JPH08269057A - Hexahydropyrazinoquinoline derivative - Google Patents

Abstract

PURPOSE: To obtain the subject derivative excellent in serotonin IA receptor agonistic action, sedative action on mental stress, hallucination inhibitory action, having only a slight side effect such as sleepiness, etc., useful for treating and preventing anxiety, depression, hypertension, etc. CONSTITUTION: This derivative (salt) is shown by formula I or formula II [R<1> is CO-R<2> (R<3> is a 1-7C alkyl, a 3-6C cycloalkyl, etc.); R<2> is H or forms a group of formula III, etc., with R<1> and N; R<6> is a (substituted) 6-14C aryl, etc.; X is methylene or O; (m) is 2-6] such as 3-(4-phthalimidobutyl)-2,3,4,4a,5,6- hexahydro-1H-pyrazino[1,2-a]quinoline-dihydrochloride. The derivative is obtained by reacting a compound of formula IV with a compound of formula V in an inert solvent in the presence or absence of a base (preferably in the presence of the base).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a hexahydropyrazinoquinoline derivative having excellent serotonin 1A receptor (hereinafter abbreviated as 5-HT _1A receptor) agonizing action, sedative action against mental stress, and hallucinogenic inhibitory action. 5-H containing a hexahydropyrazinoquinoline derivative as an active ingredient
It relates to a T _1A receptor agonist.

[0002]

2. Description of the Related Art Journal of Medicinal Chemistry, Vol. 30, p. 1 (1987) [ J.Med.Che
m ., 30 , 1 (1987).] shows that serotonin (hereinafter referred to as 5-HT) is appetite, memory, thermoregulation, sleep, sexual behavior, anxiety,
It is described to be directly or indirectly related to physiological phenomena including depression and hallucinatory behavior. By the way, many compounds having a serotoninergic action have been known so far, and those having a hexahydropyrazinoquinoline skeleton are known as European Journal of Pharmacology, Vol. 194, p. 83 (1991) [ Eur .J.Pha
rmacol. , 194 , 83 (1991).] and Journal of Medicinal Chemistry, 35, 2369 (199).
2 years) [ J.Med.Chem ., 35 , 2369 (1992).], St. pyraquine (3-[(p-fluorobenzoyl) propyl]-
2,3,4,4a, 5,6-hexahydro-1- (H)
-Pyrazino [1,2-a] quinoline hydrochloride) and the like.

[0003]

[Chemical 4]

[0004]

DISCLOSURE OF THE INVENTION The present inventors have, for many years, earnestly studied the synthesis of hexahydropyrazinoquinoline derivatives and their pharmacological actions with the aim of developing compounds that act on superior serotonergic nerves. As a result, the hexahydropyrazinoquinoline derivative having a unique structure has a strong 5-HT _1A receptor agonistic action, a sedative action against mental stress and a hallucinogenic effect, and has few side effects such as drowsiness, anxiety, depression, and hypertension. , Schizophrenia, sleep disorders, migraine, sexual dysfunction, motion sickness, dizziness, senile dementia peripheral symptoms (particularly delirium) and the like, and has a preventive effect (particularly a therapeutic effect), and the present invention Was completed. The present invention relates to a hexahydropyrazinoquinoline derivative having an excellent 5-HT _1A receptor agonistic action, a sedative action against mental stress, and a hallucinogenic effect, a process for producing the same, and a 5-HT _1A receptor agonist having the same as an active ingredient. I will provide a.

[0005]

The hexahydropyrazinoquinoline derivative of the present invention has the general formula (I):

[0006]

Embedded image

Or having the general formula (II):

[0008]

[Chemical 6]

In the above formula, R ¹ represents a group having the formula —CO—R ³ , R ² represents a hydrogen atom, or R ¹ and R ² represent
Represents a group having the general formula (III) or (IV) which is formed with the nitrogen atom to which they are attached,

[0010]

[Chemical 7]

R ³ is a C ₁ -C ₇ alkyl group, C ₃ -C ₁₀
A cycloalkyl group, which may have 1 to 3 substituents selected from the same or different substituents from the following substituent group A C ₆ −
C ₁₄ aryl group, C ₇ -C which may have 1 to 3 substituents selected from the same or different substituent groups A below.
₄₈ aralkyl group 1, mono-C ₃ -C ₁₀ cycloalkyl amino group, is selected same or different from the following substituent group A
To a mono C ₆ -C ₁₄ arylamino group which may have 3 to 3 substituents, or 1 substituent which is selected from the following substituent group A, and is fused to a benzene ring. Good 5
A 6- to 6-membered aromatic heterocyclic group (wherein the heterocyclic ring contains 1 or 2 heteroatoms selected from the same or different from the group consisting of nitrogen atom, oxygen atom and sulfur atom), R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a C ₁ -C ₆ alkyl group, and R ⁶ is the following substituent group A
C ₆ -C ₁₄ aryl groups which may have 1 to 3 substituents, which are selected from the same or different, are represented by the substituent group A
Is a halogen atom, C ₁ -C ₆ alkyl group, halogeno C
₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -
C ₄ alkoxy C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkylthio group, C ₆ -which may have 1 to 3 substituents
C ₁₄ aryl group (the substituent is halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy), hydroxyl group, thiol group, amino group, protected amino group, carboxy group, carboxy C ₁ -C ₄ Alkyl group, formyl group, C
₂ -C ₅ alkanoyl group, C ₂ -C ₅ alkoxycarbonyl group, a carbamoyl group, a cyano group or a nitro group, X represents a methylene group or an oxygen atom, m represents an integer of 2 to 6.

The active ingredient of the 5-HT _1A receptor agonist of the present invention is a hexahydropyrazinoquinoline derivative having the above general formula (I) or general formula (II).

In the above general formula (I) or (II), the "halogen atom" in the definition of the substituent group A is, for example,
It may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom,
It is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

In the above, in the definition of R ³ , "C _1-
“C ₇ alkyl group” means, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s
-Butyl group, t-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-
Methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1, 3-dimethylbutyl group, 2,3-
Dimethylbutyl group, 2-ethylbutyl group, heptyl group,
1-methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 1-ethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, 1- It may be a linear or branched alkyl group having 1 to 7 carbon atoms such as propylbutyl group or 4,4-dimethylpentyl group, preferably C _1-.
C ₄ alkyl group, 1-methylhexyl group, 1-ethylpentyl group or 1-propylbutyl group, more preferably butyl group, isobutyl group, s-butyl group, t-butyl group or 1-ethylpentyl group. And particularly preferably t-
It is a butyl group or a 1-ethylpentyl group. In the above, “C ₁ — in the definition of R ⁴ , R ⁵ and the substituent group A
The “C ₆ alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms in the above “C ₁ -C ₇ alkyl group”, and the alkyl group of R ⁴ or R ⁵ is preferable. Is C ₁ −
It is a C ₄ alkyl group, more preferably a methyl group, an ethyl group or an isopropyl group, and particularly preferably a methyl group. The alkyl group in Substituent Group A is preferably C _1-
It is a C ₄ alkyl group, more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

In the above, "halogeno C ₁ -C ₆ alkyl group" in the definition of Substituent group A has 1 to 3 halogen atoms selected from the same or different from the above "halogen atom". C ₁ -C ₆ represents an alkyl group "bonded to groups such as fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group,
2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 3-fluoropropyl group, 3,3,3-trifluoropropyl group, 4-fluorobutyl group, dichloromethyl group, trichloromethyl group, 2-chloroethyl group, 2,2,2-trichloroethyl group, dibromomethyl group, 2-bromoethyl group, 2,2-dibromoethyl group,
2-bromobutyl group, 2-iodo-t-butyl group, 5-
It may be a fluoropentyl group or a 4-chlorohexyl group, preferably a fluoromethyl group, a difluoromethyl group,
Trifluoromethyl group, 2-fluoroethyl group, 2,2
-Difluoroethyl group or 2,2,2-trifluoroethyl group, and more preferably trifluoromethyl group.

In the above, "mono C" in the definition of R ³
_“3- C ₁₀ cycloalkyl group” is, for example, an optionally condensed 3 to 10 membered saturated ring such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, norbornyl group or adamantyl group. It may be a hydrocarbon group, preferably a cyclopentyl group or a cyclohexyl group, and more preferably a cyclohexyl group.

In the above, "C ₁ -C ₆ alkoxy group" in the definition of Substituent group A is a group in which the above "C ₁ -C ₆ alkyl group" is bonded to an oxygen atom, for example, a methoxy group. , Ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, s-butoxy group, t
-Butoxy group, pentoxy group, isopentoxy group, 2-
Methylbutoxy group, neopentoxy group, 1-ethylpropoxy group, hexyloxy group, 4-methylpentoxy group, 3-methylpentoxy group, 2-methylpetoxy group,
1-methylpentoxy group, 3,3-dimethylbutoxy group, 2,2-dimethylbutoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,3 -Dimethylbutoxy group or 2-
It may be an ethylbutoxy group, preferably a C ₁ -C ₄ alkoxy group, more preferably a methoxy group or an ethoxy group, and particularly preferably a methoxy group.

In the above, "C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl group" in the definition of Substituent group A means
A group wherein the above "C ₁ -C ₄ alkoxy group" is bound to the "C ₁ -C ₄ alkyl group", such as methoxymethyl group, 1-methoxyethyl group, 2-methoxyethyl group, 1
-Methoxypropyl group, 2-methoxypropyl group, 3-
Methoxypropyl group, 2-methoxyisopropyl group, 4
-Methoxybutyl group, 3-methoxybutyl group, 2-methoxybutyl group, ethoxymethyl group, ethoxyethyl group,
It may be an ethoxypropyl group, a propoxymethyl group, a butoxymethyl group, a butoxybutyl group or a t-butoxybutyl group, preferably a methoxymethyl group or an ethoxymethyl group, more preferably a methoxymethyl group.

In the above, "C ₁ -C ₄ alkylthio group" in the definition of Substituent group A is, for example, methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, s-butylthio group. Group or a linear or branched alkylthio group having 1 to 4 carbon atoms such as t-butylthio group, preferably methylthio group or ethylthio group, and more preferably methylthio group.

In the above, in the definition of Substituent group A, “a C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents (the substituent is halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy) ”is an aromatic hydrocarbon group having 6 to 14 carbon atoms which may have 1 to 3 substituents which are the same or different and are selected from the substituent group. Yes,
For example, phenyl group, fluorophenyl group, chlorophenyl group, dichlorophenyl group, iodophenyl group, methylphenyl group, trimethylphenyl group, butylphenyl group, methoxyphenyl group, ethoxyphenyl group, indenyl group, methylindenyl group, bromoindenyl group. Group, naphthyl group, dichloronaphthyl group, butoxynaphthyl group,
It may be a phenanthrenyl group, a butylphenanthrenyl group, an anthracenyl group or a dimethylanthracenyl group,
Preferred is a phenyl group which may have 1 or 2 substituents which are the same or different and are selected from the group consisting of fluorine, chlorine, methyl and methoxy, and more preferred are phenyl group and 4-fluorophenyl. Group, a 4-methylphenyl group or a 4-methoxyphenyl group, and particularly preferably a phenyl group.

In the above, the amino-protecting group of the "protected amino group" in the definition of Substituent group A is not particularly limited as long as it is a group generally used as an amino-protecting group. However, for example, a formyl group; a C ₂ — group such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pentanoyl group, a pivaloyl group, a valeryl group, an isovaleryl group or a hexanoyl group.
C ₇ alkanoyl group; chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, 3-fluoropropionyl group, 4,4-dichlorobutyryl group, methoxyacetyl group, butoxyacetyl group,
Such as ethoxy propionyl group or a propoxy butyryl group, halogen or C ₁ -C C ₂ -C substituted by ₄ alkoxy ₅ alkanoyl group; an acryloyl group, propioloyl group, methacryloyl group, such as crotonoyl or isocrotonoyl groups, Unsaturated C ₂ -C ₅ alkanoyl group; benzoyl group, α-naphthoyl group, β-naphthoyl group, 2-fluorobenzoyl group, 2-bromobenzoyl group, 2,4-dichlorobenzoyl group, 6-chloro-α-naphthoyl group Group, 4-toluoyl group, 4-propylbenzoyl group, 4-t-butylbenzoyl group, 2,4
6-trimethylbenzoyl group, 6-ethyl-α-naphthoyl group, 4-anisoyl group, 4-propoxybenzoyl group, 4-t-butoxybenzoyl group, 6-ethoxy-α
-Naphthoyl group, 2-ethoxycarbonylbenzoyl group, 4-t-butoxycarbonylbenzoyl group, 6-methoxycarbonyl-α-naphthoyl group, 4-phenylbenzoyl group, 4-phenyl-α-naphthoyl group, 6-α
-Naphthylbenzoyl group, 4-nitrobenzoyl group, 2
-Nitrobenzoyl group or 6-nitro-α-naphthoyl group, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄
Alkoxy, C ₂ -C ₅ alkoxycarbonyl, C ₆
-C ₁₄ Ali - may be substituted with Le or nitro, C ₇ -
C ₁₅ arylcarbonyl group; methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, s-butoxycarbonyl group, t-
Butoxycarbonyl group, chloromethoxycarbonyl group,
2,2,2-trichloroethoxycarbonyl group, 2-fluoropropoxycarbonyl group, 2-bromo-t-butoxycarbonyl group, 2,2-dibromo-t-butoxycarbonyl group, triethylsilylmethoxycarbonyl group,
2-trimethylsilyl ethoxycarbonyl group, such as 4-tripropylsilyl butoxycarbonyl group or t- butyldimethylsilyl propoxycarbonyl group, may be substituted by halogen or tri C ₁ -C ₄ alkylsilyl, C ₂ -C ₅ alkoxycarbonyl groups; C, such as a phthaloyl group; vinyl oxycarbonyl group, C ₃ -C ₆ alkenyloxycarbonyl group such as allyloxycarbonyl group, 1,3-butadienyl oxycarbonyl group or a 2-pentenyl oxycarbonyl group _8- C ₁₆ aryldicarbonyl group; benzyl group, phenethyl group, 3-phenylpropyl group, 4-phenylbutyl group, α-naphthylmethyl group, β-naphthylmethyl group, diphenylmethyl group, triphenylmethyl group, α- Naphthyldiphenylmethyl group or 9-anthry C ₇ such as a methyl group -C ₄₈
Aralkyl group; or benzyloxycarbonyl group, (1
-Phenyl) benzyloxycarbonyl group, α-naphthylmethyloxycarbonyl group, β-naphthylmethyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p
A methoxy- or nitro-substituted C ₈ -C ₅₀ aralkyloxycarbonyl group such as a -nitrobenzyloxycarbonyl group, preferably a formyl group;
C ₂ -C ₅ alkanoyl group; a trifluoroacetyl group or a methoxyacetyl group; a benzoyl group, alpha-naphthoyl group, beta-naphthoyl group, anisoyl group or nitro benzoyl group; a methoxycarbonyl group, an ethoxycarbonyl group, t-butoxycarbonyl group , 2,2,2-trichloroethoxycarbonyl group, triethylsilylmethoxycarbonyl group or 2-trimethylsilylethoxycarbonyl group; vinyloxycarbonyl group or allyloxycarbonyl group; phthaloyl group; benzyl group;
Or a benzyloxycarbonyl group or a nitrobenzyloxycarbonyl group, more preferably a formyl group, an acetyl group, a benzoyl group, a 4-anisoyl group,
4-nitrobenzoyl group, methoxycarbonyl group, ethoxycarbonyl group, butoxycarbonyl group, t-butoxycarbonyl group, phthaloyl group, benzyl group, benzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group, particularly preferably acetyl. It is a base.

In the above, "mono C" in the definition of R ³
_“3- C ₁₀ cycloalkylamino group” means the above “C ₃ -C
₁₀ cycloalkyl group "is a group bonded to an amino group,
For example, it may be a cyclopropylamino group, a cyclobutylamino group, a cyclopentylamino group, a cyclohexylamino group, a cycloheptylamino group, a norbornylamino group or an adamantylamino group, preferably a cyclopentylamino group or a cyclohexylamino group, More preferably, it is a cyclohexylamino group.

[0023] The above At a "carboxy C ₁ -C ₄ alkyl group" in the definition of substituent group A, the "C ₁ -
A group in which a carboxy group is bonded to a “C ₄ alkyl group”,
For example, carboxymethyl group, 1-carboxyethyl group,
2-carboxyethyl group, 1-carboxypropyl group,
It may be a 2-carboxypropyl group, a 3-carboxypropyl group, a 2-carboxyisopropyl group, a 4-carboxybutyl group or a 2-carboxy-t-butyl group, preferably a carboxymethyl group or a 2-carboxyethyl group. And more preferably a carboxymethyl group.

In the above, the "C ₂ -C ₅ alkanoyl group" in the definition of Substituent group A is, for example, an acetyl group, a propionyl group, a butyryl group or an isobutyryl group, and a straight chain having 2 to 5 carbon atoms. It may be a chain or branched alkanoyl group, preferably an acetyl group.

In the above, "C ₂ -C ₅ alkoxycarbonyl group" in the definition of Substituent group A means "C ₁ -C ₁ " above.
A carbonyl group bonded to "-C ₄ alkoxy group", for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, s-butoxycarbonyl group or It may be a t-butoxycarbonyl group, preferably a methoxycarbonyl group or an ethoxycarbonyl group, and particularly preferably a methoxycarbonyl group.

In the above, in the definition of R ³ and R ⁶ , "a C ₆ -C ₁₄ aryl group optionally having 1 to 3 substituents which are the same or different from the following substituent group A and are selected "
Is an aromatic hydrocarbon group having 6 to 14 carbon atoms which may have the substituent, and examples thereof include a phenyl group, a fluorophenyl group, a difluorophenyl group, a chlorophenyl group, a dichlorophenyl group, a bromophenyl group and a tolyl group. Group, xylyl group, mesityl group, ethylphenyl group, cumenyl group, butylphenyl group, t-butylphenyl group, hexylphenyl group, fluoromethylphenyl group, difluoromethylphenyl group, trifluoromethylphenyl group, 2-fluoroethylphenyl Group, 2,2-difluoroethylphenyl group, 2,2,2-trifluoroethylphenyl group, 5-fluoropentylphenyl group, methoxyphenyl group, dimethoxyphenyl group, ethoxyphenyl group, propoxyphenyl group, butoxyphenyl group, Two
-Ethylbutoxyphenyl group, methoxymethylphenyl group, methoxyethylphenyl group, t-butoxybutylphenyl group, methylthiophenyl group, ethylthiophenyl group, propylthiophenyl group, butylthiophenyl group,
Biphenylyl group, fluorobiphenylyl group, methylbiphenylyl group, naphthylphenyl group, hydroxyphenyl group, mercaptophenyl group, aminophenyl group, diaminophenyl group, butoxyaminophenyl group, carboxyphenyl group, carboxymethylphenyl group, formylphenyl group , Acetylphenyl group, methoxycarbonylphenyl group, carbamoylphenyl group, cyanophenyl group, nitrophenyl group, indenyl group, fluoroindenyl group, chloroindenyl group, methylindenyl group, trifluoromethylindenyl group, methoxyindenyl group Group, methoxymethylindenyl group, butylthioindenyl group, phenylindenyl group, hydroxyindenyl group, mercaptoindenyl group, aminoindenyl group, acetylindenyl group, Noindenyl group, nitroindenyl group, naphthyl group, fluoronaphthyl group, difluoronaphthyl group, chloronaphthyl group, dichloronaphthyl group, methylnaphthyl group, dimethylnaphthyl group, ethylnaphthyl group, butylnaphthyl group, trifluoronaphthyl group, methoxynaphthyl group. Group, ethoxynaphthyl group, butoxynaphthyl group, hydroxynaphthyl group, mercaptonaphthyl group, aminonaphthyl group, acetylnaphthyl group, cyanonaphthyl group, nitronaphthyl group, phenanthrenyl group, iodophenanthrenyl group, hexylphenanthrenyl group , Butoxybutylphenanthrenyl group, aminophenanthrenyl group, butyrylphenanthrenyl group, t-
Butoxybutylphenanthrenyl group, carbamoylphenanthrenyl group, nitrophenanthrenyl group, anthracenyl group, iodoanthracenyl group, hexylanthracenyl group, fluorohexylanthracenyl group, carboxyanthracenyl group, It may be a butoxycarbonylanthracenyl group, a cyanoanthracenyl group or a nitroanthracenyl group, the aryl group of R ³ is preferably halogen, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoro. Methyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl, ethoxymethyl, methylthio, ethylthio, phenyl, 4-
Identical or different from the group consisting of fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, hydroxyl group, thiol, amino, acetylamino, carboxy, carboxymethyl, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, cyano and nitro. A phenyl group or a naphthyl group optionally having 1 to 3 substituents, more preferably fluorine, chlorine, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,
From 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano and nitro. A phenyl group which may have 1 to 3 substituents which are the same or different from the group consisting of, and more preferably phenyl group, fluorophenyl group, chlorophenyl group, difluorophenyl group, dichlorophenyl group , Trifluoromethylphenyl group, tolyl group, xylyl group,
Mesityl group, methoxyphenyl group, cyanophenyl group or nitrophenyl group, particularly preferably phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2,3-difluorophenyl group , 2,4-difluorophenyl group, 2,5-difluorophenyl group, 2,6-difluorophenyl group,
3,4-difluorophenyl group, 3,5-difluorophenyl group, 3,4-dichlorophenyl group, p-tolyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group or 2-methoxyphenyl group And very preferably, phenyl group, 2,3-difluorophenyl group, 2,4-difluorophenyl group, 2,5-
It is a difluorophenyl group or a 3,4-dichlorophenyl group, and most preferably a phenyl group or a 2,4-difluorophenyl group. The aryl group of R ⁶ is preferably fluorine, chlorine, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2. 2-
1 to 3 selected from the same or different from the group consisting of trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano and nitro. A phenyl group which may have one substituent, and more preferably a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2,3-difluorophenyl group, 2 , 4-difluorophenyl group, 2,5-difluorophenyl group, 2,6
-Difluorophenyl group, 3,5-difluorophenyl group, 3,4-dichlorophenyl group, p-tolyl group, 3-
It is a trifluoromethylphenyl group, a 4-trifluoromethylphenyl group or a 2-methoxyphenyl group, and particularly preferably a phenyl group.

In the above, "a C ₇ -C ₄₈ aralkyl group optionally having 1 to 3 substituents selected from the same or different substituents from the following substituent group A" in the definition of R ³ is 1 to 3 of the “C ₆ -C ₁₄ aryl group” which may have a substituent are groups bonded to the “C ₁ -C ₆ alkyl group”, and examples thereof include a benzyl group and a fluorobenzyl group. Group, difluorobenzyl group, trifluorobenzyl group,
Chlorobenzyl group, dichlorobenzyl group, trichlorobenzyl group, bromobenzyl group, methylbenzyl group, dimethylbenzyl group, trimethylbenzyl group, ethylbenzyl group, fluoromethylbenzyl group, difluoromethylbenzyl group, trifluoromethylbenzyl group, fluoroethyl Benzyl group, difluoroethylbenzyl group, trifluoroethylbenzyl group, methoxybenzyl group, ethoxybenzyl group, methoxymethylbenzyl group, ethoxymethylbenzyl group, methylthiobenzyl group, ethylthiobenzyl group, phenylbenzyl group, fluorophenylbenzyl group, Hydroxybenzyl group, mercaptobenzyl group, aminobenzyl group, t-butoxycarbonylaminobenzyl group, carboxybenzyl group, carboxymethylbenzyl group, formy Benzyl group, acetylbenzyl group, methoxycarbonylbenzyl group, carbamoylbenzyl group, cyanobenzyl group, nitrobenzyl group, diphenylmethyl group, trityl group, dimethoxytrityl group, naphthylmethyl group, fluoronaphthylmethyl group, difluoronaphthylmethyl group, chloro Naphthylmethyl group, dichloronaphthylmethyl group, methylnaphthylmethyl group, dimethylnaphthylmethyl group, ethylnaphthylmethyl group, indenylmethyl group, methylindenylmethyl group, methoxyindenylmethyl group, phenanthrenylmethyl group, bromophen Nonthrenylmethyl group, butylphenanthrenylmethyl group, trifluorohexylphenanthrenylmethyl group, butoxyphenanthrenylmethyl group, anthracenylmethyl group, iodoanthracenylmethyl group Group, butyl thio-anthracenylmethyl group, a phenyl-anthracenylmethyl group, an amino-anthracenylmethyl group, phenethyl group, fluoro phenethyl group, difluoromethyl phenethyl group,
Chlorophenethyl group, dichlorophenethyl group, methylphenethyl group, trimethylphenethyl group, trifluoromethylphenethyl group, methoxymethylphenethyl group, methoxyethylphenethyl group, methylthiophenethyl group, phenylphenethyl group, methoxyphenylphenethyl group,
Hydroxyphenethyl group, mercaptophenethyl group, aminophenethyl group, t-butoxycarbonylaminophenethyl group, carboxyphenethyl group, carboxymethylphenethyl group, formylphenethyl group, acetylphenethyl group, methoxycarbonylphenethyl group, carbamoylphenethyl group, cyanophenethyl group, Nitrophenethyl group, naphthylethyl group, fluoronaphthylethyl group,
Chloronaphthylethyl group, butylthionaphthylethyl group, methoxyphenylnaphthylethyl group, benzylaminonaphthylethyl group, phenylpropyl group, fluorophenylpropyl group, chlorophenylpropyl group, dichlorophenylpropyl group, methylphenylpropyl group, dimethylphenylpropyl group, Trimethylphenylpropyl group, trifluoromethylphenylpropyl group, methoxyphenylpropyl group, dimethoxyphenylpropyl group, butoxyphenylpropyl group, butoxybutylphenylpropyl group, cyanophenylpropyl group, nitrophenylpropyl group, naphthylpropyl group, iodonaphthylpropyl Group, hexylnaphthylpropyl group, bromohexylnaphthylpropyl group, methoxynaphthylpropyl group, hexyloxyna Cylpropyl group, mercaptonaphthylpropyl group, acetylnaphthylpropyl group, phenylbutyl group, fluorophenylbutyl group, difluorophenylbutyl group, chlorophenylbutyl group, dichlorophenylbutyl group, trimethylphenylbutyl group, naphthylbutyl group, trifluoromethylnaphthylbutyl group ,
Butyrylnaphthylbutyl group, phenylnaphthylbutyl group, benzoylaminonaphthylbutyl group, butoxycarbonylnaphthylbutyl group, indenylpentyl group, fluoroindenylpentyl group, methylindenylpentyl group, anthracenylhexyl group, hexylanthracenylhexyl group A carbamoylanthracenylhexyl group or a nitroanthracenylhexyl group, preferably halogen, C ₁ -C ₄ alkyl, fluoromethyl,
Difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl, ethoxymethyl, methylthio, ethylthio, phenyl, 4- Fluorophenyl, 4-methylphenyl, 4-
Methoxyphenyl, hydroxyl group, thiol, amino, acetylamino, carboxy, carboxymethyl, formyl,
Acetyl, methoxycarbonyl, ethoxycarbonyl,
A benzyl group or a phenethyl group, which may have 1 to 3 substituents which are the same or different and are selected from the group consisting of carbamoyl, cyano and nitro, more preferably fluorine, chlorine and C ₁ -C. ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl, methylthio, phenyl, 4 -Fluorophenyl, 4
-A benzyl group which may have 1 to 3 substituents selected from the same or different from the group consisting of methylphenyl, 4-methoxyphenyl, cyano and nitro, more preferably benzyl group, Fluorobenzyl group, chlorobenzyl group, difluorobenzyl group, dichlorobenzyl group, trifluoromethylbenzyl group, methylbenzyl group, dimethylbenzyl group, trimethylbenzyl group, methoxybenzyl group, cyanobenzyl group or nitrobenzyl group, and particularly preferred Is a benzyl group.

In the above, "a mono-C ₆ -C ₁₄ arylamino group which may have 1 to 3 substituents selected from the same or different substituent groups A below in the definition of R ³ " Is a C ₆ -C ₁₄ which may have 1 to 3 substituents selected from the same or different substituents from the following substituent group A.
"Aryl group" is a group bonded to an amino group, for example, phenylamino group, fluorophenylamino group, difluorophenylamino group, chlorophenylamino group, dichlorophenylamino group, bromophenylamino group, tolylamino group, xylylamino group, mesitylamino group, Ethylphenylamino group, cumenylamino group, butylphenylamino group, t-butylphenylamino group, hexylphenylamino group, fluoromethylphenylamino group, difluoromethylphenylamino group, trifluoromethylphenylamino group, 2-fluoroethylphenylamino Group, 2,2-difluoroethylphenylamino group, 2,
2,2-trifluoroethylphenylamino group, 5-fluoropentylphenylamino group, methoxyphenylamino group, dimethoxyphenylamino group, ethoxyphenylamino group, propoxyphenylamino group, butoxyphenylamino group, 2-ethylbutoxyphenylamino Group, methoxymethylphenylamino group, methoxyethylphenylamino group, t-butoxybutylphenylamino group, methylthiophenylamino group, ethylthiophenylamino group, propylthiophenylamino group, butylthiophenylamino group, biphenylylamino group, Fluorobiphenylylamino group, methylbiphenylylamino group, naphthylphenylamino group, hydroxyphenylamino group, mercaptophenylamino group, aminophenylamino group, diaminophenyl Amino group, butoxyaminophenylamino group, carboxyphenylamino group, carboxymethylphenylamino group, formylphenylamino group, acetylphenylamino group, methoxycarbonylphenylamino group, carbamoylphenylamino group, cyanophenylamino group, nitrophenylamino group , Indenylamino group, fluoroindenylamino group, chloroindenylamino group, methylindenylamino group, trifluoromethylindenylamino group, methoxyindenylamino group, methoxymethylindenylamino group, butylthioindenylamino group Group, phenylindenylamino group, hydroxyindenylamino group, mercaptoindenylamino group, aminoindenylamino group, acetylindenylamino group, cyanoindenylamino group , Nitroindenylamino group, naphthylamino group, fluoronaphthylamino group, difluoronaphthylamino group, chloronaphthylamino group, dichloronaphthylamino group, methylnaphthylamino group, dimethylnaphthylamino group, ethylnaphthylamino group, butylnaphthylamino group , Trifluoronaphthylamino group, methoxynaphthylamino group, ethoxynaphthylamino group, butoxynaphthylamino group, hydroxynaphthylamino group, mercaptonaphthylamino group, aminonaphthylamino group, acetylnaphthylamino group, cyanonaphthylamino group, nitronaphthylamino group Group, phenanthrenylamino group, iodophenanthrenylamino group, hexylphenanthrenylamino group, butoxybutylphenanthrenylamino group, aminophenanthrenylamino group Mino group, butyrylphenanthrenylamino group, t-butoxybutylphenanthrenylamino group, carbamoylphenanthrenylamino group, nitrophenanthrenylamino group, anthracenylamino group, iodoanthracenylamino group A hexylanthracenylamino group, a fluorohexylanthracenylamino group, a carboxyanthracenylamino group, a butoxycarbonylanthracenylamino group, a cyanoanthracenylamino group or a nitroanthracenylamino group, preferably Is
Halogen, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl ,
Ethoxymethyl, methylthio, ethylthio, phenyl,
The same or selected from the group consisting of 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, hydroxyl group, thiol, amino, acetylamino, carboxy, carboxymethyl, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, cyano and nitro. It may have 1 to 3 substituents selected differently,
A phenylamino group or a 2-naphthylamino group, more preferably fluorine, chlorine, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-
Fluoroethyl, 2,2-difluoroethyl, 2,2
1 selected from the same or different from the group consisting of 2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano and nitro. To a phenylamino group which may have 3 substituents, more preferably a phenylamino group, a fluorophenylamino group, a chlorophenylamino group, a difluorophenylamino group, a dichlorophenylamino group,
A trifluoromethylphenylamino group, a tolylamino group, a xylylamino group, a mesitylamino group, a methoxyphenylamino group, a cyanophenylamino group or a nitrophenylamino group, particularly preferably a phenylamino group or a 2,4 difluorophenylamino group. is there.

