JPH1180098A - Amine derivative, its production and agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce the subject new derivative, comprising a specific amine derivative containing an aromatic ring, having inhibiting actions on the amyloid β protein production and secretion and useful for the prophylaxis, therapy or the like of nervous degeneration disease such as Alzheimer disease or senile dementia, neuronal disorders or the like. SOLUTION: This new amine derivative (salt) is represented by formula I [Ar is a (substituted)ring-aggregated aromatic group or a (substituted)condensed aromatic group; X is a direct bond, S, SO, SO2 , oxo, a (substituted) 1-6C alkylene or the like; Y is a (substituted) 1-6C bivalent aliphatic hydrocarbon group which may be intermediated with O or S; R<1> and R<2> are each H or a (substituted) lower alkyl or each of R<1> and R<2> together with the adjacent nitrogen atom forms a (substituted)nitrogen- containing heterocyclic ring; A-ring is represented by the formula X-Ar or a (substituted)benzene ring; B-ring is represented by the formula Y-NR<1> R<1> , a (substituted)4- to 8-membered ring or the liked, has inhibiting actions on the amyloid βprotein production and secretion and is useful as a prophylactic and therapeutic agent or the like for Alzheimer disease. The amine derivative is produced by carrying out an aminating reaction or the like of a compound (salt) represented by formula II (L is an eliminable group) or the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an amine derivative having an excellent inhibitory effect on amyloid β protein production / secretion, a method for producing the same, and a disease caused by amyloid β protein, for example, a neurodegenerative disease (eg, Alzheimer's disease, senility) Dementia,
Down syndrome, Parkinson's disease, etc.), amyloid angiopathy, agents effective for the prevention and treatment of neuronal damage in cerebrovascular disorders and the like.

[0002]

2. Description of the Related Art Alzheimer's disease is a neurodegenerative disease characterized by the formation of senile plaques and neurofibrillary tangles together with neuronal degeneration and loss. The senile plaque most characteristic of Alzheimer's disease contains amyloid β protein (hereinafter sometimes abbreviated as Aβ) as a main component (Biochem. Biophys.
s. Commun. 122, 1131 (1984)), in which biological components are deposited in the brain. Aβ consisting of 40 or 42 amino acids (hereinafter abbreviated as Aβ _1-40 and Aβ _1-42 , respectively) is known to be toxic to nerve cells and induce neurofibrillary tangles. . In addition, among patients with familial Alzheimer's disease, APP (Amyloid Precurso
r Protein) gene may be mutated, and it has been pointed out that cells transfected with this mutated gene have increased production and secretion of Aβ (eg Nature 360, 672 (1
992), Science 259, 514 (1993), Science 264
Vol., 1336 (1994)). Therefore, a drug that inhibits the production and secretion of Aβ is effective for the prevention and treatment of diseases caused by Aβ (eg, Alzheimer's disease, Down's syndrome, etc.). On the other hand, it has been reported that secretory APP has a neurotrophic factor-like action (Neuron, 10, 243-254, 1993). Such neurotrophic factor-like effects include (1) survival of nerve cells and
Maintenance action, (2) synapse formation promoting action, (3) neuronal cell death protecting action, (4) long-term potentiating action in hippocampus and the like. For this reason, drugs that promote the secretion of secretory APP include (1) neurodegenerative diseases (eg,
Alzheimer's disease, Down's syndrome, senile dementia, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, diabetic neuropathy, Huntington's chorea, multiple sclerosis, etc.), (2) cerebrovascular disorders (eg Cerebral infarction, cerebral hemorrhage, etc.), head injury or spinal cord injury. Further, EP-A-652009 discloses a peptide derivative having a protease inhibitory action and an Aβ production inhibitory action at a cellular level.

On the other hand, the following compounds are known as bicyclic amine compounds. 1) JP-A-2-96552 (USP 5,137,901) discloses the following formula

Embedded image Wherein Y is a linear or branched, substituted or unsubstituted alkylene chain having up to 6 carbon atoms, Z
Is a group such as —NR ² R ³ or —OR ⁴ , R ² and R ³ are the same or different and are hydrogen, alkyl, alkenyl or cycloalkyl, or aryl optionally substituted by halogen or the like, and R ⁴ is hydrogen , Alkyl or alkenyl, R ¹ is hydrogen, alkyl, aralkyl, heteroarylalkyl or a group-(Y ¹ -Z ¹ ) (Y ¹ and Z
¹ are the same or different wherein Y and Z as defined above), A and D has the formula -CH _2, O, S, or an NR ^13, or C = C or C = NH double bond -CH or portion of N, provided that a only or D only oxygen, sulfur or N-R ^13, R ¹³ is hydrogen, alkyl, alkoxy, acyl, alkoxycarbonyl or alkylsulphonyl, B represents the formula -CH _2,

Embedded image E and F are the same or different and are hydrogen, alkyl,
Alkoxy, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy or formula -CONR ² R
³ groups, a compound represented by R ² and R ³ are described above and as defined, E and F form a substituted or unsubstituted carbocycle having 6 carbon atoms together] are serotonin receptor It has an effect of an agonist, a partial agonist and an antagonist on the body, and is described as suitable for treatment of diseases of the central nervous system. 2) JP-A-63-77842 discloses the following formula:

Embedded image Wherein n is 1 or 2, A is carbonyl, and R ₇ is a hydrogen atom, or A is a formula: —CHR ₈ — (R ₈ represents a hydrogen atom, alkanoyloxy or alkoxycarbonyl), and R ₇ is A hydrogen atom or R ₇ and R ₈ together form another bond, E is a linear alkylene of 3 or 4 carbon atoms which may be substituted by alkyl, G may be substituted by alkyl Linear alkylene having 2 to 5 carbon atoms, R ₁ is a hydrogen atom, trifluoromethyl,
Nitro, amino, alkylamino, dialkylamino,
An alkyl group, hydroxy, alkoxy or phenylalkoxy, R ₂ is hydrogen, a halogen atom, hydroxy, alkoxy, phenylalkoxy or alkyl, or R ₁ and R ₂ together having 1 or 2 carbon atom alkylenedioxy, R ₃ is A hydrogen atom, an alkenyl or alkyl having 3 to 5 carbon atoms, R ₄ represents a hydrogen atom, a halogen atom, alkyl, etc., R ₅ represents a hydrogen atom, a halogen atom, alkyl, etc., and R ₆ represents a hydrogen atom, a halogen atom, alkyl, etc. The compound represented by the formula has a heart rate lowering effect and a heart O ₂ -reducing effect, and is suitable for the treatment of sinus tachycardia and the prevention and treatment of ischemic heart disease. ing. 3) WO 92/15558 has the following formula

Embedded image [Wherein n represents an integer of 1 to 4] is described as an intermediate of a compound having a thromboxane A ₂ antagonistic action. 4) WO 95/32967 has the following formula

Embedded image Wherein A is CONR, R is a hydrogen atom or C _1-6 alkyl, and Q contains 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom or a sulfur atom which may have a substituent. A 5- to 7-membered ring, R ₁ is a hydrogen atom, halogen, etc., R ₂ and R
₃ is a hydrogen atom, halogen, etc., R ₄ and R ₅ are each a hydrogen atom or C _1-6 alkyl, R ₆ is a halogen, etc., R ₇ and R ₈ are each a hydrogen atom, C _1-6 alkyl, aralkyl or adjacent A 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms selected from an oxygen atom, a nitrogen atom or a sulfur atom, which may have a substituent together with a nitrogen atom, m is 0 to 4, and n
Represents 0, 1 or 2], which describes that the amide derivative has 5HT _1D antagonistic activity and is useful for treating central nervous system diseases. 5) EP-A-754455 has the following formula:

Embedded image Wherein X is a hydrogen atom, halogen, alkoxy, alkyl, alkylthio, aryl, aryloxy, R is a hydrogen atom, CH ₃ or another aliphatic, acyclic or aryl radical, R ′ is a hydrogen atom, '' Represents a hydrogen atom or the like] or a salt thereof has a monoamine oxidase (MAO) inhibitory activity and is useful as a neuroprotective agent in central nervous system degenerative diseases (Parkinson's disease, Alzheimer's disease, etc.) Are listed.

[0004]

The conventional Aβ production inhibitors for treating Alzheimer's disease have problems in oral absorbability and stability, and are not satisfactory as pharmaceuticals.
There is an urgent need to develop compounds that differ in chemical structure from the above-mentioned known compounds, have excellent Aβ production / secretion inhibitory effects, and are sufficiently satisfactory as pharmaceuticals.

[0005]

Means for Solving the Problems The present inventors have conducted various studies on compounds having Aβ production / secretion inhibitory activity, and

Embedded image [Wherein each symbol has the same meaning as described below], the benzene ring (ring A) of the skeleton represented by the formula -X-Ar (wherein each symbol has the same meaning as below) Having the characteristic of a chemical structure in that it is substituted with

Embedded image [Wherein, Ar represents an optionally substituted ring-assembling aromatic group or an optionally substituted condensed aromatic group, X represents (i) a bond, (ii) —S -, -SO- or-
SO ₂ —, (iii) C- _optionally having 1 to 3 substituents selected from oxo and C _1-6 alkyl
_1-6 alkylene, C _2-6 alkenylene or C _2-6 alkynylene, (iv) —CO—O— or (v) formula — (CH ₂ ) p
-X ¹ -,-(CH ₂ ) p-X ^1- (CH ₂ ) q-,-(CH ₂ ) r-
CO-X ^1- , -SO ₂ -NR ^8- or-(CH ₂ ) r-S
O ₂ —NR ⁸ — (wherein X ¹ is an oxygen atom or NR ⁸ , R ⁸
Is a hydrogen atom, an optionally substituted hydrocarbon group or acyl, p is an integer of 0 to 5, q is an integer of 1 to 5, p + q is an integer of 1 to 5, and r is 1 to 4
Y represents a divalent C _1-6 aliphatic hydrocarbon group which may be via an oxygen atom or a sulfur atom and may have a substituent. And R ¹ and R ² each represent a hydrogen atom or a lower alkyl which may have a substituent, or R ¹ and R ² represent a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom. A ring is formed, and the A ring represents a benzene ring which may further have a substituent in addition to the group represented by the formula -X-Ar (wherein each symbol has the same meaning as described above), Ring B has the formula -Y-NR ¹
And a 4- to 8-membered ring which may further have a substituent, in addition to the group represented by R ² (wherein each symbol has the same meaning as described above). However, when the condensed ring formed by ring A and ring B is an indole ring, the group represented by the formula -X-Ar (wherein each symbol has the same meaning as described above) is the same as that of the indole ring.
Substitution at the-, 6- or 7-position. ] Or a salt thereof (hereinafter abbreviated as compound (I)) for the first time, and compound (I) has unexpectedly excellent Aβ production and secretion based on its unique chemical structure. Having an inhibitory effect, and further comprising a compound (I)

Embedded image [In the formula, Ar ′ is an aromatic group which may have a substituent,
The other symbols have the same meanings as described above), or a salt thereof (hereinafter abbreviated as compound (I ′)) unexpectedly has an excellent Aβ production / secretion inhibitory action, For the first time, the present inventors have found that they are sufficiently satisfactory as pharmaceuticals, such as low toxicity, and based on these findings, completed the present invention.

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

Embedded image [In the formula, Ar represents a ring-assembling aromatic group which may have a substituent or a condensed aromatic group which may have a substituent, and X represents a bond or a group having 1 to 6 atoms. Wherein Y is a divalent C _1-6 aliphatic hydrocarbon group which may be via an oxygen atom or a sulfur atom and may have a substituent, and R ¹ and R ² are Each represents a hydrogen atom or a lower alkyl which may have a substituent, or R ¹ and R ² together with an adjacent nitrogen atom form a nitrogen-containing heterocyclic ring which may have a substituent; formula
A benzene ring which may further have a substituent in addition to the group represented by -X-Ar (wherein each symbol has the same meaning as described above), and the ring B is a group represented by the formula -Y-NR ¹ R ² (wherein each symbol has the same meaning as described above), and represents a 4- to 8-membered ring which may further have a substituent in addition to the group represented by the above formula) or a salt thereof. ,

(2) Ar is (i) a C _6-14 aromatic hydrocarbon,
Two or three aromatic rings selected from 5 to 14-membered aromatic heterocycles containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to C _6-14 quinone and carbon atoms are single bonds With a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6 cycloalkyl as a substituent Optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, 5 to 7 membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl - carbonyl,
C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl- Carbamoyl, di-C
_1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _{6 -10} aryl - carboxamide, C _1-6 alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _6-10 aryl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- −C _1-6
Alkyl-carbamoyloxy, di-C _1-6 alkyl-
A ring-assembled aromatic group optionally having 1 to 5 substituents selected from carbamoyloxy, C _6-10 aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy, or (ii) a halogen atom , C _1-3 alkylenedioxy, 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, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl , C
_1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono -C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formyl Amino, C _1-6 alkyl-
Carboxamide, C _6-10 aryl-carboxamide, C
_1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C
_6-10 aryl-carbonyloxy, C _1-6 alkoxy-
Carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy,
C _6-10 aryl - carbamoyloxy, substituents selected from nicotinoyloxy oxy and C _6-10 aryloxy 1
Or a fused 2 or 3 cyclic C _10-14 aryl optionally having 5 to 5 carbon atoms or a heteroatom selected from nitrogen, sulfur and oxygen
9 to 14 membered aromatic heterocyclic group containing from 4 to 4,

R ⁸ is (a) a hydrogen atom, (b) (1) a halogen atom, (2) C _1-3 alkylenedioxy, (3) nitro,
(4) cyano, (5) optionally halogenated C _1-6 alkyl, (6) optionally halogenated C _3-6 cycloalkyl, (7) optionally halogenated C _{1 -6} alkoxy, (8) optionally halogenated C _1-6 alkylthio, (9) hydroxy, (10) amino, (11) mono-C _1-6 alkylamino, (12) di-C _{1- 6-} alkylamino, (13) formyl, carboxy, carbamoyl, C
_1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono -C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl or C
_6-10 arylsulfonyl, (14) formylamino, C _1-6
Alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide or C _1-6
Alkylsulfonylamino, (15) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy,
C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy or nicotinoyloxy, (16) 5-7 Membered cyclic amino, (17) sulfo, (18) halogen atom, C _1-3
Alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl optionally, optionally halogenated C _3-6 also be cycloalkyl, optionally halogenated C _1-6 alkoxy optionally halogenated C _1-6 which may be
Alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 Alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6
Alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C
_6-10 arylsulfonyl, formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _1-6 alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy, nicotine Phenyl optionally having 1 to 5 substituents selected from noyloxy and C _6-10 aryloxy or 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen in addition to carbon. Including a 5- or 6-membered aromatic heterocyclic group, (19) C _6-14 aromatic hydrocarbon, C _6-14 quinone and nitrogen other than carbon atom 1 to 4 heteroatoms selected from atoms, sulfur atoms and oxygen atoms
And two or three aromatic rings selected from 5- to 14-membered aromatic heterocycles including a single bond are directly connected by a single bond, and a halogen atom, C _1-3 alkylenedioxy, 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, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-
Carbonyl, C _6-10 aryloxy-carbonyl, C
_7-16 aralkyloxy-carbonyl, 5 or 6 membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl,
Di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-
Carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C
_1-6 alkylsulfonyl, _C6-10 arylsulfonyl,
Formylamino, C _1-6 alkyl-carboxamide, C
_6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6
Alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl A ring-assembled aromatic group optionally having 1 to 5 substituents selected from carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy, and (20) a halogen atom, C
_1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl optionally, optionally halogenated C _3-6 also be cycloalkyl, optionally halogenated C _1-6 alkoxy optionally Optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6
Alkylamino, di -C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl - carbonyl, C _1-6 alkoxy -
Carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C
_1-6 alkyl - carbamoyl, di -C _{1 -6} alkyl - carbamoyl, C _6-10 aryl - carbamoyl, 5 or 6
Membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C
_6-10 arylsulfonyl, formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _1-6 alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy, nicotine Condensed 2 optionally having 1 to 5 substituents each selected from noyloxy and C _6-10 aryloxy
Or a substituent 1 to 5 selected from a 9 to 14-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a tricyclic C _10-14 aryl or carbon atom C _6-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl optionally fused to a benzene ring, C _6-14 aryl or C _7-19 aralkyl, or

[0009] (c) formyl, carboxy, carbamoyl, C _1-6 alkyl - carbonyl, C _1-6 alkoxy - carbonyl, C _6-10 aryl - carbonyl, C _6-10 aryloxy - carbonyl, C ₇ - ₁₆ aralkyl Oxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C
_1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5 or 6
Membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl or C _6-10 arylsulfonyl; Y is C _1-6 alkylene,
C _2-6 alkenylene, C _2-6 alkynylene or the formula-(C
^{_{H 2) m-Y 1 -}} (CH 2) n- ( wherein, -Y ¹ - is -O -, -
S -, - SO- or -SO ₂ -, m is 0 to 4 integer, n represents 1 to 5 integer, and m + n is 1 to 5
Wherein R ¹ and R ² are each (i) a hydrogen atom or (ii) a halogen atom, C _1-3 alkylenedioxy, 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, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl , C
_1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono -C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formyl Amino, C _1-6 alkyl-
Carboxamide, C _6-10 aryl-carboxamide, C
_1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C
_6-10 aryl-carbonyloxy, C _1-6 alkoxy-
Carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy,
C _6-10 aryl - carbamoyloxy which may have nicotinoyloxy oxy, five to the substituents 1 are selected from C _6-10 aryloxy and C _6-10 aryl C _1-6
Alkyl or R ¹ and R ² together with a nitrogen atom adjacent thereto, as a substituent, (1) halogen atom, (2) C _1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) halogenation _Optionally substituted C _1-6 alkyl, (6) optionally halogenated C _3-6 cycloalkyl, (7) optionally halogenated C _1-6 alkoxy, (8) halogenated C _1-6 alkylthio, (9) hydroxy, (10) amino, (11) mono-C _1-6 alkylamino, (12) di-C _1-6 alkylamino, (13) formyl, carboxy Carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl,
C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic Ring carbamoyl,
C _1-6 alkylsulfonyl or C _6-10 arylsulfonyl, (14) formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide or C _1-6 alkylsulfonyl Amino, (15) C _1-6 alkyl-carbonyloxy,
C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy or nicotine Noyloxy, (16) 5- to 7-membered saturated cyclic amino,
(17) sulfo, (18) halogen atom, C _1-3 alkylenedioxy, 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, di-C _1-6 alkylamino, 5 to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6
Alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _{1 -6} alkyl - carbamoyl, di -C _1-6 alkyl - carbamoyl, C _6-10 aryl - carbamoyl, 5 or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl-
Carboxamide, C _6-10 aryl-carboxamide, C
_1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C
_6-10 aryl-carbonyloxy, C _1-6 alkoxy-
Carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy,
C _6-10 aryl - carbamoyloxy, substituents selected from nicotinoyloxy oxy and C _6-10 aryloxy 1
(A) phenyl or (b) optionally containing 1 to 4 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen
Or a 6-membered aromatic heterocyclic group, (19) a C _6-14 aromatic hydrocarbon, a C _6-14 quinone and a heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom other than 1 to 4
And two or three aromatic rings selected from 5- to 14-membered aromatic heterocycles including a single bond are directly connected by a single bond, and a halogen atom, C _1-3 alkylenedioxy, 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, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-
Carbonyl, C _6-10 aryloxy-carbonyl, C
_7-16 aralkyloxy-carbonyl, 5 or 6 membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl,
Di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-
Carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C
_1-6 alkylsulfonyl, _C6-10 arylsulfonyl,
Formylamino, C _1-6 alkyl-carboxamide, C
_6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6
Alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl A ring-assembled aromatic group optionally having 1 to 5 substituents selected from carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy, and (20) a halogen atom, C
_1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl optionally, optionally halogenated C _3-6 also be cycloalkyl, optionally halogenated C _1-6 alkoxy optionally Optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6
Alkylamino, di -C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl - carbonyl, C _1-6 alkoxy -
Carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C
_1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5 or 6
Membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C
_6-10 arylsulfonyl, formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _1-6 alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy, nicotine Condensed 2 optionally having 1 to 5 substituents each selected from noyloxy and C _6-10 aryloxy
Or a _9- to 14-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a tricyclic _C10-14 aryl or carbon atom, (21) oxo and (22) ) May have 1 to 5 substituents selected from C _7-19 aralkyl, and contain at least one nitrogen atom other than a carbon atom, and 1 to 3 selected from a nitrogen atom, an oxygen atom and a sulfur atom A 3- to 8-membered nitrogen-containing heterocycle optionally containing a heteroatom;
In addition to the group in which the ring A is represented by the formula -X-Ar (wherein each symbol has the same meaning as described above), a halogen atom, an optionally halogenated C _1-6 alkyl, A benzene ring optionally having 1 to 3 substituents selected from C _1-6 alkoxy, hydroxy and amino; and a ring B having the formula -Y-NR ¹ R ² (wherein each symbol is In addition to the group represented by the above), oxo,
Substituent 1 selected from C _1-6 alkyl and hydroxy
Or a formula that may further have three

Embedded image

Z is (i) a bond, (ii) C _1-4 alkylene, (iii) C _2-4 alkenylene, (iv) —O—CH ₂ —,
_{(v) -O-CH 2 -CH} 2 - or (vi) expression -NR ^8a
—CH ₂ — or —NR ^8a —CH ₂ —CH ₂ — (wherein R
^8a is (a) hydrogen atom, (b) (1) halogen atom, (2) C
_1-3 alkylenedioxy, (3) nitro, (4) cyano,
(5) C _1-6 alkyl _optionally halogenated, (6)
Optionally halogenated C _3-6 cycloalkyl,
(7) an optionally halogenated C _1-6 alkoxy,
(8) an optionally halogenated C _1-6 alkylthio,
(9) hydroxy, (10) amino, (11) mono-C _1-6 alkylamino, (12) di-C _1-6 alkylamino, (13)
Formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10
Aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl or C _6-10 arylsulfonyl, (14) formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl- Carboxamide, C _1-6
Alkoxy-carboxamide or C _1-6 alkylsulfonylamino, (15) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl- Carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy or nicotinoyloxy, (16) 5- to 7-membered saturated cyclic amino,
(17) sulfo, (18) halogen atom, C _1-3 alkylenedioxy, 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, di-C _1-6 alkylamino, 5 to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6
Alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _{1 -6} alkyl - carbamoyl, di -C _1-6 alkyl - carbamoyl, C _6-10 aryl - carbamoyl, 5 or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl-
Carboxamide, C _6-10 aryl-carboxamide, C
_1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C
_6-10 aryl-carbonyloxy, C _1-6 alkoxy-
Carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy,
C _6-10 aryl - carbamoyloxy, substituents selected from nicotinoyloxy oxy and C _6-10 aryloxy 1
5 or 6 containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, in addition to phenyl or carbon which may each have 5 to 5 carbons
Membered aromatic heterocyclic group, (19) C _6-14 aromatic hydrocarbon, C
_6-14 quinones and nitrogen atom in addition to carbon atoms, 2 or 3 selected from 5 to 14-membered aromatic heterocyclic ring containing four to no heteroatoms 1 selected from sulfur and oxygen atoms
Aromatic rings are directly connected by a single bond, and a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, Good C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl - carbonyl, C
_1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl , Di-C _1-6
Alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl -Carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-
Carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6
Alkyl-carbamoyloxy, di-C _1-6 alkyl-
(20) a halogen atom, a ring-assembled aromatic group optionally having 1 to 5 substituents selected from carbamoyloxy, C _6-10 aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy; , C _1-3 alkylenedioxy, 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, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, Carboxy, carbamoyl, C
_1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono -C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formyl Amino, C _1-6 alkyl-
Carboxamide, C _6-10 aryl-carboxamide, C
_1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C
_6-10 aryl-carbonyloxy, C _1-6 alkoxy-
Carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy,
C _6-10 aryl - carbamoyloxy, substituents selected from nicotinoyloxy oxy and C _6-10 aryloxy 1
Or a fused 2 or 3 cyclic C _10-14 aryl optionally having 5 to 5 carbon atoms or a heteroatom selected from nitrogen, sulfur and oxygen
C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl optionally having 1 to 5 substituents selected from a 9 to 14 membered aromatic heterocyclic group containing from 4 to 4;
C _3-6 cycloalkyl, C _6-14 aryl or C _7-19 aralkyl which may be condensed with a benzene ring, or
(c) formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C
_6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl -Carbamoyl, C
_6-10 aryl-carbamoyl, a 5- or 6-membered heterocyclic carbamoyl, a C _1-6 alkylsulfonyl or a C _6-10 arylsulfonyl)). Compound (I),

(3) Compound (I) wherein Ar is a ring-assembled aromatic group which may have a substituent, (4) The compound wherein the aromatic ring of the ring-assembled aromatic group is benzene, thiophene, pyridine, pyrimidine, The compound according to the above (3), which is two or three aromatic rings selected from 1,2,4-oxadiazole, 1,3,4-oxadiazole, naphthalene and benzofuran; Is a 2-, 3- or 4-biphenylyl, the compound according to the above (3), (6) Ar
Is a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, optionally halogenated Good C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6
Alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl,
C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic Ring carbamoyl,
C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _{1-6 1-6} alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy,
Di -C _1-6 alkyl - carbamoyloxy, C _{6 -10} aryl - carbamoyloxy, it may have 1 selected from nicotinoyloxy oxy and C _6-10 aryloxy three substituents 4-biphenylyl A compound (I) which is

(7) X may be an oxygen atom 2
Compound (I) which is a monovalent C _1-6 aliphatic hydrocarbon group,
(8) Compound (I) wherein X is C _1-6 alkylene,
(9) Compound (I), wherein X is a group represented by the formula — (CH ₂ ) p—X ¹ — (wherein each symbol is as defined above),
(10) The compound according to the above (9), wherein p is 1, (1)
1) The compound according to the above (10), wherein X ¹ is O,
2) The compound according to the above (10), wherein X ¹ is NR ^8b (R ^8b represents a hydrogen atom or C _1-6 alkyl-carbonyl), (13) X ¹ is a compound of the formula —SO ₂ —NR ⁸ — (formula Wherein each symbol is as defined above) (I), (14) the compound according to (13), wherein R ⁸ is a hydrogen atom, (15) Y is divalent Compound (I) which is a C _1-6 aliphatic hydrocarbon group, (16) Compound (I) wherein Y is C _1-6 alkylene, (17) R ¹ and R ² are each C _1-6 alkyl Compounds (I) and (18) wherein the ring A has the formula
A compound (I) which is a benzene ring substituted only with a group represented by -X-Ar (wherein each symbol is as defined above),

(19) Ring B is selected from oxo, C _1-6 alkyl and hydroxy, in addition to the group represented by the formula —Y-NR ¹ R ² (wherein each symbol has the same meaning as described above). Formula which may further have 1 to 3 substituents

Embedded image [Wherein, Z is (i) a bond, (ii) C _1-4 alkylene,
(iii) C _{2-4 alkenylene, (iv) -O-CH 2} -, (v)
—O—CH ₂ —CH ₂ — or (vi) a formula —NR ^8a —CH ₂
— Or —NR ^8a —CH ₂ —CH ₂ — (wherein R ^8a is (a)
Hydrogen atom, (b) (1) halogen atom, (2) C _1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated C _1-6 alkyl, ( 6) optionally halogenated C _3-6 cycloalkyl, (7) optionally halogenated C _1-6 alkoxy, (8) optionally halogenated C _1-6 alkylthio, (9 ) Hydroxy, (10) amino, (11) mono-C _1-6 alkylamino, (12) di-C _1-6 alkylamino, (13) formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl,
C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic Ring carbamoyl,
C _1-6 alkylsulfonyl or C _6-10 arylsulfonyl, (14) formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _1-6 alkoxy - carboxamide or C _1-6 alkylsulfonyl Amino, (15) C _1-6 alkyl-carbonyloxy,
C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy or nicotine Noyloxy, (16) 5- to 7-membered saturated cyclic amino, (1
7) sulfo, (18) halogen atom, C _1-3 alkylenedioxy, 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, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy- Carbonyl, C
_6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl -Carbamoyl, C
_6-10 aryl - carbamoyl, 5 or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _{1 -6} alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _6-10 aryl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyl Oxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10
Phenyl optionally having 1 to 5 substituents selected from aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy, or a hetero atom selected from nitrogen, sulfur and oxygen in addition to carbon. 5- or 6-membered aromatic heterocyclic group containing 1 to 4 atoms, (19) selected from C _6-14 aromatic hydrocarbon, C _6-14 quinone and nitrogen atom, sulfur atom and oxygen atom other than carbon atom Two or three aromatic rings selected from a 5- to 14-membered aromatic heterocycle containing 1 to 4 heteroatoms are directly connected by a single bond, and a halogen atom, C _1-3 alkylenedioxy, nitro , cyano, optionally halogenated C _1-6 alkyl optionally, optionally halogenated C _3-6 also be cycloalkyl, optionally halogenated C _1-6 alkoxy optionally, c Gen of which may be C _1-6 alkylthio, hydroxy, amino, mono--C _1-6 alkylamino, di -C _1-6 alkylamino, 5
To 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C
_6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl Carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C
_1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6
Alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6
Substitution selected from alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy A ring-assembled aromatic group optionally having 1 to 5 groups, and (20) a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, Optionally halogenated C _3-6 chloroalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio,
Hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy- Carbonyl, C
_6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl -Carbamoyl, C
_6-10 aryl - carbamoyl, 5 or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _{1 -6} alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _6-10 aryl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyl Oxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10
A condensed _bi- or tricyclic C _10-14 aryl optionally having 1 to 5 substituents selected from aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy, or a nitrogen atom other than a carbon atom And a C _1-6 which may have 1 to 5 substituents selected from a 9 to 14 membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a sulfur atom and an oxygen atom, respectively.
Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl optionally condensed with a benzene ring, C
_6-14 aryl or C _7-19 aralkyl, or (c) formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryl Oxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5 or 6
Heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl or C _{6 -10} represents an arylsulfonyl), a compound represented by the formula (I):

(20) R ^8a is a hydrogen atom, optionally halogenated C _1-6 alkyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-
Carbonyl, C _6-10 aryloxy-carbonyl, C
_7-16 aralkyloxy-carbonyl, 5 or 6 membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl,
Di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-
Carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C
The compound according to the above (19), which is _1-6 alkylsulfonyl or C _6-10 arylsulfonyl, (21) ring B is a compound of the formula —Y—NR ¹ R ² (wherein each symbol has the same meaning as described above) A compound (I), which is a 6-membered homo- or heterocyclic ring substituted only with a group represented by the formula:

Embedded image Wherein Za is C _1-3 alkylene or a formula —NR ^8c —C
H ₂ — (wherein R ^8c is a hydrogen atom, optionally halogenated C _1-6 alkyl, C _1-6 alkyl-carbonyl,
_1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl , Di-C _1-6
Alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl or C _6-10 arylsulfonyl). A compound (I),
(23) the compound according to the above (22), wherein Za is ethylene, and (24) when X is CH ₂ O, the condensed ring formed by the ring A and the ring B is

Embedded image The compound (I), (25) Ar, which is a ring represented by the formula: is a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, Optionally C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, formyl and C _1-6 2-, 3- or 4-biphenylyl optionally having 1 to 3 substituents selected from alkyl-carboxamides; C _1-3 alkylene in which X may be via an oxygen atom; Y is C _{1- 6} alkylenes; R ¹ and R ² are each C _1-6 alkyl;
(Wherein each symbol is as defined above) -X-Ar group only substituted benzene ring represented by, and in ring B wherein -Y-NR ¹ R ² (wherein each symbol is A compound (I) which is a 6-membered homo- or heterocyclic ring substituted only with a group represented by

Equation (26)

Embedded image Wherein R ⁰ is 1 to 3 halogen atoms, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _1- Selected from ₆ alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, formyl and C _1-6 alkyl-carboxamide Substituent,
R ^1a and R ^2a are each C _1-6 alkyl] or a compound thereof (I), (2)
7) Expression

Embedded image Wherein, Ar ^a is (i) a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, C _1-6 alkoxy optionally halogenated 2-, 3- or 4-biphenylyl optionally having 1 to 3 substituents selected from optionally halogenated C _1-6 alkylthio, amino, formyl and C _1-6 alkyl-carboxamide , (Ii) 4-
(2-thienyl) phenyl or 4- (3-thienyl)
Phenyl, (iii) 4- (3-pyridyl) phenyl, (i
v) 6-phenyl- optionally having C _1-6 alkoxy
3-pyridyl, (v) 5-phenyl-1,3,4-oxadiazol-2-yl, (vi) 4- (2-naphthyl) phenyl, (vii) 4- (2-benzofuranyl) phenyl, ( v
iii) 1- or 2-naphthyl, (ix) 2-quinolyl,
(x) 2-benzothiazolyl or (xi) 2-benzofuranyl; X ′ is —CH ₂ —O—, —SO ₂ —NH— or a formula
—CH ₂ —NR ⁸ ′ — (wherein R ⁸ ′ is a hydrogen atom or C _1-3
Y ′ is a group represented by the formula:
_1-6 alkylene; Z ′ is —CH ₂ —CH ₂ — or a formula —N
A group represented by R ⁸ ″ —CH ₂ — (wherein R ⁸ ″ is a hydrogen atom, C _1-3 alkyl, C _1-3 alkyl-carbonyl or C _1-3 alkylsulfonyl); and R ¹ 'and R ² '
Is a C _1-6 alkyl optionally having 1 to 5 substituents selected from di-C _1-3 alkylamino, C _1-3 alkoxy-carbonyl and phenyl, or R ¹ ′
And R ² ′, together with the adjacent nitrogen atom,
_1-3 forms pyrrolidin-1-yl, piperidino or piperazin-1-yl which may have 1 to 3 substituents selected from alkoxy-carbonyl, piperidino, phenyl and benzyl, respectively. Compound (I) which is a compound or a salt thereof,

(28) 6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, 6- (4-biphenylyl) methoxy-2-
(N, N-dimethylamino) methyltetralin, 2-
(N, N-dimethylamino) methyl-6- (4′-methoxybiphenyl-4-yl) methoxytetralin, (+)
-6- (4-Biphenylyl) methoxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin,
(+)-6- (4-Biphenylyl) methoxy-2- [2
-(N, N-diethylamino) ethyl] tetralin,
(+)-2- [2- (N, N-dimethylamino) ethyl] -6- (4'-methylbiphenyl-4-yl) methoxytetralin, (+)-2- [2- (N, N- Dimethylamino) ethyl] -6- (4'-methoxybiphenyl-4-yl) methoxytetralin, (+)-6- (2 ',
4'-dimethoxybiphenyl-4-yl) methoxy-2
-[2- (N, N-dimethylamino) ethyl] tetralin, (+)-6- [4- (1,3-benzodioxol-5-yl) phenyl] methoxy-2- [2- (N , N
-Dimethylamino) ethyl] tetralin, or (+)
-6- (3 ', 4'-dimethoxybiphenyl-4-yl)
Compound (I) which is methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin or a salt thereof,
(29) i) Equation

Embedded image [In the formula, Xa is an oxygen atom, a sulfur atom which may be oxidized, or a formula NR ⁸ (wherein R ⁸ represents a hydrogen atom, a hydrocarbon group which may have a substituent or acyl). Group, and other symbols have the same meanings as described above), the compound or a salt thereof is subjected to an alkylation reaction or an acylation reaction, and, if desired, the obtained compound is further subjected to an aryl coupling reaction. Or ii) equation

Embedded image Wherein Ya is a group obtained by removing methylene from Y, and other symbols are as defined above, or a salt thereof is subjected to a reduction reaction, or iii)

Embedded image Wherein L is a leaving group, and other symbols have the same meanings as described above, or a salt thereof, which is subjected to an amination reaction.

