
7-hexahydro-1H-3-benzazonin, 2,
3,4,5,6,7-hexahydro-1 H-4-benzazonin, etc., especially 2,3,4,5-tetrahydro-1
H-3-benzazepine, 2,3,4,5-tetrahydro-1H-2-benzazepine, 2,3-dihydro-1H
-Indole and the like are preferred.

[Chemical 43] [In the formula, R ¹ has the same meaning as described above. ] And a nitrogen-containing condensed heterocycle represented by the following. Here, R ¹ is, for example, a hydrogen atom, a C _1-4 alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, etc.), or phenyl optionally substituted with one C _1-4 alkoxy. −
C _1-3 alkyl group (for example, phenylmethyl, (4-methoxyphenyl) methyl, phenylethyl, phenylpropyl) or C _1-3 alkyl-carbonyl (for example,
Acetyl etc.) and the like are preferable. n is an expression

[Chemical 44] Is preferably an integer of 3 to 8 when it does not form a heterocycle, and n is preferably an integer of 2 to 5 when it forms a heterocycle. R ¹ -N <is preferable as X ¹ . More specifically, the following compounds belonging to the compound of formula (I) and salts thereof are preferred.

[0022]

[Table 1]

[0023]

[Table 2]

[0024]

[Table 3]

[0025]

[Table 4]

[0026]

[Table 5]

[0027]

[Table 6]

[0028]

[Table 7]

[0029]

[Table 8]

[0030]

[Table 9]

[0031]

[Table 10]

[0032]

[Table 11]

[0033]

[Table 12]

[0034]

[Table 13]

[0035]

[Table 14]

[0036]

[Table 15]

[0037]

[Table 16]

[0038]

[Table 17]

[0039]

[Table 18]

[0040]

[Table 19]

[0041]

[Table 20]

[0042]

[Table 21]

[0043]

[Table 22]

[0044]

[Table 23]

[0045]

[Table 24]

[0046]

[Table 25]

[0047]

[Table 26]

[0048]

[Table 27]

[0049]

[Table 28]

[0050]

[Table 29]

[0051]

[Table 30]

[0052]

[Table 31]

[0053]

[Table 32]

[0054]

[Table 33]

[0055]

[Table 34]

In the table, Ac represents an acetyl group and Ph represents a phenyl group.

The salts of the compounds [I] and [VII] of the present invention are preferably physiologically acceptable acid addition salts. Such salts include, for example, inorganic acids (for example,
Salts with hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) or organic acids (eg acetic acid, formic acid, propionic acid, fumaric acid,
Maleic acid, succinic acid, tartaric acid, citric acid, malic acid,
Salts with oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, etc. are used. Further, when the compounds [I] and [VII] of the present invention have an acidic group such as —COOH, the compounds [I] and [VII] are inorganic bases (for example, sodium, potassium, calcium, magnesium and the like). Salts may be formed with ammonia) such as alkali metals or alkaline earth metals) or with organic bases (such as tri-C _1-3 alkylamines such as triethylamine).

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 salts thereof described above, but in the following description, it is simply referred to as the compound [I]. The compound [I] has, for example, the formula

[Chemical formula 45] [Each symbol in the formulas has the same meaning as described above. ] The compound or its salt represented by these, and a formula

[Chemical formula 46] [Each symbol in the formulas has the same meaning as described above. ] It can manufacture by making the compound or its salt represented by these react. Examples of the leaving group represented by Y in the formula [II] 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.) and the like are used. Of these, a halogen atom is preferable. More specifically, Y is preferably halogen such as chlorine or bromine. Compound [I
Examples of the salts of I] and [III] include salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid), or organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid). Acid, succinic acid, tartar liquor, citric liquor, apple liquor, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) and salts thereof are used. Furthermore, when the compounds [II] and [III] of the present invention have an acidic group such as -COOH, the compounds [II] and [III] are inorganic bases (for example, sodium, potassium, calcium, magnesium, etc.). Alkali metals or alkaline earth metals such as ammonia) or organic bases (such as tri-C _1-3 alkylamines such as triethylamine) may form salts.

The amount of the compound [III] or a salt thereof used in this reaction is usually 1.0 to 50.0 moles, preferably 1.0 to 5 moles, relative to 1 mole of the compound [II] or a salt thereof.
It is 10.0 times the molar amount. This reaction can be carried out under cooling or heating (0 ° C to 120 ° C). The reaction time is generally 10 minutes to 48 hours, preferably 2 to 16 hours. This reaction can be carried out without using a solvent, but if necessary, the reaction can be carried out in a solvent.
As such a solvent, any solvent may be used so long as it does not inhibit the progress of this reaction. For example, lower alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol and t-butanol, dioxane and ether, Ethers such as tetrahydrofuran, aromatic hydrocarbons such as toluene, benzene and xylene, dimethylformamide, dimethylacetamide,
Amides such as hexamethylphosphonotriamide and esters such as ethyl acetate and butyl acetate are used. The amount of the solvent used is usually 0.5 to 100 ml, preferably 5 per 1 mmol of the compound [II] or a salt thereof.
~ 20 ml. Further, 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, pyridine, 4-dimethylaminopyridine, triethylamine and the like. There are organic bases. The amount of the base used is usually an equimolar amount to an excess amount, preferably 1.0 to 5.0 times the molar amount of the compound [III] or a salt thereof. Further, this reaction may be accelerated in the presence of an iodide compound (eg, sodium iodide, potassium iodide, lithium iodide) and the like, if desired. In that case, the amount of the iodide compound to be used is usually 1 to 5 times molar equivalents, preferably 1.
The amount is 0 to 1.5 times the molar amount.

[0060] Further, compounds wherein R ¹ is an acyl group which may have a hydrocarbon may have a substituent hydrogen group or a substituent [I] or a salt thereof, R ¹ is hydrogen atom Compound [I] (R = H) or a salt thereof and formula R ¹ ′ -Y ² [VIII] [wherein R ¹ ′ has a hydrocarbon group which may have a substituent or a substituent) Optionally represents an acyl group, Y ²
Represents a leaving group. ] It can also manufacture by reacting with the compound represented by these or its salt. Examples of the salt of compound [VIII] include salts with inorganic acids (for example, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid), or organic acids (for example, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, Salts with succinic acid, tartar liquor, citric liquor, apple liquor, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) are used. Further, the compound of the present invention [VI
When [II] has an acidic group such as -COOH, the compound [VIII] is an inorganic base (for example, alkali metal or alkaline earth metal such as sodium, potassium, calcium, or magnesium, ammonia) or an organic base. A salt may be formed with a base (eg, a tri-C _1-3 alkylamine such as triethylamine). Examples of the leaving group represented by Y ² include a halogen atom (eg, chlorine, bromine, iodo), C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy), C _6-10 arylsulfonyloxy. (For example, benzenesulfonyloxy, p-toluenesulfonyloxy) and the like are used. A halogen atom is particularly preferable.

