JP2003313167A - New heterocyclic derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a soluble β-amyloid precursor protein secretion promoter efficacious in treating neurodegenerative diseases and nerve cell damage at cerebrovascular disorder. <P>SOLUTION: The above purpose can be achieved by using a new compound expressed by formula (I) (R<SP>1</SP>and R<SP>2</SP>are each H, a lower alkyl, or the like; Ar<SP>1</SP>and ring B are each a (substituted) aromatic group; ring A is a (substituted) benzene ring; ring C is a 4 to 8-membered ring which may have substituents or may be condensed with a ring optionally having substituents; X is CH or N; and Y is CH or N), its salt or its prodrug. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a medicine, particularly Alzheimer's disease, Parkinson's disease, Down's syndrome, amyotrophic lateral sclerosis, prion disease (Kreuzfeld-Jakob disease),
The present invention relates to a soluble beta-amyloid precursor protein secretagogue and an apoptosis inhibitor, which are effective in the treatment of neurodegenerative diseases such as Huntington's disease, neuropathy (preferably diabetic neuropathy, etc.) and nerve cell disorders at the time of cerebrovascular disorder.

[0002]

2. Description of the Related Art A drug that suppresses the neuronal cell death in the neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease and stops the progression of the disease has not been developed. Alzheimer's disease is a disease characterized by the formation of senile plaques and neurofibrillary tangles along with neuronal degeneration and loss. Senile plaque, which is the most characteristic brain pathological image of this disease, is a beta-amyloid protein (hereinafter also abbreviated as Aβ) which is a metabolite of beta-amyloid precursor protein (hereinafter sometimes abbreviated as βAPP). ) Are extracellular deposits (Biochem. Biophys. Res. Commun.
122 , 1131 (1984); Proc. Natl. Acad. Sci. USA. 82 ,
4245 (1985); J. Neurochem. 46 , 1820 (1986); Neuron
6 , 487 (1991)). A consisting of 40 or 42 amino acids
β is toxic to nerve cells (Science 250 ,
279 (1990); Brain Res. 563 , 311 (1991); J. Neurosc
i. 12 , 376 (1992)), induces neurofibrillary tangles (Proc.
Natl. Acad. Sci. USA. 90 , 7789-7793 (1993)). βAPP is not only metabolized to Aβ,
Metabolites are also metabolized so that Aβ is not produced. Soluble beta amyloid precursor protein (soluble APP, sAPP
Is sometimes abbreviated) is secreted extracellularly (Science 24
8 , 492 (1990); Science 248 , 1122 (1990)). It has been reported that sAPP promotes neurotrophic factor action, that is, promotes nerve fiber elongation and suppresses neuronal cell death, using primary cultured neuronal cells or neuroblastoma PC12 cells (Neuron 9 , 129 (1992); Neuron 10 , 243 (199
3); Physiol. Rev. 77 , 1081 (1997)). Decreased sAPP levels in cerebrospinal fluid in patients with Alzheimer's disease have also been reported (Lancet 340 , 453 (1992); Ann. Neurol. 3
2 , 215 (1992); Proc. Natl. Acad. Sci. USA 89 , 2551
(1992); Alzheimer Disease and Associated Disorder
s 11 , 201 (1997)), therefore, in Alzheimer's disease, β
That APP metabolism leans towards Aβ production, not sAPP,
That is, it is presumed that the increase of Aβ which is a cytotoxin, the extracellular accumulation, and the decrease of sAPP which is a neurotrophic factor have extremely important functions for the onset of disease. Therefore, a compound that increases sAPP production / secretion in nervous system tissue is sA
Through the neurotrophic factor action of PP, it is expected to be used as a prophylactic / therapeutic drug for various neurodegenerative diseases because it reduces nerve cell damage due to various causes and suppresses nerve cell death. It is also possible to suppress the production of Aβ, and in particular, it is expected as a preventive / therapeutic drug for Alzheimer's disease (J. Biol. Chem. 268 , 22959 (1993); A
nn. New York Acad. Sci. 777 , 175 (1997)). actually,
Phorbol ester, an activator of protein kinase C (sometimes abbreviated as PKC) is a powerful
It is known to suppress not only sAPP secretion promoting action but also Aβ production and secretion (Proc. Natl. Acad. Sci. USA.
87 , 6003 (1990); Proc. Natl. Acad. Sci. USA. 90 , 9
195 (1993); J. Neurochem. 61 , 2326 (1993); J. Bio
l. Chem. 269 , 8376 (1994)). Therefore, attempts have been made to increase sAPP using various cells and brain tissue sections. For example, in addition to the above phorbol ester, M1
Muscarinic Receptor-Agonist (Science 258 , 30
4 (1992); Proc. Natl. Acad. Sci. USA. 89 , 10075 (1
992); J. Neurosci. 15 , 7442 (1995)), glutamate agonist (Proc. Natl. Acad. Sci. USA. 92 , 8083 (19)
95), and further serotonin agonists (J. Biol. Chem. 23 ,
4188 (1996) has been reported to promote sAPP secretion, and each agonist activates PKC, tyrosine phosphatase (tyrosine kinase) or phospholipase A2 (phospholipase A2) through its receptor. Is believed to be due to.

[0003]

From this point of view,
It was expected to find a sAPP secretagogue that could replace the above compounds.

[0004]

[Means for Solving the Problems] The inventors of the present invention have conducted diligent research and conducted research into the formula (I).

[Chemical 20] [Wherein R ¹ and R ² are the same or different,
A hydrogen atom, a lower alkyl group which may have a substituent or a hydroxy group which may have a substituent, or
R ¹ and R ² bond together to form a 4- to 7-membered ring with the adjacent carbon atom, Ar ¹ represents an aromatic group which may have a substituent, and A ring has a substituent. Represents a benzene ring which may be substituted, B ring represents an aromatic ring which may have a substituent, and C ring may be condensed with a ring which may further have a substituent. Represents a 4- to 8-membered ring which may be represented, X represents CH or N, Represents a single bond or a double bond, Y represents CH or N when the bond is a single bond, and Y represents C when the bond is a double bond. ] It was discovered that the novel compound represented by the formula [1] or a salt thereof or a prodrug thereof unexpectedly has an action of promoting the secretion of soluble beta-amyloid precursor protein, and these compounds have excellent apoptosis inhibitory action and nerve function. It was found that it has a disorder improving effect. Further, the present inventors, these compounds and the like by these actions, Alzheimer's disease, Parkinson's disease, prion disease or neuropathy (preferably diabetic neuropathy, etc.) neurodegenerative diseases, senile dementia, cerebrovascular dementia, The inventors have also found that they are useful as prophylactic / therapeutic agents for nerve cell disorders during cerebrovascular disorders, and completed the present invention based on these findings.

That is, the present invention is based on the equation (1) (I)

[Chemical 21] [Wherein R ¹ and R ² are the same or different,
A hydrogen atom, a lower alkyl group which may have a substituent or a hydroxy group which may have a substituent, or
R ¹ and R ² bond together to form a 4- to 7-membered ring with the adjacent carbon atom, Ar ¹ represents an aromatic group which may have a substituent, and A ring has a substituent. Represents a benzene ring which may be substituted, B ring represents an aromatic ring which may have a substituent, and C ring may be condensed with a ring which may further have a substituent. Represents a 4- to 8-membered ring which may be represented, X represents CH or N, Represents a single bond or a double bond, Y represents CH or N when the bond is a single bond, and Y represents C when the bond is a double bond. ] The compound or its salt represented by these, or its prodrug, (2) Formula (I ')

[Chemical formula 22] [Wherein R ¹ and R ² are the same or different,
It represents a hydrogen atom or a lower alkyl group which may have a substituent, or R ¹ and R ² bond together to form a 4- to 7-membered ring with the adjacent carbon atom, and Ar ¹ has a substituent. An optionally aromatic group, a ring A is a benzene ring which may have a substituent, a ring B is an aromatic ring which may have a substituent, and a ring C has a substituent. Is a 4- to 8-membered ring, X is CH or N, and Y is CH.
Or N is shown. ] The compound or its salt represented by these, or its prodrug, (3) Formula

[Chemical formula 23] [In the formula, B ring, C ring, and X have the same meanings as described in (1) above. ] Is the partial structure

[Chemical formula 24] [In the formula, R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group which may have a substituent or a lower alkoxy group which may have a substituent, and the B ′ ring has a substituent. Optionally represents a benzene ring, X represents CH or N, Z represents an oxygen atom, a sulfur atom, CR ⁴ R ⁵ , NR ⁶ or

[Chemical 25] (R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different,
It represents a hydrogen atom or a lower alkyl group which may have a substituent. ), M is 0 to 1, and n is 1 to
Indicates an integer of 4. ] The compound of the above (1) or a salt thereof or a prodrug thereof, wherein (4) C ring is B
The compound according to the above (1) or a salt thereof or a prodrug thereof, which is a ring in which a single ring is condensed in addition to the ring, (5) The compound or a salt thereof according to (1), wherein R ¹ is a hydrogen atom. Or its prodrug, (6) R
¹ is a hydroxy group, an alkoxy group which may have a substituent or an acyloxy group which may have a substituent, or a salt thereof or a prodrug thereof, (7) R ² Is a hydrogen atom or a lower alkyl group which may have a substituent, or a salt thereof or a prodrug thereof, (8)
Ar ¹ is a monocyclic aromatic group which may have a substituent, the compound or salt thereof described in (1) or a prodrug thereof, (9) Ar ¹ may have a substituent, respectively. Or a salt thereof or a prodrug thereof, which is a good phenyl group, a furyl group, a thienyl group or a pyridyl group, or (10) a compound of the above (1) wherein ring A is an unsubstituted benzene ring or A salt or a prodrug thereof, (11) a compound or a salt thereof or a prodrug thereof according to (1), wherein at least one of X and Y is N, (12) X is N, and Y is C. A certain compound described in (1) or a salt thereof or a prodrug thereof, (13) R ¹ is a hydrogen atom,
An alkyloxy group or an acyloxy group, R ² is a hydrogen atom or a lower alkyl group which may have a substituent, and Ar ¹ has a phenyl group which may have a substituent, or a substituent An optionally substituted furyl group, an optionally substituted thienyl group or an optionally substituted pyridyl group, wherein ring A is an unsubstituted benzene ring and ring B is substituted. Is a benzene ring which may be C
The ring is a nitrogen-containing 5 to 7-membered heterocyclic ring which may be condensed with an unsubstituted benzene ring and may have a substituent, X
Is N and Y is CH, or a salt thereof or a prodrug thereof, (14) R ¹ is a hydrogen atom or an acyloxy group, and R ² is an unsubstituted C _1-6 alkyl. Group, Ar ¹ is a phenyl group which may be substituted with an optionally halogenated C _1-6 alkoxy group, A ring is an unsubstituted benzene ring, and B ring is an unsubstituted benzene Ring and C ring is tetrahydropyrrole, hexahydropyridine, hexahydropyrazine,
Tetrahydro-1,4-oxazine, tetrahydro-
1,4-thiazine, perhydroazepine or pyrrole, X is N and Y is CH, or a compound or salt thereof or a prodrug thereof, (1
5) (−)-2,4-cis-1- (3,4-dimethoxybenzoyl) -2-
Methyl-4- (1,2,3,4-tetrahydroquinolin-1-yl) -1,
2,3,4-tetrahydroquinoline, (−)-2,4-cis-4- (3,4-
Dihydro-2H-1,4-benzoxazin-4-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline, 2,4-cis-1- (3,4-dimethoxybenzoyl) -2-
Methyl-4- (1,2,3,4-tetrahydroquinolin-1-yl) -1,
2,3,4-tetrahydroquinoline, 2,3-trans-2,4-cis-
3-acetoxy-1- (3,4-dimethoxybenzoyl) -2-methyl
-4- (1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4-
Tetrahydroquinoline, 2,4-cis-4- (3,4-dihydro-2H-
1,4-benzothiazin-4-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline, 2,4-
Cis-4- (1-benzyl-1,2,3,4-tetrahydroquinoxalin-4-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl-
1,2,3,4-tetrahydroquinoline, 2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4- (2,3,4,5-tetrahydro
-1H-1-benzazepinyl) -1,2,3,4-tetrahydroquinoline, 2,3-trans-2,4-cis-3-{[(benzylamino)
Carbonyl] oxy} -1- (3,4-dimethoxybenzoyl) -2
-Methyl-4- (2,3,4,5-tetrahydro-1H-1-benzazepinyl) -1,2,3,4-tetrahydroquinoline, 2,4-cis-4- (9H
-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline, (−)-2,4-cis-4
-(9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl)-
2-Methyl-1,2,3,4-tetrahydroquinoline, or 2-butyl-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2-dihydroquinoline or their The compound according to (1) above, which is a salt or a prodrug thereof.
(16) In the formula (I), the compound or a salt thereof or a prodrug thereof according to the above (1), wherein the configurations of the 2-position and 4-position are cis-forms.

Equation (17)

[Chemical formula 26] [Wherein R ¹ and R ² are the same or different,
A hydrogen atom, a lower alkyl group which may have a substituent or a hydroxy group which may have a substituent, or
R ¹ and R ² bond together to form a 4- to 7-membered ring with the adjacent carbon atom, Ar ¹ represents an aromatic group which may have a substituent, and A ring has a substituent. Is a benzene ring, and Q ¹ is a reactive substituent. ] The compound or its salt represented by

[Chemical 27] [In the formula, ring B represents an aromatic ring which may have a substituent, and ring C may further have a ring which may have a substituent and may have a substituent. Is a 4- to 8-membered ring. ] The compound represented by these or its salt is made to react, Formula

[Chemical 28] [In the formula, R ¹ , R ² , Ar ¹ , A ring, B ring and C ring have the same meanings as described above. ] The manufacturing method of the compound represented by these, its salt, or its prodrug, (18) Formula

[Chemical 29] [Wherein R ¹ and R ² are the same or different,
A hydrogen atom, a lower alkyl group which may have a substituent or a hydroxy group which may have a substituent, or
R ¹ and R ² bond together to form a 4- to 7-membered ring with the adjacent carbon atom, Ar ¹ represents an aromatic group which may have a substituent, and A ring has a substituent. Represents a good benzene ring. ] The compound or its salt represented by

[Chemical 30] [In the formula, Q ² represents a reactive substituent, ring B represents an aromatic ring which may have a substituent, and ring C further comprises a ring which may further have a substituent. Also represents a 4- to 8-membered ring which may have a substituent. ] The compound represented by these or its salt is made to react, Formula

[Chemical 31] [In the formula, R ¹ , R ² , Ar ¹ , A ring, B ring and C ring have the same meanings as described above. ] The manufacturing method of the compound or its salt represented by these, or its prodrug, (19) Formula

[Chemical 32] [In the formula, R ² represents a hydrogen atom, a lower alkyl group which may have a substituent or a hydroxy group which may have a substituent, and Ar ¹ represents an aromatic group which may have a substituent. Represents a group group, and ring A represents a benzene ring which may have a substituent. ] The compound or its salt represented by

[Chemical 33] [In the formula, ring B represents an aromatic ring which may have a substituent, and ring C may further have a ring which may have a substituent and may have a substituent. Is a 4- to 8-membered ring. ] The compound or its salt represented by

[Chemical 34] [In the formula, R ² , Ar ¹ , A ring, B ring and C ring have the same meanings as described above. ] The compound or its salt represented by these is manufactured, and if necessary, the hydroxy group in the said formula is replaced with R
¹ [R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a hydroxy group which may have a substituent. ] To a group represented by
formula

[Chemical 35] [In the formula, R ¹ , R ² , Ar ¹ , A ring, B ring and C ring have the same meanings as described above. ] The manufacturing method of the compound represented by these, its salt, or its prodrug, (20) Formula

[Chemical 36] [Wherein R ¹ and R ² are the same or different,
A hydrogen atom, a lower alkyl group which may have a substituent or a hydroxy group which may have a substituent, or
R ¹ and R ² bond together to form a 4- to 7-membered ring with adjacent carbon atoms, ring A represents a benzene ring which may have a substituent, and ring B may have a substituent. It represents a good aromatic ring, and the C ring may be condensed with a ring which may further have a substituent, and may have a substituent 4 to 8
Indicates a member ring. ] The compound or its salt represented by the formula A
r ¹ COOH [In the formula, Ar ¹ represents an aromatic group which may have a substituent. ] The compound represented by these or its salt is made to react, Formula

[Chemical 37] [In the formula, R ¹ , R ² , Ar ¹ , A ring, B ring and C ring have the same meanings as described above. ] The manufacturing method of the compound or its salt represented by these, or its prodrug, (21) Formula

[Chemical 38] [In the formula, R ² represents a hydrogen atom, a lower alkyl group which may have a substituent or a hydroxy group which may have a substituent, and Ar ¹ represents an aromatic group which may have a substituent. Group A, ring A represents a benzene ring which may have a substituent, ring B represents an aromatic ring which may have a substituent, and ring C further has a substituent. Is a 4- to 8-membered ring which may be condensed and may have a substituent. ] The compound or its salt represented by these is made to react with a base, Formula

[Chemical Formula 39] [In the formula, R ² , Ar ¹ , the A ring, the B ring and the C ring have the same meanings as described above, and R ¹ represents a hydrogen atom. ] The manufacturing method of the compound or its salt represented by this, or its prodrug (22) The pharmaceutical composition containing the compound or its salt, or its prodrug as described in said (1), (23).
(22) The pharmaceutical composition according to the above (22), which is a soluble beta-amyloid precursor protein secretagogue and / or an apoptosis inhibitor, (24) Alzheimer's disease, Parkinson's disease, neuropathy, senile dementia, neuronal cell disorder at the time of cerebrovascular disorder Alternatively, for the pharmaceutical composition according to the above (22), which is a preventive and / or therapeutic agent for cerebrovascular dementia, (25) for a human or other mammal, the compound according to the above (1) or a salt thereof, or a prodrug thereof. A therapeutic method comprising administering a pharmaceutical composition containing a drug, which is a soluble beta-amyloid precursor protein secretagogue and / or apoptosis inhibitor, in an effective amount, (26) to humans or other mammals And a pharmaceutical composition comprising the compound according to (1) above, a salt thereof or a prodrug thereof. Preventing and / or treating neurodegenerative diseases or neuronal disorder comprising administering effective amounts, with respect to (27) human or other mammal,
Prevention and / or treatment of Alzheimer's disease, Parkinson's disease, neuropathy, senile dementia, neuronal cell damage at the time of cerebrovascular disorder or cerebrovascular dementia, which comprises the compound according to (1) or a salt thereof or a prodrug thereof. (28) a method for producing a pharmaceutical composition which is a soluble beta-amyloid precursor protein secretagogue and / or an apoptosis inhibitor, which comprises administering an effective amount of a pharmaceutical composition which is an agent; ) Use of a compound or a salt thereof or a prodrug thereof described in (2),
9) Use of the compound according to the above (1) or a salt thereof or a prodrug thereof for producing a pharmaceutical composition which is a prophylactic and / or therapeutic agent for neurodegenerative disease or nerve cell disorder, (30) Alzheimer's disease, Parkinson's disease Disease, neuropathy, senile dementia, neuronal disorder at the time of cerebrovascular disorder or cerebrovascular dementia, or a salt thereof, or a salt thereof, for producing a pharmaceutical composition which is a preventive and / or therapeutic agent. Regarding the use of prodrugs.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The "lower alkyl group" of the "lower alkyl group optionally having substituent (s)" represented by R ¹ and R ² is, for example, C _1-6 alkyl (eg, methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the like. Preferred are methyl, ethyl and propyl.

In the above formula, the "substituent" of the "lower alkyl group which may have a substituent" represented by R ¹ and R ² is, for example, a halogen atom (eg, fluorine, chlorine, bromine, Iodine, etc.), nitro, cyano, C _1-6 alkyl-
C _6-10 aryl-C _2-6 alkenyl (eg, methylphenylethenyl, etc.), C _1-6 alkyl-carbamoyl-C _2
-6 alkenyl (eg, propylcarbamoylpentenyl, etc.), optionally halogenated C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 Alkylthio, hydroxy, optionally substituted C _6-10 aryloxy, C _6-10 aryl-C _7-16 aralkyloxy (eg, phenylbenzyloxy etc.), amino, mono-C _1-6 alkyl Amino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-C _1-6 alkylamino (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), 5- to 7-membered saturated cyclic amino which may have a substituent, acyl, acylamino, acyloxy, which has a substituent _Optionally C _6-10 aryl, C _6-10 aryl-C _1-6 alkyloxy (eg,
Phenylmethyloxy), silyloxy which may have a substituent, and the like, and among them, a halogen atom, an optionally halogenated C _1-6 alkoxy, an optionally halogenated C _1-6 alkylthio. , Hydroxy,
Optionally substituted C _6-10 aryloxy, acyl, acyloxy, mono-C _1-6 alkylamino, di-
C _1-6 alkylamino, amino, acylamino, C _6-10
Aryl, C _6-10 aryl-C _1-6 alkyloxy and the like are preferable.

"Lower alkyl group" of "lower alkyl group optionally having substituent (s)" represented by R ¹ and R ^2.
May have, for example, 1 to 13, preferably 1 to 5, the above-mentioned substituents at substitutable positions of a lower alkyl group. When the number of substituents is 2 or more, each substituent is the same. Or it may be different.

In the present specification, the "optionally halogenated C _3-6 cycloalkyl" is, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine). , Iodine, etc.) C
_3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) and the like can be mentioned. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl and the like. In the present specification, "optionally halogenated C
Examples of the " _1-6 alkoxy" include C _1-6 alkoxy (eg, fluorine, chlorine, bromine, iodine, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). , Methoxy, ethoxy, propoxy, butoxy, pentyloxy, etc.) and the like. Specific examples include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,
4,4,4-trifluorobutoxy, isobutoxy, s
ec-butoxy, pentyloxy, hexyloxy and the like can be mentioned. In the present specification, the “optionally halogenated C _1-6 alkylthio” is, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine etc.) May have C
_1-6 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) and the like can be mentioned. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like.

The above-mentioned "C which may have a substituent"_6-10A
"C of Reel Oxy"_6-10As "aryloxy",
Examples include phenyloxy and naphthyloxy.
Be done. "C which may have a substituent_6-10Aryl Oki
“Substituent” in “shi” is, for example,
Atom (eg, fluorine, chlorine, bromine, iodine, etc.), C
_1-3Alkylenedioxy (eg methylenedioxy, ethyl
Dioxy, etc.), nitro, cyano, halogenated
May be C_1-6Alkyl, even if halogenated
Good C_3-6Cycloalkyl, may be halogenated
I C_1-6Alkoxy, optionally halogenated C_1-6
Alkylthio, hydroxy, amino, mono-C_1-6Al
Kiramino (eg, methylamino, ethylamino, propylamino
Luamino, isopropylamino, butylamino, etc.),
The-C_1-6Alkylamino (eg dimethylamino, die
Tylamino, dipropylamino, dibutylamino, ethi
Rumethylamino etc.), formyl, carboxy, carba
Moyl, optionally halogenated C_1-6Alkyl-
Carbonyl, C_1-6Alkoxy-carbonyl (eg, meth
Xycarbonyl, ethoxycarbonyl, propoxycal
Bonyl, tert-butoxycarbonyl, etc.), mono-
C_1-6Alkyl-carbamoyl (eg, methylcarbamoyl
, Ethylcarbamoyl), di-C_1-6Alkyl-
Carbamoyl (eg, dimethylcarbamoyl, diethylcarboyl)
Luvamoyl, ethylmethylcarbamoyl, etc.), halogen
C which may be converted to_1-6Alkylsulfonyl, phor
Milamino, optionally halogenated C_1-6Archi
Le-carboxamide, C_1-6Alkoxy-carboxami
(Eg methoxycarboxamide, ethoxycarboxa
Amide, propoxycarboxamide, butoxycarboxa
Mid, etc.), C_1-6Alkylsulfonylamino (eg,
Cylsulfonylamino, ethylsulfonylamino
DO), C_1-6Alkyl-carbonyloxy (eg, aceto
Xy, propanoyloxy, etc.), C_1-6Alkoxy-
Carbonyloxy (eg, methoxycarbonyloxy,
Toxycarbonyloxy, Propoxycarbonyloxy
Si, butoxycarbonyloxy, etc.), mono-C_1-6A
Rukyl-carbamoyloxy (eg, methylcarbamoyl
Oxy, ethylcarbamoyloxy, etc.), di-C_1-6
Alkyl-carbamoyloxy (eg, dimethylcarbamo
Iloxy, diethylcarbamoyloxy, etc.)
1 to 5 can be mentioned.

In the present specification, the "optionally halogenated C _1-6 alkyl" is, for example, 1 to 5,
Preferably 1 to 3 halogen atoms (eg, fluorine,
C _1-6 alkyl _optionally having chlorine, bromine, iodine (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-)
Butyl, pentyl, hexyl, etc.). Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,
2-bromoethyl, 2,2,2-trifluoroethyl,
Pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-
Trifluorobutyl, isobutyl, sec-butyl, t
ert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,
6,6,6-trifluorohexyl and the like can be mentioned.
In the present specification, the “optionally halogenated C _1-6 alkyl-carbonyl” is, for example, 1 to 5,
Preferably 1 to 3 halogen atoms (eg, fluorine,
C _1-6 alkyl-carbonyl (eg, acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, etc.) which may have chlorine, bromine, iodine, etc.) and the like can be mentioned. Specific examples include acetyl, monochloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, hexanoyl and the like. In the present specification, the “optionally halogenated C _1-6 alkylsulfonyl” is, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine and the like). )
Optionally substituted C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, se
c-butylsulfonyl, tert-butylsulfonyl, etc.) and the like. Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,
4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like can be mentioned. In the present specification, “optionally halogenated C _1-6 alkyl-
Examples of the “carboxamide” include C _1-6 alkyl-carboxamide which may have 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (eg, Acetamide, etc.) and the like. Specific examples include acetamide, trifluoroacetamide, propanamide, butanamide and the like.

The "5- to 7-membered saturated cyclic amino" of the above-mentioned "5- to 7-membered saturated cyclic amino optionally having substituent (s)" is, for example, morpholino, thiomorpholino,
Piperazin-1-yl, piperidino, pyrrolidine-1-
And hexamethyleneimine-1-yl. Examples of the “substituent” of the “5- to 7-membered saturated cyclic amino _optionally having substituent (s)” include C _1-6 alkyl, _optionally substituted C _6-14 aryl, substituted A C _7-19 aralkyl which may have a group, a 5- to 10-membered aromatic heterocyclic group which may have a substituent, a C _6-10 aryl-carbonyl which may have a substituent, Examples thereof include 1 to 3 optionally halogenated C _1-6 alkyl-carbonyl, optionally halogenated C _1-6 alkylsulfonyl and the like. Examples of the “C _6-14 aryl” of the “C _6-14 aryl which may have a substituent” include naphthyl such as phenyl, 1-naphthyl or 2-naphthyl, indenyl such as 2-indenyl, and 2 -Anthril such as anthryl and the like. Examples of the “C _7-19 aralkyl” of the “C _7-19 aralkyl _optionally having a substituent” include benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-
Examples include phenyl pentyl and the like. Examples of the "5- to 10-membered aromatic heterocyclic group" of the "5- to 10-membered aromatic heterocyclic group which may have a substituent (s)" include, for example, 2-, 3-
Or pyridyl such as 4-pyridyl, indolyl such as 1-, 2- or 3-indolyl, thienyl such as 2- or 3-thienyl, and the like. “C _6-10 aryl-carbonyl _optionally having substituent (s)” “C
_“6-10 aryl-carbonyl” includes, for example, benzoyl, 1-naphthoyl, 2-naphthoyl and the like.

These "C which may have a substituent"
_6-14 aryl "," _optionally substituted C _7-19 aralkyl "," _optionally substituted 5 to 10 "
“Aromatic heterocyclic group” and “C _6-10 aryl-carbonyl _optionally having substituent (s)” may each have a “substituent”, for example, a halogen atom (eg,
Fluorine, chlorine, bromine, iodine etc.), C _1-3 alkylenedioxy (eg methylenedioxy, ethylenedioxy etc.), nitro, cyano, optionally halogenated C
_1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio,
Hydroxy, amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino,
Isopropylamino, butylamino, etc.), di-C _1-6
Alkylamino (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), formyl, carboxy, carbamoyl,
An optionally halogenated C _1-6 alkyl - carbonyl, C _{1 -6} alkoxy - carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
tert-butoxycarbonyl, etc.), mono-C _1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.) , Optionally halogenated C _1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide (eg,
Methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc.), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C
_1-6 alkyl-carbonyloxy (eg, acetoxy, propanoyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C _1-6 alkyl-
1 to 5 carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.) and the like can be mentioned.

"Acyl", "acylamino" and "acyloxy" as the "substituent" of the "optionally substituted lower alkyl group" represented by R ¹ and R ² above.
Examples of the “acyl” in formyl, carboxy,
Carbamoyl, optionally halogenated C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), having a substituent _Optionally C _6-10 aryl-carbonyl, _optionally substituted C _6-10 aryloxy-carbonyl, _optionally substituted C _7-16 aralkyloxy-carbonyl, _optionally substituted 5- or 6-membered heterocyclic carbonyl which may be substituted, 5- or 6-membered heterocyclic thiocarbonyl which may be substituted, mono-C _1-6 alkyl-carbamoyl which may be substituted, Di-C _1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), optionally substituted C _6-10 aryl - carbamoyl, C _6-10 aryl -C _1-6 alkyl - carbamoyl (e.g., phenyl methylcarbamoyl, phenyl-ethylcarbamoyl, etc.), 5 which may have a substituent
6-membered heterocyclic carbamoyl, optionally halogenated C _1-6 alkylsulfonyl, optionally substituted C _6-10 arylsulfonyl, etc., among which optionally halogenated C _{1 -6} alkyl-carbonyl, C
_1-6 alkoxy - carbonyl (e.g., ethoxycarbonyl), which may have a substituent C _6-10 aryl - carbonyl, and the like may C _{6- 10} arylsulfonyl which may have a substituent .

The above "C which may have a substituent"_6-10A
"C of reel-carbonyl"_6-10Aryl-Carbonii
Examples of “ru” include benzoyl, 1-naphthoyl,
2-naphthoyl and the like can be mentioned. The above "having a substituent
May be C_6-10Aryloxy-carbonyl "
"C _6-10For example, "aryloxy-carbonyl"
For example, phenoxycarbonyl and the like can be mentioned. The above
C which may have a substituent_7-16Aralkyl Oxy-Cal
Bonil's "C_7-16Aralkyloxy-carbonyl "
Are, for example, benzyloxycarbonyl, phenethyl
Luoxycarbonyl and the like. The above "substituent
"5- to 6-membered heterocyclic carbonyl which may have" "5-
“6-membered heterocyclic carbonyl” includes, for example, nicotinoi
Le, isonicotinoyl, 2-thenoyl or 3-tenoy
Such as tenole, 2-furoyl or 3-furoyl
Which furoyl, morpholinocarbonyl, piperidinocar
Bonyl, pyrrolidin-1-ylcarbonyl and the like can be mentioned.
Be done. The above "mono-C which may have a substituent"_1-6A
"Rukiru-Carbamoyl" "Mono-C"_1-6Alkyl-Mo
“Luvamoyl” includes, for example, methylcarbamoyl,
Examples include ethylcarbamoyl. The above "substituent
5 to 6-membered heterocyclic thiocarbonyl which may have "
Examples of the "5- or 6-membered heterocyclic thiocarbonyl" include, for example,
Morpholinothiocarbonyl, piperidinothiocarboni
L, pyrrolidin-1-ylthiocarbonyl, imidazo
Examples include ru-1-ylthiocarbonyl and the like. The above
"C which may have a substituent_6-10Aryl-carbamo
"C" of "Il"_6-10As “aryl-carbamoyl”,
For example, phenylcarbamoyl, 1-naphthylcarbamo
And 2-naphthylcarbamoyl. Previous
Note "5- or 6-membered heterocyclic carbamo which may have a substituent
Examples of the “5- or 6-membered heterocyclic carbamoyl” of “il” include
For example, 2-pyridylcarbamoyl, 3-pyridylcarbamoyl
Pyridyl such as moyl or 4-pyridylcarbamoyl
Carbamoyl, 2-thienylcarbamoyl or 3-thi
Thienylcarbamoyl such as enylcarbamoyl
Can be mentioned. The above "C which may have a substituent"_6-10A
"C of reel sulfonyl"_6-10Arylsulfonyl "
For example, benzenesulfonyl, 1-naphthalene
Sulfonyl, 2-naphthalene sulfonyl and the like can be mentioned.
It

These "C _{6-10 optionally} having substituent (s)
"Aryl-carbonyl", "optionally substituted _C6-10 aryloxy-carbonyl", "optionally substituted _C7-16 aralkyloxy-carbonyl",
"Substituent may 5- to 6-membered heterocyclic carbonyl which may have a", "an optionally substituted mono--C _1-6 alkyl - carbamoyl" may have a "substituent 5-
6-membered heterocyclic thiocarbonyl "," optionally substituted _C6-10 aryl-carbamoyl "," 5- or 6-membered heterocyclic carbamoyl optionally substituted "and" substituent has the "substituent" also good C _6-10 arylsulfonyl "have, a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, C _1-6 alkyl which may be halogenated, halogen _Optionally C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, formyl, carboxy , Carbamoyl, optionally halogenated C _1-6
Alkyl-carbonyl, C _1-6 alkoxy-carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, optionally halogenated C
_1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl-carboxamide, C
_1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6
1 to 5 substituents, preferably 1 to 3 substituents selected from alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy are mentioned, and among them, halogen. An atom, an optionally halogenated C _1-6 alkyl, an optionally halogenated C _1-6 alkoxy and the like are preferable.

The “acylamino” as the “substituent” of the “lower alkyl group optionally having substituent (s)” represented by R ¹ and R ² above includes, for example, And amino substituted by 1 or 2 “acyl” as described in detail in “Substituent” of “optional aromatic group”, preferably formylamino, optionally halogenated C _1-6 alkyl- Carboxamide, optionally substituted C _6-10 aryl-carboxamide (eg,
Phenylcarboxamide, naphthylcarboxamide, etc.), C _1-6 alkoxy-carboxamide (eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc.), C
_1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.) and the like can be mentioned.

The "acyloxy" as the "substituent" of the "lower alkyl group optionally having substituent (s)" represented by R ¹ and R ² is, for example, Oxy substituted with one "acyl" as described in detail in "Substituent" of "Aromatic aromatic group" may be mentioned, preferably C _1-6 alkyl-carbonyloxy (eg, acetoxy, propanoyloxy, etc.) Optionally substituted C _6-10 aryl-carbonyloxy (eg, benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxy) carbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy etc.), mono--C _1-6 alkyl - carbamoyloxy (e.g., Mechiruka Bamoiruokishi and ethylcarbamoyloxy), di -C _1-6 alkyl - carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy etc.), optionally C _6-10 aryl optionally having substituent - carbamoyloxy (e.g. , Phenylcarbamoyloxy, naphthylcarbamoyloxy and the like), nicotinoyloxy and the like. R ¹
And represented by R ² of "have a substituent lower alkyl group" of the "optionally substituted C _6-10 aryl" of the "substituent", "C _6-10 aryl Examples of “” include phenyl and naphthyl.
Examples of the “substituent” of the “C _6-10 aryl which may have a substituent” include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkylenedioxy (eg, , Methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di -C _1-6 alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), formyl, carboxy, Cal Moil, C _1-6 alkyl optionally halogenated - carbonyl, C _1-6
Alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-
Butoxycarbonyl, etc.), mono-C _1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _1-6 alkyl-carbamoyl (eg,
Dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), optionally halogenated C _1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl-carboxamide, C _1-6 alkoxy- Carboxamide (eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc.), C
_1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C _1-6 alkyl-carbonyloxy (eg, acetoxy, propanoyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxy) Carbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C _1-6 alkyl-carbamoyloxy (Eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.) and the like. As the "substituent" of "silyloxy optionally having substituent (s)" as the "substituent" of "lower alkyl optionally having substituent (s)" represented by R ¹ and R ² above, For example, there may be mentioned 1 to 3 C _1-6 alkyl and C _6-10 aryl. The “substituent” of the “optionally substituted hydroxy group” represented by R ¹ and R ² includes a lower alkyl group which may have a substituent and a substituent which may have a substituent. Good C _6-14 aryl group and acyl group are mentioned. "Lower alkyl group optionally having substituent (s)"
Examples of the “lower alkyl group” include C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the like. Preferred are methyl, ethyl and propyl. "Optionally substituted C _6-14 ant - Le group" - The "C _6-14 ant Le group", for example, phenyl, naphthyl such as 1-naphthyl or 2-naphthyl, 2- Indenyl such as indenyl, anthryl such as 2-anthryl and the like can be mentioned. "Acyl" of the "substituent" of the "optionally substituted hydroxy group" represented by R ¹ and R ^2, have a "substituent represented by R ¹ and R ² The same as described in the “acyl” as the “substituent” of the “optional lower alkyl group”, above all, optionally halogenated C _1-6 alkyl-carbonyl,
A carbamoyl group which may have a substituent and a thiocarbamoyl group which may have a substituent are preferable.

In the compound represented by the above formula (I), R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring with the adjacent carbon atom.

[Chemical 40] [In the formula, each symbol has the same meaning as described above. ] The compound etc. which are represented by these are mentioned. R ¹ is preferably a hydrogen atom or an optionally substituted hydroxy group.
The hydroxy group which may be substituted is preferably an alkyloxy group or an acyloxy group. R ² is preferably a hydrogen atom or a lower alkyl group which may have a substituent, more preferably a hydrogen atom or C _1-6 alkyl, still more preferably a hydrogen atom or methyl.