In the above, in the definition of R ³ , "it may have one substituent selected from the following substituent group A,
A 5- to 6-membered aromatic heterocyclic group which may be fused to a benzene ring (the heterocyclic ring contains 1 to 2 oxygen, nitrogen or sulfur atoms) is, for example, a pyrrolyl group or fluoropyrrolyl group. Group, chloropyrrolyl group, methylpyrrolyl group, methoxypyrrolyl group, aminopyrrolyl group, methoxycarbonylpyrrolyl group, imidazolyl group, fluoroimidazolyl group, chloroimidazolyl group, bromoimidazolyl group,
Iodoimidazolyl group, pyrazolyl group, methylpyrazolyl group, ethylpyrazolyl group, propylpyrazolyl group, butylpyrazolyl group, butoxybutylpyrazolyl group, oxazolyl group, fluorooxazolyl group, chlorooxazolyl group, phenyloxazolyl group, methoxy Phenyloxazolyl group, isoxazolyl group, chloroisoxazolyl group, hexylisoxazolyl group, phenylisoxazolyl group, methoxyphenylisoxazolyl group, hydroxyisoxazolyl group, mercaptoisoxazolyl Group, thiazolyl group, bromohexylthiazolyl group, hexyloxythiazolyl group, butoxybutylthiazolyl group, butylthiothiazolyl group, phenylthiazolyl group, isothiazolyl group, hydroxyisothiazolyl group, mercaptoisothiyl group Azolyl group, Minoisothiazolyl group, benzylaminoisothiazolyl group, pyridyl group, fluoropyridyl group, chloropyridyl group, methylpyridyl group, ethylpyridyl group, trifluoromethylpyridyl group, methoxypyridyl group, ethoxypyridyl group, methoxymethylpyridyl group , Methoxyethylpyridyl, methylthiopyridyl, ethylthiopyridyl, phenylpyridyl, methoxyphenylpyridyl, hydroxypyridyl, mercaptopyridyl, aminopyridyl, butoxycarbonylaminopyridyl, carboxypyridyl, carboxymethylpyridyl , Formylpyridyl group, acetylpyridyl group, methoxycarbonylpyridyl group, cyanopyridyl group, nitropyridyl group, pyrazinyl group, fluoropyrazinyl group, chloropyrazinyl group, Chirupirajiniru group, Echirupirajiniru group, trifluoromethyl pyrazinyl group, methoxy pyrazinyl group, ethoxy pyrazinyl group,
Methoxymethylpyrazinyl group, methoxyethylpyrazinyl group, methylthiopyrazinyl group, ethylthiopyrazinyl group, phenylpyrazinyl group, tolylpyrazinyl group, hydroxypyrazinyl group, mercaptopyrazinyl group, aminopyrazinyl group , T-butoxycarbonylaminopyrazinyl group, carboxypyrazinyl group, carboxymethylpyrazinyl group, formylpyrazinyl group, acetylpyrazinyl group, methoxycarbonylpyrazinyl group, carbamoylpyrazinyl group, cyanopyrazinyl group Group, nitropyrazinyl group, pyrimidinyl group, bromopyrimidinyl group, hexylpyrimidinyl group, bromohexylpyrimidinyl group, hexyloxypyrimidinyl group, pyridazinyl group, butoxybutylpyridazinyl group, butylthiopyridazinyl group, methoxyphenylpyridin Dinyl group, hydroxypyridazinyl group, indolyl group, fluoroindolyl group, chloroindolyl group, methylindolyl group, ethylindolyl group, trifluoromethylindolyl group, methoxyindolyl group, methoxymethylindolyl group , Methylthioindolyl group, phenylindolyl group, hydroxyindolyl group, aminoindolyl group, t-butoxycarbonylaminoindolyl group, carboxyindolyl group, carboxymethylindolyl group, formylindolyl group, acetylindolyl group , Methoxycarbonylindolyl group, carbamoylindolyl group, cyanoindolyl group, nitroindolyl group, quinolyl group, fluoroquinolyl group, chloroquinolyl group, methylquinolyl group, ethylquinolyl group,
Trifluoromethylquinolyl group, methoxyquinolyl group,
Ethoxyquinolyl group, methoxymethylquinolyl group, methoxyethylquinolyl group, methylthioquinolyl group, phenylquinolyl group, hydroxyquinolyl group, mercaptoquinolyl group, aminoquinolyl group, benzylaminoquinolyl group, carboxyquinolyl group , Carboxymethylquinolyl group, formylquinolyl group, acetylquinolyl group, methoxycarbonylquinolyl group, carbamoylquinolyl group, cyanoquinolyl group, nitroquinolyl group, indazolyl group,
Bromoindazolyl group, iodoindazolyl group, hexylindazolyl group, quinoxalinyl group, bromopentylquinoxalinyl group, hexyloxyquinoxalinyl group,
Butoxybutylquinoxalinyl group, butylthioquinoxalinyl group, quinazolinyl group, phenylquinazolinyl group,
Methoxyphenylquinazolinyl group, hydroxyquinazolinyl group, aminoquinazolinyl group, benzoxazolyl group, benzoylaminobenzoxazolyl group, carboxybenzoxazolyl group, carboxybutylbenzoxazolyl group, butyryl Benzoxazolyl group, benzisoxazolyl group, fluorobenzisoxazolyl group, chlorobenzisoxazolyl group, methylbenzisoxazolyl group, phenylbenzisoxazolyl group, furyl group,
Fluorofuryl group, chlorofuryl group, methylfuryl group,
Ethylfuryl group, trifluoromethylfuryl group, methoxyfuryl group, ethoxyfuryl group, methoxymethylfuryl group, ethoxymethylfuryl group, methylthiofuryl group, ethylthiofuryl group, phenylfuryl group, hydroxyfuryl group, mercaptofuryl group, amino Furyl group, acetylaminofuryl group, carboxyfuryl group, carboxymethylfuryl group, acetylfuryl group, methoxycarbonylfuryl group, carbamoylfuryl group, cyanofuryl group, nitrofuryl group, benzofuranyl group, hexylbenzofuranyl group, bromohexylbenzofuran group Nyl group, aminobenzofuranyl group, carboxybutylbenzofuranyl group, butyrylbenzofuranyl group, isobenzofuranyl group, hexyloxyisobenzofuranyl group, butoxybutylisobenzofuranyl group, Rylisobenzofuranyl group, benzylaminoisobenzofuranyl group, butoxycarbonylisobenzofuranyl group, thienyl group, fluorothienyl group, chlorothienyl group, methylthienyl group, ethylthienyl group, trifluoromethylthienyl group, methoxythienyl group Group, ethoxythienyl group, methoxymethylthienyl group, ethoxymethylthienyl group, methylthiothienyl group, ethylthiothienyl group, phenylthienyl group, hydroxythienyl group, mercaptothienyl group, aminothienyl group, acetylaminothienyl group, carboxythienyl group, Carboxymethyl thienyl group, formyl thienyl group, acetyl thienyl group, methoxycarbonyl thienyl group, carbamoyl thienyl group, cyano thienyl group, nitro thienyl group, benzo thienyl group, full Robenzochieniru group, chlorobenzoyl thienyl group which may be methyl benzothienyl group or an ethyl benzothienyl group, preferably,
Halogen, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl ,
Ethoxymethyl, methylthio, ethylthio, phenyl,
Selected from the group consisting of 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, hydroxyl group, thiol, amino, acetylamino, carboxy, carboxymethyl, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, cyano and nitro. Which may have one substituent, a pyrrolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group,
It is an indolyl group, a quinolyl group, a furyl group or a thienyl group, more preferably fluorine, chlorine, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoro. Ethyl, 2,2,2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl, methylthio, phenyl, 4-
Pyridyl group, pyrazinyl group, indolyl group, quinolyl group, furyl group or thienyl group which may have one substituent selected from the group consisting of fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano and nitro. And even more preferably, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, pyrazinyl group, 3-methylpyrazinyl group, 1-methyl-2-indolyl group, 2-quinolyl group, 3-quinolyl group. , 4-quinolyl group, 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group, 5-fluoro-2-thienyl group, 5-chloro-2-
Thienyl group, 3-methyl-2-thienyl group, 5-methyl-2-thienyl group, 3-methoxy-2-thienyl group, 5
-Fluoro-3-thienyl group, 5-chloro-3-thienyl group, 4-methyl-3-thienyl group, 5-methyl-3-
A thienyl group, a 4-methoxy-3-thienyl group or a 5-methoxy-3-thienyl group, particularly preferably a 3-pyridyl group, a pyrazinyl group, a 1-methyl-2-indolyl group, a 4-quinolyl group, 2-furyl group, 2-thienyl group,
3-thienyl group, 5-chloro-2-thienyl group, 3-methyl-2-thienyl group, 5-methyl-2-thienyl group or 4-methoxy-3-thienyl group, very preferably a pyrazinyl group. , 2-thienyl group, 3-thienyl group,
5-chloro-2-thienyl group, 3-methyl-2-thienyl group, 5-methyl-2-thienyl group or 4-methoxy-
3-thienyl group, most preferably a pyrazinyl group,
It is a 2-thienyl group or a 5-methyl-2-thienyl group.

The compound (I) or (II) of the present invention can be converted into the corresponding pharmacologically acceptable salt by treating with an acid according to a conventional method. For example, compound (I) or (II) is treated with a corresponding acid in a solvent (for example, ethers, esters or alcohols, especially ethers) at room temperature for 5 to 30 minutes, and the precipitated crystals are collected by filtration. Alternatively, it can be obtained by distilling off the solvent under reduced pressure. Such salts are, for example, hydrofluorides, hydrochlorides, hydrobromides, hydroiodes, nitrates, perchlorates, sulphates or phosphates or other mineral salts; methanesulphonic acid. Salts, sulfonates such as trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate; fumarates, succinates, citrates, tartrates, oxalates Or a carboxylate such as maleate; or an amino acid salt such as glutamate or aspartate, preferably a mineral acid salt (particularly a hydrochloride salt). The compound (I) or (I of the present invention
I) or a pharmacologically acceptable salt thereof may absorb water or have adsorbed water, or become a hydrate by being left in the atmosphere or recrystallized. Each of them or any of their mixtures are included in the present invention.

The compound (I) or (II) of the present invention has an asymmetric carbon atom in the molecule, and there exist stereoisomers having R coordination and S coordination, respectively. Any mixture of them in any proportion is included in the present invention. In the compound (I) or (II) of the present invention or a pharmacologically acceptable salt thereof, preferred compounds are those each having a specific optical rotation of (-).

In the compound (I) or (II) of the present invention, preferable compounds are those having the general formula (I), and more preferably, in the general formula (I), R ¹ Is the formula -C
A group having O—R ³ or a group having the general formula (III), wherein R ¹ and R ² are formed together with the nitrogen atom to which they are bonded, and particularly preferably, In the general formula (I), R ¹ and R ² are groups having the general formula (III) formed together with the nitrogen atom to which they are bonded.

In the compounds (I) and (II) of the present invention, preferred compounds are those in which X is a methylene group.

In the compound (I) or (II) of the present invention, preferred compounds are those in which m is an integer of 2 to 4, and more preferably m is an integer of 2 or 4. It is a thing. In the compound (I) or (II) of the present invention, (1) R ³ is preferably a C ₁ -C ₄ alkyl group, 1-methylhexyl group, 1-ethylpentyl group, 1-propylbutyl group. Group; cyclopentyl group, cyclohexyl group; halogen, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-
Fluoroethyl, 2,2-difluoroethyl, 2,2
2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl, ethoxymethyl, methylthio, ethylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, hydroxyl group, thiol, amino, acetylamino, carboxy. , Carboxymethyl,
Formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, cyano and nitro, which may have 1 to 3 substituents which may be the same or different, and which may have a phenyl group or a naphthyl group; fluorine, chlorine, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,
From 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano and nitro. A benzyl group optionally having 1 to 3 substituents selected from the same or different from the group consisting of; cyclopentylamino group or cyclohexylamino group; fluorine, chlorine, C _1-
C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C ₁
-C ₄ alkoxy, methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4
-A phenylamino group optionally having 1 to 3 substituents selected from the same or different from the group consisting of methoxyphenyl, cyano and nitro; or halogen, C ₁ -C
₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C _1-
C ₄ alkoxy, methoxymethyl, ethoxymethyl, methylthio, ethylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, hydroxyl group, thiol, amino, acetylamino, carboxy,
Pyrolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl, which may have one substituent selected from the group consisting of carboxymethyl, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, cyano and nitro. A compound having the general formula (I), which is a group, an indolyl group, a quinolyl group, a furyl group or a thienyl group, (2) R ³ is a butyl group, an isobutyl group, a s-butyl group, a t-butyl group, 1- Ethyl pentyl group; cyclopentyl group or cyclohexyl group; fluorine, chlorine, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,
From 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano and nitro. A phenyl group which may have 1 to 3 substituents selected from the same or different from the group consisting of: benzyl group, fluorobenzyl group, chlorobenzyl group, difluorobenzyl group, dichlorobenzyl group, trifluoromethylbenzyl group , Methylbenzyl group, dimethylbenzyl group, trimethylbenzyl group, methoxybenzyl group, cyanobenzyl group, nitrobenzyl group; cyclohexylamino group; phenylamino group, fluorophenylamino group, chlorophenylamino group, difluorophenylamino group, dichlorophenylamino group , Trifluoromethyl phenylamino group, tolylamino group, Kishiriruamino group, Meshichiruamino group, methoxyphenyl group, a cyano-phenylamino group or a nitro phenylamino group; or, fluorine, chlorine,
C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2
- difluoroethyl, 2,2,2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, from the group consisting of cyano and nitro A compound having the general formula (I), which is a pyridyl group, a pyrazinyl group, an indolyl group, a quinolyl group, a furyl group or a thienyl group, which may have one selected substituent, (3) R ³ is , T-butyl group, 1-ethylpentyl group, cyclohexyl group, phenyl group, fluorophenyl group, chlorophenyl group, difluorophenyl group, dichlorophenyl group, trifluoromethylphenyl group, tolyl group, xylyl group, mesityl group, methoxyphenyl group , Cyanophenyl group, nitrophenyl group, benzyl group, phenylamino group, 2 4-difluorophenylamino group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, pyrazinyl group, 3-methylpyrazinyl group, 1-methyl-2-indolyl group, 2-quinolyl group, 3-quinolyl group, 4 -Quinolyl group, 2-furyl group, 3-furyl group,
2-thienyl group, 3-thienyl group, 5-fluoro-2-
Thienyl group, 5-chloro-2-thienyl group, 3-methyl-2-thienyl group, 5-methyl-2-thienyl group, 3-
Methoxy-2-thienyl group, 5-fluoro-3-thienyl group, 5-chloro-3-thienyl group, 4-methyl-3-
A compound having the general formula (I), which is a thienyl group, a 5-methyl-3-thienyl group, a 4-methoxy-3-thienyl group or a 5-methoxy-3-thienyl group, (4) R ³
Is a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2,3-difluorophenyl group, 2,4-difluorophenyl group,
2,5-difluorophenyl group, 2,6-difluorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 3,4-dichlorophenyl group, p
-Tolyl group, 3-trifluoromethylphenyl group, 4-
Trifluoromethylphenyl group, 2-methoxyphenyl group, 3-pyridyl group, pyrazinyl group, 1-methyl-2-
Indolyl group, 4-quinolyl group, 2-furyl group, 2-thienyl group, 3-thienyl group, 5-chloro-2-thienyl group, 3-methyl-2-thienyl group, 5-methyl-2-thienyl group or A compound having the general formula (I), which is a 4-methoxy-3-thienyl group, (5) R ³ is a phenyl group, a 2,3-difluorophenyl group, a 2,4-difluorophenyl group, 2,5- Difluorophenyl group, 3,4
-Dichlorophenyl group, pyrazinyl group, 2-thienyl group, 3-thienyl group, 5-chloro-2-thienyl group, 3
A compound having the general formula (I), which is a -methyl-2-thienyl group, a 5-methyl-2-thienyl group or a 4-methoxy-3-thienyl group, (6) R ³ is a phenyl group,
A compound having the general formula (I), which is a 2,4-difluorophenyl group, a pyrazinyl group, a 2-thienyl group or a 5-methyl-2-thienyl group, (7) R ¹ and R ² are bound to each other. 2,4-dioxo-
3-thiazolidyl group, 5-mono C ₁ -C ₄ alkyl-
A compound having the general formula (I), which is a 2,4-dioxo-3-thiazolidyl group or a 5,5-diC ₁ -C ₄ alkyl-2,4-dioxo-3-thiazolidyl group or a phthalimidyl group, (8 ) R ¹ and R ² together with the nitrogen atom to which they are bound are a 2,4-dioxo-3-thiazolidyl group, 5-methyl-2,4-dioxo-3-thiazolidyl group, 5,5-dimethyl- 2,4-dioxo-3-thiazolidyl group, 5-methyl-5-ethyl-2,4-dioxo-3-thiazolidyl group, 5-ethyl-2,4-dioxo-3-thiazolidyl group, 5,5-diethyl -2,4
A compound having the general formula (I), which is a dioxo-3-thiazolidyl group or a 5-isopropyl-2,4-dioxo-3-thiazolidyl group, (9) R ¹ and R ² are bound to each other. With the nitrogen atom, 2,4-dioxo-
3-thiazolidyl group, 5,5-dimethyl-2,4-dioxo-3-thiazolidyl group or 5-isopropyl-2,
A compound having the general formula (I), which is a 4-dioxo-3-thiazolidyl group, (10) R ¹ and R ² together with the nitrogen atom to which they are bound are 5,5-dimethyl-
A compound having the general formula (I), which is a 2,4-dioxo-3-thiazolidyl group or a 5-isopropyl-2,4-dioxo-3-thiazolidyl group, (11) R ⁶ is
Fluorine, chlorine, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C ₁ -C ₄ alkoxy, Methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4
A compound having the general formula (II), which is a phenyl group optionally having 1 to 3 substituents selected from the same or different from the group consisting of: methylphenyl, 4-methoxyphenyl, cyano and nitro, (12) R ⁶ is phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2,3-difluorophenyl group, 2,4-difluorophenyl group, 2,5-difluorophenyl Group, 2,6-difluorophenyl group,
3,5-difluorophenyl group, 3,4-dichlorophenyl group, p-tolyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group or 2-methoxyphenyl group, represented by the general formula (II) A compound having the formula (I), wherein R ⁶ is a phenyl group.
A compound having I), (14) a compound in which X is methylene, (15) a compound in which m is an integer of 2 to 4,
(16) A compound in which m is 2 and a compound in which (17) m is 4 can be mentioned, and (1)-(1
It is also preferable to select 2 to 5 from the groups of 3), (14) and (15) to (17) and to arbitrarily combine them, and examples thereof include the following combinations. (18) (1) and (14), (19) (3)
And (15), (20) (4), (14) and (1
5), (21) (5), (14) and (17), (2
2) (6), (14) and (17), (23)
(7) and (14), (24) (8), (14) and (15), (25) (9), (14) and (15),
(26) (10), (14) and (17), (27)
(13), (14) and (17). Representative compounds of the present invention include, for example, the compounds listed in the following table, but the present invention is not limited to these compounds. The abbreviations in the table are as follows. Ac: acetyl Bu ^t: tert-butyl Et: ethyl 2-Fur: furyl (2-) 3-Fur: furyl (3-) Hex ^c: cyclohexyl 2-Ind: indol-2-yl Me: methyl Pent: pentyl Pent ^c : cyclopentyl Ph: phenyl Phtm: phthalimidyl Pr: propyl Pr ⁱ : isopropyl 2-Pyr: pyridyl (2-) 3-Pyr: pyridyl (3-) 4-Pyr: pyridyl (4-) Pyz: pyrazinyl (2-). 2-Quin: quinolin-2-yl 3-Quin: quinolin-3-yl 4-Quin: quinolin-4-yl 2-Thi: thienyl (2-) 3-Thi: thienyl (3-) Thiz: 2,4 -Dioxothiazolidin-3-yl

[0035]

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[0036]

[Table 1] Compound No. _{^{R 3 X m 1-1 Me -CH 2}} - 4 1-2 Et -CH 2 - 4 1-3 Pr -CH 2 - 4 1-4 Bu t -CH 2 - 2 1-5 Bu t -CH ^{_{2 - 3 1-6 Bu t -CH 2}} - 4 1-7 Bu t -O- 2 1-8 Bu t -O- 3 1-9 Bu t -O- 4 1-10 1-Et-Pent -CH _{2 - 2 1-11 1-Et-} Pent -CH 2 - 4 1-12 1-Et-Pent -O- 2 1-13 1-Et-Pent -O- 4 1-14 2-Et-Pent -CH _{2 - 2 1-15 2-Et-} Pent -CH 2 - 4 1-16 Pent c -CH 2 - 2 1-17 Pent c -CH 2 - 4 1-18 Hex c -CH 2 - 2 1-19 Hex ^{_{c -CH 2 - 3 1-20 Hex c}} -CH 2 - 4 1-21 Hex c -O- 2 1-22 Hex c -O- 4 1-23 Ph -CH 2 - 2 1-24 Ph -CH 2 _{- 3 1-25 Ph -CH 2 - 4} 1-26 Ph -CH 2 - 5 1-27 Ph -CH 2 - 6 1-28 Ph -O- 2 1-29 Ph -O- 3 1-30 Ph - O- 4 1-31 2-F-Ph -CH 2 - 2 1-32 2-F-Ph -CH 2 - 3 1-33 2-F-Ph -CH 2 - 4 1-34 2-F-Ph -O- 2 1-35 2-F-Ph -O- 3 1-36 2-F-Ph -O- 4 1-37 3-F-Ph -CH 2 - 2 1-38 3-F-Ph - _{CH 2 - 3 1-39 3-F} -Ph -CH 2 - 4 1-40 3-F-Ph -O- 2 1-41 3-F-Ph -O- 4 1-42 4-F-Ph - _{CH 2 - 2 1-43 4-F} -Ph -CH 2 - 3 1-44 4-F-Ph -CH 2 - 4 1-45 4-F-Ph -O- 2 1-46 4-F-Ph -O- 3 1-47 4-F-Ph -O- 4 1-48 2,3-diF-Ph -CH 2 - 2 1-49 2,3-diF-Ph -CH 2 - 3 1-50 2 , 3 -diF-Ph -CH _2-4 1-51 2,3-diF-Ph -O- 2 1-52 2,3-diF-Ph -O- 4 1-53 2,4-diF-Ph -CH ₂ - 2 1-54 2,4-diF-Ph -CH 2 - 3 1-55 2,4-diF-Ph -CH 2 - 4 1-56 2,4-diF-Ph -CH 2 - 5 1-57 _{2,4-diF-Ph -CH 2 -} 6 1-58 2,4-diF-Ph -O- 2 1-59 2,4-diF-Ph -O- 3 1-60 2,4-diF-Ph -O- 4 1-61 2,5-diF-Ph -CH 2 - 2 1-62 2,5-diF-Ph -CH 2 - 3 1-63 2,5-diF-Ph -CH 2 - 4 1 -64 2,5-diF-Ph -O- 2 1-65 2,5-diF-Ph -O- 4 1-66 2,6-diF-Ph -CH 2 - 2 1-67 2,6-diF _{-Ph -CH 2 - 3 1-68 2,6-} diF-Ph -CH 2 - 4 1-69 2,6-diF-Ph -O- 2 1-70 2,6-diF-Ph -O- 4 _{1-71 3,4-diF-Ph -CH 2} - 2 1-72 3,4-diF-Ph -CH 2 - 3 1-73 3,4-diF-Ph -CH 2 - 4 1-74 3, 4-diF-Ph -O- 2 1-75 3,4-diF-Ph -O- 4 1-76 3,4-diF-Ph -O- 5 1-77 3,5-diF-Ph -CH ₂ - 2 1-78 3,5-diF-Ph -CH 2 - 3 1-79 3,5-diF-Ph -CH 2 - 4 1-80 3,5-diF-Ph -O- 2 1-81 3 , 5-diF-Ph -O- 4 1-82 2,3-diCl-Ph -CH 2 - 2 1-83 2,3-diCl-Ph -CH 2 - 4 1-84 2,4-diCl-Ph _{-CH 2 - 2 1-85 2,4-diCl} -Ph -CH 2 - 4 1-86 2,5-diCl-Ph -CH 2 - 2 1-87 2,5-diCl-Ph -CH 2 - 4 _{1-88 2,6-diCl-Ph -CH 2} - 2 1-89 2,6-diCl-Ph -CH 2 - 4 1-90 3,4-diCl-Ph _{-CH 2 - 2 1-91 3,4-diCl} -Ph -CH 2 - 3 1-92 3,4-diCl-Ph -CH 2 - 4 1-93 3,4-diCl-Ph -O- 2 1 -94 3,4-diCl-Ph -O- 4 1-95 3,5-diCl-Ph -CH 2 - 2 1-96 3,5-diCl-Ph -CH 2 - 4 1-97 2-F- 3-Cl-Ph -CH _2-4 1-98 2-F-4-Cl-Ph -CH _2-4 1-99 2-F-5-Cl-Ph -CH _2-4 1-100 2-F -6-Cl-Ph -CH _2-4 1-101 3-F-2-Cl-Ph -CH _2-4 1-102 3-F-4-Cl-Ph -CH _2-4 1-103 3- F-5-Cl-Ph -CH _2-4 1-104 5-F-3-Cl-Ph -CH _2-4 1-105 2-Me-Ph -CH _2-4 1-106 2-Me-Ph -O- 4 1-107 3-Me-Ph -CH 2 - 4 1-108 3-Me-Ph -O- 4 1-109 4-Me-Ph -CH 2 - 2 1-110 4-Me-Ph _{-CH 2 - 3 1-111 4-Me} -Ph -CH 2 - 4 1-112 4-Me-Ph -O- 2 1-113 4-Me-Ph -O- 4 1-114 2-CF 3 - _{Ph -CH 2 - 2 1-115 2-} CF 3 -Ph -CH 2 - 4 1-116 2-CF 3 -Ph -O- 4 1-117 3-CF 3 -Ph -CH 2 - 2 1-118 _{3-CF 3 -Ph -CH 2 -} 3 1-119 3-CF 3 -Ph -CH 2 - 4 1-120 3-CF 3 -Ph -O- 2 1-121 3-CF 3 -Ph -O- _{4 1-122 4-CF 3 -Ph -CH} 2 - 2 1-123 4-CF 3 -Ph -CH 2 - 3 1-124 4-CF 3 -Ph -CH 2 - 4 1-125 4-CF 3 -Ph -O- 2 1-126 4-CF ₃ -Ph -O- 4 1-127 2,3-diCF ₃ -Ph -CH _2-4 1-128 3,4-diCF ₃ -Ph -CH _2- 4 1-129 2-MeO-Ph -CH ₂ - 2 1-130 2-MeO-Ph -CH 2 - 3 1-131 2-MeO-Ph -CH 2 - 4 1-132 2-MeO-Ph -O- 2 1-133 2-MeO-Ph -O - 4 1-134 3-MeO-Ph -CH 2 - 2 1-136 3-MeO-Ph -CH 2 - 4 1-137 4-MeO-Ph -CH 2 - 2 1-138 4-MeO-Ph - _{CH 2 - 3 1-139 4-MeO} -Ph -CH 2 - 4 1-140 4-MeO-Ph -O- 2 1-141 4-MeO-Ph -O- 4 1-142 4-MeOCH 2 -Ph _{-CH 2 - 2 1-143 4-MeOCH} 2 -Ph -CH 2 - 4 1-144 4-MeS-Ph -CH 2 - 4 1-145 4-Biphenyl -CH 2 - 2 1-146 4-Biphenyl - _{CH 2 - 3 1-147 4-Biphenyl} -CH 2 - 4 1-148 4-Biphenyl -O- 2 1-149 4-Biphenyl -O- 4 1-150 4-OH-Ph -CH 2 - 4 1- 151 4-SH-Ph -CH _2-4 1-152 4-NH ₂ -Ph -CH _2-4 1-153 4-NHAc-Ph -CH _2-4 1-154 4-COOH-Ph -CH _2- 4 1-155 4-CH ₂ COOH-Ph -CH _2-4 1-156 2-Ac-Ph -CH _2-4 1-157 4-MeOCO-Ph -CH _2-4 1-158 3-NH ₂ CO _{-Ph -CH 2 - 4 1-159 2-} CN-Ph -CH 2 - 2 1-160 2-CN-Ph -CH 2 - 4 1-161 3-CN-Ph -CH 2 - 2 1-162 3 _{-CN-Ph -CH 2 - 4 1-163} 4-CN-Ph -CH 2 - 2 1-164 4-CN-Ph -CH 2 - 3 1-165 4-CN-Ph -CH 2 - 4 1- 166 4-CN-Ph -O- 2 1-167 4-CN-Ph -O- 4 1-168 2-NO 2 -Ph -CH 2 - 2 1-169 2-NO 2 -Ph -CH 2 - 4 1-170 3-NO ₂ -Ph -CH _{2- 2 1-171 3-NO 2 -Ph -CH} 2 - 4 1-172 4-NO 2 -Ph -CH 2 - 2 1-173 4-NO 2 -Ph -CH 2 - 3 1-174 4-NO 2 _{-Ph -CH 2 - 4 1-175 4-} NO 2 -Ph -O- 2 1-176 4-NO 2 -Ph -O- 4 1-177 Pent c -amino -CH 2 - 2 1-178 Pent c ^{_{-amino -CH 2 - 4 1-179 Hex c}} -amino -CH 2 - 2 1-180 Hex c -amino -CH 2 - 3 1-181 Hex c -amino -CH 2 - 4 1-182 Hex c -amino ^{-O- 2 1-183 Hex c -amino -O- 4} 1-184 Ph-amino -CH 2 - 2 1-185 Ph-amino -CH 2 - 3 1-186 Ph-amino -CH 2 - 4 1- 187 Ph-amino -O- 2 1-188 Ph -amino -O- 4 1-189 2-F-Ph-amino -CH 2 - 2 1-190 2-F-Ph-amino -CH 2 - 4 1- 191 3-F-Ph-amino -CH 2 - 2 1-192 3-F-Ph-amino -CH 2 - 2 1-193 3-F-Ph-amino -CH 2 - 4 1-194 4-F- _{Ph-amino -CH 2 - 2 1-195} 4-F-Ph-amino -CH 2 - 4 1-196 2-Cl-Ph-amino -CH 2 - 2 1-197 2-Cl-Ph-amino -CH _{2 - 4 1-198 3-Cl-} Ph-amino -CH 2 - 2 1-199 3-Cl-Ph-amino -CH 2 - 4 1-200 4-Cl-Ph-amino -CH 2 - 2 1- 201 4-Cl-Ph-amino -CH 2 - 3 1-202 4-Cl-Ph-amino -CH 2 - 4 1-203 2,3-diF-Ph-amino -CH 2 - 2 1-204 2, 3-diF-Ph-amino -CH 2 - 3 1-205 2,3-diF-Ph-amino -CH 2 - 4 1-206 2,4-diF-Ph-a _{mino -CH 2 - 2 1-207 2,4-} diF-Ph-amino -CH 2 - 3 1-208 2,4-diF-Ph-amino -CH 2 - 4 1-209 2,4-diF-Ph -amino -O- 2 1-210 2,4-diF- Ph-amino -O- 4 1-211 3,4-diF-Ph-amino -CH 2 - 2 1-212 3,4-diF-Ph- _{amino -CH 2 - 3 1-213 3,4-} diF-Ph-amino -CH 2 - 4 1-214 2,3-diCl-Ph-amino -CH 2 - 2 1-215 2,3-diCl-Ph _{-amino -CH 2 - 3 1-216 2,3-} diCl-Ph-amino -CH 2 - 4 1-217 2,4-diCl-Ph-amino -CH 2 - 2 1-218 2,4-diCl- _{Ph-amino -CH 2 - 3 1-219} 2,4-diCl-Ph-amino -CH 2 - 4 1-220 2,5-diCl-Ph-amino -CH 2 - 2 1-221 2,5-diCl _{-Ph-amino -CH 2 - 3 1-222} 2,5-diCl-Ph-amino -CH 2 - 4 1-223 2-Me-Ph-amino -CH 2 - 4 1-224 3-Me-Ph- _{amino -CH 2 - 2 1-225 3-} Me-Ph-amino -CH 2 - 4 1-226 4-Me-Ph-amino -CH 2 - 4 1-227 2-MeO-Ph-amino -CH 2 - 2 1-228 2-MeO-Ph-amino -CH _2-4 1-229 3-MeO-Ph-amino -CH _2-4 1-230 4-MeO-Ph-amino -CH _2-4 1-231 1 _{-Me-2-Ind -CH 2 -} 2 1-232 1-Me-2-Ind -CH 2 - 3 1-233 1-Me-2-Ind -CH 2 - 4 1-234 1-Me-2- Ind -O- 2 1-235 1-Me- 2-Ind -O- 4 1-236 2-Pyr -CH 2 - 2 1-237 2-Pyr -CH 2 - 3 1-238 2-Pyr -CH 2 -4 1-239 3-Pyr -CH _{2- 2 1-240 3-Pyr -CH 2 -} 3 1-241 3-Pyr -CH 2 - 4 1-242 3-Pyr -O- 2 1-243 3-Pyr -O- 4 1-244 4-Pyr - _{CH 2 - 2 1-245 4-Pyr} -CH 2 - 4 1-246 Pyz -CH 2 - 2 1-247 Pyz -CH 2 - 3 1-248 Pyz -CH 2 - 4 1-249 Pyz -O- 2 1-250 Pyz -O- 4 1-251 2-Quin -CH 2 - 2 1-252 2-Quin -CH 2 - 4 1-253 3-Quin -CH 2 - 2 1-254 3-Quin -CH 2 _{- 4 1-255 4-Quin -CH 2} - 2 1-256 4-Quin -CH 2 - 3 1-257 4-Quin -CH 2 - 4 1-258 4-Quin -O- 2 1-259 4- Quin -O- 4 1-260 2-Fur -CH 2 - 2 1-261 2-Fur -CH 2 - 3 1-262 2-Fur -CH 2 - 4 1-263 2-Fur -O- 2 1- 264 2-Fur -O- 4 1-265 3 -F-2-Fur -CH 2 - 2 1-266 3-F-2-Fur -CH 2 - 4 1-267 5-F-2-Fur -CH _{2 - 2 1-268 5-F-} 2-Fur -CH 2 - 4 1-269 5-Me-2-Fur -CH 2 - 2 1-270 5-Me-2-Fur -CH 2 - 4 1- 271 5-MeO-2-Fur -CH 2 - 2 1-272 5-MeO-2-Fur -CH 2 - 4 1-273 3-Fur -CH 2 - 2 1-274 3-Fur -CH 2 - 4 1-275 3-F-3-Fur -CH 2 - 2 1-276 3-F-3-Fur -CH 2 - 4 1-277 5-F-3-Fur -CH 2 - 2 1-278 5- _{F-3-Fur -CH 2 -} 4 1-279 5-Me-3-Fur -CH 2 - 2 1-280 5-Me-3-Fur -CH 2 - 4 1-281 5-MeO-3-Fur _{-CH 2 - 2 1-282 5-MeO} -3-Fur -CH 2 - 4 1-283 2- _{Thi -CH 2 - 2 1-284 2-} Thi -CH 2 - 3 1-285 2-Thi -CH 2 - 4 1-286 2-Thi -O- 2 1-287 2-Thi -O- 4 1- 288 3-F-2-Thi -CH 2 - 2 1-289 3-F-2-Thi -CH 2 - 3 1-290 3-F-2-Thi -CH 2 - 4 1-291 5-F- _{2-Thi -CH 2 - 2 1-292} 5-F-2-Thi -CH 2 - 3 1-293 5-F-2-Thi -CH 2 - 4 1-294 3-Cl-2-Thi -CH _{2 - 2 1-295 3-Cl-} 2-Thi -CH 2 - 3 1-296 3-Cl-2-Thi -CH 2 - 4 1-297 5-Cl-2-Thi -CH 2 - 2 1- 298 5-Cl-2-Thi -CH 2 - 3 1-299 5-Cl-2-Thi -CH 2 - 4 1-300 5-Cl-2-Thi -O- 2 1-301 5-Cl-2 -Thi -O- 4 1-302 3-Me- 2-Thi -CH 2 - 2 1-303 3-Me-2-Thi -CH 2 - 3 1-304 3-Me-2-Thi -CH 2 - 4 1-305 3-Me-2- Thi -O- 2 1-306 3-Me-2-Thi -O- 4 1-307 5-Me-2-Thi -CH 2 - 2 1-308 5-Me _{-2-Thi -CH 2 - 3 1-309} 5-Me-2-Thi -CH 2 - 4 1-310 5-Me-2-Thi -O- 2 1-311 5-Me-2-Thi -O _{- 4 1-312 3-CF 3 -2} -Thi -CH 2 - 2 1-313 3-CF 3 -2-Thi -CH 2 - 3 1-314 3-CF 3 -2-Thi -CH 2 - 4 1-315 3-MeO-2-Thi -CH 2 - 2 1-316 3-MeO-2-Thi -CH 2 - 3 1-317 3-MeO-2-Thi -CH 2 - 4 1-318 3- MeO-2-Thi -O- 2 1-319 3-MeO-2-Thi -O- 4 1-320 5-MeO-2-Thi -CH 2 - 2 1-321 5-MeO-2-Thi -CH ₂ - 3 1-322 5-Me O-2-Thi -CH _2-4 1-323 5-MeO-2-Thi -O- 2 1-324 5-MeO-2-Thi -O- 4 1-325 5-MeOCH ₂ -2-Thi- _{CH 2 - 2 1-326 5-MeOCH} 2 -2-Thi -CH 2 - 3 1-327 5-MeOCH 2 -2-Thi -CH 2 - 4 1-328 3-MeS-2-Thi -CH 2 - 2 1-329 3-Ph-2- Thi -CH 2 - 2 1-330 3-Ph-2-Thi -CH 2 - 4 1-331 5-Ph-2-Thi -CH 2 - 4 1-332 3 _{-OH-2-Thi -CH 2 -} 4 1-333 3-SH-2-Thi -CH 2 - 2 1-334 5-NH 2 -2-Thi -CH 2 - 4 1-335 3-AcNH-2 -Thi -CH _2-4 1-336 3-COOH-2-Thi -CH _2-4 1-337 3-CH ₂ COOH-2-Thi -CH _2-4 1-338 3-Ac-2-Thi- _{CH 2 - 2 1-339 3-MeOCO} -2-Thi -CH 2 - 2 1-340 5-NH 2 CO-2-Thi -CH 2 - 4 1-341 5-CN-2-Thi -CH 2 - _{4 1-342 5-NO 2 -2-} Thi -CH 2 - 4 1-343 3-Thi -CH 2 - 2 1-344 3-Thi -CH 2 - 3 1-345 3-Thi -CH 2 - 4 1-346 3-Thi -O- 2 1-347 3 -Thi -O- 4 1-348 4-F-3-Thi -CH 2 - 2 1-349 4-F-3-Thi -CH 2 - 3 1-350 4-F-3-Thi -CH 2 - 4 1-351 2-Cl-3-Thi -CH 2 - 2 1-352 2-Cl-3-Thi -CH 2 - 3 1-353 2- _{Cl-3-Thi -CH 2 -} 4 1-354 4-Cl-3-Thi -CH 2 - 2 1-355 4-Cl-3-Thi -CH 2 - 3 1-356 4-Cl-3-Thi _{-CH 2 - 4 1-357 4-Me} -3-Thi -CH 2 - 2 1-358 4-Me-3-Thi -CH 2 - 3 1-359 4- _{Me-3-Thi -CH 2 -} 4 1-360 2-CF 3 -3-Thi -CH 2 - 4 1-361 4-CF 3 -3-Thi -CH 2 - 2 1-362 4-CF 3 - _{3-Thi -CH 2 - 4 1-363} 4-MeO-3-Thi -CH 2 - 2 1-364 4-MeO-3-Thi -CH 2 - 3 1-365 4-MeO-3-Thi -CH _{2 - 4 1-366 4-MeO-} 3-Thi -O- 2 1-367 4-MeO-3-Thi -O- 4 1-368 5-MeO-3-Thi -CH 2 - 2 1-369 5 _{-MeO-3-Thi -CH 2 -} 3 1-370 5-MeO-3-Thi -CH 2 - 4 1-371 2-MeOCH 2 -3-Thi -CH 2 - 4 1-372 4-MeOCH 2 - _{3-Thi -CH 2 - 2 1-373} 4-MeOCH 2 -3-Thi -CH 2 - 4 1-374 2-MeS-3-Thi -CH 2 - 4 1-375 4-MeS-3-Thi - _{CH 2 - 2 1-376 4-MeS} -3-Thi -CH 2 - 4 1-377 2-Ph-3-Thi -CH 2 - 4 1-378 4-Ph-3-Thi -CH 2 - 2 1 -379 4-Ph-3-Thi -CH 2 - 4 1-380 2-OH-3-Thi -CH 2 - 4 1-381 4-SH-3-Thi -CH 2 - 2 1-382 4-NH ₂ -3-Thi -CH _2-4 1-383 4-AcNH-3-Thi -CH _2-4 1-384 4-COOH-3-Thi -CH _2-4 1-385 5-CH ₂ COOH-3 -Thi -CH _2-4 1-386 4-Ac-3-Thi -CH _2-4 1-387 4-MeOCO-3-Thi -CH _2-4 1-388 4-NH ₂ CO-3-Thi- CH _2-4