As the hydrocarbon group which may have a substituent represented by R ¹ ′, for example, the above-mentioned hydrocarbon group which may have a substituent represented by R ¹ and the like can be used. As the optionally substituted acyl group represented by R ¹ ′, for example, the aforementioned optionally substituted acyl group represented by R ¹ is used. As the reaction conditions, for example, the same reaction conditions as those of the compound [II] or a salt thereof and the compound [III] or a salt thereof can be used. Furthermore, the compound [I] (R = H) or a salt thereof is prepared by reacting the compound [I] or a salt thereof in which R ¹ is an acyl group which may have a substituent, in the same manner as in a general hydrolysis reaction. It can also be produced by hydrolysis with an acid or a base.

The starting compound [II] or a salt thereof has, for example, the formula

[Chemical 47] [In the formula, each symbol has the same meaning as described above. ] The compound or its salt represented by these, and a formula

[Chemical 48] [In the formula, Y¹Is a leaving group, and other symbols have the same meanings as above.
Indicates. ] By reacting with a compound represented by
Can be manufactured. As a salt of compound [IX]
Are, for example, inorganic acids (eg hydrochloric acid, phosphoric acid, hydrogen bromide
Salts with acids and sulfuric acids, or organic acids (eg acetic acid, guinea acid)
Acid, propionic acid, fumaric acid, maleic acid, succinic acid,
Tartar liquor, citric liquor, apple liquor, oxalic acid, benzoic acid, methane
Sulfonic acid, benzene sulfonic acid) and salts are used
It Further, the compound [IX] of the present invention is
When it has an acidic group, compound [IX] is an inorganic base.
(Eg sodium, potassium, calcium, magne
 Do not use alkali metals such as sium or alkaline earth metals.
, Ammonia) or organic base (eg triethyl acetate)
Tri-C such as Min_1-3Form salt with alkylamine etc.)
May be done. Y¹For example, the leaving group represented by
For example, halogen atom (for example, chlorine, bromine, iodine),
C_1-6Alkylsulfonyloxy (eg, methanesulfur
Honyloxy, ethanesulfonyloxy), C_6-10Ants
Sulfonylsulfonyl (eg benzenesulfonyloxy)
, P-toluenesulfonyloxy) and the like are used.
It A halogen atom is particularly preferable. Compound [IX] or
The salt is a method known per se or a method analogous thereto.
Can be manufactured by. For example, journal
Buji Organic Chemistry (J. Org. Che
m.)34, 2235 (1969), Journal of the Objects
  Organic Chemistry (J. Org. Chem.)5
Four, 5574 (1989), Tetrahedron Letters
(Tetrahedron Lett.)35, 3023 (1977),
Retin Of The Chemical Society Of
Japan (Bull. Chem. Soc. Jpn.)56, 2300 (1
983) and the like.
It Compound [X] can be produced by a method known per se or
It can be produced by a similar method.

Compound [IX] or a salt thereof and compound [X]
The reaction with, for example, compound [X] is usually used in an amount of about 1 to 20 times, preferably about 1 to 5 times the amount of compound [IX] or a salt thereof in the presence of, for example, a Lewis acid. It can be carried out by reacting. This reaction can be carried out without using a solvent, or by reacting in a solvent if necessary. As the solvent, any solvent can be used so long as it can generally be used in a chemical reaction as long as it does not interfere with the reaction. For example, a hydrocarbon solvent (eg, pentane, hexane, benzene, toluene, nitrobenzene, etc.), halogenated Hydrocarbon solvent (eg, dichloromethane, chloroform, 1,2-
Dichloroethane, carbon tetrachloride, etc.), ether solvents (eg ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane etc.), nitroalkanes (eg nitromethane, propionitrile etc.), organic solvents such as carbon disulfide etc. are used. . Particularly, dichloromethane, 1,2-dichloroethane, nitrobenzene, carbon disulfide and the like are preferable. The amount of the solvent used is usually 0.5 to 1 per 1 mmol of the compound [IX] or a salt thereof.
It is 00 ml, preferably 5 to 20 ml. The reaction temperature is generally about -30 ° C to 150 ° C, preferably 20 ° C to 100 ° C.
It is about ℃. 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, zinc chloride, titanium chloride, tin chloride (IV), boron trifluoride, iron chloride (II), iron chloride (III), antimony pentachloride (V). ), Bismuth (III) chloride, mercury (II) chloride, hydrogen fluoride, sulfuric acid, polyphosphoric acid and the like are used, and among them aluminum chloride and the like are preferable. The amount of the Lewis acid used is usually 1 to 10 mol, preferably 2 to 10 mol, per 1 mol of compound [IX] or a salt thereof.

In the above reaction, the group in the compound [X] is

[Chemical 49] The position at which compound is introduced into compound [IX] or a salt thereof is introduced into any of the substitutable positions of ring A. For example, the skeleton of compound [IX] or a salt thereof is In the case of tetrahydroquinoline (where ring A is unsubstituted), mainly 6
Is introduced to the rank. However, other positions (5th, 7th, 8th)
The compound introduced into the position can also be produced and separated. The compound [II] or a salt thereof thus obtained can be isolated and purified by known means such as concentration, liquid conversion, phase transfer, solvent extraction, fractional distillation, distillation, crystallization, recrystallization, chromatography and the like. However, the reaction mixture may be directly used as a raw material for the next step without isolation. The starting compound [III] or a salt thereof can be produced by a method known per se or a method analogous thereto.
Compound [VIII] or a salt thereof can be produced by a method known per se or a method analogous thereto.

Further, among the compounds [I], a compound in which n is 2, that is, a compound of the formula

[Chemical 50] [In the formula, each symbol has the same meaning as described above. ] The compound or salt thereof represented by the formula

[Chemical 51] [Each symbol in the formulas has the same meaning as described above. Compound or a salt thereof represented by], wherein R ⁶ -CHO [V] [wherein, R ⁶ is as defined above. ] The compound represented by

[Chemical 52] [Each symbol in the formulas has the same meaning as described above. ] It can also manufacture by reacting with the compound represented by these or its salt. The salt of the compound [IV], for example, a salt with an inorganic acid (for example, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid), or an organic acid (for example, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, Succinic acid, tartar liquor, citric liquor, apple liquor, oxalic acid, benzoic acid, methanesulfonic acid,
A salt with benzenesulfonic acid) is used. Further, when the compound [IV] of the present invention has an acidic group such as —COOH, the compound [IV] is an inorganic base (for example, alkali metal or alkaline earth metal such as sodium, potassium, calcium, magnesium). Such as ammonia)
Alternatively, an organic base (for example, triethylamine or other tri-
A salt may be formed with a C _1-3 alkyl amine or the like). This reaction is, for example, Organic Reaction, Volume 1,
It can be carried out in the same manner as the Mannich reaction method described in p303 to 341. Specifically, for example, compound [V] and compound [III] or a salt thereof are usually used in an amount of 0.9 to 10 equivalents, preferably 1.0 to 3.0, relative to 1 equivalent of compound [IV] 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.), preferably 80 to 120 ° C.
The reaction time is generally 1 to 48 hours, preferably 2 to 24 hours. This reaction can be performed usually without a solvent or using a solvent. As the solvent, any solvent generally used in the Mannich reaction can be used as long as it does not interfere with this reaction, and an alcohol solvent such as ethanol is often used. The amount of the solvent used is usually 0.5 to 200 ml, preferably 5 to 40 ml, relative to 1 mmol of the compound [IV] 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 amount of the acid used is a catalytic amount (0.001 to 0.05 equivalents relative to 1 equivalent of the compound [IV]) with respect to the compound [IV] or a salt thereof. However, when the compound [III] or [IV] used in the reaction does not form a salt, it is preferable to use an extra amount of the acid used for forming a salt of these compounds. Compound [IV] or a salt thereof and compound [V] can be produced by a method known per se or a method analogous thereto.