The "aromatic group" of the "aromatic group which may have a substituent" represented by Ar ¹ is, for example, a monocyclic aromatic group, a ring-assembled aromatic group or a condensed aromatic group. Is mentioned. Examples of the above-mentioned "monocyclic aromatic group" include a monovalent group formed by removing any one hydrogen atom from a benzene ring, a 5- or 6-membered aromatic heterocycle.
As the "5- or 6-membered aromatic heterocycle", for example, a 5- or 6-membered aromatic ring containing at least one hetero atom (for example, 1 to 3) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. Heterocycle etc. are mentioned. In particular,
Examples thereof include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrazine, pyrimidine and pyridazine. Specific examples of the "monocyclic aromatic group" include phenyl, thienyl such as 2- or 3-thienyl, furyl such as 2- or 3-furyl, pyrrolyl such as 1-, 2- or 3-pyrrolyl, and 2; Or imidazolyl such as 4-imidazolyl, pyrazolyl such as 3- or 4-pyrazolyl, 2
Thiazolyl, such as-, 4- or 5-thiazolyl, 2
Oxazolyl, such as-, 4- or 5-oxazolyl,
Pyridyl such as 2-, 3- or 4-pyridyl, pyrazinyl such as 2-pyrazinyl, pyrimidinyl such as 2-, 4- or 5-pyrimidinyl, pyridazinyl such as 3- or 4-pyridazinyl, and the like.

The above-mentioned "ring assembly aromatic group" means that two or more (preferably 2 or 3) aromatic rings are directly connected by a single bond, and the number of bonds directly connecting the rings is a ring system. 1 from the number
Examples thereof include groups formed by removing an arbitrary one hydrogen atom from an aromatic ring aggregate having a small number. As the "aromatic ring",
Examples thereof include aromatic hydrocarbons and aromatic heterocycles. Examples of the "aromatic hydrocarbon" include, for example, 6 to 14 carbon atoms.
And monocyclic or condensed polycyclic (2 or 3 ring) aromatic hydrocarbons (eg, benzene, naphthalene, indene, anthracene, etc.) and the like. The “aromatic heterocycle” is, for example, a 5 to 14-membered, preferably 5 to 10 member containing, in addition to carbon atom, one or more (for example, 1 to 4) heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom. Member aromatic heterocycle and the like. In particular,
Thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, furan, phenoxathiine, pyrrole, imidazole, pyrazole, oxazole, isoxazole, 1,2 , 4-oxadiazole or 1,3,4-
Oxadiazoles such as oxadiazole, 1,2,4
-Thiadiazole or thiadiazole such as 1,3,4-thiadiazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-
Indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine,
Aromatic heterocycles such as thiazoles, isothiazoles, phenothiazines, flazans, phenoxazines, phthalimides, etc., or aromatic rings having 1 or more (preferably 1 or 2) of these rings (preferably monocycles) (eg, benzene) Ring etc.) and the ring formed by condensation. Examples of the aromatic ring aggregate in which these aromatic rings are directly bonded by a single bond include, for example, 2 or 3 (preferably, a benzene ring, a naphthalene ring and a 5 to 10 member (preferably 5 or 6 member) aromatic heterocycle. And an aromatic ring aggregate formed of 2). Preferred examples of the aromatic ring aggregate include benzene, naphthalene, pyridine, pyrimidine, thiophene, furan, thiazole, isothiazole, oxazole, 1,2,4-oxadiazole and 1,3,4-oxadiazole. From 2 or 3 aromatic rings selected from thiadiazoles such as oxadiazole, 1,2,4-thiadiazole or 1,3,4-thiadiazole, quinoline, isoquinoline, indole, benzothiophene, benzoxazole, benzothiazole and benzofuran It is an aromatic ring aggregate. Specific examples include biphenylyl such as 2-, 3- or 4-biphenylyl, 3- (1-naphthyl) -1,
2,4-oxadiazol-5-yl or 3- (2-
Naphthyl-substituted oxadiazolyl such as naphthyl) -1,2,4-oxadiazol-5-yl, benzofuranyl-substituted oxadiazolyl such as 3- (2-benzofuranyl) -1,2,4-oxadiazol-5-yl, 3 -Phenyl-1,2,4-oxadiazol-5-yl or 5-phenyl-1,3,4-oxadiazol-2-
Phenyl-substituted oxadiazolyl such as yl, 3- (2-
Benzoxazolyl-substituted oxadiazolyls, such as benzoxazolyl) -1,2,4-oxadiazol-2-yl, 3- (3-indolyl) -1,2,4-oxadiazol-2-yl or 3- (2-indolyl)-
Indolyl-substituted oxadiazolyl such as 1,2,4-oxadiazol-2-yl, 4-phenylthiazol-
Phenyl substituted thiazolyl such as 2-yl, 4- (2-
Benzofuranyl-substituted thiazolyl such as benzofuranyl) thiazol-2-yl, 4-phenyl-1,3-oxazol-5-yl or 5-phenyloxazol-2
Phenyl-substituted oxazolyl such as -yl, phenyl-substituted isothiazolyl such as 5-phenyl-isothiazol-4-yl, 4- (2-thienyl) phenyl or 4-
Thienyl-substituted phenyl such as (3-thienyl) phenyl, pyridyl-substituted phenyl such as 3- (3-pyridyl) phenyl or 4- (3-pyridyl) phenyl, phenyl-substituted pyridyl such as 6-phenyl-3-pyridyl, 4
Examples thereof include naphthyl-substituted phenyl such as-(2-naphthyl) phenyl, benzofuranyl-substituted phenyl such as 4- (2-benzofuranyl) phenyl, and terphenylyl such as 4,4'-terphenylyl.

Examples of the above-mentioned "condensed aromatic group" include:
Fused polycyclic (preferably 2 to 4 cyclic, preferably 2
Or a trivalent) monovalent group formed by removing any one hydrogen atom from an aromatic ring. Examples of the "fused polycyclic aromatic ring" include fused polycyclic aromatic hydrocarbons, fused polycyclic aromatic heterocycles, and the like. Examples of the “condensed polycyclic aromatic hydrocarbon” include, for example, condensed polycyclic (2 or 3 ring) aromatic hydrocarbons having 9 to 14 carbon atoms (eg,
Naphthalene, indene, anthracene, etc.) and the like. Examples of the "fused polycyclic aromatic heterocycle" include, in addition to carbon atoms, one or more heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom (for example, 1 to 4).
And a fused polycyclic aromatic heterocycle having 9 to 14 members, preferably 9 or 10 members. In particular,
Benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, isoquinoline, quinoline,
Examples thereof include aromatic heterocycles such as indole, quinoxaline, phenanthridine, phenothiazine, phenoxazine and phthalimide. Specific examples of the “fused aromatic group” include naphthyl such as 1-naphthyl or 2-naphthyl, quinolyl such as 2-quinolyl, 3-quinolyl or 4-quinolyl, benzofuranyl such as 2-benzofuranyl, 2-benzothiazolyl and the like. Benzothiazolyl, benzimidazolyl such as 2-benzimidazolyl, and indolyl such as 1-indolyl, 2-indolyl or 3-indolyl.

Among the above, the aromatic group represented by Ar ¹ is, for example, (1) phenyl, 2- or 3
-Thienyl such as cenyl, furyl such as 2- or 3-furyl, monocyclic aromatic groups such as pyridyl such as 2-, 3- or 4-pyridyl, (2) 2-, 3- or 4-
Biphenylyl such as biphenylyl, such as 3- (1-naphthyl) -1,2,4-oxadiazol-5-yl or 3- (2-naphthyl) -1,2,4-oxadiazol-5-yl Naphthyl-substituted oxadiazolyl, 3-
Benzofuranyl-substituted oxadiazolyl, such as (2-benzofuranyl) -1,2,4-oxadiazol-5-yl, 3-phenyl-1,2,4-oxadiazole-5
Phenyl-substituted oxadiazolyl such as -yl, 3- (2
-Benzoxazolyl) -1,2,4-oxadiazol-2-yl and other benzoxazolyl-substituted oxadiazolyls, 3- (3-indolyl) -1,2,4-oxadiazol-2-yl Or 3- (2-indolyl)-
Indolyl-substituted oxadiazolyl such as 1,2,4-oxadiazol-2-yl, 4-phenylthiazol-
Phenyl-substituted thiazolyl such as 2-yl, benzofuranyl-substituted thiazolyl such as 4- (2-benzofuranyl) thiazol-2-yl, phenyl-substituted oxazolyl such as 4-phenyl-1,3-oxazol-5-yl, 4-
Thienyl-substituted phenyl such as (2-thienyl) phenyl, pyridyl-substituted phenyl such as 4- (3-pyridyl) phenyl, naphthyl-substituted phenyl such as 4- (2-naphthyl) phenyl, terphenylyl such as 4,4′-terphenylyl, etc. Ring-assembled aromatic groups, (3) quinolyl such as 2-, 3- or 4-quinolyl, 1-, 2- or 3
-Fused aromatic groups such as indolyl and the like are preferred. Examples of the aromatic group represented by Ar ¹ include phenyl, thienyl such as 2- or 3-phenyl, furyl such as 2- or 3-furyl, and pyridyl such as 2-, 3- or 4-pyridyl. A cyclic aromatic group and the like are more preferable.

Examples of the “aromatic ring” of the “optionally substituted aromatic ring” represented by ring B include a monocyclic aromatic ring, a ring-assembled aromatic ring and a condensed aromatic ring. Examples of the above-mentioned “monocyclic aromatic ring” include a benzene ring, a 5- or 6-membered aromatic heterocycle, and the like. "5 or 6
Examples of the “membered aromatic heterocycle” include a 5- or 6-membered aromatic heterocycle containing one or more heteroatoms (for example, 1 to 3) selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom. Can be mentioned. Specifically, thiophene,
Furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrazine, pyrimidine, pyridazine and the like can be mentioned.

As the above-mentioned "ring-assembled aromatic ring", two or more (preferably 2 or 3) aromatic rings are directly connected by a single bond, and the number of bonds directly connecting the rings is a ring system. 1 from the number
Examples thereof include aromatic ring aggregates that are not numerous. Examples of the "aromatic ring" include aromatic hydrocarbons and aromatic heterocycles. Examples of the "aromatic hydrocarbon" include monocyclic or condensed polycyclic (2 or 3 ring) aromatic hydrocarbons having 6 to 14 carbon atoms (eg, benzene, naphthalene, indene, anthracene, etc.), etc. Is mentioned. As the “aromatic heterocycle”, for example, a nitrogen atom in addition to a carbon atom,
Examples thereof include a 5- to 14-membered, preferably 5- to 10-membered aromatic heterocycle containing one or more (for example, 1 to 4) heteroatoms selected from a sulfur atom and an oxygen atom. Specifically, thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-
b] thiophene, furan, phenoxathiin, pyrrole, imidazole, pyrazole, oxazole, isoxazole, 1,2,4-oxadiazole or 1,
Oxadiazoles such as 3,4-oxadiazole,
Thiadiazole such as 1,2,4-thiadiazole or 1,3,4-thiadiazole, pyridine, pyrazine,
Pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine,
Isoquinoline, quinoline, phthalazine, naphthyridine,
Quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine,
Aromatic heterocycles such as phenazine, thiazole, isothiazole, phenothiazine, flazan, phenoxazine and phthalimide, or one or more (preferably 1 or 2) aromatic rings of these rings (preferably monocycles) (eg , A benzene ring, etc.) and the like. Examples of the aromatic ring aggregate in which these aromatic rings are directly bonded by a single bond include, for example, 2 or 3 (preferably, a benzene ring, a naphthalene ring and a 5 to 10 member (preferably 5 or 6 member) aromatic heterocycle. And an aromatic ring aggregate formed of 2). Preferred examples of the aromatic ring aggregate include benzene, naphthalene, pyridine, pyrimidine, thiophene, furan, thiazole, isothiazole, oxazole, 1,2,4-oxadiazole and 1,3,4-oxadiazole. Oxadiazole, 1,2,4-thiadiazole or 1,
It is an aromatic ring aggregate consisting of 2 or 3 aromatic rings selected from thiadiazoles such as 3,4-thiadiazole, quinoline, isoquinoline, indole, benzothiophene, benzoxazole, benzothiazole and benzofuran. Specific examples include biphenyl and 3- (1-
Naphthyl) -1,2,4-oxadiazole or 3-
Naphthyl-substituted oxadiazoles such as (2-naphthyl) -1,2,4-oxadiazole, benzofuranyl-substituted oxadiazoles such as 3- (2-benzofuranyl) -1,2,4-oxadiazole, 3- Phenyl-1,
2,4-oxadiazole or 5-phenyl-1,
Phenyl-substituted oxadiazoles such as 3,4-oxadiazole, 3- (2-benzoxazolyl) -1,2,
Benzoxazolyl-substituted oxadiazoles such as 4-oxadiazole, 3- (3-indolyl) -1,2,4
-Oxadiazole or 3- (2-indolyl)-
Indolyl-substituted oxadiazoles such as 1,2,4-oxadiazole, phenyl-substituted thiazoles such as 4-phenylthiazole, benzofuranyl-substituted thiazoles such as 4- (2-benzofuranyl) thiazole, 4-phenyl-1,3-oxazole Or a phenyl-substituted oxazole such as 5-phenyloxazole, 5-phenyl-
Phenyl-substituted isothiazole, such as isothiazole,
Thienyl-substituted benzene such as (2-thienyl) benzene or (3-thienyl) benzene, pyridyl-substituted benzene such as (3-pyridyl) benzene or (3-pyridyl) benzene, phenyl-substituted pyridine such as 6-phenylpyridine, (2 Examples include naphthyl-substituted benzene such as -naphthyl) benzene, benzofuranyl-substituted benzene such as (2-benzofuranyl) benzene, and terphenyl such as p-terphenyl.

Examples of the above-mentioned "fused aromatic ring" include fused polycyclic (preferably 2 to 4 ring, preferably 2 or 3 ring) aromatic ring and the like. Examples of the "fused polycyclic aromatic ring" include fused polycyclic aromatic hydrocarbons, fused polycyclic aromatic heterocycles, and the like. Examples of the “condensed polycyclic aromatic hydrocarbon” include, for example, condensed polycyclic (2 or 3 ring) aromatic hydrocarbons having 9 to 14 carbon atoms (eg,
Naphthalene, indene, anthracene, etc.) and the like. Examples of the "fused polycyclic aromatic heterocycle" include, in addition to carbon atoms, one or more heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom (for example, 1 to 4).
And a fused polycyclic aromatic heterocycle having 9 to 14 members, preferably 9 or 10 members. In particular,
Benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, isoquinoline, quinoline,
Examples thereof include aromatic heterocycles such as indole, quinoxaline, phenanthridine, phenothiazine, phenoxazine and phthalimide.

Among the above, as the aromatic ring represented by the B ring, for example, (1) a monocyclic aromatic ring such as benzene, thiophene, furan and pyridine, (2) biphenyl,
Naphthyl-substituted oxadiazoles such as 3- (1-naphthyl) -1,2,4-oxadiazole or 3- (2-naphthyl) -1,2,4-oxadiazole, 3- (2
-Benzofuranyl) -1,2,4-oxadiazole and other benzofuranyl-substituted oxadiazoles, 3-phenyl-1,2,4-oxadiazole and other phenyl-substituted oxadiazoles, 3- (2-benzoxazoli) )-
Benzoxazolyl-substituted oxadiazoles such as 1,2,4-oxadiazole, 3- (3-indolyl)-
1,2,4-oxadiazole or indolyl-substituted oxadiazole such as 3- (2-indolyl) -1,2,4-oxadiazole, phenyl-substituted thiazole such as 4-phenylthiazole, 4- (2- Benzofuranyl-substituted thiazoles such as benzofuranyl) thiazole,
Phenyl-substituted oxazoles such as 4-phenyl-1,3-oxazole, thienyl-substituted benzenes such as (2-thienyl) benzene, pyridyl-substituted benzenes such as (3-pyridyl) benzene, and naphthyl-substituted benzenes such as (2-naphthyl) benzene. , Ring-assembled aromatic rings such as terphenyl such as p-terphenyl, and condensed aromatic rings such as (3) quinoline and indole are preferable. As the aromatic ring represented by ring B, for example, a monocyclic aromatic ring such as benzene is more preferable.

"4 to 8-membered ring" represented by ring C, "4 to 8-membered ring which may be condensed with a ring which may further have a substituent and which may have a substituent""Includes, for example, a 4- to 8-membered saturated ring and a 4- to 8-membered unsaturated ring. Examples of the "4- to 8-membered saturated ring" include 4- to 8-membered saturated ring hydrocarbons and 4- to 8-membered saturated heterocycles. "4-8
As the “membered saturated ring hydrocarbon”, for example, cyclobutane,
Cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like can be mentioned. As the "4- to 8-membered saturated heterocycle", for example, a 4- to 8-membered saturated heterocycle containing one or more (for example, 1 to 3) heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atoms. And so on. Specifically, tetrahydrothiophene, tetrahydrofuran, tetrahydropyrrole, tetrahydroimidazole, tetrahydropyrazole, tetrahydrothiazole, tetrahydrooxazole, hexahydropyridine, hexahydropyrazine, hexahydropyrimidine, hexahydropyridazine, tetrahydro-1,4-
Examples include oxazine, tetrahydro-1,4-thiazine, perhydroazepine, perhydro-1,4-diazepine, perhydro-1,4-oxazepine, perhydro-1,4-thiazepine and perhydroazocine.

Among the above, for example,

[Chemical 41] [Wherein, R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group which may have a substituent or a lower alkoxy group which may have a substituent, X represents CH or N, Z Is an oxygen atom, a sulfur atom, CR ⁴ R ⁵ , NR ⁶ or

[Chemical 42] (R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different,
It represents a hydrogen atom or a lower alkyl group which may have a substituent. ), M is 0 to 1, and n is 1 to
Indicates an integer of 4. ] Is preferable.

The "lower alkyl group" of the lower alkyl group which may have a substituent represented by R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is, for example, C _1-6 alkyl (eg, , Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
Hexyl etc.) and the like. Preferably methyl,
Ethyl and propyl. Examples of the halogen atom represented by R ³ include fluorine, chlorine, bromine, iodine and the like. Chlorine is preferred. Examples of the “lower alkoxy group” of the lower alkoxy group which may have a substituent represented by R ³ include C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, pentyloxy, etc.) and the like. Can be mentioned. Preferred are methoxy, ethoxy, propoxy and isopropoxy.

In the above formula, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷
The description of the "substituent" of the "lower alkyl group which may have a substituent (s)" is shown in "the lower alkyl group which may have a substituent (s)" of R ¹ and R ^2. It is the same as that described as "substituent".

In the above formula, the "substituent" of the "lower alkoxy group optionally having substituent (s)" represented by R ³ is, for example, a halogen atom (eg, fluorine, chlorine, bromine,
Iodine etc.), C _1-3 alkylenedioxy (eg methylenedioxy, ethylenedioxy etc.), nitro, cyano, optionally halogenated C _1-6 alkyl, C
_6-10 aryloxy-C _1-6 alkyl (eg, phenoxymethyl, etc.), C _1-6 alkyl-C _6-10 aryl-C _2-6
Alkenyl (eg, methylphenylethenyl, etc.), optionally halogenated C _3-6 cycloalkyl, optionally substituted C _{7 -16} aralkyl, _optionally halogenated C _{1- 6} alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, optionally substituted C _{6-1 0} aryloxy, C _6-10 aryl -
C _7-16 aralkyloxy (eg, phenylbenzyloxy etc.), amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino etc.), di-C _{1- 6} alkylamino (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), optionally substituted 5- to 7-membered saturated cyclic amino, acyl, acylamino, acyloxy and the like can be mentioned. Among them, halogen atom, C _1-3 alkylenedioxy, optionally halogenated C _1-6 alkyl, C
_6-10 aryloxy-C _1-6 alkyl, C _1-6 alkyl-
C _6-10 aryl-C _2-6 alkenyl, C _7-16 aralkyl which may have a substituent, C _1-6 alkoxy which may be halogenated, hydroxy, which may have a substituent Preferred are C _6-10 aryloxy, acyl, acyloxy and the like.

The "lower alkoxy group" of the "optionally substituted lower alkoxy group" represented by R ³ includes, for example, 1 to 13 substituents at the substitutable position of the lower alkoxy group. , Preferably 1 to 5, and when the number of substituents is 2 or more, each substituent may be the same or different. As the "C _7-16 aralkyl" in the "optionally C _7-16 aralkyl optionally having substituent (s)", for example, benzyl, phenethyl, naphthylmethyl and the like. The above "C which may have a substituent"
_6-10 The "C _6-10 aryloxy" aryloxy ", for example, phenyloxy and naphthyloxy. These "C _7-16 which may have a substituent"
Examples of the “substituent” of “aralkyl” and “C _6-10 aryloxy which may have a substituent” include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _{1- 3} alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, halogenated Optionally substituted C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-
C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-C _1-6 alkylamino (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, ethyl) Methylamino, etc.), formyl, carboxy, carbamoyl, optionally halogenated C _1-6
Alkyl-carbonyl, C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), mono-C _1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), The-C
_1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), optionally halogenated C _1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl -Carboxamide, C _1-6 alkoxy-
Carboxamide (eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc.), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C _1-6 alkyl-carbonyloxy (eg, acetoxy) , Propanoyloxy, etc.), C _1-6
Alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.),
1 to 5 di-C _1-6 alkyl-carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.) and the like can be mentioned.

The "5- to 7-membered saturated cyclic amino" of the above-mentioned "5- to 7-membered saturated cyclic amino optionally having substituent (s)" is, for example, morpholino, thiomorpholino,
Piperazin-1-yl, piperidino, pyrrolidine-1-
And hexamethyleneimine-1-yl. Examples of the “substituent” of the “5- to 7-membered saturated cyclic amino _optionally having substituent (s)” include C _1-6 alkyl, _optionally substituted C _6-14 aryl, substituted A C _7-19 aralkyl which may have a group, a 5- to 10-membered aromatic heterocyclic group which may have a substituent, a C _6-10 aryl-carbonyl which may have a substituent, Examples thereof include 1 to 3 optionally halogenated C _1-6 alkyl-carbonyl, optionally halogenated C _1-6 alkylsulfonyl and the like. Examples of the “C _6-14 aryl” of the “C _6-14 aryl which may have a substituent” include naphthyl such as phenyl, 1-naphthyl or 2-naphthyl, indenyl such as 2-indenyl, and 2 -Anthril such as anthryl and the like. Preferred is phenyl and the like. "C which may have a substituent
“C _7-19 aralkyl” of “ _7-19 aralkyl” includes, for example, benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl. , 4-phenylbutyl, 5-phenylpentyl and the like. Preferred is benzyl and the like. Examples of the “5- to 10-membered aromatic heterocyclic group” of the “5- to 10-membered aromatic heterocyclic group which may have a substituent” include, for example, 2
Pyridyl, such as-, 3- or 4-pyridyl, 1-, 2
-Or 3-indolyl and the like indolyl, 2- or 3-thienyl and the like thienyl, and the like. Pyridyl such as 2-, 3- or 4-pyridyl is preferable. Of - "carbonyl optionally having substituent C _6-10 aryl" - as the "C _6-10 aryl-carbonyl", e.g., benzoyl, 1-naphthoyl, and the like 2-naphthoyl.

These "C which may have a substituent"
_6-14 aryl "," _optionally substituted C _7-19 aralkyl "," _optionally substituted 5 to 10 "
“Aromatic heterocyclic group” and “C _6-10 aryl-carbonyl _optionally having substituent (s)” may each have a “substituent”, for example, a halogen atom (eg,
Fluorine, chlorine, bromine, iodine etc.), C _1-3 alkylenedioxy (eg methylenedioxy, ethylenedioxy etc.), nitro, cyano, optionally halogenated C
_1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio,
Hydroxy, amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino,
Isopropylamino, butylamino, etc.), di-C _1-6
Alkylamino (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), formyl, carboxy, carbamoyl,
An optionally halogenated C _1-6 alkyl - carbonyl, C _{1 -6} alkoxy - carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
tert-butoxycarbonyl, etc.), mono-C _1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.) , Optionally halogenated C _1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide (eg,
Methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc.), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C
_1-6 alkyl-carbonyloxy (eg, acetoxy, propanoyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C _1-6 alkyl-
1 to 5 carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.) and the like can be mentioned.

“Acyl” as “substituent” of “lower alkoxy group optionally having substituent (s)” represented by R ³ above, “acyl” in “acylamino” and “acyloxy” means formyl, Carboxy, carbamoyl, optionally halogenated C _1-6 alkyl-
Carbonyl, C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), optionally substituted C _6-10 aryl-carbonyl, having a substituent _Optionally substituted C _6-10 aryloxy-carbonyl, _optionally substituted C _7-16 aralkyloxy-carbonyl, _optionally substituted 5-6 membered heterocyclic carbonyl, mono- C _1-6 alkyl-carbamoyl,
Di-C _1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), optionally substituted C _6-10 aryl-carbamoyl, optionally substituted 5- or 6-membered heterocyclic carbamoyl, optionally halogenated C
_1-6 alkylsulfonyl, optionally substituted C
_{6-1 0} arylsulfonyl and the like, among which optionally halogenated C _1-6 alkyl-carbonyl, C _1-6
Examples thereof include alkoxy-carbonyl (eg, ethoxycarbonyl, etc.), optionally substituted C _6-10 aryl-carbonyl, optionally substituted C _6-10 arylsulfonyl and the like.

The above-mentioned "C which may have a substituent"_6-10A
"C of reel-carbonyl"_6-10Aryl-Carbonii
Examples of “ru” include benzoyl, 1-naphthoyl,
2-naphthoyl and the like can be mentioned. The above "having a substituent
May be C_6-10Aryloxy-carbonyl "
"C _6-10For example, "aryloxy-carbonyl"
For example, phenoxycarbonyl and the like can be mentioned. The above
C which may have a substituent_7-16Aralkyl Oxy-Cal
Bonil's "C_7-16Aralkyloxy-carbonyl "
Are, for example, benzyloxycarbonyl, phenethyl
Luoxycarbonyl and the like. The above "substituent
"5- to 6-membered heterocyclic carbonyl which may have" "5-
“6-membered heterocyclic carbonyl” includes, for example, nicotinoi
Le, isonicotinoyl, 2-thenoyl or 3-tenoy
Such as tenole, 2-furoyl or 3-furoyl
Which furoyl, morpholinocarbonyl, piperidinocar
Bonyl, pyrrolidin-1-ylcarbonyl and the like can be mentioned.
Be done. The above "C which may have a substituent"_6-10Aryl
-C of "carbamoyl"_6-10Aryl-carbamoyl "
As, for example, phenylcarbamoyl, 1-naphthyl
Examples include rucarbamoyl and 2-naphthylcarbamoyl.
To be The above-mentioned "5- or 6-membered heterocyclic group which may have a substituent"
"5- to 6-membered heterocyclic carbamoyl" of "cyclic carbamoyl"
For example, 2-pyridylcarbamoyl, 3-pyridyl
Zircarbamoyl or 4-pyridylcarbamoyl etc.
Of pyridylcarbamoyl and 2-thienylcarbamoyl
Or thienylcarbamoyl such as 3-thienylcarbamoyl
Ile, etc. The above "may have a substituent
I C_6-10"C" of "arylsulfonyl"_6-10Arylsul
“Honyl” includes, for example, benzenesulfonyl, 1-
Naphthalenesulfonyl, 2-naphthalenesulfonyl, etc.
Is mentioned.

These "C _{6-10 optionally} having substituent (s)
"Aryl-carbonyl", "optionally substituted _C6-10 aryloxy-carbonyl", "optionally substituted _C7-16 aralkyloxy-carbonyl",
"5- or 6-membered heterocyclic carbonyl optionally having substituent (s)", " _C6-10 aryl-carbamoyl _optionally having substituent (s)", "5-membered heterocyclic carbonyl _optionally having substituent (s) 5" The “substituent” of “6-membered heterocyclic carbamoyl” and “optionally substituted C _6-10 arylsulfonyl” includes halogen atom, C _1-3 alkylenedioxy, nitro, cyano, and halogenated. _Optionally C _1-6 alkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di —C _1-6 alkylamino, formyl, carboxy, carbamoyl, optionally halogenated C _1-6 alkyl-carbonyl, C
_1-6 alkoxy-carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, optionally halogenated C _1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl - carboxamide, C _{1 -6} alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl 1 to 5 substituents, preferably 1 to 3 substituents selected from carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy are mentioned, among which a halogen atom and optionally halogenated C _{1- 6} alkyl, optionally halogenated C
_1-6 alkoxy and the like are preferable.

The "acylamino" as the "substituent" of the "optionally substituted lower alkoxy group" for R ³ is, for example, the above-mentioned "optionally substituted aroma". Examples thereof include amino substituted by 1 or 2 “acyl” described in “Substituent” of “group”, preferably formylamino, optionally halogenated C _1-6 alkyl-carboxamide, substituted C _6-10 aryl-carboxamide (eg, phenylcarboxamide, naphthylcarboxamide, etc.) which may have a group, C
_1-6 alkoxy-carboxamide (eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc.), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino,
Ethylsulfonylamino etc.) and the like.

The "acyloxy" as the "substituent" of the "lower alkoxy group optionally having substituent (s)" for R ³ is, for example, the above-mentioned "aromatic optionally having substituent (s)". include oxy substituted by one "acyl" described in detail in the "substituent" of the groups ", preferably, C _1-6 alkyl - carbonyloxy (e.g., acetoxy, propanoyloxy, etc.), substituents C _6-10 aryl-carbonyloxy (eg, benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy, etc.) which may have C _1-6 alkoxy-carbonyloxy (eg,
Methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C _1-6 alkyl-carbamoyl Oxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), optionally substituted C
_6-10 aryl-carbamoyloxy (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.),
Examples include nicotinoyloxy.

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are preferably hydrogen atom or C _1-6 alkyl, more preferably hydrogen atom or methyl.

"4-8 membered ring" of "4 to 8-membered ring which may be condensed with a ring which may further have a substituent and which may have a substituent" represented by the above-mentioned C ring "4" as a ring
~ 8-membered unsaturated ring "is a non-aromatic unsaturated ring and 4-8
Member aromatic rings are included. As the "non-aromatic unsaturated ring",
Hydrocarbon rings such as cyclopentene, cyclohexene, cyclohexadiene, cycloheptene, and cycloheptadiene, and non-aromatic heterocycles such as thiazine, oxazine, oxathiin, diazepine, oxazepine, and thiazepine. Examples of the "4- to 8-membered aromatic ring" include:
Examples thereof include a benzene ring and a 5- or 6-membered aromatic heterocycle. As the “5- or 6-membered aromatic heterocycle”, for example,
A 5- or 6-membered aromatic heterocycle containing one or more (for example, 1 to 3) heteroatoms selected from nitrogen atoms, sulfur atoms and oxygen atoms in addition to carbon atoms can be mentioned. Specific examples include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrazine, pyrimidine, pyridazine and triazole.

The "having 4 to 8 membered ring optionally condensed with a ring which may further have a substituent" represented by the above-mentioned C ring "has a substituent" Examples of "which may be" and "which are condensed" and "ring" include a saturated ring and an aromatic ring.

Examples of the "saturated ring" include a 4- to 8-membered monocyclic saturated ring, a 4- to 8-membered ring-aggregated saturated ring, and a 7 to 12-membered condensed saturated ring. Examples of the "4- to 8-membered monocyclic saturated ring" include 4- to 8-membered saturated ring hydrocarbons and 4- to 8-membered saturated heterocycles. As the “4- to 8-membered saturated ring hydrocarbon”,
For example, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like can be mentioned. The “4- to 8-membered saturated heterocycle” includes, for example, 4 to 8 containing at least one hetero atom (for example, 1 to 3) selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom.
Member saturated heterocycle and the like. Specifically, tetrahydrothiophene, tetrahydrofuran, tetrahydropyrrole, tetrahydroimidazole, tetrahydropyrazole, tetrahydrothiazole, tetrahydrooxazole, hexahydropyridine, hexahydropyrazine, hexahydropyrimidine, hexahydropyridazine, tetrahydro-1,4-oxazine, tetrahydro -
1,4-thiazine, perhydroazepine, perhydro-
1,4-diazepine, perhydro-1,4-oxazepine, perhydro-1,4-thiazepine, perhydroazocine and the like. The “4- to 8-membered ring-aggregate saturated ring” has two or more (preferably two) saturated rings directly connected by a single bond, and the number of bonds directly connecting the rings is more than the number of ring systems. One example is a saturated ring assembly which is one less.
Examples of the “saturated ring” include saturated ring hydrocarbon, saturated heterocycle and the like. As the “saturated ring hydrocarbon”, for example,
Examples thereof include monocyclic or condensed polycyclic (bicyclic) saturated ring hydrocarbons having 4 to 8 carbon atoms (eg, cyclobutane, cyclopentane, etc.). As a "saturated heterocycle",
For example, one or more heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom (for example, 1 to 4).
And a 4- to 8-membered saturated heterocycle, etc. Specifically, tetrahydrothiophene, tetrahydrofuran, tetrahydropyrrole, tetrahydroimidazole, tetrahydropyrazole, tetrahydrothiazole, tetrahydrooxazole, hexahydropyridine, hexahydropyrazine, hexahydropyrimidine,
Hexahydropyridazine, tetrahydro-1,4-oxazine, tetrahydro-1,4-thiazine, perhydroazepine, perhydro-1,4-diazepine, perhydro-
And saturated heterocycles such as 1,4-oxazepine, perhydro-1,4-thiazepine and perhydroazocine. Examples of the 4- to 8-membered saturated ring assembly in which these saturated rings are directly bonded by a single bond include a saturated ring assembly formed by two members selected from a 4- to 8-membered saturated heterocycle. Preferred examples of the saturated ring assembly include cyclobutane, cyclopentane, tetrahydrothiophene, tetrahydrofuran, tetrahydropyrrole, tetrahydroimidazole, tetrahydropyrazole, tetrahydrothiazole, tetrahydrooxazole, hexahydropyridine, hexahydropyrazine, hexahydropyrimidine, hexahydropyridazine. , Tetrahydro-1,
Two selected from 4-oxazine, tetrahydro-1,4-thiazine, perhydroazepine, perhydro-1,4-diazepine, perhydro-1,4-oxazepine, perhydro-1,4-thiazepine and perhydroazocine It is a saturated ring assembly composed of saturated rings. Examples of the “7 to 12-membered condensed saturated ring” include condensed polycyclic (preferably bicyclic) saturated ring and the like. Examples of the "fused polycyclic saturated ring" include fused polycyclic saturated ring hydrocarbons and fused polycyclic saturated heterocycles. Examples of the “condensed polycyclic saturated hydrocarbon” include a condensed polycyclic (bicyclic) saturated ring hydrocarbon having 7 to 12 carbon atoms (eg, bicyclo [4.
3.0] nonane, bicyclo [4.4.0] decane, etc.)
And so on. The “fused polycyclic saturated heterocycle” includes, for example, one or more heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom (for example, 1
4 to 8 membered fused polycyclic saturated heterocycles and the like.

"Condensed ring which may further have a substituent and which may have a substituent or a 4- to 8-membered ring which is represented by ring C" is "fused Good morning "
“Aromatic ring” as “which may have a substituent”, “condensate”, and “ring” means a 4- to 8-membered monocyclic aromatic ring, 4 to
An 8-membered ring-assembled aromatic ring, a 7- to 12-membered condensed aromatic ring and the like can be mentioned. Examples of the "4- to 8-membered monocyclic aromatic ring" include a benzene ring, a 5- or 6-membered aromatic heterocycle, and the like. As the "5- or 6-membered aromatic heterocycle", for example, a 5- or 6-membered aromatic ring containing at least one hetero atom (for example, 1 to 3) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. Heterocycle etc. are mentioned. Specific examples include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrazine, pyrimidine and pyridazine. As the "4- to 8-membered ring-collecting aromatic ring", two or more (preferably two) aromatic rings are directly bonded by a single bond,
Examples thereof include aromatic ring aggregates in which the number of bonds directly connecting rings is one less than the number of ring systems. Examples of the "aromatic ring" include aromatic hydrocarbons and aromatic heterocycles. Examples of the “aromatic hydrocarbon” include benzene and the like. The "aromatic heterocycle" is, for example, a 4- to 8-membered (preferably 5-membered) containing at least one hetero atom (for example, 1 to 4) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom. And aromatic heterocycles.
Specifically, thiophene, furan, pyrrole, imidazole, pyrazole, oxazole, isoxazole,
Oxadiazole such as 1,2,4-oxadiazole or 1,3,4-oxadiazole, thiadiazole such as 1,2,4-thiadiazole or 1,3,4-thiadiazole, thiazole, isothiazole, pyridine And aromatic heterocycles such as pyrimidine and pyridazine. As the above “7 to 12 membered condensed aromatic ring”,
For example, a condensed polycyclic (preferably bicyclic) aromatic ring and the like can be mentioned. Examples of the "fused polycyclic aromatic ring" include fused polycyclic aromatic hydrocarbons, fused polycyclic aromatic heterocycles, and the like. Examples of the “condensed polycyclic aromatic hydrocarbon” include condensed polycyclic (bicyclic) aromatic hydrocarbons having 7 to 12 carbon atoms. The "fused polycyclic aromatic heterocycle" is, for example, a 7 to 12-membered one containing one or more (for example, 1 to 4) heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom. Examples include condensed polycyclic aromatic heterocycles.

The "condensed ring which may further have a substituent or a 4- to 8-membered ring which may have a substituent" represented by the above-mentioned C ring is "condensed. The “ring” of “may” and “ring optionally having substituent (s)” is preferably a monocyclic saturated ring or aromatic ring.

