JPH09221481A - Medicine comprising aromatic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine comprising a new specific aromatic compound, containing thiazolidine-2,4-dion-5-ylmethyl group, etc., and useful as a therapeutic agent, a preventing agent, etc., for insulin-resistance diseases, hyperglycemia, hyperlipemia, arteriosclerosis, etc. SOLUTION: This medicine comprises a new aromatic compound, represented by formula I R<1> and R<2> are each H or a 1-8C alkyl or R<1> and R<2> denote together a group represented by the formula (CH2 )k [(k) is 2-6]; R<3> is H, a 1-4C alkyl, a 1-4C alkoxy, a halogen or OH; A and B are each H, a 1-8C alkyl, a 7-11C aralkyl, a 1-11C aliphatic acyl or an 8-12C aromatic acyl or A and B denote together CO, CS, CH2 CH2 , SO2 , etc.; X is a group, etc., represented by the formula W-(CH2 )m -X<1> [W is an aryl, a 5- to a 6-membered ring unsaturated heterocyclic group, etc.; X<1> is a direct bond, O, S, etc.; (m) is 0-8], etc.; Y is a group represented by the formula (CH2 )n -Y<1> [Y<1> is a direct bond, O or S; (s) is 1-5]; Z is a group represented by formula II (R<5> is H, a 2-5C carboxyalkyl, etc.), etc.} and useful as a therapeutic agent, a preventing agent, etc., for diseases caused by insulin resistance, hyperglycemia, hyperlipemia, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to insulin resistance,
Hyperlipidemia, hyperglycemia, gestational diabetes
s mellitus: GDM), obesity, impaired glucose tolerance (impaire
d glucose tolerance (IGT) status, diabetic complications,
Atherosclerosis and polycystic ovary syndrome
syndrome: PCOS) and the like, and further relates to an aromatic compound having a aldose reductase inhibitory action, a pharmacologically acceptable salt thereof or an ester thereof.

[0002]

[Prior art]

1) Conventionally, many thiazolidine compounds having a blood glucose lowering action are known. For example, JP
5-22636 (Japanese Patent Publication No. 62-42903), Japanese Patent Laid-Open No. 60-51189 (Japanese Patent Publication No. 2-31079), Y.
KAWAMATSU et al., Chem.Pharm.Bull., Volume 30, 3580-
3600 pages (1982), European Patent Publication No. 0
No. 441605 and JP-A No. 6-80667. 2) Further, a compound having a thiazolidine ring having the same activity as an amino alcohol compound is disclosed in JP-A-6-25.
No. 118. 3) Further, an oxazolidine ring and a thiazolidine-2,4-
Compounds containing a dione ring and having the same activity are disclosed in JP-A-64-9979 and WO92 / 0783.
It is disclosed in No. 8 (= Tokushuhei No. 6-502145). 4) Further, a compound containing an N-hydroxyureido group and having a similar activity is disclosed in WO92 / 03425A. 5) Further, a compound containing a 2,4-dioxooxazolidin-5-ylmethylphenyl group and having a similar activity is disclosed in WO92 / 02520A. 6) Furthermore, 3,5-dioxooxadiazolidine-2-
Compounds containing an ylmethylphenyl group and having similar activity are disclosed in WO92 / 03425A. 7) Furthermore, 5- {4- [2- (2- (2-methoxy-2
-Phenyl) ethylamino) ethoxy] benzyl} thiazolidine-2,4-dione derivatives are disclosed in JP-A-61-286.
No. 376.

The relationship between these thiazolidine compounds and various diseases is described in, for example, the following documents. The action of thiazolidine compounds on hyperglycemia
Diabetes., 32 (9) , 804-810 (1983) ； Diabetes., 37 (11) ,
1549-1558 (1988) ； Prog.Clin.Biol.Res., 265 , 177-192
(1988); Metabolism., 37 (3) , 276-280 (1988); Arznei
mittelforschung., 40 (1) , 37-42 (1990) ； Arzneimittelf
orschung., 40 (2 Pt 1) , 156-162 (1990) ； Arzneimittelf
Orschung., 40 (3) , 263-267 (1990). The action of thiazolidine compounds on hyperlipidemia
Diabetes., 40 (12) , 1669-1674 (1991); Am.J.Physiol., 2
67 (1 Pt 1) , E95-E101 (1994) ； Diabetes., 43 (10) , 1203-
1210 (1994) and so on.

Arzneimittelforschun shows the effects of thiazolidine compounds on glucose intolerance and insulin resistance.
g., 40 (2 Pt 1) , 156-162 (1990) ； Metabolism., 40 (10) , 1
025-1230 (1991); Diabetes., 43 (2) , 204-211 (1994);
N.Engl.J.Med., 331 (18) , 1226-1227 (1994).

The action of thiazolidine compounds on hypertension is Metabolism., 42 (1) , 75-80 (1993); Am.J.Physi
ol., 265 (4 Pt 2) , R726-R732 (1993) ； Diabetes. 43 (2) , 2
It is reported in 04-211 (1994).

The action of thiazolidine compounds on cachexia is Endocrinology., 135 (5) , 2279-2282 (1994); Endo
It has been reported in crinology., 136 (4) , 1474-1481 (1995).

The action on nephropathy has been reported in "Diabetes, Vol. 38, Extra Issue (1995)".

The action of thiazolidine compounds on coronary artery disease is reported by Am. J. Physiol., 265 (4 Pt2) , R726-R732 (1993).
; Hypertension., 24 (2) , 170-175 (1994) and so on.

The effects of thiazolidine compounds on arteriosclerosis have been reported by Am. J. Physyol., 265 (4 Pt2) , R726-R732 (1993).
Reported in.

Furthermore, in recent years, a normal person having insulin resistance without glucose intolerance has a high risk of developing diabetes [insulin-resistant non-glucose intolerance (insulin resist).
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.

[0011]

DISCLOSURE OF THE INVENTION The present inventors have investigated insulin resistance, hyperlipidemia, hyperglycemia, gestational diabetes, obesity,
Glucose intolerance, diabetic complications, arteriosclerosis, polycystic ovary syndrome, etc. are improved, and further, aldose reductase inhibitory action is extremely high, aromatic compounds, pharmacologically acceptable salts thereof or The present invention has been completed by conducting intensive research on the ester.

The object of the present invention is "a pharmaceutical containing the above aromatic compound as an active ingredient", particularly "a disease caused by insulin resistance, hyperglycemia, diabetic complications, arteriosclerosis,
It is intended to provide a therapeutic and / or prophylactic agent for hyperlipidemia, obesity, glucose intolerance, hypertension, polycystic ovary syndrome, gestational diabetes, and insulin resistance non-glucose intolerance.

[0013]

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

[0014]

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The present invention relates to a drug containing an aromatic compound having, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient. However, in the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms. Or R ¹
And R ² together form a group — (CH ₂ ) _k — (wherein
k represents an integer of 2 to 6. ). R ³ 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, a halogen atom or hydroxy. Indicates a group.

A and B are the same or different and each is a hydrogen atom,
A straight chain or branched chain alkyl group having 1 to 8 carbon atoms, an aralkyl group having 7 to 11 carbon atoms, a straight chain or branched chain aliphatic group having 1 to 11 carbon atoms An acyl group, an araliphatic acyl group having 8 to 12 carbon atoms, an aromatic acyl group having 7 to 11 carbon atoms, a carbamoyl group, or a substituted carbamoyl group having 2 to 12 carbon atoms in total is shown. Or A and B together

[0017]

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Is shown.

X is of the formula W- (CH ₂ ) _m -X ^1- [wherein W is the same or different and is a carbon which may have 1 to 5 substituents (a) below. An aryl group having the number 6 to 10, containing 1 to 3 oxygen, sulfur or / and nitrogen atoms which may be the same or different and which may have 1 to 4 of the following substituents (a) 5- to 6-membered unsaturated heterocyclic group, containing 1 to 3 oxygen, sulfur or / and nitrogen atoms, which may be the same or different and may have 1 to 4 of the following substituents (a) A 5- to 6-membered saturated heterocyclic group containing 1 to 3 oxygen, sulfur or / and nitrogen atoms which may be the same or different and may have 1 to 4 of the following substituents (a) Is a condensed heterocyclic group.

X ¹ is a bond, an oxygen atom, a sulfur atom or a group

[0021]

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(In the formula, R ⁴ is a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, an aralkyl group having 7 to 11 carbon atoms or 6 to 10 carbon atoms. Represents an aryl group having).

M represents an integer of 0 to 8.

Here, the substitution (a) has 1 carbon atoms.
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 straight-chain or branched alkyl group having 1 to 4 carbon atoms Branched haloalkyl group, halogen atom, phenyl group, hydroxy group, nitro group or substituent (b)
An amino group optionally having 1 or 2 (the substituent (b) is a linear or branched alkyl group having 1 to 8 carbon atoms, an aralkyl having 7 to 11 carbon atoms) Group, aryl group having 6 to 10 carbon atoms, linear or branched aliphatic acyl group having 1 to 11 carbon atoms, araliphatic acyl group having 8 to 12 carbon atoms or carbon An aromatic acyl group having the number of 7 to 11) is shown. ].

Y is of the formula-(CH ₂ ) _n --Y ^1- (however,
In the formula, Y ¹ represents a bond, an oxygen atom or a sulfur atom.

N represents an integer of 1 to 5. ).

Z is

[0028]

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(Wherein R ⁵ is a hydrogen atom, a linear or branched carboxyalkyl group having 2 to 5 carbon atoms, a straight chain or branched chain having 2 to 12 carbon atoms Alkanoyloxyalkyl group, cycloalkyl-containing straight-chain or branched-chain alkanoyloxyalkyl group having 6 to 12 carbon atoms, and straight-chain or branched-chain cycloalkyl group having 5 to 17 carbon atoms Alkylcarbonyloxyalkyl groups, straight-chain or branched-chain alkoxycarbonyloxyalkyl groups having 3 to 17 carbon atoms, straight-chain or branched-chain groups having 6 to 17 carbon atoms having cycloalkyl Alkoxycarbonyloxyalkyl group or linear or branched cycloalkyloxy having 5 to 17 carbon atoms Shows the Rubo oxy alkyl group.),

[0030]

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Is shown.

Preferably, in (2) and (1), R ¹
And an aromatic compound in which R ² is the same or different and is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient. It is the drug contained.

Preferably, in (3) and (1), R ³
Is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a methoxy group, an ethoxy group, a propoxy group or a halogen atom, an aromatic compound, a pharmacologically acceptable salt thereof, or a salt thereof. It is a drug containing an ester as an active ingredient.

Preferably, (4) In (1), A and B are the same or different and each is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or 1 to 4 carbon atoms. Is an aliphatic acyl group having 6 or a carbamoyl group, or is a group in which A and B are taken together-
C (= O) -, group -C (= S) -, group -CH ₂ C (=
O)-, a group -CH ₂ CH _2-, or a group -SO _2- , an aromatic compound, a pharmacologically acceptable salt thereof or an ester thereof is a drug as an active ingredient.