[0037]

[Chemical 9]

[0038]

[Table 2] Compound No. ^{-NR 1 R 2 X m 2-1 Thiz} -CH 2 - 2 2-2 Thiz -CH 2 - 3 2-3 Thiz -CH 2 - 4 2-4 Thiz -CH 2 - 5 2-5 Thiz - _{CH 2 - 6 2-6 Thiz -O- 2} 2-7 Thiz -O- 3 2-8 Thiz -O- 4 2-9 Thiz -O- 5 2-10 Thiz -O- 6 2-11 5-Me _{-Thiz -CH 2 - 2 2-12 5-} Me-Thiz -CH 2 - 3 2-13 5-Me-Thiz -CH 2 - 4 2-14 5-Me-Thiz -CH 2 - 5 2-15 5 -Me-Thiz -O- 2 2-16 5- Me-Thiz -O- 4 2-17 5-Me-Thiz -O- 5 2-18 5-Et-Thiz -CH 2 - 2 2-19 5- _{Et-Thiz -CH 2 - 3 2-20} 5-Et-Thiz -CH 2 - 4 2-21 5-Et-Thiz -CH 2 - 5 2-22 5-Et-Thiz -O- 2 2-23 5 -Et-Thiz -O- 4 2-24 5- Et-Thiz -O- 5 2-25 5,5-diMe-Thiz -CH 2 - 2 2-26 5,5-diMe-Thiz -CH 2 - 3 _{2-27 5,5-diMe-Thiz -CH 2} - 4 2-28 5,5-diMe-Thiz -CH 2 - 5 2-29 5,5-diMe-Thiz -O- 2 2-30 5,5 -diMe-Thiz -O- 4 2-31 5,5- diMe-Thiz -O- 5 2-32 5-Pr i -Thiz -CH 2 - 2 2-33 5-Pr i -Thiz -CH 2 - 3 _{^{2-34 5-Pr i -Thiz -CH 2}} - 4 2-35 5-Pr i -Thiz -CH 2 - 5 2-36 5-Pr i -Thiz -O- 2 2-37 5-Pr i -Thiz ^{-O- 4 2-38 5-Bu t -Thiz} -CH 2 - 2 2-39 5-Bu t -Thiz -CH 2 - 3 2-40 5-Bu t -Thiz -CH 2 - 4 2-41 5 -Bu ^t -Thiz -CH ₂ - ^{5 2-42 5-Bu t -Thiz -O-} 2 2-43 5-Bu t -Thiz -O- 4 2-44 Phtm -CH 2 - 2 2-45 Phtm -CH 2 - 3 2-46 Phtm - _{CH 2 - 4 2-47 Phtm -CH 2} - 5 2-48 Phtm -CH 2 - 6 2-49 Phtm -O- 2 2-50 Phtm -O- 3 2-51 Phtm -O- 4 2-52 Phtm -O- 5 2-53 Phtm -O- 6 2-54 5 -Et-5-Me-Thiz -CH 2 - 2 2-55 5-Et-5-Me-Thiz -CH 2 - 3 2-56 5 -Et-5-Me-Thiz -CH 2 - 4 2-57 5-Et-5-Me-Thiz -CH 2 - 5 2-58 5-Et-5-Me-Thiz -O- 2 2-59 5 -Et-5-Me-Thiz -O- 3 2-60 5-Et-5-Me-Thiz -O- 4 2-61 5-Me-5-Pr-Thiz -CH 2 - 2 2-62 5- Me-5-Pr-Thiz -CH 2 - 3 2-63 5-Me-5-Pr-Thiz -CH 2 - 4 2-64 5-Me-5-Pr-Thiz -CH 2 - 5 2-65 5 -Me-5-Pr-Thiz -O- 2 2-66 5-Me-5-Pr-Thiz -O- 3 2-67 5-Me-5-Pr-Thiz -O- 4 2-68 5-Bu _{-5-Me-Thiz -CH 2 -} 2 2-69 5-Bu-5-Me-Thiz -CH 2 - 3 2-70 5-Bu-5-Me-Thiz -CH 2 - 4 2-71 5- Bu-5-Me-Thiz -CH 2 - 5 2-72 5-Bu-5-Me-Thiz -O- 2 2-73 5-Bu-5-Me-Thiz -O- 3 2-74 5-Bu -5-Me-Thiz -O- 4 2-75 5,5-diEt-Thiz -CH 2 - 2 2-76 5,5-diEt-Thiz -CH 2 - 3 2-77 5,5-diEt-Thiz _{-CH 2 - 4 2-78 5,5-diEt} -Thiz -CH 2 - 5 2-79 5,5-diEt-Thiz -O- 2 2-80 5,5-diEt-Thiz -O- 3 2- 81 5,5-d iEt-Thiz -O- 4 2-82 5- Et-5-Pr-Thiz -CH 2 - 2 2-83 5-Et-5-Pr-Thiz -CH 2 - 3 2-84 5-Et-5- _{Pr-Thiz -CH 2 - 4 2-85} 5-Et-5-Pr-Thiz -CH 2 - 5 2-86 5-Et-5-Pr-Thiz -O- 2 2-87 5-Et-5- Pr-Thiz -O- 3 2-88 5- Et-5-Pr-Thiz -O- 4 2-89 5-Pr-Thiz -CH 2 - 2 2-90 5-Pr-Thiz -CH 2 - 3 2 _{-91 5-Pr-Thiz -CH 2} - 4 2-92 5-Pr-Thiz -CH 2 - 5 2-93 5-Pr-Thiz -O- 2 2-94 5-Pr-Thiz -O- 3 2 -95 5-Pr-Thiz -O- 4 2-96 5,5-diPr-Thiz -CH 2 - 2 2-97 5,5-diPr-Thiz -CH 2 - 3 2-98 5,5-diPr- _{thiz -CH 2 - 4 2-99 5,5-} diPr-thiz -CH 2 - 5 2-100 5,5-diPr-thiz -O- 2 2-101 5,5-diPr-thiz -O- 3 2 -102 5,5-diPr-Thiz -O- 4 2-103 5,5-diPr i -Thiz -CH 2 - 2 2-104 5,5-diPr i -Thiz -CH 2 - 3 2-105 5, _{^{5-diPr i -Thiz -CH 2 -}} 4 2-106 5,5-diPr i -Thiz -CH 2 - 5 2-107 5,5-diPr i -Thiz -O- 2 2-108 5,5-diPr ^{i -Thiz -O- 3 2-109 5,5-diPr} i -Thiz -O- 4 2-110 5-Bu-Thiz -CH 2 - 2 2-111 5-Bu-Thiz -CH 2 - 3 2- _{112 5-Bu-Thiz -CH 2} - 4 2-113 5-Bu-Thiz -CH 2 - 5 2-114 5-Bu-Thiz -O- 2 2-115 5-Bu-Thiz -O- 3 2- 116 5-Bu-Thiz -O- 4 2-117 5-Bu i -Thiz -CH 2 - 2 2-118 5-Bu i _{-Thiz -CH 2 - 3 2-119 5-} Bu i -Thiz -CH 2 - 4 2-120 5-Bu i -Thiz -CH 2 - 5 2-121 5-Bu i -Thiz -O- 2 2- ^{122 5-Bu i -Thiz -O- 4} 2-123 5,5-diBu t -Thiz -CH 2 - 2 2-124 5,5-diBu t -Thiz -CH 2 - 3 2-125 5,5- _{^{diBu t -Thiz -CH 2 - 4 2-126}} 5,5-diBu t -Thiz -CH 2 - 5 2-127 5,5-diBu t -Thiz -O- 2 2-128 5,5-diBu t - ^{Thiz -O- 3 2-129 5,5-diBu t} -Thiz -O- 4

[0039]

[Chemical 10]

[0040]

[Table 3] Compound number R ⁶ X m 3-1 Ph -CH ₂ -2 3-2 Ph -CH ₂ -3 3-3 Ph -CH ₂ -4 3-4 Ph -CH ₂ -5 3-5 Ph -CH _2- 6 3-6 Ph -O- 2 3-7 Ph -O- 3 3-8 Ph -O- 4 3-9 2-F-Ph -CH 2 - 2 3-10 2-F-Ph -CH 2 - 3 3-11 2-F-Ph -CH _2-4 3-12 2-F-Ph -O- 2 3-13 2-F-Ph -O- 4 3-14 3-F-Ph -CH _2- 2 3-15 3-F-Ph -CH 2 - 3 3-16 3-F-Ph -CH 2 - 4 3-17 3-F-Ph -O- 2 3-18 3-F-Ph -O- 4 3-19 4-F-Ph -CH 2 - 2 3-20 4-F-Ph -CH 2 - 3 3-21 4-F-Ph -CH 2 - 4 3-22 4-F-Ph -O - 2 3-23 4-F-Ph -O- 4 3-24 2,3-diF-Ph -CH 2 - 2 3-25 2,3-diF-Ph -CH 2 - 3 3-26 2,3 -diF-Ph -CH _2-4 3-27 2,3-diF-Ph -O- 2 3-28 2,3-diF-Ph -O- 4 3-29 2,4-diF-Ph -CH ₂ - 2 3-30 2,4-diF-Ph -CH 2 - 3 3-31 2,4-diF-Ph -CH 2 - 4 3-32 2,4-diF-Ph -O- 2 3-33 2 , 4-diF-Ph -O- 4 3-34 2,5-diF-Ph -CH 2 - 2 3-35 2,5-diF-Ph -CH 2 - 3 3-36 2,5-diF-Ph _{-CH 2 - 4 3-37 2,6-diF} -Ph -CH 2 - 2 3-38 2,6-diF-Ph -CH 2 - 3 3-39 2,6-diF-Ph -CH 2 - 4 _{3-40 3,5-diF-Ph -CH 2} - 2 3-41 3,5-diF-Ph -CH 2 - 3 3-42 3,5-diF-Ph -CH 2 - 4 3-43 2- _{Cl-Ph -CH 2 - 2 3-44} 2-Cl-Ph -CH 2 - 3 3-45 2-Cl-Ph -CH _{2 - 4 3-46 2-Cl-} Ph -O- 2 3-47 2-Cl-Ph -O- 4 3-48 3-Cl-Ph -CH 2 - 2 3-49 3-Cl-Ph -CH _{2 - 3 3-50 3-Cl-} Ph -CH 2 - 4 3-51 3-Cl-Ph -O- 2 3-52 3-Cl-Ph -O- 4 3-53 4-Cl-Ph -CH _{2 - 2 3-54 4-Cl-} Ph -CH 2 - 3 3-55 4-Cl-Ph -CH 2 - 4 3-56 4-Cl-Ph -O- 2 3-57 4-Cl-Ph - O- 4 3-58 2-Me-Ph -CH 2 - 2 3-59 2-Me-Ph -CH 2 - 3 3-60 2-Me-Ph -CH 2 - 4 3-61 2-Me-Ph -O- 2 3-62 2-Me-Ph -O- 4 3-63 3-Me-Ph -CH 2 - 2 3-64 3-Me-Ph -CH 2 - 3 3-65 3-Me-Ph _{-CH 2 - 4 3-66 3-Me} -Ph -O- 2 3-67 3-Me-Ph -O- 4 3-68 4-Me-Ph -CH 2 - 2 3-69 4-Me-Ph _{-CH 2 - 3 3-70 4-Me} -Ph -CH 2 - 4 3-71 4-Me-Ph -O- 2 3-72 4-Me-Ph -O- 4 3-73 4-CF 3 - _{Ph -CH 2 - 2 3-74 4-} CF 3 -Ph -CH 2 - 3 3-75 4-CF 3 -Ph -CH 2 - 4 3-76 2-MeO-Ph -CH 2 - 2 3-77 _{2-MeO-Ph -CH 2 -} 3 3-78 2-MeO-Ph -CH 2 - 4 3-79 2-MeO-Ph -O- 2 3-80 2-MeO-Ph -O- 4 3-81 _{3-MeO-Ph -CH 2 -} 2 3-82 3-MeO-Ph -CH 2 - 3 3-83 3-MeO-Ph -CH 2 - 4 3-84 3-MeO-Ph -O- 2 3- 85 3-MeO-Ph -O- 4 3-86 4-MeO-Ph -CH 2 - 2 3-87 4-MeO-Ph -CH 2 - 3 3-88 4-MeO-Ph -CH 2 - 4 3 -89 4-MeO-Ph -O- 2 3-90 4-MeO-Ph -O- 4 3-91 2- _{MeS-Ph -CH 2 - 2 3-92} 3-MeS-Ph -CH 2 - 4 3-93 4-MeS-Ph -O- 4 3-94 4-Biphenyl -CH 2 - 2 3-95 4-Biphenyl _{-CH 2 - 4 3-96 4-OH} -Ph -CH 2 - 2 3-97 4-OH-Ph -CH 2 - 4 3-98 4-OH-Ph -O- 4 3-99 2-SH- _{Ph -CH 2 - 2 3-100 3-} SH-Ph -CH 2 - 4 3-101 4-SH-Ph -O- 4 3-102 2-NH 2 -Ph -CH 2 - 2 3-103 3- _{NH 2 -Ph -CH 2 - 3 3-104} 4-NH 2 -Ph -CH 2 - 4 3-105 2-AcNH-Ph -CH 2 - 2 3-106 3-AcNH-Ph -CH 2 - 4 3 -107 4-AcNH-Ph -O- 4 3-108 2-COOH-Ph -CH _2-4 3-109 3-COOH-Ph -CH _2-4 3-110 4-COOH-Ph -CH _{2-4 3-111 4-CH 2 COOH-Ph} -CH 2 - 2 3-112 4-CH 2 COOH-Ph -CH 2 - 3 3-113 4-CH 2 COOH-Ph -CH 2 - 4 3-114 4- _{Ac-Ph -CH 2 - 2 3-115} 4-Ac-Ph -CH 2 - 4 3-116 4-Ac-Ph -O- 4 3-117 4-MeOCO-Ph -CH 2 - 2 3-118 4 -MeOCO-Ph -CH _2-3 3-119 4-MeOCO-Ph -CH _2-4 3-120 2-CN-Ph -O- 2 3-121 2-CN-Ph -O- 4 3-122 3 _{-CN-Ph -CH 2 - 2 3-123} 3-CN-Ph -CH 2 - 3 3-124 3-CN-Ph -CH 2 - 4 3-125 3-CN-Ph -O- 2 3-126 3-CN-Ph -O- 4 3-127 4-NO 2 -Ph -CH 2 - 2 3-128 4-NO 2 -Ph -CH 2 - 3 3-129 4-NO 2 -Ph -CH 2 - _{4 3-130 4-NO 2 -Ph -O-} 2 3-131 4-NO 2 -Ph -O- 4 Formula (I) or (II) hexahydropyrazino quinoline derivative [formula (Ia), (I) and (II)] with a suitable compound At a is 1-6,1-
7, 1-11, 1-13, 1-17, 1-20, 1-2
3, 1-24, 1-25, 1-28, 1-30, 1-3
1, 1-33, 1-36, 1-37, 1-39, 1-4
1, 1-42, 1-44, 1-47, 1-48, 1-5
0, 1-52, 1-53, 1-55, 1-58, 1-6
0, 1-61, 1-63, 1-65, 1-66, 1-6
8, 1-70, 1-71, 1-73, 1-75, 1-7
7, 1-79, 1-81, 1-82, 1-83, 1-8
4, 1-85, 1-86, 1-87, 1-88, 1-8
9, 1-90, 1-91, 1-92, 1-105, 1-
107, 1-109, 1-111, 1-114, 1-1
15, 1-117, 1-118, 1-119, 1-12
2, 1-124, 1-129, 1-131, 1-13
6, 1-137, 1-139, 1-141, 1-14
7, 1-160, 1-162, 1-163, 1-16
5, 1-169, 1-171, 1-174, 1-17
8, 1-179, 1-181, 1-184, 1-18
6, 1-190, 1-193, 1-195, 1-19
7, 1-199, 1-202, 1-205, 1-20
6, 1-208, 1-213, 1-216, 1-21
9, 1-222, 1-231, 1-233, 1-23
8, 1-239, 1-241, 1-245, 1-24
6, 1-248, 1-252, 1-254, 1-25
5, 1-257, 1-260, 1-262, 1-28
3, 1-285, 1-288, 1-291, 1-29
3, 1-297, 1-299, 1-302, 1-30
4, 1-307, 1-309, 1-314, 1-31
5, 1-317, 1-320, 1-322, 1-34
3, 1-345, 1-350, 1-356, 1-35
9, 1-363, 1-365, 2-1, 2-2, 2-
3, 2-4, 2-5, 2-25, 2-27, 2-28,
2-32, 2-33, 2-34, 2-35, 2-40,
2-41, 2-44, 2-45, 2-46, 2-47,
2-48, 3-1, 3-2, 3-3, 3-4, 3-1
1, 3-16, 3-21, 3-45, 3-50, 3-5
5, 3-60, 3-65, 3-70, 3-73, 3-7
5, 3-78, 3-83 or 3-88 can be mentioned.

Further preferred compounds are 1-6, 1-
11, 1-20, 1-23, 1-24, 1-25, 1-
30, 1-33, 1-39, 1-44, 1-50, 1-
53, 1-55, 1-63, 1-68, 1-73, 1-
79, 1-92, 1-111, 1-119, 1-12
4, 1-131, 1-139, 1-147, 1-16
5, 1-174, 1-181, 1-186, 1-20
8, 1-233, 1-241, 1-248, 1-25
7, 1-262, 1-283, 1-285, 1-29
9, 1-302, 1-304, 1-307, 1-30
9, 1-343, 1-345, 1-365, 2-2, 2
-3, 2-4, 2-27, 2-34, 2-46 or 3-
3 can be mentioned.

Particularly preferred compounds are 1-23, 1
-25, 1-50, 1-55, 1-63, 1-92, 1
-248, 1-283, 1-285, 1-299, 1-
302, 1-309, 1-343, 1-345, 1-3
65, 2-27 or 2-34 can be mentioned.

The most preferred compound is compound number 1-23: 3- (2-benzamidoethyl) -2,3,4,4a, 5,6-hexahydro-1H
-Pyrazino [1,2-a] quinoline, Compound No. 1-25: 3- (4-benzamidobutyl) -2,3,4,4a, 5,6-hexahydro-1H
-Pyrazino [1,2-a] quinoline, compound number 1-55: 3- [4- (2,4-difluorobenzamido) butyl] -2,3,4,4a, 5
6-Hexahydro-1H-pyrazino [1,2-a] quinoline, compound number 1-248: 3- [4- (2-pyrazinecarbonylamino) butyl] -2,3,4,4a, 5
6-hexahydro-1H-pyrazino [1,2-a] quinoline, compound number 1-285: 3- [4- (2-thenoylamino) butyl] -2,3,4,4a, 5,6-hexahydro-1H -Pyrazino [1,2-a] quinoline, compound number 1-309: 3- [4- (5-methylthiophene-2-carbonylamino) butyl] -2,3
4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline, compound number 2-27: 3- [4- (5,5-dimethyl-2,4-dioxothiazolidine-3- And butyl) -2,3,4,4a, 5,6-hexahydro-1H
-Pyrazino [1,2-a] quinoline, or Compound No. 2-34: 3- [4- (5-isopropyl-2,4-dioxothiazolidin-3-yl) butyl] -2,3,4. 4a, 5,6-hexahydro-1H
Mention may be made of pyrazino [1,2-a] quinolines.

[0044]

BEST MODE FOR CARRYING OUT THE INVENTION The method for producing the compound of the present invention is shown below.

[0045]

[Chemical 11]

[0046]

[Chemical 12]

[0047]

[Chemical 13]

[0048]

Embedded image

In the above formula, R ¹ , R ² , R ³ , R ⁶ , X and m have the same meanings as described above, and R ⁷ is C _7-
C ₄₈ represents an aralkyl group, and R ⁸ is halogen or tri-C.
C ₁ -C ₄ which may be substituted with ₁ -C ₄ alkylsilyl
An alkoxycarbonyl group, R ⁹ represents a halogen atom, and Y and Y ′ represent the same or different leaving groups.

The “C ₇ -C ₄₈ aralkyl group” for R ⁷ has the same meaning as described above, and examples thereof include a benzyl group and α-
Phenethyl group, β-phenethyl group, 3-phenylpropyl group, 4-phenylbutyl group, α-naphthylmethyl group,
β-naphthylmethyl group, 1- (α-naphthyl) ethyl group, 1- (β-naphthyl) ethyl group, diphenylmethyl group, triphenylmethyl group, α-naphthyldiphenylmethyl group or 9-anthrylmethyl group It is preferably a benzyl group or an α-phenethyl group, and particularly preferably an α-phenethyl group.

R ⁸ "C ₁ -C ₄ alkoxycarbonyl group which may be substituted with halogen or tri C ₁ -C ₄ alkylsilyl is, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxy group. Carbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, s-butoxycarbonyl group, t-butoxycarbonyl group, chloromethoxycarbonyl group,
2,2,2-trichloroethoxycarbonyl group, 2-fluoropropoxycarbonyl group, 2-bromo-t-butoxycarbonyl group, 2,2-dibromo-t-butoxycarbonyl group, triethylsilylmethoxycarbonyl group,
It may be a 2-trimethylsilylethoxycarbonyl group, a 4-tripropylsilylbutoxycarbonyl group or a t-butyldimethylsilylpropoxycarbonyl group, preferably a methoxycarbonyl group, an ethoxycarbonyl group or t.
-Butoxycarbonyl group, particularly preferably t-butoxycarbonyl group.

The halogen atom for R ⁹ has the same meaning as described above, and is preferably a chlorine atom or a bromine atom.

The leaving group of Y and Y'is not particularly limited as long as it is a group capable of leaving as a nucleophilic residue.
Halogen atom such as chlorine, bromine or iodine; C ₁ such as methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy or butanesulfonyloxy
Such as trifluoromethanesulfonyloxy, 2,2,2-trichloroethane sulfonyloxy, 3,3,3-bromopropane sulfonyloxy or 4,4,4-trifluoro-butane sulfonyloxy,; -C ₄ alkanesulfonyloxy group Halogeno C ₁ -C ₄ alkanesulfonyloxy group; or benzenesulfonyloxy, α
A C ₁ -C ₄ alkyl group, such as -naphthylsulfonyloxy, β-naphthylsulfonyloxy, p-toluenesulfonyloxy, 4-t-butylbenzenesulfonyloxy, mesitylenesulfonyloxy or 6-ethyl-α-naphthylsulfonyloxy. May be a C ₆ -C ₁₀ arylsulfonyloxy group which may have 1 to 3, preferably a chlorine, bromine or iodine atom; a methanesulfonyloxy group or an ethanesulfonyloxy group; a trifluoromethanesulfonyloxy group, 2 , 2,2-trichloroethanesulfonyloxy group or pentafluoroethanesulfonyloxy group; or benzenesulfonyloxy group, p-toluenesulfonyloxy group or mesitylenesulfonyloxy group, more preferably chlorine, bromine or iodine atom. is there.

The compounds having the general formula (VI) and the compounds having the general formula (VIII), which are the starting material compounds of the present invention, are known compounds or can be produced according to known methods. it can. [For example,
Of Medicinal Chemistry, Volume 13, 516
Page (1970) [ J.Med.Chem. , 13 , 516 (1970).], Indian Journal of Chemistry, Volume 7,
Page 833 (1969) [ Indian J. Chem. , 7 , 833 (196
9).], Indian Journal of Chemistry, vol. 13, p. 462 (1975) [ Indian J. Che
m. , 13 , 462 (1975).], US Pat. No. 4,367,335, Helvetica Hemica Actor, Vol. 20, p. 1388 (1937).
Year) [ Helvetica Chimica Acta , 20 , 1388 (1937).], JP-A-50-58234, JP-B-46-33032
etc].

Method A is a method for producing compound (I).

The step A1 is the step of reacting the compound having the general formula (V) with the compound having the general formula (VI) in the presence or absence of a base (preferably in the presence) in an inert solvent. Is a step of producing a compound having the general formula (VII).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene. , Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or Ethers such as diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or sulfones such as dimethylsulfoxide or sulfolane. Obtained a Kishido acids, preferably, an ether, amides or sulfoxides, more preferably a ethers (particularly diethyl ether or tetrahydrofuran) or amides (particularly dimethylformamide).

The bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; like methyl mercaptan sodium or ethyl mercaptan sodium Mercaptan alkali metals; triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline,
N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-
Diazabicyclo [5.4.0] undec-7-ene (D
BU) organic amines; alkyllithium such as methyllithium, ethyllithium or butyllithium; lithium alkylamides such as lithium diisopropylamide or lithium dicyclohexylamide, preferably alkali metal carbonates. , Alkali metal bicarbonates, alkali metal hydrides (particularly sodium hydride), alkali metal alkoxides or alkyl lithiums, and more preferably alkali metal carbonates (sodium carbonate or potassium carbonate).

The reaction temperature will vary depending on the starting compounds, reagents, solvents, etc., but is usually -20 ° C to 100 ° C,
It is preferably 0 ° C to 50 ° C.

The reaction time varies depending on the raw material compound, reagent, solvent or reaction temperature, but is usually 10 minutes to 12 hours, preferably 30 minutes to 5 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, water is added to the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water and then with anhydrous magnesium sulfate or the like. The target compound is obtained by drying and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation, chromatography or addition of an acid to form a salt.

In the step A2, the compound having the general formula (VII) is reacted with the compound having the general formula (VIII) in the presence or absence of a base (preferably in the presence) in an inert solvent. This is a step of producing a compound having the general formula (I).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but it is, for example, an aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether; benzene. , Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or Ethers such as diethylene glycol dimethyl ether; methanol, ethanol, propanol,
Alcohols such as isopropanol, butanol or isobutanol; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or sulfoxides such as dimethylsulfoxide or sulfolane, preferably, Ethers, alcohols or amides, more preferably alcohols (particularly isopropyl alcohol or butanol).

The bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; like methyl mercaptan sodium or ethyl mercaptan sodium Mercaptan alkali metals; triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline,
N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-
Diazabicyclo [5.4.0] undec-7-ene (D
BU) organic amines; alkyllithium such as methyllithium, ethyllithium or butyllithium; or lithium alkylamides such as lithium diisopropylamide or lithium dicyclohexylamide, preferably alkali metal Carbonates or alkali metal hydrides, more preferably alkali metal carbonates (particularly sodium carbonate or potassium carbonate).

The reaction temperature varies depending on the raw material compound, reagent, solvent, etc., but is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.

The reaction time varies depending on the raw material compound, reagent, solvent or reaction temperature, but is usually 30 minutes to 24 hours, and preferably 1 hour to 12 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, if an insoluble substance is present, it is filtered off, the solvent is distilled off, or water is added to the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) Is added to extract the target compound, the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation, chromatography or addition of an acid to form a salt.

Method B is the compound (I) wherein R ¹ is of the formula-
It is a method for producing a compound (Ia) which is a group having COR ³ .

The step B1 is a compound (Ib) obtained by the method A, wherein R ¹ and R ² together with the nitrogen atom to which they are bonded form a phthalimidyl group. Is a step of producing a compound having the general formula (IX) by reacting with a base in an inert solvent.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene. , Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or Ethers such as diethylene glycol dimethyl ether; methanol, ethanol, propanol,
Alcohols such as isopropanol, butanol or isobutanol; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or sulfoxides such as dimethylsulfoxide or sulfolane, preferably, Alcohols or amides, more preferably alcohols (especially methanol or ethanol).

The base used may be, for example, hydrazines such as hydrazine or hydrazine hydrate or organic amines such as methylamine, ethylamine or butylamine, preferably hydrazines (especially hydrazine hydrate). is there.

The reaction temperature varies depending on the raw material compound, reagent, solvent, etc., but is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C. The reaction time varies depending on the raw material compound, reagent, solvent or reaction temperature, but is usually 30 minutes to 24 hours, and preferably 1 hour to 12 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, if an insoluble substance is present, it is filtered off, the solvent is distilled off, or water or alkaline water is added to the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, methylene chloride, Ether, ethyl acetate, etc.) to extract the target compound,
The extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation, chromatography or addition of an acid to form a salt.

In the step B2, the compound of the general formula (IX) is converted into the compound of the general formula (X) in the presence or absence of a base (preferably in the presence of a base) in an inert solvent (a). Or (b) in the presence of a condensing agent in an inert solvent (optionally in the presence of a base), a compound of the general formula (X
This is a step of producing a compound having the general formula (Ia) by reacting with a compound having the formula (I).

The solvent used in the step B2a is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, a fat such as hexane, heptane, ligroin or petroleum ether is used. Group hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran , Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or dimethylsulfoxide or sulphate Obtained is such sulfoxides as orchids, preferably, a halogenated hydrocarbon or an ether is more preferably ethers (particularly diethyl ether or tetrahydrofuran).

The bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; methyl mercaptan sodium or ethyl mercaptan sodium Alkali metals such as mercaptans; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N
-Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2]. Octane (DABCO) or 1,8
-Organazins such as diazabicyclo [5.4.0] undec-7-ene (DBU), preferably
Metal carbonates or organic amines, more preferably organic amines (particularly triethylamine). The reaction temperature varies depending on the raw material compound, reagent, solvent, etc., but is usually −20 ° C. to 100 ° C., and preferably 0 ° C. to 50 ° C.
° C. The reaction time varies depending on the raw material compound, reagent, solvent or reaction temperature, but is usually 10 minutes to 12 hours, and preferably 30 minutes to 6 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the target compound precipitated in the reaction solution is collected by filtration, or the solvent is distilled off, water is added to the residue, and a solvent immiscible with water (for example, benzene, methylene chloride, ether, ethyl acetate, etc.). ) Is added to extract the target compound, the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation, chromatography or addition of an acid to form a salt.