As the 4- to 8-membered ring represented by C ring, for example, a nitrogen-containing heterocycle is preferable, and particularly tetrahydropyrrole, hexahydropyridine, hexahydropyrazine, tetrahydro-1,4-oxazine, tetrahydro-
1,4-thiazine, perhydroazepine and pyrrole are preferably used.

In the above formula, "aromatic group optionally having substituent (s)", "monocyclic aromatic group optionally having substituent (s)" and "having substituent (s)" represented by Ar ¹ Optionally a phenyl group, a furyl group, a thienyl group or a pyridyl group ", A
"Benzene ring optionally having substituent (s)" represented by ring and B'ring, "aromatic ring optionally having substituent (s)" represented by ring B, "further substituent (s) represented by ring C""A ring which may have a substituent may be condensed and a 4- to 8-membered ring which may have a substituent" in "a 4- to 8-membered ring which may have a substituent". "Substituent" and "substituent" of "which may further have a ring which may be condensed"
For example, a halogen atom (eg, fluorine, chlorine,
Bromine, iodine, etc.), nitro, cyano, optionally halogenated C _1-6 alkyl, C _{6-10 aryloxy-}
C _1-6 alkyl (eg phenoxymethyl etc.), C _1-6 alkyl-C _6-10 aryl-C _2-6 alkenyl (eg methylphenylethenyl etc.), optionally halogenated C _{3- 6} cycloalkyl, optionally substituted C
_7-16 aralkyl, optionally substituted C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, optionally substituted C _6-10 aryloxy , C _6-10 aryl-C _1-6 alkyloxy
(Eg, phenylmethyloxy, etc.), C _6-10 aryl-
C _7-16 aralkyloxy (eg, phenylbenzyloxy etc.), amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino etc.), di-C _{1- 6} alkylamino (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), optionally substituted 5- to 7-membered saturated cyclic amino, acyl, acylamino, acyloxy, substituent C _6-14 aryl which may have, 5- to 10-membered aromatic heterocyclic group which may have a substituent), 5 to 7
Saturated Hajime Tamaki other than membered saturated cyclic amino (e.g., tetrahydropyran, tetrahydrofuran, 1,4-dioxane) and the like, with preference given to a halogen atom, a halogenated which may be C _1-6 alkyl, a substituent _Optionally possessed C _7-16 aralkyl, _optionally halogenated C
_1-6 alkoxy, C _6-10 aryloxy which may have a substituent, acyl, acylamino, phenyl, naphthyl, pyridyl, furyl, thienyl, tetrahydropyran, tetrahydrofuran and the like are preferable.

The "aromatic group" of the "optionally substituted aromatic group" represented by Ar ¹ includes, for example, 1 to 5 substituents at the substitutable position of the aromatic group. , Preferably 1 to 3, and when the number of substituents is 2 or more, each substituent may be the same or different. When the substituent is cyclic, the aromatic ring of the aromatic group and the substituent may be bonded to each other by a spiro bond.
Further, the “benzene ring” of the “benzene ring which may have a substituent” represented by the A ring and the B ′ ring is, for example,
The above-mentioned substituents may be present at 1 to 4, preferably 1 to 2, at substitutable positions on the benzene ring. When the number of substituents is 2 or more, each substituent may be the same or different. Good. Further, when the substituent is cyclic, the benzene ring and the substituent may be bonded to each other by a spiro bond. Further, the “aromatic ring” of the “optionally substituted aromatic ring” represented by ring B is, for example, 1 to 4 substituents at the substitutable position of the aromatic ring, preferably It may have 1 or 2, and when the number of substituents is 2 or more,
Each substituent may be the same or different. Further, when the substituent is cyclic, the aromatic ring and the substituent may be bonded to each other by a spiro bond. Further, “4 to 8” of “4 to 8 membered ring which may be condensed with a ring which may further have a substituent and which may have a substituent” represented by C ring
The “8-membered ring” may have, for example, 1 to 4, preferably 1 or 2, the above-mentioned substituents at substitutable positions on the ring. When the number of substituents is 2 or more, each substituent is May be the same or different. Further, when the substituent is cyclic, the ring and the substituent may be bonded to each other by a spiro bond. In addition, a "ring which may further have a substituent may be condensed, and a 4- to 8-membered ring which may have a substituent" represented by the C ring may be "condensed. "
The “ring” may have, for example, 1 to 4, preferably 1 or 2, the above-mentioned substituents at substitutable positions on the ring. When the number of substituents is 2 or more, each substituent is It may be the same or different. When the substituent is cyclic,
The ring and the substituent may be bonded by a spiro bond.

Examples of the “C _7-16 aralkyl” of the above “C _7-16 aralkyl _optionally having a substituent” include, for example,
Examples thereof include benzyl, phenethyl and naphthylmethyl. As the "C _1-6 alkoxy" of the "C _1-6 alkoxy optionally having substituent (s)", for example, methoxy, ethoxy, propoxy, butoxy, and the like. Examples of the “C _6-10 aryloxy” of the above “C _6-10 aryloxy _optionally having a substituent” include, for example,
Examples include phenyloxy and naphthyloxy. In the above "C _6-14 aryl which may have a substituent (s)", "C
Examples of the “ _6-14 aryl” include naphthyl such as phenyl, 1-naphthyl or 2-naphthyl, indenyl such as 2-indenyl, anthryl such as 2-anthryl and the like. Preferred is phenyl and the like. The "5- to 10-membered aromatic heterocyclic group" of the "5- to 10-membered aromatic heterocyclic group which may have a substituent (s)" is, for example, pyridyl such as 2-, 3- or 4-pyridyl, Examples include indolyl such as 1-, 2- or 3-indolyl, thienyl such as 2- or 3-thienyl, and the like. Pyridyl such as 2-, 3- or 4-pyridyl is preferable. These "C _7-16 aralkyl which may have a substituent", "C _1-6 alkoxy which may have a substituent", "C which may have a substituent"
_6-10 aryloxy "," C which may have a substituent (s)
_{Examples of} the “substituent” of “ _6-14 aryl” and “5- to 10-membered aromatic heterocyclic group optionally having substituent (s)” include, for example, a halogen atom (eg, fluorine, chlorine, bromine,
Iodine etc.), C _1-3 alkylenedioxy (eg methylenedioxy, ethylenedioxy etc.), nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _{3 -6} cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino (eg methylamino,
Ethylamino, propylamino, isopropylamino,
Butylamino, etc.), di-C _1-6 alkylamino (eg,
Dimethylamino, diethylamino, dipropylamino,
Dibutylamino, ethylmethylamino, etc.), formyl, carboxy, carbamoyl, optionally halogenated C _1-6 alkyl-carbonyl, C _1-6 alkoxy-
Carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), mono-C _1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _1-6 alkyl-carbamoyl ( (Eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), optionally halogenated C
_1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl-carboxamide, C
_1-6 alkoxy-carboxamide (eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc.), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino,
Ethylsulfonylamino etc.), C _1-6 alkyl-carbonyloxy (eg acetoxy, propanoyloxy etc.), C _1-6 alkoxy-carbonyloxy (eg methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyl) Oxy), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C _1-6 alkyl-carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), etc. 1 to 5 are mentioned.

The "5- to 7-membered saturated cyclic amino" of the above-mentioned "5- to 7-membered saturated cyclic amino optionally having substituent (s)" is, for example, morpholino, thiomorpholino,
Piperazin-1-yl, piperidino, pyrrolidine-1-
And hexamethyleneimine-1-yl. Examples of the “substituent” of the “5- to 7-membered saturated cyclic amino _optionally having substituent (s)” include C _1-6 alkyl, _optionally substituted C _6-14 aryl, substituted A C _7-19 aralkyl which may have a group, a 5- to 10-membered aromatic heterocyclic group which may have a substituent, a C _6-10 aryl-carbonyl which may have a substituent, Examples thereof include 1 to 3 optionally halogenated C _1-6 alkyl-carbonyl, optionally halogenated C _1-6 alkylsulfonyl and the like. Examples of the “C _6-14 aryl” of the “C _6-14 aryl which may have a substituent” include naphthyl such as phenyl, 1-naphthyl or 2-naphthyl, indenyl such as 2-indenyl, and 2 -Anthril such as anthryl and the like. Preferred is phenyl and the like. "C which may have a substituent
“C _7-19 aralkyl” of “ _7-19 aralkyl” includes, for example, benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl. , 4-phenylbutyl, 5-phenylpentyl and the like. Preferred is benzyl and the like. Examples of the “5- to 10-membered aromatic heterocyclic group” of the “5- to 10-membered aromatic heterocyclic group which may have a substituent” include, for example, 2
Pyridyl, such as-, 3- or 4-pyridyl, 1-, 2
-Or 3-indolyl and the like indolyl, 2- or 3-thienyl and the like thienyl, and the like. Pyridyl such as 2-, 3- or 4-pyridyl is preferable. Of - "carbonyl optionally having substituent C _6-10 aryl" - as the "C _6-10 aryl-carbonyl", e.g., benzoyl, 1-naphthoyl, and the like 2-naphthoyl.

These "C which may have a substituent"
_6-14 aryl "," _optionally substituted C _7-19 aralkyl "," _optionally substituted 5 to 10 "
“Aromatic heterocyclic group” and “C _6-10 aryl-carbonyl _optionally having substituent (s)” may each have a “substituent”, for example, a halogen atom (eg,
Fluorine, chlorine, bromine, iodine etc.), C _1-3 alkylenedioxy (eg methylenedioxy, ethylenedioxy etc.), nitro, cyano, optionally halogenated C
_1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio,
Hydroxy, amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino,
Isopropylamino, butylamino, etc.), di-C _1-6
Alkylamino (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), formyl, carboxy, carbamoyl,
An optionally halogenated C _1-6 alkyl - carbonyl, C _{1 -6} alkoxy - carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
tert-butoxycarbonyl, etc.), mono-C _1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.) , Optionally halogenated C _1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide (eg,
Methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc.), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C
_1-6 alkyl-carbonyloxy (eg, acetoxy, propanoyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C _1-6 alkyl-
1 to 5 carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.) and the like can be mentioned.

“Aromatic group optionally having substituent (s)”, “monocyclic aromatic group optionally having substituent (s)” and “substituent having substituent (s)” represented by Ar ^1. A phenyl group, a furyl group, a thienyl group or a pyridyl group ", a" benzene ring which may have a substituent "represented by A ring and B'ring, and a" substituent group represented by B ring ""Acyl" in "acyl", "acylamino" and "acyloxy" as "substituent" of "optionally substituted aromatic ring" or "4 to 8-membered ring which may have a substituent" represented by C ring.
Are formyl, carboxy, carbamoyl, optionally halogenated C _1-6 alkyl-carbonyl,
C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, te
rt-butoxycarbonyl, etc.), optionally substituted C _6-10 aryl-carbonyl, _optionally substituted C _6-10 aryloxy-carbonyl, _optionally substituted Good C _7-16 aralkyloxy-carbonyl, _optionally substituted 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl (eg, dimethyl Carbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), optionally substituted C _6-10 aryl-carbamoyl, optionally substituted 5-6 membered heterocyclic carbamoyl, halogenated a C _1-6 alkylsulfonyl, and the like optionally C _6-10 arylsulfonyl optionally having substituent, inter alia an optionally halogenated C _1-6 alkyl - Cal Alkylsulfonyl, C _1-6 alkoxy - carbonyl (e.g., ethoxycarbonyl), optionally C _6-10 aryl optionally having substituent - carbonyl which may have a substituent C _6-10 arylsulfonyl such as Is mentioned.

The above-mentioned "C which may have a substituent"_6-10A
"C of reel-carbonyl"_6-10Aryl-Carbonii
Examples of “ru” include benzoyl, 1-naphthoyl,
2-naphthoyl and the like can be mentioned. The above "having a substituent
May be C_6-10Aryloxy-carbonyl "
"C _6-10For example, "aryloxy-carbonyl"
For example, phenoxycarbonyl and the like can be mentioned. The above
C which may have a substituent_7-16Aralkyl Oxy-Cal
Bonil's "C_7-16Aralkyloxy-carbonyl "
Are, for example, benzyloxycarbonyl, phenethyl
Luoxycarbonyl and the like. The above "substituent
"5- to 6-membered heterocyclic carbonyl which may have" "5-
“6-membered heterocyclic carbonyl” includes, for example, nicotinoi
Le, isonicotinoyl, 2-thenoyl or 3-tenoy
Such as tenole, 2-furoyl or 3-furoyl
Which furoyl, morpholinocarbonyl, piperidinocar
Bonyl, pyrrolidin-1-ylcarbonyl and the like can be mentioned.
Be done. The above "C which may have a substituent"_6-10Aryl
-C of "carbamoyl"_6-10Aryl-carbamoyl "
As, for example, phenylcarbamoyl, 1-naphthyl
Examples include rucarbamoyl and 2-naphthylcarbamoyl.
To be The above-mentioned "5- or 6-membered heterocyclic group which may have a substituent"
"5- to 6-membered heterocyclic carbamoyl" of "cyclic carbamoyl"
For example, 2-pyridylcarbamoyl, 3-pyridyl
Zircarbamoyl or 4-pyridylcarbamoyl etc.
Of pyridylcarbamoyl and 2-thienylcarbamoyl
Or thienylcarbamoyl such as 3-thienylcarbamoyl
Ile, etc. The above "may have a substituent
I C_6-10"C" of "arylsulfonyl"_6-10Arylsul
“Honyl” includes, for example, benzenesulfonyl, 1-
Naphthalenesulfonyl, 2-naphthalenesulfonyl, etc.
Is mentioned.

These "C _{6-10 optionally} having substituent (s)
"Aryl-carbonyl", "optionally substituted _C6-10 aryloxy-carbonyl", "optionally substituted _C7-16 aralkyloxy-carbonyl",
"5- or 6-membered heterocyclic carbonyl optionally having substituent (s)", " _C6-10 aryl-carbamoyl _optionally having substituent (s)", "5-membered heterocyclic carbonyl _optionally having substituent (s) 5" The “substituent” of “6-membered heterocyclic carbamoyl” and “optionally substituted C _6-10 arylsulfonyl” includes halogen atom, C _1-3 alkylenedioxy, nitro, cyano, and halogenated. _Optionally C _1-6 alkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di —C _1-6 alkylamino, formyl, carboxy, carbamoyl, optionally halogenated C _1-6 alkyl-carbonyl, C
_1-6 alkoxy-carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, optionally halogenated C _1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl - carboxamide, C _{1 -6} alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl 1 to 5 substituents, preferably 1 to 3 substituents selected from carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy are mentioned, among which a halogen atom and optionally halogenated C _{1- 6} alkyl, optionally halogenated C
_1-6 alkoxy and the like are preferable.

"Aromatic group optionally having substituent (s)", "monocyclic aromatic group optionally having substituent (s)" and "substituent having substituent (s)" represented by Ar ¹ A phenyl group, a furyl group, a thienyl group or a pyridyl group ", a" benzene ring which may have a substituent "represented by A ring and B'ring, and a" substituent group represented by B ring " Examples of the “acylamino” as the “substituent” of the “optionally substituted aromatic ring” and the “optionally substituted 4- to 8-membered ring” represented by the C ring include, for example, the above-mentioned “having a substituent”. Amino which is substituted by 1 or 2 “acyl” as described in “Substituent” of “optionally substituted aromatic group” is mentioned, preferably formylamino, optionally halogenated C _1-6 Alkyl-carboxamide, optionally substituted C
_6-10 aryl-carboxamide (eg, phenylcarboxamide, naphthylcarboxamide, etc.), C _1-6 alkoxy-carboxamide (eg, methoxycarboxamide,
Ethoxycarboxamide, propoxycarboxamide,
Butoxycarboxamide, etc.), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.) and the like.

"Aromatic group optionally having substituent (s)", "monocyclic aromatic group optionally having substituent (s)" and "substituent having substituent (s)" represented by Ar ¹ A phenyl group, a furyl group, a thienyl group or a pyridyl group ", a" benzene ring which may have a substituent "represented by A ring and B'ring, and a" substituent group represented by B ring " Examples of the “acyloxy” as the “substituent” of the “optionally substituted aromatic ring” and the “optionally substituted 4- to 8-membered ring” represented by the C ring include, for example, the above-mentioned “having a substituent”. Oxy substituted with one "acyl" as described in detail in "Substituent" of "optionally substituted aromatic group" may be mentioned, preferably C _1-6 alkyl-carbonyloxy (eg, acetoxy, propanoyloxy). etc.), which may have a substituent C _6-10 aryl - carbonyloxy Examples, benzoyloxy, 1-
Naphthoyloxy, 2-naphthoyloxy, etc.), C
_1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.),
Mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C _1-6 alkyl-carbamoyloxy (eg,
Dimethylcarbamoyloxy, diethylcarbamoyloxy and the like), optionally substituted C _6-10 aryl-carbamoyloxy (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy and the like), nicotinoyloxy and the like.

In the compound represented by the above formula (I), R ¹ is preferably a hydrogen atom or an optionally substituted hydroxy group. The hydroxy group which may be substituted is more preferably an alkyloxy group or an acyloxy group. R ² is preferably a hydrogen atom or a lower alkyl group which may have a substituent, and a hydrogen atom or C
_{A 1-6} alkyl group is more preferable, and a methyl group is particularly preferable. Ar ¹ is preferably a monocyclic aromatic group which may have a substituent, more preferably a phenyl group, a furyl group, a thienyl group or a pyridyl group which may have a substituent, and a halogen atom. , A C _1-3 alkylenedioxy group, an optionally halogenated C _1-6 alkyl group or a phenyl group optionally substituted with an optionally halogenated C _1-6 alkoxy group are particularly preferable. A
The ring is preferably an unsubstituted benzene ring. As the B ring, an optionally substituted benzene ring is preferable, and an unsubstituted benzene ring is more preferable. The C ring is preferably a 5-7 membered saturated ring which may have a substituent, more preferably a 5-7 membered saturated heterocyclic ring which may have a substituent, and has a substituent. And more preferably a nitrogen-containing 5-7 membered saturated heterocycle, which may have a substituent, tetrahydropyrrole, hexahydropyridine, hexahydropyrazine, tetrahydro-1,4-oxazine, tetrahydro-1,4-thiazine , Perhydroazepine, are particularly preferred. In addition, as the C ring, a ring formed by condensing a monocyclic ring which may have a substituent in addition to the B ring (hereinafter, except for the B ring, the monocyclic rings are condensed to form 2 rings). May be referred to simply as a bicyclic fused ring), and among them, a bicyclic fused heterocycle which may have a substituent is preferable. A nitrogen-containing bicyclic condensed heterocycle which may have a substituent is more preferable, and indole and isoquinoline which may have a substituent are particularly preferable. In this case, it is preferable that carbazole and 5,6-dihydrophenanthridine are constituted by the B ring and the C ring, respectively. N is preferable as X. As Y, CH is preferable. X
It is preferable that at least one of Y and Y is N. Further, in the above formula (I), it is preferable that the configurations at the 2-position and the 4-position are cis-forms. The above formula (I)
The compound represented by, in particular, (−)-2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroquinoline-1- Yl) -1,2,3,4-tetrahydroquinoline,
(−)-2,4-cis-4- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl
-1,2,3,4-tetrahydroquinoline, 2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroquinolin-1-yl )-1,2,3,4-tetrahydroquinoline,
2,3-trans-2,4-cis-3-acetoxy-1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroquinolin-1-yl)- 1,2,3,4-tetrahydroquinoline, 2,4-cis-4- (3,4-dihydro-2H-1,4-benzothiazin-4-yl) -1
-(3,4-Dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline, 2,4-cis-4- (1-benzyl-1,2,3,4-
Tetrahydroquinoxalin-4-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline, 2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl
-4- (2,3,4,5-tetrahydro-1H-1-benzazepinyl)-
1,2,3,4-tetrahydroquinoline, 2,3-trans-2,4-cis-3-{[(benzylamino) carbonyl] oxy} -1- (3,4
-Dimethoxybenzoyl) -2-methyl-4- (2,3,4,5-tetrahydro-1H-1-benzazepinyl) -1,2,3,4-tetrahydroquinoline, 2,4-cis-4- (9H -9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline, (−)-2,4-cis-4- (9H-9-carbazolyl ) -1-
(3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline, or 2-butyl-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl)- It is preferably 1,2-dihydroquinoline.

The salt of the compound represented by the formula (I) (hereinafter sometimes abbreviated as compound (I)) is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base or an organic base. , A salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N ′, N′-dibenzylethylenediamine and the like. . Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, Examples thereof include salts with p-toluenesulfonic acid.
Suitable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine,
Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.

The prodrug of compound (I) is a compound which is converted into compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in the living body, that is, a compound which undergoes enzymatic oxidation, reduction, hydrolysis or the like. Compound that changes to (I), Compound (I) that undergoes hydrolysis by gastric acid, etc.
A compound that changes to. As a prodrug of compound (I), a compound in which the amino group of compound (I) is acylated, alkylated or phosphorylated (eg, amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, tetrahydropyranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated Compounds, etc.); A compound in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated) ,
Fumarylated, alanylated, dimethylaminomethylcarbonylated, tetrahydropyranylated compounds, etc.);
A compound in which the carboxyl group of compound (I) is esterified or amidated (eg, the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxy) Methyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-
Methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, etc.); and the like. These compounds can be produced from compound (I) by a known method. Also,
The compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.). Furthermore, the compound (I) may be an anhydride or a hydrate.

The production method of compound (I) is described below. The following description of the production method applies not only to compound (I) but also to salts and prodrugs thereof, but it may be simply referred to as compound (I) in the following description. Also,
Each compound used in the production of compound (I) also includes a salt thereof and a prodrug thereof even when abbreviated as compound (II).
Compound (I) can be produced by a known method, for example, by the method shown in the following production method. The compound (I) thus obtained is obtained from the reaction mixture by known means, for example, solvent extraction, concentration, neutralization, filtration, crystallization, recrystallization, column chromatography, high performance liquid chromatography, recrystallization and the like. The desired product can be isolated and purified with high purity from the reaction solution.

The compound (I) may be a hydrate or an anhydrate. Examples of the hydrate include monohydrate, hemihydrate, dihydrate and the like. In addition, compound (I)
May be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) and the like. When the compound (I) of the present invention or a salt thereof has an asymmetric carbon, the obtained mixture of the optically active substances (racemic form) can be obtained by a conventional optical resolution means such as an optically active acid (eg camphorsulfonic acid). Alternatively, a method for producing a salt with an optically active base (eg, 1-methylbenzylamine, etc.), various chromatography (eg, liquid chromatography using an optically active column, etc.), and separation means such as fractional recrystallization can be used to separate It can be divided into optically active forms.

"Room temperature" usually indicates 0 to 30 ° C. Each symbol in the chemical structural formulas described in the production method has the same meaning as described above unless otherwise specified. In the present specification, "leaving group"
Is a halogen atom (eg, chloro, bromo, iodo, etc.), an optionally halogenated C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), a substituent C _6-10 arylsulfonyloxy, hydroxy and the like which may be present are shown. The “substituent” of the “C _6-10 arylsulfonyloxy optionally having substituent (s)” includes a halogen atom, an optionally halogenated C _1-6 alkyl, C _1-6 alkoxy and the like. One to three can be mentioned. Specific examples of the “C _6-10 arylsulfonyloxy optionally having substituent (s)” are:
Examples thereof include benzenesulfonyloxy, p-toluenesulfonyloxy, 1-naphthalenesulfonyloxy, 2-naphthalenesulfonyloxy and the like.

In the present specification, "base" means 1) for example, hydride of alkali metal or alkaline earth metal (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metal Or alkaline earth metal amides (eg, lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc.), alkali metal Or a lower alkoxide of an alkaline earth metal (eg,
Strong bases such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.) 2) For example, alkali metal or alkaline earth metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, water) Barium oxide, etc.), alkali metal or alkaline earth metal carbonates (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal hydrogen carbonates (eg, sodium hydrogen carbonate, potassium hydrogen carbonate) Or the like); or 3) For example, triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4.0] undes-7-ene), DBN ( 1,5-diazabicyclo [4.3.0] non-5 En) amines such as is shown for example pyridine, imidazole, 2,6-lutidine and organic bases such as basic heterocyclic compounds such as. Reactions described herein, such as alkylation reactions, hydrolysis reactions,
Known methods are used for the amination reaction, esterification reaction, amidation reaction, esterification reaction, etherification reaction, oxidation reaction, reduction reaction and the like. For example, Organic Functional Group Preparations (OR
GANIC FUNCTIONAL GROUP PR
EPARATIONS) 2nd edition, Academic Press, Inc. (Academic Press, Inc.) 198
The methods described in 9-year publications and the like can be mentioned.

The specific method for producing compound (I) is shown below. Manufacturing method 1

[Chemical 43] [In the formula, each symbol has the same meaning as described above. The compound (1a) in which X is N and Y is CH in the above compound (I) is prepared by following the method described in the literature (eg, tetrahedron letters 38 (15) 2673 (1997)). Alternatively, it can be produced by substituting the compound (II) in the presence of a base. As the base, those mentioned above are used, but preferably potassium carbonate, sodium carbonate, barium carbonate, sodium hydrogen carbonate, triethylamine, N-methylmorpholine, pyridine and the like are used. The amount of base used is
It is preferably 1 to 10 equivalents. This reaction is carried out in an inert solvent. Examples of the “inert solvent” include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents and the like, and the reaction temperature is −20. C. to 200.degree. C., preferably 0.degree. C. to 50.degree. The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours. As the compound (II), commercially available anilines, anilines synthesized by the method described in New Experimental Chemistry Course, Volume 14 (III), etc. are used. The amount used is preferably 1 to 10 equivalents. When a compound in which the reactive substituent Q ¹ is a reactive substituent other than a hydroxyl group is used as the intermediate compound (III ′), such a compound (III ′) is reactively substituted for the hydroxy group of the compound (III). It can be produced by converting it into a group Q ¹ . Examples of the reactive substituent include a halogen atom (eg, chlorine, bromine, iodine, etc.), an optionally halogenated C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy). Etc.), and optionally substituted C _6-10 arylsulfonyloxy and the like. The “substituent” in the “C _6-10 arylsulfonyloxy optionally having substituent (s)” is, for example, a halogen atom (eg, chlorine, bromine, iodine, etc.), or optionally halogenated C _{1 -6} alkyl or C _1-6 alkoxy. The number of substituents is, for example, 1 to 3. Specific examples of the "optionally substituted C _{6- 10} arylsulfonyloxy" are benzenesulfonyloxy, p- toluenesulfonyloxy, 1-naphthalene sulfonyloxy, such as 2-naphthalene sulfonyloxy and the like. The “reactive substituent” is preferably a halogen atom (eg, chlorine, bromine, iodine, etc.), methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy and the like. The halogenation reaction is carried out, for example, by reacting the compound (III) with 1 to
It is carried out by reacting 10 equivalents of a halogenating agent in an inert solvent. Examples of the halogenating agent include inorganic acid halides such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride; hydrohalic acids such as hydrochloric acid and hydrobromic acid, or iodotrimethyl. Examples thereof include silyl halides such as silane, and preferably iodotrimethylsilane is used. Examples of the "inert solvent" include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, sulfoxide solvents and the like. Reaction temperature is -20 ° C to 200 ° C. , Preferably 0 ℃
To 100 ° C. The reaction time is 0.1 to 48 hours,
It is preferably 1 to 24 hours. The sulfonylation reaction is carried out, for example, by reacting compound (III) with 1 to 5 equivalents of the corresponding sulfonyl halide in the presence of a base in an inert solvent. The base is preferably potassium carbonate, sodium hydrogen carbonate, triethylamine, N-
Examples include methylmorpholine and pyridine. The amount of base used is preferably 1 to 10 equivalents. "Inert solvent"
Examples of the reaction temperature include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, and the like, and the reaction temperature is -20 ° C to 200 ° C. Preferably 0 ° C to 1
It is 00 ° C. The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours. As the compound (II), commercially available anilines, anilines synthesized by the method described in Shin Jikken Kagaku Koza 14 (III), etc. are used. The amount used is preferably 1 to 10 equivalents. As the base, those mentioned above are used, but preferably potassium carbonate,
Examples thereof include barium carbonate, sodium hydrogen carbonate, triethylamine, N-methylmorpholine and pyridine. The amount of base used is preferably 1 to 10 equivalents. This reaction is carried out in an inert solvent. Examples of the “inert solvent” include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents and the like, and the reaction temperature is −20. C. to 200.degree. C., preferably 0.degree. C. to 50.degree. The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours.

Compound (III) can be produced by reducing compound (IV) with a suitable reducing agent in an inert solvent.
Examples of the “inert solvent” include alcohol solvents,
Examples thereof include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, organic acid solvents and the like. These may be used as a mixture of two or more kinds at an appropriate ratio. Of these, methanol and ethanol are preferable. Examples of the reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride and the like. The amount of reducing agent used is usually
It is 1 to 20 equivalents, preferably 1 to 5 equivalents. The reaction temperature is generally -20 ° C to 150 ° C, preferably 0 to 50 ° C.
℃. The reaction time is generally 5 minutes to 24 hours, preferably 1 to 12 hours. Compound (IV) is compound (V)
Can be produced by subjecting compound (VI) to an amidation reaction.

This step can be carried out by a method using a dehydration condensing agent or a method in which the compound (VI) is once converted into its reactive derivative and then condensed. i) Method using dehydration condensation agent 1 equivalent of compound (V) or a salt thereof, 1 equivalent to 5 equivalents of compound
(VI) and 1 equivalent to 2 equivalents of the dehydration condensing agent are reacted in an inert solvent at room temperature for 10 hours to 24 hours. As needed,
1 equivalent to 1.5 equivalents of 1-hydroxybenzotriazole (HO
The reaction may be carried out by adding BT) and / or a catalytic amount to 5 equivalents of a base (eg, triethylamine, 4-dimethylaminopyridine, etc.). Examples of the "dehydration condensing agent" include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) and the like. Of these, WSC is preferable. As the inert solvent, for example, a nitrile solvent (preferably acetonitrile), an amide solvent (preferably dimethylformamide (DMF)), a halogenated hydrocarbon solvent (preferably dichloromethane), an ether solvent (preferably tetrahydrofuran ( THF)) or a mixture of two or more thereof.

Ii) Method using reactive derivative of compound (VI) Reactive derivative of compound (VI) and 1 equivalent to 5 equivalents (preferably 1 equivalent to 3 equivalents) of compound (V) in an inert solvent, -20 ° C
~ 50 ° C (preferably room temperature), 5 minutes to 40 hours (preferably 1
React for ~ 18 hours). If necessary, the reaction may be carried out in the coexistence of 1 equivalent to 10 equivalents, preferably 1 equivalent to 3 equivalents of the base. Examples of the “reactive derivative” of the compound (VI) include acid halides (eg, acid chloride, acid bromide, etc.), mixed acid anhydrides (eg, C _1-6 alkyl-carboxylic acid, C _6-10 aryl-carboxylic acid). Or an acid anhydride such as C _1-6 alkyl carbonic acid), active ester (eg, optionally substituted phenol, 1-hydroxybenzotriazole or N-
Esters with hydroxysuccinimide, etc.) and the like. The "phenol which may have a substituent"
The "substituent" include halogen atom, nitro, and five to no 1 optionally halogenated C _1-6 alkyl or halogenated which may be C _{1 -6} alkoxy. Specific examples of the "phenol which may have a substituent" include phenol, pentachlorophenol, pentafluorophenol, p-nitrophenol and the like. Acid halides are preferred as reactive derivatives. As the "base", sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine and the like are preferable. As the inert solvent, for example, an ether solvent, a halogenated hydrocarbon solvent, an aromatic solvent, a nitrile solvent, an amide solvent, a ketone solvent, a sulfoxide solvent, water or the like alone or in combination of two or more thereof. It can be mixed and used. Of these, pyridine, acetonitrile, THF, dichloromethane, chloroform and the like are preferable. Among them, pyridine,
Further preferred are THF, acetonitrile and the like. Compound
(V) is a known method (for example, bio-organic and
Medicinal Chemistry Letters 9 1009 (1
999)) and the like).

Production Method 2

[Chemical 44] [In the formula, each symbol has the same meaning as described above. In the above compound (I), compound (1b) in which X is CH and Y is N is compound (VIII) in the presence of a suitable base in an inert solvent, and compound (VII) [in the formula, Q ² it can be prepared by reacting with the reactive substituent Q ^1, synonym of preparation 1, wherein. As the "base", the same ones as described above are used, but potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and the like are preferable. The amount of base used is preferably
1 to 10 equivalents. As the compound (VII), for example, commercially available alkyl chloride, alkyl bromide, alkyl iodide, or those synthesized by the method described in Shin Jikken Kagaku Koza 14 (I) can be used. The amount used is preferably 1 to 20 equivalents. Examples of the “inert solvent” include alcohol solvents, ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, and the like. . These may be used as a mixture of two or more kinds at an appropriate ratio. Among them, acetonitrile, DMF, DMSO,
Acetone and the like are preferable. The reaction temperature is usually about -20 ° C.
To 100 ° C, preferably room temperature to 80 ° C.
The reaction time is, for example, about 0.5 to 48 hours.
Compound (VIII) is prepared in the same manner as in Production method 1, and compound (IX)
Can be produced by subjecting compound (VI) to an amidation reaction. Compound (IX) can be prepared by known methods (e.g., Journal of Pharmaceuticals Bulletin 32 (6) 2421 ).
(1984)) and the like). Manufacturing method 3

[Chemical formula 45] [In the formula, each symbol has the same meaning as described above. ] In the above compound (I), compound (1a) wherein X is N and Y is CH
Refers to the oxirane ring of compound (XI), for example, the method described in the literature.
(Tetrahedron Letters 39 (21) 3459 (1998), etc.) to open the ring, and the hydroxy group of the resulting compound (X) is converted into R ¹ for production. The ring-opening reaction of the oxirane ring of compound (XI) is carried out by reacting compound (II) in an inert solvent in the presence of a catalyst if necessary. As the catalyst, aluminum chloride, zinc bromide, zinc chloride, titanium tetrachloride,
Lewis acid such as titanium tetraisopropoxide, trifluoroboron diethyl ether complex, inorganic acid such as hydrochloric acid and sulfuric acid, organic acid such as acetic acid and methanesulfonic acid, alkylaluminum reagent such as trimethylaluminum and triethylaluminum, sodium hydroxide Alkali metal or alkaline earth metal hydroxides such as potassium hydroxide and lithium hydroxide, sodium carbonate, potassium carbonate,
Alkali metal or alkaline earth metal carbonates such as cesium carbonate, alkali metal or alkaline earth metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, perchloric acid such as lithium perchlorate and sodium perchlorate Alkaline earth metal hydrides such as salts, sodium hydride and potassium hydride, alkali metal or alkaline earth metal amides such as sodium amide, lithium diisopropylamide and lithium hexamethyldisilazide, sodium methoxide, sodium Lower alkoxides of alkali metals or alkaline earth metals such as ethoxide and potassium tert-butoxide, organic bases such as triethylamine and DBU, tristriphenylphosphine palladium complex, cerium nitrate diammonium (I
V) and the like metal complexes and the like, preferably trimethylaluminum, triethylaluminum, zinc bromide,
Lithium perchlorate, diammonium cerium nitrate (IV),
Potassium hydroxide or the like is used. Examples of the inert solvent include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, alcohol solvents and the like. These may be used as a mixture of two or more kinds at an appropriate ratio. Among them, acetonitrile, TH
F, dichloromethane, chloroform and the like are preferable. This reaction is carried out in an amount of 1 to 20 equivalents relative to compound (XI), preferably
1.5 to 5 equivalents of compound (II), 0.01 to 1 if necessary
It is carried out using 0 equivalent, preferably 0.1 to 2 equivalents of catalyst. The reaction temperature is generally -50 ° C to 100 ° C, preferably 0.
℃ to 50 ℃. Reaction time is usually 5 minutes to 48 minutes
The time is preferably 0.5 to 18 hours. Compound (1a)
In R, when R ¹ is hydrogen, it is described in the literature (Journal of Organic Chemistry 65 (15) 4565 (200
0), Account of Chemical Research 25 (4) 188 (19
92) etc.), the hydroxy group of compound (X) is once converted into a reactive substituent, and then the reactive substituent can be reduced to produce the compound. Examples of the reactive substituent include a halogen atom (eg, chlorine, bromine, iodine, etc.), alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), arylsulfonyloxy (benzenesulfonyloxy, p-toluenesulfonyloxy, etc.), alkyldithiocarbonyloxy (methyldithiocarbonyloxy, etc.), arylthiocarbonyloxy (imidazolylthiocarbonyloxy, etc.), aryloxythiocarbonyloxy (phenoxythiocarbonyloxy), aryl Examples thereof include selenoxycarbonyloxy (phenylselenoxycarbonyloxy), and preferably methyldithiocarbonyloxy, imidazolylthiocarbonyloxy and the like. The conversion reaction into a reactive substituent can be carried out, for example, by reacting compound (X) with 1 to 10 equivalents of an activator,
It is carried out by reacting in an inert solvent, if necessary, in the presence of a base. Examples of the activator include inorganic acid halides such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride, hydrohalic acids such as hydrochloric acid and hydrobromic acid, and iodotrimethylsilane. And the like, sulfonyl halides such as methanesulfonyl chloride, sulfonyl chlorides such as p-toluenesulfonyl chloride, thiocarbonyldiimidazole, carbon disulfide-iodomethane system and the like are used. Examples of the “inert solvent” include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, sulfoxide solvents and the like. Reaction temperature is -50 ° C to 200 ° C. , Preferably 0 ℃
To 150 ° C. The reaction time is 0.1 to 48 hours,
It is preferably 1 to 24 hours. As the base, potassium carbonate, sodium hydrogen carbonate, triethylamine, N-methylmorpholine, pyridine and the like are preferably used. The reduction reaction of the reactive substituent is carried out, for example, by reacting the reactive substituent compound with 1 to 10 equivalents or a large excess of a reducing agent in an inert solvent. As the reducing agent, diborane, sodium borohydride, borohydride reagents such as lithium triethylborohydride, aluminum hydride reagents such as lithium aluminum hydride,
Tributyltin hydride A tin reagent such as AIBN, a silane reagent such as tristrimethylsilylsilane or triethylsilane, a metal such as zinc or chromium acetate, or catalytic hydrogenation is used. Examples of the “inert solvent” include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, sulfoxide solvents, alcohol solvents and the like. The reaction temperature is -50 ° C to 200 ° C, preferably 0 ° C to 150 ° C. The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours. In the compound (1a), R ¹
Is an alkoxy group, an acyloxy group, by a known method, alkylate the hydroxy group of the compound (X),
It can be produced by acylation. One such method is Organic Functional Group Preparations (ORGANIC FUNCT).
IONAL GROUP PREPARATIONS 2nd edition, Academic Press (Academic PR)
ESS, INC. ) 1989; Comprehensive Organic Transformation (Comprehe
nsive Organic Transformations) VCH Publishers In
c., published in 1989, etc. Compound
(XI) is a method known in the literature (for example, heterocycle 41
(5) It can be produced from compound (XII) according to 897 (1995). Compound (XII) can be produced by the production method 1 in addition to the method of the literature.
The compound (III) obtained in the above can be produced by subjecting it to a usual dehydration reaction. Manufacturing method 4

[Chemical formula 46] [In the formula, each symbol has the same meaning as described above. Compound (Ia) can be produced by subjecting compound (VI) to an amidation reaction in the same manner as in the production of compound (IV) described in Production method 1. Compound (XIII) can be prepared by a method known in the literature (for example, Journal of Organic Chemistry 60).
(13) 3993 (1995)) and the like. Manufacturing method 5

[Chemical 47] [In the formula, each symbol has the same meaning as described above. Compound (Ic) can be produced by reacting compound (X) with a base in an inert solvent, if necessary, in the presence of an activator. Examples of the “base” include hydrides of alkali metals or alkaline earth metals (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), amides of alkali metals or alkaline earth metals (eg, , Lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc.), lower alkoxide of alkali metal or alkaline earth metal (eg. , Sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal or alkaline earth metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.), alkali Metal or alkaline earth metal carbonates (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal hydrogen carbonates (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), triethylamine, diisopropyl Ethylamine, N-methylmorpholine, dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4.0]]
Amines such as undes-7-ene) and DBN (1,5-diazabicyclo [4.3.0] non-5-ene), basic heterocyclic compounds such as pyridine, imidazole, and 2,6-lutidine. Can be mentioned. Among the above bases, strong bases such as sodium hydride, sodium amide and potassium hydroxide are preferable. In the presence of an activator, organic bases such as triethylamine and pyridine are preferable. Examples of the “inert solvent” include ether solvents, halogenated hydrocarbon solvents, aromatic solvents,
Nitrile-based solvent, amide-based solvent, sulfoxide-based solvent,
Examples thereof include alcohol solvents and water. Examples of the activator include inorganic acid halides such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride, hydrohalic acids such as hydrochloric acid and hydrobromic acid, and iodotrimethylsilane. Such as silyl halides, acetyl chloride, acid chlorides such as benzoyl chloride, methanesulfonyl chloride, p-
Sulfonyl chlorides such as toluenesulfonyl chloride, carbonic acid chlorides such as ethyl chlorocarbonate, acid anhydrides such as acetic anhydride and trifluoromethanesulfonic anhydride, isocyanates such as methyl isocyanate, thioisocyanates, carbonyldiimidazole, thiocarbonyldiimidazole, etc. Is used. This reaction is compound (X)
In contrast, 1 to 20 equivalents, preferably 1.5 to 5 equivalents of base, 0.01 to 10 equivalents, preferably 1 to 2 equivalents of activator are used. The reaction temperature is generally -50 ° C to 200 ° C, preferably 0 ° C to 150 ° C. The reaction time is generally 5 minutes to 48 hours, preferably 0.5 to 18 hours.