Preferably, (5) in (1), W is the same or different and is an aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents (a). , X ¹ is a bond, oxygen atom, sulfur atom or formula-
NR ⁴ '- (. Wherein, R ^4' is from 1 number hydrogen atom or a carbon a linear or branched alkyl group having 4), and is an integer of m is not 0 8 It is a medicine containing an aromatic compound, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (6) and (1), Z is

[0037]

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A pharmaceutical composition containing an aromatic compound, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (7) and (1), R ¹
And R ² are the same or different and each is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, and R ³ is a hydrogen atom, a linear chain having 1 to 4 carbon atoms. Or a branched chain alkyl group, methoxy group, ethoxy group, propoxy group or halogen atom, wherein A and B are the same or different and have 1 to 4 carbon atoms.
A linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched aliphatic acyl group having 1 to 6 carbon atoms or a carbamoyl group, or A
And B together form a group -C (= O)-, a group -C (= S)
-, group _{-CH 2 C (= O) -} , group -CH ₂ CH ₂ - or a group -SO ₂ - is, W is have identical or 1 differs to three substituents: (a) Is an aryl group having 6 to 10 carbon atoms, wherein X ¹ is a bond, an oxygen atom, a sulfur atom or the formula —NR ⁴ ′ — (wherein R ⁴ ′
Represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ) And Z is

[0040]

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A pharmaceutical containing the aromatic compound, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (8) and (1), R ¹
And an aromatic compound in which R ² is the same or different and is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, a pharmaceutically acceptable salt thereof or an ester thereof as an active ingredient. It is the drug contained.

Preferably, in (9) and (1), R ³
An aromatic compound in which is a hydrogen atom, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom,
It is a medicine containing a pharmacologically acceptable salt or an ester thereof as an active ingredient.

Preferably, in (10) and (1), A
And B are the same or different and are a hydrogen atom, a methyl group, an ethyl group, a propyl group, an acetyl group, a propionyl group, a butyryl group or a carbamoyl group, or A and B are taken together to form a group -C (= O). -, Group -C (=
S) - or a group -CH ₂ CH ₂ - in which an aromatic compound,
It is a medicine containing a pharmacologically acceptable salt or an ester thereof as an active ingredient.

Preferably, in (11) and (1), W
Are the same or different and are phenyl groups which may have 1 to 3 substituents (a), and X ¹ is a bond, an oxygen atom, a sulfur atom or —NR ⁴ ″ — (wherein R is ⁴ ''
Represents a hydrogen atom, a methyl group, an ethyl group or a propyl group. ) And an aromatic compound in which m is an integer of 0 to 6, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (12) and (1), Y
^A pharmaceutical composition comprising an aromatic compound in which ¹ is an oxygen atom or a sulfur atom, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (13) (1), Z
But

[0048]

[Chemical 21]

A pharmaceutical containing the aromatic compound, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (14) and (1), R
¹ and R ² are the same or different and each is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R ³ is a hydrogen atom, a methyl group, an ethyl group,
A methoxy group, an ethoxy group, a fluorine atom or a chlorine atom, and A and B are the same or different and are a hydrogen atom, a methyl group, an ethyl group, a propyl group, an acetyl group, a propionyl group, a butyryl group or a carbamoyl group, or A and B together form a group -C (= O)-, a group-
C (= S) - or a group -CH ₂ CH ₂ - is, W is the same or different one to three substituents (a) may have a phenyl group, X ¹ is a bond , An oxygen atom, a sulfur atom or —NR ⁴ ″ — (in the formula, R ⁴ ″ represents a hydrogen atom, a methyl group, an ethyl group or a propyl group), and m is an integer of 0 to 6, Y ¹ is an oxygen atom or a sulfur atom, and Z is

[0051]

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A pharmaceutical containing the aromatic compound, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (15) and (1), R
^An aromatic compound in which ¹ and R ² are both hydrogen atoms, or one of them is a hydrogen atom, and the other is a linear or branched alkyl group having 1 to 4 carbon atoms,
It is a medicine containing a pharmacologically acceptable salt or an ester thereof as an active ingredient.

Preferably, in (16) and (1), R
A pharmaceutical composition containing an aromatic compound in which ³ is a hydrogen atom, a methyl group, a methoxy group or a chlorine atom, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (17) (1), A
And B are the same or different and each is a hydrogen atom, a methyl group, an ethyl group, an acetyl group, a propionyl group or a carbamoyl group, or A and B are combined to form a group-
C (= O) -, group -C (= S) - or a group -CH ₂ CH
It is a medicine containing an aromatic compound which is _2- , a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (18) and (1), W
Are the same or different and may have 1 to 3 substituents (a ') (here, the substituents (a')
Is a halogen atom, methyl group, ethyl group, hydroxy group,
A phenyl group, an amino group, a dimethylamino group, a methoxy group or an ethoxy group is shown. ) And X ¹ is a bond, an oxygen atom, a sulfur atom, a group —NH— or a group —N (CH ₃ ).
An aromatic compound in which m is an integer of 0 to 6,
It is a medicine containing a pharmacologically acceptable salt or an ester thereof as an active ingredient.

Preferably, in (19) and (1), Y
A medicament containing an aromatic compound in which ¹ is an oxygen atom or a sulfur atom and n is an integer of 1 to 3, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (20) and (1), Z
But

[0059]

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A pharmaceutical containing the aromatic compound, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (21) and (1), R
¹ and R ² are both hydrogen atoms, or one of them is a hydrogen atom, and the other is a linear or branched alkyl group having 1 to 4 carbon atoms, and R ³ is a hydrogen atom. , A methyl group, a methoxy group or a chlorine atom, and A and B are the same or different and are a hydrogen atom, a methyl group, an ethyl group, an acetyl group, a propionyl group or a carbamoyl group, or A and B are combined. Group -C (= O)-, group -C (= S)-or group -CH
₂ CH ₂ — and W is the same or different and is 1 to 3
A phenyl group which may have one substituent (a ′) (wherein the substituent (a ′) is a halogen atom, a methyl group, an ethyl group, a hydroxy group, a phenyl group, an amino group, a dimethylamino group, A methoxy group or an ethoxy group), X ¹ is a bond, an oxygen atom, a sulfur atom, a group —NH— or a group —N (CH ₃ ) —, and m is an integer of 0 to 6, Y ¹ is an oxygen atom or a sulfur atom, and n is 1.
Is an integer from 3 to 3 and Z is

[0062]

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A pharmaceutical composition comprising the aromatic compound, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (22) and (1), R
^An aromatic compound in which ¹ and R ² are both hydrogen atoms or one of them is a hydrogen atom and the other is a methyl group, an ethyl group, a propyl group or an isopropyl group, a pharmacologically acceptable salt thereof or an ester thereof. It is a medicine containing as an active ingredient.

Preferably, in (23) and (1), R
A medicine containing an aromatic compound in which ³ is a hydrogen atom, a methyl group or a chlorine atom, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (24) and (1), A
Is a hydrogen atom, B is a hydrogen atom, a methyl group, an ethyl group or an acetyl group, or A and B together are a group -C (= O)-or a group -C (= S)-. It is a medicine containing an aromatic compound, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (25) and (1), W
Is a halogenated phenyl group, a phenylphenyl group, a methoxyphenyl group or a phenyl group, X ¹ is an oxygen atom or a sulfur atom, and m is an integer of 0 to 6, and a pharmacologically acceptable salt thereof. Alternatively, it is a drug containing the ester as an active ingredient.

Preferably, in (26) and (1), Y
Is a group —CH ₂ —O— or a group —CH ₂ CH ₂ —O—, an aromatic compound, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (27) and (1), R
¹ and R ² are both hydrogen atoms, or either is a hydrogen atom and the other is a methyl group, an ethyl group, a propyl group or an isopropyl group, and R ³ is a hydrogen atom,
A methyl group or a chlorine atom, A is a hydrogen atom,
B is a hydrogen atom, a methyl group, an ethyl group or an acetyl group, or A and B together form a group -C (=
O)-or a group -C (= S)-, W is a halogenated phenyl group, a phenylphenyl group, a methoxyphenyl group or a phenyl group, X ¹ is an oxygen atom or a sulfur atom, and m is 0 to Is an integer of 6 and Y is a group -CH
₂ -O- or a group -CH ₂ CH ₂ -O- and and, Z is

[0070]

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A pharmaceutical composition containing the aromatic compound, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (28) and (1), R
^An aromatic compound in which ¹ and R ² are both hydrogen atoms, or one of them is a hydrogen atom and the other is a methyl group or an ethyl group, a pharmacologically acceptable salt thereof or an ester thereof is contained as an active ingredient. It is a medicine.

Preferably, in (29) and (1), R
A medicament containing an aromatic compound in which ³ is a hydrogen atom, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (30) and (1), A
Is a hydrogen atom and B is a hydrogen atom or a methyl group, or A and B together form a group -C (= O).
-Or a drug containing an aromatic compound of group -C (= S)-, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (31) (1), W
Is a phenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group or a 4-phenylphenyl group, X ¹ is an oxygen atom, and m is an integer of 0 to 6. It is a medicine containing an aromatic compound, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably, in (32) and (1), Y
Is a group containing —CH ₂ —O—, an aromatic compound, a pharmacologically acceptable salt thereof, or an ester thereof as an active ingredient.

Preferably, in (33) (1), R
¹ and R ² are both hydrogen atoms, or either is a hydrogen atom, the other is a methyl group or an ethyl group, R ³ is a hydrogen atom, A is a hydrogen atom, and B
Is a hydrogen atom or a methyl group, or A and B together form a group -C (= O)-or a group -C (=
S)-and W is a phenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 3-methoxyphenyl group,
A 4-methoxyphenyl group or a 4-phenylphenyl group, X ¹ is an oxygen atom, m is an integer of 0 to 6, Y is a group —CH ₂ —O—, and Z is

[0078]

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A pharmaceutical containing the aromatic compound, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient.

Preferably (34) In (1), 5-
{4- [2- (3-phenyl-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4
-Dione, 5- {4- [2- (5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl)
Ethoxy] benzyl} thiazolidine-2,4-dione,
5- {4- [2- (5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidine-2,4-dione, 5-
{4- [2- (5- (3-chlorophenoxymethyl)-
2-Thioxooxazolidin-3-yl) propoxy]
Benzyl} thiazolidine-2,4-dione, 5- {4-
[2- (3- (6-phenylhexyloxy) -2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione or 5- {4- [2- (5
-(3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl) butoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient is there.

Preferably (35) (1) to (34)
A therapeutic agent and / or a preventive agent for a disease caused by insulin resistance, which comprises the aromatic compound, the pharmacologically acceptable salt thereof, or the ester thereof as an active ingredient according to any one of 1.