Equation (30)

Embedded image [Wherein R ^1b and R ^2b are each methyl or ethyl, k is 1 or 2, and * indicates the position of an asymmetric carbon], or a salt thereof, or a compound (31) (32) a composition according to the above (31), which is an inhibitor of amyloid β protein production / secretion; and (33) a preventive / therapeutic agent for a neurodegenerative disease caused by amyloid β protein. A composition according to the above (31),
(34) The composition according to (33) above, wherein the neurodegenerative disease caused by amyloid β protein is Alzheimer's disease, and (35) the amyloid β protein production / secretion inhibitory effect containing compound (I ′). .

In the above formula, the “ring-assembled aromatic group” of the “ring-assembled aromatic group optionally having substituent (s)” represented by Ar is two or more (preferably 2 or 3) A group in which an aromatic ring is directly connected by a single bond and the number of bonds directly connecting the rings is one less than the number of ring systems by removing one arbitrary hydrogen atom from an aromatic ring assembly. Examples of the “aromatic ring” include an aromatic hydrocarbon, an aromatic heterocycle, and the like. Examples of the “aromatic hydrocarbon” include monocyclic or condensed polycyclic (bicyclic or tricyclic) aromatic hydrocarbons having 6 to 14 carbon atoms (eg, benzene, naphthalene, indene, anthracene, etc.), And quinones having 6 to 14 carbon atoms (eg, p-benzoquinone, 1,4-naphthoquinone, indane-4,7-dione, etc.) and the like. Examples of the “aromatic heterocycle” include a heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
And a 5- to 14-membered, preferably 5- to 10-membered aromatic heterocyclic ring containing at least one (for example, 1 to 4) aromatic heterocycle. Specifically, thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole,
Benzothiazole, benzisothiazole, naphtho [2,
3-b] thiophene, furan, phenoxatiin, pyrrole, imidazole, pyrazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine,
H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazane,
An aromatic heterocyclic ring such as phenoxazine or phthalimide, or a ring formed by condensing one or more (preferably one or two) aromatic rings (preferably one or two) with one or more (preferably one or two) aromatic rings. Ring and the like. Examples of the aromatic ring aggregate in which these aromatic rings are directly connected by a single bond include, for example, two or three (preferably 5 or 10 membered (preferably 5 or 6 membered) aromatic heterocyclic rings selected from a benzene ring, a naphthalene ring and Are two). Specific examples of the aromatic ring assembly include biphenyl, 2-phenylnaphthalene, p-terphenyl, o-terphenyl, m-terphenyl, 2-phenylpyridine, 3-phenylpyridine, 4-phenylpyridine, and 2-phenyl Thiophene, 3-phenylthiophene, 2-phenylindole, 3-phenylindole, 5-phenyloxadiazole and the like.
Preferably, an aromatic ring aggregate composed of two or three aromatic rings selected from benzene, thiophene, pyridine, pyrimidine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, naphthalene and benzofuran. is there. Specific examples of the “ring-assembled aromatic group” include 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 4- (2
-Thienyl) phenyl, 4- (3-thienyl) phenyl, 3- (3-pyridyl) phenyl, 4- (3-pyridyl) phenyl, 6-phenyl-3-pyridyl, 5-phenyl-1,3,4- Oxadiazol-2-yl, 4-
(2-naphthyl) phenyl, 4- (2-benzofuranyl) phenyl and the like. Of these, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl and the like are preferred. Particularly preferred is 4-biphenylyl.

As the "substituent" of the "ring-containing aromatic group optionally having substituent (s)", for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkylenediamine Oxy (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.), 5- to 7-membered saturated cyclic amino, acyl, acylamino, acyloxy, C _6-10 aryloxy (eg, phenyl Oxy, naphthyloxy, etc.). The “ring-assembled aromatic group” is, for example, the above-mentioned substituent at 1 to 5 positions that can be substituted on the ring-assembled aromatic group.
, Preferably 1 to 3, and when the number of substituents is 2 or more, each substituent may be the same or different.

The above-mentioned “optionally halogenated C _1-6”
The “alkyl” includes, for example, C _1-6 alkyl (eg, methyl, ethyl) that may have 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). , 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-trifluoro Propyl, isopropyl, butyl, 4,4,4-trifluorobutyl,
Isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like. The above "halogenated C
_3-6 cycloalkyl "includes, for example, 1 to 5,
Preferably one to three halogen atoms (eg, fluorine,
And C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) which may have chlorine, bromine, iodine, etc.). Specific examples include cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl and the like can be mentioned.
The aforementioned “optionally halogenated C _1-6 alkoxy”
Is, for example, 1 to 5, preferably 1 to 3
And C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, pentyloxy, etc.) which may have multiple halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). Specific examples include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, Pentyloxy, hexyloxy and the like can be mentioned. As the “optionally halogenated C _1-6 alkylthio”,
For example, C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio) which may have 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) Butylthio, sec-butylthio, tert-butylthio, etc.). Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-
Trifluorobutylthio, pentylthio, hexylthio and the like.

The "5- to 7-membered saturated cyclic amino" includes, for example, morpholino, thiomorpholino, piperazin-1-yl, 4-substituted piperazin-1-yl, piperidino, pyrrolidin-1-yl, hexamethylene-1 -Yl and the like. As the "substituent" of the "4-substituted piperazin-1-yl", for example C _1-6 alkyl, which may have a substituent C _6-14 aryl which may have a substituent C _7-19 aralkyl, 5- to 10-membered aromatic heterocyclic group _optionally having substituent (s), acyl and the like can be mentioned. "C _6-14 aryl _optionally having substituent (s)"
As the “C _6-14 aryl”, for example, phenyl, 1
-Naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl and the like. Preferred is phenyl and the like. The “C _7-19 aralkyl” of the “C _7-19 aralkyl _optionally having substituent (s)” includes, for example, benzyl, phenethyl, diphenylmethyl, triphenylmethyl,
-Naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl and the like. Preferred is benzyl and the like. As the “5- to 10-membered aromatic heterocyclic group” of the “5- to 10-membered aromatic heterocyclic group optionally having substituent (s)”, for example, 2-, 3- or 4-
Pyridyl, 1-, 2- or 3-indolyl, 2- or 3-thienyl and the like. Preferably, 2-,
3- or 4-pyridyl and the like. These “ _optionally substituted C _6-14 aryl”, “ _optionally substituted C _7-19 aralkyl” and “ _optionally substituted 5- to 10-membered” Examples of the “substituent” that the “aromatic heterocyclic group” may have include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.),
_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.),
1 to 5 di-C _1-6 alkylamino (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), carboxy and the like. “Optionally halogenated C _1-6 alkyl”, “optionally halogenated C _3-6 cycloalkyl”, “optionally halogenated C _1-6 alkoxy” and “halogenated Examples of the "C _1-6 alkylthio which may be substituted" include the same as those described above.

The "acyl" as the "substituent" of the "4-substituted piperazin-1-yl" and the "substituent" of the "ring-assembled aromatic group optionally having substituents""Acyl","acylamino" and "acyloxy"
"Acyl" in, for example, the formula ^{:-( C = O) -R 3,} - (C = O) -OR 3, - (C = O)
—NR ³ R ⁴ , — (C ＝ S) —NHR ³ , —SO ₂ —R ^3a or —SO—R ^3a wherein R ³ is a hydrogen atom or a hydrocarbon group which may have a substituent. Or an optionally substituted heterocyclic group, R
^3a is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R ⁴ is a hydrogen atom or C
Or _1-6 alkyl, or R ³ and R ⁴ may form a nitrogen-containing heterocyclic ring together with an adjacent nitrogen atom]. The “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R ³ or R ^3a represents a group obtained by removing one hydrogen atom from a hydrocarbon compound, and includes, for example, a chain or And cyclic hydrocarbon groups (eg, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, etc.).
Among them, the following chain or cyclic hydrocarbon groups having 1 to 16 carbon atoms are preferred. a) C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, hexyl, etc.), b) C _2-6 alkenyl (eg, vinyl, allyl, isopropenyl, 2-butenyl, etc.), c) C _2-6 alkynyl (eg, ethynyl, propargyl, 2-butynyl) D) C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
The C _3-6 cycloalkyl may be condensed with one benzene ring. E) C _6-14 aryl (for example, phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl and the like) F) _C7-19 aralkyl (e.g. benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4) -Phenylbutyl,
5-phenylpentyl and the like), preferably benzyl. Among them, C _1-6 alkyl, C _6-14 aryl, C _7-19 aralkyl and the like are preferable.

As the "substituent" of the "hydrocarbon group which may 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, etc.), di-C _1-6
Examples thereof include alkylamino (eg, dimethylamino, diethylamino, ethylmethylamino, etc.), acyl, acylamino, acyloxy, 5- to 7-membered saturated cyclic amino, sulfo, and an optionally substituted aromatic group. The “hydrocarbon group” may have, for example, 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions of the hydrocarbon group, and when the number of substituents is 2 or more, Each substituent may be the same or different. Examples of the “aromatic group optionally having a substituent” include the same as the “aromatic group optionally having a substituent” represented by Ar ′ described below. The "optionally halogenated C _1-6 alkyl", "optionally C _3-6 cycloalkyl which may be halogenated", "optionally halogenated C _1-6 alkoxy optionally", "halogenated Optionally substituted C _1-6 alkylthio ”,“ 5- to 7-membered saturated cyclic amino ”,“ acyl ”,“ acylamino ”and“ acyloxy ”are the aforementioned“ optionally substituted hydrocarbon group ” And the same as those described in detail in "Substituent". Such "acyl", "acylamino"
And "acyl" in "acyloxy" includes:
The Formula :-( C = O) -R ³ in, - (C = O) -OR 3, -
^{(C = O) -NR 3 R} 4, - (C = S) -NHR 3, -SO 2 -
In R ^3a or —SO—R ^3a , R ³ is (i) a hydrogen atom, (ii) a halogen atom as a substituent, C _1-3 alkylenedioxy, 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, di-C _1-6 alkylamino or carbon optionally having 1 to 5 sulfo A hydrogen group, or (iii) a halogen atom, a C _1-3 alkylenedioxy as a substituent,
Nitro, cyano, optionally halogenated C _1-6 alkyl optionally, optionally halogenated C _3-6 also be cycloalkyl, optionally halogenated C _1-6 alkoxy optionally,
Optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C
_A heterocyclic group optionally having 1 to 5 _1-6 alkylamino or C _6-10 aryloxy, wherein R ^3a is (i) a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, , a C _1-6 alkyl which may be halogenated, optionally halogenated C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy optionally, optionally C ₁ may be halogenated _-6 alkylthio, hydroxy, amino, mono--C _1-6 alkylamino, di -C _1-6
1 alkylamino or sulfo to 5 having hydrocarbon group which may be substituted or (ii) a halogen atom as a substituent, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _{1, -6} alkyl, optionally halogenated C _3-6 also be cycloalkyl, optionally halogenated C _1-6 alkoxy optionally, a C _1-6 alkylthio which may be halogenated, hydroxy, amino, mono - It is preferably a heterocyclic group which may have 1 to 5 C _1-6 alkylamino, di-C _1-6 alkylamino or C _6-10 aryloxy.

The "heterocyclic group" of the "heterocyclic group optionally having substituent (s)" for R ³ or R ^3a is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom. 5 or 14 membered (monocyclic, 2 ring or 3 ring) heterocycle containing 1 or 2 or 1 to 4 heteroatoms, preferably (i) 5 to 14 membered (preferably 5 to 10 membered) aromatic And a monovalent group formed by removing any one hydrogen atom from an aromatic heterocyclic ring, (ii) a 5- to 10-membered non-aromatic heterocyclic ring, or (iii) a 7- to 10-membered bridged heterocyclic ring. Examples of the “5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle” include, for example, thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3 -B] thiophene, furan, phenoxathiin, pyrrole, imidazole, pyrazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1
H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-
Carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazane, phenoxazine, phthalimide, or other aromatic heterocycle, or one or more of these rings (preferably a single ring) (preferably Is one or two)
And a ring formed by condensation with an aromatic ring (e.g., a benzene ring). Examples of the above "5- to 10-membered non-aromatic heterocycle" include pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine and the like. "7
Examples of the “10-membered bridged heterocyclic ring” include quinuclidine, 7-azabicyclo [2.2.1] heptane and the like.

The "heterocyclic group" is preferably a 5- to 10-membered member containing one or two, preferably one to four heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms. (Monocyclic or bicyclic) heterocyclic groups. Specifically, for example, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2-, 3-, 4-, 5- or 8-quinolyl,
-Isoquinolyl, pyrazinyl, 2- or 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl,
Aromatic heterocyclic groups such as -indolyl, 2-indolyl and 2-isoindolinyl, for example 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3
-Or 4-pyrazolidinyl, piperidino, 2-, 3-
Or 4-piperidyl, 1- or 2-piperazinyl,
And non-aromatic heterocyclic groups such as morpholino. Among them, for example, a compound containing one to three hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
A 6-membered heterocyclic group is more preferred. Specifically, 2-thienyl, 3-thienyl, 2-pyridyl, 3-thienyl
Pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-, 2- or 3-pyrrolidinyl, 2- or 4
-Imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1
-Or 2-piperazinyl, morpholino and the like.

The "heterocyclic group optionally having substituent (s)"
May have, for example, 1 to 5, preferably 1 to 3, substituents which may be possessed by the "ring-containing aromatic group optionally having substituent (s)". When the number of substituents is two or more, each substituent may be the same or different. The "substituent" of the "optionally substituted heterocyclic group" is "acyl", "acylamino" or "acyloxy"
In the case of “acyl” in “acyl”, “acylamino” and “acyloxy”, the above-mentioned formula:
^{(C = O) -R 3,} - (C = O) -OR 3, - (C = O) -NR
^{3 R 4, - (C =} S) -NHR 3, -SO 2 -R 3a or -
In SO-R ^3a , R ³ is (i) a hydrogen atom, (ii) a halogen atom as a substituent, C _1-3 alkylenedioxy,
Nitro, cyano, optionally halogenated C _1-6 alkyl optionally, optionally halogenated C _3-6 also be cycloalkyl, optionally halogenated C _1-6 alkoxy optionally,
Optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C
_A hydrocarbon group optionally having 1 to 5 _1-6 alkylamino or sulfo, or (iii) a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, halogenated as a substituent Good C _1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino A heterocyclic group optionally having 1 to 5 mono-C _1-6 alkylamino, di-C _1-6 alkylamino or C _6-10 aryloxy, wherein R ^3a is (i) halogen as a substituent Atom, C _1-3 alkylenedioxy, 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,
A mono-C _1-6 alkylamino, a di-C _1-6 alkylamino or a hydrocarbon group optionally having 1 to 5 sulfo, or (ii) a halogen atom, a C _1-3 alkylenedi oxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6 also be cycloalkyl, optionally halogenated C _1-6 alkoxy optionally, halogenated Heterocycle optionally having 1 to 5 C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino or C _6-10 aryloxy Is preferred. “C _1-6 alkyl” represented by R ⁴
Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. Examples of the “nitrogen-containing heterocycle” formed by R ³ and R ⁴ together with an adjacent nitrogen atom include, for example, one to three nitrogen atoms containing at least one nitrogen atom in addition to a carbon atom and selected from nitrogen, sulfur and oxygen atoms And a 5- to 7-membered nitrogen-containing heterocyclic ring which may contain a hetero atom such as piperidine, morpholine, thiomorpholine, piperazine and pyrrolidine.

The above-mentioned “acyl” is preferably formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxy) Carbonyl, tert-butoxycarbonyl, etc.), C _6-10 aryl-carbonyl (eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C _6-10 aryloxy-carbonyl (eg, phenoxycarbonyl, etc.), C _{7- 16} aralkyloxy-carbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.), 5- to 6-membered heterocyclic carbonyl (eg, nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, morpholinocarbonyl , Piperidino carbo Nyl, 1-pyrrolidinylcarbonyl, etc.), mono-C _1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethyl) Methylcarbamoyl, etc.), C _6-10 aryl-carbamoyl (eg, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), 5- to 6-membered heterocyclic carbamoyl (eg, 2-pyridylcarbamoyl, 3-
Pyridylcarbamoyl, 4-pyridylcarbamoyl, 2
- thienylcarbamoyl, 3-thienylcarbamoyl, etc.), C _1-6 alkylsulfonyl (e.g., methylsulfonyl, ethyl etc. sulfonyl), C _6-10 arylsulfonyl (e.g., benzenesulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl, etc. ).

The above-mentioned “acylamino” includes, for example,
Said include amino to 1 in the "acyl" described in detail which is two substituents at the "substituent" of the "ring assembly aromatic group optionally having a substituent" is preferably the formula: -NR ⁵ COR ⁶ , —NR ⁵ COOR ^6a or —N
R ⁵ SO ₂ R ^6a wherein R ⁵ is a hydrogen atom or C _1-6 alkyl, R ⁶ is a hydrogen atom, a hydrocarbon group which may have a substituent or a substituent which may have a substituent And a heterocyclic group, R ^6a represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent. "C _1-6 alkyl" represented by R ⁵ include the same "C _1-6 alkyl" represented by R ^4.
The “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R ⁶ or R ^6a include the “substituted or substituted heterocyclic group” represented by R ³ And the "optionally substituted hydrocarbon group" and the "optionally substituted heterocyclic group". As the “acylamino”, preferably, formylamino, C _1-6 alkyl-carboxamide (eg, acetamide and the like), 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, methylsulfonyl) Amino, ethylsulfonylamino and the like).

The above-mentioned “acyloxy” includes, for example,
Said include oxy substituted by one "acyl" described in detail in the "substituent" of the "optionally optionally ring assembly aromatic group which may have a substituent" is preferably the formula: -O-COR ⁷ , -O-COOR ⁷ or -OC
Acyloxy represented by ONHR ⁷ [wherein R ⁷ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent]. Represented by R ⁷ and "optionally substituted hydrocarbon group", "optionally substituted heterocyclic group" may have a "substituent represented by R ³ The same groups as the “good hydrocarbon group” and “heterocyclic group optionally having substituent (s)” are exemplified. As "acyloxy", preferably,
C _1-6 alkyl-carbonyloxy (eg, acetoxy,
C _6-10 aryl-carbonyloxy (eg, 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, etc.), C
_6-10 aryl-carbamoyloxy (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.),
Nicotinoyloxy and the like. As "substituent" of the "optionally substituted ring assembly aromatic group" represented by Ar, preferably a halogen atom, C _1-3 alkylene Nji oxy, nitro, cyano, optionally halogenated 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.

The "condensed aromatic group" of the "condensed aromatic group optionally having substituent (s)" represented by Ar is a condensed polycyclic (preferably bi- to tetra-cyclic, preferably bi- or tri-cyclic) Formula) 1 formed by removing any one hydrogen atom from an aromatic ring
Represents a valence group. Examples of the “condensed polycyclic aromatic ring” include a condensed polycyclic aromatic hydrocarbon, a condensed polycyclic aromatic heterocycle, and the like. As the "condensed polycyclic aromatic hydrocarbon",
For example, a fused polycyclic (bi- or tricyclic) aromatic hydrocarbon having 10 to 14 carbon atoms (eg, naphthalene, indene,
Anthracene). As the "fused polycyclic aromatic heterocycle", for example, a 9 to 14 member containing one or more (for example, 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom; Preferably, a 9- or 10-membered condensed polycyclic aromatic heterocycle is exemplified. Specifically, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, isoquinoline, quinoline, indole, quinoxaline, phenanthridine, phenothiazine, phenoxazine, phthalimide and the like And an aromatic heterocycle. Specific examples of the “condensed aromatic group” include 1-naphthyl, 2
-Naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-benzofuranyl, 2-benzothiazolyl, 2-
Benzimidazolyl, 1-indolyl, 2-indolyl, 3-indolyl and the like, preferably 1-indolyl
Naphthyl, 2-naphthyl and the like. As the `` substituent '' of the `` condensed aromatic group which may have a substituent '',
The same number of "substituents" as the "substituent" of the "ring-substituted aromatic group optionally having substituent (s)" represented by Ar is mentioned. Ar is preferably a ring-assembled aromatic group which may have a substituent. Among them, the ring-assembled aromatic group is benzene, thiophene, pyridine, pyrimidine, 1,2,
4-oxadiazole, 1,3,4-oxadiazole,
2 or 3 selected from naphthalene and benzofuran
Groups consisting of two aromatic rings are more preferred, with 2-, 3- or 4-biphenylyl being particularly preferred. Preferred examples of Ar include a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated 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, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl -
Carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5 or 6
Membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _{6 -10} arylsulfonyl, formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _1-6 alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy,
Ring assembled aromatic optionally having 1 to 3 substituents selected from di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy Group. this house,
More preferably, a halogen atom, C _1-3 alkylene Nji oxy, nitro, cyano, optionally halogenated C _1-6 alkyl, C _1-6 alkoxy optionally halogenated and halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl , C _1-6 alkoxy-carbonyl,
C _6-10 aryl-carbonyl, C _{6-10 aryloxy-}
Carbonyl, C _7-16 aralkyloxy-carbonyl, 5
Or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-
Carbamoyl, di-C _1-6 alkyl-carbamoyl, C
_6-10 aryl - carbamoyl, 5 or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _{1 -6} alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _6-10 aryl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyl Oxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10
2-, 3- or 4-biphenylyl (preferably 4-biphenylyl) which may have 1 to 3 substituents selected from aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy.

The “aromatic group” of the “aromatic group optionally having substituent (s)” represented by Ar ′ includes, for example, a monocyclic aromatic group, a ring-assembled aromatic group, a condensed aromatic group and the like. Is mentioned. The “ring-assembled aromatic group” and “condensed aromatic group”
Is the same as the “ring-assembled aromatic group” and “condensed aromatic group” described in detail in the above Ar. Examples of the “monocyclic aromatic group” include a monovalent group formed by removing any one hydrogen atom from a benzene ring or a 5- or 6-membered aromatic heterocycle. "5 or 6
As the "membered aromatic heterocycle", for example, a 5- or 6-membered aromatic heterocycle containing one or more (for example, 1 to 3) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom, and the like can be mentioned. Can be Specific examples include thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine and the like. Specific examples of the “monocyclic aromatic group” include phenyl, 2- or 3-thienyl, 2- or 3-furyl,
1-, 2- or 3-pyrrolyl, 2- or 4-imidazolyl, 3- or 4-pyrazolyl, 2-, 3- or 4-pyridyl, 2-pyrazinyl, 2-, 4- or 5-
Pyrimidinyl, 3- or 4-pyridazinyl and the like. As the "substituent" of the "aromatic group which may have a substituent", the "substituent" of the "ring-containing aromatic group optionally having a substituent" represented by Ar The same number is the same. Ar ′ is preferably a ring-assembling aromatic group which may have a substituent and a condensed aromatic group which may have a substituent. More preferably, it is a ring aggregated aromatic group which may have a substituent.

The “C _1-6 alkylene” of the “C _1-6 alkylene _optionally having 1 to 3 substituents selected from oxo and C _1-6 alkyl” represented by X includes, for example, −CH ₂ −, − (CH ₂ ) ₂ −, − (CH ₂ ) ₃ −, − (CH ₂ )
₄ -,-(CH ₂ ) ₅ -,-(CH ₂ ) _6- and the like. As "C _2-6 alkenylene" in the "oxo and C _1-6 selected substituents 1 to good C _2-6 alkenylene optionally having three alkyl" represented by X, for example, -CH
_{= CH -, - CH 2 -CH} = CH -, - CH 2 -CH = CH-CH 2 -, - C
H ₂ -CH ₂ -CH = CH-, -CH = CH-CH = CH-, -CH = CH-C
_{H 2 -CH 2 -CH 2 -,} - CH 2 -CH 2 -CH 2 -CH 2 -CH = CH- , and the like. As "C _2-6 alkynylene" of "oxo and C _1-6 selected substituents 1 to good C _2-6 alkynylene optionally having three alkyl" represented by X,

Embedded image Is mentioned. The above-mentioned oxo and C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) have 1 to 3 substitutions at substitutable positions. And when the number of substituents is two or more, each substituent may be the same or different. Examples of the “hydrocarbon group optionally having substituent (s)” and “acyl” represented by R ⁸ include the same as those described in detail above. R ⁸ is
Preferably a hydrogen atom, an optionally halogenated C
_1-6 alkyl, C _1-6 alkyl-carbonyl and the like.

[0033] As X, preferably, C _1-6 alkylene _{(e.g., -CH 2 -, - (CH} 2) 2 -, - (CH 2) 3 -, - (CH 2) 4 -,
− (CH ₂ ) ₅ −, − (CH ₂ ) ₆ − etc.), Formula: − (CH ₂ ) p−X
^{_{1 -, - SO 2 -NR 8}} - wherein each symbol is as defined above] is a group represented by like. X ¹ is O or
NR ⁸ (preferably O) and R ⁸ are preferably a hydrogen atom or a C _1-3 alkyl-carbonyl (eg, acetyl and the like). X is preferably 2 which may be via an oxygen atom.
Divalent C _1-6 aliphatic hydrocarbon group (eg, C _1-6 alkylene, C
_2-6 alkenylene, C _2-6 alkynylene, etc.), more preferably, C _1-3 alkylene, —CH ₂ —O—, and the like.

The “oxygen or sulfur atom” of the “divalent C _1-6 aliphatic hydrocarbon group which may be via an oxygen atom or a sulfur atom and may have a substituent” for Y A divalent C _1-6 aliphatic hydrocarbon group which may be _interposed
As a saturated or unsaturated divalent C 1 or C 2, which may contain, for example, one or two, preferably one, oxygen atom or sulfur atom between carbon atoms or at any terminal position.
_{1-6 represents an} aliphatic hydrocarbon group. Specific examples include C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene,
Formula:-(CH ₂ ) m-Y ^1- (CH ₂ ) n- wherein -Y ¹ -is
-O -, - S -, - SO- or -SO ₂ -, m is 0
An integer of 1 to 5, n represents an integer of 1 to 5, and m + n represents an integer of 1 to 5].
Preferably, it is a divalent C _1-6 aliphatic hydrocarbon group. The “C _1-6 alkylene”, “C _2-6 alkenylene” and “C _2-6 alkynylene” are the same as “C _1-6 alkylene”, “C _2-6 alkenylene” and “C _{2-6 2-6} alkynylene ".

Examples of the “substituent” of the “divalent C _1-6 aliphatic hydrocarbon group which may be via an oxygen atom or a sulfur atom and may have a substituent” include, for example, C _{1 -6} alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
Pentyl, hexyl, etc.). The substituent may be substituted by 1 to 3 substituents at a substitutable position of the divalent C _1-6 aliphatic hydrocarbon group. When the number of substituents is 2 or more, each substituent is the same or different. May be.
Y is preferably a divalent C _1-6 aliphatic hydrocarbon group, more preferably C _1-6 alkylene.

The “lower alkyl” of the “lower alkyl optionally having substituent (s)” for R ¹ or R ² includes, for example, C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl) , Isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.). Preferred are methyl, ethyl and propyl. The `` lower alkyl optionally having substituent (s) '' is
For example, (1) a substituent which the above-mentioned “ring-assembled aromatic group optionally having” may have, or (2) C _6-10
It may have 1 to 5, preferably 1 to 3, aryl. When the number of substituents is two or more, each substituent may be the same or different. Examples of the “nitrogen-containing heterocycle” of the “nitrogen-containing heterocycle optionally having substituent (s)” formed by R ¹ and R ² together with an adjacent nitrogen atom include, for example, at least one nitrogen atom other than a carbon atom. And a 3- to 8-membered nitrogen-containing heterocyclic ring which may contain 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Specific examples include aziridine, azetidine,
Morpholine, thiomorpholine, piperidine, piperazine, pyrrolidine, hexamethyleneimine, heptamethyleneimine or an unsaturated cyclic amine thereof (eg, 1,
2,5,6-tetrahydropyridine and the like. Of these, morpholine, piperidine, piperazine,
Pyrrolidine and the like are preferred. The “nitrogen-containing heterocycle optionally having substituent (s)” includes (1) the “substituent” of the above “hydrocarbon group optionally having substituent (s)”, (2) oxo and (3) C _7-19 Substituents 1-3 selected from aralkyl
It may have a piece. Preferred substituents include, for example, C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.), 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.), 5- to 7-membered saturated cyclic amino (eg, morpholino, Piperazin-1-yl,
Piperidino, pyrrolidin-1-yl, hexamethyleneimin-1-yl and the like), C _1-6 alkyl-carboxamide (eg, acetamide and the like), C _1-6 alkoxy-carboxamide (eg, methoxycarboxamide, ethoxycarboxamide and the like), An aromatic group which may have a substituent (eg, a halogen atom, cyano, C _1-6 alkyl and C
C _6-10 aryl optionally having 1 to 3 substituents selected from _1-6 alkoxy (preferably phenyl, 1- or 2-naphthyl) or 5- or 6-membered aromatic heterocyclic group (Preferably, 2-, 3- or 4-pyridyl), oxo and the like. R ¹ and R ² are preferably C _1-6 alkyl.

The above "group represented by the formula -X-Ar"
Is substituted at a substitutable position of the ring A. "Substituent of" benzene ring which may further have a substituent in addition to the group represented by the formula -X-Ar (wherein each symbol has the same meaning as described above) "represented by ring A" Examples of "" include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), optionally halogenated C _1-6 alkyl, optionally halogenated C _1-6 alkoxy, hydroxy, amino and the like. Is mentioned. The "optionally halogenated C"
_1-6 alkyl "and" optionally halogenated C
_1-6 alkoxy "include respectively those similar to the" C _1-6 alkyl which may be halogenated ", and" optionally halogenated C _1-6 alkoxy optionally "as detailed in the Ar . One to three of these substituents may be substituted at substitutable positions of the ring A, and when the number of substituents is two or more, each substituent may be the same or different. Ring A is preferably a benzene ring substituted only with a group represented by the formula -Ar-X.

