JPH10273469A - Bicyclic quinone derivative, production and agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having excellent mitochondria function- activating action and metabolism resistance and useful as a medicine for treatment of Alzheimer's disease, etc. SOLUTION: This compound is represented by formula I (R<1> and R<2> are each a lower alkyl, etc.; X is a spacer having 1-15 number of atoms of main chain; Y is an acyl, hydroxy, etc.; A ring is a 5-8-membered ring), e.g. 8-(2- ethoxycarbonyl-5,6-dimethoxy-4,7-dioxoindan-2-yl)octanoic acid ethyl ester. The compound of formula I is obtained by reacting a compound of formula II with preferably 2-10 equivalent cerium compound [e.g. cerium(IV)ammonium nitrate] when P and P' of the compound of formula II (P and P' are each a protective group) is methyl group, e.g. in water and an inert solvent such as a nitrile-based solvent, as necessary by using a catalytic amount to 10 equivalent mineral acid (e.g. sulfuric acid), etc., at ambient temperature to 80 deg.C for 1 to 24 hr under stirring.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a bicyclic or tricyclic quinone compound having an excellent mitochondrial function activating action, a method for producing the same, and an agent effective for treating Alzheimer's disease and the like.

[0002]

2. Description of the Related Art Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are rapidly increasing with the advent of the aging society in recent years, and the demand for preventive and therapeutic drugs for these neurodegenerative diseases is increasing. Recently, one of the causes of the above-mentioned diseases has been reduced function of the mitochondrial complex. Mitochondria are present in all animal cells and are responsible for producing the energy required for cell activity via the electron transport system. However, mitochondria and mitochondrial genes are vulnerable to oxidative stress due to abnormal electron transfer (eg, radical attack by reactive oxygen species), resulting in a decrease in energy metabolism and cell degeneration. In particular, in brain cells, energy demand is high, so that mitochondria are more susceptible to degeneration, and so-called cerebral mitochondrial disorders are caused by abnormal mitochondrial electron transfer due to aging (Proceedings of National Academy of Science (Proceeding of
National Academy of Sciences) USA; 91, 8731-
8738 (1994) and the like]. Since ubiquinone, a special quinone compound, is essential in the electron transfer system as a coenzyme of the oxidation / reduction system, derivatives utilizing the quinone portion of ubiquinone have been synthesized.

As a compound having a mitochondrial function activating action and a nerve growth factor production enhancing action, idebenone [6- (10-hydroxydecyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone] is known. [JP-A-56-97223, USP 4,436,
753, JP-A-3-81218, USP 5,05
9,627, Biochemical and Biophysical Research Communications (Biochemical an
d Biophysical Research Communications) 125, 1046
-1052 (1984)].

On the other hand, the following compounds are known as bicyclic or tricyclic quinone compounds. 1) JP-A-59-128348 describes the formula

Embedded image It is described that the compound represented by the formula (1) has a prostaglandin biosynthesis inhibitory activity and is useful as a nonsteroidal anti-inflammatory analgesic. 2) Journal of the American Chemical Societ
y), 112, 1897-1905 (1990)

Embedded image Are described. 3) Journal of the Chemical Society
Perkin Transactions (Journal of the Chemi
cal Society Perkin Transactions), 1, 2979-2988 (1990)

Embedded image It is described that the compound represented by has antitumor activity. 4) Australian Journal of Chemistry, 29, 179-19
The formula on page 0 (1976)

Embedded image Are described.

[0005]

Research on drugs for suppressing mitochondrial disorders for the treatment of Alzheimer's disease and the like has been conducted mainly on antioxidants, but the chemical structure is different from that of the above known compounds. There is an urgent need to develop compounds that have an excellent mitochondrial function activating effect and are sufficiently satisfactory as pharmaceuticals.

[0006]

Means for Solving the Problems The present inventors have conducted various studies on compounds having a mitochondrial function activating effect and found that

Embedded image (Each symbol in the formula is as defined below) or 2 or 3
A compound represented by the formula:

Embedded image Wherein R ¹ and R ² are each lower alkyl, or R ¹ and R ² may be bonded to each other to form a ring, X is a spacer having 1 to 15 atoms in the main chain, Y is acyl, Hydroxyl which may have a substituent, amino which may have a substituent or an aromatic group which may have a substituent, ring A has a formula -XY (wherein each symbol is A 5- to 8-membered ring which may further have a substituent in addition to the group represented by the same meaning as above) or a salt thereof (hereinafter abbreviated as compound (I)). This compound has an unexpectedly excellent mitochondrial function activating action based on its unique chemical structure,
For the first time, they have found that they are sufficiently satisfactory as pharmaceuticals, such as having metabolic resistance, and based on these findings, have completed the present invention.

That is, the present invention relates to a compound represented by the formula (1) wherein R ¹ and R ² are each C _1-6 alkyl or R ¹ and R ² are bonded to each other

Embedded image Forming a 5- to 7-membered ring represented by the formula: X may have 1 to 3 substituents each selected from oxo and optionally halogenated C _1-6 alkyl (1) C _{1 -15} alkylene, (2) C _2-15 alkenylene or (3) C _2-15 alkynylene or formula :-( CH ₂₎ m-X ¹
−, − (CH ₂ ) m−X ² −X ¹ −, −X ¹ −X ² − (CH ₂ ) n−, −X ² −
X ^1- (CH ₂ ) n-,-(CH ₂ ) m-X ^1- (CH ₂ ) n-,-(CH ₂ ) m-X ²
− (CH ₂ ) n−, − (CH ₂ ) m−X ¹ −X ² − (CH ₂ ) n−, − (CH ₂ ) m−
X ² -X ^1- (CH ₂ ) n- or -X ² -X ¹ -X ^2- (CH ₂ ) n- wherein X ¹ is oxo and C _1-6 which may be halogenated (1) a divalent C _5-8 monocyclic non-aromatic hydrocarbon group, each of which may have 1 to 3 substituents selected from alkyl, (2) a divalent C _6-14 aromatic A hydrocarbon group or (3) a divalent 5- to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom; X ² is O, S, SO Or m ₂ and n are each an integer of 0 to 10; and m + n is an integer of 1 to 13.] Y is a group represented by the formula (1): —CO—R ³ , —CO—OR ³ , -C
^{O-NR 3 R 4, -CS} -NHR 3, -SO 2 -R 3a or in -SO-R ^3a [wherein, R ³ is (a) hydrogen atom, (b) as a substituent (i) halogen, ( ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl, (vi) optionally halogenated C _3-6 Cycloalkyl, (vii) optionally halogenated C _1-6 alkoxy, (viii) optionally halogenated C _1-6 alkylthio, (ix) hydroxy, (x) amino, (xi) mono- C _1-6 alkylamino, (xii) di-C _1-6 alkylamino, (xiii) formyl, carboxy, 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- to 6-membered heterocyclic carbonyl,
Carbamoyl, mono-C _1-6 alkyl-carbamoyl,
Di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-
Carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C
_1-6 alkylsulfonyl and C _6-10 acyl selected from arylsulfonyl, (xiv) formylamino, C _1-6
Alkyl-carboxamides, C _6-10 aryl-carboxamides, C _1-6 alkoxy-carboxamides and C _1-6
Acylamino selected from alkylsulfonylamino,
(Xv) 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-carbamoyl Oxy, C _6-10
Acyloxy selected from aryl-carbamoyloxy and nicotinoyloxy, (xvi) (xvi-1) C _1-6
Alkyl, (xvi-2) halogen, 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, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _{6 -10} aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6 Alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6
C _6-14 aryl, C _{7-16 optionally} having 1 to 5 substituents each selected from alkyl-carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy
5- to 7-membered saturated cyclic amino or 5- or 6-membered aromatic heterocyclic group and (xvi-3) _C6-10 aryl-carbonyl, which may have one or two substituents which may have one or two substituents 7-membered saturated cyclic amino, (xvii) sulfo and (xviii) (1 ′) halogen, (2 ′) C _1-3 alkylenedioxy, (3 ′) nitro, (4 ′) cyano, (5 ′) halogenated _Optionally substituted C _1-6 alkyl, (6 ′) optionally halogenated C _3-6 cycloalkyl, (7 ′)
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') (13'-1) C _1-6 alkyl, (13'-2) halogen, C _1-3 alkylenedioxy , nitro, cyano, C _1-6 alkyl which may be halogenated, halogenated which may be C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy optionally, an optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C
_6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10
Aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C
_1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyl C _6-14 aryl, C _7-16 aralkyl which may have 1 to 5 substituents selected from oxy and di-C _1-6 alkyl-carbamoyloxy, respectively, 5- to 7-membered saturated cyclic amino or A 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from a _6- to 6-membered aromatic heterocyclic group and a (13′-3) C _6-10 aryl-carbonyl, (14 ′) Formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl, mono-C
_1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5 to 6
Acyl selected from membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl, (1
5 ′) acylamino selected from formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (16 ′) 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-
Acyloxy selected from carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (17 ′) sulfo, (18 ′) C _6-10 aryl, (19 ′)
C _{6-10 optionally} having 1 to 5 substituents selected from aryloxy and (20 ′) oxo
_6-14 aryl, C _6-10 quinonyl or a substituent selected from a 5- to 14-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom Each having 1 to 5 C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-14 aryl or C
_7-16 aralkyl, or

(C) As a substituent, (i) halogen, (ii)
C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl,
(Vi) optionally halogenated C _3-6 cycloalkyl, (vii) optionally halogenated C _1-6 alkoxy, (viii) optionally halogenated C _1-6 alkylthio, ix) hydroxy, (x) amino, (xi) mono-C _1-6 alkylamino, (xii) di-C _1-6 alkylamino, (xiii) (xiii-1) C _1-6 alkyl, (xiii- 2)
Halogen, 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, C _6-10 aryl, carboxy, formyl, C _1-6
Alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-
Carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyloxy and di -C _1-6 alkyl - 1 a substituent selected from the carbamoyloxy to 5 optionally C _6-14 aryl optionally having respectively, C _{7 It} may have one or two substituents selected from _-16 aralkyl, 5- to 7-membered saturated cyclic amino or 5- to 6-membered aromatic heterocyclic group and (xiii-3) C _6-10 aryl-carbonyl. 5 to 7 membered saturated cyclic amino, (xiv) formyl, carboxy, 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, carbamoyl, 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 and C _6-10 acyl selected from arylsulfonyl, (xv) formylamino, C _1-6 alkyl - carboxamide, C _{6- 10} aryl-carboxamide, C
Acylamino selected from _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (xvi) C
_1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-
Acyloxy selected from C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (xvii) sulfo, (xviii) C
_6-10 aryl, (xix) C _6-10 aryloxy and (xix
x) 5 which may have 1 to 5 substituents selected from oxo and contains 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms
A 14-membered heterocyclic group;

When R ^3a is (a) a substituent (i) halogen,
(Ii) C _1-3 alkylenedioxy, (iii) nitro, (i
v) cyano, (v) optionally halogenated C _1-6 alkyl, (vi) optionally halogenated C _3-6 cycloalkyl, (vii) optionally halogenated C _{1- 6}
Alkoxy, (viii) optionally halogenated C
_1-6 alkylthio, (ix) hydroxy, (x) amino,
(Xi) mono-C _1-6 alkylamino, (xii) di-C _1-6
Alkylamino, (xiii) formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl Mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl Acyl selected from the group consisting of: (xiv) formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (xv) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyl Oxy, mono-
Acyloxy selected from C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (xvi) (xvi-1) C _1-6 alkyl , (Xvi-2) halogen, 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, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl,
C _6-10 aryl-carbonyl, carbamoyl, mono-C
_1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino ,
C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-
C _6-14 aryl, C _{7- optionally} having 1 to 5 substituents each selected from carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy Which may have one or two substituents selected from ₁₆ aralkyl, a 5- to 7-membered saturated cyclic amino or 5- to 6-membered aromatic heterocyclic group and (xvi-3) C _6-10 aryl-carbonyl. Or 7
Membered cyclic amino, (xvii) sulfo and (xviii)
(1 ′) halogen, (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 ′) (13′-1) C
_1-6 alkyl, (13′-2) halogen, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6 cyclo 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, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6
Alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl- Carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-
C _6-14 aryl _optionally having 1 to 5 substituents selected from C _1-6 alkyl-carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy, C
_7-16 aralkyl, _5-7 membered saturated cyclic amino or 5
A 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from a _6- to 6-membered aromatic heterocyclic group and a (13′-3) C _6-10 aryl-carbonyl, (14 ′)
Formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl, mono-C _1-6 Acyl selected from alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl, (15 ') formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _1-6 alkoxy - acylamino selected from carboxamide and C _1-6 alkylsulfonylamino, (16') C _1-6 alkyl - carbonyloxy, C _{6- 10} aryl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 Al Acyloxy selected from kill-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (17 ′) sulfo, (18 ′) C _6-10aryl , ( 19 ′) C _6-14 aryl _optionally having 1 to 5 substituents selected from C _6-10 aryloxy and (20 ′) oxo,
_{6 to 10} quinonyl or 1 to 5 substituents selected from 5 to 14-membered aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen in addition to carbon _Optionally C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-14 aryl or C _7-16 aralkyl,
Or

(B) As a substituent, (i) halogen, (ii)
C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl,
(Vi) optionally halogenated C _3-6 cycloalkyl, (vii) optionally halogenated C _1-6 alkoxy, (viii) optionally halogenated C _1-6 alkylthio, ix) hydroxy, (x) amino, (xi) mono-C _1-6 alkylamino, (xii) di-C _1-6 alkylamino, (xiii) (xiii-1) C _1-6 alkyl, (xiii- 2)
Halogen, 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, C _6-10 aryl, carboxy, formyl, C _1-6
Alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-
Carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyloxy and di -C _1-6 alkyl - 1 a substituent selected from the carbamoyloxy to 5 optionally C _6-14 aryl optionally having respectively, C _{7 It} may have one or two substituents selected from _-16 aralkyl, 5- to 7-membered saturated cyclic amino or 5- to 6-membered aromatic heterocyclic group and (xiii-3) C _6-10 aryl-carbonyl. 5 to 7 membered saturated cyclic amino, (xiv) formyl, carboxy, 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, carbamoyl, 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 and C _6-10 acyl selected from arylsulfonyl, (xv) formylamino, C _1-6 alkyl - carboxamide, C _{6- 10} aryl-carboxamide, C
Acylamino selected from _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (xvi) C
_1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-
Acyloxy selected from C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (xvii) sulfo, (xviii) C
_6-10 aryl, (xix) C _6-10 aryloxy and (xix
x) 5 which may have 1 to 5 substituents selected from oxo and contains 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms
A 14-membered heterocyclic group;

R ⁴ represents a hydrogen atom or C _1-6 alkyl; or R ³ and R ⁴ together with an adjacent nitrogen atom
(I) halogen, (ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl as a substituent, (vi) halogenated Optionally substituted C _3-6 cycloalkyl, (vii) optionally halogenated C _1-6 alkoxy, (viii) optionally halogenated C _1-6 alkylthio, (ix) hydroxy, (ix (x) amino, (xi) mono-C _1-6 alkylamino, (xii) di-C _1-6 alkylamino, (xiii) (xi
ii-1) C _1-6 alkyl, (xiii-2) halogen, 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, C _6-10 aryl,
Carboxy, formyl, C _1-6 alkyl-carbonyl,
C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _{1 -6} alkyl - carboxamide, C _1-6 alkoxy - carboxamide, C
_1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyloxy and di -C
C _6-14 aryl, C _7-16 aralkyl which may have 1 to 5 substituents each selected from _1-6 alkyl-carbamoyloxy, 5- to 7-membered saturated cyclic amino or 5- to 6-membered aromatic Heterocyclic group and (xiii-3) C
_6-10 membered 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from aryl-carbonyl,
(Xiv) formyl, carboxy, 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, 5-6 membered heterocyclic carbonyl, carbamoyl, 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 and C _6-10 acyl selected from arylsulfonyl, (xv) formylamino, C _1-6 alkyl - carboxamide, C _6- Acylamino selected from ₁₀ aryl-carboxamides, C _1-6 alkoxy-carboxamides and C _1-6 alkylsulfonylamino, (xvi) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 Acyloxy selected from alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (xvii) sulfo, xviii) selected from C _6-10 aryl, (xix) C _6-10 aryloxy and (xx) oxo Which form a 5- to 7-membered nitrogen-containing heterocyclic ring which may have 1 to 3 substituents];

(2) (a) as a substituent (i) halogen,
(Ii) C _1-3 alkylenedioxy, (iii) nitro, (i
v) cyano, (v) optionally halogenated C _1-6 alkyl, (vi) optionally halogenated C _3-6 cycloalkyl, (vii) optionally halogenated C _{1- 6}
Alkoxy, (viii) optionally halogenated C
_1-6 alkylthio, (ix) hydroxy, (x) amino,
(Xi) mono-C _1-6 alkylamino, (xii) di-C _1-6
Alkylamino, (xiii) formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl Mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl Acyl selected from the group consisting of: (xiv) formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (xv) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyl Oxy, mono-
Acyloxy selected from C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (xvi) (xvi-1) C _1-6 alkyl , (Xvi-2) halogen, 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, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl,
C _6-10 aryl-carbonyl, carbamoyl, mono-C
_1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino , C _1-6 alkyl-
It may have 1 to 5 substituents each selected from carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy. C _6-14
Aryl, C _7-16 aralkyl, 5- to 7-membered saturated cyclic amino or 5- to 6-membered aromatic heterocyclic group and (xvi-
3) 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from C _6-10 aryl-carbonyl, (xvii) sulfo and (xviii) (1 ′) halogen, (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 ′) (13′-1) C _1-6 alkyl, (1
3'-2) Halogen, 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, C _6-10 aryl, carboxy, formyl, C
_1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-
Carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyloxy and di -C _1-6 alkyl - 1 a substituent selected from the carbamoyloxy to 5 optionally C _6-14 aryl optionally having respectively, C _{7 -16} aralkyl, 5- or 7-membered saturated cyclic amino or 5- or 6-membered aromatic heterocyclic group and (13′-3) C _6-10 aryl-carbonyl having 1 or 2 substituents good 5 to 7 membered saturated cyclic amino, (14 ') formyl, carboxy, 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, carbamoyl, 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 and C _6-10 acyl selected from arylsulfonyl, (15 ') formylamino, C _1-6 alkyl - carboxamide, C _{6 -10} aryl-carboxamide, C
_1-6 alkoxy - acylamino selected from carboxamide and C _1-6 alkylsulfonylamino, (16 ') C
_1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-
Acyloxy, (17 ′) sulfo, (18 ′) C _6-10 aryl, (19 ′) C _6-10 selected from C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy A C _6-14 aryl, a C _6-10 quinonyl or a carbon atom which may have 1 to 5 substituents selected from aryloxy and (20 ′) oxo; A substituent selected from a 5 to 14-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from 1 to 5
Optionally having _1-6 alkyl, C _2-6 alkenyl,
C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-14 aryl or C _7-16 aralkyl,

Formula (b): -CO-R ³ , -CO-OR ³ ,
^{-CO-NR 3 R 4, -CS} -NHR 3, -SO 2 -R 3a or wherein each symbol is as defined above] -SO-R ^3a or acyl, represented by (c) Hydroxy optionally having a 5- to 10-membered aromatic heterocyclic group; (3) (a) halogen as a substituent, (ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) ) Cyano,
(V) an optionally halogenated C _1-6 alkyl, (v
i) optionally halogenated C _3-6 cycloalkyl,
(Vii) optionally halogenated C _1-6 alkoxy,
(Viii) optionally halogenated C _1-6 alkylthio, (ix) hydroxy, (x) amino, (xi) mono-C
_1-6 alkylamino, (xii) di -C _1-6 alkylamino, (xiii) formyl, carboxy, 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 to 6
Membered heterocyclic carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C
Acyl selected from _6-10 arylsulfonyl, (xiv)
Formylamino, C _1-6 alkyl-carboxamide, C
_Acylamino selected from _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (xv) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C
Acyloxy selected from _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy,
(Xvi) (xvi-1) C _1-6 alkyl, (xvi-2) halogen,
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, C _6-10
Aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl- Carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6
Alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy and dialkyl C _6-14 aryl, C _7-16 aralkyl optionally having 1 to 5 substituents selected from —C _1-6 alkyl-carbamoyloxy, 5- to 7-membered saturated cyclic amino or 5- to 6-membered 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from an aromatic heterocyclic group and (xvi-3) C _6-10 aryl-carbonyl, (xvii) sulfo and (xviii) (1 ′) halogen, (2 ′) C _1-3 alkylenedioxy, (3 ′) nitro, (4 ′) cyano, (5 ′) optionally halogenated C _1-6 alkyl, (6 ′ ) Halogenated May be C
_3-6 cycloalkyl, (7 ') optionally halogenated C _1-6 alkoxy optionally, (8') optionally halogenated a C _1-6 alkylthio, (9 ') hydroxy, (10') Amino, (11 ′) mono-C _1-6 alkylamino, (12 ′) di-
C _1-6 alkylamino, (13 ′) (13′-1) C _1-6 alkyl, (13′-2) halogen, 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, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di -C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6
Alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-
C _6-14 aryl, C _7-16 aralkyl, 5- to 7-membered saturated cyclic amino, which may have 1 to 5 substituents each selected from carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy, or A 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from a 5- to 6-membered aromatic heterocyclic group and (13'-3) _C6-10 aryl-carbonyl, (14 ' ) Formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C
Acyl selected from _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl, (15 ′) formylamino, C _{1 -6alkyl-} carboxamide, _C6-10aryl- carboxamide,
C _1-6 alkoxy - acylamino selected from carboxamide and C _1-6 alkylsulfonylamino, (16 ')
C _1-6 alkyl-carbonyloxy, C _6-10 aryl-
Carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-
Acyloxy, (17 ′) sulfo, (18 ′) C _6-10 aryl, (19 ′) C _6-10 selected from C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy A C _6-14 aryl, a C _6-10 quinonyl or a carbon atom which may have 1 to 5 substituents selected from aryloxy and (20 ′) oxo; A substituent selected from a 5 to 14-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from 1 to 5
Optionally having _1-6 alkyl, C _2-6 alkenyl,
C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-14 aryl or C _7-16 aralkyl, and (b) a compound of the formula: —CO—
^{R 3, -CO-OR 3,} -CO-NR 3 R 4, -CS-NH
R ³ , —SO ₂ —R ^3a or —SO—R ^3a [wherein each symbol has the same meaning as described above], may have one or two substituents selected from acyl. Amino; (4) as a substituent, (i) C _1-6 alkyl, (ii) halogen, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, halogenated _Optionally 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, C
_6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10
Aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C
_1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyl C _6-14 aryl, C _7-16 aralkyl which may have 1 to 5 substituents selected from oxy and di-C _1-6 alkyl-carbamoyloxy, respectively, 5- to 7-membered saturated cyclic amino or A 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from a _6- to 6-membered aromatic heterocyclic group and (iii) C _6-10 aryl-carbonyl; or

(5) As a substituent, (i) halogen, (ii)
C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl,
(Vi) optionally halogenated C _3-6 cycloalkyl, (vii) optionally halogenated C _1-6 alkoxy, (viii) optionally halogenated C _1-6 alkylthio, ix) hydroxy, (x) amino, (xi) mono-C _1-6 alkylamino, (xii) di-C _1-6 alkylamino, (xiii) (xiii-1) C _1-6 alkyl, (xiii- 2)
Halogen, 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, C _6-10 aryl, carboxy, formyl, C _1-6
Alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-
Carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyloxy and di -C _1-6 alkyl - 1 a substituent selected from the carbamoyloxy to 5 optionally C _6-14 aryl optionally having respectively, C _{7 It} may have one or two substituents selected from _-16 aralkyl, 5- to 7-membered saturated cyclic amino or 5- to 6-membered aromatic heterocyclic group and (xiii-3) C _6-10 aryl-carbonyl. 5 to 7 membered saturated cyclic amino, (xiv) formyl, carboxy, 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, carbamoyl, 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 and C _6-10 acyl selected from arylsulfonyl, (xv) formylamino, C _1-6 alkyl - carboxamide, C _{6- 10} aryl-carboxamide, C
Acylamino selected from _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (xvi) C
_1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-
Acyloxy selected from C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (xvii) sulfo, (xviii) C
_6-10 aryl, (xix) C _6-10 aryloxy and (xix
x) C _6-14 aryl, C _6-10 quinonyl optionally having 1 to 5 substituents selected from oxo, or 1 to 4 selected from nitrogen, sulfur and oxygen in addition to carbon. 5 to 1 containing two heteroatoms
A 4-membered aromatic heterocyclic group; and

Ring A may further comprise, as substituents, (1) carboxy, (2) C _1-6 alkoxy-carbonyl, (3) carbamoyl, (4) mono- or di-C _1-6 alkylamino-carbonyl, 5) C optionally having hydroxy
_1-6 alkyl, (6) oxo, and (7) as a substituent (i) halogen, (ii) C _1-3 alkylenedioxy, (ii)
i) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl, (vi) optionally halogenated C _3-6 cycloalkyl, (vii) halogenated also a C _1-6 alkoxy, (viii) a C _1-6 alkylthio which may be halogenated, (ix) hydroxy,
(X) amino, (xi) mono-C _1-6 alkylamino, (xi
i) di-C _1-6 alkylamino, (xiii) formyl, carboxy, 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, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6
Acyl selected from alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl, (xiv) formylamino, C _1-6 alkyl- Carboxamide, C _6-10 aryl-carboxamide, C
Acylamino selected from _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (xv) C
_1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-
Acyloxy selected from C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (xvi) (xvi-1) C _1-6 alkyl, (xvi-2) halogen, 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, halogen Optionally substituted C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6
Alkylamino, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di -C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6
Alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-
C _6-14 aryl, C _7-16 aralkyl which may have 1 to 5 substituents each selected from carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy, a 5- to 7-membered saturated cyclic amino or A 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from a 5- or 6-membered aromatic heterocyclic group and (xvi-3) _C6-10 aryl-carbonyl, (xvii) sulfo And (xviii) (1 ′) halogen, (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 A Kiruamino, (12 ') di -C _1-6 alkylamino, (13') (13 '
-1) C _1-6 alkyl, (13'-2) halogen, 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, C _6-10 aryl, carboxy, formyl, C _{1- 6} alkyl-carbonyl, C
_1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _{1- 6} alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6
Alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyloxy and di -C _1-6
1 substituents selected from alkyl-carbamoyloxy
A C _6-14 aryl _optionally having 5 to 5 each,
It has one or two substituents selected from C _7-16 aralkyl, 5- to 7-membered saturated cyclic amino or 5- to 6-membered aromatic heterocyclic group and (13′-3) C _6-10 aryl-carbonyl. 5- to 7-membered saturated cyclic amino, (1
4 ') formyl, carboxy, 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, 5-6 membered heterocyclic carbonyl, carbamoyl, 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 and C _6-10 acyl selected from arylsulfonyl, (15 ') formylamino, C _1-6 alkyl - carboxamide, C _{6 Acylamino} selected from _-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (16 ′) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C ₁ Acyloxy selected from _-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (17 ′)
A substituent selected from sulfo, (18 ′) C _6-10 aryl, (19 ′) C _6-10 aryloxy and (20 ′) oxo;
A C _6-14 aryl _optionally having 5 to 5 each,
A C _6-10 quinonyl or 1 to 5 substituents each selected from a 5- to 14-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen other than carbon atoms; It has 1 to 3 substituents selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl and C _6-14 aryl which may have And may contain one double bond other than the portion condensed with the quinone ring, and may contain 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen in addition to carbon. The compound according to the above (1), which is an optionally 5- to 8-membered homo-heterocycle,

(3) The compound according to the above (1), wherein R ¹ and R ² are each C _1-6 alkyl, and (4) the above (1), wherein X is a spacer having 2 to 15 atoms in the main chain. Wherein (5) X is (1) a substituent selected from oxo and optionally halogenated C _1-6 alkyl;
And optionally 1 to 3 C _1-15 alkylene or formula (2):-(CH ₂ ) m-X ¹ -,-(CH ₂ ) m-X ² -X ^1- , -X ¹
−X ² − (CH ₂ ) n−, −X ² −X ¹ − (CH ₂ ) n−, − (CH ₂ ) m−X ¹ −
_{(CH 2) n -, -} (CH 2) m-X 2 - (CH 2) n -, - (CH 2) m-X 1 -X 2
− (CH ₂ ) n−, − (CH ₂ ) m−X ² −X ¹ − (CH ₂ ) n− or −X ² −
X ¹ -X ^2- (CH ₂ ) n- wherein X ¹ may have 1 to 3 substituents each selected from oxo and optionally halogenated C _1-6 alkyl Good (1) divalent C _5-8 monocyclic non-aromatic hydrocarbon group, (2) divalent C _6-14
An aromatic hydrocarbon group or (3) a divalent 5- to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms; X
² is O, S, SO or SO ₂ ; m and n are each 0
And an integer of 10 to 10; and m + n represents an integer of 1 to 13].
(6) X ¹ is a divalent C _6-14 aromatic hydrocarbon group, X ² is O,
wherein m is an integer of 0 to 10, n is an integer of 1 to 5, and m + n is an integer of 2 to 10, (7) the compound according to the above (5), wherein Y is a hydroxy optionally substituted; The compound according to the above (1), wherein the ring (8) has the formula
Formula which may further have a substituent in addition to the group represented by -XY:

Embedded image The compound according to the above (1), which is a ring represented by
(9) R ¹ and R ² are each C _1-6 alkyl; X is (1) C _2-8 alkylene or (2) :-( CH ₂₎ m-X
¹ −, − (CH ₂ ) m−X ² −X ¹ −, −X ¹ −X ² − (CH ₂ ) n−, −X ²
−X ¹ − (CH ₂ ) n−, − (CH ₂ ) m−X ¹ − (CH ₂ ) n−, − (CH ₂ ) m−
X ² − (CH ₂ ) n−, − (CH ₂ ) m−X ¹ −X ² − (CH ₂ ) n−, − (CH ₂ ) m
-X ² -X ^1- (CH ₂ ) n- or -X ² -X ¹ -X ^2- (CH ₂ ) n- wherein X ¹ is a divalent C _6-14 aromatic hydrocarbon group, X ² is O, m
Is an integer of 0 to 10, n is an integer of 1 to 5, and m + n is an integer of 2 to 10];
Is optionally substituted hydroxy; and ring A is of the formula:

Embedded image A compound according to the above (1), which is a ring represented by

(10) Y is a substituent (i) halogen, (ii) C _1-3 alkylenedioxy, (iii) nitro,
(Iv) cyano, (v) optionally halogenated C _1-6
Alkyl, (vi) optionally halogenated C _3-6 cycloalkyl, (vii) optionally halogenated C _3-6 cycloalkyl
_1-6 alkoxy, (viii) optionally halogenated C _1-6 alkylthio, (ix) hydroxy, (x) amino,
(Xi) mono-C _1-6 alkylamino, (xii) di-C _1-6
Alkylamino, (xiii) formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl Mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl Acyl selected from the group consisting of: (xiv) formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (xv) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyl Oxy, mono-
Acyloxy selected from C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (xvi) (xvi-1) C _1-6 alkyl , (Xvi-2) halogen, 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, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl,
C _6-10 aryl-carbonyl, carbamoyl, mono-C
_1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino ,
C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-
C _6-14 aryl, C _{7- optionally} having 1 to 5 substituents each selected from carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy Which may have one or two substituents selected from ₁₆ aralkyl, a 5- to 7-membered saturated cyclic amino or 5- to 6-membered aromatic heterocyclic group and (xvi-3) C _6-10 aryl-carbonyl. Or 7
Membered cyclic amino, (xvii) sulfo and (xviii)
(1 ′) halogen, (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 ′) (13′-1) C
_1-6 alkyl, (13′-2) halogen, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6 cyclo 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, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6
Alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl- Carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-
C _6-14 aryl _optionally having 1 to 5 substituents selected from C _1-6 alkyl-carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy, C
_7-16 aralkyl, _5-7 membered saturated cyclic amino or 5
A 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from a _6- to 6-membered aromatic heterocyclic group and a (13′-3) C _6-10 aryl-carbonyl, (14 ′)
Formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl, mono-C _1-6 Acyl selected from alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl, (15 ') formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _1-6 alkoxy - acylamino selected from carboxamide and C _1-6 alkylsulfonylamino, (16') C _1-6 alkyl - carbonyloxy, C _6-10 aryl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 Al Le - carbamoyloxy, di -C _1-6 alkyl - carbamoyloxy, C _6-10 aryl - acyloxy selected from carbamoyloxy and nicotinoyloxy oxy, (17 ') sulfo, (18') C _6-10 aryl, ( 19 ′) C _6-14 aryl _optionally having 1 to 5 substituents selected from C _6-10 aryloxy and (20 ′) oxo,
_6-10 having 1 to 3 substituents selected from a 5- to 14-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to quinonyl or carbon atom The compound according to the above (9), which is hydroxy substituted with phenyl which may be optionally substituted;

(11) R ¹ and R ² are each C _1-6 alkyl; X is (1) C _1-8 alkylene or (2)
^{_{(CH 2) m'-X 2}} '-X 1' -, - X 1 '-X 2' - (CH 2) n'- , or -
(CH ₂ ) m′−X ² ′ −X ¹ ′ − (CH ₂ ) n′− wherein X ¹ ′ is 1,4-
Phenylene, X ² 'is O, m' is an integer of 1 to 4, and n 'is 1 or 2]; Y is (1) carboxy, (2) a substituent represented by (i) C _1-6 alkoxy,
(Ii) amino, (iii) mono- or di-C _1-6 alkylamino or (iv) C _1-6 alkyl, carbonyl having a 6-membered saturated cyclic amino optionally having phenyl or piperidino, (3 ) As a substituent, (i) halogen, C
_1-3 alkylenedioxy, cyano, C _1-6 alkyl, C
Phenyl optionally having 1 to 3 substituents selected from _1-6 alkoxy and mono-C _1-6 alkyl-carbamoyl, (ii) C _1-6 alkyl-carbonyl, (iii)
Mono- or di-C _1-6 alkyl-carbamoyl, (i
v) pyridyl or (v) hydroxy optionally having quinolyl, (4) C _1-6 alkyl and C _1-6 alkyl-
An amino optionally having one or two substituents selected from carbonyl, (5) phenyl as a substituent,
(Ii) benzyl optionally having phenyl, (iii)
6 optionally having piperidino or (iv) pyridyl
Membered cyclic amino, (6) phenyl, (7) C _6-10 quinonyl optionally having one or two C _1-6 alkoxy,
(8) phthalimide, (9) pyridyl optionally having oxo, (10) quinolyl optionally having oxo,
(11) benzotriazolyl or (12) benzimidazolyl; and ring A further has carboxy,
C _1-6 alkoxy-carbonyl, carbamoyl, mono-
Or a formula optionally having di-C _1-6 alkyl-carbamoyl, hydroxy-C _1-6 alkyl or phenyl:

Embedded image A compound according to the above (1), which is a ring represented by

Equation (12):

Embedded image Wherein R ^1a and R ^2a are each C _1-3 alkyl; q
Is an integer of 1 to 4; and R is 1 to 3 halogen, C _1-3 alkylenedioxy, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _{1- 6} alkoxy, C _1-6 alkoxy-carbonyl, formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide or C _1-6 alkylsulfonylamino] (13) 2- [8- (4-chlorophenoxy) octyl] -5,6-dimethoxyindane-4,7-dione, 4- [2 -(2,3-dimethoxy-
1,4-dioxo-4,5,6,7,8,9-hexahydro-
1H-benzo [a] cyclohepten-7-yl) ethoxy] ethyl benzoate or 7- [2- (4-chlorophenoxy) ethyl] -2,3-dimethoxy-4,5,6,
The compound according to the above (1), which is 7,8,9-hexahydro-1H-benzo [a] cycloheptene-1,4-dione;

Embedded image Wherein P and P ′ are protecting groups and other symbols have the same meanings as described above, respectively, or a salt thereof is subjected to a quinone formation reaction to produce compound (I). Method, (15) a pharmaceutical composition comprising compound (I), (16) a composition according to (15), which is a mitochondrial function activator, (17) Parkinson's disease, Alzheimer's disease, amyotrophic lateral cord The present invention relates to the composition or the like according to the above (16), which is an agent for preventing or treating sclerosis or Huntington's disease. In the above formula, the “lower alkyl” represented by 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.). Preferably it is methyl. R ¹
And R ² are combined to form one another as the "ring", for example lower alkylene in R ¹ and R ^2, like 5-7 membered ring consisting of lower alkenylene and the like. Preferable examples include a 5- to 7-membered ring formed by a methylene chain. More preferably, it is a 5- to 6-membered ring with a methylene chain.