Preferably (36) (1) to (34)
A therapeutic agent and / or a preventive agent for hyperglycemia, which comprises the aromatic compound, the pharmacologically acceptable salt thereof or the ester thereof as an active ingredient.

Preferably (37) (1) to (34)
A therapeutic agent and / or a preventive agent for diabetic complications, which comprises the aromatic compound, the pharmacologically acceptable salt thereof, or the ester thereof as an active ingredient.

Preferably (38) (1) to (34)
A therapeutic agent and / or a preventive agent for an arteriosclerosis containing the aromatic compound, the pharmacologically acceptable salt thereof or the ester thereof as an active ingredient.

Preferably (39) (1) to (34)
A therapeutic agent and / or prophylactic agent for hyperlipidemia, which comprises the aromatic compound, the pharmacologically acceptable salt thereof, or the ester thereof as an active ingredient.

Preferably (40) (1) to (34)
The therapeutic and / or prophylactic agent for obesity containing the aromatic compound, the pharmacologically acceptable salt or the ester thereof according to any one of 1. as an active ingredient.

Preferably (41) (1) to (34)
A therapeutic agent and / or a prophylactic agent for glucose intolerance, which comprises the aromatic compound, the pharmacologically acceptable salt thereof, or the ester thereof as an active ingredient.

Preferably (42) (1) to (34)
A therapeutic agent and / or a preventive agent for hypertension, comprising the aromatic compound, the pharmacologically acceptable salt thereof, or the ester thereof as an active ingredient according to any one of 1.

Preferably (43) (1) to (34)
A therapeutic agent and / or a preventive agent for polycystic ovary syndrome, which comprises the aromatic compound, the pharmacologically acceptable salt thereof or the ester thereof as an active ingredient according to any one of 1.

Preferably (44) (1) to (34)
A therapeutic and / or prophylactic drug for gestational diabetes, which comprises the aromatic compound, the pharmacologically acceptable salt thereof, or the ester thereof as an active ingredient.

Preferably (45) (1) to (34)
2. An insulin-resistant non-glucose intolerant therapeutic agent and / or preventive agent, which comprises the aromatic compound, the pharmacologically acceptable salt thereof, or the ester thereof described in any one of 1. as an active ingredient.

That is, the aromatic compound of the present invention, a pharmacologically acceptable salt thereof or an ester thereof is insulin resistant,
It improves hyperlipidemia, hyperglycemia, gestational diabetes, obesity, glucose intolerance, diabetic complications, arteriosclerosis and polycystic ovary syndrome, and further has an aldose reductase inhibitory action. Therefore, the aromatic compound of the present invention, a pharmacologically acceptable salt thereof or an ester thereof is used for hyperlipidemia, hyperglycemia, obesity, glucose intolerance, insulin resistance non-glucose intolerance, hypertension, osteoporosis, adverse effects. Liquid quality, fatty liver, diabetic complications (eg retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.),
It is useful as a preventive and / or therapeutic drug for arteriosclerosis and the like. Further, it is useful as a preventive and / or therapeutic agent for diseases caused by insulin resistance such as gestational diabetes, polycystic ovary syndrome and the like other than the above diseases.

In particular, the present invention comprises an aromatic compound selected from (1) to (34), a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient, a disease caused by insulin resistance, and hyperglycemia. , Diabetic complications, arteriosclerosis,
Provided are prophylactic and / or therapeutic agents for hyperlipidemia, obesity, glucose intolerance, hypertension, polycystic ovary syndrome, gestational diabetes, and insulin-resistant non-glucose intolerance.

When R ¹ and R ² are the same or different and each 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, 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, 1,1,3 3-tetramethylbutyl and the like can be mentioned. 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. Particularly preferred are a methyl group and an ethyl group.

In addition, R ¹ and R ² together form a group-.
When (CH ₂ ) _k − (in the formula, k represents an integer of 2 to 6) is shown, examples of the group include ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene. Preferred are trimethylene, tetramethylene and pentamethylene.

When R ³ represents a linear or branched alkyl group having 1 to 4 carbon atoms, examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl and s-. Butyl, t-butyl, etc. can be mentioned. Preferred is methyl.

When R ³ represents a linear or branched alkoxy group having 1 to 4 carbon atoms, examples of the alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s. -Butoxy, t-butoxy and the like can be mentioned. Preferred is methoxy.

When R ³ represents a halogen atom, the halogen atom is, for example, fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

A and B are the same or different and have 1 carbon atom
When a linear or branched alkyl group having 8 to 8 is shown, examples of the alkyl group include R ¹
And the same alkyl groups as mentioned for R ² can be mentioned.

A and B are the same or different and each has 7 carbon atoms.
When an aralkyl group having 1 to 11 carbon atoms is shown, the aralkyl group of the aralkyl group has 1 to 5 carbon atoms.
A straight-chain or branched alkylene having 1 unit, for example, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, 4-phenylbutyl, 1 −
Examples thereof include phenylbutyl, 5-phenylpentyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. Preferred is benzyl and 2-phenylethyl, and most preferred is benzyl.

A and B are the same or different and have 1 carbon atom
When a linear or branched aliphatic acyl group having 1 to 11 is shown, examples of the aliphatic acyl group include formyl, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, pivaloyl, pentanoyl, hexanoyl, Examples thereof include heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl and the like. Preferred are acetyl, propionyl, butyryl, isobutyryl and pivaloyl, and most preferred are acetyl and pivaloyl.

A and B are the same or different and each has 8 carbon atoms.
When showing an araliphatic acyl group having 1 to 12,
Examples of the araliphatic acyl group include phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, 5-phenylpentanoyl, 6-phenylhexanoyl and the like. Phenylacetyl and phenylpropionyl are preferred, and phenylacetyl is most preferred.

A and B are the same or different and each has 7 carbon atoms.
When the aromatic acyl group having 1 to 11 is shown, examples of the aromatic acyl group include benzoyl, 1-naphthoyl, 2-naphthoyl and the like. Preferably it is benzoyl.

When A and B are the same or different and each represents a substituted carbamoyl group having 2 to 12 carbon atoms, the substituted carbamoyl group is represented by the formula:

[0105]

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(In the formula, R ⁶ and / or R ⁷ are the same or different and each is a hydrogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms, or 7 to 1 carbon atoms.
An aralkyl group having 1 or an aryl group having 6 to 10 carbon atoms is shown. However, the case where R ⁶ and R ⁷ are both hydrogen atoms is excluded. ).

When R ⁶ and / or R ⁷ are the same or different and each represents a linear or branched alkyl group having 1 to 10 carbon atoms, the alkyl group is, for example, the above-mentioned one. Alkyl groups similar to those mentioned for R ¹ and R ² , as well as nonyl and decyl can be mentioned. Preferred are methyl, ethyl and propyl, and most preferred are methyl and ethyl.

When R ⁶ and / or R ⁷ are the same or different and each represents an aralkyl group having a carbon number of 7 to 11, the aralkyl group includes, for example, the same aralkyl groups as described in the above A and B. be able to. Preferred is benzyl and 2-phenyl, and most preferred is benzyl.

When R ⁶ and / or R ⁷ are the same or different and each represents an aryl group having 6 to 10 carbon atoms, examples of the aryl group include phenyl, 1-naphthyl, 2-naphthyl and the like. You can Preferred is phenyl.

Therefore, as the substituted carbamoyl group described here, R ⁶ and R ⁷ in the above formula are hydrogen atoms, a linear or branched alkyl group having 1 to 10 carbon atoms, and ⁷ carbon atoms. A group consisting of a combination of groups selected from an aralkyl group having 1 to 11 and an aryl group having 6 to 10 carbon atoms. However,
Except when both R ⁶ and R ⁷ are hydrogen atoms.

As such a substituted carbamoyl group,
For example, 1) methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, s-butylcarbamoyl, t-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, heptylcarbamoyl,
A substituted carbamoyl group consisting of a combination of a hydrogen atom and an alkyl group such as octylcarbamoyl, nonylcarbamoyl, decylcarbamoyl; 2) dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N-methyl-N-propylcarbamoyl,
N-methyl-N-isopropylcarbamoyl, N-methyl-N-butylcarbamoyl, N-methyl-N-pentylcarbamoyl, N, N-diethylcarbamoyl, N-
Ethyl-N-propylcarbamoyl, N-ethyl-N-
A substituted carbamoyl group consisting of a combination of an alkyl group and an alkyl group such as butylcarbamoyl, dipropylcarbamoyl, N-propyl-N-butylcarbamoyl, N, N-dibutylcarbamoyl; 3) benzylcarbamoyl, 2-phenylethylcarbamoyl, A substituted carbamoyl group consisting of a combination of a hydrogen atom and an aralkyl group, such as 1-phenylethylcarbamoyl, 3-phenylpropylcarbamoyl, 4-phenylbutylcarbamoyl, 5-phenylpentylcarbamoyl, 1-naphthylmethylcarbamoyl and 2-naphthylmethylcarbamoyl. 4) N-methyl-N-benzylcarbamoyl, N-ethyl-N-benzylcarbamoyl, N-propyl-N-benzylcarbamoyl, N-butyl-N-benzylcarbamoyl, A substituted carbamoyl group consisting of a combination of an alkyl group such as -methyl-N- (2-phenylethyl) carbamoyl and an aralkyl group; 5) N-methyl-N-phenylcarbamoyl, N-ethyl-N-phenylcarbamoyl, N -Propyl-N-phenylcarbamoyl, N-butyl-N-phenylcarbamoyl, N-methyl-N-naphthylcarbamoyl, N-
A substituted carbamoyl group consisting of a combination of an alkyl group and an aryl group such as ethyl-N-naphthylcarbamoyl; 6) A substituted carbamoyl group consisting of a combination of a hydrogen atom and an aryl group such as phenylcarbamoyl; 7) such as diphenylcarbamoyl A substituted carbamoyl group composed of a combination of an aryl group and an aryl group; and the like.

X is of the formula W- (CH ₂ ) _m -X ^1- (wherein
X ¹ , m and W have the same meanings as described above. ) Is shown; X ¹ is

[0113]

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When R ⁴ represents a straight chain or branched chain alkyl group having 1 to 8 carbon atoms, the alkyl group may be, for example, R ¹ and R described above.
The same alkyl groups as mentioned in ² can be mentioned.
Preferred is methyl.

When R ⁴ represents an aralkyl group having 7 to 11 carbon atoms, examples of the aralkyl group include the same aralkyl groups as described in A and B above. Preferred are benzyl and 2-phenyl,
Optimal is benzyl.

When R ⁴ represents an aryl group having 6 to 10 carbon atoms, examples of the aryl group include the same aryl groups as described above for R ⁶ and / or R ⁷ . Preferred is phenyl.

