JPH09165371A - Medicine containing heterocyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine containing, as active ingredient, a specific hetetrocyclic compound, having effects of remedying hyperlipemia, hyperglycemia, arteriosclerosis, etc., and aldose reductase inhibitory action, also high in safety, thus useful for preventing and treating these diseases. SOLUTION: This medicine contains, as active ingredient, a compound (salt) of the formula [X is (aza)indole ring group, (aza)indoline ring group, imidazopyri(mi)dine ring group, etc.; Y is O or S; Z is 2,4-dioxothiazolidin-5-ylidenemethyl, 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxoxazolidin-5-ylmethyl, 3,5- dioxoxadiazolidin-2-ylmethyl or N-hydroxyureidomethyl; R is H, a 1-4C (branched) alkyl(oxy), halogen, etc.; (m) is 1-5], e.g. 5-[4-(3-methnylimidazo[5,4- b]pyridin-2-ylmethoxy)benzyl]thiazolidine-2,4-dione.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to hyperlipidemia, hyperglycemia, obesity, impaired glucose tolerance (impaired glucose toleranc).
e: IGT) status, insulin resistance, non-glucose intolerance (insul)
in resistant non-IGT: NGT condition, insulin resistance, cachexia, psoriasis, diabetic complications, arteriosclerosis, hypertension, osteoporosis, polycystic ovary syndrome
ovary syndrome: PCOS), fatty liver and gestational diabetes mellitus (GDM) and the like, and further relates to a heterocyclic compound having a aldose reductase inhibitory action or a pharmacologically acceptable salt thereof.

[0002]

[Prior art]

(1) Conventionally, many compounds are known as thiazolidine compounds having a blood glucose lowering action. For example, JP-A-55-22636 (JP-B-62-42903), JP-A-60-51189 (JP-B-2-31079),
Y. KAWAMATSU et al., Chem. Pharm. Bull., Volume 30, 35
80-3600 (1982), European Patent Publication No. 0441605, and the like.

(2) Further, the following compounds are disclosed as compounds containing a heterocyclic group.

2-1) The general formula in JP-A-61-286376

[0005]

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[In the formula, R ¹ and R ² represent hydrogen or an optionally substituted hydrocarbon residue, and R ¹ and R ² may combine to form a condensed ring. X represents an oxygen atom or a sulfur atom, and A represents a lower alkylene group], and a thiazolidinedione derivative or a salt thereof is disclosed.

2-2) JP-A-5-213913 discloses compounds represented by the following formula (I), enantiomers, diastereomers and epimers thereof, and addition salts thereof with a pharmaceutically acceptable acid. Has been done.

[0008]

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In the above formula, the dotted line represents the presence or absence of a double bond, and R represents one of the following groups:

[0010]

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In the above formulas A _{1 to} A ₄ , X is a sulfur atom, an oxygen atom, or an NH group which is substituted with an unsubstituted or linear or branched (C ₁ -C ₆ ) alkyl group. R ₁ is a hydrogen atom, a halogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group,
Represents a straight chain or branched (C ₁ -C ₆ ) alkoxy group, a trifluoromethyl group or a cyano group, and n
Is equal to 1, 2 or 3;

[0012]

[Chemical 6]

In the above formula B, A represents a 5- or 6-membered unsaturated, partially saturated or fully saturated ring;

[0014]

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In the above formula D, Y is a nitrogen atom or C
Represents an H group, and R ₂ and R ₃ are the same or different and each represents a hydrogen atom, a halogen atom, a linear or branched (C ₁ -C ₆ ) alkyl group, or a linear or branched (C 1 ₁ -C ₆₎ an alkoxy group, or R ₂
And R ₃ together with the carbon atom to which they are attached form a 5- or 6-membered saturated ring which may contain one or two oxygen atoms;

[0016]

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In the above formula E, R ₂ and R ₃ are as defined above;

[0018]

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In the above formula F, R ₄ is a hydrogen atom, unsubstituted or substituted by a phenyl group,
Represents a linear or branched (C ₁ -C ₆ ) alkyl group;

[0020]

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In the above formula H, R ₅ represents a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group;

[0022]

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2-3) WO92 / 07850A (= Tokushuhei 6-502144) has the general formula

[0024]

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(In the formula, A ¹ is an alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group,
Represents a substituted or unsubstituted heterocyclic group, A ² represents a benzene ring which may have up to 3 substituents, R ¹ represents a hydrogen atom, an alkyl group, a substituted or unsubstituted aralkyl group,
It may represent a substituted or unsubstituted aryl group, and A ¹ and R ¹ may together represent a C _3-4 polymethylene group, or polymethylene may together represent a phenylene group. R ² , R
³ is a hydrogen atom and together represents a bond. X represents an oxygen atom or a sulfur atom, and n represents an integer of 2 to 6. ) Are disclosed.

2-4) WO92 / 07839A (= Tokushuhei 6-502146) has the general formula

[0027]

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(Wherein R ¹ and R ² independently represent an alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, and R ¹ and R ² are taken together to form a bridging group ( Methylene which may have a substituent, O, S
Atom, phenylene group). R ³ and R ⁴ represent a hydrogen atom or, together, a bond, and A ¹ represents a benzene ring which may have up to 3 substituents. X represents O or S, and n represents an integer of 2 to 6. ) Are disclosed.

2-5) Others, JP-A-61-85372
JP-A-1-131169, JP-A-2-83384
Nos. And the like disclose compounds having a thiazolidine ring.

(3) Further, an oxazolidine-2,4-dione compound having a blood glucose lowering action is disclosed in JP-A-3-170.
478, WO92 / 02520A and the like.

(4) Further, a compound containing an N-hydroxyureido group or a 3,5-dioxooxadiazolidin-2-ylmethylphenyl group and having a similar activity is described in WO92 / 03425A (= Special Table Flat 5-508
654). The relationship between these thiazolidine compounds and various diseases is described in the following documents, for example. The action of thiazolidine compounds on hyperglycemia is Diabetes., 32 (9) , 804-810 (1983);
Diabetes., 37 (11) , 1549-1558 (1988); Pro
g.Clin.Biol.Res., 265 , 177-192 (1988); Metabol
ism., 37 (3) , 276-280 (1988); Arzneimittelforsch
ung., 40 (1) , 37-42 (1990); Arzneimittelforsch
ung., 40 (2, Pt 1) , 156-162 (1990) ； Arzneimitt
elforschung., 40 (3) , 263-267 (1990) ;.

The action of thiazolidine compounds on hyperlipidemia is Diabetes., 40 (12) , 1669-1674 (1991);
Am.J.Physiol., 267 (1, Pt 1) , E95-E101 (1994);
Diabetes., 43 (10) , 1203-1210 (1994) ;.

The effects of thiazolidine compounds on glucose intolerance and insulin resistance are shown by Arzneimittelforschu
ng., 40 (2, Pt 1) , 156-162 (1990) ； Metabolis
m., 40 (10) , 1025-1030 (1991); Diabetes., 43
(2) , 204-211 (1994); N.Engl.J.Med., 331 (18) , 1
226-1227 (1994) ;.

The effect of thiazolidine compounds on hypertension is Metabolism., 42 (1) , 75-80 (1993); A
mJPhysiol., 265 (4, Pt 2) , R726-R732 (1993); D
iabetes. 43 (2) , 204-211 (1994) ;.

The action of thiazolidine compounds on cachexia is described in Endocrinology., 135 (5) , 2279-2282 (1994);
Endocrinology., 136 (4) , 1474-1481 (1995) ;.

The effect on nephropathy is “diabetes”, 38
Volume Extra edition, (1995) (The 38th Annual Meeting of the Diabetes Society of Japan Program / Abstracts: 38th Annual Meeting of the Diabetes Society, 1995) ;.

The effect of thiazolidine compounds on coronary artery disease was reported by Am. J. Physiol., 265 (4, Pt 2) , R726-R73.
2 (1993); Hypertension., 24 (2) , 170-175 (1994);
Have been reported in.

The action of thiazolidine compounds on arteriosclerosis is described by Am. J. Physyol., 265 (4, Pt 2) , R726-R73.
2 (1993) ;.

Furthermore, in recent years, a normal person having insulin resistance without glucose intolerance has a high risk of developing diabetes [insulin resistance non-glucose intolerance (insulin regist).
antnon-IGT: NGT). ] That is N.Engl.J.Me
d., 331 (18) , 1226-1227 (1994) ;. It is suggested that a drug that improves insulin resistance is useful as a preventive drug for the onset of diabetes in normal individuals as described above.

[0040]

DISCLOSURE OF THE INVENTION The present inventors have found that hyperlipidemia, hyperglycemia, obesity, glucose intolerance, insulin resistance non-glucose intolerance, insulin resistance, cachexia, psoriasis, Diabetic complications, arteriosclerosis, hypertension, osteoporosis,
Heterogeneous studies of highly active and highly safe heterocyclic compounds or pharmacologically acceptable salts thereof, which improve polycystic ovary syndrome, fatty liver, gestational diabetes, etc., and have an aldose reductase inhibitory action, have been conducted. Completed the invention.

That is, the object of the present invention is "a pharmaceutical containing the above-mentioned heterocyclic compound or a pharmacologically acceptable salt thereof as an active ingredient", particularly "hyperlipidemia, hyperglycemia, obesity, glucose intolerance, Insulin resistance non-glucose intolerance, insulin resistance, cachexia, psoriasis, diabetic complications (eg retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.), arteriosclerosis, hypertension, osteoporosis, further Preventive and / or therapeutic agents for polycystic ovary syndrome, fatty liver, gestational diabetes, etc. "
Is to provide.

[0042]

The present invention provides (1) general formula (1)

[0043]

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[Wherein X represents an indole ring group, an indoline ring group, an azaindole ring group, an azaindoline ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings have 1 to 3 groups. You may have the substitution part (a) mentioned later.

Y represents an oxygen atom or a sulfur atom.

Z is

[0047]

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(Hereinafter, these are referred to as 2,4-dioxothiazolidine-5-yridenylmethyl group, 2,4-dioxothiazolidin-5-ylmethyl group, 2,4-dioxooxazolidin-5-ylmethyl group, 3,5 -Dioxooxadiazolidin-2-ylmethyl group and N-hydroxyureidomethyl group).

R is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, or a halogen atom. , A hydroxy group, a nitro group, and an amino group which may have a substituent (b) (the substituent (b) is a linear or branched alkyl group having 1 to 8 carbon atoms, a carbon atom). Linear or branched aralkyl group having 7 to 11 carbon atoms, aryl group having 6 to 10 carbon atoms, linear or branched aliphatic acyl having 1 to 11 carbon atoms Group, an araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms) or an aralkyl group having 7 to 11 carbon atoms.

M represents an integer of 1 to 5.

Here, the substitution component (a) has 1 to 4 carbon atoms.
Straight-chain or branched alkyl group having 1 to 4 carbon atoms, straight-chain or branched alkoxy group having 1 to 4 carbon atoms, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group , A linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, an amino group which may have a substituent (b) (the substituent (b) Has 1 carbon
A straight-chain or branched alkyl group having 8 to 8 carbon atoms, a straight-chain or branched aralkyl group having 7 to 11 carbon atoms, an aryl group having 6 to 10 carbon atoms, and a carbon number A linear or branched aliphatic acyl group having 1 to 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms, or an aromatic acyl group having 7 to 11 carbon atoms is shown. ), An aryl group having 6 to 10 carbon atoms which may have a substituent (c) (the substituent (c) is a linear or branched alkyl group having 1 to 4 carbon atoms). A group, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group or a substituent (b) A good amino group) or a linear or branched aralkyl group having 7 to 11 carbon atoms which may have a substituent (c). ] The heterocyclic compound or its pharmacologically acceptable salt which has these as an active ingredient is related with the pharmaceutical.

(2) In (1), X represents an indole ring group, an indoline ring group, an azaindole ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings are 1
It may have 3 to 3 substitution parts (a) mentioned later. Here, the substituent (a) is a straight chain or branched chain alkyl group having 1 to 4 carbon atoms, a straight chain or branched chain alkoxy group having 1 to 4 carbon atoms, and benzyl. Oxy group, halogen atom, hydroxy group,
An acetoxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, an amino group optionally having a substituent (b) The substituent (b) has 1 to 8 carbon atoms.
A straight-chain or branched alkyl group having 6 to 10 carbon atoms, a straight-chain or branched aralkyl group having 7 to 11 carbon atoms, an aryl group having 6 to 10 carbon atoms, and 1 to 1 carbon atoms A linear or branched aliphatic acyl group having 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms is shown. ), An aryl group having 6 to 10 carbon atoms which may have at least one substituent (c) (the substituent (c) is a straight chain or branched chain having 1 to 4 carbon atoms). Chain alkyl group, carbon number 1
A linear or branched alkoxy group having 4 to 4 halogen atoms, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group or an amino group which may have a substituent (b)) or A heterocyclic compound having a linear or branched aralkyl group having 7 to 11 carbon atoms which may have at least one substituent (c); or a pharmaceutically acceptable compound thereof. It is a drug containing a salt as an active ingredient.

Preferably, (3) In (1), X represents an indole ring group, an indoline ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings have 1 to 3 substituents described later. You may have (a). Here, the substituent (a) is a straight chain or branched chain alkyl group having 1 to 4 carbon atoms, a straight chain or branched chain alkoxy group having 1 to 4 carbon atoms, and benzyl. An oxy group, a halogen atom, a hydroxy group, an acetoxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group,
A nitro group, an amino group which may have a substituent (b) (the substituent (b) is a linear or branched alkyl group having a carbon number of 1 to 8, a carbon number of 7 to 11) Or straight-chain or branched aralkyl group having 6 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, straight-chain or branched aliphatic acyl group having 1 to 11 carbon atoms, carbon number An araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms), and 6 to 10 carbon atoms optionally having at least one substituent (c). An aryl group having 1 to 4 carbon atoms (the substituent (c) is a straight chain or branched chain alkyl group having 1 to 4 carbon atoms, a straight chain or branched chain group having 1 to 4 carbon atoms) Alkoxy group, halogen atom, hydroxy group, A group (b), a phenyl group, a trifluoromethyl group or an amino group which may have a substituent (b)) or a carbon number of 7 to 11 which may have at least one substituent (c). And a heterocyclic compound having a linear or branched aralkyl group having: or a pharmacologically acceptable salt thereof as an active ingredient.

Preferably, (4) In (1), X represents an indole ring group, an indoline ring group or an imidazopyridine ring group, and these rings have 1 to 3 substituents (a) described later. You may have.

Here, the substitution component (a) has 1 to 4 carbon atoms.
Straight-chain or branched alkyl group having 1 to 4 carbon atoms, straight-chain or branched alkoxy group having 1 to 4 carbon atoms, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group , A linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, an amino group which may have a substituent (b) (the substituent (b) Has 1 carbon
A straight-chain or branched alkyl group having 8 to 8 carbon atoms, a straight-chain or branched aralkyl group having 7 to 11 carbon atoms, an aryl group having 6 to 10 carbon atoms, and a carbon number A linear or branched aliphatic acyl group having 1 to 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms, or an aromatic acyl group having 7 to 11 carbon atoms is shown. ) An aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents (c) (wherein the substituent (c) has 1 to 4 carbon atoms).
Linear or branched alkyl group having 1 to 4 carbon atoms, linear or branched alkoxy group having 1 to 4 carbon atoms, halogen atom, hydroxy group, nitro group, phenyl group, trifluoromethyl A group or an amino group which may have a substituent (b)) or a linear or branched chain having 7 to 11 carbon atoms which may have 1 to 3 substituents (c). A heterocyclic compound having a group of aralkyl group or a pharmaceutically acceptable salt thereof is contained as an active ingredient.

(5) In (1), X represents an indoline ring group or an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) described later. Good. here,
Substituent (a) is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a benzyloxy group, A heterocyclic compound having a halogen atom, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group or a phenyl group; or a pharmacologically acceptable salt thereof. It is a drug contained as an active ingredient.

Preferably, (6) In (1), X represents an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) described later. Here, the substituent (a) is a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a benzyloxy group, a fluorine atom, a chlorine atom, a phenylthio group, a methylthio group, an ethylthio group or A medicinal product comprising a heterocyclic compound having a phenyl group; or a pharmacologically acceptable salt thereof as an active ingredient.

(7) In (1), R is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms,
A heterocyclic compound having a linear or branched alkoxy group having 1 to 4 carbon atoms or a halogen atom; or a pharmacologically acceptable salt thereof is contained as an active ingredient.

Preferably, (8) In (1), R is a hydrogen atom, a methoxy group,
A pharmaceutical composition comprising a heterocyclic compound having an ethoxy group, a fluorine atom or a chlorine atom; or a pharmacologically acceptable salt thereof as an active ingredient.

Preferably, (9) in (1), R is a hydrogen atom or a methoxy group; or a heterocyclic compound having: or a pharmacologically acceptable salt thereof as an active ingredient.

Preferably, (10) in (1), R is a hydrogen atom; or a heterocyclic compound having: or a pharmacologically acceptable salt thereof as an active ingredient.

Preferably, (11) in (1), Y is an oxygen atom, or a heterocyclic compound having: or a pharmacologically acceptable salt thereof as an active ingredient.

(12) In (1), Z is 2,4-dioxothiazolidine-5-yridenylmethyl group, 2,4-dioxothiazolidin-5-ylmethyl group or 2,4-dioxooxazolidine. A drug containing a heterocyclic compound having a -5-ylmethyl group or a pharmacologically acceptable salt thereof as an active ingredient.

(13) In (1), Z is preferably a 2,4-dioxothiazolidine-5-yridenylmethyl group or 2,4-
And a heterocyclic compound having a dioxothiazolidin-5-ylmethyl group; or a pharmacologically acceptable salt thereof as an active ingredient.

Preferably, (14) in (1), Z represents a 2,4-dioxothiazolidin-5-ylmethyl group; or a heterocyclic compound or a pharmacologically acceptable salt thereof is contained as an active ingredient. It is a medicine that does.

(15) In (1), X represents an indole ring group, an indoline ring group, an azaindole ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings have 1 to 3 groups. May have a substitution component (a) described later. Y represents an oxygen atom or a sulfur atom. Z is 2,4
-Dioxothiazolidine-5-yridenylmethyl group,
2,4-dioxothiazolidin-5-ylmethyl group,
2,4-dioxooxazolidin-5-ylmethyl group,
It shows a 3,5-dioxooxadiazolidin-2-ylmethyl group or an N-hydroxyureidomethyl group. R
Represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, or a halogen atom. m represents an integer of 1 to 5. Here, the substituent (a) is a straight chain or branched chain alkyl group having 1 to 4 carbon atoms, a straight chain or branched chain alkoxy group having 1 to 4 carbon atoms, and benzyl. It has an oxy group, a halogen atom, a hydroxy group, an acetoxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, and a substituent (b). An optionally substituted amino group (the substituent (b) is a linear or branched alkyl group having 1 to 8 carbon atoms, 7 to 11 carbon atoms)
Or straight-chain or branched aralkyl group having 6 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, straight-chain or branched aliphatic acyl group having 1 to 11 carbon atoms, carbon number An araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms is shown. ), An aryl group having 6 to 10 carbon atoms which may have at least one substituent (c) (the substituent (c) is a straight chain or branched chain having 1 to 4 carbon atoms). It has a chain alkyl group, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group or a substituent (b). An optionally substituted amino group) or a linear or branched aralkyl group having 7 to 11 carbon atoms which may have at least one substituent (c). It is a medicine containing a ring compound or a pharmacologically acceptable salt thereof as an active ingredient.

(16) In (1), X represents an indole ring group, an indoline ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings are 1 to 3 substituents described later. You may have (a). Y represents an oxygen atom. Z represents a 2,4-dioxothiazolidine-5-yridenylmethyl group, a 2,4-dioxothiazolidin-5-ylmethyl group or a 2,4-dioxooxazolidin-5-ylmethyl group. R represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, or a halogen atom. m represents an integer of 1 to 5. Here, the substitution (a) has 1 carbon atom.
A straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms, a benzyloxy group, a halogen atom,
Hydroxy group, acetoxy group, phenylthio group, linear or branched alkylthio group having 1 to 4 carbon atoms, trifluoromethyl group, nitro group, amino optionally having substituent (b) Group (the substituent (b) is a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched aralkyl group having 7 to 11 carbon atoms, carbon An aryl group having 6 to 10 carbon atoms, a linear or branched aliphatic acyl group having 1 to 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms, or 7 to 7 carbon atoms And an aryl group having 6 to 10 carbon atoms which may have at least one substituent (c) (wherein the substituent (c) has 1 carbon atom). Have 4 to 4 Linear or branched alkyl group, linear or branched alkoxy group having 1 to 4 carbon atoms, halogen atom, hydroxy group, nitro group, phenyl group, trifluoromethyl group or substituted An amino group which may have a substituent (b)) or a linear or branched aralkyl group having 7 to 11 carbon atoms which may have at least one substituent (c). Or a pharmacologically acceptable salt thereof having the formula;

(17) In (1), X represents an indole ring group, an indoline ring group or an imidazopyridine ring group, and these rings each have 1 to 3 substituents (a) described later. You may have. Y represents an oxygen atom. Z is a 2,4-dioxothiazolidine-5-yridenylmethyl group or
A 2,4-dioxothiazolidin-5-ylmethyl group is shown. R represents a hydrogen atom, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom. m represents an integer of 1 to 5. Here, the substituent (a) is a straight chain or branched chain alkyl group having 1 to 4 carbon atoms, a straight chain or branched chain alkoxy group having 1 to 4 carbon atoms, and benzyl. Oxy group, halogen atom, hydroxy group,
An acetoxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, an amino group optionally having a substituent (b) The substituent (b) has 1 to 8 carbon atoms.
A straight-chain or branched alkyl group having 6 to 10 carbon atoms, a straight-chain or branched aralkyl group having 7 to 11 carbon atoms, an aryl group having 6 to 10 carbon atoms, and 1 to 1 carbon atoms A linear or branched aliphatic acyl group having 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms is shown. ) An aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents (c) (the substituent (c) may be a linear or substituted aryl group having 1 to 4 carbon atoms) Branched alkyl group, carbon number 1
A linear or branched alkoxy group having 4 to 4 halogen atoms, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group or an amino group which may have a substituent (b)) or A heterocyclic compound having a linear or branched aralkyl group having 7 to 11 carbon atoms which may have 1 to 3 substituents (c); or a pharmacologically acceptable thereof Is a drug containing a salt as an active ingredient.

(18) In (1), X represents an indoline ring group or an imidazopyridine ring group, and these rings are 1 to 3
You may have the below-mentioned substitution part (a). Y represents an oxygen atom. Z is 2,4-dioxothiazolidine-
A 5-ylmethyl group is shown. R represents a hydrogen atom or a methoxy group. m represents an integer of 1 to 5. Here, the substituent (a) is a straight chain or branched chain alkyl group having 1 to 4 carbon atoms, a straight chain or branched chain alkoxy group having 1 to 4 carbon atoms, and benzyl. A heterocyclic compound having an oxy group, a halogen atom, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group or a phenyl group; Is a drug containing a salt as an active ingredient.

(19) In (1), X represents an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) described later. Y represents an oxygen atom. Z is a 2,4-dioxothiazolidin-5-ylmethyl group
Is shown. R represents a hydrogen atom. m represents an integer of 1 to 5. Here, the substituent (a) is a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a benzyloxy group, a fluorine atom, a chlorine atom, a phenylthio group, a methylthio group, an ethylthio group or A medicinal product comprising a heterocyclic compound having a phenyl group; or a pharmacologically acceptable salt thereof as an active ingredient.

Preferably, (20) In (1), 1) 5- {4- (3-methylimidazo [5,4-b]]
Pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione, 2) 5- [4- (5-chloro-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2 , 4-dione, 3) 5- [4- (5-methoxy-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, 4) 5- [4 -(5-Hydroxy-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, 5) 5- [4- (5-ethoxy-3-methylimidazo [ 5,4-b] Pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, or 6) 5- [4- (5-isopropoxy-3-methylimidazo [5,4-b] ] Pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, or a pharmacologically acceptable salt thereof, is a medicament containing as an active ingredient.

Preferably, (21) a disease caused by insulin resistance, which comprises, as an active ingredient, the heterocyclic compound or the pharmaceutically acceptable salt thereof described in any one of (1) to (20) A therapeutic and / or prophylactic agent.

[22] Preferably, (22) a therapeutic agent for hyperglycemia, which comprises the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (20) as an active ingredient, and / or It is a preventive drug.

[23] Preferably, (23) a therapeutic agent for diabetic complications and / or a therapeutic agent containing the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (20) as an active ingredient. It is a preventive drug.

(24) A therapeutic agent for arteriosclerosis which contains the heterocyclic compound or the pharmacologically acceptable salt thereof according to any one of (1) to (20) as an active ingredient, and / or It is a preventive drug.

(25) A therapeutic agent for hyperlipidemia containing the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (20) as an active ingredient, and / or Or a preventive drug.

(26) A therapeutic agent for obesity and / or prophylaxis containing the heterocyclic compound or the pharmacologically acceptable salt thereof according to any one of (1) to (20) as an active ingredient It is a medicine.

(27) A therapeutic agent for glucose intolerance and / or a compound containing the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (20) as an active ingredient. It is a preventive drug.

Preferably, (28) a therapeutic agent and / or prophylactic for hypertension containing the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (20) as an active ingredient It is a medicine.

Preferably, (29) a therapeutic agent for polycystic ovary syndrome containing the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (20) as an active ingredient, and / or Or a preventive drug.

(30) A therapeutic agent for gestational diabetes and / or prophylaxis containing the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (20) as an active ingredient. It is a medicine.

(31) Insulin-resistant non-glucose intolerance treatment comprising the heterocyclic compound or the pharmacologically acceptable salt thereof according to any one of (1) to (20) as an active ingredient. A drug and / or preventive drug.

(32) An aldose reductase inhibitor containing the heterocyclic compound described in any one of (1) to (20) or a pharmacologically acceptable salt thereof as an active ingredient. .

That is, the heterocyclic compound of the present invention or a pharmacologically acceptable salt thereof is a hyperlipidemia, hyperglycemia, obesity, glucose intolerance state, insulin resistance non-glucose intolerance state, insulin resistance, It improves cachexia, psoriasis, diabetic complications, arteriosclerosis, hypertension, osteoporosis, polycystic ovary syndrome, fatty liver and gestational diabetes, and also has an aldose reductase inhibitory action.

Therefore, the heterocyclic compound of the present invention or a pharmacologically acceptable salt thereof is hyperlipidemia, hyperglycemia, obesity, glucose intolerance, insulin resistance non-glucose intolerance, cachexia, psoriasis, Diabetes complications (eg retinopathy, nephropathy, neuropathy, cataracts, coronary artery disease, etc.), arteriosclerosis, fatty liver, hypertension, osteoporosis, polycystic ovary syndrome and gestational diabetes and other diseases caused by insulin resistance. Preventive medicine and /
It is also useful as a therapeutic drug.

Particularly, the present invention comprises a disease caused by insulin resistance, which comprises a heterocyclic compound selected from (1) to (20) or a pharmacologically acceptable salt thereof as an active ingredient,
Preventive agent for hyperglycemia, diabetic complications, arteriosclerosis, hyperlipidemia, obesity, glucose intolerance, hypertension, polycystic ovary syndrome, gestational diabetes, insulin-resistant non-glucose intolerance and /
Or provide a remedy.