The solvent used in the step B2b is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, a fat such as hexane, heptane, ligroin or petroleum ether is used. Group hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran , Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or dimethylsulfoxide or sulphate Obtained is such sulfoxides as orchids, preferably, a halogenated hydrocarbon or an ether, more preferably a halogenated hydrocarbon (particularly methylene chloride).

The condensing agent used is not particularly limited as long as it is generally used in the field of organic chemistry. For example, dicyclohexylcarbodiimide (DC
C), diethyl cyanophosphonate (DEPC), di (2
-Pyridyl) disulfide and triphenylphosphine, 2-chloro-1-methylpyridinium iodide or ethyl chlorocarbonate, preferably diethyl cyanophosphonate.

The bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; like methyl mercaptan sodium or ethyl mercaptan sodium Mercaptan alkali metal; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-)
It may be an organic amine such as dimethylamino) pyridine, N, N-dimethylaniline or N, N-diethylaniline, preferably a metal carbonate or an organic amine, more preferably an organic amine ( Especially triethylamine).

The reaction temperature will vary depending on the starting compounds, reagents, solvents, etc., but is usually -20 ° C to 100 ° C,
It is preferably 0 ° C to 50 ° C. The reaction time varies depending on the starting compound, the reagent, the solvent or the reaction temperature, but is usually 10 minutes to 24 hours, and preferably 30 minutes to 12 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction,
The target compound precipitated in the reaction solution is filtered or the solvent is distilled off, water is added to the residue, and a solvent immiscible with water (for example, benzene, methylene chloride, ether, ethyl acetate, etc.) is added to the target compound. Is extracted, the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation, chromatography or addition of an acid to form a salt.

Method C is a method for producing compound (II).

In the step C1, the compound represented by the general formula (XIV) is converted into the compound represented by the general formula (XII) in the presence or absence of a base (preferably in the presence of a base) in an inert solvent (a). Or by reacting with a compound having the general formula (XIII) in the presence of a condensing agent (in the presence of a base, if necessary) in an inert solvent (b). XV), which is a step of producing a compound having XV) and is performed in the same manner as Step B2.

Step C2 is carried out by reacting a compound having the general formula (XV) with a compound having the general formula (VIII) in the presence or absence (preferably in the presence) of a base in an inert solvent. Is a step of producing a compound having the general formula (II), and is performed in the same manner as Step A2. Method D is a method for producing compound (VIII), which is a raw material for method A. In the method D, the target compound obtained in any of the steps can be optically resolved as desired (preferably the optical resolution in the step D1).

Step D1 is the reaction of the compound having the general formula (XVI) with the compound having the general formula (XVII) in the presence of a condensing agent in an inert solvent (and optionally a base). Is a step of producing a compound having the general formula (XVIII), and is performed in the same manner as in step B2b. The general formula (XVII obtained in this step
The compound having I) is used in a method generally used in the field of organic chemistry, for example, natural resolution (spontaneous crystallization), a method utilizing asymmetric adsorption (silica gel column chromatography or high performance liquid chromatography, etc.). Method) or a splitting reagent (for example, tartaric acid,
It can be optically resolved by a method of forming a diastereomer with mandelic acid or 10-camphorsulfonic acid, etc., and preferably by silica gel column chromatography.

Step D2 is a step of producing a compound having the general formula (XIX) by reacting the compound having the general formula (XVIII) with a reducing agent in an inert solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, Chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably ethers (Especially tetrahydrofuran).

The reducing agent used is not particularly limited as long as it can be used in a usual reduction reaction. For example, sodium borohydride, lithium borohydride, lithium aluminum hydride, hydride A metal hydride such as diisobutylaluminum or aluminum hydride,
Aluminum isopropoxide, diborane or borane-
It may be a methyl sulfide complex, preferably a borane-methyl sulfide complex.

The reaction temperature varies depending on the starting compounds, the solvent, the reducing agent used, etc., but it is usually -20 ° C to 10 ° C.
It is 0 ° C., preferably 0 ° C. to 50 ° C.

The reaction time varies depending on the raw material compound, the solvent, the reducing agent used, the reaction temperature and the like, but is usually 12 hours to 120 hours, preferably 48 hours to 96 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is complete, an acid (preferably hydrochloric acid) is added to the reaction solution, and then the target compound precipitated in the reaction solution is filtered off, or an acid (preferably hydrochloric acid) is added to the reaction solution to prepare a reagent. After decomposing, etc., the reaction solution is made alkaline, a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water, then with anhydrous magnesium sulfate, etc. The target compound is obtained by drying and evaporating the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In the step D3, the compound having the general formula (XIX) is treated with a compound of the formula (R ⁸ ) ₂ O or R ^8- in an inert solvent.
This is a step of producing a compound having the general formula (XX) by reacting with a compound having Y [preferably a compound having the formula (R ⁸ ) ₂ O].

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, Chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably ethers (Especially dioxane).

The reaction temperature will vary depending on the starting compounds, reagents, solvents, etc., but is usually -20 ° C to 100 ° C,
It is preferably 0 ° C to 50 ° C.

The reaction time varies depending on the starting compounds, reagents, solvent, reaction temperature and the like, but is usually 10 minutes to 12 hours, and preferably 1 hour to 3 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture by a conventional method. For example, after the reaction is completed, water is added to the reaction solution to make it alkaline, if necessary, and then a solvent immiscible with water (for example, benzene, ether,
The target compound is extracted by adding (ethyl acetate etc.), the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The step D4 is carried out by reacting the compound having the general formula (XX) with a halogenoacetyl halide in the presence or absence of a base (preferably in the presence) in an inert solvent. It is a step of producing a compound having (XXI).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, Chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably ethers (Especially tetrahydrofuran).

The bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; methyl mercaptan sodium or ethyl Mercaptan alkali metal such as sodium mercaptan; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N,
N-dimethylaniline, N, N-diethylaniline,
1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.
0] Undec-7-ene (DBU) can be organic amines, preferably organic amines (especially pyridine).

The halogenoacetyl halide used is
For example, it may be chloroacetyl chloride, bromoacetyl chloride, iodoacetyl chloride, chloroacetyl bromide, bromoacetyl bromide or iodoacetyl iodide, preferably chloroacetyl chloride or bromoacetyl chloride, particularly preferably chloroacetyl chloride. Is.

The reaction temperature will vary depending on the starting compounds, reagents, solvents, etc., but is usually -20 ° C to 100 ° C,
It is preferably 0 ° C to 50 ° C.

The reaction time varies depending on the starting compounds, reagents, solvent, reaction temperature and the like, but is usually 5 minutes to 12 hours, preferably 10 minutes to 1 hour.

After completion of the reaction, the target compound of this step is collected from the reaction mixture by a conventional method. For example, after the reaction is completed, water is added to the reaction solution, a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water and then dried over anhydrous magnesium sulfate or the like. The target compound is obtained by drying and evaporating the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. The compound obtained in this step can be used in the next step without purification.

In the step D5, the compound having the general formula (XXI) is deprotected by reacting it with an acid in an inert solvent (a), and then (b) in an inert solvent. By reacting with a base, the compound of the general formula (XXI
Is a step of producing a compound having I).

The solvent used in the step D5a is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Hydrogens; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether. It is possible, preferably ethers (particularly tetrahydrofuran).

The acid used is, for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; methanesulfonic acid, trifluoromethanesulfonic acid. A sulfonic acid such as ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; or acetic acid, trifluoroacetic acid, fumaric acid, succinic acid,
It may be a carboxylic acid such as citric acid, tartaric acid, oxalic acid or maleic acid, preferably a carboxylic acid (especially trifluoroacetic acid).

The reaction temperature varies depending on the raw material compound, reagent, solvent, etc., but is usually -20 ° C to 100 ° C,
It is preferably 0 ° C to 50 ° C.

The reaction time varies depending on the starting compounds, reagents, solvent, reaction temperature and the like, but is usually 5 minutes to 12 hours, and preferably 10 minutes to 2 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture by a conventional method. For example, after the reaction is completed, water is added to the reaction solution, a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water and then dried over anhydrous magnesium sulfate or the like. The target compound is obtained by drying and evaporating the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. The compound obtained in this step can be used in the next step without purification.

The solvent used in the step D5b is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but it is, for example, hexane, heptane, ligroin or a fat such as petroleum ether. Group hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol; formamide,
It may be an amide such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or a sulfoxide such as dimethyl sulfoxide or sulfolane, preferably an amide (particularly dimethylformamide).

The bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; methyl mercaptan sodium or ethyl mercaptan sodium Alkali metals such as mercaptans; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N
-Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2]. Octane (DABCO) or 1,8
-Organazins such as diazabicyclo [5.4.0] undec-7-ene (DBU), preferably
Alkali metal carbonates or alkali metal hydrides, more preferably alkali metal carbonates (particularly sodium carbonate or potassium carbonate).

The reaction temperature varies depending on the raw material compound, reagent, solvent, etc., but is usually -20 ° C to 150 ° C,
It is preferably 0 ° C to 100 ° C.

The reaction time varies depending on the raw material compounds, reagents, solvent, reaction temperature and the like, but is usually 5 minutes to 12 hours, preferably 10 minutes to 2 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, water is added to the reaction solution, a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water and then dried over anhydrous magnesium sulfate or the like. The target compound is obtained by drying and evaporating the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step D6 is a step of producing a compound having the general formula (XXIII) by reacting the compound having the general formula (XXII) with a reducing agent in an inert solvent. The same is done.

In the step D7, the compound having the general formula (XXIII) is contacted with a reducing agent in an inert solvent (optionally in the presence of ammonium formate) to give a compound having the general formula (VIII). It is a process to do.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but it is, for example, an aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether; benzene. , Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or Ethers such as diethylene glycol dimethyl ether; methanol, ethanol, propanol,
Alcohols such as isopropanol, butanol or isobutanol; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide or sulfolane; fatty acids such as acetic acid; or above. It may be a mixed solvent of an organic solvent and water, preferably alcohols (especially methanol or ethanol).
Is.

The reducing agent used may be, for example, palladium black, palladium carbon, platinum, Raney-nickel,
Palladium on carbon is preferred.

The reaction temperature varies depending on the starting compounds, the solvent, the reducing agent used, etc., but it is usually 0 ° C. to 150 ° C.
And is preferably 50 ° C. to 100 ° C.

The reaction time varies depending on the raw material compound, solvent, reducing agent used, reaction temperature and the like, but is usually 10 minutes to 12 hours, and preferably 30 minutes to 2 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the catalyst is filtered off, the solvent is distilled off, or water is added to the residue obtained by distilling off the solvent, and then a solvent immiscible with water (for example, benzene, ether, acetic acid The desired compound is extracted by adding ethyl etc.), the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the desired compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The hexahydropyrazinoquinoline derivative (I) or (II) of the present invention or a pharmacologically acceptable salt thereof has an excellent 5-HT _1A receptor agonistic action, sedative action against mental stress, or hallucination suppression. Since it has an action and weak toxicity or side effects (especially sleepiness etc.), anxiety, depression, hypertension, schizophrenia, sleep disorders, migraine, sexual dysfunction, motion sickness, dizziness or senile dementia peripheral symptoms ( In particular, it is useful as a therapeutic or preventive drug (particularly a therapeutic drug) for delirium, etc.

When the compound (I) or (II) of the present invention or a pharmacologically acceptable salt thereof is used as a therapeutic or prophylactic agent (particularly a therapeutic agent) for the above-mentioned neurological diseases,
As such or as a mixture with suitable pharmacologically acceptable excipients, diluents and the like, orally using tablets, capsules, granules, powders or syrups, or parenterally using injections or suppositories. Can be administered locally. These formulations include excipients such as lactose, sucrose, glucose,
Sugar derivatives such as mannitol and sorbitol; corn starch, potato starch, α-starch, dextrin, starch derivatives such as carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose. Calcium, cellulose derivatives such as sodium carboxymethyl cellulose internally crosslinked; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicates, silicate derivatives such as magnesium aluminometasilicate; phosphate derivatives such as calcium phosphate; carbonic acid. A carbonate derivative such as calcium; a sulfate derivative such as calcium sulfate, etc.), a binder (for example, the aforementioned excipients; gelatin; poly; Nylpyrrolidone; Maglogol, etc.), disintegrating agents (for example, the aforementioned excipients; croscarmellose sodium, sodium carboxymethyl starch, chemically modified starch such as cross-linked polyvinylpyrrolidone, cellulose derivatives, etc.), lubricants (For example, talc; stearic acid; calcium stearate,
Metal stearates such as magnesium stearate; colloidal silica; Luxs such as bee gum and gallow; boric acid; glycols; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylic acid salts such as sodium benzoate; sulfuric acid. Sulfates such as sodium;
Leucine; lauryl sulphates such as sodium lauryl sulphate, magnesium lauryl sulphate; silicic acid anhydrides, silicic acids such as silicic acid hydrates; starch derivatives in the above excipients), stabilizers (eg methylparaben, propylparaben Paraoxybenzoates such as; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol; benzalkonium chloride;
Phenols, phenols such as cresols; thimerosal; acetic anhydride; sorbic acid, etc.), flavoring agents (eg, commonly used sweeteners, acidulants, flavors, etc.), diluents, injection solvents (eg, It is produced by a known method using additives such as water, ethanol, glycerin, etc.). The amount used varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 1 mg / day (preferably 10 m / day).
g), an upper limit of 2000 mg (preferably 400 mg),
In the case of intravenous administration, the daily lower limit is 0.1 mg
(Preferably 1 mg), upper limit 500 mg (preferably 3 mg)
It is desirable to administer 00 mg) to an adult 1 to 6 times daily depending on the condition. Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples and Formulation Examples, but the scope of the present invention is not limited thereto. In the description of the NMR spectrum, the abbreviation nd
Indicates that the cleavage pattern is unknown due to overlap with solvent or other signal.

[0122]

【Example】

Example 1 3- (4-phthalimidobutyl) -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline dihydrochloride (Exemplified compound number: 2-46) (a) 3- (4-phthalimidobutyl) -2,3
4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline 2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (4.54g ) And N-
(4-Bromobutyl) phthalimide (6.81 g) was dissolved in dimethylformamide (50 ml), potassium carbonate (3.7 g) was added, and the mixture was stirred at 100 ° C for 30 min. After cooling the reaction solution, it was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and a small amount of ether was added to the obtained oily substance for crystallization. Hexane was added and the mixture was collected by filtration to obtain the target compound (7.51 g, 80%). Melting point: 82-86 ° C; NMR spectrum (CDCl ₃ ) δppm: 1.5-
2.0 (6H, m), 1.92 (1H, t, J = 11H
z), 2.21 (1H, dt, J = 11Hz, J = 3H
z), 2.42 (2H, t, J = 7Hz), 2.6-
2.75 (1H, m), 2.75-2.95 (3H,
m), 2.95-3.1 (2H, m), 3.65-3.
8 (1H, nd), 3.73 (2H, t, J = 7H
z), 6.69 (1H, t, J = 7Hz), 6.78
(1H, d, J = 8Hz), 6.97 (1H, d, J =
7Hz), 7.08 (1H, t, J = 7Hz), 7.7
-7.8 (2H, m), 7.8-7.9 (2H, m).

(B) 3- (4-phthalimidobutyl)
-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline dihydrochloride 3- (4-phthalimidobutyl) -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline (120 mg) was dissolved in ethanol (10 ml), excess 10N hydrochloric acid / methanol solution was added, and the mixture was left at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol to quantitatively obtain the target compound as colorless needle crystals. Melting point: 220-224 [deg.] C.

Example 2 3- (4-benzamidobutyl) -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline monohydrochloride (Exemplified compound number: 1-25) (a) 3- (4-benzamidobutyl) -2,3
4,4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (240 mg) was dissolved in tetrahydrofuran (15 ml), and triethylamine (165 [mu] was stirred at room temperature.
1) and benzoyl chloride (125 μl) were added dropwise. After stirring at room temperature for 1 hour, the precipitated crystals were filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: methanol = 20: 1) to give the desired compound (284 m
g, 76%). Mp: 135-137 ° C.; NMR spectrum (CDCl ₃₎ δppm: 1.5
5-1.8 (5H, m), 1.8-1.86 (1H,
m), 1.89 (1H, t, J = 11Hz), 2.17
(1H, dt, J = 12Hz, J = 3Hz), 2.42
(2H, t, J = 7Hz), 2.69 (1H, ddd,
J = 16 Hz, J = 5 Hz, J = 4 Hz), 2.75-
2.92 (3H, m), 2.92-3.02 (2H,
m), 3.50 (2H, q, J = 6Hz, changed to 3.49 (2H, t, J = 6Hz) by adding D ₂ O), 3.
74 (1H, dt, J = 12, J = 3Hz), 6.55
−6.75 (1H, br.s, disappeared by addition of D ₂ O), 6.69 (1H, t, J = 7 Hz), 6.78
(1H, d, J = 8Hz), 6.98 (1H, d, J =
7 Hz), 7.08 (1H, t, J = 7 Hz), 7.3
8-7.5 (3H, m), 7.74 (2H, d, J = 7)
Hz); IR spectrum (KBr) ν _max cm ^-1 : 327
7,1641.

(B) 3- (4-benzamidobutyl)
-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride 3- (4-benzamidobutyl) obtained in Example 2a
2,2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (282 mg) was dissolved in ethyl acetate (15 ml), and 4N hydrogen chloride-ethyl acetate solution (190 μl) was added. Dropped. After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration to give the desired compound (232m
g, 75%). Melting point: 193-200 ° C. (decomposition); NMR spectrum (DMSO-d ₆ ) δ ppm:
1.5-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.66 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.75-
2.9 (2H, m), 3.0-3.2 (4H, m),
3.25-3.45 (3H, nd), 3.5-3.65
(2H, m), 4.08 (1H, d, J = 9Hz),
6.69 (1H, t, J = 7Hz), 6.90 (1H,
d, J = 8 Hz), 6.98 (1H, d, J = 7H
z), 7.06 (1H, t, J = 7 Hz), 7.47
(2H, t, J = 7Hz), 7.53 (1H, t, J =
7 Hz), 7.86 (2H, d, J = 7 Hz), 8.5
6 (1H, t, J = 6Hz), 10.35-10.55
(1H, br.s); IR spectrum (KBr) ν _max cm ⁻¹ : 3261.
2552, 2515, 2474, 1649.

Example 3 3- (4-benzamidobutyl) -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline dihydrochloride (Exemplified compound number: 1-25) 3- (4-phthalimidobutyl) obtained in Example 1a
-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (531 mg) was dissolved in ethanol (10 ml), and hydrazine hydrate (166
μl) was added and the mixture was heated under reflux for 6 hours. After cooling to room temperature, the mixture was filtered, the solvent was distilled off under reduced pressure, and the obtained residue was vacuum dried. The residue was dissolved in tetrahydrofuran (10 ml), and triethylamine (760 μ was added under ice-cooling stirring.
1) and benzoyl chloride (158 μl) were added, and the mixture was stirred at room temperature for 2 hours. After water was added to the reaction solution, the solvent was evaporated under reduced pressure, and the obtained residue was added to saturated aqueous sodium hydrogen carbonate solution. After extracting the product with methylene chloride,
The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: 4% ethanol / methylene chloride solution), an excess of 10N hydrochloric acid / methanol solution was added, and the mixture was left at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized using ethanol to obtain the target compound (471 mg, 79%) as colorless needle crystals. Mp: 199-203 ° C.; NMR Spectrum _{(DMSO-d 6) δppm:} 1.
5-2.1 (6H, m), 2.7-2.9 (3H,
m), 3.0-3.2 (4H, m), 3.2-3.4.
(3H, nd), 3.5-3.6 (2H, m), 4.0
-4.2 (1H, m), 6.69 (1H, t, J = 7.
3Hz), 6.90 (1H, d, J = 7.9Hz),
6.97 (1H, d, J = 7.3 Hz), 7.06 (1
H, dd, J = 7.3 Hz, J = 7.9 Hz), 7.4
-7.6 (3H, m), 7.86 (2H, d, J = 6.
6 Hz), 8.55 (1 H, t, J = 5.3 Hz).

Example 4 3- [4- (2-Fluorobenzamido) butyl]-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-33) 3- (4-aminobutyl) -2,3,3 4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (332 mg) and 2-fluorobenzoyl chloride (15
4 μl) was reacted in the same manner as in Examples 2a and 2b and post-treated to give the desired compound (255 mg, 70%).
I got Melting point: 185-200 ° C. (decomposition); NMR spectrum (DMSO-d ₆ ) δppm:
1.5-1.7 (3H, m), 1.7-1.9 (2H,
m), 1.9-2.0 (1H, m), 2.67 (1H,
dt, J = 16 Hz, J = 5 Hz), 2.75-2.9.
(2H, m), 3.0-3.2 (4H, m), 3.2-
3.45 (3H, nd), 3.45-3.65 (2H,
m), 4.07 (1H, d, J = 12Hz), 6.69
(1H, t, J = 7Hz), 6.90 (1H, d, J =
8 Hz), 6.97 (1H, d, J = 7 Hz), 7.0
6 (1H, t, J = 8Hz), 7.25-7.35 (2
H, m), 7.45-7.55 (1H, m), 7.62
(1H, dt, J = 8Hz, J = 2Hz), 8.40
(1H, t, J = 5Hz), 10.75-11.05
(1H, br.s); IR spectrum (KBr) ν _max cm ⁻¹ : 330
7, 2557, 2515, 2473, 1672.

Example 5 3- [4- (3-Fluorobenzamido) butyl]-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-39) 3- (4-aminobutyl) -2,3 4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (263 mg) and 3-fluorobenzoyl chloride (12
3 μl) was reacted in the same manner as in Examples 2a and 2b and post-treated to give the desired compound (210 mg, 49
%) Was obtained. Mp: 190-201 ℃ (decomposition); NMR Spectrum (DMSO-d ₆₎ δppm:
1.5-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.66 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.75-
2.9 (2H, m), 3.0-3.2 (4H, m),
3.2-3.5 (3H, nd), 3.55 (2H, t,
J = 12 Hz), 4.08 (1H, d, J = 11H
z), 6.69 (1H, t, J = 7Hz), 6.90
(1H, d, J = 8Hz), 6.98 (1H, d, J =
7 Hz), 7.06 (1H, t, J = 8 Hz), 7.3
8 (1H, dt, J = 9Hz, J = 2Hz), 7.53
(1H, dt, J = 8Hz, J = 6Hz), 7.67
(1H, dd, J = 8Hz, J = 2Hz), 7.73
(1H, d, J = 8Hz), 8.68 (1H, t, J =
6 Hz), 10.5-10.9 (1 H, br.s); IR spectrum (KBr) ν _max cm _-1 : 328
6,256,154,2473,1656.

Example 6 3- [4- (4-fluorobenzamido) butyl]-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline dihydrochloride (Exemplified compound number: 1-44) 3- (4-aminobutyl) -2,3 4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (200 mg) was dissolved in tetrahydrofuran (10 ml), and triethylamine (118 μm) was added with stirring under ice cooling.
1) and 4-fluorobenzoyl chloride (102 μl) were added, and the mixture was stirred at room temperature for 2 hours. After water was added to the reaction solution, the solvent was evaporated under reduced pressure, and the obtained residue was added to saturated aqueous sodium hydrogen carbonate solution. After extracting the product with methylene chloride, the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: 4% ethanol / methylene chloride solution), an excess of 10 N hydrochloric acid / methanol solution was added, and the mixture was allowed to stand at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized using ethanol to obtain the target compound (228 mg, 65%) as colorless needle crystals. Melting point: 234 ° C (decomposition).

Example 7 3- [4- (2,3-Difluorobenzamido) butyl] -2,3,4,4a, 5,6-hexahydro-1H
-Pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-50) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (177 mg) and 2,3-difluorobenzoyl chloride (90 μl) were reacted as in Examples 2a and 2b,
By post-treatment, the target compound (172 mg, 60
%) Was obtained. Mp: 172-174 ° C.; NMR Spectrum (DMSO-d ₆₎ δppm:
1.5-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.67 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.75-
2.9 (2H, m), 3.0-3.2 (4H, m),
3.25-3.4 (3H, nd), 3.5-3.6 (2
H, m), 4.09 (1H, d, J = 8 Hz), 6.7
0 (1H, t, J = 7Hz), 6.91 (1H, d, J
= 8 Hz), 6.98 (1H, d, J = 7 Hz), 7.
06 (1H, t, J = 8Hz), 7.25-7.35
(1H, m), 7.41 (1H, dd, J = 8Hz, J
= 6 Hz), 7.5-7.6 (1 H, m), 8.56
(1H, t, J = 5Hz), 10.4-10.7 (1
H, br. s); IR spectrum (KBr) ν _max cm ^-1 : 326
2, 2584, 2569, 2489, 1664.

Example 8 3- [4- (2,4-Difluorobenzamido) butyl] -2,3,4,4a, 5,6-hexahydro-1H
-Pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-55) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (332 mg) and 2,4-difluorobenzoyl chloride (160 μl) were reacted in the same manner as in Examples 2a and 2b, and post-treated to give the target compound (191 mg ，
44%). Mp: 190-197 ° C. (decomposition); NMR Spectrum (DMSO-d ₆₎ δppm:
1.5-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.05 (1H, m), 2.67.
(1H, dt, J = 16Hz, J = 5Hz), 2.75
-2.9 (2H, m), 3.0-3.2 (4H, m),
3.29 (2H, dd, J = 13Hz, J = 7Hz),
3.3-3.4 (1H, nd), 3.54 (2H, t,
J = 13 Hz), 4.08 (1H, d, J = 11H
z), 6.69 (1H, t, J = 7Hz), 6.90
(1H, d, J = 8Hz), 6.98 (1H, d, J =
7 Hz), 7.06 (1H, t, J = 8 Hz), 7.1
8 (1H, dt, J = 9Hz, J = 3Hz), 7.36
(1H, ddd, J = 11Hz, J = 9Hz, J = 2H
z), 7.70 (1H, dt, J = 8Hz, J = 7H
z), 8.40 (1H, t, J = 5Hz), 10.6-
10.9 (1H, br.s); IR spectrum (KBr) ν _max cm ⁻¹ : 323
7,2569,2536,2517,2477,166
0.

Example 9 3- [4- (2,5-Difluorobenzamido) butyl] -2,3,4,4a, 5,6-hexahydro-1H
-Pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-63) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (177 mg) and 2,5-difluorobenzoyl chloride (90 μl) were reacted as in Examples 2a and 2b,
By post-treatment, the target compound (176 mg, 72
%) Was obtained. Mp: 168-172 ° C.; NMR Spectrum (DMSO-d ₆₎ δppm:
1.5-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.05 (1H, m), 2.67.
(1H, dt, J = 16Hz, J = 5Hz), 2.75
-2.9 (2H, m), 3.0-3.2 (4H, m),
3.25-3.45 (3H, nd), 3.54 (2H,
t, J = 13 Hz), 4.08 (1H, d, J = 11H)
z), 6.69 (1H, t, J = 7Hz), 6.90
(1H, d, J = 8Hz), 6.98 (1H, d, J =
7 Hz), 7.06 (1H, t, J = 8 Hz), 7.3
-7.5 (3H, m), 8.50 (1H, t, J = 5H
z), 10.65-10.95 (1H, br.s); IR spectrum (KBr) ν _max cm ^-1 : 323
7,2562,2539,2510,2479,166
2.

Example 10 3- [4- (2,6-Difluorobenzamido) butyl] -2,3,4,4a, 5,6-hexahydro-1H
-Pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-68) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (171 mg) and 2,6-difluorobenzoyl chloride (90 μl) were reacted as in Examples 2a and 2b,
By post-treatment, the target compound (146.4 mg,
Yield 55%) was obtained. Melting point: 194-200 ° C. (decomposition); NMR spectrum (DMSO-d ₆ ) δ ppm:
1.5-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.67 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.81 (2
H, ddd, J = 16Hz, J = 11Hz, J = 5H
z), 3.0-3.2 (4H, m), 3.2-3.4.
(3H, nd), 3.5-3.6 (2H, m), 4.0
9 (1H, d, J = 8Hz), 6.69 (1H, t, J
= 7 Hz), 6.90 (1H, d, J = 8 Hz), 6.
97 (1H, d, J = 7Hz), 7.06 (1H, t,
J = 8Hz), 7.18 (2H, t, J = 8Hz),
7.52 (1H, tt, J = 8Hz, J = 7Hz),
8.79 (1H, t, J = 6Hz), 10.4-10.
6 (1H, br.s); IR spectrum (KBr) ν _max cm ⁻¹ : 320
4,2566,2538,2503,2469,165
9.

Example 11 3- [4- (3,4-Difluorobenzamido) butyl] -2,3,4,4a, 5,6-hexahydro-1H
-Pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-73) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (177 mg) and 3,4-difluorobenzoyl chloride (90 μl) were reacted as in Examples 2a and 2b,
The target compound (92.6 mg, yield 33%) was obtained by the post-treatment. Mp: 168-174 ° C. (decomposition); NMR Spectrum (DMSO-d ₆₎ δppm:
1.55-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.66 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.75-
2.9 (2H, m), 3.0-3.2 (4H, m),
3.2-3.45 (3H, nd), 3.5-3.65
(2H, m), 4.0-4.15 (1H, m), 6.6
9 (1H, t, J = 7Hz), 6.90 (1H, d, J
= 8 Hz), 6.97 (1H, d, J = 7 Hz), 7.
06 (1H, t, J = 8Hz), 7.56 (1H, d
t, J = 10 Hz, J = 8 Hz), 7.7-7.8 (1
H, m), 7.92 (1H, ddd, J = 12Hz, J
= 8 Hz, J = 2 Hz), 8.68 (1 H, t, J = 5)
Hz), 10.15-10.55 (1H, br.s)
IR spectrum (KBr) ν _max cm ⁻¹ : 328
1,2583,2518,2477,1652.

Example 12 3- [4- (3,5-Difluorobenzamido) butyl] -2,3,4,4a, 5,6-hexahydro-1H
-Pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-79) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (177 mg) and 3,5-difluorobenzoyl chloride (90 μl) were reacted as in Examples 2a and 2b,
The target compound (146 mg, yield 51%) was obtained by post-treatment. Mp: 174-177 ° C. (decomposition); NMR Spectrum (DMSO-d ₆₎ δppm:
1.55-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.66 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.75-
2.9 (2H, m), 2.95-3.25 (4H,
m), 3.25-3.45 (3H, nd), 3.5-
3.65 (2H, m), 4.0-4.15 (1H,
m), 6.69 (1H, t, J = 7Hz), 6.90
(1H, d, J = 8Hz), 6.97 (1H, d, J =
7 Hz), 7.06 (1H, t, J = 8 Hz), 7.4
-7.5 (1H, m), 7.58 (2H, dd, J = 8)
Hz, J = 2 Hz), 8.76 (1H, t, J = 5H
z), 10.25-10.55 (1H, br.s); IR spectrum (KBr) ν _max cm ^-1 : 328
5,2600,2580,2514,2501,165
6.

Example 13 3- [4- (3,4-dichlorobenzamido) butyl]
-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-92) 3- (4-aminobutyl) -2,3 , 4, 4a, 5, 6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (230 mg) and 3,4-dichlorobenzoyl chloride (215 mg) were reacted in the same manner as in Examples 2a and 2b and post-treated to give the desired compound (174 mg). ，
36%). Melting point: 192-201 ° C. (decomposition); NMR spectrum (DMSO-d ₆ ) δppm:
1.5-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.66 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.75-
2.9 (2H, m), 3.0-3.2 (4H, m),
3.2-3.5 (3H, nd), 3.5-3.6 (2
H, m), 4.09 (1H, d, J = 10 Hz), 6.
70 (1H, t, J = 7Hz), 6.90 (1H, d,
J = 8 Hz), 6.98 (1H, d, J = 7 Hz),
7.06 (1H, t, J = 8Hz), 7.77 (1H,
d, J = 9 Hz), 7.85 (1H, dd, J = 9H)
z, J = 2 Hz), 8.10 (1H, d, J = 2H)
z), 8.76 (1H, t, J = 5Hz), 10.2-
10.45 (1H, br.s); IR spectrum (KBr) ν _max cm ^-1 : 326
4,2580,2477,1653,1642.

Example 14 3- [4- (4-methylbenzamido) butyl] -2,
3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline dihydrochloride (Exemplified compound number:
1-111) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (200 mg), 4-toluoyl chloride (112 μl)
And triethylamine (118 μl) were reacted in the same manner as in Example 6 and post-treated to give the target compound (19
9 mg, 57%) was obtained. Melting point: 208-211 [deg.] C.

Example 15 3- [4- (3-trifluoromethylbenzamido) butyl] -2,3,4,4a, 5,6-hexahydro-1
H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-119) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (240 mg) and 3-trifluoromethylbenzoyl chloride (160 μl) were reacted in the same manner as in Examples 2a and 2b and post-treated to give the target compound (296m
g, 65%) was obtained. Mp: 185-188 ° C.; NMR Spectrum (DMSO-d ₆₎ δppm:
1.55-1.7 (3H, m), 1.7-1.9 (2
H, m), 1.9-2.0 (1H, m), 2.66 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.75-
2.9 (2H, m), 3.0-3.2 (4H, m),
3.25-3.4 (3H, nd), 3.5-3.6 (2
H, m), 4.08 (1H, d, J = 9 Hz), 6.6
9 (1H, t, J = 7Hz), 6.90 (1H, d, J
= 8 Hz), 6.97 (1H, d, J = 7 Hz), 7.
06 (1H, t, J = 8Hz), 7.73 (1H, t,
J = 8Hz), 7.92 (1H, d, J = 8Hz),
8.19 (1H, d, J = 8Hz), 8.20 (1H,
s), 8.85 (1H, t, J = 5Hz), 10.4−
10.6 (1H, br.s); IR spectrum (KBr) ν _max cm ⁻¹ : 330
5,2438,1664.