The “group represented by the formula —Y—NR ¹ R ² ” is substituted at a substitutable position of the ring B. A 4- to 8-membered group which may further have a substituent in addition to the group represented by the formula -Y-NR ¹ R ² (wherein each symbol is as defined above) represented by ring B The “4- to 8-membered ring” of the “ring” may contain one double bond other than the portion fused to the ring A, and is selected from an oxygen atom, a nitrogen atom and a sulfur atom other than a carbon atom Mention may be made of 4- to 8-membered homo- or heterocycles which may contain 1 to 3 heteroatoms. As a specific example, the expression

Embedded image Z represents (i) a bond, (ii) C _1-4 alkylene, (iii) C
_{2-4 alkenylene, (iv) -O-CH 2} -, (v) -O-C
H ₂ —CH ₂ — or (vi) a ring represented by the formula —NR ^8a —CH ₂ — or —NR ^8a —CH ₂ —CH ₂ — wherein R ^8a has the same meaning as R ⁸ described above. Is mentioned. R ^8a is preferably a hydrogen atom, optionally halogenated C _1-6 alkyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryl Oxy-carbonyl, C _7-16 aralkyloxy-
Carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C
_1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5 or 6
Membered carbamoyl, C _1-6 alkylsulfonyl or C _6-10 arylsulfonyl. More preferred are a hydrogen atom, optionally halogenated C _1-6 alkyl, C _1-6 alkyl-carbonyl and C _1-3 alkylsulfonyl. Z is preferably C _1-3 alkylene,
—NR ^8a —CH ₂ — and the like. More preferably, it is ethylene. The “4- to 8-membered ring” is preferably a group represented by the formula

Embedded image [Wherein, Z is as defined above]. Preferably, it is a 6-membered homo- or heterocyclic ring which does not contain a double bond except at the portion fused to the ring A and which may contain one oxygen atom or imino other than a carbon atom. "Substitution of 4- to 8-membered ring which may further have a substituent in addition to the group represented by the formula -Y-NR ¹ R ² (wherein each symbol has the same meaning as described above)" Examples of the “group” include oxo, C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), hydroxy and the like. The substituent is 1 at a substitutable position.
Three to three substituents may be substituted, and when the number of substituents is two or more, each substituent may be the same or different. B
The ring is preferably a 6-membered homo- or heterocyclic ring substituted only with a group represented by the formula -Y-NR ¹ R ² (wherein each symbol has the same meaning as described above). In addition, the ring B has the formula

Embedded image Wherein Za is C _1-3 alkylene or a formula —NR ^8c —C
H ₂ — (wherein R ^8c is a hydrogen atom, optionally halogenated C _1-6 alkyl, C _1-6 alkyl-carbonyl,
_1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl , Di-C _1-6
Alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl or C _6-10 arylsulfonyl), and other symbols are as defined above. Are also preferred. Of these, Za is preferably ethylene. The fused ring formed by the ring A and the ring B is preferably a compound represented by the formula

Embedded image Is a ring represented by

In compound (I) and compound (I '), Ar
And Ar ′ are a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated 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 and C _1-6 alkyl - to the substituents 1 are selected from carboxamide 3
Ring-assembled aromatic groups (preferably 2
-, 3- or 4-biphenylyl), X is C _1-3 alkylene optionally interposed by an oxygen atom, Y is C _1-6 alkylene, R ¹ and R ² are each C _1-6 alkyl, and ring A is formula
A benzene ring having only a group represented by -X-Ar (wherein the definitions of the symbols are as defined above), and a ring B having the formula -Y-NR
^A compound which is a 6-membered homo- or heterocyclic ring having only a group represented by ¹ R ² (wherein the definition of each symbol is as defined above) is preferable. More preferably, the formula

Embedded image Wherein R ⁰ is 1 to 3 halogen atoms, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _1- Selected from ₆ alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, formyl and C _1-6 alkyl-carboxamide Substituent,
R ^1a and R ^2a are each C _1-6 alkyl]. Also, the formula

Embedded image Wherein, Ar ^a is (i) a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, C _1-6 alkoxy optionally halogenated 2-, 3- or 4-biphenylyl optionally having 1 to 3 substituents selected from optionally halogenated C _1-6 alkylthio, amino, formyl and C _1-6 alkyl-carboxamide , (Ii) 4-
(2-thienyl) phenyl or 4- (3-thienyl)
Phenyl, (iii) 4- (3-pyridyl) phenyl, (i
v) 6-phenyl- optionally having C _1-6 alkoxy
3-pyridyl, (v) 5-phenyl-1,3,4-oxadiazol-2-yl, (vi) 4- (2-naphthyl) phenyl, (vii) 4- (2-benzofuranyl) phenyl, (vii) vii
i) 1- or 2-naphthyl, (ix) 2-quinolyl, (x)
2-benzothiazolyl or (xi) 2-benzofuranyl; X 'is _{-CH 2 -O -, - SO 2} -NH- or formula -
A group represented by CH ₂ —NR ⁸ ′-, wherein R ⁸ ′ is a hydrogen atom or C _1-3 alkyl-carbonyl; Y ′ is C _1-6
Alkylene; Z ′ is —CH ₂ —CH ₂ — or a formula —N
A group represented by R ⁸ ″ —CH ₂ — (wherein R ⁸ ″ is a hydrogen atom, C _1-3 alkyl, C _1-3 alkyl-carbonyl or C _1-3 alkylsulfonyl); and R ¹ 'and R ² '
Is a C _1-6 alkyl optionally having 1 to 5 substituents selected from di-C _1-3 alkylamino, C _1-3 alkoxy-carbonyl and phenyl, or R ¹ ′
And R ² ′, together with the adjacent nitrogen atom,
_1-3 forms pyrrolidin-1-yl, piperidino or piperazin-1-yl which may have 1 to 3 substituents selected from alkoxy-carbonyl, piperidino, phenyl and benzyl, respectively. Compounds are also preferred. More preferably, 6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, 6- (4-biphenylyl) methoxy-2- (N, N-dimethylamino) methyl Tetralin, 2- (N, N-dimethylamino) methyl-6
(4'-methoxybiphenyl-4-yl) methoxytetralin, (+)-6- (4-biphenylyl) methoxy-
2- [2- (N, N-dimethylamino) ethyl] tetralin, (+)-6- (4-biphenylyl) methoxy-2
-[2- (N, N-diethylamino) ethyl] tetralin, (+)-2- [2- (N, N-dimethylamino) ethyl] -6- (4'-methylbiphenyl-4-yl) methoxytetralin , (+)-2- [2- (N, N-dimethylamino) ethyl] -6- (4'-methoxybiphenyl-4-yl) methoxytetralin, (+)-6
(2 ′, 4′-dimethoxybiphenyl-4-yl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, (+)-6- [4- (1,3-benzodioxy) Sole-5-yl) phenyl] methoxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin,
(+)-6- (3 ', 4'-dimethoxybiphenyl-4-
Yl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin and salts thereof.

Examples of the salts of compound (I) and compound (I ′) include salts with inorganic bases, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic and acidic salts. And salts with amino acids. 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, magnesium salt and barium salt; aluminum salt and the like. Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like. Preferred examples of the salt with an inorganic acid include, for example, 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, p -Salts with toluenesulfonic acid and the like. Preferable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. It is. Of these, pharmaceutically acceptable salts are preferred. For example, when the compound (I) or (I ′) has an acidic functional group, an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium) Salts, etc.), ammonium salts, etc.,
When the compound (I) or (I ') has a basic functional group, an inorganic salt such as hydrochloride, sulfate, phosphate, hydrobromide or acetate, maleate, fumaric acid salt,
Organic salts such as succinate, methanesulfonate, p-toluenesulfonate, citrate, tartrate and the like can be mentioned.

The production method of compound (I) is described below. Compound (I) can be produced by a method known per se, for example, by the methods shown in the following production methods 1 to 4. Compound (I ′) is produced according to the method for producing compound (I). The compounds described in the following production methods 1 to 4 also include cases in which salts are formed, and examples of the salts include the same as the salts of compound (I). “Room temperature” indicates 0 to 30 ° C. For example, in the compound (I), X is an oxygen atom, an optionally oxidized sulfur atom (S, SO, SO ₂ ) or a group represented by the formula NR ⁸ (R ⁸ has the same meaning as described above). When the compound is contained, compound (I) is produced according to the following production method. When X does not contain an oxygen atom, a sulfur atom which may be oxidized, and NR ⁸ , it can be similarly produced. Each symbol in the chemical structural formulas described in the scheme has the same meaning as described above unless otherwise specified. Manufacturing method 1

Embedded image In the above formulas, Xa represents a group in which an oxygen atom, represented a good sulfur atom or the formula NR ⁸ be oxidized.

(Step 1) Compound (II) is subjected to an alkylation reaction or an acylation reaction to obtain compound (Ia). The “alkylation reaction” and the “acylation reaction” can be performed by a method known per se, for example, an organic functional group preparations (ORGANIC FUNCTIONAL GROUP).
PREPARATIONS) Second Edition, Academic Press (ACADE)
MIC PRESS, INC.) According to the method described in 1989 and the like. Specifically, compound (II) and a compound of the formula Ar-Xb-L
[Wherein Xb is a group obtained by removing Xa from X, and L represents a leaving group or hydroxy] to obtain a compound (Ia). As the "leaving group" represented by L,
For example, it has a halogen atom (eg, chloro, bromo, iodo, etc.), optionally halogenated C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), and a substituent. And _optionally C _6-10 arylsulfonyloxy. Examples of the "substituent" of the "C _6-10 arylsulfonyloxy optionally having substituents", 1 to 3 halogen atoms, a C _1-6 alkyl or C ₁ may be halogenated _-6 alkoxy and the like. "C optionally having substituent (s)
Specific examples of " _6-10 arylsulfonyloxy" include benzenesulfonyloxy, p-toluenesulfonyloxy, 1-naphthalenesulfonyloxy, 2-naphthalenesulfonyloxy and the like. Compound (II) can be produced by a method known per se, for example, a method of the following schemes 2 to 4 or a method analogous thereto. For example, when L is a leaving group, compound (II) and an equivalent to excess amount of the formula Ar
A compound represented by -Xb-L (wherein each symbol is as defined above) is reacted in an inert solvent. If necessary, a base is added to carry out the reaction. If Xa is NR ^8, bases is not always necessary. The reaction temperature is −20 ° C. to 100 ° C., preferably room temperature (0 ° C. to 30 ° C.) to 80 ° C.). The reaction time is 0.5 hours to 1 day. As the inert solvent,
For example, an alcohol solvent, an ether solvent, a halogenated hydrocarbon solvent, an aromatic solvent, a nitrile solvent, an amide solvent, a ketone solvent, a sulfoxide solvent, water alone, or a mixture of two or more of these. Can be used. Among them, acetonitrile, N, N-dimethylformamide (DMF), acetone, ethanol, pyridine and the like are preferable. Examples of the “base” include 1) 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,
Strong bases such as sodium hexamethyldisilazide and potassium hexamethyldisilazide), lower alkoxides of alkali metals or alkaline earth metals (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide); 2) For example, 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, carbonate Inorganic bases such as potassium carbonate, cesium carbonate, etc., hydrogen carbonates of alkali metals or alkaline earth metals (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.); and 3) for example, triethylamine, diisopropylethylamine, N-methylmorpholine, dimethyl Aminopyridine, BU (1,8- diazabicyclo [5.4.0] undec -7
Amines such as -ene) and DBN (1,5-diazabicyclo [4.3.0] non-5-ene), and organic bases such as basic heterocyclic compounds such as pyridine, imidazole and 2,6-lutidine. No. Preferred reaction conditions are
For example, in the case of an alkylation reaction, compound (II), 1 equivalent to
A compound represented by 2 equivalents of the formula Ar-Xb-L (wherein each symbol is as defined above) and 1 to 5 equivalents of a base (eg, potassium carbonate, sodium hydride, sodium hydroxide, etc.) 1 hour to 20 in acetonitrile or DMF
Stir for hours. The preferred reaction temperature varies depending on the base used. For example, when sodium hydride is used, room temperature is used, and when potassium carbonate is used, room temperature to 80 ° C. is preferable. Preferred reaction conditions are, for example, for an acylation reaction,
Compound (II), 1 equivalent to 1.5 equivalents of the formula Ar-Xb-L
Wherein each symbol in the formula is as defined above, and 1 to 5 equivalents of a base (e.g., sodium hydride,
Sodium hydroxide, potassium carbonate, sodium bicarbonate, triethylamine, etc.) with an inert solvent (eg, water,
In ethyl acetate, DMF, acetonitrile, pyridine alone or a mixed solvent of two or more thereof), the mixture is stirred at room temperature for 1 hour to 6 hours.

When L is hydroxy, compound (II) is subjected to the Mitsunobu reaction. The Mitsunobu reaction is represented by, for example, the compound (II) and 1 to 3 equivalents (preferably 1.1 to 2 equivalents) of the formula Ar-Xb-L, wherein each symbol is as defined above. A method in which a compound is stirred in an inert solvent for 1 to 24 hours in the presence of 1 to 2 equivalents of a triarylphosphine (eg, triphenylphosphine) and 1 to 2 equivalents of DEAD (diethyl azodicarboxylate). No. Examples of the inert solvent include ether solvents and the like. Preferably, tetrahydrofuran (THF) is used.
It is.

[0044]

Embedded image In the above formula, W represents a hydrogen atom or a protecting group, and Ya represents a group obtained by removing methylene from Y. As the “protecting group” represented by W, the same as the “protecting group for hydroxy” described below can be mentioned. W is preferably C _1-6 alkyl, optionally substituted benzyl. (Step 2) Compound (III) is subjected to an amidation reaction to obtain compound (IV). Compound (III) is a known compound that can be easily obtained.
No. 96552, Japanese Patent Application Laid-Open No. 6-206581, or Journal of Medicinal Chemistry (J.
Med. Chem.), P. 1326, 1989, and the like. Also, in the compound (III), Xa is a typical example of a compound in which X is an oxygen atom and W is methyl (1) 1,
2,3,4-tetrahydro-6-methoxynaphthalene-2
A method for synthesizing acetic acid is described in, for example, Synthetic Communications (Synth. Commun.) 11, 803-809, 1981.
For example, the method of synthesizing (2) 1,2,3,4-tetrahydro-6-methoxynaphthalene-2-carboxylic acid and 1,2,3,4-tetrahydro-6-methoxynaphthalene-2-butyric acid is as follows: Journal of Chemical Society Perkin Transaction I (J. Chem. Soc. Perkin Tra
ns. I) pp. 1889-1893, 1976, respectively. Also, in the compound (III), 6-amino-1,2,3,4-tetrahydro-naphthalene-2-, which is a typical example of a compound in which Xa is an imino and W is a hydrogen atom,
The method for synthesizing carboxylic acid and its ethyl ester is described in Zh
ur. Obschch. Khim., p. 1446, 1952 and the like. In addition, compound (III) is a compound of the formula: 7-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-3-acetic acid or 8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H In the case of -1-benzazepine-4-carboxylic acid, Journal of American Chemical Society (J. Am. Chem. Soc.), Vol. 77, 5932-5933.
P., 1995, prepared according to the method described in 7-Methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-
In the case of 3-carboxylic acid, it is produced according to the method described in JP-A-7-126267.

The above-mentioned “amidation reaction” may be carried out according to a method known per se. For example, (1) compound (III) and compound represented by the formula HNR ¹ R ² in the presence of a dehydrating condensing agent And (2) a method of reacting a reactive derivative of compound (III) with a compound represented by the formula HNR ¹ R ² . In the above reaction (1), the compound (III), 1 equivalent to 5 equivalents of the compound represented by the formula HNR ¹ R ² and 1 equivalent to 2 equivalents of the dehydration condensing agent are added in an inert solvent at room temperature for 10 hours to Incubate for 24 hours. If necessary, the reaction may be carried out by adding 1 to 1.5 equivalents of 1-hydroxybenzotriazole (HOBT) and / or 1 to 5 equivalents of a base (eg, triethylamine and the like). Examples of the “dehydration condensing agent” include dicyclohexylcarbodiimide (DCC), 1-ethyl-3
-(3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) and the like. Among them, WSC is preferable. Examples of the inert solvent include nitrile solvents (preferably acetonitrile), amide solvents (preferably DMF), halogenated hydrocarbon solvents (preferably dichloromethane), and ether solvents (preferably TH).
F) alone or a mixture of two or more of them. In the above reaction (2), a reactive derivative of the compound (III) and 1 to 5 equivalents (preferably 1 to 3 equivalents) of the compound represented by the formula HNR ¹ R ² are reacted in an inert solvent at −20 ° C. ５０50 ° C. (preferably room temperature), 5 minutes to 40 hours (preferably 1 hour to 18 hours). If necessary, the reaction may be carried out in the presence of 1 to 10 equivalents, preferably 1 to 3 equivalents of a base. Examples of the “reactive derivative” of the compound (III) 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 acid anhydride with C _1-6 alkyl carbonic acid, etc.), active ester (eg, optionally substituted phenol, 1-hydroxybenzotriazole or N
-Esters with hydroxysuccinimide, etc.). As the "substituent" of the "phenol which may have a substituent", halogen atom, nitro, it is a C _1-6 alkyl or halogenated optionally halogenated C _1-6 Alkoxy includes 1 to 5 alkoxy groups. Specific examples of “phenol that may have a substituent” include phenol, pentachlorophenol, pentafluorophenol, p-nitrophenol, and the like. The reactive derivative is preferably an acid halide. As the “base”, those similar to the base described in detail in Step 1 above can be mentioned. Preferably, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine And so on. 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 may be used alone or as a mixture of two or more thereof. it can. Among them, acetonitrile, dichloromethane, chloroform and the like are preferable.

(Step 3) Compound (IV) is subjected to a reduction reaction to obtain compound (V). The reduction reaction can be carried out by a method known per se, for example, ORGANIC FUNCTIONAL GROUP P.
REPARATIONS) 2nd edition, Academic Press (ACADEMI)
C PRESS, INC.) According to the method described in 1989 and the like. Specifically, (1) a method of reacting compound (IV) with a metal hydride, (2) a method of reacting compound (IV) with a metal, or (3) a method of reacting compound (IV) with a catalytic reduction reaction And the like. In the above reaction (1),
Compound (IV) and 1 to 20 equivalents (preferably 1 to 6 equivalents) of a metal hydride are reacted in an inert solvent. As the “metal hydride”, for example, aluminum hydride, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium cyanoborohydride, borane complex (eg, borane-THF complex, Catecholborane, etc.),
Examples include dibutylaluminum hydride, and mixtures of these metal hydrides with Lewis acids (eg, aluminum chloride, titanium tetrachloride, cobalt chloride, etc.) or phosphorus oxychloride. Preferred metal hydrides include
Examples thereof include lithium aluminum hydride and aluminum hydride. Examples of the inert solvent include ether solvents. The reaction temperature varies depending on the metal hydride used, but is usually from -70 ° C to 100 ° C, and from room temperature to 80 ° C when lithium aluminum hydride is used. When a borane complex is used, the temperature is from room temperature to 100 ° C, preferably from room temperature to 60 ° C. The reaction time ranges from 1 hour to 48 hours. In the above reaction (2), compound (IV) and 1 equivalent to
20 equivalents (preferably 2 to 6 equivalents) of the metal are reacted in an inert solvent. Examples of the “metal” include zinc, iron, sodium, and potassium. Examples of the inert solvent include organic acids (eg, acetic acid, propionic acid, methanesulfonic acid, etc.), ether solvents, and aromatic solvents. Solvents, hydrocarbon solvents and the like may be used alone or in combination of two or more. Preferred are ether solvents. The reaction temperature depends on the metal used, but is usually -7.
0 ° C to 100 ° C, and room temperature to 80 ° C when zinc is used. The reaction time is 1 hour to 10 hours. In the above reaction (3), compound (IV), a catalyst amount of 10 equivalents of a metal catalyst (eg, Raney nickel) and a phosphorus sulfide compound (eg, phosphorus pentasulfide, phosphorus sulfide, etc.) are reacted with an inert solvent (eg, alcohol). The reaction is carried out at room temperature to 100 ° C. under a hydrogen pressure of 1 to 100 atm for 1 to 48 hours. In this step 3, by selecting the reaction conditions, the functional groups such as carbonyl and lactam present in the molecule of compound (IV) can be reduced to hydroxy, cyclic amino and the like, respectively. For example, when the condensed ring formed by ring A and ring B of compound (IV) is 2-oxo-1,2,3,4-tetrahydroquinoline or 2-oxo-2,3,4,5-tetrahydro-1H- In the case of 1-benzazepine, 1,2,3,4-tetrahydroquinoline and 2,3,4,5-tetrahydro-
1H-1-Benzazepine is obtained respectively. Specifically, compound (IV) and 1 equivalent to excess amount, preferably 1 equivalent to 5 equivalents, of a borane complex are mixed in an ether solvent at room temperature to 100 ° C, preferably at room temperature to 60 ° C, for 0.1 hour to 4 hours.
The reaction is carried out for 8 hours, preferably for 1 to 5 hours.

(Step 4) Compound (V) is subjected to a deprotection reaction to obtain compound (IIa). In compound (V), the compound in which W is a protecting group is subjected to a deprotection reaction known per se. The deprotection reaction is performed, for example, according to the method described in the aforementioned Organic Functional Group Preparations. Specifically, for example, a method using an acid, a catalytic reduction method,
Examples thereof include a hydrolysis method and a nucleophilic substitution method, which are variously selected depending on the protecting group of W. For example, when W is C _1-6 alkyl (preferably methyl), compound (V) and 1 to 100 equivalents of an acid are used in a solvent-free or inert solvent,
React at -78 ° C to 200 ° C for 5 minutes to 24 hours. Examples of the acid include mineral acids (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid), Lewis acids (eg, aluminum chloride, boron tribromide, etc.), silicon halide reagents (eg, iodotrimethylsilane) , Bromotrimethylsilane, etc.). As the inert solvent, for example, water, a halogenated hydrocarbon solvent, acetic acid or the like alone or as a mixture of two or more thereof is used. Preferred reaction conditions include compound (V) and 5 to 100 equivalents of hydrobromic acid in water or acetic acid at 100 ° C to 130 ° C for 1 hour to 5 hours.
Let react for hours.

For example, when W is benzyl which may have a substituent, compound (V) is usually subjected to a catalytic reduction method. Compound (V) and a catalytic amount of a metal catalyst (eg, Raney nickel, platinum oxide, metallic palladium, palladium-
Carbon and the like are reacted in an inert solvent (for example, an alcohol solvent or the like) under a hydrogen pressure of from room temperature to 100 ° C. and from 1 to 100 atm for 1 to 48 hours. Preferably, the compound (V) and a catalytic amount of palladium-carbon are reacted in an alcohol solvent (eg, ethanol or the like) under a hydrogen pressure of 1 to 10 atm at room temperature to 50 ° C for 1 hour to 10 hours. For example, when W is C _1-6 alkyl-carbonyl, benzoyl, C _7-10 aralkyl-carbonyl, compound (V) is subjected to a hydrolysis reaction. Compound (V) and 2 to 100 equivalents (preferably 5 to 10 equivalents) of an alkali in an inert solvent at room temperature to 120 ° C, preferably at room temperature to 60 ° C, for 5 minutes to 100 hours, preferably for 1 hour to 20
Let react for hours. Examples of the alkali include hydroxides of inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide. Among them, sodium hydroxide is preferably used as an inert solvent, for example, water, an alcohol-based solvent, an ether-based solvent or the like, or a mixture of two or more thereof. Among them,
A mixed solvent of water-methanol is preferred. As preferable reaction conditions, the solvent is a mixed solvent of water and methanol, the reaction temperature is room temperature to 60 ° C., and the reaction time is 5 hours to 10 hours.

[0049]

Embedded image In the above formula, R ⁹ represents a carboxy protecting group, and L represents a leaving group. As the “carboxy-protecting group” for R ⁹ ,
It can be mentioned those similar to the "protecting group of the carboxy" below, preferably a C _1-6 alkyl. As the “leaving group” represented by L, those similar to the aforementioned L can be mentioned. (Step 5) Compound (VI) is subjected to a reduction reaction to give compound (VI
I get. Compound (VI) is a readily available compound, and can be obtained, for example, by subjecting compound (III) to a known esterification reaction. The reduction reaction is carried out according to a method known per se, for example, the method described in the aforementioned Organic Functional Group Preparations. The reaction conditions are substantially the same as those in Step 3, and among them, a method using a metal hydride is preferable.
Specifically, the compound (VI) and 1 to 20 equivalents (preferably 1 to 6 equivalents) of a metal hydride (preferably lithium aluminum hydride) are reacted in an inert solvent. As the inert solvent, for example, an ether solvent, an alcohol solvent, an aromatic solvent, or the like may be used alone, or a mixture of two or more thereof may be used. The reaction temperature varies depending on the metal hydride used, but is usually from -70 ° C to 100 ° C, and from room temperature to 50 ° C when lithium aluminum hydride is used.
Is preferred.

(Step 6) A leaving group is introduced into compound (VII) to give compound (VIII). When L is a halogen in the compound (VIII), the compound (VII) is reacted with a halogenating agent. As the halogenating agent, for example, commercially available halogenating reagents (eg, hydrobromic acid, phosphorus tribromide, phosphorus pentachloride,
When using thionyl chloride), it may be performed according to a method known per se. When, for example, hydrobromic acid is used as the halogenating agent, compound (VII) may be reacted with 1.5 to 5 equivalents of hydrobromic acid at 80 ° C to 130 ° C for 1 hour to 18 hours. When performing the reaction by preparing a halogenating agent,
1 to 1.5 equivalents of bromine or iodine and the same amount of triphenylphosphine are mixed at room temperature in an inert solvent (eg, a nitrile-based solvent, an ether-based solvent, etc.) to form a halogenating agent. And compound (VII)
In the same solvent at room temperature for 0.5 to 18 hours, preferably 0.5 to 3 hours.

In the compound (VIII), when L is a sulfonyloxy (eg, methanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy, etc.), the compound (VII) is used in an amount of 1 equivalent to an excess (preferably 1 equivalent). To 1.5 equivalents) of a sulfonylating reagent (eg, methanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride, etc.) and a base in an inert solvent at -50.
C. to 50.degree. C., preferably at room temperature, for 1 hour to 24 hours. Examples of the “base” include the organic bases described in detail in Step 1 above, among which amines such as triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, pyridine, imidazole, 2,6-lutidine and the like And the like are preferred. The amount of the base to be used is 1 equivalent to 8 equivalents relative to the sulfonylation reagent. As the inert solvent, for example, a halogenated hydrocarbon-based solvent, a nitrile-based solvent, an ester-based solvent, or the like may be used alone or in combination of two or more. Further, the sulfonyloxy group of the obtained compound (VIII) may be subjected to an iodination reaction. Compound (VIII) and 1
Equivalent to 10 equivalents (preferably 1 equivalent to 3 equivalents) of sodium iodide or potassium iodide is added to an inert solvent (eg,
Ketone solvents, ether solvents, etc.), room temperature to 100
C., preferably 30 ° C. to 60 ° C., for 1 hour to 24 hours.

(Step 7) Compound (VIII) is subjected to an amination reaction to obtain compound (IX). The amination reaction is performed according to a method known per se, for example, the method described in the aforementioned Organic Functional Group Preparations and the like. Specifically, compound (VIII) and 1 equivalent to
5 equivalents (preferably 1 to 2 equivalents) of the formula HNR ¹ R ²
Is carried out in an inert solvent at room temperature to 100 ° C, preferably at room temperature to 50 ° C, for 0.5 hour to 1 day. Usually, 1 equivalent to 5 equivalents (preferably 1 equivalent
(3 equivalents to 3 equivalents) of the base. The "base"
Examples thereof include the bases described in detail in Step 1 above, and among them, tertiary amines such as triethylamine, and alkali metal or alkaline earth metal carbonates are preferable. Examples of the inert solvent include water, alcohol solvents, ether solvents, halogenated hydrocarbon solvents,
Aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents and the like can be used alone or in combination of two or more. Among them, acetonitrile, N, N-dimethylformamide (DM
F), acetone, ethanol and the like are preferred. Preferred reaction conditions include compound (VIII), 1 equivalent to 2 equivalents of the compound represented by the formula HNR ¹ R ² and 1 equivalent to 3 equivalents of a base (eg, potassium carbonate, triethylamine, etc.).
With an inert solvent (eg, acetonitrile, DMF, etc.)
Medium, room temperature to 50 ° C., and a method of stirring for 10 hours to 1 day. (Step 8) Compound (IX) is subjected to a deprotection reaction to obtain compound (IIa). The deprotection reaction may be performed under the same reaction conditions as in Step 4.

In the compound (II), the compound wherein Y is methylene may be obtained in accordance with the following scheme 4.

Embedded image In the above formula, the ring B ′ is a ring B having oxo, R ¹⁰ and R ¹¹ are each C _1-6 alkyl, and benzyl optionally having 1 to 3 halogens or nitro as a substituent. .

(Step 9) The compound (X) is subjected to a Mannich reaction to obtain a compound (XI). Compound (X) is a readily available compound, and can be easily synthesized by a method known per se. The Mannich reaction may be performed according to a method known per se, for example, a method described in WO92 / 05143 or the like. Specifically, compound (X), excess formaldehyde or paraformaldehyde and 1 to 5 equivalents (preferably 1 to 2 equivalents) of a secondary amine (eg, a compound of formula H
NR ¹⁰ R ¹¹ ) or 1 equivalent to 10
An equivalent (preferably 1 to 5 equivalents) of dimethylmethylene ammonium salt (eg, hydrochloride, iodate, etc.) is reacted in an inert solvent at room temperature to 80 ° C. for 1 hour to 48 hours. If necessary, an equivalent to excess amount of an acid (eg, a mineral acid such as hydrochloric acid) may be added. As the inert solvent, for example, an ether-based solvent, an alcohol-based solvent, a nitrile-based solvent, water, or the like may be used alone or as a mixture of two or more thereof. In the compound represented by the formula HNR ¹⁰ R ¹¹ , R ¹⁰
When each of R ¹¹ and R ¹¹ is C _1-6 alkyl, the obtained compound (XI) is subjected to the reaction of Step 12 without going through the next Step 10.

(Step 10) Compound (XII) which is a quaternary amine salt is obtained from compound (XI). Following the step 9,
Compound (XI) and 1 to 3 equivalents (preferably 1.1 equivalents)
Equivalent to 1.5 equivalent) of a C _1-6 alkyl halide (eg, methyl iodide, etc.) in an inert solvent (eg, ketone solvent, alcohol solvent, etc.) for 0.1 hour at room temperature to reflux condition. The reaction is carried out for 24 hours, preferably 0.5 hour to 2 hours. (Step 11) Compound (XII) is subjected to an amination reaction to obtain compound (XIII). The amination reaction may be performed under the same reaction conditions as in Step 7. Specifically, the compound (XI
I) and 1 to 5 equivalents (preferably 1 to 3 equivalents) of the compound represented by the formula HNR ¹ R ² in an inert solvent at room temperature to 100 ° C., preferably room temperature to 50 ° C., 0.5
It is performed by stirring for 1 hour to 1 day. Usually, 1 to 3 equivalents (preferably 1 to 2 equivalents) of a base is added to carry out the reaction. As the “base”, for example, the step 1
And the like. Among them, tertiary amines such as triethylamine, carbonates of alkali metals or alkaline earth metals, etc. are preferable. As the inert solvent,
For example, water, alcohol solvents, ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents,
An amide-based solvent, a ketone-based solvent, a sulfoxide-based solvent, or the like can be used alone or as a mixture of two or more of these. Above all, acetonitrile, DMF, acetone,
Ethanol is preferred. Preferred reaction conditions include compound (XII), 1 equivalent to 2 equivalents of the compound represented by the formula HNR ¹ R ² and 1 equivalent to 3 equivalents of a base (eg, potassium carbonate, triethylamine, etc.) in an inert solvent ( Eg, acetonitrile, DMF, etc.) at room temperature to 50
And stirring for 10 hours to 1 day.

(Step 12) Compound (XIII) is subjected to a reduction reaction to obtain compound (XIV) via compound (XIIIa). The reduction reaction is carried out according to a method known per se, for example, the method described in the aforementioned Organic Functional Group Preparations. Specifically, the compound (1) (X
III) and a metal hydride, (2) a method of reacting the compound (XIII) with a metal, or (3) a method of subjecting the compound (XIII) to a catalytic reduction reaction. In the above reaction (1), compound (XIII) and 1 to 20 equivalents (preferably 2 to 6 equivalents) of metal hydride are reacted in an inert solvent. Examples of the “metal hydride” include lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, diborane, dibutylaluminum hydride and the like. When lithium aluminum hydride is used as the inert solvent, an ether solvent is
When using sodium borohydride, an alcohol solvent or the like is preferable. The reaction temperature varies depending on the metal hydride used, but is usually -70 ° C to 100 ° C, preferably 0 ° C.
C. to 80C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours. The above reaction (2)
In the above, compound (XIII) and an excess amount (preferably 1 to 100 equivalents) of a metal (eg, zinc powder) are added in an inert solvent,
The reaction is performed at room temperature to 100 ° C for 1 hour to 24 hours. In the reaction (2), the reduction may further proceed to give the compound (XIV) in some cases. As the inert solvent, for example, an organic acid (eg, acetic acid or the like), an ether solvent or the like is used alone or in combination of two or more. In the above reaction (3),
Compound (XIII) and a catalytic amount of a metal catalyst (eg, Raney nickel, platinum oxide, metal palladium, palladium-carbon, etc.) in an inert solvent (eg, alcoholic solvent, etc.)
The reaction is carried out at room temperature to 100 ° C. under a hydrogen pressure of 1 to 100 atm for 1 to 48 hours. If necessary, a catalytic amount to an excess amount of an organic acid (eg, acetic acid, etc.) or a mineral acid (eg, perchloric acid,
Hydrochloric acid) may be added. In the reaction (3), the reduction may further proceed to give the compound (XIV) in some cases.

The obtained compound (XIIIa) is subjected to a reductive dehydration reaction to obtain a compound (XIV). The reductive dehydration reaction includes a method known per se, for example, a catalytic reduction method, a method using an organic silyl reagent, and the like. As the catalytic reduction method, a compound (XIIIa) and a catalytic amount of a metal catalyst (eg, Raney nickel, platinum oxide, metallic palladium, palladium-carbon, etc.) are mixed with an inert solvent (eg, an alcohol-based solvent).
A method in which the reaction is carried out under a hydrogen pressure of 1 to 100 atm and room temperature to 100 ° C. for 1 hour to 48 hours is preferable. As needed,
A catalytic amount to an excess amount of an organic acid (eg, acetic acid, etc.) or a mineral acid (eg, perchloric acid, hydrochloric acid, etc.) may be added. As a method using an alkylsilane reagent, a compound (XIII
a), an alkylsilane reagent (eg, triethylsilane, phenyldimethylsilane, etc.) and an acid (eg, an organic acid such as trifluoroacetic acid) in a solvent-free or inert solvent (eg, a halogenated hydrocarbon solvent) 0 ° C-100
C., preferably 0 ° C. to 30 ° C., for 10 minutes to 24 hours. The amount of the alkylsilane reagent to be used depends on the amount of the compound (XIII
1 equivalent to 10 equivalents, preferably 1 equivalent to
5 equivalents. The amount of the acid to be used is a catalytic amount to an excess amount, preferably 1 to 5 equivalents, relative to compound (XIIIa). (Step 13) In compound (XIV), when W is a protecting group, compound (XIV) is subjected to a deprotection reaction to give compound (I
Ib). The deprotection reaction may be performed under the same reaction conditions as in Step 4.

Manufacturing method 2

Embedded image (Step 14) Compound (XV) is subjected to an alkylation reaction or an acylation reaction to obtain compound (XVI). Compound (XV)
Is obtained by subjecting a compound in which W is a hydrogen atom in compound (III) to an esterification reaction known per se. The alkylation reaction and the acylation reaction may be performed in the same manner as in the reaction described in the above step 1. (Step 15) Compound (XVI) is subjected to a hydrolysis reaction known per se, and then to an amidation reaction to obtain compound (XVII). The amidation reaction may be carried out in the same manner as the reaction described in the above step 2. (Step 16) Compound (XVII) is subjected to a reduction reaction to obtain compound (Ib). The reduction reaction may be performed in the same manner as in the reaction described in Step 3.