Further, the compound [I] or a salt thereof can be obtained by the above-mentioned method, for example, a compound of the formula

[Chemical 53] [In the formula, each symbol has the same meaning as described above. It can also be produced by hydrolyzing the ester portion (COOR ² ) of the compound represented by the above formula or a salt thereof, and then decarboxylation. The hydrolysis and decarboxylation reaction can be carried out according to a method known per se. In addition, compound [I] or a salt thereof can also be produced, for example, by reducing compound [I] or a salt thereof in which R ¹ is a carboxylic acid acyl group according to a conventional method. In this reaction,
If necessary, the functional group (eg, ketone) of the compound [I] (R ¹ = carboxylic acid acyl group) may be converted to, for example, ethylene glycol or another alcohol (eg, methanol,
It is preferable that the acetal is protected with acetic acid (eg, ethanol), and then deprotected with an acid, a base, or heating after the reduction reaction.

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 formyl which may have a substituent, C _1-6 alkyl-carbonyl (eg, acetyl,
Ethylcarbonyl etc.), benzoyl, C _1-6 alkyl-oxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl etc.), phenyloxycarbonyl (eg phenoxycarbonyl etc.), C _7-15 aralkyloxy-carbonyl (eg benzyl) Oxycarbonyl, fluorenyloxycarbonyl, etc.), trityl,
For example, phthaloyl is used. As these substituents, a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), a nitro group, etc. are used. The number of substituents is about 1 to 3. Examples of the protective group for the carboxyl group include C _1-6 alkyl _optionally having a substituent (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.), phenyl, Trityl, silyl and the like are used. As these substituents, a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), formyl, C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl,
(Butylcarbonyl, etc.), nitro group, etc. are used, and the number of substituents is about 1 to 3. Examples of the hydroxyl-protecting group include C which may have a substituent.
_1-6 alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.),
Phenyl, C _7-10 aralkyl (eg benzyl etc.), formyl, C _1-6 alkyl-carbonyl (eg acetyl, ethylcarbonyl etc.), phenyloxycarbonyl (eg phenoxycarbonyl etc.),
C _7-10 aralkyl-carbonyl (eg benzyloxycarbonyl etc.), pyranyl, furanyl, silyl and the like are used. As these substituents, a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.),
C _1-6 alkyl, phenyl, C _7-10 aralkyl, nitro group and the like are used, and the number of substituents is about 1 to 4. Further, as a method for removing the protective group, a method known per se or a method analogous thereto is used, and examples thereof include acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine,
A method of treating with sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like is used.

Further, the compound [VII] of the present invention or a salt thereof is, for example, the starting compound [II], [IV] and [IX].
Or the groups in their salts

[Chemical 54] But

[Chemical 55] Can be produced by using a compound similar to the above-mentioned compound [I] or a salt thereof.

The compound [I] or a salt thereof and the compound [VII] or a salt thereof thus obtained can be isolated and purified by an ordinary separation means such as recrystallization, distillation and chromatography. When thus obtained compound [I] or a salt thereof and compound [VII] or a salt thereof are obtained in a free form, it can be converted into a salt by a method known per se or a method analogous thereto, and conversely with a salt. When obtained, it can be converted into a free form or another salt by a method known per se or a method analogous thereto. The compound [I] or a salt thereof and the compound [VII] or a salt thereof include stereoisomers based on the presence of an asymmetric carbon atom, and these can be separated into an optically active form by a usual optical resolution means. it can.

The compound [I] or a salt thereof and the compound [VII] or a salt thereof of the present invention act on the central nervous system of mammals and have a strong cholinesterase inhibitory activity, and are effective in humans or animals (for example, mice). It exhibits an excellent anti-amnestic effect against various amnesia-inducing effects. Further, the compound [I] of the present invention or a salt thereof and the compound [VII] or a salt thereof have a monoamine (eg, norepinephrine, serotonin, etc.) reuptake inhibitory activity, and are excellent in human or animal. Shows actions such as depression. The compound [I] or a salt thereof and the compound [VII] or a salt thereof of the present invention have an excellent separation between the action on the central nerve and the action on the peripheral nerve as compared with physostigmine, and have anti-amnestic action and antidepressant action. In the dose showing the action of, there is no convulsive action, salivation action, peripheral nerve action such as diarrhea, or it is extremely slight, the action duration is long, the toxicity is low, and it is markedly effective by oral administration. The acute toxicity (LD ₅₀ ) of the compound [I] or its salt and [VII] or its salt of the present invention is 100 mg.
/ Kg or more. Therefore, the compound of the present invention is useful as a safe drug for improving brain function in mammals including humans. Examples of useful target diseases of the compound of the present invention include senile dementia, Alzheimer's disease, Huntington's chorea, hyperkinesia, and mania.
It can be used for the prevention or treatment of the above-mentioned diseases. In addition, the compound of the present invention is effective not only for the learning and memory disorders of the above-mentioned diseases, but also for the related symptoms such as depression, decreased motivation, emotional disorders, and decreased spontaneous activity. The compound of the present invention is usually formulated with a pharmaceutically acceptable carrier or excipient and may be orally or parenterally administered to mammals including humans. The dosage form of the preparation may be either an oral preparation (eg powder, tablets, granules, capsules) or a parenteral preparation (eg suppositories, injections). These preparations can be prepared by a method known per se. The dose varies depending on the type and symptom of the target disease, but generally in adults (as of 60 kg), when administered orally, it is about 0.0 per day.
It is 1 mg to 50 mg, preferably 0.1 to 30 mg, and more preferably 0.5 to 10 mg.

[0071]

EXAMPLES The present invention will be described in more detail below with reference to Examples, Reference Examples, Formulation Examples and Experimental Examples, but the present invention is not limited thereto. Elution by column chromatography in Experimental Examples and Reference Examples was performed under observation by TLC (Thin Layer Chromatography) unless otherwise specified. For TLC observation, Merck as a TLC plate
The company made 60F _254, a solvent used as an elution solvent in column chromatography as a developing solvent, employing a UV detector as a detection method. Also, 48% HBr was sprayed on the spot on the TLC plate, heated and hydrolyzed, then sprayed with ninhydrin reagent, and heated again to change from red to magenta, which is also used as a detection method. The elution fraction containing the substances was confirmed and collected. Unless otherwise specified, silica gel for columns is Kieselgel 6 manufactured by Merck.
0 (70-230 mesh) was used. In addition, "normal temperature"
Alternatively, “room temperature” usually means about 5 ° C. to 40 ° C., and “normal pressure” means around 1 atm. Also,
Unless otherwise specified,% indicates weight percentage.