When W represents an aryl group having 6 to 10 carbon atoms which may be the same or different and has 1 to 5 substituents (a), the unsubstituted aryl group includes For example, the same aryl group as described for R ⁶ and / or R ⁷ can be mentioned. When the aryl has a substituent (a), it may be the same or different and 1
Those having from 3 to 3 substituents (a) are preferred,
The one having one substitution (a) is optimal.

The substitution component (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 straight-chain or branched alkyl group having 1 to 4 carbon atoms Branched haloalkyl group, halogen atom, phenyl group, hydroxy group, nitro group or substituent (b)
An amino group optionally having 1 or 2 (the substituent (b) is a linear or branched alkyl group having 1 to 8 carbon atoms, an aralkyl having 7 to 11 carbon atoms) Group, aryl group having 6 to 10 carbon atoms, linear or branched aliphatic acyl group having 1 to 11 carbon atoms, araliphatic acyl group having 8 to 12 carbon atoms or carbon An aromatic acyl group having the number of 7 to 11) is shown. Details of the replacement (a) will be described below.

Therefore, examples of the aryl group substituted with the substituent (a) as described above include 2-chlorophenyl,
3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-methylphenyl, 3-methylphenyl,
4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-t-butylphenyl, 3-t-butylphenyl, 4-t-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl Four
-Methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylphenyl, 3-phenylphenyl, 4-phenylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4
-Nitrophenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-methylaminophenyl, 3-methylaminophenyl, 4-methylaminophenyl, 2-N, N-dimethylaminophenyl, 3-N ，
N-dimethylaminophenyl, 4-N, N-dimethylaminophenyl 2-N-acetyl-N-methylaminophenyl, 3-N-acetyl-N-methylaminophenyl,
4-N-acetyl-N-methylaminophenyl, 2-benzylaminophenyl, 3-benzylaminophenyl,
4-benzylaminophenyl, 2-N-methyl-N-phenylaminophenyl, 3-N-methyl-N-phenylaminophenyl, 4-N-methyl-N-phenylaminophenyl, 2-trifluoromethylphenyl, 3 -Trifluoromethylphenyl, 4-trifluoromethylphenyl,
4-hydroxy-3,5-dimethylphenyl, 3,5-
Di-t-butyl-4-hydroxyphenyl, 4-hydroxy-2,3,5-trimethylphenyl and 2,5-
Examples include dimethylphenyl.

Next, W is the same or different and 5 to 6 containing 1 to 3 oxygen, sulfur or / and nitrogen atoms which may have 1 to 4 substituents (a).
When a membered-ring unsaturated heterocyclic group is shown, examples of the group include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 1-pyrrolyl,
2-pyrrolyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 5-pyrimidinyl, 2-pyranyl, 4-pyranyl, 3-isoxazolyl, 4-isoxazolyl,
5-isoxazolyl, 2-oxazolyl, 5-oxazolyl and the like can be mentioned.

5- to 6-membered ring saturated hetero groups containing 1 to 3 oxygen, sulfur or / and nitrogen atoms, in which W may be the same or different and may have 1 to 4 substituents (a). When a ring group is shown, examples of the group include 2-tetrahydrofuryl, 3-tetrahydrofuryl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 1-pyrrolidinyl, 3-pyrrolidinyl, 2-piperazyl, piperidino, 2-piperidyl, Morpholino, 3-morpholinyl,
2-tetrahydropyranyl, 4-tetrahydropyranyl, 1,4-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl and the like can be mentioned.

When W represents a fused heterocyclic group containing 1 to 3 oxygen, sulfur or / and nitrogen atoms which may be the same or different and which may have 1 to 4 substituents (a). As the group, for example, 2-benzofuranyl, 2-
2 H -chromenil, 2-benzothienyl, 2-indolinyl, 3-indolinyl, 2-dihydrobenzofuranyl, 2-chromanyl, 1,4-benzodioxan-2-
Ilyl, 4-quinolyl, 1-isoquinolyl and the like can be mentioned.

Of these heterocyclic groups, preferably 1
5 to 6-membered unsaturated, saturated and fused heterocyclic groups containing 1 to 2 oxygen, sulfur or / and nitrogen atoms, optimally 1 to 2 oxygen, sulfur or / and nitrogen atoms 5 to 6-membered saturated and unsaturated heterocyclic groups contained therein. The group is preferably 1 to 4,
More preferably, it may have 1 to 2 substituents (a).

The substitution component (a) has 1 to 4 carbon atoms.
When a straight-chain or branched-chain alkyl group having a number of R ³ is shown, examples of the alkyl group include the same alkyl groups as described above for R ³ . Preferably it is methyl, ethyl, most preferably methyl.

When the substituent (a) represents a straight chain or branched chain alkoxy group having 1 to 4 carbon atoms,
Examples of the alkoxy group include the same alkoxy groups as described for R ³ . Preferred are methoxy and ethoxy, and most preferred is methoxy.

When the substituent (a) represents a linear or branched haloalkyl group having 1 to 4 carbon atoms, the haloalkyl group is, for example, chloromethyl,
Fluoromethyl, trichloromethyl, trifluoromethyl,
Dichloromethyl, difluoromethyl, 2,2,2-trichloroethyl, 2-chloroethyl, 2-fluoroethyl,
2,2,2-tribromoethyl and the like can be mentioned. It is preferably a haloalkyl group having 1 or 2 carbon atoms.

When the substitution component (a) represents a halogen atom,
Examples of the halogen atom include fluorine, chlorine, bromine,
Iodine, preferably fluorine or chlorine.

The substitution (a) is 1 or 2 as the substitution (b).
When it is an optionally substituted amino group, the substituent (b) is a linear or branched alkyl group having 1 to 8 carbon atoms, or an aralkyl having 7 to 11 carbon atoms. Group, aryl group having 6 to 10 carbon atoms, linear or branched aliphatic acyl group having 1 to 11 carbon atoms, araliphatic acyl group having 8 to 12 carbon atoms or carbon An aromatic acyl group having the numbers 7 to 11 is shown.

When the substituent (b) represents 1) a linear or branched alkyl group having 1 to 8 carbon atoms, examples of the alkyl group include R ¹ and R The same alkyl groups as mentioned in ² can be mentioned.

2) When an aralkyl group having 7 to 11 carbon atoms is shown, examples of the aralkyl group include the same aralkyl groups as described in A and B above.

3) When an aryl group having 6 to 10 carbon atoms is shown, the aryl group is, for example, the above-mentioned R.
Aryl groups similar to those mentioned for ⁶ and / or R ⁷ can be mentioned.

4) When a linear or branched aliphatic acyl group having 1 to 11 carbon atoms is shown, the aliphatic acyl group is, for example, the same aliphatic acyl group as described in A and B above. An acyl group can be mentioned.

5) When an araliphatic acyl group having 8 to 12 carbon atoms is shown, examples of the araliphatic acyl group include the same araliphatic acyl groups as described in A and B above. it can.

6) When an aromatic acyl group having 7 to 11 carbon atoms is shown, examples of the aromatic acyl group include the same aromatic acyl groups as those described in A and B above.

Therefore, when the substituent (a) is an amino group which may have the substituent (b), the following groups can be mentioned.

1) Examples of the amino group having one linear or branched alkyl group having 1 to 8 carbon atoms as a substituent include, for example, methylamino, ethylamino, propylamino, isopropylamino and butyl. Amino, isobutylamino, s-butylamino, t-butylamino, pentylamino, 2-pentylamino, 3-pentylamino, 2-methylbutylamino, 3-methylbutylamino, 1,1-dimethylpropylamino, 1, Two
-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,
Heptylamino, 2-heptylamino, 3-heptylamino, 4-heptylamino, 3,3-dimethylpentylamino, octylamino, 1-methylheptylamino,
2-ethylhexylamino, 1,1,3,3-tetramethylbutylamino and the like can be mentioned.

Examples of the amino group having two linear or branched alkyl groups having 1 to 8 carbon atoms as a substituent include, for example, dimethylamino and N-methyl-N.
-Ethylamino, N-methyl-N-propylamino, N
-Methyl-N isopropylamino, N-methyl-N-butylamino, N-methyl-N-pentylamino, N, N
-Diethylamino, N-ethyl-N-propylamino,
N-ethyl-N-butylamino, dipropylamino, N
-Propyl-N-butylamino, N, N-dibutylamino and the like can be mentioned.

2) Examples of the aralkylamino group having 7 to 11 carbon atoms include benzylamino, 2-phenylethylamino, 1-phenylethylamino and 3-
Examples thereof include phenylpropylamino, 2-phenylpropylamino, 1-phenylpropylamino, 4-phenylbutylamino, 1-phenylbutylamino, 5-phenylpentylamino, 1-naphthylmethylamino, 2-naphthylmethylamino and the like. it can.

3) Examples of the arylamino group having 6 to 10 carbon atoms include phenylamino, 1-naphthylamino, 2-naphthylamino and the like.

4) Examples of the linear or branched aliphatic acylamino group having 1 to 11 carbon atoms include formylamino, acetylamino, propionylamino, isopropionylamino, butyrylamino and the like. .

5) Examples of the araliphatic acylamino group having 8 to 12 carbon atoms include phenylacetylamino, 3-phenylpropionylamino, 4-phenylbutyrylamino, 5-phenylpentanoylamino,
6-phenylhexanoylamino etc. can be mentioned.

6) Examples of the aromatic acylamino group having 7 to 11 carbon atoms include benzoylamino and 1
-Naphthoylamino, 2-naphthoylamino and the like can be mentioned.

Z is

[0144]

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When R ⁵ represents 1) a linear or branched carboxyalkyl group having 1 to 2 carbon atoms, the carboxyalkyl group may be, for example, carboxymethyl or 1- Examples thereof include carboxyethyl, 2-carboxyethyl, 1-carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 4-carboxybutyl, 1-carboxy-1-methylethyl and the like.

2) When a linear or branched alkanoyloxyalkyl group having 2 to 12 carbon atoms is shown, the alkanoyloxyalkyl group is preferably an alkanoyl moiety having 1 to 6 carbon atoms. And the alkyl moiety has 1 to 6 carbon atoms, preferably 1
Have 4 to 4.

Examples of such alkanoyloxyalkyl groups include acetoxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, 1-pivaloyloxyethyl, 1-acetoxyethyl, 1-isobutyryloxyethyl, 1-pivaloyloxypropyl, 2-methyl-1-pivaloyloxypropyl, 2-pivaloyloxypropyl, 1-isobutyryloxyethyl, 1-isobutyryloxy Propyl, 1-acetoxypropyl, 1
-Acetoxy-2-methylpropyl, 1-propionyloxyethyl, 1-propionyloxypropyl, 2-
Examples thereof include acetoxypropyl and 1-butyryloxyethyl.