Manufacturing method 3

Embedded image In the above formula, L represents a leaving group. "Leaving group" represented by L
And the same as described above. (Step 17) Compound (XVIII) is subjected to an amination reaction,
Compound (I) is obtained. Compound (XVIII) is easily synthesized according to a method known per se, and examples of the synthesis include, for example, the method described in Scheme 7 below. The amination reaction may be performed in the same manner as in the reaction described in the above step 7.

Embedded image (Step 18) Compound (XVI) is subjected to a reduction reaction to obtain compound (XIX). The reduction reaction may be performed in the same manner as in the reaction described in Step 5 above. (Step 19) A leaving group is introduced into compound (XIX) to obtain compound (XVIIIa). The introduction reaction of the leaving group may be carried out in the same manner as the reaction described in the above Step 6.

Production method 4

Embedded image In the above formula, K is an aromatic group which may have a substituent, G
Represents halogen (eg, bromo, iodo) or trifluoromethanesulfonyloxy. Examples of the “aromatic group optionally having substituent (s)” for K include the same as the “aromatic group optionally having substituent (s)” for Ar ′. (Step 20) Compound (II) is subjected to the same reaction as in Step 1 to obtain compound (XX). (Step 21) Compound (XX) is subjected to an aryl coupling reaction to obtain compound (Ic). The aryl coupling reaction is carried out by a method known per se, for example, Acta. Chemica Scandinavia, 221-230.
Page, 1993 and the like.
Specifically, compound (XX), 1 equivalent to 2 equivalents of an aryl metal compound and 1 equivalent to 10 equivalents of a base are combined with 0.01 equivalent.
The reaction is carried out in an inert solvent at room temperature to 150 ° C, preferably 80 ° C to 150 ° C, for 1 hour to 48 hours in the presence of an equivalent to 1 equivalent, preferably 0.01 to 0.5 equivalent of a transition metal catalyst.
Examples of the “aryl metal compound” include an arylboronic acid derivative, an arylzinc derivative, and the like.
As the “base”, for example, an aqueous solution of sodium carbonate, sodium hydrogen carbonate and the like can be mentioned. "Transition metal catalyst"
Examples thereof include a palladium catalyst and a nickel catalyst. Examples of the “palladium catalyst” include tetrakis (triphenylphosphine) palladium (0), palladium acetate, bis (triphenylphosphine) palladium (II) chloride, palladium-carbon and the like. Examples of the “nickel catalyst” include tetrakis (triphenylphosphine) nickel (0). As the inert solvent, for example, water, an alcohol-based solvent, an aromatic-based solvent, or the like is used alone or in combination of two or more. Preferably, water, ethanol, toluene or the like is used alone or in combination of two or more.

In the case where an optical isomer is present in the compound which is a synthetic intermediate described in the above-mentioned production methods 1 to 4, as a method for obtaining the “optical isomer of the synthetic intermediate”, a method known per se, For example, a method derived from an optically active compound, or a method of subjecting a racemate to an optical resolution method or an asymmetric synthesis method may be mentioned. The “optical splitting method” includes the same as the optical splitting method described later. The "asymmetric synthesis method" includes a method known per se, for example, an asymmetric reduction reaction, an asymmetric oxidation reaction, an asymmetric alkylation reaction, and the like. These reactions are described in New Experimental Chemistry, Vol. Ed., Maruzen Co., Ltd., 1992, etc. Of these, an asymmetric reduction reaction is preferred. The "asymmetric reduction reaction" includes, for example, a reduction reaction using an asymmetric metal hydride, an asymmetric hydrogenation reaction and the like, and among them, an asymmetric hydrogenation reaction is preferable. Examples of the “asymmetric hydrogenation reaction” include a reaction using an asymmetric metal catalyst.
An asymmetric hydrogenation reaction performed in the presence of a transition metal-optically active phosphine complex. For example, the production methods 1-4
Compounds (III), (IV), (V), (VI), (VI
In I), (XVI) and (XVII), the ring B is, for example, of the formula:

Embedded image [Wherein Zb is as defined above for Z], the compound represented by the ring represented by the formula (1) can be subjected to an asymmetric hydrogenation reaction to produce each optical isomer.

Embedded image In the formula, * represents the position of the asymmetric carbon, and each symbol has the same meaning as described above. Examples of the "asymmetric hydrogenation reaction" include compounds (III
b), (IVb), (Vb), (VIb), (VIIb), (XVIb)
Or (XVIIb) in the presence of about 0.0001 equivalent to 1 equivalent (preferably about 0.001 equivalent to 0.1 equivalent) of a transition metal-optically active phosphine complex in an inert solvent at room temperature to 1 equivalent.
00 ° C (preferably about 50 ° C to 80 ° C), 5 kg / cm ² to 1
00 kg / cm ² (preferably 50 kg / cm ^{2 to} 100 kg / c
m ² ) under a hydrogen pressure of 1 hour to 48 hours (preferably 1 hour to 6 hours) to give compounds (IIIc), (IVc) and (V
c), (VIc), (VIIc), (XVIc) or a method for obtaining (XVIIc). Compounds (IIIb), (IVb), (V
The concentrations of b), (VIb), (VIIb), (XVIb) and (XVIIb) in the reaction solution are 1 to 1000 mg / ml, preferably 50 to 300 mg / ml. If desired, Lewis acid (eg, boron trifluoride-ether complex, aluminum chloride, titanium tetrachloride, cobalt chloride, etc.), mineral acid (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.) may be contained in the reaction solution. May be added in an appropriate amount. The “transition metal” of the “transition metal-optically active phosphine complex” includes, for example, ruthenium, rhodium, iridium, palladium, nickel, and the like. Among them, ruthenium is preferred. The optically active phosphine in the “transition metal-optically active phosphine complex” includes
There are two optical isomers, the (R) configuration and the (S) configuration. By performing asymmetric reduction using one of the optically active phosphines of the (R) configuration and the (S) configuration,
The desired optical isomer can be selectively obtained.

Examples of the “optically active phosphine” include:
For example, (R) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl [(R)-(BINAP)], (S)-
2,2'-bis (diphenylphosphino) -1,1'-binaphthyl [(S)-(BINAP)], (R) -2,2'-bis (di-p
-Tolylphosphino) -1,1′-binaphthyl [(R)-(pt
olyl-BINAP)], (S) -2,2'-bis (di-p-tolylphosphino) -1,1'-binaphthyl [(S)-(p-tolyl-B
INAP)] (JP-A-61-63690); (R)-
2,2'-bis [di- (3,5-dimethylphenyl) phosphino] -1,1'-binaphthyl [(R)-(3,5-xylyl-BINA
P)], (S) -2,2'-bis [di- (3,5-dimethylphenyl) phosphino] -1,1'-binaphthyl [(S)-
(3,5-xylyl-BINAP)] (JP-A-3-255090); (R) -2,2'-bis (diphenylphosphino)
-5,5 ', 6,6', 7,7 ', 8,8'-octahydro-1,
1′-binaphthyl [(R)-(H ₈ -BINAP)], (S) -2,2 ′
-Bis (diphenylphosphino) -5,5 ', 6,6', 7,
7 ', 8,8'-octahydro-1,1'-binaphthyl [(S)-
(H ₈ -BINAP)] (JP-A-4-139140) and the like. The above “(R)” and “(S)” indicate the absolute configuration of the optically active phosphine. The “transition metal-optically active phosphine complex” includes, as a ligand, a halogen (eg, chloro, etc.), an amine (eg, triethylamine, etc.), an organic acid
(Eg, acetic acid), C _6-14 aryl (eg, benzene)
And the like. The “transition metal-optically active phosphine complex” may be used without isolation and purification after preparation. As a preferred example of the “transition metal-optically active phosphine complex”, the “ruthenium-optically active phosphine complex” includes the following compounds formed from ruthenium and either (R) configuration or (S) configuration optically active phosphine. And the like. Bis [[(R) or (S)-[2,2'-bis (diphenylphosphino) -1,1 '
-Binaphthyl]] dichlororuthenium] triethylamine:
[RuCl ₂ [(R) or (S)-(BINAP)]] ₂ NEt ₃ Screw
[[(R) or (S)-[2,2'-bis (di-p-tolylphosphino) -1,1'-binaphthyl]] dichlororuthenium] triethylamine: [RuCl ₂ [(R) or (S)- (p-tolyl-BINAP)]] ₂ NE
abbreviated as t _3. Bis [[(R) or (S)-[2,2′-bis (di- (3,5-dimethylphenyl) phosphino) -1,1′-binaphthyl]] dichlororuthenium] triethylamine: [RuCl ₂ [( (R) or (S)-
(3,5-xylyl-BINAP)]] Abbreviated as ₂ NEt ₃ . Bis [[(R) or (S)-[2,2′-bis (diphenylphosphino) -5,5 ′, 6,6 ′, 7,7 ′, 8,8′-octahydro-1,
1′-Binaphthyl]] dichlororuthenium] triethylamine: Abbreviated as [RuCl ₂ [(R) or (S)-(H ₈ -BINAP)]] ₂ NEt ₃ . [(R) or (S)-[2,2'-bis (diphenylphosphino)
-1,1'-Binaphthyl]] ruthenium diacetate: Ru (CH ₃
CO ₂ ) ₂ [(R) or (S)-(BINAP)]. [(R) or (S)
-[2,2′-bis (di-p-tolylphosphino) -1,1′-binaphthyl]] ruthenium diacetate: Ru (CH ₃ CO ₂ ) ₂ [(R) or (S)-(p-tolyl- BINAP)]. [(R) or (S)-[2,
2'-bis [di- (3,5-dimethylphenyl) phosphino-1,
1'-binaphthyl]] ruthenium diacetate: Ru (CH ₃ CO ₂ )
₂ Abbreviated as [(R) or (S)-(3,5-xylyl-BINAP)]. [(R) or (S)-[2,2'-bis (diphenylphosphino) -5,5 ',
6,6 ′, 7,7 ′, 8,8′-octahydro-1,1′-binaphthyl]] ruthenium diacetate: Ru (CH ₃ CO ₂ ) ₂ [(R) or
(S) - abbreviated as (H ₈ -BINAP)]. As an inert solvent, for example,
A hydrocarbon solvent, an amide solvent, an aromatic solvent, an ether solvent, a halogenated hydrocarbon solvent, an alcohol solvent, a ketone solvent, a sulfoxide solvent, a nitrile solvent, or a mixture of two or more thereof. Used as Preferably, an alcohol solvent is used, and more preferably, ethanol is used.

The “alcohol solvent” includes, for example, methanol, ethanol, isopropanol, tert.
-Butanol and the like. Examples of the “ether solvent” include diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, and 1,2-dimethoxyethane. Examples of the “halogenated hydrocarbon solvent” include dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride and the like. Examples of the “aromatic solvent” include benzene, toluene, xylene, pyridine and the like. As the "hydrocarbon solvent", for example,
Hexane, pentane, cyclohexane and the like can be mentioned. Examples of the “amide solvent” include, for example, N, N-
Examples include dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone, and the like.
Examples of the “ketone-based solvent” include acetone and methyl ethyl ketone. Examples of the “sulfoxide-based solvent” include dimethyl sulfoxide (DMSO). Examples of the “nitrile solvent” include acetonitrile, propionitrile and the like. Examples of the “ester solvent” include ethyl acetate.

In each of the above reactions, when the starting compound has amino, carboxy, hydroxy, or carbonyl as a substituent, a protecting group generally used in peptide chemistry or the like may be introduced into these groups. After the reaction, the desired compound can be obtained by removing the protecting group as necessary. Examples of the amino-protecting group include formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl,
tert-butoxycarbonyl, etc.), benzoyl, C _7-10
Aralkyl-carbonyl (eg, benzylcarbonyl, etc.), C _7-14 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, etc.), trityl, phthaloyl, N, N-dimethylaminomethylene, silyl ( Examples include trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl and the like, and _C2-6 alkenyl (eg, 1-allyl and the like). These groups may be substituted with one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, etc.) or nitro. . Examples of the carboxy protecting group include C _1-6 alkyl (eg, methyl,
Ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), C _7-11 aralkyl (eg, benzyl etc.), phenyl, trityl, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert. -Butyl diethylsilyl and the like), _C2-6 alkenyl (eg, 1-allyl and the like) and the like. These groups may be substituted with one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, etc.) or nitro. . Examples of the hydroxy protecting group include C _1-6 alkyl (eg, methyl,
Ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, C _7-10 aralkyl (eg, benzyl etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl etc.), benzoyl, C _7-10 aralkyl-carbonyl (eg, benzylcarbonyl), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl) And C _2-6 alkenyl (eg, 1-allyl and the like). These groups include one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl (eg, methyl, ethyl, propyl, etc.), C _1-6 alkoxy (eg, methoxy) , Ethoxy, propoxy, etc.)
Or it may be substituted by nitro or the like. Examples of the carbonyl protecting group include, for example, cyclic acetal (eg, 1,3
-Dioxane), acyclic acetal (eg, di-C
_1-6 alkyl acetal) and the like. In addition, these protective groups can be removed by a method known per se, for example, Protective Groups in Organic Synthesis.
is), according to the method described in John Wiley and Sons (1980). For example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide, etc.), A reduction method or the like is used.

Compound (I) can be isolated and purified by known means, for example, solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like. The starting compound of compound (I) or a salt thereof can be isolated and purified by the same known means as described above.
It may be used as a raw material in the next step as a reaction mixture without isolation. Compound (I) may be a hydrate or a non-hydrate. When the compound (I) contains an optical isomer, a stereoisomer, a position isomer, and a rotamer, these are also contained as the compound (I), and are synthesized by a synthesis method and a separation method known per se. Can be obtained as a single item. For example, when the compound (I) has an optical isomer, the optical isomer resolved from the compound is also included in the compound (I). The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method. As the optical resolution method, a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method and the like are used. 1) Fractional recrystallization method Racemic and optically active compounds (for example, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid,
(+)-1-phenethylamine, (−)-1-phenethylamine, cinchonine, (−)-cinchonidine, brucine, etc.), which are separated by a fractional recrystallization method, and if necessary, a neutralization step is carried out. To obtain free optical isomers 2) Chiral column method A method in which a racemate or a salt thereof is applied to a column for separation of optical isomers (chiral column) to be separated. For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh) or CHIRAL series manufactured by Daicel, and water, various buffer solutions (eg, phosphate buffer solution), Solvents (eg, ethanol, methanol, isopropanol, acetonitrile,
Trifluoroacetic acid, diethylamine, etc.) alone or as a mixed solution to separate the optical isomers. In the case of gas chromatography, for example, separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences). 3) Diastereomer method A racemic mixture is made into a diastereomer mixture by a chemical reaction with an optically active reagent, and the mixture is converted into a single substance by a usual separation means (eg, fractional recrystallization, chromatography, etc.). And then separating optically active reagent sites by a chemical treatment such as a hydrolysis reaction to obtain optical isomers. For example, when the compound (I) has hydroxy or primary or secondary amino in the molecule, the compound and an optically active organic acid (for example, MPTA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], ( −)
-Menthoxyacetic acid or the like) to give a diastereomer of an ester form or an amide form, respectively. On the other hand, when the compound (I) has a carboxylic acid group, the compound is subjected to a condensation reaction with an optically active amine or an alcohol reagent to obtain an amide or ester diastereomer, respectively. The separated diastereomer is converted into an optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis reaction. During the above process, the formula

Embedded image Wherein R ^1b and R ^2b are each methyl or ethyl, k is 1 or 2, and * indicates the position of an asymmetric carbon. The optical isomer of the compound represented by the formula or a salt thereof is a novel compound.

Compound (I) has an excellent inhibitory action on amyloid β protein production and secretion and an excellent secretory APP secretion promoting action, and thus has a neurodegenerative disease; amyloid angiopathy; cerebrovascular disorder (eg, cerebral infarction, Cerebral hemorrhage), head injury, or neuropathy due to spinal cord injury. Compound (I ') also has an inhibitory effect on amyloid β protein production / secretion and secretory APP
Has a secretion promoting action. Compounds (I) and (I ′) have low toxicity. For example, in an acute toxicity test using mice, the compound obtained in Example 12 described below
No deaths were observed when 0 mg / kg was orally administered. Furthermore, compounds (I) and (I ') also have excellent brain-localizing properties. Therefore, compounds (I) and (I ′)
Is a safe and prophylactic / therapeutic agent for neurodegenerative diseases in mammals such as humans; amyloid angiopathy; cerebrovascular disorders (eg, cerebral infarction, cerebral hemorrhage, etc.); Further, it is also useful as an agent for improving various mental disorders (eg, depression, anxiety, threatening neurosis, sleep disorders, etc.) caused by neurodegeneration and neuropathy. Compounds (I) and (I ')
Is preferably a neurodegenerative disease (eg, Alzheimer's disease, Down's syndrome, senile dementia, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, diabetic neuropathy, Huntington's chorea, multiple sclerosis ), More preferably as a prophylactic / therapeutic agent for neurodegenerative diseases caused by amyloid β protein (eg, Alzheimer's disease, Down's syndrome, etc.), particularly preferably as a prophylactic / therapeutic agent for Alzheimer's disease Useful. Compounds (I) and (I ′) are anti-dementia drugs (eg,
Acetylcholinesterase inhibitors). Compounds (I) and (I ′) can be formulated according to a means known per se, and compound (I) or (I ′) as it is or a pharmacologically acceptable carrier can be appropriately used in the formulation step By mixing an appropriate amount, a pharmaceutical composition such as a tablet (including a sugar-coated tablet and a film-coated tablet), a powder, a granule, a capsule, a (including a soft capsule), a liquid, an injection, a suppository, a sustained release agent, etc. It can be safely administered parenterally or parenterally (eg, topically, rectally, intravenously, etc.). In the pharmaceutical composition of the present invention, the content of compound (I) or (I ′) is 0.1 to 100% by weight of the whole agent. The dose depends on the subject,
Although it varies depending on the administration route, disease, etc., for example, as an active ingredient (compound (I) or (I ′)), at a time, as an oral agent for an adult (about 60 kg) for an adult (about 60 kg) as an active ingredient (compound (I) or (I ′)). ~ 500mg, preferably about 1 ~
The dose is 100 mg, more preferably 5 to 100 mg, which can be administered once or several times a day.

Examples of the pharmacologically acceptable carrier used in the production of the composition of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients and lubricants in solid preparations. Solvent, dissolution aid, suspending agent, isotonic agent, buffer, soothing agent, etc. in liquid preparations. Also, if necessary,
Additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can also be used. Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. Disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. As a solubilizer, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine,
Examples include sodium carbonate and sodium citrate. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, carboxy Examples include hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like. As preservatives, for example, paraoxybenzoic acid esters,
Chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like can be mentioned. Examples of the antioxidant include sulfite, ascorbic acid, and the like.

[0068]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention further includes the following reference examples,
The present invention will be described in detail with reference to examples and experimental examples, but these examples are merely examples, do not limit the present invention, and may be changed without departing from the scope of the present invention. “Room temperature” in the following Reference Examples and Examples indicates 0 to 30 ° C., and anhydrous magnesium sulfate or anhydrous sodium sulfate was used for drying the organic layer. "%" Means weight percent unless otherwise specified. The infrared absorption spectrum was measured by a diffuse reflection method using a Fourier transform infrared spectrophotometer. Abbreviations used in other texts have the following meanings. s: singlet d: doublet t: triplet q: quartet m: multiplet br: broad J: coupling constant Hz: hertz ( Hertz) CDCl ₃ : deuterated chloroform THF: tetrahydrofuran DMF: N, N-dimethylformamide DMSO: dimethylsulfoxide WSC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ¹ H NMR: proton nuclear magnetic resonance (usually CDCl ₃ free body
Measured in ) IR: Infrared absorption spectrum

[0069]

【Example】

Reference Example 1 6-methoxy-2-piperidinomethyl-1-tetralone
Hydrochloride N- (6-methoxy-1-oxo-2-tetralinyl) methyl-N, N, N-trimethylammonium iodide (1.137
g), piperidine (0.36 ml), triethylamine (0.55
ml) was added to acetonitrile (300 ml). The reaction solution was stirred at room temperature for 2 hours, concentrated, added with water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 2), treated with 4N hydrochloric acid-ethyl acetate solution, and the resulting salt was treated with methanol-
Recrystallization from ethyl acetate gave the title compound (0.586 g). Melting point: 182-183 ° C

The following Reference Examples Compounds 2 and 3 were synthesized in the same manner as in Reference Example 1. Reference Example 2 2- (N-benzylamino) methyl-6-methoxy-1-
Tetralone hydrochloride Melting point: 166-169 ° C Recrystallization solvent: methanol-ethyl acetate Reference Example 3 2- (N, N-dibenzylamino) methyl-6-methoxy-1
-Tetralone Melting point: 91-92 ° C Recrystallization solvent: Ethyl acetate-diisopropyl ether Reference Example 4 2- (N, N-dimethylamino) methyl-7-methoxytetralin hydrochloride 2- (N, N-dimethylamino) methyl- 7-methoxy-1-
1N-Sodium hydroxide was added to tetralone hydrochloride (8.46 g) to give a free form, which was extracted with ethyl acetate. The extract was dried and concentrated. Methanol solution of the residue (150 ml)
To the mixture was added sodium borohydride (2.32 g) under ice cooling, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, concentrated under reduced pressure, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. Residue in ethanol (10
0 ml), concentrated hydrochloric acid (6.4 g) and 10% palladium-carbon (0.7 g) were added, and the mixture was catalytically reduced at 60 ° C. and 5 atm of hydrogen pressure for 8 hours. The catalyst was filtered off from the reaction solution, and the filtrate was concentrated. The residue was recrystallized from methanol-ethyl acetate to give the title compound (6.53 g). Melting point: 212-213 ° C

The following Reference Examples Compounds 5 to 7 were synthesized in the same manner as in Reference Example 4. Reference Example 5 2- (N, N-dimethylamino) methyl-6-methoxytetralin hydrochloride Melting point: 197-199 ° C Recrystallization solvent: methanol-ethyl acetate Reference Example 6 2- (N-benzylamino) methyl-6- Methoxytetralin hydrochloride Melting point: 174-177 ° C Recrystallization solvent: methanol-diethyl ether Reference Example 7 6-methoxy-2-piperidinomethyltetraline hydrochloride Melting point: 215-216 ° C Recrystallization solvent: methanol-diethylether

Reference Example 8 2-Iodomethyl-6-methoxytetralin 2-hydroxymethyl-6-methoxytetralin (1.888
g, J. Med. Chem., 37, 526, 1994) and pyridine (4.0 ml) in acetonitrile (20 ml).
Under ice cooling, p-toluenesulfonyl chloride (2.06 g) was added. After the reaction solution was stirred at room temperature for 24 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. Acetone solution of the residue (30 m
To l), sodium iodide (2.20 g) was added. Reaction solution
After heating under reflux for 16 hours, the mixture was concentrated. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium thiosulfate and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 1: 2) to give the title compound (2.506
g) was obtained. ^{1 H NMR δ: 1.38-1.60 (1H} , m), 1.80-2.11 (2H, m),
2.45 (1H, dd, J = 16Hz, 8Hz), 2.76―3.00 (3H, m), 3.
26 (2H, d, J = 6Hz), 3.77 (3H, s), 6.60―6.74 (2H,
m), 7.00 (1H, d, J = 8Hz)

Reference Example 9 2- (N, N-dipropylamino) methyl-6-methoxytetralin hydrochloride 2-iodomethyl-6-methoxytetralin (0.918 g,
Reference example compound 8), dipropylamine (0.83 ml) and potassium carbonate (0.90 g) were added to DMF (15 ml). After the reaction solution was stirred at room temperature for 20 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 1), and then treated with a 4N hydrochloric acid-ethyl acetate solution to obtain a hydrochloride.
The resulting salt was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (0.409 g). Melting point: 135-137 ° C

Reference Example 10 6-Methoxy-2- (N-methylamino) methyltetralin hydrochloride N- (6-methoxy-1-oxo-2-tetralinyl) methyl-N, N, N-trimethylammonium iodide ( 44.5
g), a solution of N-benzyl-N-methylamine (14.4 g) and triethylamine (18 ml) in acetonitrile (400 ml) were heated under reflux for 16 hours. After concentrating the reaction solution, water (200 ml) was added to the residue, and a 1N aqueous sodium hydroxide solution was added to adjust the pH.
And extracted with ethyl acetate (200 ml). The organic layer was washed with water, dried and concentrated. The residue was dissolved in methanol (200 ml), sodium borohydride (7.1 g) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. After concentrating the reaction mixture, add water (200
ml), a 1N aqueous sodium hydroxide solution was added until the pH reached 9, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by alumina column chromatography (developing solvent: ethyl acetate: hexane = 1: 1). Concentrated hydrochloric acid (26 ml)
ml) and 10% palladium-carbon (3 g) were added. After the reaction solution was catalytically reduced under a normal hydrogen pressure for 48 hours, the catalyst was filtered off from the reaction solution, and the filtrate was concentrated. The precipitated crystals were washed with acetone to give the title compound (8.17 g). Melting point: 192-193 ° C

Reference Example 11 2-Aminomethyl-6-methoxytetralin hydrochloride The title compound was synthesized in the same manner as in Reference Example 10. Melting point: 217-218 ° C Recrystallization solvent: ethanol-diisopropyl ether Reference Example 12 N- (6-methoxy-2-tetralinyl) methylacetamide 2-aminomethyl-6-methoxytetralin hydrochloride (1.
Acetyl chloride (0.67 g) was added to a pyridine solution (15 ml) of 5 g of Reference Example Compound 11), and the reaction solution was stirred at room temperature for 16 hours, and then ethyl acetate was added to the reaction solution. The organic layer was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-diisopropyl ether to give the title compound (960 mg). Melting point: 96-97 ℃

Reference Example 13 N, N-dimethyl- (6-methoxy-2-tetralin) acetamide (6-methoxy-2-tetralin) acetic acid (1.491 g), dimethylamine hydrochloride (0.846 g), WSC (1.726 g) ), 1-
Hydroxybenzotriazole (1.069 g) and triethylamine (2.8 ml) in acetonitrile (30 ml)
Added. After the reaction solution was stirred at room temperature for 20 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried and concentrated.
The residue was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 1: 1) to give the title compound (1.667 g). ¹ H NMR δ: 1.34-1.57 (1H, m), 1.91-2.08 (1H, m),
2.22-2.51 (2H, m), 2.36 (2H, s), 2.77-2.94 (3H, m),
2.98 (3H, s), 3.02 (3H, s), 3.77 (3H, s), 6.59
6.72 (2H, m), 6.96 (1H, d, J = 8Hz)

Reference Example 14 2- [2- (N, N-dimethylamino) ethyl] -6-methoxytetralin hydrochloride N, N-dimethyl- (6-methoxy-2-tetralin) acetamide (1.613 g, Reference Example) Compound 13) in THF (20 m
To l), lithium aluminum hydride (0.25 g) was added. After the reaction solution was stirred at room temperature for 6 hours, water was added to the reaction solution. The insolubles were filtered off from the reaction solution, and the filtrate was concentrated. The residue was treated with a 4N hydrochloric acid-ethyl acetate solution to form a hydrochloride, and further recrystallized from methanol-ethyl acetate to obtain the title compound (1.247 g). Melting point: 183-185 ° C. Reference Example 15 2- [N-benzyl-N- (3,3-diphenylpropyl) amino] methyl-6-methoxytetralin 2- (N-benzylamino) methyl-6-methoxytetralin hydrochloride (0.602 g Reference example compound 6), 3,3-diphenylpropyl iodide (0.803 g) and potassium carbonate (0.800 g) were added to DMF (20 ml). Allow the reaction to proceed at room temperature
After stirring for 4 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated.
The residue was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 1: 1) to give the title compound (0.335 g). ¹ H NMR δ: 1.11-1.40 (1H, m), 1.70-2.05 (2H, m),
2.13-2.48 (7H, m), 2.62-2.88 (3H, m), 3.54 (2H,
s), 3.76 (3H, s), 3.98 (1H, t, J = 8Hz), 6.55-6.70
(2H, m), 6.95 (1H, d, J = 8Hz), 7.04-7.38 (15H, m)

Reference Example 16 2- (N, N-dimethylamino) methyl-6-hydroxytetraline hydrochloride 2- (N, N-dimethylamino) methyl-6-methoxytetraline hydrochloride (0.365 g, Reference Example Compound 5 ) Was added to 48% hydrobromic acid (10 ml), and the reaction solution was heated under reflux for 3 hours.
Allowed to cool. The reaction solution was neutralized with a 1N aqueous sodium hydroxide solution, a 10% potassium carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated.
The residue was subjected to alumina column chromatography (developing solvent;
After purification with ethyl acetate: hexane = 1: 2), the mixture was treated with a 4N hydrochloric acid-ethyl acetate solution to obtain a hydrochloride. The obtained salt was washed with ethyl acetate to obtain the title compound (0.211 g). Melting point: 221-224 ° C

The following Reference Examples Compounds 17 to 22 were synthesized in the same manner as in Reference Example 16. Reference Example 17 2- (N, N-dipropylamino) methyl-6-hydroxytetralin hydrochloride Melting point: 173-175 ° C. Recrystallization solvent: methanol-diisopropyl ether Reference Example 18 2- [N-benzyl-N- (3 , 3-Diphenylpropyl) amino] methyl-6-hydroxytetralin ¹ H NMR δ: 1.10-1.34 (1H, m), 1.68-2.02 (2H, m),
2.12-2.48 (7H, m), 2.57-2.87 (3H, m), 3.55 (2H,
d, J = 2Hz), 3.98 (1H, t, J = 8Hz), 6.48−6.60 (2H,
m), 6.89 (1H, d, J = 8Hz), 7.04-7.34 (15H, m) Reference Example 19 6-Hydroxy-2-piperidinomethyltetralin hydrochloride Melting point: 216-218 ° C Recrystallization solvent: methanol Diethyl ether Reference Example 20 2- [2- (N, N-dimethylamino) ethyl] -6-hydroxytetralin Melting point: 114-116 ° C. Recrystallization solvent: ethyl acetate-hexane Reference Example 21 2- (N, N-dimethyl) Amino) methyl-7-hydroxytetralin hydrochloride Melting point: 197-198 ° C Recrystallization solvent: methanol-ethyl acetate Reference Example 22 6-Hydroxy-2- (N-methylamino) methyltetralin hydrochloride Melting point: 229-230 ° C Crystal solvent: methanol-ethyl acetate

Reference Example 23 N- [6- (4-Biphenylyl) methoxy-2-tetralinyl] methylacetamide N- (6-methoxy-2-tetralinyl) methylacetamide (730 mg, Reference Example Compound 12) in methylene chloride ( 15 m
l) To the solution at 0 ° C. was added boron tribromide (1.57 g). The reaction solution was warmed to room temperature and stirred for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of potassium carbonate, dried and concentrated. Residue in DMF (20
ml), and 4- (iodomethyl) biphenyl (1.35
g) and potassium carbonate (1.36 g) were added. The reaction was stirred at room temperature for 16 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate: hexane = 1: 1). The obtained crude crystals were recrystallized from ethyl acetate-diisopropyl ether to give the title compound (75
0 mg). Melting point: 144-145 ° C Reference Example 24 Methyl (6-hydroxy-2-tetralin) acetate (15.22 g) of methyl (6-methoxy-2-tetralin) acetic acid (48)
% Hydrobromic acid (100 ml) and the reaction was heated to reflux for 3 hours. After cooling the reaction solution, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The obtained residue was treated with methanol (20
0 ml) and thionyl chloride (6.0 ml) was added dropwise at 0 ° C. The reaction solution was stirred at room temperature for 2 hours, and then concentrated. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the title compound (9.566 g). ^{1 H NMR δ: 1.32-1.55 (1H} , m), 1.84-2.00 (1H, m),
2.10-2.48 (4H, m), 2.70-2.89 (3H, m), 3.71 (3H,
s), 4.80 (1H, s), 6.52--6.64 (2H, m), 6.91 (1H, d,
(J = 8Hz)

Reference Example 25 Methyl [6- (2-naphthyl) methoxy-2-tetralin] acetate Methyl (6-hydroxy-2-tetralin) acetate (0.608
g, Reference Example Compound 24), 2-naphthylmethyl bromide (0.
737 g) and potassium carbonate (0.59 g) in DMF (20 ml)
Added. After the reaction solution was stirred at room temperature for 5 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 1: 4) and recrystallized from ethyl acetate-hexane to give the title compound (0.624 g). Melting point: 73-75 ° C Reference Example 26 Methyl 2- (2-hydroxyethyl) -6- (2-naphthyl) methoxytetralin [6- (2-naphthyl) methoxy-2-tetralin] acetate (0.712 g, Reference example compound) 25) THF solution (10 ml)
To this was added lithium aluminum hydride (75 mg).
After the reaction solution was stirred at room temperature for 2 hours, water was added. The insolubles were filtered off from the reaction solution, and the filtrate was concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the title compound (0.
451 g) were obtained. Melting point: 90-91 ° C

Reference Example 27 2- (2-Iodoethyl) -6- (2-naphthyl) methoxytetralin 2- (2-hydroxyethyl) -6- (2-naphthyl) methoxytetralin (0.712 g, Reference Example Compound 26) And a solution of pyridine (0.19 ml) in dichloromethane (15 ml) at 0 ° C.
Then, p-toluenesulfonyl chloride (0.301 g) was added. After stirring the reaction solution at room temperature for 24 hours, 1N hydrochloric acid was added, and the mixture was extracted with dichloromethane. The organic layer was washed with water, saturated aqueous sodium bicarbonate and saturated saline, dried and concentrated. The residue was dissolved in acetone (10 ml), and sodium iodide (0.371 g) was added. The reaction solution was heated under reflux for 4 hours and concentrated. A saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium thiosulfate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 10),
The title compound (0.451 g) was obtained. ^{1 H NMR δ: 1.30-1.60 (1H} , m), 1.75-2.02 (4H, m),
2.26-2.46 (1H, m), 2.72-2.89 (3H, m), 3.30 (2H,
t, J = 7Hz), 5.19 (2H, s), 6.72-6.83 (2H, m), 6.98
(1H, d, J = 8Hz), 7.42--7.57 (3H, m), 7.78-7.91 (4
H, m) Reference Example 28 [6- (4-biphenylyl) methoxy-2-tetralin]
Methyl acetate (6-hydroxy-2-tetralin) methyl acetate (4.407
g, 60% in a DMF solution (100 ml) of Reference Example Compound 24) at 0 ° C.
Oily sodium hydride (1.034 g) was added. Reaction solution 4
After stirring at 0 ° C. for 1 hour, the mixture was cooled again to 0 ° C. and 4- (chloromethyl) biphenyl (4.466 g) was added. After the reaction solution was stirred at room temperature for 14 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The obtained crude crystals were washed with diisopropyl ether to give the title compound (3.995 g). Melting point: 65-70 ° C

Reference Example 29 [6- (4-Biphenylyl) methoxy-2-tetralin]
Acetic acid [6- (4-biphenylyl) methoxy-2-tetralin]
Methyl acetate (3.480 g, Reference Example Compound 28) was added to THF (80 m
l) and methanol (40 ml), and 1N aqueous sodium hydroxide solution (20 ml) was added. The reaction solution was stirred at room temperature for 7 hours, and then concentrated. 1N Hydrochloric acid was added to the residue until it became acidic, and the mixture was extracted with a mixed solvent of ethyl acetate and THF. The organic layer was washed with saturated saline, dried, and concentrated. The obtained crude crystals were recrystallized from THF-diisopropyl ether to give the title compound (2.956 g). Melting point: 167-169 ° C Reference Example 30 [6- (4-biphenylyl) methoxy-2-tetralin]
-N, N-dimethylacetamide [6- (4-biphenylyl) methoxy-2-tetralin]
Acetic acid (1.866 g, Reference Example Compound 29), dimethylamine hydrochloride (0.553 g), WSC (1.512 g), 1-hydroxybenzotriazole (0.764 g), and triethylamine (2.1 ml) were mixed with acetonitrile (50 ml) and THF. (50 m
l). After stirring the reaction solution at room temperature for 20 hours, 1
N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate and saturated saline, dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the title compound (1.497 g). Melting point: 114-119 ° C

Reference Example 31 6-acetylamino-2- (N, N-dimethylamino) methyltetralin N, N-dimethylmethyleneammonium chloride (2.04 g)
) Was added to a solution of 6-acetylamino-1-tetralone (1.692 g) in THF (40 ml), and the mixture was stirred at room temperature for 24 hours and concentrated. A 10% aqueous potassium carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was dissolved in methanol (50 ml), and sodium borohydride (0.86 g) was added. After the reaction solution was stirred at room temperature for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. Residue in methanol (50 m
l), 10% palladium on carbon (0.4 g) and 1N
Hydrochloric acid (20 ml) was added, and the mixture was subjected to catalytic reduction at a hydrogen pressure of 1 atm for 12 hours. The reaction solution was filtered to remove palladium-carbon, and the filtrate was concentrated. Then, a 10% aqueous solution of potassium carbonate was added to the reaction solution to give a free product, which was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The obtained crude crystals were washed with ethyl acetate-
Recrystallization from hexane gave the title compound (1.862 g). Melting point: 104-107 ° C Reference Example 32 6-Amino-2- (N, N-dimethylamino) methyltetralin Hydrochloride of 6-acetylamino-2- (N, N-dimethylamino) methyltetralin (0.879 g, reference Example compound 31) with 2
Added to N hydrochloric acid. After heating the reaction solution to reflux for 90 minutes, a 1N aqueous sodium hydroxide solution was added to the reaction solution until pH 9 was reached,
Extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was subjected to alumina column chromatography (developing solvent; ethyl acetate: hexane = 1:
Purification in 1) gave the title compound (0.231 g). ^{1 H NMR δ: 1.24-1.47 (1H} , m), 1.60-2.00 (3H, m),
2.13-2.40 (2H, m), 2.24 (6H, s), 2.66-2.89 (3H, m),
3.23-3.73 (2H, br), 6.42-6.52 (2H, m), 6.89 (1H, d,
(J = 8Hz)

Reference Example 33 6- (4-Bromobenzyl) oxy-2- (N, N-dimethylamino) methyltetralin 2- (N, N-dimethylamino) methyl-6-hydroxytetralin (5.0 g, Reference Example) Compound 16) was dissolved in DMF (130 ml) and 60% oily sodium hydride (1.46 g) was added at 0 ° C. The reaction was warmed to room temperature and stirred for 1 hour. The reaction solution was cooled again to 0 ° C., and 4-bromobenzyl bromide (1
0.0 g) of a DMF solution (20 ml) was added. Reaction at room temperature
After stirring for 2 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 10),
The title compound (3.4 g) was obtained. ¹ H NMR δ: 1.2-1.5 (1H, m), 1.7-2.1 (2H, m), 2.1-
2.5 (3H, m), 2.24 (6H, s), 2.7-3.0 (3H, m), 4.97 (2
H, s), 6.6-6.8 (2H, m), 7.00 (1H, d, J = 8Hz), 7.28
(2H, d, J = 8Hz), 7.50 (2H, d, J = 8Hz).