X represents “1 to 15 atoms in the main chain.
"Spacer" means an interval between 1 ring and Y in which 1 to 15 main chain atoms are continuous. In the present specification, “the number of atoms in the main chain” is counted so as to minimize the number of atoms existing between the ring A and Y regardless of the presence or absence of a hetero atom. For example, the number of atoms of 1,2-cyclopentylene is 2, the number of atoms of 1,3-cyclopentylene is 3, the number of atoms of 1,4-phenylene is 4,
-The number of atoms of naphthylene is 5, the number of atoms of 2,6-naphthylene is 6, and the number of atoms of 2,6-pyridinediyl is 3. The "It 1 -C backbone 15 spacer" is, -O -, - S -, - SO -, - SO 2 -, which may have a substituent divalent acyclic hydrocarbon group A main chain having 1 to 15 atoms selected from a divalent cyclic hydrocarbon group which may have a substituent and a divalent heterocyclic group which may have a substituent. And a valence group. The divalent groups may form X by combining 1 to 4 types or 1 to 4 types, and when two or more divalent groups are bonded, each group may be the same or different. Examples of the "divalent acyclic hydrocarbon group which may have a substituent" in the "divalent acyclic hydrocarbon group" include, for example, alkylene, alkenylene, alkynylene and the like. Preferably, it has 1 to 1 carbon atoms.
5 straight-chain ones are preferred.

The “substituent” of the “optionally substituted bivalent acyclic hydrocarbon group” includes, for example, oxo,
And optionally halogenated C _1-6 alkyl. The “optionally halogenated C _1-6 alkyl” includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). And C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.). Specific examples include methyl,
Chloromethyl, difluoromethyl, trichloromethyl,
Trifluoromethyl, ethyl, 2-bromoethyl, 2,
2,2-trifluoroethyl, pentafluoroethyl,
Propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoro Pentyl, hexyl, 6,6,6-trifluorohexyl and the like can be mentioned. These substituents are 1 to 5 at substitutable positions.
Each substituent may be the same or different when the number of substituents is two or more. Preferred examples of the “optionally substituted bivalent acyclic hydrocarbon group” include oxo and optionally halogenated C 2
It 1 respectively a substituent selected from _1-6 alkyl 3
(1) C _1-15 alkylene, (2) C
Examples thereof include _2-15 alkenylene and (3) C _2-15 alkynylene. Examples of “C _1-15 alkylene _optionally having 1 to 3 substituents selected from oxo and optionally halogenated C _1-6 alkyl” include, for example, —CH ₂ —, — (CH ₂ ) _2- , -CH ₂ -CO-, -CH ₂ -CH (CH
_{3) -, - CH 2 -C} (CH 3) 2 -, - (CH 2) 3 -, - CH 2 -CO-CH 2
−, − (CH ₂ ) ₄ −, − (CH ₂ ) ₅ −, − (CH ₂ ) ₆ −, − (CH ₂ ) ₇
−, − (CH ₂ ) ₈ −, − (CH ₂ ) ₉ −, − (CH ₂ ) ₁₀ −, − (CH ₂ ) ₁₁
−, − (CH ₂ ) ₁₂ −, − (CH ₂ ) ₁₃ −, − (CH ₂ ) ₁₄ −, − (CH ₂ )
₁₅ − and the like. Examples of “C _2-15 alkenylene optionally having 1 to 3 substituents selected from oxo and optionally halogenated C _1-6 alkyl” include, for example, —CH ＝ CH—, —CH ₂ -CH = CH-, -CH = CH
_{-CH (CH 3) -, -} CH 2 -CH = CH-CH 2 -, - CH 2 -CH 2 -CH
= CH -, - CH = CH -CH = CH -, - CH = CH-CH 2 -CH 2 -CH
_{2 -, - CH 2 -CH 2} -CH 2 -CH 2 -CH = CH- , and the like. "Oxo and optionally halogenated C _1-6
As the C _2-15 alkynylene optionally having 1 to 3 substituents selected from alkyl,

Embedded image Is mentioned. Preferred examples of the “ _optionally substituted bivalent acyclic hydrocarbon group” include C _1-15 alkylene.

The “divalent cyclic hydrocarbon group” of the “divalent cyclic hydrocarbon group optionally having substituent (s)” includes, for example, a divalent monocyclic non-aromatic hydrocarbon group And divalent aromatic hydrocarbon groups. Examples of the "divalent monocyclic non-aromatic hydrocarbon group" include a divalent monocyclic non-aromatic hydrocarbon group having 5 to 8 carbon atoms. For example, C _5-8 cycloalkane, a divalent group formed by removing any two hydrogen atoms from C _5-8 cycloalkene, and specific examples thereof are 1,2-cyclopentylene, 1,1
3-cyclopentylene, 1,2-cyclohexylene,
1,3-cyclohexylene, 1,4-cyclohexylene, 1,2-cycloheptylene, 1,3-cycloheptylene, 1,4-cycloheptylene, 3-cyclohexene-1,4-ylene, 3-cyclohexene-1,2- Ylene, 2,5-cyclohexadiene-1,4-ylene and the like. Among them, C _5-8 cycloalkylene is preferred.

The "divalent aromatic hydrocarbon group" includes, for example, a divalent aromatic hydrocarbon group having 6 to 14 carbon atoms. For example, a 6 to 14 member (preferably 6 members) such as benzene, naphthalene, indene, anthracene and the like.
To 10-membered) cyclic (monocyclic, bicyclic or tricyclic)
Examples thereof include divalent groups formed by removing any two hydrogen atoms from an aromatic hydrocarbon. Specific examples thereof include 1,2-phenylene, 1,3-phenylene, 1,4-phenylene,
4-naphthylene, 1,6-naphthylene, 2,6-naphthylene, 2,7-naphthylene, 1,5-indenylene,
2,5-indenylene and the like. The “divalent cyclic hydrocarbon group” is preferably a divalent C _6-10 aromatic hydrocarbon group, more preferably 1,2-phenylene, 1,3-phenylene, 1,4 -Phenylene and the like, particularly preferably 1,4-phenylene. Examples of the “substituent” of the “optionally substituted bivalent cyclic hydrocarbon group” include 1 to 3 oxo and the above-mentioned optionally halogenated C _1-6 alkyl. Can be

The “divalent heterocyclic group” of the “divalent heterocyclic group optionally having substituent (s)” includes, for example, 1 selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
Or (i) 5 containing 2 or 1 to 4 heteroatoms
To a 14-membered (preferably 5- to 10-membered) aromatic heterocyclic ring, (ii) a 6- to 10-membered non-aromatic heterocyclic ring, or (ii)
i) A divalent group formed by removing any two hydrogen atoms from a 7- to 10-membered bridged heterocyclic ring. Examples of the above “5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle” include, for example, thiophene, benzo [b] thiophene, benzo [b] furan, benzimidazole, benzotriazole, benzoxazole, benzothiazole , Benzisothiazole, naphtho [2,3-b] thiophene, furan, phenoxathiin, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,
Pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline,
Quinoline, phthalazine, naphthyridine, quinoxaline,
Aromatic heterocycles such as quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazane, phenoxazine, phthalimide, and the like (preferably monocyclic) )
And a ring formed by condensing with one or more (preferably one or two) aromatic rings (eg, benzene ring and the like). Examples of the “6- to 10-membered non-aromatic heterocycle” include pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine and the like. Examples of the “7- to 10-membered hetero-bridged ring” include quinuclidine,
7-Azabicyclo [2,2,1] heptane and the like. As the “divalent heterocyclic group”, preferably 5 to 1
From a zero-membered aromatic heterocycle (eg, thiophene, pyridine, indole, quinoline, isoquinoline, phthalazine, etc.) or a 6-10 membered non-aromatic heterocycle (eg, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, etc.) Examples thereof include a divalent group formed by removing two hydrogen atoms, and specific examples thereof include 2,5-thiophenediyl, 2,6-pyridinediyl, 1,2-indolediyl, 1,3-indolediyl, , 4-quinolinediyl, 1,4-isoquinolinediyl, 1,4-phthalazinediyl, 1,3-pyrrolidinediyl, 1,4-piperidinediyl, 1,4-piperazinediyl and the like. Examples of the “substituent” of the “optionally substituted bivalent heterocyclic group” include oxo and the above-mentioned optionally halogenated C
_Examples thereof include 1 to 5, preferably 1 to 3, _1-6 alkyl and the like.

Specific examples of the "spacer having 1 to 15 atoms in the main chain" include 1 to 3 substituents each selected from oxo and optionally halogenated C _1-6 alkyl. which may be (1) C _1-15 alkylene, (2) C _2-15 alkenylene or (3) C _2-15 alkynylene; and formula ^{_{:-( CH 2) m-X 1}} -, - (CH 2) m ^{-X 2 -X 1 -, - X} 1 -X 2 -
(CH ₂ ) n−, −X ² −X ¹ − (CH ₂ ) n−, − (CH ₂ ) m−X ¹ − (CH ₂ ) n
−, − (CH ₂ ) m−X ² − (CH ₂ ) n−, − (CH ₂ ) m−X ¹ −X ² − (C
H ₂ ) n−, − (CH ₂ ) m−X ² −X ¹ − (CH ₂ ) n− or −X ² −X ¹ −
X ^2- (CH ₂ ) n- wherein X ¹ is a divalent cyclic hydrocarbon group which may have a substituent or a divalent heterocyclic group which may have a substituent, X ² is O, S, SO or SO ₂ , m and n each represent an integer of 0 to 10, and m + n represents an integer of 1 to 13]. "A divalent cyclic hydrocarbon group optionally having substituent (s)" for X ¹
And "a divalent heterocyclic group optionally having substituent (s)"
Are the same as those described in detail for X above. X is preferably (1) C _1-15 alkylene optionally having 1 to 3 substituents selected from oxo and optionally halogenated C _1-6 alkyl or (2) a formula:- (CH ₂ ) m−X ¹ −, − (CH ₂ ) m−X ² −X ¹ −, −X ¹
−X ² − (CH ₂ ) n−, −X ² −X ¹ − (CH ₂ ) n−, − (CH ₂ ) m−X ¹ −
_{(CH 2) n -, -} (CH 2) m-X 2 - (CH 2) n -, - (CH 2) m-X 1 -X 2
− (CH ₂ ) n−, − (CH ₂ ) m−X ² −X ¹ − (CH ₂ ) n− or −X ² −
X ¹ -X ^2- (CH ₂ ) n- wherein X ¹ may have 1 to 3 substituents each selected from oxo and optionally halogenated C _1-6 alkyl Good (1) divalent C _5-8 monocyclic non-aromatic hydrocarbon group, (2) divalent C _6-14 aromatic hydrocarbon group or (3) other than carbon atom, nitrogen atom, sulfur atom and A divalent 5- to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atoms; X ² is O, S, SO or SO ₂ ; m and n are each an integer of 0 to 10; Represents an integer of 1 to 13]. X ¹ is preferably a divalent C
_{6-14 is an} aromatic hydrocarbon group. X ² is preferably O. m is preferably an integer of 0 to 10. n
Is preferably an integer of 1 to 5. m + n is preferably an integer of 2 to 10. Among them, the case where X ¹ is phenylene and X ² is O ² is preferable.

Examples of the "acyl" represented by Y include, for example, formulas:-(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
Which represents _1-6 alkyl, or R ³ and R ⁴ may form a nitrogen-containing heterocyclic ring which may have a substituent 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, butenyl, isobutenyl, sec-butenyl, etc.), c) _C2-6 alkynyl (eg, ethynyl, propargyl, butynyl, 1-hexynyl, etc.), d) _C3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, etc.),
The C _3-6 cycloalkyl may be fused to one benzene ring. E) C _6-14 aryl (for example, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-indenyl, 2-
-Anthryl), preferably phenyl, f) _C7-16 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 _7-16 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
Alkylamino (eg, dimethylamino, diethylamino, etc.), acyl, acylamino, acyloxy, optionally substituted 5- to 7-membered saturated cyclic amino, sulfo, optionally substituted aromatic group, etc. Is mentioned. 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. The “optionally halogenated C _1-6 alkyl” is the aforementioned X
And the same as the “optionally halogenated C _1-6 alkyl” described above.

The above "C _3-6 which may be halogenated"
Examples of the “cycloalkyl” include C _3-6 cycloalkyl (eg, cycloalkyl) which may have 1 to 5, preferably 1 to 3, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). Propyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.).
Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, and the like. Examples of the “optionally halogenated C _1-6 alkoxy” include 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
And a C _1-6 alkoxy which may have the following. 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. The above "halogenated C
Examples of “ _1-6 alkylthio” include C _1-6 alkylthio which may have 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (eg, Methylthio, ethylthio, propylthio, isopropylthio, n-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 “acyl” includes, for example, the aforementioned Y
And the same as the "acyl" represented by. Preferably, formyl, carboxy, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, t-butoxycarbonyl, etc.), C _{1-6 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, Thenoyl, furoyl, morpholinocarbonyl, piperazinocarbonyl, pyrrolidinocarbonyl, etc.), carbamoyl, mono-C _1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _1-6 alkyl-carbamoyl ( E.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), _C6-10aryl- carbamoyl (e.g., 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 (eg, methylsulfonyl, ethyl Sulfonyl), C _6-10 arylsulfonyl (eg, benzenesulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl, etc.) and the like. Examples of the “acylamino” include, for example, an amino substituted with one or two of the “acyl” represented by the above Y, and preferably have 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.

The "C _1-6 alkyl" represented by R ⁵ may, R ⁴
And the same as the “C _1-6 alkyl” represented by. The “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R ⁶ or R ^6a include the “substituted and substituted” 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), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.). As the “acyloxy”, for example, “acyl” represented by Y
And oxy substituted by 1 and preferably has the formula: —O—COR ⁷ , —O—COOR ⁷ or —O—C
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, naphthylcarbonyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyl) Oxy), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C _1-6 alkyl-carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), C _6-10 aryl-carbamoyloxy (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), nicotinoyloxy and the like.

The "5- to 7-membered optionally substituted cyclic amino" which is mentioned as an example of the "substituent" of the "hydrocarbon group which may have a substituent" Examples of the "7-membered saturated cyclic amino" include morpholino,
Piperazin-1-yl, piperidino, pyrrolidin-1-
Yl, hexamethyleneimin-1-yl, thiomorpholino and the like. The “optionally substituted 5”
And the "substituent" of the "7-membered saturated cyclic amino" includes
_1-6 alkyl, C _6-14 aryl _optionally having a substituent, C _7-16 aralkyl _optionally having a substituent, 5- to 7-membered saturated cyclic _optionally having a substituent Amino (eg, morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, hexamethyleneimine-1
-Yl, thiomorpholino, etc.), an optionally substituted 5- or 6-membered aromatic heterocyclic group, acyl or the like. As the “C _6-14 aryl” of the “C _6-14 aryl _optionally having substituent (s)”, those similar to the “C _6-14 aryl” described in detail in the aforementioned R ³ can be mentioned.
Preferred is phenyl and the like. As the “C _7-16 aralkyl” of the “C _7-16 aralkyl _optionally having substituent (s)”, those similar to the “C _7-16 aralkyl” described in detail in the aforementioned R ³ can be mentioned. Preferred is benzyl and the like.
As the “5- to 6-membered aromatic heterocyclic group” of the “5- or 6-membered aromatic heterocyclic group which may have a substituent”, 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 are used.

As the substituent of these optionally substituted 5- to 7-membered saturated cyclic amino, “C _6-14 aryl _optionally having substituent (s)”, “C _6-14 aryl _optionally having substituent (s)” C _7-16 aralkyl ”,“ _optionally substituted 5- to 7-membered saturated cyclic amino ”and“ optionally substituted 5- to 6-membered aromatic heterocyclic group ” Examples of the “substituent” which may be present include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro , Cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C
_3-6 cycloalkyl, optionally halogenated C _1-6
Alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-C
_1-6 alkylamino (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), C _6-10 aryl (eg, phenyl, etc.), carboxy, formyl, C _1-6 alkyl-carbonyl (eg, for example, acetyl, propionyl, etc.), C _1-6 alkoxy - carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl), carbamoyl, mono--C _1-6 alkyl - carbamoyl (e.g., methylcarbamoyl, ethyl Carbamoyl, etc.), di-C _1-6 alkyl-carbamoyl (eg,
Dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.), formylamino, C _1-6 alkyl-carboxamide (eg,
Acetamide, etc.), C _1-6 alkoxy-carboxamide (eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc.), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.),
C _1-6 alkyl-carbonyloxy (eg, acetoxy,
Propionyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _1-6 alkyl-
Carbamoyloxy (eg, methylcarbamoyloxy,
Ethylcarbamoyloxy, etc.) and _1-5 di-C1-6alkyl-carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.). “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" are the same as those described above. As the “acyl”, the “acyl” represented by the aforementioned Y
And the same. Preferably, benzoyl,
And C _6-10 aryl-carbonyl such as 1-naphthoyl and 2-naphthoyl.

Examples of the "aromatic group" of the "aromatic group which may have a substituent" include an aromatic hydrocarbon group and an aromatic heterocyclic group. The "aromatic hydrocarbon group"
As monocyclic or fused polycyclic (bi- or tri-cyclic) aromatic hydrocarbons having 6 to 14 carbon atoms (eg, benzene, naphthalene, indene, anthracene, etc.);
Or a monovalent group formed by removing any hydrogen atom from quinone having 6 to 14 carbon atoms (eg, p-benzoquinone, 1,4-naphthoquinone, indane-4,7-dione, etc.). Specific examples include phenyl,
C _6-14 aryl such as 1-naphthyl, 2-naphthyl, 1-indenyl, anthryl and the like, for example, indane-4,7-
And C _6-10 quinonyl such as dion-1-yl, indan-4,7-dione-2-yl, p-benzoquinone-2-yl, and 1,4-naphthoquinone-2-yl.
Of these, C _6-10 aryl such as phenyl, 1-naphthyl and 2-naphthyl, and C _6-10 quinonyl such as indane-4,7-dione-2-yl and p-benzoquinone-2-yl are preferred. The “aromatic heterocyclic group” is, for example, a 5- to 14-membered member containing one or more (eg, 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom in addition to a carbon atom, preferably a 5-membered atom. And a 10-membered aromatic heterocyclic group. Specifically, thiophene, benzo [b] thiophene, benzo [b] furan, benzimidazole, benzotriazole, benzoxazole,
Benzothiazole, benzisothiazole, naphtho [2,
3-b] thiophene, furan, phenoxathiin, pyrrole, imidazole, pyrazole, pyridine, pyrazine,
Pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine,
Isoquinoline, quinoline, phthalazine, naphthyridine,
Quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine,
Phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furan, phenoxazine,
Aromatic heterocycles such as phthalimide, or a ring formed by condensing one or more (preferably one or two) aromatic rings (eg, benzene rings) of one or more (preferably one or two) of these rings Examples include a monovalent group formed by removing an arbitrary hydrogen atom. Preferred examples of the “aromatic heterocyclic group” include a 5- or 6-membered aromatic heterocyclic group which may be condensed with one benzene ring. Specific examples include 2-, 3- or 4-pyridyl, 2-, 3-, 4
-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl,
2-benzothiazolyl, 2-benzo [b] thienyl, benzo [b] furanyl, 2- or 3-thienyl, phthalimide and the like. More preferably, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-
Quinolyl, 1-isoquinolyl, 1- or 2-indolyl, 2-benzothiazolyl, phthalimide and the like.

The "aromatic group optionally having substituent (s)"
Examples of the "substituent" include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano, halogenated C that may be
_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.), optionally substituted 5- to 7-membered saturated cyclic amino, acyl, acylamino, acyloxy, sulfo, C _{6 -10} aryl (eg, phenyl, naphthyl, etc.), C _6-10 aryloxy (eg, phenyloxy,
Naphthyloxy), oxo and the like. The “optionally halogenated C _1-6 alkyl”, the “optionally halogenated C _3-6 cycloalkyl”,
“Optionally halogenated C _1-6 alkoxy”,
"Optionally halogenated C _1-6 alkylthio",
The “optionally substituted 5- to 7-membered saturated cyclic amino”, “acyl”, “acylamino” and “acyloxy” are the same as the “substituted hydrocarbon group” described above. And the same as those described in detail in “Group”. The "aromatic group" is, for example,
The aromatic group may have 1 to 5, preferably 1 to 3 at substitutable positions, and when the number of substituents is 2 or more, each substituent may be the same or different.

The "heterocyclic group" of the "optionally substituted heterocyclic group" 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 heterocycle, (ii) a 6- to 10-membered non-aromatic heterocyclic ring, or (iii) a 7- to 10-membered bridged heterocyclic ring. The above “5- to 14-membered aromatic heterocycle”, “6
Examples of the “10-membered non-aromatic heterocyclic ring” and “hetero-bridged ring” include the same as those described in detail for the “divalent heterocyclic group” for X. The "heterocyclic group" is preferably a 5- to 10-membered (monocyclic) containing one or two, preferably one to four heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms. Formula or bicyclic) heterocyclic group. Specifically, for example, 2-
Or 3-thienyl, 2-, 3- or 4-pyridyl,
2- or 3-furyl, 2-, 3-, 4-, 5- or 8-quinolyl, 4-isoquinolyl, pyrazinyl, 2- or 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3- Isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 2-
Aromatic heterocyclic groups such as 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
Non-aromatic heterocyclic groups such as piperazinyl and morpholino; Of these, for example, nitrogen atoms other than carbon atoms,
A 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from a sulfur atom and an oxygen atom is more preferred. Specifically, 2-thienyl, 3-thienyl, 2-thienyl
Pyridyl, 3-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)"
Is, for example, the above-mentioned "optionally substituted aromatic group"
Has 1 to 5, preferably 1 to 5 substituents
You may have three. When the number of substituents is two or more, each substituent may be the same or different. As the “C _1-6 alkyl” represented by R ⁴ , for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
c-butyl, tert-butyl, pentyl, hexyl and the like. The “nitrogen-containing heterocycle” of the “nitrogen-containing heterocycle optionally having substituent (s)” formed by R ³ and R ⁴ together with the adjacent nitrogen atom includes, for example, at least one
And a 5- to 7-membered nitrogen-containing heterocycle optionally containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Examples include morpholine, piperazine, azetidine and the like. It is preferably a 6-membered nitrogen-containing heterocyclic ring. The "nitrogen-containing heterocyclic ring optionally having substituent (s)" has, for example, 1 to 3 substituents which the "aromatic group optionally having substituent (s)" may have. May be. When the number of substituents is two or more, each substituent may be the same or different.

Preferred examples of the "acyl" represented by Y include the following:-(C = O) -R ³ ,-(C = O) -OR ³ ,-(C = O)
—NR ³ R ⁴ , —SO ₂ —R ^3a [wherein each symbol has the same meaning as described above], and the like. More preferred acyls include, for example, formyl, carboxy, C
_1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), carbamoyl, mono-C _1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _{1- 6} alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C _6-10 aryl-carbamoyl (eg, phenylcarbamoyl, naphthylcarbamoyl, etc.), C _1-6 alkylsulfonyl (eg,
Methylsulfonyl, ethylsulfonyl and the like). Of these, carboxy and C _1-6 are more preferred.
Alkoxy-carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl and the like.

The “optionally substituted hydroxy” represented by Y includes, for example, the aforementioned “optionally substituted hydrocarbon group”, “acyl”,
Hydroxy which may have one "aromatic heterocyclic group" etc. is mentioned. Among preferred substituents optionally may be hydrocarbon groups having a, more preferably, 1 substituent respectively to three optionally having C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, C _3-6 cycloalkyl, C _6-14 aryl or C _7-16 aralkyl. Particularly preferred are (i) halogen, (ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v)
Optionally halogenated C _1-6 alkyl, (vi) optionally halogenated C _3-6 cycloalkyl, (vi
i) optionally halogenated C _1-6 alkoxy, (vi
ii) optionally halogenated C _1-6 alkylthio,
(Ix) hydroxy, (x) amino, (xi) mono--C _1-6 alkylamino, (xii) di -C _1-6 alkylamino, (xi
ii) formyl, carboxy, 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, 5-6 membered heterocyclic carbonyl, carbamoyl, 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 and C _6-10 acyl selected from arylsulfonyl, (xiv) formylamino, C _1-6 alkyl - carboxamide, C _6- Acylamino selected from ₁₀ aryl-carboxamides, C _1-6 alkoxy-carboxamides and C _1-6 alkylsulfonylamino, (xv) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 Acyloxy selected from alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (xvi)
(Xvi-1) C _1-6 alkyl, (xvi-2) halogen, 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, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl - carbonyl, C _1-6 alkoxy - carbonyl, C _6-10 aryl -
Carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6
Alkylsulfonyl, formylamino, C _1-6 alkyl - carboxamide, C _1-6 alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl -
It may have 1 to 5 substituents each selected from carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy. C _6-14
Aryl, C _7-16 aralkyl, 5- to 7-membered saturated cyclic amino or 5- to 6-membered aromatic heterocyclic group and (xvi-
3) 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from C _6-10 aryl-carbonyl, (xvii) sulfo and (xviii) (1 ′) halogen, (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 ′) (13′-1) C _1-6 alkyl, (1
3'-2) Halogen, 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, C _6-10 aryl, carboxy, formyl, C
_1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-
Carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyloxy and di -C _1-6 alkyl - 1 a substituent selected from the carbamoyloxy to 5 optionally C _6-14 aryl optionally having respectively, C _{7 -16} aralkyl, 5- or 7-membered saturated cyclic amino or 5- or 6-membered aromatic heterocyclic group and (13′-3) C _6-10 aryl-carbonyl having 1 or 2 substituents good 5 to 7 membered saturated cyclic amino, (14 ') formyl, carboxy, 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, carbamoyl, 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 and C _6-10 acyl selected from arylsulfonyl, (15 ') formylamino, C _1-6 alkyl - carboxamide, C _{6 -10} aryl-carboxamide, C
_1-6 alkoxy - acylamino selected from carboxamide and C _1-6 alkylsulfonylamino, (16 ') C
_1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-
Acyloxy, (17 ′) sulfo, (18 ′) C _6-10 aryl, (19 ′) C _6-10 selected from C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy A C _6-14 aryl, a C _6-10 quinonyl or a carbon atom which may have 1 to 5 substituents selected from aryloxy and (20 ′) oxo; C _6-14 aryl (preferably phenyl) _optionally having 1 to 3 substituents selected from a selected 5 to 14-membered aromatic heterocyclic group containing 1 to 4 heteroatoms containing 1 to 4 hetero atoms.

The “optionally substituted amino” represented by Y includes (i) as the substituent, for example, the aforementioned “optionally substituted hydrocarbon group” and “acyl”
Or two or more aminos which may have one or two or (ii) a 5- to 7-membered saturated cyclic amino. As the “5- to 7-membered saturated cyclic amino”,
The “5- to 7-membered saturated cyclic amino optionally having substituents” described in detail above as “5 to 7-membered saturated cyclic amino optionally having substituents” described as the substituents that the “hydrocarbon group optionally having” may have And the same as "7-membered saturated cyclic amino". As the “optionally substituted amino” represented by Y, for example, amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, etc.), di-C _1-6
Alkylamino (eg, dimethylamino, diethylamino, ethylmethylamino, etc.), 5- to 7-membered cyclic amino (eg, morpholino, thiomorpholino, piperazine-1)
- yl, piperidino, pyrrolidin-1-yl, such as hexamethyleneimine-1-yl), C _1-6 alkyl - carboxamide (example, such as acetamido), C _6-10 aryl -
Carboxamide (eg, phenylcarboxamide, naphthylcarboxamide, etc.), C _1-6 alkoxy-carboxamide (eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc.), N′-mono-C _1-6 alkyl-ureide (eg, , N'- methylureido, N'- ethylureido, etc.), N ', N'- di -C _1-6 alkyl - ureido (e.g.,
N ′, N′-dimethylureide, N ′, N′-diethylureide, etc.), N′-mono-C _6-10 aryl-ureide (eg, N′-phenylureide, N′-naphthylureide, etc.) and the like. No. As the "aromatic group optionally having substituent (s)" for Y, those described in detail as the substituent which the aforementioned "hydrocarbon group optionally having substituent (s)" may have And the same. Y is preferably acyl, hydroxy which may have a substituent or the like. More preferably, it is hydroxy which may have a substituent.

The “group represented by the formula —XY” is
It is substituted at a substitutable position of the ring A. A formula represented by ring A, wherein each symbol is as defined above.
As the “5- to 8-membered ring” of the “5- to 8-membered ring which may have a substituent other than the group represented by And a 5- to 8-membered homo- or heterocyclic ring which may contain 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom in addition to a carbon atom. As a specific example, the expression

Embedded image And the ring represented by Among them, preferred is a 5- to 7-membered homo- or heterocyclic ring which may contain one nitrogen atom in addition to a carbon atom. More preferably, the formula

Embedded image Is a ring represented by Particularly preferably, the formula

Embedded image Is a ring represented by

A 5- to 8-membered ring which may have a substituent in addition to the group represented by the formula -XY (wherein each symbol has the same meaning as described above) represented by ring A Examples of the `` substituent '' include, for example, acyl, hydroxy optionally having a substituent, amino optionally having a substituent, a hydrocarbon group optionally having a substituent, and a substituent. And a heterocyclic group, oxo and the like which may be possessed. The “acyl”, “optionally substituted hydroxy”, “optionally substituted amino”, “optionally substituted hydrocarbon group”, “substituent Examples of the "heterocyclic group which may be possessed" include the same as those described above. Preferably, the substituent is carboxy, C _1-6 alkoxy-carbonyl, carbamoyl, mono-C _1-6 alkylamino-carbonyl, di-C _1-6 alkylamino-carbonyl, C- which may have hydroxy. Examples thereof include _1-6 alkyl, oxo, and a hydrocarbon group which may have a substituent.
The substituent may be substituted at 1 to 3 substitutable positions on the ring A, and when the number of substituents is 2 or more, each substituent and its substitution position may be the same or different. The substituent may be substituted at the same position as a group represented by the formula -XY (wherein each symbol has the same meaning as described above). Ring A is preferably of the formula

Embedded image (Wherein each symbol has the same meaning as described above).

In the compound (I), R ¹ and R ² are each C _1-6 alkyl; X is (1) C _2-8 alkylene or (2)
Formula ^{_{:-( CH 2) m-X 1}} -, - (CH 2) m-X 2 -X 1 -, - X 1 -X 2 -
(CH ₂ ) n−, −X ² −X ¹ − (CH ₂ ) n−, − (CH ₂ ) m−X ¹ − (CH ₂ ) n
−, − (CH ₂ ) m−X ² − (CH ₂ ) n−, − (CH ₂ ) m−X ¹ −X ² − (C
H ₂ ) n−, − (CH ₂ ) m−X ² −X ¹ − (CH ₂ ) n− or −X ² −X ¹ −
X ^2- (CH ₂ ) n-wherein X ¹ is a divalent C _6-14 aromatic hydrocarbon group (preferably 1,4-phenylene), X ² is O, and m is an integer of 0 to 10. , N is an integer from 1 to 5, and m
+ N represents an integer of 2 to 10]; Y is a hydroxy optionally substituted; and ring A is a group represented by the formula:

Embedded image Compounds that are rings represented by are preferred. Y is
Preferably, (i) halogen, (ii) C _1-3 as a substituent
Alkylenedioxy, (iii) nitro, (iv) cyano,
(V) an optionally halogenated C _1-6 alkyl, (v
i) optionally halogenated C _3-6 cycloalkyl,
(Vii) optionally halogenated C _1-6 alkoxy,
(Viii) optionally halogenated C _1-6 alkylthio, (ix) hydroxy, (x) amino, (xi) mono-C
_1-6 alkylamino, (xii) di -C _1-6 alkylamino, (xiii) formyl, carboxy, 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 to 6
Membered heterocyclic carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C
Acyl selected from _6-10 arylsulfonyl, (xiv)
Formylamino, C _1-6 alkyl-carboxamide, C
_Acylamino selected from _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (xv) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C
Acyloxy selected from _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy,
(Xvi) (xvi-1) C _1-6 alkyl, (xvi-2) halogen,
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, C _6-10
Aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl- Carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6
Alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy and dialkyl C _6-14 aryl, C _7-16 aralkyl optionally having 1 to 5 substituents selected from —C _1-6 alkyl-carbamoyloxy, 5- to 7-membered saturated cyclic amino or 5- to 6-membered 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from an aromatic heterocyclic group and (xvi-3) C _6-10 aryl-carbonyl, (xvii) sulfo and (xviii) (1 ′) halogen, (2 ′) C _1-3 alkylenedioxy, (3 ′) nitro, (4 ′) cyano, (5 ′) optionally halogenated C _1-6 alkyl, (6 ′ ) Halogenated May be C
_3-6 cycloalkyl, (7 ') optionally halogenated C _1-6 alkoxy optionally, (8') optionally halogenated a C _1-6 alkylthio, (9 ') hydroxy, (10') Amino, (11 ′) mono-C _1-6 alkylamino, (12 ′) di-
C _1-6 alkylamino, (13 ′) (13′-1) C _1-6 alkyl, (13′-2) halogen, 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, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di -C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6
Alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-
Carbamoyloxy and di -C _1-6 alkyl -, 1 to substituents selected from carbamoyloxy five good C _6-14 optionally having respectively aryl, C _{7- 16} aralkyl, 5- to 7-membered saturated cyclic amino or A 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from a 5- or 6-membered aromatic heterocyclic group and (13'-3) _C6-10 aryl-carbonyl, (14 ' ) Formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C
Acyl selected from _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl, (15 ′) formylamino, C _{1 -6alkyl-} carboxamide, _C6-10aryl- carboxamide,
C _1-6 alkoxy - acylamino selected from carboxamide and C _1-6 alkylsulfonylamino, (16 ')
C _1-6 alkyl-carbonyloxy, C _6-10 aryl-
Carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-
Acyloxy, (17 ′) sulfo, (18 ′) C _6-10 aryl, (19 ′) C _6-10 selected from C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy A C _6-14 aryl, a C _6-10 quinonyl or a carbon atom which may have 1 to 5 substituents selected from aryloxy and (20 ′) oxo; It is hydroxy substituted with phenyl optionally having 1 to 3 substituents selected from 5 to 14-membered aromatic heterocyclic groups containing 1 to 4 heteroatoms selected.

R ¹ and R ² are each C _1-6 alkyl; X is (1) C _1-8 alkylene or (2) Formula: — (CH
^{_{2) m'-X 2 '-X}} 1' -, - X 1 '-X 2' - (CH 2) n'- , or - (CH
^{_{2) m'-X 2 '-X}} 1' - (CH 2) n'- wherein, X ¹ 'is 1,4-phenylene, X ^2' is O, m 'is an integer of 1 to 4, and n '
Represents 1 or 2]; Y is (1) carboxy, (2) a substituent (i) C _1-6 alkoxy, (i
i) amino, (iii) mono- or di-C _1-6 alkylamino or (iv) carbonyl with 6-membered saturated cyclic amino optionally having C _1-6 alkyl, phenyl or piperidino, (3) (I) halogen, C _1-3 as a substituent
Phenyl optionally having 1 to 3 substituents selected from alkylenedioxy, cyano, C _1-6 alkyl, C _1-6 alkoxy and mono-C _1-6 alkyl-carbamoyl, (ii) C _{1 -6} alkyl - carbonyl, (iii) mono- - or di -C _1-6 alkyl - carbamoyl which may have a (iv) pyridyl or (v) quinolyl hydroxy, (4) C _1-6 alkyl and C Amino optionally having 1 or 2 substituents selected from _1-6 alkyl-carbonyl, (5) phenyl as a substituent, (ii)
One or two of benzyl optionally having phenyl, (iii) piperidino or (iv) 6-membered saturated cyclic amino optionally having pyridyl, (6) phenyl, and (7) C _1-6 alkoxy. C _6-10 quinonyl optionally having, (8) phthalimide, (9) pyridyl optionally having oxo, (10) quinolyl optionally having oxo, (11)
Benzotriazolyl or (12) benzimidazolyl;
And ring A further has carboxy, C _1-6
Alkoxy-carbonyl, carbamoyl, mono- or di-C _1-6 alkyl-carbamoyl, hydroxy-C _1-6
Formulas which may have alkyl or phenyl:

Embedded image Compounds that are rings represented by are also preferred.