When X represents an indole ring group,
Examples of the indole ring group include indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl. Can be raised.

When X represents an indoline ring group, examples of the indoline ring group include indoline-1-yl, indoline-2-yl, indoline-3-yl, indoline-4-yl, indoline-5-yl, Indoline-6-
Ill or indoline-7-yl can be mentioned.

When X represents an azaindole ring group, examples of the azaindole ring group include 4-azaindole-1-yl, 4-azaindole-2-yl, 4-azaindole-3-yl, 4 -Azaindol-5-yl, 4-azaindol-6-yl, 4-azaindol-7-yl, 5-azaindol-1-yl, 5-azaindol-2-yl, 5-azaindole-3 -Yl, 5-azaindol-4-yl, 5-azaindol-6-yl, 5-azaindol-7-yl, 6-azaindol-1-yl, 6-azaindol-2-yl, 6- Azaindol-3-yl, 6-azaindol-4-yl, 6-azaindol-5-yl, 6-azaindol-7-yl, 7-azaindol-1-yl, 7-azaindo 2-yl, 7-azaindole-3-yl, 4-7-azaindole-yl, 7-like-aza-indol-5-yl or 7-azaindole-6-yl and the like.

When X represents an azaindoline ring group, examples of the azaindoline ring group include 4-azaindoline-1-yl, 4-azaindoline-2-yl, 4-azaindoline-3-yl, and 4 -Azaindoline-5-yl, 4-azaindoline-6-yl, 4-azaindoline-7-yl, 5-azaindoline-1-yl, 5-azaindoline-2-yl, 5-azaindoline-3 -Yl, 5-azaindoline-4-yl, 5-azaindoline-6-yl, 5-azaindoline-7-yl, 6-azaindoline-1-yl, 6-azaindoline-2-yl, 6- Azaindoline-3-yl, 6-azaindoline-4-yl, 6-azaindoline-5-yl, 6-azaindoline-7-yl, 7-azaindoline-1-yl, 7-azaindo Down 2-yl, 7-Azaindorin-3-yl, 7-Azaindorin-4-yl, 7-like Azaindorin 5-yl or 7-Azaindorin-6-yl and the like.

When X represents an imidazopyridine ring group, examples of the imidazopyridine ring group include imidazo [4,4
5-b] pyridin-1-yl, imidazo [4,5-b]
Pyridin-2-yl, imidazo [4,5-b] pyridin-7-yl, imidazo [4,5-b] pyridin-5-yl, imidazo [4,5-b] pyridin-6-yl, imidazo [ 4,5-c] Pyridin-1-yl, imidazo [4,5-c] pyridin-2-yl, imidazo [4,5]
-C] pyridin-4-yl, imidazo [4,5-c] pyridin-6-yl, imidazo [4,5-c] pyridin-
7-yl, imidazo [5,4-b] pyridin-3-yl, imidazo [5,4-b] pyridin-2-yl, imidazo [5,4-b] pyridin-7-yl, imidazo [5,5 4-b] pyridin-5-yl, imidazo [5,4
-B] Pyridin-6-yl, imidazo [5,4-c] pyridin-3-yl, imidazo [5,4-c] pyridin-
2-yl, imidazo [5,4-c] pyridin-4-yl, imidazo [5,4-c] pyridin-6-yl, imidazo [5,4-c] pyridin-7-yl, imidazo [1, 2-a] pyridin-2-yl, imidazo [1,2
-A] pyridin-3-yl, imidazo [1,2-a] pyridin-8-yl, imidazo [1,2-a] pyridin-
5-yl, imidazo [1,2-a] pyridin-6-yl, imidazo [1,2-a] pyridin-7-yl and the like can be mentioned.

When X represents an imidazopyrimidine ring group,
Examples of the imidazopyrimidine ring group include imidazo [4,5-d] pyrimidin-7-yl and imidazo [4.
Examples thereof include 5-d] pyrimidin-8-yl or imidazo [4,5-d] pyrimidin-9-yl.

When R, the substituent (a) and / or the substituent (c) are the same or different and represent a linear or branched alkyl group having 1 to 4 carbon atoms, the alkyl group Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl and the like.

When R, the substituent (a) and / or the substituent (c) are the same or different and represent a linear or branched alkoxy group having 1 to 4 carbon atoms, the alkoxy group is Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy or t-butoxy.

When R, the substituent (a) and / or the substituent (c) are the same or different and represent a halogen atom, examples of the halogen atom include a bromine atom, a chlorine atom and a fluorine atom.

When R, the substituent (a) and / or the substituent (b) are the same or different and each represents an aralkyl group having 7 to 11 carbon atoms, the aralkyl group has an alkylene moiety having 1 carbon atom. A straight-chain or branched alkylene having from 5 to 5, for example, benzyl, 2-phenylethyl, 1-phenylethyl, 3
-Phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, 4-phenylbutyl, 1-phenylbutyl, 5-phenylpentyl, 1-naphthylmethyl, 2-naphthylmethyl and the like can be mentioned.

In the case where R, the substituent (a) and / or the substituent (c) are the same or different and each represents an amino group which may have the substituent (b), the substituent (b)
When 1) represents a linear or branched alkyl group having 1 to 8 carbon atoms, examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t. -Butyl, pentyl,
2-pentyl, 3-pentyl, 2-methylbutyl, 3-
Methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 1
-Dimethylbutyl, 1,2-dimethylbutyl, 1,3-
Dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-
Trimethylpropyl, 1,2,2-trimethylpropyl, heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 3,3-dimethylpentyl, octyl, 1-methylheptyl, 2-ethylhexyl or 1,1,
Examples include 3,3-tetramethylbutyl and the like. Preferably, it is a linear or branched alkyl group having 1 to 6 carbon atoms. Most preferably, it is a linear or branched alkyl group having 1 to 4 carbon atoms. Most preferably, it is a methyl group or an ethyl group.

2) When a linear or branched aralkyl group having 7 to 11 carbon atoms is shown, the aralkyl group is the same as the aralkyl group described in the above substituent (a).

3) When the aryl group having 6 to 10 carbon atoms is shown, examples of the aryl group include phenyl, 1-naphthyl, 2-naphthyl and the like.

4) When a linear or branched aliphatic acyl group having 1 to 11 carbon atoms is shown, examples of the aliphatic acyl group include formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl. , Pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl or undecanoyl.

5) When an araliphatic acyl group having 8 to 12 carbon atoms is shown, examples of the araliphatic acyl group include phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl and 5-phenylpenta. Examples thereof include noyl, 6-phenylhexanoyl, α-methylphenylacetyl or α, α-dimethylphenylacetyl.

6) When an aromatic acyl group having 7 to 11 carbon atoms is shown, examples of the aromatic acyl group include benzoyl, 1-naphthoyl and 2-naphthoyl.

Therefore, R, the substitution (a) and /
Alternatively, when the substituents (c) are the same or different and each represents an amino group which may have a substituent (b), the amino group includes, in addition to the unsubstituted amino group, for example, the following substituted amino groups. Can be raised.

1) Methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, 2-pentylamino, 3-pentylamino, 2-methylbutyl Amino, 3-methylbutylamino, 1,1-dimethylpropylamino, 1,2-dimethylpropylamino, 2,2-dimethylpropylamino,
Hexylamino, 2-hexylamino, 3-hexylamino, 2-methylpentylamino, 3-methylpentylamino, 4-methylpentylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3
-Dimethylbutylamino, 2,2-dimethylbutylamino, 2,3-dimethylbutylamino, 3,3-dimethylbutylamino, 1,1,2-trimethylpropylamino, 1,2,2-trimethylpropylamino, heptyl Amino, 2-heptylamino, 3-heptylamino, 4
Heptylamino, 3,3-dimethylpentylamino,
Examples of the substituted amino group include a combination of a hydrogen atom and alkyl, such as octylamino, 1-methylheptylamino, 2-ethylhexylamino or 1,1,3,3-tetramethylbutylamino.

2) Benzylamino, 2-phenylethylamino, 1-phenylethylamino, 3-phenylpropylamino, 2-phenylpropylamino, 1-phenylpropylamino, 4-phenylbutylamino, 1-phenylbutylamino, 5-phenylpentylamino, 1
Examples of the substituted amino group include a combination of a hydrogen atom and aralkyl such as -naphthylmethylamino or 2-naphthylmethylamino.

3) Substituted amino groups such as phenylamino, 1-naphthylamino or 2-naphthylamino which are composed of a combination of a hydrogen atom and aryl can be mentioned.

4) Formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pivaloylamino, pentanoylamino, hexanoylamino, heptanoylamino, octanoylamino, nonanoylamino, decanoylamino or undecanoyl. Examples of the substituted amino group include a combination of a hydrogen atom such as amino and an aliphatic acyl.

5) Phenylacetylamino, 3-phenylpropionylamino, 4-phenylbutyrylamino,
A substituted amino group consisting of a combination of a hydrogen atom and an araliphatic acyl such as 5-phenylpentanoylamino, 6-phenylhexanoylamino, α-methylphenylacetylamino or α, α-dimethylphenylacetylamino. You can

6) Substituted amino groups such as benzoylamino, 1-naphthoylamino or 2-naphthoylamino which are composed of a combination of a hydrogen atom and an aromatic acyl can be mentioned.

7) Dimethylamino, diethylamino, N
-Methyl-N-ethylamino or N-methyl-N
Examples of the substituted amino group include a combination of alkyl and alkyl such as -pentylamino.

8) N-ethyl-N-benzylamino, N
Mention may be made of substituted amino groups consisting of a combination of alkyl and aralkyl, such as -t-butyl-N-benzylamino or N-hexyl-N-benzylamino.

9) N-methyl-N-phenylamino, N
Examples of the substituted amino group include a combination of alkyl and aryl such as -ethyl-N-phenylamino or N-octyl-N-phenylamino.

10) N-propyl-N-acetylamino, N-pentyl-N-propionylamino or
Examples of the substituted amino group include a combination of alkyl and aliphatic acyl such as N-ethyl-N-hexanoylamino.

11) Alkyl and aromatic fats such as N-ethyl-N-phenylacetylamino, N-isopropyl-N- (2-phenylpropionyl) amino or N-methyl-N- (6-phenylhexanoyl) amino. Examples of the substituted amino group include a combination with a group acyl.

12) N-methyl-N-benzoylamino, Ns-butyl-N-benzoylamino or
Examples of the substituted amino group include a combination of alkyl and aromatic acyl such as N-heptyl-N-benzoylamino.

13) Dibenzylamino, N-benzyl-
Examples of the substituted amino group include a combination of aralkyl and aralkyl, such as N- (3-phenylpropyl) amino or N-benzyl-N- (2-naphthylmethyl) amino.

14) A substituted amino group consisting of a combination of aralkyl and aryl such as N-benzyl-N-phenylamino or N- (3-phenylpropyl) -N-phenylamino can be mentioned.

15) N-benzyl-N-acetylamino, N-benzyl-N-propionylamino or
A substituted amino group such as N-benzyl-N-pentanoylamino and a combination of aralkyl and aliphatic acyl can be mentioned.

16) A substituted amino group consisting of a combination of aralkyl and araliphatic acyl such as N-benzyl-N-phenylacetylamino or N-benzyl-N- (4-phenylbutyryl) amino can be mentioned. it can.

17) A substituted amino group consisting of a combination of aralkyl and aromatic acyl such as N-benzyl-N-benzoylamino or N- (2-phenylethyl) -N-benzoylamino can be mentioned.

18) A substituted amino group consisting of a combination of aryl and aryl such as diphenylamino, N- (1-naphthyl) -N-phenylamino or N- (2-naphthyl) -N-phenylamino. You can

19) N-phenyl-N-acetylamino, N-phenyl-N-propionylamino or
Examples of the substituted amino group include a combination of aryl such as N-phenyl-N-hexanoylamino and aliphatic acyl.

20) A substituted amino group consisting of a combination of aryl and araliphatic acyl such as N-phenyl-N-phenylacetylamino or N-phenyl-N- (4-phenylbutyryl) amino can be mentioned. it can.

21) A substituted amino group consisting of a combination of aryl and aromatic acyl such as N-phenyl-N-benzoylamino or N-phenyl-N- (2-naphthoyl) amino can be mentioned.

22) Diacetylamino, N-acetyl-
Mention may be made of a substituted amino group consisting of a combination of aliphatic acyl and aliphatic acyl such as N-propionylamino or N-butyryl-N-hexanoylamino.

23) Aliphatic and araliphatic acyls such as N-acetyl-N-phenylacetylamino, N-acetyl-N- (4-phenylbutyryl) amino or N-butyryl-N-phenylacetylamino. A substituted amino group consisting of a combination of

24) A substituted amino group consisting of a combination of an aliphatic acyl and an aromatic acyl such as N-acetyl-N-benzoylamino or N-butyryl-N- (2-naphthoyl) amino can be mentioned.

25) N, N-diphenylacetylamino, N-phenylacetyl-N- (2-phenylpropionyl) amino or N-phenylacetyl-N-
Examples of the substituted amino group include a combination of an araliphatic acyl and an araliphatic acyl such as (4-phenylbutyryl) amino.

26) N-phenylacetyl-N-benzoylamino or N-phenylacetyl-N- (2
Examples of the substituted amino group include a combination of araliphatic acyl and aromatic acyl such as -naphthoyl) amino.

27) Dibenzoylamino or N-
Examples of the substituted amino group include a combination of aromatic acyl and aromatic acyl such as benzoyl-N- (2-naphthoyl) amino.

When the substituent (a) represents a linear or branched alkylthio group having 1 to 4 carbon atoms, examples of the alkylthio group include methylthio, ethylthio, propylthio, isopropylthio and butylthio. , Isobutylthio, s-butylthio, t-butylthio, and the like.

When the substituent (a) represents an aryl group having 6 to 10 carbon atoms which may have the substituent (c), examples of the unsubstituted aryl group include phenyl and 1-naphthyl. Alternatively, 2-naphthyl and the like can be mentioned. Further, the substitution (c) has 1 to 4 carbon atoms.
Linear or branched alkyl group having 1 to 4 carbon atoms, linear or branched alkoxy group having 1 to 4 carbon atoms, halogen atom, hydroxy group, nitro group, phenyl group, trifluoromethyl Group, when it is an amino group which may have a substituent (b), a linear or branched alkyl group having 1 to 4 carbon atoms, a straight chain having 1 to 4 carbon atoms The branched or branched alkoxy group, the halogen atom, and the amino group which may have a substituent (b) have already been described above.

When the substituent (a) represents an aryl group having 6 to 10 carbon atoms which may have the substituent (c), the aryl group is, for example, the above-mentioned unsubstituted aryl group. In addition, the following substituted aryl groups can be mentioned.

1) For example, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-isobutylphenyl, 4-s-butylphenyl, 4-t-butylphenyl, 4-methyl-1-naphthyl, 5-ethyl-1-naphthyl, 8-propyl-1-naphthyl, 4-isopropyl-1-naphthyl, 5-butyl-1-naphthyl, 4-isobutyl-1-naphthyl, 4- s-Butyl-1-naphthyl, 4-t-butyl-1-naphthyl, 4-methyl-2-
Naphthyl, 5-ethyl-2-naphthyl, 8-propyl-
2-naphthyl, 4-isopropyl-2-naphthyl, 5-
Butyl-2-naphthyl, 8-isobutyl-2-naphthyl, 4-s-butyl-2-naphthyl or 5-t-
An aryl group having a linear or branched alkyl having 1 to 4 carbon atoms such as butyl-2-naphthyl; 2) eg 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4 -Isopropoxyphenyl, 4-butoxyphenyl, 4-isobutoxyphenyl, 4-s-butoxyphenyl, 4-t-butoxyphenyl, 4-methoxy-1-naphthyl, 5-ethoxy-
1-naphthyl, 8-propoxy-1-naphthyl, 4-isopropoxy-1-naphthyl, 5-butoxy-1-naphthyl, 4-isobutoxy-1-naphthyl, 4-s-butoxy-1-naphthyl, 4-t -Butoxy-1-naphthyl, 4-methoxy-2-naphthyl, 5-ethoxy-2-
Naphthyl, 8-propoxy-2-naphthyl, 4-isopropoxy-2-naphthyl, 5-butoxy-2-naphthyl, 8-isobutoxy-2-naphthyl, 4-s-butoxy-2-naphthyl or 5-t-butoxy. An aryl group having a linear or branched alkoxy having 1 to 4 carbon atoms such as 2-naphthyl; 3) 4-phenyl bromide, 4-phenyl chloride, 4
-Phenyl fluoride, 4-phenyl phenyl, 3-phenyl chloride, 3-fluorophenyl, 3-phenyl phenyl bromide, 3-phenyl phenyl iodide, 4-naphthyl bromide, 4-naphthyl chloride 4-naphthyl , 4-fluoro-1-naphthyl, 4-iodo-1-naphthyl, 5-chloro-1-naphthyl, 5-fluoro-1-naphthyl, 5-bromo-1-naphthyl, 8-chloro-1- -Naphthyl, 4-fluorinated-2-naphthyl, 4-bromo-2-naphthyl, 4-chloro-2-naphthyl, 4-iodo-2-naphthyl, 5-bromo-2-naphthyl, 5-chloro -2-naphthyl, 5-fluorinated-2-naphthyl or 5-iodinated-2
An aryl group having a halogen atom such as naphthyl; 4) eg 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-
Aryl having hydroxy such as 1-naphthyl, 5-hydroxy-1-naphthyl, 8-hydroxy-1-naphthyl, 4-hydroxy-2-naphthyl, 5-hydroxy-2-naphthyl or 8-hydroxy-2-naphthyl Group; 5) For example, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-nitro-1-naphthyl,
Aryl group having nitro such as 5-nitro-1-naphthyl, 8-nitro-1-naphthyl, 4-nitro-2-naphthyl, 5-nitro-2-naphthyl or 8-nitro-2-naphthyl; 6) For example, 3-phenylphenyl, 4-phenylphenyl, 4-phenyl-1-naphthyl, 5-phenyl-1
Aryl groups having phenyl such as -naphthyl, 8-phenyl-1-naphthyl, 4-phenyl-2-naphthyl, 5-phenyl-2-naphthyl or 8-phenyl-2-naphthyl; 7) eg 3-trifluoro Methylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethyl-
1-naphthyl, 5-trifluoromethyl-1-naphthyl, 8-trifluoromethyl-1-naphthyl, 4-trifluoromethyl-2-naphthyl, 5-trifluoromethyl-2-naphthyl or 8-trifluoromethyl-
Aryl group having trifluoromethyl such as 2-naphthyl; 8) For example, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 4-amino-1-naphthyl
Or an aryl group having an unsubstituted amino such as 8-amino-2-naphthyl; as an aryl group having a substituted amino, i) for example, 3-methylaminophenyl, 4-ethylaminophenyl, 3-propylaminophenyl, 3 An aryl having a substituted amino consisting of a combination of a hydrogen atom and an alkyl such as isopropylaminophenyl, 4-butylaminophenyl or 3-isobutylaminophenyl; ii) eg 4-benzylaminophenyl, 4- (2-
A combination of a hydrogen atom and aralkyl such as phenylethylamino) phenyl, 4- (1-phenylethylamino) phenyl, 4- (4-phenylbutylamino) phenyl or 4- (1-naphthylmethylamino) phenyl. Aryl having a substituted amino; iii) eg 4-phenylaminophenyl or
Aryl having a substituted amino consisting of a combination of a hydrogen atom and aryl such as 4- (1-naphthylamino) phenyl; iv) eg 4-formylaminophenyl, 4-acetylaminophenyl, 4-butyrylaminophenyl, 4 −
Pivaloylaminophenyl, 4-hexanoylaminophenyl, 4-octanoylaminophenyl or 4
An aryl having a substituted amino consisting of a combination of a hydrogen atom and an aliphatic acyl, such as undecanoylaminophenyl; v) eg 4-phenylacetylaminophenyl, 4-
(4-phenylbutyrylamino) phenyl, 4- (6-
Phenylhexanoylamino) phenyl, 4- (α-methylphenylacetylamino) phenyl or 4-
Aryl having substituted amino consisting of a combination of hydrogen atom and araliphatic acyl such as (α, α-dimethylphenylacetylamino) phenyl; vi) for example 4-benzoylaminophenyl, 4- (1
An aryl having a substituted amino consisting of a combination of a hydrogen atom and an aromatic acyl such as -naphthoylamino) phenyl or 4- (2-naphthoylamino) phenyl; vii) for example 4-dimethylaminophenyl, 4-diethylaminophenyl Or an aryl having a substituted amino consisting of a combination of alkyl and alkyl such as 4- (N-methyl-N-ethylamino) phenyl; viii) eg 4- (N-ethyl-N-benzylamino) phenyl, 4- Aryl having a substituted amino consisting of a combination of alkyl and aralkyl such as (Nt-butyl-N-benzylamino) phenyl or 4- (N-hexyl-N-benzylamino) phenyl; ix) e.g. 4- ( N-methyl-N-phenylamino)
Aryl having a substituted amino consisting of a combination of alkyl and aryl such as phenyl or 4- (N-octyl-N-phenylamino) phenyl; x) eg 4- (N-propyl-N-acetylamino)
Aryl having a substituted amino consisting of a combination of alkyl and aliphatic acyl such as phenyl or 4- (N-ethyl-N-hexanoylamino) phenyl; xi) eg 4- (N-ethyl-N-phenylacetylamino) ) Phenyl or 4- [N-methyl-N- (6
An aryl having a substituted amino consisting of a combination of an alkyl such as -phenylhexanoyl) amino] phenyl and an araliphatic acyl; xii) for example 4- (N-methyl-N-benzoylamino) phenyl or 4- (N- Aryl having a substituted amino consisting of a combination of alkyl and aromatic acyl such as heptyl-N-benzoylamino) phenyl; xiii) eg 4-dibenzylaminophenyl or 4- [N-benzyl-N- (2-naphthyl). Methyl)
Aryl having a substituted amino consisting of a combination of aralkyl and aralkyl such as amino] phenyl; xiv) eg 4- (N-benzyl-N-phenylamino) phenyl or 4- [N- (3-phenylpropyl) -N Aryl having a substituted amino consisting of a combination of aralkyl and aryl, such as -phenylamino] phenyl; xv) eg 4- (N-benzyl-N-acetylamino) phenyl or 4- (N-benzyl-N-pentanoyl) Aryl having a substituted amino consisting of a combination of an aralkyl such as amino) phenyl and an aliphatic acyl; xvi) eg 4- (N-benzyl-N-phenylacetylamino) phenyl or 4- [N-benzyl-
An aryl having a substituted amino consisting of a combination of an aralkyl such as N- (4-phenylbutyryl) amino] phenyl and an araliphatic acyl; xvii) eg 4- (N-benzyl-N-benzoylamino) phenyl or 4 An aryl having a substituted amino consisting of a combination of an aralkyl such as-[N- (2-phenylethyl) -N-benzoylamino] phenyl and an aromatic acyl; xviii) eg 4- (diphenylamino) phenyl or 4- [ Aryl having a substituted amino consisting of a combination of aryl and aryl such as N- (2-naphthyl) -N-phenylamino] phenyl; xix) eg 4- (N-phenyl-N-acetylamino) phenyl or 4- (N-phenyl-N-hexanoylamino) phenyl Aryl having a substituted amino consisting of aryl and aliphatic acyl Una; xx) for example 4-(N-phenyl--N- phenylacetylamino) phenyl or 4- [N- phenyl--N-
Aryl having a substituted amino consisting of a combination of aryl such as (4-phenylbutyryl) amino] phenyl and araliphatic acyl; xxi) aryl such as 4- (N-phenyl-N-benzoylamino) phenyl An aryl having a substituted amino consisting of a combination of a and an aromatic acyl; xxii) a fatty acyl and an aliphatic acyl such as 4-diacetylaminophenyl or 4- (N-butyryl-N-hexanoylamino) phenyl Xxiii) Aliphatic acyl and araliphatic such as, for example, 4- (N-acetyl-N-phenylacetylamino) phenyl or 4- (N-butyryl-N-phenylacetylamino) phenyl. Substituted amino consisting of combination with group acyl Xxiv) for example 4- (N-acetyl-N-benzoylamino) phenyl or 4- [N-butyryl-N-
Aryl having a substituted amino consisting of a combination of aliphatic and aromatic acyls such as (2-naphthoyl) amino] phenyl; xxv) eg 4- (N, N-diphenylacetylamino) phenyl or 4- [N- Phenylacetyl-
Aryl having a substituted amino consisting of a combination of araliphatic acyl and araliphatic acyl such as N- (4-phenylbutyryl) amino] phenyl; xxvi) eg 4- (N-phenylacetyl-N-benzoylamino) ) Phenyl or aryl having a substituted amino consisting of a combination of araliphatic acyl and aromatic acyl such as 4- [N-phenylacetyl-N- (2-naphthoyl) amino] phenyl; xxvii) eg 4-dibenzoyl Aminophenyl
Or an aryl having a substituted amino consisting of a combination of aromatic acyl and aromatic acyl such as 4- [N-benzoyl-N- (2-naphthoyl) amino] phenyl;

When the substituent (a) represents an aralkyl group having 7 to 11 carbon atoms which may have the substituent (c), the unsubstituted aralkyl group may have an alkylene moiety having 1 carbon atom. A straight-chain or branched alkylene having from 5 to 5, for example, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, 4
-Phenylbutyl, 1-phenylbutyl, 5-phenylpentyl, 1-naphthylmethyl, 2-naphthylmethyl and the like can be mentioned.

Further, the substituent (c) has a linear or branched alkyl group having 1 to 4 carbon atoms, and 1 carbon atom.
To a linear or branched alkoxy group having 4 to 4, a halogen atom, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group, and an amino group which may have a substituent (b). In this case, a straight chain or branched chain alkyl group having 1 to 4 carbon atoms, a straight chain or branched chain alkoxy group having 1 to 4 carbon atoms, a halogen atom, a substituent (b) The amino group which may have has already been described above.

When the substituent (a) represents an aralkyl group having 7 to 11 carbon atoms which may have the substituent (c), the aralkyl group is, for example, the above-mentioned unsubstituted aralkyl group. In addition, the following substituted aralkyl groups can be mentioned.