Example 16 3- [4- (4-trifluoromethylbenzamido) butyl] -2,3,4,4a, 5,6-hexahydro-1
H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-124) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (266 mg) and 4-trifluoromethylbenzoyl chloride (160 µl) were reacted in the same manner as in Examples 2a and 2b, and post-treated to give the desired compound (131m
g, 42%). Mp: 198-204 ° C. (decomposition); NMR Spectrum (DMSO-d ₆₎ δppm:
1.55-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.66 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.75-
2.9 (2H, m), 3.0-3.2 (4H, m),
3.25-3.4 (3H, nd), 3.45-3.6.
(2H, m), 4.08 (1H, d, J = 9Hz),
6.69 (1H, t, J = 7Hz), 6.90 (1H,
d, J = 8 Hz), 6.97 (1H, d, J = 7H
z), 7.06 (1H, t, J = 8Hz), 7.86
(2H, d, J = 8Hz), 8.06 (2H, d, J =
8 Hz), 8.81 (1H, t, J = 5 Hz), 10.
4-1.55 (1H, br.s); IR spectrum (KBr) ν _max cm ⁻¹ : 329
7,2596,2486,1650.

Example 17 3- [4- (2-methoxybenzamido) butyl]-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-131) 3- (4-aminobutyl) -2,3,3 4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (250 mg) and 2-methoxybenzoyl chloride (14
5 μl) was reacted in the same manner as in Examples 2a and 2b and post-treated to give the desired compound (191 mg, 57%).
I got Mp: 168-170 ° C.; NMR Spectrum (DMSO-d ₆₎ δppm:
1.5-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.67 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.75-
2.9 (2H, m), 3.0-3.2 (4H, m),
3.2-3.45 (3H, nd), 3.5-3.65
(2H, m), 3.89 (3H, s), 4.09 (1
H, d, J = 10 Hz), 6.70 (1H, t, J = 7)
Hz), 6.90 (1H, d, J = 8 Hz), 6.98
(1H, d, J = 7Hz), 7.03 (1H, t, J =
7Hz), 7.06 (1H, t, J = 7Hz), 7.1
4 (1H, d, J = 9Hz), 7.46 (1H, dt,
J = 8Hz, J = 2Hz), 7.71 (1H, dd, J
= 8 Hz, J = 2 Hz), 8.23 (1H, t, J = 6)
Hz), 10.25-10.45 (1H, br.s)
IR spectrum (KBr) ν _max cm ⁻¹ : 336
0,2457,1642.

Example 18 3- [4- (4-Methoxybenzamido) butyl]-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline dihydrochloride (Exemplified compound number: 1-139) 3- (4-aminobutyl) -2,3 4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (200 mg), 4-anisoyl chloride (145 mg)
And triethylamine (118 μl) were reacted in the same manner as in Example 6 and post-treated to give the target compound (23
6 mg, 66%) was obtained. Melting point: 215-219 [deg.] C.

Example 19 3- [4- (4-phenylbenzamido) butyl]-
2,3,4,4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline dihydrochloride (Exemplified compound number: 1-147) 3- (4-aminobutyl) -2,3 4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (200 mg), 4-biphenylcarbonyl chloride (1
84 mg) and triethylamine (118 μl) were reacted in the same manner as in Example 6 and post-treated to obtain the target compound (69 mg, 17%). Melting point: 194-198 [deg.] C.

Example 20 3- [4- (4-cyanobenzamido) butyl] -2,
3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number:
1-165) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (332 mg) and 4-cyanobenzoyl chloride (224
mg) was reacted in the same manner as in Examples 2a and 2b and post-treated to obtain the target compound (215 mg, 44%). Mp: 206-218 ℃ (decomposition); NMR Spectrum (DMSO-d ₆₎ δppm:
1.55-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.66 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.7-2.
9 (2H, m), 3.0-3.2 (4H, m), 3.2
5-3.4 (3H, nd), 3.55 (2H, t, J =
12Hz), 4.07 (1H, d, J = 11Hz),
6.69 (1H, t, J = 7Hz), 6.90 (1H,
d, J = 8 Hz), 6.98 (1H, d, J = 7H
z), 7.06 (1H, t, J = 8 Hz), 7.97
(2H, d, J = 8Hz), 8.03 (2H, d, J =
8 Hz), 8.86 (1H, t, J = 5 Hz), 10.
65-10.85 (1H, br.s); IR spectrum (KBr) ν _max cm ^-1 : 321
6,2578,2558,2538,2521,247
8, 2229, 1649.

Example 21 3- [4- (4-nitrobenzamido) butyl] -2,
3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline dihydrochloride (Exemplified compound number:
1-174) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (200 mg), 4-nitrobenzoyl chloride (157
mg) and triethylamine (118 μl) in Example 6
The target compound (235 mg, 63%) was obtained by reacting in the same manner as above and post-treating. Melting point: 213-216 [deg.] C.

Example 22 3- (2-benzamidoethyl) -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline monohydrochloride (Exemplified compound number: 1-23) 3- (2-aminoethyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (280 mg) and benzoyl chloride (145 μl) were reacted in the same manner as in Examples 2a and 2b and post-treated to give the desired compound (158 mg, 41%). Obtained. Mp: 179-184 ° C. (decomposition); NMR Spectrum (DMSO-d ₆₎ δppm:
1.55-1.7 (1H, m), 1.85-2.0 (1
H, m), 2.6-2.7 (1H, m), 2.75-
3.0 (2H, m), 3.0-3.2 (2H, m),
3.2-3.5 (4H, nd), 3.6-3.85 (3
H, m), 4.05-4.2 (1H, m), 6.69.
(1H, t, J = 7Hz), 6.91 (1H, d, J =
7 Hz), 6.97 (1H, d, J = 7 Hz), 7.0
6 (1H, t, J = 8Hz), 7.49 (2H, t, J
= 7 Hz), 7.56 (1H, t, J = 7 Hz), 7.
93 (2H, d, J = 7 Hz), 8.8-9.0 (1
H, br. s), 10.5-10.9 (1H, br.
s); IR spectrum (KBr) ν _max cm ⁻¹ : 330
0,2582,2501,1653.

Example 23 3- [2- (2,4-Difluorobenzamido) ethyl] -2,3,4,4a, 5,6-hexahydro-1H
-Pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-53) 3- (2-aminoethyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (222 mg) and 2,4-difluorobenzoyl chloride (130 μl) were reacted in the same manner as in Examples 2a and 2b, and post-treated to give the target compound (173 mg ，
46%). Melting point: 175-182 ° C. (decomposition); NMR spectrum (DMSO-d ₆ ) δ ppm:
1.6-1.7 (1H, m), 1.9-2.0 (1H,
m), 2.67 (1H, dt, J = 16Hz, J = 5H
z), 2.81 (1H, ddd, J = 16Hz, J = 1
1Hz, J = 5Hz), 2.85-3.0 (1H,
m), 3.0-3.2 (2H, m), 3.2-3.6.
(3H, nd), 3.6-3.8 (4H, m), 4.1
1 (1H, d, J = 13Hz), 6.70 (1H, t,
J = 7 Hz), 6.92 (1 H, d, J = 8 Hz),
6.98 (1H, d, J = 7Hz), 7.06 (1H,
t, J = 8 Hz), 7.22 (1H, dt, J = 8H)
z, J = 2 Hz), 7.40 (1H, ddd, J = 11)
Hz, J = 9 Hz, J = 2 Hz), 7.81 (1H,
q, J = 8 Hz), 8.67 (1H, br.s), 1
0.5-10.7 (1H, br.s); IR spectrum (KBr) ν _max cm ⁻¹ : 337
8,2582,2466,1659.

Example 24 3- (3-benzamidopropyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline monohydrochloride (Exemplified compound number: 1-24) 3- (3-aminopropyl) -2,3,4,4a, 5
6-Hexahydro-1H-pyrazino [1,2-a] quinoline (209 mg) and benzoyl chloride (110 μl) were reacted in the same manner as in Examples 2a and 2b and post-treated to give the desired compound (128 mg, 37%). Got Mp: 183-189 ° C. (decomposition); NMR Spectrum (DMSO-d ₆₎ δppm:
1.55-1.7 (1H, m), 1.9-2.1 (3
H, m), 2.66 (1H, dt, J = 16Hz, J =
5Hz), 2.7-2.95 (2H, m), 3.0-
3.25 (4H, m), 3.25-3.5 (3H, n
d), 3.58 (2H, t, J = 12Hz), 4.08
(1H, d, J = 9Hz), 6.69 (1H, t, J =
7 Hz), 6.90 (1 H, d, J = 8 Hz), 6.9
7 (1H, d, J = 7Hz), 7.06 (1H, t, J
= 8 Hz), 7.48 (2H, t, J = 8 Hz), 7.
54 (1H, t, J = 7Hz), 7.88 (2H, d,
J = 7 Hz), 8.70 (1H, t, J = 6 Hz), 1
0.55-1.75 (1H, br.s); IR spectrum (KBr) ν _max cm ^-1 : 330
5, 2553, 2473, 1645.

Example 25 3- (4-pivaloylaminobutyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline monohydrochloride (Exemplified compound number: 1-6) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (250 mg) and pivaloyl chloride (164 μl) were reacted in the same manner as in Examples 2a and 2b and post-treated to give the desired compound (125 mg, 35%). Obtained. Melting point: 193-200 ° C. (decomposition); NMR spectrum (DMSO-d ₆ ) δ ppm:
1.10 (9H, s), 1.4-1.5 (2H, m),
1.55-1.75 (3H, m), 1.9-2.0 (1
H, m), 2.67 (1H, dt, J = 16Hz, J =
5Hz), 2.75-2.9 (2H, m), 3.0-
3.2 (6H, m), 3.3-3.4 (1H, nd),
3.45-3.6 (2H, m), 4.08 (1H, d,
J = 10 Hz), 6.69 (1 H, t, J = 7 Hz),
6.90 (1H, d, J = 8Hz), 6.98 (1H,
d, J = 7 Hz), 7.06 (1H, t, J = 7H
z), 7.53 (1H, t, J = 5Hz), 10.4−
10.6 (1H, br.s); IR spectrum (KBr) ν _max cm ⁻¹ : 330
6, 2559, 2524, 2475, 1648.

Example 26 3- [4- (2-ethylhexanoylamino) butyl]
-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-11) 3- (4-aminobutyl) -2,3 , 4, 4a, 5, 6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (190 mg) and 2-ethylhexanoyl chloride (20
0 μl) was reacted in the same manner as in Examples 2a and 2b and post-treated to give the desired compound (74.8 mg, 48).
%) Was obtained. Melting point: 115-121 ° C .; NMR spectrum (DMSO-d ₆ ) δppm:
0.79 (3H, t, J = 7Hz), 0.84 (3H,
t, J = 7 Hz), 1.1-1.5 (10 H, m),
1.55-1.8 (3H, m), 1.9-2.05 (2
H, m), 2.67 (1H, dt, J = 16Hz, J =
5Hz), 2.75-2.9 (2H, m), 3.0-
3.2 (6H, m), 3.25-3.45 (1H, n
d), 3.45-3.6 (2H, m), 4.08 (1
H, d, J = 10 Hz), 6.69 (1H, t, J = 7)
Hz) 6.90 (1H, d, J = 8Hz), 6.98
(1H, d, J = 7Hz), 7.06 (1H, t, J =
8 Hz), 7.89 (1H, t, J = 6 Hz), 10.
5-10.7 (1H, br.s); IR spectrum (KBr) ν _max cm ⁻¹ : 328
4,2581,2473,1649. Example 27 3- (4-Cyclohexylcarbonylaminobutyl)-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-20) 3- (4-aminobutyl) -2,3,3 4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (230 mg) and cyclohexylcarbonyl chloride (1
40 μl) was reacted in the same manner as in Examples 2a and 2b and post-treated to give the desired compound (131 mg, 43
%) Was obtained. Mp: 190-196 ° C. (decomposition); NMR Spectrum (DMSO-d ₆₎ δppm:
1.1-1.5 (7H, m), 1.55-1.8 (8
H, m), 1.9-2.0 (1H, m), 2.07 (1
H, tt, J = 11 Hz, J = 3 Hz), 2.67 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.75-
2.9 (2H, m), 2.95-3.2 (6H, m),
3.25-3.45 (1H, nd), 3.45-3.6
(2H, m), 4.08 (1H, d, J = 10Hz),
6.69 (1H, t, J = 7Hz), 6.90 (1H,
d, J = 8 Hz), 6.98 (1H, d, J = 7H
z), 7.06 (1H, t, J = 8Hz), 7.75
(1H, t, J = 5Hz), 10.4-10.6 (1
H, br. s); IR spectrum (KBr) ν _max cm ^-1 : 326
8, 2565, 2480, 2409, 1655.

Example 28 3- [4- (3-Cyclohexylureido) butyl]-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (Exemplified compound number: 1-1
81) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (213 mg) was dissolved in THF (10 ml) and cyclohexyl isocyanate (110 μl) was stirred at room temperature.
Was dripped. After standing overnight, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: methanol = 10: 1) to obtain the target compound (190 mg, 60%). Mp: 133-137 ° C.; NMR spectrum (CDCl ₃₎ δppm: 1.0
5-1.2 (3H, m), 1.25-1.4 (2H,
m), 1.5-1.65 (3H, m), 1.65-1.
8 (6H, m), 1.85-2.0 (3H, m), 2.
12 (1H, t, J = 11 Hz), 2.40 (1H, d
t, J = 11 Hz, J = 2 Hz), 2.57 (2H,
t, J = 8 Hz), 2.71 (1H, dt, J = 16H)
z, J = 5 Hz), 2.89 (1H, ddd, J = 16)
Hz, J = 11 Hz, J = 5 Hz), 3.0-3.15
(2H, m), 3.15-3.3 (3H, m), 3.4
5-3.6 (1H, m), 3.82 (1H, d, J = 1
2Hz), 4.29 (1H, d, J = 8Hz), 4.7
5-5.05 (1H, br.s), 6.72 (1H,
t, J = 7 Hz), 6.79 (1H, d, J = 8H
z), 6.99 (1H, d, J = 7Hz), 7.09
(1H, t, J = 8 Hz); IR spectrum (KBr) ν _max cm ⁻¹ : 333
1,1630.

Example 29 3- [4- (3-phenylureido) butyl] -2,
3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (Exemplary compound number: 1-18
6) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (242 mg) and phenyl isocyanate (120 μm)
l) was reacted in the same manner as in Example 28 and post-treated to obtain the target compound (230 mg, 65%). Mp: 155-157 ° C.; NMR Spectrum (DMSO-d ₆₎ δppm:
1.4-1.7 (5H, m), 1.76 (1H, t, J
= 11 Hz), 1.8-1.9 (1H, m), 2.04
(1H, dt, J = 11 Hz, J = 3 Hz), 2.31
(2H, t, J = 6Hz), 2.4-2.8 (3H,
m), 2.8-3.0 (3H, m), 3.09 (2H,
q, J = 6 Hz), 3.75 (1H, d, J = 13H)
z), 6.14 (1H, t, J = 6Hz), 6.60
(1H, t, J = 7Hz), 6.79 (1H, d, J =
8 Hz), 6.86 (1H, d, J = 7 Hz), 6.9
1 (1H, d, J = 6Hz), 6.99 (1H, d, J
= 8 Hz), 7.20 (2H, t, J = 8 Hz), 7.
37 (2H, d, J = 8Hz), 8.38 (1H, b
r. s); IR spectrum (KBr) ν _max cm ⁻¹ : 330
5,1642.

Example 30 3- [4- [3- (2,4-difluorophenyl) ureido] butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] ] Quinoline (Exemplified Compound Number: 1-208) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (242 mg) and 2,4-difluorophenyl isocyanate (130 μl) were reacted in the same manner as in Example 28,
By post-treatment, the target compound (360 mg, 93
%) Was obtained. Mp: 106-109 ° C.; NMR spectrum (CDCl ₃₎ δppm: 1.5
5-2.0 (6H, m), 1.93 (1H, t, J = 1
1Hz), 2.20 (1H, dt, J = 12Hz, J =
3Hz), 2.35-2.5 (2H, m), 2.65-
2.8 (1H, m), 2.8-3.1 (5H, m),
3.25-3.4 (2H, m), 3.78 (1H, d,
J = 12 Hz), 5.1-5.9 (1H, br.s),
6.27 (1H, br.s), 6.70 (1H, t, J
= 7 Hz), 6.75-6.9 (3H, m), 6.98
(1H, d, J = 7Hz), 7.09 (1H, t, J =
8Hz), 7.98 (1H, dt, J = 10Hz, J =
6 Hz); IR spectrum (KBr) ν _max cm ^-1 : 332
8,1686.

Example 31 3- [4- (3-thenoylamino) butyl] -2,3
4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number:
1-345) (a) 3- [4- (3-thenoylamino) butyl]-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (238 mg), 3-thenoyl acid (118 mg) and dichloromethane (5 ml) in a mixture at room temperature with stirring triethylamine (230 μl) and diethyl cyanophosphonate (DEPC). , 240 μl) was added dropwise. After standing overnight at room temperature, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the target compound (275 mg, 81%). NMR spectrum (CDCl ₃ ) δ ppm: 1.6
-1.9 (6H, m), 1.94 (1H, t, J = 11)
Hz), 2.22 (1H, dt, J = 11 Hz, J = 3)
Hz), 2.46 (2H, t, J = 7Hz), 2.6-
2.75 (1H, m), 2.8-2.95 (3H,
m), 2.95-3.1 (2H, m), 3.47 (2
H, q, J = 6 Hz), 3.76 (1H, dt, J = 1)
2Hz, J = 2Hz), 6.35-6.55 (1H, b
r. s), 6.70 (1H, t, J = 7Hz), 6.7
9 (1H, d, J = 8Hz), 6.98 (1H, d, J
= 7 Hz), 7.09 (1H, t, J = 8 Hz), 7.
31 (1H, dd, J = 5Hz, J = 3Hz), 7.3
8 (1H, d, J = 5Hz), 7.84 (1H, d, J
= 3 Hz); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 345
6,1652.

(B) 3- [4- (3-thenoylamino) butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride 3- [ 4- (3-thenoylamino) butyl] -2,3
4,4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline (257 mg) was reacted in the same manner as in Example 2b and post-treated to give the desired compound (190 mg, 67%). ) Got. Mp: 198-203 ° C. (decomposition); NMR Spectrum (DMSO-d ₆₎ δppm:
1.5-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.66 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.75-
2.9 (2H, m), 3.0-3.2 (4H, m),
3.27 (2H, dd, J = 13Hz, J = 7Hz),
3.3-3.45 (1H, nd), 4.08 (1H,
d, J = 9 Hz), 6.69 (1H, t, J = 7H
z), 6.90 (1H, d, J = 8 Hz), 6.97
(1H, d, J = 7Hz), 7.06 (1H, t, J =
8Hz), 7.51 (1H, dd, J = 5Hz, J = 1
Hz), 7.58 (1H, dd, J = 5Hz, J = 3H
z), 8.14 (1H, dd, J = 3Hz, J = 1H
z), 8.41 (1H, t, J = 6Hz), 10.45
-10.65 (1H, br.s); IR spectrum (KBr) ν _max cm ^-1 : 327
4, 2579, 2540, 2483, 1645.

Example 32 3- [4- (1-Methylindole-2-carbonylamino) butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline Monohydrochloride (Exemplified Compound Number: 1-233) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (171 mg) and 1-methylindole-2-carboxylic acid (120 mg) were reacted in the same manner as in Examples 31a and 31b, and post-treated to give the desired compound. (184
mg, 65%). Melting point: 197-208 ° C. (decomposition); NMR spectrum (DMSO-d ₆ ) δ ppm:
1.55-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.66 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.75-
2.9 (2H, m), 3.0-3.25 (4H, m),
3.25-3.45 (3H, nd), 3.5-3.65
(2H, m), 3.99 (3H, s), 4.09 (1
H, d, J = 9 Hz), 6.69 (1H, t, J = 7H)
z), 6.90 (1H, d, J = 8 Hz), 6.97
(1H, d, J = 7Hz), 7.0-7.15 (3H,
nd), 7.27 (1H, t, J = 8 Hz), 7.53
(1H, d, J = 8Hz), 7.63 (1H, d, J =
8 Hz), 8.58 (1 H, t, J = 6 Hz), 10.
4-10.55 (1H, br.s); IR spectrum (KBr) ν _max cm ⁻¹ : 330
0, 2425, 2405, 2359, 1653.

Example 33 3- (4-nicotinoylaminobutyl) -2,3,4
4a, 5,6-hexahydro-1H-pyrazino [1,2
-A] quinoline monohydrochloride (Exemplified compound number: 1-24
1) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (266 mg) and nicotinoyl chloride hydrochloride (192 m
g) was reacted in the same manner as in Examples 2a and 2b and post-treated to obtain the target compound (184 mg, 63%). Melting point: 207-210 ° C. (decomposition); NMR spectrum (DMSO-d ₆ ) δ ppm:
1.55-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.66 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.75-
2.9 (2H, m), 3.0-3.25 (4H, m),
3.25-3.45 (3H, nd), 3.45-3.6
(2H, m), 4.80 (1H, d, J = 8Hz),
6.69 (1H, t, J = 7Hz), 6.90 (1H,
d, J = 8 Hz), 6.97 (1H, d, J = 7H
z), 7.06 (1H, t, J = 8Hz), 7.51
(1H, dd, J = 8Hz, J = 5Hz), 8.21
(1H, dt, J = 8Hz, J = 2Hz), 8.71
(1H, dd, J = 5Hz, J = 2Hz), 8.78
(1H, t, J = 5Hz), 9.03 (1H, d, J =
2 Hz), 10.5-10.7 (1 H, br.s); IR spectrum (KBr) ν _max cm ^-1 : 325
5,256,154,2476,1652.

Example 34 3- [4- (2-Pyrazinecarbonylamino) butyl]
-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-248) 3- (4-aminobutyl) -2,3 , 4, 4a, 5, 6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (171 mg) and pyrazine-2-carboxylic acid (86 m
g) was reacted in the same manner as in Examples 31a and 31b and post-treated to give the target compound (96.5 mg, 42
%) Was obtained. Mp: 168-174 ° C.; NMR Spectrum (DMSO-d ₆₎ δppm:
1.55-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.66 (1
H, dt, J = 16 Hz, J = 4 Hz), 2.75-
2.9 (2H, m), 3.0-3.2 (4H, m),
3.25-3.45 (3H, nd), 3.45-3.6
5 (2H, m), 4.07 (1H, d, J = 9Hz),
6.69 (1H, t, J = 7Hz), 6.90 (1H,
d, J = 8 Hz), 6.97 (1H, d, J = 7H
z), 7.06 (1H, t, J = 8Hz), 8.74
(1H, d, J = 2Hz), 8.88 (1H, d, J =
2Hz), 9.04 (1H, t, J = 6Hz), 9.2
0 (1H, d, J = 1 Hz), 10.4-10.7 (1
H, br. s); IR spectrum (KBr) ν _max cm ^-1 : 327
6, 2586, 2562, 2468, 1674.

Example 35 3- [4- (4-quinolinecarbonylamino) butyl]
-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-257) 3- (4-aminobutyl) -2,3 , 4, 4a, 5, 6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (171 mg) and quinoline-4-carboxylic acid (120
mg) was reacted in the same manner as in Examples 31a and 31b and post-treated to give the target compound (122 mg, 48 mg).
%) Was obtained. Mp: 159-164 ° C.; NMR Spectrum (DMSO-d ₆₎ δppm:
1.55-1.7 (3H, m), 1.8-1.9 (2
H, m), 1.9-2.0 (1H, m), 2.67 (1
H, dt, J = 16 Hz, J = 6 Hz), 2.75-
2.9 (2H, m), 3.0-3.25 (4H, m),
3.25-3.45 (1H, nd), 3.40 (2H,
dd, J = 13 Hz, J = 7 Hz), 3.57 (2H,
t, J = 13 Hz), 4.09 (1H, d, J = 10H)
z), 6.70 (1H, t, J = 7Hz), 6.91
(1H, d, J = 8Hz), 6.98 (1H, d, J =
7Hz), 7.06 (1H, t, J = 8Hz), 7.5
8 (1H, d, J = 4Hz), 7.68 (1H, t, J
= 8 Hz), 7.82 (1H, t, J = 8 Hz), 8.
09 (1H, d, J = 8Hz), 8.15 (1H, d,
J = 8Hz), 8.85 (1H, t, J = 6Hz),
8.98 (1H, d, J = 4Hz), 10.5-1
0.75 (1H, br.s); IR spectrum (KBr) ν _max cm ^-1 : 323
6,2585,2499,2474,1656.

Example 36 3- [4- (2-Furoylamino) butyl] -2,3
4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number:
1-262) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (250 mg) and 2-furoyl chloride (105 μl) were reacted in the same manner as in Examples 2a and 2b and post-treated to give the desired compound (131 mg, 40%). ) Got. Melting point: 184-190 ° C. (decomposition); NMR spectrum (DMSO-d ₆ ) δppm:
1.5-1.85 (5H, m), 1.9-2.0 (1
H, m), 2.66 (1H, dt, J = 16Hz, J =
5Hz), 2.75-2.9 (2H, m), 3.0-
3.2 (4H, m), 3.26 (2H, dd, J = 13)
Hz, J = 7 Hz), 3.3-3.4 (1H, nd),
3.45-3.6 (2H, m), 4.08 (1H, d,
J = 9 Hz), 6.62 (1H, dd, J = 3 Hz, J
= 2 Hz), 6.69 (1H, t, J = 7 Hz), 6.
90 (1H, d, J = 8Hz), 6.97 (1H, d,
J = 7Hz), 7.06 (1H, t, J = 8Hz),
7.09 (1H, d, J = 3Hz), 7.83 (1H,
s), 8.44 (1H, t, J = 6Hz), 10.3−
10.6 (1H, br.s); IR spectrum (KBr) ν _max cm ⁻¹ : 324
9, 2585, 2542, 2482, 1662.

Example 37 3- [2- (2-thenoylamino) ethyl] -2,3
4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number:
1-283) 3- (2-aminoethyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (222 mg) and 2-thenoyl chloride (115 μl) were reacted in the same manner as in Examples 2a and 2b and post-treated to give the desired compound (231 mg, 71%). ) Got. Mp: 186-198 ℃ (decomposition); NMR Spectrum (DMSO-d ₆₎ δppm:
1.55-1.7 (1H, m), 1.9-2.0 (1
H, m), 2.67 (1H, dt, J = 16Hz, J =
5Hz), 2.81 (1H, ddd, J = 16Hz, J
= 11 Hz, J = 5 Hz), 2.91 (1H, q, J =
11 Hz), 3.05-3.2 (2H, m), 3.25
-3.6 (3H, nd), 3.6-3.8 (4H,
m), 4.10 (1H, d, J = 10 Hz), 6.70
(1H, t, J = 7Hz), 6.91 (1H, d, J =
8 Hz), 6.98 (1H, d, J = 7 Hz), 7.0
6 (1H, t, J = 8Hz), 7.17 (1H, t, J
= 4 Hz), 7.79 (1H, d, J = 4 Hz), 7.
91 (1H, d, J = 3Hz), 9.00 (1H, b
r. s), 10.7-10.95 (1H, br.s)
IR spectrum (KBr) ν _max cm ⁻¹ : 327
0,2590,2472,1642.

Example 38 3- [2- (3-thenoylamino) ethyl] -2,3
4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number:
1-343) 3- (2-Aminoethyl) -2,3,4,4a, 5,6
Example 31-Hexahydro-1H-pyrazino [1,2-a] quinoline (222 mg), 3-thenoyl acid (124 mg) and diethyl cyanophosphonate (240 μl)
The target compound (223 mg, 65%) was obtained by reacting in the same manner as in a and 31b and post-treating. Mp: 187-195 ° C. (decomposition); NMR Spectrum (DMSO-d ₆₎ δppm:
1.58-1.7 (1H, m), 1.9-2.0 (1
H, m), 2.67 (1H, dt, J = 16Hz, J =
5Hz), 2.81 (1H, ddd, J = 16Hz, J
= 11 Hz, J = 5 Hz), 2.91 (1H, q, J =
11 Hz), 3.05-3.2 (2H, m), 3.2-
3.6 (3H, nd), 3.6-3.8 (4H, m),
4.10 (1H, d, J = 9Hz), 6.70 (1H,
t, J = 7 Hz), 6.91 (1H, d, J = 8H
z), 6.98 (1H, d, J = 7Hz), 7.06
(1H, t, J = 8Hz), 7.58 (1H, dd, J
= 5 Hz, J = 1 Hz), 7.61 (1 H, dd, J =
5Hz, J = 3Hz), 8.26 (1H, d, J = 2H)
z), 8.82 (1H, br.s), 10.7-11.
0 (1H, br.s); IR spectrum (KBr) ν _max cm ⁻¹ : 329
0,2651,2591,2476,1650.

Example 39 3- [2- (3-Methylthiophene-2-carbonylamino) ethyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline Monohydrochloride (Exemplified Compound No. 1-302) 3- (2-aminoethyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (222 mg), 3-methylthiophene-2-carboxylic acid (137 mg) and diethyl cyanophosphonate (2
40 μl) was reacted in the same manner as in Examples 31a and 31b and post-treated to give the desired compound (242 mg,
70%). Mp: 174-186 ℃ (decomposition); NMR Spectrum (DMSO-d ₆₎ δppm:
1.58-1.7 (1H, m), 1.9-2.0 (1
H, m), 2.45 (3H, s), 2.67 (1H, d
t, J = 16 Hz, J = 5 Hz), 2.81 (1H, d
dd, J = 16 Hz, J = 11 Hz, J = 5 Hz),
2.92 (1H, q, J = 11 Hz), 3.05-3.
2 (2H, m), 3.2-3.6 (3H, nd), 3.
6-3.8 (4H, m), 4.11 (1H, d, J = 1
1 Hz), 6.70 (1 H, t, J = 7 Hz), 6.9
2 (1H, d, J = 8Hz), 6.979 (1H, d,
J = 8 Hz), 6.983 (1H, d, J = 5 Hz),
7.06 (1H, t, J = 8Hz), 7.61 (1H,
d, J = 5 Hz), 8.28 (1H, t, J = 5H)
z), 10.6-10.8 (1H, br.s); IR spectrum (KBr) ν _max cm ^-1 : 330
0, 2552, 2526, 2446, 1641.

Example 40 3- [2- (5-Methylthiophene-2-carbonylamino) ethyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline Monohydrochloride (Exemplified Compound Number: 1-307) 3- (2-aminoethyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (222 mg), 5-methylthiophene-2-carboxylic acid (137 mg) and diethyl cyanophosphonate (2
40 μl) was reacted in the same manner as in Examples 31a and 31b and post-treated to give the desired compound (185 mg,
60%) was obtained. Melting point: 201-210 ° C. (decomposition); NMR spectrum (DMSO-d ₆ ) δ ppm:
1.55-1.7 (1H, m), 1.9-2.0 (1
H, m), 2.47 (3H, s), 2.67 (1H, d
t, J = 16 Hz, J = 5 Hz), 2.81 (1H, d
dd, J = 16 Hz, J = 11 Hz, J = 5 Hz),
2.85-3.0 (1H, m), 3.0-3.2 (2
H, m), 3.2-3.6 (3H, nd), 3.6-
3.8 (4H, m), 4.10 (1H, d, J = 11H
z), 6.70 (1H, t, J = 7Hz), 6.87
(1H, d, J = 4Hz), 6.91 (1H, d, J =
8 Hz), 6.98 (1H, d, J = 7 Hz), 7.0
6 (1H, t, J = 8Hz), 7.69 (1H, d, J
= 4 Hz), 8.85 (1H, br.s), 10.6-
10.9 (1H, br.s); IR spectrum (KBr) ν _max cm ⁻¹ : 326
9, 2710, 2663, 2590, 2501, 246
5,1644.

Example 41 3- [4- (2-thenoylamino) butyl] -2,3
4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number:
1-285) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (330 mg) and 2-thenoyl chloride (140 μl) were reacted in the same manner as in Examples 2a and 2b and post-treated to give the desired compound (341 mg, 65%). ) Got. Mp: 198-214 ℃ (decomposition); NMR Spectrum _{(DMSO-d 6) δppm:} 1.
5-1.7 (3H, m), 1.7-1.85 (2H,
m), 1.9-2.0 (1H, m), 2.66 (1H,
dt, J = 16 Hz, J = 4 Hz), 2.75-2.9
(2H, m), 3.0-3.2 (4H, m), 3.28
(2H, dd, J = 13Hz, J = 7Hz), 3.3-
3.4 (3H, nd), 4.0-4.15 (1H,
m), 6.69 (1H, t, J = 7Hz), 6.89
(1H, d, J = 8Hz), 6.97 (1H, d, J =
7 Hz), 7.06 (1H, t, J = 8 Hz), 7.1
5 (1H, t, J = 4Hz), 7.74 (1H, d, J
= 4 Hz), 7.79 (1H, d, J = 4 Hz), 8.
59 (1H, t, J = 5Hz), 10.4-10.7
(1H, br.s); IR spectrum (ν _max cm ^-1 ): 3249, 25
83, 2542, 2486, 1636.

Example 42 3- [4- (5-chlorothiophene-2-carbonylamino) butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline Monohydrochloride (Exemplified Compound Number: 1-299) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (213 mg) and 5-chlorothiophene-2-carboxylic acid (135 mg) were reacted in the same manner as in Examples 31a and 31b, and post-treated to give the desired compound. (127
mg, 35%). Melting point: 196-205 ° C. (decomposition); NMR spectrum (DMSO-d ₆ ) δ ppm:
1.5-1.85 (5H, m), 1.9-2.0 (1
H, m), 2.66 (1H, dt, J = 16Hz, J =
4Hz), 2.80 (1H, ddd, J = 16Hz, J
= 11 Hz, J = 6 Hz), 3.0-3.2 (4H,
m), 3.2-3.4 (3H, nd), 3.45-3.
65 (2H, m), 4.08 (1H, d, J = 9H
z), 6.69 (1H, t, J = 7Hz), 6.90
(1H, d, J = 8Hz), 6.97 (1H, d, J =
7 Hz), 7.06 (1H, t, J = 8 Hz), 7.1
9 (1H, d, J = 4Hz), 7.69 (1H, d, J
= 4 Hz), 8.72 (1H, t, J = 5 Hz), 1
0.25-10.65 (1H, br.s); IR spectrum (KBr) ν _max cm ^-1 : 319
9,2671,591,1641.