Compound (I) is more preferably a compound of the formula:

Embedded image Wherein R ^1a and R ^2a are each C _1-3 alkyl; q
Is an integer of 1 to 4; and R is 1 to 3 halogen, C _1-3 alkylenedioxy, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _{1- 6} alkoxy, C _1-6 alkoxy-carbonyl, formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide or C _1-6 alkylsulfonylamino] Or a salt thereof. A specific example of compound (I) is 2- [8- (4-chlorophenoxy) octyl] -5,6-dimethoxyindane-4,7.
-Dione, 4- [2- (2,3-dimethoxy-1,4-dioxo-4,5,6,7,8,9-hexahydro-1H-benzo [a] cyclohepten-7-yl) ethoxy] benzoate Ethyl acid or 7- [2- (4-chlorophenoxy) ethyl] -2,3-dimethoxy-4,5,6,7,8,9
-Hexahydro-1H-benzo [a] cycloheptene-
1,4-dione and the like.

Examples of the salt of compound (I) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids,
Salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned. Preferable examples of the metal salt include an alkali metal salt such as a sodium salt and a potassium salt; an alkaline earth metal salt such as a calcium salt, a magnesium salt and a barium salt; an aluminum salt. 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.
Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be Of these, pharmaceutically acceptable salts are preferred. For example, when the compound (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 salt, etc.), ammonium Salts, etc., and when the compound (I) has a basic functional group, an inorganic salt such as hydrochloride, sulfate, phosphate, hydrobromide or acetate, maleate, fumaric acid Organic salts such as salts, succinates, methanesulfonates, p-toluenesulfonates, citrates, tartrates and the like can be mentioned.

The method for producing compound (I) is described below. Compound (I) can be produced, for example, by a method shown in the following scheme, in addition to a method known per se. The compounds shown in the following schemes include those forming salts, and examples of the salts include the same as the salts of compound (I).

Embedded image In the above formula, P and P 'each represent a protecting group, and other symbols have the same meanings as described above. As the "protecting group" represented by P or P ', those used in the field of organic synthesis reactions can be used as long as they do not hinder the reaction. Often, preferably methyl, benzyl and the like are used.

(Step 1) Compound (II) is subjected to a quinone formation reaction to obtain compound (I). Compound (II) can be produced by a method known per se, for example, the method of the following scheme 2 or a method analogous thereto. In step 1, the step of removing P and P 'of compound (II) and the step of oxidizing may be performed simultaneously or separately. For example, when P and P 'are methyl, a method of reacting compound (II) with a cerium compound (eg, CAN [cerium (IV) ammonium nitrate] or the like) to obtain compound (I) may be mentioned. The reaction is carried out with the compound (I
I) and an excess amount (preferably 2 to 10 equivalents) of a cerium compound in an inert solvent (eg, a mixed solvent of water and a nitrile solvent) at room temperature (0 to 30 ° C) to 80 ° C,
It is performed by stirring for 24 hours. If necessary, the reaction may be carried out with a catalytic amount to 10 equivalents of a mineral acid (eg, sulfuric acid or the like) or an organic acid (eg, 2,6-pyridinedicarboxylic acid or the like). Compound (II) and 2 to 10 equivalents of silver (II) oxide or a chromic acid reagent (eg, pyridinium chlorochromate, Collins reagent, etc.) can be prepared by a method known per se, for example, tetrahedron letters (Tetrahedro).
n Lett.), vol. 94, p. 227 (1980) and the like, and a method of obtaining the compound (I) is also used.

For example, when P and P ′ are benzyl,
The compound (II) is subjected to a catalytic reduction method known per se to obtain a hydroquinone form (compound (IIa)), and then, if necessary, the isolated compound (IIa) is subjected to an oxidation reaction known per se to give a compound ( I get. In the catalytic reduction method, compound (II) and a catalytic amount of a metal catalyst (eg, Raney nickel, platinum oxide,
Metal palladium, palladium-carbon, etc.) in an alcoholic solvent under a hydrogen pressure of 1 to 100 atm, preferably 1 to 5 atm at room temperature to 100 ° C for 1 to 48 hours. The oxidation reaction in the next step is carried out by the compound (II
a) and 2 to 10 equivalents of an oxidizing agent are stirred in an inert solvent at room temperature to 50 ° C for 1 to 24 hours. As the inert solvent, water, an ether-based solvent, a halogenated hydrocarbon-based solvent, or the like can be used alone or in combination of two or more. As the oxidizing agent,
For example, a chromium compound (eg, chromic anhydride, Jones reagent, etc.), a manganese compound (manganese dioxide, potassium permanganate, etc.), silver oxide, ferric oxide, Fremy's salt and the like can be mentioned. Preferred are ferric oxide, flemy salt and the like. The compound (I) obtained in the step 1 may be used alone or each of known deprotection reactions, acylation reactions, amidation reactions, esterification reactions, amination reactions, hydrolysis reactions, and alkylation reactions, if necessary. The desired product may be obtained by subjecting the reaction to a combination of two or more. These reactions are described, for example, in Comprehensive Organic Transformation.
ormations) VCH Publishers Inc. (1989), Richard Lar
ock etc. may be used.

[0049]

Embedded image In the above formula, a group represented by -CO-Q is a carboxylic acid or a reactive derivative thereof, Q 'is a hydrogen atom or a halogen,
Y ′ is a group convertible to Y, and other symbols have the same meanings as described above. Q is preferably hydroxy, C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), halogen (eg, bromo, chloro, fluoro, etc.), optionally substituted C
_6-10 aryloxy, _optionally substituted C _7-12
Aralkyloxy, C _1-6 alkyl-carbonyloxy (eg, acetyloxy, propionyloxy, etc.), C
_1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, butoxycarbonyloxy, propoxycarbonyloxy, etc.). The “C _6-10 aryloxy” of the “C _6-10 aryloxy _optionally having substituent (s)” includes, for example, phenyloxy, naphthyloxy and the like. Examples of the “substituent” of the “ _optionally substituted C _6-10 aryloxy” include 1 to 5 nitro, halogen, and the like. Specific examples of “ _optionally substituted C _6-10 aryloxy” include phenoxy, pentachlorophenyloxy, pentafluorophenyloxy, p-nitrophenyloxy and the like. The "C which may have a substituent"
_7-12 aralkyloxy "," C _7-12 aralkyloxy "
Examples include benzyloxy and the like.
"C _7-12 aralkyloxy _optionally having substituent (s)"
As the “substituent” of the above, the same substituents as the above-mentioned “C _6-10 aryloxy _optionally having substituent (s)” are used. Specific examples of “ _optionally substituted C _7-12 aralkyloxy” include benzyloxy, p-chlorobenzyloxy and the like. The “halogen” represented by Q ′ preferably includes bromo, chloro and the like.

Y ′ may be any group as long as it can be converted to Y. For example, (i) “acyl, hydroxy optionally having substituents, Optionally substituted amino, optionally substituted aromatic group "and (ii) halogen, nitro, cyano, azide, silylated hydroxy, silylated amino, silylated carboxy, Acetal-protected carbonyl and the like. The “silyl” of the “silylated hydroxy”, “silylated amino” and “silylated carboxy” includes, for example,
Examples include trimethylsilyl, triethylsilyl, dimethylphenylsilyl, dimethyl-t-butylsilyl, diethyl-t-butylsilyl and the like. Examples of the “acetal” of the “carbonyl protected with an acetal” include, for example,
Cyclic acetal such as 1,3-dioxolane, di-C
_Acyclic acetal such as _1-6 alkyl acetal; When Y ′ is a halogen, if necessary, acyl, hydroxy optionally having a substituent, acyl according to a method known per se, for example, a method described in the above-mentioned comprehensive organic transformation (1989), etc.
The compound is converted to an amino which may have a substituent. Y '
Is nitro, cyano or azide, if necessary, is converted to amino according to a method known per se, for example, the method described in the above-mentioned Comprehensive Organic Transformation (1989). Y ′ is preferably C _1-6
Alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), silyloxy (eg, trimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy, dimethyl
-t-butylsilyloxy, diethyl-t-butylsilyloxy, etc.), phthalimide and the like.

(Step 2) Compound (III) is subjected to a cyclization reaction known per se to give compound (IV). Compound (III) can be produced by a method known per se, for example, the method of the following scheme 3 or a method analogous thereto. As the cyclization reaction,
For example, there are the following two methods. (1) In the compound (III), when Q ′ is a hydrogen atom,
For example, a cyclization reaction is performed using an acid. In the reaction, Q
Is preferably hydroxy, halogen and the like. This reaction is carried out by reacting compound (III) with a catalytic amount to an excess amount, preferably 1 to 5 equivalents of an acid in an inert solvent at -70 to 100
C., for 10 minutes to 24 hours. As the acid,
For example, Lewis acids (eg, aluminum chloride, stannic chloride, titanium tetrachloride, boron trifluoride diethyl ether, etc.), mineral acids (eg, sulfuric acid, polyphosphoric acid, etc.), organic acids (eg, p-toluenesulfonic acid, Trifluoromethanesulfonic acid, methanesulfonic acid, etc.), and organic silicon derivatives (eg, trifluoromethanesulfonic acid trimethylsilyl ether, etc.). As the inert solvent,
For example, halogenated hydrocarbon solvents, aromatic solvents and the like can be used alone or as a mixture of two or more thereof.

(2) When Q 'is a halogen in the compound (III), a cyclization reaction is carried out by a halogen-metal exchange reaction using, for example, an organometallic reagent. In the reaction, Q is preferably C _1-6 alkoxy, phenyloxy and the like. This reaction is carried out by reacting compound (III) and an excess amount, preferably 1 to 5 equivalents, of an organometallic reagent in an inert solvent with -12.
0 to 50 ° C, preferably -90 to -50 ° C, 0.5 to 1
The reaction is performed for 8 hours. Examples of the organometallic reagent include alkyllithium (eg, C _1-6 alkyllithium such as methyllithium, ethyllithium, butyllithium, sec-butyllithium and tert-butyllithium), aryllithium (eg, phenyllithium and the like). C _6-10 aryllithium, etc.), Grignard reagents (eg, methyl magnesium bromide, ethyl magnesium bromide, butyl magnesium bromide, sec-butyl magnesium bromide, C _1-6 alkyl magnesium bromide such as tert-butyl magnesium bromide, phenyl magnesium bromide) C _6-10 arylmagnesium bromide, etc.),
Examples thereof include alkyl zinc (eg, C _1-6 alkyl zinc such as dimethyl zinc, diethyl zinc, dibutyl zinc, etc.) and C _6-10 aryl sodium (eg, phenyl sodium etc.). As the inert solvent, an ether solvent, an aromatic solvent, or the like can be used alone or as a mixture of two or more of them. Preferably, ethyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane and the like are mentioned.

(Step 3) Compound (IV) is subjected to a reduction reaction to obtain compound (V). The reduction reaction includes a method known per se, for example, a method using a metal hydride or a catalytic reduction method (eg, Organic Functional Group Preparations (ORGANIC FUNCTI).
ONAL GROUP PREPARATIONS) 2nd edition, the method described in Academic Press, Inc. (ACADEMIC PRESS, INC.). The reduction reaction with a metal hydride is performed by reacting compound (IV) with a metal hydride 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. Among them, metal hydrides such as lithium aluminum hydride are preferable. The amount of the metal hydride to be used is 1 to 20 equivalents, preferably 2 to 6 equivalents, relative to compound (IV). The reaction temperature in the reaction using a metal hydride is -70 to 100C, preferably 0 to 50C. The reaction time is 0.1 to 6 hours, preferably 0.5 to 2 hours. In the catalytic reduction method, the compound (IV) and a catalytic amount of a metal catalyst (eg, Raney nickel, platinum oxide, metal palladium, palladium-carbon, etc.) are mixed in an inert solvent (eg, an alcohol solvent) with a concentration of 1 to 100. The reaction is carried out at room temperature to 100 ° C. for 1 to 48 hours under an atmospheric hydrogen pressure.

(Step 4) Compound (V) is subjected to a reductive dehydration reaction to obtain compound (VI). Examples of the reductive dehydration reaction include a catalytic reduction method known per se, a method using an organic silyl reagent (such as an alkylsilane reagent), and the like. In the catalytic reduction method, the compound (V) 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 solvent).
Medium, under hydrogen pressure of 1 to 100 atm, room temperature to 100 ° C, 1 to 1
The reaction is carried out for 48 hours. As needed,
A catalytic amount to an excessive amount of an organic acid (eg, acetic acid, etc.) or a mineral acid (eg, hydrochloric acid, etc.) may be added. In the method using an alkylsilane reagent, compound (V), an alkylsilane reagent, and an acid are prepared in an inert solvent (eg, a halogenated hydrocarbon solvent) at 0 to 100 ° C, preferably 0 to 30 ° C for 10 minutes to The reaction is carried out for 24 hours. Examples of the alkylsilane reagent include triethylsilane and phenyldimethylsilane. The amount of the alkylsilane reagent to be used is 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound (V). Examples of the acid include an organic acid (eg, trifluoroacetic acid and the like). The amount of the acid to be used is a catalytic amount to an excess amount, preferably 1 to 5 equivalents, relative to compound (V).

(Step 5) Compound (IV) is subjected to a reduction reaction to obtain compound (VI). Examples of the reduction reaction include a method using a metal. Compound (IV) and an excess (1 to 100 equivalents) of metal (eg, zinc dust, etc.)
In an inert solvent (eg, ether solvents, acetic acid, etc.)
The stirring is performed at room temperature to 100 ° C. for 1 to 24 hours. (Step 6) Compound (VI) is subjected to a known organic synthesis reaction to give compound (II). Examples of the organic synthesis reaction include an etherification reaction, a deprotection reaction, an oxidation reaction, a reduction reaction, an alkylation reaction, an acylation reaction, an amination reaction, a hydroxylation reaction, and a hydrolysis reaction. These reactions may be performed, for example, according to the method described in the above-mentioned Comprehensive Organic Transformation (1989). For example, when Y ′ is a halogen in compound (VI), it can be substituted with a nitrogen atom or an oxygen atom by a substitution reaction. As the “reaction to replace with a nitrogen atom”, the compound (VI) and 1 equivalent to an excess amount, preferably 1 to 5 equivalents of an amine are reacted in a solvent-free or inert solvent at room temperature to 2
A method of stirring at 00 ° C., preferably 50 to 100 ° C., for 0.5 to 18 hours is exemplified. Examples of the amines include ammonia, mono-C _1-6 -alkylamine (eg, methylamine, ethylamine, etc.), di-C _1-6 -alkylamine (eg, dimethylamine, diethylamine, etc.), 5- to 7-membered And cyclic amines (eg, morpholine, piperazine, piperidine, pyrrolidine, hexamethyleneimine, etc.). As the inert solvent, for example, an alcohol-based solvent, an ether-based solvent, an amide-based solvent, a nitrile-based solvent or the like can be used alone, or a mixture of two or more thereof can be used. Examples of the "reaction to replace with an oxygen atom" include (1) compound (VI) and a metal salt of an organic acid in an amount of 1 equivalent to an excess amount, preferably 1.5 to 10 equivalents (eg, sodium acetate, potassium acetate, silver acetate) ) In an inert solvent (eg, an alcohol-based solvent) at room temperature to 100 ° C,
Reaction for 0.5 to 24 hours to obtain an acyloxy form, or (2) compound (VI) and 1 equivalent to excess,
Preferably, 1.1 to 10 equivalents of an alkali metal (eg, sodium hydroxide, potassium hydroxide, etc.) or silver oxide is added to an inert solvent (eg, water or an alcohol-based solvent alone or in a mixed solvent) at room temperature to room temperature. A method of reacting at 100 ° C. for 0.5 to 24 hours to obtain a hydroxy compound is exemplified.
For example, when Y ′ in compound (VI) is nitro or azide, the compound may be converted to amino by a reduction reaction known per se.

When Y 'is hydroxy or amino in compound (VI), the desired product can be obtained by subjecting it to an alkylation or acylation reaction known per se. Specifically, compound (VI) is used in an amount of 1 to 3 equivalents, preferably 1.1 to 2 equivalents.
An equivalent of a compound represented by the formula: LY ″ (wherein L represents a leaving group, Y ″ represents an acyl or a hydrocarbon group which may have a substituent) and an inert solvent Let react inside. As the "leaving group" for L, when Y ″ is acyl, for example, halogen (eg, chloro, bromo, iodo, etc.), C _1-4 alkyl optionally substituted with 1 to 3 halogens Sulfonyloxy (eg, methanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), C _6-10 arylsulfonyloxy optionally substituted with 1 to 4 halogen or C _1-6 alkyl (eg, p-toluenesulfonyloxy, Benzenesulfonyloxy, p-bromobenzenesulfonyloxy, etc.), C _1-6 alkyl-
Carbonyloxy (eg, methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, butylcarbonyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.) ), Phenoxycarbonyloxy and the like. When Y ″ is an optionally substituted hydrocarbon group, examples of the “leaving group” represented by L include halogen, C _1-4 optionally substituted with 1 to 3 halogens. Alkylsulfonyloxy and C _6-10 arylsulfonyloxy optionally substituted with 1 to 4 halogen atoms. As the “acyl” represented by Y ″, for example, those similar to the “acyl” represented by Y above can be mentioned. Examples of the `` hydrocarbon group optionally having a substituent '' represented by Y '' include, for example, `` hydroxy optionally having a substituent '' or `` having a substituent And the "hydrocarbon group which may have a substituent" which is described in detail as the "substituent" of "may be amino". As the inert solvent, for example, water, 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 alone or a mixture thereof. Two or more kinds can be used as a mixture. Among them, ethanol, acetonitrile, DMF, acetone and the like are preferable. The reaction temperature is room temperature to 100 ° C, preferably room temperature to 50 ° C. The reaction time is 0.5 to 24 hours. If necessary, 1 to 3 equivalents of a base may be added to the above reaction. The base is not always essential in the alkylation reaction of the amino group.

Examples of the base include (1) hydrides of alkali metals or alkaline earth metals (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metals and alkaline earth metals. Metal amides (eg, lithium amide, sodium amide,
Lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethylsilazide, sodium hexamethylsilazide, potassium hexamethylsilazide, etc.), lower alkoxides of alkali metals or alkaline earth metals (eg, sodium methoxide, sodium ethoxide, potassium) (2) For example, a hydroxide of an alkali metal or an alkaline earth metal (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.), an alkali metal or Alkaline earth metal carbonates (eg, sodium carbonate,
Inorganic bases such as potassium carbonate, cesium carbonate and the like, and alkali metal or alkaline earth metal hydrogen carbonate (eg, sodium hydrogen carbonate, potassium hydrogen carbonate and the like); or (3) for example, triethylamine, diisopropylethylamine, N-methyl Morpholine, dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4.0]-
Amines such as 7-undecene) 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. And the like.

When Y ′ in the compound (VI) is C _1-6 alkoxy-carbonyl or C _6-10 aryloxy-carbonyl, it can be converted to hydroxymethyl by a reduction reaction. The reduction reaction may be performed according to a method known per se, for example, the method described in the above-mentioned Comprehensive Organic Transformation (1989). For example, compound (VI) and 1 to 20 equivalents, preferably 2 to
A method of reacting 6 equivalents of a metal hydride in an inert solvent can be used. Examples of the metal hydride include aluminum hydride, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, diborane, dibutylaluminum hydride, and the like. Among them, lithium aluminum hydride is preferable. Examples of the inert solvent include ether solvents (preferably, THF, ethyl ether, etc.), alcohol solvents, aromatic solvents (preferably, toluene), hydrocarbon solvents (preferably, hexane) and the like, or a mixture thereof. A mixture of more than one species can be used. The reaction temperature is -70 to 100C. The preferred reaction temperature varies depending on the reducing agent to be used.

When Y 'is carbamoyl or N-substituted carbamoyl in compound (VI), it can be converted to the corresponding aminomethyl or N-substituted aminomethyl by a reduction reaction, respectively. For example, Y 'is carbamoyl, mono-
N—C _1-6 alkyl-carbamoyl or di-N—C _1-6
In the case of alkyl-carbamoyl and the like, they can be converted to aminomethyl, mono-N-C _1-6 alkylaminomethyl or di-N-C _1-6 alkylaminomethyl by subjecting them to a reduction reaction. Specific examples of the reduction reaction include a method in which compound (VI) and 1 to 20 equivalents, preferably 2 to 6 equivalents, of a metal hydride are reacted in an inert solvent. Examples of the metal hydride include aluminum hydride, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, diborane, dibutylaluminum hydride, and the like. Among them, lithium aluminum hydride is preferable. As the inert solvent, ether solvents (preferably, THF, ethyl ether, etc.),
An alcohol solvent, an aromatic solvent (preferably toluene), a hydrocarbon solvent (preferably hexane), or the like can be used alone, or a mixture of two or more thereof can be used. The reaction temperature is -70 to 100C. The preferred reaction temperature varies depending on the reducing agent used. For example, in the case of lithium aluminum hydride, the reaction temperature is 40 to 80 ° C.

In compound (VI), Y 'is hydrolysable acyl (eg, C _1-6 alkoxy-carbonyl, C _6-10
Aryloxycarbonyl) can be converted to carboxy by a hydrolysis reaction. The hydrolysis reaction may be performed according to a known alkali hydrolysis reaction and an acid hydrolysis reaction. The alkaline hydrolysis reaction is carried out using the compound (V
I) is reacted with an alkali in an inert solvent. Examples of the alkali include a hydroxide of an alkali metal or alkaline earth metal such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide.
Among them, sodium hydroxide is preferable. The amount of the alkali to be used is 2 to 100 equivalents, preferably 5 to 10 equivalents, relative to compound (VI). As the inert solvent, for example,
Water, alcohol solvents, ether solvents and the like can be used alone or as a mixture of two or more thereof.
Among them, a mixed solvent of water-methanol is preferable. The reaction temperature is 10 to 120 ° C, preferably 50 to 120 ° C. The reaction time is 0.5 to 100 hours, preferably 1 hour.
~ 50 hours. As a preferred reaction example, the inert solvent is a mixed solvent of water and methanol, and the reaction temperature is 50 to 12
0 ° C., reaction time 1 to 10 hours. In the acid hydrolysis reaction, compound (VI) and an excess amount, preferably 1 to 10 equivalents of a mineral acid (eg, hydrochloric acid, sulfuric acid, phosphoric acid, etc.) are added in the presence of a solvent at room temperature to 120 ° C., preferably 60 to 100 ° C. ° C, 0.
What is necessary is just to stir for 5 to 18 hours. As the solvent, water and an organic acid (eg, acetic acid or the like) can be used as a mixture. Of these, dilute hydrochloric acid alone or acetic acid is preferred.

In compound (I), when ring A is a 5-membered homocyclic ring, compound (VI ′) may be obtained, for example, according to the following scheme 3, and then subjected to step 6 to obtain compound (II ′). it can. Compound (II ′) is included in compound (II).

Embedded image In the above formula, each symbol has the same meaning as described above.

(Step 7) Compound (VII) is subjected to a bromination reaction to obtain compound (VIII). Compound (VII) is a known compound that can be obtained, and can be obtained by a method known per se, for example, Journal of Organic Chemistry (Jounal o).
f Organic Chemistry), vol. 54, p. 3872 (1987). Compound (VII) and 1
~ 1.5 equivalents of a brominating reagent (e.g., bromine, N-bromosuccinimide (NBS), etc.) in an inert solvent (e.g., a single or mixed solvent such as a halogenated hydrocarbon solvent, an ester solvent, acetic acid, etc.) , -20 to 100 ° C, preferably 0 ° C to room temperature, for 0.1 to 18 hours. (Step 8) Compound (VIII) is subjected to a radical bromination reaction to obtain compound (IX). Compound (VIII), 1 to 1.5
Equivalent amount of brominating reagent (eg, NBS, etc.) and catalyst amount １1
An equivalent amount of a radical generator (eg, perbenzoic acid, 2,2′-azobis (isobutyronitrile) (AIBN), etc.) in an inert solvent (eg, ethyl acetate, halogenated hydrocarbon solvent, etc.) at room temperature ~ 100 ° C, preferably 50-80 ° C,
React for 0.1 to 18 hours.

(Step 9) Compound (IX) and Formula

Embedded image (Wherein, W is a hydrogen atom, nitro, acyl, hydroxy which may have a substituent, amino which may have a substituent, a hydrocarbon group which may have a substituent or a substituent And the other symbols have the same meanings as described above), and are reacted in an inert solvent to give compound (III ′). “Acyl”, “optionally substituted hydroxy”, “optionally substituted amino”, “optionally substituted hydrocarbon group” and “ Examples of the "heterocyclic group optionally having substituent (s)" include the same as those described in detail as the substituent which ring A may have. In this reaction, Q is preferably C _1-6 alkoxy, benzyloxy and the like. The amount of compound (X) to be used is 1 to 1.5 equivalents relative to compound (IX). The reaction temperature is room temperature to 100 ° C, preferably room temperature to 50 ° C. The reaction time is 0.5 to 24 hours. Usually, the reaction is carried out by adding 1 to 3 equivalents of a base.

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, or a mixture thereof may be used. Two or more kinds can be used as a mixture. Among them, acetonitrile, DMF, acetone, ethanol 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.) and amides of alkali metals or alkaline earth metals. (Eg, lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethylsilazide, sodium hexamethylsilazide, potassium hexamethylsilazide, etc.), lower alkoxides of alkali metals or alkaline earth metals (eg, , Sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.); (2) For example, hydroxides of alkali metals or alkaline earth metals (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide) , Barium hydroxide ), Alkali metal or alkaline earth metal carbonates (eg, sodium carbonate,
Inorganic bases such as potassium carbonate, cesium carbonate and the like, and alkali metal or alkaline earth metal hydrogen carbonate (eg, sodium hydrogen carbonate, potassium hydrogen carbonate and the like); or (3) for example, triethylamine, diisopropylethylamine, N-methyl Morpholine, dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4.0]-
Amines such as 7-undecene) and DBN (1,5-diazabicyclo [4.3.0] non-5-ene), and aromatic compounds such as pyridine, imidazole and basic heterocyclic compounds such as 2,6-lutidine. Group amines and the like.

(Step 10) Compound (III ') is subjected to a cyclization reaction to obtain compound (IV'). Compound (III ′) is converted to an ether solvent (preferably THF, ethyl ether, etc.)
Medium, cooled to −100 to −60 ° C., and added with 1 to 2 equivalents, preferably 1 to 1.2 equivalents of an alkali metal reagent,
Stir at 00 ° C to -20 ° C for 0.5 to 6 hours. Examples of the alkali metal reagent include the alkyl lithium, aryl lithium, Grignard reagent, alkyl zinc, and C _6-10 aryl sodium used in Step 2 above. (Step 11) Compound (IV ′) is subjected to a reduction reaction to obtain compound (VI ′). The reduction reaction is performed in Steps 3, 4 and 5 described above.
May be performed in combination. For example, the reduction reaction of ketone to hydroxy in the first step is performed by compound (IV ′) and 1
A method of reacting 10 to 10 equivalents of sodium borohydride in an alcohol-based solvent at 0 to 50 ° C., preferably at room temperature, for 0.5 to 18 hours is exemplified. For example, as the reductive dehydration reaction in the second step, the catalytic reduction method in the above step 4 is preferable. Among them, compound (IV ′) and a palladium-carbon catalyst are prepared in an alcoholic solvent under a hydrogen pressure of 1 to 5 atm.
Reactions with stirring for 18 hours are preferred. In the compound (VI ′) obtained in Step 11, for example, when W is C _1-6 alkoxy-carbonyl, it may be subjected to a decarboxylation reaction.
The decarboxylation reaction is performed under acidic conditions, for example, the compound (V
I ′) and an organic acid (eg, acetic acid or the like) or a mineral acid (preferably sulfuric acid, hydrochloric acid, perchloric acid or the like) at room temperature to 100 ° C.
C., preferably 60 to 100 C., for 1 to 24 hours.

(Step 12) Compound (II ') is obtained from compound (VI') according to the same method as in the above step 6. When ring A is a nitrogen-containing 6-membered ring in compound (I), compound (II ″) can also be obtained according to, for example, scheme 4 below. Compound (II ″) is included in compound (II).

Embedded image In the above formula, each symbol has the same meaning as described above. (Step 13) Compound (XI) is subjected to an acylation reaction to obtain compound (XII). In the acylation reaction, the compound (XI) is subjected to the same reaction conditions as the halogen-metal exchange described in Step 2 above, and is then used in an amount of 1 equivalent to an excess amount, preferably 1 to 1.5.
The reaction is carried out by adding an equivalent amount of ethyl chlorocarbonate and then stirring at the same temperature or at room temperature for 1 to 15 hours. Preferred reaction temperatures are from -70 to -20C.

(Step 14) Compound (XII) is subjected to a bromination reaction to obtain compound (XIII). The reaction is performed under the same reaction conditions as in Step 8. (Step 15) Compound (XIII) is subjected to a cyanation reaction to obtain compound (XIV). Compound (XIII) and 1 to 5 equivalents of a cyanating agent (eg, sodium cyanide, potassium cyanide, etc.) in an inert solvent (eg, DMF, DMSO, water, etc.) are added at room temperature to 100 ° C., preferably 40 to 70 ° C. 1 to
Stir for 18 hours, preferably 2-5 hours. (Step 16) Compound (XIV) is subjected to a cyclization reaction to obtain compound (XV). As the cyclization reaction, a catalytic reduction method is generally used. Compound (XIV) and a catalytic amount of a metal catalyst (eg, Raney nickel, platinum oxide, metallic palladium,
Palladium-carbon or the like, preferably Raney nickel)
In an inert solvent (eg, ethanol saturated with ammonia) under hydrogen pressure of 1 to 100 atm, room temperature to 100 ° C,
Incubate for 1 to 48 hours. Preferred reaction conditions include:
Under hydrogen pressure of 4 to 10 atm, 40 to 100 ° C, 1 to 10 hours. (Step 17) Compound (XV) is subjected to a reduction reaction to obtain compound (XVI). As the reduction reaction, a method using various metal hydride reagents is preferable. For example, a reduction reaction with a metal hydride described in Step 3 above can be mentioned, and preferable reaction conditions include an excess amount of a metal hydride such as lithium aluminum hydride, aluminum hydride, or diborane and an ether-based solvent such as THF. Method. (Step 18) Compound (II ′) is obtained from compound (XVI) according to the same method as in Step 6.

When ring A is a 7-membered homocyclic ring in compound (I), compound (VI ″) is obtained, for example, according to the following scheme 5, and then subjected to step 6 above to give compound (I)
I '''). Compound (II ′ ″) is included in compound (II).

Embedded image In the above formula, L ¹ and L ² are each a leaving group, and other symbols are as defined above. As the “leaving group” for L ¹ or L ² , those similar to the “leaving group” for L above can be mentioned. L ¹ and L ² are each a halogen (eg, chloro, bromo, iodo, etc.), a C _1-4 alkylsulfonyl optionally substituted with 1 to 3 halogens (eg, methanesulfonyloxy, trifluoromethanesulfonyloxy) And C _6-10 arylsulfonyloxy optionally substituted with 1 to 4 C _1-6 alkyl or halogen (eg, p-toluenesulfonyloxy, benzenesulfonyloxy, p-bromobenzenesulfonyloxy, etc.) and the like. Is preferred.

(Step 19) Compound (XVII) is subjected to a 7-membered ring-forming reaction and then to a decarboxylation reaction to obtain compound (XVIII). Compound (XVII) is a method known per se,
For example, Chemisch Berichte,
1879 (1957), Journal of Chemical Society, 426 (196
It is manufactured according to the method described in 6). Compound (XVI
In I), for example, when P, P ′, R ¹ and R ² are each methyl and L ¹ and L ² are each chloro, the above-mentioned Chemisch Berichte, p. 1879 (195)
The method may be performed according to the method described in 7). Compound (XVII)
Wherein, for example, P, P ′, R ¹ and R ² are each methyl,
When L ¹ and L ² are each bromo, the above-mentioned Journal of Chemical Society
l Society), p. 426 (1966) and the like. The seven-membered ring formation reaction is carried out by reacting compound (XVII) with 0.5
The reaction is carried out by reacting .about.1.5 equivalents of diethyl 1,3-acetonedicarboxylate in an inert solvent in the presence of a base. Examples of the base include the strong bases, inorganic bases, and organic bases described above. Of these, inorganic bases are preferred. More preferably, an alkali metal or alkaline earth metal hydroxide (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.), an alkali metal or alkaline earth metal carbonate (eg, sodium carbonate) , Potassium carbonate, cesium carbonate, etc.). The amount of the base used is 2 equivalents or more, preferably 2 to 4 equivalents, based on diethyl 1,3-acetonedicarboxylate. Examples of the inert solvent include water, alcohol solvents, ether solvents, halogenated hydrocarbon solvents, aromatic solvents,
Nitrile-based solvents, amide-based solvents, ketone-based solvents, sulfoxide-based solvents and the like can be used alone or in combination of two or more. Among them, nitrile solvents such as acetonitrile are preferred. Reaction temperature is from room temperature to 1
00 ° C., preferably room temperature. The reaction time is 0.1 to 2
4 hours. The obtained crude product is subjected to a decarboxylation reaction in the next step to obtain a compound (XVIII). The decarboxylation reaction is performed according to a method known per se. Usually the crude product and excess, preferably 1 to 10 equivalents of mineral acid (eg hydrochloric acid, sulfuric acid,
Phosphoric acid) in an inert solvent. As the inert solvent, water and an organic acid (eg, acetic acid and the like) can be mixed and used. Among them, it is preferable to carry out this reaction in diluted hydrochloric acid alone or in a mixed solvent of acetic acid and diluted hydrochloric acid.
The reaction temperature is from room temperature to 120 ° C, preferably from 60 to 120 ° C.
It is. The reaction time is 0.5 to 24 hours.

(Step 20) The obtained compound (XVIII) is subjected to a method known per se, for example, the method described in Scheme 6 below to obtain compound (VI ″). For example, the compound (V
In I ″), the compound (VI ″ ′) in which X is alkylene can be produced by the method of Scheme 6 below. (Step 21) Compound (II ″ ′) is obtained from compound (VI ″) according to the same method as in Step 6 described above.

[0071]

Embedded image In the above formula, k is an integer of 0 to 14, and other symbols have the same meanings as described above. (Step 22) Compound (XVIII) is added to Witti
g) The compound (XIX) is obtained by subjecting it to a reaction. In the present reaction, k is preferably an integer of 0 to 10. Y ′ is preferably acyl, more preferably carboxy or C _1-6.
Alkoxy-carbonyl. The Wittig reaction is
The reaction is carried out by reacting compound (XVIII) with a Wittig reagent in an inert solvent in the presence of a base. The Wittig reagent may be purchased commercially or may be obtained by a method known per se, for example, Journal of Medicinal Chemistry, vol. 28, p. 287 (1
985) It can be manufactured according to the method described. The amount of the Wittig reagent to be used is 1 equivalent or more, preferably 1-2 equivalents, relative to compound (XVIII). Examples of the base include the strong bases, inorganic bases, and organic bases described above. Among them, preferred are strong bases. More preferred are sodium hydride, lithium diisopropylamide, lithium dicyclohexylamide, sodium methoxide, sodium ethoxide, potassium t-butoxide and the like. The amount of the base used is 1 equivalent or more based on the Wittig reagent. For example, when the Wittig reagent has no carboxy or hydroxy, the amount of the base used is preferably 1 to 2 equivalents to the Wittig reagent. When the Wittig reagent has carboxy or hydroxy, the amount of the base used is preferably 2 to 4 equivalents to the Wittig reagent. As the inert solvent, for example, water, 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 alone or a mixture thereof. Two or more kinds can be used as a mixture. Among them, ethanol, toluene, DMF and the like are preferable. The reaction temperature is room temperature to 100 ° C, preferably room temperature to 50 ° C. The reaction time is 0.5 to 24 hours.