3) When a linear or branched alkanoyloxyalkyl group having 2 to 12 carbon atoms having cycloalkyl is shown, it has 3 carbon atoms as a substituent.
Alkanoyloxyalkyl groups having cycloalkyl having from 1 to 7. As the alkanoyloxyalkyl group, the alkanoyl moiety preferably has 2 to 6 carbon atoms, and the alkyl moiety has 1 to 6 carbon atoms.
, Preferably 1 to 4.

Examples of the cycloalkyl-substituted alkanoyloxyalkyl group include cyclohexylacetoxymethyl, 1- (cyclohexylacetoxy) ethyl, 1- (cyclohexylacetoxy) propyl, 2-methyl-1- (cyclohexylacetoxy).
Examples thereof include propyl, cyclopentylacetoxymethyl, 1- (cyclopentylacetoxy) ethyl, 1- (cyclopentylacetoxy) propyl, 2-methyl-1- (cyclopentylacetoxy) propyl and the like.

4) When a linear or branched cycloalkylcarbonyloxyalkyl group having 5 to 17 carbon atoms is shown, the cycloalkylcarbonyloxyalkyl group has a cycloalkyl moiety of 3 carbon atoms.
It has from 1 to 10, preferably from 3 to 7, and is monocyclic or polycyclic.

As such a cycloalkyl moiety,
For example, in addition to the above, geranyl, neryl, linalyl, phytyl, menthyl (preferably m- or p-menthyl),
Examples include tsudyl, caryl, pinanyl, bornyl, notocalyl, norpinalyl, norbornyl, menthenyl, camphenyl, norborneryl, adamantyl and the like.

The alkyl moiety has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, most preferably methyl, ethyl,
Propyl. Further, the cycloalkyl moiety may have a substituent having at least one alkyl having 1 to 4 carbon atoms on the ring, and examples of such alkyl include methyl, ethyl, propyl, butyl and the like. Can be raised.

Such a linear or branched cycloalkylcarbonyloxy having 5 to 17 carbon atoms which may have at least one alkyl having 1 to 4 carbon atoms on the ring. Examples of the alkyl group include 1-methylcyclohexylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxyethyl, 1-cycloheptylcarbonyloxyethyl, 1-methylcyclopentylcarbonyloxymethyl, 2 -Methyl-1- (1-methylcyclohexylcarbonyloxy) propyl, 1- (1-methylcyclohexylcarbonyloxy) propyl, 2-
(1-Methylcyclohexylcarbonyloxy) propyl, 1- (cyclohexylcarbonyloxy) propyl, 2- (cyclohexylcarbonyloxy) propyl, 2-methyl-1- (1-methylcyclopentylcarbonyloxy) propyl, 1- (1-methyl Cyclopentylcarbonyloxy) propyl, 2- (1-methylcyclopentylcarbonyloxy) propyl, 1- (cyclopentylcarbonyloxy) propyl, 2- (cyclopentylcarbonyloxy) propyl, 1- (1-methylcyclopentylcarbonyloxy) ethyl, 1- (1
-Methylcyclopentylcarbonyloxy) propyl,
Examples thereof include adamantylcarbonyloxymethyl and 1-adamantylcarbonyloxyethyl.

5) When a linear or branched alkoxycarbonyloxyalkyl group having 3 to 17 carbon atoms is shown, the alkoxycarbonyloxyalkyl group has an alkoxy moiety having 1 to 10 carbon atoms.
, Preferably 1 to 6, more preferably 1 to 4, and the alkyl moiety has 1 to 6 carbons, preferably 1 to 4 carbons. A 1- (alkoxycarbonyloxy) ethyl group is particularly preferable, and such an alkoxycarbonyloxyalkyl group is, for example, 1
-Methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl,
1-butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl, 1-s-butoxycarbonyloxyethyl, 1-t-butoxycarbonyloxyethyl, 1- (1-ethylpropoxycarbonyloxy)
Examples thereof include ethyl and 1- (1,1-dipropylbutoxycarbonyloxy) ethyl.

As the other alkoxycarbonyloxyalkyl group, both the alkoxy moiety and the alkyl moiety have 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples of such an alkoxycarbonyloxyalkyl group include 2-methyl-1- (isopropoxycarbonyloxy) propyl, 2- (isopropoxycarbonyloxy) propyl, isopropoxycarbonyloxymethyl, t-butoxycarbonyloxymethyl, methoxy. Examples thereof include carbonyloxymethyl and ethoxycarbonyloxymethyl.

6) When a straight-chain or branched alkoxycarbonyloxyalkyl group having 3 to 17 carbon atoms having cycloalkyl is shown, it has cycloalkyl having 3 to 7 carbon atoms as a substituent. It is an alkoxycarbonyloxyalkyl group. The alkoxycarbonyloxyalkyl group has an alkoxycarbonyl moiety having 2 to 6 carbon atoms and an alkyl moiety having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

Examples of such an alkoxycarbonyloxyalkyl group substituted with cycloalkyl include cyclopropylmethoxycarbonyloxymethyl, cyclobutylmethoxycarbonyloxymethyl, cyclopentylmethoxycarbonyloxymethyl, cyclohexylmethoxycarbonyloxymethyl, 1- ( Examples thereof include cyclopropylmethoxycarbonyloxy) ethyl, 1- (cyclobutylmethoxycarbonyloxy) ethyl, 1- (cyclopentylmethoxycarbonyloxy) ethyl, 1- (cyclohexylmethoxycarbonyloxy) ethyl and the like.

7) When a linear or branched cycloalkyloxycarbonyloxyalkyl group having 5 to 17 carbon atoms is shown, the cycloalkyloxycarbonyloxyalkyl group is a cycloalkyloxycarbonyloxyalkyl group having a carbon number of It has 3 to 10, preferably 3 to 7, and is monocyclic or polycyclic. Alkyl part has 1 carbon
Having 6 to 6, preferably 1 to 4, most preferably methyl, ethyl, propyl. Further, the cycloalkyl moiety may have at least one alkyl having 1 to 4 carbon atoms as a substituent on the ring,
Examples of such alkyl include methyl, ethyl,
Propyl, butyl, etc. can be mentioned.

Such a linear or branched cycloalkyloxycarbonyl having 5 to 17 carbon atoms, which may have at least one alkyl having 1 to 4 carbon atoms on the ring. Examples of the oxyalkyl group include 1-methylcyclopentyloxycarbonyloxymethyl, 1-methylcyclohexyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, 1-cyclopentyloxycarbonyloxyethyl, 1-cyclo Heptyloxycarbonyloxyethyl, 2-methyl-1- (1-methylcyclohexyloxycarbonyloxy) propyl, 1- (1-methylcyclohexyloxycarbonyloxy) propyl, 2-
(1-methylcyclohexyloxycarbonyloxy)
Propyl, 1- (cyclohexyloxycarbonyloxy) propyl, 2- (cyclohexyloxycarbonyloxy) propyl, 2-methyl-1- (1-methylcyclopentyloxycarbonyloxy) propyl, 1-
(1-methylcyclopentyloxycarbonyloxy)
Propyl, 2- (1-methylcyclopentyloxycarbonyloxy) propyl, 1- (cyclopentyloxycarbonyloxy) propyl, 2- (cyclopentyloxycarbonyloxy) propyl, 1- (1-methylcyclopentyloxycarbonyloxy) ethyl, 1-
(1-methylcyclopentyloxycarbonyloxy)
Propyl, adamantyloxycarbonyloxymethyl, 1-adamantyloxycarbonyloxyethyl,
And so on.

The compound of the present invention represented by the general formula (I) can be converted into an ester according to a conventional method when R ⁵ in Z represents a carboxyalkyl group. The group forming such ester is preferably a linear or branched alkyl group having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, isobutyl, t-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl , 2-methylpentyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1-methyl-1-ethylpropyl, heptyl, 1-methyl-1
-Ethylbutyl, 2-methyl-2-ethylbutyl, octyl, 1-methylheptyl, 2-ethylhexyl, 1,
It is 1,3,3-tetramethylbutyl.

The compound of the above-mentioned general formula (I) of the present invention is, when B is a hydrogen atom, an alkyl group or an aralkyl group, when W in X has an amino group as a substituent, or when X ¹ in X is a group. When it is —NR ⁴ —, it can be converted into a pharmaceutically acceptable salt according to a conventional method. Examples of such salts include hydrohalic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, and other hydrohalic acid salts;
Inorganic acid salts such as nitrates, perchlorates; sulfates; phosphates; salts of lower alkanesulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid; benzenesulfonic acid, p-toluenesulfonic acid Salts of amino acids such as glutamic acid, aspartic acid; salts of carboxylic acids such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid, maleic acid; be able to.

Furthermore, when R ⁵ in Z is a hydrogen atom or a carboxyalkyl group, the compound having the general formula (I) can be converted into a pharmaceutically acceptable 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 and barium;
Examples thereof include inorganic salts such as magnesium salts; aluminum salts; amine salts such as ammonia, methylamine, dimethylamine and dicyclohexylamine; organic base salts such as basic amino acid salts such as lysine and arginine.

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

That is, the formula (A)

[0165]

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(Wherein R ¹ , R ² , R ³ , A, B, X,
Y and Z have the same meaning as described above. ), The carbon atom with * ¹ is an asymmetric carbon atom,
Further, the carbon atom marked with * ² is an asymmetric carbon atom when R ¹ and R ² are different groups.

Furthermore, Z is

[0168]

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In the formula (wherein R ⁵ has the same meaning as described above), the carbon atom marked with * ³ is an asymmetric carbon atom. In the general formula (I), stereoisomers based on these asymmetric carbon atoms and equal and non-equal 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 compound having the general formula (I), Z is

[0171]

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In the case of, the compound in which R ⁵ is a hydrogen atom is
The existence of various tautomers is possible. For example, as shown below.

[0173]

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[0174]

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In the above-mentioned general formula (I), all tautomers and isomers based on them, which are equal and non-equivalent, 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, the present invention includes, when the compound having the general formula (I) and the ester thereof and salts thereof form a solvate (for example, a hydrate), all of them are included.

Further, the present invention includes a compound which becomes a compound having the general formula (I) by being metabolized in vivo, that is, a prodrug of the compound having the general formula (I).

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

[0179]

[Table 1]

[0180]

[Table 2]

[0181]

[Table 3]

[0182]

[Table 4]

[0183]

[Table 5]

[0184]

[Table 6]

[0185]

[Table 7]

[0186]

[Table 8]

[0187]

[Table 9]

[0188]

[Table 10]

[0189]

[Table 11]

[0190]

[Table 12]

[0191]

[Table 13]

[0192]

[Table 14]

[0193]

[Table 15]

[0194]

[Table 16]

[0195]

[Table 17]

[0196]

[Table 18]

[0197]

[Table 19]

[0198]

[Table 20]

[0199]

[Table 21]

[0200]

[Table 22]

[0201]

[Table 23]

[0202]

[Table 24]

[0203]

[Table 25]

[0204]

[Table 26]

[0205]

[Table 27]

[0206]

[Table 28]

In Tables 1 to 7, Me = methyl,
Et = ethyl, iPr = isopropyl, Bu = butyl, iBu = isobutyl, tBu = tert-butyl, Pn = pentyl, Ph = phenyl, Bz = benzyl, Ac = acetyl.

