JPH1149765A - Heterocyclic compound, its production, and preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound, showing, e.g. neutrodegeneration inhibitory or β-amyloid toxicity inhibitory action, and useful for prevention or treatment of neurodegenerative diseases. SOLUTION: This compound is shown by formula I (R<1> and R<2> are each H or a hydrocarbon, where R<1> and R<2> form a 3- to 8-membered ring together with C; R<2> is H, a lower alkyl or aromatic; R<4> is an aromatic or aliphatic hydrocarbon or an acyl; X and Y are each O, S; and A-ring is an X-R<4> or benzene ring) or its salt, e.g. 3-(4-isopropylphenyl)-5-(4-methoxybenzyloxy)-2,2,4,6,7- pentamethyl-2,3-dihydrobenzofuran. The compound shown by formula I is obtained by reacting a compound shown by formula II with a compound shown by the formula R<4> -L (L is an eliminable group). The compound shown by formula I is low in toxicity and side effect, and useful for prevention or treatment of various diseases, e.g. Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and peripheral neuropathy.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to a novel heterocyclic compound, a method for producing the same, and a medicament containing the same. For more information,
The present invention relates to a compound having a neurodegenerative inhibitory action, β-amyloid toxicity inhibitory effect and the like, and which is effective for prevention and treatment of neurodegenerative diseases and the like.

TECHNICAL FIELD OF THE INVENTION

[0002]

2. Description of the Related Art Neurodegenerative diseases are progressive diseases that cause the destructive damage of nerve cell death. As major neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease and peripheral neuropathy represented by diabetic neuropathy are known. Many are associated with aging and, in fact, increase in age with age, but can sometimes develop at middle to younger ages. As a result of research on the structure and function of the brain, the roles of neurotransmitters and neurotrophic factors are gradually being elucidated, but much remains unknown about the causes of neurodegenerative diseases. Only Parkinson's disease has been linked to a specific neurotransmitter, dopamine, and L-dopa, a precursor of dopamine, is used as a drug to reduce neurological symptoms and restore function. However, L-dopa does not suppress the progress of neurodegeneration, and the effect of L-dopa is gradually lost as the disease progresses, that is, degeneration or loss of dopamine nerves. In Alzheimer's disease, many types of neurons such as acetylcholine neurons and monoamine neurons are degenerated.
As a drug against this disease, cholinesterase inhibitors are on the market or under development. However, even in this case, L in Parkinson's disease
-Like dopa, it is not a symptomatic treatment that temporarily improves neurological symptoms. Thus, no drug has been reported that protects neurons from the toxicity of factors that cause cell death and suppresses the progression of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. In addition, cell death in neurodegenerative diseases is said to be caused by toxicity of factors specific to each disease. For example, in Alzheimer's disease, endogenous β
Amyloid is considered as a factor that causes cell death. β-amyloid is a protein that constitutes senile plaque, a neuropathological feature found in the brain of Alzheimer's disease patients, and consists of 40 to 43 amino acids. It has been shown that when this β-amyloid is added to a primary culture of hippocampal neurons, neuronal cell death occurs [Science (scie
245), p. 417-420, 1989], and that the aggregation of β-amyloid is essential for the development of its toxicity [Neurobiology of Aging (N.
eurobiology of Aging), Vol. 13, pp. 587-590, 1992 and Journal of Molecular Biology (Jo
urnal of Molecular Biology), 218, 149-163, 1
991]. Regarding the mechanism of β-amyloid toxicity expression, 1) β-amyloid forms an ion channel and allows calcium ions to flow in, 2) β-amyloid promotes the generation of free radicals, 3) β-amyloid is tau protein kinase I (TPK -I) is activated, and tau phosphorylation is enhanced. 4) β-amyloid activates microglia, and neurotoxin is secreted from microglia. However, no conclusion has been reached yet. Recently, IGF-1 (insulin-like growth factor), NGF
A neurotrophic factor (neurotrophin) such as (nerve growth factor) suppresses apoptosis of nerve cells due to β-amyloid and the like, and its mechanism is TPK-I / GSK-3β (glycogen synthase) by activation of PI-3 kinase. Inhibition of kinase 3) has been shown to be involved [Journal of Neuroscience (J.
Neurosci., 11, 2552-2563, 1991, Science, 267, 2003-2006, 1995, and The Journal of Biological Chemistry.
(J. Biol. Chem.), 272, 154-161, 1997]. β
Inhibition of PI-3 kinase by amyloid, T
When PK-I / GSK-3β is activated, inhibition of pyruvate dehydrogenase (PDH) affects the acetylcholine synthesis reaction system, and the acetylcholine content also decreases.
This is consistent with the decreased acetylcholine content in the brain of Alzheimer's disease patients. Conversely, activating PI-3 kinase not only prevents neuronal cell death but also reduces acetylcholine content in the brain. It is expected to bring about an increase in neurological symptoms. Further TPK
Inhibition of -I / GSK-3β can also be expected to increase brain glucose utilization, which is reduced in Alzheimer's disease [The Journal of Biological
Chemistry (J. Biol. Chem.), 269, 3568-3573
Page, 1994 and Endocrinolog
y), 125, pp. 314-320, 1989]. Accordingly, it is considered that a compound having a low molecular weight and excellent in the ability to enter the brain and having a neurotrophic factor-like action can suppress nerve cell death in a neurodegenerative disease such as Alzheimer's disease and improve neurological symptoms.

[0003] The following compounds are known as dihydrobenzofuran compounds having an effect on neurodegenerative diseases (such as Parkinson's disease and Alzheimer's disease). 1) Formula

Embedded image Wherein R is lower alkyl, R ⁰ is hydrogen or acyl,
R ¹ and R ² are the same or different and may be a lower alkyl which may have a substituent, or R ¹ and R ² may have a butadienylene which may have a substituent, and R ³ and R ⁴ are each Hydrogen or an alkyl which may have a substituent, or polymethylene as R ³ and R ^4, and R ⁵ represents a lower alkyl which may have a substituent, an aromatic ring group or a heterocyclic group] Compounds represented (EP-A-273647 and JP-A-1-272578). 2) Formula

Embedded image [In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom, an acyl group, an alkoxycarbonyl group, an aliphatic group or an aromatic ring group which may have a substituent, R ³ , R ⁴ and R ⁵ are The same or different, an optionally acylated hydroxyl group, an amino, alkoxy or aliphatic group which may each have a substituent, or two of R ³ , R ⁴ and R ⁵ have a substituent also form also good carbocyclic have good, R ⁶ and R ⁷ are the same or different which may have a substituent aliphatic group addition R ^6,
And at least one α-position methylene of R ^7, R ⁸
And R ⁹ are the same or different and each represent a hydrogen atom or an aliphatic group or an aromatic ring group which may have a substituent, respectively, or a salt thereof (EP-A-4).
83772 and JP-A-5-140142). Further, the following compounds have been reported as benzofuran-based and dihydrobenzofuran-based compounds. 3) Formula for prevention and treatment of β-amyloid-related neurological diseases such as Alzheimer's disease and Down's syndrome

Embedded image [Wherein A is -O-, -S (O) m-, -N (R ¹¹ )
—, —CH ₂ CH ₂ — or —CH ＝ CH—, m is 0, 1
Or 2, X is a bond or C _1-4 alkylidenyl, R ²
Is -NR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are each C _1-6 alkyl, etc.), R is hydroxy, halogen, C _3-8 cycloalkyl, C _2-7 alkanoyloxy, C _1-6 alkoxy , Phenyl, etc., R ¹ is hydroxy, halogen, hydrogen atom, C _3-8 cycloalkyl, C _2-7 alkanoyloxy,
C _1-6 alkoxy, phenyl, etc.] or a pharmacologically acceptable salt thereof (WO 95 /
17095). 4) Formula having 5- or 12-lipoxygenase inhibitory action

Embedded image Wherein R ¹ is hydrogen or lower alkyl, R ² is carboxy, alkoxycarbonyl, cyano, halogen, aryl or a methyl or carboxy, alkoxycarbonyl, cyano, halogen, aryl or heterocyclic group substituted with a heterocyclic group. An optionally substituted chain hydrocarbon residue having 2 to 15 carbon atoms having no lower alkyl at the α-position, R ³ is lower alkyl, R ⁴ is hydrogen or acyl, R
⁵ and R ⁶ each represent lower alkyl or lower alkoxy, or R ⁵ and R ⁶ represent butadienylene], or a salt thereof (EP-A-345593 and JP-A-2-76869). 5) Formula having 5-lipoxygenase inhibitory action

Embedded image [In the formula, R ¹ is hydrogen or lower alkyl, n is 1 to 6, X is an oxidized sulfur atom, an oxygen atom or an imino optionally having a substituent, R ² is methyl or methylene, Methine or an organic residue via a quaternary carbon, R ³ is lower alkyl, R ⁴ is hydrogen or acyl, R ⁵
And R ⁶ each represent lower alkoxy or lower alkyl, or R ⁵ and R ⁶ represent butadienylene]] or a salt thereof (EP-A-345592 and JP-A-2-76870).

6) Formula having an anti-bone-reducing action

Embedded image Wherein R is a hydrogen atom or methyl, R ¹ and R ² are each methyl or ethyl, or R ¹ and R ² are a saturated heterocyclic ring, and X is bromo, chloro, fluoro or a hydrogen atom. Or a pharmacologically acceptable salt thereof (EP-A-722726). The following compounds are known as indole compounds. 7) endothelin receptor antagonist, a formula useful as a treatment for cerebrovascular disease

Embedded image Wherein R ₁ is -X (CH ₂ ) nAr, -X (CH ₂ ) nR
_8, etc., R ₂ is hydrogen or Ar or the like, P ₁ is -X (CH ₂₎ n
R _8, P ₂ is -X (CH ₂₎ nR _8, etc., R ₃ is hydrogen, R _11, O
H, C _1-8 alkoxy, S (O) qR ₁₁ , N (R ₆ ) ₂ , B
r, F, I, Cl, CF 3, NHCOR 6, -R 11 CO 2
R _7, -XR ₉ -Y, XY or -X (CH ₂₎ nR _8, even where methylene -X (CH ₂₎ nR ₈ is unsubstituted 1
More than five - (CH ₂₎ may be substituted with NAR, R ₈
Is hydrogen, R ₁₁ etc., R ₉ is C _1-10 alkyl, C _2-10 alkenyl, phenyl etc., R ₁₁ is C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl etc., and X is ( CH ₂ ) n, O, S (O)
q and Y are CH ₃ or —X (CH ₂ ) n Ar, Ar is phenyl, naphthyl, etc., q is 0, 1 or 2, and n is an integer of 0 to 6], or a pharmacological compound thereof. Tolerable salts (WO 94/14434 and JP-T-Hei 8-5)
04826 gazette). 8) Formula having anticholesterol biosynthesis action

Embedded image C _1-6 alkyl, C _3-6 cycloalkyl or phenyl-
(CH ₂ ) m- (wherein, R ₄ , R ₅ , and R _5a are hydrogen and the like, m represents 1, 2 or 3), R ₂ is hydrogen, C _1-4 alkyl,
C _3-6 cycloalkyl, C _1-4 alkoxy, phenoxy,
R ₃ is hydrogen, C _1-3 alkyl, C _1-3
X is-, such as alkoxy, phenoxy, benzyloxy, etc.
(CH ₂₎ n-or -CH = CH-, n is 0, 1, 2 or 3, R ₆ is or a salt thereof represents hydrogen or C _1-3 alkyl] (WO 84/02131) .

[0005]

SUMMARY OF THE INVENTION A compound having the action of suppressing the cytotoxicity of β-amyloid protein and protecting nerve cells. Protecting nerve cells from the toxicity of factors that cause cell death, preventing neurodegenerative diseases. It provides the development of compounds useful as therapeutic agents.

[0006]

Means for Solving the Problems As a result of diligent search, the present inventors have found that a benzene ring fused with a 5-membered heterocyclic ring has the formula -X
-R ⁴ wherein with the features of the chemical structure of which is optionally substituted with a substituent (each symbol is the following as defined in the formula) is represented by

Embedded image [Wherein, R ¹ and R ² are each a hydrogen atom or a hydrocarbon group which may have a substituent, or R ¹ and R ² may have a substituent together with an adjacent carbon atom. R ³ represents a hydrogen atom, a lower alkyl which may have a substituent or an aromatic group which may have a substituent, and R ⁴ represents a (1) substituent. An aromatic group which may have (2) an aliphatic hydrocarbon group which has an aromatic group which may have a substituent and which may further have a substituent, or (3) acyl , X and Y are each an oxygen atom or an optionally oxidized sulfur atom, -
- - is a single bond or a double bond, A ring wherein -X-R
⁴ represents a benzene ring which may have a substituent in addition to the group represented by the formula (each symbol has the same meaning as described above). However, - - - is a single bond, and X and Y are when the oxygen atom, R ⁴ is not acyl. ] Novel compound represented by [hereinafter, the compound (I) abbreviated sometimes] and first synthesized that Compound (I) is peculiar chemical substituents -X-R ⁴ on the condensed benzene ring Having unexpectedly excellent cytotoxicity of β-amyloid protein based on its structure;

Embedded image [Wherein, R ^4a represents an aromatic group which may have a substituent, an aliphatic hydrocarbon group which may have a substituent or acyl, and Xa represents an oxygen atom or a sulfur atom which may be oxidized. , Ya represents an oxygen atom, oxidized sulfur atom which may be or may imino which may have a substituent group, - - - is a single bond or a double bond, Aa ring is formula -Xa-R ^4a (in the formula Each symbol has the same meaning as described above), and in addition to the group represented by benzene ring which may further have a substituent other than amino which may be substituted, each other symbol has the same meaning as described above. Show. However, - - - is a single bond, and when Xa and Ya is an oxygen atom, R ^4a is not acyl. Or a salt thereof (hereinafter may be abbreviated as compound (Ia)) and compound (I) are also excellent based on the specific chemical structure of substituent -Xa-R ^4a on the condensed benzene ring. Having a cytotoxic inhibitory effect of β-amyloid protein,
Furthermore, they have found for the first time that these compounds have extremely low toxicity, are excellent in the ability to migrate into the brain, and are sufficiently satisfactory as drugs having an inhibitory effect on neurodegeneration, and based on these findings, completed the present invention. .