(Step 23) Compound (VI ''') is obtained by subjecting compound (XIX) to a catalytic reduction reaction. In the catalytic reduction reaction, compound (XIX) and a catalytic amount of a metal catalyst (eg, Raney nickel, platinum oxide, metallic palladium, palladium-
Carbon and the like in an inert solvent under a hydrogen pressure of 1 to 100 atm. As the inert solvent,
For example, water, alcohol solvents, ether solvents, ester solvents, halogenated hydrocarbon solvents, aromatic solvents,
Nitrile solvents, amide solvents and the like can be used alone or as a mixture of two or more thereof. Among them,
Methanol, ethanol, ethyl acetate and the like are preferred. The reaction temperature is from room temperature to 100 ° C. The reaction time is between 1 and 48 hours.

In the compound (I), when the condensed ring consisting of the ring A and quinone and Y are each indane-4,7-dione, for example, the compound (II ″ ″) according to the following scheme 7
You can also get Compound (II '''') is compound (II)
include.

Embedded image In the above formula, each symbol has the same meaning as described above.

(Step 24) Compound (XX) and formula: L ³
-X-L ⁴ (wherein L ³ and L ⁴ are each a leaving group, X
Is as defined above) in an inert solvent in the presence of a base to give compound (XXI). L ³
Alternatively, the “leaving group” represented by L ^{4 includes the same} as the “leaving group” represented by L. L ³ and L ⁴ are each halogen (eg, chloro, bromo, iodo, etc.), C _1-4 alkylsulfonyloxy optionally substituted with 1 to 3 halogens (eg, methanesulfonyloxy, trifluoromethanesulfonyl) Oxy), C _6-10 arylsulfonyloxy optionally substituted with 1 to 4 C _1-6 alkyl or halogen (eg, p-toluenesulfonyloxy, benzenesulfonyloxy, p-bromobenzenesulfonyloxy, etc.) Are preferred. Compound (XX) can be easily obtained as a commercial product. The amount of compound (XX) to be used is represented by the formula: L ³ -X-
Relative to the compound represented by L ^4, 2 to 4 equivalents, preferably 2 to 2.5 equivalents. Examples of the base include the aforementioned strong bases and organometallic reagents. Among them, lithium diisopropylamide, lithium dicyclohexylamide, butyl lithium, sec-butyl lithium, t-butyl lithium and the like are preferable. The amount of the base used is the compound (X
X) is at least 2 equivalents, preferably 2 to 3 equivalents. As the inert solvent, for example, an ether solvent, a halogenated hydrocarbon solvent, an aromatic solvent, an amide solvent, a sulfoxide solvent, or the like can be used alone or as a mixture of two or more thereof. Among them, THF alone or a mixed solvent of THF and DMF, DMSO or the like is preferable. The reaction temperature is -70 ° C to room temperature, preferably -20 to 3
0 ° C. The reaction time is 0.5 to 24 hours.

(Step 25) Compound (XXI) is subjected to intramolecular Friedel-Crafts reaction to give compound (XXII)
Get. As the intramolecular Friedel-Crafts reaction,
For example, ORGANIC FUNCTIONAL GROUP PREPARA
TIONS) 2nd edition, Academic Press (ACADEMICPRES)
S, INC.). Above all, a reaction using polyphosphoric acid is preferable. In this case, the amount of polyphosphoric acid used may be an excess amount, and is preferably 5 to 50 equivalents. The reaction temperature is from room temperature to 100 ° C., preferably 50
１００100 ° C. The reaction time is 0.5 to 24 hours. (Step 26) Compound (XXIII) is obtained by subjecting compound (XXII) to a reduction reaction. The reduction reaction may be performed in one step using a catalytic reduction reaction, or may be performed under the same reaction conditions as in the combination of Step 3 and Step 4 described above. In the catalytic reduction method, compound (XXII) and a catalytic amount of a metal catalyst (eg, Raney nickel, platinum oxide, metallic palladium, palladium-
Carbon and the like in an inert solvent (eg, an organic acid such as acetic acid, an alcohol-based solvent, etc.) under a hydrogen pressure of 1 to 100 atm. The reaction temperature is from room temperature to 100 ° C. Reaction time is 1 to
48 hours. If necessary, add the amount of catalyst or 1
An equivalent amount of a mineral acid (eg, perchloric acid, hydrochloric acid, etc.) may be added. (Step 27) After subjecting compound (XXIII) to a bromination reaction in the same manner as in the above step 7, bromo is substituted with methoxy to obtain compound (II ″ ″). Examples of the reaction for substituting bromo with methoxy include, for example, Tetrahedron Letters (Tetrahed
ron Letters), vol. 34, p. 1007 (1993). (Step 28) Compound (II ″ ″) is subjected to the same reaction as in Step 1 above to obtain compound (XXIV). Compound (XXIV) is included in compound (I).

Examples of the “alcohol-based solvent” include, for example, methanol, ethanol, isopropanol, tert.
-Butanol and the like. The above-mentioned “ether solvent”
Examples thereof include ethyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and the like. Examples of the “halogenated hydrocarbon solvent” include, for example, dichloromethane, chloroform, 1,
2-dichloroethane, carbon tetrachloride and the like. Examples of the “aromatic solvent” include benzene, toluene, xylene, pyridine and the like. Examples of the “hydrocarbon solvent” include hexane, pentane, cyclohexane and the like. The “amide solvent”
Are, for example, N, N'-dimethylformamide (D
MF), N, N'-dimethylacetamide 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 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, ethylcarbonyl, t-butylcarbonyl, etc.),
C _1-6 alkyloxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), benzoyl, C _7-10 aralkyl-carbonyl (eg, benzyl carbonyl, etc.), C _7-10 aralkyloxy-carbonyl (eg, benzylcarbonyl) For example, benzyloxycarbonyl, 9
-Fluorenylmethoxycarbonyl, etc.), trityl,
Phthaloyl, N, N-dimethylaminomethylene, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, dimethyl-t-butylsilyl, diethyl-
t-butylsilyl and the like, C _2-6 alkenyl (eg, 1-allyl and the like) and the like. These groups may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) or nitro. Examples of the carboxy protecting group include C _1-6 alkyl (eg,
Methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, etc., phenyl, trityl, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, dimethyl-t-butylsilyl, diethyl-)
t-butylsilyl and the like, C _2-6 alkenyl (eg, 1-allyl and the like) and the like. These groups may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) or nitro.

Examples of the hydroxy-protecting group include phenyl, 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, etc.), tetrahydropyranyl, tetrahydrofuranyl, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, dimethyl-t-butylsilyl, diethyl-t-butylsilyl, etc.), C _2-6 alkenyl ( For example, 1-allyl and the like). These groups have one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C
_It may be substituted with _1-6 alkyl (eg, methyl, ethyl, n-propyl and the like) or nitro and the like. As the carbonyl protecting group, for example, a cyclic acetal (eg,
1,3-dioxolane, etc.), 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.
ynthesis), published by John Wiley and Sons (1980). For example, acids, bases, ultraviolet light,
A method using hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, reduction, and the like are 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 each compound is obtained 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 A salt is formed with a racemic compound and an optically active compound (for example, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−) tartaric acid, etc.), and this is formed. A method of separating by a fractional recrystallization method and obtaining a free optical isomer through a neutralization step, if desired. 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 buffers (eg, phosphate buffer), organic The optical isomers are separated by developing a solvent (eg, ethanol, methanol, acetonitrile) alone or as a mixed solution. Also, for example, in the case of gas chromatography,
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 and an optically active amine or alcohol reagent are subjected to a condensation reaction 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.

Since compound (I) has an excellent mitochondrial function activating action, antioxidant action, etc., symptoms caused by reduced mitochondrial function or abnormal mitochondrial electron transfer, such as muscle weakness, retinitis pigmentosa, visual impairment, ataxia, It can suppress convulsions, movement disorders, cerebral infarction-like episodes, hearing loss, peripheral nerve disorders and the like. Also,
The toxicity of compound (I) is low. Thus, compound (I)
It is useful as a preventive / therapeutic agent for diseases caused by reduced mitochondrial function and / or abnormal mitochondrial electron transfer in mammals such as humans at low doses. Examples of the disease include neurodegenerative diseases (eg, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, etc.) and other central nervous system diseases (eg, cerebrovascular dementia,
Schizophrenia, depression, etc., mitochondrial diseases (eg, chronic progressive external ophthalmoplegia syndrome, Cairns-Sayer (Kear
ns-Sayre syndrome, MERRF (myoclonus epilepsy with r
agged-red fibers), MELAS (mitochondrial myopathy,
encephalopathy lactic acidosis and stroke-like epi
sodes), Leigh encephalopathy, Alpers (Al
pers) disease, Leber disease, Pearson
on) disease), cardiovascular diseases (eg, cardiomyopathy such as dilated cardiomyopathy, arteriosclerosis, myocardial infarction, peripheral arterial occlusion, angina pectoris, congestive heart failure, hypertension, cardiogenic shock, acute・
Chronic renal failure), non-insulin-dependent diabetes mellitus, visual impairment, presbycusis, liver damage, cancer and the like.
[Reference: Proceeding of National Academy of Sciences
Academy of Sciences) USA, 91, 8731-8738 (199
4) etc.] Compound (I) has an excellent nerve growth factor secretion promoting action, β
Since it also has an amyloid-induced nerve cell death inhibitory effect, it is also useful as a preventive and therapeutic agent for central nervous diseases of mammals such as humans (eg, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, etc.). Among them, preferably,
Agents for preventing and / or treating neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease, and more preferably agents for preventing and / or treating Alzheimer's disease. Compound (I) may be used in combination with an anti-dementia drug.

The compound (I) can be formulated according to a method known per se, and a pharmaceutical composition can be prepared by mixing an appropriate amount of the compound (I) as it is or a pharmacologically acceptable carrier in the formulation step. Products, such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules, (including soft capsules), liquids,
They can be safely administered orally or parenterally (eg, topically, rectally, intravenously, etc.) as injections, suppositories, sustained release agents and the like. In the pharmaceutical composition of the present invention, the content of compound (I) is 0.1 to 100% by weight based on the whole preparation. The dosage varies depending on the administration target, administration route, disease, etc.
For example, as a therapeutic drug for Alzheimer's disease, adults (about 60k
In contrast to g), as an oral preparation, the dose is about 0.1 to 2000 mg, preferably about 15 to 300 mg as an active ingredient (compound (I)) at a time. Can be.

Examples of the pharmacologically acceptable carrier used in the production of the pharmaceutical composition of the present invention include various organic or inorganic carrier materials commonly used as pharmaceutical materials. Agents, binders, disintegrants; solvents in liquid formulations, solubilizers, suspending agents, tonicity agents,
Buffers, soothing agents and the like can be mentioned. If necessary, additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used. Excipients include, for example, lactose, sucrose, D-mannitol, starch,
Corn starch, crystalline cellulose, light silicic anhydride and the like can be mentioned. 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. As the solvent, for example, water for injection, alcohol,
Propylene glycol, macrogol, sesame oil, corn oil and the like. As the solubilizer, for example, polyethylene glycol, propylene glycol, D
-Mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate;
Examples include hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, 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. Examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite, ascorbic acid, and the like.

[0085]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention further includes the following reference examples,
Examples, formulation examples, experimental examples will be described in detail,
These examples are merely illustrative and do not limit the invention, and may be varied without departing from the scope of the invention. The following reference examples, "room temperature" in the examples,
The temperature was 0 to 30 ° C, and anhydrous magnesium sulfate or anhydrous sodium sulfate was used for drying the organic solvent. "%"
Means weight percent unless otherwise specified. 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: dimethyl sulfoxide CAN: cerium (IV) ammonium nitrate NBS: N-bromosuccinimide AIBN: 2,2′-azobis (isobutyro) Nitrile) LDA: lithium diisopropylamide ¹ H-NMR: proton nuclear magnetic resonance (usually measured in free form in CDCl ₃ )

[0086]

【Example】

Reference Example 1 1,2,3,4-tetramethoxy-5-methylbenzene 2,3-dimethoxy-5-methyl-1,4-benzoquinone (50 g, 0.274 mol) in diethyl ether (330
ml) solution, sodium dithionite (95.4 g, 0.
(548 mol) in water (330 ml) and shaken for 15 minutes. The ether layer was washed with saturated saline, dried, and concentrated under reduced pressure. The obtained crystals were washed with hexane and washed with 2,3-dimethoxy-5-methyl-1,4-hydroquinone (46.
1 g). 2,3-dimethoxy-5-methyl-1,4
Dimethylsulfuric acid (126 g, 1.00 mol) was added to hydroquinone (46.1 g, 0.250 mol) followed by ethanol. A methanol solution of sodium methoxide (28%, 241 g, 1.25 mol) was added dropwise to the mixture, and the mixture was concentrated under reduced pressure. After adding water, extract with ethyl acetate,
The organic layer was washed with water and saturated saline, dried, and concentrated under reduced pressure. The residue was purified by alumina column chromatography (hexane: ethyl acetate = 25: 1) to obtain the title compound (51.6 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 3.78 (3H, s),
3.82 (3H, s), 3.87 (3H, s), 3.93 (3H, s), 6.45 (1H, s) Reference Example 2 1-bromo-2,3,4,5-tetramethoxy-6-methylbenzene 1 Bromine (46.7 g, 0.292 mol) was added dropwise to a solution of 2,2,3,4-tetramethoxy-5-methylbenzene (51.6 g, 0.243 mol) in acetic acid (100 ml) at room temperature.
After stirring the reaction solution for 15 minutes, it was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water, and saturated saline, dried, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give the title compound (59.
1 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 2.30 (3H, s), 3.79 (3H, s),
3.85 (3H, s), 3.91 (6H, s)

Reference Example 3 1-bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene 1-bromo-2,3,4,5-tetramethoxy-6-methylbenzene (49.5 g, 0 .170 mol), N-bromosuccinimide (31.8 g, 0.179 mol) and A
IBN (558 mg, 3.40 mmol) in ethyl acetate (30
0 ml) solution was heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure and then diluted with hexane. The resulting crystals were separated by filtration, and the filtrate was concentrated to give the title compound (62.6 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 3.86 (3H, s), 3.91 (3H, s),
3.95 (3H, s), 3.98 (3H, s), 4.71 (2H, s) Reference Example 4 Ethyl 8-bromooctanoate To a solution of 8-bromooctanoic acid (50.0 g, 0.224 mol) in ethanol (500 ml) Thionyl chloride (8.15m
l, 0.112 mol) was added dropwise under ice-cooling, and the reaction solution was added at room temperature for 1 hour.
Stir for 2 hours. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution 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 under reduced pressure. The obtained crude product is subjected to alumina column chromatography (hexane).
And the title compound (51.6 g) was obtained. Oil ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.96 (10H, m), 1.26
(3H, t, J = 7.1Hz), 2.29 (2H, t, J = 7.3Hz), 3.41 (2H, t, J = 6.
8Hz), 4.13 (2H, q, J = 7.1Hz)

Reference Example 5 Ethyl 2,9-diethoxycarbonylnonanoate sodium ethoxide (4.61 g, 67.7 mmol) was added to a solution of ethanol (170 ml) in diethyl malonate (9.
85 g, 61.5 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 15 minutes.
7 mmol) was added. After the reaction solution was refluxed for 2 hours, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain the title compound (13.7 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.2-2.0 (21H, m), 2.28 (2
H, t, J = 7.4Hz), 3.31 (1H, t, J = 7.6Hz), 4.05-4.30 (6H, m) Reference Example 6 10- (6-bromo-2,3,4,5-tetramethoxy) Ethyl phenyl) -9,9-diethoxycarbonyldecanoate Sodium hydride (60% oily, 1.29 g, 32.2 mm
ol) in THF (90 ml) was added dropwise a solution of ethyl 2,9-diethoxycarbonylnonanoate (8.86 g, 26.8 mmol) in THF (10 ml) at room temperature. After stirring the reaction solution for 2 hours, 1-bromo-6-bromomethyl-2,3,4,
5-tetramethoxybenzene (10.9 g, 29.5 mmol
A solution of l) in THF (10 ml) was added dropwise at room temperature and the mixture was further stirred for 2 hours. After adding a saturated aqueous solution of ammonium chloride to the reaction solution, the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, dried, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 4: 1) to obtain the title compound (10.9 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.1-1.8 (21H, m), 2.27 (2
H, t, J = 7.5Hz), 3.51 (2H, s), 3.71 (3H, s), 3.82 (3H, s),
3.88 (3H, s), 3.93 (3H, s), 4.04-4.30 (6H, m)

Reference Example 7 Ethyl 8- (2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl) octanoate 10- (6-Bromo-2,3,4,5-tetramethoxy) A hexane solution of n-butyllithium (1.68 M, 1
3.1 ml, 22.0 mmol) were added dropwise at -70 ° C or lower under a nitrogen stream. After stirring the reaction solution for 15 minutes, acetic acid (1.71 g,
A solution of 28.5 mmol) in THF (10 ml) was added dropwise below -70 ° C. After the temperature of the reaction solution was raised to room temperature, it was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate 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 evaporated under reduced pressure. To a solution of the crude product in ethanol (80 ml) was added sodium borohydride (923 mg, 24.4 mmol) under ice-cooling. The reaction solution was stirred for 6 hours after warming to room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried. The crude product obtained by evaporating the solvent under reduced pressure was separated by silica gel column chromatography (hexane: ethyl acetate = 10: 1-5: 1).
8- (2-ethoxycarbonyl-1-hydroxy-4,
Ethyl 5,6,7-tetramethoxyindan-2-yl) octanoate (3.77 g) was obtained. Ethyl 8- (2-ethoxycarbonyl-1-hydroxy-4,5,6,7-tetramethoxyindan-2-yl) octanoate (3.7
7g, 7.59mmol) at room temperature with trifluoroacetic acid (40m
l) and triethylsilane (4.85 ml, 30.4 m)
mol) was added and stirred for 15 minutes. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 to 10: 1) to obtain the title compound (1.31 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.80 (18H, m), 2.27
(2H, t, J = 7.5Hz), 2.85 (2H, d, J = 16.2Hz), 3.41 (2H, d, J = 1
6.2Hz), 3.83 (6H, s), 3.89 (6H, s), 4.12 (2H, q, J = 7.3H
z), 4.16 (2H, q, J = 7.3Hz)

Reference Example 8 8- (2-carboxy-4,5,6,7-tetramethoxyindan-2-yl) octanoic acid 8- (2-ethoxycarbonyl-4,5,6,7-tetramethoxyindane -2-yl) ethyl octoate (20
0mg, 0.416mmol) in ethanol (4ml) and aqueous sodium hydroxide solution (3M, 0.553ml, 1.66mm)
ol) was heated to reflux for 12 hours. After the reaction solution was concentrated under reduced pressure, the solution was made acidic by adding 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2-ethyl acetate) to obtain the title compound (88.6 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.84 (12H, m), 2.34
(2H, t, J = 7.0Hz), 2.86 (2H, d, J = 16.3Hz), 3.45 (2H, d, J = 1
6.3 Hz), 3.82 (6H, s), 3.88 (6H, s) Reference Example 9 8- (2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl) octanoic acid 8- (2 Ethyl ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl) octanoate (36
7 mg, 0.764 mmol) in ethanol (8 ml) and an aqueous sodium hydroxide solution (1N, 0.764 ml, 0.764).
After stirring for 6 hours at room temperature, an aqueous sodium hydroxide solution (1N, 0.153 ml, 0.153 mmol) was added, and the mixture was stirred at room temperature for 6 hours. After concentrating the reaction solution under reduced pressure, 1N
The solution was made acidic by adding hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 2) to obtain the title compound (78.6 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.16-1.80 (12H, m), 1.26
(3H, t, J = 7.0Hz), 2.33 (2H, t, J = 7.5Hz), 2.85 (2H, d, J = 1
6.1Hz), 3.41 (2H, d, J = 16.1Hz), 3.83 (6H, s), 3.89 (6H,
s), 4.16 (2H, q, J = 7.0Hz)

Reference Example 10 N- [8- (2-ethoxycarbonyl-4,5,6,7-
Tetramethoxyindan-2-yl) octanoyl] morpholine 8- (2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl) octanoic acid (114 mg,
0.252 mmol), morpholine (0.110 ml, 1.26 m)
mol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (96.6 mg, 0.504 mmol)
And 1-hydroxybenzotriazole monohydrate (7
A suspension of 7.2 mg (0.504 mmol) in THF (4.0 ml) was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 1: 1) to obtain the title compound (123 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.16-1.80 (12H, m), 1.26
(3H, t, J = 7.0Hz), 2.29 (2H, t, J = 7.5Hz), 2.84 (2H, d, J = 1
6.2Hz), 3.41 (2H, d, J = 16.2Hz), 3.40-3.52 (2H, m), 3.54-
3.74 (6H, m), 3.83 (6H, s), 3.89 (6H, s), 4.16 (2H, q, J = 7.
0 Hz) Reference Example 11 8- (2-carbamoyl-4,5,6,7-tetramethoxyindan-2-yl) octanamide 8- (2-carboxy-4,5,6,7-tetramethoxyindan-2 -Yl) octanoic acid (105 mg, 0.24
Oxalyl chloride (0.086 ml, 0.988 mmol) in a THF (5.0 ml) solution of DMF (7 mmol) and a catalytic amount of DMF at room temperature.
l) was added. After stirring the reaction solution for 30 minutes, it was concentrated under reduced pressure.
The residue was dissolved in THF (5.0 ml). 2 THF solutions
It was added dropwise to 8% aqueous ammonia (5.0 ml) under ice cooling. After stirring the reaction solution for 5 minutes, water was added, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated saline, dried, and concentrated under reduced pressure to obtain the title compound (103 mg). Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.76 (12H, m), 2.21
(2H, t, J = 7.5Hz), 2.89 (2H, d, J = 15.8Hz), 3.34 (2H, d, J = 1
5.8Hz), 3.83 (6H, s), 3.89 (6H, s), 5.3-5.7 (4H, m)

Reference Example 12 Ethyl 2- (8-hydroxyoctyl) -4,5,6,7-tetramethoxy-2-indanecarboxylate 8- (2-ethoxycarbonyl-4,5,6,7-tetramethoxy) Indan-2-yl) octanoic acid (847 mg,
To a solution of 1.87 mmol) in THF (9.0 ml) was added a solution of a borane complex in THF (1 M, 3.74 ml, 3.74 mmol) under ice-cooling. The reaction was warmed to room temperature and stirred for 2 hours. After adding 1N hydrochloric acid to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (713 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.16-1.80 (14H, m), 1.26
(3H, t, J = 7.0Hz), 2.85 (2H, d, J = 16.1Hz), 3.41 (2H, d, J = 1
6.1Hz), 3.63 (2H, t, J = 6.6Hz), 3.83 (6H, s), 3.89 (6H,
s), 4.16 (2H, q, J = 7.0 Hz) Reference Example 13 8- (2-hydroxymethyl-4,5,6,7-tetramethoxyindan-2-yl) octanol 8- (2-ethoxycarbonyl-) Ethyl 4,5,6,7-tetramethoxyindan-2-yl) octanoate (31
5 mg, 0.634 mmol) of diethyl ether (6.0 ml)
Lithium aluminum hydride (72.1m
g, 1.90 mmol). The reaction solution was stirred for 1 hour after warming to room temperature. 1N hydrochloric acid was added to the reaction solution under ice cooling,
Extracted with ethyl acetate. The organic layer was washed with saturated saline and dried. The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1 to 1: 1) to give the title compound (239m
g) was obtained. Oil ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.70 (14H, m), 2.67
(2H, d, J = 16.1Hz), 2.83 (2H, d, J = 16.1Hz), 3.51 (2H, br.
s), 3.64 (2H, t, J = 6.6Hz), 3.82 (6H, s), 3.89 (6H, s)

Reference Example 14 2- (8-hydroxyoctyl) -4,5,6,7-tetramethoxy-2-indanecarboxylic acid 2- (8-hydroxyoctyl) -4,5,6,7-tetramethoxy Ethyl-2-indanecarboxylate (708m
g, 1.61 mmol) in ethanol (10 ml) was added aqueous sodium hydroxide (3N, 1.07 ml, 3.22 mmol). The reaction solution was heated under reflux for 6 hours, concentrated under reduced pressure, made acidic by adding 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 2) to give the title compound ( 335 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.12-1.84 (14H, m), 2.87
(2H, d, J = 16.5Hz), 3.46 (2H, d, J = 16.5Hz), 3.64 (2H, t, J =
6.6Hz), 3.83 (6H, s), 3.89 (6H, s) Reference Example 15 N-methyl-2- (8-hydroxyoctyl) -4,5,
6,7-tetramethoxy-2-indanecarboxamide methylammonium chloride (247 mg, 3.66 mmol),
1-ethyl-3- (3-dimethylaminopropyl) hydrochloride
Carbodiimide (420 mg, 2.19 mmol), 1-hydroxybenzotriazole monohydrate (335 mg, 2.1
9 mmol) and triethylamine (1.02 ml, 7.31)
mmol) in THF (3.0 ml) was added to a suspension of 2- (8-hydroxyoctyl) -4,5,6,7-tetramethoxy-2-.
T of indanecarboxylic acid (300 mg, 0.731 mmol)
An HF (3.0 ml) solution was added at room temperature. After stirring for 12 hours, the reaction solution was concentrated under reduced pressure. Water was added to the residue, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by alumina column chromatography (ethyl acetate) to obtain the title compound (277 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.16-1.76 (14H, m), 2.83
(3H, d, J = 4.8Hz), 2.88 (2H, d, J = 15.8Hz), 3.30 (2H, d, J = 1
5.8Hz), 3.62 (2H, t, J = 6.6Hz), 3.82 (6H, s), 3.89 (6H,
s), 5.50-5.66 (1H, m)

Reference Example 16 Ethyl 8- (4,5,6,7-tetramethoxyinden-2-yl) octanoate 10- (6-Bromo-2,3,4,5-tetramethoxyphenyl) -9, To a solution of ethyl 9-diethoxycarbonyldecanoate (3.53 g, 5.70 mmol) in THF (40 ml) was added a solution of n-butyllithium in hexane (1.68 M, 6.60 M).
13 ml, 10.3 mmol) was added dropwise at -70 ° C or lower under a nitrogen stream. After stirring for 15 minutes, acetic acid (1.71 g,
28.5 mmol) in THF (10 ml) was added dropwise at -70 ° C or lower, and the temperature was raised to room temperature. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried. The solvent was distilled off under reduced pressure, and the obtained crude product was dissolved in a mixture of acetic acid (30 ml) and 10% HCl (10 ml), and the mixture was stirred at 80 ° C. for 36 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1).
A crude product of-(4,5,6,7-tetramethoxy-1-oxoindan-2-yl) octanoic acid (1.30 g) was obtained. Crude product of 8- (4,5,6,7-tetramethoxy-1-oxoindan-2-yl) octanoic acid (1.3
0 g, ca. Thionyl chloride (0.723 ml, 9.90 mmol) was added to a solution of 3.30 mmol) in ethanol (30 ml) under ice-cooling, and the mixture was warmed to room temperature and stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, and then dried. The solvent was distilled off under reduced pressure to obtain a crude product of ethyl 8- (4,5,6,7-tetramethoxy-1-oxoindan-2-yl) octanoate (1.31 g). A solution of a crude product of ethyl 8- (4,5,6,7-tetramethoxy-1-oxoindan-2-yl) octanoate (1.31 g, ca. 3.10 mmol) in a solution of ethanol (13 ml) under ice cooling. After adding sodium borohydride (235 mg, 6.20 mmol), the mixture was heated to room temperature and stirred for 6 hours. After the reaction solution was concentrated under reduced pressure, water was added thereto, and 10% hydrochloric acid was added to make the solution neutral, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline and dried. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 2:
8- (1-hydroxy-4,5,
A crude product of ethyl 6,7-tetramethoxyindan-2-yl) octanoate (575 mg) was obtained. 8- (1-hydroxy-4,5,6,7-tetramethoxyindane-2
-Yl) ethyl octoate crude product (575 mg, ca.
1.35 mmol) was added with trifluoroacetic acid (6.0 ml) at room temperature, and then triethylsilane (0.862 ml, 5.40 mmol) was added.
l) was added and stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-8: 1) to obtain the title compound (410 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.76 (10H, m), 1.26
(3H, t, J = 7.0Hz), 2.30 (2H, t, J = 7.6Hz), 2.44 (2H, t, J = 7.
5Hz), 3.31 (2H, s), 3.90 (6H, s), 3.96 (6H, s), 4.13 (2H, s
q, J = 7.0Hz), 6.55 (1H, s)

Reference Example 17 Ethyl 8- (4,5,6,7-tetramethoxyindan-2-yl) octanoate Ethyl 8- (4,5,6,7-tetramethoxyinden-2-yl) octanoate (310 mg, 0.763 mmol) and 10% palladium on carbon (60 mg) in ethanol (6.0 m
l) The suspension was stirred at room temperature under a stream of hydrogen for 4 hours. The palladium carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (310 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.74 (12H, m), 1.26
(3H, t, J = 7.0Hz), 2.30 (2H, t, J = 7.5Hz), 2.30-2.56 (3H, t, J = 7.5Hz)
m), 2.98-3.14 (2H, m), 3.83 (6H, s), 3.89 (6H, s), 4.13
(2H, q, J = 7.0Hz) Reference Example 18 8- (4,5,6,7-tetramethoxyindan-2-yl) octanol 8- (4,5,6,7-tetramethoxyindan-2- To a solution of ethyl yl) octanoate (150 mg, 367 mmol) in diethyl ether (3.0 ml) was added lithium aluminum hydride (41.8 mg, 1.10 mmol) under ice-cooling. The reaction was warmed to room temperature and stirred for 1 hour. The reaction mixture was added with 1N hydrochloric acid under ice-cooling, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline and dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-4: 1) to obtain the title compound (138 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.70 (14H, m), 2.32-
2.58 (3H, m), 2.96-3.16 (2H, m), 3.65 (2H, t, J = 6.6Hz),
3.83 (6H, s), 3.89 (6H, s)

Reference Example 19 Ethyl 4-benzyloxyphenylacetate 4-Hydroxyphenylacetic acid (10.0 g, 55.5 mmol)
l), DMF of benzyl bromide (7.93 ml, 66.6 mmol) and potassium carbonate (23.1 g, 167 mmol)
(100 ml) The suspension was stirred at room temperature for 6 hours. Water was added to the reaction solution, followed by extraction with diethyl ether. The organic layer was washed with water and saturated saline and then dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-hexane: ethyl acetate = 10: 1) to obtain the title compound (14.6 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t,
J = 7.2 Hz), 3.55 (2H, s), 4.1
4 (2H, q, J = 7.2 Hz), 5.05 (2H,
s), 6.93 (2H, d, J = 8.6 Hz),
7.20 (2H, d, J = 8.6 Hz), 7.26-
7.50 (5H, m) Reference Example 20 ethyl 2- (4-benzyloxyphenyl) -2-ethoxycarbonylacetate ethyl 4-benzyloxyphenylacetate (13.1 g,
48.5 mmol) and ethyl chlorocarbonate (9.25 ml, 9
A solution of LDA in heptane (2.0 M, 36.4 ml, 72.8 mmol) was added dropwise to a solution of 7.0 mmol) in THF (130 ml) under a nitrogen stream at -70 ° C or lower. After stirring the reaction solution for 15 minutes, a saturated aqueous ammonium chloride solution was added, the temperature was raised to room temperature, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline and dried, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with hexane to obtain the title compound (13.8 g). Further, it was recrystallized from hexane. Crystal: mp 65-66 ° C

Reference Example 21 Ethyl 2- (4-benzyloxyphenyl) -3- (6-bromo-2,3,4,5-tetramethoxyphenyl) -2-ethoxycarbonylpropionate 2- (4-benzyloxy) Phenyl) -2-ethoxycarbonylacetate ethyl (12.0 g, 35.1 mmol), 1-
Bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene (16.9 g, 45.6 mmol) and potassium carbonate (14.5 g, 105 mmol) in DMF (120 m
l) After the suspension was stirred at room temperature for 6 hours, 1-bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene (2.60 g, 7.02 mmol) was added, and the mixture was stirred at room temperature for 6 hours. . Water was added to the reaction solution, followed by extraction with diethyl ether. The organic layer was washed with water and saturated saline and then dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by recrystallization (hexane-ethyl acetate) to obtain the title compound (11.0 g). Crystal: mp 93-94 ° C Reference Example 22 2- (4-benzyloxyphenyl) -4,5,6,7-
Ethyl tetramethoxy-1-oxo-2-indanecarboxylate Ethyl 2- (4-benzyloxyphenyl) -3- (6-bromo-2,3,4,5-tetramethoxyphenyl) -2-ethoxycarbonylpropionate (10.0g, 15.8m
mol) in THF (100 ml) and a hexane solution of n-butyllithium (1.68 M, 11.3 ml, 19.0 mmol).
l) was added dropwise at -90 ° C or lower under a nitrogen stream. Reaction solution is 3
After stirring for 0 min, acetic acid (1.86 g, 31.6 mmol) in TH
An F (10 ml) solution was added dropwise at -90 ° C or lower, and the temperature was raised to room temperature. The reaction solution was diluted with diethyl ether, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, and then dried. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (hexane to: ethyl acetate = 10: 1 to 5:
Purification according to 1) gave the title compound (3.78 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.1 Hz), 3.4
4 (1H, d, J = 17.4Hz), 3.89 (3H, s), 3.90 (3H, s), 4.00 (3H,
s), 4.03 (3H, s), 3.85-4.28 (1H, m), 4.20 (2H, q, J = 7.1H
z), 5.04 (2H, s), 6.94 (2H, d, J = 9.0Hz), 7.26-7.50 (7H,
m)

Reference Example 23 2- (4-benzyloxyphenyl) -4,5,6,7-
Ethyl tetramethoxy-2-indanecarboxylate 2- (4-benzyloxyphenyl) -4,5,6,7-
Ethyl tetramethoxy-1-oxo-2-indanecarboxylate (3.78 g, 7.46 mmol) was added to ethanol (40
mmol) and sodium borohydride (564) under ice-cooling.
mg, 14.9 mmol). The reaction solution was heated to room temperature and stirred for further 6 hours. 10% after adding water to the reaction solution
The solution was made neutral by adding hydrochloric acid, and extracted with ethyl acetate.
The organic layer was washed with water and saturated saline and dried. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 2: 1) to give 2- (4-benzyloxyphenyl) -1.
Ethyl-hydroxy-4,5,6,7-tetramethoxy-2-indanecarboxylate (3.02 g) was obtained. 2-
(4-benzyloxyphenyl) -1-hydroxy-
Trifluoroacetic acid (30 ml) was added to ethyl 4,5,6,7-tetramethoxy-2-indanecarboxylate (3.02 g, 5.94 mmol) under ice-cooling, and then triethylsilane (3.80 ml, 23.8 mmol) was added. 30
After stirring for minutes, the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, and then dried. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-8: 1) to give the title compound (1.
73g) was obtained. Oil ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.2Hz), 3.1
9 (2H, d, J = 15.6Hz), 3.86 (6H, s), 3.90 (6H, s), 3.98 (2H,
d, J = 15.6Hz), 4.05 (2H, q, J = 7.2Hz), 5.05 (2H, s), 6.94 (2
(H, d, J = 8.8Hz), 7.26-7.48 (7H, s) Reference Example 24 2- (4-benzyloxyphenyl) -4,5,6,7-
Tetramethoxy-2-indanecarboxylic acid 2- (4-benzyloxyphenyl) -4,5,6,7-
Ethyl tetramethoxy-2-indanecarboxylate (15
Sodium hydroxide solution (3N, 0.204 ml, 0.612) in a solution of 0 mg, 0.305 mmol) in ethanol (4 ml).
mmol) and heated under reflux for 6 hours. After the reaction solution was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue to make the solution acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried,
The crude product obtained by evaporating the solvent under reduced pressure was purified by recrystallization (hexane-ethyl acetate) to give the title compound (108 mg).
I got Crystal: mp 171-172 ° C