Example 43 3- [4- (3-Methylthiophene-2-carbonylamino) butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline Monohydrochloride (Exemplified Compound Number: 1-304) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (228 mg) and 3-methylthiophene-2-carboxylic acid (125 mg) were reacted in the same manner as in Examples 31a and 31b, and post-treated to give the desired compound. (198
mg, 56%). Mp: 178-182 ° C.: NMR Spectrum (DMSO-d ₆₎ δppm:
1.5-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.41 (3
H, s), 2.66 (1H, dt, J = 16Hz, J =
5Hz), 2.80 (2H, ddd, J = 16Hz, J
= 11 Hz, J = 6 Hz), 3.0-3.2 (4H,
m), 3.25 (2H, dd, J = 13Hz, J = 7H
z), 3.25-3.45 (1H, nd), 3.45-
3.65 (2H, m), 4.08 (1H, d, J = 9H
z), 6.69 (1H, t, J = 7Hz), 6.90
(1H, d, J = 8Hz), 6.96 (1H, d, J =
7 Hz), 6.97 (1H, d, J = 8 Hz), 7.0
6 (1H, t, J = 8Hz), 7.56 (1H, d, J
= 5 Hz), 8.00 (1H, t, J = 6 Hz), 1
0.4-10.65 (1H, br.s); IR spectrum (KBr) ν _max cm ^-1 : 334
9, 3259, 2526, 2473, 1629.

Example 44 3- [4- (5-Methylthiophene-2-carbonylamino) butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline Monohydrochloride (Exemplified Compound No. 1-309) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (213 mg) and 5-methylthiophene-2-carboxylic acid (117 mg) were reacted in the same manner as in Examples 31a and 31b, and post-treated to give the desired compound. (189
mg, 60%). Melting point: 208-217 ° C. (decomposition); NMR spectrum (DMSO-d ₆ ) δ ppm:
1.5-1.85 (5H, m), 1.9-2.0 (1
H, m), 2.45 (3H, s), 2.66 (1H, d
t, J = 16 Hz, J = 5 Hz), 2.75-2.9
(2H, m), 2.9-3.2 (4H, m), 3.25
(2H, dd, J = 13Hz, J = 7Hz), 3.25
-3.4 (1H, nd), 3.5-3.65 (2H,
m), 4.0-4.15 (1H, m), 6.69 (1
H, t, J = 7 Hz, 6.83 (1H, d, J = 4H)
z), 6.90 (1H, d, J = 8 Hz), 6.97
(1H, d, J = 7Hz), 7.06 (1H, t, J =
8 Hz), 7.55 (1H, d, J = 4 Hz), 8.4
-8.5 (1H, br.s), 10.3-10.55
(1H, br.s); IR spectrum (KBr) ν _max cm ⁻¹ : 325
4,2558,2470,1630.

Example 45 3- [4- (4-Methoxythiophen-3-carbonylamino) butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline Monohydrochloride (Exemplified Compound Number: 1-365) 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline (213 mg) and 4-methoxythiophene-3-carboxylic acid (130 mg) were reacted in the same manner as in Examples 31a and 31b, and post-treated to give the desired compound. (19
8 mg, 57%) was obtained. Melting point: 172-177 ° C .; NMR spectrum (DMSO-d ₆ ) δppm:
1.5-1.7 (3H, m), 1.7-1.85 (2
H, m), 1.9-2.0 (1H, m), 2.66 (1
H, dt, J = 16 Hz, J = 4 Hz), 2.7-2.
9 (2H, m), 2.95-3.2 (4H, m), 3.
25-3.45 (3H, nd), 3.45-3.65.
(2H, m), 3.88 (3H, s), 4.07 (1
H, d, J = 12 Hz), 6.69 (1H, t, J = 7)
Hz), 6.76 (1H, d, J = 4Hz), 6.90
(1H, d, J = 8Hz), 6.97 (1H, d, J =
7 Hz), 7.06 (1H, t, J = 8 Hz), 7.8
1 (1H, t, J = 6Hz), 8.00 (1H, d, J
= 4 Hz), 10.3-10.6 (1H, br.s)
IR spectrum (KBr) ν _max cm ⁻¹ : 340
3,3339,2562,2465,1642.

Example 46 3- [4- (2,4-Dioxothiazolidin-3-yl) butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a ] Quinoline monohydrochloride
(Exemplified compound number: 2-3) (a) 3- [4- (2,4-dioxothiazolidine-
3-yl) butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline 2,3,4,4a, 5,6-hexahydro-1H-pyrazino [ 1,2-a] quinoline (105 mg) and 3-
(4-Bromobutyl) thiazolidine-2,4-dione (140 mg) was dissolved in DMF (2 ml), potassium carbonate (68 mg) was added, and the mixture was stirred at 100 ° C. for 1 hr. After cooling, ethyl acetate was added, followed by washing with water, and the organic layer was dried using anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the target compound (198 mg, 99%) as a pale red oily substance. NMR spectrum (CDCl ₃ ) δppm: 1.45
-2.0 (6H, m), 1.91 (1H, t, J = 11
Hz), 2.19 (1H, dt, J = 11Hz, J = 3)
Hz), 2.38 (2H, t, J = 7Hz), 2.6-
2.75 (1H, m), 2.75-3.1 (5H,
m), 3.67 (2H, t, J = 7Hz), 3.75
(1H, d, J = 11Hz), 3.94 (2H, s),
6.69 (1H, t, J = 7Hz), 6.79 (1H,
d, J = 8 Hz), 6.98 (1H, d, J = 7H
z), 7.08 (1H, t, J = 8Hz).

(B) 3- [4- (2,4-dioxothiazolidin-3-yl) butyl] -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline monohydrochloride 3- [4- (2,4-dioxothiazolidin-3-yl) butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (180m
g) was dissolved in a mixed solvent of ether (5 ml) and ethyl acetate (2 ml), and a 4N hydrogen chloride-ethyl acetate solution (120 μl) in ethyl acetate (1 ml) was added dropwise. After stirring at room temperature for 30 minutes, the precipitated crystals were collected by filtration and dried to obtain the target compound (144.6 mg, 73%). Mp: 176-181 ° C.; NMR Spectrum (DMSO-d ₆₎ δppm:
1.5-1.8 (5H, m), 1.9-2.0 (2H,
m), 2.66 (1H, dt, J = 16Hz, J = 5H
z), 2.75-2.9 (2H, m) 3.0-3.2.
(4H, m), 3.25-3.45 (1H, nd),
3.45-3.6 (4H, m), 4.08 (1H, d,
J = 9 Hz), 4.21 (2H, s), 6.69 (1
H, t, J = 7 Hz), 6.90 (1H, d, J = 8H)
z), 6.97 (1H, d, J = 7Hz), 7.06
(1H, t, J = 8Hz), 10.3-10.5 (1
H, br. s); IR spectrum (ν _max cm ^-1 ): 2352, 17
52, 1678.

Example 47 3- [3- (2,4-Dioxothiazolidin-3-yl) propyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a ] Quinoline Fumarate (Exemplified Compound Number: 2-2) (a) 3- [3- (2,4-dioxothiazolidine-
3-yl) propyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline 2,3,4,4a, 5,6-hexahydro-1H-pyrazino [ 1,2-a] quinoline (140 mg) and 3-
(3-Bromopropyl) thiazolidine-2,4-dione (178 mg) was reacted in the same manner as in Example 46a and post-treated to give the target compound (206 mg, 80 mg).
%) As an oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.6
-1.95 (5H, m), 2.12 (1H, dt, J =
11Hz, J = 3Hz), 2.42 (2H, t, J = 7)
Hz), 2.6-3.05 (6H, m), 3.7-3.
8 (1H, nd), 3.74 (2H, t, J = 7H
z), 3.91 (2H, s), 6.69 (1H, t, J
= 7 Hz), 6.78 (1H, d, J = 8 Hz), 6.
98 (1H, d, J = 7Hz), 7.08 (1H, t,
J = 8 Hz).

(B) 3- [3- (2,4-dioxothiazolidin-3-yl) propyl] -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline fumarate 3- [3- (2,4-dioxothiazolidin-3-yl) propyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a ] Quinoline (100
mg) in methanol (5 ml), and this solution was stirred at room temperature for fumaric acid (34 mg) in methanol (2 m).
l) Add to the solution and stir at room temperature for 15 minutes. The solvent was evaporated under reduced pressure, ether (15 ml) was added to the obtained residue, followed by ultrasonic treatment for 1 hour, and the precipitated crystals were collected by filtration,
The target compound (105.8 mg, 79%) was obtained. Melting point: 163-165 ° C .; NMR spectrum (DMSO-d ₆ ) δppm:
1.55-1.65 (1H, m), 1.70 (2H, q
uint, J = 7 Hz), 1.78 (2H, t, J = 1)
1Hz), 1.85 (1H, ddd, J = 13Hz, J
= 6 Hz, J = 3 Hz), 2.04 (1 H, dt, J =
11Hz, J = 3Hz), 2.34 (1H, t, J = 7)
Hz), 2.55-2.62 (1H, m), 2.65
(1H, dd, J = 12Hz, J = 3Hz), 2.75
-2.95 (4H, m), 3.57 (2H, t, J = 7
Hz), 3.77 (1H, d, J = 12 Hz), 4.1
6 (2H, s), 6.60 (1H, t, J = 7Hz),
6.62 (2H, s), 6.80 (1H, d, J = 8H
z), 6.91 (1H, d, J = 7 Hz), 6.99
(1H, t, J = 7 Hz); IR spectrum (KBr) ν _max cm ⁻¹ : 254
9, 2463, 1746, 1679.

Example 48 3- [5- (2,4-Dioxothiazolidin-3-yl) pentyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] ] Quinoline monohydrochloride (Exemplified compound number: 2-4) 2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (137 mg) and 3- (5
-Bromopentyl) thiazolidine-2,4-dione (1
94 mg) was reacted in the same manner as in Examples 46a and 46b and post-treated to give the desired compound (180 mg,
71%). Mp: 161-164 ° C.; NMR Spectrum (DMSO-d ₆₎ δppm:
1.2-1.35 (2H, m), 1.5-1.8 (5
H, m), 1.9-2.0 (1H, m), 2.66 (1
H, dt, J = 16 Hz, J = 5 Hz), 2.75-
2.9 (2H, m), 3.0-3.15 (4H, m),
3.2-3.4 (1H, nd), 3.45-3.6 (4
H, m), 4.07 (1H, d, J = 10 Hz), 6.
69 (1H, t, J = 7Hz), 6.90 (1H, d,
J = 8 Hz), 6.97 (1H, d, J = 7 Hz),
7.06 (1H, t, J = 8Hz), 10.4-10.
6 (1H, br.s); IR spectrum (KBr) ν _max cm ^-1 : 245
2,1741,1677.

Example 49 3- [4- (5,5-Dimethyl-2,4-dioxothiazolidin-3-yl) butyl] -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline monohydrochloride (Exemplified compound number: 2-27) 2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (163 mg) and 3- (4
-Bromobutyl) -5,5-dimethylthiazolidine-
2,4-dione (243 mg) was added to Examples 46a and 46.
The target compound (149.8 mg, 56%) was obtained by reacting in the same manner as in b and performing post-treatment. Mp: 155-160 ° C.; NMR Spectrum (DMSO-d ₆₎ δppm:
1.5-1.8 (5H, m), 1.66 (6H, s),
1.9-2.0 (1H, m), 2.66 (1H, dt,
J = 16 Hz, J = 5 Hz), 2.73-2.9 (2
H, m), 2.9-3.2 (4H, m), 3.2-3.
4 (1H, nd), 3.43 to 3.63 (4H, m),
4.07 (1H, d, J = 11Hz), 6.69 (1
H, t, J = 7 Hz), 6.90 (1H, d, J = 8H)
z), 6.97 (1H, d, J = 7Hz), 7.06
(1H, t, J = 8Hz), 10.7-10.9 (1
H, br. s); IR spectrum (KBr) ν _max cm ^-1 : 254
7, 2458, 1747, 1679.

Example 50 3- [4- (5-Isopropyl-2,4-dioxothiazolidin-3-yl) butyl] -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline monohydrochloride (Exemplified compound number: 2-34) 2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (186 mg) and 3- (4
-Bromobutyl) -5-isopropylthiazolidine-
2,4-dione (305 mg) was added to Examples 46a and 46.
The target compound (96.4 mg, 24%) was obtained by carrying out a post-treatment by reacting in the same manner as in b. Mp: 164-167 ° C.; NMR Spectrum (DMSO-d ₆₎ δppm:
0.88 (3H, d, J = 7Hz), 0.99 (3H,
d, J = 7 Hz), 1.5-1.75 (5H, m),
1.9-2.0 (1H, m), 2.66 (1H, dt,
J = 16 Hz, J = 5 Hz), 2.75-2.9 (2
H, m), 3.0-3.2 (4H, m), 3.2-3.
4 (2H, nd), 3.45-3.6 (2H, nd),
4.08 (1H, d, J = 9Hz), 4.71 (1H,
d, J = 4Hz), 6.70 (1H, t, J = 7H
z), 6.90 (1H, d, J = 8Hz), 6.98
(1H, d, J = 7Hz), 7.06 (1H, t, J =
8 Hz), 10.35-10.55 (1H, br.s)
IR spectrum (KBr) ν _max cm ⁻¹ : 255
6, 2464, 1747, 1679.

Example 51 3- (3-phthalimidopropyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] quinoline (Exemplified compound number: 2-45) 2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (240 mg) and N- (3
-Bromopropyl) phthalimide (342 mg) was reacted in the same manner as in Example 1a and post-treated to obtain the target compound (453 mg, 95%) as a yellow oily substance. NMR spectrum (CDCl ₃ ) δ ppm: 1.6
-2.0 (7H, m), 2.05-2.2 (1H,
m), 2.45 (2H, t, J = 7Hz), 2.5-
3.0 (6H, m), 3.68 (1H, d, J = 13H
z), 3.79 (2H, t, J = 7Hz), 6.67.
(1H, t, J = 7Hz), 6.73 (1H, d, J =
8 Hz), 6.95 (1H, d, J = 7 Hz), 7.0
6 (1H, t, J = 8Hz), 7.65-7.75 (2
H, m), 7.8-7.9 (2H, m). Example 52 3- (2-phthalimidoethyl) -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline (Exemplified compound number: 2-44) 2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (410 mg) and N- (2
-Bromoethyl) phthalimide (560 mg) was reacted in the same manner as in Example 1a and post-treated to obtain the target compound (580 mg, 74%). Melting point: 129-132 ° C .; NMR spectrum (CDCl ₃ ) δppm: 1.6
5-1.95 (2H, m), 1.99 (1H, t, J =
11Hz), 2.27 (1H, dt, J = 11Hz, J
= 3 Hz), 2.66 (2H, t, J = 6 Hz), 2.
7-3.0 (5H, m), 3.0-3.15 (1H,
m), 3.70 (1H, d, J = 12 Hz), 3.86
(2H, t, J = 7Hz), 6.67 (1H, t, J =
7 Hz), 6.76 (1H, d, J = 8 Hz), 6.9
6 (1H, d, J = 7Hz), 7.06 (1H, t, J
= 8 Hz), 7.65-7.75 (2H, m), 7.8
-7.9 (2H, m); IR spectrum (KBr) ν _max cm ^-1 : 177
0,1709.

Example 53 3- (4-benzamidobutyl) -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [2,1-c]
-1,4-Benzoxazine monohydrochloride (Exemplified compound number: 1-30) 2,3,4,4a, 5,6-hexahydro-1H-pyrazino [2,1-c] -1,4-benzoxazine and N −
(4-Bromobutyl) phthalimide was reacted in the same manner as in Example 1a, Reference Example 1, Example 2a and then 2b, and post-treated to obtain the target compound as colorless needle crystals. Melting point: 189-191 [deg.] C.

Example 54 3- (4-phenylcarbamoylbutyl) -2,3
4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline dihydrochloride (Exemplified compound number:
3-3) 2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (162 mg) and 4-phenylcarbamoylbutyl bromide (220 mg) were dissolved in isopropanol (15 ml). Sodium carbonate was added and the mixture was heated under reflux for 8 hours. After cooling, the mixture was filtered, the solvent was evaporated under reduced pressure, water was added to the obtained residue, the mixture was extracted with ethyl acetate, the organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluent: 1
Purification using 0% ethanol / methylene chloride solution,
An excess of 10N hydrochloric acid / methanol solution was added, and the mixture was left at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized with ethanol to give the target compound (230 m
g, 61%) as colorless needles. Mp: 218 ° C. (decomposition); NMR Spectrum (DMSO-d ₆₎ δppm:
1.5-1.7 (3H, m), 1.7-1.9 (2H,
m), 1.9-2.0 (1H, m), 2.40 (2H,
t, J = 7.3 Hz), 2.6-2.9 (3H, m),
3.0-3.2 (4H, m), 3.4-3.6 (3H,
m), 4.06 (1H, d, J = 11.9 Hz), 6.
69 (1H, t, J = 7.3 Hz), 6.89 (1H,
d, J = 8.6 Hz), 6.9-7.2 (3H, m),
7.29 (2H, t, J = 7.3Hz, J = 8.6H
z), 7.45 (1H, br.s), 7.63 (2H,
d, J = 7.9 Hz), 10.08 (1H, s), 1
1.00 (1H, br.s).

Example 55 (−)-3- (4-phthalimidobutyl) -2,3
4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (Exemplified compound number: 2-46) (-)-2,3,4,4a, 5,6-hexahydro-1
H-pyrazino [1,2-a] quinoline (0.71 g),
N- (4-bromobutyl) phthalimide (1.07 g)
And potassium carbonate (0.52 g) were reacted in the same manner as in Example 1 (a) and post-treated to obtain the target compound (1.26 g, 85%). Optical rotation ([α] _D ²⁴ ): −6.8 ^o (C = 1.0)
8, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 29
46, 2824, 1771, 1712, 1602; NMR spectrum (CDCl ₃ ) δ ppm: 1.5
3-1.95 (6H, m), 1.92 (1H, t, J =
10.9Hz), 2.18 (1H, dt, J = 2.9H
z, J = 11.2 Hz), 2.38 (2H, t, J =
7.4 Hz), 2.65-2.75 (1 H, m), 2.
75-2.95 (3H, m), 2.95-3.08 (2
H, m), 3.65-3.80 (1H, nd), 3.7.
4 (2H, t, J = 7.0Hz), 6.68 (1H,
t, J = 7.2 Hz), 6.78 (1H, d, J = 8.
2Hz), 6.97 (1H, d, J = 7.2Hz),
7.08 (1H, t, J = 8.2Hz), 7.67-
7.76 (2H, m), 7.80-7.90 (2H,
m).

Example 56 (+)-3- (4-phthalimidobutyl) -2,3
4,4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline (Exemplified compound number: 2-46) (+)-2,3,4,4a, 5,6-hexahydro-1
H-pyrazino [1,2-a] quinoline (0.90 g),
N- (4-bromobutyl) phthalimide (1.41 g)
And potassium carbonate (0.66 g) were reacted in the same manner as in Example 1 (a) and post-treated to obtain the target compound (1.57 g, 84%). Specific rotation ([α] _D ²⁴ ): +9.7 ^o (C = 1.0
0, EtOH); IR spectrum (KBr) ν _max cm ⁻¹ : 2948,
2825,1772,1713,1605; NMR spectrum (CDCl ₃ ) δppm: 1.5
3-1.96 (6H, m), 1.91 (1H, t, J =
10.9Hz), 2.18 (1H, dt, J = 2.9H
z, J = 11.2 Hz), 2.38 (2H, t, J =
7.4 Hz), 2.65-2.75 (1 H, m), 2.
75-2.95 (3H, m), 2.95-3.09 (2
H, m), 3.60-3.85 (1H, nd), 3.7.
4 (2H, t, J = 7.0Hz), 6.69 (1H,
t, J = 7.2 Hz), 6.78 (1H, d, J = 8.
2Hz), 6.97 (1H, d, J = 7.2Hz),
7.08 (1H, t, J = 8.2Hz), 7.68-
7.75 (2H, m), 7.82-7.88 (2H,
m).

Example 57 (−)-3- (2-phthalimidoethyl) -2,3
4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (Exemplified compound number: 2-44) (-)-2,3,4,4a, 5,6-hexahydro-1
H-pyrazino [1,2-a] quinoline (0.82 g),
N- (2-bromoethyl) phthalimide (1.2 g) and potassium carbonate (0.61 g) were reacted in the same manner as in Example 1 (a) and post-treated to give the desired compound (0.
93 g, 59%) was obtained. Specific rotation ([α] _D ²⁴ ): -3.9 ^o (C = 1.0
2, CHCl ₃ ); IR spectrum (KBr) ν _max cm ⁻¹ : 2932,
2818, 1767, 1708, 1604; NMR spectrum (CDCl ₃ ) δppm: 1.6
5-2.05 (2H, m), 1.99 (1H, t, J =
10.8Hz), 2.27 (1H, dt, J = 3.1H
z, J = 11.3 Hz), 2.66 (2H, t, J =
6.6 Hz), 2.70-3.00 (5H, m), 3.
00-3.15 (1H, m), 3.70 (1H, d, J
= 11.8 Hz), 3.86 (2H, t, J = 6.5H)
z), 6.67 (1H, t, J = 7.3 Hz), 6.7.
6 (1H, d, J = 8.2 Hz), 6.96 (1H,
d, J = 7.3 Hz), 7.06 (1H, t, J = 8.
2 Hz), 7.68-7.79 (2H, m), 7.81
-7.90 (2H, m).

Example 58 (+)-3- (2-phthalimidoethyl) -2,3
4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (Exemplified compound number: 2-44) (+)-2,3,4,4a, 5,6-hexahydro-1
H-pyrazino [1,2-a] quinoline (0.75 g),
N- (2-bromoethyl) phthalimide (1.11 g)
And potassium carbonate (0.55 g) were reacted in the same manner as in Example 1 (a) and post-treated to obtain the target compound (1.21 g, 84%). Specific rotation ([α] _D ²⁴ ): +4.5 ^o (C = 1.0
0, CHCl ₃ ); IR spectrum (KBr) ν _max cm ⁻¹ : 2932,
2819, 1767, 1709, 1604; NMR spectrum (CDCl ₃ ) δ ppm: 1.6
5-2.05 (2H, m), 1.99 (1H, t, J =
10.8Hz), 2.28 (1H, dt, J = 3.1H)
z, J = 11.3 Hz), 2.66 (2H, t, J =
6.6 Hz), 2.70-3.00 (5H, m), 3.
00-3.15 (1H, m), 3.71 (1H, d, J
= 11.8 Hz), 3.86 (2H, t, J = 6.5H)
z), 6.68 (1H, t, J = 7.3 Hz), 6.7.
6 (1H, d, J = 8.2 Hz), 6.97 (1H,
d, J = 7.3 Hz), 7.06 (1H, t, J = 8.
2Hz), 7.67-7.78 (2H, m), 7.82
-7.91 (2H, m).

Example 59 (-)-3- [4- (5,5-Dimethyl-2,4-dioxothiazolidin-3-yl) butyl] -2,3,4
4a, 5,6-hexahydro-1H-pyrazino [1,2
-A] Quinoline monohydrochloride (Exemplified compound number: 2-2
7) (a) (-)-3- [4- (5,5-dimethyl-2,
4-dioxothiazolidin-3-yl) butyl] -2,
3,4,4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline (-)-2,3,4,4a, 5,6-hexahydro-1
H-pyrazino [1,2-a] quinoline (0.31 g),
3- (4-bromobutyl) -5,5-dimethylthiazolidine-2,4-dione (0.46 g) and potassium carbonate (0.23 g) were reacted in the same manner as in Example 46 (a),
The target compound (0.53 g, 83
%) Was obtained. Specific rotation ([α] _D ²⁴ ): −7.0 ^o (C = 0.9
9, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 29
46,2824,1746,1681,1602; NMR spectrum (CDCl ₃ ) δppm: 1.4
6-2.00 (3H, m), 1.70 (6H, s),
1.90 (2H, t, J = 10.7Hz), 2.18
(1H, dt, J = 3.1Hz, J = 11.4Hz),
2.38 (2H, t, J = 7.3Hz), 2.65-
3.08 (6H, m), 3.65 (2H, t, J = 7.
1Hz), 3.75 (1H, dt, J = 2.6Hz, J
= 11.8 Hz), 6.69 (1H, t, J = 7.2H)
z), 6.79 (1H, d, J = 8.2Hz), 6.9.
8 (1H, d, J = 7.2 Hz), 7.09 (1H,
t, J = 8.2 Hz).

(B) (-)-3- [4- (5,5-Dimethyl-2,4-dioxothiazolidin-3-yl) butyl] -2,3,4,4a, 5,6-hexahydro -1
H-pyrazino [1,2-a] quinoline monohydrochloride (-)-3- [4- (5,5-dimethyl-2,4-dioxothiazolidin-3-yl) butyl] -2,3,4 ，
4a, 5,6-hexahydro-1H-pyrazino [1,2
-A] Quinoline (0.46 g) was reacted in the same manner as in Example 46 (b) and post-treated to obtain the target compound (0.39 g, quantitative). Specific rotation ([α] _D ²⁴ ): −10.2 ^o (C =
1.00, EtOH); melting point: 169-172 ° C; IR spectrum (KBr) ν _max cm ^-1 : 293
0,2559,2466,1743,1683; NMR Spectrum (DMSO-d ₆₎ δppm:
1.54-1.73 (5H, m), 1.66 (6H,
s), 1.93-1.99 (1H, m), 2.66 (1
H, dt, J = 4.5 Hz, J = 16.2 Hz), 2.
76-2.86 (2H, m), 2.95-3.20 (4
H, m), 3.20-3.40 (1H, nd), 3.4.
0-3.60 (4H, m), 4.07 (1H, d, J =
11.3Hz), 6.69 (1H, t, J = 7.3H)
z), 6.90 (1H, d, J = 8.3 Hz), 6.9.
7 (1H, d, J = 7.3 Hz), 7.06 (1H,
t, J = 8.3 Hz), 10.63 (1H, brs).

Example 60 (+)-3- [4- (5,5-Dimethyl-2,4-dioxothiazolidin-3-yl) butyl] -2,3,4
4a, 5,6-hexahydro-1H-pyrazino [1,2
-A] Quinoline monohydrochloride (Exemplified compound number: 2-2
7) (a) (+)-3- [4- (5,5-dimethyl-2,
4-dioxothiazolidin-3-yl) butyl] -2,
3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (+)-2,3,4,4a, 5,6-hexahydro-1
H-pyrazino [1,2-a] quinoline (0.19 g),
3- (4-Bromobutyl) -5,5-dimethylthiazolidine-2,4-dione (0.34 g) and potassium carbonate (0.17 g) were reacted in the same manner as in Example 46 (a),
By post-treatment, the target compound (0.31 g, 79
%) Was obtained. Specific rotation ([α] _D ²⁴ ): +8.5 ^o (C = 1.0
0, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 29
46,2824,1747,1681,1602; NMR spectrum (CDCl ₃ ) δppm: 1.4
5-1.99 (3H, m), 1.70 (6H, s),
1.90 (2H, t, J = 10.7Hz), 2.18
(1H, dt, J = 3.2Hz, J = 11.4Hz),
2.38 (2H, t, J = 7.2Hz), 2.65-
3.08 (6H, m), 3.65 (2H, t, J = 7.
2Hz), 3.75 (1H, dt, J = 2.6Hz, J
= 11.9 Hz), 6.69 (1H, t, J = 7.3H)
z), 6.79 (1H, d, J = 8.2Hz), 6.9.
8 (1H, d, J = 7.3 Hz), 7.08 (1H,
t, J = 8.2 Hz).

(B) (+)-3- [4- (5,5-Dimethyl-2,4-dioxothiazolidin-3-yl) butyl] -2,3,4,4a, 5,6-hexahydro -1
H-pyrazino [1,2-a] quinoline monohydrochloride (+)-3- [4- (5,5-dimethyl-2,4-dioxothiazolidin-3-yl) butyl] -2,3,4 ，
4a, 5,6-hexahydro-1H-pyrazino [1,2
-A] Quinoline (0.28 g) was reacted in the same manner as in Example 46 (b) and post-treated to obtain the target compound (0.30 g, quantitative). Specific rotation ([α] _D ²⁴ ): +10.5 ^o (C = 1.
00, EtOH); Melting point: 169-172 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 293
1,2553,2462,1744,1679; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.54-1.74 (5H, m), 1.66 (6H,
s), 1.94-1.99 (1H, m), 2.66 (1
H, dt, J = 4.6 Hz, J = 16.1 Hz), 2.
76-2.84 (2H, m), 2.95-3.20 (4
H, m), 3.20-3.40 (1H, nd), 3.4.
0-3.60 (4H, m), 4.07 (1H, d, J =
12.6 Hz), 6.69 (1H, t, J = 7.3H)
z), 6.90 (1H, d, J = 8.3 Hz), 6.9.
7 (1H, d, J = 7.3 Hz), 7.06 (1H,
t, J = 8.3 Hz), 10.90 (1H, brs).

Example 61 (-)-3- [4- (2,4-Difluorobenzamido) butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] Quinoline monohydrochloride
(Exemplified compound number: 1-55) (a) (-)-3- [4- (2,4-difluorobenzamido) butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [ 1,2-a] quinoline (-)-3- (4-aminobutyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (0.30 g), 2,4-difluorobenzoyl chloride (0.16 ml) and triethylamine (0.19 ml) were reacted in the same manner as in Example 2 (a),
By post-treatment, the target compound (0.36 g, 78
%) Was obtained. Specific rotation ([α] _D ²⁴ ): −9.2 ^o (C = 1.0
1, EtOH); IR spectrum (KBr) ν _max cm ⁻¹ : 327
0,2931,2859,2807,2771,164
7, 1620, 1603; NMR spectrum (CDCl ₃ ) δ ppm: 1.5
6-1.90 (7H, m), 2.18 (1H, dt, J
= 3.2 Hz, J = 11.5 Hz), 2.41 (2H,
t, J = 6.8 Hz), 2.65-3.05 (6H,
m), 3.51 (2H, q, J = 5.9Hz), 3.7
2-3.77 (1H, m), 6.69 (1H, t, J =
7.3 Hz), 6.77-7.15 (6H, m), 8.
05-8.15 (1H, m).

(B) (-)-3- [4- (2,4-difluorobenzamido) butyl] -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline monohydrochloride (-)-3- [4- (2,4-difluorobenzamido) butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline ( 0.31
g) was reacted in the same manner as in Example 2 (b) and post-treated to obtain the target compound (0.25 g, 74%). Specific rotation ([α] _D ²⁴ ): -9.1 ^o (C = 1.0
0, EtOH); Melting point: 160-165 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 324
6,2939,2476,1659,1618,160
2; NMR spectrum (DMSO-d ₆ ) δppm:
1.53-1.68 (3H, m), 1.75-1.82
(2H, m), 1.95-2.00 (1H, m), 2.
67 (1H, dt, J = 4.6Hz, J = 16.1H
z), 2.76-2.86 (2H, m), 3.00-
3.19 (4H, m), 3.29 (2H, dd, J =
6.7 Hz, J = 12.9 Hz), 3.30-3.40
(1H, nd), 3.54 (2H, t, J = 12.4H
z), 4.08 (1H, d, J = 11.1 Hz), 6.
69 (1H, t, J = 7.3 Hz), 6.90 (1H,
d, J = 8.3 Hz), 6.98 (1H, d, J = 7.
3Hz), 7.06 (1H, t, J = 8.3Hz),
7.17 (1H, dt, J = 2.3Hz, J = 8.4H
z), 7.36 (1H, ddd, J = 2.0 Hz, J =
9.3 Hz, J = 10.5 Hz), 7.70 (1H, d
t, J = 6.9 Hz, J = 8.4 Hz), 8.40 (1
H, t, J = 4.8 Hz), 10.78 (1H, br
s).

Example 62 (+)-3- [4- (2,4-Difluorobenzamido) butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] Quinoline monohydrochloride
(Exemplified compound number: 1-55) (a) (+)-3- [4- (2,4-difluorobenzamido) butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [ 1,2-a] quinoline (+)-3- (4-aminobutyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (0.30 g), 2,4-difluorobenzoyl chloride (0.15 ml) and triethylamine (0.16 ml) were reacted in the same manner as in Example 2 (a),
By post-treatment, the target compound (0.41 g, 89
%) Was obtained. Specific rotation ([α] _D ²⁴ ): +8.2 ^o (C = 1.0
0, EtOH); IR spectrum (KBr) ν _max cm ⁻¹ : 326
9,2931,2859,2807,2771,164
6,1620,1603; NMR spectrum (CDCl ₃ ) δppm: 1.5
5-1.94 (7H, m), 2.18 (1H, dt, J
= 3.2 Hz, J = 11.5 Hz), 2.41 (2H,
t, J = 6.8 Hz), 2.65-3.03 (6H,
m), 3.51 (2H, q, J = 5.9Hz), 3.7
1-3.77 (1H, m), 6.69 (1H, t, J =
7.3 Hz), 6.77-7.11 (6H, m), 8.
05-8.14 (1H, m).

(B) (+)-3- [4- (2,4-difluorobenzamido) butyl] -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline monohydrochloride (+)-3- [4- (2,4-difluorobenzamido) butyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline ( 0.38
g) was reacted in the same manner as in Example 2 (b) and post-treated to obtain the target compound (0.41 g, quantitative). Specific rotation ([α] _D ²⁴ ): +8.2 ^o (C = 1.0
0, EtOH); Melting point: 154-156 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 324
4,2940,2476,1659,1618,160
1; NMR spectrum (DMSO-d ₆ ) δppm:
1.53-1.67 (3H, m), 1.75-1.83
(2H, m), 1.94-2.00 (1H, m), 2.
67 (1H, dt, J = 4.6Hz, J = 16.1H
z), 2.76-2.86 (2H, m), 3.00-
3.20 (4H, m), 3.29 (2H, dd, J =
6.7 Hz, J = 12.9 Hz), 3.30-3.40
(1H, nd), 3.54 (2H, t, J = 12.4H
z), 4.08 (1H, d, J = 11.4 Hz), 6.
70 (1H, t, J = 7.3 Hz), 6.90 (1H,
d, J = 8.3 Hz), 6.98 (1H, d, J = 7.
3Hz), 7.06 (1H, t, J = 8.3Hz),
7.17 (1H, dt, J = 2.6Hz, J = 8.5H
z), 7.36 (1H, ddd, J = 2.0 Hz, J =
9.3 Hz, J = 10.5 Hz), 7.70 (1H, d
t, J = 6.8 Hz, J = 8.5 Hz), 8.41 (1
H, t, J = 5.0 Hz), 10.75 (1H, br
s).