In Tables 1 to 6, when the substituent R ³ is a group other than a hydrogen atom, the substituent R ³ is o to Y.
It indicates that it may be bonded to either-or m-.

In Table 7, o-, m- and p- in parentheses are shown together with specific examples of the substituent R ³ or the substituent Z.
Represents the position of R ³ or Z with respect to Y.

In the above table, (1) the exemplified compound numbers are preferably 1-2, 1-
4, 1-48, 1-49, 1-51, 1-6
4, 1-69, 1-79, 1-91, 1-92,
1-93, 1-94, 1-95, 1-128, 1-
158, 1-159, 1-160, 1-161, 1-1
62, 1-163, 1-164, 1-165, 1-16
6, 1-167, 1-168, 1-169, 1-17
0, 1-171, 1-173, 1-176, 1-17
7, 1-179, 1-180, 1-181, 1-18
4, 1-186, 1-187, 1-188, 1-18
9, 1-190, 1-191, 1-192, 1-19
3, 1-195, 1-197, 1-200, 1-20
1, 1-204, 1-205, 1-206, 1-20
7, 1-208, 1-209.

(2) More preferably, the exemplified compound number is 1
-2, 1-4, 1-51, 1-64, 1-6
9, 1-79, 1-91, 1-93, 1-94,
1-95, 1-158, 1-159, 1-160, 1
-161, 1-162, 1-164, 1-169, 1-
170, 1-173, 1-177, 1-179, 1-1
80, 1-181, 1-186, 1-187, 1-18
8, 1-189, 1-190, 1-191, 1-19
2, 1-193, 1-195, 1-204, 1-20
5, 1-206, 1-209.

(3) More preferably, the exemplified compound number is 1
-2, 1-4, 1-64, 1-91, 1-9
3, 1-94, 1-95, 1-159, 1-161,
1-162, 1-164, 1-173, 1-179, 1
-186, 1-191, 1-193, 1-195, 1-
205, 1-206.

(4) More preferably, the exemplified compound number is 1
-2) 5- {4- [2- (3-phenyl-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione, 1-93) 5- {4- [2-
(5- (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl) ethoxy] benzyl} thiazolidine-2,4-dione, 1-94) 5- {4- [2
-(5- (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidine-2,4-dione, 1-95) 5- {4-
[2- (5- (3-chlorophenoxymethyl) -2-thioxooxazolidin-3-yl) propoxy] benzyl} thiazolidine-2,4-dione, 1-162) 5
-{4- [2- (3- (6-phenylhexyloxy))
2-Hydroxypyropyramino) propoxy] benzyl} thiazolidine-2,4-dione, 1-191) 5
-{4- [2- (5- (3-chlorophenoxymethyl))
2-oxooxazolidin-3-yl) butoxy] benzyl} thiazolidine-2,4-dione.

(5) More preferably, the exemplified compound number is 1
-2) 5- {4- [2- (3-phenyl-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione, 1-94) 5- {4- [2-
(5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidine-2,4-dione, 1-95) 5- {4-
[2- (5- (3-chlorophenoxymethyl) -2-thioxooxazolidin-3-yl) propoxy] benzyl} thiazolidine-2,4-dione.

[0215]

BEST MODE FOR CARRYING OUT THE INVENTION

 Manufacturing method (I)

[0216]

Embedded image

(In the formula, X, Y, R ¹ , R ³ A, B and Z have the same meanings as described above.) The first step is a step of producing a compound having the general formula (3). It is obtained by reacting an aminoalcohol having the general formula (1) (described later) with a compound having the general formula (2) (for example, a halogenoacetone and a phenol compound according to a conventional method. JP-A-6-25118). Cf.).

The reaction is carried out with an anhydrous alkali metal carbonate such as anhydrous sodium carbonate or anhydrous potassium carbonate, an anhydrous alkali metal sulfate such as anhydrous sodium sulfate, or an alkaline earth metal chloride such as anhydrous calcium chloride. It is carried out in the presence or absence of an anhydride, an anhydride of an alkaline earth metal sulfate such as anhydrous magnesium sulfate, or a dehydrating agent such as a molecular sieve.

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; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride. Ethers; ethers such as diethyl ether, tetrahydrofuran, dioxane; dimethylformamide,
Amides such as dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol and ethanol; sulfoxides such as dimethyl sulfoxide; sulfolane; or a mixed solvent thereof is preferably used.

The reaction temperature is ice-cooling or heating under reflux.

The reaction time varies depending on the reaction reagent, reaction temperature and the like, but is usually 0.5 hour to 10 hours.

The reaction is preferably carried out in a solvent of hydrocarbons or alcohols for 1 hour to 5 hours under ice cooling or under heating under reflux. More preferably, it is carried out by heating under reflux in benzene for 1 to 3 hours and dehydrating.

The second step is a step of producing the compound having the general formula (4), which can be obtained by reducing the compound having the general formula (3).

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

When the compound having the above general formula (3) is hydrogenated in the presence of a reducing agent, examples of the reducing agent used include lithium borohydride, sodium borohydride, sodium cyanoborohydride and hydrogen. Metal hydrides such as lithium aluminum hydride and diisopropyl aluminum hydride are used.

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 temperature is ice-cooling or heating.

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

The reaction is preferably carried out in the presence of sodium borohydride or sodium cyanoborohydride in a solvent of alcohols for 1 hour to 1 day under ice cooling to 50.
Performed at ° C.

When the compound having the above general formula (3) is hydrogenated in the presence of a catalyst, the catalyst used is preferably a catalytic hydrogenation catalyst such as palladium-carbon or platinum oxide.

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, ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide and dimethylacetamide; methanol, ethanol and isopropanol. Suitable alcohols; organic acid esters such as methyl acetate and ethyl acetate; or mixed solvents thereof are preferably used.

The third step is a step for producing the compound having the general formula (5), which can be obtained by alkylating, aralkylating, acylating or carbamoylating the compound having the general formula (4).

Alkylation and aralkylation are usually carried out in the presence or absence of a deoxidizing agent, alkyl halide, aralkyl halide, alkane sulfonic acid or aryl sulfonic acid (eg methane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid). A) with an alkyl or aralkyl ester of). 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,
Ethers such as tetrahydrofuran and dioxane;
Amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane; sulfolane or a mixed solvent thereof. Is preferably used.

The reaction temperature is ice-cooling or warming.

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

Acylation is usually carried out in the presence or absence of a deoxidizing agent. The acylating agent used is usually an acyl halide or an acid anhydride.

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; sulfoxides such as dimethyl sulfoxide; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; sulfolane or a mixed solvent thereof is preferable. Used for.

The reaction temperature is ice-cooling or warming. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 0.5 hour to several days.

Also, when A and B are taken together,

[0240]

Embedded image

When represented, carbonylating agents (for example, phosgene, diphosgene, triphosgene, carbonyldiimidazole, chloroformates such as ethyl chloroformate), thiocarbonylating agents (for example, thiophosgene, thiocarbonyldiimidazole, etc.) , Oxalyl chloride, haloacetyl halides (eg, chloroacetyl chloride, bromoacetyl bromide, etc.), sulfuryl chloride, halomethanesulfonyl halides (eg, chloromethanesulfonyl chloride, etc.) as reaction reagents. Used.

The reaction is usually carried out in the presence or absence of a deoxidizing agent. When a deoxidizing agent is used, the deoxidizing agent used is, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine; and inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate. is there.

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; chloroform, methylene chloride, 1,2-dichloroethane, carbon tetrachloride. Halogenated hydrocarbons such as; ethers such as diethyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; N,
Urea such as N'-dimethylimidazolidinone; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile and propionitrile; sulfolane; or a mixed solvent thereof is preferably used.

The reaction temperature is ice-cooling or heating under reflux. It is preferably carried out under ice cooling to 50 ° C.

The reaction time varies depending on the reaction reagent, reaction temperature, type of solvent and the like, but is usually 0.5 hour to 50 hours, preferably 5 hours to 50 hours.

Production Method (II)

[0247]

Embedded image

[0248]

Embedded image

(Wherein X, A, B, R ¹ , R ² , R ³ ,
n and Z have the same meaning as described above. R represents a linear or branched lower alkyl group, and Y ² represents an oxygen atom or a sulfur atom. Halo represents a halogen atom such as a chlorine atom, a bromine atom and an iodine atom. Z'is Z
Shows a group in which R ⁵ is a triphenylmethyl group. ) The fourth step is a step of producing the compound having the general formula (6), and is obtained by alkylating, aralkylating, acylating or carbamoylating the compound having the general formula (1). The reaction can be carried out according to the third step of the above production method (I).

The fifth step is a step for producing the compound having the general formula (8), wherein the compound having the general formula (6) and the compound having the general formula (7) are present in the presence of a base, or It is obtained by reacting in the absence. When B is an acyl group or a carbamoyl group, it is preferable to react a compound having the general formula (6) with a base such as sodium hydride and then reacting a compound having the general formula (7). .

The reaction is generally and preferably effected 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; sulfoxides such as dimethyl sulfoxide; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; sulfolane or a mixed solvent thereof is preferable. Used for.

The reaction temperature is ice-cooling or warming. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 0.5 hour to several days.

The sixth step is a step for producing the compound having the general formula (9), which can be obtained by reducing the compound having the general formula (8). Examples of the reducing agent used include metal hydrides such as sodium borohydride, lithium borohydride, lithium aluminum hydride, and diisobutylaluminum 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 temperature is ice-cooling or heating.

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

The reaction is preferably carried out in the presence of lithium borohydride in a solvent of alcohols for 1 hour to 1 day at room temperature to reflux temperature.

The seventh step is a step of producing the compound having the general formula (11), which comprises reacting the compound having the general formula (9) with the compound having the general formula (10) by a conventional Mitsunobu reaction (O). .Mitsunobu, Synthesis, 1
Page (1981)), followed by detriphenylmethylation reaction (second step).

That is, the first-step 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 for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride. 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 ice-cooling to warming, preferably ice-cooling to 60 ° C.

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

The second step reaction is usually carried out by contacting with an acid such as acetic acid, trifluoroacetic acid, hydrochloric acid or the like in the presence or absence of a solvent, or by subjecting to a catalytic hydrogenation reaction in a solvent. .

The reaction of contacting with an acid in the presence or absence of a solvent can be achieved by a conventional method (for example, TWGreen, Protective Groups in Organic Synthesis (Protective Gross)).
ups in Organic Synthesis), John Wiley &Sons; JF
W.McOmie, Protective Groups in Organic Chemistry
Chemistry), PlenumPress).