That is, the present invention provides: 1) Compound (I); 2) R¹And R^TwoIs (i) a hydrogen atom or (i
i) (1) halogen atom, (2) C_1-3Alkylene dioxy
(3) nitro, (4) cyano, (5) halogenated
May be C_1-6Alkyl, (6) halogenated
May be C_2-6Alkenyl, (7) halogenated
Good C_2-6Alkynyl, (8) even when halogenated
Good C_3-6Cycloalkyl, (9) C_6-14Aryl, (1
0) optionally halogenated C_1-6Alkoxy, (1
1) C which may be halogenated_1-6Alkylthio,
(12) hydroxy, (13) amino, (14) mono-C_1-6
Alkylamino, (15) mono-C_6-14Arylamino,
(16) Di-C_1-6Alkylamino, (17) di-C_6-14A
Reel amino, (18) formyl, carboxy, carbamo
Il, C_1-6Alkyl-carbonyl, C_3-6Cycloalkyl
Le-carbonyl, C_1-6Alkoxy-carbonyl, C
_6-14Aryl-carbonyl, C_7-16Aralkyl-Carbo
Nil, C_6-14Aryloxy-carbonyl, C_{7- 16}Ara
Alkyloxycarbonyl, 5- to 6-membered heterocyclic carbonyl
Le, Mono-C_1-6Alkyl-carbamoyl, di-C_1-6A
Lucyl-carbamoyl, C_6-14Aryl-carbamoy
5 to 6-membered heterocyclic carbamoyl, C_1-6Alkylsul
Honyl, C_6-14Arylsulfonyl, C_1-6Alkyls
Rufinil and C_6-14Selected from arylsulfinyl
Acyl, (19) formylamino, C_1-6Alkyl-
Carboxamide, C_6-14Aryl-carboxamide, C
_1-6Alkoxy-carboxamide, C_1-6Alkylsulfo
Nilamino and C_6-14From arylsulfonylamino
Acylamino of choice, (20) C_1-6Alkyl-carbo
Nyloxy, C_6-14Aryl-carbonyloxy, C
_1-6Alkoxy-carbonyloxy, mono-C_1-6Archi
Ru-carbamoyloxy, di-C_1-6Alkyl-carba
Moyloxy, C_6-14Aryl-carbamoyloxy and
Acyloxy selected from and nicotinoyloxy,
(21) C_1-6Alkyl, C_6-14Aryl and 5 to
1 to 3 substituents selected from a 10-membered aromatic heterocyclic group
A 5- to 7-membered saturated cyclic amino optionally having (2)
2) 5- to 10-membered aromatic heterocyclic group and (23) sulfo
Each having 1 to 5 substituents selected from
Good C_1-6Alkyl, C_2-6Alkenyl, C_2-6Archi
Nil, C_3-6Cycloalkyl or C_6-14Aryl;
Or R¹And R^TwoTogether with adjacent carbon atoms_1-6Al
Kill, C_6-14Aryl, C_7-16Aralkyl, amino, mo
No-C_1-6Alkylamino, mono-C_6-14Arylami
No, Di-C_1-6Alkylamino, di-C_6-14Aryla
Selected from mino and 5- to 10-membered aromatic heterocyclic groups
C optionally having 1 to 3 substituents_3-8
Forming a cycloalkane or a 3- to 8-membered heterocycle;^Three
Is (i) a hydrogen atom, (ii) (1) a halogen atom, (2) C
_1-3Alkylenedioxy, (3) nitro, (4) cyano,
(5) C which may be halogenated_1-6Alkyl,
(6) C which may be halogenated_2-6Alkenyl,
(7) C which may be halogenated_2-6Alkynyl,
(8) C which may be halogenated_3-6Cycloalkyl
Le, (9) C_6-14Aryl, (10) halogenated
May be C_1-6Alkoxy, (11) halogenated
May be C_1-6Alkylthio, (12) hydroxy, (1
3) Amino, (14) Mono-C_1-6Alkylamino, (15)
Mono-C_6-14Arylamino, (16) cy-C_1-6Alkyria
Mino, (17) Di-C_6-14Arylamino, (18) Horumi
Carboxy, carbamoyl, C_1-6Alkyl-cal
Bonil, C_3-6Cycloalkyl-carbonyl, C_1-6Al
Coxy-carbonyl, C_6-14Aryl-carbonyl, C
_7-16Aralkyl-carbonyl, C_6-14Aryloxy-
Carbonyl, C_7-16Aralkyloxy-carbonyl, 5
6-membered heterocyclic carbonyl, mono-C_1-6Alkyl-cal
Bamoyl, Di-C_1-6Alkyl-carbamoyl, C_6-14
Aryl-carbamoyl, 5- to 6-membered heterocyclic carbamoy
Le, C_1-6Alkylsulfonyl, C_6-14Arylsulfo
Nil, C_1-6Alkylsulfinyl and C_6-14Ally
Acyl selected from rusulfinyl, (19) formylure
Mino, C_1-6Alkyl-carboxamide, C_6-14Ally
Le-carboxamide, C_1-6Alkoxy-carboxami
C_1-6Alkylsulfonylamino and C_6-14Ants
Acylamino selected from sulphonylamino, (2
0) C_1-6Alkyl-carbonyloxy, C_6-14Aryl
-Carbonyloxy, C_1-6Alkoxy-carbonylo
Kishi, Mono-C_1-6Alkyl-carbamoyloxy, di
-C_1-6Alkyl-carbamoyloxy, C_6-14Ally
From carbamoyloxy and nicotinoyloxy
Acyloxy of choice, (21) C_1-6Alkyl, C_6-14
Selected from aryl and 5- to 10-membered aromatic heterocyclic groups
5 to 7 which may have 1 to 3 substituents
Membered cyclic amino, (22) 5- to 10-membered aromatic heterocycle
Group and a substituent selected from (23) sulfo are 1 to 5
C that may have_1-6Alkyl, or (iii)
(1) halogen atom, (2) C_1-3Alkylenedioxy,
(3) nitro, (4) cyano, (5) halogenated
May be C_1-6Alkyl, (6) even if halogenated
Good C_2-6Alkenyl, (7) optionally halogenated
C_2-6Alkynyl, (8) optionally halogenated
C_3-6Cycloalkyl, (9) optionally halogenated
C_1-6Alkoxy, (10) may be halogenated
C_1-6Alkylthio, (11) hydroxy, (12) ami
No, (13) Mono-C_1-6Alkylamino, (14) di-C
_1-6Alkylamino, (15) C_1-6Alkyl, C_6-14Ants
Or a 5- to 10-membered aromatic heterocyclic group
5- to 7-membered saturated group which may have 1 to 3 substituents
Japanese cyclic amino, (16) formyl, carboxy, carbamo
Il, C_1-6Alkyl-carbonyl, C_3-6Cycloalkyl
Le-carbonyl, C_1-6Alkoxy-carbonyl, C
_6-14Aryl-carbonyl, C_7-16Aralkyl-Carbo
Nil, C_6-14Aryloxy-carbonyl, C_7-16Ara
Alkyloxycarbonyl, 5- to 6-membered heterocyclic carbonyl
Le, Mono-C_1-6Alkyl-carbamoyl, di-C_1-6A
Lucyl-carbamoyl, C_6-14Aryl-carbamoy
5 to 6-membered heterocyclic carbamoyl, C_1-6Alkylsul
Honyl, C_6-14Arylsulfonyl, C_1-6Alkyls
Rufinil and C_6-14Selected from arylsulfinyl
Acyl, (17) formylamino, C_1-6Alkyl-
Carboxamide, C_6-14Aryl-carboxamide, C
_1-6Alkoxy-carboxamide, C_1-6Alkylsulfo
Nilamino and C_6-14From arylsulfonylamino
Acylamino of choice, (18) C_1-6Alkyl-carbo
Nyloxy, C_6-14Aryl-carbonyloxy, C
_1-6Alkoxy-carbonyloxy, mono-C_1-6Archi
Ru-carbamoyloxy, di-C_1-6Alkyl-carba
Moyloxy, C_6-14Aryl-carbamoyloxy and
Acyloxy selected from and nicotinoyloxy,
(19) Sulfo, (20) C_6-14Aryl and (21) C
_6-141 to 3 substituents selected from aryloxy
C that each may have_6-14Aryl or carbon source
Other than nitrogen, sulfur, and oxygen
5- to 14-membered aromatic containing 1 to 4 hetero atoms
Heterocyclic group; R^FourIs (i) (1) halogen atom, (2) C_1-3
Alkylenedioxy, (3) nitro, (4) cyano,
(5) C which may be halogenated_1-6Alkyl,
(6) C which may be halogenated_2-6Alkenyl,
(7) C which may be halogenated_2-6Alkynyl,
(8) C which may be halogenated_3-6Cycloalkyl
, (9) optionally halogenated C_1-6Alkoki
C, (10) C which may be halogenated_1-6Alkyl
Thio, (11) hydroxy, (12) amino, (13) mono-
C_1-6Alkylamino, (14) di-C_1-6Alkylam
No, (15) C_1-6Alkyl, C_6-14Aryl and 5
No substituent selected from 10-membered aromatic heterocyclic groups
A 5- to 7-membered saturated cyclic amino optionally having 3
(16) formyl, carboxy, carbamoyl, C_1-6A
Alkyl-carbonyl, C_3-6Cycloalkyl-carboni
Le, C_1-6Alkoxy-carbonyl, C_6-14Aryl-
Carbonyl, C_7-16Aralkyl-carbonyl, C_6-14A
Reeloxy-carbonyl, C_7-16Aralkyloxy-
Carbonyl, 5-6 membered heterocyclic carbonyl, mono-C_1-6
Alkyl-carbamoyl, di-C_1-6Alkyl-carba
Moyle, C_6-14Aryl-carbamoyl, 5-6 membered complex
Ring carbamoyl, C_1-6Alkylsulfonyl, C_6-14A
Reel sulfonyl, C_1-6Alkylsulfinyl and
C_6-14Acyl selected from arylsulfinyl, (1
7) Formylamino, C_1-6Alkyl-carboxamides,
C_6-14Aryl-carboxamide, C_1-6Alkoxy-
Carboxamide, C_1-6Alkylsulfonylamino and
And C_6-14Acyl selected from arylsulfonylamino
Amino, (18) C_1-6Alkyl-carbonyloxy, C
_6-14Aryl-carbonyloxy, C_1-6Alkoxy-
Carbonyloxy, mono-C_1-6Alkyl-carbamoy
Luoxy, di-C_1-6Alkyl-carbamoyloxy,
C_6-14Aryl-carbamoyloxy and nicotinoi
Acyloxy selected from ruoxy, (19) sulfo,
(20) C_6-14Aryl and (21) C_6-14Aryloxy
Each having 1 to 3 substituents selected from
May be C_6-14A nitrogen source other than an aryl or carbon atom
A heteroatom selected from a hydrogen atom, a sulfur atom and an oxygen atom
A 5- to 14-membered aromatic heterocyclic group containing 1 to 4, (i
i) (1) halogen atom, (2) C_1-3Alkylene dioxy
(3) nitro, (4) cyano, (5) halogenated
May be C_1-6Alkyl, (6) halogenated
May be C_2-6Alkenyl, (7) halogenated
Good C_2-6Alkynyl, (8) even when halogenated
Good C_3-6Cycloalkyl, (9) halogenated
Good C_1-6Alkoxy, (10) halogenated
Good C_1-6Alkylthio, (11) hydroxy, (12)
Amino, (13) mono-C_1-6Alkylamino, (14) di
-C_1-6Alkylamino, (15) C_1-6Alkyl, C_6-14
Selected from aryl and 5- to 10-membered aromatic heterocyclic groups
5 to 7 which may have 1 to 3 substituents
Membered cyclic amino, (16) formyl, carboxy, cal
Bamoyl, C_1-6Alkyl-carbonyl, C_3-6Cycloa
Alkyl-carbonyl, C_1-6Alkoxy-carbonyl,
C_6-14Aryl-carbonyl, C_7-16Aralkyl-cal
Bonil, C_6-14Aryloxy-carbonyl, C_7-16A
Aralkyloxy-carbonyl, 5-6 membered heterocyclic carbonyl
Le, Mono-C_1-6Alkyl-carbamoyl, di-C_1-6A
Lucyl-carbamoyl, C_6-14Aryl-carbamoy
5 to 6-membered heterocyclic carbamoyl, C_1-6Alkylsul
Honyl, C_6-14Arylsulfonyl, C_1-6Alkyls
Rufinil and C_6-14Selected from arylsulfinyl
Acyl, (17) formylamino, C_1-6Alkyl-
Carboxamide, C_6-14Aryl-carboxamide, C
_1-6Alkoxy-carboxamide, C_1-6Alkylsulfo
Nilamino and C_6-14From arylsulfonylamino
Acylamino of choice, (18) C_1-6Alkyl-carbo
Nyloxy, C_6-14Aryl-carbonyloxy, C
_1-6Alkoxy-carbonyloxy, mono-C_1-6Archi
Ru-carbamoyloxy, di-C_1-6Alkyl-carba
Moyloxy, C_6-14Aryl-carbamoyloxy and
Acyloxy selected from and nicotinoyloxy,
(19) Sulfo, (20) C_6-14Aryl and (21) C
_6-141 to 3 substituents selected from aryloxy
C that each may have_6-14Aryl or carbon source
Other than nitrogen, sulfur, and oxygen
5- to 14-membered aromatic containing 1 to 4 hetero atoms
Having 1 to 3 heterocyclic groups, and further
And (1) halogen atom, (2) C_1-3Alkylene dioxy
(3) nitro, (4) cyano, (5) halogenated
May be C_1-6Alkyl, (6) halogenated
May be C_2-6Alkenyl, (7) halogenated
Good C_2-6Alkynyl, (8) even when halogenated
Good C_3-6Cycloalkyl, (9) C_6-14Aryl, (1
0) optionally halogenated C_1-6Alkoxy, (1
1) C which may be halogenated_1-6Alkylthio,
(12) hydroxy, (13) amino, (14) mono-C_1-6
Alkylamino, (15) mono-C_6-14Arylamino,
(16) Di-C_1-6Alkylamino, (17) di-C_6-14A
Reel amino, (18) formyl, carboxy, carbamo
Il, C_1-6Alkyl-carbonyl, C_3-6Cycloalkyl
Le-carbonyl, C_1-6Alkoxy-carbonyl, C
_6-14Aryl-carbonyl, C_7-16Aralkyl-Carbo
Nil, C_6-14Aryloxy-carbonyl, C_7-16Ara
Alkyloxycarbonyl, 5- to 6-membered heterocyclic carbonyl
Le, Mono-C_1-6Alkyl-carbamoyl, di-C_1-6A
Lucyl-carbamoyl, C_6-14Aryl-carbamoy
5 to 6-membered heterocyclic carbamoyl, C_1-6Alkylsul
Honyl, C_6-14Arylsulfonyl, C_1-6Alkyls
Rufinil and C_6-14Selected from arylsulfinyl
Acyl, (19) formylamino, C_1-6Alkyl-
Carboxamide, C_6-14Aryl-carboxamide, C
_1-6Alkoxy-carboxamide, C_1-6Alkylsulfo
Nilamino and C_6-14From arylsulfonylamino
Acylamino of choice, (20) C_1-6Alkyl-carbo
Nyloxy, C_6-14Aryl-carbonyloxy, C
_1-6Alkoxy-carbonyloxy, mono-C_1-6Archi
Ru-carbamoyloxy, di-C_1-6Alkyl-carba
Moyloxy, C_6-14Aryl-carbamoyloxy and
Acyloxy selected from and nicotinoyloxy,
(21) C_1-6Alkyl, C_6-14Aryl and 5 to
1 to 3 substituents selected from a 10-membered aromatic heterocyclic group
A 5- to 7-membered saturated cyclic amino optionally having (2)
2) 5- to 10-membered aromatic heterocyclic group and (23) sulfo
Each having 1 to 5 substituents selected from
Good C_1-6Alkyl, C_2-6Alkenyl, C_2-6Archi
Nil or C_3-6Cycloalkyl, or (iii) a formula-
(C = O) -R^Five,-(C = O) -OR^Five,-(C = O) -NR
^FiveR⁶,-(C = S) -NHR^Five, -SO_Two-R^5a Or −
SO-R^5a[Wherein, R^FiveAre (a) hydrogen atoms, (b) (1)
Logen atom, (2) C_1-3Alkylenedioxy, (3) d
Toro, (4) cyano, (5) optionally halogenated
C_1-6Alkyl, (6) optionally halogenated C
_2-6Alkenyl, (7) optionally halogenated C
_2-6Alkynyl, (8) optionally halogenated C
_3-6Cycloalkyl, (9) optionally halogenated
C_1-6Alkoxy, (10) optionally halogenated
C_1-6Alkylthio, (11) hydroxy, (12) ami
No, (13) Mono-C_1-6Alkylamino, (14) di-C
_1-6Alkylamino, (15) C_1-6Alkyl, C_6-14Ants
Or a 5- to 10-membered aromatic heterocyclic group
5- to 7-membered saturated group which may have 1 to 3 substituents
Japanese cyclic amino, (16) formyl, carboxy, carbamo
Il, C_1-6Alkyl-carbonyl, C_3-6Cycloalkyl
Le-carbonyl, C_1-6Alkoxy-carbonyl, C
_6-14Aryl-carbonyl, C_7-16Aralkyl-Carbo
Nil, C_6-14Aryloxy-carbonyl, C_7-16Ara
Alkyloxycarbonyl, 5- to 6-membered heterocyclic carbonyl
Le, Mono-C_1-6Alkyl-carbamoyl, di-C_1-6A
Lucyl-carbamoyl, C_6-14Aryl-carbamoy
5 to 6-membered heterocyclic carbamoyl, C_1-6Alkylsul
Honyl, C_6-14Arylsulfonyl, C_1-6Alkyls
Rufinil and C_6-14Selected from arylsulfinyl
Acyl, (17) formylamino, C_1-6Alkyl-
Carboxamide, C_6-14Aryl-carboxamide, C
_1-6Alkoxy-carboxamide, C_1-6Alkylsulfo
Nilamino and C_6-14From arylsulfonylamino
Acylamino of choice, (18) C_1-6Alkyl-carbo
Nyloxy, C_6-14Aryl-carbonyloxy, C
_1-6Alkoxy-carbonyloxy, mono-C_1-6Archi
Ru-carbamoyloxy, di-C_1-6Alkyl-carba
Moyloxy, C_6-14Aryl-carbamoyloxy and
Acyloxy selected from and nicotinoyloxy,
(19) Sulfo, (20) C_6-14Aryl and (21) C
_6-141 to 3 substituents selected from aryloxy
C that each may have_6-14Aryl or carbon source
Other than nitrogen, sulfur, and oxygen
5- to 14-membered aromatic containing 1 to 4 hetero atoms
A heterocyclic group, or (c) (1) (1 ′) a halogen atom,
(2 ') C_1-3Alkylenedioxy, (3 ') nitro,
(4 ′) cyano, (5 ′) optionally halogenated C
_1-6Alkyl, (6 ′) optionally halogenated C_2-6
Alkenyl, (7 ′) optionally halogenated C_2-6
Alkynyl, (8 ') optionally halogenated C_3-6
Cycloalkyl, (9 ′) optionally halogenated C
_1-6Alkoxy, (10 ') optionally halogenated C
_1-6Alkylthio, (11 ') hydroxy, (12') ami
No, (13 ') Mono-C_1-6Alkylamino, (14 ') di-
C_1-6Alkylamino, (15 ') C_1-6Alkyl, C_6-14
Selected from aryl and 5- to 10-membered aromatic heterocyclic groups
5 to 7 which may have 1 to 3 substituents
Membered cyclic amino, (16 ') formyl, carboxy,
Rubamoyl, C_1-6Alkyl-carbonyl, C_3-6Cyclo
Alkyl-carbonyl, C_1-6Alkoxy-carboni
Le, C_6-14Aryl-carbonyl, C_7-16Aralkyl-
Carbonyl, C_6-14Aryloxy-carbonyl, C
_7-16Aralkyloxy-carbonyl, 5-6 membered heterocyclic ring
Rubonyl, mono-C_1-6Alkyl-carbamoyl, di-
C_1-6Alkyl-carbamoyl, C_6-14Aryl-cal
Bamoyl, 5- to 6-membered heterocyclic carbamoyl, C_1-6Archi
Rusulfonyl, C_6-14Arylsulfonyl, C_1-6Al
Killsulfinyl and C_6-14Aryl sulfinyl?
Acyl selected from (17 ') formylamino, C_1-6Al
Kill-carboxamide, C_6-14Aryl-carboxami
C_1-6Alkoxy-carboxamide, C_1-6Alkyl
Sulfonylamino and C_6-14Arylsulfonylami
Acylamino selected from the group consisting of (18 ') C_1-6Alkyl-
Carbonyloxy, C_6-14Aryl-carbonyloxy
Si, C_1-6Alkoxy-carbonyloxy, mono-C_1-6
Alkyl-carbamoyloxy, di-C_1-6Alkyl-
Carbamoyloxy, C_6-14Aryl-carbamoylo
Acyloxy selected from xy and nicotinoyloxy
Si, (19 ') sulfo, (20') C_6-14Aryl and (2
1 ') C_6-14No one substituent selected from aryloxy
C which each may have_6-14Aryl or
From nitrogen, sulfur and oxygen atoms other than carbon atoms
5 to 14 members containing 1 to 4 heteroatoms selected
Aromatic heterocyclic group, (2) halogen atom, (3) C_1-3Al
Killenedioxy, (4) Nitro, (5) Cyano, (6) C
C which may be formed into a log_1-6Alkyl, (7) halogen
C which may be_2-6Alkenyl, (8) halogen
C which may be_2-6Alkynyl, (9) halogenated
C that may be_3-6Cycloalkyl, (10) halogen
C which may be_1-6Alkoxy, (11) halogen
C which may be_1-6Alkylthio, (12) hydr
Roxy, (13) amino, (14) mono-C_1-6Alkyria
Mino, (15) Di-C_1-6Alkylamino, (16) C_1-6A
Luquil, C_6-14Aryl and 5- to 10-membered aromatic compounds
Even if it has 1 to 3 substituents selected from
Good 5- to 7-membered saturated cyclic amino, (17) formyl,
Ruboxy, carbamoyl, C_1-6Alkyl-carboni
Le, C_3-6Cycloalkyl-carbonyl, C_1-6Alkoki
C-carbonyl, C_6-14Aryl-carbonyl, C_7-16
Aralkyl-carbonyl, C_6-14Aryloxy-cal
Bonil, C_7-16Aralkyloxy-carbonyl, 5-6
Membered heterocyclic carbonyl, mono-C_1-6Alkyl-carbamo
Il, Di-C_1-6Alkyl-carbamoyl, C_6-14Ants
Carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C
_1-6Alkylsulfonyl, C_6-14Arylsulfonyl,
C_1-6Alkylsulfinyl and C_6-14Arylsul
Acyl selected from finyl, (18) formylamino,
C_1-6Alkyl-carboxamide, C_6-14Aryl-ka
Luboxamide, C_1-6Alkoxy-carboxamide, C
_1-6Alkylsulfonylamino and C_6-14Aryls
Acylamino selected from rufonylamino, (19) C
_1-6Alkyl-carbonyloxy, C_6-14Aryl-ka
Rubonyloxy, C_1-6Alkoxy-carbonyloxy
Shi, Mono-C_1-6Alkyl-carbamoyloxy, di-
C_1-6Alkyl-carbamoyloxy, C_6-14Aryl
-Selected from carbamoyloxy and nicotinoyloxy
Selected from acyloxy and (20) sulfo
C which may have 1 to 5 substituents_1-6A
Luquil, C_2-6Alkenyl, C_2-6Alkynyl or C
_3-6Cycloalkyl, R^5aIs (a) (1) a halogen atom,
(2) C_1-3Alkylenedioxy, (3) nitro, (4)
Ano, (5) optionally halogenated C_1-6Archi
(6) optionally halogenated C_2-6Alkene
(7) C which may be halogenated_2-6Alkini
(8) C which may be halogenated_3-6Cycloal
Kill, (9) C which may be halogenated_1-6Alkoki
C, (10) C which may be halogenated_1-6Alkyl
Thio, (11) hydroxy, (12) amino, (13) mono-
C_1-6Alkylamino, (14) di-C_1-6Alkylam
No, (15) C_1-6Alkyl, C_6-14Aryl and 5
No substituent selected from 10-membered aromatic heterocyclic groups
A 5- to 7-membered saturated cyclic amino optionally having 3
(16) formyl, carboxy, carbamoyl, C_1-6A
Alkyl-carbonyl, C_3-6Cycloalkyl-carboni
Le, C_1-6Alkoxy-carbonyl, C_6-14Aryl-
Carbonyl, C_7-16Aralkyl-carbonyl, C_6-14A
Reeloxy-carbonyl, C_7-16Aralkyloxy-
Carbonyl, 5-6 membered heterocyclic carbonyl, mono-C_1-6
Alkyl-carbamoyl, di-C_1-6Alkyl-carba
Moyle, C_6-14Aryl-carbamoyl, 5-6 membered complex
Ring carbamoyl, C_1-6Alkylsulfonyl, C_6-14A
Reel sulfonyl, C_1-6Alkylsulfinyl and
C_6-14Acyl selected from arylsulfinyl, (1
7) Formylamino, C_1-6Alkyl-carboxamides,
C_6-14Aryl-carboxamide, C_1-6Alkoxy-
Carboxamide, C_1-6Alkylsulfonylamino and
And C_6-14Acyl selected from arylsulfonylamino
Amino, (18) C_1-6Alkyl-carbonyloxy, C
_6-14Aryl-carbonyloxy, C_1-6Alkoxy-
Carbonyloxy, mono-C_1-6Alkyl-carbamoy
Luoxy, di-C_1-6Alkyl-carbamoyloxy,
C_6-14Aryl-carbamoyloxy and nicotinoi
Acyloxy selected from ruoxy, (19) sulfo,
(20) C_6-14Aryl and (21) C_6-14Aryloxy
Each having 1 to 3 substituents selected from
May be C_6-14A nitrogen source other than an aryl or carbon atom
A heteroatom selected from a hydrogen atom, a sulfur atom and an oxygen atom
A 5- to 14-membered aromatic heterocyclic group containing 1 to 4,
Is (b) (1) (1 ') halogen atom, (2') C_1-3Archi
Rangeoxy, (3 ') nitro, (4') cyano, (5 ') c
C which may be formed into a log_1-6Alkyl, (6 ') halo
C which may be genated_2-6Alkenyl, (7 ') halo
C which may be genated_2-6Alkynyl, (8 ') halo
C which may be genated_3-6Cycloalkyl, (9 ')
Optionally halogenated C_1-6Alkoxy, (10 ')
Optionally halogenated C_1-6Alkylthio, (1
1 ′) hydroxy, (12 ′) amino, (13 ′) mono-C_1-6
Alkylamino, (14 ') di-C_1-6Alkylamino,
(15 ') C_1-6Alkyl, C_6-14Aryl and 5 to
1 to 3 substituents selected from a 10-membered aromatic heterocyclic group
A 5- to 7-membered saturated cyclic amino optionally having (1)
6 ') formyl, carboxy, carbamoyl, C_1-6Al
Kill-carbonyl, C_3-6Cycloalkyl-carboni
Le, C_1-6Alkoxy-carbonyl, C_6-14Aryl-
Carbonyl, C_7-16Aralkyl-carbonyl, C_6-14A
Reeloxy-carbonyl, C_7-16Aralkyloxy-
Carbonyl, 5-6 membered heterocyclic carbonyl, mono-C_1-6
Alkyl-carbamoyl, di-C_1-6Alkyl-carba
Moyle, C_6-14Aryl-carbamoyl, 5-6 membered complex
Ring carbamoyl, C_1-6Alkylsulfonyl, C_6-14A
Reel sulfonyl, C_1-6Alkylsulfinyl and
C_6-14Acyl selected from arylsulfinyl, (1
7 ') Formylamino, C_1-6Alkyl-carboxami
C_6-14Aryl-carboxamide, C_1-6Alkoki
C-carboxamide, C_1-6Alkylsulfonylamino
And C_6-14A selected from arylsulfonylamino
Silamino, (18 ') C_1-6Alkyl-carbonyloxy
Si, C_6-14Aryl-carbonyloxy, C_1-6Arco
Xy-carbonyloxy, mono-C_1-6Alkyl-cal
Bamoyloxy, di-C_1-6Alkyl-carbamoylo
Kissi, C_6-14Aryl-carbamoyloxy and nico
Acyloxy selected from tynoyloxy, (19 ')
Ruho, (20 ') C_6-14Aryl and (21 ') C_6-14Ants
1 to 3 substituents selected from
C that you may have_6-14Other than aryl or carbon atom
Hetero selected from nitrogen, sulfur and oxygen
5- to 14-membered aromatic heterocyclic ring containing 1 to 4 atoms
Group, (2) halogen atom, (3) C_1-3Alkylene dioxy
(4) nitro, (5) cyano, (6) halogenated
May be C_1-6Alkyl, (7) halogenated
May be C_2-6Alkenyl, (8) halogenated
Good C_2-6Alkynyl, (9) even when halogenated
Good C_3-6Cycloalkyl, (10) halogenated
May be C_1-6Alkoxy, (11) halogenated
May be C_1-6Alkylthio, (12) hydroxy, (1
3) Amino, (14) Mono-C_1-6Alkylamino, (15)
Di-C_1-6Alkylamino, (16) C_1-6Alkyl, C
_6-14From aryl and 5- to 10-membered heteroaromatic groups
5 which may have 1 to 3 substituents selected
7-membered saturated cyclic amino, (17) formyl, carboxy,
Carbamoyl, C_1-6Alkyl-carbonyl, C_3-6Shiku
Loalkyl-carbonyl, C_1-6Alkoxy-carboni
Le, C_6-14Aryl-carbonyl, C_7-16Aralkyl-
Carbonyl, C_6-14Aryloxy-carbonyl, C
_7-16Aralkyloxy-carbonyl, 5-6 membered heterocyclic ring
Rubonyl, mono-C_1-6Alkyl-carbamoyl, di-
C_1-6Alkyl-carbamoyl, C_6-14Aryl-cal
Bamoyl, 5- to 6-membered heterocyclic carbamoyl, C_1-6Archi
Rusulfonyl, C_6-14Arylsulfonyl, C_1-6Al
Killsulfinyl and C_6-14Aryl sulfinyl?
Acyl selected from (18) formylamino, C_1-6Al
Kill-carboxamide, C_6-14Aryl-carboxami
C_1-6Alkoxy-carboxamide, C_1-6Alkyl
Sulfonylamino and C_6-14Arylsulfonylami
Acylamino selected from the group consisting of (19) C_1-6Alkyl-
Carbonyloxy, C_6-14Aryl-carbonyloxy
Si, C_1-6Alkoxy-carbonyloxy, mono-C_1-6
Alkyl-carbamoyloxy, di-C_1-6Alkyl-
Carbamoyloxy, C_6-14Aryl-carbamoylo
Acyloxy selected from xy and nicotinoyloxy
1 to 5 substituents selected from the group consisting of
C that each may have_1-6Alkyl, C_2-6Al
Kenil, C_2-6Alkynyl or C_3-6Cycloalkyl,
And R⁶Is a hydrogen atom or C_1-6Is alkyl)
Wherein the ring A further comprises (1) a halogen atom
Child, (2) C_1-3Alkylenedioxy, (3) nitro,
(4) cyano, (5) optionally halogenated C_1-6
Alkyl, (6) optionally halogenated C_2-6Al
Kenyl, (7) optionally halogenated C_2-6Archi
Nyl, (8) optionally halogenated C_3-6Cycloa
Alkyl, (9) optionally halogenated C_1-6Arco
Xy, (10) optionally halogenated C_1-6Archi
Lucio, (11) hydroxy, (12) amino, (13) mono
-C_1-6Alkylamino, (14) di-C_1-6Alkylam
No, (15) C_1-6Alkyl, C_6-14Aryl and 5
No substituent selected from 10-membered aromatic heterocyclic groups
A 5- to 7-membered saturated cyclic amino optionally having 3
(16) formyl, carboxy, carbamoyl, C_1-6A
Alkyl-carbonyl, C_3-6Cycloalkyl-carboni
Le, C_1-6Alkoxy-carbonyl, C_6-14Aryl-
Carbonyl, C_7-16Aralkyl-carbonyl, C_6-14A
Reeloxy-carbonyl, C_7-16Aralkyloxy-
Carbonyl, 5-6 membered heterocyclic carbonyl, mono-C_1-6
Alkyl-carbamoyl, di-C_1-6Alkyl-carba
Moyle, C_6-14Aryl-carbamoyl, 5-6 membered complex
Ring carbamoyl, C_1-6Alkylsulfonyl, C_6-14A
Reel sulfonyl, C_1-6Alkylsulfinyl and
C_6-14Acyl selected from arylsulfinyl, (1
7) Formylamino, C_1-6Alkyl-carboxamides,
C_6-14Aryl-carboxamide, C_1-6Alkoxy-
Carboxamide, C_1-6Alkylsulfonylamino and
And C_6-14Acyl selected from arylsulfonylamino
Amino, (18) C_1-6Alkyl-carbonyloxy, C
_6-14Aryl-carbonyloxy, C_1-6Alkoxy-
Carbonyloxy, mono-C_1-6Alkyl-carbamoy
Luoxy, di-C_1-6Alkyl-carbamoyloxy,
C_6-14Aryl-carbamoyloxy and nicotinoi
Acyloxy selected from ruoxy, (19) sulfo,
(20) C_6-14Aryl and (21) C_6-14Aryloxy
May have 1 to 3 substituents selected from
The compound according to the above 1), which is a benzene ring; 3) R¹And R^TwoMay each have a substituent
C_1-6Alkyl, or R¹And R^TwoIs adjacent to a carbon atom
3- to 8-membered allo, which may have a substituent, or
4) The compound as described in 1) above, which forms a heterocyclic ring;^ThreeBefore is an aromatic group which may have a substituent
5) The compound described in 1) above;^FourHas (1) an aromatic group which may have a substituent
Aliphatic hydrocarbons which may further have a substituent
6) The compound according to the above 1), wherein X is an oxygen atom; 7) the compound according to the above 1), wherein Y is an oxygen atom; X-R^FourIs the 5-position of the benzofuran ring
9) the compound according to the above 7), wherein

Embedded image Wherein each symbol is as defined above, or a salt thereof, the compound according to the above 1); 10) wherein R ¹ and R ² are each (1) a C _6-14 aryl, (2) C _1-6 alkoxy, (3) C _1-6 alkylthio,
(4) hydroxy, (5) amino, (6) mono-C _1-6 alkylamino, (7) mono-C _6-14 arylamino, (8)
Di-C _1-6 alkylamino, (9) di-C _6-14 arylamino, (10) carboxy, (11) C _1-6 alkylsulfonyl, (12) C _6-14 arylsulfonyl, (13) C _1-6
Even if it has 1 to 3 substituents selected from alkylsulfinyl, (14) C _6-14 arylsulfinyl and (15) C _1-6 alkyl, C _6-14 aryl and 5- to 10-membered aromatic group C may have 1 to 3 substituents selected from good 5- to 7-membered saturated cyclic amino
_1-6 alkyl or is, or together with the carbon atom to which R ¹ and R ² are adjacent, C _1-6 alkyl, C _6-14 aryl, C
_7-16 aralkyl and 5 to form three 3 which may have to 8-membered homocyclic or heterocyclic ring, 1 to substituents selected from the 10-membered aromatic heterocyclic group; R ³ is (1) a halogen atom , (2) C _1-6 alkyl, (3) C _1-6 alkoxy,
(4) mono -C _1-6 alkylamino, (5) di -C _1-6 alkylamino and (6) C _1-6 alkyl is selected from C _6-14 aryl and 5- to 10-membered aromatic group substituted Group 1
Phenyl, 1-naphthyl, 2-naphthyl, and 2-phenyl which each may have 1 to 3 substituents selected from 5 to 7-membered saturated cyclic amino which may have 3 to 3 members
Tiniel, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 1-
Isoquinolyl, 1-indolyl, 2-indolyl or 2-benzothiazolyl; R ⁴ represents (i) (1) a halogen atom, (2) C _1-6 alkyl, (3) C _1-6 alkoxy,
(4) hydroxy, (5) amino, (6) mono-C _1-6 alkylamino, (7) di-C _1-6 alkylamino, (8) carboxy and (9) C _1-6 alkyl, C _{6 -14} aryl may have 1 to 3 substituents selected from 5 to 10 membered aromatic groups, and may have 1 to 3 substituents selected from 5 to 7 membered saturated cyclic amino, respectively. Good phenyl, 1-naphthyl, 2-naphthyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 1-indolyl, 2-indolyl or 2-
It has benzothiazolyl, and, further carboxy or C _1-6 alkoxy as substituents - carbonyls have they be C _1-6 alkyl or (ii) a halogen atom,, C _1-6 alkyl, C _1-6 C _1-6 alkyl-carbonyl optionally having 1 to 3 substituents each selected from alkoxy, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino and carboxy; C _3-6 cycloalkyl-carbonyl, C _6-14 aryl-carbonyl or C _7-16 aralkyl-carbonyl; X is an oxygen atom; Y is an oxygen atom; and ring A may be further halogen atom or halogenated. Good C _1-6 alkyl, optionally halogenated C _1-6 alkoxy, amino, mono-C _1-6 alkylamino and di-C
1) The compound according to the above 1), which is a benzene ring optionally having 1 to 3 substituents selected from _1-6 alkylamino; 11) R ¹ and R ² are each a C _6-14 aryl, C
_1-6 alkoxy, C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, mono-C _6-14 arylamino, di-C _1-6 alkylamino, di-C _6-14 arylamino ,
Carboxy, C _1-6 alkylsulfonyl, C _6-14 arylsulfonyl, C _1-6 alkylsulfinyl and C
_6-14 arylsulfinyl is C _1-6 alkyl _optionally having 1 to 3 substituents, or R ¹ and R ² together with adjacent carbon atoms are C _1-6 alkyl, Forming a piperidine optionally having 1 to 3 substituents selected from _6-14 aryl and C _7-16 aralkyl; wherein R ³ is a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, amino, Phenyl optionally having 1 to 3 substituents selected from mono-C _1-6 alkylamino and di-C _1-6 alkylamino; R ⁴ represents (i) a halogen atom, C _1-6 alkyl, Phenyl or pyridyl optionally having 1 to 3 substituents each selected from C _1-6 alkoxy, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino and carboxy; C _1-6 alkyl having Is the formula (ii)-(C = O)-
R ^{5 ′ wherein} R ^{5 ′} is a halogen atom, C _1-6 alkyl, C
Phenyl or phenyl-C optionally having 1 to 3 substituents selected from _1-6 alkoxy, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino and carboxy, respectively X is an oxygen atom; _1-6 acyl represented by alkyl as] Y is an oxygen atom;
And ring A further comprises a halogen atom, an optionally halogenated C _1-6 alkyl, an optionally halogenated C _1-6 alkoxy, amino, mono-C _1-6 alkylamino and di-C ₁ , 1 to substituents selected from _-6 alkylamino is benzene ring which may have three above 1) compounds described; 12)

Embedded image Wherein R ¹ and R ² are each a C _1-6 alkyl _optionally having a 6-membered saturated cyclic amino substituted with phenyl, or R ¹ and R ² together with an adjacent carbon atom R3 forms a piperidine substituted with C _1-6 alkyl or C _7-16 aralkyl; R ³ is (i) a hydrogen atom, or (i
i) a substituent selected from (1) C _1-6 alkyl, (2) di-C _1-6 alkylamino and (3) a 6-membered saturated cyclic amino optionally having C _1-6 alkyl; Phenyl optionally having 1 to 3 substituent (s); R ⁴ is (i) phenyl optionally having 1 to 3 substituent (s) selected from nitro and C _1-6 alkyl-carboxamide, (ii) C _1- Phenyl, quinolyl optionally having 1 to 3 substituents each selected from ₆ alkoxy, C _1-6 alkylthio, C _1-6 alkoxy-carbonyl, C _1-6 alkylsulfonyl and C _1-6 alkylsulfinyl Or C _1-6 alkyl or C _2-6 alkenyl which each has 1 to 3 pyridyls and may further have phenyl, carboxy or C _1-6 alkoxy-carbonyl as a substituent, or (iii) Formula − (C O) -R 5 ^'acyl represented ^by' wherein, R 5 ^'' is a phenyl substituted with C _1-6 alkoxy]; and ring A ^'are, to no further 1 3 C _{1- 6} ) is a benzene ring which may have an alkyl group] 13) 3- (4-isopropylphenyl) -5- (4-
(Methoxybenzyloxy) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran, 3- (4-
(Isopropylphenyl) -2,4,6,7-tetramethylbenzofuran-5-yl 4-methoxybenzoate, 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -2,4,6,7 -Tetramethylbenzofuran, 3- (4-isopropylphenyl)-
5- (4-methoxybenzyloxy) -1 ′, 4,6
7-tetramethylspiro [benzofuran-2 (3H),
4'-piperidine] or a salt thereof; the compound of the above 1);

Embedded image Wherein each symbol is as defined above, or a salt thereof and a compound represented by the formula R ⁴ -L, wherein L is a leaving group and R ⁴ is as defined above. A method for producing compound (I), which comprises reacting the compound or a salt thereof; 15) a pharmaceutical composition containing compound (I); 16) a neurodegenerative inhibitor as described in 15) above. 17) The composition according to the above 15), which is a β-amyloid toxicity inhibitor; 18) The composition according to the above 15), which is a preventive / therapeutic agent for neurodegenerative disease; 19) a compound containing the compound (Ia) 20) The inhibitor according to the above 19), which is a β-amyloid toxicity inhibitor; and 21) The inhibitor according to the above 19), which is a preventive / therapeutic agent for neurodegenerative diseases.