The compound (I) or a salt thereof or a prodrug thereof has an excellent soluble beta-amyloid precursor protein secretagogue activity and has low toxicity, and has a low toxicity in humans and mammals (eg, mouse, rat, guinea pig, rabbit). , Dogs, cats, cows, pigs, sheep, monkeys, chimpanzees, etc.), it can be used as a safe soluble beta-amyloid precursor protein secretagogue, and can be used as an apoptosis inhibitor or an agent for improving neurological dysfunction. Therefore, the compound (I) or a salt thereof or a prodrug thereof is treated with Alzheimer's disease, Parkinson's disease, prion disease or neuropathy (preferably,
It can be safely used for humans and mammals as a prophylactic / therapeutic drug for neurodegenerative diseases such as diabetic neuropathy, etc., senile dementia, cerebrovascular dementia, and neuronal cell damage at the time of cerebrovascular disorder.

When the compound (I) or a salt thereof or a prodrug thereof is used as a medicine, it is orally mixed with an appropriate pharmacologically acceptable carrier, excipient, diluent, etc. (Eg powders, granules, tablets,
Capsules (including soft capsules and microcapsules), syrups, etc., parenteral administration (eg, injection,
Safely orally or parenterally administered as a pharmaceutical composition of an external preparation (eg, nasal preparation, transdermal preparation, etc.), suppository (eg, rectal suppository, vaginal suppository, etc.), pellets, etc. can do.

These preparations can be produced, for example, by applying known methods generally used in the production of preparations. The compounding ratio of the compound (I) in the preparation varies depending on its form, but is preferably about 10 to 95% by weight in the above-mentioned oral administration agent, for example, about 0.001 to 95 in the above-mentioned parenteral administration agent. Weight percent is preferred.

For example, injectable preparations include compound (I) as a solubilizer (eg, β-cyclodextrin) and a dispersant (eg,
Tween 80 (Atlas Powder, USA), HCO60 (Nikko Chemicals), carboxymethylcellulose, sodium alginate, etc., preservative (eg, methylparaben, propylparaben, benzyl alcohol, chlorobutanol, etc.), isotonic Aqueous injections can be prepared by conventional methods with agents (eg, sodium chloride, glycerin, sorbitol, glucose, etc.), or vegetable oils (eg, olive oil, sesame oil, peanut oil, cottonseed oil, corn oil, etc.), propylene glycol, etc. Alternatively, it may be dissolved, suspended or emulsified as appropriate to be molded into an oil injection. The orally-administered preparation can be prepared by adding the compound (I) to, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrant (eg, starch, calcium carbonate, etc.), a binder (eg, starch, gum arabic, carboxy). Methylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) are appropriately added and compression-molded, then if necessary, taste masking, enteric coating Alternatively, it can be produced by applying a coating or the like by a known method for the purpose of sustainability. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, and Eudragit (produced by ROHM Co., Ltd. , West Germany,
Methacrylic acid, acrylic acid copolymer), pigments (eg, titanium oxide, red iron oxide, etc.) and the like are appropriately used.

The compound (I) of the present invention can be used as a solid, semi-solid or liquid external preparation. For example, as a solid external preparation, compound (I) may be used as it is, or an excipient (eg, glycol, mannitol, starch,
Microcrystalline cellulose, etc.), thickeners (eg, natural gums, cellulose derivatives, acrylic acid polymers, etc.) added,
It can also be produced by mixing and forming a powdery composition. The semi-solid external preparation is preferably produced by a conventional method and used as an aqueous or oily gel or ointment. The liquid external preparation can also be produced by making it an oily or aqueous suspension by the means used for producing an injection or a means similar thereto.
In addition, solid, semi-solid or liquid external preparations, pH regulators (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoic acid esters, chlorobutanol) , Benzalkonium chloride, etc.) may be added appropriately. Specifically, for example, vaseline,
It can also be used as an ointment containing lanolin or the like as a base and usually containing about 0.1 to about 100 mg of the compound (I) of the present invention. Compound (I) can also be made into an oily or aqueous solid, semisolid or liquid suppository. Examples of oily bases for producing suppositories include higher fatty acid glycerides (eg, cacao butter, Witepsols (manufactured by Dynamite Nobel), etc.), intermediate fatty acids (eg, migliol acid (manufactured by Dynamite Nobel)). Etc.) or vegetable oil (eg, sesame oil, soybean oil, cottonseed oil, etc.) and the like are appropriately used. Further, as the aqueous base, for example, polyethylene glycols, propylene glycol, etc. are used, and as the aqueous gel base, for example, natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers, etc. are appropriately used.

The dose of the compound (I) or a salt thereof or a prodrug thereof varies depending on the target disease, the target human or mammal, symptoms, age, weight, symptoms, dosage form, administration method, administration period, etc. For example, when administered orally in the treatment of Alzheimer's disease, humans or mammals 6
Usually, about 0.1 to 100 mg, preferably about 0.1 to 50 mg, more preferably about 1 to 50 m of Compound (I) or a salt thereof or a prodrug thereof per 0 kg body weight.
g, especially about 2.5 to 50 mg, which is administered in 1 to 3 divided doses daily. Of course, since the dose varies depending on various conditions as described above, a dose smaller than the above dose may be sufficient in some cases, or a dose exceeding the range may be administered in some cases.

[0077]

EXAMPLES Hereinafter, examples and experimental examples will be described in order to explain the present invention in more detail, but the present invention is not limited to these examples and experimental examples.

Reference Example 1 cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4
-Tetrahydro-4-quinolinol

[Chemical 48] 1) 1- (3,4-Dimethoxybenzoyl) -2-methyl-2,3-dihydro-4 (1H) -quinolinone Literature Known methods (Bioorganic and Medicinal Chemistry Letters
9 1009 (1999)) was added to 2-methyl-2,3-dihydro-4 (1H) -quinolone (1.19 g, 7.38 mmol) in pyridine (15 m).
Dissolved in 1,3,4-dimethoxybenzoyl chloride 1.63g
(8.12 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated, ethyl acetate and water were added for extraction. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/2), and the eluate was recrystallized from ethyl acetate-hexane to give the desired product, cis- 1- (3,4-dimethoxybenzoyl) -2-methyl-2,3-
1.57 g (yield 65%) of dihydro-4 (1H) -quinolinone was obtained as white crystals. Elemental analysis value Calculated as C ₁₉ H ₁₉ NO ₄ : C, 70.14; H, 5.89; N, 4.31 Experimental value: C, 70.18; H, 5.86; N, 4.46 2) cis-1- (3,4-dimethoxy Benzoyl) -2-methyl-1,2,
Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-2,3-dihydro-4 (1H) -quinolinone obtained with 3,4-tetrahydro-4-quinolinol 1) 4.65 g (14.3 mmol)
Was dissolved in a mixed solution of 40 ml of methanol and 80 ml of THF, 540 mg (14.3 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was recrystallized from THF-hexane to give the desired product, cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-. 4-quinolinol
3.84 g (yield 82%) was obtained as white crystals. Calculated elemental analysis _{C 19 H 21 NO 4: C} , 69.71; H, 6.47; N, 4.28 Found: C, 69.88; H, 6.51 ; N, 4.18

Reference Example 2 1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-
4-quinolinol

[Chemical 49] 1) 1- (3,4-dimethoxybenzoyl) -2,3-dihydro-4
1- (3,4-dimethoxybenzoyl) -2,3- from (1H) -quinolinone 2,3-dihydro-4 (1H) -quinolone 2.60 g (16.54 mmol) in the same manner as in Reference Example 1-1). 4.42 g of dihydro 4 (1H) -quinolinone (yield 86
%) As white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.90 (2H, t, J = 6.3Hz), 3.80 (3H,
s), 3.90 (3H, s), 4.35 (2H, t, J = 6.3Hz), 6.76 (1H,
d, J = 8.4Hz), 6.95 (1H, d, J = 7.5Hz), 7.03-7.29 (4H,
m), 8.01 (1H, dd, J = 1.2Hz, 7.8Hz). 2) Obtained with 1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinol 1) 1- (3,4-dimethoxybenzoyl) -2,3-dihydro-4 (1H) -quinolinone 2.00g
From (14.3 mmol), white crystals of 1.54 g (yield 77%) of 1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinol in the same manner as in Reference Example 1-2) were obtained. Got as. ¹ H-NMR (CDCl ₃ ) δ: 2.05-2.13 (1H, m), 2.21-2.27 (1H,
m), 3.76 (3H, s), 3.76-3.84 (1H, m), 3.88 (3H, s), 4.
09-4.20 (1H, m), 4.89-4.90 (1H, m), 6.74 (1H, d, J = 7.
8Hz), 6.88 (1H, d, J = 7.8Hz), 6.96-7.12 (4H, m), 7.45
(1H, d, J = 6.0Hz).

Example 1 4- (Tetrahydroquinolin-1-yl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline

[Chemical 50] 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
400 mg (1.28 mmol) of 2,3,4-tetrahydro-4-quinolinol was dissolved in chloroform (10 ml), 638 mg (3.19 mmol) of iodotrimethylsilane was added under ice cooling, and the mixture was stirred for 2 hours. The reaction solution was concentrated, THF (10 ml) was added to the residue and dissolved, 1,2,3,4-tetrahydroquinoline 511 mg (3.84 mmol), barium carbonate 505 mg.
(2.56 mmol) was added, and the mixture was stirred at room temperature for 48 hours. The insoluble material was removed by filtration and then concentrated. The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/3), and the eluate was recrystallized from diethyl ether-hexane to give the desired product 4 -(Tetrahydroquinolin-1-yl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline 20
2 mg (37% yield) was obtained as white crystals. Elemental analysis value Calculated as C ₂₂ H ₂₁ N ₃ O ・ 0.20H ₂ O: C, 75.05; H, 6.62; N, 6.48 Experimental value: C, 74.88; H, 6.65; N, 6.31 Melting point: 88-90 ℃ (Crystallization solvent: diethyl ether-
Hexane)

Example 2 4- (2,3-Dihydro-1H-indol-1-yl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline

[Chemical 51] 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
In the same manner as in Example 1, from 2,3,4-tetrahydro-4-quinolinol (390 mg, 1.19 mmol) and indoline (425 mg, 3.57 mmol), the desired 4- (2,3-dihydro-1H-indole-) was obtained. 268 mg (yield 54%) of 1-yl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline was obtained as white crystals. Melting point: 121-123 ° C (crystallization solvent: ethyl acetate-hexane) FABMS (pos) 415.1 [M + H ⁺ ]

Example 3 4- (1′-benzylspiro [indoline-3,4′-piperidine] -1
-Yl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline

[Chemical 52] 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
250 mg (0.76 mmol) of 2,3,4-tetrahydro-4-quinolinol and
1'-benzyl spiro [indoline-3,4'-piperidine] 532mg
From (1.91 mmol), the target compound was obtained in the same manner as in Example 1.
4- (1'-benzylspiro [indoline-3,4'-piperidine] -1
211 mg (48% yield) of 2-yl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline were obtained as white crystals. Melting point: 155-157 ° C (crystallization solvent: diisopropyl ether-hexane) FABMS (pos) 574.2 [M + H ⁺ ]

Example 4 1- (3,4-Dimethoxybenzoyl) -2-methyl-4- (tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 53] Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 40 obtained in Reference Example 1
0 mg (1.22 mmol) and 1,2,3,4-tetrahydroquinoline 487 mg
From (3.66 mmol), the target compound was obtained in the same manner as in Example 1.
1- (3,4-dimethoxybenzoyl) -2-methyl-4- (tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydroquinoline
216 mg (40% yield) was obtained as a colorless oil. (Cis: trans = 1.6: 1) FABMS (pos) 465.2 [M + Na ⁺ ]

Reference Example 3 3- (3,4-dimethoxybenzoyl) -2-methyl-1a, 2,3,7b-tetrahydrooxyreno [2,3-c] quinoline

[Chemical 54] 10.2 g (0.033mo) of 1- (3,4-dimethoxybenzoyl) -2-methyl-1,2-dihydroquinoline synthesized by a method known in the literature
l) was dissolved in 50 ml of chloroform, and 17.08 g (0.099 mol) of metaperbenzoic acid was added over 1 hour under ice cooling. After stirring for 6 hours, ethyl acetate and an aqueous sodium thiosulfate solution were added for liquid separation, and the organic layer was washed with an aqueous sodium hydrogen carbonate solution and water, and then concentrated. The residue was subjected to silica gel column chromatography (developing solvent: chloroform), and the eluate was recrystallized from diisopropyl ether-hexane to give the title compound (7.3 g, yield 68%) as white crystals. Melting point 123-124 ℃

Reference Example 4 2,4-cis-4- (9H-9-carbazolyl) -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 55] According to a method known in the literature (J. Org. Chem. 1995, 60, 3993), benzotriazole 11.9 g (100 mmol), aniline 9.1 ml (100 m
mol) was dissolved in 200 ml of diethyl ether, and 6.1 ml (110 mmol) of acetaldehyde was added dropwise under ice cooling. The mixture was stirred at room temperature for 15 minutes and left at -20 ° C overnight. The crystallized product was collected by filtration, washed with diethyl ether and dried, and α-methyl-N-
Phenyl-1H-benzotriazole-1-methanamine 22.3g
Was obtained as white crystals. Obtained α-methyl-N-phenyl
-1H-benzotriazole-1-methanamine 2.31g (10mmo
l) and 1.93 g (10 mmol) of 9-vinylcarbazole were suspended in 10 ml of chloroform, and 20 mg of paratoluenesulfonic acid monohydrate was suspended.
(0.105 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with chloroform, the organic layer was washed with 10% aqueous sodium carbonate solution and water, and then concentrated. The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/10) to obtain 644 mg of the title compound (two-step yield 20%) as white crystals. ¹ H NMR (CDCl ₃ ) δ 1.27 (d, J = 6.3 Hz, 3H), 2.04-2.1
6 (m, 1H), 2.45 (q, J = 11.8 Hz, 1H), 3.74-3.85 (m,
1H), 3.90 (br s, 1H), 6.13 (dd, J = 11.9,6.4 Hz,
1H), 6.47 (t, J = 8.2 Hz, 1H), 6.63 (d, J = 8.3 H
z, 2H), 6.86-6.88 (m, 1H), 7.04 (t, J = 7.7 Hz, 1
H), 7.15 (dt, J = 7.3, 1.4 Hz, 2H), 7.22-7.30 (m,
1H), 7.40-7.60 (m, 2H), 8.08-8.15 (m, 2H)

Reference Example 5 2,4-cis-4- (9H-9-carbazolyl) -2-ethyl-1,2,3,4-tetrahydroquinoline

[Chemical 56] The title compound (1.79 g, two-step yield 39%) was obtained as white crystals from 0.91 g (15 mmol) of propylaldehyde by the same method as in Reference Example 4. ¹ H NMR (CDCl ₃ ) δ 0.98 (t, J = 7.4 Hz, 3H), 1.56-1.
66 (m, 2H), 2.15-2.22 (m, 2H), 2.41 (q, J = 12.0 H
z, 1H), 3.54-3.62 (m, 1H), 3.95 (br s, 1H), 6.13
(dd, J = 11.8, 6.3 Hz, 1H), 6.47 (t, J = 7.4 Hz, 1
H), 6.64 (t, J = 7.0 Hz, 2H), 6.80-7.51 (m, 7H), 8.
08-8.15 (m, 2H).

Reference Example 6 2,4-cis-4- (9H-9-carbazolyl) -2-propyl-1,2,3,4-
Tetrahydroquinoline

[Chemical 57] The title compound (1.67 g, two-step yield 27%) was obtained as white crystals from butyraldehyde (3.54 g, 40 mmol) in the same manner as in Reference Example 4. ¹ H NMR (CDCl ₃ ) δ 0.97 (t, J = 7.2 Hz, 3H), 1.30-1.
60 (m, 4H), 2.10-2.25 (m, 1H), 2.45 (q, J = 12.0 H
z, 1H), 3.60-3.75 (m, 1H), 3.95 (br s, 1H), 6.13 (d
d, J = 11.8, 6.3 Hz, 1H), 6.47 (t, J = 7.4 Hz, 1
H), 6.64 (t, J = 7.0 Hz, 2H), 6.80-7.60 (m, 7H), 8.
08-8.15 (m, 2H). FABMS (pos) 340.2 [M ⁺ ]

Reference Example 7 2,4-cis-2-butyl-4- (9H-9-carbazolyl) -1,2,3,4-tetrahydroquinoline

[Chemical 58] From 3.45 g (40 mmol) of valeric aldehyde, the title compound (2.12 g, 2-step yield: 23%) was obtained as white crystals by a method similar to that in Reference Example 4. ¹ H NMR (CDCl ₃ ) δ 0.91 (t, J = 6.8 Hz, 3H), 1.20-1.
80 (m, 6H), 2.10-2.25 (m, 1H), 2.44 (q, J = 11.7 H
z, 1H), 3.70-3.85 (m, 1H), 3.95 (br s, 1H), 6.12 (d
d, J = 11.8, 6.2 Hz, 1H), 6.40-6.70 (m, 3H), 6.80-
6.90 (m, 1H), 7.00-7.50 (m, 6H), 8.00-8.15 (m, 2
H). FABMS (pos) 354.1 [M ⁺ ]

Reference Example 8 2,4-cis-4- (9H-9-carbazolyl) -2-isobutyl-1,2,3,
4-tetrahydroquinoline

[Chemical 59] From 3.54 g (40 mmol) of isovaleric acid aldehyde, 2.52 g (2-step yield 54%) of the title compound was obtained as white crystals in the same manner as in Reference Example 4. ¹ H NMR (CDCl ₃ ) δ 0.95-0.98 (m, 6H), 1.35-1.60 (m,
2H), 1.70-1.85 (m, 1H), 2.10-2.20 (m, 1H), 2.38-2.
50 (m, 1H), 3.70-3.80 (m, 1H), 3.95 (br s, 1H), 6.1
3 (dd, J = 11.8, 6.3 Hz, 1H), 6.40-6.90 (m, 4H),
7.00-7.40 (m, 6H), 7.40-7.60 (m, 2H), 8.00-8.20
(m, 2H).

Reference Example 9 2,4-cis-4- (9H-9-carbazolyl) -2- (2-phenylethyl) -1,2,3,4-tetrahydroquinoline

[Chemical 60] The title compound (2.98 g, two-step yield 60%) was obtained as a colorless oil from 5.37 g (40 mmol) of 3-phenylpropionaldehyde in the same manner as in Reference Example 4. ¹ H NMR (CDCl ₃ ) δ 1.80-2.00 (m, 2H), 2.15-2.30 (m,
1H), 2.50-2.80 (m, 2H), 3.55-3.75 (m, 1H), 4.16 (br
s, 1H), 6.11 (dd, J = 11.9, 6.3 Hz, 1H), 6.45-6.7
0 (m, 4H), 6.80-6.90 (m, 1H), 7.00-7.50 (m, 7H), 7.
80-7.90 (m, 1H), 8.00-8.15 (m, 3H).

Reference Example 10 2,4-cis-2-[(benzyloxy) methyl] -4- (9H-9-carbazolyl) -1,2,3,4-tetrahydroquinoline

[Chemical formula 61] From 10 g (66.6 mmol) of benzyloxyacetaldehyde,
In the same manner as in Reference Example 4, 10.9 g of the title compound (2-step yield 60%) was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 2.00-2.12 (m, 1H), 2.44 (q, J = 1
1.9 Hz, 1H), 3.47 (t, J = 9.0 Hz, 1H), 3.59 (dd, J
= 9.0, 3.6 Hz, 1H), 3.9-4.15 (m, 1H), 4.58 (s, 2H),
6.17 (dd, J = 13.9, 6.5 Hz, 1H), 6.40-6.90 (m, 4
H), 7.00-7.50 (m, 11H), 8.07-8.14 (m, 2H).

Reference Example 11 2,4-cis-4- (9H-9-carbazolyl) -2- (2-cyanoethyl)-
1,2,3,4-tetrahydroquinoline

[Chemical formula 62] From 7.73 g (93.0 mmol) of β-cyanopropionaldehyde,
In the same manner as in Reference Example 4, the title compound (2.95 g, two-step yield 25%) was obtained as white crystals. Melting point: 178-179 ° C (crystallization solvent: diethyl ether-hexane) ¹ H NMR (CDCl ₃ ) δ1.93-2.10 (m, 2H), 2.10-2.18 (m,
1H), 2.35-3.65 (m, 3H), 3.80-4.00 (m, 2H), 6.15 (d
d, J = 11.6, 6.2 Hz, 1H), 6.53 (t, J = 7.5 Hz, 1
H), 6.68 (t, J = 7.6 Hz, 2H), 6.79-6.86 (m, 1H),
7.08 (t, J = 7.5 Hz, 2H), 7.13-7.39 (m, 3H), 7.52
(d, J = 3.6 Hz, 2H), 8.08-8.15 (m, 2H).

Reference Example 12 2,4-cis-4- (9H-9-carbazolyl) -5,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical formula 63] From 5.50 g (35.9 mmol) of 3,5-dimethoxyaniline, the title compound (1.18 g, 2-step yield 9%) was obtained as white crystals by a method similar to that in Reference Example 4. ¹ H NMR (CDCl ₃ ) δ 1.24 (d, J = 6.2, 3H), 2.31-2.37
(m, 2H), 2.95 (s, 3H), 2.56 (m, 1H), 3.73 (s, 3H),
3.88 (s, 1H), 5.66 (s, 1H), 5.87 (s, 1H), 6.09 (t,
J = 9.7 Hz, 1H), 6.79-6.86 (m, 1H), 7.10-7.22 (m,
4H), 7.46-7.57 (m, 2H), 8.03-8.09 (m, 2H).

Reference Example 13 2,4-cis-4- (9H-9-carbazolyl) -5,8-dimethoxy-2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 64] From 1.70 g (11.1 mmol) of 2,5-dimethoxyaniline, 1.60 g of the title compound (two-step yield 38%) in the same manner as in Reference Example 4.
Was obtained as white crystals. ¹ H NMR (CDCl ₃ ) δ1.30 (d, J = 6.2, 3H), 2.36-2.44
(m, 2H), 2.86 (s, 3H), 3.55 (m, 1H), 3.87 (s, 3H),
4.51 (s, 1H), 5.95 (d, J = 8.7 Hz, 1H), 6.17 (t, J
= 9.4 Hz, 1H), 6.61 (d, J = 8.7 Hz, 1H), 7.06-7.2
3 (m, 4H), 7.47-7.58 (m, 2H), 8.02-8.09 (m, 2H).

Reference Example 14 2,4-cis-4- (9H-9-carbazolyl) -8-methoxy-2-methyl
-1,2,3,4-tetrahydroquinoline

[Chemical 65] From 2.11 g (13.8 mmol) of 2-methoxyaniline, 1.74 g (two-step yield 44%) of the title compound was obtained as white crystals in the same manner as in Reference Example 4. ¹ H NMR (CDCl ₃ ) δ1.32 (d, J = 6.3, 3H), 2.14 (dd,
J = 12.7, 6.4 Hz, 1H), 2.48 (m, 1H), 3.77 (m, 1H),
3.90 (s, 3H), 4.41 (s, 1H), 6.18 (m, 1H), 6.29 (t,
J = 7.8 Hz, 1H), 6.44 (t, J = 7.9 Hz, 1H), 6.68
(d, J = 7.8 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 7.13
-7.25 (m, 2H), 7.48-7.50 (m, 2H), 8.09-8.14 (m, 2
H).

Reference Example 15 2,4-cis-4- (9H-9-carbazolyl) -6-methoxy-2-methyl
-1,2,3,4-tetrahydroquinoline

[Chemical formula 66] The title compound (2.3 g, 2-step yield: 35%) was obtained as white crystals from 2.94 g (23.9 mmol) of 4-methoxyaniline in the same manner as in Reference Example 4 (mixture of cis and trans). 2,4-cis ¹ H NMR (CDCl ₃ ) δ1.19 (d, J = 6.3 Hz, 3H), 2.01-2.
12 (m, 1H), 2.35 (q, J = 12.0 Hz, 1H), 3.35 (s, 3
H), 3.59 (br s, 1H), 3.65-3.72 (m, 1H), 6.07 (m, 1
H), 6.24 (m, 1H), 6.60-7.00 (m, 3H), 7.10-7.47 (m,
5H), 8.00-8.12 (m, 2H). 2,4-trans ¹ H NMR (CDCl ₃ ) δ1.14 (d, J = 6.3 Hz, 3H), 1.80-2.
10 (m, 1H), 2.34-2.37 (m, 1H), 3.46 (s, 3H), 3.43-
3.52 (m, 1H), 3.85 (br s, 1H), 5.87-5.90 (m, 1H),
6.50 (m, 1H), 6.60-7.00 (m, 3H), 7.10-7.47 (m, 5
H), 8.00-8.12 (m, 2H).

Example 5 (−)-2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroquinolin-1-yl)- 1,2,3,
4-tetrahydroquinoline

[Chemical formula 67] 2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroquinoline-1-obtained in Example 4
Yl) -1,2,3,4-tetrahydroquinoline (145 mg) was collected by chiral HPLC (column: CHIRALPAK AD, developing solvent: ethanol / hexane = 1/1) and concentrated to dryness to give 23 mg of the title compound as white. Obtained as a powder. In the analysis of optical rotation by Shodex OR-2 (wavelength 470nm), this compound
The symbol (-) is shown. ¹ H-NMR (CDCl ₃ ) δ: 1.38 (d, J = 6.2Hz, 3H), 1.69-1.80 (m, 1
H), 1.97-2.16 (m, 2H), 2.69-2.77 (m, 1H), 2.84-2.92 (m, 2
H), 3.34-3.38 (m, 2H), 3.61 (s, 3H), 3.86 (s, 3H), 4.77-4.89
(m, 2H), 6.49 (d, J = 8.2Hz, 1H), 6.60-6.66 (m, 3H), 6.73 (d, J
= 8.4Hz, 1H), 6.94-7.10 (m, 6H). [Α] D = −449.2 ° (C = 1.01, EtOH)

Example 6 (+)-2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroquinolin-1-yl)- 1,2,3,
4-tetrahydroquinoline

[Chemical 68] 2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroquinoline-1-obtained in Example 4
Yl) -1,2,3,4-tetrahydroquinoline (145 mg) was collected by chiral HPLC (column: CHIRALPAK AD, developing solvent: ethanol / hexane = 1/1) and concentrated to dryness to give 24 mg of the title compound as white. Obtained as a powder. In the analysis of optical rotation by Shodex OR-2 (wavelength 470nm), this compound
The sign of (+) is shown. ¹ H-NMR (CDCl ₃ ) δ: 1.38 (d, J = 6.2Hz, 3H), 1.69-1.80 (m, 1
H), 1.97-2.16 (m, 2H), 2.69-2.77 (m, 1H), 2.84-2.92 (m, 2
H), 3.34-3.38 (m, 2H), 3.61 (s, 3H), 3.86 (s, 3H), 4.77-4.89
(m, 2H), 6.49 (d, J = 8.2Hz, 1H), 6.60-6.66 (m, 3H), 6.73 (d, J
= 8.4Hz, 1H), 6.94-7.10 (m, 6H). [Α] D = ＋ 408.2 ° (C = 1.00, EtOH)

Example 7 (−)-2,4-trans-1- (3,4-dimethoxybenzoyl) -2-
Methyl-4- (1,2,3,4-tetrahydroquinolin-1-yl) -1,
2,3,4-tetrahydroquinoline

[Chemical 69] 2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1.2.3.4-tetrahydroquinoline-1-obtained in Example 4
Yl) -1,2,3,4-tetrahydroquinoline (145 mg) was collected by chiral HPLC (column: CHIRALPAK AD, developing solvent: ethanol / hexane = 1/1) and concentrated to dryness to give 36 mg of the title compound as white. Obtained as a powder. In the analysis of optical rotation by Shodex OR-2 (wavelength 470nm), this compound
The symbol (-) is shown. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (d, J = 6.9Hz, 3H), 1.80-2.00 (m, 2
H), 2.09-2.17 (m, 1H), 2.25-2.40 (m, 1H), 2.80-2.84 (m, 2
H), 3.14 (t, J = 5.2Hz, 2H), 3.76 (s, 3H), 3.89 (s, 3H), 5.00-
5.20 (m, 1H), 5.34 (dd, J = 11.2,7.4Hz, 1H), 6.63 (t, J = 7.3H
z, 1H), 6.71-6.80 (m, 3H), 6.85-7.10 (m, 6H), 7.34 (d, J = 7.4
Hz, 1H).

Example 8 (+)-2,4-trans-1- (3,4-dimethoxybenzoyl) -2-
Methyl-4- (1,2,3,4-tetrahydroquinolin-1-yl) -1,
2,3,4-tetrahydroquinoline

[Chemical 70] 2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroquinoline-1-obtained in Example 4
Yl) -1,2,3,4-tetrahydroquinoline (145 mg) was collected by chiral HPLC (column: CHIRALPAK AD, developing solvent: ethanol / hexane = 1/1) and concentrated to dryness to give 36 mg of the title compound as white. Obtained as a powder. In the analysis of optical rotation by Shodex OR-2 (wavelength 470nm), this compound
The sign of (+) is shown. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (d, J = 6.9Hz, 3H), 1.80-2.00 (m, 2
H), 2.09-2.17 (m, 1H), 2.25-2.40 (m, 1H), 2.80-2.84 (m, 2
H), 3.14 (t, J = 5.2Hz, 2H), 3.76 (s, 3H), 3.89 (s, 3H), 5.00-
5.20 (m, 1H), 5.34 (dd, J = 11.2,7.4Hz, 1H), 6.63 (t, J = 7.3H
z, 1H), 6.71-6.80 (m, 3H), 6.85-7.10 (m, 6H), 7.34 (d, J = 7.4
Hz, 1H).

Example 9 4- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) -1-
(3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 71] Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 40 obtained in Reference Example 1
The title compound (320 mg, yield 59%) was obtained as a colorless oil from 0 mg (1.22 mmol) and 3,4-dihydro-2H-1,4-benzoxazine (495 mg, 3.66 mmol) in the same manner as in Example 1. It was
(Cis: trans = 1: 2.3) Elemental analysis value Calculated as C ₂₇ H ₂₈ N ₂ O ₄ : C, 72.95; H, 6.35; N, 6.30 Experimental value: C, 72.76; H, 6.37; N, 6.24

Example 10 (−)-2,4-cis-4- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) -1- (3,4-dimethoxybenzoyl)- 2-methyl
-1,2,3,4-tetrahydroquinoline

[Chemical 72] 4- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3 obtained in Example 9 320 mg of 4,4-tetrahydroquinoline, chiral H
After fractionation by PLC (column: CHIRALPAK AD, developing solvent: ethanol / hexane = 1/1), the mixture was concentrated to dryness to obtain 21 mg of the title compound as a white powder. ShodexOR-2 (wavelength 47
In the analysis of optical rotation by 0 nm), this compound showed a sign of (-). ¹ H-NMR (CDCl ₃ ) δ: 1.38 (d, J = 6.2Hz, 3H), 1.50-1.80 (m, 1
H), 2.67-2.75 (m, 1H), 3.49 (brs, 2H), 3.62 (s, 3H), 3.86 (s,
3H), 4.36 (brs, 2H), 4.75-4.95 (m, 2H), 6.60-6.80 (m, 6H),
6.89-6.97 (m, 3H), 7.02-7.10 (m, 2H).

Example 11 (+)-2,4-cis-4- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) -1- (3,4-dimethoxybenzoyl)- 2-methyl
-1,2,3,4-tetrahydroquinoline

[Chemical formula 73] 4- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3 obtained in Example 9 320 mg of 4,4-tetrahydroquinoline, chiral H
After fractionation by PLC (column: CHIRALPAK AD, developing solvent: ethanol / hexane = 1/1) and concentration to dryness, 26 mg of the title compound was obtained as a white powder. ShodexOR-2 (wavelength 47
The compound showed a (+) sign in the analysis of optical rotation by 0 nm). ¹ H-NMR (CDCl ₃ ) δ: 1.38 (d, J = 6.2Hz, 3H), 1.50-1.80 (m, 1
H), 2.67-2.75 (m, 1H), 3.49 (brs, 2H), 3.62 (s, 3H), 3.86 (s,
3H), 4.36 (brs, 2H), 4.75-4.95 (m, 2H), 6.60-6.80 (m, 6H),
6.89-6.97 (m, 3H), 7.02-7.10 (m, 2H).

Example 12 (−)-2,4-trans-4- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) -1- (3,4-dimethoxybenzoyl)- 2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 74] 4- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3 obtained in Example 9 320 mg of 4,4-tetrahydroquinoline, chiral H
After fractionation by PLC (column: CHIRALPAK AD, developing solvent: ethanol / hexane = 1/1) and concentration to dryness, 50 mg of the title compound was obtained as a white powder. ShodexOR-2 (wavelength 47
In the analysis of optical rotation by 0 nm), this compound showed a sign of (-). ¹ H-NMR (CDCl ₃ ) δ: 1.31 (d, J = 6.9Hz, 3H), 2.10-2.28 (m, 2
H), 3.13-3.29 (m, 2H), 3.20-3.35 (m, 1H), 3.80 (s, 3H), 3.89
(s, 3H), 4.24 (t, J = 4.8Hz, 2H), 5.30 (dd, J = 11.0,7.6Hz, 1
H), 6.60-6.70 (m, 1H), 6.76-6.87 (m, 5H), 6.90-7.03 (m, 3
H), 7.09 (d, J = 1.8Hz, 1H), 7.36 (d, J = 7.2Hz, 1H).