The following Reference Examples Compounds 34 to 40 were synthesized in the same manner as in Reference Example 33. Reference Example 34 6- (3-Bromobenzyl) oxy-2- (N, N-dimethylamino) methyltetralin ¹ H NMR δ: 1.2-1.5 (1H, m), 1.7-2.1 (2H, m), 2.1-
2.5 (3H, m), 2.24 (6H, s), 2.7-3.0 (3H, m), 4.99 (2
H, s), 6.6-6.8 (2H, m), 7.01 (1H, d, J = 8Hz), 7.1-7.
5 (3H, m), 7.59 (1H, s). Reference Example 35 6- (2-Bromobenzyl) oxy-2- (N, N-dimethylamino) methyltetralin ¹ H NMR δ: 1.2-1.5 (1H, m), 1.7-2.1 (2H, m), 2.1-
2.5 (3H, m), 2.24 (6H, s), 2.7-3.0 (3H, m), 5.09 (2
H, s), 6.7-6.8 (2H, m), 7.02 (1H, d, J = 8Hz), 7.17
(1H, td, J = 7Hz, 2Hz), 7.32 (1H, td, J = 7Hz, 2Hz),
Reference Example 36 6-benzyloxy-2- (N, N-dimethylamino) methyltetralin hydrochloride Melting point: 196-198 ° C Recrystallization solvent: methanol-ethyl acetate Reference Example 37 6- (2-chlorobenzyl) oxy-2- (N, N-dimethylamino) methyltetralin hydrochloride Melting point: 203-207 ° C Recrystallization solvent: methanol-diethyl ether Reference Example 38 6- (2,4-dichlorobenzyl) oxy −2- (N, N-dimethylamino) methyltetralin hydrochloride Melting point: 217-218 ° C. Recrystallization solvent: methylene chloride-diethyl ether Reference Example 39 6- (4-benzyloxybenzyl) oxy-2- (N, N -
Dimethylamino) methyltetralin hydrochloride Melting point: 208-209 ° C Recrystallization solvent: ethanol-ethyl acetate Reference Example 40 2- [N-benzyl-N- (3,3-diphenylpropyl) amino] methyl-6- (2, 4-Dichlorobenzyl) oxytetralin hydrochloride Amorphous powder ¹ H NMR δ: 1.12-1.35 (1H, m), 1.72-2.06 (2H, m),
2.14-2.48 (7H, m), 2.54-2.88 (3H, m), 3.55 (2H, d,
J = 2Hz), 3.98 (1H, t, J = 7Hz), 5.07 (2H, s), 6.63-
6.74 (2H, m), 6.96 (1H, d, J = 8Hz), 7.06-7.34 (15H,
m), 7.37-7.53 (3H, m). IR (KBr): 3058, 3028, 2925, 2572, 1592, 1500, 1234,
747, 701cm ^-1 .

Reference Example 41 Methyl [6- (4-bromobenzyl) oxy-2-tetralin] acetate Methyl (6-hydroxy-2-tetralin) acetate (17.5
g), 4-bromobenzyl bromide (24.0 g) and potassium carbonate (30.6 g) were added to DMF (160 ml). After the reaction solution was stirred at room temperature for 12 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The obtained crude crystals were recrystallized from toluene-diisopropyl ether to give the title compound (31.0 g). Melting point: 78-79 ° C. Reference Example 42 [6- (4-Bromobenzyl) oxy-2-tetralin] acetic acid Methyl [6- (4-bromobenzyl) oxy-2-tetralin] acetate (31.0 g) in methanol (200 ml)
A 1N aqueous sodium hydroxide solution (200 ml) was added. The reaction solution was stirred at 80 ° C. for 4 hours and concentrated. 1N Hydrochloric acid was added to the residue until acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the title compound (29.4
g) was obtained. Melting point: 145-146 ° C. Reference Example 43 Methyl 3- (6-methoxy-2-methoxycarbonyl-1-oxo-2-tetralin) propionate Methyl (6-methoxy-1-oxo-2-tetralin) carboxylate (J Am. Chem. Soc, 78, 461, 1951;
To a solution of 21 g) in methanol (100 ml) was added a 28% solution of sodium methoxide in methanol (17.3 g). A methanol solution of methyl acrylate (9.7 ml) (100
ml) and stirred at room temperature for 3 hours. The reaction solution was poured into a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-diisopropyl ether to give the title compound (19.7 g). Melting point: 66-67 ℃

Reference Example 44 3- (6-Methoxy-1-oxo-2-tetralin) propionic acid Methyl 3- (6-methoxy-2-methoxycarbonyl-1-oxo-2-tetralin) propionate (17.7 g) 6N hydrochloric acid (150 ml) was added to an acetic acid solution (30 ml), and the mixture was heated under reflux for 2 hours. Water (200 ml) was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain the title compound (13.3 g). Melting point: 129-130 ° C Reference Example 45 Methyl 4- (6-methoxy-1-oxo-2-tetralin) butyrate 3- (6-methoxy-1-oxo-2-tetralin) carboxylate (20 g), 4- Ethyl bromocrotonate (26.
4 g) and potassium carbonate (23.6 g) were added to DMF (300 ml). After stirring the reaction solution at 80 ° C. for 12 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. Residue in ethanol (200 m
10% palladium-carbon (3.0 g) was added to l), and the mixture was subjected to catalytic reduction at room temperature under a hydrogen pressure of 1 atm for 12 hours. The catalyst was filtered off from the reaction solution, and the filtrate was concentrated. 6N in acetic acid solution (50 ml) of the residue
Hydrochloric acid (100 ml) was added, and the mixture was heated under reflux for 4 hours. Water (200 ml) was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-diisopropyl ether to give the title compound (14.0 g). Melting point: 91-92 ° C Reference Example 46 3- (6-Methoxy-2-tetralin) propionic acid 3- (6-Methoxy-1-oxo-2-tetralin) propionic acid (10 g) in acetic acid (50 ml) Perchloric acid (0.25 ml)
And 10% palladium-carbon (1.0 g) were added, and the mixture was catalytically reduced at room temperature under a hydrogen pressure of 1 atm for 24 hours. The catalyst was filtered off from the reaction solution, and the filtrate was concentrated. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with water and saturated saline,
After drying, it was concentrated. The obtained crude crystals were recrystallized from toluene-diisopropyl ether to give the title compound (6.6 g). Melting point: 114-115 ° C. Reference Example 47 4- (6-Methoxy-2-tetralin) butyric acid The title compound was synthesized in the same manner as in Reference Example 46. Melting point: 100-101 ° C Recrystallization solvent: toluene-diisopropyl ether

Reference Example 48 [6- (4-bromobenzyl) oxy-2-tetralin]
-N, N-dimethylacetamide [6- (4-bromobenzyl) oxy-2-tetralin]
Acetic acid (15.0 g), dimethylamine hydrochloride (4.24 g), WS
C (12.0 g), 1-hydroxybenzotriazole (6.13
g) and triethylamine (16.7 ml) were added to a mixed solvent of acetonitrile (200 ml) and THF (200 ml).
After the reaction solution was stirred at room temperature for 12 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous layer solution and saturated saline, dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the title compound (14.3 g). Melting point: 86-87 ° C. The following Reference Examples Compounds 49 to 50 were synthesized in the same manner as in Reference Example 48. Reference Example 49 N, N-dimethyl-3- (6-methoxy-2-tetralin) propionamide Oil ¹ H NMR δ: 1.32-1.54 (1H, m), 1.60-1.84 (3H, m),
1.84-2.02 (1H, m), 2.26-2.50 (3H, m), 2.70-2.90 (3
H, m), 2.95 (3H, s), 3.03 (3H, s), 3.76 (3H, s), 6.
56-6.72 (2H, m), 6.97 (1H, d, J = 8 Hz). Reference Example 50 N, N-dimethyl-4- (6-methoxy-2-tetralin) butanamide Oil ¹ H NMR δ: 1.30- 1.50 (3H, m), 1.60-1.84 (3H, m),
1.84-2.00 (1H, m), 2.24-2.44 (3H, m), 2.70-2.90 (3
H, m), 2.95 (3H, s), 3.01 (3H, s), 3.76 (3H, s), 6.
56-6.72 (2H, m), 6.97 (1H, d, J = 8 Hz). Reference Example 51 6- (4-Bromobenzyl) oxy-2- [2- (N, N-dimethylamino) ethyl] tetralin hydrochloride Salt [6- (4-bromobenzyl) oxy-2-tetralin]
-N, N-dimethylacetamide (13.8 g) in THF (30
0 ml) was added lithium aluminum hydride (1.95 g). After stirring the reaction solution at room temperature for 2 hours, a 1N aqueous sodium hydroxide solution was added to the reaction solution. The insolubles were filtered off from the reaction solution, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate to methanol), and then treated with a 4N hydrochloric acid-ethyl acetate solution to obtain a hydrochloride. The resulting salt is recrystallized with methanol-ethyl acetate,
The title compound (10.5 g) was obtained. Melting point: 200-202 ℃

The following Reference Examples Compounds 52 to 53 were synthesized in the same manner as in Reference Example 51. Reference Example 52 2- [3- (N, N-dimethylamino) propyl] -6-methoxytetralin hydrochloride Melting point: 163-164 ° C. Recrystallization solvent: methanol-diisopropyl ether Reference Example 53 2- [4- (N, N-dimethylamino) butyl] -6-methoxytetralin hydrochloride Melting point: 144-145 ° C Recrystallization solvent: methanol-diisopropyl ether Reference Example 54 2- [3- (N, N-dimethylamino) propyl] -6-hydroxy Tetraline hydrochloride 2- [3- (N, N-dimethylamino) propyl] -6-methoxytetraline hydrochloride (3.6 g) is treated with 48% hydrobromic acid (20%).
ml), and the reaction solution was heated under reflux for 3 hours and then allowed to cool. The reaction solution was neutralized with a 1N aqueous sodium hydroxide solution, a 10% aqueous potassium carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was recrystallized from methanol-diisopropyl ether to give the title compound (2.0 g). Melting point: 110-111 ° C. Reference Example 55 2- [4- (N, N-dimethylamino) butyl] -6-hydroxytetralin hydrochloride The title compound was synthesized in the same manner as in Reference Example 54. Melting point: 123-124 ° C Recrystallization solvent: methanol-diisopropyl ether

Reference Example 56 N, N-dimethyl- (6-methoxy-1-oxo-2-tetralin) acetamide (6-methoxy-1-oxo-2-tetralin) acetic acid (Eur. J. Med. Che)
m. , 25, 765, 1990; 53.8 g, 230
mmol) in acetonitrile solution (1 L) and dimethylamine hydrochloride (24.3 g, 298 mmol) and WSC (66.0 g, 344 mmo).
l), 1-hydroxybenztriazole hydrate (35.1
g, 230 mmol). Triethylamine (96 ml, 689 mmol) was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-toluene to obtain the title compound (34 g). Melting point: 102-104 ° C. Reference Example 57 N, N-dimethyl- [6-methoxy-2- (3,4-dihydronaphthalene)] acetamide N, N-dimethyl- (6-methoxy-1-oxo-2-tetralin ) Acetamide (44.7 g, 180 mmol) in methanol (1 L) was added to sodium borohydride (15 g, 397 mmo).
l) was added in three portions under ice cooling. The reaction solution was stirred at room temperature for 2 hours, neutralized with 1N hydrochloric acid, concentrated under reduced pressure until the amount of the reaction solution was reduced to about one-third, added with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried,
It was concentrated under reduced pressure. A toluene solution of the residue (700 ml) was p-toluenesulfonic acid hydrate (700 mg,
4.06 mmol) and heated under reflux for 30 minutes. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 1 to ethyl acetate) to obtain the title compound (37.5 g). ¹ H NMR δ: 2.30 (2H, t, J = 8.0 Hz), 2.83 (2H, t, J =
8.0 Hz), 2.99 (3H, s), 3.04 (3H, s), 3.26 (2H, s),
3.79 (3H, s), 6.21 (1H, s), 6.62-6.72 (2H, m), 6.86
-6.96 (1H, m).

Reference Example 58 (-)-N, N-dimethyl- (6-methoxy-2-tetralin) acetamide N, N-dimethyl- [6-methoxy-2- (3,4-dihydronaphthalene)] acetamide ( 18.03 g, 73.50 mmol) and [RuCl
₂ [(R)-(BINAP)]] ₂ A solution of NEt ₃ (1.24 g, 0.734 mmol) and degassed ethanol (160 ml) was transferred to an autoclave, and hydrogen pressure was 100 kg / cm ² at 70 ° C. Stirred for 6 hours. The reaction solution is concentrated to dryness under reduced pressure, and the residue is subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate =
1: 2) to give the title compound (15.5 g, 98.3% ee). Melting point: 70-71 ° C Recrystallization solvent: ethyl acetate-hexane [α] _D ²⁵ = -61.3 ° (c = 1.00, chloroform) Elemental analysis: C ₁₅ H ₂₁ NO ₂ Calculated: C, 72.84; H, 8.56 N, 5.66 Found: C, 72.76; H, 8.49; N, 5.79. Reference Example 59 (+)-N, N-dimethyl- (6-methoxy-2-tetralin) acetamide N, N-dimethyl- [6 -Methoxy-2- (3,4-dihydronaphthalene)] acetamide (18.06 g, 73.50 mmol)
[RuCl ₂ [(S)-(BINAP)]] ₂ NEt ₃ (1.24 g, 0.734 mmol) added with degassed ethanol (160 ml) was transferred to an autoclave, and hydrogen pressure was 100 kg / cm ² , 70 kg Stirred at C for 6 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 2) to give the title compound (15.8 g, 98.7% e.
e.). Melting point: 71-72 ° C Recrystallization solvent: ethyl acetate-hexane [α] _D ²⁵ = + 63.7 ° (c = 1.00, chloroform) Elemental analysis: As C ₁₅ H ₂₁ NO ₂ Calculated: C, 72.84; H, 8.56; N, 5.66 Found: C, 72.68; H, 8.42; N, 5.65 Reference Example 60 (+)-2- [2- (N, N-dimethylamino) ethyl] -6
-Methoxytetralin hydrochloride (+)-N, N-dimethyl- (6-methoxy-2-tetralin) acetamide (0.870 g) in THF solution (15 ml)
Lithium aluminum hydride (0.203 g) was added. The reaction solution was stirred at room temperature for 50 minutes, heated to reflux for 30 minutes, and allowed to cool. Water was added to the reaction solution, the insolubles were separated from the reaction solution by filtration, and the filtrate was concentrated. The residue was subjected to alumina column chromatography (eluent: hexane to ethyl acetate: hexane = 1: 10).
After purification by 1: 4), the solution was treated with a 4N hydrochloric acid-ethyl acetate solution to obtain a hydrochloride. The resulting salt was recrystallized from methanol-diisopropyl ether to give the title compound (0.749 g). Melting point: 195-197 ° C [α] _D ²⁰ = + 68.2 ° (c = 0.55, methanol)

Reference Example 61 (+)-2- [2- (N, N-dimethylamino) ethyl] -6
-Hydroxytetralin hydrochloride (+)-2- [2- (N, N-dimethylamino) ethyl] -6
-Methoxytetralin hydrochloride (0.602 g) was added to 48% hydrobromic acid (10 ml),
The reaction solution was refluxed for 3.5 hours, and then allowed to cool. The reaction solution was neutralized with a 1N aqueous sodium hydroxide solution, a 10% potassium carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was treated with a 4N hydrochloric acid-ethyl acetate solution to obtain a hydrochloride. The resulting salt was recrystallized from methanol-diisopropyl ether to obtain the title compound (0.490 g). Melting point: 213-215 ° C. [α] _D ²⁰ = + 69.1 ° (c = 0.52, methanol) Reference Example 62 (−)-2- [2- (N, N-dimethylamino) ethyl] -6
-Methoxytetralin hydrochloride (-)-N, N-dimethyl- (6-methoxy-2-tetralin) acetamide (0.807 g) in THF solution (15 ml)
Lithium aluminum hydride (0.130 g) was added. The reaction solution was stirred at room temperature for 15 minutes, heated to reflux for 15 minutes, and allowed to cool. Water was added to the reaction solution, the insolubles were separated from the reaction solution by filtration, and the filtrate was concentrated. The residue was subjected to alumina column chromatography (developing solvent; hexane to ethyl acetate: hexane = 1:
After purification in 4), the solution was treated with a 4N hydrochloric acid-ethyl acetate solution to obtain a hydrochloride. The resulting salt was recrystallized from methanol-diisopropyl ether to give the title compound (0.683 g). Melting point: 193-195 ° C [α] _D ²⁰ = -68.0 ° (c = 0.49, methanol)

Reference Example 63 (-)-2- [2- (N, N-dimethylamino) ethyl] -6
-Hydroxytetralin hydrochloride (-)-2- [2- (N, N-dimethylamino) ethyl] -6
-Methoxytetralin hydrochloride (0.563 g) was added to 48% hydrobromic acid (10 ml), and the reaction solution was refluxed for 4 hours and then allowed to cool. The reaction solution was neutralized with a 1N aqueous sodium hydroxide solution,
A 10% potassium carbonate solution was added, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated saline, dried, and concentrated. The residue was treated with a 4N hydrochloric acid-ethyl acetate solution to obtain a hydrochloride. The resulting salt was recrystallized from methanol-diisopropyl ether to give the title compound (0.480 g). Melting point: 213-215 ° C. [α] _D ²⁰ = −69.9 ° (c = 0.55, methanol) Reference Example 64 6- (4-Biphenylyl) methoxy-2- (2-hydroxyethyl) tetralin Lithium aluminum hydride (4.71 g) ) THF suspension (2
6- (4-biphenylyl) methoxy-2 under ice-cooling.
-A solution of methyl tetralin acetate (24.0 g) in THF (50 ml)
Was added. After stirring the reaction solution at room temperature for 2 hours, a saturated aqueous solution of sodium potassium tartrate was added to the reaction solution. The insolubles were filtered off from the reaction solution, and the filtrate was concentrated. The residue was recrystallized from ethyl acetate-hexane to give the title compound (22.1 g). Melting point: 101-102 ° C Reference Example 65 6- (4-biphenylyl) methoxy-2- (2-iodoethyl) tetralin Triphenylphosphine (12.5 g) in THF solution (200 m)
To l), imidazole (3.25 g) and iodine (12.1 g) were added. 6- (4-Biphenylyl) methoxy-2-
THF for (2-hydroxyethyl) tetralin (13.15 g)
The solution (100 ml) was added at room temperature. After the reaction solution was stirred at room temperature for 5 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium thiosulfate and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (eluent: toluene) to give the title compound (13.2 g). ^{1 H NMR δ: 1.30-1.60 (1H} , m), 1.75-2.00 (4H,
m), 2.20-2.46 (1H, m), 2.72-2.92 (3H, m), 3.3
0 (2H, t, J = 7Hz), 5.07 (2H, s), 6.70−6.84 (2H,
m), 6.99 (1H, d, J = 8Hz), 7.14-7.66 (9H, m).

Reference Example 66 (+)-6- (4-bromobenzyl) oxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride (+)-2- [2- (N, N-dimethylamino) ethyl] -6
-Hydroxytetralin (9.2 g) in toluene (180 m
l) Add 60% oily sodium hydride (2.0 g) to the suspension
Stirred at 50 ° C. for 30 minutes. A solution of 4-bromobenzyl chloride (9.7 g) in toluene (45 ml) was added to the reaction solution, and the mixture was heated under reflux for 1 hour. Water was added to the reaction solution and concentrated. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. Ethyl acetate: hexane = 1: 4 was added to the residue, and insolubles were removed by filtration. The filtrate was concentrated, and the residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 50 to 1: 4), converted into a hydrochloride, and concentrated. The obtained crude crystals were washed with diisopropyl ether to give the title compound (17.0 g). Melting point: 191-193 ° C. [α] _D ²⁰ = + 44.1 ° (c = 0.99, methanol) Reference Example 67 N, N-diethyl- (6-methoxy-1-oxo-2-tetralin) acetamide (6-methoxy) 1-oxo-2-tetralin) acetic acid (30
To a solution of g) in acetonitrile (500 ml) were added diethylamine (18.7 g), WSC (36.8 g), and 1-hydroxybenzotriazole (19.6 g). The reaction solution was stirred at room temperature for 2 days and concentrated. After diluting the residue with ethyl acetate, the organic layer was separated.
Washed sequentially with 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline.
The organic layer was dried and concentrated. The residue is subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate =
Purification by 1: 1) and recrystallization from ethyl acetate-diisopropyl ether gave the title compound (26.8 g). Melting point: 88-89 ° C

Reference Example 68 N, N-diethyl- [6-methoxy-2- (3,4-dihydronaphthalene)] acetamide N, N-diethyl- (6-methoxy-1-oxo-2-tetralin) acetamide ( Sodium borohydride (6.54 g) was added to a methanol (400 ml) solution of 25 g) under ice-cooling. After stirring at room temperature for 30 minutes, 1N hydrochloric acid was added dropwise to the reaction solution to neutralize it. After the reaction solution was concentrated, it was extracted with ethyl acetate. The organic layer was washed sequentially with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried and concentrated. The residue was dissolved in degassed toluene (300 ml), and p-toluenesulfonic acid monohydrate (20 mg) was added. The reaction solution was heated under reflux for 1 hour and then cooled to room temperature. Ethyl acetate was added to the reaction solution, washed with saturated aqueous sodium hydrogen carbonate, dried and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 1) to give the title compound (23.1 g). ^{1 H NMR δ: 1.10-1.25 (6H} , m), 2.31 (2H, t, J = 7.
6 Hz), 2.82 (2H, t, J = 7.6 Hz), 3.23 (2H, s),
3.26-3.48 (4H, m), 3.78 (3H, s), 6.22 (1H, s),
6.62-6.72 (2H, m), 6.84-6.96 (1H, m). Reference Example 69 (+)-N, N-diethyl- (6-methoxy-2-tetralin) acetamide N, N-diethyl- [6- Methoxy-2- (3,4-dihydronaphthalene)] acetamide (10.0 g) and Ru ₂ Cl ₄ [(S)
−BINAP] ₂ NEt ₃ (618 mg) degassed ethanol (170
ml) was added to the autoclave and the hydrogen pressure was 100
The mixture was stirred at 70 ° C. for 6 hours at kg / cm ² . The reaction solution is concentrated, and the residue is subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate = 2: 1) and alumina column chromatography (developing solvent; hexane: ethyl acetate = 4:
Purification in 1) gave the title compound (8.8 g). [Α] _D ²⁰ = + 54.0 ° (c = 1.000, methanol) ¹ H NMR δ: 1.00-1.22 (6H, m), 1.30-1.56 (1H,
m), 1.88−2.08 (1H, m), 2.20−2.50 (4H, m), 2.7
0−3.00 (3H, m), 3.26−3.46 (4H, m), 3.77 (3H, m
s), 6.60-6.75 (2H, m), 6.96 (1H, d, J = 8.0Hz). Optical purity: 94% ee (analyzed by HPLC :)

Reference Example 70 (-)-N, N-diethyl- (6-methoxy-2-tetralin) acetamide N, N-diethyl- [6-methoxy-2- (3,4-dihydronaphthalene)] acetamide ( 10.0 g) and Ru ₂ Cl ₄ [(R)
−BINAP] ₂ NEt ₃ (618 mg) degassed ethanol (170
ml) was added to the autoclave and the hydrogen pressure was 100
The mixture was stirred at 70 ° C. for 6 hours at kg / cm ² . The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 2: 1) to give the title compound (8.
88 g) were obtained. [Α] _D ²⁰ = −53.0 ° (c = 0.799, methanol) ¹ H NMR δ: 1.00-1.22 (6H, m), 1.30-1.56 (1H,
m), 1.88−2.08 (1H, m), 2.20−2.50 (4H, m), 2.7
0−3.00 (3H, m), 3.26−3.46 (4H, m), 3.77 (3H, m
s), 6.60-6.75 (2H, m), 6.96 (1H, d, J = 8.0 Hz). Optical purity: 93.7% ee (analyzed by HPLC :) Reference Example 71 (+)-2- [2- (N , N-Diethylamino) ethyl] -6
-Methoxytetralin hydrochloride To a THF solution (150 ml) of (+)-N, N-diethyl- (6-methoxy-2-tetralin) acetamide (8.8 g) was added lithium aluminum hydride (1.45 g). After stirring the reaction solution at room temperature for 2 hours, a 1N aqueous sodium hydroxide solution was added to the reaction solution. The insolubles were removed by filtration, and the filtrate was concentrated. The residue was purified by alumina column chromatography (developing solvent; hexane: ethyl acetate = 10: 1) and converted into a hydrochloride,
Recrystallization from methanol-diisopropyl ether gave the title compound (5.4 g). Melting point: 144-145 ° C. [α] _D ²⁰ = + 61.5 ° (c = 1.000, methanol) Reference Example 72 (−)-2- [2- (N, N-diethylamino) ethyl] -6
-Methoxytetralin hydrochloride The title compound was obtained in the same manner as in Reference Example 71. Melting point: 144-145 ° C (recrystallization solvent: methanol-diisopropyl ether) [α] _D ²⁰ = -60.8 ° (c = 0.55, methanol)

Reference Example 73 (+)-2- [2- (N, N-diethylamino) ethyl] -6
-Hydroxytetralin (+)-2- [2- (N, N-diethylamino) ethyl] -6
-Methoxytetralin hydrochloride (5.2 g) was added to 48% hydrobromic acid (10 ml), and the reaction solution was refluxed for 4 hours and then allowed to cool. The reaction solution was neutralized with a 1N aqueous sodium hydroxide solution, a 10% aqueous potassium carbonate solution was added, and the mixture was extracted with a solution of ethyl acetate: THF = 1: 1. The organic layer was washed with saturated saline, dried, and concentrated. The residue was recrystallized from methanol-diisopropyl ether to give the title compound (4.5 g). Melting point: 102-104 ° C. [α] _D ²⁰ = + 73.8 ° (c = 0.226, methanol) Reference Example 74 (−)-2- [2- (N, N-diethylamino) ethyl] -6
-Hydroxytetralin The title compound was synthesized from the compound of Reference Example 72 in the same manner as in Reference Example 73. Melting point: 103-104 ° C (recrystallization solvent: methanol-diisopropyl ether) [α] _D ²⁰ = -73.4 ° (c = 1.001, methanol) Reference Example 75 [6- (4-biphenylyl) methoxy-2-tetralin]
-N- [2- (N, N-dimethylamino) ethyl] -N-methylacetamide hydrochloride [6- (4-biphenylyl) methoxy-2-tetralin]
Oxalyl chloride (0.28 ml) was added to a solution of acetic acid (999 mg, Reference Example Compound 29) in THF (15 ml) at 0 ° C. After adding 2 drops of DMF to the reaction solution, the reaction solution was stirred at room temperature for 2 hours. After concentrating the reaction mixture, the residue was acetonitrile (30 ml)
And THF (10 ml). A solution of N, N, N'-trimethylethylenediamine (309 mg) and triethylamine (0.56 ml) in acetonitrile (5 ml) was added to the reaction solution at 0 ° C.
Added in. After stirring the reaction solution at room temperature for 1 hour, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 2) to give a hydrochloride, which was further recrystallized from methanol-diisopropyl ether to obtain the title compound (1.159 g). Melting point: 190-194 ° C

Reference Example 76 [6- (4-biphenylyl) methoxy-2-tetralin]
-N- [2- (N, N-diethylamino) ethyl] -N-methylacetamide hydrochloride [6- (4-biphenylyl) methoxy-2-tetralin]
Oxalyl chloride (0.13 ml) was added to a solution of acetic acid (501 mg, Reference Example Compound 29) in THF (15 ml) at 0 ° C. After adding 2 drops of DMF to the reaction solution, the reaction solution was stirred at room temperature for 40 minutes. After concentrating the reaction mixture, the remaining acetonitrile (20 m
l) To the solution was added a solution of N, N-diethyl-N'-methylethylenediamine (216 mg) and triethylamine (0.28 ml) in acetonitrile (10 ml) at 0 ° C. After stirring the reaction solution at room temperature for 45 minutes, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 2), converted into a hydrochloride, and recrystallized from ethanol-diisopropyl ether to give the title compound (603 mg). Melting point: 148-151 ° C Reference Example 77 [6- (4-biphenylyl) methoxy-2-tetralin]
-N-methylacetamide [6- (4-biphenylyl) methoxy-2-tetralin]
A mixture of acetic acid (1.180 g, Reference Example Compound 29), methylamine hydrochloride (0.496 g), 1-hydroxybenzotriazole (0.509 g), WSC (0.719 g) and triethylamine (1.4 ml) was added to THF (30 ml) and The mixture was stirred in acetonitrile (30 ml) at room temperature for 10 days. 10% in the reaction solution
An aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate and saturated saline, dried and concentrated. The obtained crude crystals were washed with diisopropyl ether to give the title compound (0.947 g). Melting point: 156-159 ° C Reference Example 78 [6- (4-biphenylyl) methoxy-2-tetralin]
-N-ethylacetamide [6- (4-biphenylyl) methoxy-2-tetralin]
Acetic acid (4.051 g, Reference Example Compound 29), ethylamine hydrochloride (1.143 g), 1-hydroxybenzotriazole (1.6
47 g), WSC (2.536 g) and triethylamine (4.5
ml) and a mixture of THF (80 ml) and acetonitrile (80 ml) was stirred at room temperature for 1 day. A 10% aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline,
After drying, it was concentrated. The obtained crude crystals were washed with diisopropyl ether to give the title compound (4.216 g). Melting point: 168-172 ° C

Reference Example 79 2- (4-benzylpiperazin-1-yl) methyl-6-methoxytetralin dihydrochloride 2-iodomethyl-6-methoxytetralin (1.209 g,
Reference example compound 8), 1-benzylpiperazine (0.852 g)
And potassium carbonate (0.853 g) were added to DMF (15 ml). After stirring the reaction solution at room temperature for 18 hours, water was added to the reaction solution,
Extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate),
After hydrochlorination, the obtained crude crystals were washed with diethyl ether to give the title compound (1.217 g). Melting point: 227-230 ° C (decomposition) Reference Example 80 2- (4-benzylpiperazin-1-yl) methyl-6-hydroxytetralin dihydrochloride 2- (4-benzylpiperazin-1-yl) methyl-6-methoxy Tetralin dihydrochloride (0.849 g) is added to concentrated hydrochloric acid (20 m
In addition to l), the reaction solution was heated to reflux for 6 hours and then allowed to cool. The precipitated crude crystals were collected by filtration and washed with ethanol, methanol and diethyl ether to give the title compound (0.523 g). Melting point: 230-236 ° C (decomposition) Reference Example 81 Dimethyl (4-methoxy-2-nitrophenyl) methylidenemalonate 4-methoxy-2-nitrobenzaldehyde (21.3 g, Or
g. Synth., V, p. 139, described in 1973), dimethyl malonate (16.5 g), piperidine (2.5 ml) and acetic acid (0.
A solution of 25 ml) in methanol (125 ml) was heated to reflux for 24 hours. After concentrating the reaction solution, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of potassium carbonate and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 1: 2) to give the title compound (25 g). ^{1 H NMR δ: 3.67 (3H} , s), 3.88 (3H, s), 3.92 (3H,
s), 7.16 (1H, dd, J = 8.8, 2.6 Hz), 7.36 (1H, d,
J = 8.8 Hz), 7.70 (1H, d, J = 2.6 Hz), 8.14 (1H,
s).