Example 63 (-)-3- (4-benzamidobutyl) -2,3
4,4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number:
1-25) (a) (-)-3- (4-benzamidobutyl)-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (-)-3- (4-aminobutyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (0.30 g), benzoyl chloride (0.1
5 ml) and triethylamine (0.19 ml) were reacted in the same manner as in Example 2 (a) and post-treated to give
The target compound (0.37 g, 88%) was obtained. Specific rotation ([α] _D ²⁴ ): −8.9 ^o (C = 1.0
4, EtOH); IR spectrum (KBr) ν _max cm ⁻¹ : 327
8, 2930, 2860, 2810, 1638, 160
2; NMR spectrum (CDCl ₃ ) δ ppm: 1.5
5-1.80 (5H, m), 1.80-1.86 (1
H, m), 1.89 (1H, t, J = 10.9Hz),
2.18 (1H, dt, J = 3.2Hz, J = 11.3
Hz), 2.42 (2H, t, J = 6.8Hz), 2.
69 (1H, ddd, J = 16.0Hz, J = 5.2H
z, J = 3.7 Hz), 2.75-2.92 (3H,
m), 2.92-3.02 (2H, m), 3.51 (2
H, q, J = 6.1 Hz), 3.74 (1H, dt, J
= 2.8 Hz, J = 12.3 Hz), 6.64 (1H,
brs), 6.70 (1H, t, J = 7.3Hz),
6.79 (1H, d, J = 8.1Hz), 6.98 (1
H, d, J = 7.3 Hz), 7.07 (1H, t, J =
8.1 Hz), 7.35-7.50 (3H, m), 7.
75 (2H, d, J = 6.7 Hz).

(B) (-)-3- (4-benzamidobutyl) -2,3,4,4a, 5,6-hexahydro-
1H-Pyrazino [1,2-a] quinoline monohydrochloride (−)-3- (4-benzamidobutyl) -2,3
4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (0.35 g) was used in Example 2.
A target compound (0.31 g, 80%) was obtained by reacting in the same manner as in (b) and post-treating. Specific rotation ([α] _D ²⁴ ): −9.2 ^o (C = 1.0
0, EtOH); Melting point: 176-179 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 330
6,2944,2587,2473,1655,160
2,1578; NMR Spectrum (DMSO-d ₆₎ δppm:
1.55-1.67 (3H, m), 1.75-1.83
(2H, m), 1.95-1.99 (1H, m), 2.
66 (1H, dt, J = 4.5Hz, J = 16.1H
z), 2.76-2.87 (2H, m), 3.00-
3.20 (4H, m), 3.24-3.45 (3H,
m), 3.52-3.58 (2H, m), 4.07 (1
H, d, J = 10.0 Hz, 6.69 (1 H, t, J
= 7.3 Hz), 6.90 (1H, d, J = 8.3H)
z), 6.97 (1H, d, J = 7.3 Hz), 7.0
6 (1H, t, J = 8.3Hz), 7.47 (2H,
t, J = 7.3 Hz), 7.53 (1H, t, J = 7.
3Hz), 7.87 (2H, d, J = 7.3Hz),
8.57 (1H, t, J = 5.5Hz), 10.70
(1H, brs).

Example 64 (+)-3- (4-benzamidobutyl) -2,3
4,4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number:
1-25) (a) (+)-3- (4-benzamidobutyl)-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (+)-3- (4-aminobutyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (0.24 g), benzoyl chloride (0.1
1 ml) and triethylamine (0.13 ml) were reacted in the same manner as in Example 2 (a) and post-treated to give
The target compound (0.29 g, 86%) was obtained. Specific rotation ([α] _D ²⁴ ): +10.1 ^o (C = 1.
00, EtOH); IR spectrum (KBr) ν _max cm ⁻¹ : 327
6,2930,2861,2810,1637,160
2; NMR spectrum (CDCl ₃ ) δ ppm: 1.5
5-1.80 (5H, m), 1.80-1.86 (1
H, m), 1.89 (1H, t, J = 10.9Hz),
2.18 (1H, dt, J = 3.2Hz, J = 11.3
Hz), 2.42 (2H, t, J = 6.8Hz), 2.
69 (1H, ddd, J = 16.0Hz, J = 5.2H
z, J = 3.7 Hz), 2.75-2.92 (3H,
m), 2.92-3.02 (2H, m), 3.50 (2
H, q, J = 6.1 Hz), 3.74 (1H, dt, J
= 2.8 Hz, J = 12.3 Hz), 6.65 (1H,
brs), 6.70 (1H, t, J = 7.3Hz),
6.78 (1H, d, J = 8.1Hz), 6.98 (1
H, d, J = 7.3 Hz), 7.06 (1H, t, J =
8.1 Hz), 7.37-7.51 (3H, m), 7.
75 (2H, d, J = 6.7 Hz).

(B) (+)-3- (4-benzamidobutyl) -2,3,4,4a, 5,6-hexahydro-
1H-pyrazino [1,2-a] quinoline monohydrochloride (+)-3- (4-benzamidobutyl) -2,3
4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (0.27 g) was used in Example 2.
A target compound (0.30 g, quantitative) was obtained by reacting in the same manner as in (b) and post-treating. Specific rotation ([α] _D ²⁶ ): +8.6 ^o (C = 1.0
2, EtOH); Melting point: 179-181 ° C; IR spectrum (KBr) ν _max cm ^-1 : 330
3,2943, 2577, 2469, 1653, 160
2,1578; NMR Spectrum (DMSO-d ₆₎ δppm:
1.54-1.67 (3H, m), 1.74-1.82
(2H, m), 1.95-1.99 (1H, m), 2.
66 (1H, dt, J = 4.5Hz, J = 16.1H
z), 2.76-2.87 (2H, m), 3.00-
3.20 (4H, m), 3.27-3.45 (3H,
m), 3.52-3.58 (2H, m), 4.07 (1
H, d, J = 9.9 Hz), 6.69 (1H, t, J =
7.3 Hz), 6.90 (1H, d, J = 8.3H)
z), 6.97 (1H, d, J = 7.3 Hz), 7.0
6 (1H, t, J = 8.3Hz), 7.47 (2H,
t, J = 7.3 Hz), 7.53 (1H, t, J = 7.
3Hz), 7.86 (2H, d, J = 7.3Hz),
8.56 (1H, t, J = 5.5Hz), 10.50
(1H, brs).

Example 65 (-)-3- [2- (2-thenoylamino) ethyl]-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-283) (a) (-)-3- [2- ( 2-Thenoylamino) ethyl] -2,3,4,4a, 5,6-hexahydro-1
H-pyrazino [1,2-a] quinoline (-)-3- (2-aminoethyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (0.27 g), 2-thenoyl chloride (0.
14 ml) and triethylamine (0.32 ml) were reacted in the same manner as in Example 2 (a) and post-treated to obtain the target compound (0.33 g, 84%). Specific rotation ([α] _D ²³ ): −8.5 ^° (C = 1.0
0, EtOH); IR spectrum (KBr) ν _max cm ⁻¹ : 328
9, 2939, 2815, 1625, 1602; NMR spectrum (CDCl ₃ ) δ ppm: 1.7
1-1.94 (2H, m), 2.05 (1H, t, J =
10.6 Hz), 2.33 (1H, dt, J = 3.2H
z, J = 11.4 Hz), 2.63 (2H, t, J =
6.0 Hz), 2.68-3.10 (6H, m), 3.
56 (2H, q, J = 5.6Hz), 3.80 (1H,
dt, J = 2.7 Hz, J = 11.6 Hz), 6.72
(1H, t, J = 7.3 Hz), 6.77 (1H, br
s), 6.81 (1H, d, J = 8.1Hz), 6.9.
8-7.13 (3H, m), 7.45-7.50 (2
H, m).

(B) (-)-3- [2- (2-Thenoylamino) ethyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride Salt (-)-3- [2- (2-thenoylamino) ethyl]-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (0.29 g) was used in Example 2.
The reaction was carried out in the same manner as in (b) and post-treatment was carried out to obtain the target compound (0.24 g, 77%). Specific rotation ([α] _D ²⁴ ): -2.2 ^o (C = 1.0)
0, EtOH); Melting point: 185-191 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 327
6,2938,2920,2590,1645,160
2; NMR spectrum (DMSO-d ₆ ) δppm:
1.57-1.66 (1H, m), 1.80-1.99
(1H, m), 2.67 (1H, dt, J = 4.5H
z, J = 16.1 Hz), 2.81 (1H, ddd, J
= 5.5 Hz, J = 10.9 Hz, J = 16.2 H
z), 2.91 (1H, q, J = 10.3Hz), 3.
00-3.20 (2H, m), 3.20-3.60 (3
H, nd), 3.60-3.80 (4H, m), 4.1
1 (1H, d, J = 10.0Hz), 6.70 (1H,
t, J = 7.3 Hz), 6.91 (1H, d, J = 8.
3Hz), 6.98 (1H, d, J = 7.3Hz),
7.07 (1H, t, J = 8.3Hz), 7.18 (1
H, t, J = 4.3 Hz) 7.79 (1H, d, J =
5.0Hz), 7.85 (1H, d, J = 3.4H
z), 8.90 (1H, brs), 10.35 (1H,
brs).

Example 66 (+)-3- [2- (2-thenoylamino) ethyl]-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-283) (a) (+)-3- [2- ( 2-Thenoylamino) ethyl] -2,3,4,4a, 5,6-hexahydro-1
H-pyrazino [1,2-a] quinoline (+)-3- (2-aminoethyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (0.25 g), 2-thenoyl chloride (0.
14 ml) and triethylamine (0.18 ml) were reacted in the same manner as in Example 2 (a) and post-treated to obtain the target compound (0.32 g, 87%). Specific rotation ([α] _D ²⁴ ): +8.8 ^o (C = 1.0
0, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 32
87, 2936, 2815, 1630, 1602; NMR spectrum (CDCl ₃ ) δ ppm: 1.7
3-1.95 (2H, m), 2.05 (1H, t, J =
10.6 Hz), 2.33 (1H, dt, J = 3.2H
z, J = 11.4 Hz), 2.62 (2H, t, J =
6.0 Hz), 2.67-3.10 (6H, m), 3.
56 (2H, q, J = 5.6Hz), 3.80 (1H,
dt, J = 2.7 Hz, J = 11.6 Hz), 6.73
(1H, t, J = 7.3 Hz), 6.75 (1H, br
s), 6.82 (1H, d, J = 8.1Hz), 6.9.
8-7.14 (3H, m), 7.45-7.50 (2
H, m).

(B) (+)-3- [2- (2-Thenoylamino) ethyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride Salt (+)-3- [2- (2-thenoylamino) ethyl]-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (0.31 g) was used in Example 2.
The reaction was carried out in the same manner as in (b) and post-treatment was carried out to obtain the target compound (0.34 g, quantitative). Specific rotation ([α] _D ²⁴ ): +2.3 ^o (C = 1.0
1, EtOH); melting point: 185-190 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 326
4,2941,9222,2556,1644,160
2; NMR spectrum (DMSO-d ₆ ) δppm:
1.59-1.69 (1H, m), 1.90-2.05
(1H, m), 2.67 (1H, dt, J = 4.5H
z, J = 16.2 Hz), 2.81 (1H, ddd, J
= 5.5 Hz, J = 10.9 Hz, J = 16.2 H
z), 2.91 (1H, q, J = 10.3Hz), 3.
00-3.20 (2H, m), 3.20-3.60 (3
H, nd), 3.60-3.80 (4H, m), 4.1
1 (1H, d, J = 10.1Hz), 6.70 (1H,
t, J = 7.3 Hz), 6.91 (1H, d, J = 8.
3Hz), 6.98 (1H, d, J = 7.3Hz),
7.06 (1H, t, J = 8.3Hz), 7.18 (1
H, t, J = 4.3 Hz), 7.79 (1H, d, J =
5.0Hz), 7.89 (1H, d, J = 3.4H
z), 8.98 (1H, brs), 10.71 (1H,
brs).

Example 67 (-)-3- [2- (3-thenoylamino) ethyl]-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-343) (a) (-)-3- [2- ( 3-Thenoylamino) ethyl] -2,3,4,4a, 5,6-hexahydro-1
H-pyrazino [1,2-a] quinoline (-)-3- (2-aminoethyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (0.26 g), 3-thenoyl acid (0.1
5g), diethyl cyanophosphonate (0.18 ml) and triethylamine (0.32 ml) were added in Example 31.
A target compound (0.23 g, 61%) was obtained by reacting in the same manner as in (a) and post-treating. Specific rotation ([α] _D ²⁴ ): −8.7 ^o (C = 1.0
5, EtOH); IR spectrum (KBr) ν _max cm ⁻¹ : 328
5,2936,2812,1639,1603; NMR spectrum (CDCl ₃ ) δppm: 1.7
5-1.94 (2H, m), 2.04 (1H, t, J =
10.6 Hz), 2.32 (1H, dt, J = 3.1H
z, J = 11.4 Hz), 2.63 (2H, t, J =
6.0 Hz), 2.69-3.05 (6H, m), 3.
57 (2H, q, J = 5.7Hz), 3.80 (1H,
dt, J = 2.7 Hz, J = 11.6 Hz), 6.72
(1H, t, J = 7.3 Hz), 6.70 (1H, br
s), 6.81 (1H, d, J = 8.3 Hz), 7.0
0 (1H, d, J = 7.3 Hz), 7.10 (1H,
t, J = 8.2 Hz), 7.32-7.38 (2H,
m), 7.86 (1H, dd, J = 1.3 Hz, J =
3.2 Hz).

(B) (-)-3- [2- (3-Thenoylamino) ethyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride Salt (-)-3- [2- (3-thenoylamino) ethyl]-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (0.22 g) was used in Example 3.
The target compound (0.17 g, 71%) was obtained by performing a reaction and performing a post-treatment in the same manner as in 1 (b). Specific rotation ([α] _D ²⁴ ): -2.7 ^o (C = 1.0
4, EtOH); Melting point: 171-177 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 327
7, 3058, 2938, 2584, 1650, 160
3; NMR spectrum (DMSO-d ₆ ) δppm:
1.57-1.68 (1H, m), 1.90-2.05
(1H, m), 2.67 (1H, dt, J = 4.5H
z, J = 16.1 Hz), 2.81 (1H, ddd, J
= 5.5 Hz, J = 10.9 Hz, J = 16.2 H
z), 2.91 (1H, q, J = 11.1Hz), 3.
00-3.20 (2H, m), 3.20-3.60 (3
H, nd), 3.60-3.80 (4H, m), 4.1
0 (1H, d, J = 11.2Hz), 6.70 (1H,
t, J = 7.3 Hz), 6.91 (1H, d, J = 8.
3Hz), 6.98 (1H, d, J = 7.3Hz),
7.06 (1H, t, J = 8.3Hz), 7.57 (1
H, dd, J = 1.0 Hz, J = 5.0 Hz), 7.6
1 (1H, dd, J = 3.0Hz, J = 4.8Hz),
8.23 (1H, d, J = 1.9Hz), 8.76 (1
H, brs), 10.51 (1H, brs).

Example 68 (+)-3- [2- (3-thenoylamino) ethyl]-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-343) (a) (+)-3- [2- ( 3-Thenoylamino) ethyl] -2,3,4,4a, 5,6-hexahydro-1
H-pyrazino [1,2-a] quinoline (+)-3- (2-aminoethyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (0.25 g), 3-thenoyl acid (0.1
5 g), diethyl cyanophosphonate (0.18 ml) and triethylamine (0.16 ml) were used in Example 31.
A target compound (0.27 g, 73%) was obtained by reacting in the same manner as in (a) and post-treating. Specific rotation ([α] _D ²⁴ ): +9.4 ^o (C = 1.0
0, EtOH); IR spectrum (KBr) ν _max cm ⁻¹ : 328
7,2936,2813,1639,1603; NMR spectrum (CDCl ₃ ) δppm: 1.7
6-1.93 (2H, m), 2.05 (1H, t, J =
10.6 Hz), 2.33 (1H, dt, J = 3.2H
z, J = 11.4 Hz), 2.64 (2H, t, J =
6.0 Hz), 2.68-3.07 (6H, m), 3.
57 (2H, q, J = 5.7Hz), 3.80 (1H,
dt, J = 2.7 Hz, J = 11.6 Hz), 6.71
(1H, t, J = 7.3 Hz), 6.76 (1H, br
s), 6.81 (1H, d, J = 8.3 Hz), 7.0
0 (1H, d, J = 7.3 Hz), 7.10 (1H,
t, J = 8.3 Hz), 7.31-7.38 (2H,
m), 7.86 (1H, dd, J = 1.3 Hz, J =
3.2 Hz).

(B) (+)-3- [2- (3-Thenoylamino) ethyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline monohydrochloride Salt (+)-3- [2- (3-thenoylamino) ethyl]-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (0.26 g) was used in Example 3.
The target compound (0.29 g, quantitative) was obtained by reacting in the same manner as in 1 (b) and post-treating. Specific rotation ([α] _D ²⁴ ): +2.5 ^o (C = 1.0
0, EtOH); Melting point: 174-178 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 328
1,3057,2941,2554,1651,160
2; NMR spectrum (DMSO-d ₆ ) δppm:
1.59-1.69 (1H, m), 1.90-2.05
(1H, m), 2.67 (1H, dt, J = 4.5H
z, J = 16.0 Hz, 2.81 (1H, ddd, J
= 5.5 Hz, J = 10.9 Hz, J = 16.2 H
z), 2.91 (1H, q, J = 11.1Hz), 3.
00-3.20 (2H, m), 3.20-3.60 (3
H, nd), 3.60-3.80 (4H, m), 4.1
1 (1H, d, J = 11.0 Hz), 6.70 (1H,
t, J = 7.3 Hz), 6.91 (1H, d, J = 8.
3Hz), 6.98 (1H, d, J = 7.3Hz),
7.06 (1H, t, J = 8.3Hz), 7.57 (1
H, dd, J = 1.0 Hz, J = 5.0 Hz), 7.6
1 (1H, dd, J = 3.0Hz, J = 4.8Hz),
8.24 (1H, d, J = 1.9Hz), 8.79 (1
H, brs), 10.64 (1H, brs).

Example 69 (-)-3- [4- (2-pyrazinecarbonylamino)
Butyl] -2,3,4,4a, 5,6-hexahydro-
1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-248) (a) (−)-3- [4- (2-pyrazinecarbonylamino) butyl] -2,3,4 , 4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline (−)-3- (4-aminobutyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (0.47 g), 2-pyrazinoyl chloride (0.31 g) and triethylamine (0.30 ml)
Was reacted in the same manner as in Example 2 (a) and post-treated to obtain the target compound (0.55 g, 83%). Specific rotation ([α] _D ²⁴ ): −9.2 ^o (C = 1.0
2, EtOH); IR spectrum (KBr) ν _max cm ⁻¹ : 331
2, 2936, 2812, 1656, 1603; NMR spectrum (CDCl ₃ ) δ ppm: 1.5
5-2.00 (7H, m), 2.20 (1H, J = 3.
2Hz, J = 11.4Hz), 2.42 (2H, t, J
= 7.0 Hz), 2.62-3.13 (6H, m),
3.54 (2H, q, J = 6.3Hz), 3.76 (1
H, dt, J = 2.6 Hz, J = 11.8 Hz), 6.
70 (1H, t, J = 7.3 Hz), 6.79 (1H,
d, J = 8.1 Hz), 6.98 (1H, d, J = 7.
3Hz), 7.06 (1H, t, J = 8.1Hz),
7.99 (1H, brs), 8.50 (1H, dd, J
= 1.5 Hz, J = 2.4 Hz), 8.74 (1H,
d, J = 2.4 Hz), 9.41 (1H, d, J = 1.
5 Hz).

(B) (-)-3- [4- (2-pyrazinecarbonylamino) butyl] -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline monohydrochloride (-)-3- [4- (2-pyrazinecarbonylamino)
Butyl] -2,3,4,4a, 5,6-hexahydro-
1H-pyrazino [1,2-a] quinoline (0.44 g)
Was reacted in the same manner as in Example 2 (b) and post-treated to obtain the target compound (0.48 g, quantitative). Specific rotation ([α] _D ²⁶ ): −9.8 ^o (C = 1.0
2, EtOH); melting point: 190-194 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 336
5,2928,2591,1664,1603; NMR Spectrum (DMSO-d ₆₎ δppm:
1.56-1.68 (3H, m), 1.70-1.83
(2H, m), 1.91-2.00 (1H, m), 2.
66 (1H, dt, J = 4.6Hz, J = 16.1H
z), 2.75-2.86 (2H, m), 3.00-
3.20 (4H, m), 3.20-3.45 (3H, n
d), 3.45-3.65 (2H, m), 4.07 (1
H, d, J = 10.7 Hz), 6.69 (1 H, t, J
= 7.3 Hz), 6.90 (1H, d, J = 8.1H)
z), 6.97 (1H, d, J = 7.3 Hz), 7.0
6 (1H, t, J = 8.1Hz), 8.74 (1H,
t, J = 1.8 Hz), 8.88 (1H, d, J = 2.
3Hz), 9.04 (1H, t, J = 6.0Hz),
9.20 (1H, d, J = 1.4Hz), 10.63
(1H, brs).

Example 70 (+)-3- [4- (2-pyrazinecarbonylamino)
Butyl] -2,3,4,4a, 5,6-hexahydro-
1H-pyrazino [1,2-a] quinoline monohydrochloride (Exemplified compound number: 1-248) (a) (+)-3- [4- (2-pyrazinecarbonylamino) butyl] -2,3,4 , 4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline (+)-3- (4-aminobutyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (0.13 g), 2-pyrazinoyl chloride (0.08 g) and triethylamine (0.08 ml)
Was reacted in the same manner as in Example 2 (a) and post-treated to obtain the target compound (0.16 g, 86%). Specific rotation ([α] _D ²⁴ ): +9.3 ^o (C = 1.0
4, EtOH); IR spectrum (KBr) ν _max cm ⁻¹ : 331
6, 2936, 2812, 1656, 1602; NMR spectrum (CDCl ₃ ) δ ppm: 1.5
5-2.00 (7H, m), 2.20 (1H, J = 3.
2Hz, J = 11.4Hz, 2.41 (2H, t, J
= 7.0 Hz), 2.60-3.12 (6H, m),
3.54 (2H, q, J = 6.3Hz), 3.75 (1
H, dt, J = 2.6 Hz, J = 11.8 Hz), 6.
70 (1H, t, J = 7.3 Hz), 6.79 (1H,
d, J = 8.1 Hz), 6.99 (1H, d, J = 7.
3Hz), 7.07 (1H, t, J = 8.1Hz),
7.98 (1H, brs), 8.50 (1H, dd, J
= 1.5 Hz, J = 2.4 Hz), 8.75 (1H,
d, J = 2.4 Hz), 9.42 (1H, d, J = 1.
5 Hz).

(B) (+)-3- [4- (2-pyrazinecarbonylamino) butyl] -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline monohydrochloride (+)-3- [4- (2-pyrazinecarbonylamino)
Butyl] -2,3,4,4a, 5,6-hexahydro-
1H-pyrazino [1,2-a] quinoline (0.11 g)
Was reacted in the same manner as in Example 2 (b) and post-treated to obtain the target compound (0.12 g, quantitative). Specific rotation ([α] _D ²⁶ ): +9.3 ^o (C = 0.9
9, EtOH); melting point: 190-194 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 339
8,2942,2590,1663,1604; NMR Spectrum (DMSO-d ₆₎ δppm:
1.57-1.68 (3H, m), 1.70-1.83
(2H, m), 1.91-2.00 (1H, m), 2.
66 (1H, dt, J = 4.6Hz, J = 16.2H
z), 2.75-2.86 (2H, m), 3.00-
3.20 (4H, m), 3.20-3.45 (3H, n
d), 3.45-3.65 (2H, m), 4.07 (1
H, d, J = 11.4 Hz), 6.69 (1 H, t, J
= 7.3 Hz), 6.90 (1H, d, J = 8.1H)
z), 6.98 (1H, d, J = 7.3 Hz), 7.0
6 (1H, t, J = 8.1Hz), 8.74 (1H,
t, J = 1.8 Hz), 8.88 (1H, d, J = 2.
3Hz), 9.04 (1H, t, J = 6.0Hz),
9.20 (1H, d, J = 1.4 Hz), 10.70
(1H, brs).

Reference Example 1 3- (4-aminobutyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline 3- (4-phthalimidobutyl) -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline (0.8 g) was dissolved in ethanol (20 ml), 80% hydrazine hydrate (250 μl) was added,
The mixture was heated under reflux for 15.5 hours. After distilling off the solvent under reduced pressure and adding a saturated aqueous sodium hydrogen carbonate solution to the obtained residue,
It was extracted with methylene chloride, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the target compound (0.49 g, 9
2%) as an oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.4
-1.7 (4H, nd), 1.7-2.0 (2H,
m), 1.90 (1H, t, J = 11Hz), 2.18
(1H, dt, J = 11 Hz, J = 3 Hz), 2.38
(2H, t, J = 7Hz), 2.65-3.1 (6H,
m), 2.73 (2H, t, J = 7Hz), 3.76
(1H, d, J = 12Hz), 6.69 (1H, t, J
= 7 Hz), 6.80 (1H, d, J = 8 Hz), 6.
98 (1H, d, J = 7 Hz), 7.09 (1H, t,
J = 8 Hz).

Reference Example 2 3- (3-aminopropyl) -2,3,4,4a, 5
6-Hexahydro-1H-pyrazino [1,2-a] quinoline 3- (3-phthalimidopropyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (426 mg) and 80% hydrazine hydrate (107 μl) were reacted in the same manner as in Reference Example 1 and post-treated to obtain the target compound (209 mg, 75%) as a yellow oily substance. NMR spectrum (CDCl ₃ ) δ ppm: 1.6
-1.95 (4H, m), 1.90 (1H, t, J = 1
1Hz), 2.18 (1H, dt, J = 11Hz, J =
3Hz), 2.44 (2H, t, J = 7Hz), 2.6
5-3.1 (6H, m), 2.78 (2H, t, J = 7)
Hz), 3.76 (1H, dt, J = 12Hz, J = 3)
Hz), 6.69 (1H, t, J = 7Hz), 6.79
(1H, d, J = 8Hz), 6.98 (1H, d, J =
7 Hz), 7.08 (1 H, t, J = 8 Hz).

Reference Example 3 3- (2-Aminoethyl) -2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline 3- (2-phthalimidoethyl) -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline (0.53 g) and 80% hydrazine hydrate (1
80 μl) was reacted in the same manner as in Reference Example 1 and post-treated to obtain the target compound (0.28 g, 83%) as an oily substance. NMR spectrum (CDCl ₃ ) δ ppm: 1.6
5-2.0 (2H, m), 1.96 (1H, t, J = 1
1 Hz), 2.24 (1H, dt, J = 11H, J = 3
Hz), 2.45 (2H, t, J = 6Hz), 2.65
-2.75 (1H, m), 2.75-3.1 (5H,
m), 2.83 (2H, t, J = 6Hz), 3.75
(1H, d, J = 12Hz), 6.69 (1H, t, J
= 7 Hz), 6.80 (1H, d, J = 8 Hz), 6.
98 (1H, d, J = 7 Hz), 7.09 (1H, t,
J = 8 Hz).

Reference Example 4 3- (4-Bromobutyl) -5,5-dimethylthiazolidine-2,4-dione 5,5-dimethylthiazolidine-
2,4-dione (1.5 g) and 1,4-dibromobutane (10.8 g) were dissolved in DMF (30 ml), and 55% oily sodium hydride (450 mg) was added little by little under ice-cooling stirring, Stir at room temperature for 4 hours. The reaction mixture was poured into brine, extracted with ethyl acetate, the extract was washed with water, and dried with anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluent: hexane, then hexane:
Purification using ethyl acetate = 4: 1) gave the target compound (1.89 g, 65%) as an oily substance. NMR spectrum (CDCl ₃ ) δ ppm: 1.7
-1.95 (4H, m), 1.71 (6H, s), 3.
42 (2H, t, J = 7 Hz), 3.65 (2H, t,
J = 7 Hz); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 17
48,1683. Reference Example 5 3- (4-Bromobutyl) -5-isopropylthiazolidine-2,4-dione 5-isopropylthiazolidine-
2,4-dione (0.57 g), 1,4-dibromobutane (3.9 g) and 55% oily sodium hydride (16
0 mg) was reacted in the same manner as in Reference Example 4 and post-treated to obtain the target compound (740 mg, 70%) as an oily substance. NMR spectrum (CDCl ₃ ) δppm: 0.9
5 (3H, d, J = 7Hz), 1.07 (3H, d, J
= 7 Hz), 1.7-1.95 (4H, m), 2.55
-2.7 (1H, m), 3.42 ((2H, t, J = 7
Hz), 3.64 (2H, t, J = 7Hz), 4.26
(1H, d, J = 4 Hz); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 17
49,1683.

Reference Example 6 4-phenylcarbamoylbutyl bromide Aniline (2.28 ml) and triethylamine (3.
84 ml) was dissolved in tetrahydrofuran (100 ml), and 5-bromovaleryl chloride (5.00
g) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were filtered off, the solvent was evaporated under reduced pressure, the obtained residue was suspended in ethyl acetate, washed with water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1) to obtain the target compound (5.95 g, 93%). Rf value: 0.5 (developing agent; hexane: ethyl acetate =
3: 1); NMR spectrum (CDCl ₃ ) δppm: 1.8
-2.0 (4H, m), 2.39 (2H, t, J = 6.
6 Hz, J = 7.3 Hz), 3.42 (2H, t, J =
6.6 Hz, J = 5.9 Hz), 7.10 (1H, t,
J = 7.3 Hz), 7.26-7.34 (2H, m),
7.43 (1H, br.s), 7.51 (2H, d, J
= 7.9 Hz).

Reference Example 7 (-)-2,3,4,4a, 5,6-hexahydro-1
H-pyrazino [1,2-a] quinoline (a) (+)-2- [N- (1-phenylethyl) carbamoyl] -1,2,3,4-tetrahydroquinoline and (-)-2- [ N- (1-phenylethyl) carbamoyl] -1,2,3,4-tetrahydroquinoline 1,2,3,4-tetrahydroquinoline-2-carboxylic acid (30.7 g), (S)-(-)- 1-Phenylethylamine (24.3 ml) and triethylamine (2
6.4 ml) was dissolved in methylene chloride (150 ml) and diethyl cyanophosphonate (28.
9 ml) was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was washed with saturated saline and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was purified using silica gel column chromatography,
(+)-2- [N- (1-phenylethyl) carbamoyl] -1,2,3,4-tetrahydroquinoline (18.
2g, 37%) and (-)-2- [N- (1-phenylethyl) carbamoyl] -1,2,3,4-tetrahydroquinoline (19.3g, 40%). Physical data of (+)-2- [N- (1-phenylethyl) carbamoyl] -1,2,3,4-tetrahydroquinoline Specific rotation ([α] _D ²² ): +80.6 ^o (C = 1 ．
00, CHCl ₃ ); IR spectrum (CHCl ₃ ) ν
_max cm ⁻¹ : 3389, 2934, 1664, 16
08; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
8 (3H, d, J = 7.0 Hz), 1.85-1.97
(1H, m), 2.22-2.33 (1H, m), 2.
42-2.53 (1H, m), 2.63-2.74 (1
H, m), 3.95-4.25 (2H, m), 5.08
-5.20 (1H, m), 6.66 (1H, d, J =
7.9 Hz), 6.73 (1H, t, J = 7.2H
z), 6.97-7.08 (3H, m), 7.13-
7.35 (5H, m). Physical data of (−)-2- [N- (1-phenylethyl) carbamoyl] -1,2,3,4-tetrahydroquinoline Specific optical rotation ([α] _D ²⁴ ): -30.0 ^o (C = 1.
00, CHCl ₃ ); IR spectrum (CHCl ₃ ) ν
_max cm ⁻¹ : 2980, 2943, 2857, 16
83; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
4 (3H, d, J = 6.9 Hz), 1.85-2.00
(1H, m), 2.31-2.42 (1H, m), 2.
53-2.66 (1H, m), 2.73-2.82 (1
H, m), 3.98 (1H, q, J = 5.0 Hz),
4.10 (1H, brs), 5.12-5.23 (1
H, m), 6.60 (1H, d, J = 7.9 Hz),
6.73 (1H, t, J = 7.3Hz), 6.99-
7.07 (3H, m), 7.25-7.37 (5H,
m).

(B) (-)-2- [N- (1-phenylethyl) aminomethyl] -1,2,3,4-tetrahydroquinoline (+)-2 obtained in Reference Example 7 (a). -[N- (1-Phenylethyl) carbamoyl] -1,2,3,4-tetrahydroquinoline (10.77 g) was dissolved in anhydrous tetrahydrofuran (150 ml), and borane-methyl was stirred under ice-cooling under a nitrogen atmosphere. Sulfide complex (1
0.0M, 30 ml) was added dropwise, and the mixture was stirred at room temperature for 3 days. After 6N hydrochloric acid was added to inactivate the excess borane-methyl sulfide complex, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
The organic layer was washed with saturated saline and dried with anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure,
The target compound (8.95 g, 88%) was obtained as a colorless oily substance. Specific rotation ([α] _D ²⁴ ): −54.4 ^° (C = 0.
99, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 3
408, 2963, 2932, 2846, 1605, 1
584; NMR spectrum (CDCl ₃ ) δppm: 1.3
7 (3H, d, J = 6.6Hz), 1.45-1.60
(1H, m), 1.80-1.89 (1H, m), 2.
39 (1H, dd, J = 9.2Hz, J = 11.7H
z), 2.63-2.87 (3H, m), 3.25-
3.35 (1H, m), 3.79 (1H, q, J = 6.
6 Hz), 4.30-4.53 (1H, brs), 6.
50 (1H, d, J = 7.9 Hz), 6.57 (1H,
t, J = 7.3 Hz), 6.91-6.99 (2H,
m), 7.19-7.37 (5H, m).