Reference Example 25 Ethyl 2- (4-hydroxyphenyl) -4,5,6,7-tetramethoxy-2-indanecarboxylate 2- (4-benzyloxyphenyl) -4,5,6,7-
Ethyl tetramethoxy-2-indanecarboxylate (10
5 mg, 0.213 mmol) and 10% palladium on carbon (32 m
A suspension of g) in ethanol (5.0 ml) was stirred at room temperature under 1 atm of hydrogen for 4 hours. The palladium carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (81.5 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.2Hz), 3.1
9 (2H, d, J = 15.6Hz), 3.86 (6H, s), 3.90 (6H, s), 3.97 (2H,
d, J = 15.6Hz), 4.05 (2H, q, J = 7.2Hz), 4.97 (1H, br.s), 6.
79 (2H, d, J = 8.7 Hz), 7.28 (2H, d, J = 8.7 Hz) Reference Example 26 2- [4- (4-ethoxycarbonyl-1-oxabutyl) phenyl] -4,5,6, 7-tetramethoxy-2-
Ethyl indanecarboxylate Ethyl 2- (4-hydroxyphenyl) -4,5,6,7-tetramethoxy-2-indanecarboxylate (81.5 m
g, 0.203 mmol) in DMF (2 ml) under ice-cooling with sodium hydride (60% oily, 9.8 mg, 0.244 mmol).
Was added. After stirring at room temperature for 30 minutes, ethyl 4-bromobutyrate (0.0600 ml, 0.406 mmol) was added dropwise to the reaction solution at room temperature, and the mixture was stirred for 3 hours. Water was added to the reaction solution, followed by extraction with diethyl ether. The organic layer was washed with water and saturated saline and then dried. The crude product obtained by evaporating the solvent was subjected to silica gel column chromatography (hexane: ethyl acetate = 1).
0: 1-5: 1) to give the title compound (85.1 m
g) was obtained. Oil ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.0Hz), 1.2
5 (3H, t, J = 7.1Hz), 2.00-2.20 (2H, m), 2.51 (2H, t, J = 7.1H
z), 3.18 (2H, d, J = 15.8Hz), 3.80-4.22 (8H, m), 3.86 (6H,
s), 3.89 (6H, s), 6.84 (2H, d, J = 8.8Hz), 7.32 (2H, d, J = 8.
8Hz)

Reference Example 27 2- [4- (4-carboxy-1-oxabutyl) phenyl] -4,5,6,7-tetramethoxy-2-indanecarboxylic acid 2- [4- (4-ethoxycarbonyl-) 1-oxabutyl) phenyl] -4,5,6,7-tetramethoxy-2-
Ethyl indanecarboxylate (342 mg, 0.662 mmol)
To a solution of l) in ethanol (4 ml) was added an aqueous sodium hydroxide solution (3N, 0.440 ml, 1.32 mmol), and the mixture was refluxed for 6 hours. The reaction solution was concentrated under reduced pressure, and water was added.
The solution was made acidic by adding 0% hydrochloric acid and extracted with ethyl acetate.
The organic layer was washed with saturated saline and dried. The crude product obtained by evaporating the solvent under reduced pressure was recrystallized (hexane-ethyl acetate).
To give the title compound (300 mg). crystal:
mp 148-150 ° C Reference Example 28 Ethyl 2- (6-bromo-2,3,4,5-tetramethoxybenzyl) -2-ethoxycarbonyl-6- (4-methoxycarbonylphenoxy) hexanoate 2-ethoxycarbonyl- Ethyl 6- (4-methoxycarbonylphenoxy) hexanoate (8.55 g, 23.3)
sodium hydride (60% oily, 1.02 g, 25.6 mmol) was added to a DMF (80 ml) solution of this compound under ice-cooling. 2,3,4,5-tetramethoxybenzene (9.
A solution of 47 g (25.6 mmol) in DMF (10 ml) was added dropwise at room temperature and stirred for 6 hours. Water was added to the reaction solution, followed by extraction with diethyl ether. The organic layer was washed with water and saturated saline, and then dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1-5: 1) to give the title compound (1
5.0 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, t, J = 7.1Hz), 1.3
5-1.90 (6H, m), 3.53 (2H, s), 3.73 (3H, s), 3.82 (3H, s),
3.88 (3H, s), 3.89 (3H, s), 3.93 (3H, s), 3.97 (2H, t, J = 6.
4Hz), 4.02-4.32 (4H, m), 6.87 (2H, d, J = 9.0Hz), 7.97 (2H
(H, d, J = 9.0Hz)

Reference Example 29 4,5,6,7-Tetramethoxy-2- [4- (4-methoxycarbonylphenoxy) butyl] -1-oxo-2
-Ethyl indanecarboxylate Ethyl 2- (6-bromo-2,3,4,5-tetramethoxybenzyl) -2-ethoxycarbonyl-6- (4-methoxycarbonylphenoxy) hexanoate (3.00
g, 4.58 mmol) in THF (30 ml) was added to a hexane solution of n-butyllithium (1.68 M, 3.27 ml,
(5.50 mmol) was added dropwise at -90 ° C or lower under a nitrogen stream.
After stirring for minutes, the mixture was heated to -78 ° C and stirred for 15 minutes. To the reaction mixture, a solution of acetic acid (1.38 g, 22.9 mmol) in THF (5 ml) was added dropwise at -70 ° C or lower, and the temperature was raised to room temperature. The extract was washed with saline and dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by recrystallization (hexane-ethyl acetate) to obtain the title compound (1.22 g). Crystal: mp 116-118 ° C Reference Example 30 Methyl 4- [4- (4,5,6,7-tetramethoxy-1-oxoindan-2-yl) butoxy] benzoate 4,5,6,7-tetramethoxy -2- [4- (4-methoxycarbonylphenoxy) butyl] -1-oxo-2
-Ethyl indanecarboxylate (3.00 g, 5.65 mmol)
l) was dissolved in a mixture of acetic acid (30 ml) and concentrated hydrochloric acid (10 ml) and stirred at 80 ° C for 12 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and saturated saline and dried.
The crude product obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1).
Separation with ethyl acetate) and 4- [4- (4,5,6,7-
A crude product of tetramethoxy-1-oxoindan-2-yl) butoxy] benzoic acid (1.65 g) was obtained. 4-
Crude product of [4- (4,5,6,7-tetramethoxy-1-oxoindan-2-yl) butoxy] benzoic acid (1.65 g, ca. 3.71 mmol), potassium carbonate (1.
14g, 11.1 mmol) and methyl iodide (0.693)
ml, 11.1 mmol) in DMF (15 ml) at room temperature.
Stir for 2 hours. Dilute the reaction with diethyl ether,
The organic layer was washed with water and saturated saline and dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by recrystallization (hexane-ethyl acetate) to obtain the title compound (1.60 g). Crystal: mp 75-77 ° C

Reference Example 31 4- [4- (4,5,6,7-tetramethoxyindane-
Methyl 2-yl) butoxy] benzoate Methanol of methyl 4- [4- (4,5,6,7-tetramethoxy-1-oxoindan-2-yl) butoxy] benzoate (1.54 g, 3.36 mmol) Sodium borohydride (254 mg, 6.7 mg) was added to the solution (15 ml) under ice cooling.
(2 mmol) was added, and the mixture was heated to room temperature and stirred for 6 hours.
After adding water to the reaction solution, hydrochloric acid was added to make the solution neutral,
The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline and then dried. The solvent was distilled off under reduced pressure to obtain methyl 4- [4- (1-hydroxy-4,5,6,7-tetramethoxyindan-2-yl) butoxy] benzoate (1.50 g).
Methyl 4- [4- (1-hydroxy-4,5,6,7-tetramethoxyindan-2-yl) butoxy] benzoate (1.50 g, 3.26 mmol), concentrated hydrochloric acid (0.0652 m2)
l, 0.652 mmol) and 10% palladium on carbon (30
(0 mg) in methanol (30 ml) was stirred at room temperature under a stream of hydrogen for 4 hours. After removing the palladium carbon by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by recrystallization (hexane) to obtain the title compound (1.25 g). Crystal: mp 68-71 ° C Reference Example 32 4- [4- (4,5,6,7-tetramethoxyindane-
2-yl) butoxy] phenylmethanol 4- [4- (4,5,6,7-tetramethoxyindane-
2-yl) butoxy] methyl benzoate (400 mg, 0.1 mg).
Lithium aluminum hydride (68.3 mg, 1.80 mm) was added to a solution of 900 mmol) in diethyl ether (10 ml) under ice cooling.
ol), and the mixture was heated to room temperature and stirred for 1 hour. Under ice cooling 1
After adding N hydrochloric acid, the mixture was extracted with ethyl acetate.
The extract was washed with saturated saline and dried. The solvent was distilled off under reduced pressure to obtain the title compound (370 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.48-1.94 (6H, m), 2.32-
2.60 (3H, m), 2.96-3.16 (2H, m), 3.83 (6H, s), 3.89 (6H, m
s), 3.98 (2H, t, J = 6.4Hz), 4.62 (2H, s), 6.89 (2H, d, J = 8.
6Hz), 7.29 (2H, d, J = 8.6Hz)

Reference Example 33 4- [4- (4,5,6,7-tetramethoxyindane-
2-yl) butoxy] benzoic acid 4- [4- (4,5,6,7-tetramethoxyindane-
2-yl) butoxy] methyl benzoate (920 mg, 2.
Aqueous solution of sodium hydroxide (3N, 1.04 ml, 3.12 mmol) was added to a methanol (10 ml) solution of
Heated to reflux for an hour. After water was added to the reaction solution, 1N hydrochloric acid was added to make the solution acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried, and the solvent was distilled off under reduced pressure to obtain a crude product. Purification by recrystallization (hexane-ethyl acetate) gave the title compound (855 mg). Crystal: mp 136-138 ° C. Reference Example 34 N, N-dimethyl-4- [4- (4,5,6,7-tetramethoxyindan-2-yl) butoxy] benzamide 4- [4- (4,5 , 6,7-Tetramethoxyindane-
2-yl) butoxy] benzoic acid (400 mg, 0.929 m
mol), dimethyl ammonium chloride (150 mg, 1.86)
mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (357 mg, 1.86 mmol)
l), 1-hydroxybenzotriazole monohydrate (2
85 mg, 1.86 mmol) and triethylamine (0.7
A suspension of 77 ml (5.57 mmol) in THF (16 ml) was stirred at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by alumina column chromatography (ethyl acetate) and then recrystallized (hexane-ethyl acetate) to obtain the title compound (408 mg). Crystal: mp 99-102 ° C. Reference Example 35 Acetic acid 8- (4,5,6,7-tetramethoxyindane-2)
-Yl) octyl 8- (4,5,6,7-tetramethoxyindan-2-yl) octanol (1.20 g) in pyridine (6.0 g)
acetic anhydride (0.555 ml) at room temperature. 1
After stirring for 2 hours, the reaction solution was concentrated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate = 10: 1) to obtain the title compound (1.25 g). Crystal: mp 47-48 ° C Reference Example 36 8- (4,5,6,7-tetramethoxyindan-2-yl) octyl N-ethylcarbamate 8- (4,5,6,7-tetramethoxyindane-2) To a solution of (-yl) octanol (1.20 g) and ethyl isocyanate (0.517 ml) in THF (12 ml) was added one drop of pyridine. After stirring at 40 ° C. for 12 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate = 2: 1) to obtain the title compound (1.42 g). Crystal: mp 85-86 ° C Reference Example 37 8- (4,5,6,7-tetramethoxyindan-2-yl) octylmethanesulfonate 8- (4,5,6,7-tetramethoxyindan-2-yl) ) Methanesulfonyl chloride (0.494 ml) was added dropwise to a solution of octanol (1.95 g) and triethylamine (1.11 ml) in acetonitrile (20 ml) under ice-cooling. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. Organic layer is saturated aqueous sodium bicarbonate, water,
The extract was washed with saturated saline and dried. The solvent is distilled off under reduced pressure,
The title compound (2.36 g) was obtained. Oil ¹ H-NMR (CDCl ₃ ) δ: 1.16-1.86 (14H, m), 2.28-
2.58 (3H, m), 2.90-3.18 (2H, m), 3.01 (3H, s), 3.83 (6H, m
s), 3.89 (6H, s), 4.23 (2H, t)

Reference Example 38 2- (8-Iodooctyl) -4,5,6,7-tetramethoxyindan 8- (4,5,6,7-tetramethoxyindan-2-yl) octyl methanesulfonate (2 .36 g), sodium iodide (2.38 g) and acetone (20 ml)
Was heated to reflux for 3 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous solution of sodium sulfite, water, and saturated saline, and then dried. The solvent was distilled off under reduced pressure to obtain the title compound (2.44 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.16-1.94 (14H, m), 2.28-
2.58 (3H, m), 2.94-3.16 (2H, m), 3.19 (2H, t), 3.83 (6H, m
s), 3.89 (6H, s) Reference Example 39 N- [8- (4,5,6,7-tetramethoxyindane-
2-yl) octyl] -N, N-dimethylamine 2- (8-iodooctyl) -4,5,6,7-tetramethoxyindane (1.20 g), dimethylamine hydrochloride (411 mg), potassium carbonate ( 1.74 g) and DM
The mixture of F (12 ml) was stirred at room temperature for 12 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 10: 1) to obtain the title compound (620 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.16-1.94 (14H, m), 2.10-
2.60 (5H, m), 2.21 (6H, s), 2.92-3.16 (2H, m), 3.83 (6H, m
s), 3.89 (6H, s) Reference Example 40 1- [8- (4,5,6,7-tetramethoxyindane-
2-yl) octyl] -4-phenylpiperidine hydrochloride 2- (8-iodooctyl) -4,5,6,7-tetramethoxyindane (1.00 g), 4-phenylpiperidine (711 mg), potassium carbonate ( 1.45 g) and D
The mixture of MF (10 ml) was stirred for 12 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 20: 1), converted into a hydrochloride, and recrystallized (ethanol-diisopropyl ether) to obtain the title compound (860 mg). Crystal: mp 183-185 ° C

Reference Example 41 N- [8- (4,5,6,7-tetramethoxyindane-
2-yl) octyl] phthalimide 2- (8-iodooctyl) -4,5,6,7-tetramethoxyindane (1.98 g) in DMF (10 ml)
To this was added potassium phthalimide (924 mg). After stirring at room temperature for 12 hours, the reaction solution was diluted with ethyl acetate. The organic layer was washed with water and saturated saline and dried. The solvent was distilled off under reduced pressure, and the residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 10: 1).
Further, recrystallization from hexane gave the title compound (1.74).
g) was obtained. Crystal: mp 64-65 ° C. Reference Example 42 N- [8- (4,5,6,7-tetramethoxyindane-
2-yl) octyl] amine N- [8- (4,5,6,7-tetramethoxyindane-
2-yl) octyl] phthalimide (384 mg), hydrazine monohydrate (194 mg) and ethanol (8 ml)
Was refluxed for 6 hours. After cooling the reaction solution to room temperature, the crystals were separated by filtration and the filtrate was concentrated. The residue was diluted with ethyl acetate, washed with a 1M aqueous solution of potassium carbonate, water and saturated saline, and dried. The solvent was distilled off under reduced pressure to obtain the title compound (260 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.16-1.60 (14H, m), 2.28-
2.80 (5H, m), 2.94-3.16 (2H, m), 3.83 (6H, s), 3.89 (6H, m
s) Reference Example 43 N- [8- (4,5,6,7-tetramethoxyindane-
2-yl) octyl] acetamide 8- (4,5,6,7-tetramethoxyindan-2-yl) octylamine (878 mg), sodium carbonate (2.54 g), water (16 ml) and ethyl acetate (16 m)
Acetyl chloride (0.341 ml) was added dropwise to the mixture of l) under ice cooling. After stirring for 15 minutes, the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and further recrystallized (hexane-ethyl acetate) to obtain the title compound (0.830 g). Crystal: mp 57-61 ° C

Reference Example 44 1- [8- (4,5,6,7-tetramethoxyindane-
2-yl) octyl] -4- (2-pyridyl) piperazine 2- (8-iodooctyl) -4,5,6,7-tetramethoxyindane (1.20 g), 1- (2-pyridyl)
Piperazine (823 mg), potassium carbonate (1.04 g)
And a mixture of DMF (12 ml) was stirred at room temperature for 12 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate.
The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 10: 1) to obtain the title compound (1.16 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.16-1.86 (14H, m), 2.26-
2.64 (9H, m), 2.94-3.16 (2H, m), 3.56 (4H, t), 3.83 (6H, m
s), 3.89 (6H, s), 6.56-6.70 (2H, m), 7.40-7.54 (1H, m),
8.14-8.24 (1H, m) Reference Example 45 1- [8- (4,5,6,7-tetramethoxyindane-
2-yl) octyl] -4-piperidinopiperidine dihydrochloride 2- (8-iodooctyl) -4,5,6,7-tetramethoxyindane (1.18 g), 4-piperidinopiperidine (835 mg) ), Potassium carbonate (1.03 g) and DMF (10 ml) were stirred at room temperature for 12 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane to hexane-ethyl acetate = 4: 1), converted to a hydrochloride, and recrystallized (ethanol-ethyl acetate).
After that, the title compound (1.08 g) was obtained. Crystal: mp 220 ° C (decomposition) Reference Example 46 1- [8- (4,5,6,7-tetramethoxyindane-
2-yl) octyl] -4-diphenylmethylpiperazine 2- (8-iodooctyl) -4,5,6,7-tetramethoxyindane (1.17 g), 1-diphenylmethylpiperazine (1.24 g), carbonic acid Potassium (1.70g)
And a mixture of DMF (10 ml) was stirred at room temperature for 12 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 10: 1) to obtain the title compound (1.19 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.16-1.74 (14H, m), 2.24-
2.60 (13H, m), 2.94-3.16 (2H, m), 3.82 (6H, s), 3.89 (6H, m
s), 4.21 (1H, s), 7.10-7.46 (10H, m)

Reference Example 47 4- [8- (4,5,6,7-tetramethoxyindane-
2-yl) octyl] morpholine hydrochloride 2- (8-iodooctyl) -4,5,6,7-tetramethoxyindane (806 mg), morpholine (294 m
g), potassium carbonate (467 mg) and DMF (8 ml)
Was stirred at room temperature for 12 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane-ethyl acetate = 10: 1), converted to a hydrochloride, and recrystallized (ethanol-diisopropyl ether) to give the title compound (55
6 mg) were obtained. Crystal: mp 123-124 ° C Reference Example 48 4-Benzyl-1- [8- (4,5,6,7-tetramethoxyindan-2-yl) octyl] piperazine dihydrochloride 2- (8-iodooctyl) -4,5,6,7-tetramethoxyindane (830 mg), 1-benzylpiperazine (613 mg), potassium carbonate (481 mg) and DMF
(8 ml) was stirred at room temperature for 12 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 4: 1) and converted into a hydrochloride.
After recrystallization (ethanol-diisopropyl ether), the title compound (870 mg) was obtained. Crystal: mp 208-212 ° C. Reference Example 49 2- [8- (4-chlorophenoxy) octyl] -4,
5,6,7-tetramethoxyindane 2- (8-iodooctyl) -4,5,6,7-tetramethoxyindane (830 mg), 4-chlorophenol (269 mg), potassium carbonate (481 mg) and DMF
(8 ml) was stirred at room temperature for 12 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 10: 1) to obtain the title compound (776 mg). Crystal: mp 38-42 ° C

Reference Example 50 Ethyl 4- (3-chloropropoxy) benzoate Ethyl 4-hydroxybenzoate (50.0 g), 1-bromo-3-chloropropane (56.8 g), potassium carbonate (125 g) and acetonitrile (500 ml) was stirred at 40 ° C. for 48 hours. After the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with diethyl ether. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 20: 1) to obtain the title compound (66.5 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H,
t), 2.14-2.40 (2H, m), 3.75
(2H, t), 4.17 (2H, t), 4.35
(2H, q), 6.92 (2H, d), 8.00
(2H, d) Reference Example 51 Ethyl 4- (3-iodopropoxy) benzoate Ethyl 4- (3-chloropropoxy) benzoate (26.
A mixture of 5 g), sodium iodide (49.0 g) and acetone (300 ml) was heated at reflux for 24 hours. After water was added to the reaction solution, the mixture was extracted with diethyl ether. The organic layer was washed with a 5% aqueous solution of sodium sulfite, water, and saturated saline, and then dried. The solvent was distilled off under reduced pressure to give the title compound (3
4.4 g) were obtained. Oil ¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H, t), 2.18-2.42 (2
H, m), 3.37 (2H, t), 4.10 (2H, t), 4.35 (2H, q), 6.92 (2H,
d), 8.00 (2H, d) Reference Example 52 Ethyl 2-ethoxycarbonyl-5- (4-ethoxycarbonylphenoxy) pentanoate Sodium ethoxide (90%, 6.79 g) in ethanol solution (250 ml) was added to malonic acid. Diethyl (12.0
g) was added dropwise under ice cooling. The reaction was warmed to room temperature and
After stirring for minutes, ethyl 4- (3-iodopropoxy) benzoate (25.0 g) was added dropwise under ice cooling. The reaction was warmed to room temperature and stirred for a further 12 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (hexane to hexane-
Purify with ethyl acetate = 10: 1) to give the title compound (13.
0 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, t), 1.38 (3H, t),
1.77-1.97 (2H, m), 2.00-2.20 (2H, m), 3.42 (1H, t), 4.0
4 (2H, t), 4.21 (4H, q), 4.35 (2H, q), 6.90 (2H, d), 7.99 (2
H, d)

Reference Example 53 Ethyl 3- (2-bromo-3,4,5,6-tetramethoxyphenyl) -2-ethoxycarbonyl-2- [3- (4-ethoxycarbonylphenoxy) propyl] propionate 2- DM of ethyl ethoxycarbonyl-5- (4-ethoxycarbonylphenoxy) pentanoate (25.9 g)
F solution (200 ml) and sodium hydride (60
% Oily, 3.11 g). The reaction was warmed to room temperature and stirred for another 30 minutes. 1-bromo-6 was added to the reaction solution.
A solution of -bromomethyl-2,3,4,5-tetramethoxybenzene (28.8 g) in DMF (50 ml) was added dropwise under ice cooling. The reaction solution was warmed to room temperature, stirred for 6 hours, added with water, and extracted with diethyl ether. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 7: 1) to obtain the title compound (42.6 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, t), 1.38 (3H, t),
1.70-2.00 (4H, m), 3.56 (2H, s), 3.73 (3H, s), 3.81 (3H,
s), 3.80-4.04 (2H, m), 3.87 (3H, s), 3.93 (3H, s), 4.08-
4.30 (4H, m), 4.34 (2H, q), 6.86 (2H, d), 7.97 (2H, d) Reference Example 54 2- [3- (4-ethoxycarbonylphenoxy) propyl] -4,5,6 , 7-Tetramethoxy-1-oxo-
Ethyl 2-indanecarboxylate Ethyl 3- (2-bromo-3,4,5,6-tetramethoxyphenyl) -2-ethoxycarbonyl-2- [3- (4-ethoxycarbonylphenoxy) propyl] propionate (40 2.0 g) in a THF solution (400 ml).
-Butyl lithium in hexane (1.68 M, 41.8)
ml) was added dropwise at −100 ° C. or lower under a nitrogen stream, and the temperature was raised to −78 ° C. over 30 minutes. The reaction solution was cooled again to -100 ° C, a solution of acetic acid (7.33 g) in THF (20 ml) was added dropwise, and the temperature was raised to room temperature. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 7: 1) to obtain the title compound (29.7 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, t), 1.37 (3H, t),
1.58-2.38 (4H, m), 2.97 (1H, d), 3.60 (1H, d), 3.91 (6H,
s), 3.94-4.10 (2H, m), 3.98 (3H, s), 4.05 (3H, s), 4.16 (2
H, q), 4.34 (2H, q), 6.86 (2H, d), 7.97 (2H, d)

Reference Example 55 Methyl 4- [3- (4,5,6,7-tetramethoxy-1-oxoindan-2-yl) propoxy] benzoate 2- [3- (4-ethoxycarbonylphenoxy) propyl] -4,5,6,7-tetramethoxy-1-oxo-
A mixture of ethyl 2-indanecarboxylate (14.9 g), acetic acid (75 ml) and concentrated hydrochloric acid (75 ml) was stirred at 80 ° C. for 6 hours and then heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue, potassium carbonate (19.5 g), methyl iodide (8.77 ml) and D
A mixture of MF (100 ml) was stirred at room temperature for 12 hours.
The reaction solution was diluted with diethyl ether, and the organic layer was washed with water and saturated saline and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 5: 1), and recrystallized (hexane-ethyl acetate) to give the title compound (9.85 g).
I got Crystal: mp 68-70 ° C Reference Example 56 4- [3- (4,5,6,7-tetramethoxyindane-
Methyl 2- [yl] propoxy] benzoate A solution of methyl 4- [3- (4,5,6,7-tetramethoxy-1-oxoindan-2-yl) propoxy] benzoate (9.20 g) in methanol (100 ml). To the mixture was added sodium borohydride (1.57 g) under ice cooling. After heating to room temperature and stirring for 4 hours, the reaction solution was diluted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (100 ml), concentrated hydrochloric acid (0.041 ml) and 10% palladium on carbon (1.84 g) were added, and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 12 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 8: 1), recrystallized from hexane, and treated with the title compound (7.85).
g) was obtained. Crystal: mp 70-72 ° C Reference Example 57 4- [3- (4,5,6,7-tetramethoxyindane-
2-yl) propoxy] benzoic acid 4- [3- (4,5,6,7-tetramethoxyindane-
2-yl) propoxy] methyl benzoate (7.35 g) in methanol (7
Sodium hydroxide aqueous solution (3N, 8.57 m
l) was added, and the mixture was heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized (hexane-ethyl acetate) to obtain the title compound (6.58 g). Crystal: mp 160-161 ° C

Reference Example 58 N, N-dimethyl-4- [3- (4,5,6,7-tetramethoxyindan-2-yl) propoxy] benzamide 4- [3- (4,5,6,7 -Tetramethoxyindane-
2-yl) propoxy] benzoic acid (2.00 g), dimethylamine hydrochloride (783 mg), 1-ethyl-3-hydrochloride
(3-Dimethylaminopropyl) carbodiimide (1.
84 g), a mixture of 1-hydroxybenzotriazole monohydrate (1.47 g), triethylamine (4.01 ml) and THF (40 ml) were stirred at room temperature for 12 hours.
The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 1: 2-ethyl acetate) to give the title compound (2.
12 g) were obtained. Oil ¹ H-NMR (CDCl ₃ ) δ: 1.56-2.00 (4H, m), 2.36-
2.64 (3H, m), 2.94-3.22 (8H, m), 3.84 (6H, s), 3.89 (6H, m
s), 4.02 (2H, d), 6.90 (2H, d), 7.40 (2H, d) Reference Example 59 4,5,6,7-Tetramethoxy-2- [3- (4-dimethylaminomethylphenoxy) Propyl] indan hydrochloride N, N-dimethyl-4- [3- (4,5,6,7-tetramethoxyindan-2-yl) propoxy] benzamide (1.34 g) in THF (13 ml) was treated with hydrogen. Lithium aluminum chloride (229 mg) was added. After heating under reflux for 1 hour, a saturated aqueous solution of Rochelle salt was added to the reaction solution at room temperature.
The precipitate was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 4: 1). 17g) was obtained. Crystal: mp 172-175 ° C. Reference Example 60 4,5,6,7-tetramethoxy-2- [3- [4-
[(4-Piperidinopiperidino) carbonyl] phenoxy] propyl] indane hydrochloride 4- [3- (4,5,6,7-tetramethoxyindane-
2-yl) propoxy] benzoic acid (2.00 g), 4-
Piperidinopiperidine (1.62 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.84 g), 1-hydroxybenzotriazole monohydrate (1.47 g), triethylamine (2. 01ml)
And a mixture of THF (40 ml) was stirred at room temperature for 12 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate.
The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 1: 2), converted into a hydrochloride, and recrystallized (ethanol-diisopropyl ether) to give the title compound (2.85 g). Crystal: mp 201-204 ° C

Reference Example 61 4,5,6,7-Tetramethoxy-2- [3- [4-
[(4-Piperidinopiperidino) methyl] phenoxy]
Propyl] indane dihydrochloride In a THF suspension (15 ml) of lithium aluminum hydride (200 mg) was added 4,5,6,7-tetramethoxy-2-
A solution of [3- [4-[(4-piperidinopiperidino) carbonyl] phenoxy] propyl] indane (1.49 g) in THF (10 ml) was added. After heating under reflux for 1 hour, a saturated aqueous solution of Rochelle salt was added to the reaction solution at room temperature. The precipitate was separated by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 4: 1), converted into a hydrochloride, and recrystallized from ethanol to give the title compound ( 1.11 g). Crystal: mp 259-266 ° C (decomposition) Reference Example 62 2,3,4,5-Tetramethoxy-6-methylbenzaldehyde Chlorination of 1,2,3,4-tetramethoxy-5-methylbenzene (20.0 g) Titanium tetrachloride (20.6 ml) was added to the methylene solution (100 ml) under ice-cooling, and further 1,
1-Dichlorodimethyl ether (11.0 ml) was added under ice cooling. The reaction was warmed to room temperature and stirred for a further 8 hours. The reaction solution was added to ice water and extracted with diethyl ether. The organic layer was washed with water and saturated saline and dried. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane to hexane-ethyl acetate = 10: 1).
And the title compound (21.5 g) was obtained. Oil ¹ H-NMR (CDCl ₃ ) δ: 2.46 (3H, s), 3.77 (3H, s),
3.91 (3H, s), 3.95 (3H, s), 4.03 (3H, s), 10.44 (1H, s) Reference Example 63 2,3,4,5-tetramethoxy-6-methylphenylmethanol Lithium aluminum hydride (2.37 g) in diethyl ether (150 ml) was suspended in 2,3,4,5-tetramethoxy-6-methylbenzaldehyde (15.0 g).
Was added dropwise under ice-cooling.
After stirring for 30 minutes, 10% hydrochloric acid was added to the reaction solution, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (hexane to hexane-
Purification with ethyl acetate = 2: 1) gave the title compound (14.2).
g) was obtained. Oil ¹ H-NMR (CDCl ₃ ) δ: 2.27 (3H,
s), 3.79 (3H, s), 3.89 (3H,
s), 3.90 (3H, s), 3.92 (3H,
s), 4.62-4.74 (2H, m)

Reference Example 64 5-Bromomethyl-1,2,3,4-tetramethoxy-6
-Methylbenzene 2,3,4,5-Tetramethoxy-6-methylphenylmethanol (44.4 g) in a THF solution (200 ml)
Phosphorus tribromide (29.8 g) was added dropwise under ice cooling. After stirring for 1 hour, the reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and a saturated saline solution and then dried.
The solvent was distilled off under reduced pressure to obtain the title compound (54.4 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 2.27 (3H, s), 3.79 (3H, s),
3.89 (3H, s), 3.93 (3H, s), 3.95 (3H, s), 4.61 (2H, s) Reference Example 65 5,6-bis (bromomethyl) -1,2,3,4-tetramethoxybenzene 5-bromomethyl-1,2,3,4-tetramethoxy-6
-Methylbenzene (54.4 g), NBS (34.7 g)
And AIBN (585 mg) in ethyl acetate (500
was heated to reflux for 1.5 hours, and NBS (6.
31 g) and AIBN (117 mg) were added, and the mixture was further heated under reflux for 1.5 hours. The reaction solution was water, saturated aqueous sodium bicarbonate,
The extract was washed with water and saturated saline and then dried. The solvent was distilled off under reduced pressure to obtain the title compound (68.0 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 3.93 (6H, s), 3.95 (6H, s),
4.72 (4H, s) Reference Example 66 1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cyclohepten-7-one 5,6-bis (bromomethyl)- Potassium carbonate (48.1 g) was added to a solution of 1,2,3,4-tetramethoxybenzene (44.5 g) and ethyl 1,3-acetonedicarboxylate (46.9 g) in acetonitrile (450 ml) under ice-cooling. . After stirring the reaction solution for 30 minutes, it was heated to room temperature and further stirred for 12 hours. After water was added to the reaction solution, concentrated hydrochloric acid was added to make the reaction solution acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was dissolved in acetic acid (333 ml), concentrated hydrochloric acid (111 ml) was added, and the mixture was stirred at 100 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (ethyl acetate) and recrystallized (hexane-ethyl acetate) to give the title compound (23.4 g). Crystal: mp 77-78 ° C

Reference Example 67 2- (1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-7-
(Ilidene) ethyl acetate Sodium hydride (60% oily, 1.42 g) in THF
(30 ml), and ethyl diethylphosphonoacetate (7.98 g) was added dropwise under ice-cooling, followed by stirring for 15 minutes. The reaction solution was warmed to room temperature, stirred for 1 hour and then 1,2,3,4-
Tetramethoxy-6,7,8,9-tetrahydro-5H-
Benzo [a] cyclohepten-7-one (5.00 g)
(20 ml) was added dropwise at room temperature. After stirring for another 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 10: 1) to obtain the title compound (5.72 g). Crystal: mp 61-63 ° C Reference Example 68 2- (1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-7-
Yl) ethyl acetate 2- (1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-7-
A 10% palladium-carbon (550 mg) was added to an ethanol solution (110 ml) of (ylidene) ethyl acetate (5.50 g), and the mixture was stirred at room temperature and 1 atm of hydrogen pressure for 12 hours. The catalyst was filtered off from the reaction solution, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 10: 1) to give the title compound (5.44).
g) was obtained. Oil ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.24 (2H, m), 1.27 (3
H, t), 1.88-2.54 (7H, m), 3.14-3.34 (2H, m), 3.75 (6H, s),
3.91 (6H, s), 4.14 (2H, q) Reference Example 69 2- (1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-7-
Yl) ethanol To a suspension of lithium aluminum hydride (486 mg) in diethyl ether (20 ml) was added 2- (1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a]. ] Cyclohepten-7-yl) ethyl acetate (3.
A solution (00 g) of diethyl ether (10 ml) was added dropwise under ice cooling. After stirring for 30 minutes, 10% hydrochloric acid was added to the reaction solution,
Dilute with water and extract with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 1: 1) to obtain the title compound (2.60 g). Crystal: mp 64-66 ° C

Reference Example 70 2- (1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-7-
Yl) ethyl methanesulfonate 2- (1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-7-
(Il) Methanesulfonyl chloride (0.750 ml) was added dropwise to an acetonitrile solution (50 ml) of ethanol (2.50 g) and triethylamine (1.68 ml) under ice-cooling.
After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water, and saturated saline, and then dried. The solvent was distilled off under reduced pressure to obtain the title compound (3.12 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 0.92-1.20 (2H, m), 1.60-
2.10 (5H, m), 2.28-2.52 (2H, m), 3.02 (3H, s), 3.16-3.36
(2H, m), 3.76 (6H, s), 3.91 (6H, s), 4.29 (2H, t) Reference Example 71 7- (2-Iodoethyl) -1,2,3,4-tetramethoxy-6, 7,8,9-tetrahydro-5H-benzo [a] cycloheptene 2- (1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-7-
Yl) ethyl methanesulfonate (3.12 g), sodium iodide (3.61 g) and acetone (40 m
The mixture of l) was heated to reflux for 1 hour. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous solution of sodium sulfite, water, and saturated saline, and then dried. The solvent was distilled off under reduced pressure to obtain the title compound (3.29 g). Crystal: mp 75-82 ° C Reference Example 72 2- (1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-7-
Yl) acetic acid 2- (1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-7-
Yl) Ethyl acetate (2.29 g) in methanol (2
Sodium hydroxide aqueous solution (3N, 3.25 ml)
Was added and the reaction solution was heated to reflux for 6 hours. The reaction solution was concentrated under reduced pressure, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized (hexane-ethyl acetate) to obtain the title compound (1.81 g). Crystal: mp 109-111 ° C