Reference Example 82 Dimethyl (4-methoxy-2-nitrobenzyl) malonate A solution of dimethyl (4-methoxy-2-nitrophenyl) methylidenemalonate (25 g) in methanol (200 ml) was added under ice-cooling. Sodium borohydride (3.36 g) was added. After stirring the reaction solution at room temperature for 1 hour, a 1N aqueous hydrochloric acid solution was added dropwise to the reaction solution to neutralize it. The reaction solution was concentrated and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate and saturated saline, dried and concentrated. The residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1:
Purification in 4) gave the title compound (19 g). ^{1 H NMR δ: 3.44 (2H} , d, J = 7.2 Hz), 3.71 (6H,
s), 3.86 (3H, s), 3.80−4.00 (1H, m), 7.08 (1H,
dd, J = 10.8, 2.4 Hz), 7.28 (1H, d, J = 10.8 Hz),
7.52 (1H, d, J = 2.4 Hz). Reference Example 83 1,2,3,4-Tetrahydro-7-methoxy-2-oxo-3-
Quinolinecarboxylic acid (4-Methoxy-2-nitrobenzyl) 10% palladium-carbon (2.0 g) was added to a solution of dimethyl malonate (19 g) in ethanol (200 ml) at room temperature and a hydrogen pressure of 1 atm for 24 hours. Catalytic reduction was performed. After stirring the reaction at 80 ° C. for another 24 hours,
The catalyst was filtered off from the reaction solution, and the filtrate was concentrated. THF residue
(250 ml) and a mixed solvent of methanol (250 ml), and a 1N aqueous sodium hydroxide solution (126 ml) was added dropwise under ice cooling. The reaction solution was stirred at room temperature for 72 hours and concentrated. The residue was acidified by adding 1N hydrochloric acid, and the precipitated crystals were collected by filtration. The obtained crude crystals were washed with acetone to give the title compound (11.7
g) was obtained. Melting point: 145-146 ° C (decomposition) Reference Example 84 1,2,3,4-Tetrahydro-7-methoxy-N, N-dimethyl-2-oxo-3-quinolinecarboxamide 1,2,3,4-tetrahydro- 7-methoxy-2-oxo-3-
Quinolinecarboxylic acid (3.74 g), dimethylamine hydrochloride (3.44 g), 1-hydroxybenzotriazole (2.85 g)
g) and triethylamine (8.5 g) in acetonitrile (400 ml) were added with WSC (6.5 g). The reaction solution was stirred at room temperature for 24 hours and concentrated. Add ethyl acetate to the residue,
The organic layer was washed with a 1N aqueous hydrochloric acid solution, a 10% aqueous potassium carbonate solution and saturated saline, dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the title compound (1.
63 g) were obtained. Melting point: 209-210 ° C

Reference Example 85 3- (N, N-dimethylamino) methyl-1,2,3,4-tetrahydro-7-methoxyquinoline dihydrochloride 1,2,3,4-tetrahydro-7-methoxy-N , N-dimethyl-2-oxo-3-quinolinecarboxamide (1.63 g)
To a solution of THF (100 ml) was added 1M borane-THF complex (60 ml). The reaction was heated at reflux for 24 hours. After concentrating the reaction solution,
6N hydrochloric acid (30 ml) was added to the residue, and the mixture was heated under reflux for 4 hours. The reaction solution was made basic by adding a 6N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of potassium carbonate and saturated saline, dried and concentrated. Leftovers
The product was converted into a dihydrochloride and recrystallized from methanol-diisopropyl ether to give the title compound (1.27 g). Melting point: 150-151 ° C Reference Example 86 3- (N, N-dimethylamino) methyl-1,2,3,4-tetrahydro-7-quinolinol 3- (N, N-dimethylamino) methyl-1,2, 48% of 3,4-tetrahydro-7-methoxyquinoline dihydrochloride (1.0 g)
The hydrobromic acid solution (10 ml) was heated to reflux for 4 hours. The reaction solution was poured into a 10% aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the title compound (0.81
g). The dihydrochloride salt of the title compound showed a melting point of 151-152 ° C. (Recrystallization solvent: methanol-diisopropyl ether) Reference Example 87 Methyl 2,3,4,5-tetrahydro-8-methoxy-2-oxo-1H-1-benzazepine-4-carboxylate methyl 4-hydroxyimino-6- Methoxytetralin-2-carboxylate (2.909 g, Journal of
Medicinal Chemistry, 1978, Volume 21, 1105-10
Page) with polyphosphoric acid (30.22 g) at 100 ° C for 1.5
After heating for an hour, the mixture was cooled. Ice water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The obtained crude crystals were washed with ethyl acetate-
Recrystallization from hexane gave the title compound (2.125 g). Melting point: 114-116 ° C

Reference Example 88 2,3,4,5-Tetrahydro-8-methoxy-2-oxo-1H
Methyl 1-benzazepine-4-carboxylate 2,3,4,5-tetrahydro-8-methoxy-2-oxo-1H-1-benzazepine-4-carboxylate (5.
To a solution of 035 g) in methanol (60 ml) was added a 1N aqueous sodium hydroxide solution (40 ml). After the reaction solution was stirred at room temperature for 6.5 hours, the reaction solution was made acidic by adding 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The obtained crude crystals were washed with diethyl ether to give the title compound (4.253 g). Melting point: 202-204 ° C Reference Example 89 Methyl (1,2,3,4-tetrahydro-7-hydroxy-2-
Oxo-3-quinoline) acetate 2,3,4,5-tetrahydro-8-methoxy-2-oxo-1H
48% of 1-benzazepine-4-carboxylic acid (4.013 g)
After heating and refluxing with hydrobromic acid (40 ml) for 14 hours,
Cool. Water was added to the reaction solution, which was extracted with ethyl acetate.
The organic layer was washed with water and saturated saline, dried and concentrated. Thionyl chloride (1.3 ml) was added dropwise to the residual methanol solution (100 ml) at 0 ° C. After stirring the reaction solution at room temperature for 3 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The obtained crude crystals were washed with diethyl ether to give the title compound (3.239)
g) was obtained. Melting point: 174-177 ° C Reference Example 90 Methyl [7- (4-biphenylyl) methoxy-1,2,3,4-
Tetrahydro-2-oxo-3-quinoline] acetate methyl [1,2,3,4-tetrahydro-7-hydroxy-2-
Oxo-3-quinoline] acetate (3.025 g), 4-chloromethylbiphenyl (2.864 g), potassium carbonate (2.1
A solution of 37 g) in DMF (80 ml) was stirred at room temperature for 5 days. Water was added to the reaction solution, which was extracted with a mixture of ethyl acetate and THF. The organic layer was washed with water and saturated saline, dried,
Concentrated. The obtained crude crystals were washed with ethyl acetate-hexane to give the title compound (4.540 g). Melting point: 174-178 ° C

Reference Example 91 Methyl [7- (4-biphenylyl) methoxy-1,2,3,4-tetrahydro-2-oxo-3-quinoline] acetate [7- (4-biphenylyl) methoxy-1,2, 3,4-
Methanol (30 ml) in a THF solution (60 ml) of tetrahydro-2-oxo-3-quinoline] acetate (2.475 g)
And a 1N aqueous sodium hydroxide solution (12 ml).
After stirring the reaction solution at room temperature for 2 days, 1N hydrochloric acid was added to the reaction solution to make it acidic, and the mixture was extracted with a mixture of ethyl acetate and THF. The organic layer was washed with water and saturated saline, dried and concentrated.
The obtained crude crystals were washed with diisopropyl ether to give the title compound (1.895 g). Melting point: 193-206 ° C (decomposition) Reference Example 92 [7- (4-biphenylyl) methoxy-1,2,3,4-tetrahydro-2-oxo-3-quinoline] -N, N-dimethylacetamide [7 -(4-biphenylyl) methoxy-1,2,3,4-tetrahydro-2-oxo-3-quinoline] acetic acid (1.616 g),
Dimethylamine hydrochloride (0.674 g), 1-hydroxybenzotriazole (0.648 g), WSC (0.980 g), N-
A mixture of methyl morpholine (2.0 ml), THF (50 ml) and acetonitrile (50 ml) was stirred at room temperature for 2 days.
A 10% aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate and saturated saline, dried and concentrated. The obtained crude crystals were washed with diisopropyl ether to give the title compound (1.557 g). Melting point: 199-202 ° C. Reference Example 93 N, N-dimethyl- (6-hydroxy-1-oxo-2-tetralin) acetamide (6-hydroxy-1-oxo-2)
-Tetralin) acetic acid (1.672 g, described in EP140684), dimethylamine hydrochloride (0.754 g), 1-hydroxybenzotriazole (1.468 g), WSC (2.255 g) and triethylamine (3.1 ml) in THF (30 ml) and acetonitrile (30 ml) at room temperature. The reaction was stirred at room temperature for 36 hours. A 10% aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate and saturated saline, dried and concentrated.
The obtained crude crystals were recrystallized from methanol-diisopropyl ether to give the title compound (0.744 g). Melting point: 181-186 ° C

Reference Example 94 [6- (4-Biphenylyl) methoxy-1-oxo-2-tetralin] -N, N-dimethylacetamide N, N-dimethyl- (6-hydroxy-1-oxo-2-tetralin) To a DMF solution (5 ml) of acetamide (0.313 g) and 4-chloromethylbiphenyl (0.300 g) was added 60% oily sodium hydride (80 mg), and the reaction solution was stirred at room temperature for 15 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 2: 1),
The obtained crude crystals were washed with diisopropyl ether to give the title compound (0.200 g). Melting point: 131-135 ° C Reference Example 95 [6- (4-biphenylyl) methoxy-2- (3,4-dihydronaphthalene)]-N, N-dimethylacetamide [6- (4-biphenylyl) methoxy-1-oxo -2-tetralin] -N, N-dimethylacetamide (0.954
To a mixed solution (20 ml) of ethyl acetate (20 ml) and methanol of g), sodium borohydride (0.175 g) was added at room temperature. After stirring the reaction solution at room temperature for 30 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was dissolved in toluene (30 ml), and pyridinium p-toluenesulfonic acid (0.030
Heated to reflux with g) for 1.5 hours. After cooling, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate and saturated saline, dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the title compound (0.779 g). Melting point: 125-130 ° C Reference Example 96 6- (4-Biphenylyl) methoxy-2- [2- (imidazol-1-yl) ethyl] tetralin The title compound was synthesized in the same manner as in Example 38. Melting point: 145-146 ° C Recrystallization solvent: ethyl acetate-hexane

Reference Example 97 2- [6- (4-biphenylyl) methoxy-2-tetralin] ethyl-N, N-dimethylamine oxide m-chlorobenzoate 6- (4-biphenylyl) methoxy-2- [2 − (N, N
-Dimethylamino) ethyl] tetralin hydrochloride (1.26
9 g, Example compound 12) as a free form, acetone (15
ml). To this solution was added 70% m-chloroperbenzoic acid (0.777 g) at 0 ° C. After the reaction solution was stirred at 0 ° C. for 25 minutes, the precipitated crude crystals were collected by filtration. The crystals were further washed with ethyl acetate and diethyl ether, and recrystallized from THF-ethyl acetate to obtain the title compound (0.811 g). Melting point: 125-128 ° C Reference Example 98 2- [6- (4-biphenylyl) methoxy-2-tetralin] ethyl-N, N-diethylamine oxide 6- (4-biphenylyl) methoxy-2- [2- (N, N
-Diethylamino) ethyl] tetralin hydrochloride (134
mg) as a free form and dissolved in acetone (5 ml). 70% m-chloroperbenzoic acid (83 mg g) was added to this solution at 0 ° C.
Added in. After stirring at 0 ° C. for 1 hour, a 1N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the title compound (120 mg). Melting point: 99-104 ° C

Reference Example 99 (+)-6- (2-Bromopyridin-5-yl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin dihydrochloride (+)-2- [ 2- (N, N-dimethylamino) ethyl]-
6-Hydroxytetralin (0.220 g) DMF solution (5 ml)
To the mixture was added 60% oily sodium hydride (0.049 g) at room temperature. The reaction was stirred at 50 ° C. for 30 minutes. The reaction solution was cooled to 0 ° C. and treated with 2-bromo-5-pyridylmethyl bromide (0.4
A solution of 62 g) in THF (5 ml) was added dropwise. Reaction mixture at 0 ° C
After stirring for an hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 4), converted into a dihydrochloride, and recrystallized from ethanol-ethyl acetate to obtain the title compound (295 mg). Melting point: 171-181 ° C (decomposition) [α] _D ²⁰ = + 41.2 ° (c = 0.500, methanol) Reference Example 100 N- [2- (N, N-dimethylamino) methyl-6-tetralinyl] -4 -Biphenylcarboxamide hydrochloride 6-amino-2- (N, N-dimethylamino) methyltetralin (0.216 g, Reference Example Compound 32) in pyridine (10 ml)
Dissolved in 4-biphenylcarbonyl chloride (0.311
g) was added. After the reaction solution was stirred at room temperature for 12 hours, pyridine was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 1) and treated with 4N hydrochloric acid-ethyl acetate to obtain a hydrochloride. The resulting salt was recrystallized from methanol-ethyl acetate to give the title compound (0.224 g). ^{Mp:> 250 ℃ 1 H NMR δ} : 1.24-1.54 (1H, m), 1.84-2.10 (2H, m),
2.20-2.50 (3H, m), 2.26 (6H, s), 2.79-3.01 (3H,
m), 7.10 (1H, d, J = 8Hz), 7.28-7.54 (5H, m), 7.60-
7.82 (5H, m), 7.94 (2H, d, J = 8Hz). IR (KBr): 3028, 2910, 2640, 1658, 1538, 1417, 746,
701 cm ^-1 .

Example 1 6- (4-Biphenylyl) methoxy-2- (N, N-dimethylamino) methyltetralin hydrochloride

Embedded image 2- (N, N-dimethylamino) methyl-6-hydroxytetralin (0.151 g, free base of Reference Example Compound 16) in DMF
(5 ml) and 60% oily sodium hydride (92 m
g) was added at 0 ° C. The reaction was warmed to room temperature and stirred for 30 minutes. The reaction solution was cooled again to 0 ° C, and 4- (chloromethyl) was added.
Biphenyl (0.183 g) was added, and the mixture was stirred at room temperature for 3 hours.
Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 1 to ethyl acetate: methanol = 10:
The product was purified in 1) and treated with 4N hydrochloric acid-ethyl acetate to obtain a hydrochloride. The resulting salt was recrystallized from methanol-diethyl ether to obtain the title compound (0.210 g). Melting point: 229-233 ° C. The following Example compounds 2 to 11 were synthesized in the same manner as in Example 1. Example 2 2- (N, N-dimethylamino) methyl-6- (2-naphthyl) methoxytetralin hydrochloride

Embedded image Melting point: 228-229 ° C Recrystallization solvent: methanol-ethyl acetate Example 3 6- (2'-cyanobiphenyl-4-yl) methoxy-2-
(N, N-dimethylamino) methyltetralin hydrochloride

Embedded image Melting point: 202-203 ° C Recrystallization solvent: ethanol-ethyl acetate Example 4 7- (4-biphenylyl) methoxy-2- (N, N-dimethylamino) methyltetralin hydrochloride

Embedded image Melting point: 232-233 ° C Recrystallization solvent: ethanol-ethyl acetate Example 5 2- (N, N-dimethylamino) methyl-7- (2-naphthyl) methoxytetralin hydrochloride

Embedded image Melting point: 201-202 ° C Recrystallization solvent: ethanol-ethyl acetate

Example 6 6- (4-Biphenylyl) methoxy-2- (N-methylamino) methyltetralin hydrochloride

Embedded image Melting point: 189-190 ° C Recrystallization solvent: ethanol-ethyl acetate Example 7 6- (2-Naphthyl) methoxy-2-piperidinomethyltetralin hydrochloride

Embedded image Melting point: 215-218 ° C (decomposition) Recrystallization solvent: methanol-diethyl ether Example 8 2- [N-benzyl-N- (3,3-diphenylpropyl) amino] methyl-6- (2-naphthyl) methoxytetralin Hydrochloride

Embedded image Amorphous powder ¹ H NMR δ: 1.12-1.36 (1H, m), 1.70-2.05 (2H, m),
2.13-2.48 (7H, m), 2.61-2.89 (3H, m), 3.55 (2H,
d, J = 2Hz), 3.98 (1H, t, J = 8Hz), 5.18 (2H, s), 6.6
9-6.81 (2H, m), 6.96 (1H, d, J = 8Hz), 7.04-7.34
(15H, m), 7.41-7.56 (3H, m), 7.78-7.90 (4H, m). IR (KBr): 3058, 3028, 2925, 2578, 1602, 1500, 1452,
1270, 1232, 747, 701cm ^-1 .

Example 9 6- (4-Biphenylyl) methoxy-2- (N, N-dipropylamino) methyltetralin hydrochloride

Embedded image Melting point: 164-166 ° C. Recrystallization solvent: methanol-diisopropyl ether Example 10 6- [N-acetyl-N- (4-biphenylyl) methyl] amino-2- (N, N-dimethylamino) methyltetralin hydrochloride

Embedded image Recrystallization solvent: methanol-ethyl acetate Melting point: 179-182 ° C Example 11 6- [N-acetyl-N- (2-naphthyl) methyl] amino-2
― (N, N-dimethylamino) methyltetralin hydrochloride

Embedded image Amorphous powder ¹ H NMR δ: 1.20-1.45 (1H, m), 1.76-2.00 (2H, m),
1.93 (3H, s), 2.08−2.44 (3H, m), 2.24 (6H, s),
2.64-2.76 (2H, m), 2.82-2.96 (1H, m), 5.02 (2H, m
s), 6.64-6.76 (2H, m), 6.98 (1H, d, J = 8Hz), 7.36
―7.50 (3H, m), 7.61 (1H, br s), 7.70―7.86 (3H,
m). IR (KBr): 3394, 2929, 2669, 1648, 1500, 1401, 1295,
821, 757 cm ^-1 .

Example 12 6- (4-Biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin hydrochloride

Embedded image [6- (4-biphenylyl) methoxy-2-tetralin]
-N, N-dimethylacetamide (1.497 g, Reference Example Compound 3
0) was dissolved in anhydrous THF (20 ml), and lithium aluminum hydride (0.222 g) was added. The reaction solution was stirred at room temperature for 40 minutes and then heated to reflux for 40 minutes. After cooling the reaction solution, water was added, insolubles were removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate:
Hexane = 1: 1-ethyl acetate-ethyl acetate: methanol =
Purified by 10: 1), and treated with 4N hydrochloric acid-ethyl acetate to obtain a hydrochloride. The resulting salt was recrystallized from methanol-diisopropyl ether to give the title compound (1.022 g). Melting point: 223-226 ° C (decomposition) Example 13 2- [2- (N, N-dipropylamino) ethyl] -6- (2
-Naphthyl) methoxytetralin hydrochloride

Embedded image 2- (2-Iodoethyl) -6- (2-naphthyl) methoxytetralin (0.193 g, Reference Example Compound 27) was added to DMF (5 ml).
And N, N-dipropylamine (0.09 ml) and anhydrous potassium carbonate (0.135 g) were added. After the reaction solution was stirred at room temperature for 5 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated.
The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 1 to ethyl acetate: methanol = 10: 1), and treated with 4N hydrochloric acid-ethyl acetate to obtain a hydrochloride. The resulting salt was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (0.105 g)
I got Melting point: 146-148 ° C

Example 14 6- (2-Naphthyl) methoxy-2- [2- (4-phenylpiperidino) ethyl] tetralin hydrochloride

Embedded image The title compound was synthesized in the same manner as in Example 13. Melting point: 229-234 ° C (decomposition) Recrystallization solvent: methanol-diisopropyl ether Example 15 6- (4-Biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] -3,4-dihydro Naphthalene

Embedded image [6- (4-Biphenylyl) methoxy-2- (3,4-dihydronaphthalene)]-N, N-dimethylacetamide (205 m
To a solution of g) in THF (10 ml) was added lithium aluminum hydride (20 mg) at 0 ° C. Water was added to the reaction solution, insolubles were removed by filtration, and the filtrate was concentrated. The residue was subjected to alumina column chromatography (developing solvent; ethyl acetate: hexane = 1:
Purification in 4) and the obtained crude crystals were recrystallized from ethyl acetate: hexane to give the title compound (46 mg). Melting point: 123-126 ° C

Example 16 N- [2- (N, N-dimethylamino) methyltetralin-6
-Yl] -2-naphthalenesulfonamide hydrochloride

Embedded image The title compound was synthesized in the same manner as in Reference Example 100. Amorphous powder ¹ H NMR δ: 1.16-1.40 (1H, m), 1.72-1.97 (2H, m),
2.08-2.38 (3H, m), 2.21 (6H, s), 2.60-2.90 (3H,
m), 6.74-6.84 (2H, m), 6.90 (1H, d, J = 8Hz), 7.52
―7.68 (2H, m), 7.72 (1H, dd, J = 9Hz, 2Hz), 7.82―
7.94 (3H, m), 8.36 (1H, br s). IR (KBr): 3394, 2927, 2698, 1614, 1504, 1320, 1156,
962, 821, 751,657 cm ^-1 . Example 17 6- [N- (4-biphenylyl) methyl] amino-2- (N, N
-Dimethylamino) methyltetralin

Embedded image 1M was added to a THF solution (3 ml) of N- [2- (N, N-dimethylamino) methyl-6-tetralinyl] -4-biphenylcarboxamide (0.172 g, free base of the compound of Reference Example 100).
Borane-THF complex (2 ml) was added, and the reaction solution was heated to reflux for 1 hour. After water was added to the reaction solution, 6N hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was made basic by adding a 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. Alumina column chromatography (developing solvent; ethyl acetate:
The product was purified by hexane = 1: 4) and further recrystallized from ethyl acetate-hexane to obtain the title compound (0.060 g). Melting point: 106-108 ° C

Example 18 2- (N, N-dimethylamino) methyl-6- (4'-methoxybiphenyl-4-yl) methoxytetralin hydrochloride

Embedded image 6- (4-bromobenzyl) oxy-2- (N, N-dimethylamino) methyltetralin (374 mg, Reference Example Compound 33)
And tetrakistriphenylphosphine palladium (35 mg) were dissolved in toluene (8 ml), and an ethanol solution (1 ml) of 4-methoxyphenylboronic acid (198 mg) and a 2M aqueous sodium carbonate solution (1 ml) were added. The reaction solution was refluxed for 6 hours under an argon atmosphere. A saturated saline solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 10) and treated with 4N hydrochloric acid-ethyl acetate to obtain a hydrochloride. The resulting salt was recrystallized from ethanol-ethyl acetate to give the title compound (0.290 g). Melting point: 210-211 ° C. The following Example compounds 19 to 35 were synthesized in the same manner as in Example 18. Example 19 2- (N, N-dimethylamino) methyl-6- (4'-methylbiphenyl-4-yl) methoxytetralin hydrochloride

Embedded image Melting point: 226-228 ° C Recrystallization solvent: ethanol-ethyl acetate Example 20 2- (N, N-dimethylamino) methyl-6- (4'-formylbiphenyl-4-yl) methoxytetralin hydrochloride

Embedded image Melting point: 234-235 ° C Recrystallization solvent: ethanol-ethyl acetate

Example 21 2- (N, N-dimethylamino) methyl-6- (4'-methylthiobiphenyl-4-yl) methoxytetralin hydrochloride

Embedded image Melting point: 235-237 ° C Recrystallization solvent: ethanol-ethyl acetate Example 22 2- (N, N-dimethylamino) methyl-6- (4'-fluorobiphenyl-4-yl) methoxytetralin hydrochloride

Embedded image Melting point: 223-224 ° C. Recrystallization solvent: ethanol-ethyl acetate Example 23 2- (N, N-dimethylamino) methyl-6- (3′-nitrobiphenyl-4-yl) methoxytetraline hydrochloride

Embedded image Melting point: 223-224 ° C. Recrystallization solvent: ethanol-ethyl acetate Example 24 2- (N, N-dimethylamino) methyl-6- (3′-methoxybiphenyl-4-yl) methoxytetralin hydrochloride

Embedded image Melting point: 207-208 ° C Recrystallization solvent: ethanol-ethyl acetate Example 25 2- (N, N-dimethylamino) methyl-6- (2'-methoxybiphenyl-4-yl) methoxytetralin hydrochloride

Embedded image Melting point: 140-141 ° C Recrystallization solvent: ethanol-ethyl acetate Example 26 2- (N, N-dimethylamino) methyl-6- [3 ', 5'-bis (trifluoromethyl) biphenyl-4-yl] Methoxytetralin hydrochloride

Embedded image Melting point: 196-197 ° C Recrystallization solvent: ethanol-ethyl acetate

Example 27 2- (N, N-dimethylamino) methyl-6- [4- (3-thienyl) benzyl] oxytetralin hydrochloride

Embedded image Melting point: 222-223 ° C Recrystallization solvent: ethanol-ethyl acetate Example 28 2- (N, N-dimethylamino) methyl-6- [4- (2-thienyl) benzyl] oxytetralin hydrochloride

Embedded image Melting point: 227-228 ° C Recrystallization solvent: methanol-diisopropyl ether Example 29 2- (N, N-dimethylamino) methyl-6- [4- (3-pyridyl) benzyl] oxytetralin dihydrochloride

Embedded image Melting point: 212-213 ° C Recrystallization solvent: methanol-diisopropyl ether Example 30 6- (3-Biphenylyl) methoxy-2- (N, N-dimethylamino) methyltetralin hydrochloride

Embedded image Melting point: 186-190 ° C Recrystallization solvent: ethanol-ethyl acetate

Example 31 2- (N, N-dimethylamino) methyl-6- (4'-methoxybiphenyl-3-yl) methoxytetralin hydrochloride

Embedded image Melting point: 182-183 ° C. Recrystallization solvent: ethanol-ethyl acetate Example 32 2- (N, N-dimethylamino) methyl-6- (4′-fluorobiphenyl-3-yl) methoxytetralin hydrochloride

Embedded image Melting point: 171-172 ° C. Recrystallization solvent: ethanol-ethyl acetate Example 33 6- (2-Biphenylyl) methoxy-2- (N, N-dimethylamino) methyltetralin hydrochloride

Embedded image Melting point: 173-174 ° C Recrystallization solvent: ethanol-ethyl acetate Example 34 2- (N, N-dimethylamino) methyl-6- (4'-methoxybiphenyl-2-yl) methoxytetralin hydrochloride

Embedded image Melting point: 170-171 ° C. Recrystallization solvent: ethanol-ethyl acetate Example 35 2- (N, N-dimethylamino) methyl-6- (4′-fluorobiphenyl-2-yl) methoxytetralin hydrochloride

Embedded image Melting point: 172-174 ° C Recrystallization solvent: ethanol-ethyl acetate

Example 36 6- (4-Biphenylyl) methoxy-2- (N-ethylamino) methyltetralin hydrochloride

Embedded image N- [6- (4-biphenylyl) methoxy-2-tetralinyl)] methylacetamide (500 mg, Reference Example Compound 23)
Was dissolved in THF (10 ml), lithium aluminum hydride (50 mg) was added, and the mixture was stirred at room temperature for 1 hour. An aqueous solution of potassium sodium tartrate was added to the reaction mixture under ice-cooling, insolubles were removed by filtration, and the filtrate was concentrated. The residue was treated with 4N hydrochloric acid-ethyl acetate, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.138 g). Melting point: 229-230 ° C. Example 37 2- (N, N-dimethylamino) methyl-6- (4′-ethylbiphenyl-4-yl) methoxytetralin hydrochloride

Embedded image 2- (N, N-dimethylamino) methyl-6-hydroxytetralin (300 mg, free base of Reference Example Compound 16), (4 ′
-Ethylbiphenyl-4-yl) methanol (372 mg)
And triphenylphosphine (460 mg) in THF (5 m
l) and diethyl azodicarboxylate (305 m
g) was added dropwise. After stirring the reaction solution at room temperature for 4 hours, the solvent was distilled off. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried, and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 10), and treated with a 4N hydrochloric acid-ethyl acetate solution to obtain a hydrochloride. The resulting salt was recrystallized from ethanol-diisopropyl ether to give the title compound (310 mg). Melting point: 229-230 ° C. Example 38 6- (4-Biphenylyl) methoxy-2- [2- (N, N-diethylamino) ethyl] tetralin hydrochloride

Embedded image 6- (4-biphenylyl) -2- (2-iodoethyl) methoxytetralin (2.50 g), diethylamine (1.03 g)
And potassium carbonate (1.95 g) were added to DMF (20 ml). After the reaction solution was stirred at room temperature for 24 hours, water was added. The precipitated crystals were collected by filtration, washed with ethyl acetate, and recrystallized from ethanol-diisopropyl ether. Crystals 4N hydrochloric acid-
Treatment with ethyl acetate gave the hydrochloride salt. The resulting salt was recrystallized from ethanol-diisopropyl ether to give the title compound (1.53 g). Melting point: 141-143 ° C

The following Example compounds 39 to 42 were synthesized in the same manner as in Example 38. Example 39 6- (4-Biphenylyl) methoxy-2- [2- (pyrrolidin-1-yl) ethyl] tetralin hydrochloride

Embedded image Melting point: 197-199 ° C Recrystallization solvent: methanol-diisopropyl ether Example 40 6- (4-Biphenylyl) methoxy-2- (2-piperidinoethyl) tetralin hydrochloride

Embedded image Melting point: 196-198 ° C Recrystallization solvent: methanol-diisopropyl ether Example 41 6- (4-Biphenylyl) methoxy-2- [2- (4-piperidinopiperidino) ethyl] tetralin dihydrochloride

Embedded image Melting point: 288-291 ° C Recrystallization solvent: methanol-diisopropyl ether Example 42 6- (4-Biphenylyl) methoxy-2- [2- (4,4-dihydroxypiperidino) ethyl] tetralin hydrochloride

Embedded image Melting point: 155-160 ° C Recrystallization solvent: methanol-diisopropyl ether

Example 43 6- (3'-Aminobiphenyl-4-yl) methoxy-2-
[2- (N, N-dimethylamino) ethyl] tetralin 2
Hydrochloride

Embedded image 6- (4-bromobenzyl) oxy-2- [2- (N, N-dimethylamino) ethyl] tetralin (3.00 g) and tetrakistriphenylphosphinepalladium (0.45 g)
A solution of 3-aminophenylboronic acid (1.3 g) in ethanol (10 ml) and a 2M aqueous solution of sodium carbonate (10 ml) were added to a toluene solution (80 ml). Under argon atmosphere,
The reaction was heated at reflux for 12 hours. A saturated saline solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 2), and treated with 4N hydrochloric acid-ethyl acetate to obtain a hydrochloride. The resulting salt was recrystallized from methanol-diisopropyl ether to give the title compound (0.78 g). Melting point: 205-206 ° C. Example 44 2- [2- (N, N-dimethylamino) ethyl] -6-[(4'-methoxybiphenyl-4-yl) methoxy] tetralin hydrochloride

Embedded image The title compound was synthesized in the same manner as in Example 43. Melting point: 182-185 ° C Recrystallization solvent: methanol-diisopropyl ether

Example 45 6- (4-Biphenylyl) methoxy-2- [3- (N, N-dimethylamino) propyl] tetralin hydrochloride

Embedded image 60% was added to a DMF solution (20 ml) of 2- [3- (N, N-dimethylamino) propyl] -6-hydroxytetralin (1.00 g).
Oily sodium hydride (0.258 g) was added at 0 ° C. The reaction was warmed to room temperature and stirred for 30 minutes. The reaction solution was cooled again to 0 ° C., 4- (chloromethyl) biphenyl (1.04 g) was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by alumina column chromatography (developing solvent; toluene to toluene: ethyl acetate = 1: 1) and treated with 4N hydrochloric acid-ethyl acetate to obtain a hydrochloride. The resulting salt was recrystallized from methanol-diisopropyl ether to give the title compound (1.30 g). Melting point: 161-163 ° C. Example 46 6- (4-Biphenylyl) methoxy-2- [4- (N, N-dimethylamino) butyl] tetraline hydrochloride The title compound was synthesized in the same manner as in Example 45.