When the catalytic hydrogenation reaction is carried out in a solvent, the catalyst used may be 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, for example, benzene, toluene, xylene, hexane, hydrocarbons such as heptane, diethyl ether, dioxane, ethers such as tetrahydrofuran, methanol, Alcohols such as ethanol and isopropanol, acids such as formic acid, acetic acid and propionic acid, amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide, or a mixed solvent thereof is preferably used.

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

The reaction is usually carried out under atmospheric pressure or pressure. It is preferably carried out under pressure.

The reaction time varies depending on the pressure, temperature, catalyst and the like, but is usually several hours to several days, preferably 1 hour to 3 days.

The eighth step is a step for producing a compound having the above general formula (12), wherein the compound having the above general formula (9) is treated with 4-diamine in the presence of a base such as sodium hydride.
Fluorobenzaldehyde, or 2-methoxy-4-
It is obtained by reacting with a 4-fluorobenzaldehyde derivative such as fluorobenzaldehyde and 3-methyl-4-fluorobenzaldehyde.

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 for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethylacetamide. Amides such as dimethylformamide and hexamethylphosphoric triamide, or a mixed solvent thereof are preferably used.

The reaction temperature is ice-cooling or heating.

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

The ninth step is a step for producing the compound having the general formula (13), which can be obtained by reacting the compound having the general formula (12) 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, examples of the catalyst used include sodium acetate, piperidinium acetate or piperidinium benzoate.

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 for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; ethers such as diethyl ether, tetrahydrofuran, dioxane; methanol, Alcohols such as ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and 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 mixed solvents thereof are preferably used.

The reaction is carried out under heating.

The tenth step is a step for producing the compound having the general formula (14), which is carried out by subjecting the compound having the general formula (13) to reduction by a catalytic hydrogenation reaction or reduction with a metal hydride. can get.

When the compound having the general formula (13) is subjected to a catalytic hydrogenation reaction, the catalyst used may be 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, for example, benzene, toluene, xylene, hexane, hydrocarbons such as heptane, diethyl ether, dioxane, ethers such as tetrahydrofuran, methanol, Alcohols such as ethanol and isopropanol, acids such as formic acid, acetic acid and propionic acid, amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide, or a mixed solvent thereof is preferably used.

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

The reaction is usually carried out under atmospheric pressure or pressure. It is preferably carried out under pressure.

The reaction time varies depending on the pressure, temperature, catalyst and the like, but is usually several hours to several days, preferably 1 hour to 3 days.

Next, when the compound having the general formula (13) is subjected to reduction with a metal hydride, the reaction is
It can be carried out according to the method disclosed in O93 / 1309.

The eleventh step is a step for producing the compound having the general formula (15), which comprises reacting the compound having the general formula (12) with hydroxylamine (hydrochloride) and then reducing the compound. can get.

The reaction of the compound having the above general formula (12) with hydroxyamine (hydrochloride) 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, benzene,
Hydrocarbons such as toluene, xylene, hexane, heptane; ethers such as diethyl ether, tetrahydrofuran, dioxane; methanol, ethanol,
Alcohols such as isopropanol; Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; Halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; Acetonitrile, propionitrile, etc. Nitriles; esters such as ethyl formate and ethyl acetate, amines such as pyridine and triethylamine, or mixed solvents thereof are preferably used.

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

The reduction reaction to be carried out next can be carried out according to the reaction carried out in the presence of a reducing agent in the second step of the above-mentioned production method (I).

The twelfth step is a step of producing the compound having the general formula (16), which can be obtained by reacting the compound having the general formula (15) with trimethylsilyl isocyanate.

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, heptane; ethers such as diethyl ether, tetrahydrofuran, 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 mixtures thereof are preferably used.

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

The thirteenth step is a step for producing the compound having the general formula (17), which can be obtained by reacting the compound having the general formula (15) with chlorocarbonyl isocyanate.

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, heptane; ethers such as diethyl ether, tetrahydrofuran, 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 mixed solvents thereof are preferably used.

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

The reaction time varies depending on the reaction temperature, the solvent used and the like, but is usually several tens of minutes to 1 day.

Production Method (III)

[0296]

Embedded image

(Wherein X, A, B, R ¹ , R ² and n
Has the same meaning as described above. Q represents an alcohol protecting group such as t-butyldimethylsilyl. This production method is a method for producing the compound (intermediate) having the general formula (9) in the production method (II).

The 14th step is a step for producing the compound having the general formula (20), which is obtained by reacting the compound having the general formula (18) with the compound having the general formula (19). .

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 for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; ethers such as diethyl ether, tetrahydrofuran, dioxane; methanol, Alcohols such as ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and 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 mixed solvents thereof are preferably used.

The reaction is carried out under heating. Preferably 50
℃ to under reflux.

The 15th step is a step for producing the compound having the general formula (21), and the compound having the general formula (20) is carried out according to the third step of the production method (I). can get.

The 16th step is a step for producing the compound having the general formula (9), and is accomplished by removing the alcohol protecting group Q from the compound having the general formula (21).

The reaction is usually carried out by contacting the compound having the general formula (21) with an acid such as acetic acid, trifluoroacetic acid, hydrochloric acid or hydrofluoric acid in the presence or absence of a solvent, or by fluorinating the compound. It is carried out by contacting with a fluoride ion such as tributylammonium or by subjecting it to a catalytic hydrogenation reaction in a solvent.

The reaction of contacting with an acid or a fluoride ion in the presence or absence of a solvent can be achieved by a conventional method (eg, TWGreen, Protective Groups in Organic Synthesis). ), John
Wiley &Sons; JFWMcOmie, Protective Groups in Organic Chemistry (Protecti
ve Groups in Organic Chemistry), Plenum Press).

When the catalytic hydrogenation reaction is carried out in a solvent, the catalyst used may be 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, for example, benzene, toluene, xylene, hexane, hydrocarbons such as heptane, diethyl ether, dioxane, ethers such as tetrahydrofuran, methanol, Alcohols such as ethanol and isopropanol, acids such as formic acid, acetic acid and propionic acid, amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide, or a mixed solvent thereof is preferably used.

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

The reaction is usually carried out under atmospheric pressure or pressure. It is preferably carried out under pressure.

The reaction time varies depending on the pressure, temperature, catalyst and the like, but is usually several hours to several days, preferably 1 hour to 3 days.

The compound having the general formula (19) used in the 14th step is produced by the following step.

[0311]

Embedded image

(In the formula, R ¹ , R ² and n have the same meanings as described above. Boc represents a t-butoxycarbonyl group.) That is, the compound having the general formula (19) is N-Boc-ization of the compound having formula (22), then
It is obtained by O-silylation and then de-Boc reaction. These reactions can be achieved by carrying out according to a conventional method (eg, TWGreen, Protective Groups in Organic Synthesis (Pr
otective Groups in Organic Synthesis), John Wiley
&Sons; JFWMcOmie, Protective Groups
In Organic Chemistry (Protective Group
s in Organic Chemistry), Plenum Press).

Production Method (IV)

[0314]

Embedded image

(In the formula, X and Boc have the same meanings as described above.) In this production method, in the compound having the general formula (6) in the production method (II), A and B are combined. Is a method for producing a compound having the above general formula (27), which represents a carbonyl group.

The 17th step is a step for producing the compound having the general formula (26), and after reacting the compound having the general formula (25) with sodium hydride (the first step)
Step) and reacting the compound having the general formula (18) (second step).

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, for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; ethers such as diethyl ether, tetrahydrofuran, 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 mixed solvents thereof are used. Preferred are amides. The first step is achieved by reacting under ice cooling or heating for 0.5 hours to 5 hours.

The second step is achieved by reacting at room temperature to 100 ° C. for 1 hour to several days.

The 18th step is a step for producing a compound having the general formula (27), which is accomplished by subjecting the compound having the general formula (26) to a de-Boc reaction (eg, TWGreen, Protective Group). Sin Organic Synthesis (Protective Group
s in Organic Synthesis), John Wiley &Sons; JFWM
cOmie, Protective Groups in Organic Chem
mistry), Plenum Press).

Production Method (V)

[0321]

Embedded image

(In the formula, X and Halo have the same meanings as described above.) This production method comprises the production method (I) and the production method (II).
Is a method for producing the compound having the general formula (1).

The nineteenth step is a step for producing the compound having the general formula (30), which is obtained by reacting the compound having the general formula (29) with the compound having the general formula (28). . The reaction is usually performed in the presence or absence of a base. Examples of the base used include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, alkali metal hydrides such as sodium hydride, 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 for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; ethers such as diethyl ether, tetrahydrofuran, dioxane; methanol, Alcohols such as ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and 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 mixed solvents thereof.

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

The twentieth step is a step of producing the compound having the general formula (1), and can be obtained by reacting the compound having the general formula (30) with ammonia.

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 for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; ethers such as diethyl ether, tetrahydrofuran, dioxane; methanol, Alcohols such as ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; dichloromethane, chloroform, 1,2
Halogenated hydrocarbons such as dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as methyl formate, ethyl formate and ethyl acetate; water or mixed solvents thereof are preferably used.

The reaction is carried out at room temperature or under heating, under atmospheric pressure or in a sealed tube.

The twenty-first step is a step of producing the compound having the general formula (31), and reacting the compound having the general formula (30) with an alkali metal azide such as lithium azide, sodium azide or potassium azide. It is obtained by

The reaction 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 for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; ethers such as diethyl ether, tetrahydrofuran, dioxane; methanol, Alcohols such as ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; dichloromethane, chloroform, 1,2
Halogenated hydrocarbons such as dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as methyl formate, ethyl formate and ethyl acetate, or mixed solvents thereof are preferably used.

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

The twenty-second step is a step for producing the compound having the general formula (1), and reacting the compound having the general formula (31) with lithium aluminum hydride, or by reacting the compound having the general formula (31). It is obtained by subjecting a compound having a catalytic hydrogenation reaction.

The reaction of the compound having the above general formula (31) with lithium aluminum hydride 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, benzene,
Hydrocarbons such as toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; 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 used, etc., but it is usually several tens of minutes to 1 day.

When the compound having the above general formula (31) is subjected to catalytic hydrogenation reaction, the catalyst may be 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 for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; ethers such as diethyl ether, tetrahydrofuran, dioxane; methanol, Alcohols such as ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and 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 mixed solvents thereof are preferably used.

The reaction is usually carried out at room temperature or under heating and under atmospheric pressure or under pressure.

Production Method (VI)

[0340]

Embedded image

(Wherein X, A, B, R ¹ , R ² , R ³ ,
Y ² , R, n and Halo have the same meanings as described above. ) The 23rd step is a step of producing the compound having the general formula (32), and is obtained by reacting the compound having the general formula (9) with fluoro-4-nitrobenzene in the presence of a base.