In the above formula, the “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by R ¹ or R ² includes, for example, a chain or cyclic hydrocarbon group (eg, Alkyl, alkenyl, alkynyl, cycloalkyl, aryl and the like). Among them, a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable.
As the “alkyl”, for example, C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the like are preferable. “Alkenyl” includes, for example, C _2-6 alkenyl (eg, vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-
Butenyl and the like are preferred. As “alkynyl”, for example, C _2-6 alkynyl (eg, ethynyl, propargyl, butynyl, 1-hexynyl, etc.) and the like are preferable. “Cycloalkyl” includes, for example, C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, etc.) are preferred. As the “aryl”, for example, C _6-14 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the like) and the like are preferable. Examples of the “substituent” of the “optionally substituted hydrocarbon group” represented by R ¹ or R ² include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-3 Alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _2-6
Alkenyl, optionally halogenated C _2-6 alkynyl, optionally halogenated C _3-6 cycloalkyl, C _6-14 aryl (eg, phenyl, 1-naphthyl, 2
-Naphthyl, biphenylyl, 2-anthryl and the like), optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy,
Amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, etc.), mono-C _6-14 arylamino (eg, phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), di-C _1-6 alkylamino (eg, dimethylamino, diethylamino, etc.), di-C _6-14 arylamino (eg, diphenylamino, etc.), acyl, acylamino, acyloxy, 5- to 7-membered which may have a substituent Saturated cyclic amino, 5- to 10-membered aromatic heterocyclic group (eg, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, -, 3-, 4- or 5-isoquinolyl, 1
-, 2- or 3-indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, benzo [b] furanyl, etc.), sulfo and the like. The "hydrocarbon group"
Represents, for example, 1 to 5
, Preferably 1 to 3, and when the number of substituents is 2 or more, each substituent may be the same or different.

The above-mentioned “optionally halogenated C _1-6”
Examples of the “alkyl” include C _1-6 alkyl (eg, methyl, ethyl) which may have 1 to 5, preferably 1 to 3, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). , Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.). Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoro Propyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6- Trifluorohexyl and the like. The “optionally halogenated C _2-6 alkenyl” includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). And C _2-6 alkenyl (eg, vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.) and the like. Specific examples include vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, 3,3,3-trifluoro-1-propenyl,
4,4,4-trifluoro-1-butenyl and the like. Examples of the “optionally halogenated C _2-6 alkynyl” include, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _2-6 alkynyl (eg,
Ethynyl, propargyl, butynyl, 1-hexynyl and the like). Specific examples include ethynyl, propargyl, butynyl, 1-hexynyl, 3,3,3-
Trifluoro-1-propynyl, 4,4,4-trifluoro-1-butynyl and the like. As the “optionally halogenated C _3-6 cycloalkyl”,
For example, C _3-6 cycloalkyl optionally having 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (eg, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl) and the like. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl and the like can be mentioned. Examples of the “optionally halogenated C _1-6 alkoxy” include, for example, 1 to 5,
Preferably one to three halogen atoms (eg, fluorine,
C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, optionally having chlorine, bromine, iodine, etc.)
Pentyloxy, hexyloxy, etc.). Specific examples include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-
Trifluoroethoxy, propoxy, isopropoxy,
Butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like. Examples of the “optionally halogenated C _1-6 alkylthio” include, for example, 1 to 5
, Preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
_1-6 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) and the like. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like.

The above-mentioned “acyl” includes, for example, formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), C _3-6 cycloalkyl-carbonyl (eg, cyclopropylcarbonyl, cyclopentylcarbonyl) , Cyclohexylcarbonyl, etc.), C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C _6-14 aryl-carbonyl (eg, benzoyl, 1-naphthoyl, 2- Naphthoyl, etc.), C _7-16 aralkyl-carbonyl (eg, phenylacetyl, phenylpropionyl, etc.), C _6-14 aryloxy-carbonyl (eg, phenoxycarbonyl, etc.), C _7-16 aralkyloxy-carbonyl (eg, benzyl) Oxycal Bonyl, phenethyloxycarbonyl, etc.), 5- to 6-membered heterocyclic carbonyl (eg, nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperidinocarbonyl, 1-pyrrolidinylcarbonyl),
Mono -C _1-6 alkyl - carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.), di -C _1-6 alkyl - carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.),
C _6-14 aryl-carbamoyl (eg, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), 5- to 6-membered heterocyclic carbamoyl (eg, 2-
Pyridylcarbamoyl, 3-pyridylcarbamoyl, 4
-Pyridylcarbamoyl, 2-thienylcarbamoyl,
3-thienylcarbamoyl, etc.), C _1-6 alkylsulfonyl (e.g., methylsulfonyl and ethyl sulfonyl), C _6-14 arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl), C _{1 And} C- _6-14 arylsulfinyl (eg, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.). Examples of the “acylamino” include formylamino, C _1-6 alkyl-carboxamide (eg, acetamide), C _6-14 aryl-carboxamide (eg, phenylcarboxamide, naphthyl carboxamide, etc.), C _1-6 alkoxy-carboxamide. (Eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc.), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.),
C _6-14 arylsulfonylamino (eg, phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino and the like) and the like. As the “acyloxy”, for example, C _1-6 alkyl-
Carbonyloxy (eg, acetoxy, propionyloxy, etc.), C _6-14 aryl-carbonyloxy (eg, benzoyloxy, naphthylcarbonyloxy, etc.), C
_1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.),
Mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C _1-6 alkyl-carbamoyloxy
(Eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), C _6-14 aryl-carbamoyloxy (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), nicotinoyloxy and the like.

The “5- to 7-membered saturated cyclic amino” of the “optionally substituted 5- to 7-membered saturated cyclic amino” includes, for example, morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidine -1-yl and the like. The “optionally substituted 5”
Examples of the “substituent” of the “-to 7-membered saturated cyclic amino” include C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, hexyl, etc.), C _6-14 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl), 5 to 1
A 0-membered aromatic heterocyclic group (eg, 2- or 3-thienyl, 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 and the like. Or three.
“Optionally substituted 3” formed by R ¹ and R ²
Examples of the “3- to 8-membered homocyclic ring” of the “to 8-membered homocyclic ring” include C _3-8 cycloalkanes such as cyclopropane, cyclobutane, cyclopentane and cyclohexane. The “3- to 8-membered heterocycle” of the “optionally substituted 3- to 8-membered heterocycle” formed by R ¹ and R ² includes, for example, aziridine, azetidine, morpholine, thiomorpholine, piperazine And 3- to 8-membered heterocycles such as piperidine, pyrrolidine, hexamethyleneimine, heptamethyleneimine and hexahydropyrimidine. Examples of the “substituent” of the “optionally substituted 3- to 8-membered homo- or heterocyclic ring” formed by R ¹ and R ² include, for example, C _1-6 alkyl (eg, methyl, ethyl Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), C _6-14 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, etc.), C _7-16 aralkyl (eg, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, etc.), amino, mono-C _1-6 alkylamino (eg, methylamino,
Ethyl-amino), mono-C _6-14 arylamino (eg, phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), di-C _1-6 alkylamino (eg, dimethylamino, diethylamino, etc.), di- -C _6-14 arylamino (eg, diphenylamino, etc.), 5 to 1
A 0-membered aromatic heterocyclic group (eg, 2- or 3-thienyl, 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 and the like. Or three.
Examples of “lower alkyl” of “lower alkyl optionally having substituent (s)” for R ³ include C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl) Tert-butyl, pentyl, hexyl, etc.). The “substituent” of the “optionally substituted lower alkyl” represented by R ³ includes the “optionally substituted hydrocarbon group” represented by the above R ¹ or R ² The same number as the “substituent” is used.

The "aromatic group" of the "aromatic group optionally having substituent (s)" for R ³ includes an aromatic hydrocarbon group and an aromatic heterocyclic group. Examples of the "aromatic hydrocarbon group" include a monocyclic or condensed polycyclic (bi- or tricyclic) aromatic hydrocarbon group having 6 to 14 carbon atoms. Specific examples thereof include C _6-14 aryl such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl and anthryl. 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, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, furan, isoindolizine, xanthrene, phenoxatiin, 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,
Aromatic heterocycles such as thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazane, phenoxazine, or one or more (preferably one or two) aromatic rings (preferably one or two) of these rings Examples thereof include a monovalent group formed by removing an arbitrary hydrogen atom from a ring formed by condensation with a benzene ring. Preferred examples of the “aromatic heterocyclic group” include a 5- or 6-membered aromatic heterocyclic group which may be condensed with one benzene ring. As specific examples, 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 And the like. More preferred are 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 3-quinolyl, 1-isoquinolyl, 1- or 2-indolyl, 2-benzothiazolyl and the like. Examples of the “substituent” of the “aromatic group which may have a substituent” include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkylenedioxy (eg, methylene Dioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _2-6
Alkenyl, optionally halogenated C _2-6 alkynyl, 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 (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino etc.), di -C _1-6 alkylamino (e.g., dimethylamino , Diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), an optionally substituted 5- to 7-membered saturated cyclic amino, acyl, acylamino, acyloxy, sulfo, C _6-14 aryl (eg, phenyl , 1-naphthyl, 2
-Naphthyl, etc.), C _6-14 aryloxy (eg, phenyloxy, naphthyloxy, etc.) and the like. The aforementioned “optionally halogenated C _1-6 alkyl”;
"Optionally halogenated C _2-6 alkenyl",
"Optionally halogenated C _2-6 alkynyl",
"Optionally halogenated C _3-6 cycloalkyl", "optionally halogenated C _1-6 alkoxy", "optionally halogenated C _1-6 alkylthio", Examples of the optionally substituted 5- to 7-membered saturated cyclic amino, “acyl”, “acylamino” and “acyloxy” include the “optionally substituted hydrocarbon” represented by R ¹ or R ² above. `` Substituent '' of `` group ''
And the same as those described in detail above. The "aromatic group" may have, for example, 1 to 3 substituents at substitutable positions, and when the number of substituents is 2 or more,
Each substituent may be the same or different.

As the "aromatic group optionally having substituent (s)" for R ³ , a halogen atom, C _1-3
Alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _2-6 alkenyl, optionally halogenated C _2-6 alkynyl, 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, 5- to 7-membered saturated cyclic amino which may have a substituent, acyl, acylamino, acyloxy, sulfo, C _6-14 aryl, C _6-14 aryloxy Phenyl, 2-, 3- or 4 each optionally substituted with 1 to 3 groups
-Pyridyl, 2- or 3-quinolyl, 1-isoquinolyl and the like. As the “aromatic group optionally having substituent (s)” for R ⁴ , the same as the “aromatic group optionally having substituent (s)” for R ³ can be 1 to 3 , Preferably one or two. As the "aliphatic hydrocarbon group" of the "aliphatic hydrocarbon group which has an aromatic group which may have a substituent and may further have a substituent" represented by R ⁴ , For example, alkyl, alkenyl, alkynyl, cycloalkyl and the like can be mentioned. Among them, C _1-10 alkyl, C _2-10 alkenyl, C
Preferred are _2-10 alkynyl, C _3-10 cycloalkyl and the like. As the “alkyl”, for example, C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the like are preferable. “Alkenyl” includes, for example, C _2-6 alkenyl (eg, vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-
Butenyl and the like are preferred. As “alkynyl”, for example, C _2-6 alkynyl (eg, ethynyl, propargyl, butynyl, 1-hexynyl, etc.) and the like are preferable. “Cycloalkyl” includes, for example, C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, etc.) are preferred. Among them, C _1-6 alkyl is preferred. Similarly to Examples of the "aliphatic hydrocarbon group" has the "optionally substituted aromatic group", for example, the "optionally substituted aromatic group" represented by R ³ One to three
Are listed. Preferably as the "an optionally substituted aromatic group", halogen atom, C _1-3 alkylenedioxy, nitro, cyano, C _1-6 alkyl which may be halogenated, halogenated May be C
_2-6 alkenyl, optionally halogenated C _2-6 alkynyl, 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, an optionally substituted 5- to 7-membered saturated cyclic amino, acyl, acylamino, acyloxy, sulfo, C _6-14 aryl, C _6-14 aryloxy, a substituent 1 to 1 Phenyl, 2-, 3- or 4-pyridyl, 2- or 3-quinolyl, 1-isoquinolyl, etc. each of which may be substituted by three. As the “substituent” that the “aliphatic hydrocarbon group” may further have, “substituted group” of the “optionally substituted hydrocarbon group” for R ¹ or R ² The same groups as those described above are used in the same number. This "substituent"
Preferably an acyl (eg, carboxy, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl,
C _6-14 aryl-carbonyl and the like).

The "acyl" represented by R ⁴ is, for example, a group represented by the formula-(C = O) -R ⁵ ,-(C = O) -OR ⁵ ,-(C = O)
^{-NR 5 R 6, - (C} = S) -NHR 5, during -SO ₂ -R ^5a or -SO-R ^5a [wherein, R ⁵ is a hydrogen atom, an aromatic group which may have a substituent Or an aliphatic hydrocarbon group which may have a substituent, R ^5a is an aromatic group which may have a substituent or an aliphatic hydrocarbon group which may have a substituent, and R ⁶ is Represents a hydrogen atom or C _1-6 alkyl]. Examples of the “optionally substituted aromatic group” represented by R ⁵ or R ^5a include the aforementioned R ³
And the "aromatic group which may have a substituent". As the “aliphatic hydrocarbon group” of the “aliphatic hydrocarbon group optionally having substituent (s)” for R ⁵ or R ^5a , the “aliphatic hydrocarbon group” for R ⁴ Examples are the same as the “aliphatic hydrocarbon group” of the “aliphatic hydrocarbon group which has a good aromatic group and may further have a substituent”. "Aliphatic hydrocarbon group optionally having substituent (s)" for R ⁵ or R ^5a
Examples of the “substituent” include: (1) an aliphatic hydrocarbon which has an aromatic group which may have a substituent and which may further have a substituent represented by R ⁴ (Optionally substituted aromatic group) or (2) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
(3) C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), (4) nitro, (5) cyano, (6) optionally halogenated C _1-6 alkyl,
(7) C _2-6 alkenyl which may be halogenated,
(8) C _2-6 alkynyl which may be halogenated,
(9) optionally halogenated C _3-6 cycloalkyl, (10) optionally halogenated C _1-6 alkoxy, (11) optionally halogenated C _1-6 alkylthio, ( 12) hydroxy, (13) amino, (14) mono-
C _1-6 alkylamino (eg, methylamino, ethylamino, etc.), (15) di-C _1-6 alkylamino (eg, dimethylamino, diethylamino, etc.), (16) may have a substituent 5- to 7-membered saturated cyclic amino, (17) acyl, (18) acylamino, (19) acyloxy, (2
0) Sulfo and the like. The “optionally halogenated C _1-6 alkyl”, “optionally halogenated C _2-6 alkenyl”, “optionally halogenated C _2-6 alkynyl”, “halogenated Optionally substituted C _3-6 cycloalkyl ”,“ optionally halogenated C _1-6 alkoxy ”,“ optionally halogenated C _1-6 alkylthio ”, Good 5
To 7 membered saturated cyclic amino ", the" acyl "," acylamino "and" acyloxy ", the" substituent represented by R ¹ or R ² "may have a substituent hydrocarbon group", " The same as those described in detail can be used.
The “aliphatic hydrocarbon group” may have, for example, 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions, and when the number of the substituents is 2 or more, each substituent The groups can be the same or different. R ⁵ and R ^5a are preferably an aromatic group which may have a substituent.

The "C _1-6 alkyl" represented by R ⁶ includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
Examples include pentyl and hexyl. As the “optionally oxidized sulfur atom” represented by X or Y,
S, SO and SO ₂ are mentioned. A ring may further have in addition to the group represented by the formula -X-R ⁴ "substituent"
Examples of the substituent include the “substituent” of the “optionally substituted aromatic group” represented by R ³ . Ring A may have 1 to 3 substituents at substitutable positions. When the number of substituents is 2 or more, each substituent may be the same or different. As the “substituent” that Ring A may further have in addition to the group represented by the formula —XR ⁴ , for example, a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, halogenated _Optionally substituted C _1-6 alkyl, optionally halogenated C _2-6 alkenyl, optionally halogenated C _2-6 alkynyl, optionally halogenated C _3-6 cycloalkyl , Optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, acyl, acyloxy, sulfo, C _6-14 aryl, C _6-14 aryloxy and the like. Can be As the “aromatic group optionally having substituent (s)” and “acyl” for R ^4a , the “aromatic group optionally having substituent (s)” and “acyl” for R ⁴ And the same. As the “aliphatic hydrocarbon group optionally having substituent (s)” for R ^4a , R ⁵ or R ^{5
The same} as the “aliphatic hydrocarbon group which may have a substituent” shown in ^5a are exemplified.

The "optionally oxidized sulfur atom" represented by Xa or Ya includes the same as the "optionally oxidized sulfur atom" represented by X. Examples of the “substituent” of the “imino optionally substituted” represented by Ya include a hydrocarbon group optionally having a substituent, acyl, and the like. As the “hydrocarbon group optionally having substituent (s)”, for example, the same as the “hydrocarbon group optionally having substituent (s)” represented by R ¹ or R ² can be mentioned. Examples of the “acyl” include those similar to the “acyl” described in detail in the “substituent” of the “hydrocarbon group which may have a substituent” represented by R ¹ or R ^2. . As the “imino optionally having substituent (s)” for Ya, imino, C _1-6 alkylimino (eg, methylimino, ethylimino, etc.), C _6-14 arylimino (eg, phenylimino, - Nafuchiruimino, 2 Nafuchiruimino), C _7-16 aralkyl imino (eg, a benzylideneamino) and the like. Aa ring has the formula -Xa-R
^The “substituent” which may be further present in addition to the group represented by ^4a may be any substituent other than amino which may be substituted, and includes, 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, halogenated Good C _2-6 alkenyl,
Optionally halogenated C _2-6 alkynyl, optionally halogenated C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _{1- 6} alkylthio, hydroxy, acyl, acyloxy, sulfo and the like. The “optionally halogenated C _1-6 alkyl”, “optionally halogenated C _2-6 alkenyl”, “optionally halogenated C _2-6 alkynyl”, “halogenated _Optionally substituted C _3-6 cycloalkyl ”,“ optionally halogenated C _1-6 alkoxy ”,“ optionally halogenated C _1-6 alkylthio ”,“ acyl ”and“ acyloxy ” The “substituent” of the “hydrocarbon group which may have a substituent” represented by the above R ¹ or R ²
And the same as those described in detail above. The Aa ring may have 1 to 3 of these substituents at substitutable positions, and when the number of substituents is 2 or more, each substituent may be the same or different.

In the above formula, R ¹ and R ² are each an optionally substituted C _1-6 alkyl, or R ¹ and R ² have a substituent together with adjacent carbon atoms. It is preferred to form a 3- to 8-membered homo- or heterocyclic ring which may be substituted. R ³ is preferably an aromatic group which may have a substituent. R ⁴ and R ^4a are preferably (1) an aliphatic hydrocarbon group which may have a substituent and may further have a substituent, or (2) acyl. X and Xa are preferably oxygen atoms. Y and Y
a is preferably an oxygen atom. The group represented by the formula —XR ⁴ is preferably substituted at the 5-position of the basic skeleton as described below.

Embedded image The group represented by the formula -Xa- ^R4a is preferably substituted at the 5-position of the basic skeleton as described below.

Embedded image

As compound (I), R ¹ and R ² are preferably (1) C _6-14 aryl, (2) C _1-6 alkoxy, (3) C _1-6 alkylthio, (4) hydroxy (5) amino, (6) mono-C _1-6 alkylamino,
(7) mono-C _6-14 arylamino, (8) di-C _1-6 alkylamino, (9) di-C _6-14 arylamino, (1
0) carboxy, (11) C _1-6 alkylsulfonyl, (1
2) C _6-14 arylsulfonyl, (13) C _1-6 alkylsulfinyl, (14) C _6-14 arylsulfinyl and (15) C _1-6 alkyl, C _6-14 aryl and 5- to 10-membered aromatic A C _1-6 alkyl _optionally having 1 to 3 substituents selected from a 5- to 7-membered saturated cyclic amino optionally having 1 to 3 substituents selected from groups, or R ¹ and R ² have 1 to 3 substituents selected from C _1-6 alkyl, C _6-14 aryl, C _7-16 aralkyl and 5- to 10-membered aromatic heterocyclic group together with adjacent carbon atoms. R ³ is (1) a halogen atom, (2)
C _1-6 alkyl, (3) C _1-6 alkoxy, (4) amino,
(5) Substitution selected from mono-C _1-6 alkylamino, (6) di-C _1-6 alkylamino and (7) C _1-6 alkyl, C _6-14 aryl and 5- to 10-membered aromatic group. Group 1
Phenyl, 1-naphthyl, 2-naphthyl, and 2-phenyl which each may have 1 to 3 substituents selected from 5 to 7-membered saturated cyclic amino which may have 3 to 3 members
Tiniel, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 1-
Isoquinolyl, 1-indolyl, 2-indolyl or 2-benzothiazolyl; R ⁴ represents (i) (1) a halogen atom, (2) C _1-6 alkyl, (3) C _1-6 alkoxy,
(4) hydroxy, (5) amino, (6) mono-C _1-6 alkylamino, (7) di-C _1-6 alkylamino, (8) carboxy and (9) C _1-6 alkyl, C _{6 -14} aryl may have 1 to 3 substituents selected from 5 to 10 membered aromatic groups, and may have 1 to 3 substituents selected from 5 to 7 membered saturated cyclic amino, respectively. Good phenyl, 1-naphthyl, 2-naphthyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 1-indolyl, 2-indolyl or 2-
Has benzothiazolyl, and further carboxy or C _1-6 alkoxy - optionally having a carbonyl C _1-6
Alkyl or (ii) (1) halogen atom, (2) C _1-6
Alkyl, (3) C _1-6 alkoxy, (4) hydroxy,
(5) amino, (6) mono-C _1-6 alkylamino, (7)
Di -C _1-6 alkylamino and (8) 1 a substituent selected from carboxy to 3 substituents optionally having each C _1-6 alkyl - carbonyl, C _3-6 cycloalkyl - carbonyl, C _{6- 14} aryl-carbonyl or C
_7-16 aralkyl-carbonyl; X is an oxygen atom; Y is an oxygen atom; ring A is further halogen atom, optionally halogenated C _1-6 alkyl, optionally halogenated C _1-6 alkoxy And a benzene ring which may have 1 to 3 substituents selected from amino, mono-C _1-6 alkylamino and di-C _1-6 alkylamino. More preferably, R ¹ and R ² are each C _6-14 aryl, C _1-6 alkoxy, C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, mono-C _6-14 Arylamino, di-C _1-6 alkylamino, di-C _6-14 arylamino, carboxy, C
_1-6 alkylsulfonyl, C _6-14 arylsulfonyl,
C _1-6 alkylsulfinyl and C _6-14 arylsulfinyl or, 1 to substituents selected from the Le is three optionally having C _1-6 alkyl, or together with R ¹ and the carbon atom to which R ² is adjacent , C _1-6 alkyl, C _6-14 aryl and C _7-16 aralkyl to form a piperidine optionally having 1 to 3 substituents; R ³ is a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, amino,
Phenyl optionally having 1 to 3 substituents selected from mono-C _1-6 alkylamino and di-C _1-6 alkylamino; R ⁴ represents (i) a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, amino, mono-C
_1-6 alkylamino, C _1-6 with di -C _1-6 alkylamino and phenyl or pyridyl which may have three, respectively, 1 to substituents selected from carboxy
Alkyl, or (ii) a formula-(C = O) -R5 ^'
R ^{5 ′} represents a substituent selected from a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino and carboxy. X is an oxygen atom; three acyl represented by a is] phenyl or phenyl -C _1-6 alkyl optionally having each Y is an oxygen atom; a ring,
A halogen atom, an optionally halogenated C
_1-6 alkyl, optionally halogenated C _1-6 alkoxy, amino, mono-C _1-6 alkylamino and di-
1 to 3 substituents selected from C _1-6 alkylamino
The compound is a benzene ring which may have one or more benzene rings. Also, the formula

Embedded image Wherein R ¹ and R ² are each a C _1-6 alkyl _optionally having a 6-membered saturated cyclic amino substituted with phenyl, or R ¹ and R ² together with an adjacent carbon atom R3 forms a piperidine substituted with C _1-6 alkyl or C _7-16 aralkyl; R ³ is (i) a hydrogen atom, or (i
i) a substituent selected from (1) C _1-6 alkyl, (2) di-C _1-6 alkylamino and (3) a 6-membered saturated cyclic amino optionally having C _1-6 alkyl; Phenyl optionally having 1 to 3 substituent (s); R ⁴ is (i) phenyl optionally having 1 to 3 substituent (s) selected from nitro and C _1-6 alkyl-carboxamide, (ii) C _1- Phenyl, quinolyl optionally having 1 to 3 substituents each selected from ₆ alkoxy, C _1-6 alkylthio, C _1-6 alkoxy-carbonyl, C _1-6 alkylsulfonyl and C _1-6 alkylsulfinyl Or C _1-6 alkyl or C _2-6 alkenyl which each has 1 to 3 pyridyls and may further have phenyl, carboxy or C _1-6 alkoxy-carbonyl as a substituent, or (iii) Formula − (C O) -R 5 ^'acyl represented ^by' wherein, R 5 ^'' is a phenyl substituted with C _1-6 alkoxy]; and ring A ^'are, to no further 1 3 C _{1- 6} is a benzene ring optionally having alkyl].