Embedded image Melting point: 175-177 ° C Recrystallization solvent: methanol-diisopropyl ether

Example 47 (+)-6- (4-Biphenylyl) methoxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride

Embedded image (+)-2- [2- (N, N-dimethylamino) ethyl] -6
-Hydroxytetralin hydrochloride (0.424 g) was freed, dissolved in DMF (10 ml), added with 60% oily sodium hydride (0.106 mg) at room temperature, and stirred for 45 minutes.
The reaction was heated to 50 ° C. and stirred for 45 minutes. Reaction solution at 0 ° C
And cooled to 4- (chloromethyl) biphenyl (0.367 g)
Was added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 10 to 1: 4), and treated with 4N hydrochloric acid-ethyl acetate to obtain a hydrochloride. The resulting salt was recrystallized from methanol-diisopropyl ether to give the title compound (0.484 g). Melting point: 220-226 ° C (decomposition) [α] _D ²⁰ = + 46.0 ° (c = 0.54, methanol) Optical purity: 99% ee or more Example 48 (−)-6- (4-biphenylyl) methoxy-2 − [2−
(N, N-dimethylamino) ethyl] tetralin hydrochloride

Embedded image (−)-2- (N, N-Dimethylamino) ethyl-6-hydroxytetralin hydrochloride (0.437 g) was made into a free form, then dissolved in DMF (10 ml), and dissolved in 60% oily sodium hydride (0.122 mg). ) Was added at room temperature. The reaction solution was heated to 50 ° C. and stirred for 1 hour. The reaction solution was cooled to 0 ° C., a DMF solution (5 ml) of 4- (chloromethyl) biphenyl (0.344 g) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was subjected to alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 10-
1: 4), and treated with 4N hydrochloric acid-ethyl acetate to obtain a hydrochloride. The resulting salt was recrystallized from methanol-diisopropyl ether to give the title compound (0.471 g).
Melting point: 219-225 ° C (decomposition) [α] _D ²⁰ = -45.2 ° (c = 0.52, methanol) Optical purity: 99% ee or more

Example 49 (+)-6- (4-Biphenylyl) methoxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride monohydrate

Embedded image (+)-6- (4-Biphenylyl) methoxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride (150 g) was recrystallized from a mixed solution of ethanol (2000 ml) and water (60 ml) to obtain the title compound (127 g). Melting point: 215-217 ° C. (decomposition) [α] _D ²⁰ = + 42.4 ° (c = 1.00, methanol) Example 50 (+)-6- (4-biphenylyl) methoxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin

Embedded image (+)-6- (4-Biphenylyl) methoxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride (4.50 g) was added to a mixed solvent of ethyl acetate and a 10% aqueous potassium carbonate solution, followed by extraction. The organic layer was washed with saturated saline, dried and concentrated. The residue was recrystallized from ethanol to give the title compound (3.60 g). Melting point: 83.5-84.5 ° C. [α] _D ²⁰ = + 51.7 ° (c = 1.00, methanol) Example 51 (−)-6- (4-biphenylyl) methoxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin

Embedded image (-)-6- (4-biphenylyl) methoxy-2- [2-
(N, N-Dimethylamino) ethyl] tetralin hydrochloride (3.00 g) was added to a mixed solvent of ethyl acetate and a 10% aqueous potassium carbonate solution, followed by extraction. The organic layer was washed with saturated saline, dried and concentrated. The residue was recrystallized from ethanol to give the title compound (2.20 g). Melting point: 84.2-85.2 ° C [α] _D ²⁰ = -50.1 ° (c = 0.50, methanol)

Example 52 (-)-6- (4-Biphenylyl) methoxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin fumarate

Embedded image (-)-6- (4-biphenylyl) methoxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin (1.3 g)
A solution of fumaric acid (0.39 g) in methanol (10 ml) was added to a solution of the above in methanol (10 ml) to form a salt, which was recrystallized from methanol to obtain the title compound (0.7 g). Mp: 212-213 ° C. ^{_{(decomposition) [α] D 20 = -40.4}} ° (c = 0.5, methanol) Example 53 (-) - 6- (4-biphenylyl) methoxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin citrate

Embedded image (-)-6- (4-biphenylyl) methoxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin (1.3 g)
A solution of citric acid (0.65 g) in methanol (10 ml) was added to a methanol (10 ml) solution to give a salt. The precipitated crystals were collected by filtration and washed with methanol, ethyl acetate, and diethyl ether to give the title compound (1.9 g). Melting point: 185-186 ° C (decomposition) Example 54 (+)-2- [2- (N, N-dimethylamino) ethyl] -6
-(4'-methoxybiphenyl-4-yl) methoxytetralin hydrochloride

Embedded image (+)-6- (4-bromobenzyl) oxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride (1 g), toluene (20 ml), ethanol (2.5 ml), 2
M mixture of aqueous sodium carbonate (2.5 ml) at room temperature
Stirred for minutes. Add 4-methoxyphenylboronic acid (4
65 mg) and tetrakis (triphenylphosphine) palladium (82 mg) were added, and the mixture was heated under reflux in an argon stream for 14 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 50 to 1: 4) and converted into a hydrochloride,
Recrystallization from methanol-diisopropyl ether gave the title compound (870 mg). Melting point: 230-232 ° C (decomposition) [α] _D ²⁰ = + 39.2 ° (c = 1.00, methanol)

Example 55 (+)-2- [2- (N, N-dimethylamino) ethyl] -6
-(4'-methylbiphenyl-4-yl) methoxytetralin hydrochloride

Embedded image (+)-6- (4-bromobenzyl) oxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride (1 g), toluene (20 ml), ethanol (2.5 ml), 2
M mixture of aqueous sodium carbonate (2.5 ml) at room temperature
Stirred for minutes. Add 4-methylphenylboric acid (416
mg) and tetrakis (triphenylphosphine) palladium (82 mg), and the mixture was refluxed for 5 hours under an argon stream. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was subjected to alumina column chromatography (developing solvent; ethyl acetate:
After purification with hexane = 1: 40 to 1: 4), it was converted into a hydrochloride and recrystallized from methanol-diisopropyl ether to give the title compound (660 mg). Melting point: 225-227 ° C. (decomposition) [α] _D ²⁰ = + 44.0 ° (c = 1.00, methanol) Example 56 (+)-6- (3′-aminobiphenyl-4-yl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin dihydrochloride

Embedded image (+)-6- (4-bromobenzyl) oxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride (1 g), toluene (20 ml), ethanol (2.5 ml), 2
M mixture of aqueous sodium carbonate (2.5 ml) at room temperature
Stirred for minutes. Add 3-aminophenylboric acid (474
mg) and tetrakis (triphenylphosphine) palladium (82 mg), and the mixture was heated under reflux for 14 hours under an argon stream. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 20 to 1: 2), and then converted into a dihydrochloride,
Recrystallization from methanol-diisopropyl ether gave the title compound (830 mg). Melting point: 210-211 ° C. (decomposition) [α] _D ²⁰ = + 38.3 ° (c = 1.00, methanol) Example 57 (+)-2- [2- (N, N-dimethylamino) ethyl] -6
-(3'-formylbiphenyl-4-yl) methoxytetralin hydrochloride

Embedded image (+)-6- (4-bromobenzyl) oxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride (1 g), toluene (20 ml), ethanol (2.5 ml), 2
M mixture of aqueous sodium carbonate (2.5 ml) at room temperature
Stirred for minutes. Add 3-formylphenylboric acid (4
60 mg) and tetrakis (triphenylphosphine) palladium (82 mg) were added, and the mixture was refluxed for 14 hours under an argon stream. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 20 to 1: 2) and converted into a hydrochloride,
Recrystallization from methanol-diisopropyl ether gave the title compound (590 mg). Melting point: 194-196 ° C (decomposition) [α] _D ²⁰ = + 44.0 ° (c = 1.00, methanol)

Example 58 (+)-6- (3′-acetamidobiphenyl-4-yl)
Methoxy-2- [2- (N, N-dimethylamino) ethyl]
Tetralin hydrochloride

Embedded image (+)-6- (4-bromobenzyl) oxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride (1 g), toluene (20 ml), ethanol (2.5 ml), 2
M mixture of aqueous sodium carbonate (2.5 ml) at room temperature
Stirred for minutes. 3-Acetamidophenyl boric acid (559 mg), tetrakis (triphenylphosphine)
Palladium (82 mg) was added, and the mixture was heated and refluxed for 6 hours under an argon stream. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The crude crystals were washed with ethyl acetate and diisopropyl ether, purified by alumina column chromatography (developing solvent: ethyl acetate), converted into a hydrochloride, and recrystallized from methanol-diisopropyl ether to give the title compound (610 mg). Melting point: 198-200 ° C (decomposition) [α] _D ²⁰ = + 41.0 ° (c = 0.50, methanol) Example 59 (+)-6- (2 ′, 4′-dimethoxybiphenyl-4-yl) methoxy -2- [2- (N, N-dimethylamino) ethyl] tetralin hydrochloride

Embedded image (+)-6- (4-bromobenzyl) oxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride (1 g), toluene (20 ml), ethanol (2.5 ml), 2
M mixture of aqueous sodium carbonate (2.5 ml) at room temperature
Stirred for minutes. 2,4-Dimethoxyphenyl boric acid (557 mg), tetrakis (triphenylphosphine)
Palladium (82 mg) was added, and the mixture was heated and refluxed for 14 hours under an argon stream. After cooling, water was added, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated saline, dried, and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 20 to 1: 5), converted into a hydrochloride, and recrystallized from methanol-diisopropyl ether to obtain the title compound (740 mg). Melting point: 159-161 ° C [α] _D ²⁰ = + 43.5 ° (c = 0.50, methanol)

Example 60 (+)-6- (3 ', 4'-Dimethoxybiphenyl-4-yl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin hydrochloride

Embedded image (+)-6- (4-bromobenzyl) oxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride (1 g), toluene (20 ml), ethanol (2.5 ml), 2
M mixture of aqueous sodium carbonate (2.5 ml) at room temperature
Stirred for minutes. 3,4-Dimethoxyphenyl boric acid (557 mg), tetrakis (triphenylphosphine)
Palladium (82 mg) was added, and the mixture was heated and refluxed for 5 hours under an argon stream. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 20 to 1: 5), converted into a hydrochloride, and recrystallized from methanol-diisopropyl ether to obtain the title compound (840 mg). Melting point: 228-230 ° C. (decomposition) [α] _D ²⁰ = + 42.2 ° (c = 0.50, methanol) Example 61 (+)-6- [4- (1,3-benzodioxol-5-yl)
Phenyl] methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin hydrochloride

Embedded image (+)-6- (4-bromobenzyl) oxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride (1 g), toluene (20 ml), ethanol (2.5 ml), 2
M mixture of aqueous sodium carbonate (2.5 ml) at room temperature
Stirred for minutes. 3,4-Methylenedioxyphenyl boric acid (469 mg) and tetrakis (triphenylphosphine) palladium (82 mg) were added to the reaction solution, and the mixture was added under an argon stream.
Heated to reflux for an hour. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 20 to 1: 5).
The compound was converted into a hydrochloride and recrystallized from methanol-diisopropyl ether to give the title compound (830 mg). Melting point: 220-223 ° C (decomposition) [α] _D ²⁰ = + 39.9 ° (c = 0.40, methanol)

Example 62 (+)-2- [2- (N, N-dimethylamino) ethyl] -6
-(2 ', 3', 4'-trimethoxy-6'-methylbiphenyl-
4-yl) methoxytetralin hydrochloride

Embedded image (+)-6- (4-bromobenzyl) oxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride (1 g), toluene (20 ml), ethanol (2.5 ml), 2
M mixture of aqueous sodium carbonate (2.5 ml) at room temperature
Stirred for minutes. 2,3,4-Trimethoxy-6-methylphenylboronic acid (692 mg) and tetrakis (triphenylphosphine) palladium (82 mg) were added to the reaction solution, and the mixture was refluxed for 14 hours under an argon stream. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried,
Concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 20 to 1: 6), converted into a hydrochloride, and recrystallized from methanol-diisopropyl ether to obtain the title compound (950 mg). Melting point: 222-224 ° C. (decomposition) [α] _D ²⁰ = + 37.7 ° (c = 0.50, methanol) Example 63 (+)-6- [4- (2-benzofuranyl) phenyl] methoxy-2- [ 2- (N, N-dimethylamino) ethyl] tetralin hydrochloride

Embedded image (+)-6- (4-bromobenzyl) oxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride (1 g), toluene (20 ml), ethanol (2.5 ml), 2
M mixture of aqueous sodium carbonate (2.5 ml) at room temperature
Stirred for minutes. Add 2-benzofuran boric acid (496 m
g) and tetrakis (triphenylphosphine) palladium (82 mg) were added, and the mixture was heated under reflux for 6 hours under an argon stream. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The crude crystals were washed with diisopropyl ether, further purified by alumina column chromatography (developing solvent: ethyl acetate), converted into a hydrochloride, and recrystallized from methanol-diisopropyl ether to give the title compound (730 mg). Melting point: 235-237 ° C (decomposition) [α] _D ²⁰ = + 42.2 ° (c = 0.40, methanol)

Example 64 (+)-2- [2- (N, N-dimethylamino) ethyl] -6
-[4- (2-naphthyl) phenyl] methoxytetralin hydrochloride

Embedded image (+)-6- (4-bromobenzyl) oxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin hydrochloride (1 g), toluene (20 ml), ethanol (2.5 ml), 2
M mixture of aqueous sodium carbonate (2.5 ml) at room temperature
Stirred for minutes. 2-Naphthalene boric acid (526 m
g) and tetrakis (triphenylphosphine) palladium (82 mg) were added, and the mixture was heated under reflux in an argon stream for 14 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was subjected to alumina column chromatography (developing solvent; ethyl acetate:
After purification with hexane = 1: 20 to 1: 7), it was converted to a hydrochloride and recrystallized from methanol-diisopropyl ether to obtain the title compound (850 mg). Melting point: 233-235 ° C. (decomposition) [α] _D ²⁰ = + 40.6 ° (c = 0.40, methanol) Example 65 2- [2- (N, N-dimethylamino) ethyl] -6-[(4 '
-Methylbiphenyl-4-yl) methoxy] tetralin hydrochloride

Embedded image The title compound was synthesized in the same manner as in Example 43. Melting point: 208-209 ° C Recrystallization solvent Ethanol Example 66 6- (4-Biphenylyl) methoxy-2- [2- (3-ethoxycarbonylpiperidino) ethyl] tetralin

Embedded image The title compound was synthesized in the same manner as in Example 38. Melting point: 97-98 ° C Recrystallization solvent Ethyl acetate: hexane

Example 67 6- (4-Biphenylyl) methoxy-2-[(3-aza-4
-Ethoxycarbonyl-3-methyl) butyl] tetralin hydrochloride

Embedded image The title compound was synthesized in the same manner as in Example 38. Melting point: 126-128 ° C Recrystallization solvent Ethanol Example 68 6- (4-Biphenylyl) -2- (2-aminoethyl) tetralin hydrochloride

Embedded image To a solution of 6- (4-biphenylyl) methoxy-2- (2-iodoethyl) tetralin (0.4 g) in DMF (10 ml) was added potassium phthalimide (0.4 g), and the mixture was stirred at room temperature for 2 days.
Water was added to the reaction solution, and the precipitate was collected by filtration. Hydrazine monohydrate (5 ml) was added to a solution of the precipitate in ethanol (40 ml). The reaction solution was stirred at 50 ° C. for 3 hours and concentrated. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. Dissolve the residue in ethanol (20 ml) and add 4N hydrochloric acid / ethyl acetate (2 ml)
Was added and concentrated. The residue was recrystallized from methanol-ethyl acetate to give the title compound (0.37 g). Melting point: 262-265 ° C. Example 69 2- (N, N-dimethylamino) methyl-6- (2-quinolyl) methoxytetralin dihydrochloride

Embedded image 2- (N, N-dimethylamino) methyl-6-hydroxytetralin (153 mg, free form of Reference Example Compound 16) and
To a solution of 2-chloromethylquinoline hydrochloride (189 mg) in DMF (5 ml) was added potassium carbonate (260 mg), and the reaction solution was stirred at room temperature for 26 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 2) to give the dihydrochloride, and then recrystallized from methanol-ethyl acetate to obtain the title compound (191 mg). Melting point: 187-190 ° C (decomposition)

Example 70 2- (N, N-dimethylamino) methyl-6- (5-phenyl-1,3,4-oxadiazol-2-yl) methoxytetralin

Embedded image 2- (N, N-dimethylamino) methyl-6-hydroxytetralin (206 mg, free form of Reference Example Compound 16) and
Potassium carbonate (215 ml) was added to a solution of 2-chloromethyl-5-phenyl-1,3,4-oxadiazole (231 mg) in DMF (5 ml).
mg) was added and the reaction was stirred at room temperature for 15 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was subjected to alumina column chromatography (developing solvent; ethyl acetate:
Purification with hexane = 1: 2) gave the title compound (307 mg). ^{1 H NMR δ: 1.22-1.49 (1H} , m), 1.84-2.03 (2H, m),
2.07-2.44 (3H, m), 2.24 (6H, s), 2.74-2.96 (3H, m),
5.28 (2H, s), 6.74-6.95 (2H, m), 7.03 (1H, d), 7.4
4-7.60 (3H, m), 8.02-8.11 (2H, m). Example 71 6- (5-Phenyl-1,3,4-oxadiazol-2-yl) methoxy-2-piperidinomethyl Tetralin hydrochloride

Embedded image 6-hydroxy-2-piperidinomethyltetralin (141
mg, free form of Reference Example Compound 19) and 2-chloromethyl-5-phenyl-1,3,4-oxadiazole (148 mg)
Potassium carbonate (143 mg) was added to a DMF solution (3 ml) of
The reaction was stirred at room temperature for 24 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue is subjected to silica gel column chromatography (developing solvent; ethyl acetate: methanol =
10: 1) and alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 4) to give a hydrochloride, and then recrystallized from methanol-diethyl ether to obtain the title compound (175 mg). . Melting point: 217-219 ° C (decomposition)

Example 72 6- (2-Benzothiazolyl) methoxy-2-piperidinomethyltetralin hydrochloride

Embedded image Potassium carbonate (327 mg) was added to a DMF solution (10 ml) of 6-hydroxy-2-piperidinomethyltetralin hydrochloride (205 mg, Reference Example Compound 19) and 2-chloromethylbenzothiazole (183 mg), The reaction was stirred at room temperature for 4 days and at 60 ° C. for 7 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline,
After drying, it was concentrated. The residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: methanol = 10:
After purification by 1) and alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 4) to give a hydrochloride, recrystallization from methanol-ethyl acetate gave the title compound (158 mg). Melting point: 229 DEG-232 DEG C. Example 73 6- (2'-cyanobiphenyl-4-yl) methoxy-2-
[2- (N, N-dimethylamino) ethyl] tetralin hydrochloride

Embedded image DMF of 2- [2- (N, N-dimethylamino) ethyl] -6-hydroxytetralin (72 mg, Reference Example Compound 20) and 4-bromomethyl-2'7-cyanobiphenyl (106 mg)
60% oily sodium hydride (36 mg) was added to the solution (3 ml).
C. and the reaction was stirred at 0.degree. C. for 40 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 4), converted into a hydrochloride, and recrystallized from methanol-diisopropyl ether to obtain the title compound (75 mg). Melting point: 201-206 ° C

Example 74 6- (4-Biphenylyl) methoxy-2-[[[N- [2-
(N, N-dimethylamino) ethyl] -N-methyl] amino] ethyl] tetralin dihydrochloride

Embedded image [6- (4-biphenylyl) methoxy-2-tetralin]
To a solution of -N- [2- (N, N-dimethylamino) ethyl] -N-methylacetamide (495 mg) in THF (20 ml) was added lithium aluminum hydride (94 mg) at 0 ° C. The reaction solution was stirred at room temperature for 50 minutes and then heated under reflux for 2 hours. After cooling the reaction solution, water was added, insolubles were removed by filtration, and the filtrate was concentrated.
The residue was converted into a dihydrochloride, and recrystallized from methanol-ethyl acetate to obtain the title compound (346 mg). Melting point: 248-258 ° C (decomposition) Example 75 6- (4-Biphenylyl) methoxy-2-[[[N- [2-
(N, N-diethylamino) ethyl] -N-methyl] amino] ethyl] tetralin dihydrochloride

Embedded image [6- (4-biphenylyl) methoxy-2-tetralin]
-N- [2- (N, N-diethylamino) ethyl] -N-methylacetamide hydrochloride (320 mg) was obtained as a free form, and THF
Dissolved in the solution (20 ml). To this solution lithium aluminum hydride (68 mg) was added at 0 ° C. Reaction at room temperature
After stirring for 4.5 hours, the mixture was heated under reflux for 30 minutes. After cooling the reaction solution, water was added, insolubles were removed by filtration, and the filtrate was concentrated. The residue was converted into a dihydrochloride, washed with ethyl acetate and diisopropyl ether, and precipitated from methanol-diisopropyl ether to give the title compound (281 mg) as an amorphous powder. IR (KBr): 3314, 2926, 2635, 1611, 1505, 1
267, 1235, 1163, 1011,774 cm ^-1 .

Example 76 6- (4-Biphenylyl) methoxy-2- [2- (N-methylamino) ethyl] tetralin

Embedded image [6- (4-biphenylyl) methoxy-2-tetralin]
-N-methylacetamide (3.958 g) in THF (50 m
To 1), 1M borane-THF complex (35 ml) was added at room temperature. The reaction was heated at reflux for 1 hour. After cooling the reaction solution, add water and 6
N hydrochloric acid (20 ml) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The reaction solution was made basic by adding a 1N aqueous sodium hydroxide solution,
Extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was subjected to alumina column chromatography (developing solvent; ethyl acetate: hexane =
Purification by 1: 1) and the obtained crude crystals were recrystallized from ethyl acetate-hexane to give the title compound (343 mg). Melting point: 75-76 ° C. Example 77 6- (4-Biphenylyl) methoxy-2- [2- (N-methylamino) ethyl] tetralin hydrochloride

Embedded image [6- (4-biphenylyl) methoxy-2-tetralin]
-N-methylacetamide (580 mg) in THF (15 m
To 1), 1M borane-THF complex (5 ml) was added at room temperature. The reaction solution was stirred at room temperature for 2.5 hours and then heated under reflux for 8 hours. After cooling the reaction solution, water and 6N hydrochloric acid (10 ml) were added at 0 ° C., and the mixture was stirred at room temperature for 8 hours. The reaction solution was basified by adding a 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 1), converted into a hydrochloride, and washed with ethyl acetate to obtain the title compound (167 mg). Melting point: 233-237 ° C (decomposition)

Example 78 6- (4-Biphenylyl) methoxy-2- [2- (N-ethylamino) ethyl] tetralin

Embedded image [6- (4-biphenylyl) methoxy-2-tetralin]
-N-ethylacetamide (4.009 g) in 1M borane-THF
The complex salt (20 ml) was added at room temperature. The reaction was heated at reflux for 5 hours. After cooling the reaction solution, water and 6N hydrochloric acid (10 ml) were added at 0 ° C.
And stirred at room temperature for 63 hours. The reaction solution was basified by adding a 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate: hexane to give the title compound (2.851 g). Melting point: 83-85 ° C. Example 79 6- (4-Biphenylyl) methoxy-2- [2- (N-ethylamino) ethyl] tetralin hydrochloride

Embedded image 6- (4-Biphenylyl) methoxy-2- [2- (N-ethylamino) ethyl] tetralin (1.009 g) was used as a hydrochloride. The resulting salt was washed with methanol, ethyl acetate and diethyl ether to obtain the title compound (810 mg). Melting point: 244-249 ° C (decomposition)

Example 80 2- (4-benzylpiperazin-1-yl) methyl-6-
(2-naphthyl) methoxytetralin dihydrochloride

Embedded image To a solution of 2- (4-benzylpiperazin-1-yl) methyl-6-hydroxytetralin (250 mg) in DMF (20 ml) was added 60
% Oily sodium hydride (30 mg) was added and stirred for 30 minutes. Add 2-naphthylmethyl bromide (162 mg) to the reaction mixture
An MF (10 ml) solution was added dropwise. After the reaction solution was stirred at room temperature for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent; ethyl acetate: hexane = 1: 1) to give the dihydrochloride, and then recrystallized from methanol-ethyl acetate to give the title compound (240 mg). Melting point: 210-212 ° C Example 81 7- (4-Biphenylyl) methoxy-3- (N, N-dimethylamino) methyl-1,2,3,4-tetrahydroquinoline hydrochloride

Embedded image 3- (dimethylamino) methyl-1,2,3,4-tetrahydro-7-quinolinol (344 mg), 4-biphenylylmethanol (368 mg) and triphenylphosphine (525 m
g) in THF (20 ml) was added to diethyl azodicarboxylate (3
48 mg) was added dropwise. The reaction solution was stirred at room temperature for 1 hour, poured into 1N hydrochloric acid, and washed with ethyl acetate. The aqueous layer was neutralized with a 1N aqueous sodium hydroxide solution, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 4), converted to a hydrochloride, and further recrystallized from ethanol-diisopropyl ether to give the title compound (214 mg). Melting point: 183-184 ° C. Example 82 (+)-6- (4-biphenylyl) methoxy-2- [2-
(N, N-diethylamino) ethyl] tetralin hydrochloride

Embedded image (+)-2- [2- (N, N-diethylamino) ethyl] -6
To a solution of -hydroxytetralin (4.5 g) in DMF (60 ml) was added 60% oily sodium hydride (1.46 g) at 0 ° C.
After stirring the reaction solution at room temperature for 30 minutes, a solution of 4-chloromethylbiphenyl (4.08 g) in DMF (40 ml) was added dropwise under ice cooling.
The reaction solution was stirred for 2 hours, poured into water, neutralized with a 1N aqueous hydrochloric acid solution, and added with a saturated aqueous sodium hydrogen carbonate solution (50 ml).
Extracted with a 1: 1 solution. The organic layer was dried and concentrated. The residue was purified by silica gel chromatography (developing solvent; ethyl acetate to ethyl acetate: triethylamine = 4: 1), converted to a hydrochloride, and further recrystallized from ethanol-diisopropyl ether to obtain the title compound (6 g). Melting point: 151-153 ° C [α] _D ²⁰ = +42.1 ゜ (c = 0.504, methanol) Optical purity 97.6% ee (determined by HPLC)

Example 83 (-)-6- (4-Biphenylyl) methoxy-2- [2-
(N, N-diethylamino) ethyl] tetralin hydrochloride

Embedded image The title compound was synthesized in the same manner as in Example 82. Recrystallization solvent: ethanol-diisopropyl ether Melting point: 151-153 ° C. [α] _D ²⁰ = -40.6 ゜ (c = 0.500, methanol) Optical purity 98.9% ee (determined by HPLC) Example 84 6- (4-biphenylyl) Methoxy-2- [2- (N-dimethylamino) ethyl] -3,4-dihydronaphthalene hydrochloride

Embedded image 6- (4-biphenylyl) methoxy-2- [2- (N-dimethylamino) ethyl] -3,4-dihydronaphthalene (44
mg) as the hydrochloride salt. The resulting salt was crystallized from methanol-diisopropyl ether to give the title compound (43 mg). Melting point: 233-243 ° C (decomposition) Example 85 7- (4-Biphenylyl) methoxy-3- [2- (N, N-dimethylamino) ethyl] -1,2,3,4-tetrahydroquinoline dihydrochloride

Embedded image [7- (4-Biphenylyl) methoxy-1,2,3,4-tetrahydro-2-oxo-3-quinoline] -N, N-dimethylacetamide (1.407 g) was added to 1M borane-THF complex salt (15 ml) at room temperature. Added in. The reaction was stirred at room temperature for 15 hours. After cooling the reaction solution, water was added and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. Methanol (20 ml) and 1N aqueous sodium hydroxide solution (20 ml) were added to the remaining THF solution (50 ml), and the reaction solution was heated under reflux for 5 days. After cooling the reaction solution, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 4), converted into a dihydrochloride, and recrystallized from ethanol to obtain the title compound (647 mg). Melting point: 185-192 ° C (decomposition)

Example 86 1-acetyl-7- (4-biphenylyl) methoxy-3-
[2- (N, N-dimethylamino) ethyl] -1,2,3,4-tetrahydroquinoline

Embedded image Triethylamine (0.33) was added to a solution of 7- (4-biphenylyl) methoxy-3- [2- (N, N-dimethylamino) ethyl] -1,2,3,4-tetrahydroquinoline (250 mg) in THF (17 ml). acetyl chloride (0.09 ml) under ice-cooling.
Was added dropwise. After stirring for 1 hour under ice cooling, the reaction solution was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 20 to 1: 6). The precipitated crystals are washed with diisopropyl ether,
The title compound (210 mg) was obtained. Melting point: 62.0-63.5 ° C Example 87 7- (4-Biphenylyl) methoxy-3- [2- (N, N-dimethylamino) ethyl] -1-ethyl-1,2,3,4-tetrahydroquinoline dihydrochloride salt

Embedded image 1-acetyl-7- (4-biphenylyl) methoxy-3-
To a solution of [2- (N, N-dimethylamino) ethyl] -1,2,3,4-tetrahydroquinoline (120 mg) in THF (1.5 ml) was added 1M borane-THF complex salt (0.9 ml) under ice-cooling. It was dropped. After stirring at room temperature for 15 minutes, the reaction was heated to reflux for 15 minutes.
After cooling, a small amount of water was added to the reaction solution, and a 12N aqueous sodium hydroxide solution (1.5 ml) was added, followed by heating under reflux for 16 hours.
After cooling, water was added and extracted with diethyl ether. The organic layer was washed with saturated saline, dried, and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 20 to 1: 7) to obtain the dihydrochloride,
Recrystallization from methanol-diisopropyl ether gave the title compound (101 mg). Melting point: 173-175 ° C (decomposition) Example 88 (+)-2- [2- (N, N-dimethylamino) ethyl] -6
-(6-phenyl-3-pyridyl) methoxytetralin
Dihydrochloride

Embedded image (+)-2- [2- (N, N-dimethylamino) ethyl] -6
-DMF solution (5 ml) of hydroxytetralin (0.221 g)
To this was added 60% oily sodium hydride (0.053 g) at room temperature. The reaction was stirred at 50 ° C. for 1 hour. The reaction was cooled to 0 ° C. and 6-phenyl-3-pyridylmethyl bromide (76%,
0.366 g) of a THF solution (5 ml) was added dropwise. Reaction solution at 0 ° C
After stirring for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated.
The residue was subjected to alumina column chromatography (developing solvent;
After purification with ethyl acetate: hexane = 1: 4) to give the dihydrochloride, recrystallization from ethanol-ethyl acetate gave the title compound (265 mg). Melting point: 218-220 ° C [α] _D ²⁰ = + 43.5 ° (c = 0.504, methanol)

Example 89 (+)-2- [2- (N, N-dimethylamino) ethyl] -6
-[6- (methoxyphenyl) -3-pyridyl] methoxytetralin dihydrochloride

Embedded image (+)-6- (2-bromopyridin-5-yl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin dihydrochloride (0.2 g), toluene (8 ml), ethanol ( 1 ml) and a 2M aqueous solution of sodium carbonate (1 ml) were stirred at room temperature for 10 minutes. 4-Methoxyphenylboric acid (89 mg) and tetrakis (triphenylphosphine) palladium (27 mg) were added to the reaction solution, and the mixture was heated under reflux in an argon stream for 15 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 4), converted into a dihydrochloride, and recrystallized from ethanol-ethyl acetate to obtain the title compound (176 mg). Melting point: 223-231 ° C. (decomposition) [α] _D ²⁰ = + 41.1 ° (c = 0.494, methanol) Example 90 7- (4-biphenylyl) methoxy-3- [2- (N, N-dimethylamino) ) Ethyl] -1,2,3,4-tetrahydro-1-
Methylsulfonylquinoline hydrochloride

Embedded image To a solution of 7- (4-biphenylyl) methoxy-3- [2- (N, N-dimethylamino) ethyl] -1,2,3,4-tetrahydroquinoline (110 mg) in pyridine (5 ml) was cooled with ice. Below, methanesulfonyl chloride (0.03 ml) was added dropwise. The reaction was stirred at room temperature for 3 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 2), converted into a hydrochloride, and recrystallized from ethanol-ethyl acetate to obtain the title compound (88 mg). Melting point: 236-240 ° C (decomposition)

Example 91 (+)-6- (2-Benzofuranyl) methoxy-2- [2-
(N, N-dimethylamino) ethyl] tetralin

Embedded image (+)-2- [2- (N, N-dimethylamino) ethyl] -6
-DMF solution (5 ml) of hydroxytetralin (0.217 g)
To the mixture was added 60% oily sodium hydride (0.052 g) at room temperature. The reaction was stirred at 50 ° C. for 1 hour. The reaction solution was cooled to 0 ° C., and a THF solution (5 ml) of 2-chloromethylbenzofuran (0.187 g) was added dropwise. After stirring the reaction solution at 0 ° C. for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by alumina column chromatography (developing solvent; ethyl acetate: hexane = 1: 4), and then recrystallized from ethyl acetate-hexane to obtain the title compound (17 mg). ^{_{Mp: 75-77 ℃ [α] D 20}} = + 56.8 ° (c = 0.253, methanol)

Formulation Example 1 (1) Compound obtained in Example 12 50 mg (2) Lactose 34 mg (3) Maize starch 10.6 mg (4) Maize starch (paste) 5 mg (5) Magnesium stearate 0.4 mg (6) Carboxymethylcellulose calcium 20 mg Total 120 mg The above (1) to (6) were mixed according to a conventional method, and tabletted with a tablet machine to obtain tablets.