Reference Example 73 4- [2- (1,2,3,4-tetramethoxy-6,7,8,
Ethyl 9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethoxy] benzoate 7- (2-iodoethyl) -1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro- 5H-benzo [a] cycloheptene (1.00 g), ethyl 4-hydroxybenzoate (593 mg), potassium carbonate (987 m2)
A mixture of g) and DMF (10 ml) was stirred at room temperature for 12 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 15: 1), and recrystallized (hexane-ethyl acetate) to give the title compound (910 mg). Crystal: mp 129-131 ° C. Reference Example 74 4- [2- (1,2,3,4-tetramethoxy-6,7,8,
9-Tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethoxy] phenylmethanol To a suspension of lithium aluminum hydride (91.8 mg) in diethyl ether (10 ml) was added 4- [2- (1,2, Three,
4-tetramethoxy-6,7,8,9-tetrahydro-5
A solution of ethyl H-benzo [a] cyclohepten-7-yl) ethoxy] benzoate (553 mg) in THF (10 m
l) was added dropwise under ice cooling. After stirring for 15 minutes, 10
% Hydrochloric acid, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane-ethyl acetate,
The title compound (320 mg) was obtained. Crystal: mp 114-116 ° C Reference Example 75 4- [2- (1,2,3,4-tetramethoxy-6,7,8,
9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethoxy] benzoic acid 4- [2- (1,2,3,4-tetramethoxy-6,7,8,
Ethyl 9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethoxy] benzoate (1.77
g), a mixture of aqueous sodium hydroxide (3N, 1.93 ml) and methanol (30 ml) was heated to reflux for 6 hours. The reaction solution was concentrated under reduced pressure, water was added, hydrochloric acid was added to make the solution acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized from THF-diisopropyl ether to give the title compound (1.34 g). Crystal: mp 190-192 ° C

Reference Example 76 7- [2- (4-Chlorophenoxy) ethyl] -1,2,
3,4-tetramethoxy-6,7,8,9-tetrahydro-
5H-benzo [a] cycloheptene 7- (2-iodoethyl) -1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene (1.64 g), 4 A mixture of -chlorophenol (602 mg), potassium carbonate (1.08 g) and DMF (16 ml) was stirred at room temperature for 12 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (toluene) to obtain the title compound (1.58 g). Crystal: mp 98-102 ° C Reference Example 77 7- [2- (4-phenylphenoxy) ethyl] -1,
2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene 7- (2-iodoethyl) -1,2,3,4-tetramethoxy-6,7,8 , 9-Tetrahydro-5H-benzo [a] cycloheptene (1.64 g), 4-hydroxybiphenyl (797 mg), potassium carbonate (1.08 g)
And a mixture of DMF (16 ml) was stirred at room temperature for 12 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (toluene) to obtain the title compound (1.73 g). Crystal: mp 115-120 ° C. Reference Example 78 1- (tert-butyl) -1,1-dimethylsilyl (8-
Chlorooctyl) ether 8-chlorooctanol (24.3 g) and tert-butyldimethylchlorosilane (26.8 g) in DMF (2
To this solution, imidazole (25.2 g) was added under ice-cooling. The reaction solution was warmed to room temperature, stirred for 12 hours, and diluted with diethyl ether. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane to hexane:
Purification with diethyl ether = 25: 1) gave the title compound (40.7 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 0.05 (6H, s), 0.89 (9H, s),
1.20-1.86 (12H, m), 3.53 (2H, t), 3.60 (2H, t)

Reference Example 79 1- (tert-butyl) -1,1-dimethylsilyl (8-
Iodooctyl) ether 1- (tert-butyl) -1,1-dimethylsilyl (8-
A mixture of chlorooctyl) ether (40.7 g), sodium iodide (43.8 g) and acetone (400 ml) was heated at reflux for 12 hours. After the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with a 5% aqueous solution of sodium sulfite, water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane to hexane: diethyl ether = 25: 1) to give the title compound (36.4).
g) was obtained. Oil ¹ H-NMR (CDCl ₃ ) δ: 0.05 (6H, s), 0.89 (9H, s),
1.14-1.94 (12H, m), 3.19 (2H, t), 3.60 (2H, t) Reference Example 80 10-[[1- (tert-butyl) -1,1-dimethylsilyl] oxy] -2-phenyl LDA in heptane (2.000) in ethyl decanoate THF (100 ml)
M, 48.3 ml) was added under a nitrogen stream, and a solution of ethyl phenylacetate (12.2 g) in THF (10 ml) was added to -7.
The solution was added dropwise at 0 ° C or lower. After stirring for 30 minutes, a solution of 1- (tert-butyl) -1,1-dimethylsilyl (8-iodooctyl) ether (25.0 g) in THF (10 ml) was added dropwise at −70 ° C. or less, and over 15 minutes The temperature was raised to 0 ° C. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 30: 1) to give the title compound (21.2 g).
I got Oil ¹ H-NMR (CDCl ₃ ) δ: 0.04 (6H, s), 0.89 (9H, s),
0.94-2.18 (17H, m), 3.51 (1H, t), 3.58 (2H, t), 4.00-4.
26 (2H, m), 7.16-7.36 (5H, m) Reference Example 81 2- (2-bromo-3,4,5,6-tetramethoxybenzyl) -10-[[1- (tert-butyl)- Ethyl 1,1-dimethylsilyl] oxy] -2-phenyldecanoate THF (150 ml) in heptane solution of LDA (2.000)
M, 33.6 ml) under a nitrogen stream, and then 10-[[1
-(Tert-butyl) -1,1-dimethylsilyl] oxy] -2-phenyldecanoate ethyl (18.2 g) T
An HF (20 ml) solution was added dropwise below -70 ° C. After stirring for 30 minutes, 1-bromo-6-bromomethyl-2,3,4,
THF of 5-tetramethoxybenzene (19.9 g)
(20 ml) The solution was added dropwise at -70 ° C or lower, and the temperature was raised to room temperature over 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-
Purification with hexane-ethyl acetate = 30: 1) gave the title compound (21.2 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 0.04 (6H, s), 0.89 (9H, s),
0.94-2.24 (17H, m), 3.40 (1H, d), 3.58 (2H, t), 3.68 (3
H, s), 3.68 (3H, s), 3.68 (1H, d), 3.84 (3H, s), 3.88 (3H,
s), 4.16-4.30 (2H, m), 7.00-7.18 (5H, m)

Reference Example 82 8- (4,5,6,7-tetramethoxy-1-oxo-2
-Phenylsoindan-2-yl) octanol 2- (2-bromo-3,4,5,6-tetramethoxybenzyl) -10-[[1- (tert-butyl) -1,1-dimethylsilyl] oxy ] To a solution of ethyl 2-phenyldecanoate (3.00 g) in THF (30 ml) was added dropwise a hexane solution of n-butyllithium (1.68 M, 2.82 ml) at -100 ° C or lower under a nitrogen stream. -7 over minutes
The temperature was raised to 8 ° C. After stirring for 30 minutes, a saturated aqueous ammonium chloride solution was added to the reaction solution, the temperature was raised to room temperature, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline and dried, and the solvent was distilled off under reduced pressure. Residue in THF (30 ml)
In tetrabutylammonium fluoride
The F solution (1.00 M, 6.47 ml) was added at room temperature. After stirring for 6 hours, the reaction solution was purified by silica gel column chromatography (ethyl acetate), and further purified by silica gel column chromatography (hexane-hexane-ethyl acetate = hexane).
2: 1) to give the title compound (1.63 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.00-2.22 (14H, m), 3.21
(1H, d), 3.51 (1H, d), 3.61 (2H, t), 3.89 (3H, s), 3.91 (3
H, s), 3.96 (3H, s), 4.04 (3H, s), 7.00-7.46 (5H, m) Reference Example 83 8- (4,5,6,7-tetramethoxy-2-phenylindane-2) -Yl) octanol To a suspension of lithium aluminum hydride (231 mg) in diethyl ether (14 ml) was added aluminum chloride (811).
mg) under ice-cooling and then the temperature was raised to room temperature. After stirring for 15 minutes, the reaction solution was ice-cooled, and diethyl 8- (4,5,6,7-tetramethoxy-1-oxo-2-phenyl-1-oxoindan-2-yl) octanol (1.39 g) was added. An ether solution (7 ml) was added dropwise. After stirring for 15 minutes, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 2: 1) to obtain the title compound (1.00 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 0.94-1.72
(14H, m), 3.08-3.34 (4H, m),
3.58 (2H, t), 3.85 (6H, s),
3.91 (6H, s), 7.14-7.42 (5H,
m) Reference Example 84 8- (4,5,6,7-Tetramethoxy-2-phenylindan-2-yl) octanal A solution of oxalyl chloride (0.394 ml) in THF (36 m2).
To l), a THF solution (2.4 ml) of dimethylsulfoxide (468 mg) was added dropwise at -70 ° C or lower under a nitrogen stream. 1
After stirring for 0 minutes, a THF solution (12 ml) of 8- (4,5,6,7-tetramethoxy-2-phenylindan-2-yl) octanol (1.00 g) was added dropwise to the reaction solution at -70 ° C or lower. did. After stirring for 15 minutes, the reaction solution was further
After stirring at 0 ° C. to −50 ° C. for 1 hour, triethylamine (2.30 ml) was added. The reaction was heated to 0 ° C.
After stirring for 0 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 4: 1) to obtain the title compound (985 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.70 (12H, m), 2.34
(2H, dt), 3.20 (4H, s), 3.85 (6H, s), 3.91 (6H, s), 7.14-
7.42 (5H, m), 9.71 (1H, t)

Reference Example 85 8- (4,5,6,7-tetramethoxy-2-phenylindan-2-yl) octanoic acid 8- (4,5,6,7-tetramethoxy-2-phenylindan- A mixture of 2-yl) octanal (985 mg), sodium dihydrogen phosphate (72.6 mg), 30% aqueous hydrogen peroxide (0.435 ml), acetonitrile (10 ml) and water (4 ml) was added to sodium chlorite ( 80%, 3
55 mg) of an aqueous solution (14 ml) was added dropwise over 30 minutes under ice cooling. After stirring for 30 minutes, an aqueous solution of sodium sulfite was added to the reaction solution, and the mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane to hexane-ethyl acetate = 1: 1).
Purification in 2) gave the title compound (665 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.70 (12H, m), 2.27
(2H, t), 3.20 (4H, s), 3.85 (6H, s), 3.91 (6H, s), 7.14-
7.42 (5H, m) Reference Example 86 2- (8-iodooctyl) -4,5,6,7-tetramethoxy-2-phenylindane 8- (4,5,6,7-tetramethoxy-2-phenyl) A solution of indan-2-yl) octanol (2.65 g) and triethylamine (1.25 ml) in acetonitrile (2
Methanesulfonyl chloride (0.557 ml) was added dropwise to the mixture under ice-cooling. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. Water layer, 1N
The extract was washed with hydrochloric acid, water and saturated saline and dried, and the solvent was distilled off under reduced pressure. A mixture of the residue, sodium iodide (2.70 g) and acetone (60 ml) was heated at reflux for 3 hours.
Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
The extract was washed with an aqueous solution of sodium sulfite, water and saturated saline and then dried. The solvent was distilled off under reduced pressure to give the title compound (3.27 g).
I got Oil ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.84 (14H, m), 3.13
(2H, t), 3.20 (4H, s), 3.85 (6H, s), 3.91 (6H, s), 7.14-
7.40 (5H, m) Reference Example 87 4-benzyl-1- [8- (4,5,6,7-tetramethoxy-2-phenylindan-2-yl) octyl] piperazine dihydrochloride 2- (8- (Iodooctyl) -4,5,6,7-tetramethoxy-2-phenylindane (800 mg), 1-benzylpiperazine (511 mg), potassium carbonate (1.00)
A mixture of g) and DMF (8 ml) was stirred at room temperature for 12 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 20: 1), converted into a hydrochloride, and recrystallized (ethanol-diisopropyl ether) to give the title compound (804 mg). Crystal: mp 218-221 ° C

Reference Example 88 5,6,7-Trimethoxy-2- [6- (5,6,7-trimethoxy-1-oxo-2,3-dihydro-1H-2-
Indenyl) hexyl] -1-indanone 3- (3,4,5-trimethoxyphenyl) propionic acid (12 g) in THF (200 ml) was LDA (1.9).
(M / THF solution; 60 ml) was added dropwise while maintaining the internal temperature at -10 ° C or lower. After stirring at 0 ° C. for 3 hours, 2
The pH was adjusted to 3 by adding N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. Polyphosphoric acid (100 ml) was added to the residue, and the reaction solution was heated and stirred at 60 ° C. for 4 hours. After cooling, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with water, dried and concentrated under reduced pressure. The residue was subjected to alumina column chromatography, purified by eluting with ethyl acetate, and crystallized from ethyl acetate-hexane to obtain the title compound (4.5 g). The compound recrystallized from ethanol showed the following melting points. Crystal: mp 129-130 ° C. Reference Example 89 4,5,6-trimethoxy-2- [6- (4,5,6-trimethoxy-2,3-dihydro-1H-2-indenyl)
Hexyl] indane 5,6,7-trimethoxy-2- [6- (5,6,7-trimethoxy-1-oxo-2,3-dihydro-1H-2-
Indenyl) hexyl] -1-indanone (4.5 g)
To a solution of acetic acid (50 ml) was added 10% Pd-carbon (1 g) and perchloric acid (1 ml). The reaction solution was subjected to a catalytic reduction reaction at 50 ° C. for 6 hours under a hydrogen pressure of 4 to 5 atm. After removing the catalyst, the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, washed with water, dried and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The fraction of the title compound was concentrated and recrystallized from ethyl acetate / hexane to give the title compound (4.5).
g) was obtained. Crystal: mp 69-70 ° C Reference Example 90 1,6-bis- (4-bromo-5,6,7-trimethoxyindan-2-yl) hexane 4,5,6-trimethoxy-2- [6- ( 4,5,6-trimethoxy-2,3-dihydro-1H-2-indenyl)
[Hexyl] indane (1.67 g), bromide (0.260 ml) was added dropwise at room temperature to a mixture of sodium acetate (1.10 g) and acetic acid (17 ml). After stirring for 30 minutes,
A 5% aqueous solution of sodium sulfite was added to the reaction mixture under ice cooling,
It was concentrated under reduced pressure. After water was added to the residue, the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried, and concentrated under reduced pressure. The residue was purified by alumina column chromatography (ethyl acetate) to obtain the title compound (2.10 g). Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.14-1.64 (12H, m), 2.26-
2.72 (6H, m), 2.94-3.28 (4H, m), 3.87 (12H, s), 3.88 (6H, m
s)

Reference Example 91 1,6-bis- (4,5,6,7-tetramethoxyindan-2-yl) hexane 1,6-bis- (4-bromo-5,6,7-trimethoxyindane -2-yl) hexane (2.10 g), copper (I) bromide (230 mg), ethyl acetate (0.625 ml) and methanol solution of sodium methoxide (28%, 10%).
(0 ml) was heated at reflux for 12 hours. The reaction mixture was added to water, concentrated hydrochloric acid was added to make the mixture acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue is subjected to alumina column chromatography (hexane-hexane-ethyl acetate = 8: 1)
The title compound (1.22 g) was obtained. Crystal: mp 100-108 ° C Reference Example 92 4,5,6,7-tetramethoxy-2- [4- [4- (morpholinocarbonyl) phenoxy] butyl] indane 4- [4- (4,5,6, 7-tetramethoxyindane-
2-yl) butoxy] benzoic acid (3.50 g), morpholine (1.42 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.12 g),
1-hydroxybenzotriazole monohydrate (2.45
g), triethylamine (2.30 ml) and THF
(70 ml) was stirred at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water, and saturated saline, and then dried. The solvent was distilled off under reduced pressure to obtain the title compound (4.00 g). Crystal: mp 64-72 ° C. Reference Example 93 4,5,6,7-Tetramethoxy-2- [4- [4- (morpholinomethyl) phenoxy] butyl] indane hydrochloride 4,5,6,7-tetramethoxy Lithium aluminum hydride (365 mg) was added to a THF solution (23 ml) of -2- [4- [4- (morpholinocarbonyl) phenoxy] butyl] indane (2.26 g) under ice-cooling. Heated to reflux for an hour. A 1N aqueous sodium hydroxide solution was added to the reaction solution at room temperature, and the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by alumina column chromatography (hexane to hexane: ethyl acetate = 10: 1) to obtain a hydrochloride, which was recrystallized from ethanol-diisopropyl ether to obtain the title compound (1.28 g). Crystal: mp 164-166 ° C

Reference Example 94 1- [2- (1,2,3,4-tetramethoxy-6,7,8,
9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethyl] -1H-benzo [d] imidazole 7- (2-iodoethyl) -1,2,3,4-tetramethoxy-6,7,8 A mixture of 1,9-tetrahydro-5H-benzo [a] cycloheptene (1.50 g), benzimidazole (443 mg), sodium carbonate (760 mg) and DMF (15 ml) was stirred at 70 ° C. for 8 hours.
Water was added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate and THF. The organic layer was washed with water and saturated saline, and then dried. The solvent was distilled off under reduced pressure, diethyl ether was added, the resulting crystals were separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 1: 2) and recrystallized from hexane-ethyl acetate to obtain the title compound (480 mg). Crystal: mp 121-123 ° C Reference Example 95 3- [2- (1,2,3,4-tetramethoxy-6,7,8,
9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethoxy] pyridine 7- (2-iodoethyl) -1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H- A mixture of benzo [a] cycloheptene (1.20 g), 3-hydroxypyridine (816 mg), potassium carbonate (2.38 g) and DMF (12 ml) was stirred at room temperature for 12 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (ethyl acetate) and recrystallized from hexane-ethyl acetate.
The title compound (430 mg) was obtained. Crystal: mp 111-113 ° C. Reference Example 96 1- [2- (1,2,3,4-tetramethoxy-6,7,8,
9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethyl] -1,2-dihydro-2-pyridinone and 2- [2- (1,2,3,4-tetramethoxy-6,7 , 8,9-Tetrahydro-5H-benzo [a]
Cyclohepten-7-yl) ethoxy] pyridine 7- (2-iodoethyl) -1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene (1.50 g) A mixture of 2-hydroxypyridine (407 mg), potassium carbonate (987 mg) and DMF (15 ml) was stirred at room temperature for 12 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, the resulting crystals were collected by filtration, and further recrystallized from hexane-ethyl acetate to give 2- [2-
(1,2,3,4-Tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethoxy] pyridine (830 mg) was obtained. Crystal: mp. 132-135 ° C. The filtrate is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (hexane to hexane: ethyl acetate = 4:
1), 1- [2- (1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethyl] -1, 2-
Dihydro-2-pyridinone (434 mg) was obtained. Crystal: mp. 84-87 ° C

Reference Example 97 1- [2- (1,2,3,4-tetramethoxy-6,7,8,
9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethyl] -1,2-dihydro-2-quinolinone, and 2- [2- (1,2,3,4-tetramethoxy-6,7 , 8,9-Tetrahydro-5H-benzo [a]
Cyclohepten-7-yl) ethoxy] quinoline 7- (2-iodoethyl) -1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene (1.50 g) , 2-quinolinol (621 mg), potassium carbonate (987 mg) and DM
A mixture of F (15 ml) was stirred at room temperature for 12 hours. Further, the reaction solution was stirred at 60 ° C. for 6 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue for crystallization to obtain crystals and a filtrate. The crystals were recrystallized from hexane-ethyl acetate to give 2- [2- (1,2,
3,4-tetramethoxy-6,7,8,9-tetrahydro-
5H-benzo [a] cyclohepten-7-yl) ethoxy] quinoline (680 mg) was obtained. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 10: 1).
-[2- (1,2,3,4-tetramethoxy-6,7,8,9
-Tetrahydro-5H-benzo [a] cycloheptene-
7-yl) ethyl] -1,2-dihydro-2-quinolinone (712 mg) was obtained. 1- [2- (1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethyl] -1,
2-dihydro-2-quinolinone crystal: mp. 85-92 ° C 2- [2- (1,2,3,4-tetramethoxy-6,7,8,
9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethoxy] quinoline crystal: mp. 175-177 ° C Reference Example 98 1- [2- (1,2,3,4-tetramethoxy-6,7,8,
9-Tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethyl] -1H-benzotriazole 1,2,3-benzoate in a suspension of sodium hydride (60% oil, 230 mg) in THF (6 ml). Triazole (680
mg) in THF (6 ml) was added dropwise under ice cooling. The reaction solution was heated to room temperature, stirred for 30 minutes, and then treated with 7- (2-iodoethyl) -1,2,3,4-tetramethoxy-6,7,8,9-.
Tetrahydro-5H-benzo [a] cycloheptene (1.20 g) was added, and the mixture was stirred for 12 hours. Further, after heating and refluxing the reaction solution for 6 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane-hexane: ethyl acetate = 4: 1), and recrystallized from hexane-ethyl acetate to obtain the title compound (920 mg). Crystal: mp. 99-101 ° C

Example 1 8- (2-ethoxycarbonyl-5,6-dimethoxy-
Ethyl 4,7-dioxoindan-2-yl) octanoate Ethyl 8- (2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl) octanoate (10
A solution of CAN (342 mg, 0.624 mmol) in water (1 ml) was added dropwise to a solution of 0 mg, 0.208 mmol) in acetonitrile (2 ml) under ice-cooling. After stirring the reaction solution for 15 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-hexane: ethyl acetate = 4: 1) to obtain the title compound (69 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.1-1.8 (18H, m), 2.28 (2
(H, t, J = 7.5Hz), 2.64-2.82 (2H, m), 3.24-3.42 (2H, m), 3.
99 (6H, s), 4.04-4.24 (4H, m) Example 2 8- (2-carboxy-5,6-dimethoxy-4,7-dioxoindan-2-yl) octanoic acid 8- (2-carboxy- 4,5,6,7-Tetramethoxyindan-2-yl) octanoic acid (88.6 mg, 0.20
9 mmol) in acetonitrile (2 ml).
A solution of 7 mg, 0.523 mmol) in water (1 ml) was added dropwise under ice-cooling, and the mixture was stirred for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate), and recrystallized from hexane-ethyl acetate to obtain the title compound (32 mg). Was. Crystal: mp 119-123 ° C Example 3 8- (2-ethoxycarbonyl-5,6-dimethoxy-
4,7-dioxoindan-2-yl) octanoic acid 8- (2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl) octanoic acid (78.6 m
g, 0.174 mmol) in acetonitrile (2 ml).
A solution of AN (238 mg, 0.435 mmol) in water (1 ml) was added dropwise under ice-cooling, and the mixture was stirred for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried. The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1 to ethyl acetate) to give the title compound (50
mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.14-1.84
(12H, m), 1.27 (3H, t, J = 7.2H
z), 2.34 (2H, t, J = 7.3 Hz),
2.66-2.82 (2H, m), 3.24-3.4
2 (2H, m), 4.00 (6H, s), 4.17
(2H, q, J = 7.2 Hz)

Example 4 N- [8- (2-ethoxycarbonyl-5,6-dimethoxy-4,7-dioxoindan-2-yl) octanoyl] morpholine N- [8- (2-ethoxycarbonyl-4,5) , 6,7-
Tetramethoxyindan-2-yl) octanoyl] morpholine (123 mg, 0.236 mmol) in acetonitrile (2.5 ml) was added to CAN (323 mg, 0.590 mmol).
A solution of l) in water (1.2 ml) was added dropwise under ice cooling and stirred for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 1) to obtain the title compound (66.6 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.80 (12H, m), 1.26
(3H, t, J = 7.2Hz), 2.22-2.38 (2H, m), 2.64-2.82 (2H, m),
3.22-3.54 (4H, m), 3.56-3.74 (6H, m), 3.99 (6H, s), 4.17
(2H, q, J = 7.2Hz) Example 5 8- (2-carbamoyl-5,6-dimethoxy-4,7-
Dioxoindan-2-yl) octanamide 8- (2-carbamoyl-4,5,6,7-tetramethoxyindan-2-yl) octanamide (103 mg,
0.244 mmol) in acetonitrile (2.0 ml).
A solution of AN (334 mg, 0.610 mmol) in water (1.0 ml) was added dropwise under ice-cooling, and the mixture was stirred for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by alumina column chromatography (ethyl acetate), and recrystallized from ethyl acetate to obtain the title compound (35 mg). Crystal: mp 140-143 ° C Example 6 Ethyl 2- (8-hydroxyoctyl) -5,6-dimethoxy-4,7-dioxo-2-indanecarboxylate 2- (8-hydroxyoctyl) -4,5, Ethyl 6,7-tetramethoxy-2-indanecarboxylate (80 mg,
0.182 mmol) in acetonitrile (2.0 ml).
A solution of AN (249 mg, 0.455 mmol) in water (1.0 ml) was added dropwise under ice-cooling, and the mixture was stirred for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 2: 1) to give the title compound (44 m
g) was obtained. Oil ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.80 (14H, m), 1.26
(3H, t, J = 7.2Hz), 2.64-2.82 (2H, m), 3.24-3.40 (2H, m),
3.56-3.72 (2H, m), 3.99 (6H, s), 4.17 (2H, q, J = 7.2Hz)

Example 7 8- (2-hydroxymethyl-5,6-dimethoxy-4,
7-dioxoindan-2-yl) octanol 8- (2-hydroxymethyl-4,5,6,7-tetramethoxyindan-2-yl) octanol (147 mg,
0.371 mmol) in acetonitrile (4.0 ml).
A solution of AN (509 mg, 0.928 mmol) in water (1.0 ml) was added dropwise under ice cooling, and the mixture was stirred for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 2), and recrystallized from hexane-ethyl acetate to give the title compound (35 mg). Obtained. Crystals: mp 59-61 ° C. Example 8 N-methyl-2- (8-hydroxyoctyl) -5,6
-Dimethoxy-4,7-dioxo-2-indanecarboxamide N-methyl-2- (8-hydroxyoctyl) -4,5,
6,7-Tetramethoxy-2-indanecarboxamide (255 mg, 0.602 mmol) in acetonitrile (5.0
solution of CAN (828 mg, 1.51 mmol) in water (1.
0 ml) solution was added dropwise under ice cooling and stirred for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (hexane:
After purification by ethyl acetate (2: 1 to 1: 2), recrystallization from ethyl acetate gave the title compound (106 mg). Crystal: mp 120-123 ° C Example 9 8- (5,6-dimethoxy-4,7-dioxoindane-
Ethyl 2- (yl) octanoate A solution of ethyl 8- (4,5,6,7-tetramethoxyindan-2-yl) octanoate (100 mg, 0.245 mmol) in acetonitrile (2.0 ml) was prepared by adding CAN (336 mg,
(0.613 mmol) in water (1.0 ml) was added dropwise under ice cooling.
Stir for 5 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1), and recrystallized from hexane to give the title compound (15 mg).
I got Crystal: mp 39-40 ° C

Example 10 2- (8-Hydroxyoctyl) -5,6-dimethoxyindan-4,7-dione 8- (4,5,6,7-tetramethoxyindan-2-yl) octanol (138 mg, 0.338 mmol) in acetonitrile (3.0 ml) was added to CAN (463 mg, 0.8).
(45 mmol) in water (1.0 ml) was added dropwise under ice-cooling, and the mixture was stirred for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 2: 1), and recrystallized from hexane-diethyl ether to give the title compound (29.8 mg). ) Got. Crystals: mp 56-58 ° C Example 11 ethyl 2- (4-benzyloxyphenyl) -5,6-dimethoxy-4,7-dioxo-2-indanecarboxylate 2- (4-benzyloxyphenyl) -4, 5,6,7-
Ethyl tetramethoxy-2-indanecarboxylate (35
A solution of CAN (976 mg, 1.78 mmol) in water (1.0 ml) was added to a solution of 0 mg, 0.711 mmol) in acetonitrile (7.0 ml).
The solution was added dropwise under ice cooling and stirred for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried. The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (hexane:
Ethyl acetate = 5: 1). Further recrystallization from hexane-ethyl acetate gave the title compound (178 mg). Crystals: mp 94-97 ° C Example 12 2- (4-benzyloxyphenyl) -5,6-dimethoxy-4,7-dioxo-2-indanecarboxylic acid 2- (4-benzyloxyphenyl) -4,5 , 6,7-
Tetramethoxy-2-indanecarboxylic acid (288 mg,
0.620 mmol) was added and dissolved in acetonitrile (6.0 ml) and ethyl acetate (6.0 ml). CA in the reaction solution
A solution of N (850 mg, 1.55 mmol) in water (2.0 ml) was added dropwise under ice-cooling, and the mixture was further stirred for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (ethyl acetate).
And purified. Recrystallization from hexane-ethyl acetate gave the title compound (81 mg). Crystal: mp 170-175 ° C

Example 13 Ethyl 2- [4- (4-ethoxycarbonyl-1-oxabutyl) phenyl] -5,6-dimethoxy-4,7-dioxo-2-indanecarboxylate Ethoxycarbonyl-1-oxabutyl) phenyl] -4,5,6,7-tetramethoxy-2-
Ethyl indanecarboxylate (300 mg, 0.581 mmol
l) in acetonitrile (6.0 ml) was added to CAN (795).
mg, 1.45 mmol) in water (1.0 ml) was added dropwise under ice-cooling, and the mixture was stirred for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried.
The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 10:
1-5: 1) to give the title compound (200 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.1Hz), 1.2
6 (3H, t, J = 7.1Hz), 2.01-2.20 (2H, m), 2.50 (2H, t, J = 7.3H
z), 3.16 (2H, d, J = 16.3Hz), 3.87 (2H, d, J = 16.3Hz), 3.99
(2H, t, J = 6.0Hz), 4.00 (6H, s), 4.08 (2H, q, J = 7.1Hz), 4.
14 (2H, q, J = 7.1Hz), 6.84 (2H, d, J = 8.9Hz), 7.22 (2H, d, J =
8.9 Hz) Example 14 2- [4- (4-carboxy-1-oxabutyl) phenyl] -5,6-dimethoxy-4,7-dioxo-2-indanecarboxylic acid 2- [4- (4-carboxy- 1-Oxabutyl) phenyl] -4,5,6,7-tetramethoxy-2-indanecarboxylic acid (250 mg, 0.543 mmol) in a mixed solution of acetonitrile (2.0 ml) and ethyl acetate (2.0 ml). (663 mg, 1.21 mmol) in water (1.0 ml) was added dropwise under ice-cooling, and the mixture was stirred for 15 minutes.
g, 0.484 mmol) in water (0.5 ml).
Stirred for minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated saline solution (Wako Pure Chemical Industries, Ltd.) and then dried. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by florisil column chromatography (ethyl acetate-ethyl acetate: methanol = 1: 1) and recrystallized from ethyl acetate to obtain the title compound (38 mg). . Crystals: mp 173-177 ° C Example 15 Ethyl 4- [4- (5,6-dimethoxy-4,7-dioxoindan-2-yl) butoxy] benzoate 4- [4- (4,5,6,7) -Tetramethoxyindane-
2-yl) butoxy] ethyl benzoate (100 mg, 0.1 mg).
218 mmol) in acetonitrile (2.0 ml)
A solution of N (299 mg, 0.545 mmol) in water (1.0 ml) was added dropwise under ice cooling, and the mixture was stirred for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 8: 1). Further recrystallization (hexane-ethyl acetate) gave the title compound (45.
0 mg) were obtained as crystals. Crystal: mp 97-99 ° C

Example 16 4- [4- (5,6-Dimethoxy-4,7-dioxoindan-2-yl) butoxy] phenylmethanol 4- [4- (4,5,6,7-tetramethoxyindan-
2-yl) butoxy] phenylmethanol (370 mg,
0.888 mmol) in acetonitrile (8.0 ml).
A solution of AN (1.24 g, 2.27 mmol) in water (1.0 ml) was added dropwise under ice cooling, and the mixture was further stirred for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 2: 1).
Further recrystallization (hexane-ethyl acetate) gave the title compound (150 mg) as crystals. Crystal: mp 72-75 ° C Example 17 4- [4- (5,6-Dimethoxy-4,7-dioxoindan-2-yl) butoxy] benzoic acid 4- [4- (4,5,6,7-) Tetramethoxyindane-
2-yl) butoxy] benzoic acid (400 mg, 0.929 m
mol) in acetonitrile (8.0 ml).
A solution of 27 g (2.32 mmol) in water (2.0 ml) was added dropwise under ice cooling and stirred for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried. The crude product obtained by evaporating the solvent under reduced pressure was separated by silica gel column chromatography (ethyl acetate) and purified by recrystallization (hexane-ethyl acetate) to obtain the title compound (200 mg) as crystals. Crystals: mp 149-153 ° C Example 18 N, N-dimethyl-4- [4- (5,6-dimethoxy-
4,7-Dioxoindan-2-yl) butoxy] benzamide N, N-dimethyl-4- [4- (4,5,6,7-tetramethoxyindan-2-yl) butoxy] benzamide (358 mg, 0.782 mmol) Acetonitrile (8.0)
A solution of CAN (1.07 g, 1.96 mmol) in water (1.0 ml) was added dropwise to the solution under ice-cooling, and the mixture was stirred for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried. The solvent was distilled off under reduced pressure,
The obtained crude product was separated by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 1: 2), and then purified by recrystallization (diisopropyl ether-ethyl acetate) to give the title compound (153 mg) as crystals. Obtained. Crystal: mp 80-83 ° C

Example 19 2- (8-acetoxyoctyl) -5,6-dimethoxyindane-4,7-dione acetic acid 8- (4,5,6,7-tetramethoxyindane-2
-Yl) octyl (1.25 g) in acetonitrile (13 ml) was added to an aqueous solution of CAN (4.19 g) (13 ml).
l) was added dropwise under ice cooling. After stirring for 15 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 10: 1), recrystallized (hexane-diethyl ether), and then the title compound (700 mg) was obtained.
I got Crystal: mp 47-48 ° C Example 20 8- (5,6-dimethoxy-4,7-dioxoindane-
2- (yl) octyl N-ethylcarbamate 8- (4,5,6,7-tetramethoxyindan-2-yl) octyl N-ethylcarbamate (1.22 g) in acetonitrile (12 ml) was added to CAN (3. 83
g) (12 ml) was added dropwise under ice cooling. After stirring for 15 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 4: 1), and recrystallized (hexane-ethyl acetate) to obtain the title compound (630 mg). Crystal: mp 85-86 ° C Example 21 N- [8- (5,6-Dimethoxy-4,7-dioxoindan-2-yl) octyl] -N, N-dimethylamine hydrochloride N- [8- (4 , 5,6,7-Tetramethoxyindane-
2-yl) octyl] -N, N-dimethylamine (62
0 mg), pyridine-2,6-dicarboxylic acid (660 m
g), a mixture of CAN (2.17 g), acetonitrile (6 ml) and water (3 ml) was added dropwise to a solution of acetonitrile (6 ml) and water (3 ml) under ice-cooling. After stirring for 15 minutes, an aqueous solution (1.0 ml) of CAN (866 mg) was added dropwise under ice cooling. After stirring for further 15 minutes, saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (ethyl acetate), converted into a hydrochloride, and recrystallized (ethanol-diisopropyl ether) to give the title compound (33).
0 mg). Crystal: mp 139-141 ° C (decomposition)