As the compound (Ia), R ¹ and R ² are preferably (1) C _6-14 aryl, (2) C _1-6
Alkoxy, (3) C _1-6 alkylthio, (4) hydroxy, (5) amino, (6) mono-C _1-6 alkylamino,
(7) mono-C _6-14 arylamino, (8) di-C _1-6 alkylamino, (9) di-C _6-14 arylamino, (1
0) carboxy, (11) C _1-6 alkylsulfonyl, (1
2) C _6-14 arylsulfonyl, (13) C _1-6 alkylsulfinyl, (14) C _6-14 arylsulfinyl and (15) C _1-6 alkyl, C _6-14 aryl and 5- to 10-membered aromatic A C _1-6 alkyl _optionally having 1 to 3 substituents selected from a 5- to 7-membered saturated cyclic amino optionally having 1 to 3 substituents selected from groups, or R ¹ and R ² have 1 to 3 substituents selected from C _1-6 alkyl, C _6-14 aryl, C _7-16 aralkyl and 5- to 10-membered aromatic heterocyclic group together with adjacent carbon atoms. R ³ is (1) a halogen atom, (2)
C _1-6 alkyl, (3) C _1-6 alkoxy, (4) amino,
(5) Substitution selected from mono-C _1-6 alkylamino, (6) di-C _1-6 alkylamino and (7) C _1-6 alkyl, C _6-14 aryl and 5- to 10-membered aromatic group. Group 1
Phenyl, 1-naphthyl, 2-naphthyl, and 2-phenyl which each may have 1 to 3 substituents selected from 5 to 7-membered saturated cyclic amino which may have 3 to 3 members
Tiniel, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 1-
Isoquinolyl, 1-indolyl, 2-indolyl or 2-benzothiazolyl; R ^4a represents (i) (1) a halogen atom, (2) C _1-6 alkyl, (3) C _1-6 alkoxy,
(4) hydroxy, (5) amino, (6) mono-C _1-6 alkylamino, (7) di-C _1-6 alkylamino, (8) carboxy and (9) C _1-6 alkyl, C _{6 -14} aryl may have 1 to 3 substituents selected from 5 to 10 membered aromatic groups, and may have 1 to 3 substituents selected from 5 to 7 membered saturated cyclic amino, respectively. Good phenyl, 1-naphthyl, 2-naphthyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 1-indolyl, 2-indolyl or 2-
Has benzothiazolyl, and further carboxy or C _1-6 alkoxy - optionally having a carbonyl C _1-6
Alkyl or (ii) (1) halogen atom, (2) C _1-6
Alkyl, (3) C _1-6 alkoxy, (4) hydroxy,
(5) amino, (6) mono-C _1-6 alkylamino, (7)
C _1-6 alkyl-carbonyl, C _3-6 cycloalkyl-carbonyl, C _{6- optionally} having 1 to 3 substituents each selected from di-C _1-6 alkylamino and (8) carboxy ₁₄ aryl - carbonyl or C _7-16 aralkyl - carbonyl; Xa is an oxygen atom; Ya is an oxygen atom; Aa ring is further halogen atoms, be C _1-6 alkyl and halogenated optionally halogenated The compound is a benzene ring which may have 1 to 3 substituents selected from good C _1-6 alkoxy.
More preferably, R ¹ and R ² are each C _6-14
Aryl, C _1-6 alkoxy, C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, mono-
C _6-14 arylamino, di-C _1-6 alkylamino, di-C _6-14 arylamino, carboxy, C _1-6 alkylsulfonyl, C _6-14 arylsulfonyl, C _1-6 alkylsulfinyl and C ₆ C _{1-6 optionally} having 1 to 3 substituent (s) selected from _-14 arylsulfinyl
Alkyl or R ¹ and R ² together with adjacent carbon atoms may be C _1-6 alkyl, C _6-14 aryl and C
Forming a piperidine optionally having 1 to 3 substituents selected from _7-16 aralkyl; R ³ is a halogen atom,
C _1-6 alkyl, C _1-6 alkoxy, amino, mono-C
_1-6 alkylamino and di -C _1-6, 1 to substituents selected from alkylamino three optionally having phenyl; is R ^4a (i) a halogen atom, C _1-6 alkyl, C _{1- 6}
C _1- having phenyl or pyridyl optionally having 1 to 3 substituents each selected from alkoxy, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino and carboxy; ₆ alkyl, or (ii) a formula — (C −O) —R ^{5 ′ wherein} R ^{5 ′} is a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, amino, mono-C _{1- 6} alkylamino, di-C
Phenyl or phenyl-C _1-6 alkyl optionally having 1 to 3 substituents selected from _1-6 alkylamino and carboxy]; Xa is an oxygen atom; Ya is oxygen Atom; the Aa ring may further have 1 to 3 substituents selected from a halogen atom, an optionally halogenated C _1-6 alkyl and an optionally halogenated C _1-6 alkoxy. It is a compound that is a good benzene ring.

Specific examples of the compounds (I) and (Ia) include 3- (4-isopropylphenyl) -5- (4-
(Methoxybenzyloxy) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran, 3- (4-
(Isopropylphenyl) -2,4,6,7-tetramethylbenzofuran-5-yl 4-methoxybenzoate, 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -2,4,6,7 -Tetramethylbenzofuran, 3- (4-isopropylphenyl)-
5- (4-methoxybenzyloxy) -1 ′, 4,6
7-tetramethylspiro [benzofuran-2 (3H),
4′-piperidine], 3- (4-isopropylphenyl) -5- (3-pyridylmethyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran and salts thereof. Of these, 3-
(4-isopropylphenyl) -5- (4-methoxybenzyloxy) -2,2,4,6,7-pentamethyl-
2,3-dihydrobenzofuran, 3- (4-isopropylphenyl) -2,4,6,7-tetramethylbenzofuran-5-yl 4-methoxybenzoate, 3- (4
-Isopropylphenyl) -5- (4-methoxybenzyloxy) -2,4,6,7-tetramethylbenzofuran, 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -1 ′, 4 , 6,7-tetramethylspiro [benzofuran-2 (3H), 4'-piperidine] and salts thereof.

The salts of compound (I) and compound (Ia) include, for example, 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. 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. Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. It is. Of these, pharmaceutically acceptable salts are preferred. For example, when the compound (I) or (Ia) 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) ), An inorganic salt such as a salt with ammonium, an ammonium salt, etc., and a compound (I)
Or when (Ia) has a basic functional group, an inorganic salt such as hydrochloride, sulfate, phosphate, hydrobromide or acetate, maleate, fumarate, or succinic acid Salt, methanesulfonate, p-toluenesulfonate,
Organic salts such as citrate and tartrate are exemplified.

The method for producing the compounds (I) and (Ia) is described below. Compound (I) of the present invention can be prepared by a method known per se, for example, EP-A-273647, JP-A 1-2
No. 72578, EP-A-483772,
JP-A-140142, EP-A-345593, JP-A-2-76869, EP-A-345592, JP-A-2-76870, and the like. It can be obtained by the method shown in the equation. Compound (Ia) can be obtained by a method known per se, for example, WO 94 /
14434, Japanese Patent Publication No. Hei 8-504826, WO8
It is obtained by the method described in 4/02131 or the like or a method analogous thereto. Each symbol of the compound in the schematic diagram of the following reaction formula has the same meaning as described above. The compounds in the reaction schemes include those forming salts, and examples of the salts include the same as the salts of compound (I).

[0023]

Embedded image Compound (I) is obtained by combining compound (II) with a compound of formula R ⁴ -L
Is a leaving group and R ⁴ has the same meaning as described above).
Examples of the "leaving group" represented by L include hydroxy,
A halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an optionally halogenated C _1-5 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, etc.), And C _6-10 arylsulfonyloxy which may be present. "C _6-10 arylsulfonyloxy optionally having substituent (s)" includes:
For example, C _1-6 which may have 1 to 3 substituents selected from C _1-6 alkyl, C _1-6 alkoxy and nitro
_6-10 arylsulfonyloxy (eg, phenylsulfonyloxy, naphthylsulfonyloxy, etc.) and the like, and specific examples include benzenesulfonyloxy, m
-Nitrobenzenesulfonyloxy, p-toluenesulfonyloxy and the like.

(1) R ⁴ has “an aromatic group which may have a substituent” or “an aromatic group which may have a substituent”, and further has a substituent. The case of the "aliphatic hydrocarbon group" is described below. The compound (II) is reacted with the compound (III) in the presence of a base, if desired. The amount of compound (III) to be used is about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (II). Examples of the "base" include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, and the like. Tertiary amines such as dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, sodium Metal amides such as amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide,
Metal alkoxides such as potassium tert-butoxide; The amount of the base to be used is about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (II). This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.For example, alcohols such as methanol, ethanol, and propanol, diethyl ether, tetrahydrofuran, dioxane,
Ethers such as 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; dichloromethane, chloroform, carbon tetrachloride; Solvents such as halogenated hydrocarbons such as 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethylsulfoxide, and a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually
The temperature is 20 to 200 ° C, preferably 0 to 150 ° C.

In place of the above reaction, the Mitsunobu reaction (Synthesis, 1981, pp. 1-27) can also be used. The reaction is performed by reacting L in compound (II) and compound (III).
With OH in the presence of azodicarboxylates (eg, diethyl azodicarboxylate, etc.) and phosphines (eg, triphenylphosphine, tributylphosphine, etc.). Compound (III)
Wherein the amount of the compound in which L is OH is the amount of the compound (II) 1
It is about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per mol. The amounts of the "azodicarboxylates" and "phosphines" used are about 1.0 to 5.0 mol, respectively, per 1 mol of compound (II).
Preferably it is about 1.0 to 2.0 moles. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane, and hexane; N-dimethylformamide, N,
Solvents such as amides such as N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, and sulfoxides such as dimethylsulfoxide or Preferred are mixed solvents thereof. The reaction time is usually from 5 minutes to 48
Time, preferably 30 minutes to 24 hours. The reaction temperature is usually -20 to 200 ° C, preferably 0 to 1
00 ° C.

(2) The case where R ⁴ is “acyl” is described below. The compound (II) is reacted with the compound (III) in the presence of a base or an acid, if desired. The amount of compound (III) to be used is about 1.0 to 5.0 based on 1 mol of compound (II).
0 mol, preferably about 1.0 to 2.0 mol. Examples of the “base” include organic bases such as triethylamine and pyridine. As the "acid",
For example, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like can be mentioned. The amount of the “base” to be used is about 0.1 to 10 equivalents, relative to compound (II),
Preferably it is 0.8 to 2 equivalents. The amount of the “acid” to be used is about 0.1 to 10 equivalents, relative to compound (II),
Preferably it is 0.8 to 3 equivalents. This reaction is advantageously performed without a solvent or in a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane, and hexane; Amides such as N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; dimethyl sulfoxide and the like And solvents such as nitrogen-containing aromatic hydrocarbons such as sulphoxides, pyridine, lutidine and quinoline, and mixed solvents thereof. The reaction temperature is about -20 to 150 ° C, preferably 0 to 100 ° C. The reaction time is generally 5 minutes to 24 hours, preferably 10 minutes to 5 hours. The product (I) obtained as described above can be used as a reaction solution or as a crude product in the next reaction. It can be easily purified by separation means such as chromatography.

Compound (II) can be prepared by a method known per se, for example, E
P-A-273647, JP-A-1-272578, EP-A-483772, JP-A-5-140142
Publication, EP-A-345593, JP-A-2-7686
No. 9, EP-A-345592, JP-A-2-768
No. 70, JP-A-57-122080 and the like, or a method analogous thereto. Compound (III) can be easily obtained as a commercially available product, and can also be produced according to a method known per se or a method analogous thereto. When compound (II) is benzofuran (compound (IIa)), it can also be produced by the method described in the following reaction formula 2.

[0028]

Embedded image In the above formulas, L 'indicates a leaving group, R ⁷ is a group formed by removing one methylene hydrogen atoms or R ^1, hal is a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and. Examples of the “leaving group” represented by L ′ include hydroxy, halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, etc.) And C _6-10 arylsulfonyloxy which may have a substituent. “C _6-10 arylsulfonyloxy optionally having substituent (s)” includes, for example, C _1-6 alkyl, C _1-6
C _6-10 arylsulfonyloxy (eg, phenylsulfonyloxy, naphthylsulfonyloxy, etc.) which may have 1 to 3 substituents selected from alkoxy and nitro, and specific examples include benzenesulfonyl Oxy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy and the like.

Compound (IV) is easily commercially available,
It can also be produced by a method known per se. Compound (VI) is produced by reacting phenolate anion generated by treating compound (IV) with a base and compound (V) represented by the formula R ⁷ -CHL'-CH = CH-R ^3. You. As the "base", for example, sodium hydroxide, inorganic bases such as alkali metal hydroxides such as potassium hydroxide, sodium methoxide, sodium ethoxide, alkali metal alcoholates such as potassium tert-butoxide, sodium hydride, Alkali metal hydrides such as potassium hydride, sodium amide, lithium diisopropylamide, metal amides such as lithium hexamethyldisilazide, potassium hydrogen carbonate, sodium carbonate,
And basic salts such as potassium carbonate and sodium acetate. The amount of the base to be used is about 0.5-5 mol, preferably about 1-3 mol, per 1 mol of compound (IV). This reaction is advantageously performed using a solvent inert to the reaction. Examples of such a solvent include alcohols such as methanol, ethanol, and propanol; hydrocarbons such as cyclohexane, hexane, benzene, toluene, and xylene; tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, and the like. Ethers, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, sulfoxides such as dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc. Of halogenated hydrocarbons, water or a mixed solvent thereof is preferred. The reaction time is usually 10 minutes to 8
Time, preferably 30 minutes to 3 hours. The reaction temperature is generally 0 to 120 ° C, preferably 25 to 100 ° C.
° C. The product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be separated by a usual separation means (eg, recrystallization, distillation, chromatography, etc.). Can be easily purified.

Compound (VII) is produced by subjecting compound (VI) to Claisen rearrangement. This reaction is advantageously performed without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol, and propanol, cyclohexane, hexane, benzene, toluene, xylene, hydrocarbons such as mesitylene, formic acid, and acetic acid. Organic acids, ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether and diisopropyl ether, anilines such as N, N-dimethylaniline and N, N-diethylaniline, dichloromethane, chloroform, carbon tetrachloride, Halogenated hydrocarbons such as 1,2-dichloroethane or a mixed solvent thereof are used. This reaction may be performed using an acid catalyst, if desired. As the acid catalyst, Lewis acids such as aluminum chloride and boron tribromide are used. The amount of the acid catalyst to be used is, for example, in the case of a Lewis acid, usually about 0.1 to 20 mol, preferably about 0.1 to 5 mol, per 1 mol of compound (VI). The reaction time is usually 30 minutes to 24 hours, preferably 1 to 6 hours. The reaction temperature is usually -70 to 300 ° C, preferably 150 to 250 ° C.
° C. The product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be separated by a usual separation means (eg, recrystallization, distillation, chromatography, etc.). Can be easily purified.

Compound (VIII) is produced by reacting compound (VII) with a halogenating reagent. Examples of the “halogenating reagent” include halogens such as bromine, chlorine, and iodine, imides such as N-bromosuccinimide, and halogen adducts such as benzyltrimethylammonium iododichloride and benzyltrimethylammonium tribromide. . The amount of halogenating reagent used is
It is about 1-5 mol, preferably about 1-2 mol, per 1 mol of compound (VII). This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, hydrocarbons such as benzene, toluene, cyclohexane and hexane, N, N-dimethylformamide,
Amides such as N, N-dimethylacetamide; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; sulfoxides such as dimethylsulfoxide; acetic acid , Organic acids such as propionic acid, nitroalkanes such as nitromethane,
Aromatic amines such as pyridine, lutidine and quinoline, or a mixed solvent thereof are used. This reaction is performed, if desired, in the presence of a base or a radical initiator, or under light irradiation. As the `` base '', for example, sodium carbonate, calcium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate, basic salts such as potassium acetate, pyridine, aromatic amines such as lutidine, triethylamine, tripropylamine, tributylamine, Tertiary amines such as cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, and the like. The amount of the base to be used is about 0.8 to 10 mol per 1 mol of compound (VII). Examples of the "radical initiator" include benzoyl peroxide, azobisisobutyronitrile, and the like. The amount of the radical initiator to be used is about 0.01 to 1 mol per 1 mol of compound (VII). In the case of light irradiation,
A halogen lamp can be used. The reaction temperature is generally -50 to 150C, preferably 0 to 100C. The reaction time is generally 5 minutes to 24 hours, preferably 10 minutes to 12 hours. The product remains the reaction solution,
Alternatively, it can be used as a crude product in the next reaction,
It can be isolated from the reaction mixture according to a conventional method, and can be easily purified by usual separation means (eg, recrystallization, distillation, chromatography, etc.).

Compound (IIa) is produced by treating compound (VIII) with a base. Examples of the "base" include inorganic bases such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, for example, triethylamine, 1,8-diazabicyclo [5,4,0] -7-undecene, pyridine and the like. Organic bases, sodium methoxide, sodium ethoxide, alkali metal alcoholates such as potassium tert-butoxide, sodium hydride,
Examples include alkali metal hydrides such as potassium hydride, metal amides such as sodium amide, lithium diisopropylamide, and lithium hexamethyldisilazide; and basic salts such as potassium hydrogen carbonate, sodium carbonate, potassium carbonate, and sodium acetate. Can be The amount of the base to be used is about 0.5-10 mol, preferably about 1-5 mol, per 1 mol of compound (VIII). This reaction is advantageously performed using a solvent inert to the reaction. Examples of such a solvent include alcohols such as methanol, ethanol, and propanol; hydrocarbons such as cyclohexane, hexane, benzene, toluene, and xylene;
Ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether and diisopropyl ether; N, N-dimethylformamide;
Amides such as N-dimethylacetamide, hexamethylphosphoric triamide, sulfoxides such as dimethylsulfoxide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, water or a mixed solvent thereof. Are preferred.
The reaction time is generally 10 minutes to 24 hours, preferably 30 minutes.
Minutes to 12 hours. The reaction temperature is usually 0 to 12
0 ° C., preferably 25 to 100 ° C. The product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be separated by a usual separation means (eg, recrystallization, distillation, chromatography, etc.). Can be easily purified.

In each of the above-mentioned reactions, when the starting compound has amino, carboxy or hydroxy as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. Alternatively, the desired compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group include formyl or C _1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.) each having a substituent, phenylcarbonyl, C _1-6 alkoxy-carbonyl (e.g., methoxy). Carbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, C
_7-10 aralkyloxy-carbonyl (such as benzyloxycarbonyl), trityl, phthaloyl and the like are used. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6
Alkyl-carbonyl (e.g., acetyl, propionyl, valeryl, etc.), nitro and the like are used, and the number of substituents is about 1 to 3. Examples of the carboxy protecting group include C _1-6 which may have a substituent.
Alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like are used. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, butylcarbonyl, etc.), nitro, C _1-6 alkyl (Eg, methyl, ethyl, tert-butyl, etc.), C _6-10 aryl (eg, phenyl, naphthyl, etc.), and the number of substituents is about 1 to 3. Examples of the hydroxy-protecting group include formyl, or C _1-6 alkyl each optionally having a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.),
Phenyl, C _7-11 aralkyl (eg, benzyl etc.), C _1-6 alkyl-carbonyl (eg, acetyl, propionyl etc.), phenyloxycarbonyl,
_C7-11 aralkyloxy-carbonyl (for example, benzyloxycarbonyl), tetrahydropyranyl, tetrahydrofuranyl, silyl and the like are used. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl (eg, methyl, ethyl, tert-butyl, etc.), C _7-11 aralkyl (eg, benzyl, etc.) ), C _6-10 aryl (eg, phenyl, naphthyl, etc.), nitro and the like, and the number of substituents is about 1 to 4. As a method for removing the protecting group, a method known per se or a method analogous thereto is used.For example, an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride,
A method of treating with palladium acetate or the like or a reduction reaction is used.

The starting compound of the compound (I) may form a salt, and is not particularly limited as long as the reaction is achieved. For example, the same compounds as the salts that the compound (I) may form may be used. Salts and the like are used. When the configuration isomer (E, Z form) of compound (I) isomerized, it can be isolated and purified by ordinary separation means such as extraction, recrystallization, distillation, chromatography and the like, Pure compounds can be prepared. Also, a new experimental chemistry course
14 (edited by the Chemical Society of Japan), pp. 251-253, 4th edition Experimental Chemistry Lecture 19 (edited by The Chemical Society of Japan), heating, acid catalyst, transition metal complex The double bond isomerization can be advanced by a metal catalyst, a radical species catalyst, light irradiation or a strong base catalyst to obtain a corresponding pure isomer. Compound (I)
Is a stereoisomer depending on the type of the substituent,
The present invention includes both the isomer alone and a mixture thereof. Compounds (I) and (Ia) may be hydrates or non-hydrates.

In any case, if desired, a deprotection reaction, an acylation reaction, an alkylation reaction, a hydrogenation reaction, an oxidation reaction, a reduction reaction, a carbon chain extension reaction, and a substituent exchange reaction may be used alone or in each case. Compound (I) can be synthesized by combining two or more.
When the desired product is obtained in a free state by the above reaction, it may be converted to a salt according to a conventional method, and when obtained as a salt, it may be converted to a free form or another salt according to a conventional method. Can also. Compound (I) thus obtained
Can be isolated and purified from the reaction solution by known means such as phase transfer, concentration, solvent extraction, fractionation, crystallization, recrystallization, chromatography and the like. Compound (I)
Is present as a configurational isomer (a configuration isomer), a diastereomer, a conformer, or the like, each of which can be isolated by the above separation and purification means, if desired. When the compound (I) is a racemate, it can be separated into d-form and l-form by ordinary optical resolution means. The compound (I) or compound (Ia) of the present invention has an inhibitory action on neurodegeneration, an inhibitory action on β-amyloid-induced neuronal cell death, or an action on neurotrophic factor, and has low toxicity and few side effects. Useful. Compound (I) or compound (Ia) of the present invention can be used for mammals (for example,
Acts on mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.) as neurodegenerative inhibitors, neurotrophic factor-like substances, or as beta-amyloid toxicity inhibitors, resulting in neuronal cell death Suppress. Compound (I) or compound (Ia) has a choline-based activating action (for example, choline acetyltransferase activity-enhancing action, etc.), and increases the content of acetylcholine to activate nerve functions. From these facts, compound (I) or compound (Ia) is a neurodegenerative disease (for example,
It is effective against Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, etc., peripheral neuropathy (eg, diabetic neuropathy, etc.), and a preventive / therapeutic agent for these diseases Used as

Compound (I) or compound (I) of the present invention
a) is a low-toxic, pharmaceutical composition containing a pharmacologically acceptable carrier as it is or according to a method known per se, for example, tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (Including soft capsules), orally or parenterally (eg, topically, rectally, intravenously, etc.) as a liquid, injection, suppository, sustained release, patch, chewing gum, etc. it can. The content of compound (I) or compound (Ia) in the preparation of the present invention is about 0.01 to 100% by weight of the whole preparation.
It is. The dose varies depending on the administration subject, administration route, disease and the like. For example, when administered as an oral agent to an adult as a therapeutic agent for Alzheimer's disease, about 0% as the active ingredient compound (I) or compound (Ia) is used. .1-20 mg / kg body weight, preferably about 0.2-10 mg
/ Kg body weight, more preferably about 0.5 to 10 mg / kg
The body weight can be administered once or several times a day. Still other active ingredients [eg, cholinesterase inhibitors (eg, Aricept (donepezil), etc.),
Brain function enhancers (eg, idebenone, vinpocetine, etc.),
Parkinson's disease therapeutic agent (eg, L-dopa etc.), neurotrophic factor, etc.]. The other active ingredient and compound (I) or (Ia) are mixed according to a method known per se, and one pharmaceutical composition (eg, tablet, powder, granule, capsule (including soft capsule), liquid, injection) Suppositories, sustained-release preparations, etc.) and may be used in combination. Alternatively, they may be separately formulated and administered to the same subject simultaneously or with a time interval.