1) For example, 4-methylbenzyl, 4-ethylbenzyl, 4-propylbenzyl, 4-isopropylbenzyl, 4-butylbenzyl, 4-isobutylbenzyl, 4-s-butylbenzyl, 4-t-butylbenzyl, 4-methyl-1-naphthylmethyl, 5-ethyl-1
-Naphthylmethyl, 8-propyl-1-naphthylmethyl, 4-isopropyl-1-naphthylmethyl, 5-butyl-1-naphthylmethyl, 4-isobutyl-1-naphthylmethyl, 4-s-butyl-1-naphthylmethyl , 4-
t-butyl-1-naphthylmethyl, 4-methyl-2-naphthylmethyl, 5-ethyl-2-naphthylmethyl, 8-
Propyl-2-naphthylmethyl, 4-isopropyl-2
-Naphthylmethyl, 5-butyl-2-naphthylmethyl,
8-isobutyl-2-naphthylmethyl, 4-s-butyl-2-naphthylmethyl or 5-t-butyl-2-
Aralkyl groups having a linear or branched alkyl having 1 to 4 carbon atoms such as naphthylmethyl; 2) eg 4-methoxybenzyl, 4-ethoxybenzyl, 4-propoxybenzyl, 4-isopropoxy. Benzyl, 4-butoxybenzyl, 4-isobutoxybenzyl, 4-s-butoxybenzyl, 4-t-butoxybenzyl, 4-methoxy-1-naphthylmethyl, 5-ethoxy-1-naphthylmethyl, 8-propoxy-1. -Naphthylmethyl, 4-isopropoxy-1-naphthylmethyl, 5-butoxy-1-naphthylmethyl, 4-isobutoxy-1-naphthylmethyl, 4-s-butoxy-1-naphthylmethyl, 4-t-butoxy-1 -Naphthylmethyl, 4-methoxy-2-naphthylmethyl, 5-ethoxy-2-naphthylmethyi , 8-propoxy-2-naphthylmethyl, 4-isopropoxy-2-naphthylmethyl, 5
-Butoxy-2-naphthylmethyl, 8-isobutoxy-
Aralkyl having straight or branched chain alkoxy having 1 to 4 carbon atoms, such as 2-naphthylmethyl, 4-s-butoxy-2-naphthylmethyl or 5-t-butoxy-2-naphthylmethyl. Group; 3) For example, 4-benzyl bromide, 4-benzyl chloride, 4
-Benzyl fluoride, 4-benzyl iodide, 3-benzyl chloride, 3-fluorobenzyl, 3-benzyl bromide, 3-benzyl iodide, 4-naphthylmethyl 4-bromide, 4-chloro-
1-naphthylmethyl, 4-fluorinated-1-naphthylmethyl, 4-iodinated-1-naphthylmethyl, 5-chloro-1-naphthylmethyl, 5-fluorinated-1-naphthylmethyl, 5-
1-naphthylmethyl bromide, 8-naphthylmethyl 8-chloride, 2-naphthylmethyl 4-fluoride, -2 bromide-2
-Naphthylmethyl, 4-naphthyl-2-naphthylmethyl, 4
2-naphthylmethyl iodide, 2-naphthylmethyl bromide, 5-naphthylmethyl chloride, 5-naphthylmethyl, 5-fluoride-
Aralkyl groups having a halogen atom such as 2-naphthylmethyl or 5-iodo-2-naphthylmethyl; 4) For example, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 4-hydroxy-
1-naphthylmethyl, 5-hydroxy-1-naphthylmethyl, 8-hydroxy-1-naphthylmethyl, 4-hydroxy-2-naphthylmethyl, 5-hydroxy-2-naphthylmethyl or 8-hydroxy-2-naphthylmethyl 5) For example, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-nitro-1-naphthylmethyl, 5-nitro-1-naphthylmethyl, 8-nitro-
Aralkyl groups having a nitro such as 1-naphthylmethyl, 4-nitro-2-naphthylmethyl, 5-nitro-2-naphthylmethyl or 8-nitro-2-naphthylmethyl; 6) eg 3-phenylbenzyl, 4- Phenylbenzyl, 4-phenyl-1-naphthylmethyl, 5-phenyl-1-naphthylmethyl, 8-phenyl-1-naphthylmethyl, 4-phenyl-2-naphthylmethyl, 5-phenyl-2-naphthylmethyl or 8- Phenyl-2
An aralkyl group having a phenyl such as naphthylmethyl; 7) for example, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-trifluoromethyl-
1-naphthylmethyl, 5-trifluoromethyl-1-naphthylmethyl, 8-trifluoromethyl-1-naphthylmethyl, 4-trifluoromethyl-2-naphthylmethyl, 5-trifluoromethyl-2-naphthylmethyl or 8 -Trifluoromethyl-2-naphthylmethyl
An aralkyl group having a trifluoromethyl group such as 8) or a non-aralkyl group such as 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 4-amino-1-naphthylmethyl or 8-amino-2-naphthylmethyl. An aralkyl group having a substituted amino; examples of the aralkyl group having a substituted amino include i), for example, 3-methylaminobenzyl, 4-ethylaminobenzyl, 3-propylaminobenzyl, 3-isopropylaminobenzyl, 4-butylaminobenzyl or 3. Aralkyl having a substituted amino consisting of a combination of hydrogen atom and alkyl, such as isobutylaminobenzyl; ii) eg 4-benzylaminobenzyl, 4- (2-
A combination of a hydrogen atom and aralkyl such as phenylethylamino) benzyl, 4- (1-phenylethylamino) benzyl, 4- (4-phenylbutylamino) benzyl or 4- (1-naphthylmethylamino) benzyl. Aralkyl having a substituted amino; iii) eg 4-phenylaminobenzyl or
Aralkyl having a substituted amino consisting of a combination of hydrogen atom and aryl such as 4- (1-naphthylamino) benzyl; iv) eg 4-formylaminobenzyl, 4-acetylaminobenzyl, 4-butyrylaminobenzyl, 4 −
Pivaloylaminobenzyl, 4-hexanoylaminobenzyl, 4-octanoylaminobenzyl or 4
An aralkyl having a substituted amino consisting of a combination of a hydrogen atom and an aliphatic acyl such as undecanoylaminobenzyl; v) eg 4-phenylacetylaminobenzyl, 4-
(4-phenylbutyrylamino) benzyl, 4- (6-
Phenylhexanoylamino) benzyl, 4- (α-methylphenylacetylamino) benzyl or 4-
Aralkyl having a substituted amino consisting of a combination of hydrogen atom and araliphatic acyl such as (α, α-dimethylphenylacetylamino) benzyl; vi) for example 4-benzoylaminobenzyl, 4- (1
An aralkyl having a substituted amino consisting of a combination of a hydrogen atom and an aromatic acyl, such as -naphthoylamino) benzyl or 4- (2-naphthoylamino) benzyl; vii) eg 4-dimethylaminobenzyl, 4-diethylaminobenzyl Or an aralkyl having a substituted amino consisting of a combination of alkyl and alkyl such as 4- (N-methyl-N-ethylamino) benzyl; viii) eg 4- (N-ethyl-N-benzylamino) benzyl, 4- Aralkyls having a substituted amino consisting of a combination of alkyl and aralkyl such as (Nt-butyl-N-benzylamino) benzyl or 4- (N-hexyl-N-benzylamino) benzyl; ix) e.g. 4- ( N-methyl-N-phenylamino)
Aralkyl having a substituted amino consisting of a combination of alkyl and aryl such as benzyl or 4- (N-octyl-N-phenylamino) benzyl; x) eg 4- (N-propyl-N-acetylamino)
Aralkyl having a substituted amino consisting of a combination of alkyl and aliphatic acyl such as benzyl or 4- (N-ethyl-N-hexanoylamino) benzyl; xi) eg 4- (N-ethyl-N-phenylacetylamino) ) Benzyl or 4- [N-methyl-N- (6
An aralkyl having a substituted amino consisting of a combination of an alkyl such as -phenylhexanoyl) amino] benzyl and an araliphatic acyl; xii) eg 4- (N-methyl-N-benzoylamino) benzyl or 4- (N- Aralkyl having a substituted amino consisting of a combination of alkyl and aromatic acyl such as heptyl-N-benzoylamino) benzyl; xiii) eg 4-dibenzylaminobenzyl or 4- [N-benzyl-N- (2-naphthyl) Methyl)
Aralkyl having a substituted amino consisting of a combination of aralkyl and aralkyl such as amino] benzyl; xiv) eg 4- (N-benzyl-N-phenylamino) benzyl or 4- [N- (3-phenylpropyl) -N Aralkyl having a substituted amino consisting of a combination of aralkyl and aryl such as -phenylamino] benzyl; xv) eg 4- (N-benzyl-N-acetylamino) benzyl or 4- (N-benzyl-N-pentanoyl) Aralkyl having a substituted amino consisting of a combination of aralkyl such as amino) benzyl and aliphatic acyl; xvi) eg 4- (N-benzyl-N-phenylacetylamino) benzyl or 4- [N-benzyl-
An aralkyl having a substituted amino consisting of a combination of an aralkyl such as N- (4-phenylbutyryl) amino] benzyl and an araliphatic acyl; xvii) for example 4- (N-benzyl-N-benzoylamino) benzyl or 4 An aralkyl having a substituted amino consisting of a combination of an aralkyl such as-[N- (2-phenylethyl) -N-benzoylamino] benzyl and an aromatic acyl; xviii) eg 4-diphenylaminobenzyl or 4- [N- Aralkyl having a substituted amino consisting of a combination of aryl and aryl such as (2-naphthyl) -N-phenylamino] benzyl; xix) eg 4- (N-phenyl-N-acetylamino) benzyl or 4- (N -Phenyl-N-hexanoylamino) benzyl Aryl and aralkyl having substituted amino consisting of an aliphatic acyl such as; xx) for example 4-(N-phenyl--N- phenylacetylamino) benzyl or 4- [N- phenyl--N-
Aralkyl having a substituted amino consisting of a combination of aryl such as (4-phenylbutyryl) amino] benzyl and araliphatic acyl; xxi) aryl such as 4- (N-phenyl-N-benzoylamino) benzyl An aralkyl having a substituted amino consisting of a combination of ## STR3 ## and an aromatic acyl; xxii) a fatty acyl and an aliphatic acyl such as 4-diacetylaminobenzyl or 4- (N-butyryl-N-hexanoylamino) benzyl Aralkyl having a substituted amino consisting of a combination; xxiii) aliphatic acyl and araliphatic such as 4- (N-acetyl-N-phenylacetylamino) benzyl or 4- (N-butyryl-N-phenylacetylamino) benzyl Substitution consisting of combination with group acyl Aralkyl having amino; xxiv) eg 4- (N-acetyl-N-benzoylamino) benzyl or 4- [N-butyryl-N-
Aralkyl having a substituted amino consisting of a combination of an aliphatic acyl and an aromatic acyl such as (2-naphthoyl) amino] benzyl; xxv) eg 4- (N, N-diphenylacetylamino) benzyl or 4- [N- Phenylacetyl-
Aralkyl having a substituted amino consisting of a combination of araliphatic acyl and araliphatic acyl such as N- (4-phenylbutyryl) amino] benzyl; xxvi) eg 4- (N-phenylacetyl-N-benzoylamino) ) Benzyl or aralkyl having a substituted amino consisting of a combination of araliphatic acyl and aromatic acyl such as 4- [N-phenylacetyl-N- (2-naphthoyl) amino] benzyl; xxvii) eg 4-dibenzoyl Aminobenzyl
Or aralkyl having a substituted amino consisting of a combination of aromatic acyl and aromatic acyl such as 4- [N-benzoyl-N- (2-naphthoyl) amino] benzyl;

Therefore, when X is 1 to 3 substituents (a)
Examples of the indole ring group, the indoline ring group, the azaindole ring group, the azaindoline ring group, the imidazopyridine ring group, and the imidazopyrimidine ring group include 3-triphenylmethylindol-1-yl and 1-methylindole-3. -Yl, 1-methylindol-2-yl, 1-ethylindol-2-yl, 5-methoxy-1,2-dimethylindol-3-yl, 5-hydroxy-1-methylindol-3-yl, 1 -Isopropylindol-3-yl, 2-ethyl-1-
Methylindol-3-yl, 5-methoxy-1-methylindol-3-yl, 5-hydroxy-1,2
-Dimethylindol-3-yl, 5-butoxy-1
-Methylindol-3-yl, 1,4,7-trimethylindol-3-yl, 1,6-dimethylindol-3-yl, 5-bromo-6-chloro-1-methylindol-3-yl, 5 -Bromoindole-3
-Yl, 5-hydroxy-1-isobutylindol-3-yl, 5-fluoro-1-methylindole-
2-yl, 5-chloro-1-methylindole-2-
Ill, 5-hydroxy-1-methylindole-2-
5-methoxy-1-methylindol-2-yl, 5-bromo-1-methylindol-2-yl,
1-ethyl-5-nitroindol-2-yl,
1,5-Dimethylindol-2-yl, 5-amino-1-methylindol-2-yl, 5-acetamido-1-methylindol-2-yl, 5-benzoylamino-1-ethylindol-2-yl , 1-methyl-5-methylaminoindol-2-yl, 5-butylamino-1-methylindol-2-yl, 5-
(N-benzoyl-N-methylamino) -1-methylindol-2-yl, 1-methyl-5-phenylaminoindol-2-yl, 5-acetamidoindol-2-yl, 5-benzoylamino-1- Butylindol-2-yl, 4-chloro-1-methylindol-2-yl, 3-methoxy-1-methylindol-2-yl, 6-fluoro-1-methylindol-
2-yl, 6-chloro-1-ethylindole-2-
Yl, 6-methoxy-1-methylindol-2-yl, 5,6-dimethoxy-1-methylindole-2
-Yl, 7-methoxyindol-2-yl, 1-
Methylindol-5-yl, 1-butylindol-5-yl, 1-ethylindol-5-yl, 1-
Methylindol-4-yl, 1-isopropylindol-4-yl, 1-butylindol-4-yl
An indole ring group such as; for example, 5-methoxyindoline-1-yl, 1-methylindoline-2-yl,
Indoline ring groups such as 1-ethylindoline-2-yl, 1-propylindoline-2-yl, 1-butylindoline-2-yl or 1-isopropylindoline-2-yl; eg 1-methyl-7-aza Azaindole ring such as indole-3-yl, 1-isopropyl-7-azaindol-3-yl, 1-methyl-7-azaindol-2-yl or 1-methyl-6-azaindol-2-yl Group; for example, 1-
Methyl-7-azaindoline-2-yl, 1-ethyl-7-azaindoline-2-yl, 1-isopropyl-7-azaindoline-2-yl or 1-butyl-
An azaindoline ring group such as 7-azaindoline-2-yl; for example, 7-methylimidazo [4,5-b] pyridin-2-yl, 1-butylimidazo [4,5-b]
Pyridin-2-yl, 1-methylimidazo [4,5-
b] Pyridin-2-yl, 1-propylimidazo [4,
5-b] pyridin-2-yl, 5-chloro-1-methylimidazo [4,5-b] pyridin-2-yl, 5-methoxy-1-methylimidazo [4,5-b] pyridine-2
-Yl, 6,8-dibromoimidazo [1,2-a] pyridin-2-yl, 8-hydroxyimidazo [1,2-
a] pyridin-2-yl, 6-chloroimidazo [1,
2-a] pyridin-2-yl, 2-methylimidazo [1,2-a] pyridin-7-yl, 2-ethylimidazo [1,2-a] pyridin-8-yl, 3-methylimidazo [5 , 4-b] Pyridin-2-yl, 3-ethylimidazo [5,4-b] pyridin-2-yl, 3,
7-Dimethylimidazo [5,4-b] pyridin-2-yl, 5-chloro-3-methylimidazo [5,4-b]
Pyridin-2-yl, 5-chloro-3-phenylimidazo [5,4-b] pyridin-2-yl, 5-bromo-3-methylimidazo [5,4-b] pyridin-2-yl, 3- Methyl-6-trifluoromethylimidazo [5,4-b] pyridin-2-yl, 3-isopropyl-6-trifluoromethylimidazo [5,4-b] pyridin-2-yl, 3- (3-chloro Benzyl) imidazo [5,4-b] pyridin-2-yl, 3-benzylimidazo [5,4-b] pyridin-2-yl, 3-
(4-chlorobenzyl) imidazo [5,4-b] pyridin-2-yl, 3- (4-phenylbenzyl) imidazo [5,4-b] pyridin-2-yl, 6-bromo-
3-Methylimidazo [5,4-b] pyridin-2-yl, 6-bromo-3-ethylimidazo [5,4-b] pyridin-2-yl, 6-bromo-3-phenylimidazo [5,4] -B] pyridin-2-yl, 6-chloro-
3-Methylimidazo [5,4-b] pyridin-2-yl, 3-butyl-6-chloroimidazo [5,4-b]
Pyridin-2-yl, 5-methoxy-3-methylimidazo [5,4-b] pyridin-2-yl, 3-ethyl-5-methoxyimidazo [5,4-b] pyridin-2-
Ile, 5-methoxy-3-propylimidazo [5,4
-B] pyridin-2-yl, 5-methoxy-3-phenylimidazo [5,4-b] pyridin-2-yl, 3
-Benzyl-5-methoxyimidazo [5,4-b] pyridin-2-yl, 3- (3-chlorophenyl) -5-
Methoxyimidazo [5,4-b] pyridin-2-yl,
5-hydroxy-3-methylimidazo [5,4-b]
Pyridin-2-yl, 3-ethyl-5-hydroxyimidazo [5,4-b] pyridin-2-yl, 3-benzyl-5-hydroxyimidazo [5,4-b] pyridin-2-yl, 3- Phenylimidazo [5,4-b] pyridin-2-yl, 3- (4-chlorophenyl) imidazo [5,4-b] pyridin-2-yl, 3- (3-
Chlorophenyl) imidazo [5,4-b] pyridine-2
-Yl, 3- (2-methylphenyl) imidazo [5,
4-b] pyridin-2-yl, 5-chloro-3- (3
-Chlorophenyl) imidazo [5,4-b] pyridine-
2-yl, 5-methoxy-3- (3-methoxyphenyl) imidazo [5,4-b] pyridin-2-yl, 5
-Hydroxy-3,6-dimethylimidazo [5,4-
b] pyridin-2-yl, 5-methoxy-3,6-dimethylimidazo [5,4-b] pyridin-2-yl,
3-Methylimidazo [5,4-b] pyridin-5-yl, 2,3-dimethylimidazo [5,4-b] pyridin-5-yl, 3-ethyl-2-methylimidazo [5,4-b] ] Pyridin-5-yl, 3-methyl-2
-Phenylimidazo [5,4-b] pyridin-5-yl, 2- [2- (3,5-di-t-butyl-4-hydroxyphenyl) ethyl] -3-methylimidazo [5.
4-b] pyridin-5-yl, 2- (3-chlorophenyl) -3-methylimidazo [5,4-b] pyridine-
5-yl, 3-methyl-5-phenylthioimidazo [5,4-b] pyridin-2-yl, 5-butylthio-
3-Methylimidazo [5,4-b] pyridin-2-yl, 3-methyl-5-phenylimidazo [5,4-b]
Pyridin-2-yl, 5- (3,5-di-t-butyl-4-hydroxyphenylthio) -3-methylimidazo [5,4-b] pyridin-2-yl, 5-ethoxy-
3-Methylimidazo [5,4-b] pyridin-2-yl, 5-isopropoxy-3-methylimidazo [5,5
4-b] pyridin-2-yl, 5-acetoxy-3-
Methylimidazo [5,4-b] pyridin-2-yl,
3-Ethyl-5-phenoxy-6-trifluoromethylimidazo [5,4-b] pyridin-2-yl, 7-chloro-3-methylimidazo [5,4-b] pyridine-2
-Yl, 7-chloro-3-propylimidazo [5,4
-B] pyridin-2-yl, 6-hydroxy-3,
5,7-Trimethylimidazo [5,4-b] pyridine-
2-yl, 3,5,7-trimethyl-6-nitroimidazo [5,4-b] pyridin-2-yl, 6-amino-3,5,7-trimethylimidazo [5,4-b] pyridine- 2-yl, 3-methyl-5-methylaminoimidazo [5,4-b] pyridin-2-yl, 5-dimethylamino-3-methylimidazo [5,4-b] pyridine-2
-Yl, 5- (N-butyl-N-ethylamino) -3-
Methylimidazo [5,4-b] pyridin-2-yl,
3-Methyl-5-phenylaminoimidazo [5,4-
b] Pyridin-2-yl, 5-benzylamino-3-
Methylimidazo [5,4-b] pyridin-2-yl,
5- (N-ethyl-N-phenylamino) -3-methylimidazo [5,4-b] pyridin-2-yl, 5-acetamido-3-methylimidazo [5,4-b] pyridin-2-yl 5-benzoylamino-3-methylimidazo [5,4-b] pyridin-2-yl, 3-methyl-6-nitroimidazo [5,4-b] pyridin-2-
Yl, 6-amino-3-methylimidazo [5,4-
b] pyridin-2-yl, 6-benzoylamino-3
-Methylimidazo [5,4-b] pyridin-2-yl,
6-valeryl-3-butylimidazo [5,4-b] pyridin-2-yl, 5-benzyloxy-3-methylimidazo [5,4-b] pyridin-2-yl, 2-hydroxy-3-methyl Imidazo [5,4-b] pyridin-5-yl, 2-hydroxy-3H-imidazo [5,5
4-b] pyridin-5-yl, 2-hydroxy-3-
Phenylimidazo [5,4-b] pyridin-5-yl,
2-Methylthio-3H-imidazo [5,4-b] pyridin-5-yl, 3-methyl-2-methylthioimidazo [5,4-b] pyridin-5-yl, 3-benzyl-2-butylthioimidazo [5,4-b] Pyridine-5
-Yl, 5-t-butylamino-3-methylimidazo [5,4-b] pyridin-2-yl, 5-t-butylamino-3-propylimidazo [5,4-b] pyridin-2-yl , 3,5,7-Trimethylimidazo [5,
4-b] pyridin-2-yl, 3- (3-chlorophenyl) -5,7-dimethylimidazo [5,4-b] pyridin-2-yl, 3- (3,5-di-t-butyl- Four
-Hydroxybenzyl) -5,7-dimethylimidazo [5,4-b] pyridin-2-yl, 5-acetoxy-3-methylimidazo [5,4-b] pyridin-2-yl, 5-acetoxy-3 -Ethylimidazo [5,4-
b] pyridin-2-yl, 6-methoxy-3-methylimidazo [5,4-c] pyridin-2-yl, 1-methylimidazo [4,5-c] pyridin-2-yl or 1-butylimidazo [4,5-c] pyridine-2-
An imidazopyridine ring group such as yl; for example, 3-methylimidazo [5,4-d] pyrimidin-2-yl, 3
-Ethylimidazo [5,4-d] pyrimidin-2-yl or 3- (3-methylbenzyl) imidazo [5,5
And an imidazopyrimidine ring group such as 4-d] pyrimidin-2-yl.

The compound of the present invention represented by the general formula (1) can be converted into a pharmaceutically acceptable salt according to a conventional method. The pharmacologically acceptable salt of the compound having the general formula (1) is not particularly limited as long as it is medically used and pharmacologically acceptable as compared with the heterocyclic compound having the general formula (1). Absent.

The heterocyclic compound having the general formula (1) of the present invention can be converted into an acid addition salt according to a conventional method.
Examples of such salts include salts of hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid; inorganic acids such as nitrates, perchlorates, sulfates and phosphates. salt;
Salts of lower alkanesulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid;
Arylsulfonic acid salts such as benzenesulfonic acid and p-toluenesulfonic acid; amino acid salts such as glutamic acid and aspartic acid; acetic acid, fumaric acid, tartaric acid,
And carboxylic acid salts such as oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and citric acid.

Further, the compound having the general formula (1) can be converted into a metal salt according to a conventional method. Examples of such salts include salts of alkali metals such as lithium, sodium and potassium; salts of alkaline earth metals such as calcium, barium and magnesium; aluminum salts; and the like.

The compound having the general formula (1) has various isomers.

That is, in the indoline ring or the azaindoline ring, when the ring has a substituent at the 2-position or 3-position, the substitution position becomes an asymmetric carbon and Z is 2,4-dioxothiazolidine-5-. When it represents an ylmethyl or 2,4-dioxooxazolidin-5-ylmethyl group, the 5-position of the thiazolidine ring and the 5-position of the oxazolidine ring are asymmetric carbon atoms. In the general formula (1), all stereoisomers based on these asymmetric carbon atoms and mixtures of equivalent and unequal amounts of these isomers are represented by a single formula. Therefore, in the present invention, all of these isomers and a mixture of these isomers are also included.

Further, in the compound having the general formula (1), Z is 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxooxazolidin-5-ylmethyl, 2,4-dioxothiazolidine- In the case of showing 5-yridenylmethyl or 3,5-dioxooxadiazolidin-2-ylmethyl, it is possible that various tautomers exist. For example, as shown below.

[0146]

Embedded image

[0147]

Embedded image

[0148]

Embedded image

[0149]

Embedded image

In the above general formula (1), tautomers based on these and equal and non-equivalent mixtures of these isomers are all represented by a single formula. Therefore, in the present invention, all of these isomers and a mixture of these isomers are also included.

Further, in the present invention, when the compound having the general formula (1) or a pharmacologically acceptable salt thereof forms a solvate (for example, a hydrate), these are all included.

Further, the present invention includes all compounds, so-called prodrugs, which are metabolized in vivo to be converted into the compound having the general formula (1) or a salt thereof.

Specific examples of the compound having the above-mentioned general formula (1) of the present invention include the compounds shown in the following table.

[0154]

[Table 1]

[0155]

[Table 2]

[0156]

[Table 3]

[0157]

[Table 4]

[0158]

[Table 5]

[0159]

[Table 6]

[0160]

[Table 7]

[0161]

[Table 8]

[0162]

[Table 9]

[0163]

[Table 10]

[0164]

[Table 11]

[0165]

[Table 12]

[0166]

[Table 13]

[0167]

[Table 14]

[0168]

[Table 15]

[0169]

[Table 16]

[0170]

[Table 17]

[0171]

[Table 18]

[0172]

[Table 19]

[0173]

[Table 20]

[0174]

[Table 21]

[0175]

[Table 22]

[0176]

[Table 23]

[0177]

[Table 24]

[0178]

[Table 25]

[0179]

[Table 26]

[0180]

[Table 27]

[0181]

[Table 28]

[0182]

[Table 29]

[0183]

[Table 30]

[0184]

[Table 31]

[0185]

[Table 32]

[0186]

[Table 33]

[0187]

[Table 34]

[0188]

[Table 35]

[0189]

[Table 36]

[0190]

[Table 37]

[0191]

[Table 38]

[0192]

[Table 39]

[0193]

[Table 40]

[0194]

[Table 41]

[0195]

[Table 42]

[0196]

[Table 43]

[0197]

[Table 44]

[0198]

[Table 45]

[0199]

[Table 46]

[0200]

[Table 47]

[0201]

[Table 48]

[0202]

[Table 49]

[0203]

[Table 50]

[0204]

[Table 51]

[0205]

[Table 52]

[0206]

[Table 53]

[0207]

[Table 54]

[0208]

[Table 55]

[0209]

[Table 56]

[0210]

[Table 57]

[0211]

[Table 58]

[0212]

[Table 59]

[0213]

[Table 60]

[0214]

[Table 61]

[0215]

[Table 62]

[0216]

[Table 63]

[0219]

[Table 64]

[0218]

[Table 65]

[0219]

[Table 66]

[0220]

[Table 67]

[0221]

[Table 68]

[0222]

[Table 69]

[0223]

[Table 70]

[0224]

[Table 71]

[0225]

[Table 72]

[0226]

[Table 73]

[0227]

[Table 74]

[0228]

[Table 75]

[0229]

[Table 76]

[0230]

[Table 77]

[0231]

[Table 78]

[0232]

[Table 79]

[0233]

[Table 80]

[0234]

[Table 81]

[0235]

[Table 82]

[0236]

[Table 83]

[0237]

[Table 84]

[0238]

[Table 85]

[0239]

[Table 86]

[0240]

[Table 87]

[0241]

[Table 88]

[0242]

[Table 89]

[0243]

[Table 90]

[0244]

[Table 91]

[0245]

[Table 92]

[0246]

[Table 93]

[0247]

[Table 94]

[0248]

[Table 95]

[0249]

[Table 96]

[0250]

[Table 97]

[0251]

[Table 98]

[0252]

[Table 99]

[0253]

[Table 100]

[0254]

[Table 101]

[0255]

[Table 102]

[0256]

[Table 103]

[0257]

[Table 104]

[0258]

[Table 105]

[0259]

[Table 106]

[0260]

[Table 107]

[0261]

[Table 108]

[0262]

[Table 109]

[0263]

[Table 110]

[0264]

[Table 111]

[0265]

[Table 112]

[0266]

[Table 113]

[0267]

[Table 114]

[0268]

[Table 115]

[0269]

[Table 116]

[0270]

[Table 117]

[0271]

[Table 118]

[0272]

[Table 119]

In Tables 1 to 5, Me = methyl,
Et = ethyl, Pr = propyl, iPr
= Isopropyl, Bu = butyl, iBu = isobutyl, tBu = tert-butyl, Bz = benzyl, Ac = acetyl, Tr = triphenylmethyl,
Is shown.