(C) (-)-2- [N- (1-phenylethyl) -N'-tert-butoxycarbonylaminomethyl] -1,2,3,4-tetrahydroquinoline In Reference Example 7 (b) The obtained (-)-2- [N- (1-phenylethyl) aminomethyl] -1,2,3,4-tetrahydroquinoline (8.75 g) was added to dioxane (100).
ml), di-tert-butyl di-carbonate (8.5 ml) was added dropwise under stirring at room temperature, and the mixture was stirred at room temperature for 2 times.
Stir for hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated saline, and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
The obtained residue was purified by silica gel column chromatography to give the object compound (9.01 g, 7
5%) as a colorless oil. Specific rotation ([α] _D ²⁴ ): −83.3 ^° (C = 3.
42, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 29
80, 2936, 1681, 1605; NMR spectrum (CDCl ₃ ) δ ppm: 1.3
5-1.60 (2H, m), 1.47 (9H, s),
1.52 (3H, d, J = 8.5Hz), 2.53-
2.63 (2H, m), 2.95-3.15 (2H,
m), 3.15-3.30 (1H, m), 4.00-
4.40 (1H, brs), 5.25-5.55 (1
H, m), 6.42 (1H, d, J = 7.9 Hz),
6.56 (1H, t, J = 7.5Hz), 6.87-
6.96 (2H, m), 7.14-7.36 (5H,
m).

(D) (-)-3- (1-phenylethyl) -2,3,4,4a, 5,6-hexahydro-1-
Oxopyrazino [1,2-a] quinoline (−)-2- [N- (1-phenylethyl) -N′-tert-butoxycarbonylaminomethyl] -1,
After 2,3,4-tetrahydroquinoline (9.0 g) was dissolved in tetrahydrofuran (90 ml), pyridine (3.0 ml) and chloroacetyl chloride (2.2 ml) were added dropwise under stirring under ice cooling in a nitrogen atmosphere. The mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
The obtained residue was dissolved in tetrahydrofuran (40 ml), trifluoroacetic acid (50 ml) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, the obtained residue was dissolved in dimethylformamide (50 ml), potassium carbonate (5.6 g) was added, and the mixture was stirred at 50 ° C. for 1 hr. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the target compound (6.08).
g, 81%) as a colorless powder. Specific rotation ([α] _D ²⁴ ): −1.88 ^° (C = 2.
18, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 29
80,2809,1650; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
1 (3H, d, J = 6.6 Hz), 1.81-1.91
(1H, m), 2.07-2.23 (1H, m), 2.
54 (1H, dd, J = 6.1Hz, J = 11.8H
z), 2.79-2.97 (3H, m), 3.26-
3.45 (2H, m), 3.42 (1H, q, J = 6.
6Hz), 3.55-3.64 (1H, m), 7.03
-7.20 (3H, m), 7.22-7.39 (5H,
m), 7.92 (1H, d, J = 7.8Hz).

(E) (-)-3- (1-phenylethyl) -2,3,4,4a, 5,6-hexahydro-1H
-Pyrazino [1,2-a] quinoline (-)-3- (1-phenylethyl) -2,3,4,4a, 5,6-hexahydro- obtained in Reference Example 7 (d)
1-oxopyrazino [1,2-a] quinoline (6.0
g) was dissolved in anhydrous tetrahydrofuran (180 ml), and the borane-methyl sulfide complex (10.0 M, 20 ml) was added dropwise under nitrogen atmosphere with ice-cooling stirring, and the mixture was stirred at room temperature for 4 days. After completion of the reaction, excess borane-methyl sulfide complex was inactivated with 6N hydrochloric acid, the pH of the solution was made alkaline with saturated aqueous sodium hydrogen carbonate solution, and then extracted with ethyl acetate.
The organic layer was washed with saturated saline and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the target compound (4.53 g, 79%).
Was obtained as a colorless powder. Specific rotation ([α] _D ²⁴ ): −33.9 ^o (C = 1.
32, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 29
77, 2936, 2822, 1602; NMR spectrum (CDCl ₃ ) δ ppm: 1.3
9 (3H, d, J = 6.7Hz), 1.69-2.00
(3H, m), 2.10 (1H, dt, J = 3.1H
z, J = 10.9 Hz), 2.65-2.95 (4H,
m), 3.02-3.12 (2H, m), 3.37 (1
H, q, J = 6.7 Hz), 3.61-3.67 (1
H, m), 6.67 (1H, t, J = 7.3 Hz),
6.73 (1H, d, J = 8.3Hz), 6.97 (1
H, d, J = 7.3 Hz), 7.05 (1H, t, J =
8.3 Hz), 7.21-7.39 (5H, m).

(F) (-)-2,3,4,4a, 5
6-Hexahydro-1H-pyrazino [1,2-a] quinoline (-)-3- (1-phenylethyl) -2,3,4,4a, 5,6-obtained in Reference Example 7 (e) Hexahydro-
1H-pyrazino [1,2-a] quinoline (4.48 g)
Was dissolved in methanol (75 ml), and under a nitrogen atmosphere,
10% Palladium-carbon (4.5 g) and ammonium formate (4.8 g) were added at room temperature, and the mixture was heated under reflux for 1 hr. After the catalyst was filtered off, the solvent was distilled off under reduced pressure, saturated saline was added to the obtained residue, the mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (2.25 g, 78%) as an oily substance. Specific rotation ([α] _D ²⁴ ): −20.3 ^° (C = 0.
97, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 29
48, 2839, 1603; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
9-1.99 (3H, m), 2.58-3.15 (8
H, m), 3.75 (1H, dt, J = 2.5Hz, J
= 11.8 Hz), 6.70 (1H, t, J = 7.2H)
z), 6.79 (1H, d, J = 8.2Hz), 6.9.
8 (1H, d, J = 7.2 Hz), 7.08 (1H,
t, J = 8.2 Hz).

Reference Example 8 (+)-2,3,4,4a, 5,6-hexahydro-1
H-pyrazino [1,2-a] quinoline (a) (+)-2- [N- (1-phenylethyl) aminomethyl] -1,2,3,4-tetrahydroquinoline In Reference Example 7 (a) The obtained (−)-2- [N- (1-phenylethyl) carbamoyl] -1,2,3,4-tetrahydroquinoline (9.0 g) was reacted in the same manner as in Reference Example 7 (b), and The target compound (7.
1 g, 83%) was obtained. Specific rotation ([α] _D ²⁴ ): +29.8 ^o (C = 1.
00, EtOH); IR spectrum (KBr) ν _max cm ⁻¹ : 3413,
3395, 2958, 2925, 2842, 1604,
1583; NMR spectrum (CDCl ₃ ) δppm: 1.3
8 (3H, d, J = 6.6 Hz), 1.49-1.66
(1H, m), 1.80-1.90 (1H, m), 2.
44-2.84 (4H, m), 3.16-3.25 (1
H, m), 3.75 (1H, q, J = 6.6 Hz),
4.42 (1H, brs), 6.50 (1H, d, J =
7.9 Hz), 6.58 (1H, t, J = 7.2H
z), 6.91-6.99 (2H, m), 7.21-
7.37 (5H, m).

(B) (-)-2- [N- (1-phenylethyl) -N'-tert-butoxycarbonylaminomethyl] -1,2,3,4-tetrahydroquinoline In Reference Example 8 (a) The obtained (+)-2- [N- (1-phenylethyl) aminomethyl] -1,2,3,4-tetrahydroquinoline (6.01 g) was reacted in the same manner as in Reference Example 7 (c), The target compound (7.2 g, 87%) was obtained by post-treatment. Specific rotation ([α] _D ²⁵ ): -15.8 ^o (C =
1.00, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 33
81, 974, 2928, 2851, 1689, 16
07; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
4-1.72 (2H, m), 1.46 (9H, s),
1.53 (3H, d, J = 8.5Hz), 1.78-
1.88 (1H, m), 2.60-2.82 (2H,
m), 2.95-3.45 (3H, m), 5.30-
5.65 (1H, brs), 6.00-6.25 (1
H, m), 6.54 (1H, t, J = 7.5 Hz),
6.86-6.93 (2H, m), 7.16-7.46
(5H, m).

(C) (+)-3- (1-phenylethyl) -2,3,4,4a, 5,6-hexahydro-1-
Oxopyrazino [1,2-a] quinoline (−)-2- [N- (1-phenylethyl) -N′-tert-butoxycarbonylaminomethyl] -1,2 obtained in Reference Example 8 (b) 3,4-Tetrahydroquinoline (5.40 g) was reacted in the same manner as in Reference Example 7 (d) and post-treated to give the desired compound (3.86 g,
86%). Specific rotation ([α] _D ²⁵ ): +20.3 ^o (C = 1.
00, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 36
20, 2979, 2937, 2900, 1650; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
3 (3H, d, J = 6.7 Hz), 1.82-1.91
(2H, m), 2.31 (1H, dd, J = 8.6H
z, J = 12.0 Hz), 2.81-3.02 (3H,
m), 3.10 (1H, d, J = 16.5 Hz), 3.
43 (1H, q, J = 6.7 Hz), 3.63-3.7.
3 (1H, m), 3.77 (1H, dd, J = 2.4H
z, J = 16.5 Hz), 7.02-7.21 (3H,
m), 7.25-7.50 (5H, m), 8.02 (1
H, d, J = 8.4 Hz).

(D) (-)-3- (1-phenylethyl) -2,3,4,4a, 5,6-hexahydro-1H
-Pyrazino [1,2-a] quinoline (+)-3- (1-phenylethyl) -2,3,4,4a, 5,6-hexahydro- obtained in Reference Example 8 (c)
1-oxopyrazino [1,2-a] quinoline (4.77)
g) was reacted in the same manner as in Reference Example 7 (e) and post-treated to obtain the target compound (4.02 g, 88%). Specific rotation ([α] _D ²⁴ ): −10.6 ^° (C = 1.
00, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 29
78, 2937, 2820, 1732, 1602; NMR spectrum (CDCl ₃ ) δ ppm: 1.3
9 (3H, d, J = 6.7 Hz), 1.57-1.86
(3H, m), 2.24 (1H, dt, J = 3.1H
z, J = 11.3 Hz), 2.59-2.99 (5H,
m), 3.14-3.30 (1H, m), 3.36 (1
H, q, J = 6.7 Hz), 3.79 (1H, dt, J
= 2.8 Hz, J = 11.8 Hz), 6.67 (1H,
t, J = 7.2 Hz), 6.79 (1H, d, J = 8.
2Hz), 6.95 (1H, d, J = 7.2Hz),
7.07 (1H, t, J = 8.2Hz), 7.22-
7.39 (5H, m).

(E) (+)-2,3,4,4a, 5
6-Hexahydro-1H-pyrazino [1,2-a] quinoline (-)-3- (1-phenylethyl) -2,3,4,4a, 5,6-obtained in Reference Example 8 (d) Hexahydro-
1H-pyrazino [1,2-a] quinoline (4.30
g), 10% palladium-carbon (4.30 g) and ammonium formate (4.60 g) were reacted in the same manner as in Reference Example 7 (f) and post-treated to give the target compound (2.1).
8 g, 79%) was obtained. Optical rotation ([α] _D ²⁴ ): +22.0 ^o (C = 1.0
0, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 29
50,2842,1605; NMR spectrum (CDCl ₃ ) δppm: 1.4
5-1.99 (3H, m), 2.58-3.16 (8
H, m), 3.75 (1H, dt, J = 2.5Hz, J
= 11.7 Hz), 6.69 (1H, t, J = 7.3H)
z), 6.79 (1H, d, J = 8.2Hz), 6.9.
8 (1H, d, J = 7.3 Hz), 7.08 (1H,
t, J = 8.2 Hz).

Reference Example 9 (-)-3- (4-aminobutyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (-)-3- (4-phthalimidobutyl) -2,3
4,4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline (1.20 g) and 80% hydrazine hydrate (0.37 ml) were reacted in the same manner as in Reference Example 1 and post-treated. The target compound (0.66
g, 83%). Specific rotation ([α] _D ²⁴ ): −10.3 ^° (C = 0.
99, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 29
41, 2849, 2824, 1602; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
0-1.66 (6H, nd), 1.6-1.94 (2
H, m), 1.90 (1H, t, J = 10.9Hz),
2.18 (1H, dt, J = 3.3Hz, J = 11.4
Hz), 2.38 (2H, t, J = 7.4Hz), 2.
65-3.10 (6H, m), 2.73 (2H, t, J
= 6.6 Hz), 3.75 (1H, d, J = 12.0H
z), 6.68 (1H, t, J = 7.2 Hz), 6.7.
9 (1H, d, J = 8.2 Hz), 6.98 (1H,
d, J = 7.2 Hz), 7.08 (1H, t, J = 8.
2 Hz).

Reference Example 10 (+)-3- (4-aminobutyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (+)-3- (4-phthalimidobutyl) -2,3
4,4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline (1.20 g) and 80% hydrazine hydrate (0.45 ml) were reacted in the same manner as in Reference Example 1 and post-treated. The target compound (0.71
g, 89%). Specific rotation ([α] _D ²⁴ ): +10.2 ^o (C = 1.
00, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 29
41, 2849, 2823, 1602; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
0-1.66 (6H, nd), 1.6-1.95 (2
H, m), 1.90 (1H, t, J = 10.9Hz),
2.19 (1H, dt, J = 3.3Hz, J = 11.4
Hz), 2.38 (2H, t, J = 7.4Hz), 2.
65-3.10 (6H, m), 2.73 (2H, t, J
= 6.6 Hz), 3.75 (1H, d, J = 12.0H
z), 6.67 (1H, t, J = 7.2Hz), 6.7.
8 (1H, d, J = 8.2 Hz), 6.98 (1H,
d, J = 7.2 Hz), 7.07 (1H, t, J = 8.
2 Hz).

Reference Example 11 (-)-3- (2-aminoethyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (-)-3- (2-phthalimidoethyl) -2,3
4,4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline (0.88 g) and 80% hydrazine hydrate (0.31 ml) were reacted in the same manner as in Reference Example 1 and post-treated. The target compound (0.54
g, 96%). Specific rotation ([α] _D ²⁴ ): −11.6 ^o (C = 1.
29, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 29
45, 2823, 1602; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
9 (2H, brs), 1.68-1.99 (2H,
m), 1.95 (1H, t, J = 10.6Hz), 2.
23 (1H, dt, J = 3.2Hz, J = 11.4H
z), 2.44 (2H, t, J = 6.1 Hz), 2.6
5-2.75 (1H, m), 2.75-3.10 (5
H, m), 2.82 (2H, t, J = 6.1 Hz),
3.74 (1H, d, J = 11.8Hz), 6.69
(1H, t, J = 7.3 Hz), 6.79 (1H, d,
J = 8.2 Hz), 6.98 (1H, d, J = 7.3H)
z), 7.08 (1H, t, J = 8.2Hz).

Reference Example 12 (+)-3- (2-aminoethyl) -2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (+)-3- (2-phthalimidoethyl) -2,3
4,4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline (0.80 g) and 80% hydrazine hydrate (0.32 ml) were reacted in the same manner as in Reference Example 1 and post-treated. The target compound (0.51
g, quantitative). Specific rotation ([α] _D ²⁴ ): +12.6 ^o (C = 1.
00, EtOH); IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 294
5,2823,1602; NMR spectrum (CDCl ₃ ) δppm: 1.5
8 (2H, brs), 1.68-2.01 (2H,
m), 1.95 (1H, t, J = 10.6Hz), 2.
24 (1H, dt, J = 3.2Hz, J = 11.4H
z), 2.45 (2H, t, J = 6.1 Hz), 2.6
5-2.75 (1H, m), 2.75-3.10 (5
H, m), 2.83 (2H, t, J = 6.1 Hz),
3.75 (1H, d, J = 11.8 Hz), 6.69
(1H, t, J = 7.3 Hz), 6.80 (1H, d,
J = 8.2 Hz), 6.98 (1H, d, J = 7.3H)
z), 7.09 (1H, t, J = 8.2 Hz).

Reference Example 13 2-Pyrazinoyl chloride-2-pyrazinecarboxylic acid (1.0 g) was suspended in tetrahydrofuran (5 ml), and dimethylformamide (0.4 ml) and oxalyl were stirred under a nitrogen atmosphere under ice-cooling. Chloride (0.83 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure to obtain the target compound (1.15 g, quantitative).

Test Example 1 5-HT _1A Receptor Binding Test Rat (male Wistar rat, body weight 200 to 300)
g, Japan SLC), the brain was removed and the hippocampus was removed. After measuring the weight, 10 times volume of 50 mM Tris-HCl buffer (pH 7.7) was added and homogenized with Polytron. To the pellet obtained by centrifugation (39000 xg, 15 minutes, 4 ° C), 10 volumes of the above buffer solution was added, and
Incubated at 0 ° C for 10 minutes. Again, the pellet obtained by centrifugation was washed once with 10 times the volume of the above buffer solution,
The amount of protein was measured and diluted with the above-mentioned buffer solution so as to be 200 μg protein / ml. Manganese chloride (final concentration 2 mM) was added to the hippocampal membrane suspension thus obtained, and the mixture was incubated at 37 ° C. for 30 minutes. This hippocampal membrane suspension (0.
5 ml) tritium labeled 8-hydroxy-2
-Dipropylaminotetralin (final concentration 0.5 nM, hereinafter abbreviated as [ ³ H] -8-OH-DPAT) and a test compound (10 ^-10 to 10 ^-7 M) were added, and the mixture was incubated at 25 ° C for 40 minutes. . After completion of the incubation, the radioactivity bound to the membrane was measured with a liquid scintillation counter. [ ³ H] -8-OH of test compound at each concentration
From the -DPAT binding inhibition rate, the concentration showing 50% inhibition (I
The _C50 value) was calculated.

Test Example 2 Stress EEG Measurement Method (Effect on α-Band Component of Cerebral Cortex EEG Increased When Subjected to Psychological Stress) 1 group of 4-6 Wistar male adult rats (body weight: 25)
0-350 g, Japan SLC) was used. Basically Iwa
ta and Mikuni's method { Psychopharmacology , Vol. 71, 117 (1980) [ Psychoph
armacology , 71 , 117 (1980).]}.
Under pentobarbital anesthesia (50 mg / kg, i.p.
p. ) To record the electroencephalogram of the animal in the sensorimotor cortex
A pair of silver ball electrodes (diameter: 0.5 mm) was attached, and the ground electrode was fixed to a socket with dental cement, and penicillin G was intramuscularly injected for the purpose of preventing infection. It was used in the experiment after the wound was healed at least 1 week after the operation. In the experiment, grid on the floor (diameter: 5 mm, spacing: 1
0mm) transparent acrylic observation box (200x
Place the animal in a 300x500 mm, stress cage, leave it for 45 seconds, then give an electric shock for 15 seconds (0.3 millisecond duration, 100 V rectangular wave pulse at 10 Hz) to cut off the electric shock and simultaneously raise the animal in a cage. Return to. After repeating this operation about 15 times every minute, put the animal in the stress cage without giving electric shock (mental stress load), record the electroencephalogram for 10 seconds, analyze the frequency, and analyze the power by ATAC450 (Nihon Kohden). ) Was used for analysis.
Separately, the EEG of the same time (10 seconds) was recorded and analyzed in the breeding cage, and only 130% or more of the animals in which the alpha wave band component under stress was in the breeding cage at rest were selected, and paired t -Test test was performed to confirm a significant (P <0.05) increase, and it was used in an experiment for examining drug effects. Each test compound was suspended in 0.5% CMC or 0.5% tragacanth solution, and the concentration was adjusted so that the administration volume was 1 ml / kg. It was administered orally or intraperitoneally. 15, 30, 45, and 60 seconds after administration, the same mental stress as above was applied, and the α band component ratio was determined over time. The average α band component ratio at each time after administration is compared to the average α band component ratio before administration.
The ed t-test was used for the test, and a case where there was a significant decrease (P <0.05) in two consecutive time zones was determined as (+).

As a result of the test, Examples 2, 8, 22, 34,
The compound of 41, 44, 49, 50 or 59 is strong 5
-HT _1A receptor agonistic activity, and also excellent sedative and hallucinogenic effects on mental stress.

Formulation Example 1 Hard Capsules Each of the standard dichotomous hard gelatin capsules contains 100 m
Unit capsules are prepared by charging g of the compound of Example 8, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate, washed and dried to give hard capsules.

[0232]

INDUSTRIAL APPLICABILITY The hexahydropyrazinoquinoline derivative (I) or (II) of the present invention or a pharmacologically acceptable salt thereof has an excellent 5-HT _1A receptor agonistic action, a sedative action against mental stress, or Since it has a hallucinogenic effect and weak toxicity or side effects (especially drowsiness), anxiety, depression,
Hypertension, schizophrenia, sleep disorders, migraine, sexual dysfunction,
Symptoms of motion sickness, dizziness or senile dementia (particularly delirium)
It is useful as a therapeutic drug or a preventive drug (particularly a therapeutic drug) for etc.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/495 AEN A61K 31/495 AEN 31/535 AAH 31/535 AAH AAL AAL AAN AAN ACV ACV C07D 498/04 C07D 498/04 112T (72) Inventor Junichi Sakai 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company (72) Toshiyuki Tonohiro 1-2-2 Hiromachi, Shinagawa-ku, Tokyo 58 Sankyo Co., Ltd. (72) Inventor Masahiko Sugimoto 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Takao Hara 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company (72) Inventor Marie Hisamoto 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company (72) Inventor Hiroshi Honma Hiromachi, Shinagawa-ku, Tokyo Chome No. 2 58 No. Sankyo Co., the company (72) inventor Kazuo Koyama Shinagawa-ku, Tokyo Hiromachi 1-chome, No. 2 58 No. Sankyo shares in the company

Claims (21)

[Claims] 1. A compound represented by the general formula (I): Or a compound represented by the general formula (II): [Wherein R ¹ represents a group having the formula —CO—R ³ , R ² represents a hydrogen atom, or R ¹ and R ² together with the nitrogen atom to which they are bonded are represented by the general formula ( A group having III) or (IV) is shown below: R ³ is a C ₁ -C ₇ alkyl group, a C ₃ -C ₁₀ cycloalkyl group, or a C ₆ -C which may have 1 to 3 substituents selected from the same or different substituent groups A below. ₁₄ aryl groups, the same or different selected from the following substituent group A 1
To C ₇ -C ₄₈ aralkyl group which may have 3 to 3 substituents, mono C ₃ -C ₁₀ cycloalkylamino group, and 1 to 3 substituents selected from the same or different substituent groups A below. 5-membered mono-C ₆ -C ₁₄ arylamino group which may have a group or one substituent selected from the following substituent group A, which may be fused to a benzene ring To a 6-membered aromatic heterocyclic group (the heterocyclic ring contains 1 or 2 heteroatoms selected from the same or different from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom), R ⁴ And R ⁵ are the same or different and each is a hydrogen atom or C ₁
Represents a —C ₆ alkyl group, R ⁶ represents a C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the same or different substituent groups A as described below, Group A is a halogen atom, a C ₁ -C ₆ alkyl group,
Halogeno C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl group, C ₁
-C ₄ alkylthio group, 1 to 3 substituents a have optionally C ₆ -C ₁₄ aryl group (the substituent is halogen, C
₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy),
Hydroxyl group, thiol group, amino group, protected amino group,
A carboxy group, a carboxy C ₁ -C ₄ alkyl group, a formyl group, a C ₂ -C ₅ alkanoyl group, a C ₂ -C ₅ alkoxycarbonyl group, a carbamoyl group, a cyano group or a nitro group, and X represents a methylene or oxygen atom. And m represents an integer of 2 to 6. ] The hexahydropyrazino quinoline derivative which has these, or its pharmacologically acceptable salt. 2. The method according to claim 1, wherein R ³ is C ₁ -C ₄ alkyl group, 1-methylhexyl group, 1-ethylpentyl group, 1-propylbutyl group; cyclopentyl group, cyclohexyl group; halogen, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-
Fluoroethyl, 2,2-difluoroethyl, 2,2
2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl, ethoxymethyl, methylthio, ethylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, hydroxyl group, thiol, amino, acetylamino, carboxy. , Carboxymethyl,
Formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, cyano and nitro, which may have 1 to 3 substituents which may be the same or different, and which may have a phenyl group or a naphthyl group; fluorine, chlorine, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,
From 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano and nitro. A benzyl group optionally having 1 to 3 substituents selected from the same or different from the group consisting of; cyclopentylamino group or cyclohexylamino group; fluorine, chlorine, C _1-
C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C ₁
-C ₄ alkoxy, methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4
-A phenylamino group optionally having 1 to 3 substituents selected from the same or different from the group consisting of methoxyphenyl, cyano and nitro; or halogen, C ₁ -C
₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C _1-
C ₄ alkoxy, methoxymethyl, ethoxymethyl, methylthio, ethylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, hydroxyl group, thiol, amino, acetylamino, carboxy,
Pyrolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl, which may have one substituent selected from the group consisting of carboxymethyl, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, cyano and nitro. A hexahydropyrazinoquinoline derivative having the general formula (I), which is a group, an indolyl group, a quinolyl group, a furyl group or a thienyl group, or a pharmaceutically acceptable salt thereof. ^{3. The} butyl group, isobutyl group, s-butyl group, t-butyl group, 1-ethylpentyl group; cyclopentyl group or cyclohexyl group; fluorine, chlorine, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl,
1-3 selected from the same or different group selected from the group consisting of methylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano and nitro.
Phenyl group which may have one substituent; benzyl group, fluorobenzyl group, chlorobenzyl group, difluorobenzyl group, dichlorobenzyl group, trifluoromethylbenzyl group, methylbenzyl group, dimethylbenzyl group, trimethylbenzyl group, Methoxybenzyl group, cyanobenzyl group, nitrobenzyl group; cyclohexylamino group; phenylamino group, fluorophenylamino group, chlorophenylamino group, difluorophenylamino group, dichlorophenylamino group, trifluoromethylphenylamino group, tolylamino group, xylylamino group , Meshichiruamino group, methoxyphenyl group, a cyano-phenylamino group or a nitro phenylamino group; or, fluorine, chlorine, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoperazine Methyl, 2-fluoroethyl,
From 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano and nitro. May have one substituent selected from the group consisting of:
A hexahydropyrazinoquinoline derivative having the general formula (I), which is a pyridyl group, a pyrazinyl group, an indolyl group, a quinolyl group, a furyl group or a thienyl group, or a pharmaceutically acceptable salt thereof. 4. The method according to claim 1, wherein R ³ is a t-butyl group,
1-ethylpentyl group, cyclohexyl group, phenyl group, fluorophenyl group, chlorophenyl group, difluorophenyl group, dichlorophenyl group, trifluoromethylphenyl group, tolyl group, xylyl group, mesityl group, methoxyphenyl group, cyanophenyl group, nitro Phenyl group, benzyl group, phenylamino group, 2,4-difluorophenylamino group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, pyrazinyl group, 3-methylpyrazinyl group, 1-methyl-2-indolyl group , 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 2-furyl group,
3-furyl group, 2-thienyl group, 3-thienyl group, 5-
Fluoro-2-thienyl group, 5-chloro-2-thienyl group, 3-methyl-2-thienyl group, 5-methyl-2-thienyl group, 3-methoxy-2-thienyl group, 5-fluoro-3-thienyl group Group, 5-chloro-3-thienyl group, 4
-Methyl-3-thienyl group, 5-methyl-3-thienyl group, 4-methoxy-3-thienyl group or 5-methoxy-
A hexahydropyrazinoquinoline derivative having the general formula (I), which is a 3-thienyl group, or a pharmaceutically acceptable salt thereof. 5. The method according to claim 1, wherein R ³ is a phenyl group or 2
-Fluorophenyl group, 3-fluorophenyl group, 4-
Fluorophenyl group, 2,3-difluorophenyl group,
2,4-difluorophenyl group, 2,5-difluorophenyl group, 2,6-difluorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group,
3,4-dichlorophenyl group, p-tolyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2-methoxyphenyl group, 3-pyridyl group,
Pyrazinyl group, 1-methyl-2-indolyl group, 4-quinolyl group, 2-furyl group, 2-thienyl group, 3-thienyl group, 5-chloro-2-thienyl group, 3-methyl-2-
A hexahydropyrazinoquinoline derivative having the general formula (I), which is a thienyl group, a 5-methyl-2-thienyl group or a 4-methoxy-3-thienyl group, or a pharmaceutically acceptable salt thereof. 6. The method according to claim 1, wherein R ³ is a phenyl group,
2,3-difluorophenyl group, 2,4-difluorophenyl group, 2,5-difluorophenyl group, 3,4-dichlorophenyl group, pyrazinyl group, 2-thienyl group, 3
-Thienyl group, 5-chloro-2-thienyl group, 3-methyl-2-thienyl group, 5-methyl-2-thienyl group or 4-methoxy-3-thienyl group, which has the general formula (I) A hydropyrazinoquinoline derivative or a pharmacologically acceptable salt thereof. 7. The method according to claim 1, wherein R ³ is a phenyl group,
A hexahydropyrazinoquinoline derivative having the general formula (I), which is a 2,4-difluorophenyl group, a pyrazinyl group, a 2-thienyl group or a 5-methyl-2-thienyl group, or a pharmaceutically acceptable salt thereof. 8. The method according to claim 1, wherein R ¹ and R ² together with the nitrogen atom to which they are attached are 2,4-dioxo-3-.
Thiazolydyl group, 5-mono C ₁ -C ₄ alkyl-2,4
- dioxo-3-thiazolidyl group or 5,5-di-C ₁ -
A hexahydropyrazinoquinoline derivative having the general formula (I), which is a C ₄ alkyl-2,4-dioxo-3-thiazolidyl group or a phthalimidyl group, or a pharmaceutically acceptable salt thereof. 9. The method according to claim 1, wherein R ¹ and R ² together with the nitrogen atom to which they are attached are 2,4-dioxo-3-.
Thiazolydyl group, 5-methyl-2,4-dioxo-3-
Thiazolidyl group, 5,5-dimethyl-2,4-dioxo-3-thiazolidyl group, 5-methyl-5-ethyl-2,
4-dioxo-3-thiazolidyl group, 5-ethyl-2,
4-dioxo-3-thiazolidyl group, 5,5-diethyl-2,4-dioxo-3-thiazolidyl group or 5-isopropyl-2,4-dioxo-3-thiazolidyl group, having general formula (I) A hexahydropyrazinoquinoline derivative or a pharmacologically acceptable salt thereof. 10. The method according to claim 1, wherein R ¹ and R ² together with the nitrogen atom to which they are attached are 2,4-dioxo-3.
-Thiazolidyl group, 5,5-dimethyl-2,4-dioxo-3-thiazolidyl group or 5-isopropyl-2,4
A general formula (I) which is a -dioxo-3-thiazolidyl group.
A hexahydropyrazinoquinoline derivative having: or a pharmacologically acceptable salt thereof. 11. The method according to claim 1, wherein R ¹ and R ² together with the nitrogen atom to which they are attached are 5,5-dimethyl-
A hexahydropyrazinoquinoline derivative having the general formula (I), which is a 2,4-dioxo-3-thiazolidyl group or a 5-isopropyl-2,4-dioxo-3-thiazolidyl group, or a pharmaceutically acceptable salt thereof. 12. The method according to claim 1, wherein R ⁶ is fluorine, chlorine,
C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2
- difluoroethyl, 2,2,2-trifluoroethyl, C ₁ -C ₄ alkoxy, methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, from the group consisting of cyano and nitro A hexahydropyrazinoquinoline derivative having the general formula (II) or a pharmaceutically acceptable salt thereof, which is a phenyl group which may have 1 to 3 substituents which are the same or different and are selected from each other. 13. The method according to claim 1, wherein R ⁶ is a phenyl group,
2-fluorophenyl group, 3-fluorophenyl group, 4
-Fluorophenyl group, 2,3-difluorophenyl group, 2,4-difluorophenyl group, 2,5-difluorophenyl group, 2,6-difluorophenyl group, 3,5
Hexahydro having the general formula (II), which is a difluorophenyl group, a 3,4-dichlorophenyl group, a p-tolyl group, a 3-trifluoromethylphenyl group, a 4-trifluoromethylphenyl group or a 2-methoxyphenyl group. A pyrazinoquinoline derivative or a pharmacologically acceptable salt thereof. 14. The hexahydropyrazinoquinoline derivative having the general formula (II), wherein R ⁶ is a phenyl group according to claim 1, or a pharmaceutically acceptable salt thereof. 15. The hexahydropyrazinoquinoline derivative according to claim 1, wherein X is methylene, or a pharmaceutically acceptable salt thereof, according to one of claims 1 to 14. 16. The hexahydropyrazinoquinoline derivative according to claim 1, wherein m is an integer of 2 to 4, or a pharmacologically acceptable salt thereof. 17. The hexahydropyrazinoquinoline derivative according to claim 1, wherein m is 2, or a pharmaceutically acceptable salt thereof. 18. The hexahydropyrazinoquinoline derivative according to claim 1, wherein m is 4, or a pharmaceutically acceptable salt thereof. 19. The protective group of the "protected amino group" according to claim 1, wherein the protecting group is a formyl group, a C ₂ -C ₇ alkanoyl group; a halogen or a C ₁ -C ₄ alkoxy-substituted C group.
₂ -C ₅ alkanoyl group; unsaturated C ₂ -C ₅ alkanoyl group; a halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₂ -C ₅ alkoxycarbonyl, C ₆ -C ₁₄
C ₇ -C ₁₅ arylcarbonyl group which may be substituted with aryl or nitro; C ₂ -C ₅ alkoxycarbonyl group which may be substituted with halogen or tri-C ₁ -C ₄ alkylsilyl; C ₃ -C ₆ alkenyloxycarbonyl group, C ₈ -C ₁₆ aryl dicarbonyl groups; C ₇ -C ₄₈ aralkyl group; a or methoxy or nitro-substituted C ₈ -C ₅₀ optionally aralkyloxycarbonyl group hexa A hydropyrazinoquinoline derivative or a pharmacologically acceptable salt thereof. 20. 3- (2-Benzamidoethyl) -2,
3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline, 3- (4-benzamidobutyl) -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline, 3- [4- (2,4-difluorobenzamido) butyl] -2,3,4,4a, 5,6-hexahydro-1H
-Pyrazino [1,2-a] quinoline, 3- [4- (2-pyrazinecarbonylamino) butyl]
-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline, 3- [4- (2-thenoylamino) butyl] -2,3
4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline, 3- [4- (5-methylthiophene-2-carbonylamino) butyl] -2,3,4,4a, 5 , 6-hexahydro-1H-pyrazino [1,2-a] quinoline, 3- [4- (5,5-dimethyl-2,4-dioxothiazolidin-3-yl) butyl] -2,3,4, 4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline or 3- [4- (5-isopropyl-2,4-dioxothiazolidin-3-yl) butyl] -2,3,4,4a,
5,6-Hexahydro-1H-pyrazino [1,2-a]
Quinoline or a pharmacologically acceptable salt thereof. 21. A 5-HT _1A receptor agonist comprising the hexahydropyrazinoquinoline derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 20 as an active ingredient.