Example 22 5,6-Dimethoxy-2- [8- (4-phenylpiperidino) octyl] indan-4,7-dione hydrochloride 1- [8- (4,5,6,7- Tetramethoxy-2-yl) octyl] -4-phenylpiperidine (760 m
g), pyridine-2,6-dicarboxylic acid (697 mg), acetonitrile (7.6 ml) and water (7.6 ml) in a mixture of CAN (2.29 g), acetonitrile (3.8 ml)
And a solution of water (3.8 ml) was added dropwise under ice cooling. After stirring for 15 minutes, an aqueous solution (2.0 ml) of CAN (762 mg) was added dropwise under ice cooling. After stirring for further 15 minutes, saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to form a hydrochloride, and then recrystallized (ethanol-diisopropyl ether) to give the title compound (500 m
g) was obtained. Crystals: mp 162-164 ° C (decomposition) Example 23 N- [8- (5,6-Dimethoxy-4,7-dioxoindan-2-yl) octyl] phthalimide N- [8- (4,5,6, 7-tetramethoxyindane-
2-yl) octyl] phthalimide (470 mg), pyridine-2,6-dicarboxylic acid (475 mg), acetonitrile (10 ml) and water (5 ml) in a mixture of CAN
(1.56 g), a mixture of acetonitrile (1.5 ml) and water (1.5 ml) were added dropwise under ice cooling. After stirring for 15 minutes, a solution of CAN (520 mg) in water (2.0 ml) was added dropwise under ice cooling. After stirring for an additional 15 minutes, the reaction was diluted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried.
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-hexane-ethyl acetate =
Purification by 5: 1) and recrystallization (hexane-ethyl acetate) gave the title compound (336 mg). Crystals: mp 91-93 ° C Example 24 N- [8- (5,6-Dimethoxy-4,7-dioxoindan-2-yl) octyl] acetamide N- [8- (4,5,6,7-tetra) Methoxyindane
2-yl) octyl] acetamide (700 mg), pyridine-2,6-dicarboxylic acid (857 mg), acetonitrile (7.0 ml), ethyl acetate (7.0 ml) and water (7.0 ml) were added to CAN ( A mixture of 3.75 g), acetonitrile (3.5 ml) and water (3.5 ml) was added dropwise under ice cooling. After stirring for 15 minutes, the reaction was diluted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized (hexane-ethyl acetate) to obtain the title compound (495 mg). Crystal: mp 93-96 ° C

Example 25 5,6-Dimethoxy-2- [8- [4- (2-pyridyl) piperazin-1-yl] octyl] indane-4,
7-dione 1- [8- (4,5,6,7-tetramethoxyindane-
2-yl) octyl] -4- (2-pyridyl) piperazine (1.07 g), pyridine-2,6-dicarboxylic acid (1.05 g), THF (20 ml) and water (10 ml)
To a mixture of the above, an aqueous solution (10 ml) of CAN (4.55 g) was added.
Was added dropwise under ice cooling. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 5: 1), recrystallized (hexane-ethyl acetate), and then subjected to purification of the title compound (220
mg). Crystals: mp 80-84 ° C Example 26 5,6-Dimethoxy-2- [8- (4-piperidinopiperidino) octyl] indane-4,7-dione dihydrochloride 1- [8- (4 , 5,6,7-Tetramethoxyindane-
2-yl) octyl] -4-piperidinopiperidine (8
02 mg), pyridine-2,6-dicarboxylic acid (777 m
g), a mixture of THF (16 ml) and water (8 ml)
An aqueous solution (8 ml) of CAN (3.37 g) was added dropwise under ice cooling. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and dried, and the solvent was distilled off under reduced pressure. After purifying the residue by alumina column chromatography (ethyl acetate),
The compound was converted into a hydrochloride and recrystallized (methanol) to give the title compound (570 mg). Crystals: mp 220 DEG C. (decomposition) Example 27 5,6-Dimethoxy-2- [8- (4-diphenylmethylpiperazin-1-yl) octyl] indane-4,7
-Dione 1- [8- (4,5,6,7-tetramethoxyindane-
2-yl) octyl] -4-diphenylmethylpiperazine (1.00 g), pyridine-2,6-dicarboxylic acid (8
To a mixture of 32 mg), THF (20 ml) and water (10 ml), an aqueous solution (10 ml) of CAN (3.61 g) was added dropwise under ice cooling. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 5: 1), and recrystallized (hexane-ethyl acetate) to obtain the title compound (370 mg). Crystal: mp 112-114 ° C

Example 28 5,6-Dimethoxy-2- (8-morpholinooctyl)
Indane-4,7-dione hydrochloride 4- [8- (4,5,6,7-tetramethoxyindane-
2-yl) octyl] morpholine (489 mg), pyridine-2,6-dicarboxylic acid (561 mg), THF (10 m
l) and water (5 ml) in a mixture of CAN (2.46 g)
Aqueous solution (5 ml) was added dropwise under ice cooling. After stirring for 15 minutes
A saturated aqueous sodium hydrogen carbonate 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (ethyl acetate), converted into a hydrochloride, and recrystallized (ethanol-diisopropyl ether) to give the title compound (360 mg). Crystals: mp 142-147 [deg.] C (decomposition) Example 29 2- [8- (4-benzylpiperazin-1-yl) octyl] -5,6-dimethoxyindan-4,7-dione 4-benzyl-1- [ 8- (4,5,6,7-tetramethoxyindan-2-yl) octyl] piperazine (67
6mg), pyridine-2,6-dicarboxylic acid (647m)
g), a mixture of THF (14 ml) and water (7 ml)
An aqueous solution (7 ml) of CAN (2.83 g) was added dropwise under ice cooling. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (3
80 mg). Crystal: mp 80-81 ° C Example 30 2- [8- (4-chlorophenoxy) octyl] -5,
6-dimethoxyindane-4,7-dione 2- [8- (4-chlorophenoxy) octyl] -4,
5,6,7-tetramethoxyindane (676 mg), pyridine-2,6-dicarboxylic acid (712 mg), THF (1
4 ml) and water (7 ml) in a mixture of CAN (3.11).
A solution of g) in water (7 ml) was added dropwise under ice cooling. After stirring for 15 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane to hexane-ethyl acetate = 10: 1),
After recrystallization (hexane-diethyl ether), the title compound (320 mg) was obtained. Crystal: mp 64-66 ° C

Example 31 4- [3- (5,6-dimethoxy-4,7-dioxoindan-2-yl) propoxy] benzoic acid 4- [3- (4,5,6,7-tetramethoxyindane-
2-yl) propoxy] benzoic acid (1.20 g), pyridine-2,6-dicarboxylic acid (1.44 g), THF (2
4 ml) and water (12 ml) in a mixture of CAN (6.3).
Aqueous solution (12 ml) was added dropwise under ice-cooling. After stirring for 15 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate to obtain the title compound (868 mg). Crystal: mp 171-174 ° C Example 32 N, N-dimethyl-4- [3- (5,6-dimethoxy-
4,7-Dioxoindan-2-yl) propoxy] benzamide N, N-dimethyl-4- [3- (4,5,6,7-tetramethoxyindan-2-yl) propoxy] benzamide (700 mg), pyridine- 2,6-dicarboxylic acid (79
An aqueous solution (7 ml) of CAN (3.44 g) was added dropwise to a mixture of 2 mg), THF (14 ml) and water (7 ml) under ice-cooling. After stirring for 15 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized (hexane-ethyl acetate) to give the title compound (438).
mg). Crystals: mp 100-102 ° C Example 33 5,6-Dimethoxy-2- [3- (4-dimethylaminomethylphenoxy) propyl] indan-4,7-dione hydrochloride 4,5,6,7-tetramethoxy -2- [3- (4-dimethylaminomethylphenoxy) propyl] indane (9
48 mg), pyridine-2,6-dicarboxylic acid (1.02)
g), THF (19 ml) and water (9.5 ml) were added dropwise with an aqueous solution of CAN (4.42 g) (9.5 ml) under ice cooling. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue is subjected to alumina column chromatography (ethyl acetate)
After purification by hydrochloride, the title compound (770 mg) was obtained via recrystallization (ethanol-diisopropyl ether). Crystal: mp 170 ° C (decomposition)

Example 34 5,6-Dimethoxy-2- [3- [4-[(4-piperidinopiperidino) carbonyl] phenoxy] propyl]
Indane-4,7-dione hydrochloride 4,5,6,7-tetramethoxy-2- [3- [4-
[(4-piperidinopiperidino) carbonyl] phenoxy] propyl] indane (1.00 g), pyridine-2,
A solution of CAN (3.85 g) in water (10 ml) was added dropwise to a mixture of 6-dicarboxylic acid (887 mg), THF (20 ml) and water (10 ml) under ice-cooling. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (ethyl acetate), converted into a hydrochloride, and recrystallized (ethanol-diisopropyl ether) to give the title compound (560 mg). Crystals: mp 176-182 [deg.] C (decomposition) Example 35 5,6-dimethoxy-2- [3- [4-[(4-piperidinopiperidino) methyl] phenoxy] propyl] indane-4,7-. Dione dihydrochloride 4,5,6,7-tetramethoxy-2- [3- [4-
[(4-Piperidinopiperidino) methyl] phenoxy]
Propyl] indane (849 mg), pyridine-2,6-
To a mixture of dicarboxylic acid (772 mg), THF (16 ml) and water (8 ml), an aqueous solution (8 ml) of CAN (3.35 g) was added dropwise under ice cooling. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer
The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (ethyl acetate), converted into a hydrochloride, and recrystallized (methanol) to give the title compound (530 mg). Crystals: mp 220 DEG C. (decomposition) Example 36 5,6-Dimethoxy-2- [4- [4-[(4-methylpiperazin-1-yl) carbonyl] phenoxy] butyl] indane-4,7-dione 4 -[4- (5,6-dimethoxy-4,7-dioxoindan-2-yl) butoxy] benzoic acid (500 mg), 1
-Methylpiperazine (250 mg), 1-ethyl-3 hydrochloride
-(3-dimethylaminopropyl) carbodiimide (4
79 mg), 1-hydroxybenzotriazole monohydrate (383 mg), triethylamine (0.697 ml) and T
A mixture of HF (20 ml) was stirred at room temperature for 10 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (ethyl acetate) and recrystallized (ethyl acetate-diisopropyl ether) to give the title compound (297 mg). Crystal: mp 97-100 ° C

Example 37 5,6-Dimethoxy-2- [4- [4-[(4-phenylpiperazin-1-yl) carbonyl] phenoxy] butyl] indane-4,7-dione 4- [4- ( 5,6-dimethoxy-4,7-dioxoindan-2-yl) butoxy] benzoic acid (500 mg), 1
-Phenylpiperazine (406 mg), 1-ethyl hydrochloride-
3- (3-dimethylaminopropyl) carbodiimide (479 mg), 1-hydroxybenzotriazole monohydrate (383 mg), triethylamine (0.697 ml)
And a mixture of THF (20 ml) was stirred at room temperature for 6 hours. After water was added to the reaction solution, the mixture was extracted with a mixture of THF and ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized from THF-diisopropyl ether to give the title compound (400 m
g) was obtained. Crystals: mp 154-159 ° C Example 38 5,6-Dimethoxy-2- [4- [4-[(4-phenylpiperidino) carbonyl] phenoxy] butyl] indan-4,7-dione 4- [4 -(5,6-Dimethoxy-4,7-dioxoindan-2-yl) butoxy] benzoic acid (626 mg), 4
-Phenylpiperidine hydrochloride (617 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (598 mg), 1-hydroxybenzotriazole monohydrate (478 mg), triethylamine (1.30 m
A mixture of l) and THF (12 ml) was stirred at room temperature for 6 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated saline, and dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-diethyl ether to give the title compound (482 mg). Crystals: mp 90-94 ° C Example 39 2- [8- (4-Benzylpiperazin-1-yl) octyl] -5,6-dimethoxy-2-phenylindane-
4,7-dione 4-benzyl-1- [8- (4,5,6,7-tetramethoxy-2-phenylindan-2-yl) octyl] piperazine (713 mg), pyridine-2,6-dicarboxylic acid (597 mg), an aqueous solution (7 ml) of CAN (2.59 g) was added dropwise to a mixture of THF (14 ml) and water (7 ml) under ice-cooling. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (hexane-hexane-ethyl acetate = 8: 1), recrystallized (hexane-diethyl ether), and the title compound (310
mg). Crystal: mp 78-80 ° C

Example 40 2- (8-Hydroxyoctyl) -5,6-dimethoxy-2-phenylindane-4,7-dione 8- (4,5,6,7-tetramethoxy-2-phenylindane- 2-yl) octanol (1.00 g), pyridine-2,6-dicarboxylic acid (1.13 g), THF (2 g)
0 ml) and water (10 ml) in a mixture of CAN (4.9).
An aqueous solution (2 ml) (10 ml) was added dropwise under ice cooling. After stirring for 15 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 4: 1) to obtain the title compound (542 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 0.80-1.78 (14H, m), 2.96-
3.24 (4H, m), 3.60 (2H, t), 4.01 (6H, s), 7.14-7.40 (5H,
m) Example 41 8- (5,6-Dimethoxy-4,7-dioxo-2-phenylindan-2-yl) octanoic acid 8- (4,5,6,7-Tetramethoxy-2-phenylindan- 2-yl) octanoic acid (465 mg), pyridine-2,6-dicarboxylic acid (511 mg), THF (10 m
l) and water (5 ml) in a mixture of CAN (2.22 g)
Aqueous solution (5 ml) was added dropwise under ice cooling. After stirring for 15 minutes
Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 2: 1), and recrystallized (hexane-diethyl ether) to obtain the title compound (220 mg). Crystal: mp 63-66 ° C. Example 42 1,6-bis- (5,6-dimethoxy-4,7-dioxoindan-2-yl) hexane 1,6-bis- (4,5,6,7-tetra) (Methoxyindan-2-yl) hexane (1.07 g), pyridine-2,6
-To a mixture of dicarboxylic acid (1.92 g), THF (40 ml) and water (10 ml), an aqueous solution (10 ml) of CAN (8.44 g) was added dropwise under ice cooling. After stirring for 15 minutes, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Water the organic layer,
After washing with a saturated saline solution and drying, the solvent was distilled off under reduced pressure.
The residue was purified by alumina column chromatography (ethyl acetate) and recrystallized (hexane-ethyl acetate) to obtain the title compound (430 mg). Crystal: mp 144-147 ° C

Example 43 5,6-Dimethoxy-2- [4- [4- (morpholinocarbonyl) phenoxy] butyl] indan-4,7-dione 4,5,6,7-tetramethoxy-2- [4 -[4- (morpholinocarbonyl) phenoxy] butyl] indane (1.50 g), pyridine-2,6-dicarboxylic acid (1.
An aqueous solution (15 ml) of CAN (7.02 g) was added dropwise to a mixture of 60 g), THF (30 ml) and water (15 ml) under ice-cooling. After stirring for 15 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 and dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (965 mg). Crystals: mp 128 DEG-131 DEG C. Example 44 5,6-Dimethoxy-2- [4- [4- (morpholinomethyl) phenoxy] butyl] indane-4,7-dione hydrochloride 4,5,6,7-tetra Methoxy-2- [4- [4- (morpholinomethyl) phenoxy] butyl] indane (1.
04g), pyridine-2,6-dicarboxylic acid (1.08)
g), an aqueous solution (11 ml) of CAN (4.71 g) was added dropwise to a mixture of THF (22 ml) and water (11 ml) under ice-cooling. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is saturated aqueous sodium bicarbonate,
The extract was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure.
The residue was purified by alumina column chromatography (ethyl acetate) to give a hydrochloride, which was recrystallized from ethanol-diisopropyl ether to give the title compound (730 mg). Crystals: mp 160 DEG-164 DEG C. (decomposition) Example 45 2- (2,3-dimethoxy-1,4-dioxo-4,5,
Ethyl 6,7,8,9-hexahydro-1H-benzo [a] cyclohepten-7-yl) acetate 2- (1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H- Benzo [a] cycloheptene-7-
Il) To a mixture of ethyl acetate (800 mg), pyridine-2,6-dicarboxylic acid (1.14 g), THF (16 ml) and water (8 ml) was added an aqueous solution (8 ml) of CAN (4.98 g) under ice cooling. It was dropped. After stirring for 15 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 4: 1) to give the title compound (6
04 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 0.86-1.20 (2H, m), 1.26 (3
H, t), 1.80-1.98 (2H, m), 2.08-2.34 (5H, m), 3.10-3.28 (2
H, m), 3.99 (6H, s), 4.14 (2H, q)

Example 46 7- (2-Hydroxyethyl) -2,3-dimethoxy-
4,5,6,7,8,9-hexahydro-1H-benzo [a] cycloheptene-1,4-dione 2- (1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro -5H-benzo [a] cycloheptene-7-
Il) To a mixture of ethanol (800 mg), pyridine-2,6-dicarboxylic acid (1.29 g), THF (16 ml) and water (8 ml), an aqueous solution (8 ml) of CAN (5.65 g) was added dropwise under ice cooling. did. After stirring for 15 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 2: 1), and recrystallized (hexane-ethyl acetate) to obtain the title compound (479 mg). Crystal: mp 63-64 ° C Example 47 2- (2,3-Dimethoxy-1,4-dioxo-4,5,
6,7,8,9-Hexahydro-1H-benzo [a] cyclohepten-7-yl) acetic acid 2- (1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo) [A] Cycloheptene-7-
Yl) acetic acid (800 mg), pyridine-2,6-dicarboxylic acid (1.24 g), THF (16 ml) and water (8 ml).
To a mixture of l), an aqueous solution of CAN (5.42 g) (8 ml)
Was added dropwise under ice cooling. After stirring for 15 minutes, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water,
After washing with a saturated saline solution and drying, the solvent was distilled off under reduced pressure.
The residue was recrystallized from ethyl acetate to give the title compound (450
mg). Crystal: mp 130-132 ° C Example 48 4- [2- (2,3-Dimethoxy-1,4-dioxo-)
Ethyl 4,5,6,7,8,9-hexahydro-1H-benzo [a] cyclohepten-7-yl) ethoxy] benzoate 4- [2- (1,2,3,4-tetramethoxy-6, 7,8,
Ethyl 9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethoxy] benzoate (650 mg),
Pyridine-2,6-dicarboxylic acid (712 mg), THF
(28 ml) and water (7 ml) in a mixture of CAN (3.
(09 g) was added dropwise under ice-cooling, and the mixture was stirred for 45 minutes. The reaction solution was heated to room temperature, stirred for 15 minutes, added with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 2: 1), and recrystallized (hexane-ethyl acetate) to obtain the title compound (430 mg). Crystal: mp 104-106 ° C

Example 49 7- [2- [4- (Hydroxymethyl) phenoxy] ethyl] -2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo [a] cycloheptene -1,4
-Dione 4- [2- (1,2,3,4-tetramethoxy-6,7,8,
9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethoxy] phenylmethanol (261 m
g), pyridine-2,6-dicarboxylic acid (314 mg), T
To a mixture of HF (6 ml) and water (3 ml) was added CAN
(1.38 g) in water (3 ml) was added dropwise under ice cooling. 1
After stirring for 5 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane-ethyl acetate = 2: 1) and recrystallized (hexane-ethyl acetate) to obtain the title compound (106 mg). Crystal: mp 57-59 ° C Example 50 4- [2- (2,3-Dimethoxy-1,4-dioxo-
4,5,6,7,8,9-Hexahydro-1H-benzo [a] cyclohepten-7-yl) ethoxy] benzoic acid 4- [2- (1,2,3,4-tetramethoxy-6,7 , 8,
9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethoxy] benzoic acid (1.00 g), pyridine-2,6-dicarboxylic acid (1.16 g), THF (4
0 ml) and water (10 ml) in a mixture of CAN (5.0 ml).
An aqueous solution (10 ml) of 9 g) was added dropwise under ice cooling. After stirring for 15 minutes, water was added to the reaction solution, and the mixture was extracted with a mixture of ethyl acetate and THF. The organic layer was washed with water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized from THF-ethyl acetate to give the title compound (400 mg). Crystal: mp 190-195 ° C Example 51 7- [2- (4-Chlorophenoxy) ethyl] -2,3
-Dimethoxy-4,5,6,7,8,9-hexahydro-1
H-benzo [a] cycloheptene-1,4-dione 7- [2- (4-chlorophenoxy) ethyl] -1,2,
3,4-tetramethoxy-6,7,8,9-tetrahydro-
5H-benzo [a] cycloheptene (1.38 g), pyridine-2,6-dicarboxylic acid (1.64 g), THF
(52 ml) and water (13 ml) in a mixture of CAN
An aqueous solution (13 ml) of (7.18 g) was added dropwise under ice cooling.
After stirring for 15 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (ethyl acetate) and recrystallized (hexane-ethyl acetate) to obtain the title compound (1.02 g). Crystal: mp 117-119 ° C

Example 52 2,3-Dimethoxy-7- [2- (4-phenylphenoxy) ethyl] -4,5,6,7,8,9-hexahydro-
1H-benzo [a] cycloheptene-1,4-dione 7- [2- (4-phenylphenoxy) ethyl] -1,
2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene (1.53
g), pyridine-2,6-dicarboxylic acid (1.66 g),
To a mixture of THF (60 ml) and water (15 ml) was added CA
An aqueous solution (15 ml) of N (7.24 g) was added dropwise under ice cooling. After stirring for 15 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (ethyl acetate) and recrystallized (hexane-ethyl acetate) to obtain the title compound (550 mg). Crystals: mp 109-112 ° C Example 53 7- [2- (1H-Benzo [d] imidazol-1-yl) ethyl] -2,3-dimethoxy-4,5,6,7,8,9
-Hexahydro-1H-benzo [a] cycloheptene-
1,4-dione 1- [2- (1,2,3,4-tetramethoxy-6,7,8,
9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethyl] -1H-benzo [d] imidazole (380 mg), pyridine-2,6-dicarboxylic acid (4
To a mixture of 65 mg), THF (8 ml) and water (4 ml) was added dropwise an aqueous solution (4 ml) of CAN (2.03 g) under ice-cooling. After stirring for 15 minutes, a saturated aqueous sodium bicarbonate solution was added to the reaction solution,
Extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (240 mg). Crystals: mp 159-163 ° C Example 54 2,3-Dimethoxy-7- [2- (3-pyridyloxy) ethyl] -4,5,6,7,8,9-hexahydro-1
H-benzo [a] cycloheptene-1,4-dione 3- [2- (1,2,3,4-tetramethoxy-6,7,8,
9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethoxy] pyridine (470 mg), pyridine-2,6-dicarboxylic acid (607 g), THF (10 m
l) and water (5 ml) in a mixture of CAN (2.65 g)
Aqueous solution (5 ml) was added dropwise under ice cooling. After stirring for 15 minutes
A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, and then dried.
The solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (ethyl acetate) and recrystallized from hexane-ethyl acetate to obtain the title compound (310 mg). Crystal: mp 80-82 ° C

Example 55 2,3-Dimethoxy-7- [2- (2-oxo-1,2-
Dihydro-1-pyridyl) ethyl] -4,5,6,7,8,
9-hexahydro-1H-benzo [a] cycloheptene-1,4-dione 1- [2- (1,2,3,4-tetramethoxy-6,7,8,
9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethyl] -1,2-dihydro-2-pyridinone (334 mg), pyridine-2,6-dicarboxylic acid (433 mg), THF (8 ml) and water (4 ml), an aqueous solution (4 ml) of CAN (1.89 g) was added dropwise to the mixture under ice cooling. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate 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 and dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized from diisopropyl ether to give the title compound (195 mg).
I got Crystal: mp 85-89 ° C Example 56 2,3-Dimethoxy-7- [2- (2-pyridyloxy) ethyl] -4,5,6,7,8,9-hexahydro-1
H-benzo [a] cycloheptene-1,4-dione 2-
[2- (1,2,3,4-tetramethoxy-6,7,8,9-
Tetrahydro-5H-benzo [a] cycloheptene-7
-Yl) ethoxy] pyridine (700 mg), pyridine-
2,6-dicarboxylic acid (907 mg), THF (14 ml)
An aqueous solution (7 ml) of CAN (3.97 g) was added dropwise to a mixture of and water (7 ml) under ice cooling. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 1: 2) to obtain the title compound (490 mg). Oil ¹ H-NMR (CDCl ₃ ) δ: 0.92-1.20 (2H, m), 1.50-
2.34 (7H, m), 3.07-3.27 (2H, m), 3.85-4.05 (2H, m), 3.99
(6H, s), 6.11-6.22 (1H, m), 6.52-6.61 (1H, m), 7.18-7.3
9 (2H, m)

Example 57 2,3-Dimethoxy-7- [2- (2-oxo-1,2-
Dihydro-1-quinolyl) ethyl] -4,5,6,7,8,
9-hexahydro-1H-benzo [a] cycloheptene-1,4-dione 1- [2- (1,2,3,4-tetramethoxy-6,7,8,
9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethyl] -1,2-dihydro-2-quinolinone (612 mg), pyridine-2,6-dicarboxylic acid (702 mg), THF (12 ml) and water (6 ml), an aqueous solution (6 ml) of CAN (3.07 g) was added dropwise under ice-cooling. After stirring for 15 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane: ethyl acetate = 8: 1), and recrystallized from hexane-ethyl acetate to obtain the title compound (310 mg). Crystal: mp 88-90 ° C Example 58 2,3-Dimethoxy-7- [2- (2-quinolyloxy) ethyl] -4,5,6,7,8,9-hexahydro-1
H-benzo [a] cycloheptene-1,4-dione 2-
[2- (1,2,3,4-tetramethoxy-6,7,8,9-
Tetrahydro-5H-benzo [a] cycloheptene-7
-Yl) ethoxy] quinoline (580 mg), pyridine-
2,6-dicarboxylic acid (667 mg), THF (18 ml)
An aqueous solution (6 ml) of CAN (2.92 g) was added dropwise to a mixture of water and water (6 ml) under ice-cooling. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate 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 and dried, and the solvent was distilled off under reduced pressure. Recrystallize from ethyl acetate to give the title compound (350m
g) was obtained. Crystal: mp 134-136 ° C

Example 59 7- [2- (1H-Benzotriazol-1-yl) ethyl] -2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo [a Cycloheptene-1,4-
Dione 1- [2- (1,2,3,4-tetramethoxy-6,7,8,
9-tetrahydro-5H-benzo [a] cyclohepten-7-yl) ethyl] -1H-benzotriazole (80
0mg), pyridine-2,6-dicarboxylic acid (973m
g), a mixture of THF (16 ml) and water (8 ml)
An aqueous solution (8 ml) of CAN (4.25 g) was added dropwise under ice cooling. After stirring for 15 minutes, a 10% aqueous potassium carbonate 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 and dried, and the solvent was distilled off under reduced pressure. The residue was purified by alumina column chromatography (ethyl acetate) and recrystallized from hexane-ethyl acetate to obtain the title compound (580 mg). Crystal: mp. 91-93 ° C Example 60 4- [2- (2,3-dimethoxy-1,4-dioxo-
4,5,6,7,8,9-Hexahydro-1H-benzo [a] cyclohepten-7-yl) ethoxy] -1-benzenecarbonitrile 7- (2-hydroxyethyl) -2,3-dimethoxy-
4,5,6,7,8,9-hexahydro-1H-benzo [a] cycloheptene-1,4-dione (103 mg),
To a THF solution (2 ml) of p-cyanophenol (127 mg) and triphenylphosphine (126 mg) was added a THF solution (1 ml) of diethyl azodicarboxylate (90 mg) at room temperature. The reaction solution was stirred at room temperature for 2 hours and concentrated. The residue was purified by alumina column chromatography (developing solvent: ethyl acetate / hexane = 1/4), and the obtained crude crystals were recrystallized from ethyl acetate / hexane to give the title compound (118 mg). Crystal: mp. 105-107 ° C

Example 61 2,3-Dimethoxy-7- [2- (4-methoxyphenoxy) ethyl] -4,5,6,7,8,9-hexahydro-
1H-benzo [a] cycloheptene-1,4-dione 7- (2-hydroxyethyl) -2,3-dimethoxy-
4,5,6,7,8,9-hexahydro-1H-benzo [a] cycloheptene-1,4-dione (56 mg), p
To a THF solution (1 ml) of -methoxyphenol (78 mg) and triphenylphosphine (69 mg) was added a THF solution (1 ml) of diethyl azodicarboxylate (45 mg) at room temperature. The reaction solution was stirred at room temperature for 2 hours and concentrated. The residue was purified by alumina column chromatography (developing solvent: ethyl acetate / hexane = 1/4) to give the title compound (68
mg). Crystal: mp. 76-77 ° C Recrystallization solvent; ethyl acetate / hexane Example 62 7- [2- (4-Fluorophenoxy) ethyl] -2,
3-dimethoxy-4,5,6,7,8,9-hexahydro-
1H-benzo [a] cycloheptene-1,4-dione 7- (2-hydroxyethyl) -2,3-dimethoxy-
4,5,6,7,8,9-hexahydro-1H-benzo [a] cycloheptene-1,4-dione (102 mg),
To a THF solution (2 ml) of p-fluorophenol (129 mg) and triphenylphosphine (132 mg) was added a THF solution (1 ml) of diethyl azodicarboxylate (81 mg) at room temperature. The reaction solution was stirred at room temperature for 2 hours and concentrated.
The residue was subjected to alumina column chromatography (developing solvent:
Purification with ethyl acetate / hexane = 1/10) and the obtained crude crystals were recrystallized from diisopropyl ether to give the title compound (99 mg). Crystal: mp 91-93 ° C

Example 63 2,3-Dimethoxy-7- [2- (4-methylphenoxy) ethyl] -4,5,6,7,8,9-hexahydro-1
H-benzo [a] cycloheptene-1,4-dione 7- (2-hydroxyethyl) -2,3-dimethoxy-
4,5,6,7,8,9-hexahydro-1H-benzo [a] cycloheptene-1,4-dione (103 mg),
To a THF solution (2 ml) of p-cresol (118 mg) and triphenylphosphine (121 mg) was added a THF solution (1 ml) of diethyl azodicarboxylate (87 mg) at room temperature. The reaction solution was stirred at room temperature for 2 hours and concentrated. The residue was purified by alumina column chromatography (developing solvent: ethyl acetate / hexane = 1/10), and further recrystallized from diisopropyl ether / hexane to give the title compound (8
0 mg). Crystal: mp 56-57 ° C

Example 64 2,3-Dimethoxy-7- [2- (3,5-dimethoxyphenoxy) ethyl] -4,5,6,7,8,9-hexahydro-1H-benzo [a] cycloheptene- 1,4-dione 7- (2-hydroxyethyl) -2,3-dimethoxy-
4,5,6,7,8,9-hexahydro-1H-benzo [a] cycloheptene-1,4-dione (103 mg),
To a THF solution (2 ml) of 3,5-dimethoxyphenol (168 mg) and triphenylphosphine (125 mg) was added a THF solution of diethyl azodicarboxylate (81 mg) (1 m 2).
l) was added at room temperature. The reaction solution was stirred at room temperature for 2 hours and concentrated. The residue was purified by alumina column chromatography (developing solvent: ethyl acetate / hexane = 1/4), and further recrystallized from ethyl acetate / hexane to obtain the title compound (108 mg). Crystal: mp 63-65 ° C Example 65 7- [2- (4-acetamidophenoxy) ethyl]-
2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo [a] cycloheptene-1,4-dione 7- (2-hydroxyethyl) -2,3-dimethoxy-
4,5,6,7,8,9-hexahydro-1H-benzo [a] cycloheptene-1,4-dione (101 mg),
A THF solution (1 mg) of diethyl azodicarboxylate (81 mg) was added to a THF solution (3 ml) of p-hydroxyacetanilide (166 mg) and triphenylphosphine (126 mg).
l) was added at room temperature. After stirring the reaction at room temperature for 80 minutes,
Concentrated. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/1) and alumina column chromatography (developing solvent: ethyl acetate / hexane = 1/1).
Recrystallization from hexane gave the title compound (93 mg). Crystal: mp 151-154 ° C Example 66 2,3-Dimethoxy-7- [2- (3,4-methylenedioxyphenoxy) ethyl] -4,5,6,7,8,9-hexahydro-1H- Benzo [a] cycloheptene-1,4
-Dione 7- (2-hydroxyethyl) -2,3-dimethoxy-
4,5,6,7,8,9-tetrahydro-1H-benzo [a] cycloheptene-1,4-dione (102 mg),
Sesamol (153 mg), triphenylphosphine (1
To a solution of 22 mg) in THF (2 ml) was added a solution of diethyl azodicarboxylate (87 mg) in THF (1 ml) at room temperature.
The reaction solution was stirred at room temperature for 1 hour and concentrated. The residue was subjected to alumina column chromatography (developing solvent: ethyl acetate /
Purification with hexane (1/4) and further recrystallization from diethyl ether / hexane gave the title compound (104 mg). Crystal: mp 75-78 ° C

Example 67 2,3-Dimethoxy-7- (2-phenoxyethyl)-
4,5,6,7,8,9-hexahydro-1H-benzo [a] cycloheptene-1,4-dione 7- (2-hydroxyethyl) -2,3-dimethoxy-
4,5,6,7,8,9-hexahydro-1H-benzo [a] cycloheptene-1,4-dione (100 mg),
Phenol (109 mg), triphenylphosphine (1
To a solution of 27 mg) in THF (2 ml) was added a solution of diethyl azodicarboxylate (82 mg) in THF (1 ml) at room temperature.
The reaction solution was stirred at room temperature for 140 minutes and concentrated. The residue was purified by alumina column chromatography (developing solvent: ethyl acetate / hexane = 1/10), and further recrystallized from ethyl acetate / hexane to obtain the title compound (78 mg). Crystal: mp 71-72 ° C Example 68 2,3-Dimethoxy-7- [2- (3,4,5-trimethoxyphenoxy) ethyl] -4,5,6,7,8,9-hexahydro-1H -Benzo [a] cycloheptene-1,4
-Dione 7- (2-hydroxyethyl) -2,3-dimethoxy-
4,5,6,7,8,9-hexahydro-1H-benzo [a] cycloheptene-1,4-dione (165 mg),
3,4,5-Trimethoxyphenol (335 mg), triphenylphosphine (201 mg) in THF solution (3 ml)
To this was added a solution of diethyl azodicarboxylate (148 mg) in THF (1 ml) at room temperature. The reaction solution was stirred at room temperature for 25 minutes and concentrated. The residue was purified by alumina column chromatography (developing solvent: ethyl acetate / hexane = 1/4), and further recrystallized from ethyl acetate / hexane to obtain the title compound (210 mg). Crystal: mp 91-93 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.94-1.18 (2H, m), 1.72 (2
H, q), 1.86-2.03 (3H, m), 2.22 (2H, dd), 3.19 (2H, dd), 3.
79 (3H, s), 3.85 (6H, s), 3.96 (2H, t), 4.00 (6H, m), 6.14
(2H, s) The chemical structural formulas of the compounds obtained in Examples 1 to 68 are shown in [Table 1] to [Table 5].

[0150]

[Table 1]

[0151]

[Table 2]

[0152]

[Table 3]

[0153]

[Table 4]

[0154]

[Table 5]

Formulation Example 1 (1) Compound obtained in Example 10 50 mg (2) Lactose 34 mg (3) Corn starch 10.6 mg (4) Corn starch (paste-like) 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 (Method) Male 12-week-old JCl: Wistar rats were used for the experiment.
After sacrifice of the rat by decapitation, the brain was immediately removed and 1 ml containing 10 ml of 150 mM KCl per brain.
0 mM Tris hydrochloric acid buffer (pH 7.4) was added, and the mixture was homogenized with a Teflon homogenizer. Homogenate,
After centrifugation at 2,200 rpm at 4 ° C. for 10 minutes, the supernatant was taken and used for the experiment. Take 250 μl of the homogenate supernatant into a 96-well plate, add the test substance, and add
Incubated for minutes. When glutamic acid and succinic acid are added, the concentrations are 5.0 mM and 2.5 mM, respectively.
M was added before incubation. The thiobarbituric acid (TBA) method was used for the quantification of the produced lipid peroxide. After the incubation, add 50 μl of 3
After adding 5% perchloric acid, the mixture was centrifuged at 2,000 rpm and 4 ° C. for 10 minutes.
Transferred to the well plate. 100 μl of TBA (5
mg / ml TBA in 50% acetic acid).
Allowed to react for hours. After the reaction, the mixture was cooled to room temperature, and the absorbance at 532 nm was measured.

On the other hand, a calibration curve was prepared using tetraethoxypropane as a substrate of TBA, and the concentration of lipid peroxide when a test substance was added was determined. Similarly, the concentration of lipid peroxide when the brain homogenate was incubated for 30 minutes without addition of the test substance and the concentration of lipid peroxide when 35% perchloric acid was added before the incubation (without addition of the test substance) were determined. The inhibition rate was determined according to the following equation. The 50% inhibitory concentration (IC ₅₀ ) was calculated using the log-probit method. Inhibition amount (%) = [(CA) / (CB)] × 100 A: Concentration of lipid peroxide when test substance was added B: Percentage when 35% perchloric acid was added before incubation Lipid oxidized concentration C: Lipid peroxide concentration when no test substance was added (Results) The results are shown in [Table 6].