Experimental Example 1 Amyloid β protein production / secretion inhibitory activity in human neuroblastoma IMR-32 cells was examined (Reference: Science, vol. 264, p. 1336 (1994), Biochemistry 34). Volume, p. 10272 (199
5) etc.). (Method) a) Experimental materials Human neuroblastoma IMR-32 cells: American Type Culture Center (American Type Culture Center)
Culture Center). Dulbecco's modified Ea
gle's medium, abbreviated as DMEM): purchased from Nissui Pharmaceutical. Fetal calf serum (abbreviated as FCS) and penicillin (5000 U / ml) / streptomycin (5 mg / m2)
l) Mixed solution: purchased from Bio White Tucker. Phosphate / saline buffer
e, PBS): Purchased from Flow Laboratories. Block Ace (trade name): Purchased from Dainippon Pharmaceutical. Bovine serum albumin (abbreviated as BSA): purchased from Sigma. Culture flask: Falcon manufactured. 48-well multiwell plate: manufactured by Coaster. Aβ _1-40 standard product and Aβ _1-42 standard product: purchased from Bachem. Other reagents: Use commercial grade products. b) Experimental method (1) Culture of IMR-32 cells IMR-32 cells were confluent at 37 ° C. in a flask containing 10% FCS / DMEM culture solution (Falcon, 750 ml) in 10% carbon dioxide / 90% air. (Fully filled). After the culture, the IMR-32 cells were seeded in a 48-well multiwell plate at 2.5 × 10 ⁵ cells / well, and further cultured for 3 days under the same conditions, and the culture solution was removed by suction. The DMF solution containing the test substance was dissolved in 0.5 ml of 0.5% BSA / DMEM, added to the above plate, and further cultured for 24 hours. As a control, a DMF solution containing no test substance was 0.5%.
A solution dissolved in 0.5 ml of BSA / DMEM was used.
The supernatant was collected and stored at −20 ° C. or lower until the measurement of Aβ. (2) Aβ enzyme immunoassay (EIA) BAN-50 antibody or BNT-7 as primary antibody
Seven antibodies were used. When measuring Aβ _1-40 , BA-27 antibody was used as a secondary antibody. When measuring Aβ _1-42 , a BC-05 antibody was used as a secondary antibody. 0.1M
A BAN-50 antibody or a BNT-77 antibody dissolved in a carbonate buffer (pH 9.6) at a concentration of 15 μg / ml was added to a polyethylene microtiter plate in an amount of 100 μl each, and left at 4 ° C. overnight. After washing the plate surface three times with PBS, 200 μl of a block solution (25% block ace / 0.1% sodium azide / PBS) was added. In this state, keep the temperature at 4 ° C until the addition of the supernatant in (1).
Saved in. Immediately before the addition of the supernatant, the plate surface was washed three times with PBS, and then the primary reaction buffer (20 mM phosphate buffer, pH 7.0; 400 mM NaCl; 2 mM EDTA;
50% of 10% Block Ace; 0.2% BSA; 0.05% Sodium Azide) was added. In addition, 100
μβ supernatant and Aβ diluted in primary reaction buffer ( _1-40
Or Aβ _1-42 standard (1000, 2
100, 40 and 8 pg / ml)
Was added and left at 4 ° C. overnight. The plate was washed three times with PBS, and a buffer for a secondary reaction (20 mM phosphate buffer, pH 7.0; 400 mM NaCl: 2 mM EDTA;
HRP-labeled secondary antibody (BA-
27 antibody or BC-05 antibody, HRP: horseradish peroxidase (100μ)
l was added. After leaving at room temperature for 6 hours, PBS
After washing twice, 100 μl of a coloring reaction solution (TMB Peroxidase Substrate (trade name), manufactured by Kirkegaard & Perry Lab.) Was added. Leave at room temperature for 8-10 minutes, and add 1M phosphoric acid solution 1
Add 00μl to the plate to stop the reaction, plate reader (Corona, MTP-32 microplate reader)
Was used for colorimetric determination (measurement wavelength: 450 nm). (Results) For each dose of compound, 4 wells were used. The inhibitory effect of the compound (10 μM) on the production and secretion of Aβ _1-40 and Aβ _1-42 was shown as a ratio (%) to the control. The results are shown in [Table 1].

[Table 1] From these results, it was confirmed that compound (I) and compound (I ′) of the present invention have an amyloid β protein production / secretion inhibitory action.

[00143]

The compound (I) of the present invention has excellent amyloid β protein production / secretion inhibitory activity and excellent secretory AP
It has a secretion promoting action of P, has low toxicity, and has excellent translocation into the brain, so it has neurodegenerative diseases; amyloid angiopathy; neuropathy due to cerebrovascular disorders, head trauma, or spinal cord injury. It is also useful as a prophylactic / therapeutic agent and as an agent for improving various mental disorders (eg, depression, anxiety, threatening neurosis, sleep disorders, etc.) caused by neurodegeneration and neuropathy. Compound (I ') also has an inhibitory effect on amyloid β protein production / secretion and secretory APP
It is useful for the above diseases because of its secretion promoting action. Compounds (I) and (I ′) are preferably a neurodegenerative disease (eg, Alzheimer's disease, Down's syndrome, senile dementia, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral cord sclerosis, diabetic neuropathy) , Huntington's chorea, multiple sclerosis, etc.), more preferably as a prophylactic / therapeutic agent for neurodegenerative diseases caused by amyloid β protein (eg, Alzheimer's disease, Down's syndrome, etc.). Is useful as a prophylactic / therapeutic agent for Alzheimer's disease.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/275 AED A61K 31/275 AED 31/34 31/34 31/40 31/40 31/41 31/41 31/44 31 / 44 31/445 31/445 31/47 31/47 31/495 31/495 C07C 217/74 C07C 217/74 233/43 233/43 255/54 255/54 271/12 271/12 311/21 311 / 21 323/19 323/19 C07D 211/14 C07D 211/14 211/44 211/44 211/58 211/58 211/60 211/60 213/30 213/30 215/14 215/14 215/20 215 / 20 271/10 271/10 295/08 295/08 Z A 307/80 307/80 333/16 333/16 // C07C 225/18 C07C 225/18 C07M 7:00

Claims (35)

[Claims] (1) Formula (1) [Wherein, Ar represents an optionally substituted ring-assembling aromatic group or an optionally substituted condensed aromatic group, X represents (i) a bond, (ii) —S -, -SO- or-
SO ₂ —, (iii) C- _optionally having 1 to 3 substituents selected from oxo and C _1-6 alkyl
_1-6 alkylene, C _2-6 alkenylene or C _2-6 alkynylene, (iv) —CO—O— or (v) formula — (CH ₂ ) p
-X ¹ -,-(CH ₂ ) p-X ^1- (CH ₂ ) q-,-(CH ₂ ) r-
CO-X ^1- , -SO ₂ -NR ^8- or-(CH ₂ ) r-S
O ₂ —NR ⁸ — (wherein X ¹ is an oxygen atom or NR ⁸ , R ⁸
Is a hydrogen atom, an optionally substituted hydrocarbon group or acyl, p is an integer of 0 to 5, q is an integer of 1 to 5, p + q is an integer of 1 to 5, and r is 1 to 4
Y represents a divalent C _1-6 aliphatic hydrocarbon group which may be via an oxygen atom or a sulfur atom and may have a substituent. And R ¹ and R ² each represent a hydrogen atom or a lower alkyl which may have a substituent, or R ¹ and R ² represent a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom. A ring is formed, and the A ring represents a benzene ring which may further have a substituent in addition to the group represented by the formula -X-Ar (wherein each symbol has the same meaning as described above), Ring B has the formula -Y-NR ¹
And a 4- to 8-membered ring which may further have a substituent, in addition to the group represented by R ² (wherein each symbol has the same meaning as described above). However, when the condensed ring formed by ring A and ring B is an indole ring, the group represented by the formula -X-Ar (wherein each symbol has the same meaning as described above) is the same as that of the indole ring.
Substitution at the-, 6- or 7-position. Or a salt thereof. 2. Ar is (i) a C _6-14 aromatic hydrocarbon;
_6-14 quinones and nitrogen atom in addition to carbon atoms, 2 or 3 selected from 5 to 14-membered aromatic heterocyclic ring containing four to no heteroatoms 1 selected from sulfur and oxygen atoms
Aromatic rings are directly connected by a single bond, and a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, Good C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl - carbonyl, C
_1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl , Di-C _1-6
Alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl -Carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-
Carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6
Alkyl-carbamoyloxy, di-C _1-6 alkyl-
A ring-assembled aromatic group optionally having 1 to 5 substituents selected from carbamoyloxy, C _6-10 aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy, or (ii) a halogen atom , C _1-3 alkylenedioxy, 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, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl , C
_1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono -C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formyl Amino, C _1-6 alkyl-
Carboxamide, C _6-10 aryl-carboxamide, C
_1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C
_6-10 aryl-carbonyloxy, C _1-6 alkoxy-
Carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy,
C _6-10 aryl - carbamoyloxy, substituents selected from nicotinoyloxy oxy and C _6-10 aryloxy 1
Or a fused 2 or 3 cyclic C _10-14 aryl optionally having 5 to 5 carbon atoms or a heteroatom selected from nitrogen, sulfur and oxygen
A 9- to 14-membered aromatic heterocyclic group containing from 4 to 4, R ⁸
Is (a) hydrogen atom, (b) (1) halogen atom, (2) C _1-3
Alkylenedioxy, (3) nitro, (4) cyano, (5)
Optionally halogenated C _1-6 alkyl, (6) optionally halogenated C _3-6 cycloalkyl, (7)
Optionally halogenated C _1-6 alkoxy, (8) optionally halogenated C _1-6 alkylthio, (9) hydroxy, (10) amino, (11) mono-C _1-6 alkylamino (12) di-C _1-6 alkylamino, (13) formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 Aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5 or 6
Heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl or C _{6 -10} arylsulfonyl, (14) formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6
Alkoxy-carboxamide or C _1-6 alkylsulfonylamino, (15) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl- Carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy or nicotinoyloxy, (16) 5- to 7-membered saturated cyclic amino,
(17) sulfo, (18) halogen atom, C _1-3 alkylenedioxy, 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, di-C _1-6 alkylamino, 5 to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6
Alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _{1 -6} alkyl - carbamoyl, di -C _1-6 alkyl - carbamoyl, C _6-10 aryl - carbamoyl, 5 or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl-
Carboxamide, C _6-10 aryl-carboxamide, C
_1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C
_6-10 aryl-carbonyloxy, C _1-6 alkoxy-
Carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy,
C _6-10 aryl - carbamoyloxy, substituents selected from nicotinoyloxy oxy and C _6-10 aryloxy 1
5 or 6 containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, in addition to phenyl or carbon which may each have 5 to 5 carbons
Membered aromatic heterocyclic group, (19) C _6-14 aromatic hydrocarbon, C
_6-14 quinones and nitrogen atom in addition to carbon atoms, 2 or 3 selected from 5 to 14-membered aromatic heterocyclic ring containing four to no heteroatoms 1 selected from sulfur and oxygen atoms
Aromatic rings are directly connected by a single bond, and a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, Good C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl - carbonyl, C
_1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl , Di-C _1-6
Alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl -Carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-
Carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6
Alkyl-carbamoyloxy, di-C _1-6 alkyl-
(20) a halogen atom, a ring-assembled aromatic group optionally having 1 to 5 substituents selected from carbamoyloxy, C _6-10 aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy; , C _1-3 alkylenedioxy, 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, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, Carboxy, carbamoyl, C
_1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono -C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formyl Amino, C _1-6 alkyl-
Carboxamide, C _6-10 aryl-carboxamide, C
_1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C
_6-10 aryl-carbonyloxy, C _1-6 alkoxy-
Carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy,
C _6-10 aryl - carbamoyloxy, substituents selected from nicotinoyloxy oxy and C _6-10 aryloxy 1
Or a fused 2 or 3 cyclic C _10-14 aryl optionally having 5 to 5 carbon atoms or a heteroatom selected from nitrogen, sulfur and oxygen
C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl optionally having 1 to 5 substituents selected from a 9 to 14 membered aromatic heterocyclic group containing from 4 to 4;
C _3-6 cycloalkyl, C _6-14 aryl or C _7-19 aralkyl which may be condensed with a benzene ring, or
(c) formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C
_6-10 aryl - carbonyl, C _6-10 aryloxy - carbonyl, C ₇ - ₁₆ aralkyloxy - carbonyl, 5
Or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-
Carbamoyl, di-C _1-6 alkyl-carbamoyl, C
_6-10 aryl-carbamoyl, 5 or 6 membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl or C _6-10 arylsulfonyl; wherein Y is C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene or a formula − (CH ₂ ) m−Y ¹ −
(CH ₂ ) n- (wherein -Y ¹ -is -O-, -S-, -SO
— Or —SO ₂ —, m is an integer of 0 to 4, n is an integer of 1 to 5, and m + n is an integer of 1 to 5); R ¹ and R ² are each (i) Hydrogen atom or (ii) halogen atom, C _1-3 alkylenedioxy, 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, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy- Carbonyl, C
_6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl -Carbamoyl, C
_6-10 aryl - carbamoyl, 5 or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _{1 -6} alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _6-10 aryl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyl Oxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10
Aryl-carbamoyloxy, nicotinoyloxy,
With C _6-10 aryloxy and C _6-10 nitrogen atom without substituent 1 selected from aryl to which may have five to a C _1-6 alkyl or R ¹ and R ^2, are adjacent, as a substituent (1) halogen atom, (2) C _1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated C _1-6 alkyl, (6) halogenated which may be C _3-6 cycloalkyl, (7) optionally halogenated C _1-6 alkoxy optionally, (8) a C _1-6 alkylthio which may be halogenated, (9) hydroxy,
(10) amino, (11) mono-C _1-6 alkylamino, (1
2) di-C _1-6 alkylamino, (13) formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C
_1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl , Di-C _1-6
Alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl or C _6-10 arylsulfonyl, (14) formylamino, C _1-6 alkyl-carboxamide, C
_6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide or C _1-6 alkylsulfonylamino,
(15) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy,
Di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy or nicotinoyloxy,
(16) 5- to 7-membered saturated cyclic amino, (17) sulfo,
(18) halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6
Alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl,
C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic Ring carbamoyl,
C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _{1-6 1-6} alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy,
It may have 1 to 5 substituents each selected from di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy (a) Phenyl or (b)
5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen other than carbon, (19) C _6-14 aromatic hydrocarbon, C _6-14 quinone And two or three aromatic rings selected from 5 to 14-membered aromatic heterocycles containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms other than carbon atoms, directly connected by a single bond. As a substituent, a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino,
To 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C
_6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl Carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C
_1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6
Alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6
Substitution selected from alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy A ring-assembled aromatic group optionally having 1 to 5 groups, and (20) a halogen atom, C _1-3 alkylenedioxy, 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, di -C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6
Alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _{1 -6} alkyl - carbamoyl, di -C _1-6 alkyl - carbamoyl, C _6-10 aryl - carbamoyl, 5 or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl-
Carboxamide, C _6-10 aryl-carboxamide, C
_1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C
_6-10 aryl-carbonyloxy, C _1-6 alkoxy-
Carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy,
C _6-10 aryl - carbamoyloxy, substituents selected from nicotinoyloxy oxy and C _6-10 aryloxy 1
Or a fused 2 or 3 cyclic C _10-14 aryl optionally having 5 to 5 carbon atoms or a heteroatom selected from nitrogen, sulfur and oxygen
A 9- to 14-membered aromatic heterocyclic group containing from 4 to 4, (2
1) It may have 1 to 5 substituents selected from oxo and (22) C _7-19 aralkyl, and contains at least one nitrogen atom other than a carbon atom, and includes a nitrogen atom, an oxygen atom and a sulfur atom. A selected 3- to 8-membered nitrogen-containing heterocycle optionally containing 1 to 3 heteroatoms; wherein the ring A is represented by the formula -X-Ar (wherein each symbol is as defined above) Having 1 to 3 substituents selected from a halogen atom, an optionally halogenated C _1-6 alkyl, an optionally halogenated C _1-6 alkoxy, hydroxy and amino, A good benzene ring;
And ring B other than a group represented by the formula -Y-NR ¹ R ² (wherein each symbol has the same meaning as described above), oxo, C _1-6
Formulas which may further have 1 to 3 substituents selected from alkyl and hydroxy Z represents (i) a bond, (ii) C _1-4 alkylene, (iii) C
_{2-4 alkenylene, (iv) -O-CH 2} -, (v) -O-C
H ₂ —CH ₂ — or (vi) Formula —NR ^8a —CH ₂ — or —NR ^8a —CH ₂ —CH ₂ — (wherein R ^8a is (a) a hydrogen atom, (b) (1) a halogen atom (2) C _1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated C _1-6 alkyl, (6) optionally halogenated C _{3 -6} cycloalkyl, (7) optionally halogenated C _1-6 alkoxy, (8) optionally halogenated C _1-6 alkylthio, (9) hydroxy,
(10) amino, (11) mono-C _1-6 alkylamino, (1
2) di-C _1-6 alkylamino, (13) formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C
_1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl , Di-C _1-6
Alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl or C _6-10 arylsulfonyl, (14) formylamino, C _1-6 alkyl-carboxamide, C
_6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide or C _1-6 alkylsulfonylamino,
(15) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy,
Di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy or nicotinoyloxy,
(16) 5- to 7-membered saturated cyclic amino, (17) sulfo,
(18) a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _{3 -6} cycloalkyl, an optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6
Alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl,
C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic Ring carbamoyl,
C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _{1-6 1-6} alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy,
Phenyl or carbon optionally having 1 to 5 substituents each selected from di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy A 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to the atom, (19) C _6-14 aromatic hydrocarbon, C _6-14 quinone and 5 to 1 containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms
Two or three aromatic rings selected from a 4-membered aromatic heterocycle are directly connected by a single bond, and a halogen atom, C
_1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl optionally, optionally halogenated C _3-6 also be cycloalkyl, optionally halogenated C _1-6 alkoxy optionally Optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6
Alkylamino, di -C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl - carbonyl, C _1-6 alkoxy -
Carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C
_1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5 or 6
Membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C
_6-10 arylsulfonyl, formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _1-6 alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy, nicotine A ring-assembled aromatic group optionally having 1 to 5 substituents selected from noyloxy and C _6-10 aryloxy,
And (20) a halogen atom, C _1-3 alkylenedioxy, 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, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy- Carbonyl, C
_6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl -Carbamoyl, C
_6-10 aryl - carbamoyl, 5 or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _{1 -6} alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _6-10 aryl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyl Oxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10
A condensed _bi- or tricyclic C _10-14 aryl optionally having 1 to 5 substituents selected from aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy, or a nitrogen atom other than a carbon atom And a C _1-6 which may have 1 to 5 substituents selected from a 9 to 14 membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a sulfur atom and an oxygen atom, respectively.
Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl optionally condensed with a benzene ring, C
_6-14 aryl or C _7-19 aralkyl, or (c) formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryl Oxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5 or 6
Heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl or C _{6 -10} represents an arylsulfonyl).] The 4- to 8-membered ring represented by the formula: 3. The compound according to claim 1, wherein Ar is a ring-assembled aromatic group which may have a substituent. 4. The aromatic ring of a ring-assembled aromatic group, wherein the aromatic ring is selected from benzene, thiophene, pyridine, pyrimidine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, naphthalene and benzofuran. 4. The compound according to claim 3, which is three aromatic rings. 5. The compound according to claim 3, wherein the ring-assembled aromatic group is 2-, 3- or 4-biphenylyl. 6. Ar is a halogen atom, C_1-3Alkylene
Dioxy, nitro, cyano, halogenated
C_1-6Alkyl, optionally halogenated C_3-6Shi
Chloroalkyl, optionally halogenated C_1-6Al
Coxy, optionally halogenated C_1-6Alkyl
E, hydroxy, amino, mono-C_1-6Alkylam
No, Di-C_1-6Alkylamino, 5- to 7-membered saturated cyclic
Amino, formyl, carboxy, carbamoyl, C_1-6
Alkyl-carbonyl, C_1-6Alkoxy-carboni
Le, C_6-10Aryl-carbonyl, C_6-10Aryloxy
C-carbonyl, C_7-16Aralkyloxy-carboni
5- or 6-membered heterocyclic carbonyl, mono-C_1-6Al
Kill-carbamoyl, di-C_1-6Alkyl-carbamoy
Le, C_6-10Aryl-carbamoyl, 5- or 6-membered complex
Ring carbamoyl, C_1-6Alkylsulfonyl, C_6-10A
Reelsulfonyl, formylamino, C_1-6Alkyl-
Carboxamide, C_6-10Aryl-carboxamide, C
_1-6Alkoxy-carboxamide, C_1-6Alkylsulfo
Nilamino, C_1-6Alkyl-carbonyloxy, C
_6-10Aryl-carbonyloxy, C_1-6Alkoxy-
Carbonyloxy, mono-C_1-6Alkyl-carbamoy
Luoxy, di-C_1-6Alkyl-carbamoyloxy,
C_6-10Aryl-carbamoyloxy, nicotinoylo
Kishi and C_6-101 to 1 selected from aryloxy
4-biphenylyl optionally having three substituents
A compound according to claim 1, wherein 7. A divalent C, wherein X may be via an oxygen atom.
The compound according to claim 1, which is a _1-6 aliphatic hydrocarbon group. 8. The compound according to claim 1, wherein X is C _1-6 alkylene. 9. The compound according to claim 1, wherein X is a group represented by the formula-(CH ₂ ) p-X ^1- (wherein each symbol is as defined in claim 1). 10. The compound according to claim 9, wherein p is 1. 11. The compound according to claim 10, wherein X ¹ is O. 12. X ¹ is NR ^8b (R ^8b is a hydrogen atom or C
_1-6 alkyl-carbonyl). 13. The compound according to claim 1, wherein X ¹ is a group represented by the formula —SO ₂ —NR ⁸ — (wherein each symbol is as defined in claim 1). 14. The compound according to claim 13, wherein R ⁸ is a hydrogen atom. 15. The compound according to claim 1, wherein Y is a divalent C _1-6 aliphatic hydrocarbon group. 16. The compound according to claim 1, wherein Y is C _1-6 alkylene. 17. The compound according to claim 1, wherein R ¹ and R ² are each C _1-6 alkyl. 18. The compound according to claim 1, wherein ring A is a benzene ring substituted only with a group represented by the formula -X-Ar (wherein each symbol is as defined in claim 1). . (19) a ring B other than a group represented by the formula -Y-NR ¹ R ² (wherein each symbol is as defined in the above (1)), oxo, C _1-6 alkyl and hydroxy Formula which may further have 1 to 3 substituents selected from [Wherein, Z is (i) a bond, (ii) C _1-4 alkylene,
(iii) C _{2-4 alkenylene, (iv) -O-CH 2} -, (v)
—O—CH ₂ —CH ₂ — or (vi) a formula —NR ^8a —CH ₂
— Or —NR ^8a —CH ₂ —CH ₂ — (wherein R ^8a is (a)
Hydrogen atom, (b) (1) halogen atom, (2) C _1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated C _1-6 alkyl, ( 6) optionally halogenated C _3-6 cycloalkyl, (7) optionally halogenated C _1-6 alkoxy, (8) optionally halogenated C _1-6 alkylthio, (9 ) Hydroxy, (10) amino, (11) mono-C _1-6 alkylamino, (12) di-C _1-6 alkylamino, (13) formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl,
C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic Ring carbamoyl,
C _1-6 alkylsulfonyl or C _6-10 arylsulfonyl, (14) formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _1-6 alkoxy - carboxamide or C _1-6 alkylsulfonyl Amino, (15) C _1-6 alkyl-carbonyloxy,
C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy or nicotine Noyloxy, (16) 5- to 7-membered saturated cyclic amino, (1
7) sulfo, (18) halogen atom, C _1-3 alkylenedioxy, 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, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy- Carbonyl, C
_6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl -Carbamoyl, C
_6-10 aryl - carbamoyl, 5 or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _{1 -6} alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _6-10 aryl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyl Oxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10
Phenyl optionally having 1 to 5 substituents selected from aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy, or a hetero atom selected from nitrogen, sulfur and oxygen in addition to carbon. 5- or 6-membered aromatic heterocyclic group containing 1 to 4 atoms, (19) selected from C _6-14 aromatic hydrocarbon, C _6-14 quinone and nitrogen atom, sulfur atom and oxygen atom other than carbon atom Two or three aromatic rings selected from a 5- to 14-membered aromatic heterocycle containing 1 to 4 heteroatoms are directly connected by a single bond, and a halogen atom, C _1-3 alkylenedioxy, nitro , cyano, optionally halogenated C _1-6 alkyl optionally, optionally halogenated C _3-6 also be cycloalkyl, optionally halogenated C _1-6 alkoxy optionally, c Gen of which may be C _1-6 alkylthio, hydroxy, amino, mono--C _1-6 alkylamino, di -C _1-6 alkylamino, 5
To 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C
_6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl Carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C
_1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6
Alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6
Substitution selected from alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy A ring-assembled aromatic group optionally having 1 to 5 groups, and (20) a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, Optionally halogenated C _3-6 chloroalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio,
Hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy- Carbonyl, C
_6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl -Carbamoyl, C
_6-10 aryl - carbamoyl, 5 or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl, formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _{1 -6} alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _6-10 aryl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyl Oxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10
A condensed _bi- or tricyclic C _10-14 aryl optionally having 1 to 5 substituents selected from aryl-carbamoyloxy, nicotinoyloxy and C _6-10 aryloxy, or a nitrogen atom other than a carbon atom And a C _1-6 which may have 1 to 5 substituents selected from a 9 to 14 membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a sulfur atom and an oxygen atom, respectively.
Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl optionally condensed with a benzene ring, C
_6-14 aryl or C _7-19 aralkyl, or (c) formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryl Oxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5 or 6
Heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl or C _{6 -10} represents an arylsulfonyl).] The 4- to 8-membered ring represented by the formula: (20) R ^8a is a hydrogen atom, an optionally halogenated C _1-6 alkyl, C _1-6 alkyl-carbonyl,
_1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl , Di-C _1-6
Alkyl - carbamoyl, C _6-10 aryl - carbamoyl, 5 or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl or C _6-10 compound of claim 19 wherein the arylsulfonyl. 21. A 6-membered homo- or heterocyclic ring in which ring B is substituted only with a group represented by the formula -Y-NR ¹ R ² (wherein each symbol is as defined in claim 1). The compound according to claim 1, which is 22. The ring B having the formula Wherein Za is C _1-3 alkylene or a formula —NR ^8c —C
H ₂ — (wherein R ^8c is a hydrogen atom, optionally halogenated C _1-6 alkyl, C _1-6 alkyl-carbonyl,
_1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl, mono-C _1-6 alkyl-carbamoyl , Di-C _1-6
Alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl or C _6-10 arylsulfonyl). A compound according to claim 1. 23. The compound according to claim 22, wherein Za is ethylene. 24. When X is CH ₂ O, the condensed ring formed by ring A and ring B is of the formula: The compound according to claim 1, which is a ring represented by the formula: 25. Ar is a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated 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 and C _1-6
2-, 3- or 4-biphenylyl optionally having 1 to 3 substituents selected from alkyl-carboxamides; C _1-3 alkylene in which X may be via an oxygen atom; Y is C _{1- 6} alkylenes; R ¹ and R ² are each C
_1-6 alkyl; A ring is (wherein each symbol is claim 1, wherein as defined above shows a) the formula -X-Ar a benzene ring substituted only the group represented by in; and ring B wherein -Y -NR ¹ R ² (wherein each symbol is claim 1, wherein as defined above shows a) a compound of claim 1 wherein the 6-membered homocyclic or heterocyclic ring substituted only with a group represented by. 26. A compound of the formula Wherein R ⁰ is 1 to 3 halogen atoms, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _1- Selected from ₆ alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, formyl and C _1-6 alkyl-carboxamide Substituent,
R ^1a and R ^2a are each C _1-6 alkyl] or a salt thereof. 27. The formula Wherein, Ar ^a is (i) a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, C _1-6 alkoxy optionally halogenated 2-, 3- or 4-biphenylyl optionally having 1 to 3 substituents selected from optionally halogenated C _1-6 alkylthio, amino, formyl and C _1-6 alkyl-carboxamide , (Ii) 4-
(2-thienyl) phenyl or 4- (3-thienyl)
Phenyl, (iii) 4- (3-pyridyl) phenyl, (i
v) 6-phenyl- optionally having C _1-6 alkoxy
3-pyridyl, (v) 5-phenyl-1,3,4-oxadiazol-2-yl, (vi) 4- (2-naphthyl) phenyl, (vii) 4- (2-benzofuranyl) phenyl, ( v
iii) 1- or 2-naphthyl, (ix) 2-quinolyl,
(x) 2-benzothiazolyl or (xi) 2-benzofuranyl; X ′ is —CH ₂ —O—, —SO ₂ —NH— or a formula
—CH ₂ —NR ⁸ ′ — (wherein R ⁸ ′ is a hydrogen atom or C _1-3
Y ′ is a group represented by the formula:
_1-6 alkylene; Z ′ is —CH ₂ —CH ₂ — or a formula —N
A group represented by R ⁸ ″ —CH ₂ — (wherein R ⁸ ″ is a hydrogen atom, C _1-3 alkyl, C _1-3 alkyl-carbonyl or C _1-3 alkylsulfonyl); and R ¹ 'and R ² '
Is a C _1-6 alkyl optionally having 1 to 5 substituents selected from di-C _1-3 alkylamino, C _1-3 alkoxy-carbonyl and phenyl, or R ¹ ′
And R ² ′, together with the adjacent nitrogen atom,
_1-3 forms pyrrolidin-1-yl, piperidino or piperazin-1-yl which may have 1 to 3 substituents selected from alkoxy-carbonyl, piperidino, phenyl and benzyl, respectively. The compound according to claim 1, which is a compound or a salt thereof. 28. 6- (4-biphenylyl) methoxy-2
-[2- (N, N-dimethylamino) ethyl] tetralin, 6- (4-biphenylyl) methoxy-2- (N, N
-Dimethylamino) methyltetralin, 2- (N, N-
Dimethylamino) methyl-6- (4'-methoxybiphenyl-4-yl) methoxytetralin, (+)-6-
(4-biphenylyl) methoxy-2- [2- (N, N-
Dimethylamino) ethyl] tetralin, (+)-6
(4-biphenylyl) methoxy-2- [2- (N, N-
Diethylamino) ethyl] tetralin, (+)-2-
[2- (N, N-dimethylamino) ethyl] -6- (4 ′
-Methylbiphenyl-4-yl) methoxytetralin,
(+)-2- [2- (N, N-dimethylamino) ethyl] -6- (4'-methoxybiphenyl-4-yl) methoxytetralin, (+)-6- (2 ', 4'-dimethoxy Biphenyl-4-yl) methoxy-2- [2- (N,
N-dimethylamino) ethyl] tetralin, (+)-6
-[4- (1,3-benzodioxol-5-yl) phenyl] methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin or (+)-6- (3 ′,
4'-dimethoxybiphenyl-4-yl) methoxy-2
The compound according to claim 1, which is-[2- (N, N-dimethylamino) ethyl] tetralin or a salt thereof. (29) i) The formula: [In the formula, Xa is an oxygen atom, a sulfur atom which may be oxidized, or a formula NR ⁸ (wherein R ⁸ represents a hydrogen atom, a hydrocarbon group which may have a substituent or acyl). And the other symbols have the same meanings as defined in claim 1), or a salt thereof is subjected to an alkylation reaction or an acylation reaction. Subject to a ring reaction, or ii) [Wherein Ya is a group obtained by removing methylene from Y, and other symbols are as defined in claim 1] or a salt thereof, or subjected to a reduction reaction, or iii) 10) Wherein L is a leaving group, and other symbols have the same meanings as described in claim 1) or a salt thereof is subjected to an amination reaction. Manufacturing method. 30. The formula [Wherein, R ^1b and R ^2b are each methyl or ethyl, k is 1 or 2, and * indicates the position of an asymmetric carbon], or a salt thereof. 31. A pharmaceutical composition comprising the compound according to claim 1. 32. The composition according to claim 31, which is an amyloid β protein production / secretion inhibitor. 33. The composition according to claim 31, which is a preventive or therapeutic agent for a neurodegenerative disease caused by amyloid β protein. 34. The composition according to claim 33, wherein the neurodegenerative disease caused by amyloid β protein is Alzheimer's disease. 35. The formula: [In the formula, Ar ′ represents an aromatic group which may have a substituent, X represents (i) a bond, (ii) —S—, —SO— or —
SO ₂ —, (iii) C- _optionally having 1 to 3 substituents selected from oxo and C _1-6 alkyl
_1-6 alkylene, C _2-6 alkenylene or C _2-6 alkynylene, (iv) -CO-O- or (v) Formula - (CH ₂₎ p
-X ¹ -,-(CH ₂ ) p-X ^1- (CH ₂ ) q-,-(CH ₂ ) r-
CO-X ^1- , -SO ₂ -NR ^8- or-(CH ₂ ) r-S
O ₂ —NR ⁸ — (wherein X ¹ is an oxygen atom or NR ⁸ , R ⁸
Is a hydrogen atom, an optionally substituted hydrocarbon group or acyl, p is an integer of 0 to 5, q is an integer of 1 to 5, p + q is an integer of 1 to 5, and r is 1 to 4
Y represents a divalent C _1-6 aliphatic hydrocarbon group which may be via an oxygen atom or a sulfur atom and may have a substituent. And R ¹ and R ² each represent a hydrogen atom or a lower alkyl which may have a substituent, or R ¹ and R ² represent a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom. A ring is formed, and the A ring represents a benzene ring which may further have a substituent in addition to the group represented by the formula -X-Ar (wherein each symbol has the same meaning as described above), Ring B has the formula -Y-NR ¹
R ² (wherein each symbol has the same meaning as described above), and represents a 4- to 8-membered ring which may further have a substituent in addition to the group represented by the above formula) or a salt thereof. Amyloid β protein production / secretion inhibitor comprising: