JP2000351779A - Amine derivative compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an amine derivative compound having excellent insulin resistance-improving actin, etc., having little adverse effect, further having high antitumor activity and useful as an active ingredient for prophylactic agents and/or therapeutic agents for diabetes mellitus, etc. SOLUTION: This amine derivative compound is represented by formula I [R1 is carbamoyl or the like; R2 and R3 are each H, a 1-10C alkyl or the like; W1 to W3 are each a single bond or the like; X, Y and Q are each O or S; Z is CH or the like; Ar is benzene ring or the like; L is 1-4 substituent groups on aryl ring and represents H, a 1-6C alkyl or the like], e.g. 1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H- benzimidazol-6-yloxy]phenyl)-3-ethylurea. The compound of formula I can be obtained by reacting, e.g. a compound of formula II with iso(thio)cyanic acids of formula III (R4 is a substituent group such as 1-10C alkyl; T is O or S) in an inert solvent in the presence or absence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an excellent insulin resistance improving action, a blood glucose lowering action, an anti-inflammatory action, an immunoregulatory action, an aldose reductase inhibitory action, a 5-lipoxygenase inhibitory action, and a lipid peroxide production inhibitory action. The present invention relates to an amine derivative compound having a PPAR activating action, an anti-osteoporotic action, a leukotriene antagonizing action, an adipocyte promoting action, a cancer cell growth inhibitory action, and a calcium antagonizing action, or a pharmaceutically acceptable salt thereof.

[0002] The present invention further provides diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, and diabetic complications containing the above-mentioned amine derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient. Disease (eg, retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.), arteriosclerosis,
Gestational diabetes, polycystic ovary syndrome, cardiovascular disease (for example, ischemic heart disease, etc.), atherosclerosis or cell damage caused by ischemic heart disease (for example, caused by stroke) Brain damage, etc.), gout, inflammatory diseases (eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia) Quality, autoimmune diseases, pancreatitis, etc.), cancer, osteoporosis, cataract and the like.

[0003] The present invention further provides an amine derivative compound or a pharmaceutically acceptable salt thereof, an RXR activator,
Sulfonylurea agent, α-glucosidase inhibitor, aldose reductase inhibitor, biguanide agent, statin compound, squalene synthesis inhibitor, fibrate compound,
LDL catabolism promoter, angiotensin II antagonist, angiotensin converting enzyme inhibitor, antitumor agent and FBPase
Pharmaceutical composition comprising a combination of at least one inhibitor
(Especially preferred are antitumor agents, preventive agents and / or therapeutic agents for diabetes or diabetic complications.)

[0004]

2. Description of the Related Art It has been reported that thiazolidine compounds and oxazolidine compounds are useful as preventive or therapeutic agents for various diseases such as diabetes and hyperlipidemia.

For example, an oxazolidinedione derivative having a blood glucose and blood lipid lowering action is disclosed in (1) Japanese Patent Application Laid-Open No. Hei 7-110945.
And (2) Japanese Patent Application Laid-Open No. H7-165735. However, the compound of the invention according to this publication has a relatively long-chain aliphatic hydrocarbon oxazolidinedione structure (the compound of the present invention has a thiazolidinedione or oxazolidinedionemethyl structure), and also has a benzimidazole. Or, it may have an imidazopyridine structure, but the portion has only a relatively small substituent such as a hydrocarbon group. (The compound of the present invention requires a benzimidazole or imidazopyridine structure, and the substituted portion is an amino group. And a relatively large one which essentially requires a group and an aryl group.), Which differs from the compound of the present invention in its structure.

An azolidinedione derivative having an antidiabetic effect is disclosed in (3) US Pat. No. 5,985,884. However, the compound of the present invention according to this publication differs from the compound of the present invention in that it cannot have a benzimidazole or imidazopyridine structure having an amino group in the substituted part.

Further, a thiazolidinedione compound capable of controlling blood sugar level well has been disclosed in (4)
It is disclosed in JP-A-213913. However, the compound of the present invention according to the gazette differs from the compound of the present invention in that, when it has a benzimidazole structure, it also requires a piperidine structure and the like, and its substitution is relatively small. Is what you do.

[0008]

SUMMARY OF THE INVENTION The present inventors have studied the synthesis of a series of amine derivative compounds and their pharmacological activities over many years, and as a result, have found that amine derivative compounds having a novel structure have excellent properties. Insulin resistance improving action, blood glucose lowering action, anti-inflammatory action, immunomodulatory action, aldose reductase inhibitory action, 5-lipoxygenase inhibitory action,
It has a lipid peroxide production inhibitory action, a PPAR activating action, an anti-osteoporosis action, a leukotriene antagonizing action, an adipocyte promoting action, a cancer cell growth inhibitory action, and a calcium antagonizing action, and has few side effects. The present inventors have found that they have a characteristic of high activity, and have completed the present invention.

Another object of the present invention is to provide the above-mentioned amine derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient, comprising diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, Diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.), arteriosclerosis,
Gestational diabetes, polycystic ovary syndrome, cardiovascular disease (for example, ischemic heart disease, etc.), atherosclerosis or cell damage caused by ischemic heart disease (for example, caused by stroke) Brain damage, etc.), gout, inflammatory diseases (eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia) Quality, autoimmune disease, pancreatitis, etc.), cancer, osteoporosis, cataract and the like.

Further, another object of the present invention is to provide the above-mentioned amine derivative compound or a pharmaceutically acceptable salt thereof,
Activator, sulfonylurea agent, α-glucosidase inhibitor, aldose reductase inhibitor, biguanide, statin compound, squalene synthesis inhibitor, fibrate compound, LDL catabolism promoter, angiotensin II antagonist, angiotensin converting enzyme inhibitor A pharmaceutical composition comprising a combination of at least one of an antitumor agent and an FBPase inhibitor (particularly preferably an antitumor agent, a prophylactic and / or therapeutic agent for diabetes or diabetic complications). It is.

[0011]

The present invention provides a compound represented by the general formula (I):

[0012]

Embedded image[Wherein, R₁Is a carbamoyl group (substituted α to be described
Or it may have two. ), Thiocarbamoyl group
(It may have one or two substitutions α described below.
No. ), A sulfonyl group (having one substituent α described later)
You. ) Or a carbonyl group (having one substituent α described later)
ing. ) And R_TwoAnd R_ThreeAre the same or different hydrogen
Atom, C₁-C_TenAlkyl group, C₆-C_TenAryl group (described below)
It may have 1 to 3 substituents β. ) Or C₇-C
₁₆An aralkyl group (substituted β is
It may have three to three. ) And W₁, W_TwoAnd W_Three
Are the same or different and are a single bond or C₁-C₈Indicates an alkylene group
X, Y and Q represent an oxygen atom or a sulfur atom, and Z is
= CH- represents a group or a nitrogen atom, and Ar represents a benzene ring or
A naphthalene ring; L is 1 to 4 on an Ar ring
Is a hydrogen atom, C₁-C₆Alkyl group, C₆-C_Ten
An aryl group (having 1 to 3 substituents β described later,
Is also good. ) Or C₇-C₁₆Aralkyl group (after the aryl moiety
It may have 1 to 3 substitutions β described above. )
And the substitution α is (i) C₁-C_TenAlkyl group, (ii) C₁-C₆Halo
Genoalkyl group, (iii) C_Three-C_TenCycloalkyl group, (iv) C
₆-C_TenAryl group (having 1 to 3 substituents γ described later
May be. ), (V) C₇-C₁₆Aralkyl group (aryl moiety
May have 1 to 3 substitutions γ described later.
No. ), (Vi) C_Four-C₁₁Cycloalkylcarbonyl group, (vii)
C₇-C₁₁Arylcarbonyl group (described later in the aryl portion)
It may have 1 to 3 substitutions γ. ), (Viii) C₈-
C₁₇Aralkylcarbonyl group (substituted in the aryl
It may have 1 to 3 substitutions γ. ), (Ix)
An aromatic ring group (which may have 1 to 3 substituents γ described below)
No. ), (X) heteroaromatic carbonyl group (substituted γ described below)
May be provided. ), (Xi) C₁-C₆Alkyl
Sulfonyl group, (xii) C₁-C₆Halogenoalkylsulfonyl
Group, (xiii) C₆-C_TenArylsulfonyl group (aryl moiety
May have 1 to 3 substitutions γ described later.
No. ) Or (xiv) C₇-C₁₆Aralkylsulfonyl group (ant
May have 1 to 3 substituents γ described later in the
Good. ), And the substitution β is (i) C₁-C₆Alkyl group, (i
I c₁-C₆Halogenoalkyl group, (iii) C₁-C ₆Alkoxy
Group, (iv) halogen atom, (v) hydroxy group, (vi) C₆-C_Ten
An aryl group (having 1 to 3 substituents δ described below;
Is also good. ), (Vii) C₇-C₁₆Aralkyl group (in the aryl moiety
It may have 1 to 3 substitutions δ described below. ),
(viii) cyano group, (ix) nitro group, or (x) amino group (described later)
May have one or two substituents δ. )
And the substitution γ is (i) C₁-C₆Alkyl group, (ii) C₁-C₆Haloge
Noalkyl group, (iii) C₁-C ₆Alkoxy group, (iv) halogen
Atom, (v) hydroxy group, (vi) cyano group, (vii) nitro
Group, (viii) C_Three-C_TenCycloalkyl group, (ix) C₆-C_TenAlly
Group (substituted as C₁-C₆Alkyl group, C₁-C₆Halogeno
Alkyl group, C₁-C₆One alkoxy group and one halogen atom
You may have up to three. ), (X) C₇-C₁₆Aralkyl group
(Substituent on aryl is C₁-C₆Alkyl group, C₁-C₆
Halogenoalkyl group, C₁-C₆Alkoxy group, halogen source
It may have one to three children. ), (Xi) C₁-C₇fat
Group acyl group, (xii) C₁-C₇Aliphatic acyloxy group, (xiii)
Amino group, (xiv) di C₁-C₆Alkylamino group, or (xv) C₁
-C_FourRepresents an alkylenedioxy group, the substitution δ is (i) C₁-C
_TenAlkyl group, (ii) C₆-C_TenAryl group (substituted as C
₁-C₆Alkyl group, C₁-C₆Halogenoalkyl group, C₁-C₆Al
It may have 1 to 3 oxy groups and 1 to 3 halogen atoms
No. ), (Iii) C₇-C₁₆Aralkyl groups (substituted on aryl
As C₁-C₆Alkyl group, C₁-C₆A halogenoalkyl group,
C₁-C₆Having 1 to 3 alkoxy groups and halogen atoms
May be. ), (Iv) C₁-C₇Aliphatic acyl group, (v) C_Four-C₁₁
Cycloalkylcarbonyl group, (vi) C₇-C₁₁Aryl cal
Bonyl group (as a substituent, C₁-C₆Alkyl group, C₁-C₆Halo
Genoalkyl group, C₁-C₆Alkoxy group, halogen atom
You may have 1 to 3 pieces. ), (Vii) C₈-C₁₇Aralki
Carbonyl group (as a substituent on aryl, C₁-C₆Al
Kill group, C₁-C₆Halogenoalkyl group, C₁-C₆Alkoxy
And 1 to 3 halogen atoms. ),
(viii) a heteroaromatic carbonyl group (as a substituent, C₁-C₆A
Lucyl group, C₁-C₆Halogenoalkyl group, C₁-C₆Alkoxy
And 1 to 3 halogen atoms. )
Show. ] Or a pharmacologically acceptable amine compound having the same
Permissible salt. In the specification of the present application, "Cal
`` Bamoyl group '' means H_TwoN (C = O)-group, where the group is substituted
When the hydrogen atom on the nitrogen atom is substituted
Shall be replaced.

The term "thiocarbamoyl group" refers to an H ₂ N (C = S)-group. When the group has a substituent, the hydrogen atom on the nitrogen atom is replaced by the substituent. .

"Alkyl group" is defined as 1 alkyl group formed by the loss of one hydrogen atom from a linear or branched aliphatic hydrocarbon.
A valence group.

The "aryl group" refers to a monovalent group formed by the removal of one hydrogen atom bonded to the ring of an aromatic hydrocarbon.

The "aralkyl group" refers to a monovalent group in which one hydrogen atom of the aforementioned alkyl group has been substituted with the aforementioned aryl group.

The term "alkylene group" refers to a divalent group formed by losing two hydrogen atoms from a carbon atom of a linear or branched aliphatic hydrocarbon.

The term "halogenoalkyl group" refers to a monovalent group in which one or more hydrogen atoms of the above-mentioned alkyl group have been substituted with halogen atoms.

The term "cycloalkyl group" refers to a monovalent, optionally condensed, cyclic aliphatic hydrocarbon group.

The "cycloalkylcarbonyl group" refers to a monovalent group in which the above-mentioned cycloalkyl group is substituted by a carbonyl group.

The term "arylcarbonyl group" refers to a monovalent group in which the above-mentioned aryl group is substituted by a carbonyl group.

The "aralkylcarbonyl group" refers to a monovalent group in which the above-mentioned aralkyl group is substituted by a carbonyl group.

"Heteroaromatic group" means a heteroatom selected from the group consisting of oxygen, nitrogen and sulfur.
Refers to a monocyclic or polycyclic aromatic heterocyclic group having 1 to 3 aromatic groups.

The term "heteroaromatic carbonyl group" refers to a monovalent group in which the above-mentioned heteroaromatic ring group is substituted by a carbonyl group.

The "alkylsulfonyl group" refers to a monovalent group in which the above-mentioned alkyl group is substituted by a sulfonyl group.

The term "arylsulfonyl group" refers to a monovalent group in which the above-mentioned aryl group is substituted by a sulfonyl group.

The term "aralkylsulfonyl group" refers to a monovalent group in which the aralkyl group is substituted by a sulfonyl group.

The term "alkoxy group" refers to a monovalent group formed by the loss of the hydrogen atom of the hydroxyl group of a linear or branched alcohol.

The term "dialkylamino group" refers to a monovalent group in which two of the above-mentioned alkyl groups are the same or different and are bonded to two nitrogen atoms.

The term "alkylenedioxy group" refers to a divalent group in which both ends of a linear or branched alkylene are substituted with oxygen atoms.

The "aliphatic acyl group" refers to a monovalent group in which the above-mentioned alkyl group is substituted by a carbonyl group.

The "aliphatic acyloxy group" refers to a monovalent group in which an oxygen atom is bonded to the carbonyl of the aforementioned aliphatic acyl group.

“C _m -C _n ” means having m to n carbon atoms. When R ₂ , R ₃ , α and δ represent a “C ₁ -C ₁₀ alkyl group”, “C ₁ -C ₁₀ ” and “alkyl” have the same meanings as described above. As the group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, s-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-
Ethylpropyl, hexyl, 4-methylpentyl (isohexyl), 3-methylpentyl, 2-methylpentyl, 1-methylpentyl (s-hexyl), 3,3-dimethylbutyl, 2,2
-Dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-
Ethyl butyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylhexyl Methylheptyl,
3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl Methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl,
6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-
Dimethyl octyl or 7,7-dimethyl octyl can be mentioned. R ₂ and α are preferably a C ₁ -C ₈ alkyl group, more preferably a C ₁ -C ₆ alkyl group. R ₃ and δ are preferably C ₁ -C ₈ alkyl groups, more preferably C ₁ -C ₆ alkyl groups, more preferably C ₁ -C ₄ alkyl groups, more preferably Is a C ₁ -C ₂ alkyl group, most preferably a methyl group.

When R ₂ , R ₃ and L represent a “C ₆ -C ₁₀ aryl group (which may have 1 to 3 substituents β described later)”, α is “C ₆ -C 10 ₁₀ aryl groups (substituted γ described below)
May be provided. )) And β is a “C ₆ -C ₁₀ aryl group (substituent δ described later is 1 to 3
You may have one. )), “C ₆ -C ₁₀ ” and “aryl” have the same meaning as described above, and “substituted β is 1
"May have 1 to 3 substituents γ" and "may have 1 to 3 substituents δ" respectively. , Γ, δ, or 1 to 3 identical or different substituents β, γ, δ. The aryl moiety can include, for example, phenyl, indenyl, or naphthyl.

R ₂ , R ₃ and L represent a C ₇ -C ₁₆ aralkyl group
(The aryl moiety may have 1 to 3 substituents β described later.), Α is a C ₇ -C ₁₆ aralkyl group (the aryl moiety has 1 to 3 substituents γ described later.) And β represents a “C ₇ -C ₁₆ aralkyl group (the aryl moiety may have 1 to 3 substituents δ described below.)”. In the case, “C ₇ -C ₁₆ ”, “aralkyl”, “may have 1 to 3 substituents β”, “may have 1 to 3 substituents γ”, and “substitution” "It may have 1 to 3 components δ"] is as defined above. Examples of the aralkyl moiety include benzyl, naphthylmethyl, indenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1 -Naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4 -Naphthylbutyl, 5-phenylpentyl, 5-naphthylpentyl, 6-phenylhexyl or 6-naphthylhexyl.

W₁, W_TwoAnd W_ThreeIs "C₁-C₈Alkylene group "
To indicate "C₁-C₈"And" alkylene "are as described above.
Is synonymous with Such groups include, for example, methylene,
Chilmethylene, ethylene, propylene, trimethylene,
1-methylethylene, tetramethylene, 1-methyltrimethyl
Len, 2-methyltrimethylene, 3-methyltrimethylene,
1-methylpropylene, 1,1-dimethylethylene, pentame
Tylene, 1-methyltetramethylene, 2-methyltetramethyl
Len, 3-methyltetramethylene, 4-methyltetramethyle
1,1-dimethyltrimethylene, 2,2-dimethyltrimethyl
Len, 3,3-dimethyltrimethylene, hexamethylene, 1-
Methylpentamethylene, 2-methylpentamethylene,
Tylpentamethylene, 4-methylpentamethylene, 5-methyl
Lupentamethylene, 1,1-dimethyltetramethylene, 2,2-
Dimethyltetramethylene, 3,3-dimethyltetramethyl
1,4-dimethyltetramethylene, heptamethylene, 1-
Methylhexamethylene, 2-methylhexamethylene, 5-methyl
Tyl hexamethylene, 3-ethylpentamethylene, octa
Methylene, 2-methylheptamethylene, 5-methylheptame
Tylene, 2-ethylhexamethylene, 2-ethyl-3-methyl
Pentamethylene or 3-ethyl-2-methylpentamethyle
Can be mentioned. Suitably linear C₁-C ₆Al
A kylene group, more preferably a linear C₁-C_FourArchire
And more preferably a linear C₁-C_TwoAlkylene group
It is. W_ThreeIs optimally a methylene group.

When L, β and γ represent a “C ₁ -C ₆ alkyl group”, “C ₁ -C ₆ ” and “alkyl group” have the same meanings as described above. Examples of the group include methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, s-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl (isohexyl), 3-methylpentyl, 2-methylpentyl, 1-methylpentyl
(s-hexyl), 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl
A dimethylbutyl, 2,3-dimethylbutyl, or 2-ethylbutyl group can be mentioned. It is preferably a C ₁ -C ₄ alkyl group, and more preferably a C ₁ -C ₂ alkyl group.

When α, β and γ represent “C ₁ -C ₆ halogenoalkyl group”, “C ₁ -C ₆ ” and “halogenoalkyl group” have the same meanings as described above. As the group, for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-bromoethyl Chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl or 2,2-dibromoethyl can be mentioned. It is preferably a C ₁ -C ₄ halogenoalkyl group, and more preferably a C ₁ -C ₂ halogenoalkyl group.

When α and γ represent “C ₃ -C ₁₀ cycloalkyl group”, “C ₃ -C ₁₀ ” and “cycloalkyl group” have the same meaning as described above. Such groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl or adamantyl. Preferably it is cyclopropyl, cyclohexyl or adamantyl, more preferably cyclohexyl or adamantyl.

When α and δ represent “C ₄ -C ₁₁ cycloalkylcarbonyl group”, “C ₄ -C ₁₁ ” and “cycloalkylcarbonyl group” have the same meanings as described above. As the group, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptyl carbonyl, norbornyl carbonyl, or adamantyl carbonyl can be mentioned, preferably a C ₄ -C ₇ cycloalkylcarbonyl is there.

When α represents “C ₇ -C ₁₁ arylcarbonyl group (the aryl moiety may have 1 to 3 substituents γ described below)”, “C ₇ -C ₁₁ ”, “C ₇ -C ₁₁ ” The “arylcarbonyl group” and “may have 1 to 3 substituents γ” are the same as those described above. The arylcarbonyl moiety can include, for example, benzoyl, 1- or 2-indancarbonyl, or 1- or 2-naphthoyl, preferably benzoyl.

When α represents “C ₈ -C ₁₇ aralkylcarbonyl group (the aryl moiety may have 1 to 3 substituents γ described later)”, “C ₈ -C ₁₇ ”, “C ₈ -C ₁₇ aralkylcarbonyl group” may be used. The “aralkylcarbonyl group” and “may have 1 to 3 substituents γ” are the same as those described above. Examples of the aralkylcarbonyl moiety include phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, 5-phenylpentanoyl, 6-phenylhexanoyl, naphthylacetyl,
Examples thereof include 4-naphthylbutyryl and 6-naphthylhexanoyl, preferably phenyl C ₂ -C ₇ alkylcarbonyl, and more preferably phenyl C ₂ -C ₅ alkylcarbonyl.

When α represents “heteroaromatic group (may have 1 to 3 substituents γ described later)”, “heteroaromatic group” and “1 to 3 substituents γ” "May be possessed" has the same meaning as described above. Examples of the heteroaromatic ring portion include, for example, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazoyl,
5-membered heteroaromatic ring such as thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl or thiadiazolyl; 6-membered heteroaromatic ring such as pyranyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; or 7-membered heteroaromatic such as azepinyl A ring can be mentioned, and is preferably a 5- or 6-membered heteroaromatic ring group.

When α represents a “heteroaromatic carbonyl group (may have 1 to 3 substituents γ described later)”, the “heteroaromatic carbonyl group” and “1 to 3 substituents γ” Three
"May be present" is synonymous with the above.
As the heteroaromatic ring carbonyl moiety, for example, furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl,
5 such as oxazolylcarbonyl, isoxazoylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl, triazolylcarbonyl, or thiadiazolylcarbonyl
Membered heteroaromatic ring carbonyl; pyranylcarbonyl, nicotinoyl, isonicotinoyl, pyridazinylcarbonyl,
6-membered heteroaromatic ring carbonyls such as pyrimidinylcarbonyl or pyrazinylcarbonyl; and 7-membered heteroaromatic ring carbonyls such as azepinylcarbonyl can be mentioned, and preferably 5 or 6-membered heteroaromatic ring carbonyl.

When α represents a “C ₁ -C ₆ alkylsulfonyl group”, “C ₁ -C ₆ ” and “alkylsulfonyl group” have the same meanings as described above. Examples of the group include methanesulfonyl, ethanesulfonyl, propanesulfonyl,
Isopropanesulfonyl, butanesulfonyl, isobutanesulfonyl, s-butanesulfonyl, t-butanesulfonyl, pentanesulfonyl, isopentanesulfonyl,
2-methylbutanesulfonyl, neopentanesulfonyl,
1-ethylpropanesulfonyl, hexanesulfonyl, 4-
Methylpentanesulfonyl, 3-methylpentanesulfonyl, 2-methylpentanesulfonyl, 3,3-dimethylbutanesulfonyl, 2,2-dimethylbutanesulfonyl, 1,1-dimethylbutanesulfonyl, 1,2-dimethylbutanesulfonyl, 1, 3- dimethyl butane sulfonyl, 2,3-dimethylbutane sulfonyl, or 2-ethyl-butane sulfonyl can be mentioned, preferably a C ₁ -C ₄ alkylsulfonyl group, C ₁ -C ₂ alkyl and more preferably It is a sulfonyl group, most preferably methanesulfonyl.

When α represents “C ₁ -C ₆ halogenoalkylsulfonyl group”, “C ₁ -C ₆ ” and “halogenoalkylsulfonyl group” have the same meanings as described above. Examples of the group include trifluoromethanesulfonyl, trichloromethanesulfonyl, difluoromethanesulfonyl, dichloromethanesulfonyl, dibromomethanesulfonyl, fluoromethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, 2,2,2-trichloroethanesulfonyl, 2 -Bromoethanesulfonyl, 2-chloroethanesulfonyl, 2-fluoroethanesulfonyl, 2-iodoethanesulfonyl,
Examples thereof include 3-chloropropanesulfonyl, 4-fluorobutanesulfonyl, 6-iodohexanesulfonyl, and 2,2-dibromoethanesulfonyl, preferably C ₁ -C ₄
A halogenoalkylsulfonyl group, more preferably C ₁
—C ₂ halogenoalkylsulfonyl, most preferably trifluoromethanesulfonyl.

When α represents “C ₆ -C ₁₀ arylsulfonyl group (the aryl moiety may have 1 to 3 substituents γ described later)”, “C ₆ -C ₁₀ ”, “C ₆ -C ₁₀ ”, The “arylsulfonyl group” and “may have 1 to 3 substituents γ” are the same as those described above. Examples of the arylsulfonyl moiety include phenylsulfonyl, indenylsulfonyl, and naphthylsulfonyl,
Preferably it is phenylsulfonyl.

When α represents a “C ₇ -C ₁₆ aralkylsulfonyl group (the aryl moiety may have 1 to 3 substituents γ described below)”, “C ₇ -C ₁₆ ”, “C ₇ -C ₁₆ ” “Aralkylsulfonyl group” and “may have 1 to 3 substituents γ” are the same as those described above. Examples of the aralkylsulfonyl moiety include, for example, benzylsulfonyl, naphthylmethylsulfonyl, indenylmethylsulfonyl, 1-phenethylsulfonyl, 2-phenethylsulfonyl, 1-naphthylethylsulfonyl, 2-naphthylethylsulfonyl,
1-phenylpropylsulfonyl, 2-phenylpropylsulfonyl, 3-phenylpropylsulfonyl, 1-naphthylpropylsulfonyl, 2-naphthylpropylsulfonyl,
3-naphthylpropylsulfonyl, 1-phenylbutylsulfonyl, 2-phenylbutylsulfonyl, 3-phenylbutylsulfonyl, 4-phenylbutylsulfonyl, 1-naphthylbutylsulfonyl, 2-naphthylbutylsulfonyl, 3-
Naphthylbutylsulfonyl, 4-naphthylbutylsulfonyl, 5-phenylpentylsulfonyl, 5-naphthylpentylsulfonyl, 6-phenylhexylsulfonyl, or 6-
Examples include naphthylhexylsulfonyl, preferably phenyl C ₁ -C ₆ alkylsulfonyl, and more preferably phenyl C ₁ -C ₄ alkylsulfonyl.

When β and γ represent a “C ₁ -C ₆ alkyl group”, “C ₁ -C ₆ ” and “alkyl group” have the same meanings as described above. As the group, R ₂ , R ₃ , α and δ are represented by “C ₁ -C ₁₀
Alkyl group '' among the groups mentioned when indicating 1 to 6 carbon atoms
And is preferably a C ₁ -C ₄ alkyl group, more preferably a C ₁ -C ₂ alkyl group.

When β and γ represent “C ₁ -C ₆ alkoxy group”, “C ₁ -C ₆ ” and “alkoxy group” have the same meanings as described above. Such groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, 1-ethylpropoxy, hexyloxy, 4-methylpent Toxi,
3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,
Examples thereof include 2,3-dimethylbutoxy and 2-ethylbutoxy, preferably a C ₁ -C ₄ alkoxy group, and more preferably a C ₁ -C ₂ alkoxy group.

When β and γ represent a “halogen atom”,
Examples of the group include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Preferably it is a fluorine atom, a chlorine atom or a bromine atom, more preferably a fluorine atom or a chlorine atom.

[0052] As γ and δ are "C ₆ -C ₁₀ aryl group (substituent, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenoalkyl groups, C ₁
It may have a -C ₆ alkoxy group and 1 to 3 halogen atoms. ) '', The C ₁ -C ₆ alkyl group, the C ₁ -C ₆ halogenoalkyl group, the C ₁ -C ₆ alkoxy group, and the halogen atom, which are the substituents, are the groups described in the definition of each group described above. Can be mentioned. As the group, for example, in addition to the unsubstituted aryl group described above as the aryl moiety, as a group having a substituent, 4-methylphenyl, 4-methylnaphthyl, 3,4-dimethylphenyl, 2,3,4-trimethylphenyl , 4-propylphenyl, 4-propylnaphthyl, 2-,
3- or 4-trifluoromethylphenyl, 2-, 3-,
Or 4-trifluoromethylnaphthyl, 3,4-ditrifluoromethylphenyl, 2,3,4-trifluoromethylphenyl, 4-tetrafluoropropylphenyl, 4-tetrafluoropropylnaphthyl, 4-methoxyphenyl, 4-
Methoxynaphthyl, 3,4-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 4-propoxyphenyl, 4-propoxynaphthyl, 4-fluorophenyl, 4-fluoronaphthyl, 3,4-difluorophenyl, or 2, 3,4-trifluorophenyl, preferably a phenyl group (as a substituent, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenoalkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom And more preferably a phenyl group (as a substituent, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenoalkyl group, a C ₁ -C ₆ alkoxy group) And one halogen atom), and most preferably a phenyl group.

Γ and δ represent a “C ₆ -C ₁₀ aralkyl group (C ₁ -C ₆ alkyl group, C ₁ -C ₆ halogenoalkyl group, C ₁ -C ₆ alkoxy group, halogen atom May have 1 to 3). ”), The C ₁ -C ₆ alkyl group, C ₁ -C ₆ halogenoalkyl group, C ₁
Examples of the —C ₆ alkoxy group and the halogen atom include the groups described in the definition of each group described above. As the group, for example, in addition to the unsubstituted aralkyl group described above as the aralkyl moiety, as a group having a substituent, 4-methylbenzyl, 2,3,4-trimethylbenzyl, 4-methylphenethyl, 2,3,4- Trimethylphenethyl, 4- (4-methylphenyl) butyl, 2-, 3-, or 4-trifluoromethylbenzyl, 3,4-ditrifluoromethylbenzyl, 2,3,4-trifluoromethylbenzyl, 4-tetra Fluoropropylbenzyl, 4-trifluoromethylphenethyl, 3,4-
Ditrifluoromethylphenethyl, 2,3,4-trifluoromethylphenethyl, 4-tetrafluoropropylphenethyl, 4- (4-trifluoromethylphenyl) butyl, 4-
(4-tetrafluoropropyl) butyl, 6- (4-trifluoromethylphenyl) hexyl, 6- (4-tetrafluoropropylphenyl) hexyl, 2-, 3-, or 4-trifluoromethylnaphthylmethyl, 4- Tetrafluoropropylnaphthylmethyl, 4- (4-trifluoromethylnaphthyl) butyl, 4- (4-tetrafluoropropylnaphthyl) butyl,
4-methoxybenzyl, 2,3,4-trimethoxybenzyl, 4-
Methoxyphenethyl, 2,3,4-trimethoxyphenethyl,
4- (4-methoxyphenyl) butyl, 4-fluorobenzyl,
2,3,4-trifluorobenzyl, 4-fluorophenethyl,
2,3,4-trifluorophenethyl, 4- (4-fluorophenyl) butyl, and preferably phenyl C _1-
C ₆ as substituents on alkyl groups (on aryl, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenoalkyl groups, C ₁ -C ₆ alkoxy group,
It may have 1 to 3 halogen atoms. ), More preferably a phenyl C ₁ -C ₄ alkyl group (as a substituent on the aryl, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenoalkyl group, a C ₁ -C ₆ alkoxy group, a halogen 1 to 3 atoms
You may have one. ), And more preferably phenyl C
_{A 1-} C ₂ alkyl group (having 1 to 3 halogen atoms as a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenoalkyl group, a C ₁ -C ₆ alkoxy group, Phenyl C ₁ -C ₂ alkyl group (a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenoalkyl group, a C ₁ -C ₆ alkoxy group as a substituent on the aryl) And one halogen atom), and most preferably a phenyl C ₁ -C ₂ alkyl group.

When γ and δ represent “C ₁ -C ₇ aliphatic acyl group”, “C ₁ -C ₇ ” and “aliphatic acyl group” have the same meanings as described above. As the group, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl, or crotonoyl can be mentioned, preferably be a C ₁ -C ₅ aliphatic acyl group ,
More preferably, it is a C ₁ -C ₃ aliphatic acyl group, most preferably acetyl.

When γ represents a “C ₁ -C ₇ aliphatic acyloxy group”, “C ₁ -C ₇ ” and “aliphatic acyloxy group” have the same meanings as described above. Examples of the group include formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, acryloyloxy, methacryloyloxy, or crotonoyloxy. , Preferably C ₁
-C a ₅ aliphatic acyloxy group, more preferably a C ₁ -C ₃ aliphatic acyloxy group, and most preferably acetyloxy.

When γ represents “di C ₁ -C ₆ alkylamino group”, “C ₁ -C ₆ ” and “dialkylamino group” have the same meanings as described above. Examples of the group include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino or N-ethyl-N-isopropylamino, It is preferably a di-C ₁ -C ₄ alkylamino group, more preferably di-C _1-.
C ₂ alkylamino group.

When γ represents a “C ₁ -C ₄ alkylenedioxy group”, “C ₁ -C ₄ ” and “alkylenedioxy group have the same meanings as described above. Dioxy, ethylenedioxy, trimethylenedioxy,
Examples include tetramethylenedioxy or propylenedioxy. It is preferably a C ₁ -C ₃ alkylenedioxy group, and more preferably a C ₁ -C ₂ alkylenedioxy group.

Δ represents a “C ₇ -C ₁₁ arylcarbonyl group (substituted as a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenoalkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom of 1 to 3 ) "), The substituted C ₁
Examples of the -C ₆ alkyl group, C ₁ -C ₆ halogenoalkyl group, C ₁ -C ₆ alkoxy group, and halogen atom include the groups described in the definition of each group described above. Such groups include, for example, the unsubstituted C ₇ -C
_{11 In} addition to the aromatic acyl group, as a group having a substituent, 4-
Methylbenzoyl, 4-methylnaphthoyl, 3,4-dimethylbenzoyl, 2,3,4-trimethylbenzoyl, 4-propylbenzoyl, 4-propylnaphthoyl, 2-, 3-, or
4-trifluoromethylbenzoyl, 2-, 3-, or 4-
Trifluoromethylnaphthoyl, 3,4-ditrifluoromethylbenzoyl, 2,3,4-trifluoromethylbenzoyl, 4-tetrafluoropropylbenzoyl, 4-tetrafluoropropylnaphthoyl, 4-methoxybenzoyl,
4-methoxynaphthoyl, 3,4-dimethoxybenzoyl, 2,
3,4-trimethoxybenzoyl, 4-propoxybenzoyl, 4-propoxynaphthoyl, 4-fluorobenzoyl,
4-fluoronaphthoyl, 3,4-difluorobenzoyl, or 2,3,4-trifluorobenzoyl can be mentioned,
Preferably, it is a benzoyl group (as a substituent, it may have a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenoalkyl group, a C ₁ -C ₆ alkoxy group, and 1 to 3 halogen atoms). And
More preferably a benzoyl group (as a substituent, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenoalkyl group, a C ₁ -C ₆ alkoxy group,
It may have one halogen atom. ).

Δ represents a “C ₈ -C ₁₇ aralkylcarbonyl group (C ₁ -C ₆ alkyl group, C ₁ -C ₆ halogenoalkyl group, C ₁ -C ₆ alkoxy group, halogen atom May have 1 to 3). "), The substituted C ₁ -C ₆ alkyl group, C ₁ -C ₆ halogenoalkyl group, C ₁ -C ₆ alkoxy group, and halogen atom The groups mentioned in the definition of each group described above can be exemplified. Examples of the group include, in addition to the unsubstituted C ₈ -C ₁₂ araliphatic acyl group mentioned as the aralkylcarbonyl moiety in the definition of α, as a group having a substituent, 4-methylphenylacetyl, 4- (4-methyl ) Phenylbutyryl, 6- (4-methyl) naphthylhexanoyl, 2-, 3- or 4-trifluoromethylphenylacetyl, 4-tetrafluoropropylphenylacetyl, 4- (4-trifluoromethyl) phenylbutyryl , 6- (4-trifluoromethyl) phenylhexanoyl,
4-trifluoromethylnaphthylacetyl, 6- (4-trifluoromethyl) naphthylhexanoyl, 4-methoxyphenylacetyl, 4- (4-methoxy) phenylbutyryl, 6- (4
-Methoxy) naphthylhexanoyl, 4-fluorophenylacetyl, 4- (4-fluoro) phenylbutyryl, or 6- (4
-Fluoro) naphthylhexanoyl,
Preferably, a phenyl C ₂ -C ₇ alkylcarbonyl group (a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenoalkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom of 1 to 3
You may have one. ), And more preferably phenyl C
As ₂ -C ₇ alkylcarbonyl group (substituent, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenoalkyl groups, C ₁ -C ₆ alkoxy group,
It may have 1 to 3 halogen atoms. ), And most preferably, a phenyl C ₂ -C ₇ alkylcarbonyl group (substituted as a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenoalkyl group, a C ₁ -C ₆ alkoxy group, May be included.)

Δ is a heteroaromatic carbonyl group (C ₁ -C ₆ alkyl group, C ₁ -C ₆ halogenoalkyl group, C ₁
It may have a -C ₆ alkoxy group and 1 to 3 halogen atoms. )), The C ₁ -C ₆ alkyl group, C ₁ -C ₆ halogenoalkyl group, C ₁ -C ₆ alkoxy group, and halogen atom, which are the substituents, are the groups listed in the definition of each group described above. Can be mentioned. As the group, for example, α
In addition to the unsubstituted heterocyclic carbonyl group listed as a heteroaromatic ring carbonyl moiety in the definition of, as a group having a substituent,
Methylfurylcarbonyl, methylthienylcarbonyl,
Methylpyrrolylcarbonyl, methylnicotinoyl, trifluoromethylfurylcarbonyl, trifluoromethylthienylcarbonyl, trifluoromethylpyrrolcarbonyl, trifluoromethyloxazolylcarbonyl,
Trifluoromethylthiazolylcarbonyl, trifluoromethylnicotinoyl, tetrafluoropropylfurylcarbonyl, tetrafluoropropylthienylcarbonyl, tetrafluoropropylpyrrolylcarbonyl, methoxyfurylcarbonyl, methoxythienylcarbonyl,
Methoxypyrrolylcarbonyl, methoxynicotinoyl,
Examples thereof include fluorofurylcarbonyl, fluorothienylcarbonyl, fluoropyrrolylcarbonyl and fluoronicotinoyl, preferably a 5- or 6-membered heteroaromatic carbonyl group (substituted as a C ₁ -C ₆ alkyl group, C ₁ -C ₆ halogenoalkyl group, C ₁ -C ₆ alkoxy group, and may have 1 to 3 halogen atoms.)
More preferably, a 5- or 6-membered heteroaromatic carbonyl group having one or two (C ₁ -C ₆ alkyl group, C ₁
It may have a -C ₆ halogenoalkyl group, a C ₁ -C ₆ alkoxy group, and 1 to 3 halogen atoms. ), And optimally a 5- or 6-membered heteroaromatic carbonyl group having 1 or 2 (as a substituent, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenoalkyl group, a C ₁ -C ₆ alkoxy group) , One halogen atom
You may have one. ).

According to the above definitions of the substituents γ and δ, when α represents a “C ₆ -C ₁₀ aryl group (may have 1 to 3 substituents γ)”, the substituent γ is The group having, for example, 2-, 3- or 4-methylphenyl, dimethylphenyl, trimethylphenyl, 2-, 3- or 4-isopropylphenyl, 2,3-, 2,4- or 3,4-diisopropyl Phenyl, 2,4,6- or 3,4,5-triisopropylphenyl, 2-, 3- or 4-trifluoromethylphenyl, ditrifluoromethylphenyl, trifluoromethylphenyl, methoxyphenyl, dimethoxyphenyl, 2- , 3- or 4-fluorophenyl, 2,3-,
2,4- or 3,4-difluorophenyl, 2,4,6- or 3,4,5-trifluorophenyl, 2-, 3- or 4-chlorophenyl, dichlorophenyl, trichlorophenyl,
Hydroxyphenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-nitrophenyl, cyclopropylphenyl, cyclohexylphenyl, adamantylphenyl, biphenyl, (methylphenyl) phenyl, (trifluoromethylphenyl) phenyl , (Methoxyphenyl) phenyl, (fluorophenyl) phenyl, (chlorophenyl) phenyl, benzylphenyl, (methylbenzyl) phenyl, (trifluoromethylbenzyl) phenyl, (methoxybenzyl) phenyl, (fluorobenzyl)
Phenyl, (chlorobenzyl) phenyl, acetylphenyl, acetyloxyphenyl, aminophenyl, dimethylaminophenyl, diethylaminophenyl, 3,4- or 2,3-methylenedioxyphenyl, 3,4- or 2,3-
Ethylenedioxyphenyl, methylnaphthyl, dimethylnaphthyl, trimethylnaphthyl, isopropylnaphthyl, diisopropylnaphthyl, triisopropylnaphthyl, trifluoromethylnaphthyl, ditrifluoromethylnaphthyl, trifluoromethylnaphthyl, methoxynaphthyl, dimethoxynaphthyl, fluoronaphthyl,
Difluoronaphthyl, trifluoronaphthyl, chloronaphthyl, dichloronaphthyl, trichloronaphthyl, cyanonaphthyl, nitronaphthyl, cyclopropylnaphthyl, cyclohexylnaphthyl, adamantylnaphthyl,
Phenylnaphthyl, (methylphenyl) naphthyl, (trifluoromethylphenyl) naphthyl, (methoxyphenyl) naphthyl, (fluorophenyl) naphthyl, (chlorophenyl) naphthyl, benzylnaphthyl, (methylbenzyl) naphthyl, (trifluoromethylbenzyl) naphthyl , (Methoxybenzyl) naphthyl, (fluorobenzyl)
Naphthyl, (chlorobenzyl) naphthyl, acetylnaphthyl, acetyloxynaphthyl, aminonaphthyl, dimethylaminonaphthyl, diethylaminonaphthyl, methylenedioxynaphthyl, or ethylenedioxynaphthyl, preferably a phenyl group (substituted γ And more preferably a phenyl group (which may have one or two substituents γ).
And most preferably a phenyl group (which may have one substituent γ).

When α represents a “C ₇ -C ₁₆ aralkyl group (the aryl moiety may have 1 to 3 substituents γ)”, the group having the substituent γ includes, for example, methyl Benzyl, dimethylbenzyl, trimethylbenzyl, isopropylbenzyl, diisopropylbenzyl, triisopropylbenzyl, 2-, 3- or 4-trifluoromethylbenzyl, ditrifluoromethylbenzyl, trifluoromethylbenzyl, methoxybenzyl, dimethoxybenzyl, fluorobenzyl, Difluorobenzyl, trifluorobenzyl, chlorobenzyl, dichlorobenzyl, trichlorobenzyl, hydroxybenzyl,
Cyanobenzyl, nitrobenzyl, cyclopropylbenzyl, cyclohexylbenzyl, adamantylbenzyl, phenylbenzyl, (methylphenyl) benzyl,
(Trifluoromethylphenyl) benzyl, (methoxyphenyl) benzyl, (fluorophenyl) benzyl, (chlorophenyl) benzyl, benzylbenzyl, (methylbenzyl) benzyl, (trifluoromethylbenzyl) benzyl, (methoxybenzyl) benzyl, (fluoro Benzyl)
Benzyl, (chlorobenzyl) benzyl, acetylbenzyl, acetyloxybenzyl, aminobenzyl, dimethylaminobenzyl, diethylaminobenzyl, methylenedioxybenzyl, ethylenedioxybenzyl, methylphenethyl, dimethylphenethyl, trimethylphenethyl, isopropylphenethyl, diisopropylphenethyl, Triisopropylphenethyl, trifluoromethylphenethyl, ditrifluoromethylphenethyl, trifluoromethylphenethyl, methoxyphenethyl, fluorophenethyl, difluorophenethyl, trifluorophenethyl, chlorophenethyl, hydroxyphenethyl, cyanophenethyl, nitrophenethyl, cyclopropylphenethyl, cyclohexylphenethyl , Adamantyl phenethyl, Phenylphenethyl, benzylphenethyl, acetylphenethyl, acetyloxyphenethyl, aminophenethyl, dimethylaminophenethyl, diethylaminophenethyl, methylenedioxyphenethyl, ethylenedioxyphenethyl, methylnaphthylmethyl, dimethylnaphthylmethyl, trimethylnaphthylmethyl, isopropylnaphthylmethyl, diisopropyl Naphthylmethyl, triisopropylnaphthylmethyl, trifluoromethylnaphthylmethyl, ditrifluoromethylnaphthylmethyl, trifluoromethylnaphthylmethyl, methoxynaphthylmethyl, fluoronaphthylmethyl, difluoronaphthylmethyl, trifluoronaphthylmethyl, chloronaphthylmethyl, hydroxynaphthylmethyl , Cyanonaphthylmethyl, nitronaphthyl Methyl,
Cyclopropylnaphthylmethyl, cyclohexylnaphthylmethyl, adamantylnaphthylmethyl, phenylnaphthylmethyl, benzylnaphthylmethyl, acetylnaphthylmethyl, acetyloxynaphthylmethyl, aminonaphthylmethyl, dimethylaminonaphthylmethyl, diethylaminonaphthylmethyl, methylenedioxynaphthylmethyl, ethylene Examples thereof include dioxynaphthylmethyl, preferably a phenyl C ₁ -C ₆ alkyl group (which may have 1 to 3 substituents γ in the aryl portion), and more preferably phenyl C ₁ -C ₆ alkyl group. _A C ₁ -C ₄ alkyl group (which may have 1 to 3 substituents γ in the aryl moiety), and more preferably a phenyl C ₁ -C ₂ alkyl group (where the aryl moiety has 1 to 3 substituents γ). or it may have three.), and optimally phenyl C ₁ -C ₄ alkyl Is a group (a substituent γ on the aryl moiety may have one.).

When α represents a “C ₇ -C ₁₁ arylcarbonyl group (the aryl moiety may have 1 to 3 substituents γ)”, the group having a substituent γ includes, for example, Methylbenzoyl, dimethylbenzoyl, trimethylbenzoyl, isopropylbenzoyl, diisopropylbenzoyl, triisopropylbenzoyl, trifluoromethylbenzoyl, methoxybenzoyl, fluorobenzoyl, difluorobenzoyl, trifluorobenzoyl, chlorobenzoyl, dichlorobenzoyl, hydroxybenzoyl, cyanobenzoyl, nitro Benzoyl, acetylbenzoyl, acetyloxybenzoyl, aminobenzoyl, dimethylaminobenzoyl, methylenedioxybenzoyl, methylnaphthoyl,
Isopropyl naphthoyl, diisopropyl naphthoyl,
Triisopropylnaphthoyl, trifluoromethylnaphthoyl, methoxynaphthoyl, fluoronaphthoyl, difluoronaphthoyl, trifluoronaphthoyl, chloronaphthoyl, dichloronaphthoyl, hydroxynaphthoyl, cyanonaphthoyl, nitronaphthoyl, acetylnaphthoyl, Examples thereof include acetyloxynaphthoyl, aminonaphthoyl, dimethylaminonaphthoyl, and methylenedioxynaphthoyl, and preferably a benzoyl group (which may have 1 to 3 substituents γ), More preferably, it is a benzoyl group (which may have one or two substituents γ), and most preferably a benzoyl group (which may have one substituent γ).

When α represents a “C ₈ -C ₁₇ aralkylcarbonyl group (the aryl moiety may have one to three substituents γ described below)”, the group having the substituent γ includes For example, methylphenylacetyl, isopropylphenylacetyl, diisopropylphenylacetyl, triisopropylphenylacetyl, trifluoromethylphenylacetyl, methoxyphenylacetyl, fluorophenylacetyl, difluorophenylacetyl, trifluorophenylacetyl, chlorophenylacetyl, dichlorophenylacetyl, hydroxyphenyl Acetyl, cyanophenylacetyl, nitrophenylacetyl, acetylphenylacetyl, acetyloxyphenylacetyl, aminophenylacetyl, dimethylaminophenylacetyl, Dioxy phenylacetyl, 4- (methylphenyl) butyl, 4- (isopropylphenyl) butyl, 4- (diisopropylphenyl) butyl, 4-
(Triisopropylphenyl) butyl, 4- (trifluoromethylphenyl) butyl, 4- (fluorophenyl) butyl, 4- (difluorophenyl) butyl, 4- (trifluorophenyl) butyl, 4- (chlorophenyl) butyl, 4 -(Hydroxyphenyl) butyl, 4- (cyanophenyl) butyl, 4
-(Nitrophenyl) butyl, 4- (acetylphenyl) butyl, 4- (acetyloxyphenyl) butyl, 4- (aminophenyl) butyl, 4- (dimethylaminophenyl) butyl, 4
-(Methylenedioxyphenyl) butyl, preferably a phenyl C ₂ -C ₇ alkylcarbonyl group (which may have 1 to 3 substituents γ), more preferably A phenyl C ₂ -C ₅ alkylcarbonyl group (which may have 1 to 3 substituents γ), and most preferably a phenyl C ₂ -C ₅ alkylcarbonyl group (which has 1 substituent γ ).

When α represents “heteroaromatic ring (may have 1 to 3 substituents γ)”, the group having the substituent γ includes, for example, methylfuryl, isopropylfuryl, trifluoro Methylfuryl, cyanofuryl, nitrofuryl, fluorofuryl, chlorofuryl, methylthienyl, isopropylthienyl, trifluoromethylthienyl, cyanothienyl, nitrothienyl, fluorothienyl, chlorothienyl, methylpyrrolyl, isopropylpyrrolyl, trifluoromethylpyrrolyl, cyanopyrolyl Nitropyrrolyl, fluoropyrrolyl, chloropyrrolyl, methylpyridyl, isopropylpyridyl, trifluoromethylpyridyl, cyanopyridyl, nitropyridyl, fluoropyridyl, or chloropyridyl. Or a 6-membered heteroaromatic ring (which may have 1 to 3 substituents γ), and more preferably a 5- or 6-membered heteroaromatic ring (having 1 or 2 substituents γ). And most preferably a 5- or 6-membered heteroaromatic ring (which may have one substituted γ).

Α is a “heteroaromatic carbonyl group (substituted γ
May be provided. )), The group having a substituent γ includes, for example, methylfurylcarbonyl, isopropylfurylcarbonyl, trifluoromethylfurylcarbonyl, cyanofurylcarbonyl, nitrofurylcarbonyl, fluorofurylcarbonyl, chlorofurylcarbonyl, methylthienylcarbonyl , Isopropylthienylcarbonyl, trifluoromethylthienylcarbonyl, cyanothienylcarbonyl, nitrothienylcarbonyl, fluorothienylcarbonyl, chlorothienylcarbonyl, methylpyrrolylcarbonyl,
Isopropylpyrrolylcarbonyl, trifluoromethylpyrrolylcarbonyl, cyanopyrrolylcarbonyl, nitropyrrolylcarbonyl, fluoropyrrolylcarbonyl,
Chloropyrrolylcarbonyl, methylnicotinoyl, isopropylnicotinoyl, trifluoromethylnicotinoyl, cyanonicotinoyl, nitronicotinoyl, fluoronicotinoyl, or chloronicotinoyl, preferably a 5- or 6-membered heteroaromatic A ring carbonyl group (which may have 1 to 3 substituent (s));
More preferably, a 5- or 6-membered heteroaromatic carbonyl group
(May have one or two substituents γ), and is most preferably a 5- or 6-membered heteroaromatic carbonyl group
(It may have one substitution γ).

When α represents a “C ₆ -C ₁₀ arylsulfonyl group (the aryl moiety may have 1 to 3 substituents γ)”, the group having the substituent γ includes, for example, Methylphenylsulfonyl, isopropylphenylsulfonyl, trifluoromethylphenylsulfonyl, methoxyphenylsulfonyl, fluorophenylsulfonyl, chlorophenylsulfonyl, hydroxyphenylsulfonyl, cyanophenylsulfonyl, nitrophenylsulfonyl, cyclohexylphenylsulfonyl, adamantylphenylsulfonyl, biphenylsulfonyl, benzylphenyl Sulfonyl, acetylphenylsulfonyl, acetyloxyphenylsulfonyl, aminophenylsulfonyl, dimethylaminophenylsulfonyl, methylenedioxyphen Rusulfonyl, methylnaphthylsulfonyl, dimethylnaphthylsulfonyl, trimethylnaphthylsulfonyl, isopropylnaphthylsulfonyl, trifluoromethylnaphthylsulfonyl, methoxynaphthylsulfonyl, fluoronaphthylsulfonyl, chloronaphthylsulfonyl, cyanonaphthylsulfonyl, nitronaphthylsulfonyl, cyclohexylnaphthylmanyl Naphthylsulfonyl, phenylnaphthylsulfonyl, benzylnaphthylsulfonyl, acetylnaphthylsulfonyl, acetyloxynaphthylsulfonyl, aminonaphthylsulfonyl, dimethylaminonaphthylsulfonyl, or methylenedioxynaphthylsulfonyl, preferably a phenylsulfonyl group (substituted may have 1 to 3 γ ), More preferably a phenylsulfonyl group (which may have one or two substituents γ), and most preferably a phenylsulfonyl group (having one substituent γ). Is also good).

When α represents a “C ₇ -C ₁₆ aralkylsulfonyl group (the aryl moiety may have 1 to 3 substituents γ)”, the group having the substituent γ includes, for example, Methylbenzylsulfonyl, isopropylbenzylsulfonyl, trifluoromethylbenzylsulfonyl, methoxybenzylsulfonyl, fluorobenzylsulfonyl, chlorobenzylsulfonyl, hydroxybenzylsulfonyl, cyanobenzylsulfonyl, nitrobenzylsulfonyl, cyclohexylbenzylsulfonyl, adamantylbenzylsulfonyl, phenylbenzylsulfonyl, Benzylbenzylsulfonyl, acetylbenzylsulfonyl, acetyloxybenzylsulfonyl, aminobenzylsulfonyl, dimethylaminobenzylsulfonyl, methylenedione Shi benzylsulfonyl,
Methylphenethylsulfonyl, isopropylphenethylsulfonyl, trifluoromethylphenethylsulfonyl, methoxyphenethylsulfonyl, fluorophenethylsulfonyl, chlorophenethylsulfonyl, hydroxyphenethylsulfonyl, cyanophenethylsulfonyl, nitrophenethylsulfonyl, cyclohexylphenethylsulfonyl, adamantylphenethylsulfonyl, adamantylphenethylsulfonyl Benzylphenethylsulfonyl, acetylphenethylsulfonyl, acetyloxyphenethylsulfonyl, aminophenethylsulfonyl, dimethylaminophenethylsulfonyl, methylenedioxyphenethylsulfonyl, methylnaphthylmethylsulfonyl, isopropylnaphthylmethylsulfonyl, trifluoromethylna Tylmethylsulfonyl, methoxynaphthylmethylsulfonyl, fluoronaphthylmethylsulfonyl, chloronaphthylmethylsulfonyl, hydroxynaphthylmethylsulfonyl, cyanonaphthylmethylsulfonyl, nitronaphthylmethylsulfonyl, cyclohexylnaphthylmethylsulfonyl, adamantylnaphthylmethylsulfonyl, phenylnaphthylmethylsulfonyl, benzyl Naphthylmethylsulfonyl, acetylnaphthylmethylsulfonyl, acetyloxynaphthylmethylsulfonyl, aminonaphthylmethylsulfonyl,
Examples thereof include dimethylaminonaphthylmethylsulfonyl and methylenedioxynaphthylmethylsulfonyl, preferably a phenyl C ₁ -C ₆ alkylsulfonyl group (which may have 1 to 3 substituents γ). And more preferably a phenyl C ₁ -C ₄ alkylsulfonyl group (which may have 1 to 3 substituents γ), and more preferably a phenyl C ₁ -C ₂ alkylsulfonyl group (substitution may have 1 to 3 γ), and most preferably phenyl C _1-
A C ₂ alkylsulfonyl group (which may have one substituent γ).

When β represents a “C ₆ -C ₁₀ aryl group (may have 1 to 3 substituents δ)”, the group having a substituent δ includes, for example, methylphenyl, isopropyl Phenyl, biphenyl, benzylphenyl, acetylphenyl, cyclohexylphenyl, adamantylphenyl, benzoylphenyl, phenylacetylphenyl, nicotinoylphenyl, methylnaphthyl, isopropylnaphthyl, phenylnaphthyl, benzylnaphthyl, acetylnaphthyl, cyclohexylnaphthyl, adamantylnaphthyl, benzoylnaphthyl Phenylacetylnaphthyl or nicotinoylnaphthyl, preferably a phenyl group (which may have 1 to 3 substituents δ), and more preferably a phenyl group (substitution δ Has one or two Is have may be.),
Most preferably, it is a phenyl group (which may have one substituent δ).

When β represents a “C ₇ -C ₁₆ aralkyl group (optionally having 1 to 3 substituents δ in the aryl moiety)”, the group having the substituent δ is, for example, methyl Benzyl, isopropylbenzyl, phenylbenzyl,
Benzylbenzyl, acetylbenzyl, cyclohexylbenzyl, adamantylbenzyl, benzoylbenzyl, phenylacetylbenzyl, nicotinoylbenzyl, methylphenethyl, isopropylphenethyl, phenylphenethyl, benzylphenethyl, acetylphenethyl, cyclohexylphenethyl, adamantylphenethyl, benzoylphenethyl, phenylacetylphenethyl , Nicotinoylphenethyl, methylnaphthylmethyl, isopropylnaphthylmethyl, phenylnaphthylmethyl, benzylnaphthylmethyl, acetylnaphthylmethyl, cyclohexylnaphthylmethyl, adamantylnaphthylmethyl, benzoylnaphthylmethyl, phenylacetylnaphthylmethyl, or nicotinoylnaphthylmethyl Can be good The (which may have 1 to 3 of substituents δ on the aryl portion.) Phenyl C ₁ -C ₆ alkyl group and, still preferably phenyl C ₁ -C ₄ alkyl group
(Which may have 1 to 3 substituents δ in the aryl moiety), and more preferably a phenyl C ₁ -C ₂ alkyl group
(The aryl moiety may have one to three substituents δ), and most preferably, a phenyl C ₁ -C ₂ alkyl group (the aryl moiety may have one substituent δ) ).

When β represents “an amino group optionally having one or two substituents δ”, examples of the group include amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, N-ethyl-N
-Methylamino, dipropylamino, dibutylamino,
Dipentylamino, dihexylamino, phenylamino, 1- or 2-indenylamino, 1- or 2-naphthylamino, benzylamino, 1- or 2-naphthylmethylamino, 1- or 2-indenylmethylamino, 1- or 2-
Phenethylamino, 1-, 2- or 3-phenylpropylamino, 4-phenylbutylamino, 1-phenylbutylamino, 5-phenylpentylamino, 6-phenylhexylamino, dibenzylamino, formylamino, acetylamino, propionyl Amino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino,
Pivaloylamino, hexanoylamino, acryloylamino, methacryloylamino, crotoylamino, cyclopropylcarbonylamino, cyclohexylcarbonylamino, adamantylcarbonylamino, benzoylamino, 1- or 2-naphthoylamino, 1-indancarbonylamino, 1- or 2-naphthoylamino, phenylacetylamino, 3-phenylpropionylamino, 4-phenylbutyrylamino, 5-phenylpentanoylamino, 6-phenylhexanoylamino, pyrrolylcarbonylamino, imidazolylcarbonylamino, pyrazolylcarbonylamino, Triazolylcarbonylamino, tetrazolylcarbonylamino, nicotinoylamino, isonicotinoylamino, pyrazinylcarbonylamino, pyrimidinylcarbo Amino, pyridazinylcarbonylamino, thiazolylcarbonylamino, oxazolylcarbonylamino, oxadiazolylcarbonylamino, thiadiazolylcarbonylamino, N, N-diacetylamino, N-formyl-N-hexylamino, N -Acetyl-N-methylamino, N-acetyl-N-ethylamino, N-acetyl-N-propylamino, N-acetyl-N-
Butylamino, N-acetyl-N-pentylamino, N-acetyl-N-hexylamino, N-benzoyl-N-methylamino, N-benzoyl-N-ethylamino, N-benzoyl-N-propylamino, N- Benzoyl-N-butylamino, N-benzoyl-N-pentylamino, N-benzoyl
-N-hexylamino, N-benzoyl-N-phenylamino, N-benzyl-N-benzoylamino, N-hexyl-
N-1-naphthoylamino, N-hexyl-N-2-naphthoylamino, N-hexyl-N-phenylacetylamino, N-
Butyl-N-nicotinoylamino, N-hexyl-N-nicotinoylamino, N-isonicotinoyl-N-hexylamino, or 4-trifluoromethylphenylcarbamoylamino, preferably an amino group (substituted May have one or two C ₁ -C ₁₀ alkyl or C ₁ -C ₇ aliphatic acyl), and more preferably an amino group (C ₁ -C ₆ alkyl or C ₁ -C _2, 1 to aliphatic acyl may have two.) a.

According to the above definitions of the substituents α and β, when R ₁ represents a “carbamoyl group (may have one or two substituents α)”, the group having a substituent includes For example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, s-butylcarbamoyl, t-
Butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, decylcarbamoyl, trifluoromethylcarbamoyl, tetrafluoropropylcarbamoyl, cyclopropylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl, adamantylcarbamoyl, phenylcarbamoyl, methylphenylcarbamoyl, isopropylphenylcarbamoyl, diisopropylphenylcarbamoyl, Triisopropylphenylcarbamoyl, 2-, 3- or 4-trifluoromethylphenylcarbamoyl, 2-, 3- or 4-methoxyphenylcarbamoyl, fluorophenylcarbamoyl, difluorophenylcarbamoyl, trifluorophenylcarbamoyl, 2-, 3- or 4-chlorophenylcarbamoyl, dichlorofu Carbamoylmethyl, hydroxy phenylcarbamoyl, 2,5-dimethyl-4-hydroxy-phenylcarbamoyl, 2, 5-t-butyl-4-hydroxy-phenylcarbamoyl, cyano-phenylcarbamoyl,
Nitrophenylcarbamoyl, cyclopropylphenylcarbamoyl, cyclohexylphenylcarbamoyl,
Adamantylphenylcarbamoyl, biphenylcarbamoyl, benzylphenylcarbamoyl, acetylphenylcarbamoyl, acetyloxyphenylcarbamoyl, aminophenylcarbamoyl, dimethylaminophenylcarbamoyl, diethylaminophenylcarbamoyl, methylenedioxyphenylcarbamoyl, ethylenedioxyphenylcarbamoyl, 1- or 2- Naphthylcarbamoyl, benzylcarbamoyl, methylbenzylcarbamoyl, isopropylbenzylcarbamoyl, diisopropylbenzylcarbamoyl, triisopropylbenzylcarbamoyl, trifluoromethylbenzylcarbamoyl, methoxybenzylcarbamoyl, fluorobenzylcarbamoyl, difluorobenzylcarbamoyl, trifluorobe Benzylcarbamoyl, 2-, 3- or 4-chlorobenzylcarbamoyl, dichlorobenzylcarbamoyl, hydroxybenzylcarbamoyl, cyanobenzylcarbamoyl, nitrobenzylcarbamoyl,
Cyclopropylbenzylcarbamoyl, cyclohexylbenzylcarbamoyl, adamantylbenzylcarbamoyl, phenylbenzylcarbamoyl, benzylbenzylcarbamoyl, acetylbenzylcarbamoyl, acetyloxybenzylcarbamoyl, aminobenzylcarbamoyl, dimethylaminobenzylcarbamoyl, methylenedioxybenzylcarbamoyl, phenethylcarbamoyl, trifluoro Methylphenethylcarbamoyl,
Fluorophenethylcarbamoyl, cyclopropylcarbonylcarbamoyl, cyclohexylcarbonylcarbamoyl, adamantylcarbonylcarbamoyl, benzoylcarbamoyl, phenylacetylcarbamoyl, 4-
Phenylbutylcarbamoyl, pyrrolylcarbamoyl,
Furylcarbamoyl, thienylcarbamoyl, 2-, 3- or 4-pyridylcarbamoyl, pyrrolylcarbonylcarbamoyl, furylcarbonylcarbamoyl, thienylcarbonylcarbamoyl, nicotinoylcarbamoyl,
Examples thereof include methanesulfonylcarbamoyl, trifluoromethylcarbamoyl, benzenesulfonylcarbamoyl, toluenesulfonylcarbamoyl, and benzylsulfonylcarbamoyl, and are preferably a carbamoyl group (which may have one substitution α). More preferably, a carbamoyl group (C ₁ -C ₁₀ alkyl, C
₃ -C ₁₀ cycloalkyl which may have 1 to 3 the substituents gamma C ₆ -C ₁₀ aryl group, or a substituent gamma which may have 1 to 3 C ₆ -C ₁₀ aryl And an aralkyl group having a C ₁ -C ₆ alkyl. ).

R ₁ is a thiocarbamoyl group (substituted α is 1
Or you may have two. )), The substituted group includes, for example, methylthiocarbamoyl, ethylthiocarbamoyl, propylthiocarbamoyl, isopropylthiocarbamoyl, butylthiocarbamoyl, s-butylthiocarbamoyl, t-butylthiocarbamoyl, pentylthiocarbamoyl , Hexylthiocarbamoyl, decylthiocarbamoyl, cyclopropylthiocarbamoyl, cyclopentylthiocarbamoyl, cyclohexylthiocarbamoyl, adamantylthiocarbamoyl, phenylthiocarbamoyl, methylphenylthiocarbamoyl, isopropylphenylthiocarbamoyl, diisopropylphenylthiocarbamoyl, triisopropylphenylthiocarbamoyl , 2-,
3- or 4-trifluoromethylphenylthiocarbamoyl, 2-, 3- or 4-methoxyphenylthiocarbamoyl, fluorophenylthiocarbamoyl, difluorophenylthiocarbamoyl, trifluorophenylthiocarbamoyl, 2-, 3- or 4-chlorophenyl Thiocarbamoyl, dichlorophenylthiocarbamoyl, 2,5-
Dimethyl-4-hydroxyphenylthiocarbamoyl, 2,5
-t-butyl-4-hydroxyphenylthiocarbamoyl,
Hydroxyphenylthiocarbamoyl, cyanophenylthiocarbamoyl, nitrophenylthiocarbamoyl,
Cyclohexylphenylthiocarbamoyl, adamantylphenylthiocarbamoyl, biphenylthiocarbamoyl, benzylphenylthiocarbamoyl, acetylphenylthiocarbamoyl, acetyloxyphenylthiocarbamoyl, aminophenylthiocarbamoyl, dimethylaminophenylthiocarbamoyl, methylenedioxyphenylthiocarbamoyl, 1- Or 2-naphthylthiocarbamoyl, benzylthiocarbamoyl, methylbenzylthiocarbamoyl, isopropylbenzylthiocarbamoyl, diisopropylbenzylthiocarbamoyl, triisopropylbenzylthiocarbamoyl, trifluoromethylbenzylthiocarbamoyl, fluorobenzylthiocarbamoyl, difluorobenzylthiocarbamoyl, trifluoro Robenzylthiocarbamoyl, 2
-, 3- or 4-chlorobenzylthiocarbamoyl, dichlorobenzylthiocarbamoyl, hydroxybenzylthiocarbamoyl, cyanobenzylthiocarbamoyl,
Nitrobenzylthiocarbamoyl, cyclopropylbenzylthiocarbamoyl, cyclohexylbenzylthiocarbamoyl, adamantylbenzylthiocarbamoyl,
Acetylbenzylthiocarbamoyl, acetyloxybenzylthiocarbamoyl, aminobenzylthiocarbamoyl, dimethylaminobenzylthiocarbamoyl, methylenedioxybenzylthiocarbamoyl, cyclopropylcarbonylthiocarbamoyl, cyclohexylcarbonylthiocarbamoyl, adamantylcarbonylthiocarbamoyl, benzoylthiocarbamoyl, phenyl Acetylthiocarbamoyl, 2-, 3- or 4-pyridylthiocarbamoyl, nicotinoylthiocarbamoyl, methanesulfonylthiocarbamoyl, trifluoromethylthiocarbamoyl, benzenesulfonylthiocarbamoyl, toluenesulfonylthiocarbamoyl, or benzylsulfonylthiocarbamoyl Yes, preferably thiocarbamoy Group (which may have one substituent fraction alpha.) And, still preferably C ₁ -C ₁₀ alkyl as thiocarbamoyl group (substituent is, C ₃ -C ₁₀ cycloalkyl, C ₆
A —C ₁₀ aryl group (which may have 1 to 3 substituents γ described below), or a C ₇ -C ₁₆ aralkyl group (an aryl moiety has 1 to 3 substituents γ described later) May be.)
May be substituted by one. ).

When R ₁ represents a “sulfonyl group having one substituted α”, the group includes, for example, methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, s-butanesulfonyl , T-butanesulfonyl, pentanesulfonyl, hexanesulfonyl, cyclopropanesulfonyl,
Cyclopentylsulfonyl, cyclohexanesulfonyl, adamantanesulfonyl, benzenesulfonyl, toluenesulfonyl, isopropylbenzenesulfonyl,
Diisopropylbenzenesulfonyl, triisopropylbenzenesulfonyl, trifluoromethylbenzenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, hydroxybenzenesulfonyl, cyanobenzenesulfonyl, nitrobenzenesulfonyl, cyclohexylbenzenesulfonyl, adamantylbenzenesulfonyl, acetylbenzenesulfonyl, acetyloxybenzenesulfonyl, Aminobenzenesulfonyl, dimethylaminobenzenesulfonyl, methylenedioxybenzenesulfonyl, 1- or 2-naphthalenesulfonyl, phenylmethylsulfonyl, or pyridinesulfonyl, preferably a sulfonyl group (C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, aryl group (substituent which will be described later γ 1 may have three.), Or C ₇ -C ₁₆ aralkyl group (which may have 1 to 3 of substituents γ described later on the aryl moiety.) 1 substituted with Is also good).

When R ₁ represents a “carbonyl group (having one substituent α)”, the group having a substituent includes, for example, acetyl, propionyl, butyryl, isopropylcarbonyl, butylcarbonyl, s -Butylcarbonyl, t-butylcarbonyl, pentylcarbonyl,
Hexylcarbonyl, decylcarbonyl, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl, phenylcarbonyl, methylphenylcarbonyl, isopropylphenylcarbonyl, diisopropylphenylcarbonyl, triisopropylphenylcarbonyl, 2-, 3- or 4-trifluoromethyl Phenylcarbonyl, 2-, 3-
Or 4-methoxyphenylcarbonyl, fluorophenylcarbonyl, difluorophenylcarbonyl, trifluorophenylcarbonyl, 2-, 3- or 4-chlorophenylcarbonyl, dichlorophenylcarbonyl, 2,
5-dimethyl-4-hydroxyphenylcarbonyl, 2,5-t-
Butyl-4-hydroxyphenylcarbonyl, hydroxyphenylcarbonyl, cyanophenylcarbonyl, nitrophenylcarbonyl, cyclohexylphenylcarbonyl, adamantylphenylcarbonyl, biphenylcarbonyl, benzylphenylcarbonyl, acetylphenylcarbonyl, acetyloxyphenylcarbonyl,
Aminophenylcarbonyl, dimethylaminophenylcarbonyl, methylenedioxyphenylcarbonyl, 1- or 2-naphthylcarbonyl, benzylcarbonyl, methylbenzylcarbonyl, isopropylbenzylcarbonyl, diisopropylbenzylcarbonyl, triisopropylbenzylcarbonyl, trifluoromethylbenzylcarbonyl, fluoro Benzylcarbonyl, difluorobenzylcarbonyl, trifluorobenzylcarbonyl, 2-, 3- or 4-chlorobenzylcarbonyl, dichlorobenzylcarbonyl, hydroxybenzylcarbonyl, cyanobenzylcarbonyl, nitrobenzylcarbonyl, cyclopropylbenzylcarbonyl, cyclohexylbenzylcarbonyl, adamantyl Benzyl carbonyl, acetyl benzyl Carbonyl, acetyloxybenzylcarbonyl, aminobenzylcarbonyl, dimethylaminobenzylcarbonyl, methylenedioxybenzylcarbonyl, cyclopropylcarbonylcarbonyl,
Cyclohexylcarbonylcarbonyl, adamantylcarbonylcarbonyl, benzoylcarbonyl, phenylacetylcarbonyl, 2-, 3- or 4-pyridylcarbonyl, nicotinoylcarbonyl, methanesulfonylcarbonyl, trifluoromethylcarbonyl, benzenesulfonylcarbonyl, toluenesulfonylcarbonyl, or benzylsulfonyl Carbonyl can be mentioned,
Preferably a carbonyl group (C ₁ -C ₁₀ alkyl as a substituent, C
₃ -C ₁₀ cycloalkyl, aryl group (which may have 1 to 3 of substituents γ to be described later.), Or C ₇ -C ₁₆ aralkyl group (substituent γ 1 to 3 to be described later in the aryl moiety May be substituted.). ).

When R ₂ , R ₃ and L represent a “C ₆ -C ₁₀ aryl group (which may have 1 to 3 substituents β)”, the group having a substituent includes: For example, methylphenyl, isopropylphenyl, trifluoromethylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl, hydroxyphenyl, biphenyl, benzylphenyl, cyanophenyl, nitrophenyl, aminophenyl, dimethylaminophenyl, diethylaminophenyl, or 1- or 2- Naphthyl can be mentioned, preferably a phenyl group (which may have 1 to 3 substituents β), and more preferably a phenyl group (with 1 substituent β).
Or you may have two. ), And most preferably a phenyl group (one may be substituted with the substituent β).

R ₂ , R ₃ and L represent a C ₇ -C ₁₆ aralkyl group
(It may have 1 to 3 substituents β in the aryl moiety.) ”.
For example, methylbenzyl, isopropylbenzyl, trifluoromethylbenzyl, methoxybenzyl, fluorobenzyl, chlorobenzyl, hydroxybenzyl, phenylbenzyl, cyanobenzyl, nitrobenzyl, aminobenzyl, dimethylaminobenzyl, methylphenethyl, isopropylphenethyl, trifluoromethylphenethyl , Methoxyphenethyl, fluorophenethyl, chlorophenethyl, hydroxyphenethyl, phenylphenethyl, cyanophenethyl, nitrophenethyl, aminophenethyl, dimethylaminophenethyl, methylnaphthylmethyl, isopropylnaphthylmethyl, trifluoromethylnaphthylmethyl, methoxynaphthylmethyl, fluoronaphthylmethyl , Chloronaphthylmethyl, hydroxynaphthylmethyl, Ano naphthylmethyl, nitro naphthylmethyl, there may be mentioned amino-naphthylmethyl, or dimethylamino naphthylmethyl, preferably phenyl C ₁ -C ₆ alkyl group (substituent β 1 to 3 in the aryl part
You may have one. ), And more preferably phenyl C
_{A 1-} C ₄ alkyl group (which may have 1 to 3 substituents β in the aryl moiety), more preferably phenyl C _1-
A C ₂ alkyl group (which may have 1 to 3 substituents β in the aryl moiety); and most preferably a phenyl C ₁ -C ₂ alkyl group (having 1 substituent β in the aryl moiety). ). The amine derivative compound of the compound (I) of the present invention can be converted into a salt according to a conventional method. Such salts include, for example, alkali metal salts such as sodium, potassium and lithium salts; alkaline earth metal salts such as calcium and magnesium salts; aluminum salts;
Metal salts such as iron salts, zinc salts, copper salts, nickel salts, and cobalt salts; inorganic salts such as ammonium salts; t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, Ethylenediamine salt, N-methylglucamine salt, guanidine salt,
Diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-N-phenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxy Amine salts such as organic salts such as methyl) aminomethane salt; hydrohalides such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid; nitrates, perchlorates, sulfates, Inorganic salts such as phosphates, or methanesulfonic acid,
Salts of lower alkanesulfonic acids such as trifluoromethanesulfonic acid and ethanesulfonic acid; arylsulfonic acid salts such as benzenesulfonic acid and p-toluenesulfonic acid; salts of amino acids such as glutamic acid and aspartic acid; fumaric acid , Succinic acid, citric acid, tartaric acid,
Organic acids such as salts of carboxylic acids such as oxalic acid and maleic acid; and amino acid salts such as ornithate, glutamate and aspartate, and are preferably hydrohalic acid salts or organic acids. Acid salt.

The compounds of the present invention also include various isomers. For example, the thiazolidine ring and the oxazolidine ring of the amine derivative compound of the general formula (I) include an asymmetric carbon,
In addition, since an asymmetric carbon may be present on the substituent, it has an optical isomer.

That is, the amine derivative compound represented by the general formula (I) has R-configuration and S-configuration stereoisomers. Each of them, or any proportion thereof, is encompassed by the present invention. Such a stereoisomer can be obtained by synthesizing an amine derivative compound of compound (I) using an optically active raw material compound or by subjecting the synthesized amine derivative compound of compound (I) to a usual optical resolution method or separation method as desired. Can be obtained by performing optical division using

Further, the amine derivative compound of the compound (I) of the present invention absorbs water by leaving it in the air or recrystallizing, thereby adsorbing water or forming a hydrate. In the case where such a solvate is formed, all of these are included in the present invention.

Further, the amine derivative compound of the compound (I) of the present invention may absorb some other solvent to form a solvate, and such a compound is also included in the present invention.

Further, the present invention also includes all compounds which are metabolized in vivo and converted into the amine derivative compound of the compound (I) of the present invention or a pharmacologically acceptable salt thereof, so-called prodrugs.

Further, as an agent for forming a pharmaceutical composition in combination with the amine derivative compound of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof, a sulfonylurea agent, α-
Glucosidase inhibitor, aldose reductase inhibitor, biguanide agent, statin compound, squalene synthesis inhibitor, fibrate compound, LDL catabolism promoter, angiotensin II antagonist, angiotensin converting enzyme inhibitor, antitumor agent and FBPase inhibitor Can be mentioned.

In the above, the sulfonylurea agent is
A drug that promotes insulin secretion, for example,
Tolbutamide, acetohexamide, tolazamide, chlorpropamide and the like can be mentioned.

In the above, an α-glucosidase inhibitor is a drug which has an action of inhibiting digestion enzymes such as amylase, maltase, α-dextrinase and sucrase to delay the digestion of starch and sucrose. ,
Acarbose, N- (1,3-dihydroxy-2-propyl) valiolamine (general name: voglibose), miglitol and the like can be mentioned.

In the above, aldose reductase inhibitors are agents that inhibit diabetic complications by inhibiting the rate-limiting enzyme in the first step of the polyol pathway, such as tolrestat, epalrestat, 2,7-
Difluoro-spiro (9H-fluorene-9,4'-imidazolidin) -2 ', 5'-dione (generic name: imirestat), 3-[(4-
Bromo-2-fluorophenyl) methyl] -7-chloro-3,4-dihydro-2,4-dioxo-1 (2H) -quinazolineacetic acid (generic name:
Zenarestat), 6-fluoro-2,3-dihydro-2 ', 5'-dioxo-spiro [4H-1-benzopyran-4,4'-imidazolidine] -2-carboxamide (SNK-860), zopolrestat, sorbinyl And 1-[(3-bromo-2-benzofuranyl) sulfonyl] -2,4-imidazolidinedione (M-16209).

In the above, the biguanide agent is a drug having an anaerobic glycolysis-promoting action, an insulin action enhancement at the periphery, suppression of glucose absorption from the intestinal tract, suppression of hepatic gluconeogenesis, inhibition of fatty acid oxidation, and the like. For example, phenformin, metformin, buformin and the like can be mentioned.

In the above description, the statin compound is a drug which lowers blood cholesterol by inhibiting hydroxymethylglutaryl-CoA (HMG-CoA) reductase, for example, pravastatin and its sodium salt, simvastatin, lovastatin Atorvastatin, cerivastatin, fluvastatin and the like.

In the above description, the squalene synthesis inhibitor is a drug that lowers blood cholesterol by inhibiting squalene synthesis. For example, (S) -α-
(Bis (2,2-dimethyl-1-oxopropoxy) methoxy)
Phosphinyl-3-phenoxybenzenebutanesulfonic acid monopotassium salt (BMS-188494) and the like can be mentioned.

In the above, the fibrate compound refers to a compound that inhibits triglyceride synthesis and secretion in the liver,
A drug that lowers blood triglycerides by activating lipoprotein lipase. Nicofibrate, pyrifibrate, ronifibrate, simfibrate, theofibrate and the like can be mentioned.

In the above, the LDL catabolic promoter is L
DL (low density lipoprotein) is a drug that lowers blood cholesterol by increasing the receptor, for example, the compound described in JP-A-7-346144 or a salt thereof,
Specifically, N- [2- [4-bis (4-fluorophenyl) methyl-1-piperazinyl] ethyl] -7,7-diphenyl-2,4,6-
Heptatrienoic acid amide and the like can be mentioned.

The above-mentioned statins, squalene synthesis inhibitors, fibrate compounds and LDL catabolism promoters may be replaced by other drugs having an effect of lowering blood cholesterol and triglycerides. Examples of such agents include nicotinic acid derivative preparations such as nicomol and niceritrol; antioxidants such as probucol; and ion exchange resin preparations such as cholestyramine.

In the above, an angiotensin II antagonist is a drug that strongly suppresses an increase in blood pressure caused by angiotensin II and lowers blood pressure. Examples of such a drug include losartan potassium, candesartan cilexetil, valsartan, telmisartan, olmesartan, and the like.

[0094] In the above, an angiotensin converting enzyme inhibitor is a drug which lowers blood pressure and partially lowers blood glucose in diabetic patients by inhibiting angiotensin converting enzyme. Examples thereof include captopril, enalapril and alacepril. , Delapril, ramipril, lisinopril, imidapril, benazepril, selonapril, cilazapril, enalaprilate,
Fosinopril, mobertopril, perindopril, quinapril, spirapril, temocapril, trandolapril and the like.

In the above, the FBPase inhibitor refers to liver
Fructose-1,6-biphosphat, a gluconeogenetic rate-limiting enzyme in the gut
It has an inhibitory effect on ase (FBPase),
And / or a prophylactic agent. Having the general formula (I)
In the amine derivative compound, preferably, (1) R₁Is a carbamoyl group (having one substituted α
You may. ), Thiocarbamoyl group (having one substituent α)
May be. ), A sulfonyl group (having one substituent α
I have. ) Or a carbonyl group (having one substituent α)
You. ) Or a pharmacologically acceptable amine derivative compound thereof
Salt. (2) R₁Is a carbamoyl group (having one substituted α
You. ), A thiocarbamoyl group (having one substituted α)
You. ), A sulfonyl group (having one substituent α),
Or a carbonyl group (having one substituent α).
An amine derivative compound or a pharmacologically acceptable salt thereof. (3) R₁Is a carbamoyl group (having one substituted α
You. ), A thiocarbamoyl group (having one substituted α)
You. ) Or a carbonyl group (having one substituent α)
You. ) Or a pharmacologically acceptable amine derivative compound thereof
Salt. (4) R₁Is a carbamoyl group (having one substituted α
You. ) Or a pharmacologically acceptable amine derivative compound thereof
Salt. (5) R₁Is a thiocarbamoyl group (having one substituted α
ing. ) Or a pharmacologically acceptable amine derivative compound
Salt to be carried. (6) R₁Is a carbonyl group (having one substituted α
You. ) Or a pharmacologically acceptable amine derivative compound thereof
Salt. (7) R_TwoIs a hydrogen atom, C₁-C_TenAlkyl group, phenyl
Group (which may have 1 to 3 substituents β), or
Benzyl group (having 1 to 3 substituents β in the phenyl moiety)
May be. ) Or its pharmacology
Above acceptable salts. (8) R_TwoIs a hydrogen atom, C₁-C_TenAlkyl group, phenyl
Group (which may have one substituent β), or benzyl
Group (may have one substituent β in the phenyl moiety)
Amine derivative compound or a pharmacologically acceptable compound thereof
salt. (9) R_TwoIs a hydrogen atom, or C₁-C_TenIndicates an alkyl group
An amine derivative compound or a pharmacologically acceptable salt thereof. (10) R_TwoIs a hydrogen atom, or C₁-C₆Indicates an alkyl group
An amine derivative compound or a pharmacologically acceptable salt thereof. (11) R_TwoIs an amine derivative compound showing a hydrogen atom or
Is a pharmacologically acceptable salt. (12) R_TwoBut C₁-C₆Amine derivatization showing alkyl group
Or a pharmacologically acceptable salt thereof. (13) R_ThreeIs a hydrogen atom, C₁-C₆Alkyl group, phenyl
Group (which may have 1 to 3 substituents β), or
Benzyl group (having 1 to 3 substituents β in the phenyl moiety)
May be. ) Or its pharmacology
Above acceptable salts. (14) R_ThreeIs a hydrogen atom, C₁-C₆Alkyl group, phenyl
Group (which may have one substituent β), or benzyl
Group (may have one substituent β in the phenyl moiety)
Amine derivative compound or a pharmacologically acceptable compound thereof
salt. (15) R_ThreeIs a hydrogen atom, or C₁-C_FourIndicates an alkyl group
An amine derivative compound or a pharmacologically acceptable salt thereof. (16) R_ThreeBut C₁-C_TwoAmine derivatization showing alkyl group
Or a pharmacologically acceptable salt thereof. (17) R_ThreeIs an amine derivative compound showing a methyl group or
Is a pharmacologically acceptable salt. (18) W₁, W_TwoAnd W_ThreeIs a single bond or C₁-C₆
Amine derivative compound showing alkylene group or pharmacologically
Acceptable salt. (19) W₁, W_TwoAnd W_ThreeIs a single bond or C₁-C_Four
Amine derivative compound showing alkylene group or pharmacologically
Acceptable salt. (20) W₁And W_TwoIs a single bond or C₁-C_FourAl
Represents a kylene group;_ThreeBut C₁-C_TwoAmine showing an alkylene group
Derivatives or pharmacologically acceptable salts thereof. (21) W₁And W_TwoIs a single bond or C₁-C_TwoAl
Represents a kylene group;_ThreeIs an amine derivative showing a methylene group
A somatic compound or a pharmacologically acceptable salt thereof. (22) W₁And W_TwoRepresents a single bond;_ThreeBut Metile
Amine derivative compound showing a thiol group or its pharmacologically acceptable
Salt. (23) X represents an oxygen atom or a sulfur atom, and Y represents an acid
An amine derivative compound in which Q represents a sulfur atom and Q represents a sulfur atom
Or a pharmacologically acceptable salt thereof. (24) X represents an oxygen atom, and Y represents an oxygen atom
And Q is an amine derivative compound representing a sulfur atom or
Pharmacologically acceptable salt. (25) An amine derivative compound in which Z represents a = CH- group or
Is a pharmacologically acceptable salt. (26) an amine derivative compound in which Z represents a nitrogen atom or
Its pharmacologically acceptable salts. (27) An amine derivative compound in which Ar represents a naphthalene ring
Or a pharmacologically acceptable salt thereof. (28) An amine derivative compound in which Ar represents a benzene ring
Or a pharmacologically acceptable salt thereof. (29) L is 1 to 4 substituents on the Ar ring
Yes, hydrogen atom, C₁-C₆Alkyl group, phenyl group (substituted
It may have 1 to 3 β. ) Or benzyl group
(It may have 1 to 3 substituents β in the phenyl moiety.
No. ) Or a pharmacologically acceptable amine derivative compound thereof
Salt. (30) L is 1 to 4 substituents on the Ar ring
Yes, each hydrogen atom, C₁-C₆Alkyl group, phenyl
Group (which may have 1 to 3 substituents β), or
Benzyl group (having 1 to 3 substituents β in the phenyl moiety)
May be. ) Or its pharmacology
Above acceptable salts. (31) L is 1 to 4 substituents on the Ar ring
Yes, each hydrogen atom, or C₁-C₆Indicates an alkyl group
An amine derivative compound or a pharmacologically acceptable salt thereof. (32) L is 1 to 4 substituents on the Ar ring
Yes, each hydrogen atom, or C₁-C_FourIndicates an alkyl group
An amine derivative compound or a pharmacologically acceptable salt thereof. (33) an amine derivative compound in which L represents a hydrogen atom, or
Its pharmacologically acceptable salts. (34) The substitution α is (i) C₁-C_TenAlkyl group, (ii) C_Five-C
_TenCycloalkyl group, (iii) C₆-C_TenAryl group (substituted γ
May be provided. ), (Iv) phenyl C₁-C₆
Alkyl group (having 1 to 3 substituents γ in the phenyl moiety
May be. ), (V) phenylcarbonyl group (phenyl
The portion may have 1 to 3 substitutions γ. ), (V
i) a heteroaromatic ring group (which may have 1 to 3 substituents γ)
No. ), (Vii) C₁-C_FourAlkylsulfonyl group, (viii) C₁-C_Four
Halogenoalkylsulfonyl group, or (ix) phenylsulfone
Honyl group (having 1 to 3 substituents γ in the phenyl moiety
May be. ) Or its pharmacology
Above acceptable salts. (35) When the substitution α is (i) C₁-C₈Alkyl group, (ii) C_Five-C_Ten
Cycloalkyl group, (iii) C₆-C_TenAryl group (substituted γ
You may have 1 to 3 pieces. ), (Iv) phenyl C ₁-C_FourA
Alkyl group (having 1 to 3 substituents γ in the phenyl moiety
May be. ), (V) pyridyl group, (vi) methanesulfonyl
Group, (vii) a trifluoromethanesulfonyl group, or (vii
i) phenylsulfonyl group (substituted γ is 1
It may have three to three. )
Or a pharmacologically acceptable salt thereof. (36) The substitution α is (i) C₁-C₈Alkyl group, (ii) C_Five-C_Ten
Cycloalkyl group, (iii) C₆-C_TenAryl group (substituted γ
You may have 1 to 3 pieces. ), (Iv) phenyl C ₁-C_FourA
Alkyl group (having 1 to 3 substituents γ in the phenyl moiety
May be. ), (V) pyridyl group, or (vi) phenyls
A rufonyl group (having 1 to 3 substituents γ in the phenyl moiety)
May be. Amine derivative compound or a drug thereof
A physiologically acceptable salt. (37) The substitution α is (i) C₁-C_FourAlkyl group, (ii) C_Five-C_Ten
Cycloalkyl group, (iii) C₆-C_TenAryl group (substituted γ
You may have 1 to 3 pieces. ), (Iv) benzyl group (Fe
May have 1 to 3 substituents γ in the nyl portion.
No. ) Or (v) an amine derivative compound showing a pyridyl group or
Is a pharmacologically acceptable salt. (38) When the substitution α is (i) C₁-C_FourAlkyl group, (ii) C_Five-C_Ten
Cycloalkyl group, (iii) C₆-C_TenAryl group (substituted γ
You may have 1 to 3 pieces. ) Or (iv) pyridyl group
Amine derivative compound or a pharmacologically acceptable compound thereof
salt. (39) When the substitution α is C₁-C_FourAmine induction showing an alkyl group
Conductive compounds or pharmacologically acceptable salts thereof. (40) When the substitution α is C_Five-C_TenA representing a cycloalkyl group;
A min derivative compound or a pharmacologically acceptable salt thereof. (41) The substitution α is a phenyl group (substitution γ is 1 to 3
You may have one. An amine derivative compound showing
Its pharmacologically acceptable salts. (42) Amine derivatization wherein the substituted α represents a pyridyl group
Or a pharmacologically acceptable salt thereof. (43) The substitution β is (i) C₁-C_FourAlkyl group, (ii) C₁-C_Two
Halogenoalkyl group, (iii) C₁-C_FourAn alkoxy group, (iv)
A halogen atom, (v) a hydroxy group, (vi) a cyano group, (vii)
A toro group, or (viii) an amino group (substituent δ is 1 or 2
You may have. ) Or an amine derivative compound
Pharmacologically acceptable salts of (44) The substitution β is (i) C₁-C_FourAlkyl group, (ii) trif
A fluoromethyl group, (iii) C ₁-C_TwoAlkoxy group, (iv) halogen
An atom that represents a hydrogen atom, (v) a hydroxy group, or (vi) an amino group.
A min derivative compound or a pharmacologically acceptable salt thereof. (45) When the substitution β is (i) C₁-C_FourAlkyl group, (ii) halogen
Derivatization of amine atom or (iii) hydroxy group
Or a pharmacologically acceptable salt thereof. (46) The substitution γ is (i) C₁-C₆Alkyl group, (ii) C₁-C_Four
Halogenoalkyl group, (iii) C₁-C₆An alkoxy group, (iv)
A halogen atom, (v) a hydroxy group, (vi) a cyano group, (vii)
Toro group, (viii) phenyl group, (ix) benzyl group, (x) C₁-C_Five
Aliphatic acyl group, (xi) amino group, or (xii) C₁-C_FourArchi
Amine derivative compound showing a dioxy group or its pharmacology
Above acceptable salts. (47) When the substitution γ is (i) C₁-C₆Alkyl group, (ii) C₁-C_Two
Halogenoalkyl group, (iii) C₁-C_FourAn alkoxy group, (iv)
A halogen atom, (v) a hydroxy group, (vi) a cyano group, (vii)
Toro group, (viii) C₁-C_TwoAliphatic acyl group, or (ix) C₁-C_FourA
Amine derivative compound showing a alkylenedioxy group or its compound
Pharmacologically acceptable salt. (48) The substitution γ is (i) C₁-C₆Alkyl group, (ii) trif
A fluoromethyl group, (iii) C ₁-C_FourAlkoxy group, (iv) halogen
Atom, (v) hydroxy group, (vi) cyano group, (vii) nitro
Group, (viii) C₁-C_TwoAliphatic acyl group, or (ix) C₁-C_FourArchi
Amine derivative compound showing a dioxy group or its pharmacology
Above acceptable salts. (49) The substitution γ is (i) C₁-C_FourAlkyl group, (ii) trif
A fluoromethyl group, (iii) a halogen atom, or (iv) nitro
Derivative compound showing a group or its pharmacologically acceptable
salt. (50) The substitution γ is C₁-C_FourAlkyl group or halogen
Amine derivative compound showing an atom or its pharmacologically acceptable
Salt. (51) The substitution δ is (i) C₁-C_FourAlkyl group, (ii) phenyl
Group, (iii) benzyl group, (iv) C₁-C_FiveAliphatic acyl group, or
Is (v) an amine derivative compound showing a benzoyl group or a
Pharmacologically acceptable salt. (52) When the substitution δ is C₁-C_FourAlkyl group, or C₁-C_Twofat
Amine derivative compound showing an aromatic acyl group or its pharmacologically acceptable
Salt to be carried. Also, an amine derivative having the general formula (I)
In the compound of the formula (1) to (6), R₁And select
R from (7) to (12)_TwoAnd select (13) through (1)
7) to R_ThreeAnd select W from (18) to (22).₁, W
_TwoAnd W_ThreeAnd select X, Y from (23) or (24).
And Q, and select Z from (25) or (26)
Then, Ar is selected from (27) or (28), and (2)
L is selected from 9) to (33), and (34) to (42)
Is selected from, and β is selected from (43) to (45),
Select γ from (46) to (50), and select (51) or
Compounds selected by combining δ from (52) are also suitable.
is there.

For example, an amine derivative having the general formula (I)
Among the conductor compounds, the following compounds are also suitable. (53) R₁Is a carbamoyl group (having one substituent α
May be. ), Thiocarbamoyl group (has one substituted α
It may be. ), Sulfonyl group (having one substituent α)
ing. ) Or a carbonyl group (having one substituent α)
You. ) And R_TwoIs a hydrogen atom, C₁-C_TenAlkyl group,
Enyl group (which may have one substituent β), or
Benzyl group (even if there is one substituent β in the phenyl moiety)
Good. ) And R_ThreeIs a hydrogen atom, C₁-C₆Alkyl group,
A phenyl group (which may have one substituent β), or
Benzyl group (having one substituent β in the phenyl moiety
Is also good. ) And W₁, W_TwoAnd W_ThreeBut each is a single bond
Or C₁-C_FourX represents an alkylene group, and X represents an oxygen atom or sulfur
A yellow atom, Y represents an oxygen atom, and Q represents a sulfur atom
Z represents a = CH- group, and Ar represents a benzene ring
Wherein L is 1 to 4 substituents on the Ar ring
Yes, each hydrogen atom, C₁-C ₆Alkyl group, phenyl
Group (which may have 1 to 3 substituents β), or
Benzyl group (having 1 to 3 substituents β in the phenyl moiety)
May be. ), The substitution α is (i) C₁-C₈Alkyl
Group, (ii) C_Five-C_TenCycloalkyl group, (iii) C₆-C_{1 0}Ally
(Which may have 1 to 3 substituents γ), (iv)
Phenyl C₁-C_FourAlkyl group (substituted γ is 1
It may have three to three. ), (V) pyridyl group, (vi)
Tansulfonyl group, (vii) trifluoromethanesulfonyl
Or (viii) a phenylsulfonyl group (phenyl moiety
May have 1 to 3 substitutions γ. ),
The substitution β is (i) C₁-C_FourAlkyl group, (ii) trifluoromethyl
A tyl group, (iii) C₁-C_TwoAlkoxy group, (iv) halogen atom,
(v) a hydroxy group, or (vi) an amino group, and a substituted γ
But (i) C₁-C₆Alkyl group, (ii) C₁-C_FourHalogenoalkyl
Group, (iii) C₁-C ₆Alkoxy group, (iv) halogen atom, (v)
Hydroxy group, (vi) cyano group, (vii) nitro group, (viii)
Phenyl group, (ix) benzyl group, (x) C₁-C_FiveAliphatic acyl
Group, (xi) amino group, or (xii) C₁-C_FourAlkylenedioxy
Derivative compound showing a group or its pharmacologically acceptable
salt. (54) R₁Is a carbamoyl group (having one substituent α
I have. ), A thiocarbamoyl group (having one substituted α)
You. ), A sulfonyl group (having one substituent α),
Or a carbonyl group (having one substituent α).
Then R_TwoIs a hydrogen atom, or C₁-C_TenRepresents an alkyl group,
R_ThreeIs a hydrogen atom, or C₁-C_FourRepresents an alkyl group;₁Passing
And W_TwoIs a single bond or C₁-C_FourIndicates an alkylene group
Then W_ThreeBut C₁-C_TwoX represents an alkylene group;
Or a sulfur atom, Y represents an oxygen atom, and Q represents a sulfur atom.
Represents a yellow atom, Z represents a = CH- group, and Ar represents
L represents 1 to 4 positions on an Ar ring;
A hydrogen atom or a C₁-C_FourAlkyl group
And the substitution α is (i) C₁-C₈Alkyl group, (ii) C_Five-C_Ten
Cycloalkyl group, (iii) C₆-C_{1 0}Aryl group (substituted γ
You may have 1 to 3 pieces. ), (Iv) phenyl C₁-C_FourA
Alkyl group (having 1 to 3 substituents γ in the phenyl moiety
May be. ), (V) pyridyl group, or (vi) phenyls
A rufonyl group (having 1 to 3 substituents γ in the phenyl moiety)
May be. ), The substitution γ is (i) C₁-C₆Archi
(Ii) trifluoromethyl group, (iii) C₁-C_FourAlkoki
(Iv) halogen atom, (v) hydroxy group, (vi) shea
Group, (vii) nitro group, (viii) C₁-C_TwoAliphatic acyl group, or
Is (ix) C₁-C_FourAmine derivatives showing alkylenedioxy groups
A compound or a pharmacologically acceptable salt thereof. (55) R₁Is a carbamoyl group (having one substituent α
I have. ), A thiocarbamoyl group (having one substituted α)
You. ) Or a carbonyl group (having one substituent α)
You. ) And R_TwoRepresents a hydrogen atom;_ThreeBut C₁-C_TwoA
A rualkyl group;₁And W_TwoIs a single bond or C₁
-C_TwoAn alkylene group;_ThreeRepresents a methylene group, and X
Represents an oxygen atom, Y represents an oxygen atom, and Q represents sulfur.
Represents a yellow atom, Z represents a = CH- group, and Ar represents
L represents a hydrogen atom, and the substitution α is represented by
(I c₁-C_FourAlkyl group, (ii) C_Five-C_TenCycloalkyl group, (i
ii) C₆-C_{1 0}Aryl group (having 1 to 3 substituents γ
Is also good. ), (Iv) benzyl group (substituted γ
You may have 1 to 3 pieces. ) Or (v) a pyridyl group
And the substitution γ is (i) C₁-C₆Alkyl group, (ii) C₁-C_TwoC
A logenoalkyl group, (iii) C₁-C _FourAlkoxy group, (iv) halo
Gen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro
B group, (viii) C₁-C_TwoAliphatic acyl group, or (ix) C₁-C_FourAl
Amine derivative compound showing a killenedioxy group or its drug
A physiologically acceptable salt. Further, an amino acid having the general formula (I)
Among the derivative compounds, the following compounds are also suitable. (56) R₁Is a carbamoyl group (substituted α is 1 or
You may have two. ), Thiocarbamoyl group (substituted
may have one or two α. ) Or sulfo
A nyl group (having one substituent α);_Twoas well as
R_ThreeIs a hydrogen atom, C₁-C_TenAlkyl group, C₆-C_Ten
Aryl group (which may have 1 to 3 substituents β)
No. ) Or C₇-C₁₆Aralkyl group (substituted on aryl moiety
It may have 1 to 3 β. ) And W₁, W_Two
And W_ThreeIs a single bond or C₁-C₈Indicates an alkylene group
And X, Y and Q each represent an oxygen atom or a sulfur atom
Z represents a ＝ CH— group or a nitrogen atom, and Ar represents
L represents a benzene ring or a naphthalene ring;
1 to 4 substituents, hydrogen atom, C₁-C₆Archi
Group, C₆-C_TenAryl group (having 1 to 3 substituents β
May be. ) Or C₇-C₁₆Aralkyl group (aryl moiety
May have 1 to 3 substituents β. ),
The substitution α is (i) C₁-C_TenAlkyl group, (ii) C₁-C₆Halogeno
Alkyl group, (iii) C_Three-C_TenCycloalkyl group, (iv) C₆-C
_TenAryl group (which may have 1 to 3 substituents γ)
No. ), (V) C₇-C₁₆Aralkyl group (substituted on aryl moiety
It may have 1 to 3 γ. ), (Vi) C_Four-C₁₁Shiku
Loalkylcarbonyl group, (vii) C₇-C₁₁Aryl carb
Nyl group (having 1 to 3 substituents γ in the aryl moiety)
You may. ), (Viii) C₈-C₁₇Aralkylcarbonyl group (A
The reel portion may have one to three replacement parts γ.
No. ), (Ix) a heteroaromatic group (having 1 to 3 substituents γ
May be. ), (X) heteroaromatic carbonyl group (substituted γ
May be provided. ), (Xi) C₁-C₆Alkyl
Sulfonyl group, (xii) C₁-C₆Halogenoalkylsulfonyl
Group, (xiii) C₆-C_TenArylsulfonyl group (aryl moiety
May have 1 to 3 substitutions γ. ) Or (xi
v) C₇-C₁₆Aralkylsulfonyl group (substituted with aryl moiety)
It may have 1 to 3 components γ. ) Indicates replacement
β is (i) C₁-C₆Alkyl group, (ii) C₁-C₆Halogeno archi
Group (iii) C₁-C ₆Alkoxy group, (iv) halogen atom,
(v) a hydroxy group, (vi) C₆-C_TenAryl group (substitution δ is 1
It may have three to three. ), (Vii) C₇-C₁₆Aralkyl
Group (even if the aryl moiety has 1 to 3 substituents δ)
Good. ), (Viii) cyano, (ix) nitro, or (x)
(Which may have one or two substituents δ).
And the substitution γ is (i) C₁-C₆Alkyl group, (ii) C₁-C₆Halo
Genoalkyl group, (iii) C₁-C ₆Alkoxy group, (iv) halogen
Atom, (v) hydroxy group, (vi) cyano group, (vii) nitro
Group, (viii) C_Three-C_TenCycloalkyl group, (ix) C₆-C_TenAlly
Group (substituted as C₁-C₆Alkyl group, C₁-C₆Halogeno
Alkyl group, C₁-C₆One alkoxy group and one halogen atom
You may have up to three. ), (X) C₇-C₁₆Aralkyl group
(Substituent on aryl is C₁-C₆Alkyl group, C₁-C₆
Halogenoalkyl group, C₁-C₆Alkoxy group, halogen source
It may have one to three children. ), (Xi) C₁-C₇fat
Group acyl group, (xii) C₁-C₇Aliphatic acyloxy group, (xiii)
Amino group, (xiv) di C₁-C₆Alkylamino, or (xv) C₁-C
_FourRepresents an alkylenedioxy group, the substitution δ is (i) C₁-C_Ten
Alkyl group, (ii) C₆-C_TenAryl group (substituted as C ₁
-C₆Alkyl group, C₁-C₆Halogenoalkyl group, C₁-C₆Al
It may have 1 to 3 oxy groups and 1 to 3 halogen atoms
No. ), (Iii) C₇-C₁₆Aralkyl groups (substituted on aryl
As minutes, C₁-C₆Alkyl group, C₁-C₆Halogenoalkyl
Group, C₁-C₆Has 1 to 3 alkoxy groups and halogen atoms
It may be. ), (Iv) C₁-C₇Aliphatic acyl group, (v) C_Four
-C₁₁Cycloalkylcarbonyl group, (vi) C₇-C₁₁Aryl
Carbonyl group (substituted as C₁-C₆Alkyl group, C₁-C₆
Halogenoalkyl group, C₁-C₆Alkoxy group, halogen source
It may have one to three children. ), (Vii) C₈-C₁₇A
Aralkylcarbonyl group (substituted on aryl, C₁-
C₆Alkyl group, C₁-C₆Halogenoalkyl group, C₁-C₆Arco
It may have 1 to 3 xy groups and 1 to 3 halogen atoms
No. ) Or (viii) a heteroaromatic carbonyl group (substituted and
Then C₁-C₆Alkyl group, C₁-C₆Halogenoalkyl group, C₁
-C₆Having 1 to 3 alkoxy groups and 1 to 3 halogen atoms
You may. ). ] Or an amine derivative compound having
Is a pharmacologically acceptable salt. Examples of the compound of the present invention
For example, the compounds described in Tables 1 to 6 may be mentioned.
Although the present invention is limited to these compounds,
There is no. The compounds in Tables 1 and 2 correspond to (I-1)
The compounds of the structural formulas shown in Tables 3 to 6 are represented by (I-
It has the structural formulas of 2) to (I-5). However, the abbreviation in the table is
It is as follows. Ac: acetyl group, Ada (1): 1-adama
Antyl group, Ada (1) c: 1-adamantylcarbonyl group, Bo
z: benzoyl group, Bu: butyl group, tBu: t-butyl group,
Bz: benzyl group, EdO: ethylenedioxy group, Et: ethyl
Group, Hx: hexyl group, cHx: cyclohexyl group, cHx
c: cyclohexylcarbonyl group, MdO: methylenedioxy
Si group, Me: methyl group, Nic: nicotinoyl, iNic: iso
Nicotinoyl, Np: naphthyl group, Ph: phenyl group, cP
n: cyclopentyl group, cPn: cyclopentylcarbonyl
Group, Pr: propyl group, cPrc: cyclopropylcarbonyl
Group, iPr: isopropyl group, sPr: s-propyl group, Py
r: pyridyl group.

[0097]

[Table 1]

[0098]

[Table 2]

[0099]

[Table 3]

[0100]

[Table 4]

[0101]

[Table 5]

[0102]

[Table 6]

[0103]

[Table 7]

[0104]

[Table 8]

[0105]

[Table 9]

[0106]

[Table 10]

[0107]

[Table 11]

[0108]

[Table 12]

[0109]

[Table 13]

[0110]

[Table 14]

[0111]

[Table 15]

[0112]

[Table 16]

[0113]

[Table 17]

[0114]

[Table 18]

[0115]

[Table 19]

[0116]

[Table 20]

[0117]

[Table 21]

[0118]

[Table 22]

[0119]

[Table 23]

[0120]

[Table 24]

[0121]

[Table 25]

[0122]

[Table 26]

[0123]

[Table 27]

[0124]

[Table 28]

[0125]

[Table 29]

[0126]

[Table 30]

[0127]

[Table 31]

[0128]

[Table 32]

[0129]

[Table 33]

[0130]

[Table 34]

[0131]

[Table 35]

[0132]

[Table 36]

[0133]

[Table 37]

[0134]

[Table 38]

[0135]

[Table 39]

[0136]

[Table 40]

[0137]

[Table 41]

[0138]

[Table 42]

[0139]

[Table 43]

[0140]

[Table 44]

[0141]

[Table 45]

[0142]

[Table 46] In the above table, preferably, the exemplified compound number, (1-2)
1- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3-ethylurea
(1-8) 1- (adamantan-1-yl) -3- (4- [2- [4-
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) urea, (1-9) 1- (4- [2- [4--
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3-phenylurea, (1-59) 1-
(2,4-difluorophenyl) -3- (4- [2- [4- (2,4-
Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) urea, (1-165) 1- (adamantan-1-)
Yl) -3- [2- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-
Benzimidazol-6-yloxy] phenyl) ethyl]
Urea, (1-172) 1- [2- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-)
Methyl-1H-benzimidazol-6-yloxy] phenyl) ethyl] -3- (4-trifluoromethylphenyl) urea, (1-174) 1- (2,4-difluorophenyl) -3-
[2- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) ethyl] urea, (1
-192) 1- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-
Benzimidazol-6-yloxy] -2,6-dimethylphenyl) -3- (4-nitrophenyl) urea, (1-196)
1- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -1-n-hexyl- 3
-Phenylurea, (1-202) 1- (4- [2- [4- (2,4-
Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -1-n-hexyl-3- (4-trifluoromethylphenyl) urea, (1-203) ) 1- (4- [2- [4-
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -1-n-hexyl-3- (4-fluorophenyl) urea, ( 1-210) 1- (adamantan-1-yl) -3- (7- [2- [4- (2,4-dioxothiazolidine-5-
Ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] naphthalen-1-yl) urea, (1-213) 1- (2,6-diisopropylphenyl)
-3- (7- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] naphthalen-1-yl) urea,
(1-217) 1- (7- [2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -1-methyl-
1H-benzimidazol-6-yloxy] naphthalene-
1-yl) -3- (4-trifluoromethylphenyl) urea,
(1-223) 1-benzyl-3- (7- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl]
-1-Methyl-1H-benzimidazol-6-yloxy]
Naphthalen-1-yl) urea, (1-232) 1- [4- (2-
[2- [4- (2,4-dioxothiazolidine-5-ylmethyl)
Phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] ethyl) phenyl] -3- (4-trifluoromethylphenyl) urea, (1-284) 1- (4- [2-
[4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6
-Yloxy] phenyl) -3- (c-hexyl) thiourea,
(1-299) 1-benzyl-3- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl]
-1-Methyl-1H-benzimidazol-6-yloxy]
Phenyl) thiourea, (1-300) 1-benzyl-3- (7
-[2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] naphthalen-1-yl) thiourea,
(1-312) 1- (4-chlorophenyl) -3- (4- [2- [4
-(2,4-Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6-
Yloxy] -2,6-dimethylphenyl) thiourea, (1-
316) N- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-
Benzimidazol-6-yloxy] phenyl) methanesulfonamide, (2-5) 1- (3- [2- [4- [2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl]-
1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3-n-hexylurea, (2-9) 1- (3- [2-
[4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6
-Yloxy] phenyl) -3-phenylurea, (2-24)
1- (3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (2-tri Fluoromethylphenyl) urea, (2-26) 1- (3- [2- [4-
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (4-trifluoromethylphenyl) urea, (2-29) 1- (3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (4-fluoro Phenyl) urea, (2-41) 1-
(3-cyanophenyl) -3- (3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-)
Methyl-1H-benzimidazol-6-yloxy] phenyl) urea, (2-82) 1- (3- [2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -1-)
Methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (4-trifluoromethyl) benzylurea, (2-
190) 1- (2-t-butyl-5- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-)
Methyl-1H-benzimidazol-6-yloxymethyl] phenyl) -3- (4-trifluoromethylphenyl) urea, (3-70) 1- (4- [2- [4- (2,4-di) Oxothiazolidine-5-ylmethyl) phenoxymethyl] -3-methyl
-3H-imidazo [4,5-b] pyridin-5-ylthio] -2,
6-dimethylphenyl) -3- (4-trifluoromethylphenyl) urea, (6-1) N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-Methyl-1H-benzimidazol-6-yloxy] phenyl] acetamide, (6-4) N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl]]
-1-Methyl-1H-benzimidazol-6-yloxy]
Phenyl] -Nn-hexylacetamide, (6-7) N-
[4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] cyclopentanecarboxamide, (6- 8) N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1
H-benzimidazol-6-yloxy] phenyl] cyclohexanecarboxylic acid amide, (6-10) N- [4- [2-
[4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6
-Yloxy] phenyl] benzamide, (6-11) N-
[4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] naphthalene-2-carboxylic acid amide, ( 6-19) 2,4-Difluoro-N- [4- [2
-[4- (2,4-Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-
6-yloxy] phenyl] benzamide, (6-21) 3
-Chloro-N- [4- [2- [4- (2,4-dioxothiazolidine)
-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] benzamide, (6-36) N- [4- [2- [4- (2,4-dioxo) Thiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl
-1H-benzimidazol-6-yloxy] phenyl] nicotinamide, (6-37) N- [4- [2- [4- (2,4-
Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] isonicotinamide, (6-51) 3,5
-Di-t-butyl-N- [2- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-]
Methyl-1H-benzimidazol-6-yloxy] phenyl) ethyl] -4-hydroxybenzamide, (6-56)
2- (3-chlorophenyl) -N- [2- [4- [2- [4- (2,4-
Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] ethyl] acetamide, (6-59) N- [2
-[4- [2- [4- (2,4-Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] ethyl] nicotinamide or its pharmacology And the above-mentioned acceptable salts.

More preferably, the exemplified compound number, (1-2)
1- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3-ethylurea
(1-8) 1- (adamantan-1-yl) -3- (4- [2- [4-
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) urea, (1-9) 1- (4- [2- [4--
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3-phenylurea, (1-174)
1- (2,4-difluorophenyl) -3- [2- (4- [2- [4-
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) ethyl] urea, (1-192) 1- (4
-[2- [4- (2,4-Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] -2,6-dimethylphenyl) -3- (4
-Nitrophenyl) urea, (1-203) 1- (4- [2- [4-
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -1-n-hexyl-3- (4-fluorophenyl) urea, ( 1-213) 1- (2,6-diisopropylphenyl) -3- (7- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1
[H-benzimidazol-6-yloxy] naphthalene-1-
Yl) urea, (1-223) 1-benzyl-3- (7- [2- [4
-(2,4-Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6-
[Iloxy] naphthalen-1-yl) urea, (1-284)
1- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (c-hexyl )
Thiourea, (1-300) 1-benzyl-3- (7- [2- [4-
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] naphthalen-1-yl) thiourea, (1-312)
1- (4-chlorophenyl) -3- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl]-
1-methyl-1H-benzimidazol-6-yloxy]-
2,6-dimethylphenyl) thiourea, (1-316) N-
(4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) methanesulfonamide, (2-9) 1- (3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-
1H-benzimidazol-6-yloxy] phenyl) -3
-Phenylurea, (2-24) 1- (3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl]
-1-Methyl-1H-benzimidazol-6-yloxy]
Phenyl) -3- (2-trifluoromethylphenyl) urea,
(2-26) 1- (3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1
H-benzimidazol-6-yloxy] phenyl) -3-
(4-trifluoromethylphenyl) urea, (2-29) 1
-(3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (4-fluorophenyl ) Urea, (2-82) 1- (3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-)
Methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (4-trifluoromethyl) benzylurea, (6-
1) N- [4- [2- [4- (2,4-dioxothiazolidine-5)
-Ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] acetamide, (6-4) N- [4- [2- [4- (2,4-dioxothiazolidine-5)] -Ylmethyl) phenoxymethyl] -1-methyl-
1H-benzimidazol-6-yloxy] phenyl] -N
-n-hexylacetamide, (6-7) N- [4- [2- [4-
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] cyclopentanecarboxylic acid amide,
(6-10) N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1
H-benzimidazol-6-yloxy] phenyl] benzamide, (6-11) N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-)
Methyl-1H-benzimidazol-6-yloxy] phenyl] naphthalene-2-carboxylic acid amide, (6-19) 2,
4-difluoro-N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-
1H-benzimidazol-6-yloxy] phenyl] benzamide, (6-21) 3-chloro-N- [4- [2- [4-]
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] benzamide, (6-36) N- [4-
[2- [4- (2,4-dioxothiazolidine-5-ylmethyl)
[Phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] nicotinamide, (6-3
7) N- [4- [2- [4- (2,4-dioxothiazolidine-5)
-Ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] isonicotinamide, (6-51) 3,5-di-t-butyl-N- [2-
(4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) ethyl] -4-hydroxybenzamide, 6-56) 2- (3-chlorophenyl) -N- [2- [4- [2- [4- (2,4-dioxothiazolidine)]
-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] ethyl] acetamide, (6-59) N- [2- [4- [2- [4- (2, 4-
Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] ethyl] nicotinamide or a pharmaceutically acceptable salt thereof.

Optimally, the exemplified compound number, (1-2) 1-
(4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3-ethylurea, (1-
8) 1- (adamantan-1-yl) -3- (4- [2- [4- (2,
4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) urea, (1-174) 1- (2,4-difluorophenyl) -3- [ 2- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl)
Ethyl] urea, (1-223) 1-benzyl-3- (7- [2-
[4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6
-Yloxy] naphthalen-1-yl) urea, (1-284)
1- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (c-hexyl )
Thiourea, (1-316) N- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl]-
1-methyl-1H-benzimidazol-6-yloxy] phenyl) methanesulfonamide, (2-9) 1- (3- [2-
[4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6
-Yloxy] phenyl) -3-phenylurea, (2-24)
1- (3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (2-tri Fluoromethylphenyl) urea, (2-26) 1- (3- [2- [4-
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (4-trifluoromethylphenyl) urea, (2-29) 1- (3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (4-fluoro Phenyl) urea, (6-1) N- [4-
[2- [4- (2,4-dioxothiazolidine-5-ylmethyl)
[Phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] acetamide, (6-7) N
-[4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] cyclopentanecarboxamide, (6 -10) N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl]-
1-methyl-1H-benzimidazol-6-yloxy] phenyl] benzamide, (6-19) 2,4-difluoro-
N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] benzamide; (6-
36) N- [4- [2- [4- (2,4-dioxothiazolidine-
5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] nicotinamide, (6-37) N- [4- [2- [4- (2,4-dioxo) Thiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] isonicotinamide, (6-59) N- [2- [4- [2
-[4- (2,4-Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-
6-yloxy] phenyl] ethyl] nicotinamide or a pharmaceutically acceptable salt thereof.

[0145]

BEST MODE FOR CARRYING OUT THE INVENTION The compound having the general formula (I) of the present invention can be produced according to the following method. Method A

[0146]

Embedded image In the above formula, R ₂ , R ₃ , W ₁ , W ₂ , W ₃ , X, Y, Q, Z, Ar, and
L has the same meaning as described above, R ₄ represents a group selected from the substituent α included in the definition of the group of R ₁ , and T represents an oxygen atom or a sulfur atom.

Method A is a method for producing a compound (Ia) in which R ₁ is a carbamoyl group or a thiocarbamoyl group which may be substituted in the compound (I).

Step A1 is a step for producing a compound having the general formula (Ia), and a compound having the general formula (II) and a compound having the general formula (III) in an inert solvent in the presence or absence of a base. By reacting an isocyanic acid or an isothiocyanic acid having

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene , Toluene, xylene; aromatic hydrocarbons; chloroform, dichloromethane, 1,2-dichloroethane, halogenated hydrocarbons, such as carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Amides such as N, N-dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; or a mixed solvent of the above solvents; preferably, aliphatic hydrocarbons or aromatic hydrocarbons. Hydrogens, halogenated hydrocarbons, ethere S, a mixed solvent of amides or the solvent (more preferably an aromatic hydrocarbon, an ether or an amide, particularly preferably toluene, tetrahydrofuran or N, N- dimethylformamide) is.

The base used in the above reaction is not particularly limited as long as it does not affect the reaction, but is preferably an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; Alkali metal hydroxides such as lithium oxide, sodium hydroxide and potassium hydroxide; lithium methoxide, sodium methoxide,
Alkali metal alkoxides such as sodium ethoxide and potassium tert-butoxide; ammonia such as aqueous ammonia and concentrated ammonia-methanol are used.

The reaction temperature varies depending on the starting compound, solvent and the like, but is usually from -20 ° C to 150 ° C (preferably 0 ° C
To 60 ° C.).

The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 30 minutes to 5 days (preferably 5 hours to 72 hours).

After completion of the reaction, the target compound (Ia) of this reaction is collected from the reaction mixture according to a conventional method. For example, when the target compound is an insoluble precipitate, it is obtained by filtering and then washing with a solvent. In other cases, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated, washed with water or the like, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, or the like. It is obtained by removing the solvent after drying. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. Method B

[0154]

Embedded image In the above formula, R ₂ , R ₃ , W ₁ , W ₂ , W ₃ , X, Y, Q, Z, Ar, and
L represents the same meaning as described above, R ₅ and R ₆ each represent a group selected from the substituent α included in the definition of the group R ₁ , W represents an alkoxy group, a nitrogen-substituted imidazole group Or a p-nitrophenyloxy group.

Method B is a method for producing a compound (Ib) in which R ₁ is a carbamoyl group which may be substituted in the compound (I).

Step B1 is a step for producing a compound having the general formula (Ib). The compound having the general formula (II) is combined with the compound having the general formula (II) in an inert solvent in the presence or absence of a base. By reacting with a compound having the following formula:

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene, Aromatic hydrocarbons such as toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; such as N, N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide And amides (particularly preferably N, N-dimethylformamide).

Bases used in the above reaction include, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; lithium methoxide, sodium methoxide, sodium Alkali metal alkoxides such as ethoxide and potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N , N
-Diethylaniline, 1,5-diazabicyclo [4.3.0] nona
-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABC
O), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU)
Organic amines such as
(Particularly preferably triethylamine).

The reaction temperature varies depending on the starting compound, the solvent and the like, but is usually -20 ° C to 150 ° C (preferably 0 ° C
To 60 ° C.).

The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 30 minutes to 5 days (preferably 5 hours to 72 hours).

After completion of the reaction, the target compound (Ib) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by appropriately neutralizing the reaction mixture and, if the target compound is an insoluble precipitate, filtering out and then washing with a solvent. In cases other than the above, an immiscible organic solvent such as water and ethyl acetate is added, the organic layer containing the target compound is separated, washed with water or the like, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, or the like. It is obtained by removing the solvent after drying. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified.

The compound having the general formula (IV) can be obtained by reacting an amine with a chlorocarbonate or 1,1'-carbonyldiimidazole.

The compounds having the general formula (II) are very useful as intermediates for synthesizing the compounds including the compounds of the present invention, which have an insulin resistance-improving action, hypoglycemic action, etc., and compounds having other actions. It is. It is preferably a compound having the following general formula (II ′), and more preferably a compound having the following general formula (II ″).

[0164]

Embedded image In the above formula, R ₃ , W ₁ , W ₂ , W ₃ , X, Y, Q, Z, Ar, and L
Has the same meaning as described above. C method

[0165]

Embedded image In the above formula, R ₂ , R ₃ , W ₁ , W ₂ , W ₃ , X, Y, Q,
Z, Ar, and L have the same meanings as described above;
₇ represents a group selected from the substituent α included in the definition of the group R ₁ .

Method C is a method for producing compound (Ic) in which R ₁ is a substituted sulfonyl group in compound (I).

Step C1 is a step for producing a compound having the general formula (Ic). The compound having the general formula (II) and the compound having the general formula (V) are prepared in an inert solvent in the presence or absence of a base. The reaction is carried out by reacting a sulfonyl chloride having the following formula:

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene, Aromatic hydrocarbons such as toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; such as N, N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide And amides (particularly preferably N, N-dimethylformamide).

The base used in the above reaction includes, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; lithium methoxide, sodium methoxide, sodium Alkali metal alkoxides such as ethoxide and potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N , N
-Diethylaniline, 1,5-diazabicyclo [4.3.0] nona
-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABC
O), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU)
Organic amines such as
(Particularly preferably triethylamine).

The reaction temperature varies depending on the starting compound, solvent and the like, but is usually from -20 ° C to 150 ° C (preferably 0 ° C
To 60 ° C.).

The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 30 minutes to 5 days (preferably 5 hours to 72 hours).

After completion of the reaction, the target compound (Ic) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by appropriately neutralizing the reaction mixture and, if the target compound is an insoluble precipitate, filtering out and then washing with a solvent. In cases other than the above, an immiscible organic solvent such as water and ethyl acetate is added, the organic layer containing the target compound is separated, washed with water or the like, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, or the like. It is obtained by removing the solvent after drying. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. C 'method

[0173]

Embedded image In the above formula, R ₂ , R ₃ , W ₁ , W ₂ , W ₃ , X, Y, Q,
Z, Ar, L, and R ₇ have the same meaning as described above.

The method C ′ is a method for producing a compound (Ic ′) in which R ₁ is a substituted carbonyl group in the compound (I).

The step C′1 is a step for producing a compound having the general formula (Ic ′). The compound having the general formula (II) and the compound having the general formula (V ′) are prepared in an inert solvent. , In the presence of (a) a base, by (b) an active ester method or (c) a mixed acid anhydride method. (a) when the compound having the general formula (V ′) is an acid chloride or an acid anhydride, condensing the compound having the general formula (II) and the compound having the general formula (V ′) in the presence of a base This is a reaction that causes

The inert solvent used in this reaction is not particularly limited as long as it is inert to this reaction.
Aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether And N, N-dimethylformamide;
Amides such as dimethylacetamide and hexamethylphosphoric triamide; or a mixed solvent of the above solvents;
Preferred are amides (particularly preferred are N, N-dimethylformamide).

The base used in this reaction is, for example, an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; an alkali metal bicarbonate such as lithium hydrogen carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; lithium hydroxide,
Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine;
N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5-
Ene, 1,4-diazabicyclo [2.2.2] octane (DABCO),
Organic amines such as 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), preferably organic amines (particularly preferably triethylamine).

The reaction temperature varies depending on the starting compound, solvent and the like, but is usually from -20 ° C to 150 ° C (preferably 0 ° C
To 60 ° C.).

The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 30 minutes to 5 days (preferably 5 hours to 72 hours). (b) Active ester methodThe active ester method comprises, in an inert solvent, a compound having the general formula (II) and a compound having the general formula (V ′) in an inert solvent in the presence of a condensing agent and a base or The reaction is carried out in the absence (preferably in the presence).

The active esterifying agent used in this reaction is
For example, N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-
N-hydroxy compounds such as 2,3-dicarboximide; disulfide compounds such as dipyridyl disulfide; carbodiimides such as 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide and dicyclohexylcarbodiimide; carbonyldiimidazole; The reaction is suitably performed in the presence of a condensing agent such as triphenylphosphine.

As the inert solvent used in this reaction, for example, the same inert solvents as those used in the above (a) can be mentioned.

As the base used in this reaction, for example, the same bases as those used in the above (a) can be mentioned.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -70 ° C to 150 ° C (preferably from -10 ° C to 100 ° C) in the active esterification reaction.

The reaction time varies depending on the starting compound, the reagent, the reaction temperature and the like, but is usually 30 minutes to 80 hours (preferably 1 hour to 48 hours). (c) Mixed acid anhydride method When the compound having the general formula (V ′) is a carboxylic acid,
In an inert solvent, in the presence or absence of a base (preferably,
In the presence), reacting a compound having the general formula (V ') with a mixed acid anhydride agent to produce mixed acid anhydrides, and then mixing the mixed acid anhydrides and general formula (II) in an inert solvent. The reaction is carried out by reacting a compound having the same.

The mixed acid anhydride agent used in this reaction is as follows:
For example, ethyl chloroformate, ethyl chlorocarbonate, carbonic C ₁ -C ₄ alkyl halides such as chloroformate isobutyl;
C ₁ -C ₅ alkanoyl halides, such as pivaloyl chloride; di (C ₁ -C ₄ alkyl) or di (C ₆ -C ₁₄ ), such as diethyl cyanophosphonate, diphenyl cyanophosphonate
Aryl cyano phosphoric acid, preferably, (a particularly preferred, diethyl cyanophosphonate) di (C ₁ -C ₄ alkyl) or di (C ₆ -C _{1 4} aryl) cyanophosphonate is.

The inert solvent and base used in this reaction are not particularly limited as long as they do not inhibit the reaction and dissolve the starting materials to some extent. For example, those used in the above (a) can be used. The same inert solvents and bases can be mentioned.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually -50 ° C to 100 ° C (preferably 0 ° C
To 60 ° C).

The reaction time varies depending on the starting compound, the reagent, the reaction temperature and the like, but is usually 30 minutes to 72 hours (preferably 1 hour to 24 hours).

In the method C ′, after completion of the reaction, the target compound (Ic ′) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by appropriately neutralizing the reaction mixture and, if the target compound is an insoluble precipitate, filtering out and then washing with a solvent. In cases other than the above, an immiscible organic solvent such as water and ethyl acetate is added, the organic layer containing the target compound is separated, washed with water or the like, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, or the like. It is obtained by removing the solvent after drying. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. D method

[0190]

Embedded image In the above formula, R ₂ , R ₃ , W ₁ , W ₂ , W ₃ , X, Y, Q, Z, Ar, and L
Has the same significance as described above, and Boc represents a t-butoxycarbonyl group.

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

Step D1 is a step for producing a compound having the general formula (VIII). The reactive derivative of the compound having the general formula (VII) (acid halide, active ester or mixed acid) is prepared in an inert solvent. (Anhydrides) and a compound having the general formula (VI).

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene, Aromatic hydrocarbons such as toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; formamide, N, N-dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide And sulfoxides such as dimethylsulfoxide; sulfolane; or a mixed solvent of the above solvents; and preferably ethers (particularly preferably tetrahydrofuran). (a) Acid halide methodAcid halide method is a method of halogenating compound (VII) in an inert solvent (for example, thionyl chloride, thionyl bromide, oxalic acid chloride, oxalic acid dichloride, phosphorus oxychloride, phosphorus trichloride, (Phosphorus pentachloride or the like) to produce an acid halide, and react the acid halide with the compound (VI) in an inert solvent in the presence or absence (preferably in the presence) of a base. This is done by:

The base used in the above reaction includes, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; lithium methoxide, sodium methoxide, sodium Alkali metal alkoxides such as ethoxide and potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N , N-
Diethylaniline, 1,5-diazabicyclo [4.3.0] nona-
5-ene, 1,4-diazabicyclo [2.2.2] octane (DABC
O), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU)
Organic amines such as
(Particularly preferably, triethylamine).

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction.
Aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogens such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride Hydrocarbons; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone; formamide, N, N-dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide Amides such as dimethyl sulfoxide; sulfolane; and preferably halogenated hydrocarbons, ethers or amides (particularly preferably, dichloromethane, chloroform, tetra Hydrofuran or N, N-dimethylformamide).

The reaction temperature varies depending on the starting compounds, reagents and the like, but the reaction between the halogenating agent and the compound (VII) and the reaction between the acid halides and the compound (VI) are usually -20 ° C to 150 ° C. Preferably, the halogenating agent and the compound (VI
The reaction with I) is from -10 ° C to 100 ° C, and the reaction between the acid halides and the compound (VI) is from -20 ° C to 100 ° C.

The reaction time varies depending on the starting compound, the reagent, the reaction temperature and the like. However, the reaction between the halogenating agent and the compound (VII) and the reaction between the acid halides and the compound (VI) are usually 3 hours.
It is 0 minute to 80 hours (preferably 1 hour to 48 hours). (b) Active ester method The active ester method comprises reacting compound (VII) with an active esterifying agent in an inert solvent to produce active esters, and then in an inert solvent in the presence or absence of a base. (Preferably in the presence), by reacting with compound (VI).

The active esterifying agent used in the above reaction is, for example, N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide or the like. Compounds; disulfide compounds such as dipyridyl disulfide; carbodiimides such as dicyclohexylcarbodiimide; carbonyldiimidazole; triphenylphosphine;

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether. Aromatic hydrocarbons such as benzene, toluene and xylene; dichloromethane, 1,
Halogenated hydrocarbons such as 2-dichloroethane and carbon tetrachloride; diethyl ether, diisopropyl ether,
Tetrahydrofuran, dioxane, dimethoxyethane,
Ethers such as diethylene glycol dimethyl ether; ketones such as acetone; formamide, N,
Amides such as N-dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; sulfolane;
And ethers or amides (particularly preferred are dioxane, tetrahydrofuran or N, N-dimethylformamide).

Examples of the base used in the above reaction include the same bases as those used in the above-mentioned acid halide method.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -70 ° C to 150 ° C (preferably from -10 ° C to 100 ° C) in the active esterification reaction. In the reaction with (VI), the temperature is −20 ° C. to 100 ° C. (preferably 0 ° C. to 50 ° C.). The reaction time varies depending on the starting compound, the reagent, the reaction temperature, and the like.
Hours to 48 hours). (c) Mixed acid anhydride method The mixed acid anhydride method is to react the compound (VII) with a mixed acid anhydride agent in an inert solvent, in the presence or absence (preferably, in the presence) of a base, After producing the mixed acid anhydrides, the reaction is carried out by reacting the mixed acid anhydrides with the compound (VI) in an inert solvent.

The base used in the above reaction includes, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; lithium methoxide, sodium methoxide, sodium Alkali metal alkoxides such as ethoxide and potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N , N
-Diethylaniline, 1,5-diazabicyclo [4.3.0] nona
-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABC
O), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU)
Organic amines such as
(Particularly preferably, triethylamine).

Examples of the mixed anhydride agent used in the above reaction include C ₁ -C ₄ alkyl halides such as ethyl chlorocarbonate and isobutyl chlorocarbonate; C ₁ -C ₅ alkanoyl such as pivaloyl chloride. Halide: di (C ₁ -C ₄ alkyl) or di (C ₆ -C ₁₄ ) aryl cyanophosphoric acid such as diethyl cyanophosphonate, diphenyl cyanophosphonate, and preferably di (C ₁ -C ₄ Alkyl) or di (C ₆ -C ₁₄ aryl) cyanophosphoric acid (particularly preferably diethyl cyanophosphonate).

The inert solvent used for producing the mixed acid anhydrides is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, hexane, heptane, ligroin Or aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride; diethyl ether Ethers such as isopropyl, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, N, N-dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; dimethyl Sulfoxy like sulfoxide S; sulfolane; are, preferably, ethers or amides (particularly preferably is tetrahydrofuran or N, N- dimethylformamide) is.

The reaction temperature in the reaction for producing mixed acid anhydrides varies depending on the starting compounds, reagents and the like.
-50 ° C to 100 ° C (preferably 0 ° C to 60 ° C).

The reaction time in the reaction for producing mixed acid anhydrides varies depending on the starting compounds, reagents, reaction temperature and the like, but is usually 30 minutes to 72 hours (preferably 1 hour to 24 hours). is there.

The reaction between the mixed acid anhydrides and the compound (VI) is as follows:
The reaction is carried out in an inert solvent in the presence or absence (preferably in the presence) of a base, and the base and the inert solvent used in the reaction for producing the mixed acid anhydrides described above are used. It is the same as the one.

The reaction temperature in the reaction of the mixed acid anhydrides with the compound (VI) varies depending on the starting compounds, reagents and the like.
Usually, -30 ° C to 100 ° C (preferably 0 ° C to 80 ° C)
° C).

The reaction time in the reaction of the mixed acid anhydrides with the compound (VI) varies depending on the starting compound, the reagent, the reaction temperature and the like, but is usually 5 minutes to 24 hours (preferably 30 minutes).
Minutes to 16 hours).

When di (C ₁ -C ₄ alkyl) cyanophosphoric acid or di (C ₆ -C ₁₄ aryl) cyanophosphoric acid is used in this reaction, compound (VI) and compound (VI) may be used in the presence of a base. (VII) can also be reacted directly.

After completion of the reaction, the target compound (VIII) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified.

Step D2 is a step for producing a compound having the general formula (II), which is carried out by reacting the compound having the general formula (VIII) with an acid in the presence or absence of an inert solvent. Will be

The acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a usual reaction, and examples thereof include hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and the like.
Inorganic acids such as phosphoric acid; Bronsted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, and organic acids such as trifluoromethanesulfonic acid; zinc chloride, Lewis acids such as tin chloride, boron trichloride, fluorine trichloride, bromine trichloride; acidic ion exchange resins; preferably inorganic or organic acids (particularly preferably hydrochloric acid, acetic acid or trifluoroacetic acid). ).

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol, t-butanol, isoamyl alcohol Le, diethylene glycol, glycerin, octanol, cyclohexanol, alcohols such as methyl cellosolve; formamide, N,
Amides such as N-dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; water; or water or a mixed solvent of the above solvents; preferably halogenated hydrocarbons, ethers, alcohols Or water (particularly preferably, dichloromethane, 1,4-dioxane, ethanol or water).

The reaction temperature depends on the starting compound, the acid used,
Usually varies from -20 ° C to boiling point
(Preferably 0 ° C. to 50 ° C.).

The reaction time depends on the starting compound, the acid used,
Although it depends on the solvent and the reaction temperature, it is usually 15 minutes to 4 minutes.
8 hours (preferably 30 minutes to 20 hours).

After completion of the reaction, the target compound (II) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated.
It is obtained by washing with water or the like, drying with anhydrous sodium sulfate or the like, and distilling off the solvent. If necessary, the target compound obtained is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, and applying chromatography. Can be separated and purified. Method E

[0218]

Embedded image In the above formula, R ₂ , R ₃ , W ₁ , W ₂ , X, Z, Ar, L and Boc have the same meanings as described above.

Method E is a method for producing compound (VI).

Step E1 is a step for producing a compound having the general formula (VI), and is carried out by reducing the compound (IX). This reaction uses a catalytic reduction reaction or a general nitro group reduction method of zinc-acetic acid method, tin-alcohol method or tin-hydrochloric acid method in an inert solvent, and sodium dithionite as a reducing agent. It is performed using.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol, t-butanol, isoamyl alcohol Le, diethylene glycol, glycerin, octanol, cyclohexanol, alcohols such as methyl cellosolve; formamide, N,
Amides such as N-dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; water; or water or a mixed solvent of the above solvents; preferably halogenated hydrocarbons, ethers, alcohols Or water (particularly preferably, dichloromethane, 1,4-dioxane, ethanol or water).

The reaction temperature depends on the starting compound, the acid used,
Usually varies from -20 ° C to boiling point
(Preferably 0 ° C. to 50 ° C.).

The reaction time depends on the starting compound, the acid used,
Although it depends on the solvent and the reaction temperature, it is usually 15 minutes to 4 minutes.
8 hours (preferably 30 minutes to 20 hours).

After completion of the reaction, the target compound (VI) of this reaction is collected from the reaction mixture according to a conventional method. For example, in the case of a catalytic reduction reaction, after filtering off the catalyst from the reaction mixture,
It is obtained by distilling off the solvent. In cases other than those described above, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added thereto. Is separated, washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and then the solvent is distilled off. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. F method

[0225]

Embedded image In the above formula, R ₂ , R ₃ , W ₁ , W ₂ , X, Z, Ar, L, and Boc have the same meanings as described above, and Hal represents the halogen atom.

Method F is a method for producing compound (IX).

Step F1 is a step of preparing the compound of the general formula (XI) in the presence of a base in an inert solvent in the presence of a compound of the general formula (XI) in an inert solvent. It is performed by

The base used in the above reaction is, for example, an alkali metal carbonate such as lithium carbonate, sodium carbonate and potassium carbonate; an alkali metal bicarbonate such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; lithium methoxide, sodium methoxide, sodium Alkali metal alkoxides such as ethoxide and potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N , N
-Diethylaniline, 1,5-diazabicyclo [4.3.0] nona
-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABC
O), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU)
Organic amines such as the above, and preferably alkali metal hydrides (particularly preferably sodium hydride).

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; N, N-dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide Such amides; or a mixed solvent of the above solvents; and preferably amides (particularly preferably N, N-dimethylformamide).

The reaction temperature varies depending on the starting compound, the base used, the solvent and the like, but is usually from -50 ° C to 200 ° C.
° C (preferably 0 ° C to 120 ° C).

The reaction time varies depending on the starting compound, base used, solvent, reaction temperature and the like, but is usually 30 minutes to 24 hours (preferably 1 hour to 10 hours).

After completion of the reaction, the target compound (IX) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated.
It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. G method

[0233]

Embedded image In the above formula, R ₃ , W ₂ , W ₃ , X, Y, Q, Z, Ar and L have the same meaning as described above.

Method G is different from method D in compound (II) in which W ₁ is a single bond and R ₁ and R ₂ are both hydrogen atoms.
This is a method for producing (IIa).

The step G1 is a step for producing the compound (IIa), which is carried out by reducing the compound (XII). This step is carried out in the same manner as the step E1.

After completion of the reaction, the target compound (IIa) of this reaction is collected from the reaction mixture according to a conventional method. For example, in the case of a catalytic reduction reaction, the catalyst can be obtained by filtering off the catalyst from the reaction mixture and then distilling off the solvent. In cases other than those described above, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added thereto. Is separated, washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and then the solvent is distilled off. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. H method

[0237]

Embedded image In the above formula, R ₃ , W ₂ , W ₃ , X, Y, Q, Z, Ar, L and Hal are
It has the same significance as described above.

Method H is a method for producing compound (XII).

Step H1 is a step for producing a compound (XII) by reacting a compound having the general formula (XII) with a compound having the general formula (XIV) in an inert solvent in the presence of a base. This step is performed in the same manner as the F1 step.

After completion of the reaction, the target compound (XII) of the reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. I method

[0241]

Embedded image In the above formula, R ₃ , W ₂ , W ₃ , X, Z, Ar, L and Hal have the same meaning as described above.

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

Step I1 is a step for producing a compound having the general formula (XVII), and in the presence or absence of an inert solvent, a compound having the general formula (XV) and a compound having the general formula (XVI) The reaction is carried out.

The inert solvent used in reacting compound (XV) with compound (XVI) is not particularly limited as long as it is inert to the reaction. For example, hexane, heptane, ligroin, petroleum Aliphatic hydrocarbons such as ethers; aromatic hydrocarbons such as benzene, toluene and xylene; diethyl ether, diisopropyl ether,
Tetrahydrofuran, dioxane, dimethoxyethane,
Ethers such as diethylene glycol dimethyl ether; methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol, t
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, N, N-dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide Organic acids such as acetic acid and propionic acid; sulfoxides such as dimethyl sulfoxide; sulfolane; or a mixed solvent of the above solvents.

The reaction temperature at the time of reacting the compound (XV) with the compound (XVI) depends on the starting compound, the base used, the solvent and the like, but is usually 0 ° C. to 200 ° C. (preferably 5 ° C.).
0 ° C to 150 ° C).

The reaction time for reacting the compound (XV) with the compound (XVI) varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually from 1 hour to 50 hours.
(Preferably 5 to 24 hours).

After completion of the reaction, the target compound (XVII) of the reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified.

Step I2 is a step of producing a compound having the general formula (XVIII). The compound having the general formula (XVII) is reacted with a halogenating agent (for example, thionyl chloride) in the presence or absence of an inert solvent. , Thionyl bromide, oxalic acid chloride, oxalic acid dichloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, etc.).

The inert solvent used for reacting the compound (XVII) with the halogenating agent is not particularly limited as long as it is inert to the reaction. For example, hexane, heptane, ligroin, petroleum Aliphatic hydrocarbons such as ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride;
Or a mixed solvent of the above solvents.

The reaction temperature at which the compound (XVII) is reacted with the halogenating agent varies depending on the starting compound, the solvent used and the like, but is usually from -20 ° C to 150 ° C (preferably -20 ° C).
10 ° C to 100 ° C).

The reaction time for reacting the compound (XVII) with the halogenating agent varies depending on the starting compound, the solvent used, the reaction temperature and the like, but is usually 30 minutes to 80 hours (preferably 1 hour to 80 hours). 48 hours).

After completion of the reaction, the desired compound (XVIII)
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. And dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and then the solvent is distilled off. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified.

The step I3 is a step for producing a compound having the general formula (XIX). In the presence or absence of an inert solvent, the compound having the general formula (XVIII) is converted to a nitrating agent (for example, a mixed acid, Nitric acid, ammonium boron tetrafluoride, etc.).

The inert solvent used in reacting the compound (XVIII) with the nitrating agent is not particularly limited as long as it is inert to the reaction. For example, hexane, heptane, ligroin, petroleum ether Aliphatic hydrocarbons such as chloroform; dichloromethane, 1,2-dichloroethane, halogenated hydrocarbons such as carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether And the like; methanol, ethanol, N-propanol, isopropanol
, N-butanol, isobutanol, t-butanol,
Alcohols such as isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, N, N-dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; acetic acid, propion Organic acids such as acids; sulfoxides such as dimethyl sulfoxide; sulfolane; acetonitrile; or a mixed solvent of the above solvents.

The reaction temperature for reacting the compound (XVIII) with the nitrating agent varies depending on the starting compound, the solvent used and the like, but is usually from -20 ° C to 100 ° C (preferably -20 ° C).
10 ° C to 50 ° C).

The reaction time for reacting the compound (XVIII) with the halogenating agent varies depending on the starting compound, the solvent used, the reaction temperature and the like, but is usually from 15 minutes to 48 hours.
(Preferably 30 minutes to 24 hours).

After completion of the reaction, the target compound (XIX) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound can be eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. The compound of the present invention having the general formula (I) or a pharmacologically acceptable salt thereof is excellent in PPARγ activating action, insulin resistance improving action, blood glucose lowering action, anti-inflammatory action, immunomodulating action, aldose reduction. Enzyme inhibitory action, 5-lipoxygenase inhibitory action, lipid peroxide production inhibitory action, PPAR activating action, anti-osteoporosis action, leukotriene antagonism, adipocyte promotion action, cancer cell growth inhibitory action, calcium antagonistic action, diabetes Hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.),
Arteriosclerosis, gestational diabetes, polycystic ovary syndrome, cardiovascular disease (e.g., ischemic heart disease etc.), cell damage caused by non-atherosclerosis or ischemic heart disease (e.g., Gout, inflammatory diseases (eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, acne, sunburn,
Psoriasis, eczema, allergic disease, asthma, GI ulcer, cachexia, autoimmune disease, pancreatitis. ), Cancer, osteoporosis,
It is useful as a prophylactic and / or therapeutic agent for cataracts and the like.

Further, a compound having the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof, and an RXR activator (RXR
Agonists), α-glucosidase inhibitors, aldose reductase inhibitors, biguanides, statin compounds, squalene synthesis inhibitors, fibrate compounds, LDL catabolism promoters, angiotensin converting enzyme inhibitors and FBP
Also useful are pharmaceutical compositions comprising at least one ase inhibitor (particularly preferred are preventive and / or therapeutic agents for diabetes or diabetic complications).

When the compound having the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is used as the above-mentioned therapeutic or prophylactic agent, the compound itself or an appropriate pharmacologically acceptable salt is used. For example, they can be mixed with excipients, diluents and the like, and administered orally, for example, in tablets, capsules, granules, powders or syrups, or parenterally in injections or suppositories.

These preparations may contain excipients (eg, lactose,
Sugar derivatives such as white sugar, glucose, mannitol, sorbitol; corn starch, potato starch,
Starch derivatives such as α-starch and dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; organic excipients such as pullulan: and light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and metasilicate aluminate Inorganic excipients such as silicate derivatives such as magnesium; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate. ), Lubricants (eg, metal salts of stearic acid such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as veegum, gay wax; boric acid; adipic acid; Sodium sulfate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; Derivatives, etc.), binders (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and
The same compounds as the above-mentioned excipients can be mentioned. ),
Disintegrants (eg, cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; chemically modified starches such as carboxymethylstarch, sodium carboxymethylstarch, crosslinked polyvinylpyrrolidone). Celluloses), stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenol and cresol Phenols, such as; thimerosal; dehydroacetic acid; and sorbic acid, and flavoring agents (for example, commonly used). Is, sweetener, acidulant, may be mentioned perfumes.), It is prepared in a known manner by using additives such as diluents.

The dosage varies depending on the condition, age, administration method and the like. For example, in the case of oral administration,
The lower limit is 0.001 mg / kg body weight (preferably 0.01 mg / kg body weight), and the upper limit is 500 mg / kg body weight (preferably 50 mg / kg body weight).
In the case of intravenous administration, the lower limit is 0.005 mg / kg body weight (preferably 0.05 mg / kg body weight) and the upper limit is 50 mg / kg body weight (preferably 5 mg / kg body weight) in the case of intravenous administration. Is preferably administered once or several times a day depending on the condition.

[0262]

The present invention will be described in more detail with reference to the following Examples, Reference Examples and Test Examples, but the scope of the present invention is not limited thereto. Example 1 1- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] -2,6-dimethylphenyl) -3
-(4-Trifluoromethylphenyl) urea (Exemplified Compound No. 1-187) 288 mg of 5- [4- [6- (4-amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazole- A mixture of 2-ylmethoxy] benzyl] thiazolidine-2,4-dione dihydrochloride, 112 mg of isocyanic acid α, α, α-trifluoro p-tolyl, 121 mg of triethylamine and 10 ml of anhydrous tetrahydrofuran was stirred at room temperature for 40 hours. did. After concentrating the reaction mixture, water was added, and the precipitated crystals were collected by filtration and washed with water and ethyl acetate to obtain 257 mg of the title compound.

Melting point: 206-208 ° C. Example 2 1- (4-chlorophenyl) -3- (4- [2- [4- (2,4-di
Xothiazolidine-5-ylmethyl) phenoxymethyl]-
1-methyl-1H-benzimidazol-6-yloxy]-
2,6-dimethylphenyl) thiourea (exemplified compound number 1-
312) 288 mg of 5- [4- [6- (4-amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione dihydrochloride Salt, 102 mg 4-chlorophenyl isothiocyanate, 121 mg triethylamine and 10 ml
Of anhydrous tetrahydrofuran was stirred at room temperature for 23 hours. After the reaction mixture was concentrated, water was added, and the precipitated crystals were collected by filtration and purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 3/1) to obtain 215 mg of the title compound.

Melting point: 160-162 ° C. Example 3 1- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] -2,6-dimethylphenyl) -3
-(4-Nitrophenyl) urea (Exemplified Compound No. 1-192) 288 mg of 5- [4- [6- (4-amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazole-2- A mixture of ylmethoxy] benzyl] thiazolidine-2,4-dione dihydrochloride, 98 mg of 4-nitrophenyl isocyanate, 121 mg of triethylamine, 10 ml of anhydrous tetrahydrofuran and 10 ml of anhydrous N, N-dimethylformamide for 23 hours at room temperature Stirred. After concentrating the reaction mixture, water was added, and the precipitated crystals were collected by filtration and purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 182 mg of the title compound.

Melting point: 178-180 ° C. Example 41- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3-phenylurea
 (Exemplified Compound No. 1-9) 400 mg of 5- [4- [6- (4-aminophenoxy) -1-me
Tyl-1H-benzimidazol-2-ylmethoxy] ben
[Jill] thiazolidine-2,4-dione dihydrochloride, 99mg
Of phenyl isocyanate, 153 mg of triethyl alcohol
And 8 ml of anhydrous N, N-dimethylformamide
The reaction and purification were carried out in the same manner as in Example 1 to obtain 326 m
g of the title compound were obtained.

Melting point: 164.5-168.3 ° C. Example 5 1- (2,4-difluorophenyl) -3- (4- [2- [4- (2,
4-dioxothiazolidine-5-ylmethyl) phenoxime
[Tyl] -1-methyl-1H-benzimidazol-6-ylo
[Xy] phenyl) urea (Exemplified Compound No. 1-59) 400 mg of 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4 -Dione dihydrochloride, 94mg
2,4-difluorophenyl isocyanate, 153m
The reaction and purification were carried out in the same manner as in Example 1 using g of triethylamine and 8 ml of anhydrous N, N-dimethylformamide to obtain 394 mg of the title compound.

Melting point: 203 ° C. (decomposition point). Example 6 1- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3- (phenyl) thio
Urea (Exemplified Compound No. 1-286) 400 mg of 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione-2 Hydrochloride, 113m
A mixture of g of phenyl isothiocyanate, 153 mg of triethylamine and 8 ml of anhydrous N, N-dimethylformamide was stirred at room temperature for 4 hours. After evaporating the solvent from the reaction solution, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was recrystallized from ethanol-ethyl acetate (5: 1) to obtain 347 mg of the title compound. .

Melting point: 129.6-130.9 ° C. Example 7 1- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3- (naphthalene-1
-Yl ) thiourea (Exemplified Compound No. 1-298) 400 mg of 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4 -Dione dihydrochloride, 148m
A mixture of 1 g of 1-naphthyl isothiocyanate, 153 mg of triethylamine and 8 ml of anhydrous N, N-dimethylformamide was stirred at room temperature for 1 hour and then left overnight. After evaporating the solvent from the reaction solution, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 3/2 → 2/1). → 4/1 → 1 /
Purification in 0) gave 301 mg of the title compound.

Melting point: 185.8-188.1 ° C. Example 8 1- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3- (naphthalene-1
-Yl) urea (Exemplified Compound No. 1-103) 400 mg of 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4- Dione dihydrochloride, 129m
Using 1 g of 1-naphthyl isocyanate, 153 mg of triethylamine and 8 ml of anhydrous N, N-dimethylformamide, the reaction was carried out and purified in the same manner as in Example 1.
92 mg of the title compound were obtained.

Melting point: 210.7-214.4 ° C. Example 9 1- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3- (c-hexyl)
Thiourea (Exemplified Compound No. 1-284) 400 mg of 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione. Dihydrochloride, 329m
g of hexyl isothiocyanate, 153 mg of triethylamine and 8 ml of anhydrous N, N-dimethylformamide were reacted and purified in the same manner as in Example 1.
65 mg of the title compound were obtained.

Melting point: 173.1-174.0 ° C. Example 10 1- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3- (4-trifluoro)
(Romethylphenyl ) urea (Exemplified Compound No. 1-26) 400 mg of 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4 -Dione dihydrochloride, 144m
g of isocyanic acid α, α, α-trifluoro p-tolyl,
153 mg of triethylamine and 8 ml of anhydrous N,
The reaction and purification were conducted using N-dimethylformamide in the same manner as in Example 1 to obtain 230 mg of the title compound.

Melting point: 178.6-180.2 ° C. Example 11 1-benzyl-3- (4- [2- [4- (2,4-dioxothiazolyl)
Zin-5-ylmethyl) phenoxymethyl] -1-methyl-1
H-benzimidazol-6-yloxy] phenyl) thio
Urea (Exemplified Compound No. 1-299) 400 mg of 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione-2 Hydrochloride, 248m
A mixture of g of benzyl isothiocyanate, 153 mg of triethylamine and 8 ml of anhydrous N, N-dimethylformamide was stirred at room temperature for 3.5 hours. After evaporating the solvent from the reaction solution, water was added, and the mixture was extracted with ethyl acetate.
The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 2/1 → 3/1 → 4/1), and recrystallized from ethyl acetate to obtain 291 mg of the title compound. Was done.

Melting point: 174.8-177.2.degree. Example 12 1- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3-ethylurea (Exemplified Compound No. 1-2) 400 mg of 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] ] Benzyl] thiazolidine-2,4-dione dihydrochloride, 108m
g of ethyl isocyanate, 153 mg of triethylamine and 8 ml of anhydrous N, N-dimethylformamide were reacted and purified in the same manner as in Example 1 to obtain 327 m
g of the title compound were obtained.

Melting point: 226.7-230.2 ° C. Example 13 1- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3- (2,6-diiso
Propylphenyl) urea (Exemplified Compound No. 1-17) 400 mg of 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4- Dione dihydrochloride, 247m
g of 2,6-diisopropylphenyl isocyanate, 1
53 mg of triethylamine and 8 ml of anhydrous N, N-
The reaction and purification were conducted using dimethylformamide in the same manner as in Example 1 to obtain 474 mg of the title compound.

Melting point: 221.5-224.9 ° C. Example 14 1- (adamantan-1-yl) -3- (4- [2- [4- (2,4-di
Oxothiazolidine-5-ylmethyl) phenoxymethyl]
-1-Methyl-1H-benzimidazol-6-yloxy]
Phenyl) urea (Exemplified Compound No. 1-8) 400 mg of 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione・ Dihydrochloride, 284m
g of 1-adamantyl isocyanate, 153 mg of triethylamine and 8 ml of anhydrous N, N-dimethylformamide at room temperature for 4.5 hours and at 50 ° C. for 2.5 hours.
And stirred at 80 ° C. for 4.5 hours. After evaporating the solvent from the reaction solution, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1/1 → 2/1 → 3/1) and recrystallized from ethyl acetate to obtain 192 mg of the title compound. Was done.

Melting point: 164.0-166.6.degree. Example 15 1- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -1-n-hexyl-3
-(4-Trifluoromethylphenyl) urea (Exemplified Compound No. 1-202) 0.39 g of 5- [4- [6- (4-n-hexylaminophenoxy) -1-methyl-1H-benzimidazole-2 -Ylmethoxy] benzyl] thiazolidine-2,4-dione, 0.1
A mixture of 5 g of α, α, α-trifluoro p-tolyl isocyanate and 20 ml of anhydrous tetrahydrofuran was left at room temperature for 2 days. After evaporating the solvent from the reaction solution, water was added, and the mixture was extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was reprecipitated from ether-diisopropyl ether to give 0.37
g of the title compound were obtained.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 2/1): Rf value =
0.49. Example 16 1- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -1-n-hexyl-3
-(4-Fluorophenyl) urea (Exemplary Compound No. 1-20
3) 0.39 g of 5- [4- [6- (4-n-hexylaminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione, 0.1
1 g of 4-fluorophenyl isocyanate and 20
A mixture of ml of anhydrous tetrahydrofuran was left at room temperature for 2 days. After concentrating the reaction solution, water was added, the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 3/2) and then reprecipitated from ethyl acetate-diisopropyl ether to give a residue. 32 g of the title compound were obtained.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 2/1): Rf value =
0.45. Example 17 1- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -1-n-hexyl-3
- phenyl urea (Compound No. 1-196) 0.39 g of 5- [4- [6- (4- n- hexyl-aminophenoxy) -1-methyl -1H- benzoimidazol-2-ylmethoxy] benzyl] thiazolidine - 2,4-dione, 95m
A mixture of g of phenyl isocyanate and 20 ml of anhydrous tetrahydrofuran was left at room temperature for 2 days. After concentrating the reaction solution, water was added, the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 3/2), and reprecipitated from diethyl ether-n-hexane to give 0. .30 g of the title compound were obtained.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 2/1): Rf value =
0.56. Example 18 N- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) methanesulfonami
De (Compound No. 1-316) of 5- 400mg [4- [6- (4- aminophenoxy) -1-methyl -1H- benzoimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione and secondary Hydrochloride, 89mg
Of methanesulfonyl chloride, 234 mg of triethylamine and 8 ml of anhydrous N, N-dimethylformamide were stirred at room temperature for 3.5 hours. After evaporating the solvent from the reaction solution, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous sodium sulfate.
The solvent was distilled off. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane =
(3/1 → 4/1 → 1/0) and recrystallized from ethyl acetate to obtain 159 mg of the title compound.

Melting point: 224.8-226.5 ° C. Example 19 N- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -p-toluenesulfo
Amide (Exemplified Compound No. 1-319) 400 mg of 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione. Hydrochloride, 153m
A mixture of g of p-toluenesulfonyl chloride, 234 mg of triethylamine and 8 ml of anhydrous N, N-dimethylformamide was stirred at room temperature for 2.5 hours. After evaporating the solvent from the reaction solution, water was added, and the mixture was extracted with ethyl acetate.
The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 2/1 → 4/1), and recrystallized from ethyl acetate-diisopropyl ether to obtain 237 mg of the title compound. Was.

Melting point: 132.0-135.6 ° C. Example 201- (3- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3-phenylurea
 (Exemplified Compound No. 2-9) 400 mg of 5- [4- [6- (3-aminophenoxy) -1-me
Tyl-1H-benzimidazol-2-ylmethoxy] ben
[Jill] thiazolidine-2,4-dione dihydrochloride, 99mg
Of phenyl isocyanate, 153 mg of triethyl alcohol
And 8 ml of anhydrous N, N-dimethylformamide
The reaction and purification were carried out in the same manner as in Example 1 to obtain 319 m
g of the title compound were obtained.

Melting point: 165.3-166.8 ° C. Example 21 1- (3- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3- (4-trifluoro)
(Romethylphenyl ) urea (Exemplified Compound No. 2-26) 400 mg of 5- [4- [6- (3-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4 -Dione dihydrochloride, 144m
g of isocyanic acid α, α, α-trifluoro p-tolyl,
153 mg of triethylamine and 8 ml of anhydrous N,
The reaction and purification were conducted using N-dimethylformamide in the same manner as in Example 1 to obtain 362 mg of the title compound.

Melting point: 192.5-194.1 ° C. Example 22 1- (3- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3- (3-trifluoro)
(Romethylphenyl ) urea (Exemplified Compound No. 2-25) 400 mg of 5- [4- [6- (3-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4 -Dione dihydrochloride, 149m
g of isocyanic acid α, α, α-trifluoro m-tolyl,
153 mg of triethylamine and 4 ml of anhydrous N,
The mixture of N-dimethylformamide was stirred at room temperature for 2 hours. After the solvent was distilled off from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 2/1 → ethyl acetate), and then methanol-diisopropyl ether (1: 1).
Recrystallization from 3) gave 239 mg of the title compound.

Melting point: 161.8-163.4 ° C. Example 23 1- (3- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3- (4-fluorophenyl
( Enyl) urea (Exemplified Compound No. 2-29) 400 mg of 5- [4- [6- (3-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione・ Dihydrochloride, 109m
g of 4-fluorophenyl isocyanate, 153 mg
The reaction and purification were carried out in the same manner as in Example 1 by using triethylamine and 4 ml of anhydrous N, N-dimethylformamide, to obtain 211 mg of the title compound.

Melting point: 168.7-170.9 ° C. Example 24 1- (3- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3- (2-trifluoro)
(Romethylphenyl ) urea (Exemplified Compound No. 2-24) 400 mg of 5- [4- [6- (3-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4 -Dione dihydrochloride, 210m
g of isocyanic acid α, α, α-trifluoro o-tolyl,
153 mg of triethylamine and 8 ml of anhydrous N,
The reaction and purification were carried out using N-dimethylformamide in the same manner as in Example 1 to obtain 452 mg of the title compound.

Melting point: 160.7-164.4 ° C. Example 25 1- (3- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3-n-hexyluria
Elemental (Exemplified Compound No. 2-5) 400 mg of 5- [4- [6- (3-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione. Hydrochloride, 280m
A mixture of g of n-hexyl isocyanate, 153 mg of triethylamine and 8 ml of anhydrous N, N-dimethylformamide was stirred at room temperature for 7 hours and then left overnight. After the solvent was distilled off from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (eluent: ethyl acetate / n-hexane = 3/1 → 4/1 → ethyl acetate → ethyl acetate / methanol = 15/1), and recrystallized from ethyl acetate. This gave 298 mg of the title compound.

Melting point: 143.7-146.9.degree. Example 26 1- (3-cyanophenyl) -3- (3- [2- [4- (2,4-di
Xothiazolidine-5-ylmethyl) phenoxymethyl]-
1-methyl-1H-benzimidazol-6-yloxy] f
Enyl) urea (Exemplified Compound No. 2-41) 400 mg of 5- [4- [6- (3-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione・ Dihydrochloride, 260m
g of 3-cyanophenyl isocyanate, 153 mg of triethylamine and 8 ml of anhydrous N, N-dimethylformamide were stirred at room temperature for 4 hours, and then stirred for 50 hours.
Stirred at 2.5 ° C. for 2.5 hours. After the solvent was distilled off from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 3 /
(1 → ethyl acetate) and recrystallized from methanol to obtain 260 mg of the title compound.

Melting point: 148.4-154.0 ° C. Example 271- (3- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3-p-tolylurea
 (Exemplified Compound No. 2-12) 109 mg of p-toluic acid, 209 mg of phosphorus azide
Diphenyl acid, 314 mg of triethylamine and 8
The mixture of anhydrous toluene was stirred at 80 ° C. for 1 hour.
Was. After returning the reaction solution to room temperature, 400 mg of 5- [4- [6
-(3-Aminophenoxy) -1-methyl-1H-benzimida
Zol-2-ylmethoxy] benzyl] thiazolidine-2,4
-Dione dihydrochloride and 4 ml of anhydrous N, N-dimethyl
Add formamide and continue stirring at the same temperature for 2.5 hours.
Was. After evaporating the solvent from the reaction mixture, water was added and acetic acid was added.
Extracted with ethyl. After washing the extract with saturated saline, anhydrous
It was dried over sodium sulfate and the solvent was distilled off. Got
The residue was purified by silica gel column chromatography (eluent
Agent: ethyl acetate / n-hexane = 3/2 → 3/1 → acetic acid
(Ethyl), then filter off the methanol-insoluble product.
Was. In addition, reverse-phase preparative high-performance liquid chromatography (solvent
Solvent: acetonitrile / water = 50/50 → 55/45
→ 60/40) to give 27 mg of the title compound.
Obtained.

Melting point: 173.0-175.2 ° C. Example 28 1- (adamantan-1-yl) -3- (3- [2- [4- [2,4-di
Oxothiazolidine-5-ylmethyl) phenoxymethyl]
-1-Methyl-1H-benzimidazol-6-yloxy]
Phenyl) urea (Exemplified Compound No. 2-8) 400 mg of 5- [4- [6- (3-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione・ 142 mg of dihydrochloride
Of 1-adamantyl isocyanate, 153 mg of triethylamine and 4 ml of anhydrous N, N-dimethylformamide were stirred at room temperature for 3 hours. After the solvent was distilled off from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate /
(n-hexane = 3/1 → 4/1 → ethyl acetate), and the methanol-insoluble product was collected by filtration. Furthermore, reverse-phase preparative high-performance liquid chromatography (elution solvent: acetonitrile / water = 50/50 → 60/40 → 65/35 → 7)
(0/30) to give 66 mg of the title compound.

Melting point: 227.1-231.4 ° C. Example 29 1- (benzo [1,3] dioxol-5-yl) -3- (3- [2-
[4- (2,4-dioxothiazolidine-5-ylmethyl) fe
Nonoxymethyl] -1-methyl-1H-benzimidazole-6
-Yloxy ] phenyl) urea (Exemplified Compound No. 2-72) 133 mg of piperonyl acid, 217 mg of diphenyl azide phosphate, 314 mg of triethylamine and 8 m
A mixture of 1 anhydrous toluene was stirred at 80 ° C. for 1 hour.
The reaction solution was returned to room temperature, and 400 mg of 5- [4- [6- (3-aminophenoxy) -1-methyl-1H-benzimidazole-
2-ylmethoxy] benzyl] thiazolidine-2,4-dione dihydrochloride and 4 ml of anhydrous N, N-dimethylformamide were added, followed by stirring at the same temperature for 1 hour and then left overnight. After the solvent was distilled off from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (eluent: ethyl acetate / n-hexane = 3/1 → 1/0), and the methanol-diisopropyl ether (5: 1) -insoluble product was collected by filtration. . Furthermore, reverse phase preparative high performance liquid chromatography (elution solvent: acetonitrile / water = 50)
/ 50) to give 26 mg of the title compound.

Melting point: 179.2-182.4 ° C. Example 30 1- (3- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl) -3- (4-trifluoro)
( Romethyl) benzyl urea (Exemplified Compound No. 2-82) In 8 ml of anhydrous N, N-dimethylformamide solution containing 130 mg of 1,1′-carbonyldiimidazole, 13
5 mg of 4- (trifluoromethyl) benzylamine was added dropwise, and the mixture was stirred at room temperature for 2 hours. Then, 400mg of 5
-[4- [6- (3-Aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione dihydrochloride and 153 mg of triethylamine were added, and the mixture was added at 60 ° C. After stirring for 1 hour, it was left at room temperature overnight. After the solvent was distilled off from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (eluent: ethyl acetate), and the methanol-insoluble product was collected by filtration. Furthermore, reverse phase preparative high performance liquid chromatography (elution solvent: acetonitrile / water = 50 /
Purification by (50 → 60/40) yielded 102 mg of the title compound.

Melting point: 127.9-132.4 ° C. Example 31 1- (2,4-difluorophenyl) -3- [2- (4- [2- [4-
(2,4-dioxothiazolidine-5-ylmethyl) phenoxy
[Scimethyl] -1-methyl-1H-benzimidazole- 6-i
[Roxy] phenyl) ethyl] urea (Exemplary Compound No. 1-1)
74) 0.3 g of 5- (4- [6- [4- (2-aminoethyl) phenoxy] -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl) thiazolidine-2,4-dione-2 To a mixture of hydrochloride, 65 mg of triethylamine and 5 ml of anhydrous N, N-dimethylformamide, 81 mg of 2,4-difluorophenyl isocyanate was added, and the mixture was stirred at room temperature for 4.5 hours and then left for 2 days. After concentration, the reaction solution was diluted with water and tetrahydrofuran, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. Ethyl acetate was added to the obtained residue, and the precipitated product was collected by filtration and washed with ethyl acetate to obtain 0.2 g of the title compound.

Melting point: 161-164 ° C. Example 32 1- (2,6-diisopropylphenyl) -3- [2- (4- [2-
[4- (2,4-dioxothiazolidine-5-ylmethyl) fe
Nonoxymethyl] -1-methyl-1H-benzimidazole-6
-Yloxy] phenyl) ethyl] urea hydrochloride ( hydrochloride of Exemplified Compound No. 1-168) 0.4 g of 5- (4- [6- [4- (2-aminoethyl) phenoxy] -1-methyl- 1H-benzimidazol-2-ylmethoxy] benzyl) thiazolidine-2,4-dione dihydrochloride, 0.14 g 2,6-diisopropylphenyl isocyanate, 0.18 g N, N-diisopropylethylamine and 15 ml anhydrous The reaction was carried out and purified in the same manner as in Example 31 using N, N-dimethylformamide, and the obtained 1- (2,6-diisopropylphenyl) -3- [2- (4- [2-
-[4- (2,4-Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-
6-yloxy] phenyl) ethyl] urea was dissolved in 10 ml of tetrahydrofuran, 5 ml of 4N hydrochloric acid / ethyl acetate was added, and the mixture was stirred at room temperature for 1.5 hours. Then 15
After adding ml of diethyl ether and further stirring for 1 hour, the precipitated product was collected by filtration and washed with ethyl acetate and n-hexane to obtain 0.4 g of the title compound.

Melting point: 153-155 ° C. Example 33 1- (adamantan-1-yl) -3- [2- (4- [2- [4- (2,
4-dioxothiazolidine-5-ylmethyl) phenoxime
[Tyl] -1-methyl-1H-benzimidazol-6-ylo
[Xy] phenyl) ethyl] urea dihydrochloride ( dihydrochloride of Exemplified Compound No. 1-165) 0.3 g of 5- (4- [6- [4- (2-aminoethyl) phenoxy] -1-methyl -1H-benzimidazol-2-ylmethoxy] benzyl) thiazolidine-2,4-dione dihydrochloride, 94 mg of 1-adamantyl isocyanate, 65 mg
Using 1 mg of triethylamine and 15 ml of anhydrous N, N-dimethylformamide, the reaction and purification were carried out in the same manner as in Example 31 to obtain 1- (adamantan-1-yl) -3.
1- [2- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) ethyl] urea
It was dissolved in 0 ml of tetrahydrofuran, 10 ml of 4N hydrochloric acid / 1,4-dioxane was added, and the mixture was stirred at room temperature for 3 hours. The precipitated product was collected by filtration and washed with tetrahydrofuran and n-hexane to obtain 0.3 g of the title compound.

Melting point: 174-176 ° C. Example 34 1- [2- (4- [2- [4- (2,4-dioxothiazolidine-5-
Ylmethyl) phenoxymethyl] -1-methyl-1H-benzo
Imidazol-6-yloxy] phenyl) ethyl] -3- (4
-Trifluoromethylphenyl ) urea hydrochloride ( hydrochloride of Exemplified Compound No. 1-172) 0.3 g of 5- (4- [6- [4- (2-aminoethyl) phenoxy] -1-methyl-1H -Benzimidazol-2-ylmethoxy] benzyl) thiazolidine-2,4-dione dihydrochloride, 97 mg of α, α, α-trifluoro p-tolyl isocyanate, 65 mg of triethylamine and 5 ml
Example 3 using anhydrous N, N-dimethylformamide
The reaction and purification were carried out in the same manner as 1 to obtain 1- [2- (4- [2-
[4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6
-Iyloxy] phenyl) ethyl] -3- (4-trifluoromethylphenyl) urea was dissolved in 10 ml of tetrahydrofuran, 10 ml of 4N hydrochloric acid / 1,4-dioxane was added, and the mixture was stirred at room temperature for 3 hours. Then, 50 ml of diethyl ether was added, and the mixture was further stirred for 30 minutes. The precipitated product was collected by filtration and washed with ethyl acetate to give 0.3 g.
The title compound was obtained.

Melting point: 153-156 ° C. Example 35 4-chloro-N- [2- (4- [2- [4- (2,4-dioxothiazo)
Lysin-5-ylmethyl) phenoxymethyl] -1-methyl-
1H-benzimidazol-6-yloxy] phenyl) e
[Tyl ] benzenesulfonamide hydrochloride ( hydrochloride of Exemplified Compound No. 1-342) 0.4 g of 5- (4- [6- [4- (2-aminoethyl) phenoxy] -1-methyl-1H-benzo) Imidazol-2-ylmethoxy] benzyl) thiazolidine-2,4-dione dihydrochloride, 0.27 g of N, N-diisopropylethylamine and 15 ml of anhydrous N, N-dimethylformamide in a mixture of 0.15 g of 4- Chlorobenzenesulfonyl was added, and the mixture was stirred at room temperature for 3.5 hours. After concentrating the reaction solution,
Dilute with water and tetrahydrofuran and extract with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue obtained is 10
The mixture was dissolved in ml of tetrahydrofuran, 5 ml of 4N hydrochloric acid / ethyl acetate was added, and the mixture was stirred at room temperature for 1.5 hours. Then, 10 ml of diethyl ether was added, and the mixture was added at room temperature for 30 minutes.
After stirring for 30 minutes and irradiating with ultrasonic waves for another 30 minutes, the precipitated product was collected by filtration and washed with acetone, ethyl acetate and n-hexane to obtain 0.3 g of the title compound.

Melting point: 155-160 ° C. Example 36N- [2- (4- [2- [4- (2,4-dioxothiazolidine-5-
Ylmethyl) phenoxymethyl] -1-methyl-1H-benzo
Imidazol-6-yloxy] phenyl) ethyl] -2,4,
6-triisopropylbenzenesulfonamide hydrochloride
 (Hydrochloride of Exemplified Compound No. 1-336) 0.3 g of 5- (4- [6- [4- (2-aminoethyl) phenoxy)
[S] -1-methyl-1H-benzimidazol-2-ylmeth
[Xy] benzyl) thiazolidine-2,4-dione dihydrochloride
Salt, 0.17 g triethylamine and 10 ml
0.17 g of water N, N-dimethylformamide mixture
2,4,6-triisopropylbenzenesulfonyl chloride
Was added and stirred at room temperature for 4.5 hours. Solvent from reaction solution
After evaporation, water was added and extracted with ethyl acetate. Extract
Was washed with saturated saline and dried over anhydrous sodium sulfate.
And the solvent was distilled off. The obtained residue is applied to a silica gel column.
Chromatography (elution solvent: ethyl acetate / n-hexa
= 2/1) and dissolved in 15 ml of ethyl acetate
Then, add 2 ml of 4N hydrochloric acid / 1,4-dioxane and add
Stirred at warm for 20 minutes. The precipitated product was collected by filtration and
Washing with ethyl gives 0.28 g of the title compound.
Was.

Melting point: 134-136 ° C. Example 37 1- [4- (2- [2- [4- (2,4-dioxothiazolidine-5-
Ylmethyl) phenoxymethyl] -1-methyl-1H-benzo
Imidazol-6-yloxy] ethyl) phenyl] -3- (4
-Trifluoromethylphenyl) urea (Exemplary Compound No. 1-
232) 0.4 g of 5- (4- [6- [2- (4-aminophenyl) ethoxy] -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl) thiazolidine-2,4-dione and 10
0.17 ml of a mixture of N, N-dimethylformamide
g of isocyanic acid α, α, α-trifluoro p-tolyl was added, and the mixture was stirred at room temperature for 2 hours and left overnight. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, ethyl acetate-diethyl ether
(1: 1) A mixed solvent was added, and the precipitated product was collected by filtration and washed with diethyl ether to obtain 0.4 g of the title compound.

Melting point: 145-147 ° C. Example 38 1- (4-Chlorophenyl) -3- [4- (2- [2- [4- (2,4-
Dioxothiazolidine-5-ylmethyl) phenoxymethi
L] -1-Methyl-1H-benzimidazol-6-yloxo
[S] ethyl) phenyl] urea (Exemplary Compound No. 1-235) 0.4 g of 5- (4- [6- [2- (4-aminophenyl) ethoxy] -1-methyl-1H-benzimidazole-2- Ylmethoxy] benzyl) thiazolidine-2,4-dione and 10
0.15 ml of N, N-dimethylformamide mixture
g of 4-chlorophenyl isocyanate was added, and the mixture was stirred at room temperature for 1 hour and left overnight. Add water to the reaction solution,
After extraction with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, diethyl ether was added, and the precipitated product was collected by filtration and recrystallized from tetrahydrofuran-ethyl acetate to obtain 0.37 g of the title compound.

Melting point: 157-162 ° C. Example 39 1- [4- (2- [2- [4- (2,4-dioxothiazolidine-5-
Ylmethyl) phenoxymethyl] -1-methyl-1H-benzo
Imidazol-6-yloxy] ethyl) phenyl] -3- (4
-Nitrophenyl) urea hydrochloride (Exemplary Compound No. 1-23
Hydrochloride of 7) 4 g of 5- (4- [6- [2- (4-aminophenyl) ethoxy]-
1-methyl-1H-benzimidazol-2-ylmethoxy]
0.16 g of 4-nitrophenyl isocyanate was added to a mixture of (benzyl) thiazolidine-2,4-dione and 10 ml of N, N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour and left overnight. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, ethyl acetate was added, and the precipitated product was collected by filtration and subjected to normal-phase preparative medium-pressure liquid chromatography (eluent: ethyl acetate / tetrahydrofuran = 4/1). The obtained 1- [4-
(2- [2- [4- (2,4-Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] ethyl) phenyl] -3- (4-nitro (Phenyl) urea was dissolved in 10 ml of a mixed solvent of tetrahydrofuran-methanol (1: 1), 2 ml of 4N hydrochloric acid / 1,4-dioxane was added, and the mixture was stirred at room temperature for 15 minutes.
The solvent was distilled off from the reaction mixture, and the obtained residue was recrystallized from methanol-tetrahydrofuran to give 0.16 g.
The title compound was obtained.

Melting point: 170 ° C. (decomposition point). Example 40 1- (2,6-diisopropylphenyl) -3- (7- [2- [4-
(2,4-dioxothiazolidine-5-ylmethyl) phenoxy
[Scimethyl] -1-methyl-1H-benzimidazole-6-i
Ruoxy] naphthalen-1-yl) urea (Exemplary Compound No. 1-
213) 0.50 g of 5- [4- [6- (8-aminonaphthalen-2-yloxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione
Dissolve in 0 ml of N, N-dimethylformamide and add 0.2
0 g of 2,6-diisopropylphenyl isocyanate was added and left at room temperature for 5 days. After the reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 3/2 → 3 /
After subjecting to 1), recrystallization from methanol gave 0.2
4 g of the title compound were obtained.

Mp: 164-169 ° C. Example 41 1- (2,4-difluorophenyl) -3- (7- [2- [4- (2,
4-dioxothiazolidine-5-ylmethyl) phenoxime
[Tyl] -1-methyl-1H-benzimidazol-6-ylo
[Xy] naphthalen-1-yl) urea (Exemplary Compound No. 1-21)
9) 0.50 g of 5- [4- [6- (8-aminonaphthalen-2-yloxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione;
When 0.16 g of 2,4-difluorophenyl isocyanate and 10 ml of anhydrous N, N-dimethylformamide were reacted and purified in the same manner as in Example 1, 0.25 g of the product was obtained.
The title compound was obtained.

Melting point: 222-224 ° C. Example 42 1- (7- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] naphthalen-1-yl) -3- (4-
Trifluoromethylphenyl) urea (Exemplary Compound No. 1-
217) 0.50 g of 5- [4- [6- (8-aminonaphthalen-2-yloxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione,
0.19 g of isocyanic acid α, α, α-trifluoro p-
The reaction and purification were carried out in the same manner as in Example 1 using tolyl and 10 ml of anhydrous N, N-dimethylformamide.
27 g of the title compound were obtained.

Melting point: 250-254 ° C. Example 43 1- (adamantan-1-yl) -3- (7- [2- [4- (2,4-di
Oxothiazolidine-5-ylmethyl) phenoxymethyl]
-1-Methyl-1H-benzimidazol-6-yloxy]
Naphthalen-1-yl) urea (Exemplified Compound No. 1-210) 0.50 g of 5- [4- [6- (8-aminonaphthalen-2-yloxy) -1-methyl-1H-benzimidazol-2-ylmethoxy [Benzyl] thiazolidine-2,4-dione
Dissolved in 0 ml of anhydrous N, N-dimethylformamide,
Add 0.18 g of 1-adamantyl isocyanate,
Stirred at room temperature for 5 days. The solvent was distilled off from the reaction solution, and the obtained residue was subjected to reverse phase preparative high performance liquid chromatography (elution solvent: acetonitrile / water = 50/50 → 60/40 →
Purification by (70/30) yielded 0.45 g of the title compound.

Melting point: 250 ° C. (decomposition point). Example 44 1-benzyl-3- (7- [2- [4- (2,4-dioxothiazolyl)
Zin-5-ylmethyl) phenoxymethyl] -1-methyl-1
[H-benzimidazol-6-yloxy] naphthalene-1-
Yl) thiourea (exemplified compound number 1-300) 0.40 g of 5- [4- [6- (8-aminonaphthalen-2-yloxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] benzyl 1 thiazolidine-2,4-dione
Dissolve in 0 ml of anhydrous tetrahydrofuran and add 0.24 g
Was added and stirred at room temperature for 5.5 hours, followed by stirring at 50 ° C. for 9 hours. The solvent was distilled off from the reaction solution, and the obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1/1 →
Purification by 3/1) yielded 0.36 g of the title compound.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 3/1): Rf value =
0.53. Example 45 1-benzyl-3- (7- [2- [4- (2,4-dioxothiazolyl)
Zin-5-ylmethyl) phenoxymethyl] -1-methyl-1
[H-benzimidazol-6-yloxy] naphthalene-1-
Yl) urea (Exemplary Compound No. 1-223) 0.30 g of 5- [4- [6- (8-aminonaphthalen-2-yloxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine -2,4-dione,
The reaction and purification were carried out in the same manner as in Example 1 using 0.08 g of benzyl isocyanate and 6 ml of anhydrous tetrahydrofuran, to obtain 0.32 g of the title compound.

Melting point: 220-222 ° C. Example 46 1-benzenesulfonyl-3- (7- [2- [4- (2,4-dioxy)
Sothiazolidine-5-ylmethyl) phenoxymethyl] -1-
Methyl-1H-benzimidazol-6-yloxy] naph
Taren-1-yl) urea (Exemplified Compound No. 1-256) 0.40 g of 5- [4- [6- (8-aminonaphthalen-2-yloxy) -1-methyl-1H-benzimidazol-2-ylmethoxy ] Benzyl] thiazolidine-2,4-dione to 8
dissolved in anhydrous tetrahydrofuran, and 0.22 g of benzenesulfonyl isothiocyanate was added.
Stirred for hours. The solvent was distilled off from the reaction solution, and the obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 3/1), and recrystallized from tetrahydrofuran-n-hexane to give 55 mg. The title compound was obtained.

Melting point: 199-205 ° C. Example 47 N- (7- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] naphthalen-1-yl) -4-methyl
Le benzenesulfonamide (Compound No. 1-349) 0.40 g of 5- [4- [6- (8-amino-2-yloxy) -1-methyl -1H- benzimidazol-2-ylmethoxy] benzyl] Thiazolidine-2,4-dione,
0.30 g of p-toluenesulfonyl chloride, 0.16
After stirring a mixture of g of triethylamine and 8 ml of anhydrous tetrahydrofuran at 50 ° C. for 5 hours, the temperature was raised to 70 ° C., followed by stirring for 2 hours. The solvent was distilled off from the reaction solution, water was added, and the precipitated crystals were washed with water and tetrahydrofuran to obtain 0.14 g of the title compound.

Melting point: 137-144 ° C. Example 48 1- (2-tert-butyl-5- [2- [4- (2,4-dioxothiazo)
Lysin-5-ylmethyl) phenoxymethyl] -1-methyl-
1H-benzimidazol-6-yloxymethyl] phenyl
) -3- (4-Trifluoromethylphenyl) urea (Exemplified Compound No. 2-190) 0.50 g of 5- [4- [6- (3-amino-4-t-butyl) benzyloxy-1-) Methyl-1H-benzimidazole-2-
Ilmethoxy] benzyl] thiazolidine-2,4-dione.
A mixture of dihydrochloride, 0.17 g of isocyanic acid α, α, α-trifluoro p-tolyl, 0.16 g of triethylamine and 10 ml of anhydrous N, N-dimethylformamide was stirred at room temperature for 19 hours and then at 60 ° C. The temperature was raised and the mixture was further stirred for 5 hours. After the reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue is subjected to reverse phase preparative high performance liquid chromatography (eluent:
After acetonitrile / water = 55/45), recrystallization from ethyl acetate-n-hexane gave 0.18 g of the title compound.

Melting point: 200-202 ° C. Example 49 1- [2-t-butyl-5- (2- [2- [4- (2,4-dioxothioic)
Azolidine-5-ylmethyl) phenoxymethyl] -1-methyl
1H-benzimidazol-6-yloxy] ethyl) ethyl
Enyl] -3- (4-trifluoromethylphenyl) urea (Exemplified Compound No. 2-205) 0.40 g of 5- [4- [6- [2- (3-amino-4-t-butylphenyl) ethoxy] ] -1-Methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione dihydrochloride, 0.13 g of isocyanic acid α, α, α
A mixture of -trifluoro p-tolyl, 0.13 g of triethylamine and 8 ml of anhydrous N, N-dimethylformamide was stirred at room temperature for 24 hours, then heated to 60 ° C, and subsequently stirred for 2.5 hours. After the reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by reverse phase preparative high performance liquid chromatography (eluting solvent: acetonitrile / water [containing 2% triethylamine and 2% acetic acid] = 57/43) to give 0.
24 g of the title compound were obtained.

Melting point: 165-167 ° C. Example 50 1- (4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -3-methyl-3H-imidazo
[4,5-b] pyridin-5-ylthio] -2,6-dimethylphen
Nyl ) -3- (4-trifluoromethylphenyl) urea (Exemplary Compound No. 3-70) 0.37 g of 5- [4- [5- (3,5-dimethyl-4-nitrophenylthio) -3- Methyl-3H-imidazo [4,5-b] pyridin-2-ylmethoxy] benzyl] thiazolidine-2,4-
Dione, 0.44 g of 10% palladium on carbon, 10 m
A mixture of 1 liter of ethanol and 10 ml of 1,4-dioxane was stirred vigorously at room temperature under a hydrogen atmosphere for 7 hours. After the catalyst was removed by filtration from the reaction mixture, the solvent was distilled off, and the obtained residue was subjected to 15 ml of anhydrous tetrahydrofuran-anhydrous N, N-
It was dissolved in a dimethylformamide (2: 1) mixed solvent. Then, 0.38 g of α, α, α-trifluoro p-tolyl isocyanate was added, and the mixture was stirred at room temperature for 5 hours.
The temperature was raised to ° C., and the mixture was further stirred for 4 hours. After concentrating the reaction solution, water was added, the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. After distilling off the solvent from the extract,
N-Hexane was added to the obtained residue, and the precipitated product was collected by filtration and reprecipitated from ethanol-diethyl ether to obtain 0.12 g of the title compound.

Melting point: 193-195 ° C. Example 51 1- [4- [2- [4- (2,4-dioxothiazolidine-
5-ylmethyl) phenoxymethyl] -1-methyl-1H
-Benzimidazol-6-yloxy] -2,6-dimethyl
Tylphenyl] -3- (4-methoxyphenyl) urea (Exemplary Compound No. 1-189) 251 mg of 5- [4- [6- (4-amino-3,5-dimethylphenoxy) -1-methyl-1H-benzo) Imidazol-2-ylmethoxy] benzyl] thiazolidine-2,
The reaction and purification were carried out in the same manner as in Example 1 using 4-dione, 89 mg of 4-methoxyphenyl isocyanate, 61 mg of triethylamine and 10 ml of anhydrous tetrahydrofuran, to obtain 201 mg of the title compound.

Melting point: 229-231 ° C. Example 52 N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl)
Phenoxymethyl] -1-methyl-1H-benzimidazole-6
-Yloxy] phenyl] acetamide (Exemplary Compound No. 6
-1) 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,
To a solution of 400 mg of 4-dione dihydrochloride anhydrous N, N-dimethylformamide 8 ml, triethylamine 0.36 ml
And 0.06 ml of acetyl chloride were added dropwise. After stirring the reaction solution at room temperature for 1 hour, the solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 4: 1 → 1: 0 → ethyl acetate: methanol = 10: 1) to obtain a white amorphous substance. 320 mg of the compound were obtained.

Melting point: 92-95 ° C. Example 53 N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl)
Phenoxymethyl] -1-methyl-1H-benzimidazole-6
-Yloxy] phenyl] benzamide (Exemplary Compound No. 6
-10) 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,
The reaction was carried out according to Example 52 using 400 mg of 4-dione dihydrochloride, 8 ml of anhydrous N, N-dimethylformamide, 0.36 ml of triethylamine and 0.10 ml of benzoyl chloride. The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 1 →
2: 1 → 3: 1 → 4: 1) gives the target compound 2 as a white powder
47 mg were obtained.

Melting point: 200-204 ° C. Example 54 3-chloro-N- [4- [2- [4- (2,4-dioxothiazolidine-5-i
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl] benzamide (Exemplified Compound No. 6-21) 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine- 2,
The reaction was carried out according to Example 52 using 400 mg of 4-dione dihydrochloride, 8 ml of anhydrous N, N-dimethylformamide, 0.32 ml of triethylamine and 0.09 ml of 3-chlorobenzoyl chloride. The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 3: 2 → 5: 2) to give 232m of the target compound as a white powder.
g was obtained.

Melting point: 238-239 ° C. Example 55 N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl)
Phenoxymethyl] -1-methyl-1H-benzimidazole-6
-Yloxy] phenyl] isonicotinamide (Exemplified Compound No. 6-37) 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2 ,
Example 5 using 400 mg of 4-dione dihydrochloride, 8 ml of anhydrous N, N-dimethylformamide, 0.54 ml of triethylamine and 284 mg of isonicotinoyl chloride hydrochloride.
The reaction was carried out according to 2. The solvent was distilled off from the reaction mixture under reduced pressure, water and ethyl acetate were added to the residue, and the insoluble matter was collected by filtration to obtain 306 mg of the target compound as a pale yellow powder having a melting point of 222 ° C .- (decomposed).

Melting point: 222- (decomposition) ° C. Example 56 N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl)
Phenoxymethyl] -1-methyl-1H-benzimidazole-6
-Yloxy] phenyl] nicotinamide (Exemplified Compound No. 6-36) 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,
The reaction was carried out according to Example 52 using 400 mg of 4-dione dihydrochloride, 8 ml of anhydrous N, N-dimethylformamide, 0.49 ml of triethylamine and 195 mg of nicotinoyl chloride hydrochloride. The solvent was distilled off from the reaction mixture under reduced pressure, water and ethyl acetate were added to the residue, and the insoluble matter was collected by filtration to give the title compound as a pale yellow powder having a melting point of 213-215 ° C.
297 mg were obtained.

Melting point: 213-215 ° C. Example 572,4-difluoro-N- [4- [2- [4- (2,4-dioxothiazolidy
-5-ylmethyl) phenoxymethyl] -1-methyl-1H-ben
Zoimidazol-6-yloxy] phenyl] benzamide
 (Exemplified Compound No. 6-19) 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzoi
Midazol-2-ylmethoxy] benzyl] thiazolidine-2,
4-dione dihydrochloride 400 mg, anhydrous N, N-dimethylform
8 ml of muamide, 0.32 ml of triethylamine and 2,4-
Performed using 0.10 ml of difluorobenzoyl chloride
The reaction was carried out according to Example 52. Dissolve under reduced pressure from the reaction mixture
The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated saline and dried over anhydrous sodium sulfate.
Dried. Ethyl acetate was distilled off from the extract, and the residue was
Kagel column chromatography (ethyl acetate: n-
When applied to 3: 1), white powder having a melting point of 172-174 ° C
251 mg of the desired target compound was obtained.

Melting point: 172-174 ° C. Example 58 N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl)
Phenoxymethyl] -1-methyl-1H-benzimidazole-6
-Yloxy] phenyl] cyclohexanecarboxylic acid
De (Compound No. 6-8) cyclohexanecarboxylic acid 0.09ml of anhydrous N, N- dimethylformamide 8ml solution, triethylamine 0.32
ml and 0.08 ml of ethyl chloroformate were added dropwise. After stirring the reaction solution for 90 minutes, 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy]
[Benzyl] thiazolidine-2,4-dione dihydrochloride 400m
g was added and stirred at room temperature for 2 hours. Further, add this reaction solution to 5
After stirring on a 0 ° C. oil bath for 90 minutes, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was recrystallized from ethyl acetate to obtain 262 mg of the target compound as a pale orange powder.

Melting point: 182-184 ° C. Example 59 N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl)
Phenoxymethyl] -1-methyl-1H-benzimidazole-6
-Yloxy] phenyl] cyclopentanecarboxylic acid
De (Compound No. 6-7) cyclopentanecarboxylic acid 0.09 ml, anhydrous N, N- dimethylformamide 8 ml, triethylamine 0.32 ml,
0.08 ml of ethyl chloroformate and 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione dihydrochloride
The reaction was carried out according to Example 58 using 400 mg. The solvent was distilled off from the reaction mixture under reduced pressure, and water was added to the residue.
Extracted with ethyl acetate. Wash the extract with saturated saline,
Dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, water and ethyl acetate were added to the residue, and the insolubles were collected by filtration to obtain 236 mg of the target compound as a white powder.

Melting point: 227-228 ° C. Example 60 N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl)
Phenoxymethyl] -1-methyl-1H-benzimidazole-6
-Yloxy] phenyl] naphthalene-2-carboxylic acid amide
(Exemplified Compound No. 6-11) 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,
The reaction was carried out according to Example 52 using 400 mg of 4-dione dihydrochloride, 8 ml of anhydrous N, N-dimethylformamide, 0.32 ml of triethylamine and 153 mg of 2-naphthoyl chloride. The solvent was distilled off from the reaction mixture under reduced pressure, water and ethyl acetate were added to the residue, and the insoluble material was collected by filtration to obtain 337 mg of the target compound as a white powder. Melting point: 221-223 ° C. Example 61 N- [4- [2- [4- (2,4-dioxothiazolidine-5-yl)
Methyl) phenoxymethyl] -1-methyl-1H-benziimi
Dazol-6-yloxy] phenyl] -Nn-hexylurea
Cetamide hydrochloride ( Hydrochloride of Exemplified Compound No. 6-4) 502 mg of 5- [4- [6- (4-n-hexylaminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine -2,4-dione, 112
mg of acetic anhydride, 356 mg of pyridine, 37 mg of 4
A mixture of -dimethylaminopyridine and 30 ml of anhydrous tetrahydrofuran was left at room temperature for 14 hours. After concentrating the reaction solution, water was added, the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 3/1), and then treated with 20 ml of 4N hydrochloric acid / ethyl acetate. This gave 410 mg of the title compound.

Melting point: 125-128 ° C. Example 62 3,5-Di-t-butyl-N- [4- [2- [4- (2,4-dioxothiazolyl)
Zin-5-ylmethyl) phenoxymethyl] -1-methyl-1H-beta
Nzoimidazole-6-yloxy] phenyl] -4-hydroxy
Sivenzamide (Exemplified Compound No. 6-25) 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,
To a solution of 400 mg of 4-dione dihydrochloride and 204 mg of 3,5-di-t-butyl-4-hydroxybenzoic acid in 8 ml of anhydrous N, N-dimethylformamide, 0.32 ml of triethylamine
And 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (153 mg) were added. The reaction solution was stirred for 1 hour and left at room temperature overnight. Further, 0.10 ml of triethylamine and 134 mg of 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride were added to the reaction solution, and the mixture was stirred at room temperature for 8 hours and then left at room temperature overnight. The solvent was distilled off from the reaction mixture under reduced pressure, and water was added to the residue.
Extracted with ethyl acetate. Wash the extract with saturated saline,
Dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to silica gel column chromatography.
When subjected to-(ethyl acetate: n-hexane = 2: 1 → 3: 1), 176 mg of the target compound was obtained as a white powder.

Melting point: 160-162 ° C. Example 63 N- [2- [4- [2- [4- (2,4-dioxothiazolidine-5-
Ylmethyl) phenoxymethyl] -1-methyl-1H-benzo
Imidazol-6-yloxy] phenyl] ethyl] nicot
Diamide hydrochloride ( dihydrochloride of Exemplified Compound No. 6-59) 5- [4- [6- [4- (2-aminoethyl) phenoxy] -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl ] Thiazolizone-2,4-dione dihydrochloride 0.3 g,
A mixture of 0.17 g of triethylamine and 15 ml of anhydrous N, N-dimethylformamide was stirred at room temperature for 30 minutes. 0.1 g of nicotinamide hydrochloride was added to this solution, and the mixture was irradiated with ultrasonic waves for 30 minutes and then stirred at room temperature for 6 hours. After standing overnight, the solvent was distilled off, diluted with water, and extracted with a 1: 1 mixed solvent of ethyl acetate and tetrahydrofuran.
The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to liquid chromatography (LiChroprep DIOL "(MERCK), ethyl acetate: tetrahydrofuran = 3: 1) to dissolve the obtained glassy product in 5 ml of tetrahydrofuran. The mixture was added with 5 ml of a solution of 4-dioxane and irradiated with ultrasonic waves for 30 minutes, and the precipitate was collected by filtration to obtain 0.15 g of the target compound as a pale yellow powder.

Melting point: 176-180 (decomposition point) ° C. Example 64 2- (3-chlorophenyl) -N- [2- [4- [2- [4- (2,4-
Dioxothiazolidine-5-ylmethyl) phenoxymethi
L] -1-Methyl-1H-benzimidazol-6-yloxo
[Phenyl] ethyl] acetamide hydrochloride ( hydrochloride of Exemplified Compound No. 6-56) 5- [4- [6- [4- (2-aminoethyl) phenoxy] -1-methyl-1H-benzimidazole-2 -Ylmethoxy] benzyl] thiazolizone-2,4-dione dihydrochloride 0.3 g,
0.09 g of (3-chlorophenyl) acetic acid, 1-ethyl-3-
(3'-dimethylaminopropyl) carbodiimide hydrochloride
(WSC · HCl) 0.13 g, 1-hydroxybenzotriazole 0.11 g, anhydrous triethylamine 0.10
Examples 62 and 6 using 6 g, anhydrous N, N-dimethylformamide 10 ml, methanol 2 ml, 1,4-dioxane 5 ml and 4N hydrochloric acid 1,4-dioxane solution 2 ml.
The reaction and post-treatment were carried out in the same manner as in Example 3 to obtain 0.17 g of the target compound as a milky white powder.

Melting point: 131-134 ° C. Example 65 3,5-di-tert-butyl-N- [2- (4- [2- [4- (2,4-di
Oxothiazolidine-5-ylmethyl) phenoxymethi
L] -1-Methyl-1H-benzimidazol-6-yloxo
[S] phenyl) ethyl] -4-hydroxybenzamide salt
Salt (hydrochloride of Compound No. 6-51) 5- (4- [6- [4- (2-aminoethyl) phenoxy] -1-methyl -1H- benzoimidazol-2-ylmethoxy] benzyl) Chiazorizon - 0.3 g of 2,4-dione dihydrochloride,
3,5-di-t-butyl-4-hydroxybenzoic acid 0.13
g, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl) 0.13 g,
A mixture of 0.11 g of hydroxybenzotriazole, 0.106 g of anhydrous triethylamine and 10 ml of anhydrous N, N-dimethylformamide was stirred at room temperature for 4.5 hours.
The solvent was distilled off, diluted with water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to liquid chromatography (silica gel, ethyl acetate: n-hexane = 4: 1) to give a glassy product obtained in 15 ml of ethyl acetate.
And 2 ml of a 4N hydrochloric acid solution in 1,4-dioxane was added, followed by stirring at room temperature for 30 minutes. The solvent was distilled off, and the residue was crystallized from acetone to obtain 0.17 g of the target compound as a pale yellow powder having a melting point of 164 ° C to 168 ° C.

Melting point: 164-168 ° C.

[0327]

Reference Example Reference Example 1 N- [5- (4-amino-3,5-dimethylphenoxy) -2-ni
Trophenyl] -N-methylcarbamic acid t-butyl ester
3 containing sodium hydride ether 0.35 g (55 wt%)
1.10 g of 4-amino-3,5-dimethylphenol was added to 0 ml of a suspension of anhydrous N, N-dimethylformamide and stirred at room temperature for 15 minutes. Then 2.29 g of N
-(5-Chloro-2-nitrophenyl) -N-methylcarbamic acid t-butyl ester was added little by little, and the mixture was stirred at 120 ° C for 1 hour. After completion of the reaction, the solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate and the solvent was distilled off, the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1/3) to obtain 2.27 g.
The title compound was obtained.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 1/3): Rf value =
0.24. Reference Example 2 N- [5- (4-t-butoxycarbonylamino-3,5-dimethyl)
Tylphenoxy) -2-nitrophenyl] -N-methylcarb
2.27 g of N- [5- (4-amino-3,5-dimethylphenoxy) -2-nitrophenyl] -N-methylcarbamic acid of bamic acid t-butyl ester
A mixture of t-butyl ester, 1.28 g di-t-butyl dicarbonate, 0.59 g triethylamine triethylamine and 20 ml anhydrous tetrahydrofuran was heated to reflux for 6 hours. The solvent was distilled off from the reaction mixture,
Water was added and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / n-hexane = 1/10) to give 1.74.
g of the title compound were obtained.

Melting point: 154-156 ° C. Reference Example 3 N- [2-amino-5- (4-t-butoxycarbonylamino-
3,5-dimethylphenoxy) phenyl] -N-methylcarb
1.71 g of t-butyl bamic acid in N- [5- (4-t-butoxycarbonylamino)
-3,5-Dimethylphenoxy) -2-nitrophenyl] -N-
100 ml of t-butyl methylcarbamate
Of methanol and 0.2 g of 10% palladium-
Carbon was added and the mixture was stirred vigorously under a hydrogen atmosphere at room temperature for 11 hours. After completion of the reaction, the catalyst was filtered off and the solvent was distilled off.
1.56 g of the title compound were obtained.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 1/3): Rf value =
0.14. Reference Example 4 N- [5- (4-botoxycarbonylamino-3,5-dimethyl)
Phenoxy) -2- [4- (2,4-dioxothiazolidine-5
-Ylmethyl) phenoxyacetylamino] phenyl] -N
-Methylcarbamic acid t-butyl ester 1.56 g of N- [2-amino-5- (4-t-butoxycarbonylamino-3,5-dimethylphenoxy) phenyl] -N-
Methylcarbamic acid t-butyl ester, 1.05 g
A mixture of 4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxyacetic acid, 0.61 g of diethyl cyanophosphonate, 0.38 g of triethylamine and 30 ml of anhydrous tetrahydrofuran was stirred at room temperature for 19 hours with stirring. The reaction mixture was concentrated, water was added, and extracted with ethyl acetate. After drying the extract over anhydrous sodium sulfate,
The solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1).
/ 1) to give 1.89 g of the title compound.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 2/3): Rf value =
0.19. Reference Example 5 5- [4- [6- (4-amino-3,5-dimethylphenoxy)-
1-methyl-1H-benzimidazol-2-ylmethoxy]
Benzyl] thiazolidine-2,4-dione 1.88 g of N- [5- (4-t-butoxycarbonylamino)
-3,5-Dimethylphenoxy) -2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxyacetylamino] phenyl] -N-methylcarbamic acid t-butyl ester and 20 ml of 4N hydrochloric acid / 1 , 4-Dioxane mixture was stirred at room temperature for 23 hours. The reaction mixture was concentrated, water was added, neutralized with sodium bicarbonate, and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 2/1) to give 0.26 g of the title compound was gotten.

Melting point: 209-211 ° C. Reference Example 6 5- [4- [6- (4-amino-3,5-dimethylphenoxy)-
1-methyl-1H-benzimidazol-2-ylmethoxy]
Benzyl] thiazolidine-2,4-dione dihydrochloride 0.25 g of 5- [4- [6- (4-amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy [Benzyl] thiazolidine-2,4-dione and a mixture of 50 ml of 4N hydrochloric acid / ethyl acetate were stirred at room temperature for 24 hours. The insoluble product was collected by filtration and washed with ethyl acetate to give 0.25 g of the title compound.

Melting point: 165-175 ° C. Reference Example 7 N- [5- (4-t-butoxycarbonylaminophenoxy)
-2-Nitrophenyl] -N-methylcarbamic acid t-butyl
The glycol ester 15.6 g (4-hydroxyphenyl) carbamate
t-butyl ester, 21 g of N- (5-chloro-2-nitrophenyl) -N-methylcarbamic acid t-butyl ester, 3.22 g of sodium hydride (55% by weight) and 130 ml of anhydrous N, N-dimethyl The reaction and purification were carried out using formamide in the same manner as in Reference Example 1 to obtain 27.7 g of the title compound.

Silica gel thin layer chromatography (developing solvent: toluene / diisopropyl ether = 10 /
1): Rf value = 0.33. Reference Example 8 N- [2-amino-5- (4-t-butoxycarbonylaminophen)
Enoxy) phenyl] -N-methylcarbamic acid t-butyl
Glycol ester 27.7g of N- [5- (4-t- butoxycarbonylamino) -2- nitrophenyl] -N- methylcarbamate t-butyl ester, 10% palladium 1.07 g - carbon and 170ml of tetrahydrofuran - The reaction and purification were conducted in the same manner as in Reference Example 2 using a mixed solvent of ethyl acetate (9: 8) to obtain 26.2 g of the title compound.

Silica gel thin layer chromatography (developing solvent: c-hexane / tetrahydrofuran = 2/1):
Rf value = 0.37. Reference Example 9 N- [5- (4-t-butoxycarbonylaminophenoxy)
-2- [4- (2,4-dioxothiazolidine-5-ylmethyi)
Le) phenoxyacetylamino] phenyl] -N-methylca
Lubamic acid t-butyl ester 500 mg N- [2-amino-5- (4-t-butoxycarbonylaminophenoxy) phenyl] -N-methylcarbamic acid t-butyl ester, 366 mg 4- (2,4-dioxo) Thiazolidine-5-ylmethyl) phenoxyacetic acid,
Using 212 mg of diethyl cyanophosphonate, 132 mg of triethylamine and 10 ml of anhydrous tetrahydrofuran, the reaction and purification were carried out in the same manner as in Reference Example 4 to give 3
95 mg of the title compound were obtained.

Silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 2/3): Rf value =
0.51. Reference Example 10 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-
Benzimidazol-2-ylmethoxy] benzyl] thiazo
Lysine-2,4-dione dihydrochloride 27.08 g of N- [5- (4-t-butoxycarbonylaminophenoxy) -2- [4- (2,4-dioxothiazolidine-
5-ylmethyl) phenoxyacetylamino] phenyl]-
50 ml of N-methylcarbamic acid t-butyl ester
Was dissolved in 1,4-dioxane, and 150 ml of 4N hydrochloric acid / dioxane was added, followed by stirring at room temperature for 2 days. The precipitated product was collected by filtration and washed with ethyl acetate to give 14.4.
3 g of the title compound were obtained.

Melting point: 195 ° C. (decomposition point). Reference Example 11 N- [5- [4- (t-butoxycarbonyl-n-hexylamino)
No) Phenoxy] -2-nitrophenyl] -N-methylcarba
1.26 g of sodium t-butyl ester (55% by weight)
suspended in anhydrous N, N-dimethylformamide
12.1 g of N- [5- (4-t-butoxycarbonylaminophenoxy) -2-nitrophenyl] -N-methylcarbamic acid t-butyl ester was added, and the mixture was stirred at room temperature for several minutes. Next, 6.5 g of hexyl bromide was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes and further at room temperature for 1 hour. After concentration, the reaction mixture was poured into water and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (eluent: toluene / diisopropyl ether = 100/7) to give 13.8 g of the title product. Obtained.

Silica gel thin layer chromatography (developing solvent: toluene / diisopropyl ether = 100 /
7): Rf value = 0.32. Reference Example 12 N- [2-amino-5- [4- (t-butoxycarbonyl-n-f
Xylamino) phenoxy] phenyl] -N-methylcarba
Min acid t-butyl ester 13.8g of N- [5- [4- (t- butoxycarbonyl -n-
Hexylamino) phenoxy] -2-nitrophenyl] -N-
The reaction and purification were carried out in the same manner as in Reference Example 3 using t-butyl methylcarbamic acid, 1.0 g of 10% palladium-carbon and 140 ml of a mixed solvent of toluene and ethyl acetate (1: 1) to obtain 13.1 g of the title compound. The compound was obtained.

Silica gel thin layer chromatography (developing solvent: toluene / ethyl acetate = 3/1): Rf = 0.
44. Reference Example 13 5- [4- [6- (4-n-hexylaminophenoxy) -1-me
Tyl-1H-benzimidazol-2-ylmethoxy] ben
1.10 g of N- [2-Amino-5- (4-t-butoxycarbonyl-n-hexylaminophenoxy) phenyl] -N-methylcarbamic acid t-butyl ester of 4.10 g of [zil ] thiazolidine-2,4-dione ; 81 g of 4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxyacetic acid, 1.63 g of diethyl cyanophosphonate,
A mixture of 1.01 g of triethylamine and 100 ml of anhydrous tetrahydrofuran was stirred at room temperature for 28 hours. After concentrating the reaction solution, water was added, and the mixture was extracted with ethyl acetate.
The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off from the extract, and 50 ml of 4N hydrochloric acid / 50 ml was added to the obtained residue.
1,4-Dioxane was added, and the mixture was stirred at room temperature for 66 hours. The reaction mixture was poured into water, neutralized with sodium bicarbonate, and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 2/2).
Purification in 3) gave 2.89 g of the title compound.

Melting point: 177-179 ° C. Reference Example 14 N- [5- (3-t-butoxycarbonylaminophenoxy)
-2-Nitrophenyl] -N-methylcarbamic acid t-butyl
The glycol ester 15.8 g (3- hydroxyphenyl) carbamate
t-butyl ester, 18.1 g of N- (5-chloro-2-nitrophenyl) -N-methylcarbamic acid t-butyl ester, 3.3 g of sodium hydride (55% by weight) and 130 ml of anhydrous N, N -Reaction and purification were performed using -dimethylformamide in the same manner as in Reference Example 1 to give 20.1 g.
The title compound was obtained.

Silica gel thin layer chromatography (developing solvent: toluene / diisopropyl ether = 10 /
1): Rf value = 0.25. Reference Example 15 N- [2-amino-5- (3-t-butoxycarbonylaminophen)
Enoxy) phenyl] -N-methylcarbamic acid t-butyl
Glycol ester 12.6g of N- [5- (3-t- butoxycarbonylamino) -2- nitrophenyl] -N- methylcarbamate t-butyl ester, 10% palladium 1.07 g - tetrahydrofuran carbon and 120 ml - The reaction and purification were conducted in the same manner as in Reference Example 2 using a mixed solvent of ethyl acetate-toluene (1: 1: 1) to obtain 11.7 g of the title compound.

Silica gel thin layer chromatography (developing solvent: n-hexane / tetrahydrofuran = 2/1):
Rf value = 0.30. Reference Example 16 5- [4- [6- (3-aminophenoxy) -1-methyl-1H-
Benzimidazol-2-ylmethoxy] benzyl] thiazo
9.83 g of lysine-2,4-dione dihydrochloride t-butyl N- [2-amino-5- (3-t-butoxycarbonylaminophenoxy) phenyl] -N-methylcarbamic acid, 8.44 g 4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxyacetic acid,
Using 4.95 g of diethyl cyanophosphonate, 3.07 g of triethylamine and 200 ml of anhydrous tetrahydrofuran, the reaction and purification were carried out in the same manner as in Reference Example 4.
16.39 g of N- [5- (3-t-butoxycarbonylaminophenoxy) -2- [4- (2,4-dioxothiazolidine-
5-ylmethyl) phenoxyacetylamino] phenyl]-
N-methylcarbamic acid t-butyl ester was obtained. This intermediate was dissolved in 40 ml of 1,4-dioxane, and 70 ml of 4N hydrochloric acid / 1,4-dioxane was added.
After stirring at room temperature for 2 hours, the mixture was left overnight. The precipitated product was collected by filtration and washed with water and ethyl acetate to give 9.31 g.
The title compound was obtained.

Melting point: 146.5-150.8 ° C. Reference Example 17 N- [5- [4- (2-t-butoxycarbonylaminoethyl)]
Phenoxy] -2-nitrophenyl] -N-methylcarbamine
Acid t-butyl ester 10 g of 2- (4-hydroxyphenyl) ethylcarbamic acid t-butyl ester, 9.3 g of N- (5-chloro-
2-nitrophenyl) -N-methylcarbamic acid t-butyl ester, 2.0 g sodium hydride (55% by weight)
And purified using 200 ml of anhydrous N, N-dimethylformamide in the same manner as in Reference Example 1 to give 12.3.
7 g of the title compound were obtained.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 1/8): Rf value =
0.10. Reference Example 18 N- [2-amino-5- [4- (2-t-butoxycarbonylamido)
Noethyl) phenoxy] phenyl] -N-methylcarbamine
Acid t-butyl ester 12.35 g of N- [5- [4- (2-t-butoxycarbonylaminoethyl) phenoxy] -2-nitrophenyl] -N-methylcarbamic acid t-butyl ester, 1.5 g of 1
The reaction and purification were conducted in the same manner as in Reference Example 2 using 0% palladium-carbon and 120 ml of a toluene-methanol (2: 1) mixed solvent to obtain 12.05 g of the title compound.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 1/1): Rf value =
0.74. Reference Example 19 N- [5- [4- (2-t-butoxycarbonylaminoethyl)]
Phenoxy] -2- [4- (2,4-dioxothiazolidine-5-
Ylmethyl) phenoxyacetylamino] phenyl] -N-
M-carbamic acid t-butyl ester 12 g of N- [2-amino-5- [4- (2-t-butoxycarbonylaminoethyl) phenoxy] phenyl] -N-methylcarbamic acid t-butyl ester, 11.3 g of 4-tert-butyl ester (2,
4-dioxothiazolidine-5-ylmethyl) phenoxyacetic acid, 6.52 g diethyl cyanophosphonate, 4.0
The reaction and purification were conducted in the same manner as in Reference Example 4 using 4 g of triethylamine and 150 ml of anhydrous tetrahydrofuran to obtain 16.2 g of the title compound.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 1/2): Rf value =
0.11. Reference Example 20 5- (4- [6- [4- (2-aminoethyl) phenoxy] -1-me
Tyl-1H-benzimidazol-2-ylmethoxy] ben
16.1 g of N- [5- [4- (2-t-butoxycarbonylaminoethyl) phenoxy] -2- [4- (2,4-dioxo) diyl ) thiazolidine-2,4-dione dihydrochloride Thiazolidine-5-ylmethyl) phenoxyacetylamino]
[Phenyl] -N-methylcarbamic acid t-butyl ester was dissolved in 150 ml of trifluoroacetic acid and stirred at 50 ° C. for 7.5 hours. Trifluoroacetic acid was distilled off from the reaction solution, 150 ml of 4N hydrochloric acid / ethyl acetate and 300 ml of 1,4-dioxane were added to the obtained residue, and the mixture was irradiated with ultrasonic waves at room temperature for 4 hours and then left overnight. The precipitated product was collected by filtration and washed with ethyl acetate to give 11.85 g.
The title compound was obtained.

Melting point: 244 ° -247 ° C. Reference Example 21 4- (2-hydroxyethyl) phenylcarbamic acid t-
15 g of butyl ester , 2- (4-aminophenyl) ethanol, 15 g
Of triethylamine, 100 ml of water and 250 ml
To a mixture of 1,4-dioxane in 30.6 g of dicarbonate
After adding -t-butyl and stirring at room temperature for 2 hours, the mixture was left for 4 days. Water was added to the reaction mixture, extracted with ethyl acetate,
The organic layer was washed with a saturated saline solution. The extract was dried over anhydrous sodium sulfate, concentrated, and the precipitated crystals were collected by filtration to obtain 50.2 g of the title compound.

Melting point: 104-105 ° C. Reference Example 22 N- [5- [2- (4-t-butoxycarbonylaminopheni)
Le) ethoxy] -2-nitrophenyl] -N-methylcarbami
T-Butyl acid 10 g of 4- (2-hydroxyethyl) phenylcarbamic acid t-butyl ester, 10 g of N- (5-chloro-2-
Nitrophenyl) -N-methylcarbamic acid t-butyl ester, 3.9 g of sodium hydride (55% by weight)
And 200 ml of anhydrous N, N-dimethylformamide were reacted and purified in the same manner as in Reference Example 1 to give 16.4.
g of the title compound were obtained.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 1/3): Rf value =
0.46. Reference Example 23 N- [2-amino-5- [2- (4-t-butoxycarbonylamido)
Nophenyl) ethoxy] phenyl] -N-methylcarbamine
Acid t-butyl ester 16.3 g of N- [5- [2- (4-t-butoxycarbonylaminophenyl) ethoxy] -2-nitrophenyl] -N-methylcarbamic acid t-butyl ester, 2.0 g of 10
The reaction and purification were carried out in the same manner as in Reference Example 2 using a mixed solvent of 200% toluene and methanol (3: 1) with 1% of palladium-carbon to obtain 11.7 g of the title compound.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 1/2): Rf value =
0.35. Reference Example 24 N- [5- [2- (4-t-butoxycarbonylaminopheni)
Le) ethoxy] -2- [4- (2,4-dioxothiazolidine-
5-ylmethyl) phenoxyacetylamino] phenyl]-
8. N-methylcarbamic acid t-butyl ester 11.5 g of N- [2-amino-5- [2- (4-t-butoxycarbonylaminophenyl) ethoxy] phenyl] -N-methylcarbamic acid t-butyl ester 8g of 4-
2. (2,4-dioxothiazolidine-5-ylmethyl) phenoxyacetic acid, 5.7 g of diethyl cyanophosphonate,
The reaction and purification were carried out in the same manner as in Reference Example 4 using 54 g of triethylamine and 150 ml of anhydrous tetrahydrofuran, to obtain 18.3 g of the title compound.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 2/3): Rf value =
0.25. Reference Example 25 5- (4- [6- [2- (4-aminophenyl) ethoxy] -1-me
Tyl-1H-benzimidazol-2-ylmethoxy] ben
Jill) thiazolidine-2,4-dione 18.2 g of N- [5- [2- (4-t-butoxycarbonylaminophenyl) ethoxy] -2- [4- (2,4-dioxothiazolidine-5- Ylmethyl) phenoxyacetylamino]
Phenyl] -N-methylcarbamic acid t-butyl ester was dissolved in 100 ml of trifluoroacetic acid and stirred at 70 ° C. for 3.5 hours. The reaction solution was concentrated, water was added, neutralized with sodium bicarbonate, and extracted with ethyl acetate. After the extract was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give:
9.2 g of the title compound were obtained.

Melting point: 184-188 ° C. Reference Example 26 (7-hydroxynaphthalen-1-yl) carbamic acid t
- butyl ester 24.0g of 1-amino-7-naphthol, triethylamine 61.0 g, bicarbonate di 1,4 dioxane and 100ml in a mixture of water 65.8 g 300 ml -
t-Butyl was added dropwise and stirred at room temperature for 23 hours. After concentrating the reaction mixture, water was added, and the mixture was extracted with ethyl acetate.
The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. 370 ml of the obtained residue
Was dissolved in methanol, and 7.02 g of sodium methoxide was added under ice-cooling, followed by stirring at room temperature overnight. The solvent was distilled off from the reaction solution, water was added, the mixture was neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/2). , 3
2.5 g of the title compound were obtained.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 1/3): Rf value =
0.26. Reference Example 27 [7- [3- (t-butoxycarbonylmethylamino) -4-ni]
Trophenoxy] naphthalen-1-yl] carbamic acid t
-Butyl ester 30.0 g of (7-hydroxynaphthalen-1-yl) carbamic acid t-butyl ester, 33.1 g of N- (5-chloro-2-nitrophenyl) -N-methylcarbamic acid t
-Butyl ester, 10.1 g sodium hydride (55
% By weight) and 400 ml of anhydrous N, N-dimethylformamide in the same manner as in Reference Example 1.
28.8 g of the title compound were obtained.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 1/3): Rf value =
0.59. Reference Example 28 [7- [4-amino-3- (t-butoxycarbonylmethylamido)
No) phenoxy] naphthalen-1-yl] carbamic acid t
-Butyl ester 15.0 g of [7- [3- (t-butoxycarbonylmethylamino) -4-nitrophenoxy] naphthalen-1-yl] carbamic acid t-butyl ester, 1.5 g of 10% palladium-carbon and 160 ml of toluene-ethyl acetate
(1: 1) Using a mixed solvent, the reaction was carried out in the same manner as in Reference Example 2,
Purification provided 14.2 g of the title compound.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 1/2): Rf value =
0.31. Reference Example 29 (7- [3- (t-butoxycarbonylmethylamino) -4-
[4- (2,4-dioxothiazolidine-5-ylmethyl) phenyl
Enoxyacetylamino] phenoxy] naphthalene-1-a
R) Carbamic acid t-butyl ester 14.2 g of [7- [4-amino-3- (t-butoxycarbonylmethylamino) phenoxy] naphthalen-1-yl] carbamic acid t-butyl ester, 9.16 g of 4 -(2,4
-Dioxothiazolidine-5-ylmethyl) phenoxyacetic acid, 5.31 g of diethyl cyanophosphonate, 3.30
The reaction and purification were conducted in the same manner as in Reference Example 4 using g of triethylamine and 280 ml of anhydrous tetrahydrofuran to obtain 20.7 g of the title compound.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 1/1): Rf value =
0.31. Reference Example 30 5- [4- [6- (8-aminonaphthalen-2-yloxy) -1
-Methyl-1H-benzimidazol-2-ylmethoxy] be
Njiru] thiazolidine-2,4-dione 20.7g of (7- [3- (t-butoxycarbonylamino-methyl) -4- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxy-acetylamino] Phenoxy] naphthalen-1-yl) carbamic acid t-butyl ester
Dissolved in 00 ml of anhydrous tetrahydrofuran,
1N 4N hydrochloric acid / 1,4-dioxane was added, and the mixture was added at room temperature.
After stirring for 5 hours, the mixture was left overnight. The precipitated product was collected by filtration, washed with diethyl ether, and dried under reduced pressure. The obtained crude product was dissolved in 150 ml of trifluoroacetic acid, stirred at 70 ° C. for 2.5 hours, and left at room temperature overnight. The reaction mixture was concentrated, water was added, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2/1). 8.78 g of the title compound were obtained.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 2/1): Rf value =
0.30. Reference Example 31 Lithium aluminum hydride (4.0 g) of 3-amino-4-t-butylbenzyl alcohol was suspended in 150 ml of anhydrous tetrahydrofuran, and 10.0 g of 3-aluminum was added.
150 ml of anhydrous tetrahydrofuran solution containing amino-4-t-butylbenzoic acid was added dropwise at room temperature over 45 minutes, and the mixture was stirred at room temperature for 3 hours. 150 ml of the reaction mixture
After diluting with tetrahydrofuran, the mixture was cooled with ice, and unreacted lithium sodium hydride was consumed using a 15% aqueous sodium hydroxide solution. After filtering off insolubles through Celite,
The solvent was distilled off under reduced pressure to obtain 8.41 g of the title compound.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 3/1): Rf value =
0.55. REFERENCE EXAMPLE 32 2- (3-amino-4-t-butylphenyl) ethanol 4.0 g of lithium aluminum hydride was suspended in 150 ml of anhydrous tetrahydrofuran, and 11.1 g of 2- (2-amino-3-tert-butylphenyl) ethanol was suspended.
A solution of methyl 3- (4-amino-4-t-butylphenyl) acetic acid in 70 ml of anhydrous tetrahydrofuran was added dropwise at room temperature over 15 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 150 ml of tetrahydrofuran, cooled on ice, and unreacted lithium sodium hydride was consumed using a 15% aqueous sodium hydroxide solution. After removing the insoluble matter by filtration through Celite, the solvent was distilled off under reduced pressure.
10.2 g of the title compound were obtained.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 3/1): Rf value =
0.49. Reference Example 33 N- [5- (3-amino-4-t-butyl) benzyloxy-2-
Nitrophenyl] -N-methylcarbamic acid t-butyl ether
The ester 5.09 g 3- amino -4-t-butylbenzyl alcohol, the 7.40 g N-(5-chloro-2-nitrophenyl) -
N-methylcarbamic acid t-butyl ester, 1.24
g of sodium hydride (55% by weight) and 120 ml
Reference Example 1 using anhydrous N, N-dimethylformamide
The reaction and purification were carried out in the same manner as in the above to give 2.01 g of the title compound.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 1/2): Rf value =
0.43. Reference Example 34 N- [5- (3-amino-4-t-butylphenyl) ethoxy-
2-nitrophenyl] -N-methylcarbamic acid t-butyl
Glycol ester 5.03g of 2- (3-amino -4-t-butylphenyl) ethanol, 6.78 g of N-(5-chloro-2-nitrophenyl) -N- methylcarbamate t-butyl ester,
1.14 g of sodium hydride (55% by weight) and 1
Using 20 ml of anhydrous N, N-dimethylformamide,
The reaction and purification were conducted in the same manner as in Reference Example 1 to obtain 2.61 g of the title compound.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 1/2): Rf value =
0.53. Reference Example 35 N- [2-amino-5- (3-amino-4-t-butyl) benzyl
Oxyphenyl] -N-methylcarbamic acid t-butyl ester
Of ester 3.02g N- [5- (3- amino -4-t-butyl) benzyloxy-2-nitro-phenyl] -N- methylcarbamate t-butyl ester, sodium dithionite of 4.90 g, 5 A mixture of 0.91 g sodium bicarbonate, 75 ml 1,4-dioxane and 15 ml water was heated at reflux for 30 minutes. After cooling the reaction solution to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1/1). , 1.30
g of the title compound were obtained.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 1/1): Rf value =
0.35. Reference Example 36 N- [2-amino-5- (3-amino-4-t-butylphenyl)
Ethoxyphenyl] t-butyl N-methylcarbamate
2.50 g of ester t-butyl N- [5- (3-amino-4-t-butylphenyl) ethoxy-2-nitrophenyl] -N-methylcarbamate, 0.25 g of 10% palladium on carbon and 50 ml Of toluene-ethyl acetate (1:
1) The reaction and purification were carried out in the same manner as in Reference Example 2 using a mixed solvent to obtain 2.42 g of the title compound.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 1/2): Rf value =
0.14. Reference Example 37 N- [5- (3-amino-4-t-butyl) benzyloxy-2-
[4- (2,4-dioxothiazolidine-5-ylmethyl) phenyl
Phenoxyacetylamino] phenyl] -N-methylcarbami
Acid t-butyl ester 1.86 g of N- [2-amino-5- (3-amino-4-t-butyl) benzyloxyphenyl] -N-methylcarbamic acid t-butyl ester; 1.44 g of 4-tert-butyl ester (2,4-dioxothiazolidine-5-ylmethyl) phenoxyacetic acid, 0.1.
Using 84 g of diethyl cyanophosphonate, 0.52 g of triethylamine and 40 ml of anhydrous tetrahydrofuran, the reaction and purification were carried out in the same manner as in Reference Example 4 to give 1.6.
6 g of the title compound were obtained.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 2/1): Rf value =
0.53. Reference Example 38 N- [5- [2- (3-amino-4-t-butylphenyl) ethoxy]
[S] -2- [4- (2,4-dioxothiazolidine-5-ylmethyl)
Le) phenoxyacetylamino] phenyl] -N-methylca
2.33 g of rubamic acid t-butyl ester N- [2-amino-5- (3-amino-4-t-butylphenyl) ethoxyphenyl] -N-methylcarbamic acid t-butyl ester, 2.36 g of 4-tert-butyl ester (2,4-dioxothiazolidine-5-ylmethyl) phenoxyacetic acid,
Using 1.37 g of diethyl cyanophosphonate, 0.85 g of triethylamine, and 45 ml of anhydrous tetrahydrofuran, the reaction and purification were performed in the same manner as in Reference Example 4.
3.20 g of the title compound were obtained.

Silica gel thin layer chromatography (developing solvent: ethyl acetate / n-hexane = 2/1): Rf value =
0.40. Reference Example 39 5- [4- [6- (3-amino-4-t-butyl) benzyloxy]
-1-Methyl-1H-benzimidazol-2-ylmethoxy
[S] benzyl] thiazolidine-2,4-dione dihydrochloride 1.60 g of N- [5- (3-amino-4-t-butyl) benzyloxy-2- [4- (2,4-dioxo) Thiazolidine-5-ylmethyl) phenoxyacetylamino] phenyl] -N-methylcarbamic acid t-butyl ester in 20 ml of 1,
Dissolve in a mixed solvent of 4-dioxane-ethanol (1: 1), add 10 ml of 4N hydrochloric acid / 1,4-dioxane,
After stirring at room temperature for 4 hours, the mixture was left overnight. The precipitated product was collected by filtration and washed with ethyl acetate to obtain 1.28 g of the title compound.

Melting point: 152-157 ° C. Reference Example 40 5- [4- [6- [2- (3-amino-4-t-butylphenyl) d)
Toxy] -1-methyl-1H-benzimidazol-2-yl
[Methoxy] benzyl] thiazolidine-2,4-dione disalt
Acid salt 3.08g N- [5- [2- (3- amino -4-t-butylphenyl) ethoxy] -2- [4- (2,4-dioxothiazolidin
-5-ylmethyl) phenoxyacetylamino] phenyl]
30m of -N-methylcarbamic acid t-butyl ester
1N 1,4-dioxane, 30 ml of 4N hydrochloric acid / 1,4-dioxane was added, and the mixture was allowed to stand at room temperature overnight.
0 ml of ethanol was added and left for another 6 days. The precipitated product was collected by filtration and washed with ethyl acetate.
48 g of the title compound were obtained.

Melting point: 163-167 ° C. Reference Example 41 2-chloromethyl-5- (3,5-dimethylphenylthio)-
41.3 g of 3-methyl-3H-imidazo [4,5-b] pyridine 3,5-dimethylbenzenethiol;
A mixture of 1 g of 6-chloro-2-methylamino-3-nitropyridine, 207 g of potassium carbonate and 300 ml of anhydrous N, N-dimethylformamide at 80 ° C. for 1.5
Stirred for hours. After concentrating the reaction solution, water was added, the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, the obtained residue was
l of ethanol-toluene (1: 1) mixed solvent,
41.1 g of 10% palladium-carbon was added, followed by vigorous stirring at room temperature for 4 hours under a hydrogen atmosphere. After removing the catalyst from the reaction mixture by filtration, the solvent was distilled off, and 68.4 was added to the obtained residue.
g glycolic acid was added and heated to 150 ° C. 1.5
After an hour, 200 ml of 3N hydrochloric acid was added, and the mixture was further heated under reflux for 1 hour. The reaction solution was neutralized with 10% aqueous sodium bicarbonate, and the precipitated product was collected by filtration, washed with water and ethyl acetate, and then dried under reduced pressure. The resulting 5- (3,5-dimethylphenylthio) -2-hydroxymethyl-3-methyl-3H-imidazo
[4,5-b] pyridine was dissolved in 150 ml of thionyl chloride and stirred at a bath temperature of 80 ° C. for 30 minutes. Concentrate the reaction,
After water was added, the mixture was neutralized with sodium bicarbonate and extracted with ethyl acetate.
After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off,
The obtained residue is subjected to silica gel column chromatography.
Purification with (eluting solvent: ethyl acetate / n-hexane = 1/1) gave 54.3 g of the title compound.

Melting point: 87-90 ° C. Reference Example 42 2-chloromethyl-5- (3,5-dimethyl-4-nitrophenyl)
Ruthio) -3-methyl-3H-imidazo [4,5-b] pyridine 2.54 g of 2-chloromethyl-5- (3,5-dimethylphenylthio) -3-methyl-3H-imidazo [4,5 -b] pyridine in a mixture of 5 ml of sulfuric acid and 45 ml of acetic acid.
52 ml of nitric acid was added under ice-cooling, and the mixture was left at room temperature for 64 hours. The reaction solution was concentrated, water was added, neutralized with sodium bicarbonate, and extracted with ethyl acetate. After evaporating the solvent from the extract, the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1/1) to obtain 0.53 g of the title compound.

Melting point: 133-135 ° C. Reference Example 43 5- [4- [5- (3,5-dimethyl-4-nitrophenylthio)]
-3-Methyl-3H-imidazo [4,5-b] pyridin-2-yl
Methoxy] benzyl] thiazolidine-2,4-dione containing 0.12 g of sodium hydride (55% by weight) 6
0.2 ml of anhydrous N, N-dimethylformamide suspension.
31 g of 5- (4-hydroxybenzyl) thiazolidine-
2,4-dione was added and stirred at room temperature for 20 minutes. Then 0.51 g of 2-chloromethyl-5- (3,5-dimethyl
-4-Nitrophenylthio) -3-methyl-3H-imidazo
14 ml of anhydrous N, N-dimethylformamide solution containing [4,5-b] pyridine was added dropwise, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated, neutralized with 3N hydrochloric acid and sodium bicarbonate, and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate and the solvent was distilled off, the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 0.39 g of the title compound.

Silica gel thin layer chromatography (developing solvent: ethyl acetate): Rf value = 0.60.

[0371]

[Test Example] Hypoglycemic action Blood was collected from the tail vein of a KK mouse (4-5 months old) who developed diabetes, and the blood glucose level was measured. Next, the mice were divided into groups (4 mice per group) so that the average of the blood glucose levels of the mice in each group was the same, and then a powdered feed for mice (F- (1, Funabashi Farm) for 3 days. The group of mice receiving the test compound was designated as the drug-administered group. In addition, the group which received the powder feed which does not contain a test compound was set as the control group. Three days later, blood was collected from the tail vein of the mouse, and the glucose concentration in the plasma obtained by centrifugation was measured using a glucose analyzer (Gluco Lauder, A & T). The average blood glucose lowering rate was determined from the following equation. Hypoglycemic rate (%) = (average blood glucose level of control group−average blood glucose level of drug administration group) × 100 / blood glucose level of control group

[0372]

[Table 47] Test compound Blood glucose lowering rate (%) Compound of Example 2 48.9 3 49.9 4 48.6 5 36.2 9 47.1 11 32.9 12 56.1 14 63.2 16 42.9 18 61.0 31 50.5 33 30 0.434 32.8 37 35.2 40 59.3 44 47.2 45 54.1 52 58.5 53 59.6 54 43.4 55 53.8 56 63.6 57 57.3 59 56.8 60 49.8 61 54.2 63 55.7 64 43.5 From the above results, it was revealed that the compound of the present invention exhibits an excellent blood glucose lowering effect.

[0373]

[Formulation Examples] (1) Capsule Compound of Example 2 10 mg Lactose 110 mg Corn starch 58 mg Magnesium stearate 2 mg ─────── 180 mg The powder of each component shown above is mixed well and passed through a 60-mesh sieve (mesh standard is based on Tyler standard). 180 mg of the obtained powder is weighed and filled into a gelatin capsule (No. 3) to prepare a capsule. (2) Tablet Compound of Example 2 10 mg Lactose 85 mg Corn starch 34 mg Microcrystalline cellulose 20 mg Magnesium stearate 1 mg １５０ 150 mg Mix the powder of each component shown above well,
Compress to tablets of mg weight. If desired, these tablets may be coated with a sugar or film. (3) Granules Compound of Example 2 10 mg Lactose 839 mg Corn starch 150 mg Hydroxypropylcellulose 1 mg １０００ 1000 mg The powder of each component shown above is mixed well, moistened with pure water, granulated with a basket granulator, and dried to obtain granules.

[0374]

The compound having the above general formula (I) or a pharmacologically acceptable salt thereof according to the present invention has excellent insulin resistance improving action, hypoglycemic action, anti-inflammatory action, immunomodulatory action, aldose reductase. Inhibition, 5-lipoxygenase inhibitory action, lipid peroxide production inhibitory action, PPAR activating action, anti-osteoporosis action, leukotriene antagonism, adipocyte promotion, cancer cell growth inhibitory action, calcium antagonistic action, diabetes, Hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.),
Atherosclerosis, gestational diabetes, polycystic ovary syndrome, cardiovascular disease (for example, ischemic heart disease etc.), cell damage caused by non-atherosclerotic disease or ischemic heart disease (for example, Gout, inflammatory diseases (eg, osteoarthritis, pain,
Fever, rheumatoid arthritis, inflammatory bowel disease, acne, sunburn, psoriasis, eczema, allergic disease, asthma, GI ulcer,
Cachexia, autoimmune disease, pancreatitis. ), Cancer, osteoporosis, cataract and the like.

Further, the compound of the present invention having the above general formula (I) or a pharmaceutically acceptable salt thereof, an α-glucosidase inhibitor, an aldose reductase inhibitor, a biguanide agent, a statin compound, a squalene synthesis inhibitor And a pharmaceutical composition comprising a combination of at least one of a fibrate compound, an LDL catabolism promoter, an angiotensin converting enzyme inhibitor and an FBPase inhibitor (particularly preferably, a prophylactic and / or therapeutic agent for diabetes or diabetic complications. Are also useful.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 3/10 A61P 3/10 19/10 19/10 29/00 29/00 35/00 35/00 37 / 02 37/02 43/00 43/00 105 105 111 111 C07D 417/12 C07D 417/12 471/04 107 471/04 107E (72) Inventor Minoru Oguchi 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Hidehito Honma 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Toshihiko Fujiwara 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. F-term in the formula company (reference) 4C063 AA01 BB08 CC52 CC62 DD26 EE01 4C065 AA01 AA04 BB06 DD03 EE02 HH01 JJ03 JJ09 KK04 KK09 PP03 PP04 4C086 AA01 AA02 AA03 BC69 BC82 CB05 GA07 GA09 ZA10 ZB11

Claims (46)

[Claims] 1. A compound of the general formula (I)[Where R₁Is a carbamoyl group (substituted α described later is 1 or
You may have two. ), Thiocarbamoyl group (described later)
May have one or two substituents α. ),
A rufonyl group (having one substituent α described later), or
Is a carbonyl group (having one substituent α described later)
And R_TwoAnd R_ThreeIs a hydrogen atom, C₁-C_TenAlkyl group,
C₆-C_TenAryl group (having 1 to 3 substituents β described later)
May be. ) Or C₇-C₁₆Aralkyl group (aryl moiety
May have 1 to 3 substituents β described later.
No. ) And W₁, W_TwoAnd W_ThreeIs a single bond or C₁-C₈Archire
X, Y and Q each represent an oxygen atom or a sulfur atom
Z represents a = CH- group or a nitrogen atom; Ar represents a benzene ring or a naphthalene ring; L represents 1 to 4 substituents on the Ar ring;
Each hydrogen atom, C₁-C ₆Alkyl group, C₆-C_TenAryl group
(It may have 1 to 3 substituents β described later.),
Or C₇-C₁₆Aralkyl group (substituted later in the aryl moiety
It may have 1 to 3 components β. ), And the substitution α is (i) C₁-C_TenAlkyl group, (ii) C₁-C₆Halogeno
Alkyl group, (iii) C_Three-C_TenCycloalkyl group, (iv) C₆-C
_TenAryl group (having 1 to 3 substituents γ described later)
You may. ), (V) C₇-C₁₆Aralkyl group (in the aryl moiety
It may have 1 to 3 substitution components γ described later. ),
(vi) C_Four-C₁₁Cycloalkylcarbonyl group, (vii) C₇-C₁₁
Arylcarbonyl group (substituted part described later
It may have 1 to 3 γ. ), (Viii) C₈-C₁₇A
Aralkylcarbonyl group (substituted portion described later in the aryl portion)
It may have 1 to 3 γ. ), (Ix) heteroaromatic ring
Group (may have 1 to 3 substituents γ described later)
No. ), (X) heteroaromatic carbonyl group (substituted γ described below)
May be provided. ), (Xi) C₁-C₆Alkyl
Sulfonyl group, (xii) C₁-C₆Halogenoalkylsulfonyl
Group, (xiii) C₆-C_TenArylsulfonyl group (aryl moiety
May have 1 to 3 substitutions γ described later.
No. ) Or (xiv) C₇-C₁₆Aralkylsulfonyl group (ant
May have 1 to 3 substituents γ described later in the
Good. ), And the substitution β is (i) C₁-C₆Alkyl group, (ii) C₁-C₆Halogeno
Alkyl group, (iii) C₁-C ₆Alkoxy group, (iv) halogen source
(Vi) hydroxy group, (vi) C₆-C_TenAryl group (described below)
It may have 1 to 3 substitutions δ. ), (Vii) C₇-C
₁₆An aralkyl group (substituted δ described below is
It may have three to three. ), (Viii) cyano group, (ix)
A nitro group or an (x) amino group (substitution
Or two of them. ), The substitution γ is (i) C₁
-C₆Alkyl group, (ii) C₁-C₆Halogenoalkyl group, (iii) C
₁-C ₆Alkoxy group, (iv) halogen atom, (v) hydroxy
Group, (vi) cyano group, (vii) nitro group, (viii) C_Three-C_TenShiku
Loalkyl group, (ix) C₆-C_TenAryl group (as a substituent,
C₁-C₆Alkyl group, C₁-C₆Halogenoalkyl group, C₁-C₆A
May have 1 to 3 alkoxy groups and 1 to 3 halogen atoms
No. ), (X) C₇-C₁₆Aralkyl groups (substituted on aryl
As C₁-C₆Alkyl group, C₁-C₆A halogenoalkyl group,
C₁-C₆Having 1 to 3 alkoxy groups and halogen atoms
May be. ), (Xi) C₁-C₇Aliphatic acyl group, (xii) C₁-C
₇Aliphatic acyloxy group, (xiii) amino group, (xiv) di C₁-C
₆Alkylamino group, or (xv) C₁-C_FourAlkylenedioxy
And the substituent δ is (i) C₁-C_TenAlkyl group, (ii) C₆-C_TenAlly
Group (substituted as C ₁-C₆Alkyl group, C₁-C₆Halogeno
Alkyl group, C₁-C₆One alkoxy group and one halogen atom
You may have up to three. ), (Iii) C₇-C₁₆Aralkyl
Group (substituted on aryl as C₁-C₆Alkyl group, C₁-
C₆Halogenoalkyl group, C₁-C₆Alkoxy group, halogen
It may have 1 to 3 atoms. ), (Iv) C₁-C₇Fat
Aliphatic acyl group, (v) C_Four-C₁₁Cycloalkylcarbonyl
Group, (vi) C₇-C₁₁Arylcarbonyl group (as a substituent,
C₁-C₆Alkyl group, C₁-C₆Halogenoalkyl group, C₁-C₆A
May have 1 to 3 alkoxy groups and 1 to 3 halogen atoms
No. ), (Vii) C₈-C₁₇Aralkylcarbonyl group (aryl
As a substitution above, C₁-C₆Alkyl group, C₁-C₆Halogenoa
Lucyl group, C₁-C₆Alkoxy group, halogen atom 1 to
You may have three. ), (Viii) heteroaromatic carbonyl
Group (substituted as C₁-C₆Alkyl group, C₁-C₆Halogeno
Alkyl group, C₁-C₆One alkoxy group and one halogen atom
You may have up to three. ). Amine having
A derivative compound or a pharmacologically acceptable salt thereof. 2. The method according to claim 1, wherein R ₁ is a carbamoyl group (which may have one substitution α) or a thiocarbamoyl group (which may have one substitution α). , A sulfonyl group (having one substitution α), or a carbonyl group (having one substitution α), or a pharmaceutically acceptable salt thereof. 3. The method according to claim 1, wherein R ₁ is a carbamoyl group (having one substitution α), a thiocarbamoyl group (having one substitution α), and a sulfonyl group (having one substitution α). Has one substitution α)),
Or an amine derivative compound having a carbonyl group (having one substituent α) or a pharmaceutically acceptable salt thereof. 4. The method according to claim 1, wherein R ₁ is a carbamoyl group (having one substituent α).
Or a pharmacologically acceptable salt thereof. 5. The amine derivative compound according to claim 1, wherein R ₁ represents a carbonyl group (having one substituent α) or a pharmaceutically acceptable salt thereof. 6. The method according to claim 1, wherein R ₂ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl group, a phenyl group (which may have one substituent β), or a benzyl group (phenyl). Or a pharmacologically acceptable salt thereof. 7. The amine derivative compound according to claim 1, wherein R ₂ represents a hydrogen atom or a C ₁ -C ₁₀ alkyl group, or a pharmaceutically acceptable salt thereof. 8. The amine derivative compound according to claim 1, wherein R ₂ represents a hydrogen atom, or a pharmaceutically acceptable salt thereof. 9. The amine derivative compound according to claim 1, wherein R ₂ represents a C ₁ -C ₆ alkyl group, or a pharmaceutically acceptable salt thereof. 10. The method according to claim 1, wherein R ₃ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a phenyl group (which may have one substituent β), or a benzyl group (phenyl). Or a pharmacologically acceptable salt thereof. 11. The amine derivative compound according to claim 1, wherein R ₃ represents a hydrogen atom or a C ₁ -C ₄ alkyl group, or a pharmaceutically acceptable salt thereof. 12. The amine derivative compound according to claim 1, wherein R ₃ represents a C ₁ -C ₂ alkyl group, or a pharmaceutically acceptable salt thereof. 13. The amine derivative compound according to claim 1, wherein W ₁ , W ₂ and W ₃ each represent a single bond or a C ₁ -C ₄ alkylene group, or a pharmaceutically acceptable salt thereof. 14. The amine derivative compound according to claim 1, wherein W ₁ and W ₂ each represent a single bond or a C ₁ -C ₄ alkylene group, and W ₃ represents a C ₁ -C ₂ alkylene group. Its pharmacologically acceptable salts. 15. The amine derivative compound according to claim 1, wherein W ₁ and W ₂ each represent a single bond or a C ₁ -C ₂ alkylene group, and W ₃ represents a methylene group, or a pharmacologically acceptable compound thereof. Salt. 16. An amine derivative compound according to claim 1, wherein X represents an oxygen atom or a sulfur atom, Y represents an oxygen atom, and Q represents a sulfur atom, or a pharmaceutically acceptable salt thereof. 17. The method according to claim 1, wherein X represents an oxygen atom, Y represents an oxygen atom, and Q represents
An amine derivative compound having a sulfur atom or a pharmacologically acceptable salt thereof. 18. The amine derivative compound according to claim 1, wherein Z is ＝ CH—, or a pharmaceutically acceptable salt thereof. 19. The amine derivative compound according to claim 1, wherein Z represents a nitrogen atom, or a pharmaceutically acceptable salt thereof. 20. The amine derivative compound according to claim 1, wherein Ar represents a naphthalene ring, or a pharmacologically acceptable salt thereof. 21. The amine derivative compound according to claim 1, wherein Ar represents a benzene ring, or a pharmaceutically acceptable salt thereof. 22. The method according to claim 1, wherein L is 1 to 4 substituents on the Ar ring.
Each hydrogen atom, C₁-C ₆Alkyl group, phenyl group (substituted
It may have 1 to 3 β. ) Or benzyl group
(It may have 1 to 3 substituents β in the phenyl moiety.
No. ) Or a pharmacologically acceptable amine derivative compound thereof
Salt. 23. The amine derivative compound according to claim 1, wherein L is 1 to 4 substituents on the Ar ring, and each represents a hydrogen atom or a C ₁ -C ₆ alkyl group, or a pharmaceutically acceptable derivative thereof. Acceptable salt. 24. The amine derivative compound according to claim 1, wherein L represents a hydrogen atom, or a pharmaceutically acceptable salt thereof. 25. The method of claim 1 to 24, substituent α is, (i) C ₁ -C ₈ alkyl group, (ii) C ₅ -C ₁₀ cycloalkyl _{group, (iii) C 6 -C 1} 0 aryl Group (substituted γ is 1 to 3
You may have one. ), (Iv) phenyl C ₁ -C ₄ alkyl group
(The phenyl moiety may have 1 to 3 substituents γ), (v) a pyridyl group, or (vi) a phenylsulfonyl group (when the phenyl moiety has 1 to 3 substituents γ, Or a pharmacologically acceptable salt thereof. 26. The method of claim 1 to 24, substituent α is, (i) C ₁ -C ₄ alkyl group, (ii) C ₅ -C ₁₀ cycloalkyl _{group, (iii) C 6 -C 1} 0 aryl Group (substituted γ is 1 to 3
You may have one. ), (Iv) a benzyl group (which may have 1 to 3 substituents γ in the phenyl moiety), or (v)
An amine derivative compound showing a pyridyl group or a pharmacologically acceptable salt thereof. 27. The method of claim 1 to 24, substituent α is, (i) C ₁ -C ₄ alkyl group, (ii) C ₅ -C ₁₀ cycloalkyl _{group, (iii) C 6 -C 1} 0 aryl Group (substituted γ is 1 to 3
You may have one. ), (Iv) a benzyl group (which may have 1 to 3 substituents γ in the phenyl moiety), or (v)
An amine derivative compound showing a pyridyl group or a pharmacologically acceptable salt thereof. 28. The amine derivative compound according to claim 1, wherein the substituted α is a phenyl group (which may have 1 to 3 substituted γ) or a pharmaceutically acceptable salt thereof. 29. The method according to claim 1, wherein the substituent β is (i) a C ₁ -C ₄ alkyl group, (ii) a trifluoromethyl group, (iii) a C ₁ -C ₂ alkoxy group, (iv) Halogen atom,
(v) An amine derivative compound showing a hydroxy group or (vi) an amino group or a pharmaceutically acceptable salt thereof. 30. The method according to claim 1, wherein the substituent β is (i) a C ₁ -C ₄ alkyl group, (ii) a halogen atom,
Or (iii) an amine derivative compound showing a hydroxy group or a pharmacologically acceptable salt thereof. 31. The method according to claim 1, wherein the substitution γ is (i) C₁-C₆Alkyl group, (ii) C₁-C_TwoHalogeno
Alkyl group, (iii) C₁-C _FourAlkoxy group, (iv) halogen source
(V) hydroxy group, (vi) cyano group, (vii) nitro group,
(viii) C₁-C_TwoAliphatic acyl group, or (ix) C₁-C_FourAlkylene
Amine derivative compound showing dioxy group or its pharmacologically acceptable
Salt to be carried. 32. The method according to claim 1, wherein the substituent γ is (i) a C ₁ -C ₆ alkyl group, (ii) a trifluoromethyl group, (iii) a C ₁ -C ₄ alkoxy group, (iv) Halogen atom,
(v) hydroxy group, (vi) cyano group, (vii) nitro group, (vii
i) An amine derivative compound showing a C ₁ -C ₂ aliphatic acyl group or (ix) a C ₁ -C ₄ alkylenedioxy group, or a pharmaceutically acceptable salt thereof. 33. The method according to claim 1, wherein the substituent γ represents (i) a C ₁ -C ₄ alkyl group, (ii) a trifluoromethyl group, (iii) a halogen atom, or (iv) a nitro group. An amine derivative compound or a pharmacologically acceptable salt thereof. 34. The method according to claim 1, wherein the substitution δ is (i) C₁-C_FourAlkyl group, (ii) phenyl group, (i
ii) benzyl group, (iv) C ₁-C_FiveAn aliphatic acyl group, or (v)
Amine derivative compound showing an nzoyl group or its pharmacologically acceptable
Salt to be carried. 35. An amine derivative compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 33, wherein the substituent δ represents a C ₁ -C ₄ alkyl group or a C ₁ -C ₂ aliphatic acyl group. 36. The method according to claim 1, wherein R₁Is a carbamoyl group (which may have one substituent α)
No. ), A thiocarbamoyl group (having one substituted α
Is also good. ), A sulfonyl group (having one substituent α)
You. ) Or a carbonyl group (having one substituent α)
You. ), R_TwoIs a hydrogen atom, C₁-C_TenAlkyl group, phenyl group (substituted
May have one component β. ) Or benzyl group (Fe
The nyl moiety may have one substitution β. )
Then R_ThreeIs a hydrogen atom, C₁-C₆Alkyl group, phenyl group (substituted
May have one component β. ) Or benzyl group (Fe
The nyl moiety may have one substitution β. )
Then W₁, W_TwoAnd W_ThreeIs a single bond or C₁-C_FourArchire
X represents an oxygen atom or a sulfur atom, and Y represents an oxygen atom
, Q represents a sulfur atom, Z represents a = CH- group, Ar represents a benzene ring, L represents 1 to 4 substituents on the Ar ring,
Each hydrogen atom, C₁-C ₆Alkyl group, phenyl group (substituted
It may have 1 to 3 β. ) Or benzyl group
(It may have 1 to 3 substituents β in the phenyl moiety.
No. ), And the substitution α is (i) C₁-C₈Alkyl group, (ii) C_Five-C_TenCycloa
Alkyl group, (iii) C₆-C_{1 0}Aryl group (substitution γ is 1 to 3
You may have one. ), (Iv) phenyl C₁-C_FourAlkyl group
(It may have 1 to 3 substituents γ in the phenyl moiety.
No. ), (V) pyridyl group, (vi) methanesulfonyl group, (vi
i) trifluoromethanesulfonyl group, or (viii) phenyl
Rusulfonyl group (1 to 3 substituents γ in phenyl moiety)
You may have. ), And the substitution β is (i) C₁-C_FourAlkyl group, (ii) trifluoromethyl
A tyl group, (iii) C₁-C_TwoAlkoxy group, (iv) halogen atom,
(v) a hydroxy group, or (vi) an amino group, wherein the substituent γ is (i) C₁-C₆Alkyl group, (ii) C₁-C_FourHalogeno
Alkyl group, (iii) C₁-C ₆Alkoxy group, (iv) halogen source
(V) hydroxy group, (vi) cyano group, (vii) nitro group,
(viii) phenyl group, (ix) benzyl group, (x) C₁-C_FiveAliphatic
A sil group, (xi) an amino group, or (xii) C₁-C_FourAlkylenedio
Amine derivative compound showing xy group or its pharmacologically acceptable
Salt. 37. The method according to claim 1, wherein R ₁ is a carbamoyl group (having one substituent α), a thiocarbamoyl group (having one substituent α), and a sulfonyl group (having one substituent α). Has one substitution α)),
R ₂ represents a hydrogen atom or a C ₁ -C ₁₀ alkyl group; R ₃ represents a hydrogen atom or a C ₁ -C ₄ X represents an alkyl group; W ₁ and W ₂ each represent a single bond or a C ₁ -C ₄ alkylene group; W ₃ represents a C ₁ -C ₂ alkylene group; and X represents an oxygen atom or a sulfur atom. , Y represents an oxygen atom, Q represents a sulfur atom, Z represents a = CH- group, Ar represents a benzene ring, and L represents 1 to 4 substituents on the Ar ring. Each represents a hydrogen atom or a C ₁ -C ₄ alkyl group, and the substitution α is (i) a C ₁ -C ₈ alkyl group, (ii) a C ₅ -C ₁₀ cycloalkyl group, (iii) C ₆ -C _{1 0} aryl group (the substituent gamma 1 to 3
You may have one. ), (Iv) phenyl C ₁ -C ₄ alkyl group
(The phenyl moiety may have 1 to 3 substituents γ), (v) a pyridyl group, or (vi) a phenylsulfonyl group (when the phenyl moiety has 1 to 3 substituents γ, Wherein γ is (i) a C ₁ -C ₆ alkyl group, (ii) a trifluoromethyl group, (iii) a C ₁ -C ₄ alkoxy group, (iv) a halogen atom,
(v) hydroxy group, (vi) cyano group, (vii) nitro group, (vii
i) An amine derivative compound showing a C ₁ -C ₂ aliphatic acyl group or (ix) a C ₁ -C ₄ alkylenedioxy group, or a pharmaceutically acceptable salt thereof. 38. The method according to claim 1, wherein₁Is a carbamoyl group (having one or two
May be. ), Thiocarbamoyl group (substituted α
Or it may have two. ) Or a sulfonyl group (position
It has one substitution α. ), R_TwoAnd R_ThreeIs a hydrogen atom, C₁-C_TenAlkyl group,
C₆-C_TenAryl group (even if it has 1 to 3 substituents β)
Good. ) Or C₇-C₁₆Aralkyl group (substituted with aryl moiety)
It may have 1 to 3 components β. ) And W₁, W_TwoAnd W_ThreeIs a single bond or C₁-C₈Archire
X, Y and Q each represent an oxygen atom or a sulfur atom
Z represents a ＣＨCH— group or a nitrogen atom; Ar represents a benzene ring or a naphthalene ring; L represents 1 to 4 substitutions on the Ar ring;
Atom, C₁-C₆Alkyl group, C₆-C_TenAryl group (substituted β
You may have 1 to 3 pieces. ) Or C₇-C₁₆Aralki
Group having 1 to 3 substituents β in the aryl moiety
Is also good. ), And the substitution α is (i) C₁-C_TenAlkyl group, (ii) C₁-C₆Halogeno
Alkyl group, (iii) C_Three-C_TenCycloalkyl group, (iv) C₆-C
_TenAryl group (which may have 1 to 3 substituents γ)
No. ), (V) C₇-C₁₆Aralkyl group (substituted on aryl moiety
It may have 1 to 3 γ. ), (Vi) C_Four-C₁₁Shiku
Loalkylcarbonyl group, (vii) C₇-C₁₁Aryl carb
Nyl group (having 1 to 3 substituents γ in the aryl moiety)
You may. ), (Viii) C₈-C₁₇Aralkylcarbonyl group (A
The reel portion may have one to three replacement parts γ.
No. ), (Ix) a heteroaromatic group (having 1 to 3 substituents γ
May be. ), (X) heteroaromatic carbonyl group (substituted γ
May be provided. ), (Xi) C₁-C₆Alkyl
Sulfonyl group, (xii) C₁-C₆Halogenoalkylsulfonyl
Group, (xiii) C₆-C_TenArylsulfonyl group (aryl moiety
May have 1 to 3 substitutions γ. ) Or (xi
v) C₇-C₁₆Aralkylsulfonyl group (substituted with aryl moiety)
It may have 1 to 3 components γ. ), And the substitution β is (i) C₁-C₆Alkyl group, (ii) C₁-C₆Halogeno
Alkyl group, (iii) C₁-C ₆Alkoxy group, (iv) halogen source
(Vi) hydroxy group, (vi) C₆-C_TenAryl group (substituted δ
May be provided. ), (Vii) C₇-C₁₆Aral
A kill group (having 1 to 3 substituents δ in the aryl moiety)
You may. ), (Viii) cyano group, (ix) nitro group, or (x)
Amino group (may have one or two substituents δ)
And the substitution γ is (i) C₁-C₆Alkyl group, (ii) C₁-C₆Halogeno
Alkyl group, (iii) C₁-C ₆Alkoxy group, (iv) halogen source
(V) hydroxy group, (vi) cyano group, (vii) nitro group,
(viii) C_Three-C_TenCycloalkyl group, (ix) C₆-C_TenAryl group
(As a replacement, C₁-C₆Alkyl group, C₁-C₆Halogenoal
Kill group, C₁-C₆1 to 3 alkoxy groups and halogen atoms
You may have one. ), (X) C₇-C₁₆Aralkyl groups (A
C on the reel as replacement₁-C₆Alkyl group, C₁-C₆Halo
Genoalkyl group, C₁-C₆Alkoxy group, halogen atom
You may have 1 to 3 pieces. ), (Xi) C₁-C₇Aliphatic
A sil group, (xii) C₁-C₇Aliphatic acyloxy group, (xiii)
No group, (xiv) di C₁-C₆Alkylamino, or (xv) C₁-C_FourA
Represents a alkylenedioxy group, and the substitution δ is (i) C₁-C_TenAlkyl group, (ii) C₆-C_TenAlly
Group (substituted as C ₁-C₆Alkyl group, C₁-C₆Halogeno
Alkyl group, C₁-C₆One alkoxy group and one halogen atom
You may have up to three. ), (Iii) C₇-C₁₆Aralkyl
Group (substituted on aryl as C₁-C₆Alkyl group, C₁-
C₆Halogenoalkyl group, C₁-C₆Alkoxy group, halogen
It may have 1 to 3 atoms. ), (Iv) C₁-C₇Fat
Aliphatic acyl group, (v) C_Four-C₁₁Cycloalkylcarbonyl
Group, (vi) C₇-C₁₁Arylcarbonyl group (as a substituent,
C₁-C₆Alkyl group, C₁-C₆Halogenoalkyl group, C₁-C₆A
May have 1 to 3 alkoxy groups and 1 to 3 halogen atoms
No. ), (Vii) C₈-C₁₇Aralkylcarbonyl group (aryl
As a substitution above, C₁-C₆Alkyl group, C₁-C₆Halogenoa
Lucyl group, C₁-C₆Alkoxy group, halogen atom 1 to
You may have three. ) Or (viii) heteroaromatic ring
Bonyl group (substituted as C₁-C₆Alkyl group, C₁-C₆Halo
Genoalkyl group, C₁-C₆Alkoxy group, halogen atom
You may have 1 to 3 pieces. ). A having
A min derivative compound or a pharmacologically acceptable salt thereof. 39. The method according to claim 1, wherein 1- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy is used. ] Phenyl) -3-ethylurea, 1- (adamantan-1-yl) -3- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl]
-1-Methyl-1H-benzimidazol-6-yloxy]
Phenyl) urea, 1- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- Phenylurea, 1- (2,4-difluorophenyl) -3- [2- (4- [2- [4-
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) ethyl] urea, 1- (4- [2- [4- [2, 4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] -2,6-dimethylphenyl) -3
-(4-nitrophenyl) urea, 1- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] (Phenyl) -1-n-hexyl-3
-(4-fluorophenyl) urea, 1- (2,6-diisopropylphenyl) -3- (7- [2- [4-
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] naphthalen-1-yl) urea, 1-benzyl-3- (7- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1
[H-benzimidazol-6-yloxy] naphthalene-1-
Yl) urea, 1- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (c-hexyl)
Thiourea, 1-benzyl-3- (7- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1
[H-benzimidazol-6-yloxy] naphthalene-1-
Yl) thiourea, 1- (4-chlorophenyl) -3- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl]-
1-methyl-1H-benzimidazol-6-yloxy]-
2,6-dimethylphenyl) thiourea, N- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy ] Phenyl) methanesulfonamide, 1- (3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3-phenylurea, 1- (3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl)- 3- (2-trifluoromethylphenyl) urea, 1- (3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6 -Yloxy] phenyl) -3- (4-trifluoromethylphenyl) urea, 1- (3- [2- [4- ( , 4-Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (4-fluorophenyl) urea, 1- (3- [2- [ 4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (4-trifluoromethyl) benzylurea, N- [ 4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] acetamide, N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] -NN-hexylacetamide, N- [4- [2 -[4- (2,4-Dioxothiazolidine-5-ylmethyl) phenoxymethyl]- -Methyl-1H-benzimidazol-6-yloxy] phenyl] cyclopentanecarboxylic acid amide, N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-] Methyl-1H-benzimidazol-6-yloxy] phenyl] benzamide, N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H- Benzimidazol-6-yloxy] phenyl] naphthalene-2-carboxylic acid amide, 2,4-difluoro-N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-Methyl-1H-benzimidazol-6-yloxy] phenyl]
Benzamide, 3-chloro-N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-
Benzimidazol-6-yloxy] phenyl] benzamide, N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6 -Yloxy] phenyl] nicotinamide, N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] Phenyl] isonicotinamide, 3,5-di-t-butyl-N- [2- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-) Methyl-1H-benzimidazol-6-yloxy] phenyl) ethyl] -4-hydroxybenzamide, 2
-(3-Chlorophenyl) -N- [2- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl]
-1-Methyl-1H-benzimidazol-6-yloxy]
Phenyl] ethyl] acetamide, N- [2- [4- [2- [4- (2,4-dioxothiazolidine-5-
Ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] ethyl] nicotinamide, or a pharmaceutically acceptable salt thereof. 40. The method according to claim 1, wherein 1- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy is used. ] Phenyl) -3-ethylurea, 1- (adamantan-1-yl) -3- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl]
-1-Methyl-1H-benzimidazol-6-yloxy]
Phenyl) urea, 1- (2,4-difluorophenyl) -3- [2- (4- [2- [4-
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) ethyl] urea, 1-benzyl-3- (7- [2- [4 -(2,4-Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1
[H-benzimidazol-6-yloxy] naphthalene-1-
Yl) urea, 1- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (c-hexyl)
Thiourea, N- (4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) methanesulfonamide, 1- (3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3-phenylurea, 1 -(3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (2-trifluoro Methylphenyl) urea, 1- (3- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3 -(4-trifluoromethylphenyl) urea, 1- (3- [2- [4- [2,4-dioxothiazolidy 5-N-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl) -3- (4-fluorophenyl) urea, N- [4- [2- [4- (2, 4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] acetamide, N- [4- [2- [4- [2,4-dioxothiazolidine] -5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] cyclopentanecarboxamide, N- [4- [2- [4- (2,4-dioxothiazolidine-)] 5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] benzamide, 2,4-difluoro-N- [4- [2- [4- [2,4-dioxo] Thiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazo -6-yloxy] phenyl]
Benzamide, N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] nicotinamide, (6-37) N- [4- [2- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1
H-benzimidazol-6-yloxy] phenyl] isonicotinamide, N- [2- [4- [2- [4- (2,4-dioxothiazolidine-5-)]
Ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] ethyl] nicotinamide or a pharmaceutically acceptable salt thereof. 41. A medicament comprising the compound according to any one of claims 1 to 40 as an active ingredient. (42) an agent for improving insulin resistance, an agent for lowering blood sugar, an agent for preventing inflammation, or an agent for controlling immunoregulation, which comprises the compound according to any one of (1) to (40) as an active ingredient; , Aldose reductase inhibitor,
5-lipoxygenase inhibitor, lipid peroxide production inhibitor, PPAR activator, anti-osteoporosis agent, leukotriene antagonist, adipocyte promotion agent, cancer cell growth inhibitor, or calcium antagonist . 43. An agent for improving insulin resistance, comprising the compound according to any one of claims 1 to 40 as an active ingredient. 44. An agent for lowering blood sugar comprising the compound according to any one of claims 1 to 40 as an active ingredient. 45. A preventive and / or therapeutic agent for diabetes, impaired glucose tolerance, diabetic complications, or gestational diabetes, comprising the compound according to any one of claims 1 to 40 as an active ingredient. . 46. A preventive and / or therapeutic agent for diabetes comprising the compound according to any one of claims 1 to 40 as an active ingredient.