Example 13 (+)-2,4-trans-4- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) -1- (3,4-dimethoxybenzoyl)- 2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 75] 4- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3 obtained in Example 9 320 mg of 4,4-tetrahydroquinoline, chiral H
After fractionation by PLC (column: CHIRALPAK AD, developing solvent: ethanol / hexane = 1/1) and concentration to dryness, 56 mg of the title compound was obtained as a white powder. ShodexOR-2 (wavelength 47
The compound showed a (+) sign in the analysis of optical rotation by 0 nm). ¹ H-NMR (CDCl ₃ ) δ: 1.31 (d, J = 6.9Hz, 3H), 2.10-2.28 (m, 2
H), 3.13-3.29 (m, 2H), 3.20-3.35 (m, 1H), 3.80 (s, 3H), 3.89
(s, 3H), 4.24 (t, J = 4.8Hz, 2H), 5.30 (dd, J = 11.0,7.6Hz, 1
H), 6.60-6.70 (m, 1H), 6.76-6.87 (m, 5H), 6.90-7.03 (m, 3
H), 7.09 (d, J = 1.8Hz, 1H), 7.36 (d, J = 7.2Hz, 1H).

Example 14 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl)
-3-Hydroxy-2-methyl-4- (1,2,3,4-tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 76] 3- (3,4-dimethoxybenzoyl) -2-obtained in Reference Example 3
Methyl-1a, 2,3,7b-tetrahydrooxyreno [2,3-c] quinoline 500mg (1.54mmol) and 1,2,3,4-tetrahydroquinoline 4
Dissolve 09 mg (3.07 mmol) in 20 ml of THF and, under nitrogen atmosphere, 0.79 ml of trimethylaluminum (0.98M-hexane solution).
(0.77 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water (1.5 ml) was added to the reaction mixture and the mixture was stirred for 30 minutes, then anhydrous magnesium sulfate was added and the mixture was stirred for 20 minutes. The insoluble material was removed by filtration, the filtrate was concentrated, the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/2), and the eluate was recrystallized from diethyl ether-hexane to give the title. Compound 229 mg (33%) (yield 37%) was obtained as white crystals. FABMS (pos) 458.2 [M ⁺ ]

Example 15 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl)
-3-[(1H-Imidazol-1-ylcarbothioyl) oxy] -2
-Methyl-4- (1,2,3,4-tetrahydroquinolin-1-yl)-
1,2,3,4-tetrahydroquinoline

[Chemical 77] 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl) -3-hydroxy-2-methyl-4- (1,2, obtained in Example 14
3,4-Tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydroquinoline 560 mg (1.22 mmol) and 1,1'-thiocarbonyldiimidazole 617 mg (0.872 mmol) in 1,2-dichloroethane 25
It was dissolved in ml and heated under reflux for 18 hours. The reaction solution was concentrated and the residue was subjected to silica gel column chromatography (developing solvent:
Ethyl acetate / hexane = 1/1), and the title compound 370mg
(53% yield) was obtained as a yellow oil. FABMS (pos) 568.1 [M ⁺ ]

Example 16 2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4-
(1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydroquinoline

[Chemical 78] Tributyltin hydride 0.095 ml (0.352 mmol) and 2,2'-azobisisobutyronitrile 2 mg (0.012 mmol) in toluene solution
After heating and refluxing 10 ml under a nitrogen atmosphere for 30 minutes, 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl) -3-[(1H-imidazo obtained in Example 15 was used. -L-1-ylcarbothioyl) oxy] -2-methyl-4- (1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydroquinoline 100 mg
10 ml of a toluene solution of (0.176 mg) was added dropwise over 30 minutes. The reaction solution was heated under reflux for 4 hours and then concentrated, the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/3), and the eluate was recrystallized from diethyl ether-hexane to give the title compound. 27.5 mg (yield 35
%) As white crystals. Melting point: 187-189 ° C

Example 17 2,3-trans-2,4-cis-3-acetoxy-1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroquinoline -1-yl)-1,2,3,4-tetrahydroquinoline

[Chemical 79] 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl) -3-hydroxy-2-methyl-4- (1,2, obtained in Example 14
250 mg (0.55 mmol) of 3,4-tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline was dissolved in 5 ml of pyridine, and 2 ml of acetic anhydride was added dropwise, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, and concentrated. The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane =
1/2), and the eluate was recrystallized from diethyl ether-hexane to give the title compound (27.5 mg, yield 35%) as white crystals. FABMS (pos) 500.1 [M ⁺ ] Melting point: 130-131 ° C (crystallization solvent: diethyl ether-hexane)

Example 18 2,3-trans 2,4-cis-4- (3,4-dihydro-2H-1,4-benzothiazin-4-yl) -1- (3,4-dimethoxybenzoyl)- 3-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 80] 930mg (6.14mmol) 3,4-dihydro-2H-1,4-benzothiazine
To 764 mg of the title compound (yield 5
2%) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (d, J = 6.0Hz, 3H), 2.50-2.65 (m, 1
H), 3.00-3.15 (m, 1H), 3.20-3.35 (m, 1H), 3.55-3.86 (m, 9
H), 4.55-4.65 (m, 1H), 4.75-4.90 (m, 1H), 6.50-7.40 (m, 11
H).

Example 19 2,3-trans 2,4-cis-4- (3,4-dihydro-2H-1,4-benzothiazin-4-yl) -1- (3,4-dimethoxybenzoyl)- 3-
[(1H-Imidazol-1-ylcarbothioyl) oxy] -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 81] 2,3-trans-2,4-cis-4- (3,4-dihydro-2H-1,4-benzothiazin-4-yl) -1- (3,4-dimethoxybenzoyl) obtained in Example 18 580 mg (94% yield) of the title compound was obtained as a yellow oil from 500 mg (1.05 mmol) of 3-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline in the same manner as in Example 15. It was FABMS (pos) 587.1 [M + H ⁺ ]

Example 20 2,4-cis-4- (3,4-dihydro-2H-1,4-benzothiazine-4-
Yl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,
4-tetrahydroquinoline

[Chemical formula 82] 2,3-trans-2,4-cis-4- (3,4-dihydro-2H-1,4-benzothiazin-4-yl) -1- (3,4-dimethoxybenzoyl) obtained in Example 19 -3-[(1H-Imidazol-1-ylcarbothioyl) oxy] -2-methyl-1,2,3,4-tetrahydroquinoline 580 mg (0.94 mmol) in the same manner as in Example 16 ,
30 mg (yield 7%) of the title compound was obtained as white crystals. Elemental analysis value Calculated as C ₂₇ H ₂₈ N ₂ O ₃ S: C, 70.41; H, 6.13; N, 6.08 Experimental value: C, 69.91; H, 6.02; N, 6.97 Melting point: 178-180 ℃ (crystallization Solvent: Diethyl ether-hexane) The title compounds of Examples 5 to 20 are summarized in Table 1.

[Table 1]

Example 21 2,3-trans-2,4-cis-4- (1
-Benzyl-1,2,3,4-tetrahydroquinoxalin-4-yl)
1- (3,4-dimethoxybenzoyl) -3-hydroxy-2-methyl
-1,2,3,4-tetrahydroquinoline

[Chemical 83] 4-benzyl-1,2,3,4-tetrahydroquinoxaline 630mg
(2.81 mmol) and in the same manner as in Example 14, the title compound 72
0 mg (yield 61%) was obtained as white crystals. Melting point 99-102
℃

Example 22 2,3-trans-2,4-cis-4- (1-benzyl-1,2,3,4-tetrahydroquinoxalin-4-yl) 1- (3,4-dimethoxybenzoyl) -3-[(1H-Imidazol-1-ylcarbothioyl) oxy] -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 84] 2,3-trans-2,4-cis-4- (1-benzyl-1,2,3,4-tetrahydroquinoxalin-4-yl) 1-obtained in Example 21
(3,4-dimethoxybenzoyl) -3-hydroxy-2-methyl-
From 600 mg (1.09 mmol) of 1,2,3,4-tetrahydroquinoline,
In the same manner as in Example 15, 596 mg of the title compound (yield 83
%) As a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (d, J = 7.0Hz, 3H), 3.20-3.57 (m, 4
H), 3.73 (s, 3H), 3.83 (s, 3H), 4.30-4.50 (m, 2H), 5.05-5.2
0 (m, 1H), 5.35-5.51 (m, 1H), 5.80-5.95 (m, 1H), 6.58-6.75
(m, 6H), 6.89-7.00 (m, 3H), 7.02-7.32 (m, 7H), 7.30-7.42
(m, 2H), 8.14 (brs.1H).

Example 23 2,4-cis-4- (1-benzyl-1,2,3,4-tetrahydroquinoxalin-4-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl- 1,2,3,4-tetrahydroquinoline

[Chemical 85] 2,3-trans-2,4-cis-4- (1-benzyl-1,2,3,4-tetrahydroquinoxalin-4-yl) -1-obtained in Example 22
From (3,4-dimethoxybenzoyl) -3-[(1H-imidazol-1-ylcarbothioyl) oxy] -2-methyl-1,2,3,4-tetrahydroquinoline 590 mg (0.89 mmol), By a method similar to that in Example 16, 340 mg (yield 71%) of the title compound was obtained as white crystals. Melting point 192-194 ° C

Example 24 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl)
-3-hydroxy-2-methyl-4- (2,3,4,5-tetrahydro-1H-
1-benzazepinyl) -1,2,3,4-tetrahydroquinoline

[Chemical 86] 520 mg of 2,3,4,5-tetrahydro-1H-1-benzazepine (3.53
mmol) in the same manner as in Example 14 to give 300 mg of the title compound.
(Yield 26%) was obtained as white crystals. Melting point 88-92 ℃

Example 25 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl)
-3-[(1H-Imidazol-1-ylcarbothioyl) oxy] -2
-Methyl-4- (2,3,4,5-tetrahydro-1H-1-benzazepinyl) -1,2,3,4-tetrahydroquinoline

[Chemical 87] 2,3-trans-2,4-cis-1- (3,4-obtained in Example 24
Dimethoxybenzoyl) -3-hydroxy-2-methyl-4- (2,
3,4,5-Tetrahydro-1H-1-benzazepinyl)-1,2,3,4
-From 190 mg (0.41 mmol) of tetrahydroquinoline, 130 mg (yield 54%) of the title compound was obtained as a yellow oil in the same manner as in Example 15. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (d, J = 7.0Hz, 3H), 1.50-1.65 (m, 2
H), 1.75-1.90 (m, 2H), 2.41-2.50 (m, 1H), 2.60-2.75 (m, 1
H), 3.16-3.24 (m, 1H), 3.59-3.63 (m, 1H), 3.76 (s, 3H), 3.88
(s, 3H), 4.99 (d, J = 8.8Hz, 1H), 5.10-5.16 (m, 1H), 5.73 (d, J
= 8.7Hz, 1H), 6.65-7.70 (m, 1H), 6.75 (d, J = 8.4Hz, 1H), 6.85
-6.95 (m, 3H), 6.95-7.08 (m, 3H), 7.10-7.15 (m, 2H), 7.15-
7.21 (m, 1H), 7.42-7.46 (m, 1H), 7.50 (s, 1H), 8.24 (s, 1H).

Example 26 2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4-
(2,3,4,5-tetrahydro-1H-1-benzazepinyl) -1,2,
3,4-tetrahydroquinoline

[Chemical 88] 2,3-trans-2,4-cis-1- (3,4-obtained in Example 25
Dimethoxybenzoyl) -3-[(1H-imidazol-1-ylcarbothioyl) oxy] -2-methyl-4- (2,3,4,5-tetrahydro-1H-1-benzazepinyl) -1, The title compound (61 mg, yield 60%) was obtained as white crystals from 130 mg (0.22 mmol) of 2,3,4-tetrahydroquinoline in the same manner as in Example 16. Melting point 150-151 ℃

Example 27 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl)
-3-{[(hexylamino) carbonyl] oxy} -2-methyl
-4- (2,3,4,5-tetrahydro-1H-1-benzazepinyl) -1,
2,3,4-tetrahydroquinoline

[Chemical 89] 2,3-trans-2,4-cis-1- (3,4-obtained in Example 24
Dimethoxybenzoyl) -3-hydroxy-2-methyl-4- (2,
3,4,5-Tetrahydro-1H-1-benzazepinyl)-1,2,3,4
-150 mg (0.33 mmol) of tetrahydroquinoline and 101 mg (1 mmol) of triethylamine were dissolved in 10 ml of toluene, 124 mg (0.98 mmol) of hexyl isocyanate was added, and the mixture was stirred at 80 ° C for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 3/7), and the eluate was recrystallized from hexane to give the title compound (159 mg, yield 83%). Obtained as white crystals. Melting point: 152-154 ℃

Example 28 2,3-trans-2,4-cis-3-{[(benzylamino) carbonyl] oxy} -1- (3,4-dimethoxybenzoyl) -2-methyl-4- (2 , 3,4,5-Tetrahydro-1H-1-benzazepinyl)-
1,2,3,4-tetrahydroquinoline

[Chemical 90] Example 27 from 75 mg (0.50 mmol) of benzyl isocyanate
133 mg (yield 78%) of the title compound was obtained as white crystals in the same manner as in. Melting point: 173-174 ℃

Example 29 2,3-trans-2,4-cis-4- (2,3-dihydro-1H-indol-1-yl) -1- (3,4-dimethoxybenzoyl) -3-hydroxy -2-Methyl-1,2,3,4-tetrahydroquinoline

[Chemical Formula 91] The title compound (443 mg, yield 81%) was obtained as white crystals from 2,3-dihydro-1H-indole (190 mg, 1.60 mmol) in the same manner as in Example 14. Melting point 182-183 ℃

Example 30 2,4-cis-1- (3,4-dimethoxybenzoyl) -4- (1H-indol-1-yl) -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical Formula 92] 2,3-trans-2,4-cis-4- (2,3-obtained in Example 29
Dihydro-1H-indol-1-yl) -1- (3,4-dimethoxybenzoyl) -3-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline in the same manner as in Examples 15 and 16 2,4-
Cis-4- (2,3-dihydro-1H-indol-1-yl) -1- (3,4-
A mixture of dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline and the title compound (mixing ratio 2: 1) was obtained.
This mixture (85 mg) was dissolved in toluene (5 ml), orthochloranil (68 mg) was added, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/3), and the eluate was recrystallized from diisopropyl ether-hexane to give 50 mg of the title compound as white crystals. Obtained. Melting point: 226-227 ℃

Example 31 2,3-trans-2,4-cis-4- (2,3-dihydro-1H-indol-1-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl -3
-({[[2-phenylethyl) amino] carbonyl} oxy)-
1,2,3,4-tetrahydroquinoline

[Chemical formula 93] 2,3-trans-2,4-cis-4- (2,3-obtained in Example 29
Dihydro-1H-indol-1-yl) -1- (3,4-dimethoxybenzoyl) -3-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline 150 mg (0.34 mmol), phenethylisocyanate 149 mg ( The title compound (190 mg, yield 95%) was obtained as white crystals from 1.01 mmol) in the same manner as in Example 27. Melting point: 146-149 ° C Table 2 summarizes the title compounds of Examples 21-31.

[Table 2]

Example 32 2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 94] 2,4-cis-4- (9H-9-carbazolyl) -2 obtained in Reference Example 4
-Methyl-1,2,3,4-tetrahydroquinoline 361 mg (1.16 mmo
l) was dissolved in 15 ml of pyridine, 279 mg (1.39 mmol) of 3,4-dimethoxybenzoyl chloride was added under ice cooling, and the mixture was stirred at 60 ° C for 4 hours. The reaction solution was concentrated, and ethyl acetate and water were added to the residue for extraction. The organic layer was washed with water, concentrated, and the residue was washed with ethyl acetate.
-Recrystallized from hexane to give the title compound 155 mg (yield 28%)
Was obtained as white crystals. Melting point: 229-231 ° C (crystallization solvent: ethyl acetate-hexane) Elemental analysis value Calculated as C ₃₁ H ₂₈ N ₂ O ₃ 0.25H ₂ O: C, 77.40; H, 5.97; N, 5.82 Experimental value: C, 77.44; H, 5.70; N, 5.86

Example 33 (−)-2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro Quinoline

[Chemical 95] 2,4-cis-4- (9H-9-carbazolyl) obtained in Example 32
1.1 g of -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline was analyzed by chiral HPLC (column: CH
IRALPAK AD, developing solvent: ethanol / hexane = 1 /
After fractionation by 1), the mixture was concentrated to dryness to obtain 430 mg of the title compound as white crystals. In the analysis of the optical rotatory power by Shodex OR-2 (wavelength 470 nm), this compound showed the sign of (-).
Melting point: 278-280 ℃

Example 34 (+)-2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro Quinoline

[Chemical 96] 2,4-cis-4- (9H-9-carbazolyl) obtained in Example 32
1.1 g of -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline was analyzed by chiral HPLC (column: CH
IRALPAK AD, developing solvent: ethanol / hexane = 1 /
After fractionation by 1), the mixture was concentrated to dryness to obtain 470 mg of the title compound as white crystals. In the analysis of optical rotation by Shodex OR-2 (wavelength 470 nm), this compound showed the sign of (+).
Melting point: 279-280 ℃

Example 35 2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2-ethyl-1,2,3,4-tetrahydroquinoline

[Chemical 97] 2,4-cis-4- (9H-9-carbazolyl) -2 obtained in Reference Example 5
-Ethyl-1,2,3,4-tetrahydroquinoline 1.47 g (4.50 mmo
From l), in the same manner as in Example 32, 0.93 g of the title compound was obtained.
(Yield 42%) was obtained as white crystals. ¹ H NMR (CDCl ₃ ) δ0.99 (t, J = 7.3 Hz, 3H), 1.65
(m, 1H), 1.93 (m, 1H), 2.62 (m, 1H), 2.75 (m, 1H),
3.67 (s, 3H), 3.85 (s, 3H), 4.97 (m, 1H), 5.91 (m,
1H), 6.70 (t, J = 8.5 Hz, 2H), 6.80-7.35 (m, 9H),
7.50 (m, 2H), 8.19 (d, J = 7.6 Hz, 2H), FABMS (pos) 491.2 [M ⁺ ]

Example 36 (−)-2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2-ethyl-1,2,3,4-tetrahydro Quinoline

[Chemical 98] 2,4-cis-4- (9H-9-carbazolyl) obtained in Example 35
1.21 g of -1- (3,4-dimethoxybenzoyl) -2-ethyl-1,2,3,4-tetrahydroquinoline was analyzed by chiral HPLC (column: C
HIRALPAK AD, developing solvent: ethanol / hexane = 1 /
After fractionation according to 1) and concentration to dryness, 0.50 g of the title compound was obtained as white crystals. In the analysis of the optical rotatory power by Shodex OR-2 (wavelength 470 nm), this compound showed the sign of (-). Elemental analysis value Calculated as C ₃₂ H ₃₀ N ₂ O ₃ 0.25H ₂ O: C, 77.63; H, 6.21; N, 5.66 Experimental value: C, 77.98; H, 6.08; N, 5.55

Example 37 (+)-2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2-ethyl-1,2,3,4-tetrahydro Quinoline

[Chemical 99] 2,4-cis-4- (9H-9-carbazolyl) obtained in Example 35
1.21 g of -1- (3,4-dimethoxybenzoyl) -2-ethyl-1,2,3,4-tetrahydroquinoline was analyzed by chiral HPLC (column: C
HIRALPAK AD, developing solvent: ethanol / hexane = 1 /
After fractionation according to 1) and concentration to dryness, 0.47 g of the title compound was obtained as white crystals. In the analysis of optical rotation by Shodex OR-2 (wavelength 470 nm), this compound showed the sign of (+). Elemental analysis value Calculated as C ₃₂ H ₃₀ N ₂ O ₃ 0.25H ₂ O: C, 77.63; H, 6.21; N, 5.66 Experimental value: C, 77.83; H, 6.40; N, 5.57

Example 38 2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2-propyl-1,2,3,4-tetrahydroquinoline

[Chemical 100] 2,4-cis-4- (9H-9-carbazolyl) -2 obtained in Reference Example 6
-Propyl-1,2,3,4-tetrahydroquinoline 1.63 g (4.90 mm
ol), and in the same manner as in Example 32, the title compound (471 mg)
(Yield 20%) was obtained as white crystals. Melting point: 195-196 ° C (crystallization solvent: ethyl acetate-hexane) Elemental analysis value Calculated as C ₃₅ H ₃₂ N ₂ O ₃ .0.5H ₂ O: C, 77.17; H, 6.48; N, 5.45 Experimental value: C, 77.36; H, 6.50; N, 5.16

Example 39 (−)-2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2-propyl-1,2,3,4-tetrahydro Quinoline

[Chemical 101] 2,4-cis-4- (9H-9-carbazolyl) obtained in Example 38
-1- (3,4-dimethoxybenzoyl) -2-propyl-1,2,3,4-
345 mg of tetrahydroquinoline was added to chiral HPLC (column: CHIRALPAK AD, developing solvent: ethanol / hexane =
(1/1) and then concentrated to dryness to give the title compound (137 mg)
Was obtained as white crystals. In the analysis of the optical rotatory power by Shodex OR-2 (wavelength 470 nm), this compound showed the sign of (-). Melting point: 194-195 ° C

Example 40 2,4-cis-2-butyl-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline

[Chemical 102] 2.4-cis-2-butyl-4- (9H-9-carbazolyl) -1,2,3,4-tetrahydroquinoline obtained in Reference Example 7. 2.12 g (5.98 mmo
From l), in the same manner as in Example 32, 920 mg of the title compound
(Yield 30%) was obtained as white crystals. Melting point: 213 ° C (crystallization solvent: ethyl acetate-hexane) Elemental analysis value Calculated as C ₃₄ H ₃₄ N ₂ O ₃ : C, 78.74; H, 6.61; N, 5.40 Experimental value: C, 78.35; H, 6.53 ; N, 5.36

Example 41 2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2-isobutyl-1,2,3,4-tetrahydroquinoline

[Chemical 103] 2,4-cis-4- (9H-9-carbazolyl) -2 obtained in Reference Example 8
-Isobutyl-1,2,3,4-tetrahydroquinoline 1.10 g (3.10
mmol) in the same manner as in Example 32 to give the title compound 636
mg (yield 40%) was obtained as white crystals. Mp: 191-193 ° C. (crystallization solvent: THF-hexane) Elemental analysis _{C 34 H 34 N 2 O 3} · H 2 O Calculated: C, 77.39; H, 6.69 ; N, 5.31 Found: C, 77.77; H, 7.01; N, 5.03

Example 42 2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2- (2-phenylethyl) -1,2,3,4- Tetrahydroquinoline

[Chemical 104] 2,4-cis-4- (9H-9-carbazolyl) -obtained in Reference Example 9
2- (2-phenylethyl) -1,2,3,4-tetrahydroquinoline
From 2.98 g (7.40 mmol), the title compound 886 mg (yield 22%) was obtained as white crystals by a method similar to that in Example 32. Melting point: 223-225 ° C (crystallization solvent: ethyl acetate-hexane) Elemental analysis value Calculated as C ₃₈ H ₃₄ N ₂ O ₃₃ : C, 80.54; H, 6.05; N, 4.94 Experimental value: C, 80.29; H , 6.00; N, 5.05

Example 43 2-[(benzyloxy) methyl] -4- (9H-9-carbazolyl) -1
-(3,4-Dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline

[Chemical 105] From 3.27 g (7.81 mmol) of 2,4-cis-2-[(benzyloxy) methyl] -4- (9H-9-carbazolyl) -1,2,3,4-tetrahydroquinoline obtained in Reference Example 10 In the same manner as in Example 32, the title compound (1.01 g, yield 22%) was obtained as white crystals. (Cis: trans = 1: 1) mp: 203-204 ° C. (crystallization solvent: diethyl ether - ethyl acetate) Elemental analysis C ₃₈ H ₃₄ N ₂ O ₄ Calculated: C, 78.33; H, 5.83 ; N , 4.81 Experimental value: C, 77.90; H, 5.83; N, 4.76

Example 44 2,4-cis-4- (9H-9-carbazolyl) -2- (2-cyanoethyl)-
1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline

[Chemical formula 106] 2,4-cis-4- (9H-9-carbazolyl) -2 obtained in Reference Example 11
-(2-Cyanoethyl) -1,2,3,4-tetrahydroquinoline 2.00
The title compound (1.61 g, yield 55%) was obtained as white crystals from g (5.69 mmol) in the same manner as in Example 32. Melting point: 181-282 ° C (crystallization solvent: ethyl acetate-hexane) FABMS (pos) 544.2 [M + H ⁺ ]

Example 45 2,4-cis-2- {3-[(t-butoxycarbonyl) amino] propyl} -4- (9H-carbazol-9-yl) -1- (3,4-dimethoxybenzoyl )-1,2,3,4-Tetrahydroquinoline

[Chemical formula 107] 2,4-cis-4- (9H-9-carbazolyl) obtained in Example 44
-2- (2-cyanoethyl) -1- (3,4-dimethoxybenzoyl)-
400 mg (0.78 mmol) of 1,2,3,4-tetrahydroquinoline, 370 mg (1.56 mmol) of nickel (II) chloride hexahydrate, di-t-dicarbonate
Butyl 340 mg (1.56 mmol) was dissolved in a mixed solution of methanol 10 ml and THF 20 ml, and sodium borohydride 590 mg (15.6 m
mol) was added and the mixture was stirred at room temperature overnight. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was recrystallized from ethyl acetate-hexane to give the title compound (282 mg)
(Yield 56%) was obtained as white crystals. Mp: 180-181 ° C. (crystallization solvent: ethyl acetate - hexane) Elemental analysis _{C 35 H 35 N 3 O 4} · 0.3H 2 O Calculated: C, 73.01; H, 6.71 ; N, 6.72 Found: C, 73.19; H, 7.10; N, 6.42

Example 46 2,4-cis-2- (3-aminopropyl) -4- (9H-carbazole-9
-Yl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline hydrochloride

[Chemical 108] 2,4-cis-2- {3-[(t-butoxycarbonyl) amino] propyl} -4- (9H-carbazol-9-yl) -1- (3,4-dimethoxy obtained in Example 45 250 mg (0.403 mmol) of benzoyl) -1,2,3,4-tetrahydroquinoline was dissolved in 5 ml of THF, 5 ml (20 mmol) of 4N hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred at room temperature for 5 hours. After concentrating the reaction mixture, the residue is ethyl acetate.
-Recrystallized from hexane, 141 mg of the title compound (yield 67%)
Was obtained as white crystals. Melting point: 203-204 ° C (crystallization solvent: ethyl acetate-hexane) Elemental analysis value Calculated as C ₃₃ H ₃₄ N ₃ O ₃ Cl · 1.0H ₂ O: C, 69.04; H, 6.32; N, 7.32; Cl Experimental value: C, 69.20; H, 6.09; N, 7.31; Cl, 6.12 Table 3 summarizes the title compounds of Examples 32-46.

[Table 3]

Example 47 2,4-cis-4- (9H-9-carbazolyl) -5,7-dimethoxy-1-
(3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 109] 2,4-cis-4- (9H-9-carbazolyl) obtained in Reference Example 12
-5,7-Dimethoxy-2-methyl-1,2,3,4-tetrahydroquinoline (0.83 g, 2.22 mmol) was used to give 0.26 g (yield 22%) of the title compound as white in the same manner as in Example 32. Obtained as crystals. Elemental analysis value Calculated as C ₃₃ H ₃₂ N ₂ O ₅・ 0.5H ₂ O: C, 72.64; H, 6.10; N, 5.13 Experimental value: C, 72.94; H, 5.86; N, 5.18

Example 48 2,4-cis-4- (9H-9-carbazolyl) -5,8-dimethoxy-1-
(3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 110] 2,4-cis-4- (9H-9-carbazolyl) obtained in Reference Example 13
From 0.10 g (2.95 mmol) of -5,8-dimethoxy-2-methyl-1,2,3,4-tetrahydroquinoline, 0.19 g (yield 12%) of the title compound was obtained in the same manner as in Example 32. Obtained as crystals. Elemental analysis value Calculated as C ₃₃ H ₃₂ N ₂ O ₅ : C, 73.86; H, 6.01; N, 5.22 Experimental value: C, 73.56; H, 6.06; N, 5.05

Example 49 2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -8-methoxy-2-methyl-1,2,3,4-tetrahydro Quinoline

[Chemical 111] 2,4-cis-4- (9H-9-carbazolyl) obtained in Reference Example 14
-8-Methoxy-2-methyl-1,2,3,4-tetrahydroquinoline 6
The title compound (100 mg, yield 10%) was obtained as white crystals from 85 mg (2.0 mmol) in the same manner as in Example 32. Elemental analysis value Calculated as C ₃₂ H ₃₀ N ₂ O ₄ 0.25H ₂ O: C, 75.20; H, 6.01; N, 5.48 Experimental value: C, 75.36; H, 6.11; N, 5.40

Example 50 4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl)
-6-Methoxy-2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 112] 800 mg (2.34) of 4- (9H-9-carbazolyl) -6-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline obtained in Reference Example 15
mmol) in the same manner as in Example 32 to give the title compound 306
mg (yield 26%) was obtained as white crystals (mixture of cis and trans). Elemental analysis value Calculated as C ₃₂ H ₃₀ N ₂ O ₄・ 0.6H ₂ O: C, 74.28; H, 6.08; N, 5.41 Experimental value: C, 74.62; H, 6.17; N, 5.02

Example 51 2,4-cis-4- (9H-9-carbazolyl) -1- (2-furoyl) -2-
Methyl-1,2,3,4-tetrahydroquinoline

[Chemical 113] 2,4-cis-4- (9H-9-carbazolyl) -2 obtained in Reference Example 4
-Methyl-1,2,3,4-tetrahydroquinoline 600 mg (1.90 mmo
From l), in the same manner as in Example 32, 379 mg of the title compound
(Yield 49%) was obtained as white crystals. Elemental analysis value Calculated as C ₂₇ H ₂₂ N ₂ O ₂ .0.1H ₂ O: C, 79.43; H, 5.48; N, 6.86 Experimental value: C, 79.42; H, 5.54; N, 6.76 Melting point: 202-203 ℃

Example 52 2,4-cis-4- (9H-9-carbazolyl) -2-methyl-1- (2-thienoyl) -1,2,3,4-tetrahydroquinoline

[Chemical 114] 2,4-cis-4- (9H-9-carbazolyl) -2 obtained in Reference Example 4
-Methyl-1,2,3,4-tetrahydroquinoline 600 mg (1.90 mmo
From l), in the same manner as in Example 32, 250 mg of the title compound
(Yield 31%) was obtained as white crystals. Elemental analysis value C ₂₇ H ₂₂ N ₂ O ₁ S ・ Calculated as 0.2H ₂ O: C, 76.10; H, 5.30; N, 6.57 Experimental value: C, 76.40; H, 5.21; N, 6.33

Example 53 2,4-cis-4- (9H-9-carbazolyl) -2-ethyl-1- (3-thienoyl) -1,2,3,4-tetrahydroquinoline

[Chemical 115] 2,4-cis-4- (9H-9-carbazolyl) -2 obtained in Reference Example 5
-Ethyl-1,2,3,4-tetrahydroquinoline 200 mg (0.61 mmo
From l), and in the same manner as in Example 32, 90 mg of the title compound
(Yield 33%) was obtained as white crystals. Mass m / z 437.2 (M
H ⁺ ) The title compounds of Examples 47 to 53 are summarized in Table 4.

[Table 4]

Example 54 1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-
Tetrahydroquinolin-1-yl) -1,2-dihydroquinoline

[Chemical formula 116] 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl) -3-hydroxy-2-methyl-4- (1,2, obtained in Example 14
3,4-Tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydroquinoline 560 mg (1.22 mmol) and 1,1'-thiocarbonyldiimidazole 617 mg (0.872 mmol) in 1,2-dichloroethane
It was dissolved in 25 ml and heated under reflux for 18 hours. The reaction solution is concentrated,
The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/5) to give the title compound 6
6 mg (12% yield) was obtained as a yellow oil. Elemental analysis value Calculated as C ₂₈ H ₂₈ N ₂ O ₃・ 0.5H ₂ O: C, 74.81; H, 6.50; N, 6.23 Experimental value: C, 74.53; H, 6.29; N, 6.48 FABMS (pos) 441.2 [M + H ⁺ ]

Example 55 1- (3,4-dimethoxybenzoyl) -2-methyl-4- (2,3,4,5-
Tetrahydro-1H-1-benzazepinyl) -1,2-dihydroquinoline

[Chemical 117] 2,3-trans-2,4-cis-1- (3,4-obtained in Example 24
Dimethoxybenzoyl) -3-hydroxy-2-methyl-4- (2,
3,4,5-Tetrahydro-1H-1-benzazepinyl)-1,2,3,4
From 190 mg (0.41 mmol) of tetrahydroquinoline, Example 5
27 mg of the title compound (yield 15%) were obtained as white crystals in the same manner as in 4. Melting point: 151-152 ℃

Example 56 4- (3,4-dihydro-2H-1,4-benzothiazin-4-yl) -1-
(3,4-dimethoxybenzoyl) -2-methyl-1,2-dihydroquinoline

[Chemical 118] 2,3-trans-2,4-cis-4- (3,4-dihydro-2H-1,4-benzothiazin-4-yl) -1- (3,4-dimethoxybenzoyl) obtained in Example 19 -3-[(1H-Imidazol-1-ylcarbothioyl) oxy] -2-methyl-1,2,3,4-tetrahydroquinoline 580 mg (0.94 mmol) in the same manner as in Example 16 ,
42 mg (yield 10%) of the title compound was obtained as white crystals. Melting point: 166-168 ° C (crystallization solvent: diethyl ether-hexane)

Example 57 2,3-trans-2,4-cis-4- (5,6-dihydrophenanthrusin-5-yl) -1- (3,4-dimethoxybenzoyl) -3-hydroxy -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical formula 119] From 579 mg (3.20 mmol) of 5,6-dihydro-phenanthrudine, 950 mg (yield 76%) of the title compound in the same manner as in Example 14.
Was obtained as white crystals. Melting point 120-123 ℃

Example 58 4- (5,6-dihydrophenanthrusin-5-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2, -dihydroquinoline

[Chemical 120] 2,3-trans-2,4-cis-4- (5,6-obtained in Example 57
From dihydrophenanthruzin-5-yl) -1- (3,4-dimethoxybenzoyl) -3-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline (550 mg, 1.09 mmol) to Example 54 In the same manner as in the above, the title compound (120 mg, yield 23%) was obtained as white crystals. Melting point: 196-198 ° C

Example 59 2-Butyl-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2-dihydroquinoline

[Chemical 121] 2-Butyl-3- (3,4-dimethoxybenzoyl) -1a, 2,3,7b-tetrahydrooxyreno [2,3-c] quinoline 1 g (2.7 mmol) obtained in Reference Example 18 was added to THF 30 ml. The solution was dissolved in, carbazole potassium salt (554 mg, 2.7 mmol) was added, and the mixture was heated under reflux for 24 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate = 80:20), and the eluate was hexane.
-Recrystallized from ethyl acetate to give 105 mg of the title compound (yield 8
%) As white crystals. Calculated elemental analysis _{C 34 H 32 N 2 O 3} : C, 79.04; H, 6.24; N, 5.42 Found: C, 78.81; H, 6.26 ; N, 5.32 mp: 174-175 ° C. Example 54 to The title compounds up to 59 are summarized in Table 5.

[Table 5]

Reference Example 16 2,4-trans-4- (benzotriazol-1-yl) -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical formula 122] Benzotriazole 5.0 g (4.20 mmol), aniline 3.91 g
(4.20 mmol) was dissolved in 85 ml of diethyl ether, and 2.03 g (4.62 mmol) of acetaldehyde was added dropwise under ice cooling. The mixture was stirred at room temperature for 15 minutes and left at -20 ° C overnight. The crystallized product was collected by filtration, washed with diethyl ether and dried, and α-methyl-N-
Phenyl-1H-benzotriazole-1-methanamine 8.7g
Was obtained as white crystals. Obtained α-methyl-N-phenyl
-1H-benzotriazole-1-methanamine 2.86g (12mmo
l) and vinyl phthalimide 2860 mg (12.0 mmol) are suspended in chloroform 10 ml, and p-toluenesulfonic acid monohydrate 190 mg
(1.0 mmol) was added, and the mixture was stirred at room temperature for 10 hours. Water was added to the reaction solution and extracted with chloroform. The organic layer was washed with saturated aqueous sodium carbonate solution and water and then concentrated. The residue was subjected to silica gel column chromatography to give the title compound (1.03 g)
(2-step yield 25%) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ1.21 (d, J = 6.2Hz, 3H), 2.14 (m, 1H), 2.41
(d, J = 13.7Hz, 1H), 3.41 (m, 1H), 4.15 (s, 1H), 6.22 (dd, J
= 4.4,3.2Hz, 1H), 6.64-6.72 (m, 2H), 6.88 (d, J = 7.1Hz, 1
H), 7.00 (t, J = 7.1Hz, 1H), 7.19-7.29 (m, 3H), 8.03 (m, 1H),
8.03 (m, 1H) .FABMS (pos) 264.1 [M +]

Reference Example 17 3- (3,4-dimethoxybenzoyl) -2-propyl-1a, 2,3,7b-
Tetrahydrooxyreno [2,3-c] quinoline

[Chemical 123] 1- (3,4-dimethoxybenzoyl) -2-propyl-1,2-dihydroquinoline synthesized by a method known in the literature 850 mg (0.023
mol) in the same manner as in Reference Example 3 to give 540 mg of the title compound (yield
61%) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ 0.93 (t, J = 7.3Hz, 3H), 1.15-1.30 (m, 1
H), 1.35-1.58 (m, 3H), 3.66 (s, 3H), 3.83 (s, 3H), 3.86
(dd, J = 2.3,4.2Hz, 1H), 3.96 (d, J = 4.2Hz, 1H), 5.22-5.28
(m, 1H), 6.47 (d, J = 7.8Hz, 1H), 6.66 (d, J = 7.8Hz, 1H),
6.89 (d, J = 2.0Hz, 1H), 6.94-7.08 (m, 3H), 7.42 (dd, J = 1.6,
7.2Hz, 1H).