In the above table, (1) preferably, exemplary compound numbers 1-1, 1-2, 1-3, 1-6, 1-57, 1-5
9, 1-62, 1-72, 1-81, 1-91, 1-9
3, 1-106, 1-121, 1-122, 1-12
5, 1-130, 1-134, 1-135, 1-13
7, 1-140, 1-142, 1-153, 1-15
6, 1-158, 1-161, 1-177, 1-17
9, 1-180, 1-182, 1-183, 1-20
7, 1-218 and 2-100, and pharmacologically acceptable salts thereof.

(2) More preferably, Exemplified Compound Nos. 1-1, 1-57, 1-62, 1-91, 1-93, 1
-106, 1-122, 1-125, 1-130, 1-
134, 1-137, 1-140, 1-142, 1-1
53, 1-156, 1-177, 1-179, 1-18
0, 1-182, 1-183, 1-207, 1-218
And 2-100, and pharmacologically acceptable salts thereof.

(3) More preferably, Exemplified Compound Nos. 1-62, 1-93, 1-125, 1-134, 1-1
40, 1-142, 1-153, 1-177, 1-17
9, 1-182, 1-183 and 1-207, and pharmacologically acceptable salts thereof.

(4) More preferably, Exemplified Compound No. 1-93) 5- {4- (3-methylimidazo [5,5
4-b] pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione, 1-125) 5- [4- (5-chloro-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy ) Benzyl] thiazolidine-2,4-dione, 1-142) 5- [4- (5-methoxy-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy)
Benzyl] thiazolidine-2,4-dione, 1-153) 5- [4- (5-hydroxy-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione , 1-182) 5- [4- (5-ethoxy-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy)
Benzyl] thiazolidine-2,4-dione, and 1-183) 5- [4- (5-isopropoxy-3-
Methylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, and pharmacologically acceptable salts thereof.

[0278]

BEST MODE FOR CARRYING OUT THE INVENTION Next, a method for producing a compound having the general formula (1) will be described.

Production Method (I)

[0280]

Embedded image

The first step is a step for producing a compound having the above-mentioned general formula (3) (wherein X and m have the same meanings as described above), and the above-mentioned general formula (2) (wherein , X
And m have the same meanings as described above, and R 'represents a linear or branched alkyl group having 1 to 5 carbon atoms. ) Is reduced.

The reaction is usually carried out by hydrogenating in the presence of a reducing agent.

Examples of the reducing agent used include metal hydrides such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride and diisopropylaluminum hydride.

The reaction is usually suitably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction. For example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; dimethylformamide. Amides such as dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol and isopropanol; or a mixed solvent thereof is preferably used.

The reaction is carried out under cooling to warming.

The reaction time varies depending on the reaction reagent, reaction temperature and the like, but is usually 0.5 hour to several days.

The reaction is preferably carried out in the presence of lithium borohydride in alcohols or mixed solvents with alcohols for 1 hour to 1 day at room temperature to reflux, or in the presence of hydrocarbons or ethers. In solvent,
The reaction is carried out under cooling or warming for 1 hour to 10 hours in the presence of lithium aluminum hydride or diisobutylaluminum hydride.

The second step is the above-mentioned general formula (5) [in the formula, X,
Y, R and m are as defined above, and Z ′ is

[0289]

Embedded image

(Wherein Tr represents a triphenylmethyl group). A compound having the general formula (3) (wherein X and m have the same meanings as described above) and a compound having the general formula (4) (wherein Y is an integer). , R and Z 'have the same meanings as described above) with a conventional Mitsunobu reaction [O.
Mitsunobu, Synthesis, page 1, 1981
Year)].

The reaction is usually carried out in the presence of a solvent, in the presence of azo compounds and phosphines. Azo compounds as reaction reagents include diethyl azodicarboxylate and 1,1′-
(Azodicarbonyl) dipiperidine and the like are used.
As phosphines, triphenylphosphine, tributylphosphine and the like are used.

The reaction is usually suitably carried out in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; halogenated carbonization such as chloroform, dichloromethane and 1,2-dichloroethane. Hydrogens; ethers such as diethyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; or a mixed solvent thereof is preferably used.

The reaction temperature is room temperature to warming, preferably room temperature to 60 ° C.

The reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually several hours to several days, preferably 5 hours to 3 days.

The third step is the above-mentioned general formula (1) (in the formula, X,
Y, Z, R and m have the same meaning as described above. However, Z is

[0296]

Embedded image

Those that are are excluded. Is a step of producing a compound having the general formula (5) (in the formula, X, Y,
R, m and Z'have the same meanings as described above. The compound having a) is reacted with an acid such as trifluoroacetic acid, trifluoromethanesulfonic acid, acetic acid, hydrochloric acid or sulfuric acid in the presence or absence of a solvent. When a solvent is used, the solvent to be used is not particularly limited as long as it does not affect the reaction. For example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; chloroform, dichloromethane, carbon tetrachloride, etc. Halogenated hydrocarbons; ethers such as diethyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; esters such as ethyl acetate, methyl acetate; water; or These mixed solvents are preferably used. The reaction temperature is from ice cooling to room temperature. While the reaction time varies depending on the reaction reagent, reaction temperature, solvent, etc., it is generally several tens of minutes to several tens hours, and preferably 0.5 hours to 10 hours.

This step can also be achieved by subjecting the compound having the general formula (5) to a catalytic hydrogenation reaction. Examples of the catalyst used include palladium-carbon, palladium black, platinum oxide, platinum black, and the like.
Preferably it is palladium-carbon.

The reaction is usually suitably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; and halogenated hydrocarbons such as chloroform, dichloromethane, and carbon tetrachloride. Diethyl ether, tetrahydrofuran,
Ethers such as dioxane; alcohols such as methanol, ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; or a mixed solvent thereof is preferably used.

The reaction temperature is from room temperature to warming.

The reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually several hours to several days, preferably 1 hour to 1 day. Manufacturing method (II)

[0302]

Embedded image

The fourth step is the general formula (6) (wherein X,
R and m have the same meaning as described above. Wherein a base such as sodium hydride is allowed to act on the general formula (3) (wherein X and m have the same meanings as described above) (first). Stage)
Then, 2-methoxy-4-fluorobenzaldehyde, 3
P- such as -methyl-4-fluorobenzaldehyde
It is achieved by reacting with a fluorobenzaldehyde derivative (second step).

The first stage is usually suitably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; dimethylformamide Amides such as dimethylacetamide and hexamethylphosphoric triamide; or a mixed solvent thereof is preferably used.

The reaction is carried out under ice-cooling or heating.

The reaction time varies depending on the reaction reagent, reaction temperature, solvent, etc., but it is usually several tens of minutes to 1 day, and preferably 1 hour to 10 hours.

The second step is carried out by adding the p-fluorobenzaldehyde derivative to the reaction mixture after the completion of the first step reaction and reacting at room temperature or under heating.

The reaction time varies depending on the reaction reagent, reaction temperature, etc., but it is usually several tens of minutes to several days.

The fifth step is the above-mentioned general formula (7) (in the formula, X,
R and m have the same meaning as described above. ), Wherein X, R and m have the same meanings as described above.
It can be obtained by reacting a compound having a with thiazolidine-2,4-dione.

The reaction is carried out in the presence or the absence of a catalyst. When the reaction is carried out in the presence of a catalyst, the catalyst used includes, for example, sodium acetate, piperidinium acetate, piperidinium benzoate and the like.

The reaction is usually suitably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; methanol, ethanol Alcohols such as, isopropanol; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; dichloromethane, chloroform, 1,2-
Halogenated hydrocarbons such as dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as ethyl formate and ethyl acetate; or a mixed solvent thereof is preferably used.

The reaction is usually carried out under heating.

The reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually 1 hour to 50 hours.

The sixth step is the above-mentioned general formula (8) (in the formula, X,
R and m have the same meaning as described above. ), Wherein X, R and m have the same meanings as described above.
By subjecting the compound having the following formula to reduction by catalytic hydrogenation reaction. The catalyst used is, for example, palladium-carbon or palladium black, preferably palladium-carbon.

The reaction is normally and conveniently effected in the presence of solvent. The solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, dioxane, and tetrahydrofuran; Alcohols such as acetic acid, ethanol and isopropanol; organic acids such as formic acid, acetic acid and propionic acid; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide, or a mixed solvent thereof.

The reaction is carried out at room temperature or under heating.

The reaction is usually carried out under atmospheric pressure or under pressure, preferably under pressure. The reaction time varies depending on pressure, temperature, catalyst and the like, but is usually several hours to several days, preferably one hour to one day.

The process can also be achieved by reacting a metal hydride. The reaction is usually carried out in WO 93/13
09A can be carried out according to the method disclosed.

Production Method (III)

[0320]

Embedded image

The seventh step is the above-mentioned general formula (9) (in the formula, X,
R and m have the same meaning as described above. ), Wherein X, R and m have the same meanings as described above.
It can be obtained by reacting a compound having a with hydroxylamine (hydrochloride) and then reducing it.

The reaction of the compound having the above general formula (6) with hydroxylamine (hydrochloride) is usually carried out preferably in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, dioxane and tetrahydrofuran; methanol, Alcohols such as ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; acetonitrile and propionitrile Such nitriles; esters such as ethyl formate and ethyl acetate; amines such as pyridine, triethylamine, N, N-diisopropyl-N-ethylamine; or a mixed solvent thereof is preferably used.

The reaction is carried out at room temperature or under heating.

The reaction time varies depending on the reaction reagent, reaction temperature, solvent, etc., but is usually several hours to several tens hours.

Then, the reduction reaction is carried out by hydrogenating in the presence of a reducing agent. Examples of the reducing agent used include metal hydrides such as lithium aluminum hydride, diisobutylaluminum hydride, lithium borohydride, sodium borohydride, and sodium cyanoborohydride.

The reaction is usually suitably carried out in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, dioxane and tetrahydrofuran; dimethylformamide Amides such as dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol and isopropanol; or a mixed solvent thereof is preferably used.

The reaction is carried out under cooling to warming.

The reaction time varies depending on the reaction reagent, reaction temperature, solvent, etc., but it is usually several tens of minutes to 1 day.

The eighth step is the above general formula (10) (wherein
X, R and m have the same meaning as described above. ) Wherein the compound has the general formula (9)
Wherein X, R and m have the same meanings as described above, and trimethylsilyl isocyanate (trimethylsilyl isocyanate).

The reaction is usually carried out preferably in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, dioxane and tetrahydrofuran; dimethylformamide Amides such as dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; or a mixed solvent thereof.

The reaction is carried out under cooling to warming.

The reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually several tens of minutes to several days.

The ninth step is the general formula (11) (wherein
X, R and m have the same meaning as described above. Wherein a compound having the general formula (9) (where X, R and m have the same meanings as described above) is reacted with N- (chlorocarbonyl) isocyanate. Obtained by:

The reaction is usually suitably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; dimethylformamide Amides such as dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethyl formate and ethyl acetate. Such esters: or a mixed solvent thereof is preferably used.

The reaction is carried out under cooling to warming.

The reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually several tens of minutes to several tens hours.

Production Method (IV)

[0338]

Embedded image

The tenth step is the above general formula (14) (wherein
Y, R and m have the same meaning as described above, Y 'represents an oxygen atom or a sulfur atom, and Q represents a lower alkoxycarbonyl group, a formyl group, a protected formyl group, a carboxyl group or a hydroxy group. Is a process for producing a compound having the general formula (12)
Has the same meaning as described above, and Halo represents a halogen atom. ) And a compound having the general formula (13) (wherein, Y, Y 'and R have the same meanings as described above) in the presence of a base.

Examples of the base used include inorganic bases such as sodium hydride, potassium hydride, potassium carbonate and cesium carbonate, and organic bases such as triethylamine.

The reaction is usually carried out suitably in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; dimethylformamide Amides such as dimethylacetamide and hexamethylphosphoric triamide; or a mixed solvent thereof is preferably used.

The reaction is carried out under cooling to warming.

The reaction time varies depending on the reaction reagent, reaction temperature and the like, but is usually 0.5 hour to several days.

The reaction is preferably carried out in the presence of sodium hydride in the amide or a mixed solvent with the amide, for 1 hour to 10 hours, with cooling or with heating.

The compound having the above-mentioned general formula (14) produced by this step is an important intermediate since it can produce other desired compounds via them. In addition, the compound in which Q is a carboxyl group or a hydroxy group can be easily produced from a lower alkoxycarbonyl group, a formyl group or a protected formyl group by an ordinary method.

The eleventh step is the above general formula (15) (wherein
Y, Y ′, R and m have the same meanings as described above, and X represents an imidazopyridine ring group or an imidazopyrimidine ring group. And (a) the general formula (14) (wherein Y, Y ′, R and m have the same meanings as described above, and Q represents a lower alkoxycarbonyl group). It is carried out by reacting a compound having a with a 2,3-diaminopyridine derivative or a 4,5-diaminopyrimidine derivative.

When Q represents a lower alkoxycarbonyl group, it is preferably a linear or branched lower alkoxycarbonyl group having 2 to 7 carbon atoms, such as methoxycarbonyl or ethoxycarbonyl. , Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s
-Butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, 2-methylbutoxycarbonyl, 1-ethylpropoxycarbonyl, 4-
Methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl, 1-methylpentyloxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl,
Examples thereof include 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxycarbonyl, 2-ethylbutoxycarbonyl, hexyloxycarbonyl and isohexylcarbonyl. Of these, linear or branched lower alkoxycarbonyl groups having 2 to 5 carbon atoms, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl are preferred. And more preferably methoxycarbonyl and ethoxycarbonyl.

The reaction is usually carried out in the presence or absence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene and xylene; diethyl ether,
Ethers such as tetrahydrofuran and dioxane;
Amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol and butanol; acids such as acetic acid and propionic acid; and mixed solvents thereof are preferably used.

The reaction is carried out under heating.

The reaction time varies depending on the reaction reagent, reaction temperature and the like, but is usually 3 hours to several days.

The reaction is preferably carried out in the absence of a solvent at 50 ° C. to 150 ° C. for 5 hours to 2 days under heating.

(B) The general formula (14) (wherein Y,
Y ', R and m have the same meaning as described above, and Q represents a formyl group. ) Is reacted with a 2,3-diaminopyridine derivative or a 4,5-diaminopyrimidine derivative and then treated with an oxidizing agent.

The reaction is usually suitably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; diethyl ether, tetrahydrofuran, dioxane, 1,2.
Ethers such as dimethoxyethane; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; alcohols such as methanol, ethanol and isopropanol; acids such as acetic acid and propionic acid; Sulfoxides; or a mixed solvent thereof is preferably used.

The reaction is carried out at room temperature or under heating for 1 hour to several days, and then treated with an oxidizing agent.

Examples of the oxidizing agent include iodine, silver oxide, lead tetraacetate and the like, and iodine is preferable.

The treatment with the oxidizing agent is usually suitably carried out in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not affect the reaction, and for example, the solvents described above are used. Preferred are ethers. The treatment is preferably for one hour to several days under warming.

(C) The general formula (14) (wherein Y,
Y ', R and m are as defined above, and Q is a protected formyl group. )), When Q is a protected formyl group, for example, dimethoxymethyl, diethoxymethyl, 1,3-dioxan-2-yl, 1,3-dioxolan-2-yl, 1,3-dithian-2-yl , 1,3
-Dithiolan-2-yl, which can be subjected to a reaction after deprotection prior to the reaction in the eleventh step. The deprotection reaction is a conventional deprotection reaction, such as TWGree
n, Protective Groups in Organic Synthes
sis), John Wiley &Sons; JFWMcOmie, Protective Groups in Organic Chemistry,
It is achieved by following the Plenum Press.

Production Method (V)

[0359]

Embedded image

This production method (V) is a method for producing a compound having the above-mentioned general formula (14) (wherein Q, Y, Y ', R'and m have the same meanings as described above).

The twelfth step is the general formula (17) (wherein
Q, m, Y and R are as defined above. Wherein the compound having the general formula (12) (wherein Q, m and Halo have the same meanings as described above) and the compound having the general formula (16) (wherein Y And R
Has the same meaning as described above. ) Are reacted in the presence of a base. The reaction is carried out according to the tenth step shown in the above-mentioned production method (IV).

The thirteenth step is the general formula (18) (wherein
Q, m, Y and R are as defined above. ), Which is obtained by reducing the compound having the general formula (17).

The reaction is carried out by using a conventional catalytic hydrogenation reaction and a general nitro group reduction method such as a zinc-acetic acid method or a tin-hydrochloric acid method.

The fourteenth step is the general formula (19) (wherein
Q, m, Y, R and Halo are as defined above,
R 'represents a lower alkyl group. Is a step of producing a compound having the formula (1), and is obtained by subjecting the compound having the general formula (18) to a Meerwein Arrayation reaction.

The reaction is usually carried out according to the method described in JP-A-55-22657 and S. Oae et al. (Bull. Chem. Soc. Jpn., 53, 10).
65 pages (1980)).

The fifteenth step is the general formula (14) (wherein
Q, m, Y, Y 'and R have the same meaning as described above. Is a process for producing a compound having the general formula (1)
Reacting a compound having 9) with urea or thiourea,
Then, it is carried out by subjecting it to a hydrolysis reaction.

The reaction is usually carried out according to the method described in JP-A-55-22657.

The thus obtained general formula (1
4) (wherein Q, m, Y, Y ′ and R have the same meanings as described above), a compound having the same reaction as described in the above 11th step (a) or (b) can be used. By the addition, a compound having the general formula (15) (wherein Y, Y ′, R and m have the same meanings as described above, and X represents an imidazopyridine ring group or an imidazopyrimidine ring group) is obtained. To be

After the completion of the reaction, the desired compound obtained in each of the above steps can be purified, if necessary, by a conventional method such as column chromatography, recrystallization, reprecipitation or the like. For example, a solvent is added to the reaction mixture for extraction, and the solvent is distilled off from the extract. The obtained residue is purified by subjecting it to column chromatography using silica gel or the like, whereby a pure product of the target compound can be obtained.

The heterocyclic compound having the general formula (1) or a pharmacologically acceptable salt thereof of the present invention is hyperlipidemia, hyperglycemia, obesity, impaired glucose tolerance, insulin resistance, non-glucose tolerance. It improves dysfunction, insulin resistance, cachexia, psoriasis, diabetic complications, arteriosclerosis, hypertension, osteoporosis, polycystic ovary syndrome, fatty liver and gestational diabetes, and also has an aldose reductase inhibitory action.

That is, the heterocyclic compound of the present invention represented by the general formula (1) or a pharmaceutically acceptable salt thereof is hyperlipidemia, hyperglycemia, obesity, glucose intolerance, insulin resistance non-glucose tolerance. Dysfunction, insulin resistance, cachexia, psoriasis, diabetic complications (eg retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.), arteriosclerosis, hypertension, osteoporosis, polycystic ovary syndrome, It is useful as a preventive and / or therapeutic drug for fatty liver and gestational diabetes. The heterocyclic compound having the general formula (1) of the present invention or a pharmacologically acceptable salt thereof is administered in various forms. The administration form is not particularly limited and is determined according to various formulation forms, patient age, sex and other conditions, degree of disease and the like. For example, tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of an injection, it may be administered alone or mixed with an ordinary replenisher such as glucose or amino acid, and then intravenously administered. Further, if necessary, it may be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally. In the case of suppositories, they are administered rectally.

These various preparations are prepared by adding the excipient, binder, disintegrant, lubricant, solubilizer, flavoring agent
It can be formulated using known auxiliaries usually used in the field of known pharmaceutical preparations such as coating agents.

In the case of molding into tablets, those conventionally known in this field can be widely used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch,
Binding of excipients such as calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone sugar Agent, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, white sugar, stearin, cacao Decay inhibitors such as butter and hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid. , Ltd. talc, stearates,
Lubricants such as boric acid powder and polyethylene glycol can be exemplified. Furthermore, tablets are tablets that have been given a normal coating as necessary,
For example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multi-layer tablet can be used.

In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin and talc, and Arabic. Examples thereof include rubber powder, tragacanth powder, a binder such as gelatin and ethanol, a disintegrating agent such as laminaranthantene, and the like. In the case of molding in the form of suppositories, various carriers conventionally known in this field can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. it can.

When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood, and when formed into a solution, emulsion and suspension, they are diluted. All the agents conventionally used in this field can be used as the agent, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,
Examples thereof include polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. You may add.

If necessary, a coloring agent, a preservative, a fragrance,
Flavors, sweeteners, etc. and other pharmaceuticals may be included.

The amount of the active ingredient compound contained in the above-mentioned pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but it is usually 1 to 70% by weight, preferably 1 to 30% by weight in the whole composition. Is appropriate.

The dose varies depending on symptoms, age, body weight, administration method, dosage form and the like, but is usually 1 day for an adult and the upper limit is 2,000 mg (preferably 200 m).
g, more preferably 20 mg), and the lower limit is 0.
001 mg (preferably 0.01 mg, more preferably 0.1 mg) can be administered.

[0379]

EXAMPLES The present invention will be described in more detail with reference to Production Examples, Reference Examples, Examples, Test Examples and Preparation Examples, but the present invention is not limited thereto.

[0380]

[Manufacturing Example] A manufacturing example is shown below.

Production Example 1 5- [4- (Indoline-2-ylmethoxy) benze
Lu] thiazolidine-2,4-dione (exemplary compound number
1-59) 5- [4- (1-t-butoxycarbonylindoline-
2-ylmethoxy) benzyl] -3-triphenylmethylthiazolidine-2,4-dione (see Reference Example 4 described later) (3.55 g) was mixed with 30 ml of trifluoroacetic acid and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the resulting residue was subjected to silica gel column chromatography (hexane:
Purification by subjecting to ethyl acetate = 2: 1) gave 0.41 g of the desired compound. When the obtained target compound is dissolved in ethanol and water is added to give a powder, the melting point is 5
The temperature was 5.8 ° C to 58.2 ° C.

Production Example 2 5- [4- (1-methylindoline-2-ylmethoxy)
Ci) benzyl] thiazolidine-2,4-dione (exemplified
Compound number 1-62 ) 2.50 g of 5- [4- (1-methylindoline-2-ylmethoxy) benzyl] -3-triphenylmethylthiazolidine-2,4-dione (see Reference Example 7 described later) was added to dichloromethane. After dissolving in 25 ml, 3.1 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, when the reaction mixture is post-treated according to Production Example 1,
1.20 g of the expected compound having a melting point of 46.1 ° C. to 48.9 ° C. are obtained.

Production Example 3 5- {4- [2- (indoline-1-yl) ethoxy]
Benzyl} thiazolidine-2,4-dione (exemplary compound
No. 1-57) 5- {4- [2- (indoline-1-yl) ethoxy]
Benzyl} -3-triphenylmethylthiazolidine-
When 470 mg of 2,4-dione (see Reference Example 10 described later) and 3 ml of trifluoroacetic acid were used and the reaction and post-treatment were performed according to Production Example 1, the target compound having a melting point of 132.8 ° C to 135.6 ° C was obtained. 170 mg was obtained.

Production Example 4 5- {4- [2- (indol-3-yl) ethoxy]
Benzyl} thiazolidine-2,4-dione (exemplary compound
No. 1-2) 5- {4- [2- (indol-3-yl) ethoxy]
Benzyl} -3-triphenylmethylthiazolidine-
1.77 g of 2,4-dione (see Reference Example 11 described later),
53 ml of dichloromethane and trifluoroacetic acid
The reaction and post-treatment were carried out according to Preparation Example 2 using 0.3 ml to give 0.67 g of the desired compound having a melting point of 42.6 ° C to 44.5 ° C.

Production Example 5 5- {4- [2- (3-triphenylmethylindole]
-1-yl) ethoxy] benzyl} thiazolidine-2,
4-dione (exemplary compound number 1-3) 5- {4- [2- (indol-1-yl) ethoxy]
Benzyl} -3-triphenylmethylthiazolidine-
2,4-dione 2.33 g, dichloromethane 25 ml
And Production Example 2 using 3.1 ml of trifluoroacetic acid
When the reaction and post-treatment were carried out according to (1), 2.20 g of the desired compound having a melting point of 66.6 ° C. to 70.0 ° C. was obtained.

Production Example 6 5- {4- [2- (indol-1-yl) ethoxy]
Benzyl} thiazolidine-2,4-dione (exemplary compound
No. 1-1) 5- {4- [2- (indol-1-yl) ethoxy]
Benzyl} -3-triphenylmethylthiazolidine-
2.05 g of 2,4-dione (see Reference Example 14 described later),
3.1% 10% palladium-carbon and dioxane
100 ml of the mixture under hydrogen atmosphere at room temperature for 30 minutes,
The mixture was stirred at 60 ° C for 2 hours and further at 80 ° C for 3 hours. After completion of the reaction, the catalyst was filtered off from the reaction mixture and the filtrate was concentrated.
The obtained residue was purified by subjecting it to silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 1.06 g of the target compound having a melting point of 42.3 ° C to 44.6 ° C.

Production Example 7 5- {4- (3-methylimidazo [5,4-b] pyridy
N-2-ylmethoxy) benzyl} thiazolidine-2,
4-dione (exemplified compound number 1-93) 5- {4- (3-methylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl} -3-triphenylmethylthiazolidine-2,4-dione ( Reference Example 1 described later
6) 500 mg, 10% palladium-carbon 1 g
Using 100 ml of methanol and 100 ml of methanol to carry out the reaction and post-treatment according to Production Example 6, the melting point was 223 ° C to 22 ° C.
77 mg of the target compound having a temperature of 5 ° C. are obtained.

Production Example 8 5- {4- [2- (7-azaindol-1-yl) d
[Toxy] benzyl} thiazolidine-2,4-dione (eg
Compound No. 1-72) 5- {4- [2- (7-azaindol-1-yl) ethoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione (see Reference Example 19 described later). 2.
When 50 g, 50 ml of dichloromethane and 3.1 ml of trifluoroacetic acid were used and the reaction and post-treatment were carried out according to Production Example 2, the melting point was 200.0 ° C to 202.4 ° C.
0.84 g of the target compound having is obtained.

Production Example 9 5- [4- (imidazo [1,2-a] pyridin-2-i
Rumethoxy) benzyl] thiazolidine-2,4-dione
(Exemplified Compound No. 1-106) 5- {4- (imidazo [1,2-a] pyridin-2-ylmethoxy) benzyl} -3-triphenylmethylthiazolidine-2,4-dione (see Reference Example 21 described later) )
Using 3.0 g and 30 ml of trifluoroacetic acid, the reaction was carried out for 1 hour according to Production Example 1. After the reaction was completed, trifluoroacetic acid was distilled off from the reaction mixture under reduced pressure, and an aqueous potassium carbonate solution and ethyl acetate were added to the obtained residue. The precipitated insoluble material was collected by filtration, dried, and recrystallized from ethanol to obtain 0.8 g of the desired compound having a melting point of 197 ° C to 202 ° C.

Production Example 10 5- [4- (1-methylindol-2-ylmethoxy)
Ci) benzyl] thiazolidine-2,4-dione (exemplified
Compound number 1-6) 5- [4- (1-methylindol-2-ylmethoxy) benzyl] -3-triphenylmethylthiazolidine-2,4-dione (see Reference Example 24 described later) 3.24
g, 10% palladium-carbon 4.86 g and dioxane 100 ml were used and the reaction and post-treatment were carried out according to Preparation Example 6, melting point 174.3 ° C. to 175.5 ° C.
1.49 g of the target compound having is obtained.

Production Example 11 5- {4- [2- (imidazo [1,2-a] pyridine-
2-yl) ethoxy] benzyl} thiazolidine-2,4
-Dione (Exemplified compound number 1-107) 5- {4- [2- (imidazo [1,2-a] pyridine-
2-yl) ethoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione (Reference Example 27 described later)
Reference) Using 0.94 g, 4 ml of dichloromethane and 1 ml of trifluoroacetic acid, the reaction and post-treatment were carried out according to Production Example 2. The obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 2:
Purification by subjecting to 1 → ethyl acetate: tetrahydrofuran 1: 2) gave 287 mg of the target compound having a melting point of 205.9 ° C. to 207.0 ° C. (decomposition point).

Production Example 12 5- [4- (3-ethylimidazo [5,4-b] pyridy
N-2-ylmethoxy) benzyl] thiazolidine-2,
4-dione (exemplified compound number 1-121) 5- [4- (3-ethylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl] -3-triphenylmethylthiazolidine-2,4-dione ( Reference example 2 below
9) Acetic acid-water (3: 1) 12 ml to 300 mg
Was added and the mixture was stirred at 60 ° C. for 2 hours. After completion of the reaction, the reaction mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain 85 mg of the target compound having a melting point of 210 ° C to 212 ° C.

Production Example 13 5- [4- (1-methylimidazo [4,5-b] pyridy
N-2-ylmethoxy) benzyl] thiazolidine-2,
4-dione (exemplified compound number 1-122) 5- [4- (1-methylimidazo [4,5-b] pyridin-2-ylmethoxy) benzyl] -3-triphenylmethylthiazolidine-2,4-dione ( Reference Example 3 described later
1) 4.1 g, acetic acid-water (3: 1) 160 ml
Was used for the reaction and post-treatment according to Production Example 12. The obtained crude product was crystallized from ethyl acetate to give the desired compound having a melting point of 231 ° C to 232 ° C.
1.45 g was obtained.

Production Example 14 5- {4- [3- (3-methylimidazo [5,4-b]]
Pyridin-2-yl) propoxy] benzyl} thiazoli
Gin-2,4-dione (Exemplified compound number 1-123) 5- {4- [3- (3-methylimidazo [5,4-b]
Pyridin-2-yl) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione (see Reference Example 35 described later) 240 mg, acetic acid-water (3: 1)
The reaction and post-treatment were carried out according to Production Example 12 using 10 ml. The obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 3 → 0:
When purified by subjecting to 1), melting point 185 ° C to 186 ° C
93 mg of the target compound having

Production Example 15 5- [4- (3H-imidazo [5,4-b] pyridine-
2-ylmethoxy) benzyl] thiazolidine-2,4-
Dione (Exemplified Compound No. 1-91) 2,3-Diaminopyridine 200 mg to 4- (ethoxycarbonylmethoxy) benzylthiazolidine-2,4
-1.13 g of dione (see Reference Example 39 described later) was added, and the mixture was stirred at 110 ° C for 2 days. After completion of the reaction, 3N hydrochloric acid was added to the reaction mixture, and then aqueous ammonia was added,
The solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate: methanol = 1: 0 → 1).
0: 1). The crude product obtained is then crystallized from ethyl acetate, mp 247 ° -248.
400 mg of the target compound having a temperature of 0 ° C. were obtained.

Production Example 16 5- [4- (3,7-dimethylimidazo [5,4-b]]
Pyridin-2-ylmethoxy) benzyl] thiazolidine
-2,4-dione (Exemplified compound number 1-124) 5- [4- (3,7-dimethylimidazo [5,4-b]
Pyridin-2-ylmethoxy) benzyl] -3-triphenylmethylthiazolidine-2,4-dione (see Reference Example 41 described later) 1.07 g, acetic acid-water (3: 1) 1
The reaction and post-treatment were carried out according to Production Example 12 using 6 ml. The obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 1: 2).
Attached. The resulting crude product was then crystallized from ethyl acetate to give 0.28 g of the desired compound having a melting point of 205 ° C to 207 ° C.

Production Example 17 5- [4- (5-chloro-3-methylimidazo [5,4
-B] pyridin-2-ylmethoxy) benzyl] thiazo
Lysine-2,4-dione (Exemplified compound number 1-125) 5- [4- (5-chloro-3-methylimidazo [5,4
-B] pyridin-2-ylmethoxy) benzyl] -3-
Triphenylmethylthiazolidine-2,4-dione (see Reference Example 45 described later) 1.16 g, acetic acid-water (3:
1) Using 16 ml, the reaction and post-treatment were carried out according to Production Example 12. The crude product obtained was crystallized from ethyl acetate to give 0.38 g of the desired compound having a melting point of 222 ° C to 223 ° C.

Production Example 18 5- [4- (3-Methyl-6-trifluoromethylimidy]
Dazo [5,4-b] pyridin-2-ylmethoxy) ben
Zil] thiazolidine-2,4-dione (exemplary compound number
1-130) 3-Amino-2-methylamino-5-trifluoromethylpyridine 3.00 g, 5- [4- (2-oxoethoxy) benzyl] thiazolidine-2,4 in a mixture of 6 ml of ethanol and 6 ml of acetic acid. -4.16 g of dione (see Reference Example 47 described later) was added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture, 50 ml of 1,2-dimethoxyethane and 5.2 g of iodine were added to the obtained residue, and the mixture was stirred at 60 ° C for 1 day. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1). The crude product obtained was crystallized from ethyl acetate to give 520 mg of the desired compound having a melting point of 212 ° C to 214 ° C.

Production Example 19 5- [4- (3-methylimidazo [5,4-d] pyrimi
[Zin-2-ylmethoxy) benzyl] thiazolidine-
2,4-dione (Exemplified Compound No. 1-158) 5- [4- (3-Methylimidazo [5,4-d] pyrimidin-2-ylmethoxy) benzyl] -3-triphenylmethylthiazolidine-2,4- Dione (see Reference Example 51 described later) 0.24 g, acetic acid-water (3: 1) 8 ml
Was used for the reaction and post-treatment according to Production Example 12. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: ethanol = 1: 0 → 10: 1).
Purification by filtration gave 30 mg of the desired compound having a melting point of 244 ° C to 246 ° C.

Production Example 20 5- {4- [3- (4-chlorobenzyl) imidazo
[5,4-b] Pyridin-2-ylmethoxy] benz
Lu} thiazolidine-2,4-dione (exemplary compound No. 1
-134) 3-Amino-2- (4-chlorobenzyl) aminopyridine (see Reference Example 53 described later) 1.20 g, 5- [4-
(2-oxoethoxy) benzyl] thiazolidine-2,
4-dione (see Reference Example 47 described later) 1.36 g, ethanol 3 ml, acetic acid 3 ml, iodine 1.69 g and 1,2-dimethoxyethane 25 ml were used to carry out a reaction and a post-treatment according to Production Example 18. The obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 1: 2). Then
Crystallization of the resulting crude product with ethyl acetate gave:
The target compound having a melting point of 211 ° C to 213 ° C.
40 g were obtained.

Production Example 21 5- {4- [3- (4-phenylbenzyl) imidazo
[5,4-b] Pyridin-2-ylmethoxy] benz
Lu} thiazolidine-2,4-dione (exemplary compound No. 1
-135) 5- {4- [3- (4-phenylbenzyl) imidazo [5,4-b] pyridin-2-ylmethoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-
Using 0.9 g of dione (see Reference Example 55 described later) and 36 ml of acetic acid-water (3: 1), the reaction and post-treatment were carried out according to Production Example 12. The obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
When purified by subjecting to 3), the melting point is 189 ° C to 191 ° C.
450 mg of the target compound having

Production Example 22 5- [4- (6-bromo-3-methylimidazo [5,4
-B] pyridin-2-ylmethoxy) benzyl] thiazo
Lysine-2,4-dione (Exemplified Compound No. 1-137) 5- [4- (6-Bromo-3-methylimidazo [5,4
-B] pyridin-2-ylmethoxy) benzyl] -3-
Triphenylmethylthiazolidine-2,4-dione (see Reference Example 60 described later) 3.00 g, acetic acid-water (3:
1) Using 40 ml, the reaction and post-treatment were carried out according to Production Example 12. The crude product obtained was crystallized from ethyl acetate to give 1.75 g of the desired compound having a melting point of 204 ° C to 205 ° C.

Production Example 23 5- [4- (6-chloro-3-methylimidazo [5,4
-B] pyridin-2-ylmethoxy) benzyl] thiazo
Lysine-2,4-dione (Exemplified compound number 1-140) 5- [4- (6-chloro-3-methylimidazo [5,4
-B] pyridin-2-ylmethoxy) benzyl] -3-
Triphenylmethylthiazolidine-2,4-dione (see Reference Example 65 described later) 1.40 g, acetic acid-water (3:
1) Using 20 ml, the reaction and post-treatment were carried out according to Production Example 12. The crude product obtained was crystallized from ethyl acetate to give 0.75 g of the desired compound having a melting point of 203 ° C to 205 ° C.

Production Example 24 (1) 5- [4- (5-methoxy-3-methylimidazole)
Zo [5,4-b] pyridin-2-ylmethoxy) benz
Lu] thiazolidine-2,4-dione (exemplary compound number
1-142) 5- [4- (5-methoxy-3-methylimidazo [5,
4-b] pyridin-2-ylmethoxy) benzyl] -3
-Triphenylmethylthiazolidine-2,4-dione (see Reference Example 70 described below) 680 mg and acetic acid-water (3: 1) 10 ml were used and the reaction and post-treatment were carried out according to Production Example 12. The crude product obtained was crystallized from ethyl acetate to give 325 mg of the desired compound having a melting point of 258 ° C to 260 ° C.

(2) Hydrochloride of (1) 5- [4- (5-methoxy-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-obtained in (1) 2,4-dione 100m
g was added to 6 ml of 4N hydrochloric acid-ethyl acetate, the mixture was subjected to ultrasonic waves for 30 minutes, and the obtained crystals were collected by filtration to give a melting point of 2
87 mg of the target compound having a temperature of 55 ° C. to 262 ° C. were obtained.

(3) Fumarate of (1). 1/2 eth
5- [4- (5-Methoxy-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 100m obtained with Nol (1)
g was dissolved in 30 ml of methanol to give fumaric acid 29 m.
After adding g and applying ultrasonic waves for 30 minutes, the solvent was distilled off from the mixture. Ethanol was added to the obtained residue, and the crystals were collected by filtration to obtain 85 mg of the target compound having a melting point of 245 ° C to 253 ° C.

Production Example 25 5- [4- (1-methylimidazo [4,5-c] pyridy
N-2-ylmethoxy) benzyl] thiazolidine-2,
4-dione (exemplified compound number 1-156) 5- [4- (1-methylimidazo [4,5-c] pyridin-2-ylmethoxy) benzyl] -3-triphenylmethylthiazolidine-2,4-dione ( Reference Example 7 described later
4) 3.40 g, acetic acid-water (3: 1) 24 ml
Was used for the reaction and post-treatment according to Production Example 12. The obtained crude product was crystallized from ethyl acetate to give the desired compound having a melting point of 264 ° C to 265 ° C.
1.01 g was obtained.

Production Example 26 5- [4- (1-methyl-7-azaindole-2-i]
Rumethoxy) benzyl] thiazolidine-2,4-dione
(Exemplified Compound No. 1-81) 5- [4- (1-Methyl-7-azaindol-2-ylmethoxy) benzyl] -3-triphenylmethylthiazolidine-2,4-dione (see Reference Example 82 described later).
270 mg, acetic acid-water-1,4-dioxane (2: 1:
3) The reaction was carried out according to Production Example 12 using 3 ml. After completion of the reaction, the solvent was distilled off from the reaction mixture, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give a melting point of 1
157 mg of the target compound having 83 ° C to 185 ° C
was gotten.

Production Example 27 5- {4- [3- (4-phenyl) imidazo [5,4-
b] pyridin-2-ylmethoxy] benzyl} thiazoli
Din-2,4-dione (Exemplified Compound No. 1-161) 3-Amino-2-phenylaminopyridine (see Reference Example 84 described later) 2.78 g, 5- [4- (2-oxoethoxy) benzyl] thiazolidine -2,4-dione (see Reference Example 47 described later) 3.98 g, iodine 4.9 g,
Production Example 18 using a mixture of 6 ml of ethanol and 6 ml of acetic acid and 50 ml of 1,2-dimethoxyethane.
The reaction and post-treatment were carried out according to The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:
When purified by subjecting to hexane = 2: 1 to ethyl acetate), the target compound 400 having a melting point of 88 ° C. to 91 ° C. is obtained.
mg was obtained.

Production Example 28 5- [4- (3,5,7-trimethylimidazo [5,4
-B] pyridin-2-ylmethoxy) benzyl] thiazo
Lysine-2,4-dione and its trifluoroacetic acid salt
(Exemplified Compound No. 1-218) 5- [4- (3,5,7-trimethylimidazo [5,4
-B] pyridin-2-ylmethoxy) benzyl] -3-
Triphenylmethylthiazolidine-2,4-dione (see Reference Example 87 described below) 3.5 g, dichloromethane 1
The reaction was carried out according to Preparation Example 2 using 00 ml and trifluoroacetic acid 20 ml. After completion of the reaction, dichloromethane and trifluoroacetic acid were distilled off from the reaction mixture under reduced pressure, and the obtained crude product was recrystallized from ethyl acetate-hexane to give the target compound trifluorofluoride having a melting point of 226 ° C to 228 ° C. 2.4 g of acetate were obtained.

2.3 g of the above salt was added to 50 ml of ethyl acetate.
And 50 ml of an aqueous sodium hydrogen carbonate solution, and the mixture was stirred at room temperature for 30 minutes. The obtained crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 1.47 g of the target compound having a melting point of 229 ° C to 230 ° C.

Production Example 29 5- [4- (3-methyl-5-phenylthioimidazo)
[5,4-b] Pyridin-2-ylmethoxy) benz
Lu] thiazolidine-2,4-dione (exemplary compound number
1-177) 5- [4- (3-Methyl-5-phenylthioimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl] -3-triphenylmethylthiazolidine-2,4-
Dione (see Reference Example 91 described later) 1.58 g, acetic acid-
The reaction and post-treatment were carried out according to Production Example 12 using 20 ml of water (3: 1). When the obtained crude product was crystallized by adding ethyl acetate, the melting point was 166 ° C to 168 ° C.
1.02 g of the target compound having is obtained.

Production Example 30 5- [4- (5-benzyloxy-3-methylimidazo)
[5,4-b] Pyridin-2-ylmethoxy) benz
Lu] thiazolidine-2,4-dione (exemplary compound number
1-207) 5- [4- (5-Benzyloxy-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl] -3-triphenylmethylthiazolidine-2,4-
Dione (see Reference Example 95 described later) 1.00 g, acetic acid-
The reaction and post-treatment were carried out according to Production Example 12 using 12 ml of water (3: 1). The obtained crude product was crystallized by adding ethyl acetate to obtain 0.63 g of the desired compound having a melting point of 210 ° C to 211 ° C.

Production Example 31 5- [4- (5-hydroxy-3-methylimidazo)
[5,4-b] Pyridin-2-ylmethoxy) benz
Ru] thiazolidine-2,4-dione (Exemplary Compound No. 1
-153) 5- [4- (5-benzyloxy-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl] -3-triphenylmethylthiazolidine-2,4-
Dione (see Reference Example 95 below) 1.20 g, 10%
Palladium-carbon 1.80 g and methanol 50 m
The reaction and post-treatment were carried out in the same manner as in Production Example 6 using 1. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: methanol = 1: 0 → 10: 1).
Purification yielded 0.10 g of the desired compound having a melting point of 240 ° C to 242 ° C.

Production Example 32 5- [4- (5-ethoxy-3-methylimidazo [5,
4-b] pyridin-2-ylmethoxy) benzyl] thia
Zolidine-2,4-dione (Exemplified Compound No. 1-18
2) 5- [4- (5-ethoxy-3-methylimidazo [5,
4-b] pyridin-2-ylmethoxy) benzyl] -3
-Triphenylmethylthiazolidine-2,4-dione (see Reference Example 99 below) and 2.75 g of acetic acid-water (3: 1) were used to carry out a reaction and a post-treatment according to Production Example 12. The obtained crude product was crystallized by adding ethyl acetate to obtain 1.57 g of the desired compound having a melting point of 245 ° C to 246 ° C.

Production Example 33 5- [4- (5-isopropoxy-3-methylimidazo)
[5,4-b] Pyridin-2-ylmethoxy) benz
Lu] thiazolidine-2,4-dione (exemplary compound number
1-183) 5- [4- (5-isopropoxy-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl] -3-triphenylmethylthiazolidine-2,4-
The reaction and post-treatment were carried out according to Production Example 12 using 0.78 g of dione (see Reference Example 103 described later) and 12 ml of acetic acid-water (3: 1). When the obtained crude product was crystallized by adding ethyl acetate, the melting point was 210 ° C to 212 ° C.
0.40 g of the target compound having is obtained.

Example 34 5- {4- [2- (3-methylimidazo [5,4-b]]
Pyridin-2-yl) ethoxy] benzyl} thiazolidi
2,4-dione (Exemplified Compound No. 1-190) 3-amino-2-methylaminopyridine (see Reference Example 105 described later) 0.94 g, 5- [4- (3-oxopropoxy) benzyl] thiazolidine -2,4-dione (see Reference Example 107 described later) 2.10 g, ethanol 6
ml, acetic acid 3 ml, iodine 2.32 g and 1,2
-Using 30 ml of dimethoxyethane, the reaction and post-treatment were carried out according to Production Example 18. The obtained crude product was purified by subjecting it to silica gel column chromatography (ethyl acetate) to obtain 85 mg of the target compound having a melting point of 96 ° C to 100 ° C.

Production Example 35 5- [4- (3-methyl-5-phenylimidazo [5,
4-b] pyridin-2-ylmethoxy) benzyl] thia
Zolidine-2,4-dione (Exemplified Compound No. 1-17
9) 5- [4- (3-methyl-5-phenylimidazo [5,
4-b] pyridin-2-ylmethoxy) benzyl] -3
-Triphenylmethylthiazolidine-2,4-dione (see Reference Example 111 described below) (0.9 g) and acetic acid-water (3: 1) (36 ml) were used to carry out a reaction and a post-treatment according to Production Example 12. The obtained crude product was crystallized by adding ethyl acetate to obtain 420 mg of the target compound having a melting point of 211 ° C to 213 ° C.

Production Example 36 5- [4- (3-methylimidazo [5,4-b] pyridy
N-2-ylmethoxy) benzylidene] thiazolidine-
2,4-dione (Exemplified compound number 2-100) 2- (4-formylphenoxymethyl) -3-methylimidazo [5,4-b] pyridine (see Reference Example 112 described later) 0.35 g, 2,4 -Thiazolidinedione 0.
31 g, piperidine 0.26 ml and ethanol
10 ml of the mixture was heated to reflux for 4 hours. After the reaction,
The solvent was distilled off from the reaction mixture, water was added to the obtained residue for crystallization, and the residue was washed with water and ethyl acetate to give a melting point of 2
0.38 g of the target compound having 79 ° C to 281 ° C
was gotten.

[0420]

[Reference Example] A reference example is shown below.

Reference Example 1 Indoline-2-carboxylic acid ethyl A mixture of 25.2 g of indoline-2-carboxylic acid, 50 ml of ethanol and 200 ml of 4N hydrochloric acid / dioxane was stirred at room temperature for 3 days. After completion of the reaction, the reaction mixture was poured into aqueous potassium carbonate solution and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give an Rf value = 0.81.
28.1 g of the target compound having (silica gel thin layer chromatography; hexane: ethyl acetate = 2: 1) are obtained.

Reference Example 2 Indoline-2-ylmethanol Indoline-2-ethyl carboxylate (see Reference Example 1)
20m anhydrous tetrahydrofuran solution containing 5.12g
1 was added dropwise to a mixture of 80 ml of anhydrous tetrahydrofuran containing 1.20 g of lithium aluminum hydride under ice cooling. The reaction mixture was stirred at room temperature for 2 hours, sodium sulfate decahydrate was added in excess under ice cooling, and the mixture was stirred for 20 minutes. After completion of the reaction, insoluble matter was filtered off from the reaction mixture, and the filtrate was concentrated. The obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 1).
Rf value = 0.16 (silica gel thin layer chromatography; hexane: ethyl acetate = 2:
3.81 g of the target compound having 1) were obtained.

Reference Example 3 1-t-Butoxycarbonyl-2-hydroxymethyl group
Indolin- indolin-2-ylmethanol (see Reference Example 2)
In a solution of 40 ml of anhydrous tetrahydrofuran containing 4.0 g and 3.8 ml of triethylamine, di-t-
Butyl-di-carbonate (6.2 ml) was added dropwise, and the mixture was stirred at room temperature for 10 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give an Rf value = 0.46 (silica gel thin layer chromatography; hexane: 5.57 g of the target compound with ethyl acetate = 2: 1) was obtained.

Reference Example 4 5- [4- (1-t-butoxycarbonylindoline-
2-ylmethoxy) benzyl] -3-triphenylmethyl
Lthiazolidine-2,4-dione 1-t-butoxycarbonyl-2-hydroxymethylindoline (see Reference Example 3) 6.5 g, tributylphosphine 6.5 ml, anhydrous tetrahydrofuran 100 m
1 and 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione (see EP Publication 549365) 1,2 in a mixture of 12.2 g.
10 ml of an anhydrous tetrahydrofuran solution containing 6.6 g of 1 ′-(azodicarbonyl) dipiperidine and 20 ml of anhydrous dimethylformamide were added dropwise, and the mixture was stirred at room temperature for about 20 hours. After completion of the reaction, insoluble matter was filtered off from the reaction mixture, and the obtained filtrate was concentrated. The obtained residue was purified by subjecting it to silica gel column chromatography (hexane: ethyl acetate = 10: 1), and the melting point was 85.
3.70 g of the desired compound having a temperature of 4 ° C to 87.2 ° C
was gotten.

Reference Example 5 1-Methylindoline-2-carboxylic acid methyl (±) indoline-2-carboxylic acid 10.3 g, dimethylformamide 200 ml and anhydrous potassium carbonate
Methyl iodide (11.7 ml) was added dropwise to the mixture (25.4 g), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1) to give an Rf value = 0.77 (silica gel thin layer chromatography; hexane: 9.12 g of the target compound with ethyl acetate = 2: 1) was obtained.

Reference Example 6 Methyl 1-methylindoline-2-ylmethanol 1-methylindoline-2-carboxylate (see Reference Example 5) 8.0 g, lithium aluminum hydride
When the reaction and post-treatment were carried out according to Reference Example 2 using 1.91 g and tetrahydrofuran 250 ml, Rf
Target compound with value = 0.35 (silica gel thin layer chromatography; hexane: ethyl acetate = 2: 1)
6.85 g were obtained.

Reference Example 7 5- [4- (1-methylindoline-2-ylmethoxy)
Si) benzyl] -3-triphenylmethylthiazolidine
-2,4-dione 1-methylindoline-2-ylmethanol (Reference Example 6
Reference) 2.0 g, 5- (4-hydroxybenzyl)-
3-triphenylmethylthiazolidine-2,4-dione 4.73 g, tributylphosphine 2.53 ml,
1,1 '-(azodicarbonyl) dipiperidine 2.5
When 7 g and 55 ml of benzene were used and the reaction and post-treatment were carried out according to Reference Example 4, the melting point was 62.5 ° C to 6
4.39 g of the target compound having a temperature of 5.5 ° C. were obtained.

Reference Example 8 Indoline-1-ylmethylindoline acetate 0.25 g, dimethylformamide 2 m
0.40 ml of methyl bromoacetate was added dropwise to a mixture of 1 and 0.87 g of anhydrous potassium carbonate, and the mixture was stirred for 1 hour at room temperature. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the resulting residue was purified by subjecting it to silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give R
f value = 0.63 (silica gel thin layer chromatography;
0.30 g of the target compound having hexane: ethyl acetate = 2: 1) was obtained.

Reference Example 9 2- (Indoline-1-yl) ethanol methyl indoline-1-yl acetate (see Reference Example 8) 7
Using 80 mg, 200 mg of lithium aluminum hydride and 12 ml of anhydrous tetrahydrofuran, Reference Example 2
When the reaction and post-treatment are carried out according to, the Rf value = 0.31.
580 mg of the desired compound having (silica gel thin layer chromatography; hexane: ethyl acetate = 2: 1) are obtained.

Reference Example 10 5- {4- [2- (indoline-1-yl) ethoxy]
Benzyl} -3-triphenylmethylthiazolidine-
2,4-dione 2- (indoline-1-yl) ethanol (see Reference Example 9) 240 mg, 5- (4-hydroxybenzyl)-
3-triphenylmethylthiazolidine-2,4-dione 690 mg, tributylphosphine 0.37 ml,
1,1 '-(azodicarbonyl) dipiperidine 370
Rf value = 0.
88 (silica gel thin layer chromatography; hexane:
530 mg of the target compound having ethyl acetate = 2: 1)
was gotten.

Reference Example 11 5- {4- [2- (indol-3-yl) ethoxy]
Benzyl} -3-triphenylmethylthiazolidine-
2,4-dione 2- (indol-3-yl) ethanol (commercially available)
5.0 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 14.4
g, tributylphosphine 7.73 ml, 1,1'-
(Azodicarbonyl) dipiperidine (7.83 g) and anhydrous benzene (150 ml) were used and the reaction and post-treatment were carried out according to Reference Example 4, melting point 81.0 ° C to 82.
3.03 g of the target compound having a temperature of 5 ° C. was obtained.

Reference Example 12 Indol-1-yl sodium acetate methyl hydride (55% by weight) (2.0 g) was washed with hexane, dimethylformamide (80 ml) was added, and 5.0 g of indole was added to the mixture under ice cooling. 20 ml of a dimethylformamide solution containing the solution was added dropwise, and the mixture was stirred at room temperature for 1 hour. Then, 4.5 ml of methyl bromoacetate was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give an Rf value of 0.6.
6.52 g of the target compound having 6 (silica gel thin layer chromatography; hexane: ethyl acetate = 2: 1) were obtained.

Reference Example 13 2- (Indol-1-yl) ethanol methyl indol-1-yl acetate (see Reference Example 12)
When 6.20 g, 1.50 g of lithium aluminum hydride and 220 ml of anhydrous tetrahydrofuran were used for the reaction and post-treatment according to Reference Example 2, Rf value = 0.
33 (silica gel thin layer chromatography; hexane:
5.25 g of the target compound having ethyl acetate = 2: 1)
was gotten.

Reference Example 14 5- {4- [2- (indol-1-yl) ethoxy]
Benzyl} -3-triphenylmethylthiazolidine-
2,4-dione 2- (indol-1-yl) ethanol (Reference Example 13
Reference) 2.0 g, 5- (4-hydroxybenzyl)-
3-triphenylmethylthiazolidine-2,4-dione (4.81 g), tributylphosphine (3.1 ml),
1,1 '-(azodicarbonyl) dipiperidine 3.2
When 0 g and 60 ml of anhydrous benzene were used and the reaction and post-treatment were carried out according to Reference Example 4, 5.69 g of the desired compound having a melting point of 63.5 ° C to 65.9 ° C was obtained.

Reference Example 15 3-Methylimidazo [5,4-b] pyridin-2-yl
0.98 g of methanol sodium hydride (55% by weight) was washed with hexane, 100 ml of dimethylformamide was added, and further 3.35 g of imidazo [5,4-b] pyridin-2-ylmethanol (commercially available product) was added at room temperature. Stir for 6 hours. The reaction mixture was then added to methyl iodide under ice cooling.
3.51 g was added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, dimethylformamide was distilled off from the reaction mixture under reduced pressure. The obtained residue is subjected to silica gel column chromatography (ethyl acetate: ethanol = 1: 0 → 10: 1).
Purification by filtration gave 1.7 g of the desired compound having a melting point of 229 ° C to 231 ° C.

Reference Example 16 5- {4- (3-methylimidazo [5,4-b] pyridy
N-2-ylmethoxy) benzyl} -3-triphenyl
Methylthiazolidine-2,4-dione 3-methylimidazo [5,4-b] pyridin-2-ylmethanol (see Reference Example 15) 0.5 g, 5- (4-
Hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 1.43 g, tributylphosphine 0.83 ml, 1,1 '-(azodicarbonyl)
0.773 g dipiperidine and 80 ml benzene
And the reaction and post-treatment according to Reference Example 4,
Target compound having a melting point of 97 ° C to 102 ° C 0.3
g was obtained.

Reference Example 17 7-azaindole-1- sodium methyl acetate methyl hydride (55% by weight) 1.90 g, 7-azaindole 4.95 g, dimethylformamide 10
When 0 ml and 4.2 ml of methyl bromoacetate were used to carry out the reaction and post-treatment according to Reference Example 12, Rf value =
7.7 target compound having 0.33 (silica gel thin layer chromatography; hexane: ethyl acetate = 2: 1)
0 g was obtained.

Reference Example 18 2- (7-azaindol-1-yl) ethanol 7-azaindole-1-methyl acetate (see Reference Example 17) 7.50 g, lithium aluminum hydride
4. When 80 g and 260 ml of anhydrous tetrahydrofuran were used and the reaction and post-treatment were carried out according to Reference Example 2, the target compound having a melting point of 52.7 ° C to 53.3 ° C.
57 g were obtained.

Reference Example 19 5- {4- [2- (7-azaindol-1-yl) d
Toxy] benzyl} -3-triphenylmethyl thiazol
Din-2,4-dione 2- (7-azaindol-1-yl) ethanol (see Reference Example 18) 1.77 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4
-Dione 4.40 g, tributylphosphine 2.3
When 5 ml, 1,1 ′-(azodicarbonyl) dipiperidine 2.39 g and 45 ml of anhydrous benzene were used for the reaction and post-treatment according to Reference Example 4, melting point 167.
The target compound having a temperature of 5 ° C to 168.9 ° C 4.58
g was obtained.

Reference Example 20 A tetrahydrofuran solution containing 9.17 g of ethyl imidazo [1,2-a] pyridin-2-ylmethanolimidazo [1,2-a] pyridine-2-carboxylate 200
3.68 g of lithium borohydride was added to ml at room temperature, 20 ml of methanol was further added dropwise, and the mixture was left at room temperature overnight. After completion of the reaction, 10 ml of water was added to the reaction mixture, which was then concentrated, then brine was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, the obtained residue was subjected to silica gel column chromatography (ethyl acetate: ethanol = 5: 1), and recrystallized using a mixed solvent of ethyl acetate-hexane to give a melting point of 126 ° C. To 128 ° C
0.56 g of the target compound having is obtained.

Reference Example 21 5- [4- (imidazo [1,2-a] pyridin-2-i
Lumethoxy) benzyl] -3-triphenylmethylthia
Zolidine-2,4-dioneimidazo [1,2-a] pyridin-2-ylmethanol (see Reference Example 20) 920 mg, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-
2,4-dione 2.9 g, tributylphosphine
When 1.4 g, 1,1 ′-(azodicarbonyl) dipiperidine (1.65 g) and benzene (60 ml) were used and the reaction and post-treatment were carried out according to Reference Example 4, Rf value = 0.7.
1 (silica gel thin layer chromatography; ethyl acetate:
3.1 g of the target compound having ethanol = 10: 1)
was gotten.

Reference Example 22 1-Methylindole- 2-carboxylic acid Methylindole-2-carboxylic acid 5.00 g, dimethylformamide 100 ml and anhydrous potassium carbonate 13.
6.0 ml of methyl iodide was added dropwise to 0 g of the mixture and 10
The mixture was stirred at 0 ° C for 6 hours. After completion of the reaction, the reaction mixture was post-treated according to Reference Example 5 to give a melting point of 91.3 ° C to 9 ° C.
5.12 g of the target compound having a temperature of 2.8 ° C. was obtained.

Reference Example 23 20 ml of an anhydrous tetrahydrofuran solution containing 5.05 g of methyl 1-methylindol-2-ylmethanol 1-methylindole-2-carboxylate (see Reference Example 22), 1.85 g of lithium borohydride and The mixture was added dropwise to a mixture of 80 ml of anhydrous tetrahydrofuran and heated under reflux for 4 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract to obtain 4.30 g of the target compound having a melting point of 92.8 ° C to 95.2 ° C.

Reference Example 24 5- [4- (1-methylindol-2-ylmethoxy)
Si) benzyl] -3-triphenylmethylthiazolidine
-2,4-dione 1-methylindol-2-ylmethanol (Reference Example 2
3) 4.30 g, 5- (4-hydroxybenzyl) -3-triphenylmethylazolidine-2,4-dione 10.3 g, tributylphosphine 6.65 m
l, 1,1 '-(azodicarbonyl) dipiperidine
When the reaction and post-treatment were carried out according to Reference Example 4 using 6.73 g and 120 ml of benzene, the melting point was 134.3.
6.28 g of the target compound having a temperature of ℃ to 136.0 ℃
was gotten.

Reference Example 25 Imidazo [1,2-a] pyridin-2 -ylethyl acetate 2-aminopyridine 14.6 g, ethyl 4-chloroacetoacetate 25.5 g and acetonitrile 200 m.
The mixture of 1 was heated to reflux for 14.5 hours. After the reaction,
The solvent was evaporated from the reaction mixture, brine and aqueous potassium carbonate solution were added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, the resulting residue was purified by silica gel column chromatography (ethyl acetate), and the target compound 2 having Rf value = 0.33 (silica gel thin layer chromatography; ethyl acetate) was obtained. 0.65 g was obtained.

Reference Example 26 2- (2-hydroxyethyl) imidazo [1,2-a]
Pyridine imidazo [1,2-a] pyridin-2-yl ethyl acetate (Reference Example 25 reference) 2.65 g, lithium aluminum hydride 0.5g, and tetrahydrofuran 100
Using ml, the reaction and post-treatment were carried out according to Reference Example 2. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: ethanol = 20: 1 → 4: 1).
And purified to give a melting point of 120.3 ° C to 126.
1.32 g of the target compound having a temperature of 9 ° C. was obtained.

Reference Example 27 5- {4- [2- (imidazo [1,2-a] pyridine-
2-yl) ethoxy] benzyl} -3-triphenylmeth
Tyrthiazolidine-2,4-dione 2- (2-hydroxyethyl) imidazo [1,2-a]
Pyridine (see Reference Example 26) 0.80 g, 5- (4-
Hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 2.79 g, tributylphosphine 1.7 ml, 1,1 ′-(azodicarbonyl)
The reaction and post-treatment were carried out according to Reference Example 4 using 1.51 g of dipiperidine and 30 ml of benzene. The obtained crude product was purified by subjecting it to silica gel column chromatography (hexane: ethyl acetate = 1: 4 → 0: 1) to obtain the target compound having a melting point of 135.5 ° C. to 142.4 ° C. (decomposition point). 0.97 g was obtained.

Reference Example 28 3-Ethyl-2-hydroxymethylimidazo [5,4-
b] 0.878 g of sodium pyridine hydride (55% by weight) was washed with hexane, 80 ml of dimethylformamide was added, and 2-hydroxymethyl-3H-imidazo [5,4] was added.
-B] Pyridine (commercial item) (3 g) was added, and the mixture was stirred at room temperature for 2 hours. Then, 1.78 ml of ethyl iodide was added dropwise to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 2 hours and left overnight. After completion of the reaction, dimethylformamide was distilled off from the reaction mixture under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: ethanol =
Purification by subjecting to 1: 0 → 5: 1) yielded 570 mg of the desired compound having a melting point of 117 ° C. to 121 ° C.

Reference Example 29 5- [4- (3-ethylimidazo [5,4-b] pyridy
N-2-ylmethoxy) benzyl] -3-triphenyl
Methylthiazolidine- 2,4-dione 3-ethyl-2-hydroxymethylimidazo [5,4-
b] Pyridine (see Reference Example 28) 0.5 g, 5- (4
-Hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 1.313 g, tributylphosphine 0.77 ml, 1,1 '-(azodicarbonyl) dipiperidine 0.712 g and benzene 80
Using ml, the reaction and post-treatment were carried out according to Reference Example 4. The obtained crude product was purified by subjecting it to silica gel column chromatography (hexane: ethyl acetate = 1: 3) to give an Rf value = 0.55 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 3). 300 mg of the target compound having

Reference Example 30 2-Hydroxymethyl-1-methylimidazo [4,5-
b] Pyridine 2-hydroxymethyl-3H-imidazo [5,4-b]
The reaction and post-treatment were carried out according to Reference Example 15 using 45 g of pyridine (commercially available product), 13.17 g of sodium hydride (55% by weight), 20.7 ml of methyl iodide and 1.43 liters of dimethylformamide. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 1: 0 → 1: 1) to give the desired compound having a melting point of 130 ° C to 132 ° C.
3.24 g was obtained.

Reference Example 31 5- [4- (1-methylimidazo [4,5-b] pyridy
N-2-ylmethoxy) benzyl] -3-triphenyl
Methylthiazolidine-2,4-dione 2-hydroxymethyl-1-methylimidazo [4,5-
b] Pyridine (see Reference Example 30) 2.5 g, 5- (4
-Hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 6.5 g, tributylphosphine 3.47 ml, 1,1 '-(azodicarbonyl)
3.52 g dipiperidine and 1,4-dioxane
The reaction and post-treatment were carried out according to Reference Example 4 using 250 ml. The obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 0: 1).
-> Ethyl acetate: Methanol = 20: 1-> 10: 1) and refine | purified, and 4.1 g of target compounds were obtained.

Reference Example 32 A 2N aqueous sodium hydroxide solution was added to 100 ml of a methanol solution containing 10.0 g of 4-hydroxybutanoic acid γ-butyrolactone and left overnight. After completion of the reaction, 2N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saline and then dried over anhydrous sodium sulfate. When the solvent was distilled off from the extract, 3.70 g of the oily target compound was obtained.

Reference Example 33 2- (3-Hydroxypropyl) -3H-imidazo
0.83 g of 4-hydroxybutanoic acid (see Reference Example 32) was added to 0.77 g of [5,4-b] pyridine 2,3-diaminopyridine and 1
The mixture was stirred at 50 ° C for 4 hours. After the reaction was completed, the reaction mixture was mixed with 3
N hydrochloric acid was added, then aqueous ammonia was added, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: methanol = 5: 1), and then crystallized using ethyl acetate to obtain 0.83 g of the target compound having a melting point of 151 ° C to 153 ° C. .

Reference Example 34 2- (3-hydroxypropyl) -3-methylimidazo
[5,4-b] Pyridine 2- (3-hydroxypropyl) -3H-imidazo [5,4-b] pyridine (see Reference Example 33) 3.40
g, sodium hydride (55% by weight) 0.81 g, methyl iodide 1.2 ml, dimethylformamide 10
The reaction and post-treatment were carried out according to Reference Example 15 using 0 ml. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: methanol = 10: 1) and crystallized with ethyl acetate to give a melting point of 300.
3.10 g of the target compound having a temperature of ℃ or above was obtained.

Reference Example 35 5- {4- [3- (3-methylimidazo [5,4-b]]
Pyridin-2-yl) propoxy] benzyl} -3-to
Liphenylmethylthiazolidine-2,4-dione 2- (3-hydroxypropyl) -3-methylimidazo [5,4-b] pyridine (see Reference Example 34) 750 m
g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 1.83 g,
Tributylphosphine (0.98 ml), 1,1 '-(azodicarbonyl) dipiperidine (990 mg) and toluene (20 ml) were used, and the reaction and post-treatment were carried out according to Reference Example 4. The obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 0:
Purification by 1) gave 550 mg of the desired compound having a melting point of 76 ° C to 81 ° C.

Reference Example 36 Methyl 4-nitrophenoxyacetate 56 g of 4-nitrophenol, methyl 9-bromoacetate
A mixture of 0 g, 100 g of potassium carbonate and 500 ml of dimethylformamide was stirred at room temperature for 2 days. After completion of the reaction, dimethylformamide was distilled off from the reaction mixture under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous sodium sulfate. After the solvent was distilled off from the extract, crystallization was performed using hexane to obtain 63.3 g of the desired compound having a melting point of 98 ° C. to 99 ° C.

Reference Example 37 Methyl 4 -aminophenoxyacetate Methyl 4-nitrophenoxyacetate (see Reference Example 36)
When the reaction and post-treatment are carried out according to Example 6 using 30.8 g, 10% palladium-carbon 5.0 g and methanol 500 ml, it has an Rf value = 0.79 (silica gel thin layer chromatography; ethyl acetate). 25.8 g of the target compound was obtained.

Reference Example 38 4- (2-Bromo-2-butoxycarbonylethyl-1)
-Yl) Methyl phenoxyacetate Methanol-acetone (2: 5) 2 containing 25.8 g of methyl 4-aminophenoxyacetate (see Reference Example 37)
98 g of 47% hydrobromic acid was added dropwise to 63 ml of the solution under ice cooling, and subsequently 33 ml of an aqueous solution containing 12.8 g of sodium nitrite was added dropwise. After stirring for 30 minutes under ice cooling, 18.2 g of butyl acrylate was added to the reaction mixture,
The mixture was stirred for 30 minutes under ice cooling, 3.2 g of copper (I) bromide was added, and the mixture was stirred at room temperature overnight. After the completion of the reaction, the solvent was distilled off from the reaction mixture, brine was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saline and then dried over anhydrous sodium sulfate. When the solvent was distilled off from the extract, 51.7 g of a crude product containing the target compound having an Rf value of 0.46 (silica gel thin layer chromatography; hexane: ethyl acetate = 5: 1) was obtained.

Reference Example 39 5- [4- (ethoxycarbonylmethoxy) benzyl]
Thiazolidine-2,4-dione 4- (2-bromo-2-butoxycarbonylethyl-1
-Yl) Methyl phenoxyacetate (see Reference Example 38) 1
00g, thiourea 22g and ethanol 200ml
The mixture was heated to reflux for 2.5 hours. Next, 2N hydrochloric acid was added to the reaction mixture, and the mixture was refluxed for 5 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture, water was added to the obtained residue, extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off from the extract and silica gel column chromatography (ethyl acetate: hexane =
2: 5) and purified to a melting point of 105 ° C to 10 ° C.
19.4 g of the expected compound having a temperature of 6 ° C. are obtained.

Reference Example 40 3,7-Dimethyl-2-hydroxymethylimidazo
[5,4-b] Pyridine 2-hydroxymethyl-7-methyl-3H-imidazo [5,4-b] pyridine (commercial item) 5.00 g, sodium hydride (55% by weight) 1.34 g, iodide Using 2.0 ml of methyl and 120 ml of dimethylformamide, the reaction and post-treatment were carried out according to Reference Example 15.
The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 1: 0 → 10: 1) to obtain 4.4 g of the target compound having a melting point of 300 ° C. or higher.

Reference Example 41 5- [4- (3,7-dimethylimidazo [5,4-b]]
Pyridin-2-ylmethoxy) benzyl] -3-trif
Phenylmethylthiazolidine-2,4-dione 3,7-dimethyl-2-hydroxymethylimidazo [5,4-b] pyridine (see Reference Example 40) 1.50
g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 3.94 g,
Reaction and post-treatment were carried out according to Reference Example 4 using 2.11 ml of tributylphosphine, 2.14 g of 1,1 ′-(azodicarbonyl) dipiperidine and 30 ml of toluene. The obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1 →
When purified by subjecting to 1: 2), the melting point is 92 ° C to 105 ° C.
1.11 g of the target compound having a temperature of (softening) was obtained.

Reference Example 42 6-chloro-2,3-diaminopyridine 2-amino-6-chloro-3-nitropyridine (commercially available product) 12.0 g, tin (II) chloride dihydrate 78.
A mixture of 0 g and 360 ml of ethyl-2-methyl-2-propanol (9: 1) was stirred at 60 ° C. for 1 hour, and then sodium borohydride (1.32 g) was added at the same temperature.
Was added, and the mixture was further stirred at the same temperature for 3 hours. After the reaction,
The solvent was distilled off from the reaction mixture, water was added to the obtained residue, the mixture was neutralized with an aqueous potassium carbonate solution, and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the obtained residue was crystallized with ethyl acetate and hexane to give a melting point of 1
6.50 g of the target compound having 20 ° C to 122 ° C
was gotten.

Reference Example 43 5-Chloro-2-hydroxymethyl-3H-imidazo
6.60 g of glycolic acid was added to 5.00 g of [5,4-b] pyridine 6-chloro-2,3-diaminopyridine (see Reference Example 42),
The mixture was stirred at 150 ° C for 4 hours. After completion of the reaction, 3N hydrochloric acid was added to the reaction mixture, and then aqueous ammonia was added. After evaporating the solvent from the reaction mixture, the obtained residue was subjected to silica gel column chromatography (ethyl acetate: methanol =
Crystallization with 1: 0 → 10: 1) followed by ethyl acetate gave 5.33 g of the desired compound having a melting point of 224 ° C to 226 ° C.

Reference Example 44 5-Chloro-2-hydroxymethyl-3-methylimida
Zo [5,4-b] pyridine 5-chloro-2-hydroxymethyl-3H-imidazo [5,4-b] pyridine (see Reference Example 43) 3.00
g, sodium hydride (55% by weight) 0.71 g, methyl iodide 1.1 ml, dimethylformamide 70
Using ml, the reaction and post-treatment were carried out according to Reference Example 15. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: methanol = 1: 0 → 10:
When purified by subjecting to 1), the melting point is 204 ° C to 210 ° C.
1.60 g of the target compound having

Reference Example 45 5- [4- (5-chloro-3-methylimidazo [5,4]
-B] pyridin-2-ylmethoxy) benzyl] -3-
Triphenylmethylthiazolidine-2,4-dione 5-chloro-2-hydroxymethyl-3-methylimidazo [5,4-b] pyridine (see Reference Example 44) 1.2
0 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 2.83
g, tributylphosphine 1.51 ml, 1,1'-
The reaction and post-treatment were carried out according to Reference Example 4 using 1.53 g of (azodicarbonyl) dipiperidine and 25 ml of toluene. The obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1 →
1: 1) for purification, melting point 97 ° C to 99 ° C
1.29 g of the target compound having (softening) was obtained.

Reference Example 46 5- [4- (2,2-diethoxyethoxy) benzyl]
260 mg of thiazolidine-2,4-dione sodium hydride (55% by weight) was washed with toluene, 5 ml of dimethylformamide was added, and 5- (4-hydroxybenzyl) thiazolidine- was added under ice cooling.
2,4-dione (530 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Bromoacetaldehyde diethyl acetal 0.73 ml was added to the reaction mixture under ice cooling, and the mixture was stirred at 50 ° C. for 3 hours, and then dimethylformamide was distilled off under reduced pressure. Water was added to the obtained residue, and the pH was adjusted to 2 with 1N hydrochloric acid.
After adjusting to ~ 3, it 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 resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give Rf value = 0.46 (silica gel thin layer chromatography; hexane). : 600 mg of the target compound having: ethyl acetate = 2: 1) was obtained.

Reference Example 47 5- [4- (2-oxoethoxy) benzyl] thiazoli
Gin-2,4-dione 5- [4- (2,2-diethoxyethoxy) benzyl]
Thiazolidine-2,4-dione (see Reference Example 46) 1
0.07 g is dissolved in 80 ml of tetrahydrofuran,
Then, 20 ml of 6N hydrochloric acid was added and the mixture was left at room temperature overnight.
After completion of the reaction, the solvent was distilled off from the reaction mixture, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3) to give Rf value = 0.37 (silica gel thin layer chromatography; hexane). There was obtained 5.92 g of the desired compound having: ethyl acetate = 1: 2).

Reference Example 48 2-Hydroxymethyl-3H-imidazo [5,4-d]
To 2.27 g of pyrimidine 4,5-diaminopyrimidine, 8.58 g of ethyl glycolate was added, and the mixture was stirred at 140 ° C. for 2 hours. After completion of the reaction, ethyl glycolate was distilled off from the reaction mixture under reduced pressure, the resulting residue was decolorized with activated carbon, and then crystallized with ethanol to give Rf value =
Target compound having 0.27 (silica gel thin layer chromatography; ethyl acetate: methanol = 10: 1)
1.81 g was obtained.

Reference Example 49 2-t-butyldimethylsilyloxymethyl-3H-i
Midazo [5,4-d] pyrimidine 2-hydroxymethyl-3H-imidazo [5,4-d]
Pyrimidine (see Reference Example 48) 1.81 g, t-butyldimethylsilyl chloride 2.71 g, imidazole 2.45 g and dimethylformamide 100 m
The mixture of 1 was stirred at room temperature for 1 hour. After completion of the reaction, dimethylformamide was distilled off from the reaction mixture under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate.
The solvent was distilled off from the extract, and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the target compound having a melting point of 104 ° C to 107 ° C.
1.89 g was obtained.

Reference Example 50 2-Hydroxymethyl-3-methylimidazo [5,4-
d] pyrimidine 2-t-butyldimethylsilyloxymethyl-3H-imidazo [5,4-d] pyrimidine (see Reference Example 49)
1.89 g, sodium hydride (55% by weight) 0.37
g, methyl iodide (490 μl) and dimethylformamide (30 ml) were used to carry out a reaction according to Reference Example 15. After completion of the reaction, dimethylformamide was distilled off from the reaction mixture under reduced pressure, 3N hydrochloric acid was added to the obtained residue, and then aqueous ammonia was added to make the mixture alkaline. The solvent was distilled off from this mixture, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate: ethanol = 6:
When purified by subjecting to 1), the melting point is 122 ° C to 125 ° C.
0.37 g of the target compound having

Reference Example 51 5- [4- (3-methylimidazo [5,4-d] pyrimi
[Zin-2-ylmethoxy) benzyl] -3-triphenyl
Rumethylthiazolidine- 2,4-dione 2-hydroxymethyl-3-methylimidazo [5,4-
d] Pyrimidine (see Reference Example 50) 0.37 g, 5-
(4-Hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 2.51 g, tributylphosphine 1.34 ml, 1,1 '-(azodicarbonyl) dipiperidine 1.36 g and benzene 50
Using ml, the reaction and post-treatment were carried out according to Reference Example 4. The obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1 → 1 :).
2 → ethyl acetate: ethanol = 6: 1), and then reverse phase preparative high performance liquid chromatography (YMC-Pa).
ck ODS-A (trade name; YMC); acetonitrile: water: acetic acid: triethylamine = 100: 100:
1: 1) for purification, melting point 55 ° C to 65 ° C
0.24 g of the target compound having (softening) was obtained.

Reference Example 52 2- (4-chlorobenzyl) amino-3-nitropyridy
Down 2-hydroxy-3-nitropyridine 10.3g in thionyl chloride 25.5ml was added and after heating under reflux for 2.5 hours, added rapidly dimethylformamide 1.1 ml, and heated to reflux for 2.5 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture. Toluene 80 was added to the obtained residue.
20 ml of a toluene solution of 12.3 ml of 4-chlorobenzylamine was added dropwise at room temperature, and the mixture was stirred at 85 ° C. for 4 hours. After completion of the reaction, the insoluble matter was filtered off from the reaction mixture, the obtained filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off from the filtrate, and the obtained residue was crystallized using 2-propanol to obtain 12.0 g of the target compound having a melting point of 95 ° C to 96 ° C.

Reference Example 53 3-Amino-2- (4-chlorobenzyl) aminopyridy
Emissions 2- (4-chlorobenzyl) amino-3-nitropyridine (Example 52 reference) 5.00 g, tin (II) · 2
Hydrate 21.4 g, sodium borohydride 0.3
The reaction and post-treatment were carried out according to Reference Example 42 using 6 g and 150 ml of ethyl acetate-2-methyl-2-propanol (9: 1). The crude product obtained was crystallized from ethyl acetate and hexane to give 3.55 g of the desired compound having a melting point of 123 ° C to 125 ° C.

Reference Example 54 2-Hydroxymethyl-3- (4-phenylbenzyl)
1.1 g of imidazo [5,4-b] pyridine sodium hydride (55% by weight) was washed with hexane, 100 ml of dimethylformamide was added,
Furthermore, 2-hydroxymethyl-3H-imidazo [5,4
-B] 3.74 g of pyridine (commercial item) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then 4-
20 ml of a dimethylformamide solution containing 5.07 g of (chloromethyl) biphenyl was added dropwise, and the mixture was stirred at room temperature for 2 hours and left overnight. After completion of the reaction, dimethylformamide was distilled off from the reaction mixture under reduced pressure. The obtained residue was purified by subjecting it to silica gel column chromatography (hexane: ethyl acetate = 1: 3) to obtain 0.8 g of the target compound having a melting point of 163 ° C to 165 ° C.

Reference Example 55 5- {4- [3- (4-phenylbenzyl) imidazo
[5,4-b] Pyridin-2-yl-methoxy] benz
Ru} -3-triphenylmethylthiazolidine-2,4-
Dione 2-hydroxymethyl-3- (4-phenylbenzyl)
Imidazo [5,4-b] pyridine (see Reference Example 54)
0.5 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 0.7
38 g, tributylphosphine 0.43 ml, 1,
The reaction and post-treatment were carried out according to Reference Example 4 using 0.4 g of 1 ′-(azodicarbonyl) dipiperidine and 20 ml of benzene. The obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
When purified by subjecting to 2 → 1: 3), Rf value = 0.44
0.95 g of the target compound having (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 3) are obtained.