Reference Example 1 4-chloro-1- (3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) -1-
Butanone

[Chemical 56] 3-Acetyl-2,3,4,5-tetrahydro-1H-3
-Benzazepine (3.79 g) was dissolved in dichloromethane (30 ml), 4-chlorobutyryl chloride (3.38 g) and aluminum chloride (4.00 g) were added, and the mixture was stirred at room temperature (about 20 ° C) for 2 hours. The reaction solution was poured into 50 ml of ice water and the organic layer was separated, and 50 ml of 0.5 N sodium hydroxide aqueous solution and 50 m of pure water were added.
After washing with l and drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 5.40 g of an oily residue. The residue was purified by silica gel chromatography (developing solvent ethyl acetate-dichloromethane 1: 1 (V / V)) to obtain 2.92 g of the title compound as colorless crystals with a melting point of 103-106 ° C. Elemental analysis C ₁₆ H ₂₀ ClNO ₂ Calculated: C, 65.41; H, 6.86 ; N, 4.
77 Experimental value: C, 65.33; H, 6.91; N, 4.
69

Reference Example 2 The same operations as in Reference Example 1 were carried out to obtain the compounds shown in [Table 35].

[Table 35]

Reference Example 3 7-Acetyl-3- (phenylmethyl) -2,3,4,5-
Tetrahydro-1H-3-benzazepine

[Chemical 57] 2,3,4,5-Tetrahydro-1H-3-benzazepine 7.36 g, potassium carbonate 10.37 g and ethanol 7
5 ml was added, and 8.38 g of benzyl bromide was added dropwise under ice cooling over 10 minutes, and after the addition, the mixture was stirred at 25 ° C. for 2 hours. The solvent was distilled off, and the residue was purified with 100 ml of pure water and 100 ml of dichloromethane.
Was added thereto, the organic layer was separated, dried over sodium sulfate, and then the solvent was distilled off to obtain a crystalline residue. The residue was dissolved in 20 ml of methanol, 19 ml of 4N-methanolic hydrochloric acid was added, the methanol was distilled off, the residue was suspended in 100 ml of ethyl acetate, and the formed crystals were collected by filtration and washed with 30 ml of ethyl acetate. The crystals were dried under reduced pressure to obtain 11.94 g of 3- (phenylmethyl) -2,3,4,5-tetrahydro-1 H-3-benzazepine hydrochloride. The above compound (10.95 g) was dissolved in 1,2-dichloroethane (80 ml), aluminum chloride (10.67 g) and acetyl chloride (4.71 g) were added, and the mixture was stirred under reflux for 30 min. The reaction solution was poured into 150 ml of ice water, the pH of the aqueous layer was adjusted to pH 10, 150 ml of dichloromethane was added, the organic layer was separated and dried over sodium sulfate, and the solvent was distilled off to obtain 13.0 g of an oily residue. Silica gel chromatography (developing solvent)
Purification with ethyl acetate-dichloromethane 1: 2) gave 10.44 g of the title compound as colorless crystals with a melting point of 89-91 ° C. Elemental analysis value Calculated value for C ₁₉ H ₂₁ NO: C, 81.68; H, 7.58; N, 5.
01 Experimental value: C, 81.49; H, 7.61; N, 4.
86

Reference Example 4 Ethyl β- (1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl) -β-oxopropionate

[Chemical 58] (1) 1-Acetyl-2,3,4,5-tetrahydro-1H
First, 30.8 g of aluminum chloride and then 7.8 ml of acetyl chloride were gradually added to a solution of 18.9 g of -1-benzazepine in 20 ml of carbon disulfide at room temperature. After heating under reflux for 16 hours, the reaction was poured into ice water and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent was purified by chromatography (developing solvent; dichloromethane-ethyl acetate = 5: 1 (V / V)) to give pale yellow crystals. 13.5 g was obtained. Recrystallized from diethyl ether-hexane to give 1,8
-Diacetyl-2,3,4,5-tetrahydro-1H-1
-12.4 g of benzazepine were obtained as colorless crystals with a melting point of 105-108 ° C. Elemental analysis C ₁₄ H ₁₇ NO ₂ Calculated: C, 72.70; H, 7.41 ; N, 6.
Experimental value: C, 72.82; H, 7.36; N, 6.
00 (2) Diethyl carbonate 3.83 g and sodium hydride (oil-free) 1.04 g in a tetrahydrofuran 50 ml refluxing solution were charged with 1,8-diacetyl-2,3,4,5-under a nitrogen atmosphere.
A solution of 5 g of tetrahydro-1H-1-benzazepine in 50 ml of tetrahydrofuran was added dropwise. After heating under reflux for 3 hours, the reaction product was poured into ice water and extracted with dichloromethane.
The extract was dried over anhydrous sodium sulfate, the solvent was evaporated, and the resulting residue was purified by chromatography (developing solvent; dichloromethane-ethyl acetate = 5: 1 (V / V)) to give the title compound 3 Obtained 0.5 g as a colorless oil. Calculated elemental analysis _{C 17 H 21 NO 4: C} , 67.31; H, 6.98; N, 4.
62 Experimental value: C, 67.14; H, 6.83; N, 4.
63

Reference Example 5 The same operations as in Reference Example 1 were carried out to obtain the compounds shown in [Table 36].

[Table 36]

Reference Example 6 1- (3-Methyl-2,3,4,5-tetrahydro-1H
-3-benzazepin-7-yl) 2-propen-1-
On hydrochloride

[Chemical 59] 3-methyl-2,3,4,5-tetrahydro-1H-3-
1.28 g of benzazepine hydrochloride was dissolved in 30 ml of 1,2-dichloroethane, and aluminum chloride 2.1 was added at room temperature.
0.66 ml of g, 3-chloropropionyl chloride was added, and the mixture was stirred for 2 hours. The reaction solution was poured into 50 ml of ice water, the aqueous layer was adjusted to pH 9 or higher with a 40% aqueous sodium hydroxide solution, and then extracted with 50 ml of dichloromethane. The organic layer is pure water 50
After washing with ml, the extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain an oily residue. Crystallization from dichloromethane-ether gave 0.83 g of the title compound, mp 120-.
Obtained as pale yellow crystals at 123 ° C. Elemental analysis _{C 14 H 17 NO · HCl ·} H 2 O Calculated: C, 62.33; H, 7.47 ; N, 5.
19 Experimental value: C, 62.53; H, 7.65; N, 5.
Thirteen

Reference Example 7 The same operations as in Reference Example 1 were carried out to obtain the compounds shown in [Table 37].