Reference Example 18 2-Butyl-3- (3,4-dimethoxybenzoyl) -1a, 2,3,7b-tetrahydrooxyreno [2,3-c] quinoline

[Chemical formula 124] 2-Butyl-1- (3,4-dimethoxybenzoyl) -1,2-dihydroquinoline synthesized by a method known in the literature 8.00 g (0.023 mo
6.12 g of the title compound (yield 73
%) As white crystals. Melting point 133-134 ℃

Reference Example 19 1- (4-ethoxy-3-methoxybenzoyl) -2-methyl-1,2,
3,4-tetrahydro-4-quinolinol

[Chemical 125] 2-methyl-1,2,3,4-tetrahydro-4-quinolinol 7.1 g (43.5 mmol) synthesized by a method known in the literature was treated with 50 m of pyridine.
Dissolve in l, 4-ethoxy-3-methoxybenzoic acid 9.2g (46.4
4-ethoxy-3-methoxybenzoyl chloride adjusted from (mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated, ethyl acetate and water were added for extraction. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/1), and the eluate was recrystallized from ethyl acetate-hexane to give the title compound (4.4 g)
(Yield 30%) was obtained as white crystals. ¹ H NMR (CDCl ₃ ) δ 1.29 (d, J = 6.4 Hz, 3H), 1.43 (t,
J = 6.9 Hz, 3H), 1.44-1.55 (m, 1H), 2.00 (d, J =
6.2 Hz, 1H), 2.73-2.82 (m, 1H), 3.64 (s, 3H), 4.04
(q, J = 6.4 Hz, 2H), 4.79-4.88 (m, 2H), 6.57 (d,
J = 7.9 Hz, 1H), 6.63 (d, J = 8.9 Hz, 1H), 6.75-6.7
7 (m, 2H), 6.96 (dd, J = 7.7, 7.7 Hz, 1H), 7.15 (d
d, J = 7.5,7.5 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H)

Reference Example 20 1- (3,4-diethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol

[Chemical formula 126] Reference Example 1 from 2-methyl-1,2,3,4-tetrahydro-4-quinolinol 10.0 g (61.3 mmol) synthesized by a method known in the literature
In the same manner as in 9, the title compound (4.67 g, yield 21%) was obtained as white crystals. Melting point: 164-165 ° C

Reference Example 21 1- (3-Methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol

[Chemical 127] Similar to Reference Example 19 from 2-methyl-1,2,3,4-tetrahydro-4-quinolinol 3.00 g (18.3 mmol) and 3-methoxybenzoic acid 3.34 g (22.0 mmol) synthesized by known methods. By the method, 1.45 g (yield 27%) of the title compound was obtained as white crystals. (Cis: trans = 1: 1) Melting point: 148-149 ° C

Reference Example 22 1- (3,4,5-trimethoxybenzoyl) -2-methyl-1,2,3,4-
Tetrahydro-4-quinolinol

[Chemical 128] From 2-methyl-1,2,3,4-tetrahydro-4-quinolinol 3.00 g (18.3 mmol) and 3,4,5-trimethoxybenzoic acid 2.0 g (10.9 mmol) synthesized by a method known in the literature, reference In the same manner as in Example 19, the title compound (1.30 g, yield 33%) was obtained as white crystals. (Cis: trans = 1: 1)

Reference Example 23 1- (3,4-Dimethylbenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol

[Chemical formula 129] From 2-methyl-1,2,3,4-tetrahydro-4-quinolinol 1.00 g (6.12 mmol) and 3,4-dimethylbenzoic acid 1.20 g (7.96 mmol) synthesized by a method known in the literature, Reference Example 19 The title compound (1.13 g, yield 48%) was obtained as an oil in the same manner as. (Cis: trans = 1: 1) ¹ H NMR (CDCl ₃ ) δ1.25-1.28 (m, 3H), 1.44-2.78 (m, 9
H), 4.86-4.94 (m, 2H), 6.57-7.53 (m, 7H).

Reference Example 24 9- [2,4-cis-2- (3-phenylpropyl) -1,2,3,4-tetrahydroquinolin-4-yl] -9H-carbazole

[Chemical 130] Using 4.48 g (43.7 mmol) of 4-phenylbutyraldehyde and in the same manner as in Reference Example 4, the title compound (4.40 g, two-step yield 24%) was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ1.50-1.80 (m, 2H), 2.10-2.25 (m, 1
H), 2.30-2.50 (m, 1H), 2.50-2.80 (m, 4H), 3.60-3.75
(m, 1H), 6.10 (dd, J = 11.9, 6.4 Hz, 1H), 6.40-8.2
0 (m, 17H).

Reference Example 25 9- [2,4-cis-2- [3-[[tert-butyl (diphenyl) silyl]]
Oxy] propyl] -1,2,3,4-tetrahydroquinolin-4-yl] -9H-carbazole

[Chemical 131] From 6.10 g (18.7 mmol) of 4-[[tert-butyl (diphenyl) silyl] oxy] butanal, the title compound (1.08 g, 2-step yield 10%) was obtained as a colorless oil by the same method as in Reference Example 4. Obtained. ¹ H NMR (CDCl ₃ ) δ 1.03-1.06 (m, 9H), 1.70-1.85 (m, 2
H), 2.10-2.20 (m, 1H), 2.30-2.50 (m, 1H), 3.60-3.80
(m, 3H), 3.96 (br s, 1H), 6.09 (dd, J = 11.8, 6.2
Hz, 1H), 6.40-8.20 (m, 22H).

Example 60 4- (1′-benzylspiro [indoline-3,4′-piperidine] -1
-Yl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,
3,4-tetrahydroquinoline

[Chemical 132] Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 40 obtained in Reference Example 1
0 mg (1.22 mmol) and 1'-benzylspiro [indoline-3,4'-
Piperidine] In the same manner as in Example 1 from 849 mg (3.05 mmol), the title compound (376 mg, yield 44%) was obtained as a colorless oil. (Cis: trans = 1: 1.5) FABMS (pos) 588.2 [M + H ⁺ ]

Example 61 4- (2,3-dihydro-1H-indol-1-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 133] Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 4 obtained in Reference Example 1
The title compound (267 mg, yield 51%) was obtained as white crystals from 00 mg (1.22 mmol) and indoline 436 mg (3.66 mmol) in the same manner as in Example 1. (Cis: trans = 1: 1.8) Melting point: 147-148 ° C (crystallization solvent: diethyl ether-
Hexane) FABMS (pos) 451.2 [M + Na ⁺ ]

Example 62 1- (3,4-dimethoxybenzoyl) -2-methyl-4- (2,3,4,5-
Tetrahydro-1H-benzazepin-1-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 134] Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 28 obtained in Reference Example 1
From 0 mg (0.82 mmol) and 2,3,4,5-tetrahydro-1H-1-benzazepine (362 mg, 2.46 mmol) in the same manner as in Example 1,
32 mg (yield 9%) of the title compound was obtained as a colorless oil.
(Cis: trans = 1: 1.5) FABMS (pos) 479.2 [M + Na ⁺ ]

Example 63 (+)-2,4-trans-1- (3,4-dimethoxybenzoyl) -2-
Methyl-4- (2,3,4,5-tetrahydro-1H-benzazepine-1
-Yl) -1,2,3,4-tetrahydroquinoline

[Chemical 135] By the same method as in Example 5, 1-obtained in Example 62
(3,4-dimethoxybenzoyl) -2-methyl-4- (2,3,4,5-tetrahydro-1H-benzazepin-1-yl) -1,2,3,4-tetrahydroquinoline 431 mg to the title compound 198 mg Got Sh
In the analysis of optical activity with odex OR-2 (wavelength 470 nm),
This compound is indicated by the symbol (+). ¹ H NMR (CDCl ₃ ) δ (d, J = 6.6 Hz, 3H), 1.50-1.80 (m,
4H), 1.99-2.05 (m, 1H), 2.55-2.60 (m, 1H), 2.78-
2.81 (m, 2H), 2.92-2.98 (m, 1H), 3.00-3.20 (m, 1
H), 3.62 (s, 3H), 3.87 (s, 3H), 4.82 (dd, J = 8.1,
5.5 Hz, 1H), 4.89-4.95 (m, 1H), 6.63 (d, J = 8.0
Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.89-7.15 (m, 8
H), 7.51 (d, J = 7.2 Hz, 1H).

Example 64 (−)-2,4-trans-1- (3,4-dimethoxybenzoyl) -2-
Methyl-4- (2,3,4,5-tetrahydro-1H-benzazepine-1
-Yl) -1,2,3,4-tetrahydroquinoline

[Chemical 136] By the same method as in Example 5, 1-obtained in Example 62
(3,4-dimethoxybenzoyl) -2-methyl-4- (2,3,4,5-tetrahydro-1H-benzazepin-1-yl) -1,2,3,4-tetrahydroquinoline 431 mg to the title compound 199 mg Got Sh
In the analysis of optical activity with odex OR-2 (wavelength 470 nm),
This compound has a symbol (-). ¹ H NMR (CDCl ₃ ) δ (d, J = 6.6 Hz, 3H), 1.50-1.80 (m,
4H), 1.99-2.05 (m, 1H), 2.55-2.60 (m, 1H), 2.78-
2.81 (m, 2H), 2.92-2.98 (m, 1H), 3.00-3.20 (m, 1
H), 3.62 (s, 3H), 3.87 (s, 3H), 4.82 (dd, J = 8.1,
5.5 Hz, 1H), 4.89-4.95 (m, 1H), 6.63 (d, J = 8.0
Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.89-7.15 (m, 8
H), 7.51 (d, J = 7.2 Hz, 1H).

Example 65 4- (6-chloro-1,2,3,4-tetrahydroquinolin-1-yl) -1
-(3,4-Dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 137] Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 40 obtained in Reference Example 1
The title compound (216 mg, yield 37%) was obtained as a colorless oil from 0 mg (1.22 mmol) and 6-chloro-1,2,3,4-tetrahydroquinoline (614 mg, 3.66 mmol) in the same manner as in Example 1. It was
(Cis: trans = 3.4: 1) Elemental analysis value Calculated as C ₂₈ H ₂₉ N ₂ O ₃ Cl: C, 70.50; H, 6.13; N, 5.87 Experimental value: C, 70.32; H, 6.17; N, 5.86

Example 66 (+)-2,4-trans-4- (6-chloro-1,2,3,4-tetrahydroquinolin-1-yl) -1- (3,4-dimethoxybenzoyl)- 2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 138] In the same manner as in Example 5, 4-obtained in Example 65
(6-chloro-1,2,3,4-tetrahydroquinolin-1-yl) -1-
55 mg of the title compound was obtained from 150 mg of (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline. Shode
In the analysis of the optical rotation by xOR-2 (wavelength: 470 nm), this compound showed a (+) sign. ¹ H NMR (CDCl ₃ ) δ 1.36 (d, J = 6.9 Hz, 3H), 1.80-2.0
0 (m, 2H), 2.06-2.14 (m, 1H), 2.22-2.31 (m, 1H),
2.76-2.80 (m, 2H), 3.13 (t, J = 5.6 Hz, 2H), 3.77
(s, 3H), 3.89 (s, 3H), 5.00-5.15 (m, 1H), 5.26 (d
d, J = 11.2 Hz, 7.4 Hz, 1H), 6.67-6.79 (m, 3H), 6.
90-7.05 (m, 6H), 7.29 (d, J = 7.2 Hz, 1H).

Example 67 (−)-2,4-trans-4- (6-chloro-1,2,3,4-tetrahydroquinolin-1-yl) -1- (3,4-dimethoxybenzoyl)- 2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 139] In the same manner as in Example 5, 4-obtained in Example 65
(6-chloro-1,2,3,4-tetrahydroquinolin-1-yl) -1-
53 mg of the title compound was obtained from 150 mg of (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline. Shode
In the analysis of the optical rotation by xOR-2 (wavelength 470 nm), this compound showed the sign of (-). ¹ H NMR (CDCl ₃ ) δ 1.36 (d, J = 6.9 Hz, 3H), 1.80-2.0
0 (m, 2H), 2.06-2.14 (m, 1H), 2.22-2.31 (m, 1H),
2.76-2.80 (m, 2H), 3.13 (t, J = 5.6 Hz, 2H), 3.77
(s, 3H), 3.89 (s, 3H), 5.00-5.15 (m, 1H), 5.26 (d
d, J = 11.2 Hz, 7.4 Hz, 1H), 6.67-6.79 (m, 3H), 6.
90-7.05 (m, 6H), 7.29 (d, J = 7.2 Hz, 1H).

Example 68 (+)-2,4-cis-4- (6-chloro-1,2,3,4-tetrahydroquinolin-1-yl) -1- (3,4-dimethoxybenzoyl)- 2-methyl
-1,2,3,4-tetrahydroquinoline

[Chemical 140] In the same manner as in Example 5, 4-obtained in Example 65
(6-chloro-1,2,3,4-tetrahydroquinolin-1-yl) -1-
18 mg of the title compound was obtained from 150 mg of (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline. Shode
In the analysis of the optical rotation by xOR-2 (wavelength: 470 nm), this compound showed a (+) sign. ¹ H NMR (CDCl ₃ ) δ 1.38 (d, J = 6.2 Hz, 3H), 1.60-1.8
0 (m, 1H), 1.90-2.20 (m, 2H), 2.68-2.76 (m, 1H),
2.80-2.90 (m, 2H), 3.33-3.37 (m, 2H), 3.62 (s, 3
H), 3.86 (s, 3H), 4.73-4.90 (m, 2H), 6.38 (d, J =
8.8 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.60-6.73
(m, 2H), 6.85-7.10 (m, 6H).

Example 69 (−)-2,4-cis-4- (6-chloro-1,2,3,4-tetrahydroquinolin-1-yl) -1- (3,4-dimethoxybenzoyl)- 2-methyl
-1,2,3,4-tetrahydroquinoline

[Chemical 141] In the same manner as in Example 5, 4-obtained in Example 65
(6-chloro-1,2,3,4-tetrahydroquinolin-1-yl) -1-
17 mg of the title compound was obtained from 150 mg of (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline. Shode
In the analysis of the optical rotation by xOR-2 (wavelength 470 nm), this compound showed the sign of (-). ¹ H NMR (CDCl ₃ ) δ 1.38 (d, J = 6.2 Hz, 3H), 1.60-1.8
0 (m, 1H), 1.90-2.20 (m, 2H), 2.68-2.76 (m, 1H),
2.80-2.90 (m, 2H), 3.33-3.37 (m, 2H), 3.62 (s, 3
H), 3.86 (s, 3H), 4.73-4.90 (m, 2H), 6.38 (d, J =
8.8 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.60-6.73
(m, 2H), 6.85-7.10 (m, 6H).

Example 70 1- (3,4-dimethoxybenzoyl) -2-methyl-4- (6-methyl-
1,2,3,4-tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 142] Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 50 obtained in Reference Example 1
117 mg (yield 18%) of the title compound was obtained as white crystals from 0 mg (1.53 mmol) and 676 mg (4.59 mmol) of 6-methyl-1,2,3,4-tetrahydroquinoline in the same manner as in Example 1. . (Cis: trans = 1.6: 1) Elemental analysis value Calculated as C ₂₉ H ₃₂ N ₃ O ₃ : C, 76.29; H, 7.06; N, 6.14 Experimental value: C, 75.89; H, 6.94; N, 6.25 Melting point : 139-140 ° C (crystallization solvent: diethyl ether-hexane)

Example 71 N- [1- [1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,
4-Tetrahydroquinolin-4-yl] -1,2,3,4-tetrahydroquinolin-6-yl] acetamide

[Chemical 143] Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 35 obtained in Reference Example 1
0 mg (1.07 mmol) and N- (1,2,3,4-tetrahydroquinoline-6-
38 mg (yield 7%) of the title compound was obtained as a colorless oil from 475 mg (2.50 mmol) of (yl) acetamide in the same manner as in Example 1. (Cis: trans = 1: 1.7) FABMS (pos) 522.1 [M + Na ⁺ ].

Example 72 4- [1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-
Tetrahydroquinolin-4-yl] -3,4-dihydro-2H-1,4-
Benzothiazine

[Chemical 144] Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol obtained in Reference Example 1.
00g (2.93mmol) and 3,4-dihydro-2H-1,4-benzothiazine
The title compound (335 mg, yield 25%) was obtained as white crystals from 1.22 g (8.07 mmol) in the same manner as in Example 1. (Cis:
Trans = 1.5: 1) FABMS (pos) 483.1 [M + Na ⁺ ] Melting point: 113-114 ° C (crystallization solvent: diisopropyl ether-hexane)

Example 73 1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-
Tetrahydroisoquinolin-2-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 145] Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 40 obtained in Reference Example 1
0 mg (1.22 mmol) and 1,2,3,4-tetrahydroisoquinoline 48
The title compound (210 mg, yield 39%) was obtained as white crystals from 7 mg (3.66 mmol) in the same manner as in Example 1. (Cis: trans = 1: 1) Elemental analysis value Calculated as C ₂₈ H ₃₀ N ₂ O ₃ : C, 75.99; H, 6.83; N, 6.33 Experimental value: C, 75.86; H, 7.20; N, 6.32 Melting point : 128-129 ° C (crystallization solvent: diethyl ether-hexane) The title compounds of Examples 60 to 73 are summarized in Table 6.

[Table 6]

Example 74 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl)
-3-hydroxy-2-propyl-4- (1,2,3,4-tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 146] 3- (3,4-dimethoxybenzoyl) -2 obtained in Reference Example 17
-Propyl-1a, 2,3,7b-tetrahydrooxyreno [2,3-c]
The title compound (169 mg, yield 31%) was obtained as white crystals from 400 mg (1.13 mmol) of quinoline in the same manner as in Example 14. Elemental analysis value Calculated as C ₃₀ H ₃₄ N ₂ O ₄ 0.25H ₂ O: C, 73.37; H, 7.08; N, 5.70 Experimental value: C, 73.65; H, 7.04; N, 5.44 Melting point: 160-162 ° C (crystallization solvent: diisopropyl ether-hexane)

Example 75 2,4-cis-1- (3,4-dimethoxybenzoyl) -2-propyl-4
-(1,2,3,4-Tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 147] 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl) -3-hydroxy-2-propyl-4- (1, obtained in Example 74
In the same manner as in Example 15 and Example 16, from 2,3,4-tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline (353 mg, 0.72 mmol), the title compound 131 mg (2 steps Yield 39%) was obtained as white crystals. Elemental analysis value Calculated as C ₃₀ H ₃₄ N ₂ O ₃ : C, 76.57; H, 7.28; N, 5.95 Experimental value: C, 76.36; H, 7.41; N, 5.98 Melting point: 176-177 ℃ (crystallization solvent : Ethyl acetate-hexane)

Example 76 2,3-trans-2,4-cis-2-butyl-1- (3,4-dimethoxybenzoyl) -3-hydroxy-4- (1,2,3,4-tetrahydroquinoline -1-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 148] 2-Butyl-3- (3,4-dimethoxybenzoyl) -1a, 2,3,7b-tetrahydrooxyreno [2,3-c] quinoline obtained in Reference Example 18 1.10 g (3.00 mmol) and 1, The title compound (1.11 g) was prepared in the same manner as in Example 14 from 2,3,4-tetrahydroquinoline.
(Yield 74%) was obtained as white crystals. Elemental analysis value Calculated as C ₃₁ H ₃₆ N ₂ O ₄ : C, 74.37; H, 7.25; N, 5.60 Experimental value: C, 74.24; H, 7.46; N, 5.43 Melting point: 200-202 ℃ (crystallization solvent : Ethyl acetate-hexane)

Example 77 2,4-cis-2-butyl-1- (3,4-dimethoxybenzoyl) -4-
(1,2,3,4-tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 149] 2,3-trans-2,4-cis-2-butyl obtained in Example 76
-1- (3,4-dimethoxybenzoyl) -3-hydroxy-4- (1,2,
3,4-Tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline (500 mg, 1.00 mmol) was used in the same manner as in Example 15 and Example 16 to give the title compound (560 mg, 2-step yield). 62%) was obtained as white crystals. Elemental analysis value Calculated as C ₃₁ H ₃₆ N ₂ O ₃ : C, 76.83; H, 7.49; N, 5.78 Experimental value: C, 76.68; H, 7.53; N, 5.68 Melting point: 159-160 ℃ (crystallization solvent : Ethyl acetate-hexane)

Example 78 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl)
-3-[[(Isopropylamino) carbonyl] oxy] -2-methyl-4- (1,2,3,4-tetrahydroquinolin-1-yl) -1,2,3,4
-Tetrahydroquinoline

[Chemical 150] 2,3-trans-2,4-cis-1- (3,4-obtained in Example 14
Dimethoxybenzoyl) -3-hydroxy-2-methyl-4- (1,
From 2,3,4-tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline 200 mg (0.44 mmol) and isopropyl isocyanate 170 mg (2.0 mmol), the title compound 190 mg ( Yield 80%) was obtained as white crystals. Melting point 183-184 ℃

Example 79 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl)
-2-Methyl-3-[[(phenylamino) carbonyl] oxy] -4
-(1,2,3,4-Tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 151] 2,3-trans-2,4-cis-1- (3,4-obtained in Example 14
Dimethoxybenzoyl) -3-hydroxy-2-methyl-4- (1,
From 2,3,4-tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline 200 mg (0.44 mmol) and phenylisocyanate 138 mg (2.0 mmol), in the same manner as in Example 27, the title compound 138 mg ( Yield 55%) was obtained as white crystals. Melting point 233-234 ℃

Example 80 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl)
-3-Hydroxy-2-methyl-4- (7-methyl-1,2,3,4-tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 152] 3- (3,4-dimethoxybenzoyl) -2-obtained in Reference Example 3
From methyl-1a, 2,3,7b-tetrahydrooxyreno [2,3-c] quinoline 976 mg (3.00 mmol) and 7-methyl-1,2,3,4-tetrahydroquinoline 883 mg (6.00 mmol) The title compound (372 mg, yield 26%) was obtained as white crystals in the same manner as in 14. Elemental analysis value Calculated as C ₂₉ H ₃₂ N ₂ O ₄ 0.25H ₂ O: C, 73.01; H, 6.87; N, 5.87 Experimental value: C, 73.15; H, 7.08; N, 5.87 Melting point: 130-131 ° C (crystallization solvent: diisopropyl ether-hexane)

Example 81 2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4-
(7-methyl-1,2,3,4-tetrahydroquinolin-1-yl) -1,
2,3,4-tetrahydroquinoline

[Chemical 153] 2,3-trans-2,4-cis-1- (3,4-obtained in Example 80
Dimethoxybenzoyl) -3-hydroxy-2-methyl-4- (7-
Methyl-1,2,3,4-tetrahydroquinolin-1-yl) -1,2,3,
From 473 mg (1.00 mmol) of 4-tetrahydroquinoline, 320 m of the title compound was obtained in the same manner as in Example 15 and Example 16.
g (2-step yield 70%) was obtained as white crystals. Elemental analysis value Calculated as C ₂₉ H ₃₂ N ₂ O ₃ : C, 76.29; H, 7.06; N, 6.14 Experimental value: C, 76.00; H, 7.27; N, 5.93 Melting point: 197-198 ℃ (Crystallization solvent : Diisopropyl ether-hexane)

Example 82 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl)
-3-hydroxy-2-methyl-4- (6-methyl-1,2,3,4-tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 154] 3- (3,4-dimethoxybenzoyl) -2-obtained in Reference Example 3
From methyl-1a, 2,3,7b-tetrahydrooxyreno [2,3-c] quinoline 813 mg (2.50 mmol) and 6-methyl-1,2,3,4-tetrahydroquinoline 552 mg (3.74 mmol) In the same manner as in 14, the title compound (679 mg, yield 57%) was obtained as white crystals. Elemental analysis value Calculated as C ₂₉ H ₃₂ N ₂ O ₄ : C, 73.70; H, 6.83; N, 5.93 Experimental value: C, 73.39; H, 6.98; N, 5.91

Example 83 2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4-
(6-methyl-1,2,3,4-tetrahydroquinolin-1-yl) -1,
2,3,4-tetrahydroquinoline

[Chemical 155] 2,3-trans-2,4-cis-1- (3,4-obtained in Example 82
Dimethoxybenzoyl) -3-hydroxy-2-methyl-4- (6-
Methyl-1,2,3,4-tetrahydroquinolin-1-yl) -1,2,3,
In the same manner as in Examples 15 and 16, the title compound 169m was prepared from 600 mg (1.27 mmol) of 4-tetrahydroquinoline.
g (30% yield) was obtained as white crystals. Melting point: 184-185 ° C (crystallization solvent: ethyl acetate-hexane) Elemental analysis value Calculated as C ₂₉ H ₃₂ N ₂ O ₃ : C, 76.29; H, 7.06; N, 6.14 Experimental value: C, 76.14; H , 6.99; N, 6.12

Example 84 2,3-trans 2,4-cis-1- (3,4-dimethoxybenzoyl)-
3-Hydroxy-4- (6-isopropyl-1,2,3,4-tetrahydroquinolin-1-yl) -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 156] 3- (3,4-dimethoxybenzoyl) -2-obtained in Reference Example 3
From methyl-1a, 2,3,7b-tetrahydrooxyreno [2,3-c] quinoline 976 mg (3.00 mmol) and 6-isopropyl-1,2,3,4-tetrahydroquinoline 789 mg (4.50 mmol) to Example 14 In the same manner as in (1), the title compound (1.06 g, yield 71%) was obtained as white crystals. Elemental analysis value Calculated as C ₃₁ H ₃₆ N ₂ O ₄ : C, 74.37; H, 7.25; N, 5.60 Experimental value: C, 74.11; H, 7.61; N, 5.35 Melting point: 165-166 ℃ (crystallization solvent : Ethyl acetate-hexane)

Example 85 2,4-cis-4- (6-isopropyl-1,2,3,4-tetrahydroquinolin-1-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl- 1,2,3,4-tetrahydroquinoline

[Chemical 157] 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl) -3-hydroxy-4- (6-isopropyl) obtained in Example 84
-1,2,3,4-Tetrahydroquinolin-1-yl) -2-methyl-1,
From 499 mg (1.00 mmol) of 2,3,4-tetrahydroquinoline, the title compound was prepared in the same manner as in Example 15 and Example 16.
240 mg (2-step yield 50%) was obtained as white crystals. Elemental analysis value Calculated as C ₃₁ H ₃₆ N ₂ O ₃ : C, 76.83; H, 7.49; N, 5.78 Experimental value: C, 76.45; H, 7.57; N, 5.88 Melting point: 187-188 ℃ (crystallization solvent : Ethyl acetate-hexane)

Example 86 2,3-trans 2,4-cis-4- (5-chloro-1,2,3,4-tetrahydroquinolin-1-yl) -1- (3,4-dimethoxybenzoyl) -
3-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 158] 3- (3,4-dimethoxybenzoyl) -2-obtained in Reference Example 3
From methyl-1a, 2,3,7b-tetrahydrooxyreno [2,3-c] quinoline 976 mg (3.00 mmol) and 5-chloro-1,2,3,4-tetrahydroquinoline 754 mg (4.50 mmol) In the same manner as in 14, the title compound (1.01 g, yield 69%) was obtained as white crystals. Elemental analysis value Calculated as C ₂₈ H ₂₉ N ₂ O ₄ : C, 68.22; H, 5.93; N, 5.68 Experimental value: C, 68.17; H, 5.94; N, 5.56 Melting point: 205-206 ℃ (crystallization solvent : Tetrahydrofuran-hexane)

Example 87 2,4-cis-4- (5-chloro-1,2,3,4-tetrahydroquinoline
-1-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,
2,3,4-tetrahydroquinoline

[Chemical 159] 2,3-trans-2,4-cis-4- (5-chloro-1,2,3,4-tetrahydroquinolin-1-yl) -1- (3,4-dimethoxybenzoyl) obtained in Example 86 ) -3-Hydroxy-2-methyl-1,2,3,4-
From tetrahydroquinoline 493 mg (1.00 mmol), Example 1
In the same manner as in Example 5 and Example 16, 172 mg of the title compound
(2-step yield 36%) was obtained as white crystals. Elemental analysis _{C 28 H 29 ClN 2 O 3} · 0.25H 2 O Calculated: C, 69.84; H, 6.18 ; N, 5.82 Found: C, 69.64; H, 5.89 ; N, 5.61 Melting point: 194-195 ° C (crystallization solvent: diethyl ether-hexane)

Example 88 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl)
-3-hydroxy-2-methyl-4- (1,2,4,5-tetrahydro-3H-
3-benzazepin-3-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 160] 3- (3,4-dimethoxybenzoyl) -2-obtained in Reference Example 3
Methyl-1a, 2,3,7b-tetrahydrooxyreno [2,3-c] quinoline 813 mg (2.50 mmol) and 2,3,4,5-tetrahydro-1H-3
-From 552 mg (3.75 mmol) of benzazepine, in the same manner as in Example 14, the title compound (624 mg, yield 53%) was obtained as white crystals. Melting point: 191-192 ° C (crystallization solvent: ethyl acetate-hexane) ¹ H NMR (CDCl ₃ ) δ 1.32 (d, J = 6.6 Hz, 3H), 2.93-3.3
0 (m, 9H), 3.65-3.76 (m, 4H), 3.83 (s, 3H), 3.89
(d, J = 8.7 Hz, 1H), 4.55-4.63 (m, 1H), 6.54-6.62
(m, 2H), 6.71 (dd, J = 8.3, 1.8 Hz, 1H), 6.83 (d,
J = 1.7 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 7.09 (t,
J = 7.4 Hz, 1H), 7.20 (br s, 4H), 7.53 (d, J = 7.
6 Hz, 1H).

Example 89 2,3-trans-2,4-cis-1- (3,4-dimethoxybenzoyl)
-3-hydroxy-2-methyl-4- (1,2,3,4-tetrahydroisoquinolin-2-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 161] 3- (3,4-dimethoxybenzoyl) -2-obtained in Reference Example 3
Methyl-1a, 2,3,7b-tetrahydrooxyreno [2,3-c] quinoline 813 mg (2.50 mmol) and 1,2,3,4-tetrahydroisoquinoline 499 mg (3.75 mmol) in the same manner as in Example 14. The title compound (623 mg, yield 54%) was obtained as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ1.32 (d, J = 6.6Hz, 3H), 2.90-3.30 (m, 5
H), 3.67 (s, 3H), 3.83 (s, 3H), 3.85-3.89 (m, 1H), 4.02
(d, J = 8.3Hz, 1H), 4.19 (d, J = 15.0Hz, 1H), 4.34 (d, J = 15.0
Hz, 1H), 4.67-4.70 (m, 1H), 6.57-6.63 (m, 2H), 6.76-6.8
0 (m, 1H), 6.85 (m, 1H), 6.93 (t, J = 7.7Hz, 1H), 7.06-7.11
(m, 2H), 7.15-7.19 (m, 3H), 7.57 (d, J = 7.7Hz, 1H). FABMS (pos) 459.2 [M + H ⁺ ] Table 7 for the title compounds of Examples 74 to 89 Summarized in.

[Table 7]

Example 90 (+)-2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroisoquinolin-2-yl)- 1,
2,3,4-tetrahydroquinoline

[Chemical 162] In the same manner as in Example 5, 1-obtained in Example 73
(3,4-Dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroisoquinolin-2-yl) -1,2,3,4-tetrahydroquinoline 1.7 g to give the title compound 343 mg. It was Shodex OR
In the analysis of optical rotation by -2 (wavelength 470 nm), this compound showed the sign of (+). ¹ H NMR (CDCl ₃ ) δ 1.34 (d, J = 6.4 Hz, 3H), 1.64-1.7
2 (m, 1H), 2.69-2.78 (m, 1H), 2.85-2.94 (m, 4H),
3.57 (s, 3H), 3.65-3.74 (m, 2H), 3.82 (s, 3H), 3.9
0 (d, J = 14.7 Hz, 1H), 4.77-4.84 (m, 1H), 6.59-6.
63 (m, 2H), 6.79 (d, J = 1.7 Hz, 1H), 6.96-7.10 (m,
7H), 7.33 (dd, J = 7.4, 1.2 Hz, 1H).

Example 91 (−)-2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroisoquinolin-2-yl)- 1,
2,3,4-tetrahydroquinoline

[Chemical formula 163] In the same manner as in Example 5, 1-obtained in Example 73
(3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroisoquinolin-2-yl) -1,2,3,4-tetrahydroquinoline 1.7 g to obtain the title compound 314 mg. It was Shodex OR
In the analysis of the optical rotation by -2 (wavelength 470 nm), this compound showed the sign of (-). ¹ H NMR (CDCl ₃ ) δ 1.34 (d, J = 6.4 Hz, 3H), 1.64-1.7
2 (m, 1H), 2.69-2.78 (m, 1H), 2.85-2.94 (m, 4H),
3.57 (s, 3H), 3.65-3.74 (m, 2H), 3.82 (s, 3H), 3.9
0 (d, J = 14.7 Hz, 1H), 4.77-4.84 (m, 1H), 6.59-6.
63 (m, 2H), 6.79 (d, J = 1.7 Hz, 1H), 6.96-7.10 (m,
7H), 7.33 (dd, J = 7.4, 1.2 Hz, 1H).

Example 92 (+)-2,4-trans-1- (3,4-dimethoxybenzoyl) -2-
Methyl-4- (1,2,3,4-tetrahydroisoquinolin-2-yl)
-1,2,3,4-tetrahydroquinoline

[Chemical 164] In the same manner as in Example 5, 1-obtained in Example 73
(3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroisoquinolin-2-yl) -1,2,3,4-tetrahydroquinoline 1.7 g to give the title compound 411 mg. It was Shodex OR
In the analysis of the optical rotation by -2 (wavelength 470 nm), this compound showed the sign of (+). ¹ H NMR (CDCl ₃ ) δ 1.27-1.42 (m, 4H), 2.71-2.82 (m, 2
H), 2.93-3.16 (m, 3H), 3.62 (s, 3H), 3.86 (s, 3H),
3.86-3.96 (m, 2H), 4.11 (d, J = 14.7 Hz, 1H), 4.77
-4.84 (m, 1H), 6.55-6.62 (m, 2H), 6.72-6.76 (m, 2
H), 6.92 (t, J = 7.5 Hz, 1H), 7.08-7.18 (m, 5H), 7.
52 (d, J = 7.5 Hz, 1H).

Example 93 (−)-2,4-trans-1- (3,4-dimethoxybenzoyl) -2-
Methyl-4- (1,2,3,4-tetrahydroisoquinolin-2-yl)
-1,2,3,4-tetrahydroquinoline

[Chemical 165] In the same manner as in Example 5, 1-obtained in Example 73
(3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroisoquinolin-2-yl) -1,2,3,4-tetrahydroquinoline 1.7 g to obtain the title compound 451 mg. It was Shodex OR
In the analysis of the optical rotation by -2 (wavelength 470 nm), this compound showed the sign of (-). ¹ H NMR (CDCl ₃ ) δ 1.27-1.42 (m, 4H), 2.71-2.82 (m, 2
H), 2.93-3.16 (m, 3H), 3.62 (s, 3H), 3.86 (s, 3H),
3.86-3.96 (m, 2H), 4.11 (d, J = 14.7 Hz, 1H), 4.77
-4.84 (m, 1H), 6.55-6.62 (m, 2H), 6.72-6.76 (m, 2
H), 6.92 (t, J = 7.5 Hz, 1H), 7.08-7.18 (m, 5H), 7.
52 (d, J = 7.5 Hz, 1H).