TABLE 6 Lipid peroxide production inhibitory action (IC ₅₀ ; μM) Compound Brain homogenate Addition of glutamic acid and succinic acid Example 9 2.3 0.94 Example 10 1.1 0.17 As a result, the compound of the present invention ( It was confirmed that I) has the effect of suppressing the production of lipid peroxide by brain homogenate. Furthermore, the compound (I) of the present invention strongly inhibits the production of lipid peroxide which is observed when succinic acid, a substrate of the complex II of the mitochondrial electron transport system, and glutamic acid, a substrate of the complex I, are added simultaneously. I found out. This indicates that compound (I) functions to protect mitochondrial function, normalizes the energy production function in mitochondria, and strongly suppresses the production of lipid peroxide caused by an abnormality in the electron transport system. Therefore, compound (I) can normalize motor and central functions by smoothly transferring electrons from complex II in mitochondria and enhancing energy production.

[0158]

The compound (I) of the present invention exhibits excellent mitochondrial function activating action and antioxidant action, so that it can provide a clinically useful preventive / therapeutic agent for diseases such as Alzheimer's disease. Further, the compound (I) of the present invention
Excellent physical properties such as stability and crystallinity.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/215 ADS A61K 31/215 ADS 31/23 ABL 31/23 ABL 31/40 31/40 31/47 31/47 31 / 495 31/495 31/535 AED 31/535 AED C07C 46/06 C07C 46/06 50/38 50/38 225/24 225/24 C07D 209/48 C07D 211/10 211/10 211/58 211/58 213 / 64 213/64 213/65 213/65 215/22 215/22 295/10 A 295/10 Z 295/18 Z 295/18 A 209/48 Z

Claims (17)

[Claims] (1) Formula (1) Wherein R ¹ and R ² are each lower alkyl, or R ¹ and R ² may be bonded to each other to form a ring, X is a spacer having 1 to 15 atoms in the main chain, Y is acyl, Hydroxyl which may have a substituent, amino which may have a substituent or an aromatic group which may have a substituent, ring A has a formula -XY (wherein each symbol is A 5- to 8-membered ring which may further have a substituent in addition to the group represented by the same meaning as above)] or a salt thereof. 2. R ¹ and R ² are each a C _1-6 alkyl,
Or R ¹ and R ² are bonded to each other to form a compound of the formula: Forming a 5- to 7-membered ring represented by the formula: X may have 1 to 3 substituents each selected from oxo and optionally halogenated C _1-6 alkyl (1) C _{1 -15} alkylene, (2) C _2-15 alkenylene or (3) C _2-15 alkynylene or formula :-( CH ₂₎ m-X ¹
−, − (CH ₂ ) m−X ² −X ¹ −, −X ¹ −X ² − (CH ₂ ) n−, −X ² −
X ^1- (CH ₂ ) n-,-(CH ₂ ) m-X ^1- (CH ₂ ) n-,-(CH ₂ ) m-X ²
− (CH ₂ ) n−, − (CH ₂ ) m−X ¹ −X ² − (CH ₂ ) n−, − (CH ₂ ) m−
X ² -X ^1- (CH ₂ ) n- or -X ² -X ¹ -X ^2- (CH ₂ ) n- wherein X ¹ is oxo and C _1-6 which may be halogenated (1) a divalent C _5-8 monocyclic non-aromatic hydrocarbon group, each of which may have 1 to 3 substituents selected from alkyl, (2) a divalent C _6-14 aromatic A hydrocarbon group or (3) a divalent 5- to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom; X ² is O, S, SO Or m ₂ and n are each an integer of 0 to 10; and m + n is an integer of 1 to 13.] Y is a group represented by the formula (1): —CO—R ³ , —CO—OR ³ , -C
^{O-NR 3 R 4, -CS} -NHR 3, -SO 2 -R 3a or in -SO-R ^3a [wherein, R ³ is (a) hydrogen atom, (b) as a substituent (i) halogen, ( ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl, (vi) optionally halogenated C _3-6 Cycloalkyl, (vii) optionally halogenated C _1-6 alkoxy, (viii) optionally halogenated C _1-6 alkylthio, (ix) hydroxy, (x) amino, (xi) mono- C _1-6 alkylamino, (xii) di-C _1-6 alkylamino, (xiii) formyl, carboxy, 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- to 6-membered heterocyclic carbonyl,
Carbamoyl, mono-C _1-6 alkyl-carbamoyl,
Di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-
Carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C
_1-6 alkylsulfonyl and C _6-10 acyl selected from arylsulfonyl, (xiv) formylamino, C _1-6
Alkyl-carboxamides, C _6-10 aryl-carboxamides, C _1-6 alkoxy-carboxamides and C _1-6
Acylamino selected from alkylsulfonylamino,
(Xv) 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-carbamoyl Oxy, C _6-10
Acyloxy selected from aryl-carbamoyloxy and nicotinoyloxy, (xvi) (xvi-1) C _1-6
Alkyl, (xvi-2) halogen, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C
_1-6 alkyl, optionally halogenated C _{3 -6} cycloalkyl optionally have, optionally halogenated C _1-6 alkoxy optionally, a C _1-6 alkylthio which may be halogenated,
Hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _{6 -10} aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6 Alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6
C _6-14 aryl, C _{7-16 optionally} having 1 to 5 substituents each selected from alkyl-carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy
5- to 7-membered saturated cyclic amino or 5- or 6-membered aromatic heterocyclic group and (xvi-3) _C6-10 aryl-carbonyl, which may have one or two substituents which may have one or two substituents 7-membered saturated cyclic amino, (xvii) sulfo and (xviii) (1 ′) halogen, (2 ′) C _1-3 alkylenedioxy, (3 ′) nitro, (4 ′) cyano, (5 ′) halogenated _Optionally substituted C _1-6 alkyl, (6 ′) optionally halogenated C _3-6 cycloalkyl, (7 ′)
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') (13'-1) C _1-6 alkyl, (13'-2) halogen, C _1-3 alkylenedioxy , nitro, cyano, C _1-6 alkyl which may be halogenated, halogenated which may be C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy optionally, an optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C
_6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10
Aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C
_1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyl C _6-14 aryl, C _7-16 aralkyl which may have 1 to 5 substituents selected from oxy and di-C _1-6 alkyl-carbamoyloxy, respectively, 5- to 7-membered saturated cyclic amino or A 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from a _6- to 6-membered aromatic heterocyclic group and a (13′-3) C _6-10 aryl-carbonyl, (14 ′) Formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl, mono-C
_1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5 to 6
Acyl selected from membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl, (1
5 ′) acylamino selected from formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (16 ′) 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-
Acyloxy selected from carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (17 ′) sulfo, (18 ′) C _6-10 aryl, (19 ′)
C _{6-10 optionally} having 1 to 5 substituents selected from aryloxy and (20 ′) oxo
_6-14 aryl, C _6-10 quinonyl or a substituent selected from a 5- to 14-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom Each having 1 to 5 C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-14 aryl or C
_7-16 aralkyl, or (c) as a substituent (i) halogen, (ii) C _1-3 alkylenedioxy, (iii) nitro,
(Iv) cyano, (v) optionally halogenated C _1-6
Alkyl, (vi) optionally halogenated C _3-6 cycloalkyl, (vii) optionally halogenated C _3-6 cycloalkyl
_1-6 alkoxy, (viii) optionally halogenated C _1-6 alkylthio, (ix) hydroxy, (x) amino,
(Xi) mono-C _1-6 alkylamino, (xii) di-C _1-6
Alkylamino, (xiii) (xiii-1) C _1-6 alkyl,
(Xiii-2) halogen, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, halogenated Optionally C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6
Alkylamino, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di -C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6
Alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-
C _6-14 aryl, C _7-16 aralkyl, 5- to 7-membered saturated cyclic amino, which may have 1 to 5 substituents each selected from carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy, or 5- or 7-membered saturated cyclic amino optionally having one or two substituents selected from a 5- or 6-membered aromatic heterocyclic group and (xiii-3) C _6-10 aryl-carbonyl, (xiv) formyl Carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C
Acyl selected from _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl, (xv) formylamino, C _{1- 6} alkyl-carboxamide, C _6-10 aryl-carboxamide,
C _1-6 alkoxy - acylamino selected from carboxamide and C _1-6 alkylsulfonylamino, (xvi)
C _1-6 alkyl-carbonyloxy, C _6-10 aryl-
Carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-
Acyloxy selected from C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (xvii) sulfo, (xviii) C
_6-10 aryl, (xix) C _6-10 aryloxy and (xix
x) 5 which may have 1 to 5 substituents selected from oxo and contains 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms
Or a 14-membered heterocyclic group, wherein R ^3a is (a) a substituent (i)
Halogen, (ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl, (vi) optionally halogenated C _3-6 cycloalkyl, (vii) optionally halogenated C _1-6 alkoxy, (viii) optionally halogenated C _1-6 alkylthio, (ix) hydroxy, (x) amino, (xi ) Mono-C _1-6 alkylamino, (xii) di-
C _1-6 alkylamino, (xiii) formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic Acyl selected from carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl, (xiv) formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C
Acylamino selected from _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (xv) C
_1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-
Acyloxy selected from C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (xvi) (xvi-1) C _1-6 alkyl, (xvi-2) halogen, 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, halogen Optionally substituted C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6
Alkylamino, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di -C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6
Alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-
C _6-14 aryl, C _7-16 aralkyl which may have 1 to 5 substituents each selected from carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy, a 5- to 7-membered saturated cyclic amino or A 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from a 5- or 6-membered aromatic heterocyclic group and (xvi-3) _C6-10 aryl-carbonyl, (xvii) sulfo And (xviii) (1 ′) halogen, (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 A Kiruamino, (12 ') di -C _1-6 alkylamino, (13') (13 '
-1) C _1-6 alkyl, (13'-2) halogen, 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, C _6-10 aryl, carboxy, formyl, C _{1- 6} alkyl-carbonyl, C
_1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _{1- 6} alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6
Alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyloxy and di -C _1-6
1 substituents selected from alkyl-carbamoyloxy
A C _6-14 aryl _optionally having 5 to 5 each,
It has one or two substituents selected from C _7-16 aralkyl, 5- to 7-membered saturated cyclic amino or 5- to 6-membered aromatic heterocyclic group and (13′-3) C _6-10 aryl-carbonyl. 5- to 7-membered saturated cyclic amino, (1
4 ′) formyl, carboxy, 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, 5-6 membered heterocyclic carbonyl, carbamoyl, 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 and C _6-10 acyl selected from arylsulfonyl, (15 ') formylamino, C _1-6 alkyl - carboxamide, C _{6 Acylamino} selected from _-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (16 ′) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C ₁ Acyloxy selected from _-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (17 ′)
A substituent selected from sulfo, (18 ′) C _6-10 aryl, (19 ′) C _6-10 aryloxy and (20 ′) oxo;
A C _6-14 aryl _optionally having 5 to 5 each,
A C _6-10 quinonyl or 1 to 5 substituents each selected from a 5- to 14-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen other than carbon atoms; Optionally having a C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-14 aryl or C _7-16 aralkyl, or (b) as a substituent (I) halogen, (ii) C
_1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl,
(Vi) optionally halogenated C _3-6 cycloalkyl, (vii) optionally halogenated C _1-6 alkoxy, (viii) optionally halogenated C _1-6 alkylthio, ix) hydroxy, (x) amino, (xi) mono-C _1-6 alkylamino, (xii) di-C _1-6 alkylamino, (xiii) (xiii-1) C _1-6 alkyl, (xiii- 2)
Halogen, 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, C _6-10 aryl, carboxy, formyl, C _1-6
Alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-
Carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl - carbamoyloxy and di -C _1-6 alkyl - 1 a substituent selected from the carbamoyloxy to 5 optionally C _6-14 aryl optionally having respectively, C _{7 It} may have one or two substituents selected from _-16 aralkyl, 5- to 7-membered saturated cyclic amino or 5- to 6-membered aromatic heterocyclic group and (xiii-3) C _6-10 aryl-carbonyl. 5 to 7 membered saturated cyclic amino, (xiv) formyl, carboxy, 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, carbamoyl, 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 and C _6-10 acyl selected from arylsulfonyl, (xv) formylamino, C _1-6 alkyl - carboxamide, C _{6- 10} aryl-carboxamide, C
Acylamino selected from _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (xvi) C
_1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-
Acyloxy selected from C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (xvii) sulfo, (xviii) C
_6-10 aryl, (xix) C _6-10 aryloxy and (xix
x) 5 which may have 1 to 5 substituents selected from oxo and contains 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms
Or 14-membered heterocyclic group; R ⁴ represents a hydrogen atom or C _1-6 alkyl; or R ³ and R ⁴ together with an adjacent nitrogen atom represent (i) halogen, (ii) C _{1- 3} alkylenedioxy, (iii) nitro, (iv) cyano,
(V) an optionally halogenated C _1-6 alkyl, (v
i) optionally halogenated C _3-6 cycloalkyl,
(Vii) optionally halogenated C _1-6 alkoxy,
(Viii) optionally halogenated C _1-6 alkylthio, (ix) hydroxy, (x) amino, (xi) mono-C
_1-6 alkylamino, (xii) di -C _1-6 alkylamino, (xiii) (xiii-1 ) C 1-6 alkyl, (xiii-2) halogen, 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, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl,
C _6-10 aryl-carbonyl, carbamoyl, mono-C
_1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino ,
C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-
C _6-14 aryl, C _{7- optionally} having 1 to 5 substituents each selected from carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy Which may have one or two substituents selected from ₁₆ aralkyl, a 5- to 7-membered saturated cyclic amino or 5- to 6-membered aromatic heterocyclic group and (xiii-3) C _6-10 aryl-carbonyl. Or 7
Membered cyclic amino, (xiv) formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl Mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl Acyl selected from (xv) formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (xvi) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C _1-6 alkoxy-carbonyl Oxy, mono-
C _1-6 alkyl - carbamoyloxy, di -C _1-6 alkyl - carbamoyloxy, C _6-10 aryl - acyloxy selected from carbamoyloxy and nicotinoyloxy oxy, (xvii) sulfo, (xviii) C _6-10 aryl ,
(Xix) forming a 5- to 7-membered nitrogen-containing heterocyclic ring which may have 1 to 3 substituents selected from C _6-10 aryloxy and (xx) oxo; (A) as substituents (i) halogen, (ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano,
(V) an optionally halogenated C _1-6 alkyl, (v
i) optionally halogenated C _3-6 cycloalkyl,
(Vii) optionally halogenated C _1-6 alkoxy,
(Viii) optionally halogenated C _1-6 alkylthio, (ix) hydroxy, (x) amino, (xi) mono-C
_1-6 alkylamino, (xii) di -C _1-6 alkylamino, (xiii) formyl, carboxy, 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 to 6
Membered heterocyclic carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C
Acyl selected from _6-10 arylsulfonyl, (xiv)
Formylamino, C _1-6 alkyl-carboxamide, C
_Acylamino selected from _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (xv) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C
Acyloxy selected from _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy,
(Xvi) (xvi-1) C _1-6 alkyl, (xvi-2) halogen,
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, C _6-10
Aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl- Carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6
Alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy and dialkyl C _6-14 aryl, C _7-16 aralkyl optionally having 1 to 5 substituents selected from —C _1-6 alkyl-carbamoyloxy, 5- to 7-membered saturated cyclic amino or 5- to 6-membered 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from an aromatic heterocyclic group and (xvi-3) C _6-10 aryl-carbonyl, (xvii) sulfo and (xviii) (1 ′) halogen, (2 ′) C _1-3 alkylenedioxy, (3 ′) nitro, (4 ′) cyano, (5 ′) optionally halogenated C _1-6 alkyl, (6 ′ ) Halogenated May be C
_3-6 cycloalkyl, (7 ') optionally halogenated C _1-6 alkoxy optionally, (8') optionally halogenated a C _1-6 alkylthio, (9 ') hydroxy, (10') Amino, (11 ′) mono-C _1-6 alkylamino, (12 ′) di-
C _1-6 alkylamino, (13 ′) (13′-1) C _1-6 alkyl, (13′-2) halogen, 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, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di -C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6
Alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-
C _6-14 aryl, C _7-16 aralkyl, 5- to 7-membered saturated cyclic amino, which may have 1 to 5 substituents each selected from carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy, or A 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from a 5- to 6-membered aromatic heterocyclic group and (13'-3) _C6-10 aryl-carbonyl, (14 ' ) Formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C
Acyl selected from _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl, (15 ′) formylamino, C _{1 -6alkyl-} carboxamide, _C6-10aryl- carboxamide,
C _1-6 alkoxy - acylamino selected from carboxamide and C _1-6 alkylsulfonylamino, (16 ')
C _1-6 alkyl-carbonyloxy, C _6-10 aryl-
Carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-
Acyloxy, (17 ′) sulfo, (18 ′) C _6-10 aryl, (19 ′) C _6-10 selected from C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy A C _6-14 aryl, a C _6-10 quinonyl or a carbon atom which may have 1 to 5 substituents selected from aryloxy and (20 ′) oxo; A substituent selected from a 5 to 14-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from 1 to 5
Optionally having _1-6 alkyl, C _2-6 alkenyl,
C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-14 aryl or C _7-16 aralkyl, (b) formula: -CO-R ^3, -
^{CO-OR 3, -CO-NR} 3 R 4, -CS-NHR 3, -
An acyl group represented by SO ₂ —R ^3a or —SO—R ^3a wherein each symbol is as defined above, or (c) a 5- to 10-membered aromatic heterocyclic group. Good hydroxy; (3) (a) as substituents (i) halogen, (ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano,
(V) an optionally halogenated C _1-6 alkyl, (v
i) optionally halogenated C _3-6 cycloalkyl,
(Vii) optionally halogenated C _1-6 alkoxy,
(Viii) optionally halogenated C _1-6 alkylthio, (ix) hydroxy, (x) amino, (xi) mono-C
_1-6 alkylamino, (xii) di -C _1-6 alkylamino, (xiii) formyl, carboxy, 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 to 6
Membered heterocyclic carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C
Acyl selected from _6-10 arylsulfonyl, (xiv)
Formylamino, C _1-6 alkyl-carboxamide, C
_Acylamino selected from _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (xv) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, C
Acyloxy selected from _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy,
(Xvi) (xvi-1) C _1-6 alkyl, (xvi-2) halogen,
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, C _6-10
Aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl- Carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6
Alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy and dialkyl C _6-14 aryl, C _7-16 aralkyl optionally having 1 to 5 substituents selected from —C _1-6 alkyl-carbamoyloxy, 5- to 7-membered saturated cyclic amino or 5- to 6-membered 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from an aromatic heterocyclic group and (xvi-3) C _6-10 aryl-carbonyl, (xvii) sulfo and (xviii) (1 ′) halogen, (2 ′) C _1-3 alkylenedioxy, (3 ′) nitro, (4 ′) cyano, (5 ′) optionally halogenated C _1-6 alkyl, (6 ′ ) Halogenated May be C
_3-6 cycloalkyl, (7 ') optionally halogenated C _1-6 alkoxy optionally, (8') optionally halogenated a C _1-6 alkylthio, (9 ') hydroxy, (10') Amino, (11 ′) mono-C _1-6 alkylamino, (12 ′) di-
C _1-6 alkylamino, (13 ′) (13′-1) C _1-6 alkyl, (13′-2) halogen, 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, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di -C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6
Alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-
C _6-14 aryl, C _7-16 aralkyl, 5- to 7-membered saturated cyclic amino, which may have 1 to 5 substituents each selected from carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy, or A 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from a 5- to 6-membered aromatic heterocyclic group and (13'-3) _C6-10 aryl-carbonyl, (14 ' ) Formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C
Acyl selected from _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl, (15 ′) formylamino, C _{1 -6alkyl-} carboxamide, _C6-10aryl- carboxamide,
C _1-6 alkoxy - acylamino selected from carboxamide and C _1-6 alkylsulfonylamino, (16 ')
C _1-6 alkyl-carbonyloxy, C _6-10 aryl-
Carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-
Acyloxy, (17 ′) sulfo, (18 ′) C _6-10 aryl, (19 ′) C _6-10 selected from C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy A C _6-14 aryl, a C _6-10 quinonyl or a carbon atom which may have 1 to 5 substituents selected from aryloxy and (20 ′) oxo; A substituent selected from a 5 to 14-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from 1 to 5
Optionally having _1-6 alkyl, C _2-6 alkenyl,
C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-14 aryl or C _7-16 aralkyl, and (b) a compound of the formula: —CO—
^{R 3, -CO-OR 3,} -CO-NR 3 R 4, -CS-NH
R ³ , —SO ₂ —R ^3a or —SO—R ^3a [wherein each symbol has the same meaning as described above], may have one or two substituents selected from acyl. Amino; (4) as a substituent, (i) C _1-6 alkyl, (ii) halogen, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, halogenated _Optionally 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, C
_6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10
Aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C
_1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyl C _6-14 aryl, C _7-16 aralkyl which may have 1 to 5 substituents selected from oxy and di-C _1-6 alkyl-carbamoyloxy, respectively, 5- to 7-membered saturated cyclic amino or (Iii) a 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from a _6- to 6-membered aromatic heterocyclic group and (iii) C _6-10 aryl-carbonyl; or (i) a halogen, have been (ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl, (vi) halogenated Good C _3-6 cycloalkyl, (vii)
Optionally halogenated C _1-6 alkoxy, (vii
i) an optionally halogenated C _1-6 alkylthio,
(Ix) hydroxy, (x) amino, (xi) mono-C _1-6 alkylamino, (xii) di-C _1-6 alkylamino, (xi
ii) (xiii-1) C _1-6 alkyl, (xiii-2) halogen,
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, C _6-10
Aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl- Carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6
Alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy and dialkyl C _6-14 aryl, C _7-16 aralkyl optionally having 1 to 5 substituents selected from —C _1-6 alkyl-carbamoyloxy, 5- to 7-membered saturated cyclic amino or 5- to 6-membered 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from an aromatic heterocyclic group and (xiii-3) C _6-10 aryl-carbonyl, (xiv) formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl, mono-C
_1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5 to 6
Acyl selected from membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl, (x
v) formylamino, C _1-6 alkyl-carboxamide,
C _6-10 aryl-carboxamide, C _1-6 alkoxy-
Acylamino selected from carboxamide and C _1-6 alkylsulfonylamino, (xvi) C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy,
Acyloxy selected from C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy;
(Xvii) sulfo, (xviii) C _6-10 aryl, (xix) C
C _6-14 aryl, C _6-10 quinonyl or a carbon atom other than a C _6-14 aryl, C _6-10 quinonyl or carbon atom which may have 1 to 5 substituents selected from _6-10 aryloxy and (xx) oxo, and oxygen A 5- to 14-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from atoms; and ring A further comprises (1) carboxy,
(2) C _1-6 alkoxy - carbonyl, (3) carbamoyl, (4) mono - or di -C _1-6 alkylamino - carbonyl, (5) C _1-6 alkyl optionally having hydroxy, (6) oxo, and (7) as substituents (i) halogen, (ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _{1 -6} alkyl, (vi) optionally halogenated C
_3-6 cycloalkyl, (vii) optionally halogenated C _1-6 alkoxy, (viii) optionally halogenated C _1-6 alkylthio, (ix) hydroxy, (x) amino, (xi ) Mono-C _1-6 alkylamino, (xii) di-C
_1-6 alkylamino, (xiii) formyl, carboxy,
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- to 6-membered heterocyclic carbonyl, Carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 aryl Acyl selected from sulfonyl, (xiv) formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, acyl amino selected from C _1-6 alkoxy-carboxamide and C _1-6 alkylsulfonylamino, (xv ) C _1-6 alkyl - carbonyloxy, C _6-10 aryl - carbonyloxy, C _1-6 alkoxy - carbonitrile Aryloxy, mono -
Acyloxy selected from C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy, (xvi) (xvi-1) C _1-6 alkyl , (Xvi-2) halogen, 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, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl,
C _6-10 aryl-carbonyl, carbamoyl, mono-C
_1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino ,
C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-
C _6-14 aryl, C _{7- optionally} having 1 to 5 substituents each selected from carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy Which may have one or two substituents selected from ₁₆ aralkyl, a 5- to 7-membered saturated cyclic amino or 5- to 6-membered aromatic heterocyclic group and (xvi-3) C _6-10 aryl-carbonyl. Or 7
Membered cyclic amino, (xvii) sulfo and (xviii)
(1 ′) halogen, (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 ′) (13′-1) C
_1-6 alkyl, (13′-2) halogen, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6 cyclo 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, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6
Alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl- Carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-
C _6-14 aryl _optionally having 1 to 5 substituents selected from C _1-6 alkyl-carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy, C
_7-16 aralkyl, _5-7 membered saturated cyclic amino or 5
A 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from a _6- to 6-membered aromatic heterocyclic group and a (13′-3) C _6-10 aryl-carbonyl, (14 ′)
Formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl, mono-C _1-6 Acyl selected from alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl, (15 ') formylamino, C _1-6 alkyl - carboxamido, C _6-10 aryl - carboxamide, C _1-6 alkoxy - acylamino selected from carboxamide and C _1-6 alkylsulfonylamino, (16') C _1-6 alkyl - carbonyloxy, C _6-10 aryl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 Al Le - carbamoyloxy, di -C _1-6 alkyl - carbamoyloxy, C _6-10 aryl - acyloxy selected from carbamoyloxy and nicotinoyloxy oxy, (17 ') sulfo, (18') C _6-10 aryl, ( 19 ′) C _6-14 aryl _optionally having 1 to 5 substituents selected from C _6-10 aryloxy and (20 ′) oxo,
_{6 to 10} quinonyl or 1 to 5 substituents selected from 5 to 14-membered aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen in addition to carbon _Optionally having 1 to 3 substituents selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl and C _6-14 aryl It may contain one double bond other than the portion condensed with the quinone ring, and may contain 1 to 3 hetero atoms selected from nitrogen, sulfur and oxygen other than carbon. The compound according to claim 1, which is a 5- to 8-membered homo-heterocycle. 3. The compound according to claim 1, wherein R ¹ and R ² are each C _1-6 alkyl. 4. The compound according to claim 1, wherein X is a spacer having 2 to 15 atoms in the main chain. 5. X is C _1-15 alkylene optionally having 1 to 3 substituents selected from oxo and optionally halogenated C _1-6 alkyl or (2)
Formula ^{_{:-( CH 2) m-X 1}} -, - (CH 2) m-X 2 -X 1 -, - X 1 -X 2 -
(CH ₂ ) n−, −X ² −X ¹ − (CH ₂ ) n−, − (CH ₂ ) m−X ¹ − (CH ₂ ) n
−, − (CH ₂ ) m−X ² − (CH ₂ ) n−, − (CH ₂ ) m−X ¹ −X ² − (C
H ₂ ) n−, − (CH ₂ ) m−X ² −X ¹ − (CH ₂ ) n− or −X ² −X ¹ −
X ^2- (CH ₂ ) n- wherein X ¹ may have 1 to 3 substituents each selected from oxo and optionally halogenated C _1-6 alkyl (1 ) Divalent C
_5-8 monocyclic non-aromatic hydrocarbon group, (2) divalent C _6-14 aromatic hydrocarbon group or (3) 1 to 4 selected from nitrogen atom, sulfur atom and oxygen atom other than carbon atom X ² is O, S, SO or SO ₂ ; m and n are each an integer of 0 to 10; and m + n is an integer of 1 to 13 The compound according to claim 1, which is a group represented by the formula: 6. X ¹ is a divalent C _6-14 aromatic hydrocarbon group, X ²
Is O, m is an integer of 0 to 10, n is an integer of 1 to 5, and m + n is an integer of 2 to 10.
A compound as described. 7. The compound according to claim 1, wherein Y is hydroxy which may have a substituent. 8. A formula wherein the ring A may further have a substituent in addition to the group represented by the formula -XY. The compound according to claim 1, which is a ring represented by the formula: 9. R ¹ and R ² are each C _1-6 alkyl;
X is (1) C _2-8 alkylene or (2) :-( CH ₂₎ m-X
¹ −, − (CH ₂ ) m−X ² −X ¹ −, −X ¹ −X ² − (CH ₂ ) n−, −X ²
−X ¹ − (CH ₂ ) n−, − (CH ₂ ) m−X ¹ − (CH ₂ ) n−, − (CH ₂ ) m−
X ² − (CH ₂ ) n−, − (CH ₂ ) m−X ¹ −X ² − (CH ₂ ) n−, − (CH ₂ ) m
-X ² -X ^1- (CH ₂ ) n- or -X ² -X ¹ -X ^2- (CH ₂ ) n- wherein X ¹ is a divalent C _6-14 aromatic hydrocarbon group, X ² is O, m
Is an integer of 0 to 10, n is an integer of 1 to 5, and m + n is an integer of 2 to 10];
Is optionally substituted hydroxy; and ring A has the formula: The compound according to claim 1, which is a ring represented by the formula: (10) Y is a halogen atom, (i)
i) C _1-3 alkylenedioxy, (iii) nitro, (iv)
Cyano, (v) optionally halogenated C _1-6 alkyl, (vi) optionally halogenated C _3-6 cycloalkyl, (vii) optionally halogenated C _1-6 alkoxy (Viii) optionally halogenated C _1-6 alkylthio, (ix) hydroxy, (x) amino, (xi)
Mono-C _1-6 alkylamino, (xii) di-C _1-6 alkylamino, (xiii) formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl, mono-C
_1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5 to 6
Acyl selected from membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl, (xi
v) formylamino, C _1-6 alkyl-carboxamide,
C _6-10 aryl-carboxamide, C _1-6 alkoxy-
Acylamino selected from carboxamide and C _1-6 alkylsulfonylamino, (xv) C _1-6 alkyl - carbonyloxy, C _6-10 aryl - carbonyloxy,
Acyloxy selected from C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy;
(Xvi) (xvi-1) C _1-6 alkyl, (xvi-2) halogen,
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, C _6-10
Aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl- Carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6
Alkyl-carboxamide, C _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy and dialkyl C _6-14 aryl, C _7-16 aralkyl optionally having 1 to 5 substituents selected from —C _1-6 alkyl-carbamoyloxy, 5- to 7-membered saturated cyclic amino or 5- to 6-membered 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from an aromatic heterocyclic group and (xvi-3) C _6-10 aryl-carbonyl, (xvii) sulfo and (xviii) (1 ′) halogen, (2 ′) C _1-3 alkylenedioxy, (3 ′) nitro, (4 ′) cyano, (5 ′) optionally halogenated C _1-6 alkyl, (6 ′ ) Halogenated May be C
_3-6 cycloalkyl, (7 ') optionally halogenated C _1-6 alkoxy optionally, (8') optionally halogenated a C _1-6 alkylthio, (9 ') hydroxy, (10') Amino, (11 ′) mono-C _1-6 alkylamino, (12 ′) di-
C _1-6 alkylamino, (13 ′) (13′-1) C _1-6 alkyl,
(13′-2) halogen, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, halogenated _Optionally C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6
Alkylamino, C _6-10 aryl, carboxy, formyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di -C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonyl, formylamino, C _1-6 alkyl-carboxamide, C _1-6
Alkoxy-carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-
C _6-14 aryl, C _7-16 aralkyl, 5- to 7-membered saturated cyclic amino, which may have 1 to 5 substituents each selected from carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy, or A 5- to 7-membered saturated cyclic amino optionally having one or two substituents selected from a 5- to 6-membered aromatic heterocyclic group and (13'-3) _C6-10 aryl-carbonyl, (14 ' ) Formyl, carboxy, 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- to 6-membered heterocyclic carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C
Acyl selected from _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl, (15 ′) formylamino, C _{1 -6alkyl-} carboxamide, _C6-10aryl- carboxamide,
C _1-6 alkoxy - acylamino selected from carboxamide and C _1-6 alkylsulfonylamino, (16 ')
C _1-6 alkyl-carbonyloxy, C _6-10 aryl-
Carbonyloxy, C _1-6 alkoxy-carbonyloxy, mono-C _1-6 alkyl-carbamoyloxy, di-
Acyloxy, (17 ′) sulfo, (18 ′) C _6-10 aryl, (19 ′) C _6-10 selected from C _1-6 alkyl-carbamoyloxy, C _6-10 aryl-carbamoyloxy and nicotinoyloxy A C _6-14 aryl, a C _6-10 quinonyl or a carbon atom which may have 1 to 5 substituents selected from aryloxy and (20 ′) oxo; 10. The compound according to claim 9, which is hydroxy substituted with phenyl optionally having 1 to 3 substituents selected from a 5 to 14-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from the above. . 11. R ¹ and R ² are each C _1-6 alkyl; X is (1) C _1-8 alkylene or (2) Formula: — (CH ₂ )
^{m'-X 2 '-X 1'} -, - X 1 '-X 2' - (CH 2) n'- , or - (CH ₂₎
^{m'-X 2 '-X 1'} - (CH 2) n'- wherein, X ¹ 'is 1,4-phenylene, X ^2' is O, m 'is an integer of 1 to 4, and n' Represents 1 or 2]; Y represents (1) carboxy, (2) a substituent represented by (i) C _1-6 alkoxy, (ii)
Amino, (iii) mono- or di-C _1-6 alkylamino or (iv) carbonyl having 6-membered saturated cyclic amino optionally having C _1-6 alkyl, phenyl or piperidino, (3) substituent Has 1 to 3 substituents selected from (i) halogen, C _1-3 alkylenedioxy, cyano, C _1-6 alkyl, C _1-6 alkoxy and mono-C _1-6 alkyl-carbamoyl. Phenyl, (ii) C _1-6 alkyl-carbonyl, (iii) mono-
Or a substituent selected from di-C _1-6 alkyl-carbamoyl, (iv) hydroxy optionally having pyridyl or (v) quinolyl, (4) C _1-6 alkyl and C _1-6 alkyl-carbonyl. (1) phenyl, (ii) benzyl optionally having phenyl, (iii) piperidino or (iv) pyridyl. 6-membered saturated cyclic amino, (6) phenyl, (7) C _1-6 alkoxy
Or C _6-10 quinonyl optionally having two, (8) phthalimide, (9) pyridyl optionally having oxo,
(10) quinolyl optionally having oxo, (11) benzotriazolyl or (12) benzimidazolyl; and ring A is further substituted with carboxy, _C1-6 alkoxy-carbonyl, carbamoyl, mono- Or di
Formulas optionally having C _1-6 alkyl-carbamoyl, hydroxy-C _1-6 alkyl or phenyl: The compound according to claim 1, which is a ring represented by the formula: 12. A compound of the formula: Wherein R ^1a and R ^2a are each C _1-3 alkyl; q
Is an integer of 1 to 4; and R is 1 to 3 halogen, C _1-3 alkylenedioxy, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _{1- 6} alkoxy, C _1-6 alkoxy-carbonyl, formylamino, C _1-6 alkyl-carboxamide, C _6-10 aryl-carboxamide, C _1-6 alkoxy-carboxamide or C _1-6 alkylsulfonylamino] The compound according to claim 1, which is a compound or a salt thereof. 13. A compound of the formula 2- [8- (4-chlorophenoxy) octyl] -5,6-dimethoxyindane-4,7-dione, 4- [2- (2,3-dimethoxy-1,4-dioxo-). Ethyl 4,5,6,7,8,9-hexahydro-1H-benzo [a] cyclohepten-7-yl) ethoxy] benzoate or 7- [2- (4-chlorophenoxy) ethyl] -2,3 -Dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo [a] cycloheptene-1,4
The compound according to claim 1, which is -dione. 14. A compound represented by the formula: Wherein P and P ′ are protecting groups, and other symbols are as defined in claim 1. A method for producing the described compound. 15. A pharmaceutical composition comprising the compound according to claim 1. 16. The composition according to claim 15, which is a mitochondrial function activator. 17. The composition according to claim 16, which is a prophylactic / therapeutic agent for Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis or Huntington's disease.