[Table 37]

Reference Example 8 4-Bromo-1- (3-formyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) -2
-Phenyl-1-butanone

[Chemical 60] 2.93 g of the compound of Compound No. 1 obtained in Reference Example 7 was dissolved in 50 ml of dimethylformamide, 0.29 g of 60% sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes and then 4.33 ml of 1,2-dibromoethane was added. Stir for 5 hours. The reaction solution was poured into 150 ml of pure water and extracted with 150 ml of ethyl acetate. The organic layer was washed twice with 150 ml of saturated saline and then dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The oily residue was charged on silica gel (150 g) column chromatography and eluted with dichloromethane-ethyl acetate (4: 1) to obtain 1.05 g of the title compound as a colorless oil. Elemental analysis C ₂₁ H ₂₂ BrNO ₂ Calculated: C, 63.01; H, 5.54 ; N, 3.
50 Experimental value: C, 63.07; H, 5.62; N, 3.
53

Reference Example 9 Using the compound obtained in Reference Example 7, the same operation as in Reference Example 8 was carried out to obtain a compound shown in [Table 38].

[Table 38]

Example 1 1- (3-Acetyl-2,3,4,5-tetrahydro-1H
-3-benzazepin-7-yl) -4- (piperidine-
1-yl) -1-butanone

[Chemical formula 61] To a solution of 2.64 g of the compound obtained in Reference Example 1 in 50 ml of toluene was added 1.50 g of piperidine and 20 mg of KI, and the mixture was refluxed.
After stirring for a time and cooling the reaction solution, 50 ml of pure water was added to separate the organic layer and the solvent was distilled off to obtain an oily residue. The residue was purified by alumina chromatography (developing solvent ethyl acetate) to obtain 2.15 g of the title compound as a colorless powder. Elemental analysis C ₂₁ H ₃₀ N ₂ O ₂ Calculated: C, 73.65; H, 8.83 ; N, 8.
18 Experimental value: C, 73.60; H, 8.74; N, 8.
09

Example 2 1- [3- (phenylmethyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] -4-
(Piperidin-1-yl) -1-butanone dihydrochloride

[Chemical formula 62] 21 ml of concentrated hydrochloric acid was added to 2.10 g of the compound obtained in Example 1 and the mixture was heated under reflux for 16 hours. After distilling off excess concentrated hydrochloric acid under reduced pressure, 50 ml of water was added and washed with 50 ml of dichloromethane. The aqueous layer was made basic with an aqueous sodium hydroxide solution and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 1.80 g of an oily substance. A solution of 0.97 g of benzyl bromide in 5 ml of ethanol was added dropwise to a suspension of 1.80 g of the above oily substance, 1.30 g of potassium carbonate and 20 ml of ethanol, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, 30 ml of water was added, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 1.37 g of the free form of the title compound as a colorless powder with a melting point of 90-92 ° C. The obtained free form (1.0 g) was dissolved in methanol, 4N-methanolic hydrochloric acid (1.5 ml) was added, the solvent was evaporated under reduced pressure, and the obtained solid was recrystallized from methanol-ethyl acetate to give the title compound. 0.93 g was obtained as colorless crystals with a melting point of 210-215 ° C. (decomposition). Elemental analysis _{C 26 H 34 N 2 O ·} 2HCl Calculated: C, 67.38; H, 7.83 ; N, 6.
04 Experimental value: C, 67.12; H, 7.81; N, 6.
00

Example 3 Using the compound obtained in Reference Example 2, the same operation as in Example 1 was carried out to obtain the compound shown in [Table 39].

[Table 39]

Example 4 The compound shown in [Table 40] was obtained by using the compound obtained in Example 3 and performing the same operation as in Example 2.

[Table 40]

Example 5 1- [3- (phenylmethyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] -3-
(Piperidin-1-yl) -1-propanone dihydrochloride

[Chemical formula 63] To a solution of 1.40 g of the compound obtained in Reference Example 3, 1.22 g of piperidine hydrochloride, 1.5 g of paraformaldehyde and 50 ml of ethanol, 0.7 ml of concentrated hydrochloric acid was added, and the mixture was stirred under reflux for 24 hours. The solvent was distilled off, 50 ml of ethyl acetate and 50 ml of pure water were added, the aqueous layer was separated, and the pH was adjusted to 10 or more.
After extraction with water and drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 2.15 g of an oily residue. The residue was purified by alumina chromatography (developing solvent dichloromethane-ethyl acetate 9: 1) to obtain 1.4 g of an oily substance, which was dissolved in 15 ml of methanol and then 2.0 ml of 4N-methanolic hydrochloric acid was added to distill the solvent off. Recrystallization from ethyl acetate gave 1.05 g of the title compound as colorless crystals with a melting point of 163-165 ° C. Elemental analysis value Calculated as C ₂₅ H ₃₂ N ₂ O · 2HCl: C, 66.81; H, 7.62; N, 6.
23 Experimental value: C, 66.65; H, 7.64; N, 6.
17

Example 6 Using the compound obtained in Reference Example 3, the same operation as in Example 5 was carried out to obtain a compound shown in [Table 41].

[Table 41]

Example 7 7- [N-ethyl-N- (phenylmethyl) amino] -1
-(2,3,4,5-Tetrahydro-1H-1-benzazepin-8-yl) -1-heptanone fumarate

[Chemical 64] (1) Ethyl β- (1-acetyl-2, obtained in Reference Example 4
3,4,5-Tetrahydro-1H-1-benzazepine-
8-yl) -β-oxopropionate 1.7 g, 1,5
A mixture of 2.6 g of dibromopentane, 0.93 g of potassium carbonate and 50 ml of acetone was heated under reflux for 16 hours. After cooling, the solid was filtered off, the solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (developing solvent; dichloromethane-ethyl acetate = 10: 1 (V / V)). Ethyl β- (1-acetyl-2,3,4,5-
Tetrahydro-1H-1-benzazepin-8-yl)
1.8 g of -α- (5-bromopentyl) -β-oxopropionate was obtained as a viscous oil. Elemental analysis C ₂₂ H ₃₀ BrNO ₄ Calculated: C, 58.41; H, 6.68 ; N, 3.
10 Experimental value: C, 58.26; H, 6.63; N, 3.
04 (2) A solution of 0.5 g of the compound obtained in (1) and 0.3 g of N-ethylbenzylamine in 10 ml of toluene was heated under reflux for 24 hours. After cooling, the produced solid was filtered off, the solvent was distilled off under reduced pressure, and 30 ml of concentrated hydrochloric acid was added to the resulting residue. 24
After heating under reflux for an hour, excess concentrated hydrochloric acid was distilled off under reduced pressure, a 5% aqueous sodium hydroxide solution was added, and the product was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent was used for column chromatography (developing solvent; ethyl acetate-methanol = 20: 1 (V
/ V)) to give 55 mg of a colorless oil. 55 mg of the oil was treated with 16 mg of fumaric acid (1 equivalent) to give 60 mg of the title compound as an amorphous powder. Elemental analysis _{C 26 H 36 N 2 O ·} C 4 H 4 O 4 Calculated: C, 70.84; H, 7.93 ; N, 5.
51 Experimental value: C, 70.59; H, 8.04; N, 5.
47

Example 8 1- (3-Acetyl-2,3,4,5-tetrahydro-1H
-3-benzazepin-7-yl) -2- (piperidine-
1-yl) -1-ethanone hydrochloride

[Chemical 65] 1- (3-acetyl-2,3,4,5-obtained in Reference Example 2
Tetrahydro-1H-3-benzazepin-7-yl)
2.50 g of 2-chloro-1-ethanone was dissolved in 10 ml of dichloromethane, 1.7 ml of piperidine was added, and 1 was added at room temperature.
Stir for hours. It was poured into an aqueous potassium carbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain an oily residue. 5 ml of methanol was added to the residue to dissolve it, 1.7 ml of 4N-methanolic hydrochloric acid was added, and then the solvent was distilled off to obtain 1.50 g of the title compound as a colorless powder. Elemental analysis value Calculated as C ₁₉ H ₂₆ N ₂ O ₂ .HCl: C, 65.04; H, 7.76; N, 7.
98 Experimental value: C, 64.92; H, 7.81; N, 7.
87

Example 9 1- [3- (phenylmethyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] -2-
(Piperidin-1-yl) -1-ethanone dihydrochloride

[Chemical formula 66] 20 ml of concentrated hydrochloric acid is added to 1.40 g of the compound obtained in Example 8 and the mixture is stirred under reflux for 13 hours. The reaction solution was cooled to 25 ° C., 50 ml of pure water was added, washed with 50 ml of dichloromethane, the aqueous layer was adjusted to be basic with an aqueous sodium hydroxide solution, extracted with 50 ml of dichloromethane, dried over anhydrous sodium sulfate, and the solvent was distilled off to give an oily substance. 1.15 g was obtained. 0.50 g of the above oil,
A suspension of 0.31 g of potassium carbonate and 10 ml of ethanol was added dropwise with a solution of 0.30 g of benzyl bromide in 5 ml of ethanol, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off, 20 ml of dichloromethane and 20 ml of pure water were added, the organic layer was separated, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was diluted with methanol 1
The solid obtained by dissolving in 0 ml and adding 4 ml of 4N-methanolic hydrochloric acid and distilling off the solvent was recrystallized from methanol-ethyl acetate to give 0.2 g of the title compound as the melting point of 236-23.
Obtained as colorless crystals at 9 ° C. (decomposition). Elemental analysis value Calculated value as C ₂₄ H ₃₀ N ₂ O · 2HCl: C, 66.20; H, 7.41; N, 6.
43 Experimental value: C, 66.11; H, 7.39; N, 6.
38

Example 10 Using the compounds obtained in Reference Example 1 and Reference Example 5, the same operation as in Example 1 was performed [Table 42] [Table 4]
3] The compounds shown in [Table 44] and [Table 45] were obtained.

[Table 42]

[0091]

[Table 43]

[0092]

[Table 44]

[0093]

[Table 45]

Example 11 3- [4- (phenylmethyl) piperazin-1-yl]
-1- (2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl) -1-propanone trihydrochloride

[Chemical formula 67] Example 10 2.0 g of the compound of Compound No. 2 was dissolved in 100 ml of 6N hydrochloric acid, and the mixture was heated under reflux for 16 hours. The residue obtained by distilling off hydrochloric acid under reduced pressure was dissolved in water, neutralized with a 5% aqueous sodium hydroxide solution, and then extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated to give a residue, which was purified by column chromatography (developing solvent; ethyl acetate-methanol = 40: 1 (v / v)) to give the starting compound (free 1.2 g of the base compound and 0.3 g of the title compound (free base compound) were obtained. Treating 0.3 g of the title compound (free base form) with 3 equivalents of hydrochloric acid,
0.35 g of the title compound (trihydrochloride) was mp 145-14.
Obtained as a colorless powder at 9 ° C. Elemental analysis value Calculated as C ₂₄ H ₃₁ N ₃ O.3HCl: C, 59.20; H, 7.04; N, 8.
63 Experimental value: C, 59.04; H, 7.20; N, 8.
53

Example 12 1- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) -4- [4- (phenylmethyl)
Piperazin-1-yl) -1-butanone trihydrochloride

[Chemical 68] Example 10 Compound No. 17 1- (3-acetyl-2,
3,4,5-Tetrahydro-1H-3-benzazepine-
7-yl) -4- [4- (phenylmethyl) piperazin-1-yl] -1-butanone 2.17 g of concentrated hydrochloric acid 50 m
L was added and the mixture was heated under reflux for 24 hours, excess concentrated hydrochloric acid was distilled off under reduced pressure, 50 ml of water was added and the mixture was washed with 50 ml of dichloromethane
The aqueous layer is made basic with aqueous sodium hydroxide and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 2.0 g of an oily substance. The above oily substance was dissolved in methanol, 4.5 ml of 4N-methanolic hydrochloric acid was added and the solvent was distilled off. The obtained colorless crystals were suspended in 50 ml of ethyl acetate-ether (1: 1) and collected by filtration to give the title compound 2 .1
g was obtained as colorless crystals with a melting point of 201-204 ° C. Elemental analysis value Calculated as C ₂₅ H ₃₃ N ₃ O.3HCl.H ₂ O: C, 57.86; H, 7.38; N, 8.
10 Experimental value: C, 57.46; H, 7.36; N, 8.
28

Example 13 Using the compound obtained in Example 10, the same operation as in Example 11 (method A) or Example 12 (method B) was carried out to obtain a compound shown in [Table 46]. It was

[0097]

[Table 46]

Example 14 By using the compound obtained in Example 13 and performing the same operation as in Example 1, [Table 47] [Table 48] [Table 49]
The compounds shown in [Table 50] and [Table 51] were obtained.

[0099]

[Table 47]

[0100]

[Table 48]

[0101]

[Table 49]

[0102]

[Table 50]

[0103]

[Table 51]

Example 15 3-Diphenylamino-1- [3- (phenylmethyl)
-2,3,4,5-Tetrahydro-1H-3-benzazepin-7-yl] -1-propanone hydrochloride

[Chemical 69] Reference Example 5 A solution of 0.98 g of the compound No. 5 in 30 ml of 1,2-dichloroethane was added to 0.63 ml of triethylamine.
Was added, the mixture was stirred at room temperature for 1 hour, 0.56 g of diphenylamine was added, and the mixture was heated under reflux for 72 hours. After cooling to room temperature, the mixture was poured into 50 ml of pure water, 1N aqueous sodium hydroxide solution was added to adjust the pH of the aqueous layer to 12 or more, and then extracted with dichloromethane. After drying the extract over anhydrous sodium sulfate,
The solvent was distilled off to obtain an oily substance. The obtained oil was purified by silica gel column chromatography (developing solvent: dichloromethane-ethyl acetate = 4: 1 (v / v)) to obtain 0.30 g of the free base compound of the title compound as an oil.
The free base compound was added with 4N methanolic hydrochloric acid, the solvent was evaporated, and the residue was triturated with diethyl ether-hexane to give the title compound (0.25 g) as an amorphous powder. Elemental analysis value Calculated value as C ₃₂ H ₃₂ N ₂ O.HCl.H ₂ O: C, 74.62; H, 6.85; N, 5.
44 Experimental value: C, 74.29; H, 6.91; N, 5.
40

Example 16 1- (1-Acetyl-2,3-dihydro-1H-indol-5-yl) -3- [4- (phenylmethyl) piperazin-1-yl] -1-propanone dihydrochloride

[Chemical 70] Example 13 To a solution of 0.7 g of the compound No. 6 in 40 ml of dichloromethane was added dropwise 0.2 g of acetic anhydride, and the mixture was allowed to stand at room temperature for 2 hours.
Stir for hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated, and the obtained residue was crystallized from diethyl ether to obtain 0.54 g of the free base compound of the title compound as pale-yellow crystals with a melting point of 107-109 ° C. 4N methanolic hydrochloric acid (2 equivalents) was added to 0.35 g of the above free base compound, and the solvent was distilled off to obtain 0.35 g of the title compound as a crystalline powder having a melting point of 216-218 ° C. Elemental analysis _{C 24 H 29 N 3 O 2} · 2HCl · 2H 2 O Calculated: C, 57.60; H, 7.05 ; N, 8.
40 Experimental value: C, 57.47; H, 6.86; N, 8.
26

Example 17 The compound shown in [Table 52] was obtained by the same procedure as in Example 16 using the compound of Example 13.

[0107]

[Table 52]

Example 18 1- (3-Methyl-2,3,4,5-tetrahydro-1H
-3-benzazepin-7-yl) -3- [4- (phenylmethyl) piperazin-1-yl] -1-propanone trihydrochloride

[Chemical 71] 0.50 g of the compound obtained in Reference Example 6 was suspended in 30 ml of ethanol, 0.55 g of potassium carbonate and 0.42 ml of 1-benzylpiperazine were added at room temperature, and the mixture was stirred for 3 hours. 50 ml of dichloromethane and 50 ml of pure water were added to the reaction solution, the organic layer was separated, washed with 30 ml of pure water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.2 g of an oily residue. The residue was purified by alumina chromatography (developing solvent: dichloromethane-ethyl acetate = 4: 1 (v / v)),
0.17 g of oily residue was obtained. To the residue was added 3 equivalents of methanolic hydrochloric acid, and the methanol was distilled off to obtain 0.2 g of the title compound as an amorphous powder. Elemental analysis value calculated as C ₂₅ H ₃₃ N ₃ O.3HCL.2H ₂ O: C, 55.92; H, 7.51; N, 7.
83 Experimental value: C, 56.01; H, 7.78; N, 7.
83

Example 19 1- [3- (phenylmethyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] -2-
Phenyl-4- (piperidin-1-yl) -1-butanone dihydrochloride

[Chemical 72] Reference Example 9 0.92 g (2 mmol) of the compound of Compound No. 1 was dissolved in 20 ml of dichloromethane to prepare piperidine of 0.9.
9 ml (10 mmol) was added and the mixture was stirred at room temperature for 1 day. The reaction solution was 20 ml of 1N-sodium hydroxide aqueous solution and 20 pure water.
After washing with ml, it was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography [developing solvent: ethyl acetate-methanol (4: 1)] to obtain 0.53 g of the free form of the title compound as an oil. 4N-Methanolic hydrochloric acid (2 equivalents) was added to the above oil, and the solvent was evaporated under reduced pressure to give the title compound (0.58 g) as a hygroscopic amorphous powder. Elemental analysis value Calculated value as C ₃₂ H ₃₈ N ₂ O.2HC1.H ₂ O: C, 68.93; H, 7.59; N, 5.
02 Experimental value: C, 69.01; H, 7.55; N, 5.
05

Example 20 The compounds shown in [Table 53] were obtained by the same procedures as in Example 19 using the compounds obtained in Reference Examples 8 and 9.

[Table 53]

Formulation Example 1 (1) 3- [4- (phenylmethyl) piperazin-1-yl] -1- [3- (phenylmethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine -7-yl]-
1-propanone trihydrochloride (Compound No. 1 in Example 6, [Table 17]) 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 were mixed and granulated with a paste made from 15 g corn starch and 25 ml water, to which 15 g corn starch and (4) 2 g were added and the mixture was compressed on a compression tablet machine, 2000 tablets with a diameter of 3 mm were produced containing 0.5 mg of (1) per tablet.

Formulation Example 2 (1) 3- [4- (phenylmethyl) piperazin-1-yl] -1- [3- (phenylmethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine -7-yl]-
1-propanone trihydrochloride (Compound No. 1 in Example 6, [Table 17]) 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 were mixed and granulated with a paste made from 15 g corn starch and 25 ml water, to which 15 g corn starch and (4) 2 g were added and the mixture was compressed on a compression tablet machine, 2000 tablets with a diameter of 3 mm were produced containing 1.0 mg of (1) per tablet.

Experimental Example The cholinesterase inhibitory action of the compound of the present invention was examined using (acetyl- [ ³ H])-acetylcholine. That is, the S ₁ fraction of Wistar male rat cerebral cortex homogenate was used as the source of cholinesterase, (acetyl [ ³ H])-acetylcholine was added as the substrate, and the compound of the present invention was added as the analyte, and after incubation for 30 minutes. The cholinesterase activity was determined by stopping the reaction, adding a toluene-based scintillator and shaking, transferring [ ³ H] -acetic acid purified by the reaction to the toluene layer, and counting with a liquid scintillation counter. The cholinesterase inhibitory activity of the test compound was expressed as a 50% inhibitory concentration (IC ₅₀ ). The cholinesterase action of physostigmine was also measured by the same method. The obtained results are shown in [Table 54].

[0114]

[Table 54] From Table 54, it is understood that the compound of the present invention has an acetylcholinesterase inhibitory activity superior to that of physostigmine.

[0115] 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 extracted from a male JCl: Wistar rat (9 to 13 weeks old), and the cerebral cortex and hippocampus were separated. About 10-15 times as much ice-cold 0.32M sucr
Homogenize with ose (Potter type, 5 strokes),
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 ). Krebs-Ringer bicarbonate (KRB) solution (KRB: 116 mM NaCl, 4.8 mM KCl, 1.3 m)
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 in the assay. Test compound (DMSO solution with 100 times the final concentration)
After mixing 10 μl and 900 μl of 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
00 μl was added and incubated at 37 ° C. for 5 minutes.
4 ml of ice-cooled KRB was added to the assay tube and immediately filtered under reduced pressure onto Whatman CF / B filters, which were further washed twice with 4 ml of KRB. The filter was transferred to a mini vial, 4 ml of scintillator was added, and measurement was carried out with a liquid scintillation counter. Imipramine and desipramine were used as comparative drugs. All test compounds were tested at four final concentrations of 10 ⁻⁸ , 10 ⁻⁷ , 10 ⁻⁶ , 10 ⁻⁵ M. The obtained results are shown in [Table 55].

[Table 55] [Table 55] shows that the compound of the present invention has a monoamine uptake inhibitory activity superior to that of the control drugs desipramine and imipramine.