Example 94 5-[[1- [1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,
Ethyl 3,4-tetrahydro-4-quinolinyl] -1,2,3,4-tetrahydro-6-quinolinyl] oxy] pentanoate

[Chemical 166] Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol obtained in Reference Example 1.
From 0 g (3.05 mmol) and 487 mg (3.66 mmol) of ethyl 5-[(1,2,3,4-tetrahydro-6-quinolinyl) oxy] pentanoate, 760 mg (yield) of the title compound was obtained in the same manner as in Example 1. 42%) as a colorless oil. (Cis: trans = 1: 1.
2) FABMS (pos) 586.2 [M ⁺ ]

Example 95 5-[[1- [1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,
3,4-Tetrahydro-4-quinolinyl] -1,2,3,4-tetrahydro-6-quinolinyl] oxy] pentanoic acid

[Chemical 167] 5-[[1- [1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinyl] -obtained in Example 94
Ethyl 1,2,3,4-tetrahydro-6-quinolinyl] oxy] pentanoate 100 mg (0.17 mmol) was dissolved in THF (3 ml), ethanol (2 ml) and water (2 ml), and lithium hydroxide monohydrate was added. 21 mg (0.51 mmol) of the product was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 4 /
After 1), the title compound (33 mg, yield 35%) was obtained as a colorless oil. (Cis: trans = 1: 1.5) FABMS (pos) 558.2 [M ⁺ ]

Example 96 5-[[1- [1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,
3,4-Tetrahydro-4-quinolinyl] -1,2,3,4-tetrahydro-6-quinolinyl] oxy] -N-propylpentanamide

[Chemical 168] 5-[[1- [1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinyl] -obtained in Example 95
197 mg (0.35 mmol) of 1,2,3,4-tetrahydro-6-quinolinyl] oxy] pentanoic acid was dissolved in THF (10 ml), and oxalyl chloride 0.079 ml (1.05 mmol) and DMF (0.1 ml) were cooled with ice. After that, the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, the residue was dissolved in pyridine (10 ml) under ice cooling, 62 mg (1.05 mmol) of propylamine was added, and the mixture was stirred at room temperature for 16 hr. The reaction solution was diluted with ethyl acetate, washed with water, dried and concentrated, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 4/1) to give 51 mg of the title compound (yield 24%). Obtained as a colorless oil. (Cis: trans = 1: 2.8) FABMS (pos) 599.2 [M ⁺ ]

Example 97 N, N-Dimethylcarbamic acid [1- [1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinyl] -1,2 , 3,4-Tetrahydro-6-quinolinyl]

[Chemical 169] In the same manner as in Example 1, the cis-1-obtained in Reference Example 1 was obtained.
(3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 600 mg (1.83 mmol) and N, N-dimethylcarbamic acid (1,2,3,4-tetrahydro- 6-quinolinyl) 1.
From 00 g (4.58 mmol), 290 mg (yield 29%) of the title compound was obtained as white crystals. (Cis: trans = 3.3: 1) Elemental analysis value Calculated value as C ₃₁ H ₃₅ N ₃ O ₅ · 0.2H ₂ O: C, 69.83; H, 6.69; N, 7.88 Experimental value: C, 69.88; H , 6.79; N, 7.66

Example 98 N- [1- [1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,
4-Tetrahydro-4-quinolinyl] -1,2,3,4-tetrahydro-
6-quinolinyl] carbamate tert-butyl ester

[Chemical 170] Using the same method as in Example 1, cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-obtained in Reference Example 1
Tetrahydro-4-quinolinol 712 mg (2.18 mmol) and N- (1,
2,3,4-Tetrahydro-6-quinolinyl) carbamic acid tert-
From 1.35 g (5.44 mmol) of butyl, 157 mg of the title compound (yield 13
%) As white crystals. (Cis: trans = 4.
8: 1) Melting point: 192-193 ° C (crystallization solvent: diethyl ether-hexane)

Example 99 N- [1- [1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,
4-Tetrahydro-4-quinolinyl] -1,2,3,4-tetrahydro-
6-quinolinyl] butanamide

[Chemical 171] Cis-1- (3,4-dimethoxybenzoi obtained in Reference Example 1
) -2-Methyl-1,2,3,4-tetrahydro-4-quinolinol 80
0 mg (2.44 mmol) and N- (1,2,3,4-tetrahydro-6-quinolini
Same as Example 1 from 1.33 g (6.1 mmol)
The title compound (463 mg, yield 36%) was obtained as a colorless oil
Got as. (Cis: trans = 1: 1.3) ¹ H NMR (CDCl₃) δ 0.90-1.10 (m, 3H), 1.30-1.38 (m, 3
H), 1.60-2.40 (m, 11H), 3.05-3.20 (m, 1.14H), 3.30
-3.40 (m, 0.86H), 3.62 (s, 1.29H), 3.77 (s, 1.71H),
 3.86 (s, 1.29H), 3.89 (s, 1.71H), 4.76-4.83 (m,
0.86H), 5.10 (brs, 0.57H), 5.25-5.31 (m, 0.57H),
6.40-7.33 (m, 10H).

Example 100 2,4-trans-4- (benzotriazol-1-yl) -1- (3,4-
Dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 172] 2,4-trans-4- (benzotriazol-1-yl) -2-methyl-1,2,3,4-tetrahydroquinoline obtained in Reference Example 16
The title compound (630 mg, yield 98%) was obtained as white crystals from 440 mg (1.50 mmol) in the same manner as in Example 32. Elemental analysis value Calculated as C ₂₅ H ₂₄ N ₄ O ₃ 0.25H ₂ O: C, 69.35; H, 5.70; N, 12.94 Experimental value: C, 69.01; H, 5.71; N, 12.69

Example 101 2,4-cis-4- (6-benzyloxy-1,2,3,4-tetrahydroquinolin-1-yl) -1- (3,4-dimethoxybenzoyl) -2-methyl -1,2,3,4-tetrahydroquinoline

[Chemical 173] 830 mg (2.6 mmol) of cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol obtained in Reference Example 1 and 6-benzyloxy-1, The title compound (283 mg, yield 20%) was obtained as white crystals from 2.90 g (8.0 mmol) of 2,3,4-tetrahydroquinoline in the same manner as in Example 1. Elemental analysis value Calculated as C ₃₅ H ₃₆ N ₂ O ₄ 0.2H ₂ O: C, 76.12; H, 6.64; N, 5.07 Experimental value: C, 76.24; H, 6.46; N, 4.88 Melting point: 164-165 ° C The title compounds of Examples 90 to 101 are summarized in Table 8.

[Table 8]

Example 102 1- (3,4-diethoxybenzoyl) -2-methyl-4- (1,2,3,4-
Tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 174] 1- (3,4-diethoxybenzoyl) -2 obtained in Reference Example 20
-Methyl-1,2,3,4-tetrahydro-4-quinolinol 600mg
(1.70 mmol) and 1,2,3,4-tetrahydroquinoline 679 mg (5.23
mmol) in the same manner as in Example 1 to yield 267 mg of the title compound.
(Yield 34%) was obtained as white crystals. (Cis: trans = 1: 1.4) Elemental analysis C ₃₀ H ₃₄ N ₂ O ₃ Calculated: C, 76.57; H, 7.28 ; N, 5.95 Found: C, 76.49; H, 7.38 ; N, 5.99 mp : 157-158 ℃

Example 103 1- (4-ethoxy-3-methoxybenzoyl) -2-methyl-4- (1,
2,3,4-Tetrahydroquinolin-1-yl) -1,2,3,4-tetrahydroquinoline

[Chemical 175] 1- (4-ethoxy-3-methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol obtained in Reference Example 19
600 mg (1.76 mmol) and 1,2,3,4-tetrahydroquinoline 703 mg
(5.28 mmol) and in the same manner as in Example 1, the title compound 28
8 mg (36% yield) was obtained as white crystals. (Cis: trans = 2: 3) Elemental analysis value Calculated as C ₂₉ H ₃₂ N ₂ O ₃ 0.25H ₂ O: C, 75.54; H, 7.10; N, 6.08 Experimental value: C, 75.56; H, 7.05; N, 6.10 Melting point: 140-142 ° C

Example 104 5-[[1- [1- (3-methoxybenzoyl) -2-methyl-1,2,3,4-
Tetrahydro-4-quinolinyl] -1,2,3,4-tetrahydro-6-
Quinolinyl] oxy] ethyl pentanoate

[Chemical 176] 1.0 g (3.36 m of 1- (3-methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol obtained in Reference Example 21
mol) and ethyl 5-[(1,2,3,4-tetrahydro-6-quinolinyl) oxy] pentanoate 2.14 g (7.73 mmol) in the same manner as in Example 1 to give 479 mg of the title compound (yield 26% ) Was obtained as a colorless oil. (Cis: trans = 1: 3.5) FABMS (pos) 556.2 [M ⁺ ]

Example 105 5-[[1- [2-methyl-1- (3,4,5-trimethoxybenzoyl)-
Ethyl 1,2,3,4-tetrahydro-4-quinolinyl] -1,2,3,4-tetrahydro-6-quinolinyl] oxy] pentanoate

[Chemical 177] 2-Methyl-1- (3,4,5-trimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinol 1.3 obtained in Reference Example 22
g (3.6 mmol) and 5-[(1,2,3,4-tetrahydro-6-quinolinyl)
From 2.30 g (8.28 mmol) of ethyl oxy] pentanoate, 806 mg (yield 40%) of the title compound was obtained as a colorless oil in the same manner as in Example 1. (Cis: trans = 1: 1.3)

Example 106 5-[[1- [1- (3-methoxybenzoyl) -2-methyl-1,2,3,4-
Tetrahydro-4-quinolinyl] -1,2,3,4-tetrahydro-6-
Quinolinyl] oxy] pentanoic acid

[Chemical 178] 5-[[1- [1- (3-methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinyl] -1, obtained in Example 104
From 450 mg (0.81 mmol) of ethyl 2,3,4-tetrahydro-6-quinolinyl] oxy] pentanoate, 280 mg (yield 65%) of the title compound was obtained as a colorless oil in the same manner as in Example 95. (Cis: trans = 1: 3.2) FABMS (pos) 528.1 [M ⁺ ]

Example 107 5-[[1- [2-methyl-1- (3,4,5-trimethoxybenzoyl)-
1,2,3,4-Tetrahydro-4-quinolinyl] -1,2,3,4-tetrahydro-6-quinolinyl] oxy] pentanoic acid

[Chemical 179] 5-[[1- [2-methyl-1- (3,4,5-trimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinyl] -1,2 obtained in Example 105 , 3,4-Tetrahydro-6-quinolinyl] oxy]
The title compound (422 mg, yield 57%) was obtained as a colorless oil from 780 mg (1.26 mmol) of ethyl pentanoate in the same manner as in Example 95. (Cis: trans = 1: 1.3)

Example 108 5-[[1- [1- (3-methoxybenzoyl) -2-methyl-1,2,3,4-
Tetrahydro-4-quinolinyl] -1,2,3,4-tetrahydro-6-
Quinolinyl] oxy] -N-propylpentanamide

[Chemical 180] 5-[[1- [1- (3-methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinyl] -1, obtained in Example 106
2,3,4-Tetrahydro-6-quinolinyl] oxy] pentanoic acid 2
From 60 mg (0.49 mmol), 38 mg (yield 12%) of the title compound was obtained as a colorless oil in the same manner as in Example 96. (Cis: trans = 1: 4.5) ¹ H NMR (CDCl ₃ ) δ 0.93 (t, J = 7.4, 1H), 1.35 (d, J =
6.9, 1H), 1.48-3.30 (m, 18H), 3.64 (s, 0.54H), 3.7
6 (s, 2.46H), 3.93 (br s, 2H), 4.70-4.90 (m, 0.36
H), 5.03 (br s, 0.82H), 5.22 (dd, J = 11.1, 7.1, 0.8
2H) .5.52 (br s, 1H), 6.40-7.40 (m, 11H).

Example 109 5-[[1- [2-methyl-1- (3,4-dimethylbenzoyl) -1,2,3,4
-Tetrahydro-4-quinolinyl] -1,2,3,4-tetrahydro-6
-Quinolinyl] oxy] -N-propylpentanamide

[Chemical 181] 5-[[1- [1- (3,4-Dimethylbenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinyl] -obtained in Example 164
1,2,3,4-Tetrahydro-6-quinolinyl] oxy] pentanoic acid 0.20 g (0.37 mmol), 1-hydroxybenzotriazole 5
To a solution of 0 mg (0.37 mmol) N, N-dimethylformamide (3 mL)
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) 92 mg (0.48 mmol) was added and the mixture was stirred at room temperature.
Stir for 10 minutes. Add 91 μl of propylamine to this,
The mixture was stirred at room temperature for another 15 hours. Aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
To 4: 1) to give 0.14 g (yield 68%) of the title compound as an amorphous powder. (Cis: trans = 3: 2) ¹ H NMR (CDCl ₃ ) δ 0.92 (t, J = 7.4 Hz, 3H), 1.24-1.35
(m, 3H), 1.46-1.57 (m, 2H), 1.74-2.27 (m, 16H), 2.6
2-3.34 (m, 6H), 3.88-3.94 (m, 2H), 4.71-4.89 (m,
0.8H), 5.00 (br s, 0.6H), 5.18-5.24 (m, 0.6H), 5.5
4 (br s, 1H), 6.44-7.38 (m, 10H).

Example 110 5-[[1- [2-methyl-1- (3,4,5-trimethoxybenzoyl)-
1,2,3,4-Tetrahydro-4-quinolinyl] -1,2,3,4-tetrahydro-6-quinolinyl] oxy] -N-propylpentanamide

[Chemical 182] 5-[[1- [2-methyl-1- (3,4,5-trimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinyl] -1,2 obtained in Example 107 , 3,4-Tetrahydro-6-quinolinyl] oxy]
The title compound (0.22 g, yield 56%) was obtained from 0.37 g (0.62 mmol) of pentanoic acid by the same method as in Example 109. (Cis: trans = 1: 1) Melting point: 124-133 ° C. (recrystallized from hexane-ethyl acetate) ¹ H NMR (CDCl ₃ ) δ 0.90-0.95 (m, 3H), 1.34-1.39 (m, 3)
H), 1.46-1.58 (m, 2H), 1.73-2.32 (m, 10H), 2.68-3.3
8 (m, 6H), 3.62-3.93 (m, 11H), 4.70-4.88 (m, 1H),
5.10 (br s, 0.5H), 5.21-5.29 (m, 0.5H), 5.51 (br
s, 1H), 6.37-7.39 (m, 9H). The title compounds of Examples 102 to 110 are summarized in Table 9.

[Table 9]

Example 111 (+)-2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2-propyl-1,2,3,4-tetrahydro Quinoline

[Chemical 183] In the same manner as in Example 5, 2, obtained in Example 38,
4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2-propyl-1,2,3,4-tetrahydroquinoline 345
111 mg of the title compound was obtained from mg. Shodex OR-2 (wavelength 470n
The compound showed a (+) sign in the analysis of optical rotation by m). Melting point: 191-192 ° C

Example 112 (+)-2,4-cis-2-[(benzyloxy) methyl] -4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2 , 3,4-
Tetrahydroquinoline

[Chemical 184] In the same manner as in Example 5, 2-obtained in Example 43
[(Benzyloxy) methyl] -4- (9H-9-carbazolyl) -1-
29 mg of the title compound was obtained from 250 mg of (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline. Shodex OR-2
In the analysis of the optical rotatory power (wavelength: 470 nm), this compound showed a (+) sign.

Example 113 (−)-2,4-cis-2-[(benzyloxy) methyl] -4- (9H-9-
Carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4
-Tetrahydroquinoline

[Chemical 185] In the same manner as in Example 5, 2-obtained in Example 43
[(Benzyloxy) methyl] -4- (9H-9-carbazolyl) -1-
21 mg of the title compound was obtained from 250 mg of (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline. Shodex OR-2
In the analysis of the optical rotatory power (wavelength: 470 nm), this compound showed the sign of (-).

Example 114 (+)-2,4-trans-2-[(benzyloxy) methyl] -4- (9H-
9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,
3,4-tetrahydroquinoline

[Chemical 186] In the same manner as in Example 5, 2-obtained in Example 43
[(Benzyloxy) methyl] -4- (9H-9-carbazolyl) -1-
17 mg of the title compound was obtained from 250 mg of (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline. Shodex OR-2
In the analysis of the optical rotatory power (wavelength: 470 nm), this compound showed a (+) sign.

Example 115 (−)-2,4-trans-2-[(benzyloxy) methyl] -4- (9H
-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,
3,4-tetrahydroquinoline

[Chemical 187] In the same manner as in Example 5, 2-obtained in Example 43
[(Benzyloxy) methyl] -4- (9H-9-carbazolyl) -1-
14 mg of the title compound was obtained from 250 mg of (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline. Shodex OR-2
In the analysis of the optical rotatory power (wavelength: 470 nm), this compound showed the sign of (-).

Example 116 9- [2,4-cis-1- (3,4-dimethoxybenzoyl) 2- (3phenylpropyl) -1,2,3,4-tetrahydroquinolin-4-yl] -9
H-carbazole

[Chemical 188] 2.00 g (4.80 mmol) of 9- [2,4-cis-2- (3-phenylpropyl) -1,2,3,4-tetrahydroquinolin-4-yl] -9H-carbazole obtained in Reference Example 24 From the above, by the same method as in Example 32, 527 mg (yield 19%) of the title compound was obtained as white crystals. Melting point: 225-226 ° C (crystallization solvent: ethyl acetate-hexane) Elemental analysis value Calculated as C ₃₉ H ₃₆ N ₂ O ₃ · 0.5H ₂ O: C, 79.34; H, 6.32; N, 4.75 Experimental value: C, 79.38; H, 6.41; N, 4.57

Example 117 9- [2,4-cis-2- [3-[[tert-butyl (diphenyl) silyl]]
Oxy] propyl] -1- (3,4-dimethoxybenzoyl) -1,2,
3,4-Tetrahydroquinolin-4-yl] -9H-carbazole

[Chemical 189] 9- [2,4-cis-2- [3-[[tert-butyl obtained in Reference Example 25
(Diphenyl) silyl] oxy] propyl] -1,2,3,4-tetrahydroquinolin-4-yl] -9H-carbazole 1.08 g (1.82 mm
ol), and in the same manner as in Example 32, the title compound (382 mg)
(Yield 27%) was obtained as white crystals. Melting point: 209-211 ° C (crystallization solvent: ethyl acetate-hexane) ¹ H NMR (CDCl ₃ ) δ 1.00 (s, 9H), 1.67 (br s, 3H), 1.8
5-2.00 (m, 1H), 2.51-2.61 (m, 1H), 2.68-2.78 (m, 1
H), 3.44-3.71 (m, 5H), 3.85 (s, 3H), 5.01-5.06 (m,
1H), 5.90 (dd, J = 12.0, 6.7 Hz, 1H), 6.68 (d, J
= 8.2 Hz, 2H), 6.82-6.90 (m, 3H), 6.90-7.00 (m, 2
H), 7,00-7.10 (m, 1H), 7.20-7.50 (m, 9H), 7.50-7.5
5 (m, 2H), 7.59-7.63 (m, 4H), 8.20 (d, J = 6.7 Hz,
2H).

Example 118 3- [2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinolin-2-yl ]
-1-propanol

[Chemical 190] 9- [2,4-cis-2- [3-[[tert-butyl (diphenyl) silyl] oxy] propyl] -1- (3,4-dimethoxybenzoyl) -1,2 obtained in Example 117 , 3,4-Tetrahydroquinoline-4-
Il] -9H-carbazole (350 mg, 0.461 mmol) in THF (10
ml), 1N tetrabutylammonium fluoride THF solution 0.92 ml (0.922 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated, the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate), and the eluate was recrystallized from ethyl acetate-diethyl ether to give the title compound.
156 mg (yield 65%) was obtained as white crystals. Melting point: 192-194 ° C (crystallization solvent: ethyl acetate-diethyl ether) FABMS (pos) 521.2 [M + H ⁺ ]

Example 119 3- [2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinolin-2-yl ]
Propanal

[Chemical 191] 3- [2,4-cis-4- (9H-9-carbazolyl) obtained in Example 11 was added to a suspension of 1.94 g (9 mmol) of PCC in chloroform (10 ml).
A solution of 520 mg (1 mmol) of -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinolin-2-yl] -1-propanol in chloroform (10 ml) was added, and the mixture was stirred at room temperature for 6 hours. .
Add ethyl acetate and anhydrous magnesium sulfate to the reaction mixture and
After stirring for a minute, the insoluble material was filtered and then concentrated. The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/1), and the eluate was recrystallized from ethyl acetate-hexane to give the title compound (216 mg, yield 42%) as white crystals. It was FABMS (pos) 519.2 [M + H ⁺ ] ¹ H NMR (CDCl ₃ ) δ 1.90-2.20 (m, 2H), 2.55-2.86 (m, 2
H), 2.55-2.86 (m, 4H), 3.65 (s, 3H), 3.85 (s, 3H),
5.04-5.14 (m, 1H), 5.92 (dd, J = 6.1, 11.9Hz, 1H),
6.67-6.73 (m, 2H), 6.83-6.85 (m, 3H), 6.95-7.10
(m, 3H), 7.26-7.34 (m, 3H), 7.40-7.60 (m, 2H), 8.1
9 (d, J = 7.3 Hz, 2H), 9.85 (s, 1H).

Example 120 (Z) -8- [2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline -2-
Il] -N-propyl-5-octenamide

[Chemical 192] (4-Carboxybutyl) triphenylphosphonium bromide 89 mg (0.2 mmol) in THF (3 ml) and DMSO (1 ml) suspension was added dropwise with 0.25 ml (0.39 mml, 1.56 M hexane solution) of n-butyllithium under ice cooling. And stirred for 30 minutes. 3- [2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline-2-obtained in Example 11
A solution of 52 mg (0.1 mmol) of [yl] propanal in THF (4 ml) was added, and the mixture was further stirred at room temperature for 18 hours. A 1N aqueous hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate), and the eluate was recrystallized from ethyl acetate-hexane to give (Z) -8- [2,4- Cis-4-
(9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl)-
1,2,3,4-Tetrahydroquinolin-2-yl] -5-octenoic acid was obtained as a colorless oil. The obtained (Z) -8- [2,4-cis-4-
(9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl)-
1,2,3,4-Tetrahydroquinolin-2-yl] -5-octenoic acid 9
From 0 mg (0.149 mmol) and 22 mg (0.373 mmol) of n-propylamine, the title compound (6.8 mg, 2-step yield: 11%) was obtained as white crystals by a method similar to that in Example 109. ¹ H NMR (CDCl ₃ ) δ 0.85-0.91 (m, 3H), 1.40-1.80 (m, 4
H), 1.90-2.30 (m, 7H), 2.50-2.90 (m, 2H), 3.13-3.20
(m, 2H), 3.65 (s, 3H), 3.86 (s, 3H), 4.95-5.10
(m, 1H), 5.30-5.50 (m, 2H), 5.62 (br s, 1H), 5.92
(dd, J = 11.7, 5.9, 1H), 6.68-7.11 (m, 9H), 7.20-7.
60 (m, 4H), 8.21-8.18 (m, 2H).

Example 121 N- [3- [2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline- 2-yl] propyl] acetamide

[Chemical formula 193] 2,4-cis-4- (9H-9-carbazolyl) obtained in Example 44
-2- (2-cyanoethyl) -1- (3,4-dimethoxybenzoyl)-
108 mg (yield 34%) of the title compound was obtained as white crystals from 300 mg (0.58 mmol) of 1,2,3,4-tetrahydroquinoline and 118 mg (1.16 mmol) of acetic anhydride by the same method as in Example 45. Mp: 203-204 ° C. (crystallization solvent: ethyl acetate - hexane) Elemental analysis _{C 37 H 39 N 3 O 4} · 0.5H 2 O Calculated: C, 73.66; H, 6.36 ; N, 7.36 Found: C, 73.90; H, 6.08; N, 7.18

Example 122 N- [3- [2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline- 2-yl] propyl] butanamide

[Chemical 194] 2,4-cis-2- (3-aminopropyl) -obtained in Example 46
4- (9H-carbazolyl-9-yl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline hydrochloride 80 mg (0.154
mmol) was dissolved in pyridine (4 ml), n-butyryl chloride was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried and concentrated. The residue was recrystallized from diethyl ether to give the title compound (61 mg, yield 67
%) As white crystals. Melting point: 199-201 ° C (Crystallization solvent: diethyl ether) Elemental analysis value Calculated as C ₃₇ H ₃₉ N ₃ O ₄・ 0.4H ₂ O: C, 74.45; H, 6.72; N, 7.04 Experimental value: C, 74.63; H, 6.69; N, 6.75

Example 123 N- [3- [2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline- 2-yl] propyl] decanamide

[Chemical 195] 2,4-cis-2- (3-aminopropyl) -obtained in Example 46
4- (9H-carbazolyl-9-yl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline hydrochloride 200 mg (0.38
In the same manner as in Example 122, 136 mg (yield 53%) of the title compound was obtained as white crystals from 5 mmol) and 110 mg (0.577 mmol) of decanoyl chloride. ¹ H NMR (CDCl ₃ ) δ 0.86 (t, J = 6.7 Hz, 3H), 1.20-1.
40 (m, 12H), 1.50-1.80 (m, 5H), 1.90-2.10 (m, 1H),
2.20 (t, J = 7.3 Hz, 2H), 2.53-2.64 (m, 1H), 2.74-
2.84 (m, 1H), 3.20-3.50 (m, 2H), 3.65 (s, 3H), 3.8
6 (s, 3H), 4.95-5.10 (m, 1H), 5.91 (dd, J = 11.9,
5.9 Hz, 1H), 6.00-6.10 (m, 1H), 6.68-6.72 (m, 2H),
6.83-6.90 (m, 3H), 6.90-7.10 (m, 3H), 7.20-7.40
(m, 3H), 7.50-7.65 (m, 2H), 8.19 (d, J = 7.3 Hz, 2
H).

Example 124 N- [3- [2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline- 2-yl] propyl] -benzamide

[Chemical 196] 2,4-cis-2- (3-aminopropyl) -obtained in Example 46
4- (9H-carbazolyl-9-yl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoline hydrochloride 100 mg (0.19
2 mmol) and benzoyl chloride 0,044 ml (0.385 mmol),
In the same manner as in Example 122, the title compound (39.4 mg, yield 33
%) As white crystals. Melting point: 236-237 ° C (crystallization solvent: ethyl acetate-hexane) Elemental analysis value Calculated as C ₄₀ H ₃₇ N ₃ O ₄ .0.5H ₂ O: C, 75.93; H, 6.05; N, 6.64 Experimental value: C, 76.26; H, 5.99; N, 6.54

Example 125 2,4-cis-2-[(benzyloxy) methyl] -4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4 -Tetrahydroquinoline

[Chemical 197] 2.40 g (12.9 mmol) of 2,4-cis-2-[(benzyloxy) methyl] -4- (9H-9-carbazolyl) -1,2,3,4-tetrahydroquinoline obtained in Reference Example 10 was added. Dissolve in 60 ml of pyridine, and under ice-cooling, 3,4-dimethoxybenzoyl chloride 2.85 g (14.2 mmo
l) was added, and the mixture was stirred at room temperature overnight. After the reaction was stopped by adding 1 ml of methanol, the solvent was distilled off, and the residue was partitioned between ethyl acetate and an aqueous sodium hydrogen carbonate solution. The organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate /
5.39 g of the title compound (yield 72%)
Was obtained as white crystals. Melting point 243-244 ℃

Example 126 4- [2- [4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-quinolinyl] ethyl]
Ethyl benzoate

[Chemical 198] Ethyl 4- (3-formylpropyl) benzoate 4.50g (21.8mmo
From l), 1.67 g (total yield 12%) of the title compound was obtained as white crystals by the same method as in Reference Example 4 and Example 32 (cis: trans = 11: 1). Melting point 247-249 ° C. For the title compounds of Examples 111 to 126 Table 10
Summarized in.

[Table 10]

Example 127 Ethyl 5- [4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-quinolinyl] pentanoate

[Chemical formula 199] From 7.20 g (45.5 mmol) of ethyl 6-formylhexanoate, the title compound 3.50 was prepared in the same manner as in Reference Example 4 and Example 32.
g (total yield 13%) was obtained as white crystals (cis: trans =
3: 2). Melting point 195-196 ℃

Example 128 5- [4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-quinolinyl] pentanoic acid

[Chemical 200] 5- [4- (9H-9-carbazolyl) -1-obtained in Example 127
(3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-
0.20 g (0.34 mmol) of ethyl quinolinyl] pentanoate was dissolved in 10 ml of tetrahydrofuran, 5 ml of 1N NaOH and 0.11 g (0.34 mmol) of tetrabutylammonium bromide were added, and the mixture was stirred at room temperature for 4 hours.
The mixture was stirred for 4 hours at 60 ° C. The reaction mixture was partitioned with ethyl acetate and 1N HCl, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/5) to give 0.14 g of the title compound (yield:
74%) was obtained as white crystals (cis: trans = 4 :).
1). Melting point 226-228 ℃

Example 129 5- [4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-quinolinyl] -N-methylpentanamide

[Chemical 201] 5- [4- (9H-9-carbazolyl) -1-obtained in Example 128
(3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-
A mixture of 0.12 g (0.21 mmol) of quinolinyl] pentanoic acid, 5 ml of dichloromethane, 100 μl of N, N-dimethylformamide, and 24 μl of thionyl chloride was stirred at 50 ° C. for 30 minutes and then cooled with ice to 40%.
1 ml of a methylamine / methanol solution was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned with ethyl acetate and saturated brine, washed, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/4) to obtain 0.10 g (yield 83%) of the title compound as white crystals (cis: trans). = 4: 1). Melting point 224-225 ℃

Example 130 5- [4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-quinolinyl] -N-propylpentanamide

[Chemical 202] 5- [4- (9H-9-carbazolyl) -1-obtained in Example 128
(3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-
From 0.09 g (0.16 mmol) of quinolinyl] pentanoic acid and 52 μl of n-propylamine, 0.09 g (total yield 93%) of the title compound was obtained as a white powder in the same manner as in Example 129 (cis: trans = 5). : 2). FABMS 604.3 [M + H ⁺ ]

Example 131 3-[[5- [4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-quinolinyl] pentanoyl] Amino] ethyl propionate

[Chemical 203] 5- [4- (9H-9-carbazolyl) -1-obtained in Example 128
(3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-
Quinolinyl] pentanoic acid 0.50 g (0.89 mmol), β-alanine ethyl ester hydrochloride 0.15 g (1 mmol), N, N-dimethylformamide 10 ml, 1-hydroxybenzotriazole 0.14 g
(1 mmol) and 1-ethyl-3- (3-dimethylaminopropyl)
A mixture of 0.19 g (1 mmol) carbodiimide hydrochloride (WSC) was stirred overnight at room temperature. After the solvent was distilled off, the residue was partitioned with ethyl acetate and saturated brine, washed, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/7) to obtain 0.48 g (yield 81%) of the title compound as a white powder (cis: trans). = 3: 1). FABMS 662.1 [M + H ⁺ ]

Example 132 3-[[5- [4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-quinolinyl] pentanoyl] Amino] propionic acid

[Chemical 204] 3-[[5- [4- (9H-9-carbazolyl) obtained in Example 131
-1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro
From 0.45 g (0.68 mmol) of ethyl-2-quinolinyl] pentanoyl] amino] propionate, 0.29 g (yield 67%) of the title compound was obtained as a white powder in the same manner as in Example 128 (cis: trans =). 3: 1). FABMS 634.1 [M + H ⁺ ]

Example 133 5- [4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-quinolinyl] -N, N-dimethyl Pentanamide

[Chemical 205] 5- [4- (9H-9-carbazolyl) -1-obtained in Example 128
(3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-
Example 12 from quinolinyl] pentanoic acid
In the same manner as in 9, the title compound (0.12 g, yield 60%) was obtained as a white powder (cis: trans = 5: 1). FABMS 590.1 [M + H ⁺ ]

Example 134 5- [4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-quinolinyl] -N-hexyl-
N-methylpentanamide

[Chemical 206] 5- [4- (9H-9-carbazolyl) -1-obtained in Example 128
(3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-
The title compound (0.10 g, yield 71%) was obtained as a white powder from 0.12 g (0.21 mmol) of quinolinyl] pentanoic acid and 0.3 ml of N-hexyl-N-methylamine in the same manner as in Example 129. : Trance = 3: 1). FABMS 660.3 [M + H ⁺ ]

Example 135 5- [4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-quinolinyl] -1-pentanol

[Chemical formula 207] 5- [4- (9H-9-carbazolyl) -1-obtained in Example 128
(3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-
A mixture of 0.30 g (0.53 mmol) of quinolinyl] pentanoic acid, 64 mg (0.56 mmol) of N-hydroxysuccinimide, 5 ml of N, N-dimethylformamide and 113 mg (0.59 mmol) of WSC was stirred overnight at room temperature, and then 5 ml of tetrahydrofuran and hydrogen. Sodium borohydride (61 mg, 1.6 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into 10% citric acid, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/10).
The title compound (0.17 g, yield 59%) was obtained as white crystals (cis: trans = 4: 1). Melting point 239-240 ℃

Example 136 5- [4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-quinolinyl] -N, N-dimethyl -1-pentanamine

[Chemical 208] 5- [4- (9H-9-carbazolyl) -1-obtained in Example 135
(3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-
Quinolinyl] -1-pentanol 0.36 g (0.66 mmol), triphenylphosphine 198 mg (0.75 mmol), carbon tetrabromide 249 mg
A mixture of (0.75 mmol) and tetrahydrofuran (10 ml) was stirred at room temperature for 4 hours and then filtered, and the filtrate was evaporated. 2 in the residue
10 ml of M dimethylamine / tetrahydrofuran solution was added, and the mixture was stirred at room temperature overnight. After the solvent was distilled off, the residue was partitioned with chloroform and saturated saline, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/5) to obtain 0.11 g (yield 29%) of the title compound as white crystals (cis: trans = 4). : 1). Melting point 198-200 ℃

Example 137 9- [1- (3,4-dimethoxybenzoyl) -2- [5- [4- (4-fluorophenyl) -1-piperazinyl] pentyl] -1,2,3,4- Tetrahydro-4-quinolinyl] -9H-carbazole

[Chemical 209] 5- [4- (9H-9-carbazolyl) -1-obtained in Example 135
(3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-
Quinolinyl] -1-pentanol 0.13 g (0.22 mmol) and 4-
From 79 mg (0.44 mmol) of (4-fluorophenyl) piperazine,
In the same manner as in Example 136, 0.08 g of the title compound (yield 51
%) Was obtained as white crystals (cis: trans = 4:
1). Melting point 178-179 ℃

Example 138 9- [1- (3,4-dimethoxybenzoyl) -2- [5- [4- [3- (trifluoromethyl) phenyl] -1-piperidinyl] pentyl] -1,
2,3,4-Tetrahydro-4-quinolinyl] -9H-carbazole

[Chemical 210] 5- [4- (9H-9-carbazolyl) -1-obtained in Example 135
(3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-
Quinolinyl] -1-pentanol 0.19 g (0.32 mmol) and 4-
[3- (Trifluoromethyl) phenyl] piperidine 0.23g (1m
mol) to give the title compound 0.13 in the same manner as in Example 136.
g (53% yield) was obtained as white crystals (cis: trans =
3: 1). Melting point 149-150 ℃

Example 139 N- [5- [4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-quinolinyl] pentyl]- N-methylacetamide

[Chemical 211] 5- [4- (9H-9-carbazolyl) -1-obtained in Example 135
(3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-
Quinolinyl] -1-pentanol 0.12 g (0.22 mmol), triphenylphosphine 66 mg (0.25 mmol), carbon tetrabromide 83 mg (0.2
(5 mmol) and 3 ml of tetrahydrofuran at room temperature.
After stirring for time, the mixture was filtered, and the filtrate was evaporated. To the residue was added 40% methylamine / methanol solution (10 ml), and the mixture was stirred at room temperature overnight. After evaporating the solvent, the residue was dissolved in 3 ml of pyridine, 1 ml of acetic anhydride was added, and the mixture was stirred overnight at room temperature, and then 1 ml of methanol was added to stop the reaction. After the solvent was distilled off, the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, the organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane =
1/5) to give the title compound (0.09 g, yield 69%) as white crystals (cis: trans = 4: 1). Melting point 173-17
5 ° C

Example 140 9- [1- (3,4-dimethoxybenzoyl) -2- [5- (hexylthio) pentyl] -1,2,3,4-tetrahydro-4-quinolinyl] -9H
-Carbazole

[Chemical 212] 5- [4- (9H-9-carbazolyl) -1-obtained in Example 135
(3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-
Quinolinyl] -1-pentanol 0.08 g (0.15 mmol) and n-
From 0.3 ml of hexyl mercaptan, 0.01 g (yield 7%) of the title compound was obtained as white crystals by the same method as in Example 136 (cis: trans = 6: 1). Melting point 231-232 ℃

Example 141 9- [1- (3,4-dimethoxybenzoyl) -2- [5- (4-fluorophenoxy) pentyl] -1,2,3,4-tetrahydro-4-quinolinyl] -9H -Carbazole

[Chemical 213] 5- [4- (9H-9-carbazolyl) -1-obtained in Example 135
(3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-
Quinolinyl] -1-pentanol 0.12 g (0.22 mmol), 4-fluorophenol 50 mg (0.44 mmol), tetrahydrofuran 4 m
After stirring a mixture of 1, 69 μl (0.44 mmol) of diethyl azodicarboxylate and 0.11 g (0.44 mmol) of triphenylphosphine overnight at room temperature, the solvent was distilled off. The residue was partitioned with ethyl acetate and water, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane =
1/10) to give 0.13 g (yield 93%) of the title compound as white crystals (cis: trans = 4: 1). Melting point 157-159 ° C

Example 142 2,4-trans-9- [1- (3,4-dimethoxybenzoyl) -2- [5-
(4-Fluorophenoxy) pentyl] -1,2,3,4-tetrahydro-4-quinolinyl] -9H-carbazole

[Chemical 214] 5- [4- (9H-9-carbazolyl) -1-obtained in Example 135
(3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-2-
The mother liquor at the time of recrystallization of quinolinyl] -1-pentanol was concentrated, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/10) to give 0.15 g (0.27 mmol) of trans form. From the above), 0.09 g (56%) of the title compound was obtained as a colorless oily substance in the same manner as in Example 141. Elemental analysis value Calculated as C ₄₁ H ₃₉ N ₂ O ₄ : C, 76.61; H, 6.12; N, 4.36 Experimental value: C, 76.55; H, 6.41; N, 4.28 FABMS 643.2 [M + H ⁺ ] Example Table 11 for title compounds 127-142
Summarized in.