The pharmacologically acceptable carriers that may be used in the preparation of the preparation of the present invention include various organic or inorganic carrier substances commonly used as preparation materials. Agents, binders, disintegrants; solvents in liquid preparations, solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, ordinary additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used. Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, and the like. As the lubricant, for example, magnesium stearate, calcium stearate, talc,
Colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. Disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. Examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate,
Examples include 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 glycerin monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, carboxy Examples include hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like. 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, α-tocopherol and the like.

[0038]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention further includes the following reference examples,
The present invention will be described in detail with reference to Examples, Formulation Examples and Experimental Examples, which are merely examples, do not limit the present invention, and may be changed without departing from the scope of the present invention. The following reference examples, "room temperature" in the examples
Usually indicates about 10 to 35 ° C. % Indicates weight percent unless otherwise specified. Abbreviations used in other texts have the following meanings. s: singlet d: doublet t: triplet q: quartet septet: septet m: multiplet br: broad J: coupling constant (coupling) constant) Hz: Hertz CDCl ₃ : deuterated chloroform d ₆ -DMSO: deuterated dimethyl sulfoxide ¹ H-NMR: proton nuclear magnetic resonance

[0039]

【Example】

Reference Example 1 Methyl α-bromophenylacetate To a solution of α-bromophenylacetic acid (3.00 g, 13.9 mmol) in ethanol (30 mL) was added concentrated sulfuric acid (0.5 mL) at room temperature.
The mixture was refluxed for 1 hour. After cooling the reaction mixture, add 2
It was extracted twice, and the combined organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 2.50 g (yield 79%) of the desired product. Oil. ¹ H-NMR (CDCl ₃ ) δ: 3.78 (3H, s), 5.36 (1H, s), 7.2
9-7.42 (3H, m), 7.48-7.61 (2H, m). Reference Example 2 1-bromo-4- (4-morpholinyl) benzene 4- (4-morpholinyl) benzene (10.0 g, 61.3 mmo
l) in ethanol (100 mL) at 0 ° C.
g, 67.4 mmol) and stirred at room temperature for 1 hour. Pour water (100 mL) into the reaction mixture, extract twice with ethyl acetate, and combine the combined organic layers with saturated aqueous sodium bicarbonate,
After washing with water, it was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 10.7 g of the desired product (yield: 72%). 118-120 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.98-3.22 (4H, m), 3.71-3.92 (4
H, m), 6.72-6.83 (2H, m), 7.31-7.42 (2H, m). Reference Example 3 1-bromo-4- (4-methyl-1-piperazinyl) benzene 1-phenylpiperazine (10.0 g, 61.6 mmol) of N,
To a solution of N-dimethylformamide (80 mL) at 0 ° C was added sodium hydride (60% liquid paraffin dispersion, 2.70 g,
67.8 mmol) and stirred at the same temperature for 10 minutes. Iodomethane (8.74 g, 67.8 mmol) was added to the reaction solution, and
Stirred for 0 minutes. The reaction mixture was poured into water (80 mL), extracted twice with ethyl acetate, and the combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was crystallized from hexane-isopropyl ether to give 7.40 g of 1-methyl-4-phenylpiperazine. Add 0 ° C to a solution of this compound in ethanol (80 mL).
Then, bromine (7.00 g, 43.8 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. Water (80 mL) was poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 8.1 g of the desired product (yield: 52%). Melting point 78-
80 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.35 (3H, s), 2.52-2.63 (4H,
m), 3.13-3.26 (4H, m), 6.78 (2H, d, J = 8.8 Hz),
7.33 (2H, d, J = 8.8 Hz).

Reference Example 4 2-methyl-1- [4- (4-morpholinyl) phenyl] propan-1-one 1-bromo-4- (4-morpholinyl) benzene (10.0
g, 41.3 mmol) in n-butyllithium (1.6 M, 25.8 mL, 4 mL) at -78 ° C.
1.3 mmol) and stirred at the same temperature for 20 minutes. N-isobutyrylpropyleneimine (5.77 g, 45.4 mmo
l) was added and the mixture was stirred at room temperature for 30 minutes. Water to the reaction mixture
(40 mL), extracted twice with ethyl acetate, and the combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from hexane to obtain 6.50 g (yield 67%) of the desired product. 75-77 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 7.0 Hz), 3.22-
3.33 (4H, m), 3.50 (1H, septet, J = 7.0 Hz), 3.81-
3.92 (4H, m), 6.81-6.92 (2H, m), 7.85-8.95 (2H,
m). Reference Example 5 Reference Example using 2-methyl-1- [4- (4-methyl-1-piperazinyl) phenyl] propan-1-one 1-bromo-4- (4-methyl-1-piperazinyl) benzene The desired product was synthesized according to 4.
Yield 81%. 74-76 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 6.6 Hz), 2.35
(3H, s), 2.46-2.63 (4H, m), 3.32-3.41 (4H, m), 3.5
0 (1H, septet, J = 7.0 Hz), 6.84-6.92 (2H, m), 7.8
5-7.95 (2H, m). Reference Example 6 1- (2,5-dimethoxy-3,4,6-trimethylphenyl) -2-methyl-1- [4- (4-morpholinyl) phenyl] propan-1-ol 1-bromo-2,5 N-Butyllithium in a solution of -dimethoxy-3,4,6-trimethylbenzene (7.52 g, 29.0 mmol) in tetrahydrofuran (50 mL) at -78 ° C
(1.6M, 18.1 mL, 29.0 mmol) was added, and the mixture was stirred at the same temperature for 20 minutes. 2-Methyl-1- [4- (4-morpholinyl) phenyl] propan-1-one (6.15 g, 26.
4 mmol) and stirred at room temperature for 30 minutes. Pour water (40 mL) into the reaction mixture, extract three times with ethyl acetate, wash the combined organic layers with water, dry over magnesium sulfate,
Filtration and concentration under reduced pressure. The residue was crystallized from ethanol to give 8.40 g (yield 90%) of the desired product. Melting point 191-193
° C. ¹ H-NMR (CDCl ₃ ) δ: 0.87-1.10 (6H, m), 2.11 (3H,
s), 2.18 (3H, s), 2.45 (3H, s), 2.80-3.18 (8H, m),
3.62 (3H, s), 3.75-3.90 (4H, m), 6.41 (1H, brs),
6.82 (2H, d, J = 8.8 Hz), 7.34 (2H, d, J = 8.8 H
z).

Reference Example 7 1- (2,5-dimethoxy-3,4,6-trimethylphenyl) -2-methyl-1- [4- (4-methyl-1-
Reference Example 6 using piperazinyl) phenyl] propan-1-ol 2-methyl-1- [4- (4-methyl-1-piperazinyl) phenyl] propan-1-one
The desired product was synthesized according to Yield 43%. Melting point 114-116
° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, t, J = 6.6 Hz), 2.11
(3H, s), 2.18 (3H, s), 2.34 (3H, s), 2.45 (3H, s),
2.50-2.62 (4H, m), 2.76-3.00 (1H, m), 3.02 (3H, s),
3.10-3.28 (4H, m), 3.62 (3H, s), 6.40 (1H, br s),
6.84 (2H, d, J = 8.8 Hz), 7.33 (2H, d, J = 8.8 H
z). Reference Example 8 3- (4-isopropylphenyl) -2,2-dimethyl-2,3-dihydrobenzofuran-5-ol 1-bromo-2,5-dimethoxybenzene (7.2 g, 33.
2 mmol) in tetrahydrofuran (20 mL).
N-butyllithium at 1.6 ° C (1.6M, 20.8 mL, 33.2 mmol)
Was added and stirred at the same temperature for 20 minutes. 1- (4
-Isopropylphenyl) -2-methylpropane-1-
ON (5.70 g, 30.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Water (30 mL) was poured into the reaction mixture, and extracted three times with ethyl acetate. The combined organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. 48% with residue
A mixture of hydrobromic acid (30 mL) was added under an argon atmosphere.
The mixture was refluxed for 4 hours. After cooling, water (30 mL) was added to the reaction solution, extracted twice with ethyl acetate, the combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether-hexane to obtain 2.1 g (yield 70%) of the desired product. Melting point 102-10
4 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, s), 1.25 (6H, d, J =
7.0 Hz), 1.57 (3H, s), 2.90 (1H, septet, J = 7.0 H
z), 4.28 (1H, s), 4.67 (1H, s), 6.53-6.85 (3H, m),
7.02 (2H, d, J = 8.0 Hz), 7.16 (2H, d, J = 8.0 H
z). Reference Example 9 2,2,4,6,7-pentamethyl-3- [4- (4-
Morpholinyl) phenyl] -2,3-dihydrobenzofuran-5-ol 1- (2,5-dimethoxy-3,4,6-trimethylphenyl) -2-methyl-1- [4- (4-morpholinyl) phenyl] Propan-1-ol (8.00 g, 19.3 mm
ol) and 48% hydrobromic acid (100 mL) were heated to reflux for 3 hours under an argon atmosphere. After cooling, a saturated aqueous solution of sodium hydrogen carbonate (30 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether-hexane to give the desired product
6.40 g (90% yield) were obtained. 91-93 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.46 (3H, s), 1.8
2 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.98-3.24
(4H, m), 3.71-3.99 (4H, m), 4.04 (1H, s), 4.18 (1
H, s), 6.44-7.10 (4H, m).

Reference Example 10 2,2,4,6,7-pentamethyl-3- [4- (4-
Methyl-1-piperazinyl) phenyl] -2,3-dihydrobenzofuran-5-ol 1- (2,5-dimethoxy-3,4,6-trimethylphenyl) -2-methyl-1- [4- (4- Methyl-1-
Using piperazinyl) phenyl] propan-1-ol, the target compound was synthesized according to Reference Example 9. 55% yield.
159-161 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.46 (3H, s), 1.8
1 (3H, s), 2.17 (6H, s), 2.34 (3H, s), 2.48-2.65
(4H, m), 3.08-3.22 (4H, m), 4.03 (1H, s), 6.58-7.2
0 (4H, m), 1H Not confirmed. Reference Example 11 1- (4-isopropylphenyl) propan-1-ol Aluminum chloride (16.7 g, 125 mmol) and cumene (18.
0 g, 150 mmol) in carbon disulfide (30 mL).
Then, propionyl chloride (11.6 g, 125 mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water, the organic layer was separated, saturated aqueous sodium hydrogen carbonate solution,
After washing with water, drying over magnesium sulfate, filtration, and concentration under reduced pressure were performed to give 1- (4-isopropylphenyl) -propane-
24.7 g of 1-one was obtained. This compound (13.0 g, 68.4 m
mol) in ethanol (80 mL), sodium borohydride (1.29 g, 34.2 mmol) was added under ice cooling, and the mixture was added at room temperature.
Stir for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. Wash the organic layer with water, dry over magnesium sulfate,
Filtration and concentration under reduced pressure gave 11.5 g (79%) of the desired product. Oil. ¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.4 Hz), 1.25
(6H, d, J = 7.0 Hz), 1.63-1.92 (2H, m), 1.94 (1H,
br s), 2.90 (1H, septet, J = 7.0 Hz), 4.47-4.61 (1
H, m), 7.16-7.29 (4H, m). Reference Example 12 2- [1- (4-isopropylphenyl) propyl]-
3,5,6-Trimethyl-1,4-benzoquinone Under nitrogen atmosphere, 1- (4-isopropylphenyl) propan-1-ol (5.00 g, 28.0 mmol) and trimethylhydroquinone (4.30 g, 28.0 mmol) in 1, To a suspension of 2-dichloroethane (100 mL) was added dropwise boron trifluoride ethyl ether complex (1.30 g, 9.33 mmol) at 60 ° C, and the mixture was stirred at the same temperature for 3 hours. After cooling, the reaction mixture was washed with an aqueous iron (III) chloride solution and water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 30: 1) to give the desired product 5.40. g (62% yield). 61-63 ° C.
(Methanol) ¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.4 Hz), 1.22
(6H, d, J = 6.8 Hz), 1.83-2.11 (11H, m), 2.85 (1H,
septet, J = 6.8 Hz), 4.02-4.23 (1H, m), 7.02-4.24
(4H, m).

Reference Example 13 3- (4-isopropylphenyl) -2,4,6,7-
Tetramethylbenzofuran-5-ol 2- [1- (4-isopropylphenyl) propyl]-
3,5,6-trimethyl-1,4-benzoquinone (1.0
(0 g, 0.324 mmol) in ethanol (1.00 L) was stirred for 5 hours while irradiating with 400 W bromcinerite delux (manufactured by LPL Co.) while cooling with ice water to keep the room temperature. The solvent is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (hexane-ethyl acetate 20: 1).
Then, 0.90 g (yield 90%) of the target product was obtained. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J = 7.0 Hz), 1.98
(3H, s), 2.28 (3H, s), 2.30 (3H, s), 2.43 (3H, s),
2.97 (1H, septet, J = 7.0 Hz), 4.43 (1H, s), 7.26
(4H, s). Reference Example 14 2,3,6-trimethyl-4-[(3-phenyl-2-
Propenyl) oxy] phenyl acetate To a solution of 4-hydroxy-2,3,6-trimethylphenyl acetate (10.0 g, 51.5 mmol) in N, N-dimethylformamide (100 mL) was added 1-chloro-3-phenyl-2-acetate. Propene (7.86 g, 51.5 mmol) was added, followed by potassium carbonate (7.10 g, 51.5 mmol), and the mixture was stirred at 60 ° C. for 2 hours under an argon atmosphere. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from methanol to give the desired product 13.0
g (81% yield) was obtained. 104-107 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.06 (3H, s), 2.13 (3H, s), 2.1
8 (3H, s), 2.34 (3H, s), 4.66 (2H, dd, J = 5.6, 1.
2 Hz), 6.43 (1H, dt, J = 16.2, 5.6 Hz), 5.63 (1H,
s), 6.74 (1H, d, J = 16.2 Hz), 7.24-7.46 (5H, m). Reference Example 15 4-hydroxy-2,3,6-trimethyl-5- (1-
Phenyl-2-propenyl) phenyl acetate 2,3,6-trimethyl-4-[(3-phenyl-2-
Propenyl) oxy] phenyl acetate (10.0 g,
A solution of 32.2 mmol) in N, N-dimethylaniline (70 mL) was stirred at 200 ° C. for 3 hours under an argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 2N hydrochloric acid and water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to give 7.80 g of the desired product (78% yield). 136-138 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.06 (6H, s), 2.11 (3H, s), 2.
33 (3H, s), 4.83-5.18 (2H, m), 5.36 (1H, d, J = 10.
0 Hz), 6.32-6.58 (1H, m), 7.18-7.37 (5H, m), 1H Not confirmed.

Reference Example 16 2,4,6,7-Tetramethyl-3-phenylbenzofuran-5-yl acetate 4-hydroxy-2,3,6-trimethyl-5- (1-
Phenyl-2-propenyl) phenyl acetate (5.
10 g, 16.4 mmol) and calcium carbonate (2.13 g, 21.3 mmo
l) tetrahydrofuran (20 mL)-methanol (20 m
To the suspension of L) was slowly added benzyltrimethylammonium iododichloride (6.28 g, 18.0 mmol).
The reaction was stirred at room temperature for 30 minutes. After filtering off the insoluble matter, the solvent was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with a 10% aqueous sodium hydrate sulfite solution, water, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure.
5.30 g of 2-iodomethyl-4,6,7-trimethyl-3-phenyl-2,3-dihydrobenzofuran-5-
I got il acetate. This compound (5.30 g, 12.1 m
mol) and 1,8-diazabicyclo [5,4,0] -7-
Undecene (9.0 mL, 60.0 mmol) in toluene (20 mL)
The solution was stirred at 100 ° C. for 3 hours under an argon atmosphere.
Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The extract was washed with 2N hydrochloric acid and water, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 20: 1) to give the desired product 4.
0 g (79% yield) was obtained. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.85 (3H, s), 2.15 (3H, s), 2.3
0 (3H, s), 2.33 (3H, s), 2.44 (3H, s), 7.32-7.48
(5H, m). Reference Example 17 2,4,6,7-Tetramethyl-3-phenylbenzofuran-5-ol 2,4,6,7-Tetramethyl-3-phenylbenzofuran-5-yl acetate (4.00 g, 13.0 mmol) An 8 N aqueous sodium hydroxide solution (2.0 mL) was added dropwise to a mixed solution of tetrahydrofuran (32 mL) and methanol (8 mL), and the mixture was stirred at 40 ° C for 1 hour. The organic solvent was extracted by concentration under reduced pressure, 2N hydrochloric acid was added to the residue, and the product was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from isopropyl ether-hexane,
3.0 g (87% yield) of the desired product was obtained. 102-104 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.96 (3H, s), 2.28 (3H, s), 2.2
9 (3H, s), 2.44 (3H, s), 4.42 (1H, s), 7.28-7.43
(5H, m). Reference Example 18 1- (2,4-dimethoxyphenyl) -1- (4-isopropylphenyl) -2-methylpropan-1-ol 1-bromo-2,4-dimethoxybenzene and 1- (4-
The target product was synthesized according to Reference Example 6 using isopropylphenyl) -2-methylpropan-1-one. yield
56%. 80-81 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 0.75 (3H, d, J = 6.6 Hz), 1.08
(3H, d, J = 6.6 Hz), 1.20 (6H, d, J = 7.0 Hz), 2.6
6 (1H, septet, J = 7.0 Hz), 2.80 (1H, septet, J =
6.6 Hz), 3.48 (3H, s), 3.79 (3H, s), 4.71 (1H, s),
6.39-6.40 (1H, m), 6.50-6.56 (1H, m), 7.04-7.08 (2
H, m), 7.19-7.23 (2H, m), 7.40-7.44 (1H, m).

Reference Example 19 3- (4-isopropylphenyl) -2,2-dimethyl-2,3-dihydrobenzofuran-6-ol Under an argon atmosphere, 1- (2,4-dimethoxyphenyl) -1- ( 4-isopropylphenyl) -2-
Methylpropan-1-ol (5.58 g, 17.0 mmol) and 4
A mixture of 8% hydrobromic acid (30 mL) was heated at reflux for 24 hours. After cooling the reaction mixture to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, the product was extracted twice with ethyl acetate, and the combined extracts were washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. did. The residue was purified by silica gel column chromatography (hexane-
Ethyl acetate 20: 1 → 10: 1) to give 2.43 g of the desired product (yield
51%). 114-115 ° C. (Hexane) ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.24 (6H, d, J =
7.0 Hz), 1.57 (3H, s), 2.89 (1H, septet, J = 7.0 H
z), 4.25 (1H, s), 6.15 (1H, br), 6.34-6.38 (2H,
m), 6.84-6.88 (1H, m), 6.99-7.03 (2H, m), 7.13-7.1
7 (2H, m). Reference Example 20 4- (4-isopropylbenzoyl) piperidine 1-acetylisonipecotic acid (41.74 g, 243.8 mmol)
To the mixture was added thionyl chloride (200 mL), and the mixture was stirred at room temperature for 30 minutes. Petroleum ether was added to the reaction solution, and the solid was collected by filtration and washed with petroleum ether to obtain 1-acetylisonipecotinyl chloride. 1-Acetylisonipecotinyl chloride was added to cumene (120 mL) and aluminum chloride (69.6
g, 522 mmol).
Stirred at 0 ° C. for 1 hour. The reaction solution was cooled to room temperature, poured into ice water, and the product was extracted twice with ethyl acetate. The combined extracts were washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. Concentrated hydrochloric acid (100 mL) was added to the residue,
The mixture was heated under reflux for 12 hours. The reaction mixture was cooled to room temperature and washed with diethyl ether. To the obtained aqueous layer, an 8 N aqueous sodium hydroxide solution was added until the solution became basic, and the product was extracted twice with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 23.5 g of the desired product (yield 41%). 55-57 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, d, J = 6.8 Hz), 1.57-
2.70 (5H, m), 2.70-2.83 (2H, m), 2.97 (1H, septet,
J = 6.8 Hz), 3.16-3.22 (2H, m), 3.34-3.46 (1H,
m), 7.30-7.34 (2H, m), 7.87-7.91 (2H, m). Reference Example 21 1-benzyl-4- (4-isopropylbenzoyl) piperidine 4- (4-isopropylbenzoyl) piperidine (14.8
4 g, 64.15 mmol) of N, N-dimethylformamide (1
(00 mL) Potassium carbonate (9.60 g, 69.5 mmol) and benzyl bromide (8.50 g, 71.5 mmol) were added to the solution, and the mixture was stirred at room temperature for 20 hours. The mixture was poured into water and the product was extracted twice with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane to give 13.53 g (yield 66%) of the desired product. Melting point 76-77
° C. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 7.0 Hz), 1.79-
1.90 (4H, m), 2.07-2.20 (2H, m), 2.92-2.99 (3H, m),
3.15-3.30 (1H, m), 3.55 (2H, s), 7.24-7.32 (7H,
m), 7.85-7.89 (2H, m).

Reference Example 22 (1-benzyl-4-piperidyl) (2,5-dimethoxy-3,4,6-trimethylphenyl) (4-isopropylphenyl) methanol Under an argon atmosphere, 1-bromo-2,5 -Dimethoxy-3,4,6-trimethylbenzene (4.89 g, 1
8.87 mmol) in tetrahydrofuran (100 mL)
N-Butyl lithium (1.6 M, 12.0 mL, 19.2 mmo) at 8 ° C
l) was added and the mixture was stirred at the same temperature for 30 minutes. Add 1-benzyl-4- (4-isopropylbenzoyl) piperidine to the reaction mixture.
(5.02 g, 15.6 mmol) in tetrahydrofuran (10 mL)
The solution was added and stirred at room temperature for 30 minutes. Water was poured into the reaction mixture, and the product was extracted twice with ethyl acetate. The combined extracts were washed with saturated saline, dried over magnesium sulfate,
It was concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 6.54 g of the desired product (83% yield). Melting point 105-108
° C. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 6.6 Hz), 1.2-1.
5 (2H, m), 1.8-2.0 (4H, m), 2.09 (3H, s), 2.17 (3
H, s), 2.39 (3H, s), 2.4-2.5 (1H, m), 2.78-2.88 (3
H, m), 2.97 (3H, s), 3.51 (2H, s), 3.60 (3H, s),
6.37 (1H, br), 7.08-7.12 (2H, m), 7.26-7.34 (7H,
m). Reference Example 23 1'-benzyl-3- (4-isopropylphenyl)-
4,6,7-trimethylspiro [benzofuran-2 (3
H), 4'-Piperidin] -5-ol Under an argon atmosphere, (1-benzyl-4-piperidyl) (2,5-dimethoxy-3,4,6-trimethylphenyl) (4-isopropylphenyl) methanol
To a solution of (6.41 g, 12.8 mmol) in acetic acid (50 mL) was added 48% hydrobromic acid (60 mL), and the resulting mixture was heated to reflux for 15 hours. After cooling the reaction mixture to room temperature, an 8 N aqueous sodium hydroxide solution was added until the solution became basic, the product was extracted twice with ethyl acetate, and the combined extracts were washed with a saturated aqueous sodium hydrogen carbonate solution. It was dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 4.44 g (yield 76%) of the desired product. 190-192 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 7.0 Hz), 1.21-
1.41 (2H, m), 1.71-2.00 (5H, m), 2.17 (3H, s), 2.20
(3H, s), 2.27-2.90 (5H, m), 3.54 (2H, s), 4.02 (1
H, s), 6.6-7.1 (4H, m), 7.20-7.32 (5H, m), 1H Not confirmed. Reference Example 24 3- (4-Isopropylphenyl) -4,6,7-trimethylspiro [benzofuran-2 (3H), 4'-piperidin] -5-ol hydrochloride 1'-benzyl-3- (4-isopropyl) Phenyl)-
4,6,7-trimethylspiro [benzofuran-2 (3
H), 4'-Piperidin] -5-ol (3.51 g, 7.70
mmol) and a solution of triethylamine (1.1 mL, 7.9 mmol) in chloroform (40 mL) were cooled to 0 ° C., and 1-chloroethyl chloroformate (2.30 g, 16.1 mmol) was added. The reaction mixture was heated under reflux for 1 hour and concentrated under reduced pressure. Methanol (20 mL) was added to the residue, and the mixture was heated under reflux for 1 hour and concentrated under reduced pressure. The residue was crystallized from ethanol-ethyl acetate to obtain 2.80 g (yield 90%) of the desired product.
Melting point> 245 ° C (decomposition). ¹ H-NMR (d ₆ -DMSO) δ: 1.18 (6H, d, J = 6.6 Hz), 1.34
(2H, br), 1.71 (3H, s), 1.97 (2H, br), 2.08 (3H,
s), 2.11 (3H, s), 2.8-3.3 (5H, m), 4.26 (1H, s), 6.
6-7.2 (4H, m), 7.53 (1H, s), 8.78 (1H, s), 1H Not confirmed.

Reference Example 25 3- (4-isopropylphenyl) -1 ′, 4,6,7
-Tetramethylspiro [benzofuran-2 (3H),
4'-piperidin] -5-ol 3- (4-isopropylphenyl) -4,6,7-trimethylspiro [benzofuran-2 (3H), 4'-piperidin] -5-ol hydrochloride (2.80 g, 6.97 mmol), formic acid (30 mL), and 37% formalin (30 mL).
Stirred at C for 15 h. After cooling the reaction mixture to room temperature, an 8 N aqueous sodium hydroxide solution was added to make the mixture basic, and the product was extracted twice with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.), hexane-ethyl acetate 1: 1) to obtain 2.05 g (yield 77%) of the desired product. 114-117 ° C
(Ethyl acetate-hexane). ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.39 (8H, m), 1.72-2.91 (19
H, m), 4.02 (1H, m), 6.6-7.1 (4H, m), 1H Not confirmed. Reference Example 26 (1-Benzyl-4-piperidyl) (2,5-dimethoxy-3,4,6-trimethylphenyl) methanol Under an argon atmosphere, 1-bromo-2,5-dimethoxy-3,4,6- Trimethylbenzene (8.00 g, 3
0.87 mmol) in tetrahydrofuran (80 mL).
N-Butyllithium at 1.6 ° C (1.6M, 19.5 mL, 31.2 mmol)
Was added and stirred at the same temperature for 30 minutes. 1-benzyl-
A solution of 4-formylpiperidine (6.23 g, 30.65 mmol) in tetrahydrofuran (20 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Pour water into the reaction mixture and wash the product with ethyl acetate.
Extracted times. The combined extracts were washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate),
6.17 g (52% yield) of the desired product was obtained. Oily substance. ¹ H-NMR (CDCl ₃ ) δ: 1.17-2.05 (7H, m), 2.16 (3H, s),
2.17 (3H, s), 2.24 (3H, s), 2.79-2.85 (1H, m), 2.9
8-3.05 (1H, m), 3.48 (2H, s), 3.61 (3H, s), 3.75 (3
H, s), 4.59 (1H, m), 7.23-7.32 (5H, m), 1H Not confirmed. Reference Example 27 1'-benzyl-4,6,7-trimethylspiro [benzofuran-2 (3H), 4'-piperidin] -5-ol Under an argon atmosphere, (1-benzyl-4-piperidyl) (2, 5-Dimethoxy-3,4,6-trimethylphenyl) methanol (6.10 g, 15.90 mmol) in acetic acid
(30 mL) To the solution was added 48% hydrobromic acid (40 mL), and the resulting mixture was heated under reflux for 2.5 hours. After cooling the reaction mixture to room temperature, an 8 N aqueous sodium hydroxide solution was added until the solution became basic, and the product was extracted twice with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 1: 1) to give 4.60 g of the desired product (yield 8
6%). Amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.71-2.00 (6H, m), 2.10 (3H, s),
2.11 (3H, s), 2.12 (3H, s), 2.58 (2H, m), 2.87 (2
H, s), 3.56 (2H, s), 7.25-7.38 (5H, m), 1H unconfirmed.

Example 1 5-benzyloxy-3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2 , 4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
-Ol (0.5 g, 1.54 mmol) in N, N-dimethylformamide (20 mL) at 0 ° C was treated with sodium hydride (6 mL).
(0% liquid paraffin dispersion, 68 mg, 1.70 mmol) was added, and the mixture was stirred at the same temperature for 10 minutes. Benzyl bromide (290 mg, 1.70 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Pour the reaction mixture into water (30 mL) and add ethyl acetate.
After extracting twice and washing the combined organic layer with water, it was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from methanol to obtain 380 mg of the desired product (yield 60%).
79-81 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.22 (6H, d, J =
6.8 Hz), 1.50 (3H, s), 1.83 (3H, s), 2.16 (3H, s),
2.24 (3H, s), 2.86 (1H, septet, J = 6.8 Hz), 4.09
(1H, s), 4.70 (2H, s), 6.70-7.00 (2H, br), 7.09 (2
H, d, J = 8.4 Hz), 7.30-7.50 (5H, m). Example 2 5-benzyloxy-3- [4- (dimethylamino) phenyl] -2,2,4,6,7-pentamethyl-2,3
-Dihydrobenzofuran 3- [4- (dimethylamino) phenyl] -2,2,
The target product was synthesized according to Example 1 using 4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and benzyl bromide. Yield 40%. Melting point 110-11
2 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.48 (3H, s), 1.8
7 (3H, s), 2.16 (3H, s), 2.23 (3H, s), 2.91 (6H,
s), 4.04 (1H, s), 4.70 (2H, s), 6.48-7.16 (4H, m),
7.20-7.48 (5H, m). Example 3 5-benzyloxy-2,4,6,7-tetramethyl-
2- (4-phenyl-1-piperazinyl) methyl-2,
3-dihydrobenzofuran 2,4,6,7-tetramethyl-2- (4-phenyl-
The target product was synthesized according to Example 1 using 1-piperazinyl) methyl-2,3-dihydrobenzofuran-5-ol and benzyl bromide. Yield 48%. Melting point 120-12
1 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, s), 2.09 (3H, s), 2.1
6 (3H, s), 2.20 (3H, s), 2.58-2.92 (7H, m), 3.08-
3.22 (5H, m), 4.71 (2H, s), 6.78-6.94 (3H, m), 7.2
0-7.52 (7H, m).

Example 4 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) ) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
The desired product was synthesized according to Example 1 using -ol and 4-methoxybenzyl chloride. Yield 49%. Melting point 95
-96 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.49 (3H, s), 1.82 (3H, s), 2.16 (3H, s),
2.23 (3H, s), 2.86 (1H, septet, J = 7.0 Hz), 3.81
(3H, s), 4.08 (1H, s), 4.63 (2H, s), 6.70-7.18 (6
H, m), 7.35 (2H, d, J = 8.8 Hz). Example 5 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -2,2-dimethyl-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2-dimethyl-2 The target compound was synthesized according to Example 1 using 2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride. 75% yield. 124-126 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.25 (6H, d, J =
7.0 Hz), 1.57 (3H, s), 2.90 (septet, 1H, J = 7.0 H
z), 3.71 (3H, s), 4.30 (1H, s), 4.87 (2H, s), 6.65
-7.35 (11H, m). Example 6 3- [4- (dimethylamino) phenyl] -5- (4-
(Methoxybenzyloxy) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran 3- [4- (dimethylamino) phenyl] -2,2,
The target compound was synthesized according to Example 1 using 4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride. Yield 42
%. 105-107 ° C. (Ethanol) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.48 (3H, s), 1.8
4 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 2.92 (6H,
s), 3.81 (3H, s), 4.04 (1H, s), 4.58-4.69 (2H, m),
6.54-6.93 (6H, m), 7.30-7.42 (2H, m).

Example 7 5- (4-methoxybenzyloxy) -3- [4- (4
-Morpholinyl) phenyl] -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran 2,2,4,6,7-pentamethyl-3- [4- (4-
Morpholinyl) phenyl] -2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride were used to synthesize the desired product according to Example 1. Yield 38
%. 110-112 ° C. (Ethanol) ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.48 (3H, s), 1.8
3 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 3.02-3.26
(4H, m), 3.71-3.99 (7H, m), 4.05 (1H, s), 4.57-4.9
0 (2H, m), 6.60-7.00 (6H, m), 7.35 (2H, d, J = 6.8
Hz). Example 8 5- (4-methoxybenzyloxy) -2,2,4
6,7-pentamethyl-3- [4- (4-methyl-1-
Piperazinyl) phenyl] -2,3-dihydrobenzofuran 2,2,4,6,7-pentamethyl-3- [4- (4-
Methyl-1-piperazinyl) phenyl] -2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride were used to synthesize the desired product according to Example 1. Yield 42%. 121-122 ° C. (Ethyl ether-
(Hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.48 (3H, s), 1.8
3 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 2.34 (3H,
s), 2.52-2.63 (4H, m), 3.13-3.24 (4H, m), 3.81 (3
H, s), 4.05 (1H, s), 4.58-4.67 (2H, m), 6.60-7.07
(6H, m), 7.35 (2H, d, J = 8.8 Hz). Example 9 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (4-methylthiobenzyloxy) -2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
The target compound was synthesized according to Example 1 using -ol and 4- (bromomethyl) phenylmethyl sulfide. 70% yield. 118-120 ° C. (Ethanol) ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.49 (3H, s), 1.82 (3H, s), 2.16 (3H, s),
2.22 (3H, s), 2.48 (3H, s), 2.86 (1H, septet, J =
7.0 Hz), 4.08 (1H, s), 4.65 (2H, s), 6.80-7.02 (2
H, br), 7.08 (2H, d, J = 8.0 Hz), 7.25 (2H, d, J =
8.4 Hz), 7.36 (2H, d, J = 8.4 Hz).

Example 10 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- [4- (methylsulfinyl)
[Benzyloxy] -2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (4-methylthiobenzyloxy) -2,3-dihydrobenzofuran (1.50 g, 3.26 m
mol) of ethanol (80 mL) -water (8 mL), sodium periodate (0.766 g, 3.58 mmol) was added, and the mixture was refluxed for 2 hours. Ethyl acetate and water were added to the reaction mixture, and the two layers were separated.The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and dried over magnesium sulfate.
Filtration and concentration under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to give 1.23 g (79%) of the desired product.
132-134 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.22 (6H, d, J =
6.8 Hz), 1.50 (3H, s), 1.82 (3H, s), 2.17 (3H, s),
2.23 (3H, s), 2.71, 2.72 (1.5H x2, s x2), 2.86 (1
H, septet, J = 6.8 Hz), 4.09 (1H, s), 4.76 (2H,
s), 6.71-7.15 (4H, m), 7.57-7.69 (4H, m). Example 11 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- [4- (methylsulfonyl)
[Benzyloxy] -2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- [4- (methylsulfinyl)
Benzyloxy] -2,3-dihydrobenzofuran (1.
50 g, 3.15 mmol) of ethanol (80 mL)-water (8 mL)
In the mixed solution, add sodium periodate (2.02 g, 9.45 m
mol), and the mixture was heated under reflux for 18 hours. Ethyl acetate and water were added to the reaction mixture, two layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to give the desired product (1.05 g, 68%)
I got Yield 68%. 161-162 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.50 (3H, s), 1.82 (3H, s), 2.17 (3H, s),
2.22 (3H, s), 2.87 (1H, septet, J = 7.0 Hz), 3.05
(3H, s), 4.09 (1H, s), 4.80 (2H, s), 6.70-7.13 (4
H, m), 7.67 (2H, d, J = 8.4 Hz), 7.95 (2H, d, J =
8.4 Hz).

Example 12 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (3-phenyl-2-propen-1-yloxy) -2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
The desired product was synthesized according to Example 1 using -ol and 3-bromo-1-phenyl-1-propene. Yield 71
%. 106-107 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.21 (6H, d, J =
7.0 Hz), 1.49 (3H, s), 1.86 (3H, s), 2.16 (3H, s),
2.24 (3H, s), 2.85 (1H, septet, J = 7.0 Hz), 4.08
(1H, s), 4.36 (2H, d, J = 6.0 Hz), 6.42 (1H, dt, J
= 15.4, 6.0 Hz), 6.66-7.15 (5H, m), 7.20-7.48 (5
H, m). Example 13 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (2-quinolylmethyloxy)
-2,3-dihydrobenzofuran hydrochloride 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
-Ol (1.0 g, 3.08 mmol) in N, N-dimethylformamide (30 mL) at 0 ° C.
(0% liquid paraffin dispersion, 136 mg, 3.39 mmol) was added, and the mixture was stirred at the same temperature for 10 minutes. 2- (Chloromethyl) quinoline hydrochloride (730 mg, 3.39 mmol) was added to the reaction solution, and 8
The mixture was stirred at 0 ° C for 30 minutes. The reaction mixture was poured into water (40 mL), extracted twice with ethyl acetate, and the combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. After adding 4N hydrochloric acid-ethanol to the residue and distilling off the solvent, the residue was crystallized from ethanol-hexane to obtain 1.1 g of the desired product (yield 71%). 136-139 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.94 (3H, s), 1.18 (6H, d, J
= 7.0 Hz), 1.45 (3H, s), 1.78 (3H, s), 2.11 (3H, s)
s), 2.22 (3H, s), 2.85 (1H, septet, J = 7.0 Hz),
4.19 (1H, s), 4.20-4.90 (1H, br), 5.10 (1H, d, J =
15.8 Hz), 5.19 (1H, d, J = 15.8 Hz), 6.65-7.05 (2
H, br), 7.13 (2H, d, J = 8.8 Hz), 7.72-7.85 (1H,
m), 7.91-8.02 (2H, m), 8.15-8.30 (2H, m), 8.80 (1
H, d, J = 8.8 Hz).

Example 14 5- (3,3-diphenylpropyloxy) -3- (4
-Isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
The desired product was synthesized according to Example 1 using -ol and 3,3-diphenylpropylmethanesulfonate. 55% yield. Oil. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.21 (6H, d, J =
7.0 Hz), 1.45 (3H, s), 1.71 (3H, s), 2.08 (3H, s),
2.10 (3H, s), 2.48 (1H, d, J = 6.6 Hz), 2.55 (1H,
d, J = 6.6 Hz), 2.76-2.93 (1H, m), 3.60 (2H, t, J
= 6.6 Hz), 4.07 (1H, s), 4.25 (1H, t, J = 8.0 H
z), 6.60-7.00 (2H, br), 7.06 (2H, d, J = 7.6 Hz),
7.10-7.34 (10H, m). Example 15 4-[[3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl] oxymethyl] methyl benzoate 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
The target compound was synthesized according to Example 1 using -ol and methyl 4- (bromomethyl) methylbenzoate. Yield 8
2%. 108-110 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.50 (3H, s), 1.82 (3H, s), 2.16 (3H, s),
2.22 (3H, s), 2.86 (1H, septet, J = 7.0 Hz), 3.92
(3H, s), 4.09 (1H, s), 4.76 (2H, s), 6.65-7.00 (2
H, br), 7.08 (2H, d, J = 8.0 Hz), 7.51 (2H, d, J =
8.0 Hz), 8.04 (2H, d, J = 8.2 Hz).

Example 16 α-[[3- (4-isopropylphenyl) -2,2,
4,6,7-Pentamethyl-2,3-dihydrobenzofuran-5-yl] oxy] phenylacetate methyl 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
A target compound was synthesized according to Example 1 using -ol and methyl α-bromophenylacetate. 82% yield. Oil. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.21, 1.23 (6H, e
ach d, J = 7.0 Hz), 1.47 (3H, s), 1.57, 1.60 (3H,
each s), 2.00, 2.04 (3H, each s), 2.09, 2.11 (3H, e
ach s), 2.75-2.98 (1H, m), 3.70, 3.74 (3H, each
s), 4.01 (1H, s), 5.07 (1H, s), 6.60-6.95 (2H, br),
7.06 (2H, d, J = 8.0 Hz), 7.24-7.50 (5H, m). Example 17 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (2-pyridylmethyloxy)
-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
-Ol and 2-chloromethylpyridine hydrochloride,
The target compound was synthesized according to Example 1. Yield 17%. Melting point
88-89 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.51 (3H, s), 1.83 (3H, s), 2.17 (3H, s),
2.24 (3H, s), 2.86 (1H, septet, J = 7.0 Hz), 4.10
(1H, s), 4.80 (1H, d, J = 15.8 Hz), 4.89 (1H, d, J
= 15.8 Hz), 6.72-7.02 (2H, br), 7.09 (2H, d, J =
8.2 Hz), 7.15-7.25 (1H, m), 7.67-7.81 (2H, m), 8.50
-8.58 (1H, m).

Example 18 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (3-pyridylmethyloxy)
-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
Using -ol and 3-chloromethylpyridine hydrochloride,
The target compound was synthesized according to Example 1. Yield 76%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.50 (3H, s), 1.82 (3H, s), 2.16 (3H, s),
2.22 (3H, s), 2.86 (1H, septet, J = 7.0 Hz), 4.09
(1H, s), 4.73 (2H, s), 6.63-7.02 (2H, br), 7.09 (2
H, d, J = 8.2 Hz), 7.24 (1H, dd, J = 7.8, 5.0 Hz),
7.78 (1H, d, J = 7.6 Hz), 8.56 (1H, d, J = 4.0 H
z), 8.60-8.71 (1H, br). Example 19 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (4-pyridylmethyloxy)
-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
Using -ol and 4-chloromethylpyridine hydrochloride,
The target compound was synthesized according to Example 1. Yield 52%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.50 (3H, s), 1.82 (3H, s), 2.16 (3H, s),
2.21 (3H, s), 2.78-2.93 (1H, m), 4.08 (1H, s), 4.73
(2H, s), 6.62-7.01 (2H, br), 7.09 (2H, d, J = 8.4
Hz), 7.38 (2H, d, J = 5.8 Hz), 8.60 (2H, d, J =
5.8 Hz).

Example 20 3- (4-isopropylphenyl) -5- (2,4-dinitrophenyloxy) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran 3- (4- Isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
-Ol (2.0 g, 6.16 mmol) in N, N-dimethylformamide (30 mL) at 0 ° C was treated with sodium hydride (6 mL).
0% liquid paraffin dispersion, 270 mg, 6.75 mmol) was added, and the mixture was stirred at the same temperature for 20 minutes. 1-chloro-
2,4-Dinitrobenzene (1.37 g, 6.78 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. Water the reaction mixture (50 mL)
And extracted twice with ethyl acetate. The combined organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 1.5 g (yield 50%) of the desired product. Yield 50%. Melting point 1
37-139 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.57 (3H, s), 1.66 (3H, s), 2.03 (3H, s),
2.19 (3H, s), 2.86 (1H, septet, J = 7.0 Hz), 4.13
(1H, s), 6.62-6.95 (3H, m), 7.11 (2H, d, J = 8.0 H
z), 8.26 (1H, dd, J = 9.2, 2.6 Hz), 8.75-8.86 (1H,
m). Example 21 5- (2,4-bisacetylaminophenyloxy)-
3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -5- (2,4-dinitrophenyloxy) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran ( 800mg, 1.63
mmol) and 10% palladium on carbon (water) (80 mg)
Was suspended in ethanol (40 mL), and the suspension was heated to 60 ° C under a hydrogen atmosphere.
For 4 hours. The catalyst was removed by filtration and concentrated under reduced pressure to give 5-
(2,4-diaminophenoxy) -3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-
710 mg of 2,3-dihydrobenzofuran was obtained. The obtained compound (710 mg, 1.65 mmol) and triethylamine (2
90 mg, 1.70 mmol) in chloroform (30 mL).
Acetyl chloride (0.26 mL, 3.63 mmol) was added at ℃, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into water (30 mL), extracted twice with ethyl acetate, and the combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 5: 1) to obtain 640 mg (yield 76%) of the desired product. Amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, s), 1.22 (6H, d, J =
6.8 Hz), 1.52 (3H, s), 1.64 (3H, s), 2.00 (3H, s),
2.12 (3H, s), 2.18 (3H, s), 2.23 (3H, s), 2.86 (1
H, septet, J = 6.8 Hz), 4.11 (1H, s), 6.30 (1H, d,
J = 9.2 Hz), 6.60-7.03 (2H, br), 7.05 (2H, d, J =
8.4 Hz), 7.54 (1H, dd, J = 9.2, 2.6 Hz), 7.69 (1
H, br s), 8.02 (1H, s), 8.21 (1H, d, J = 2.6 Hz).

Example 22 α- [3- (4-isopropylphenyl) -2,2,2
4,6,7-Pentamethyl-2,3-dihydrobenzofuran-5-yloxy] phenylacetic acid α- [3- (4-isopropylphenyl) -2,2,
Methyl 4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yloxy] phenylacetate (1.20 g,
To a mixed solution of 2.54 mmol) in tetrahydrofuran (24 mL) -methanol (6 mL) was added a 2N aqueous sodium hydroxide solution (2.5 mL) dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, 2N hydrochloric acid was added, and ethyl acetate was added.
Extracted times. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was recrystallized from hexane to give the desired product (0.31 g, 27%) as a diastereomer mixture (mixing ratio: 8: 1). 163-166 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, s), 1.12-1.25 (6H,
m), 1.41-1.56 (6H, m), 1.92-2.10 (6H, m), 2.87 (1
H, septet, J = 6.6 Hz), 3.99 (1H, s), 5.08-5.10 (1
H, m), 5.20-6.00 (1H, br), 6.60-7.17 (4H, m), 7.20
-7.39 (5H, m). Example 23 α- [3- (4-isopropylphenyl) -2,2,
4,6,7-Pentamethyl-2,3-dihydrobenzofuran-5-yloxy] phenylacetic acid The filtrate obtained in Example 22 was concentrated under reduced pressure, and 0.50 g (43%) of an amorphous target product was obtained as a diastereomixture. (1: 3 mixing ratio). ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, s), 1.16-1.26 (6H,
m), 1.39-1.56 (6H, m), 1.91- 2.10 (6H, m), 2.84
(1H, septet, J = 6.8 Hz), 4.00 (1H, m), 5.07-5.10
(1H, s), 5.40-6.30 (1H, br), 6.50-7.14 (4H, m), 7.
20-7.40 (5H, m).

Example 24 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (3-phenyl-1-propyl) oxy-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (3-phenyl-2-propen-1-yl) oxy-2,3-dihydrobenzofuran
(800 mg, 1.82 mmol) and 10% palladium-carbon
(Water-containing) (80 mg) was suspended in ethanol (20 mL) and stirred at room temperature for 3 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was crystallized from methanol to obtain 610 mg of the desired product (yield: 76%). 78-80 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.22 (6H, d, J =
6.8 Hz), 1.48 (3H, s), 1.81 (3H, s), 2.02-2.22 (8
H, m), 2.76-2.91 (3H, m), 3.68 (2H, t, J = 6.4 H
z), 4.07 (1H, s), 6.70-6.92 (2H, br), 7.07 (2H, d,
J = 8.8 Hz), 7.15-7.32 (5H, m). Example 25 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (2-phenylethyl) oxy-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
-Ol (1.0 g, 3.08 mmol), 2-phenylethanol (414 mg, 3.39 mmol), triphenylphosphine (89
0 mg, 3.39 mmol) and diethyl azodicarboxylate (590 mg, 3.39 mmol) in tetrahydrofuran (20
mL) solution was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 1) to give the desired product (150 m).
g (11% yield). 72-74 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, s), 1.21 (6H, d, J =
7.0 Hz), 1.46 (3H, s), 1.72 (3H, s), 2.10 (3H, s),
2.12 (3H, s), 2.83 (1H, septet, J = 7.0 Hz), 3.05
(2H, t, J = 7.0 Hz), 3.85 (2H, t, J = 7.0 Hz), 4.0
3 (1H, s), 6.65-7.00 (2H, br), 7.06 (2H, d, J = 8.
0 Hz), 7.15-7.50 (5H, m).

Example 26 3- (4-isopropylphenyl) -2,4,6,7-
Tetramethylbenzofuran-5-yl 4-methoxybenzoate 3- (4-isopropylphenyl) -2,4,6,7-
Tetramethylbenzofuran-5-ol (0.90 g, 2.92
mmol) and 4-methoxybenzoyl chloride (0.55 g, 3.2
Triethylamine (0.45 mL, 3.21 mmol) was added to a solution of 1 mmol) in chloroform (15 mL) at room temperature.
Stir for 3 hours. Pour water (30 mL) into the reaction mixture, extract twice with ethyl acetate, and combine the combined organic layers with 1 N hydrochloric acid,
After washing with saturated sodium bicarbonate, it was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from ethanol to give 0.52 g (yield 79%) of the desired product. Melting point 1
13-115 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 6.8 Hz), 1.90
(3H, s), 2.18 (3H, s), 2.33 (3H, s), 2.46 (3H, s),
2.95 (1H, septet, J = 6.8 Hz), 3.89 (3H, s), 6.99
(2H, d, J = 9.0 Hz), 7.25 (4H, s), 8.20 (2H, d, J
= 8.8 Hz). Example 27 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -2,4,6,7-tetramethylbenzofuran 3- (4-isopropylphenyl) -2,4,6,7-
The target compound was synthesized according to Example 1 using tetramethylbenzofuran-5-ol and 4-methoxybenzyl chloride. Yield 64%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J = 6.8 Hz), 2.06
(3H, s), 2.31 (3H, s), 2.34 (3H, s), 2.43 (3H, s),
2.97 (1H, septet, J = 6.8 Hz), 3.82 (3H, s), 4.66
(2H, s), 6.91 (2H, d, J = 8.8 Hz), 7.26 (4H, s),
7.40 (2H, d, J = 8.8 Hz).

Example 28 2,4,6,7-Tetramethyl-3-phenylbenzofuran-5-yl 4-methoxybenzoate 2,4,6,7-Tetramethyl-3-phenylbenzofuran-5-ol and 4 The target compound was synthesized according to Example 26 using -methoxybenzoyl chloride. Yield 6
Four%. 152-154 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.88 (3H, s), 2.18 (3H, s), 2.
32 (3H, s), 2.46 (3H, s), 3.89 (3H, s), 6.99 (2H,
d, J = 9.2 Hz), 7.29-7.43 (5H, m), 8.20 (2H, d, J =
9.2 Hz). Example 29 3- (4-isopropylphenyl) -6- (4-methoxybenzyloxy) -2,2-dimethyl-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2-dimethyl-2 , 3-Dihydrobenzofuran-6-ol (1.12
g, 4.00 mmol) of N, N-dimethylformamide (15 m
L) To the solution was added sodium hydride (60% liquid paraffin dispersion, 179.0 mg, 4.48 mmol) at 0 ° C, and the mixture was stirred at the same temperature for 30 minutes. 4-methoxybenzyl chloride (636.8 m
g, 4.07 mmol) and stirred at the same temperature for 30 minutes. The reaction mixture was poured into water and the product was extracted twice with ethyl acetate.
The combined extracts were washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 5: 1) to obtain 1.19 g of the desired product (74% yield). 86-88
° C. (Hexane) ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.24 (6H, d, J =
7.0 Hz), 1.58 (3H, s), 2.89 (1H, septet, J = 7.0 H
z), 3.82 (3H, s), 4.27 (1H, s), 4.96 (2H, s), 6.47
-6.52 (2H, m), 6.90-6.95 (3H, m), 7.02 (2H, d, J =
8.1 Hz), 7.16 (2H, d, J = 8.1 Hz), 7.37 (2H, d, J
= 8.8 Hz). Example 30 1'-benzyl-3- (4-isopropylphenyl)-
5- (4-methoxybenzyloxy) -4,6,7-trimethylspiro [benzofuran-2 (3H), 4'-piperidine] 1'-benzyl-3- (4-isopropylphenyl)-
4,6,7-trimethylspiro [benzofuran-2 (3
H), 4'-Piperidin] -5-ol (824.0 mg, 1.
Sodium hydride (60% liquid paraffin dispersion, 81.4 mg, 2.04 mmol) was added to a solution of 81 mmol) in N, N-dimethylformamide (15 mL) at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. 4-methoxybenzyl chloride (319.9 mg, 2.04
mmol) and stirred at the same temperature for 30 minutes. The reaction mixture was poured into water and the product was extracted twice with ethyl acetate. The combined extracts were washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 3: 1) to give the desired product.
539 mg (52% yield) were obtained. Amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.8 Hz), 1.27-
1.39 (2H, m), 1.81 (3H, s), 1.86-1.96 (2H, m), 2.1
9 (3H, s), 2.23 (3H, s), 2.35-2.87 (5H, m), 3.52 (2
H, s), 3.80 (3H, s), 4.04 (1H, s), 4.62 (2H, s),
6.6-6.9 (4H, m), 7.04-7.08 (2H, m), 7.22-7.36 (7H,
m).

Example 31 1'-benzyl-5- (4-methoxybenzyloxy)
-4,6,7-trimethylspiro [benzofuran-2
(3H), 4'-piperidine] N, N of 1'-benzyl-4,6,7-trimethylspiro [benzofuran-2 (3H), 4'-piperidin] -5-ol (1.01 g, 2.98 mmol) -To a solution of dimethylformamide (15 mL) at 0 ° C was added sodium hydride (60% liquid paraffin dispersion, 134.6 mg, 3.37 mmol),
The mixture was stirred at the same temperature for 30 minutes. 4-methoxybenzyl chloride
(584.9 mg, 3.43 mmol), and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into water and the product was extracted twice with ethyl acetate. The combined extracts were washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate
2: 1) to give 1.15 g (yield 85%) of the desired product. 85-86 ° C (hexane). ¹ H-NMR (CDCl ₃ ) δ: 1.80-2.00 (4H, m), 2.10 (3H,
s), 2.15 (3H, s), 2.18 (3H, s), 2.60 (4H, br), 2.8
7 (2H, s), 3.58 (2H, s), 3.83 (3H, s), 4.62 (2H,
s), 6.90-6.95 (2H, m), 7.30-7.43 (7H, m). Example 32 3- (4-Isopropylphenyl) -5- (4-methoxybenzyloxy) -1 ′, 4,6,7-tetramethylspiro [benzofuran-2 (3H), 4′-piperidine] 3- ( 4-isopropylphenyl) -1 ', 4,6,7
-Tetramethylspiro [benzofuran-2 (3H),
4'-piperidin] -5-ol (509.0 mg, 1.34 mmo
l) in N, N-dimethylformamide (25 mL) solution
Sodium hydride at 60 ° C (60% liquid paraffin dispersion, 6
4.3 mg, 1.61 mmol) and stirred at the same temperature for 30 minutes.
4-methoxybenzyl chloride (244.0 mg, 1.56 mmol)
Was added and stirred at the same temperature for 30 minutes. The reaction mixture was poured into water and the product was extracted twice with ethyl acetate. The combined extracts were washed with saturated saline, dried over magnesium sulfate,
It was concentrated under reduced pressure. The residue was subjected to column chromatography (Chro
matorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical);
The residue was subjected to hexane-ethyl acetate (1: 1) to obtain 262 mg of the desired product (yield: 39%). Amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 7.0 Hz), 1.3-
1.4 (2H, m), 1.82 (3H, s), 1.99-2.04 (2H, m), 2.19
(3H, s), 2.23 (3H, s), 2.30 (3H, s), 2.37-2.70 (4
H, m), 2.82 (1H, septet, J = 7.0 Hz), 3.81 (3H,
s), 4.05 (1H, s), 4.62 (2H, s), 6.6-6.9 (4H, m),
7.05-7.09 (2H, m), 7.33-7.37 (2H, m). Example 33 3- (4-isopropylphenyl) -1 ′, 4,6,7
-Tetramethyl-5- (4-pyridylmethyloxy) spiro [benzofuran-2 (3H), 4'-piperidine] 3- (4-isopropylphenyl) -1 ', 4,6,7
-Tetramethylspiro [benzofuran-2 (3H),
4'-piperidin] -5-ol (817.7 mg, 2.15 mmo
l) in N, N-dimethylformamide (30 mL) solution at 0 ° C with sodium hydride (60% liquid paraffin dispersion, 187.3
mg, 4.98 mmol) and stirred at the same temperature for 30 minutes. 4-
Chloromethylpyridine hydrochloride (364.5 mg, 2.22 mmol)
Was added and stirred at the same temperature for 30 minutes. The reaction mixture was poured into water and the product was extracted twice with ethyl acetate. The combined extracts were washed with saturated saline, dried over magnesium sulfate,
It was concentrated under reduced pressure. The residue was subjected to column chromatography (Chro
matorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical);
The residue was subjected to hexane-ethyl acetate 4: 1) to obtain 575 mg (yield 57%) of the desired product. 96-98 ° C. (Hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 7.0 Hz), 1.34-
1.41 (2H, m), 1.82 (3H, s), 1.92-2.11 (2H, m), 2.19
(3H, s), 2.21 (3H, s), 2.30 (3H, s), 2.37-2.65 (4
H, m), 2.85 (1H, septet, J = 7.0 Hz), 4.05 (1H,
s), 4.72 (2H, s), 6.6-7.1 (4H, m), 7.36-7.39 (2H,
m), 8.58-8.61 (2H, m).

The chemical structural formulas of the compounds obtained in the above Examples are shown below.

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Formulation Example 1 (1) Compound obtained in Example 4 50 mg (2) Lactose 34 mg (3) Maize starch 10.6 mg (4) Maize 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 tableting machine to obtain tablets.

Experimental Example 1 The cytoprotective effect of human neuroblastoma SK-N-SH cells on β-amyloid toxicity was examined. (Method) a) Experimental materials Human neuroblastoma SK-N-SH cells: purchased from American Type Cell Culture (ATCC) DMEM / F-12 medium: purchased from Niken Institute of Biomedical Research, Inc. Magnesium-free phosphate saline (PBS
(-)): Purchased from Nikken Biomedical Research Institute, Ltd. N2 additive (trade name) and EDTA solution: Gibco BR
Purchased from L company A mixture of fetal bovine serum and penicillin (5000 U / ml) streptomycin (5 mg / ml): purchased from Bio White Tucker Recombinant human interferon gamma (rhIFN)
-Γ): Purchased from Wako Pure Chemical Industries, Ltd. Alamar Blue (trade name) Reagent: AccuMed International
Culture flask: Use Falcon 96-well collagen-coated multiplate: Use Iwaki Glass β-amyloid 25-35: Purchase from Bachem Other reagents: Use commercial grade b) Experimental method (1) Culture of SK-N-SH cells SK-N-SH cells were cultured with 5% FCS, 0.5% N2 supplement (trade name), 10 mM HEPES and 1% penicillin (5000 U).
/ ml) DME containing streptomycin (5mg / ml) mixture
Using the M / F-12 medium, subculture was performed in a carbon dioxide gas incubator under a mixed gas of 10% carbon dioxide / 90% air. After culturing to subconfluence, add 2.5 mM ED
PBS containing TA (-) and detached with a solution cell of 1.0 × 10 ⁴
A 96-well collagen-coated multiplate was seeded at a ratio of cells / 100 μl / well. One day later, 80 μl of the culture solution was added to 1.25 n
The medium was replaced with a DMEM / F-12 medium (containing no FCS and N2 additive) containing g / ml of rhIFN-γ, and further cultured for 24 hours was used for a cytotoxicity test. (2) Measurement of protective effect on β-amyloid 25-35-induced neurotoxicity Seed on 96-well collagen-coated multiplate and IFN
80 μl of a culture solution of SK-N-SH cells that have been pretreated with γ
Was removed, and 40 μl of β-amyloid 25-35 having a final concentration of 10 μM and a compound prepared so as to have a final concentration of 1 μM were simultaneously added to initiate a cytotoxicity test. The compound used was prepared at a concentration of 10 mM with dimethyl sulfoxide (DMSO), and β-amyloid 25-35 was prepared at a concentration of 5 mM with sterile purified water and stored frozen at -80 ° C. Was used after dilution and sonication. (3) Evaluation of Cell Survival Activity The survival activity of the surviving nerve cells three days after the start of the cytotoxicity test was measured using the cell-reducing activity of Alamar Blue (trade name) reagent as an index. Remove 20 μl of cell culture and add 20 μl of Alamar Blue (trade name) reagent,
Alamar Blue (trade name) reagent that is reduced in time is colorimetrically determined using a plate reader (Corona, MTP-32 microplate reader) (measurement wavelength 570 nm, reference wavelength 6).
00 nm). The cytoprotective effect was calculated by the following equation. Cytoprotective activity of compound = (AB) / (CB) × 10
0 (%) A: Survival activity of compound + β-amyloid added group B: Survival activity of β-amyloid added group C: Survival activity of control (Results) Using at least 4 wells per 1 dose of compound, Comparison of Dunnett
Analyzed using the test. The results are shown in the table below. Example compound Cytoprotective activity (%) 1 30.7 2 27.9 3 39.4 7 27.3 12 44.8 14 44.2 25 47.0 From these results, Compounds (I) and (Ia) Excellent β
It can be seen that it has an amyloid toxicity protective effect.

[0065]

EFFECTS OF THE INVENTION The compounds (I) and (Ia) have an excellent neurodegeneration-inhibiting action and an ability to penetrate the brain, have low toxicity, and are useful as agents for preventing and treating neurodegenerative diseases.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/495 A61K 31/495 31/535 31/535 C07D 307/81 C07D 307/81 405/06 211 405/06 211 405 / 12 215 405/12 215 491/107 491/107 // C07D 333/54 333/54

Claims (21)

[Claims] (1) Formula (1) [Wherein, R ¹ and R ² are each a hydrogen atom or a hydrocarbon group which may have a substituent, or R ¹ and R ² may have a substituent together with an adjacent carbon atom. R ³ represents a hydrogen atom, a lower alkyl which may have a substituent or an aromatic group which may have a substituent, and R ⁴ represents a (1) substituent. An aromatic group which may have (2) an aliphatic hydrocarbon group which has an aromatic group which may have a substituent and which may further have a substituent, or (3) acyl , X and Y are each an oxygen atom or an optionally oxidized sulfur atom, -
- - is a single bond or a double bond, A ring wherein -X-R
⁴ represents a benzene ring which may have a substituent in addition to the group represented by the formula (wherein each symbol has the same meaning as described above). However, - - - is a single bond, and X and Y are when the oxygen atom, R ⁴ is not acyl. Or a salt thereof. (2) R¹And R^TwoAre (i) hydrogen atoms or
Or (ii) (1) a halogen atom, (2) C_1-3Alkylene
Dioxy, (3) nitro, (4) cyano, (5) halogen
C which may be_1-6Alkyl, (6) halogenated
C that may be_2-6Alkenyl, (7) halogenated
May be C_2-6Alkynyl, (8) halogenated
May be C_3-6Cycloalkyl, (9) C_6-14Ally
, (10) C which may be halogenated_1-6Alkoki
C, (11) C which may be halogenated_1-6Alkyl
Thio, (12) hydroxy, (13) amino, (14) mono-
C_1-6Alkylamino, (15) mono-C_6-14Aryla
Mino, (16) Di-C_1-6Alkylamino, (17) di-C
_6-14Arylamino, (18) formyl, carboxy, mosquito
Rubamoyl, C_1-6Alkyl-carbonyl, C_3-6Cyclo
Alkyl-carbonyl, C_1-6Alkoxy-carboni
Le, C_6-14Aryl-carbonyl, C_7-16Aralkyl-
Carbonyl, C_6-14Aryloxy-carbonyl, C
_7-16Aralkyloxy-carbonyl, 5-6 membered heterocyclic ring
Rubonyl, mono-C_1-6Alkyl-carbamoyl, di-
C_1-6Alkyl-carbamoyl, C_6-14Aryl-cal
Bamoyl, 5- to 6-membered heterocyclic carbamoyl, C_1-6Archi
Rusulfonyl, C_6-14Arylsulfonyl, C_1-6Al
Killsulfinyl and C_6-14Aryl sulfinyl?
Acyl selected from (19) formylamino, C_1-6Al
Kill-carboxamide, C_6-14Aryl-carboxami
C_1-6Alkoxy-carboxamide, C_1-6Alkyl
Sulfonylamino and C_6-14Arylsulfonylami
Acylamino selected from the group of (20) C_1-6Alkyl-
Carbonyloxy, C_6-14Aryl-carbonyloxy
Si, C_1-6Alkoxy-carbonyloxy, mono-C_1-6
Alkyl-carbamoyloxy, di-C_1-6Alkyl-
Carbamoyloxy, C_6-14Aryl-carbamoylo
Acyloxy selected from xy and nicotinoyloxy
Shi, (21) C_1-6Alkyl, C_6-14Aryl and 5
No substituent selected from 10-membered aromatic heterocyclic groups
A 5- to 7-membered saturated cyclic amino optionally having 3
(22) 5- to 10-membered aromatic heterocyclic group and (23) sulfo
Each having 1 to 5 substituents selected from e
May be C_1-6Alkyl, C_2-6Alkenyl, C_2-6Al
Quinyl, C_3-6Cycloalkyl or C_6-14Aryl;
Or R¹And R^TwoTogether with adjacent carbon atoms_1-6A
Luquil, C_6-14Aryl, C_7-16Aralkyl, amino,
Mono-C_1-6Alkylamino, mono-C_6-14Aryla
Mino, Di-C_1-6Alkylamino, di-C_6-14Aryl
Selected from amino and 5- to 10-membered aromatic heterocyclic groups
Which may have 1 to 3 substituents
_3-8Forming a cycloalkane or a 3- to 8-membered heterocycle;
R^ThreeIs (i) hydrogen atom, (ii) (1) halogen atom, (2)
C_1-3Alkylenedioxy, (3) nitro, (4) cyano, (5)
Optionally halogenated C_1-6Alkyl, (6) halo
C which may be genated_2-6Alkenyl, (7) halogen
C which may be_2-6Alkynyl, (8) halogen
C which may be_3-6Cycloalkyl, (9) C_6-14
Aryl, (10) optionally halogenated C_1-6A
Lucoxy, (11) C which may be halogenated_1-6A
Ruquilthio, (12) hydroxy, (13) amino, (14)
Mono-C_1-6Alkylamino, (15) mono-C_6-14Ants
Amino, (16) di-C_1-6Alkylamino, (17)
Di-C_6-14Arylamino, (18) formyl, carbox
Si, carbamoyl, C_1-6Alkyl-carbonyl, C_3-6
Cycloalkyl-carbonyl, C_1-6Alkoxy-cal
Bonil, C_6-14Aryl-carbonyl, C_7-16Aralki
Le-carbonyl, C_6-14Aryloxy-carbonyl,
C_7-16Aralkyloxy-carbonyl, 5-6 membered heterocycle
Carbonyl, mono-C_1-6Alkyl-carbamoyl, di
-C_1-6Alkyl-carbamoyl, C_6-14Aryl-ka
Lubamoyl, 5- to 6-membered heterocyclic carbamoyl, C_1-6Al
Killsulfonyl, C_6-14Arylsulfonyl, C_1-6A
Rukylsulfinyl and C_6-14Arylsulfinyl
Acyl selected from (19) formylamino, C_1-6A
Alkyl-carboxamide, C_6-14Aryl-carboxa
Mid, C_1-6Alkoxy-carboxamide, C_1-6Archi
Rusulfonylamino and C_6-14Aryl sulfonylua
Acylamino selected from Mino, (20) C_1-6Alkyl
-Carbonyloxy, C_6-14Aryl-carbonyloxy
Si, C_1-6Alkoxy-carbonyloxy, mono-C_1-6
Alkyl-carbamoyloxy, di-C_1-6Alkyl-
Carbamoyloxy, C_6-14Aryl-carbamoylo
Acyloxy selected from xy and nicotinoyloxy
Shi, (21) C_1-6Alkyl, C_6-14Aryl and 5
No substituent selected from 10-membered aromatic heterocyclic groups
A 5- to 7-membered saturated cyclic amino optionally having 3
(22) 5- to 10-membered aromatic heterocyclic group and (23) sulfo
May have 1 to 5 substituents selected from e
C_1-6Alkyl, or (iii) (1) a halogen atom,
(2) C_1-3Alkylenedioxy, (3) nitro, (4)
Ano, (5) optionally halogenated C_1-6Archi
(6) optionally halogenated C_2-6Alkene
(7) C which may be halogenated_2-6Alkini
(8) C which may be halogenated_3-6Cycloal
Kill, (9) C which may be halogenated_1-6Alkoki
C, (10) C which may be halogenated_1-6Alkyl
Thio, (11) hydroxy, (12) amino, (13) mono-
C_1-6Alkylamino, (14) di-C_1-6Alkylam
No, (15) C_1-6Alkyl, C_6-14Aryl and 5
No substituent selected from 10-membered aromatic heterocyclic groups
A 5- to 7-membered saturated cyclic amino optionally having 3
(16) formyl, carboxy, carbamoyl, C_1-6A
Alkyl-carbonyl, C_3-6Cycloalkyl-carboni
Le, C_1-6Alkoxy-carbonyl, C_6-14Aryl-
Carbonyl, C_7-16Aralkyl-carbonyl, C_6-14A
Reeloxy-carbonyl, C_7-16Aralkyloxy-
Carbonyl, 5-6 membered heterocyclic carbonyl, mono-C_1-6
Alkyl-carbamoyl, di-C_1-6Alkyl-carba
Moyle, C_6-14Aryl-carbamoyl, 5-6 membered complex
Ring carbamoyl, C_1-6Alkylsulfonyl, C_6-14A
Reel sulfonyl, C_1-6Alkylsulfinyl and
C_6-14Acyl selected from arylsulfinyl, (1
7) Formylamino, C_1-6Alkyl-carboxamides,
C_6-14Aryl-carboxamide, C_1-6Alkoxy-
Carboxamide, C_1-6Alkylsulfonylamino and
And C_6-14Acyl selected from arylsulfonylamino
Amino, (18) C_1-6Alkyl-carbonyloxy, C
_6-14Aryl-carbonyloxy, C_1-6Alkoxy-
Carbonyloxy, mono-C_1-6Alkyl-carbamoy
Luoxy, di-C_1-6Alkyl-carbamoyloxy,
C_6-14Aryl-carbamoyloxy and nicotinoi
Acyloxy selected from ruoxy, (19) sulfo,
(20) C_6-14Aryl and (21) C_6-14Aryloxy
Each having 1 to 3 substituents selected from
May be C_6-14A nitrogen source other than an aryl or carbon atom
A heteroatom selected from a hydrogen atom, a sulfur atom and an oxygen atom
5 to 14-membered aromatic heterocyclic group containing 1 to 4; R^Four
Is (i) (1) halogen atom, (2) C_1-3Alkylenedio
Xy, (3) nitro, (4) cyano, (5) halogenated
C that may be_1-6Alkyl, (6) halogenated
May be C_2-6Alkenyl, (7) halogenated
May be C_2-6Alkynyl, (8) halogenated
Good C_3-6Cycloalkyl, (9) halogenated
May be C_1-6Alkoxy, (10) halogenated
May be C_1-6Alkylthio, (11) hydroxy, (1
2) Amino, (13) Mono-C_1-6Alkylamino, (14)
Di-C_1-6Alkylamino, (15) C_1-6Alkyl, C
_6-14From aryl and 5- to 10-membered heteroaromatic groups
5 which may have 1 to 3 substituents selected
7-membered saturated cyclic amino, (16) formyl, carboxy,
Carbamoyl, C_1-6Alkyl-carbonyl, C_3-6Shiku
Loalkyl-carbonyl, C_1-6Alkoxy-carboni
Le, C_6-14Aryl-carbonyl, C_7-16Aralkyl-
Carbonyl, C_6-14Aryloxy-carbonyl, C
_7-16Aralkyloxy-carbonyl, 5-6 membered heterocyclic ring
Rubonyl, mono-C_1-6Alkyl-carbamoyl, di-
C_1-6Alkyl-carbamoyl, C_6-14Aryl-cal
Bamoyl, 5- to 6-membered heterocyclic carbamoyl, C_1-6Archi
Rusulfonyl, C_6-14Arylsulfonyl, C_1-6Al
Killsulfinyl and C_6-14Aryl sulfinyl?
Acyl selected from (17) formylamino, C_1-6Al
Kill-carboxamide, C_6-14Aryl-carboxami
C_1-6Alkoxy-carboxamide, C_1-6Alkyl
Sulfonylamino and C_6-14Arylsulfonylami
Acylamino selected from the group of (18) C_1-6Alkyl-
Carbonyloxy, C_6-14Aryl-carbonyloxy
Si, C_1-6Alkoxy-carbonyloxy, mono-C_1-6
Alkyl-carbamoyloxy, di-C_1-6Alkyl-
Carbamoyloxy, C_6-14Aryl-carbamoylo
Acyloxy selected from xy and nicotinoyloxy
(19) Sulfo, (20) C_6-14Aryl and (21)
C_6-141 to 3 substituents selected from aryloxy
C that each may have_6-14Aryl or carbon
Other than atoms, select from nitrogen, sulfur and oxygen
5 to 14 membered aromatic containing 1 to 4 hetero atoms
Heterocyclic group, (ii) (1) halogen atom, (2) C_1-3A
Lucylenedioxy, (3) nitro, (4) cyano, (5)
Optionally halogenated C_1-6Alkyl, (6) halo
C which may be genated_2-6Alkenyl, (7) halogen
C which may be_2-6Alkynyl, (8) halogen
C which may be_3-6Cycloalkyl, (9) halogen
C which may be_1-6Alkoxy, (10) halogen
C which may be_1-6Alkylthio, (11) hydr
Roxy, (12) amino, (13) mono-C_1-6Alkyria
Mino, (14) Di-C_1-6Alkylamino, (15) C_1-6A
Luquil, C_6-14Aryl and 5- to 10-membered aromatic compounds
Even if it has 1 to 3 substituents selected from
Good 5- to 7-membered saturated cyclic amino, (16) formyl,
Ruboxy, carbamoyl, C_1-6Alkyl-carboni
Le, C_3-6Cycloalkyl-carbonyl, C_1-6Alkoki
C-carbonyl, C_6-14Aryl-carbonyl, C_7-16
Aralkyl-carbonyl, C_6-14Aryloxy-cal
Bonil, C_7-16Aralkyloxy-carbonyl, 5-6
Membered heterocyclic carbonyl, mono-C_1-6Alkyl-carbamo
Il, Di-C_1-6Alkyl-carbamoyl, C_6-14Ants
Carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C
_1-6Alkylsulfonyl, C_6-14Arylsulfonyl,
C_1-6Alkylsulfinyl and C_6-14Arylsul
Acyl selected from finyl, (17) formylamino,
C_1-6Alkyl-carboxamide, C_6-14Aryl-ka
Luboxamide, C_1-6Alkoxy-carboxamide, C
_1-6Alkylsulfonylamino and C_6-14Aryls
Acylamino selected from rufonylamino, (18) C
_1-6Alkyl-carbonyloxy, C_6-14Aryl-ka
Rubonyloxy, C_1-6Alkoxy-carbonyloxy
Shi, Mono-C_1-6Alkyl-carbamoyloxy, di-
C_1-6Alkyl-carbamoyloxy, C_6-14Aryl
-Selected from carbamoyloxy and nicotinoyloxy
Acyloxy, (19) sulfo, (20) C_6-14Ants
And (21) C_6-14Aryloxy
C which may have 1 to 3 substituents_6-14A
Reel or carbon atom other than nitrogen atom, sulfur atom and
5 containing 1 to 4 hetero atoms selected from oxygen atoms
Having 1 to 3 14-membered aromatic heterocyclic groups, and
Further, as a substituent, (1) a halogen atom, (2) C_1-3
Alkylenedioxy, (3) nitro, (4) cyano,
(5) C which may be halogenated_1-6Alkyl,
(6) C which may be halogenated_2-6Alkenyl,
(7) C which may be halogenated_2-6Alkynyl,
(8) C which may be halogenated_3-6Cycloalkyl
Le, (9) C_6-14Aryl, (10) halogenated
May be C_1-6Alkoxy, (11) halogenated
May be C_1-6Alkylthio, (12) hydroxy, (1
3) Amino, (14) Mono-C_1-6Alkylamino, (15)
Mono-C_6-14Arylamino, (16) di-C_1-6Archi
Ruamino, (17) di-C_6-14Arylamino, (18) ho
Rumyl, carboxy, carbamoyl, C_1-6Alkyl-
Carbonyl, C_3-6Cycloalkyl-carbonyl, C_1-6
Alkoxy-carbonyl, C_6-14Aryl-carboni
Le, C_7-16Aralkyl-carbonyl, C_6-14Arlio
Xy-carbonyl, C_7-16Aralkyloxy-carboni
5 to 6-membered heterocyclic carbonyl, mono-C_1-6Alkyl
-Carbamoyl, di-C_1-6Alkyl-carbamoyl,
C_6-14Aryl-carbamoyl, 5- to 6-membered heterocyclic carb
Moyle, C_1-6Alkylsulfonyl, C_6-14Aryls
Ruphonyl, C_1-6Alkylsulfinyl and C_6-14A
Acyl selected from reelsulfinyl, (19) Horumi
Luamino, C_1-6Alkyl-carboxamide, C_6-14A
Reel-carboxamide, C_1-6Alkoxy-carboxy
Samide, C_1-6Alkylsulfonylamino and C_6-14
Acylamino selected from arylsulfonylamino,
(20) C_1-6Alkyl-carbonyloxy, C_6-14Ants
Carbonyloxy, C_1-6Alkoxy-carboni
Luoxy, Mono-C_1-6Alkyl-carbamoyloxy
Si, Di-C_1-6Alkyl-carbamoyloxy, C_6-14
Aryl-carbamoyloxy and nicotinoyloxy
Acyloxy selected from (1), (21) C_1-6Alkyl,
C_6-14Aryl or 5- to 10-membered aromatic heterocyclic group
5 which may have 1 to 3 substituents selected from
7-membered saturated cyclic amino, (22) 5- to 10-membered aromatic
One substituent selected from a heterocyclic group and (23) sulfo
C that may have 5 each_1-6Alkyl, C
_2-6Alkenyl, C_2-6Alkynyl or C_3-6Cycloa
Or (iii) formula-(C = O) -R^Five,-(C =
O) -OR^Five,-(C = O) -NR^FiveR⁶,-(C = S) -NH
R^Five, -SO_Two-R^5a Or -SO-R^5a[Wherein, R^Five
Are (a) hydrogen atom, (b) (1) halogen atom, (2) C
_1-3Alkylenedioxy, (3) nitro, (4) cyano,
(5) C which may be halogenated_1-6Alkyl,
(6) C which may be halogenated_2-6Alkenyl,
(7) C which may be halogenated_2-6Alkynyl,
(8) C which may be halogenated_3-6Cycloalkyl
, (9) optionally halogenated C_1-6Alkoki
C, (10) C which may be halogenated_1-6Alkyl
Thio, (11) hydroxy, (12) amino, (13) mono-
C_1-6Alkylamino, (14) di-C_1-6Alkylam
No, (15) C_1-6Alkyl, C_6-14Aryl and 5
No substituent selected from 10-membered aromatic heterocyclic groups
A 5- to 7-membered saturated cyclic amino optionally having 3
(16) formyl, carboxy, carbamoyl, C_1-6A
Alkyl-carbonyl, C_3-6Cycloalkyl-carboni
Le, C_1-6Alkoxy-carbonyl, C_6-14Aryl-
Carbonyl, C_7-16Aralkyl-carbonyl, C_6-14A
Reeloxy-carbonyl, C_7-16Aralkyloxy-
Carbonyl, 5-6 membered heterocyclic carbonyl, mono-C_1-6
Alkyl-carbamoyl, di-C_1-6Alkyl-carba
Moyle, C_6-14Aryl-carbamoyl, 5-6 membered complex
Ring carbamoyl, C_1-6Alkylsulfonyl, C_6-14A
Reel sulfonyl, C_1-6Alkylsulfinyl and
C_6-14Acyl selected from arylsulfinyl, (1
7) Formylamino, C_1-6Alkyl-carboxamides,
C_6-14Aryl-carboxamide, C_1-6Alkoxy-
Carboxamide, C_1-6Alkylsulfonylamino and
And C_6-14Acyl selected from arylsulfonylamino
Amino, (18) C_1-6Alkyl-carbonyloxy, C
_6-14Aryl-carbonyloxy, C_1-6Alkoxy-
Carbonyloxy, mono-C_1-6Alkyl-carbamoy
Luoxy, di-C_1-6Alkyl-carbamoyloxy,
C_6-14Aryl-carbamoyloxy and nicotinoi
Acyloxy selected from ruoxy, (19) sulfo,
(20) C_6-14Aryl and (21) C_6-14Aryloxy
Each having 1 to 3 substituents selected from
May be C_6-14A nitrogen source other than an aryl or carbon atom
A heteroatom selected from a hydrogen atom, a sulfur atom and an oxygen atom
A 5- to 14-membered aromatic heterocyclic group containing 1 to 4,
Is (c) (1) (1 ') halogen atom, (2') C_1-3Archi
Rangeoxy, (3 ') nitro, (4') cyano, (5 ') c
C which may be formed into a log_1-6Alkyl, (6 ') halo
C which may be genated_2-6Alkenyl, (7 ') halo
C which may be genated_2-6Alkynyl, (8 ') halo
C which may be genated_3-6Cycloalkyl, (9 ')
Optionally halogenated C_1-6Alkoxy, (10 ')
Optionally halogenated C_1-6Alkylthio, (1
1 ′) hydroxy, (12 ′) amino, (13 ′) mono-C_1-6
Alkylamino, (14 ') di-C_1-6Alkylamino,
(15 ') C_1-6Alkyl, C_6-14Aryl and 5 to
1 to 3 substituents selected from a 10-membered aromatic heterocyclic group
A 5- to 7-membered saturated cyclic amino optionally having (1)
6 ') formyl, carboxy, carbamoyl, C_1-6Al
Kill-carbonyl, C_3-6Cycloalkyl-carboni
Le, C_1-6Alkoxy-carbonyl, C_6-14Aryl-
Carbonyl, C_7-16Aralkyl-carbonyl, C_6-14A
Reeloxy-carbonyl, C_7-16Aralkyloxy-
Carbonyl, 5-6 membered heterocyclic carbonyl, mono-C_1-6
Alkyl-carbamoyl, di-C_1-6Alkyl-carba
Moyle, C_6-14Aryl-carbamoyl, 5-6 membered complex
Ring carbamoyl, C_1-6Alkylsulfonyl, C_6-14A
Reel sulfonyl, C_1-6Alkylsulfinyl and
C_6-14Acyl selected from arylsulfinyl, (1
7 ') Formylamino, C_1-6Alkyl-carboxami
C_6-14Aryl-carboxamide, C_1-6Alkoki
C-carboxamide, C_1-6Alkylsulfonylamino
And C_6-14A selected from arylsulfonylamino
Silamino, (18 ') C_1-6Alkyl-carbonyloxy
Si, C_6-14Aryl-carbonyloxy, C_1-6Arco
Xy-carbonyloxy, mono-C_1-6Alkyl-cal
Bamoyloxy, di-C_1-6Alkyl-carbamoylo
Kissi, C_6-14Aryl-carbamoyloxy and nico
Acyloxy selected from tynoyloxy, (19 ')
Ruho, (20 ') C_6-14Aryl and (21 ') C_6-14Ants
1 to 3 substituents selected from
C that you may have_6-14Other than aryl or carbon atom
Hetero selected from nitrogen, sulfur and oxygen
5- to 14-membered aromatic heterocyclic ring containing 1 to 4 atoms
Group, (2) halogen atom, (3) C_1-3Alkylene dioxy
(4) nitro, (5) cyano, (6) halogenated
May be C_1-6Alkyl, (7) halogenated
May be C_2-6Alkenyl, (8) halogenated
Good C_2-6Alkynyl, (9) even when halogenated
Good C_3-6Cycloalkyl, (10) halogenated
May be C_1-6Alkoxy, (11) halogenated
May be C_1-6Alkylthio, (12) hydroxy, (1
3) Amino, (14) Mono-C_1-6Alkylamino, (15)
Di-C_1-6Alkylamino, (16) C_1-6Alkyl, C
_6-14From aryl and 5- to 10-membered heteroaromatic groups
5 which may have 1 to 3 substituents selected
7-membered saturated cyclic amino, (17) formyl, carboxy,
Carbamoyl, C_1-6Alkyl-carbonyl, C_3-6Shiku
Loalkyl-carbonyl, C_1-6Alkoxy-carboni
Le, C_6-14Aryl-carbonyl, C_7-16Aralkyl-
Carbonyl, C_6-14Aryloxy-carbonyl, C
_7-16Aralkyloxy-carbonyl, 5-6 membered heterocyclic ring
Rubonyl, mono-C_1-6Alkyl-carbamoyl, di-
C_1-6Alkyl-carbamoyl, C_6-14Aryl-cal
Bamoyl, 5- to 6-membered heterocyclic carbamoyl, C_1-6Archi
Rusulfonyl, C_6-14Arylsulfonyl, C_1-6Al
Killsulfinyl and C_6-14Aryl sulfinyl?
Acyl selected from (18) formylamino, C_1-6Al
Kill-carboxamide, C_6-14Aryl-carboxami
C_1-6Alkoxy-carboxamide, C_1-6Alkyl
Sulfonylamino and C_6-14Arylsulfonylami
Acylamino selected from the group consisting of (19) C_1-6Alkyl-
Carbonyloxy, C_6-14Aryl-carbonyloxy
Si, C_1-6Alkoxy-carbonyloxy, mono-C_1-6
Alkyl-carbamoyloxy, di-C_1-6Alkyl-
Carbamoyloxy, C_6-14Aryl-carbamoylo
Acyloxy selected from xy and nicotinoyloxy
1 to 5 substituents selected from the group consisting of
C that each may have_1-6Alkyl, C_2-6Al
Kenil, C_2-6Alkynyl or C_3-6Cycloalkyl,
R^5aIs (a) (1) halogen atom, (2) C_1-3Alkylene
Dioxy, (3) nitro, (4) cyano, (5) halogen
C which may be_1-6Alkyl, (6) halogenated
C that may be_2-6Alkenyl, (7) halogenated
May be C_2-6Alkynyl, (8) halogenated
May be C_3-6Cycloalkyl, (9) halogenated
May be C_1-6Alkoxy, (10) halogenated
May be C_1-6Alkylthio, (11) hydroxy,
(12) amino, (13) mono-C_1-6Alkylamino, (1
4) Di-C_1-6Alkylamino, (15) C_1-6Alkyl,
C_6-14Aryl or 5- to 10-membered aromatic heterocyclic group
5 which may have 1 to 3 substituents selected from
7-membered saturated cyclic amino, (16) formyl, carbox
Si, carbamoyl, C_1-6Alkyl-carbonyl, C_3-6
Cycloalkyl-carbonyl, C_1-6Alkoxy-cal
Bonil, C_6-14Aryl-carbonyl, C_7-16Aralki
Le-carbonyl, C_6-14Aryloxy-carbonyl,
C_7-16Aralkyloxy-carbonyl, 5-6 membered heterocycle
Carbonyl, mono-C_1-6Alkyl-carbamoyl, di
-C_1-6Alkyl-carbamoyl, C_6-14Aryl-ka
Lubamoyl, 5- to 6-membered heterocyclic carbamoyl, C_1-6Al
Killsulfonyl, C_6-14Arylsulfonyl, C_1-6A
Rukylsulfinyl and C_6-14Arylsulfinyl
Acyl selected from (17) formylamino, C_1-6A
Alkyl-carboxamide, C_{6-1 Four}Aryl-carboxa
Mid, C_1-6Alkoxy-carboxamide, C_1-6Archi
Rusulfonylamino and C_6-14Aryl sulfonylua
Acylamino selected from mino, (18) C_1-6Alkyl
-Carbonyloxy, C_6-14Aryl-carbonyloxy
Si, C_1-6Alkoxy-carbonyloxy, mono-C_1-6
Alkyl-carbamoyloxy, di-C_1-6Alkyl-
Carbamoyloxy, C_6-14Aryl-carbamoylo
Acyloxy selected from xy and nicotinoyloxy
(19) Sulfo, (20) C_6-14Aryl and (21)
C_6-141 to 3 substituents selected from aryloxy
C that each may have_6-14Aryl or carbon
Other than atoms, select from nitrogen, sulfur and oxygen
5 to 14 membered aromatic containing 1 to 4 hetero atoms
Group heterocyclic group, or (b) (1) (1 ′) halogen atom,
(2 ') C_1-3Alkylenedioxy, (3 ') nitro,
(4 ′) cyano, (5 ′) optionally halogenated C
_1-6Alkyl, (6 ′) optionally halogenated C_2-6
Alkenyl, (7 ′) optionally halogenated C_2-6
Alkynyl, (8 ') optionally halogenated C_3-6
Cycloalkyl, (9 ′) optionally halogenated C
_1-6Alkoxy, (10 ') optionally halogenated C
_1-6Alkylthio, (11 ') hydroxy, (12') ami
No, (13 ') Mono-C_1-6Alkylamino, (14 ') di-
C_1-6Alkylamino, (15 ') C_1-6Alkyl, C_6-14
Selected from aryl and 5- to 10-membered aromatic heterocyclic groups
5 to 7 which may have 1 to 3 substituents
Membered cyclic amino, (16 ') formyl, carboxy,
Rubamoyl, C_1-6Alkyl-carbonyl, C_3-6Cyclo
Alkyl-carbonyl, C_1-6Alkoxy-carboni
Le, C_6-14Aryl-carbonyl, C_7-16Aralkyl-
Carbonyl, C_6-14Aryloxy-carbonyl, C
_7-16Aralkyloxy-carbonyl, 5-6 membered heterocyclic ring
Rubonyl, mono-C_1-6Alkyl-carbamoyl, di-
C_1-6Alkyl-carbamoyl, C_6-14Aryl-cal
Bamoyl, 5- to 6-membered heterocyclic carbamoyl, C_1-6Archi
Rusulfonyl, C_6-14Arylsulfonyl, C_1-6Al
Killsulfinyl and C_6-14Aryl sulfinyl?
Acyl selected from (17 ') formylamino, C_1-6Al
Kill-carboxamide, C_6-14Aryl-carboxami
C_1-6Alkoxy-carboxamide, C_1-6Alkyl
Sulfonylamino and C_6-14Arylsulfonylami
Acylamino selected from the group consisting of (18 ') C_1-6Alkyl-
Carbonyloxy, C_6-14Aryl-carbonyloxy
Si, C_1-6Alkoxy-carbonyloxy, mono-C_1-6
Alkyl-carbamoyloxy, di-C_1-6Alkyl-
Carbamoyloxy, C_6-14Aryl-carbamoylo
Acyloxy selected from xy and nicotinoyloxy
Si, (19 ') sulfo, (20') C_6-14Aryl and (2
1 ') C_6-14No one substituent selected from aryloxy
C which each may have_6-14Aryl or
From nitrogen, sulfur and oxygen atoms other than carbon atoms
5 to 14 members containing 1 to 4 heteroatoms selected
Aromatic heterocyclic group, (2) halogen atom, (3) C_1-3Al
Killenedioxy, (4) Nitro, (5) Cyano, (6) C
C which may be formed into a log_1-6Alkyl, (7) halogen
C which may be_2-6Alkenyl, (8) halogen
C which may be_2-6Alkynyl, (9) halogenated
C that may be_3-6Cycloalkyl, (10) halogen
C which may be_1-6Alkoxy, (11) halogen
C which may be_1-6Alkylthio, (12) hydr
Roxy, (13) amino, (14) mono-C_1-6Alkyria
Mino, (15) Di-C_1-6Alkylamino, (16) C_1-6A
Luquil, C_6-14Aryl and 5- to 10-membered aromatic compounds
Even if it has 1 to 3 substituents selected from
Good 5- to 7-membered saturated cyclic amino, (17) formyl,
Ruboxy, carbamoyl, C_1-6Alkyl-carboni
Le, C_3-6Cycloalkyl-carbonyl, C_1-6Alkoki
C-carbonyl, C_6-14Aryl-carbonyl, C_7-16
Aralkyl-carbonyl, C_6-14Aryloxy-cal
Bonil, C_7-16Aralkyloxy-carbonyl, 5-6
Membered heterocyclic carbonyl, mono-C_1-6Alkyl-carbamo
Il, Di-C_1-6Alkyl-carbamoyl, C_6-14Ants
Carbamoyl, 5- to 6-membered heterocyclic carbamoyl, C
_1-6Alkylsulfonyl, C_6-14Arylsulfonyl,
C_1-6Alkylsulfinyl and C_6-14Arylsul
Acyl selected from finyl, (18) formylamino,
C_1-6Alkyl-carboxamide, C_6-14Aryl-ka
Luboxamide, C_1-6Alkoxy-carboxamide, C
_1-6Alkylsulfonylamino and C_6-14Aryls
Acylamino selected from rufonylamino, (19) C
_1-6Alkyl-carbonyloxy, C_6-14Aryl-ka
Rubonyloxy, C_1-6Alkoxy-carbonyloxy
Shi, Mono-C_1-6Alkyl-carbamoyloxy, di-
C_1-6Alkyl-carbamoyloxy, C_6-14Aryl
-Selected from carbamoyloxy and nicotinoyloxy
Selected from acyloxy and (20) sulfo
C which may have 1 to 5 substituents_1-6A
Luquil, C_2-6Alkenyl, C_2-6Alkynyl or C
_3-6Cycloalkyl, and R⁶Is a hydrogen atom or C_1-6
And A ring is further represented by the formula:
(1) halogen atom, (2) C_1-3Alkylene dioxy
(3) nitro, (4) cyano, (5) halogenated
May be C_1-6Alkyl, (6) halogenated
May be C_2-6Alkenyl, (7) halogenated
Good C_2-6Alkynyl, (8) even when halogenated
Good C_3-6Cycloalkyl, (9) halogenated
Good C_1-6Alkoxy, (10) halogenated
Good C_1-6Alkylthio, (11) hydroxy, (12)
Amino, (13) mono-C_1-6Alkylamino, (14) di
-C_1-6Alkylamino, (15) C_1-6Alkyl, C_6-14
Selected from aryl and 5- to 10-membered aromatic heterocyclic groups
5 to 7 which may have 1 to 3 substituents
Membered cyclic amino, (16) formyl, carboxy, cal
Bamoyl, C_1-6Alkyl-carbonyl, C_3-6Cycloa
Alkyl-carbonyl, C_1-6Alkoxy-carbonyl,
C_6-14Aryl-carbonyl, C_7-16Aralkyl-cal
Bonil, C_6-14Aryloxy-carbonyl, C_7-16A
Aralkyloxy-carbonyl, 5-6 membered heterocyclic carbonyl
Le, Mono-C_1-6Alkyl-carbamoyl, di-C_1-6A
Lucyl-carbamoyl, C_6-14Aryl-carbamoy
5 to 6-membered heterocyclic carbamoyl, C_1-6Alkylsul
Honyl, C_6-14Arylsulfonyl, C_1-6Alkyls
Rufinil and C_6-14Selected from arylsulfinyl
Acyl, (17) formylamino, C_1-6Alkyl-
Carboxamide, C_6-14Aryl-carboxamide, C
_1-6Alkoxy-carboxamide, C_1-6Alkylsulfo
Nilamino and C_6-14From arylsulfonylamino
Acylamino of choice, (18) C_1-6Alkyl-carbo
Nyloxy, C_6-14Aryl-carbonyloxy, C
_1-6Alkoxy-carbonyloxy, mono-C_1-6Archi
Ru-carbamoyloxy, di-C_1-6Alkyl-carba
Moyloxy, C_6-14Aryl-carbamoyloxy and
Acyloxy selected from and nicotinoyloxy,
(19) Sulfo, (20) C_6-14Aryl and (21) C
_6-141 to 3 substituents selected from aryloxy
2. The compound according to claim 1, which is a benzene ring which may be possessed.
Stuff. 3. R ¹ and R ² may each have an optionally substituted C _1-6 alkyl, or R ¹ and R ² may have a substituent together with adjacent carbon atoms. 2. The compound according to claim 1, which forms an 8-membered homo- or heterocyclic ring. 4. The compound according to claim 1, wherein R ³ is an aromatic group which may have a substituent. 5. R ⁴ is (1) an aliphatic group which may have a substituent and may further have a substituent, or (2) acyl. A compound according to claim 1. 6. The compound according to claim 1, wherein X is an oxygen atom. 7. The compound according to claim 1, wherein Y is an oxygen atom. 8. formula -X-R ⁴ in group A compound according to claim 7, wherein the substituted on the 5-position of the benzofuran ring represented. 9. A compound of the formula The compound according to claim 1, which is a compound represented by the formula: wherein each symbol is as defined in claim 1. or a salt thereof. 10. R ¹ and R ² are each (1) C _6-14
Aryl, (2) C _1-6 alkoxy, (3) C _1-6 alkylthio, (4) hydroxy, (5) amino, (6) mono-C
_1-6 alkylamino, (7) mono--C _6-14 arylamino, (8) di -C _1-6 alkylamino, (9) di -C _6-14
Arylamino, (10) carboxy, (11) C _1-6 alkylsulfonyl, (12) C _6-14 arylsulfonyl,
(13) C _1-6 alkylsulfinyl, (14) C _6-14 arylsulfinyl and (15) C _1-6 alkyl, C _6-14
C ₁ which may have 1 to 3 substituents selected from a 5- to 7-membered saturated cyclic amino which may have 1 to 3 substituents selected from aryl and a 5- to 10-membered aromatic group; _-6 alkyl, or R ¹ and R ^2, together with adjacent carbon atoms, are selected from C 1 _-6 alkyl, C _{6 -14} aryl, C 7 _-16 aralkyl and 5- to 10-membered aromatic heterocyclic groups to 3 which may have three from 1 substituents form a 8-membered homocyclic or heterocyclic ring; R ³ is (1)
Halogen atom, (2) C _1-6 alkyl, (3) C _1-6 alkoxy, (4) mono-C _1-6 alkylamino, (5) di-C
_1-6 alkylamino and (6) C _1-6 alkyl, C _6-14
Phenyl optionally having 1 to 3 substituents selected from 5 to 7-membered saturated cyclic amino which may have 1 to 3 substituents selected from aryl and 5- to 10-membered aromatic group , 1-naphthyl, 2-naphthyl, 2-tiniel, 3-thienyl, 2-pyridyl, 3-
Pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 1-indolyl, 2-indolyl or 2-benzothiazolyl; R ⁴ is (i) (1) a halogen atom, (2) C _1-6 alkyl , (3) C _1-6 alkoxy, (4) hydroxy, (5) amino, (6) mono-C _1-6
Alkylamino, (7) di-C _1-6 alkylamino,
(8) Carboxy and (9) 5- to 7-membered saturated cyclic amino optionally having 1 to 3 substituents selected from C _1-6 alkyl, C _6-14 aryl and 5- to 10-membered aromatic groups Phenyl, 1-naphthyl, 2-naphthyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-phenyl optionally having 1 to 3 substituents selected from
Pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 1-indolyl, 2-indolyl or 2-benzothiazolyl, and further having carboxy or _C1-6 alkoxy-carbonyl as a substituent. _Optionally C _1-6 alkyl, or (ii)
Halogen atom, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, amino, mono-C _1-6 alkylamino, di-C
C _1-6 alkyl-carbonyl, C _3-6 cycloalkyl-carbonyl, C _6-14 aryl-carbonyl or C _6-14 optionally having 1 to 3 substituents selected from _1-6 alkylamino and carboxy _7-16 aralkyl-carbonyl; X is an oxygen atom; Y is an oxygen atom; and ring A is further a halogen atom, optionally halogenated C _1-6 alkyl, optionally halogenated C _1-6
The compound according to claim 1, which is a benzene ring which may have 1 to 3 substituents selected from alkoxy, amino, mono-C _1-6 alkylamino and di-C _1-6 alkylamino. 11. R ¹ and R ² are each C _6-14 aryl, C _1-6 alkoxy, C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, mono-C
_6-14 arylamino, di -C _1-6 alkylamino, di -
Having 1 to 3 substituents selected from C _6-14 arylamino, carboxy, C _1-6 alkylsulfonyl, C _6-14 arylsulfonyl, C _1-6 alkylsulfinyl and C _6-14 arylsulfinyl; or also C _1-6 alkyl, or together with R ¹ and the carbon atom to which R ² is adjacent, C _1-6 alkyl, C _6-14 aryl and C _7-16
Forming a piperidine optionally having 1 to 3 substituents selected from aralkyl; R ³ is a halogen atom, C _1-6
Phenyl optionally having 1 to 3 substituents selected from alkyl, C _1-6 alkoxy, amino, mono-C _1-6 alkylamino and di-C _1-6 alkylamino; R
⁴ is 1) a substituent selected from halogen atom, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino and carboxy; Or C _1-6 alkyl having phenyl or pyridyl which may each have 3 to 3, or (ii) a formula — (C ＝ O) —R ^{5 ′ wherein} R ^{5 ′} is a halogen atom, C _{1- 6} alkyl, C _1-6 alkoxy, hydroxy,
Phenyl or phenyl-C _1-6 alkyl which may have 1 to 3 substituents each selected from amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino and carboxy. X is an oxygen atom; Y is an oxygen atom; and the ring A is a halogen atom, an optionally halogenated C _1-6 alkyl, or an optionally halogenated C _1-6 alkoxy. ,amino,
The compound according to claim 1, which is a benzene ring optionally having 1 to 3 substituents selected from mono-C _1-6 alkylamino and di-C _1-6 alkylamino. 12. A compound of the formula Wherein R ¹ and R ² are each a C _1-6 alkyl _optionally having a 6-membered saturated cyclic amino substituted with phenyl, or R ¹ and R ² together with an adjacent carbon atom R3 forms a piperidine substituted with C _1-6 alkyl or C _7-16 aralkyl; R ³ is (i) a hydrogen atom, or (i
i) a substituent selected from (1) C _1-6 alkyl, (2) di-C _1-6 alkylamino and (3) a 6-membered saturated cyclic amino optionally having C _1-6 alkyl; Phenyl optionally having 1 to 3 substituent (s); R ⁴ is (i) phenyl optionally having 1 to 3 substituent (s) selected from nitro and C _1-6 alkyl-carboxamide, (ii) C _1- Phenyl, quinolyl optionally having 1 to 3 substituents each selected from ₆ alkoxy, C _1-6 alkylthio, C _1-6 alkoxy-carbonyl, C _1-6 alkylsulfonyl and C _1-6 alkylsulfinyl Or C _1-6 alkyl or C _2-6 alkenyl which each has 1 to 3 pyridyls and may further have phenyl, carboxy or C _1-6 alkoxy-carbonyl as a substituent, or (iii) Formula − (C O) -R 5 ^'acyl represented ^by' wherein, R 5 ^'' is a phenyl substituted with C _1-6 alkoxy]; and ring A ^'are, to no further 1 3 C _{1- 6} is a benzene ring which may have an alkyl group]. (13) 3- (4-isopropylphenyl) -5
-(4-methoxybenzyloxy) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran, 3
-(4-isopropylphenyl) -2,4,6,7-tetramethylbenzofuran-5-yl 4-methoxybenzoate, 3- (4-isopropylphenyl) -5
(4-methoxybenzyloxy) -2,4,6,7-tetramethylbenzofuran, 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -1 ′,
4,6,7-tetramethylspiro [benzofuran-2
(3H), 4'-piperidine] or a salt thereof. 14. A compound of the formula [Wherein each symbol is as defined in claim 1] or a salt thereof and a compound represented by the formula R ⁴ -L wherein L is a leaving group and R ⁴ is the same as defined in claim 1 The method according to claim 1, wherein the compound is reacted with a compound represented by the following formula: 15. A pharmaceutical composition comprising the compound according to claim 1. 16. The composition according to claim 15, which is a neurodegeneration inhibitor. 17. The method according to claim 1, which is a β-amyloid toxicity inhibitor.
A composition according to claim 5. 18. The composition according to claim 15, which is an agent for preventing or treating a neurodegenerative disease. 19. A compound of the formula [Wherein, R ¹ and R ² are each a hydrogen atom or a hydrocarbon group which may have a substituent, or R ¹ and R ² may have a substituent together with an adjacent carbon atom. Forming an 8-membered homo- or heterocyclic ring, R ³ represents a hydrogen atom, lower alkyl optionally having substituent (s) or aromatic group optionally having substituent (s), and R ^4a has substituent (s). An optionally substituted aromatic group, an optionally substituted aliphatic hydrocarbon group or acyl, Xa is an oxygen atom or an optionally oxidized sulfur atom, Ya is an oxygen atom, an optionally oxidized sulfur Imino which may have an atom or a substituent, -
- - is a single bond or a double bond, Aa ring is formula -Xa-R
^4a (wherein each symbol has the same meaning as described above), and represents a benzene ring which may further have a substituent other than amino which may be substituted. However, --
- is a single bond, and when Xa and Ya is an oxygen atom, R
^4a is not acyl. And a salt thereof. 20. The method according to claim 1, which is a β-amyloid toxicity inhibitor.
9. The inhibitor according to 9. 21. The inhibitor according to claim 19, which is a prophylactic / therapeutic agent for a neurodegenerative disease.