[0116]

Industrial Applicability The compound of the present invention has excellent cholinesterase inhibitory activity and monoamine reuptake inhibitory activity, and is useful as a therapeutic / preventive drug for elderly dementia.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI A61K 31/55 A61K 31/55 A61P 25/28 A61P 25/28 43/00 111 43/00 111 C07D 209/14 C07D 209/14 209/44 209/44 215/12 215/12 217/04 217/04 217/06 217/06 225/06 225/06 227/02 227/02 401/06 401/06 401/12 401/12 403 / 12 403/12 405/12 405/12 417/12 417/12 471/10 101 471/10 101 102 102 102 491/113 491/113 C12N 9/99 C12N 9/99 (31) Priority claim number 4-210225 (32) Priority date August 6, 1992 (August 6, 1992) (33) Priority claiming country Japan (JP) (31) Priority claim number Japanese Patent Application No. 4-259606 (32) Priority Date September 29, 1992 (September 29, 1992) (33) Priority claiming country Japan (JP) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 223/16 A61K 31/395 A61K 31/404 A61 K 31/47 A61K 31/472 A61K 31/55 A61P 25/28 A61P 43/00 111 C07D 209/14 C07D 209/44 C07D 215/12 C07D 217/04 C07D 217/06 C07D 225/06 C07D 227/02 C07D 401/06 C07D 401/12 C07D 403/12 C07D 405/12 C07D 417/12 C07D 471/10 101 C07D 471/10 102 C07D 491/113 C12N 9/99 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (16)

(57) [Claims] 1. The formula: [In the formula, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group which may have a substituent, and the A ring may further have a substituent. Represents a benzene ring, n represents an integer of 2 to 10, R ² , R ³ and R ⁴ are the same or different and represent a hydrogen atom or a hydrocarbon group which may have a substituent, or R ³ and R ³ R ⁴ may form a heterocyclic group which may have a substituent together with the adjacent nitrogen atom, R ² may be different from each other in repeating n, and k is an integer of 0 to 3. , M represents an integer of 1 to 8. ] The condensed heterocyclic ketone derivative represented by these, or its salt. 2. R ¹ is (1) a hydrogen atom, (2) a C _1-4 alkyl group _optionally substituted with a hydroxy group, (3)
C _2-4 alkenyl group, (4) C _1-4 alkyl, halogen,
A phenyl-C _1-3 alkyl group optionally substituted by 1 to 3 selected from nitro, cyano, hydroxy, C _1-4 alkoxy and phenyl-C _1-3 alkoxy,
(5) formyl, (6) C _1-4 alkyl-carbonyl,
The compound according to claim 1, which is (7) benzoyl, (8) C _1-4 alkoxy-carbonyl, (9) pyridylcarbonyl, (10) carbamoyl or (11) mono- or di-C _1-4 alkyl-carbamoyl. 3. R ¹ is (1) hydrogen atom, (2) C _1-4 alkyl group, (3) C _1-4 alkyl, halogen, nitro, cyano, hydroxy, C _1-4 alkoxy and phenyl-.
Phenyl-C _1-3 alkyl group optionally substituted by 1 to 3 selected from C _1-3 alkoxy, (4) C _1-4
Alkyl-carbonyl, (5) benzoyl or (6)
The compound of claim 1 which is C _1-4 alkoxy-carbonyl. Wherein R ¹ is (1) hydrogen atom, (2) C _1-4 alkyl group, (3) C _1-4 alkyl - carbonyl or (4) C _1-4 optionally substituted by alkoxy The compound of claim 1 which is phenyl-C _1-3 alkyl. 5. The compound according to claim 1, wherein the sum of k and m is an integer of 2 to 6. 6. The compound according to claim 1, wherein ring A is a benzene ring. 7. The formula: Wherein n is an integer of 3 to 8 when does not form a heterocycle, and n is an integer of 2 to 5 when it forms a heterocycle. 8. The compound according to claim 1, wherein R ² is a hydrogen atom. 9. R ³ and R ⁴ are the same or different and are a C _1-4 alkyl group optionally substituted by one hydroxy group or phenyl-C optionally substituted by 1 to 3 halogens. The compound according to claim 1, which is a _1-3 alkyl group. 10. A pyrrolidinyl, piperidinyl, wherein R ³ and R ⁴ may have a substituent together with the adjacent nitrogen atom,
Forming piperazinyl, morpholinyl or 1,2,3,4-tetrahydroquinolinyl, the substituents of which are (1) formyl, (2) C _1-4 alkyl-carbonyl group, (3)
Hydroxy group, (4) oxo group, (5) pyridyl group,
(6) with a benzoyl group optionally substituted with 1 to 3 halogens, (7) 1 to 3 hydroxy groups, or pyridyl, furyl, thiazol-4-yl or 2-methylthiazol-4-yl An optionally substituted linear or branched C _1-7 alkyl group, (8) halogen,
Phenyl optionally substituted by 1 to 3 selected from hydroxy group, C _1-4 alkylenedioxy and C _1-4 alkoxy, (9) halogen, hydroxy group, C _1-4
C _7-18 aralkyl group optionally substituted by 1 to 3 selected from alkylenedioxy and C _1-4 alkoxy or (10) ω-oxo-ω- (tetrahydrobenzazepinyl) C _1- The compound of claim 1 which is ₆ alkyl. 11. R ³ and R ⁴ together with adjacent nitrogen atoms are 4
-(Phenylmethyl) -piperazin-1-yl or 4
The compound of claim 1 which forms-[(2-methylthiazol-4-yl) methyl] -piperazin-1-yl. 12. The formula: [In the formula, Y is a halogen atom, C _1-6 alkylsulfonyl
Oxy or C _6-10 arylsulfonyloxy ,
R ¹ , A ring, R ² , n, k and m have the same meanings as in claim 1. ] Or a salt thereof and a compound of the formula: [In the formula, R ³ and R ⁴ have the same meanings as in claim 1. ] The manufacturing method of the compound of Claim 1 which consists of making it react with the compound or its salt represented. 13. The formula: [In the formula, R ⁵ represents a hydrogen atom or a hydrocarbon group which may have a substituent, and R ¹ , A ring, k and m have the same meanings as described in claim 1. Compound or a salt thereof represented by], wherein R ⁶ -CHO [V] [wherein, R ⁶ represents a hydrogen atom or an optionally substituted hydrocarbon group. ] And a compound of the formula: [In the formula, R ³ and R ⁴ have the same meanings as in claim 1. ] The compound of the formula or a salt thereof [In the formula, each symbol has the same meaning as described above. ] The manufacturing method of the compound or its salt represented by these. 14. The formula: [In the formula, Y is a halogen atom, C _1-6 alkylsulfonyl
Oxy or C _6-10 arylsulfonyloxy ,
R ¹ , A ring, R ² , n, k and m have the same meanings as in claim 1. ] The compound or its salt represented by these. 15. The formula: [Wherein, X ¹ represents R ¹ -N <(R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group which may have a substituent ), and A The ring represents a benzene ring which may further have a substituent, n represents an integer of 1 to 10, and R ² , R ³ and R ⁴ are the same or different and each have a hydrogen atom or a substituent. And R ³ and R ⁴ together with the adjacent nitrogen atom may form a heterocyclic group which may have a substituent, and R ² is n.
May be different in each repetition of
Represents an integer of 0 to 3, and m represents an integer of 1 to 8. ] The cholinesterase inhibitor characterized by containing the fused heterocyclic ketone derivative represented by these, or its salt. 16. The cholinesterase inhibitor according to claim 15, which is used as a therapeutic / preventive agent for senile dementia.