[Table 11]

Example 143 2,4-cis-4- (9H-9-carbazolyl) -1- (4-ethoxy-3-methoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 215] 2,4-cis-4- (9H-9-carbazolyl) -2 obtained in Reference Example 4
-Methyl-1,2,3,4-tetrahydroquinoline 600 mg (1.92 mm
from the title compound 234m in the same manner as in Reference Example 19.
g (yield 26%) was obtained as white crystals. Elemental analysis value Calculated as C ₃₂ H ₃₀ N ₂ O ₃・ 0.45H ₂ O: C, 77.06; H, 6.25; N, 5.61 Experimental value: C, 77.39; H, 6.58; N, 5.28 Melting point: 214-215 ℃

Example 144 2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-diethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical 216] 2,4-cis-4- (9H-9-carbazolyl) -2 obtained in Reference Example 4
-Methyl-1,2,3,4-tetrahydroquinoline 600 mg (1.92 mm
ol) in the same manner as in Reference Example 20 to obtain 215 m of the title compound.
g (23% yield) was obtained as white crystals. Elemental analysis value Calculated as C ₃₃ H ₃₂ N ₂ O ₃ · 0.3H ₂ O: C, 77.71; H, 6.44; N, 5.49 Experimental value: C, 77.84; H, 6.72; N, 5.16 Melting point: 240-241 ℃

Example 145 2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-diethoxybenzoyl) -2-ethyl-1,2,3,4-tetrahydroquinoline

[Chemical 217] 2,4-cis-4- (9H-9-carbazolyl) -2 obtained in Reference Example 5
-Ethyl-1,2,3,4-tetrahydroquinoline 570 mg (1.75 mmo
From l), the title compound 517 mg was prepared in the same manner as in Reference Example 19.
(Yield 57%) was obtained as white crystals. ¹ H NMR (CDCl ₃ ) δ 0.98 (t, J = 7.4 Hz, 3H), 1.30 (t, J
= 6.9 Hz, 3H), 1.42 (t, J = 6.9 Hz, 3H), 1.63 (m, 1H),
1.93 (m, 1H), 2.63 (m, 1H), 2.77 (m, 1H), 3.77 (m,
1H), 3.90 (m, 1H), 4.02-4.13 (m, 2H), 4.95 (m, 1
H), 5.90 (m, 1H), 6.68-6.72 (m, 2H), 6.82-7.00 (m,
5H), 7.10-7.13 (m, 1H), 7.93 (m, 3H), 8.35-8.45
(m, 2H), 8.84 (d, J = 5.2 Hz, 2H).

Example 146 2,4-cis-4- (9H-9-carbazolyl) -1- (4-ethoxy-3-methoxybenzoyl) -2-propyl-1,2,3,4-tetrahydroquinoline

[Chemical 218] 2,4-cis-4- (9H-9-carbazolyl) -2 obtained in Reference Example 6
-Propyl-1,2,3,4-tetrahydroquinoline 500 mg (1.47
mmol) in the same manner as in Reference Example 19 to obtain the title compound 44m
g (6% yield) was obtained as white crystals. Elemental analysis value Calculated as C ₃₄ H ₃₄ N ₂ O ₃ : C, 78.74; H, 6.61; N, 5.40 Experimental value: C, 78.44; H, 6.48; N, 5.28 Melting point: 221-222 ℃

Example 147 2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-diethoxybenzoyl) -2-propyl-1,2,3,4-tetrahydroquinoline

[Chemical 219] 2,4-cis-4- (9H-9-carbazolyl) -2 obtained in Reference Example 6
-Propyl-1,2,3,4-tetrahydroquinoline 500 mg (1.47
mmol) in the same manner as in Reference Example 20 to obtain 79 m of the title compound.
g (10% yield) was obtained as white crystals. Elemental analysis value Calculated as C ₃₅ H ₃₆ N ₂ O ₃ 0.1H ₂ O: C, 78.65; H, 6.83; N, 5.24 Experimental value: C, 78.96; H, 7.20; N, 5.00 Melting point: 220 ℃

Example 148 2,4-cis-9- [2-butyl-1- (4-ethoxy-3-methoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinyl] -9H-carbazole

[Chemical 220] 0.64 g (2.05 mmo) of 2,4-cis-2-butyl-4- (9H-9-carbazolyl) -1,2,3,4-tetrahydroquinoline obtained in Reference Example 7
l) and 4-ethoxy-3-methoxybenzoyl chloride 0.4
Using 8 g (2.46 mmol) and in the same manner as in Reference Example 19, the title compound (0.37 g, 34%) was obtained as white crystals. Melting point 231-232 ℃ Elemental analysis value Calculated as C ₃₅ H ₃₆ N ₂ O ₃ : C, 78.92; H, 6.81; N, 5.26 Experimental value: C, 78.70; H, 6.75; N, 5.25

Example 149 2,4-cis-9- [2-butyl-1- (3,4-diethoxybenzoyl)-
1,2,3,4-Tetrahydro-4-quinolinyl] -9H-carbazole

[Chemical 221] 2,4-cis-2-butyl-4- (9H-9-carbazolyl) -1,2,3,4-tetrahydroquinoline obtained in Reference Example 7 0.50 g (1.41 mmo)
l) and 3,4-diethoxybenzoyl chloride 0.45 g (2.12
(0.1 mmol) in the same manner as in Reference Example 20 to obtain the title compound (0.20 g, 26%) as white crystals. Melting point 232-233 ℃ FABMS 547.2 [M + H ⁺ ]

Example 150 2,4-cis-9- [2-ethyl-1- (3-methoxy-4-methylthiobenzoyl) -1,2,3,4-tetrahydro-4-quinolinyl] -9H-carbazole

[Chemical 222] 2,4-cis-4- (9H-9-carbazolyl) -2 obtained in Reference Example 5
-Ethyl-1,2,3,4-tetrahydroquinoline 0.56 g (1.71 mmo
l) and 3-methoxy-4-methylthiobenzoyl chloride
The title compound (0.41 g, 47%) was obtained as white crystals from 0.51 g (2.57 mmol) in the same manner as in Example 32. Melting point 210-211 ℃ FABMS 507.0 [M + H ⁺ ]

Example 151 2,4-cis-9- [2-butyl-1- (3-methoxy-4-methylthiobenzoyl) -1,2,3,4-tetrahydro-4-quinolinyl] -9H-carbazole

[Chemical formula 223] 2,4-cis-2-butyl-4- (9H-9-carbazolyl) -1,2,3,4-tetrahydroquinoline obtained in Reference Example 7 0.47 g (1.32 mmo
l) and 3-methoxy-4-methylthiobenzoyl chloride
The title compound (0.39 g, 55%) was obtained as white crystals from 0.34 g (1.72 mmol) in the same manner as in Example 32. Melting point 230-231 ℃ FABMS 534.2 [M ⁺ ]

Example 152 2,4-cis-4- (9H-9-carbazolyl) -2- (2-cyanoethyl)-
1- (3,4-diethoxybenzoyl) -1,2,3,4-tetrahydroquinoline

[Chemical formula 224] 2,4-cis-4- (9H-9-carbazolyl) obtained in Reference Example 11
-2- (2-cyanoethyl) -1,2,3,4-tetrahydroquinoline 50
0 mg (1.42 mmol) and 3,4-diethoxybenzoic acid 478 mg (2.27 mm
from the ol) in the same manner as in Reference Example 19 to obtain 118 mg of the title compound.
(Yield 15%) was obtained as white crystals. FABMS (pos) 544.2 [M + H ⁺ ]

Example 153 2,4-cis-4- (9H-9-carbazolyl) -2- (2-cyanoethyl)-
1- (4-methoxybenzoyl) -1,2,3,4-tetrahydroquinoline

[Chemical formula 225] 2,4-cis-4- (9H-9-carbazolyl) obtained in Reference Example 11
-2- (2-Cyanoethyl) -1,2,3,4-tetrahydroquinoline 1.
0 g (2.85 mmol) and 4-methoxybenzoyl chloride 677 mg
From (4.28 mmol), the title compound was prepared in the same manner as in Example 32.
480 mg (33% yield) was obtained as white crystals. Elemental analysis value Calculated as C ₃₁ H ₂₇ N ₃ O ₂ .0.3H ₂ O: C, 77.74; H, 5.81; N, 8.77 Experimental value: C, 77.78; H, 5.74; N, 8.50

Example 154 N- [3- [2,4-cis-4- (9H-9-carbazolyl) -1- (4-methoxybenzoyl) -1,2,3,4-tetrahydroquinoline-2- Il] propyl] tert-butyl carbamate

[Chemical formula 226] 2,4-cis-4- (9H-9-carbazolyl) -2- (2-cyanoethyl) -1- (4-methoxybenzoyl) -1, obtained in Reference Example 153
The title compound (3.21 g, yield 97%) was obtained as white crystals from 3.6 g (6.98 mmol) of 2,3,4-tetrahydroquinoline in the same manner as in Example 45. ¹ H NMR (CDCl ₃ ) δ 1.42 (s, 9H), 1.50-1.70 (m, 3H),
1.80-2.00 (m, 1H), 2.50-2.63 (m, 1H), 2.71-2.81
(m, 1H), 3.17 (br s, 2H), 3.79 (s, 3H), 4.60-4.75
(m, 1H), 4.90-5.05 (m, 1H), 5.90 (dd, J = 11.9, 5.
9 Hz, 1H), 6.66-6.97 (m, 6H), 7.07 (d, J = 7.8 Hz,
1H), 7.22-7.33 (m, 5H), 7.45-7.55 (m, 2H), 8.18
(d, J = 7.7 Hz, 2H).

Example 155 3- [2,4-cis-4- (9H-9-carbazolyl) -1- (4-methoxybenzoyl) -1,2,3,4-tetrahydroquinolin-2-yl] propyl Amine hydrochloride

[Chemical 227] N- [3- [2,4-cis-4- (9H-9-carbazolyl) -1- (4-methoxybenzoyl) -1,2,3,4-tetrahydroquinoline-2 obtained in Reference Example 154 -Yl] propyl] carbamic acid tert-
The title compound (1.65 g, yield 48%) was obtained as white crystals from butyl (3.10 g, 6.55 mmol) in the same manner as in Example 46. ¹ H NMR (CDCl ₃ ) δ 1.67 (br s, 1H), 1.90 (br s, 3H),
2.47 (br s, 1H), 2.69 (br s, 1H), 3.12 (br s, 2H),
3.66 (s, 3H), 5.00 (br s, 1H), 5.86 (br s, 1H), 6.6
4-6.76 (m, 4H), 6.87-6.90 (m, 2H), 7.03 (d, J = 8.
0, 1H), 7.18-7.33 (m, 4H), 7.46 (br s, 2H), 8.11
(d, J = 7.7, 2H), 8.52 (br s, 3H).

Example 156 N- [3- [2,4-cis-4- (9H-9-carbazolyl) -1- (4-methoxybenzoyl) -1,2,3,4-tetrahydroquinoline-2- Ill] propyl] butanamide

[Chemical 228] 2,4-cis-4- (9H-9-carbazolyl) -2- (2-cyanoethyl) -1- (4-methoxybenzoyl) -1, obtained in Reference Example 153
From 200 mg (0.388 mmol) of 2,3,4-tetrahydroquinoline and 123 mg (0.776 mmol) of butyric anhydride, 60 mg (yield 28%) of the title compound was obtained as white crystals in the same manner as in Example 45. ¹ H NMR (CDCl ₃ ) δ 0.91-0.97 (m, 3H), 1.50-1.80 (m, 6
H), 1.90-2.10 (m, 1H), 2.19 (t, J = 7.3, 2H), 2.50-
2.65 (m, 1H), 2.73-2.78 (m, 1H), 3.20-3.30 (m, 1
H), 3.35-3.50 (m, 1H), 3.79 (s, 3H), 4.95-5.10 (m,
1H), 5.91 (dd, J = 11.9, 6.1, 1H), 6.12 (br s, 1H),
6.65-6.80 (m, 3H), 6.80-7.10 (m, 4H), 7.20-7.35
(m, 4H), 7.40-7.55 (m, 2H), 8.17-8.20 (m, 2H).

Example 157 5- [4- (9H-9-carbazolyl) -1- (4-methoxybenzoyl)-
Ethyl 1,2,3,4-tetrahydro-2-quinolinyl] pentanoate

[Chemical formula 229] From 4.51 g (28.5 mmol) of ethyl 6-formylhexanoate, the title compound 1.70 was prepared in the same manner as in Reference Example 4 and Example 32.
g (11% total yield) was obtained as white crystals (cis: trans =
12: 1). Melting point 167-168 ℃ FABMS 561.1 [M + H ⁺ ]

Example 158 5- [4- (9H-9-carbazolyl) -1- (4-methoxybenzoyl)-
1,2,3,4-Tetrahydro-2-quinolinyl] pentanoic acid

[Chemical 230] 5- [4- (9H-9-carbazolyl) -1-obtained in Example 157
From 1.60 g (2.85 mmol) of ethyl (4-methoxybenzoyl) -1,2,3,4-tetrahydro-2-quinolinyl] pentanoate, the title compound (1.51 g, yield 99%) was prepared in the same manner as in Example 128. ) Was obtained as a white powder (cis: trans = 12: 1). FABMS 533.1 [M + H ⁺ ] For the title compounds of Examples 143-158 Table 12
Summarized in.

[Table 12]

Example 159 3- [1- (3,4-dimethoxybenzoyl) -2-methyl-1,2-dihydro-4-quinolinyl] -1,2,4,5-tetrahydro-3H-3-benzazepine

[Chemical formula 231] 2,3-trans-2,4-cis-1- (3,4-obtained in Example 88
Dimethoxybenzoyl) -3-hydroxy-2-methyl-4- (1,
2,4,5-Tetrahydro-3H-3-benzazepin-3-yl) -1,
The title compound (160 mg, yield 29%) was obtained as a colorless oil from 560 mg (1.18 mmol) of 2,3,4-tetrahydroquinoline in the same manner as in Example 54. ¹ H NMR (CDCl ₃ ) δ 1.23 (d, J = 6.7 Hz, 3H), 2.97-3.0
9 (m, 4H), 3.56-3.60 (m, 4H), 3.67 (s, 3H), 3.85
(s, 3H), 5.46 (s, 1H), 5.68 (q, J = 6.7 Hz, 1H),
6.45 (d, J = 7.9 Hz, 1H), 6.62 (t, J = 7.3 Hz, 1
H), 6.69 (d, J = 8.4Hz, 1H), 6.85 (s, 1H), 6.93-7.
10 (m, 3H), 7.13 (s, 4H).

Example 160 4- (5-chloro-1,2,3,4-tetrahydroquinolin-1-yl) -1
-(3,4-dimethoxybenzoyl) -2-methyl-1,2-dihydroquinoline

[Chemical 232] 2,3-trans-2,4-cis-4- (5-chloro-1,2,3,4-tetrahydroquinolin-1-yl) -1- (3,4-obtained in Example 86
Dimethoxybenzoyl) -3-hydroxy-2-methyl-1,2,3,
The title compound (95 mg, yield 28%) was obtained as white crystals from 4-tetrahydroquinoline (493 mg, 1.00 mmol) in the same manner as in Example 54. Elemental analysis value Calculated as C ₂₈ H ₂₇ ClN ₂ O ₃ : C, 70.80; H, 5.73; N, 5.90 Experimental value: C, 70.54; H, 5.50; N, 5.82 Melting point: 162-163 ℃ (crystallization solvent : Diethyl ether-hexane)

Example 161 4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl)
-2-methyl-1,2-dihydroquinoline

[Chemical formula 233] 3- (3,4-dimethoxybenzoyl) -2-synthesized in Reference Example 3
1.5 g of the title compound (yield 19%) was obtained as white crystals from 5.4 g (16.6 mmol) of methyl-1a, 2,3,7b-tetrahydrooxyreno [2,3-c] quinoline in the same manner as in Example 59. Got as. Elemental analysis value Calculated as C ₃₁ H ₂₆ N ₂ O ₃ : C, 78.46; H, 5.52; N, 5.90 Experimental value: C, 78.71; H, 5.97; N, 5.86 Melting point: 184-185 ℃

Example 162 4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl)
-3-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline

[Chemical formula 234] 3- (3,4-dimethoxybenzoyl) -2-synthesized in Reference Example 3
Methyl-1a, 2,3,7b-tetrahydrooxyreno [2,3-c] quinoline was obtained from 5.4 g (16.6 mmol) in the same manner as in Example 59.
175 mg (2% yield) of the title compound was obtained as white crystals. Elemental analysis value Calculated value as C ₃₁ H ₂₈ N ₂ O ₄ · H ₂ O: C, 72.92; H, 5.92; N, 5.48 Experimental value: C, 73.22; H, 5.85; N, 5.31 Melting point: 194-195 ° C Table 13 for title compounds of Examples 159-162
Summarized in.

[Table 13]

Example 163 2,3-trans-2,4-cis-5-[[1- [1- (3,4-dimethylbenzoyl) -2-methyl-1,2,3,4-tetrahydro- 4-quinolinyl]-
Ethyl 1,2,3,4-tetrahydro-6-quinolinyl] oxy] pentanoate

[Chemical formula 235] 1.1 g (3.7 m of 2-methyl-1- (3,4, dimethylbenzoyl) -1,2,3,4-tetrahydro-4-quinolinol obtained in Reference Example 23
mol) and 1.0 g (3.7 mmol) of ethyl 5-[(1,2,3,4-tetrahydro-6-quinolinyl) oxy] pentanoate in the same manner as in Example 1 to give 0.31 g of the title compound (yield 15 %) As a colorless oil. (Cis: trans = 3: 2) ¹ H NMR (CDCl ₃ ) δ1.23-1.35 (m, 6H), 1.78-2.26 (m, 1
2H), 2.35-2.40 (m, 2H), 2.63-2.87 (m, 3H), 3.06-3.
70 (m, 3H), 3.86-3.93 (m, 2H), 4.10-4.18 (m, 2H),
4.69-4.88 (m, 0.8H), 4.96-5.04 (m, 0.6H), 5.18-5.2
4 (m, 0.6H), 6.44-7.38 (m, 10H).

Example 164 5-[[1- [1- (3,4-dimethylbenzoyl) -2-methyl-1,2,3,4
-Tetrahydro-4-quinolinyl] -1,2,3,4-tetrahydro-6
-Quinolinyl] oxy] pentanoic acid

[Chemical 236] 5-[[1- [1- (3,4-Dimethylbenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinyl] -obtained in Example 163
From 0.30 g (0.54 mmol) of ethyl 1,2,3,4-tetrahydro-6-quinolinyl] oxy] pentanoate, 0.20 g (yield 70%) of the title compound was obtained as an amorphous powder in the same manner as in Example 95. Got as. (Cis: trans = 3: 2) ¹ H NMR (CDCl ₃ ) δ1.13-1.33 (m, 3H), 1.70-2.32 (m, 1
4H), 2.40-2.44 (m, 2H), 2.63-3.32 (m, 4H), 3.91 (b
rs, 2H), 4.72-4.88 (m, 0.8H), 5.00 (br s, 0.6H),
5.18-5.24 (m, 0.6H), 6.44-7.38 (m, 10H). Table 14 for the title compounds of Examples 163-164.
Summarized in.

[Table 14]

[Experimental Example-1] s in rat-derived pheochrome cytoma PC12h cells
APP secretion promoting action and cell death suppressing action 1) Experimental material and method Experimental material Rat-derived pheochrome cytoma PC12 sub-strain PC12
The h-cells were donated by former Osaka University professor Hiroshi Hatanaka (deceased). Dulbecco's modified Eagle's medium
dified Eagle's medium: DMEM), phosphate / phosphate buffered saline (PBS), HEPES (N-2-
hydroxyethylpiperazine-N'- 2-ethanesulfonic acid)
Buffer solution (pH 7.4), horse serum (Horse serum: HS), penicillin (5000 U / ml) / streptomycin (5 mg / ml) mixture is G
ibco BRL, Fetal calfserum (FCS) is Bios
cience PTY, transferrin, insulin and progestero
ne was purchased from Sigma. The culture flask used was Falcon, and the 96-well multiwell plate with collagen coating and the 6-well multiwell plate manufactured by Iwaki Glass Co., Ltd. were used. LDH cytotoxic test Wako is more anti-βAP than Wako Pure Chemical
P and 22C11 antibodies were purchased from Chemicon. As other reagents, commercially available special grade products were used. sAPP secretion promoting action PC12h cells were grown in 10% FCS / 5% HS / penicillin-streptomycin / DMEM culture medium, and then the cells were removed by pipetting. The wells were seeded on a collagen-coated 6-well plate so as to be 50-70% confluent, and allowed to stand for 1 day. The next day, the wells were washed once with 1 ml of 10 mM HEPES / DMEM and replaced with 0.5 ml of 10 mM HEPES / DMEM culture medium, and Example No. 5 or Example No. 32 was added. The culture supernatant was collected after 5 hours. Trichloroacetic acid (final concentration 15%) was added to the culture supernatant to precipitate and concentrate the protein. SDS
-PAGE sample buffer (Daiichi Pure Chemicals) was added and boiled for 5 minutes. The sample was applied to SDS-PAGE (10/20% gel, ATTO) and transferred (2 mA / cm ² 60 min) to a PVDF membrane (Bio-Rad Laboratories). 0% with 5% skim milk.
4% with 1% Tween 20/20 mM Tris -buffered saline (pH 7.4)
Blocking was performed overnight at ℃. Anti-βAPP 22C11 antibody
It was added at a 50-fold dilution and reacted for 1 hour. The secondary antibody is HRP (hor
se-radish peroxidase) conjugated anti-mouse antibody (Zymed)
Was diluted 5000 times and used. For detection, ECL Plus (Amersham
) And digitized with LAS-1000 plus (Fujifilm) and quantified with NIH-image. Inhibition of cell death induced by glutamate PC12h cells were seeded at 2x10 ⁴ cells / cm ² in 96-well plate. The next day, while changing to a HEPES / DME medium containing 5 mg / ml transferrin, 5 mg / ml insulin and 20 nM progesterone, glutamate 1 mM and Example No. 5, No. 32
Alternatively, the solvent was added. Only the solvent was added to the control group. The number of cells surviving after 72 hours was measured. The number of cells is
It was determined by removing the culture medium, solubilizing viable cells with PBS containing 0.1% Tween 20, and measuring the LDH activity. The LDH activity of the control group was defined as 100 and expressed as% of control.

2) Results a) sAPP secretion promoting action of Examples No. 5 and No. 32 In FIG. 1, among the invention compounds, Examples No. 5 and No. 3 were selected.
It showed a sAPP secretion promoting action 5 hours after the addition of 2. The results of Western blotting when each Example compound was added are shown in the upper part of FIGS. 1 (a) and 1 (b). The amount of sAPP in the culture broth increased in both the example compounds in a concentration-dependent manner as compared with the control group. Images are shown at the bottom of Fig. 1 (a) and Fig. 1 (b).
It quantified using NIH image, and showed the average value of the increase rate of each concentration of each Example compound 3 well. Example No. 5 is 10
The concentration of nM increased about 2.0-fold and the concentration of Example No. 32 increased about 2.2-fold at the concentration of 1 nM. b) Cell death-suppressing action of Examples No. 5 and No. 32 In PC12h cells, glutamic acid in the culture medium interferes with the intracellular uptake of cystine, which is a source of glutathione. Therefore, it is known that when 1 mM or more of glutamic acid is added to the culture medium and the cells are cultured for 3 days or more, PC12h cells die by apoptosis as the intracellular glutathione amount decreases. Example No. 5 and No. 32
Both of these cells die due to the addition of 1 mM glutamate.
It was completely suppressed at a concentration of 1 µM (Fig. 2).

[0269]

INDUSTRIAL APPLICABILITY The compound of the present invention has a strong sAPP secretion promoting action and a secreted sAPP having a neurotrophic factor-like action.
Through dysfunction of cells, especially nerve cells, and apoptosis
Suppress cis. Examples of useful target disease names include Alzheimer's disease, Parkinson's disease, prion disease, diabetic neuropathies, senile dementia, and neuronal cell disorders during cerebrovascular accidents, and the prevention of these diseases. Or it can be used for therapy.

[Brief description of drawings]

FIG. 1 (a) shows that the sAPP secretion promoting action of Example No. 5 was measured by Western blotting, and the result (3
FIG. 1 (b) is a graph showing the results (average value of 3 wells) obtained by measuring the sAPP secretion promoting action of Example No. 32 by Western blotting.

FIG. 2 is a PC 12 of Example No. 5 and No. 32.
It is a graph which shows the glutamic acid induction cell death suppression effect in h cell (average value of 3 wells).

Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/498 A61K 31/498 31/538 31/538 31/541 31/541 31/55 31/55 A61P 25/00 A61P 25/00 25/16 25/16 25/28 25/28 43/00 111 43/00 111 123 123 C07D 401/04 C07D 401/04 401/14 401/14 405/14 405/14 409/14 409 / 14 413/04 413/04 417/04 417/04 417/14 417/14 471/20 471/20 (72) Inventor Toshiro Yamashita 1-7 Kasuga, Tsukuba-shi, Ibaraki 9 Takeda Kasuga Heights 1004 F-term (Reference) 4C031 LA03 4C063 AA01 AA03 BB02 CC14 CC26 CC54 CC64 DD06 DD14 EE01 4C065 AA16 AA18 BB04 CC01 DD02 EE02 HH02 KK01 PP19 QQ02 4C086 AA01 AA03 BC13 BC01 GA16 MA16 GA01 ZA01 GA01 BC16 GA01 CB01 GA14 BC07 CB09 GA14 BC07 CB09 GA14 MA07 ZA09 ZA01

Claims (30)

[Claims] 1. A compound represented by the formula (I): [Wherein R ¹ and R ² are the same or different,
A hydrogen atom, a lower alkyl group which may have a substituent or a hydroxy group which may have a substituent, or
R ¹ and R ² bond together to form a 4- to 7-membered ring with the adjacent carbon atom, Ar ¹ represents an aromatic group which may have a substituent, and A ring has a substituent. Represents a benzene ring which may be substituted, B ring represents an aromatic ring which may have a substituent, and C ring may be condensed with a ring which may further have a substituent. Represents a 4- to 8-membered ring which may be represented, X represents CH or N, Represents a single bond or a double bond, Y represents CH or N when the bond is a single bond, and Y represents C when the bond is a double bond. ] The compound or its salt represented by these, or its prodrug. 2. Formula (I ′): [Wherein R ¹ and R ² are the same or different,
It represents a hydrogen atom or a lower alkyl group which may have a substituent, or R ¹ and R ² bond together to form a 4- to 7-membered ring with the adjacent carbon atom, and Ar ¹ has a substituent. An optionally aromatic group, a ring A is a benzene ring which may have a substituent, a ring B is an aromatic ring which may have a substituent, and a ring C has a substituent. Is a 4- to 8-membered ring, X is CH or N, and Y is CH.
Or N is shown. ] The compound or its salt represented by these, or its prodrug. 3. The formula: [In the formula, B ring, C ring, and X have the same meanings as in claim 1. ] Is a partial structure represented by the formula: [In the formula, R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group which may have a substituent or a lower alkoxy group which may have a substituent, and the B ′ ring has a substituent. Optionally represents a benzene ring, X represents CH or N, Z represents an oxygen atom, a sulfur atom, CR ⁴ R ⁵ , NR ⁶ or (R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different,
It represents a hydrogen atom or a lower alkyl group which may have a substituent. ), M is 0 to 1, and n is 1 to
Indicates an integer of 4. ] The compound according to claim 1 or a salt thereof or a prodrug thereof. 4. The compound according to claim 1, a salt thereof or a prodrug thereof, wherein C ring is a ring in which a single ring is condensed in addition to B ring. 5. The compound according to claim ¹ , wherein R ¹ is a hydrogen atom, a salt thereof or a prodrug thereof. 6. The compound according to claim 1, a salt thereof or a prodrug thereof, wherein R ¹ is a hydroxy group, an alkoxy group which may have a substituent or an acyloxy group which may have a substituent. 7. The compound according to claim 1, a salt thereof or a prodrug thereof, wherein R ² is a hydrogen atom or a lower alkyl group which may have a substituent. 8. The compound according to claim 1, a salt thereof or a prodrug thereof, wherein Ar ¹ is a monocyclic aromatic group which may have a substituent. 9. The compound according to claim 1, a salt thereof or a prodrug thereof, wherein Ar ¹ is a phenyl group, a furyl group, a thienyl group or a pyridyl group, each of which may have a substituent. 10. The compound according to claim 1, a salt thereof or a prodrug thereof, wherein ring A is an unsubstituted benzene ring. 11. At least one of X and Y is N.
The compound according to claim 1, a salt thereof or a prodrug thereof. 12. The compound according to claim 1, wherein X is N and Y is C, or a salt thereof or a prodrug thereof. 13. R ¹ is a hydrogen atom, an alkyloxy group or an acyloxy group, R ² is a hydrogen atom or a lower alkyl group which may have a substituent, and Ar ¹ has a substituent. Optionally a phenyl group, a furyl group optionally having a substituent, a thienyl group optionally having a substituent or a pyridyl group optionally having a substituent,
Ring A may be an unsubstituted benzene ring, Ring B may be an optionally substituted benzene ring, Ring C may be an unsubstituted benzene ring fused, and may have a substituent. The compound or a salt thereof or a prodrug thereof according to claim 1, which is a nitrogen-containing 5 to 7-membered heterocycle, X is N and Y is CH. 14. R ¹ is a hydrogen atom or an acyloxy group, R ² is an unsubstituted C _1-6 alkyl group, and Ar ¹ is substituted with an optionally halogenated C _1-6 alkoxy group. Optionally a phenyl group, ring A is an unsubstituted benzene ring, ring B is an unsubstituted benzene ring, C
The ring is tetrahydropyrrole, hexahydropyridine, hexahydropyrazine, tetrahydro-1,4-oxazine, tetrahydro-1,4-thiazine, perhydroazepine or pyrrole, X is N and Y is CH. A compound as described above, a salt thereof, or a prodrug thereof. 15. (−)-2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroquinoline-1
-Yl)-1,2,3,4-tetrahydroquinoline, (−)-2,4-cis-4- (3,4-dihydro-2H-1,4-benzoxazin-4-yl)
-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline, 2,4-cis-1- (3,4-dimethoxybenzoyl) -2-methyl-4- (1,2,3,4-tetrahydroquinoline-1
-Yl) -1,2,3,4-tetrahydroquinoline, 2,3-trans-
2,4-cis-3-acetoxy-1- (3,4-dimethoxybenzoyl)
-2-Methyl-4- (1,2,3,4-tetrahydroquinolin-1-yl)-
1,2,3,4-tetrahydroquinoline, 2,4-cis-4- (3,4-dihydro-2H-1,4-benzothiazin-4-yl) -1- (3,4-dimethoxybenzoyl)- 2-Methyl-1,2,3,4-tetrahydroquinoline, 2,4-cis-4- (1-benzyl-1,2,3,4-tetrahydroquinoxalin-4-yl) -1- (3,4 -Dimethoxybenzoyl) -2
-Methyl-1,2,3,4-tetrahydroquinoline, 2,4-cis-1-
(3,4-Dimethoxybenzoyl) -2-methyl-4- (2,3,4,5-tetrahydro-1H-1-benzazepinyl) -1,2,3,4-tetrahydroquinoline, 2,3-trans- 2,4-cis-3-{[(benzylamino) carbonyl] oxy} -1- (3,4-dimethoxybenzoyl) -2-methyl-4- (2,3,4,5-tetrahydro-1H-1 -Benzazepinyl) -1,2,3,4-tetrahydroquinoline, 2,4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2, 3,4-tetrahydroquinoline, (−)-2,
4-cis-4- (9H-9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline, or 2-butyl-4- (9H- The compound according to claim 1, which is 9-carbazolyl) -1- (3,4-dimethoxybenzoyl) -1,2-dihydroquinoline or a salt thereof or a prodrug thereof. 16. The compound according to claim 1, wherein the steric configuration at the 2-position and 4-position in the formula (I) is the (−) isomer, or a salt thereof or a prodrug thereof. 17. The formula: [Wherein R ¹ and R ² are the same or different,
A hydrogen atom, a lower alkyl group which may have a substituent or a hydroxy group which may have a substituent, or
R ¹ and R ² bond together to form a 4- to 7-membered ring with the adjacent carbon atom, Ar ¹ represents an aromatic group which may have a substituent, and A ring has a substituent. Is a benzene ring, and Q ¹ is a reactive substituent. ] The compound or salt thereof represented by the formula: [In the formula, ring B represents an aromatic ring which may have a substituent, and ring C may further have a ring which may have a substituent and may have a substituent. Is a 4- to 8-membered ring. ] The compound represented by the formula or a salt thereof is reacted with [In the formula, R ¹ , R ² , Ar ¹ , A ring, B ring and C ring have the same meanings as described above. ] The manufacturing method of the compound represented by these, its salt, or its prodrug. 18. The formula: [Wherein R ¹ and R ² are the same or different,
A hydrogen atom, a lower alkyl group which may have a substituent or a hydroxy group which may have a substituent, or
R ¹ and R ² bond together to form a 4- to 7-membered ring with the adjacent carbon atom, Ar ¹ represents an aromatic group which may have a substituent, and A ring has a substituent. Represents a good benzene ring. ] The compound or its salt represented by the following formula: [In the formula, Q ² represents a reactive substituent, ring B represents an aromatic ring which may have a substituent, and ring C further comprises a ring which may further have a substituent. Also represents a 4- to 8-membered ring which may have a substituent. ] It is made to react with the compound or its salt represented by the formula, [In the formula, R ¹ , R ² , Ar ¹ , A ring, B ring and C ring have the same meanings as described above. ] The manufacturing method of the compound represented by these, its salt, or its prodrug. 19. The formula: [In the formula, R ² represents a hydrogen atom, a lower alkyl group which may have a substituent or a hydroxy group which may have a substituent, and Ar ¹ represents an aromatic group which may have a substituent. Represents a group group, and ring A represents a benzene ring which may have a substituent. ] The compound or its salt represented by the following formula: [In the formula, ring B represents an aromatic ring which may have a substituent, and ring C may further have a ring which may have a substituent and may have a substituent. Is a 4- to 8-membered ring. ] Represented by the formula: [In the formula, R ² , Ar ¹ , A ring, B ring and C ring have the same meanings as described above. ] The compound or its salt represented by these is manufactured, and if necessary, the hydroxy group in the said formula is replaced with R
¹ [R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a hydroxy group which may have a substituent. ] To a group represented by
Formula [In the formula, R ¹ , R ² , Ar ¹ , A ring, B ring and C ring have the same meanings as described above. ] The manufacturing method of the compound represented by these, its salt, or its prodrug. 20. The formula: [Wherein R ¹ and R ² are the same or different,
A hydrogen atom, a lower alkyl group which may have a substituent or a hydroxy group which may have a substituent, or
R ¹ and R ² bond together to form a 4- to 7-membered ring with adjacent carbon atoms, ring A represents a benzene ring which may have a substituent, and ring B may have a substituent. It represents a good aromatic ring, and the C ring may be condensed with a ring which may further have a substituent, and may have a substituent 4 to 8
Indicates a member ring. ] The compound or its salt represented by the formula A
r ¹ COOH [In the formula, Ar ¹ represents an aromatic group which may have a substituent. ] The compound of the formula or a salt thereof [In the formula, R ¹ , R ² , Ar ¹ , A ring, B ring and C ring have the same meanings as described above. ] The manufacturing method of the compound represented by these, its salt, or its prodrug. 21. The formula: [In the formula, R ² represents a hydrogen atom, a lower alkyl group which may have a substituent or a hydroxy group which may have a substituent, and Ar ¹ represents an aromatic group which may have a substituent. Group A, ring A represents a benzene ring which may have a substituent, ring B represents an aromatic ring which may have a substituent, and ring C further has a substituent. Is a 4- to 8-membered ring which may be condensed and may have a substituent. ] The compound or its salt represented by these is made to react with a base, and it has the formula: [In the formula, R ² , Ar ¹ , the A ring, the B ring and the C ring have the same meanings as described above, and R ¹ represents a hydrogen atom. ] The manufacturing method of the compound represented by these, its salt, or its prodrug. 22. A pharmaceutical composition comprising the compound according to claim 1, a salt thereof or a prodrug thereof. 23. The pharmaceutical composition according to claim 22, which is a soluble beta-amyloid precursor protein secretagogue and / or an apoptosis inhibitor. 24. The pharmaceutical composition according to claim 22, which is a prophylactic and / or therapeutic agent for Alzheimer's disease, Parkinson's disease, neuropathy, senile dementia, neuronal cell disorder at the time of cerebrovascular disorder or cerebrovascular dementia. 25. A human or other mammal,
A therapeutic method comprising administering an effective amount of a pharmaceutical composition comprising a soluble beta-amyloid precursor protein secretagogue and / or an apoptosis inhibitor comprising the compound according to claim 1, a salt thereof, or a prodrug thereof. . 26. For humans or other mammals,
A method for preventing and / or treating a neurodegenerative disease or a nerve cell disorder, which comprises administering an effective amount of a pharmaceutical composition comprising the compound according to claim 1, a salt thereof, or a prodrug thereof. 27. For humans or other mammals,
A prophylactic and / or therapeutic agent for Alzheimer's disease, Parkinson's disease, neuropathy, senile dementia, neuronal cell damage or cerebrovascular dementia at the time of cerebrovascular disorder, which comprises the compound according to claim 1 or a salt thereof or a prodrug thereof. A therapeutic method comprising administering an effective amount of the pharmaceutical composition of 28. Use of the compound according to claim 1 or a salt thereof or a prodrug thereof for producing a pharmaceutical composition which is a soluble beta-amyloid precursor protein secretagogue and / or an apoptosis inhibitor. 29. Use of the compound according to claim 1 or a salt thereof or a prodrug thereof for producing a pharmaceutical composition which is a prophylactic and / or therapeutic agent for neurodegenerative disease or nerve cell disorder. 30. A method for producing a pharmaceutical composition which is a prophylactic and / or therapeutic agent for Alzheimer's disease, Parkinson's disease, neuropathy, senile dementia, neuronal cell disorder at the time of cerebrovascular disorder or cerebrovascular dementia. Use of the described compound or a salt thereof or a prodrug thereof.