Reference Example 56 2-Amino-5-bromo-3 -nitropyridine To 25.0 g of 2-amino-5-bromopyridine, 100 ml of concentrated sulfuric acid was added, and then at 50-60 ° C., concentrated nitric acid was added.
After 8.9 ml was added dropwise over 1 hour, the mixture was stirred at 60 ° C. for 30 minutes. After completion of the reaction, the reaction mixture was poured into ice, neutralized with an aqueous sodium hydroxide solution, and crude crystals were filtered. When this crude crystal is further washed with ethanol, the melting point is 180 ° C.
19.1 g of the expected compound having a temperature of ˜182 ° C. are obtained.

Reference Example 57 5-Bromo-2,3-diaminopyridine 2-amino-5-bromo-3-nitropyridine (see Reference Example 56) 12.0 g, tin (II) chloride dihydrate
62.1 g, sodium borohydride 1.04 g and ethyl acetate-2-methyl-2-propanol (9: 1)
The reaction and post-treatment were performed according to Reference Example 42 using 300 ml. The obtained crude product was crystallized by adding ethyl acetate and hexane, and the melting point was 135 ° C to 137 ° C.
7.46 g of the target compound having a temperature of ℃ were obtained.

Reference Example 58 6-Bromo-2-hydroxymethyl-3H-imidazo
[5,4-b] pyridine 5-bromo-2,3-diaminopyridine (see Reference Example 57) 7.00 g and glycolic acid 8.50 g were used,
Reaction and post-treatment were carried out according to Reference Example 43. The obtained crude product is purified by subjecting it to silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain the target compound having a melting point of 230 ° C to 233 ° C.
7.05 g was obtained.

Reference Example 59 6-Bromo-2-hydroxymethyl-3-methylimidazole
Zo [5,4-b] pyridine 6-bromo-2-hydroxymethyl-3H-imidazo [5,4-b] pyridine (see Reference Example 58) 3.00
g, sodium hydride (55% by weight) 0.58 g, methyl iodide 0.92 ml, dimethylformamide 6
The reaction was performed according to Reference Example 15 using 0 ml. After completion of the reaction, dimethylformamide was distilled off from the reaction mixture under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, the obtained residue was subjected to silica gel column chromatography (ethyl acetate: methanol = 50: 1), and crystallized from diethyl ether to give the target compound having a melting point of 142 ° C. to 144 ° C. 1 0.40 g was obtained.

Reference Example 60 5- [4- (6-Bromo-3-methylimidazo [5,4
-B] pyridin-2-ylmethoxy) benzyl] -3-
Triphenylmethylthiazolidine-2,4-dione 6-bromo-2-hydroxymethyl-3-methylimidazo [5,4-b] pyridine (see Reference Example 59) 1.3
5 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 2.60
g, tributylphosphine 1.39 ml, 1,1′-
The reaction and post-treatment were carried out according to Reference Example 4 using 1.41 g of (azodicarbonyl) dipiperidine and 35 ml of toluene. The obtained crude product is subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
After purification by subjecting to 3.43 g of the desired compound having a melting point of 97 ° C to 100 ° C (softening).

Reference Example 61 2-amino-5-chloro-3-nitropyridine 2-amino-5-chloropyridine (commercially available) 25.0
g, concentrated sulfuric acid 100 ml, concentrated nitric acid 12.5 ml,
When the reaction and post-treatment are carried out according to Reference Example 56, the melting point is 1
18.5 g of the target compound having a temperature of 38 ° C to 139 ° C
was gotten.

Reference Example 62 5-chloro-2,3-diaminopyridine 2-amino-5-chloro-3-nitropyridine (see Reference Example 61) 12.5 g, tin (II) chloride dihydrate
82.0 g, sodium borohydride 1.35 g and ethyl acetate-2-methyl-2-propanol (9: 1)
The reaction and post-treatment were performed according to Reference Example 42 using 300 ml. The obtained crude product was crystallized by adding ethyl acetate and hexane to give a melting point of 164 ° C to 165 ° C.
8.14 g of the target compound having a temperature of ℃ were obtained.

Reference Example 63 6-Chloro-2-hydroxymethyl-3H-imidazo
[5,4-b] pyridine 5-chloro-2,3-diaminopyridine (see Reference Example 62) 7.67 g and glycolic acid 18.6 g were used,
Reaction and post-treatment were carried out according to Reference Example 43. The obtained crude product was purified by subjecting it to silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain the target compound having a melting point of 209 ° C to 211 ° C.
8.83 g was obtained.

Reference Example 64 6-chloro-2-hydroxymethyl-3-methylimidazole
Zo [5,4-b] pyridine 6-chloro-2-hydroxymethyl-3H-imidazo [5,4-b] pyridine (see Reference Example 63) 3.00
g, sodium hydride (55% by weight) 0.71 g, methyl iodide 1.03 ml, dimethylformamide 5
The reaction and post-treatment were carried out according to Reference Example 59 using 0 ml. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: methanol = 1: 0 → 50:
When purified by subjecting to 1), the melting point is 141 ° C to 142 ° C.
0.87 g of the target compound having is obtained.

Reference Example 65 5- [4- (6-chloro-3-methylimidazo [5,4]
-B] pyridin-2-ylmethoxy) benzyl] -3-
Triphenylmethylthiazolidine-2,4-dione 6-chloro-2-hydroxymethyl-3-methylimidazo [5,4-b] pyridine (see Reference Example 64) 0.5
2 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 1.23
g, tributylphosphine 0.66 ml, 1,1'-
The reaction and post-treatment were carried out according to Reference Example 4 using 0.67 g of (azodicarbonyl) dipiperidine and 20 ml of toluene. The obtained crude product is subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
Refining to give a melting point of 82 ° C to 84 ° C (softening)
1.51 g of the target compound having is obtained.

Reference Example 66 6-chloro-2-methylamino-3-nitropyridine 2,6-dichloro-3-nitropyridine (commercially available) 2
In a mixture of 9.0 g, 300 ml of ethanol and 36.6 g of sodium carbonate, 3% of methylamine was added under ice cooling.
20.0 ml of 0% ethanol solution was added dropwise at room temperature for 8
Stirred for hours. After completion of the reaction, ethanol was distilled off from the reaction mixture, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and ethanol was added to the obtained residue to crystallize to obtain 22.3 g of the desired compound having a melting point of 114 ° C.

Reference Example 67 6-methoxy-2-methylamino-3-nitropyridine 6-chloro-2-methylamino-3-nitropyridine (see Reference Example 66) 6.00 g of a methanol solution 12
To 0 ml, 19 ml of 28% methanol solution of sodium methoxide was added dropwise at room temperature, and the mixture was stirred at room temperature for 3 hours.
After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and ethanol was added to the obtained residue to crystallize to obtain 5.34 g of the desired compound having a melting point of 152 ° C to 153 ° C.

Reference Example 68 3-amino-6-methoxy-2-methylaminopyridine 6-methoxy-2-methylamino-3-nitropyridine (see Reference Example 67) 3.45 g, 10% palladium-carbon 0.70 g Using 50 ml of dioxane and 50 ml of dioxane and carrying out the reaction and post-treatment according to Example 6, Rf value =
The target compound having 0.12 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1).
6 g were obtained.

Reference Example 69 2-hydroxymethyl-5-methoxy-3-methylimi
Dazo [5,4-b] pyridine 3-amino-6-methoxy-2-methylaminopyridine (see Reference Example 68) 2.20 g, glycolic acid 3.3
A mixture of 0 g and 40 ml of toluene was heated under reflux for 4 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: methanol = 30: 1).
A target compound having a melting point of 138 ° C. to 140 ° C. 62
0 mg was obtained.

Reference Example 70 5- [4- (5-methoxy-3-methylimidazo [5,
4-b] pyridin-2-ylmethoxy) benzyl] -3
-Triphenylmethylthiazolidine-2,4-dione 2-hydroxymethyl-5-methoxy-3-methylimidazo [5,4-b] pyridine (see Reference Example 69).
25 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 0.66
g, tributylphosphine 0.35 ml, 1,1'-
The reaction and post-treatment were carried out according to Reference Example 4 using 0.36 g of (azodicarbonyl) dipiperidine and 15 ml of toluene. The obtained crude product is subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
After purification by melting, melting point 80 ℃ -85 ℃ (softening)
0.70 g of the target compound having is obtained.

Reference Example 71 2-t-butyldimethylsilyloxymethyl-1H-i
Midazo [4,5-c] pyridine 2-hydroxymethyl-1H-imidazo [4,5-c]
Pyridine (commercially available) 5.00 g, imidazole 6.8
5 g, t-butyldimethylsilyl chloride 7.58 g
And 100 ml of dimethylformamide were used for the reaction and post-treatment according to Reference Example 49. The obtained crude product was purified by subjecting it to silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain 7.40 g of the target compound having a melting point of 53 ° C to 55 ° C.
was gotten.

Reference Example 72 2-t-butyldimethylsilyloxymethyl-1-methyi
Ruimidazo [4,5-c] pyridine 2-t-butyldimethylsilyloxymethyl-1H-imidazo [4,5-c] pyridine (see Reference Example 71).
7.4 g, sodium hydride (55% by weight) 1.23
g, 2.0 ml of methyl iodide and 200 ml of dimethylformamide were used, and the reaction and post-treatment were carried out according to Reference Example 59. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: methanol = 10:
Purification by 1) gave 3.30 g of the desired compound having a melting point of 93 ° C to 95 ° C.

Reference Example 73 2-Hydroxymethyl-1-methylimidazo [4,5-
c] Pyridine 2-t-butyldimethylsilyloxymethyl-1-methylimidazo [4,5-c] pyridine (see Reference Example 72).
3.00 g, tetrahydrofuran-acetic acid-water (1:
1: 1) 60 ml of the mixture was stirred for 1 hour at room temperature and 5 hours at 60 ° C. After completion of the reaction, the solvent was distilled off from the reaction mixture, an aqueous sodium hydrogen carbonate solution was added to the obtained residue, and then the solvent of the mixture was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain 1.97 g of the target compound having a melting point of 285 ° C to 290 ° C.

Reference Example 74 5- [4- (1-methylimidazo [4,5-c] pyridy
N-2-ylmethoxy) benzyl] -3-triphenyl
Methylthiazolidine-2,4-dione 2-hydroxymethyl-1-methylimidazo [4,5-
c] Pyridine (see Reference Example 73) 1.94 g, 5-
(4-Hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione (5.71 g), tributylphosphine (3.1 ml), 1,1 ′-(azodicarbonyl) dipiperidine (3.09 g) and toluene (50 m)
The reaction and post-treatment were carried out in the same manner as in Reference Example 4 using 1. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: methanol = 1: 0 → 10: 1).
After purification by means of silica gel, 3.55 g of the desired compound having an Rf value of 0.08 (silica gel thin layer chromatography; ethyl acetate) was obtained.

Reference Example 75 2-chloro-3-formylpyridine 2-chloro-3-cyanopyridine A solution of 16.7 g of tetrahydrofuran in 200 ml of tetrahydrofuran was added at -30 ° C to -2.
Hexane of diisobutylaluminum hydride at 0 ° C 1.
200 ml of 02M solution was added dropwise over 30 minutes, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, hydrochloric acid was added to the reaction mixture at 0 ° C, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1 → 5: 1) to give an Rf value = 0.50 (silica gel thin layer chromatography). 7.0 g of the target compound are obtained, which has the following graphs; hexane: ethyl acetate = 2: 1).

Reference Example 76 2-Azide-3- (2-chloropyridin-3-yl)-
Ethyl 3-hydroxypropionate 2-chloro-3-formylpyridine (see Reference Example 75)
A mixture of 2.0 g, ethyl azide acetate 7.5 g, and sodium ethoxide ethanol 65 mM solution 87 ml was stirred at 0 ° C. for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give an Rf value = 0.61 (silica gel thin layer chromatography; hexane: 2.83 g of the target compound with ethyl acetate = 2: 1) was obtained.

Reference Example 77 2-Azide-3-t-butyldimethylsilyloxy-3
Ethyl-(2-chloropyridin-3-yl) propionate
Le 2-azide-3- (2-chloro-3-yl) -
Ethyl 3-hydroxypropionate (see Reference Example 76)
3.90 g, t-butyldimethylsilyl chloride
Using 8.6 g, 10 g of imidazole and 80 ml of dimethylformamide, the reaction and post-treatment were carried out according to Reference Example 49. The obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 8:
When purified by subjecting to 1), Rf value = 0.31 (silica gel thin layer chromatography; hexane: ethyl acetate =
5.6 g of the target compound having 3: 1) are obtained.

Reference Example 78 2-Amino-3-t-butyldimethylsilyloxy-3
Ethyl-(2-chloropyridin-3-yl) propionate
Le 2-azide -3-t-butyldimethylsilyloxy -3
Ethyl-(2-chloropyridin-3-yl) propionate (see Reference Example 77) 5.6 g, triphenylphosphine 7.5 g and tetrahydrofuran-water (8:
1) 18 ml of the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1 → methylene chloride: methanol = 50:
After purification by subjecting to 1), 5.9 g of the desired compound having Rf value = 0.59 (silica gel thin layer chromatography; methylene chloride: methanol = 15: 1) was obtained.

Reference Example 79 3-t-butyldimethylsilyloxy-3- (2- chloro)
Ropyridin-3-yl) -2-methylaminopropion
Ethyl acid 2-amino-3-t-butyldimethylsilyloxy-3
To a mixture of 0.7 g of ethyl-(2-chloropyridin-3-yl) propionate (see Reference Example 78) and 4 ml of methylene chloride-water (3: 2) at 0 ° C, 182 mg of 35% formalin, 0.1 ml of acetic acid and 121 mg of sodium cyanoborohydride was added, and the mixture was stirred at 0 ° C for 15 minutes. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saline and then dried over anhydrous sodium sulfate.
The solvent was distilled off from the extract, and the resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 8:
When purified by subjecting to 1 → 1: 1), Rf value = 0.38
200 mg of the target compound having (silica gel thin layer chromatography; hexane: ethyl acetate = 3: 1) are obtained.

Reference Example 80 1-Methyl-7-azaindole-2-carboxylic acid ethyl
Le 3-t-butyldimethylsilyloxy-3- (2-chloro-3-yl) -2-methylamino-propionic acid ethyl (Reference Example 79 reference) 994 mg, 1,5-diazabicyclo [4.3.0] Non-5-en 393m
g, a mixture of 5 ml of dimethylformamide at 150 ° C.
For 5 hours. After completion of the reaction, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate.
The extract was washed with saline and then dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the resulting residue was purified by subjecting it to silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 5: 1) to give an Rf value =
150 m of the target compound having 0.40 (silica gel thin layer chromatography; hexane: ethyl acetate = 3: 1).
g was obtained.

Reference Example 81 2-Hydroxymethyl-1-methyl-7-azaindole
Le 1-methyl-7-azaindole-2-carboxylate (Reference Example 80 reference) 130 mg, lithium aluminum hydride 23 mg, with tetrahydrofuran 2 ml, provided that the reaction and post-treatment according to Reference Example 2, Rf
Target compound 1 with a value = 0.47 (silica gel thin layer chromatography; hexane: ethyl acetate = 3: 1)
10 mg was obtained.

Reference Example 82 5- [4- (1-methyl-7-azaindole-2-i]
Lumethoxy) benzyl] -3-triphenylmethylthia
Zolidine-2,4-dione 2-hydroxymethyl-1-methyl-7-azaindole (see Reference Example 81) 103 mg, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-
2,4-dione 346 mg, diethylazodicarboxylate 166 mg, triphenylphosphine 250
A mixture of mg and tetrahydrofuran 3 ml was stirred at room temperature for 15 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 4: 1) to give an Rf value = 0.41 ( 277 mg of the target compound having silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1) are obtained.

Reference Example 83 3-Nitro-2-phenylaminopyridine 15 g of 2-chloro-3-nitropyridine, aniline
The reaction and post-treatment were carried out according to Reference Example 66 using 13.22 g, sodium carbonate 25.07 g and toluene 180 ml. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
Purification by means of 5) gave 6.9 g of the desired compound having a melting point of 66 ° C to 68 ° C.

Reference Example 84 3-amino-2-phenylaminopyridine 3-nitro-2-phenylaminopyridine (Reference Example 83
See) 6.9 g, 10% palladium-carbon 1.38.
g and ethanol 150 ml and dioxane 50 m
When the reaction and post-treatment were carried out according to Example 6 using the mixed solution of 1 l, 4.2 g of the desired compound having a melting point of 137 ° C to 140 ° C was obtained.

Reference Example 85 2-Hydroxymethyl-5,7-dimethyl-3H-imi
Dazo [5,4-b] pyridine 2,3-diamino-4,6-dimethylpyridine (commercially available product) 13.72 g, glycolic acid 25 g and toluene 200 ml are heated under reflux for 3.5 hours, and water produced is separated and removed. did. After the reaction was completed, toluene was removed by decantation, and the residual oily substance was subjected to silica gel column chromatography (ethanol: ethyl acetate = 2: 3 →
1: 1) to give a melting point of 244 ° C to 24
2.7 g of the target compound having a temperature of 6 ° C. was obtained.

Reference Example 86 2-Hydroxymethyl-3,5,7-trimethylimidazole
Zo [5,4-b] pyridine 2-hydroxymethyl-5,7-dimethyl-3H-imidazo [5,4-b] pyridine (see Reference Example 85).
6 g, sodium hydride (55% by weight) 0.64 g, methyl iodide 2.2 g and dimethylformamide 8
The reaction and post-treatment were carried out according to Reference Example 15 using 0 ml. The obtained crude product was subjected to silica gel column chromatography (ethanol: ethyl acetate = 1: 6) and then recrystallized from ethyl acetate to obtain 1.5 g of the desired compound having a melting point of 178 ° C to 179 ° C. It was

Reference Example 87 5- [4- (3,5,7-trimethylimidazo [5,4
-B] pyridin-2-ylmethoxy) benzyl] -3-
Triphenylmethylthiazolidine-2,4-dione 2-hydroxymethyl-3,5,7-trimethylimidazo [5,4-b] pyridine (see Reference Example 86) 1.4
7 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 3.58
g, tributylphosphine 1.87 g, 1,1′-
The reaction and post-treatment were carried out according to Reference Example 4 using 2.33 g of (azodicarbonyl) dipiperidine and 50 ml of toluene. The obtained crude product is subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
When purified by sol., Melting point 96 ° C-99 ° C (softening)
3.5 g of the target compound having is obtained.

Reference Example 88 2-Methylamino-3-nitro-6-phenylthiopyri
Jin sodium hydride (55 wt%) 1.54 g was washed with hexane, dimethylformamide 30ml was added,
Thiophenol (3.6 ml) was added dropwise. After stirring at room temperature for 1 hour, the reaction mixture was cooled with ice to give 6-chloro-2-methylamino-3-nitropyridine (see Reference Example 66).
Add dropwise to 6.00 g of dimethylformamide solution, 5 ° C
For 2 hours. After completion of the reaction, dimethylformamide was distilled off from the reaction mixture under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give an Rf value = 0.67 (silica gel thin layer chromatography; hexane: 8.40 g of the target compound with ethyl acetate = 3: 1) was obtained.

Reference Example 89 3-Amino-2-methylamino-6-phenylthiopyri
Zin 2-methylamino-3-nitro-6-phenylthiopyridine (see Reference Example 88) 5.40 g, 10% Valladium-carbon 1.10 g and 80 ml of methanol were used to carry out the reaction and post-treatment according to Example 6. When done, Rf
4.00 g of the expected compound with a value = 0.69 (silica gel thin layer chromatography; ethyl acetate) are obtained.

Reference Example 90 2-Hydroxymethyl-3-methyl-5-phenylthio
2.62 g of imidazo [5,4-b] pyridine 3-amino-2-methylamino-6-phenylthiopyridine (see Reference Example 89), glycolic acid
Using 2.58 g, the reaction and post-treatment were carried out according to Reference Example 43. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: methanol = 50: 1 →
10: 1) to give a melting point of 119 ° C to 1
1.80 g of the target compound having a temperature of 20 ° C. was obtained.

Reference Example 91 5- [4- (3-methyl-5-phenylthioimidazo)
[5,4-b] Pyridin-2-ylmethoxy) benz
]]-3-Triphenylmethylthiazolidine-2,4-
Dione 2-hydroxymethyl-3-methyl-5-phenylthioimidazo [5,4-b] pyridine (see Reference Example 90)
0.70 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 1.
20 g, tributylphosphine 0.64 ml, 1,
The reaction and post-treatment were carried out according to Reference Example 4 using 0.65 g of 1 '-(azodicarbonyl) dipiperidine and 25 ml of toluene. The obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate =
1: 1) for purification, melting point 90 ° C-95 ° C
1.61 g of the target compound having (softening) was obtained.

Reference Example 92 6-Benzyloxy-2-methylamino-3-nitropi
Lysine 6-chloro-2-methylamino-3-nitropyridine (see Reference Example 66) 7.00 g, sodium hydride (5
5% by weight) 1.79 g, benzyl alcohol 4.3
ml and dimethylformamide 150 ml,
Reaction and post-treatment were carried out according to Reference Example 88. When isopropanol was added to the obtained crude product for crystallization,
9.02 g of the target compound having a melting point of 149 ° C. was obtained.

Reference Example 93 3-Amino-6-benzyloxy-2-methylaminopi
Lysine 6-benzyloxy-2-methylamino-3-nitropyridine (see Reference Example 92) 8.50 g of methanol solution To 360 ml of methanol, 21.4 g of zinc was added, then 8.5 ml of acetic acid was added dropwise, and the mixture was stirred at room temperature for 1 hour. did. After completion of the reaction, insoluble matter was filtered off from the reaction mixture, and the filtrate was concentrated. Ethyl acetate was added to the obtained residue, washed with sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. When the solvent was distilled off from the reaction mixture, Rf value =
7.50 g of the target compound having 0.63 (silica gel thin layer chromatography; ethyl acetate) are obtained.

Reference Example 94 5-Benzyloxy-2-hydroxymethyl-3-methyi
Ruimidazo [5,4-b] pyridine 3-amino-6-benzyloxy-2-methylaminopyridine (see Reference Example 93) 7.50 g and glycolic acid 7.46 g were used, and the reaction and post-treatment were carried out according to Reference Example 43. Processed. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: methanol = 10:
1) and crystallized from ethyl acetate, melting point 133
4.10 g of the expected compound having a temperature of ℃ to 135 ℃ were obtained.

Reference Example 95 5- [4- (5-benzyloxy-3-methylimidazo)
[5,4-b] Pyridin-2-ylmethoxy) benz
]]-3-Triphenylmethylthiazolidine-2,4-
Dione 5-benzyloxy-2-hydroxymethyl-3-methylimidazo [5,4-b] pyridine (see Reference Example 94)
3.15 g, 5- (4-hydroxybenzyl) -3-
Triphenylmethyl thiazolidine-2,4-dione
5.50 g, tributylphosphine 2.91 ml,
1,1 '-(azodicarbonyl) dipiperidine 2.9
The reaction and post-treatment were carried out according to Reference Example 4 using 5 g and 100 ml of toluene. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 1: 2) to give a melting point of 88.
The target compound having a temperature of 90 to 92 ° C. (softening) 7.10
g was obtained.

Reference Example 96 6-Ethoxy-2-methylamino-3-nitropyridine 6-chloro-2-methylamino-3-nitropyridine (see Reference Example 66) 6.00 g, sodium hydride (5
5% by weight) 1.54 g, 2.1 ml of ethanol and 150 ml of dimethylformamide were used, and Reference Example 88.
The reaction and post-treatment were carried out according to The obtained crude product was crystallized by adding ethanol to obtain 5.10 g of the target compound having a melting point of 101 ° C.

Reference Example 97 3-Amino-6-ethoxy-2-methylaminopyridine 6-Ethoxy-2-methylamino-3-nitropyridine (see Reference Example 96) 4.95 g, 10% Palladium-carbon 1.00 g Using 100 ml of 1,4-dioxane and performing the reaction and post-treatment according to Example 6, Rf
4.20 g of the expected compound with a value = 0.57 (silica gel thin layer chromatography; ethyl acetate) are obtained.

Reference Example 98 5-Ethoxy-2-hydroxymethyl-3-methylimid
Dazo [5,4-b] pyridine 3-amino-6-ethoxy-2-methylaminopyridine (see Reference Example 97) 4.15 g, glycolic acid 5.6
Using 6 g, the reaction and post-treatment were carried out according to Reference Example 43. The obtained crude product is purified by subjecting it to silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain the target compound having a melting point of 161 ° C.
20 g were obtained.

Reference Example 99 5- [4- (5-ethoxy-3-methylimidazo [5,
4-b] pyridin-2-ylmethoxy) benzyl] -3
-Triphenylmethylthiazolidine-2,4-dione 5-ethoxy-2-hydroxymethyl-3-methylimidazo [5,4-b] pyridine (see Reference Example 98) 1.
00 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 2.25
g, tributylphosphine 1.2 ml, 1,1'-
The reaction and post-treatment were carried out according to Reference Example 4 using 1.22 g of (azodicarbonyl) dipiperidine and 60 ml of toluene. The obtained crude product is subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
Purification by means of filtration gave 2.81 g of the desired compound having a melting point of 88 ° C to 100 ° C (softening).

Reference Example 100 6-isopropoxy-2-methylamino-3-nitropi
Lysine 6-chloro-2-methylamino-3-nitropyridine (see Reference Example 66) 6.00 g, sodium hydride (5
5% by weight) 1.54 g, isopropanol 2.7 ml
And 150 ml of dimethylformamide were used to carry out the reaction and post-treatment according to Reference Example 88. The resulting crude product was crystallized by adding isopropanol to obtain 6.10 g of the desired compound having a melting point of 75 ° C to 76 ° C.

Reference Example 101 3-Amino-6-isopropoxy-2-methylaminopi
Using lysine 6-isopropoxy-2-methylamino-3-nitropyridine (see Reference Example 100) 2.38 g, 10% palladium-carbon 0.50 g and methanol 50 ml, the reaction and post-treatment were carried out according to Production Example 6. When you do, R
f value = 0.62 (silica gel thin layer chromatography;
2.00 g of the target compound having (ethyl acetate) were obtained.

Reference Example 102 5-isopropoxy-2-hydroxymethyl-3-methyi
Ruimidazo [5,4-b] pyridine 3-amino-6-isopropoxy-2-methylaminopyridine (see Reference Example 101) 1.90 g and glycolic acid 2.39 g were used and the reaction and post-treatment were carried out according to Reference Example 43. Processed. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: methanol = 10:
When purified according to 1), it has a melting point of 125 ° C to 127 ° C.
0.58 g of the target compound having is obtained.

Reference Example 103 5- [4- (5-isopropoxy-3-methylimidazo
[5,4-b] Pyridin-2-ylmethoxy) benz
]]-3-Triphenylmethylthiazolidine-2,4-
Dione 5-isopropoxy-2-hydroxymethyl-3-methylimidazo [5,4-b] pyridine (see Reference Example 102) 0.33 g, 5- (4-hydroxybenzyl)-
3-triphenylmethylthiazolidine-2,4-dione 0.69 g, tributylphosphine 0.37 ml,
1,1 '-(azodicarbonyl) dipiperidine 0.3
The reaction and post-treatment were carried out according to Reference Example 4 using 8 g and 20 ml of toluene. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give a melting point of 90 ° C. to 1: 1.
0.85 g of the target compound having a temperature of 00 ° C. (softening) was obtained.

Reference Example 104 2-methylamino-3-nitropyridine 24.9 g of 2-chloro-3-nitropyridine, 41.7 g of sodium carbonate, 22.7 ml of a 30% ethanol solution of methylamine and 250 ml of toluene were used as a reference. Reaction and workup were carried out according to Example 66. When the resulting crude product is crystallized by adding isopropanol, the desired compound having a melting point of 52 ° C. to 53 ° C. 2
4.0 g was obtained.

Reference Example 105 3-amino-2-methylaminopyridine 2-methylamino-3-nitropyridine (Reference Example 104
Reference) 5.00 g, 10% palladium-carbon 1.0
When 0 g and 80 ml of 1,4-dioxane were used and the reaction and post-treatment were carried out according to Preparation Example 6, 3.87 g of the desired compound having a melting point of 90 ° C. to 92 ° C. was obtained.

Reference Example 106 5- {4- [2- (1,3-dioxolan-2-yl)
Ethoxy] benzyl} thiazolidine-2,4-dione 5- (4-hydroxybenzyl) thiazolidine-2,4
-Dione 15.0 g, sodium hydride (55% by weight) 8.80 g, 2- (2-bromoethyl) -1,3
-Using 17 ml of dioxolane and 80 ml of dimethylformamide, the reaction and post-treatment were carried out according to Reference Example 46. The obtained crude product was purified by subjecting it to silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 6.67 g of the desired compound having a melting point of 102 ° C to 104 ° C.

Reference Example 107 5- [4- (3-oxopropoxy) benzyl] thiazo
Lysine-2,4-dione 5- {4- [2- (1,3-dioxolan-2-yl)
Ethoxy] benzyl} thiazolidine-2,4-dione (see Reference Example 106) 6.30 g, acetic acid-water (4:
1) 50 ml of the mixture was stirred at 60 ° C. for 6 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give a melting point of 48 ° C to 51 ° C. 2.20 g of the target compound having (softening) was obtained.

Reference Example 108 2-Methylamino-3-nitro-6-phenylpyridine 5.0 g of 6-chloro-2-methylamino-3-nitropyridine (see Reference Example 66) and phenylboric acid 3.9
3. To 80 ml of ethanol-toluene (1: 1), 50 ml of a 2N sodium carbonate aqueous solution and 0.34 g of 20% palladium hydroxide-carbon were added, and the mixture was added at 105 ° C. to 4.
Stir for 5 hours. After completion of the reaction, palladium hydroxide-carbon was filtered off from the reaction mixture, the solvent was distilled off from the filtrate, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and ethanol was added to the obtained residue for crystallization to obtain 4.75 g of the desired compound having a melting point of 98 ° C to 99 ° C.

Reference Example 109 3-Amino-2-methylamino-6-phenylpyridine 2-methylamino-3-nitro-6-phenylpyridine (see Reference Example 108) 5.7 g, 10% palladium-carbon 1.14 g And 200 ml of ethanol-1,4-dioxane (1: 1) were used to carry out the reaction and post-treatment according to Production Example 6, and Rf value = 0.08 (silica gel thin layer chromatography; ethyl acetate: hexane = 1). :
4.9 g of the target compound having 5) were obtained.

Reference Example 110 2-hydroxymethyl-3-methyl-5-phenylimi
Dazo [5,4-b] pyridine 3-amino-2-methylamino-6-phenylpyridine (see Reference Example 109) 4.9 g, glycolic acid 5.6
Using g, the reaction and post-treatment were carried out according to Reference Example 43. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: ethanol = 1: 0 → 10: 1).
Purification yielded 0.9 g of the desired compound having a melting point of 174 ° C to 177 ° C.

Reference Example 111 5- [4- (3-methyl-5-phenylimidazo [5,
4-b] pyridin-2-ylmethoxy) benzyl] -3
-Triphenylmethylthiazolidine-2,4-dione 2-hydroxymethyl-3-methyl-5-phenylimidazo [5,4-b] pyridine (see Reference Example 110)
0.5 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 0.9
7 g, tributylphosphine 0.57 ml, 1,1 '
Using 0.53 g of-(azodicarbonyl) dipiperidine and 50 ml of benzene, the reaction and post-treatment were carried out according to Reference Example 4. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
When purified by subjecting to 1), Rf value = 0.26 (silica gel thin layer chromatography; ethyl acetate: hexane =
0.9 g of the target compound having 1: 1) was obtained.

Reference Example 112 2- (4-formylphenoxymethyl) -3-methylii
Midazo [5,4-b] pyridine 3-methylimidazo [5,4-b] pyridin-2-ylmethanol (see Reference Example 15) 500 mg, 4-hydroxybenzaldehyde 374 mg, tributylphosphine 0.76 ml, 1,1 ′ -(Azodicarbonyl)
The reaction and post-treatment were carried out according to Reference Example 4 using 773 mg of dipiperidine and 12 ml of toluene. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 1: 0 → 50: 1) to obtain 0.37 g of the desired compound having a melting point of 124 ° C. to 125 ° C.

[0533]

Examples are shown below.

Example 1 Hypoglycemic action Each compound was added to male KK mice showing a hyperglycemic state with a body weight of 40 g or more. Polyethylene glycol 400: water =
It is orally administered by mixing it with a 1: 1 solvent.
Left for hours. Then, blood was collected from the tail vein under no anesthesia, and the blood glucose level was measured with a glucose analyzer GL-101 (trade name, manufactured by Mitsubishi Chemical Co., Ltd.) or Glucoloader-F (trade name, manufactured by Shinotest Co., Ltd.). . The blood glucose lowering rate was determined by the following equation. Hypoglycemic rate (%) = [(solvent-administered group blood glucose level-compound-administered group blood glucose level) / solvent-administered group blood glucose level] x 100 The results are shown below.

[0535]

[Table 120] Table 6 ───────────────────────────────── Manufacturing Example No. Dose (mg / kg) Blood glucose Descent rate (%) ───────────────────────────────── 1 10 13.2 2 1 27.7 3 10 27.0 5 10 16.2 6 10 20.9 7 1 24.7 9 10 27.6 10 1 11.6 13 1 34.0 15 1 13.8 17 1 37.1 20 1 24.5 22 1 10.2 23 1 21.7 ───────────────────────────────── From the table, the compounds of the present invention are excellent. It showed hypoglycemic effect.

Example 2 Inhibitory Effect of Aldose Reductase The aldose reductase of bovine lens is S. Hyman and JH.
Kinoshita [J. Biol. Chem., 240, 877 (1965)] and K. Inagaki, I. Miwa and J. Okuda [Arch. Biochem.
Biophys., 316, 337 (1982)]. And its activity is Va
rma et al. [Biochem. Pharmac., 25, 2505 (1976)
Yearly]] and measured photometrically. Inhibition of enzyme activity was measured at a concentration of 5 μg / ml of the compound of the invention.

The results are shown in the table below.

[0538]

[Table 121] Table 7 ───────────────────────────────── Manufacturing Example No. IC ₅₀ inhibition at a concentration of 5 μg / ml Rate (%) (μg / ml) ────────────────────────────────── 1 54.5 −−− 2 58.1 3.2 3 --- 3.7 4 4 --- 2.3 6 47.0 --- 7 --- 1.0 9 53.3 --- 12 --- 1.7 13- --2.6 14 53.9 --- 15 --- 2.4 16 59.1 3.7 17 --- 1.8 18 76.3 0.88 20 61.6 1.8 22 77. 2 1.8 23 94.9 1.3 25 81.6 0.89 27 91.8 0.85 ────────────────────────── ────────.

[0539]

[Test Example] A test example is shown below.

Test Example 1 Toxicity F344 male rats were used as experimental animals. Five groups were used for the experiment. The test compound is administered orally to each animal at 50
mg / ml body weight was administered for 2 weeks. The test compound is the compound obtained in Production Example 7 and Production Example 17. Animals were observed for two weeks after dosing. During that period, no abnormality due to the test compound was observed. In terms of the effective dose for each animal, a mortality of 0 indicates that the compound of the invention is very toxic.

[0541]

FORMULATION EXAMPLE A preparation containing the heterocyclic compound having the general formula (1) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient can be produced, for example, by the following method.

Formulation Example 1. When 5 g of the compound of Powder Preparation Example 2, 895 g of lactose and 100 g of corn starch were mixed with a blender,
A powder is obtained. The powder contains 5 mg of the compound of Production Example 2 per 1 g. Formulation example 2. After mixing 5 g of the compound of Granule Preparation Example 7, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 10% aqueous solution of hydroxypropylcellulose 30
Add 0 g and knead. This is granulated using an extrusion granulator and dried to obtain granules. 1g of the granules
This contains 5 mg of the compound of Production Example 7. Formulation Example 3. Capsule preparation 5 g of the compound of Production Example 17, 115 g of lactose, 58 g of corn starch and 2 g of magnesium stearate were mixed using a V-type mixer, and then No. 3 capsules were each filled with 180 mg to give a capsule preparation. The capsule is the compound of Production Example 17 per capsule.
Contains mg.

Formulation Example 4. Tablets 5 g of the compound of Production Example 24, lactose 90 g, corn starch 34 g, crystalline cellulose 20 g and magnesium stearate g were mixed with a blender and then tableted with a tablet machine to give tablets with a weight of 150 mg. The tablets are 5 mg of the compound of Production Example 24 per tablet.
It contains.

[0544]

INDUSTRIAL APPLICABILITY The heterocyclic compound of the present invention represented by the general formula (1) or a pharmaceutically acceptable salt thereof is hyperlipidemic,
Hyperglycemia, obesity, glucose intolerance, insulin resistance non-glucose intolerance, insulin resistance, cachexia, psoriasis, diabetic complications (eg retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.), It is useful as a prophylactic and / or therapeutic drug for arteriosclerosis, hypertension, osteoporosis, polycystic ovary syndrome, fatty liver and gestational diabetes.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location A61K 31/41 ABJ A61K 31/41 ABJ ABS ABS 31/42 ADP 31/42 ADP 31/425 ACN 31/425 ACN ADA ADA ADN ADN 31/435 ABX 31/435 ABX C07D 209/10 C07D 209/10 209/12 209/12 209/36 209/36 413/12 209 413/12 209 417/12 209 417/12 209 471 / 04 104 471/04 104Z 107 107Z 108 108Z 487/04 144 487/04 144 // (C07D 413/12 209: 10 263: 14) (C07D 413/12 209: 10 271: 06) (C07D 417/12 209 : 08 277: 34) (C07D 417/12 209: 10 277: 34) (72) Inventor Koichi Fujimoto 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Hiroaki Yanagisawa Tokyo 1-25-2 Hiromachi, Shinagawa-ku Sankyo Stock Company (72) Inventor Toshihiko Fujiwara 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo In-company (72) Inventor Horikoshi Ono 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. In-company (72) Takao Yoshioka 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. Inside the company

Claims (32)

[Claims] 1. A compound of the general formula (1) [Wherein, X represents an indole ring group, an indoline ring group, an azaindole ring group, an azaindoline ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings have 1 to 3 substituents described later. It may have minutes (a). Y
Represents an oxygen atom or a sulfur atom. Z is Is shown. R is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or 1 to 4 carbon atoms
Or a straight-chain or branched-chain alkoxy group, a halogen atom, a hydroxy group, a nitro group, and an amino group which may have a substituent (b) (the substituent (b) has 1 carbon atom).
A straight-chain or branched alkyl group having 8 to 8 carbon atoms, a straight-chain or branched aralkyl group having 7 to 11 carbon atoms, an aryl group having 6 to 10 carbon atoms, and a carbon number A linear or branched aliphatic acyl group having 1 to 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms, or an aromatic acyl group having 7 to 11 carbon atoms is shown. ) Or a linear or branched aralkyl group having 7 to 11 carbon atoms. m represents an integer of 1 to 5. Here, the substituent (a) is a straight chain or branched chain alkyl group having 1 to 4 carbon atoms, a straight chain or branched chain alkoxy group having 1 to 4 carbon atoms, and benzyl. An oxy group, a halogen atom, a hydroxy group, an acetoxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group,
A nitro group, an amino group which may have a substituent (b) (the substituent (b) is a linear or branched alkyl group having a carbon number of 1 to 8, a carbon number of 7 to 11) Or straight-chain or branched aralkyl group having 6 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, straight-chain or branched aliphatic acyl group having 1 to 11 carbon atoms, carbon number An araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms), and an aryl having 6 to 10 carbon atoms which may have a substituent (c). Group (the substituent (c) is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, halogen Atom, hydroxy group,
A nitro group, a phenyl group, a trifluoromethyl group or an amino group which may have a substituent (b)) or a straight chain having 7 to 11 carbon atoms which may have a substituent (c) Alternatively, it represents a branched aralkyl group. ] The heterocyclic compound which has these, or its pharmaceutical containing the pharmacologically acceptable salt as an active ingredient. 2. In [claim 1], X represents an indole ring group, an indoline ring group, an azaindole ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings are 1 to 3 as described later. It may have a substitution component (a). Here, the substituent (a) is a straight chain or branched chain alkyl group having 1 to 4 carbon atoms, a straight chain or branched chain alkoxy group having 1 to 4 carbon atoms, and benzyl. It has an oxy group, a halogen atom, a hydroxy group, an acetoxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, and a substituent (b). Optionally substituted amino group (wherein the substituent (b) is a straight chain or branched chain alkyl group having 1 to 8 carbon atoms, a straight chain or branched chain having 7 to 11 carbon atoms) Aralkyl group, aryl group having 6 to 10 carbon atoms, linear or branched aliphatic acyl group having 1 to 11 carbon atoms, araliphatic acyl having 8 to 12 carbon atoms Base or An aromatic acyl group having a prime number of 7 to 11 is shown.), An aryl group having a carbon number of 6 to 10 optionally having at least one substituent (c) (the substituent (c) is A straight chain or branched chain alkyl group having 1 to 4 carbon atoms, a straight chain or branched chain alkoxy group having 1 to 4 carbon atoms, a halogen atom,
A hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group, or an amino group which may have a substituent (b)) or at least one carbon number which may have a substituent (c) 7 to 7 A straight-chain or branched-chain aralkyl group having 11 heterocyclic compounds or a pharmacologically acceptable salt thereof is contained as an active ingredient. 3. In [Claim 1], X represents an indole ring group, an indoline ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings have 1 to 3 substituents (a) described later. May have. Here, the substituent (a) is a linear or branched alkyl group having 1 to 4 carbon atoms, or 1 carbon atom.
A straight-chain or branched-chain alkoxy group having 4 to 4, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group, and 1 to 4 carbon atoms
A linear or branched alkylthio group having
A trifluoromethyl group, a nitro group, and an amino group which may have a substituent (b) (the substituent (b) is a linear or branched alkyl group having 1 to 8 carbon atoms,
Linear or branched aralkyl group having 7 to 11 carbon atoms, aryl group having 6 to 10 carbon atoms, linear or branched aliphatic group having 1 to 11 carbon atoms An acyl group, an araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms is shown. ), An aryl group having 6 to 10 carbon atoms which may have at least one substituent (c) (the substituent (c) is a straight chain or branched chain having 1 to 4 carbon atoms). It has a chain alkyl group, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group or a substituent (b). An optionally substituted amino group) or a linear or branched aralkyl group having 7 to 11 carbon atoms which may have at least one substituent (c). A medicament containing a ring compound or a pharmaceutically acceptable salt thereof as an active ingredient. 4. In [claim 1], X represents an indole ring group, an indoline ring group or an imidazopyridine ring group, and these rings each have 1 to 3 substituents (a) described later. Good. Here, the substituent (a) is a straight chain or branched chain alkyl group having 1 to 4 carbon atoms, a straight chain or branched chain alkoxy group having 1 to 4 carbon atoms, and benzyl. An oxy group, a halogen atom, a hydroxy group, an acetoxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group,
A nitro group, an amino group which may have a substituent (b) (the substituent (b) is a linear or branched alkyl group having a carbon number of 1 to 8, a carbon number of 7 to 11) Or straight-chain or branched aralkyl group having 6 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, straight-chain or branched aliphatic acyl group having 1 to 11 carbon atoms, carbon number An araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms.) 6 to 6 carbon atoms optionally having 1 to 3 substituents (c) An aryl group having 10 (the substituent (c) is a linear or branched alkyl group having 1 to 4 carbons, a linear or branched chain having 1 to 4 carbons) Alkoxy group, halogen atom,
A hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group or an amino group which may have a substituent (b)) or a carbon number 7 which may have 1 to 3 substituents (c). A straight-chain or branched-chain aralkyl group having 1 to 11; or a heterocyclic compound having: or a pharmacologically acceptable salt thereof as an active ingredient. 5. In [Claim 1], X represents an indoline ring group or an imidazopyridine ring group, and these rings have 1 to 3 substituents (a) described later.
May be provided. Here, the substitution (a) has 1 carbon atom.
A straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms, a benzyloxy group, a halogen atom,
A heterocyclic compound having a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group or a phenyl group; or a pharmacologically acceptable salt thereof as an active ingredient Pharmaceuticals contained. 6. In [Claim 1], X represents an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) described later. Here, the substituent (a) is a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a benzyloxy group, a fluorine atom, a chlorine atom, a phenylthio group, a methylthio group, an ethylthio group or A medicine containing a heterocyclic compound having a phenyl group; or a pharmacologically acceptable salt thereof as an active ingredient. 7. In claim 1, R is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkyl group having 1 to 4 carbon atoms. A medicine containing a heterocyclic compound having a branched chain alkoxy group or a halogen atom; or a pharmacologically acceptable salt thereof as an active ingredient. 8. In [claim 1], R represents a hydrogen atom, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom; and contains a heterocyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient. Medicine. [9] The pharmaceutical composition according to [1], wherein R represents a hydrogen atom or a methoxy group; or a pharmacologically acceptable salt thereof as an active ingredient. 10. A pharmaceutical composition containing the heterocyclic compound according to claim 1 wherein R represents a hydrogen atom or a pharmaceutically acceptable salt thereof as an active ingredient. 11. A medicine according to [claim 1], wherein Y represents an oxygen atom; a heterocyclic compound having: or a pharmacologically acceptable salt thereof as an active ingredient. 12. In [Claim 1], Z is a 2,4-dioxothiazolidine-5-yridenylmethyl group, a 2,4-dioxothiazolidin-5-ylmethyl group or a 2,4-dioxooxazolidine-5-group. A drug containing a heterocyclic compound having an ylmethyl group or a pharmacologically acceptable salt thereof as an active ingredient. 13. The heterocyclic compound or its pharmacology according to claim 1, wherein Z represents a 2,4-dioxothiazolidine-5-yridenylmethyl group or a 2,4-dioxothiazolidin-5-ylmethyl group. A medicament containing the above acceptable salt as an active ingredient. [14] A drug according to [1], wherein Z represents a 2,4-dioxothiazolidin-5-ylmethyl group; or a pharmacologically acceptable salt thereof as an active ingredient. 15. In [Claim 1], X represents an indole ring group, an indoline ring group, an azaindole ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings are 1 to 3 as described later. It may have a substitution component (a). Y represents an oxygen atom or a sulfur atom. Z is 2,4-dioxothiazolidine-5
-Iridenylmethyl group, 2,4-dioxothiazolidin-5-ylmethyl group, 2,4-dioxooxazolidin-5-ylmethyl group, 3,5-dioxooxadiazolidin-2-ylmethyl group or N-hydroxyureidomethyl group Indicates a group. R is a hydrogen atom, having 1 to 4 carbon atoms
A linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms or a halogen atom. m represents an integer of 1 to 5. Here, the substitution component (a) has 1 to 4 carbon atoms.
Straight-chain or branched alkyl group having 1 to 4 carbon atoms, straight-chain or branched alkoxy group having 1 to 4 carbon atoms, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group , A linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, an amino group which may have a substituent (b) (the substituent (b) Has 1 carbon
A straight-chain or branched alkyl group having 8 to 8 carbon atoms, a straight-chain or branched aralkyl group having 7 to 11 carbon atoms, an aryl group having 6 to 10 carbon atoms, and a carbon number A linear or branched aliphatic acyl group having 1 to 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms, or an aromatic acyl group having 7 to 11 carbon atoms is shown. ), An aryl group having 6 to 10 carbon atoms which may have at least one substituent (c) (the substituent (c) is a straight chain or branched chain having 1 to 4 carbon atoms). A chain alkyl group, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, a hydroxy group, a nitro group,
Phenyl group, trifluoromethyl group or substituent (b)
An optionally substituted amino group) or a linear or branched aralkyl group having 7 to 11 carbon atoms, which may have at least one substituent (c). A pharmaceutical containing the heterocyclic compound or a pharmacologically acceptable salt thereof as an active ingredient. 16. In [Claim 1], X represents an indole ring group, an indoline ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings have 1 to 3 substituents (a) described later. May have. Y represents an oxygen atom. Z is a 2,4-dioxothiazolidine-5-yridenylmethyl group, a 2,4-dioxothiazolidin-5-ylmethyl group or 2,4
Represents a dioxooxazolidin-5-ylmethyl group.
R represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, or a halogen atom. m represents an integer of 1 to 5. here,
Substituent (a) is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a benzyloxy group, Halogen atom, hydroxy group, acetoxy group,
A phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, an amino group which may have a substituent (b) (the substituent ( b) is a linear or branched alkyl group having 1 to 8 carbon atoms, 7 to 11 carbon atoms
Or straight-chain or branched aralkyl group having 6 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, straight-chain or branched aliphatic acyl group having 1 to 11 carbon atoms, carbon number An araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms is shown. ), An aryl group having 6 to 10 carbon atoms which may have at least one substituent (c) (the substituent (c) is a straight chain or branched chain having 1 to 4 carbon atoms). It has a chain alkyl group, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group or a substituent (b). An optionally substituted amino group) or a linear or branched aralkyl group having 7 to 11 carbon atoms which may have at least one substituent (c). A medicament containing a ring compound or a pharmaceutically acceptable salt thereof as an active ingredient. 17. In [Claim 1], X represents an indole ring group, an indoline ring group or an imidazopyridine ring group, and these rings have 1 to 3 substituents (a) described later. Good. Y represents an oxygen atom. Z represents a 2,4-dioxothiazolidine-5-yridenylmethyl group or a 2,4-dioxothiazolidin-5-ylmethyl group. R represents a hydrogen atom, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom. m
Represents an integer of 1 to 5. Here, the substituent (a) is a straight chain or branched chain alkyl group having 1 to 4 carbon atoms, a straight chain or branched chain alkoxy group having 1 to 4 carbon atoms, and benzyl. Oxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group,
A linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, an amino group which may have a substituent (b) (the substituent (b) is A straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms, a straight-chain or branched-chain aralkyl group having 7 to 11 carbon atoms, and an aryl group having 6 to 10 carbon atoms A linear or branched aliphatic acyl group having 1 to 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms, or an aromatic acyl group having 7 to 11 carbon atoms; ),
An aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents (c) (the substituent (c) is a straight chain or branched chain having 1 to 4 carbon atoms) A linear alkyl group, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group or a substituent (b) Optionally an amino group) or 1
To 7 carbon atoms which may have 3 to 3 substituents (c)
A straight-chain or branched-chain aralkyl group having 1 to 11; or a heterocyclic compound having: or a pharmacologically acceptable salt thereof as an active ingredient. 18. In [Claim 1], X represents an indoline ring group or an imidazopyridine ring group, and these rings have 1 to 3 substituents (a) described later.
May be provided. Y represents an oxygen atom. Z is 2,
4-dioxothiazolidin-5-ylmethyl group is shown. R represents a hydrogen atom or a methoxy group. m represents an integer of 1 to 5. Here, the substituent (a) is a straight chain or branched chain alkyl group having 1 to 4 carbon atoms, a straight chain or branched chain alkoxy group having 1 to 4 carbon atoms, and benzyl. Oxy group, halogen atom,
A heterocyclic compound having a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group or a phenyl group; or a pharmacologically acceptable salt thereof as an active ingredient Pharmaceuticals contained. 19. In [claim 1], X represents an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) described later. Y
Represents an oxygen atom. Z represents a 2,4-dioxothiazolidin-5-ylmethyl group. R represents a hydrogen atom.
m represents an integer of 1 to 5. Here, the substituent (a) is a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a benzyloxy group, a fluorine atom, a chlorine atom, a phenylthio group, a methylthio group, an ethylthio group or A medicine containing a heterocyclic compound having a phenyl group; or a pharmacologically acceptable salt thereof as an active ingredient. 20. In [claim 1], 1) 5- {4- (3-methylimidazo [5,4-b]]
Pyridin-2-ylmethoxy) benzyl} thiazolidine-2,4-dione, 2) 5- [4- (5-chloro-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2 , 4-dione, 3) 5- [4- (5-methoxy-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, 4) 5- [4 -(5-Hydroxy-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, 5) 5- [4- (5-ethoxy-3-methylimidazo [ 5,4-b] Pyridin-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, or 6) 5- [4- (5-isopropoxy-3-methylimidazo [5,4-b] ] Pyridine-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, or a drug containing a pharmacologically acceptable salt thereof as an active ingredient. 21. Treatment of diseases caused by insulin resistance, which comprises the heterocyclic compound according to any one of [1] to [20] or a pharmacologically acceptable salt thereof as an active ingredient. Medications and / or prophylactics. 22. A therapeutic agent for hyperglycemia and / or prophylaxis containing the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of [claim 1] to [claim 20] as an active ingredient. medicine. 23. A therapeutic and / or prophylactic agent for diabetic complications, which comprises, as an active ingredient, the heterocyclic compound or the pharmacologically acceptable salt thereof according to any one of [claim 1] to [claim 20]. medicine. 24. A therapeutic and / or prophylactic agent for arteriosclerosis containing the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of [claim 1] to [claim 20] as an active ingredient. medicine. 25. A therapeutic agent for hyperlipidemia containing the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of [claim 1] to [claim 20] as an active ingredient, and / or Prophylactic drug. 26. A therapeutic and / or prophylactic agent for obesity containing the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of [claim 1] to [claim 20] as an active ingredient. . 27. A therapeutic agent for glucose intolerance and / or prophylaxis containing the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of [claim 1] to [claim 20] as an active ingredient. medicine. 28. A therapeutic and / or prophylactic agent for hypertension containing the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of [claim 1] to [claim 20] as an active ingredient. . 29. A therapeutic agent for polycystic ovary syndrome, comprising the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of [claim 1] to [claim 20] as an active ingredient, and / or Prophylactic drug. 30. A therapeutic and / or prophylactic drug for gestational diabetes comprising the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of [claim 1] to [claim 20] as an active ingredient. . 31. An insulin-resistant non-glucose intolerant therapeutic agent containing the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of [1] to [20] as an active ingredient. And / or prophylactic drugs. 32. An aldose reductase inhibitor containing the heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of [1] to [20] as an active ingredient.