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 for example, aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane; dimethylformamide, dimethyl. Amides such as acetamide and hexamethylphosphoric triamide; or a mixed solvent thereof is preferably used. The base used is not particularly limited as long as it does not affect the reaction, and includes sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, butyllithium, lithium diisopropylamide and the like. The reaction is performed under ice cooling or under heating.
The reaction time varies depending on the solvent, the reaction reagent, the reaction temperature and the like, but is usually 1 hour to several days.

The twenty-fourth step is a step for producing the compound having the general formula (33), and can be obtained by reducing the compound having the general formula (32).

The reaction is accomplished by using a conventional catalytic hydrogenation reaction and zinc-acetic acid or tin-hydrochloric acid which is a general nitro group reduction method.

The 25th step is a step for producing the compound having the general formula (34), which can be obtained by subjecting the compound having the general formula (33) to a Meerwein Arylation reaction. The reaction is usually JP-A-5
5-22657 and S.S. The method of Oae et al. (Bul
l. Chem. Soc. Jpn. 53, p. 1065 (1980)).

The 26th step is a step of producing the compound having the general formula (35), which is carried out by using the compound having the general formula (34) and the general formula H ₂ NC (= Y ² ) -NH ₂ In the above, Y ² represents an oxygen atom or a sulfur atom). The resulting compound having the general formula (35) can be isolated, but can be subjected to the 27th step without isolation. Second
Step 7 is a step of producing the compound having the general formula (36), and is achieved by subjecting the compound having the general formula (35) to an acid-catalyzed hydrolysis reaction. 26th
The reaction in the step and the 27th step is usually carried out according to JP-A 55-22.
It is carried out according to the method described in No. 657.

After completion of the reaction, the desired compound obtained in each of the above steps can be purified, if necessary, by a conventional method, for example, column chromatography, recrystallization method, reprecipitation method and 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 can be purified by subjecting it to column chromatography using silica gel or the like to obtain a pure product of the target compound.

The aromatic compound having the general formula (I) of the present invention, a pharmacologically acceptable salt thereof or an ester thereof is insulin resistance, hyperlipidemia, hyperglycemia, gestational diabetes,
It has the effect of improving obesity, glucose intolerance, diabetic complications, arteriosclerosis and polycystic ovary syndrome. Therefore, an aromatic compound having the above general formula (I) of the present invention,
The pharmacologically acceptable salt or ester thereof is hyperlipidemia, hyperglycemia, obesity, glucose intolerance, insulin resistance non-glucose intolerance, hypertension, osteoporosis, cachexia, fatty liver,
It is useful as a preventive and / or therapeutic drug for diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.), arteriosclerosis, etc. It is useful as a prophylactic and / or therapeutic agent for diseases caused by insulin resistance such as cystic ovary disease.

The compounds of general formula (I) of the present invention may be administered in various forms. Examples of the administration form include oral administration by tablets, capsules, granules, powders, syrups and the like, and parenteral administration by injections (intravenous, intramuscular, subcutaneous), drops, suppositories and the like. .
These various preparations are commonly used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizing agents, suspending agents, coating agents, and the like, in accordance with the usual methods for the main drug. It can be formulated using known adjuvants. The dose varies depending on symptoms, age, weight, administration method, dosage form, etc., but the usual dose for adults is 0.01 mg / day (preferably 0.1 m / day) as a lower limit.
g), the upper limit is 2000 mg (preferably 200 m
g) can be administered.

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

Formulation Example 1. Powder 5- {4- [2- (5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidine-2,4-dione (Exemplified Compound No. 1-92; hereinafter " Compound A ".) 5
g, lactose 895 g and corn starch 10
Mixing 0 g in a blender gives a powder. The powder contains 5 mg of compound A per day.

Formulation Example 2. After mixing 5 g of the granule compound A, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 10
% Hydroxypropylcellulose aqueous solution 300 g is added and kneaded. Granulate using an extrusion granulator,
When dried, granules are obtained. The granules contained 5 mg of Compound A per 1 g.

Formulation Example 3. Capsule compound A 5 g, lactose 115 g, corn starch 58 g and magnesium stearate 2 g
180m in No. 3 capsule after mixing using a mold mixer
Capsules are obtained by filling each g. The capsule contains 5 mg of Compound A per capsule.

Formulation Example 4. Tablet compound A (5 g), lactose (90 g), corn starch (34 g), crystalline cellulose (20 g) and magnesium stearate (g) were mixed in a blender and compressed with a tablet machine to give a tablet having a weight of 150 mg. The tablets each contain 5 mg of Compound A.

[0355]

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

The optical rotations described as the characteristics of the compounds of Production Examples and Reference Examples are values measured at room temperature.

Production Example 1 5- {4- [2- (5- (3-chlorophenoxymethymethyene
) -2-oxooxazolidin-3-yl) propoxy
[Ci] benzyl} thiazolidine-2,4-dione (exemplified
Compound number 1-94) 5- {4- [2- (5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4 -To 330 mg of dione was added 3 ml of trifluoroacetic acid under ice cooling, and the mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was neutralized by adding an aqueous sodium bicarbonate solution, and then extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 2: 3).
When purified by, melting point 50.9 ℃ to 52.5 ℃
And 160 mg of the desired compound with Rf = 0.45 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 2: 1) were obtained.

Production Example 2 5- {4- [2- (3- (3-chlorophenoxy) -2]
-Hydroxypropylamino) propoxy] benzyl}
Thiazolidine-2,4-dione (Exemplified compound number 1-
92) 3- (3-Chlorophenoxy) -2-hydroxypropylamine 100 mg and 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione
To 3 ml of a 139 mg anhydrous methanol solution, 148 mg of sodium cyanoborohydride was added under ice cooling, and the mixture was stirred at room temperature for 7 hours under a nitrogen stream. The reaction mixture was allowed to stand overnight, poured into water, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract under reduced pressure, and the resulting residue was subjected to silica gel plate chromatography (ethyl acetate:
When purified by subjecting to ethanol = 8: 1), Rf value =
Target compound 92 having 0.30 (silica gel thin layer chromatography; ethyl acetate: ethanol = 10: 1)
mg was obtained.

Production Example 3 5- {4- [2- (3-phenoxy-2-hydroxypropyl)
Ropylamino) propoxy] benzyl} thiazolidine-
2,4-dione (Exemplified Compound No. 1-16) 3-phenoxy-2-hydroxypropylamine 0.
98 g, 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione (3.39 g), sodium cyanoborohydride (1.11 g) and anhydrous methanol (60 ml) were used and the reaction and post-treatment were carried out according to Preparation Example 2. Processed. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: ethanol = 10:
Purification by 1) gave 1.92 g of the desired compound having a melting point of 64 ° C to 68 ° C.

Production Example 4 5- {4- [2- (5-phenoxymethyl-2-oxo
Oxazolidin-3-yl) propoxy] benzyl} thi
Azolidine-2,4-dione (Exemplified Compound No. 1-4
8) 5- {4- [2- (3-phenoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-
To 5 ml of a solution of 2,4-dione (500 mg) in anhydrous dimethylformamide, 211 mg of N, N'-carbonyldiimidazole was added under ice cooling, and the mixture was stirred at room temperature for 5 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 further washed with brine and dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off from the extract, the resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1 → 2: 1) to give a melting point of 54 ° C to 56 ° C. 410 mg of the target compound was obtained.

Production Example 5 5- {4- [2- (3- (3-chlorophenoxy) -2]
-Hydroxypropylamino) ethoxy] benzyl} thi
Azolidine-2,4-dione (Exemplified Compound No. 1-9
1) 3- (3-chlorophenoxy) -2-hydroxypropylamine 600 mg, 5- [4- (2-oxoethoxy) benzyl] thiazolidine-2,4-dione 800 m
g, sodium cyanoborohydride (570 mg) and anhydrous methanol (40 ml) were used to carry out a reaction and a post-treatment according to Production Example 2. Rf value = 0.35 (silica gel thin layer chromatography; ethanol: ethyl acetate =).
180 mg of the target compound having 1: 4) are obtained.

Production Example 6 5- {4- [2- (5- (3-chlorophenoxymethyi
Le) -2-oxooxazolidin-3-yl) etoki
[Ci] benzyl} thiazolidine-2,4-dione (exemplified
Compound number 1-93) 5- {4- [2- (3- (3-chlorophenoxy) -2-hydroxypropylamino) ethoxy] benzyl} thiazolidine-2,4-dione obtained in Production Example 5 18
0 mg, N, N'-carbonyldiimidazole 65 m
g and 10 ml of anhydrous dimethylformamide,
When the reaction and the post-treatment are carried out according to Production Example 4, the melting point is 58.
C-63 C and Rf value = 0.27 (silica gel thin layer chromatography; ethyl acetate: n-hexane =
53 mg of the target compound with 2: 1) were obtained.

Production Example 7 5- {4- [2- (3-phenyl-2-hydroxypro
Pyramino) propoxy] benzyl} thiazolidine-
2,4-dione (Exemplified Compound No. 1-2) 3-phenyl-2-hydroxypropylamine 550
mg and 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione (1.0 g) were suspended in anhydrous benzene (30 ml) and heated under reflux for 30 minutes while removing water, and then the solvent was removed under reduced pressure. Distilled off. The obtained oily substance was dissolved in 20 ml of anhydrous methanol, 670 mg of sodium cyanoborohydride was added under ice cooling, and the mixture was stirred in a nitrogen stream for 2 hours. After leaving the reaction mixture overnight,
The solvent was distilled off under reduced pressure. Water was added to the obtained residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: ethanol = 5: 1),
Crystallized from ethyl acetate, mp 145 ° C to 15
590 mg of the target compound having a temperature of 2 ° C. were obtained.

Production Example 8 5- {4- [2- (5-benzyl-2-oxooxazo
Lydin-3-yl) propoxy] benzyl} thiazolidi
2,4-dione (Exemplified Compound No. 1-4) 5- {4- [2- (3-phenyl-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-
The reaction and post-treatment were carried out according to Preparation Example 4 using 300 mg of 2,4-dione, 120 mg of N, N'-carbonyldiimidazole and 10 ml of anhydrous dimethylformamide. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 3:
Purification by 2) gave 200 mg of the desired compound having a melting point of 60 ° C to 70 ° C.

Production Example 9 5- {4- [2- (3- (3-chlorophenoxy) -2]
-Hydroxypropylamino) propylthio] benz
Lu} thiazolidine-2,4-dione (exemplary compound number
1-158) 3- (3-chlorophenoxy) -2-hydroxypropylamine 1.0 g, 5- [4- (2-oxopropylthio) benzyl] thiazolidine-2,4-dione 1.
Using 5 g, sodium cyanoborohydride (940 mg) and anhydrous methanol (30 ml), the reaction and post-treatment were carried out according to Production Example 2. The obtained crude product was purified by subjecting it to silica gel column chromatography (ethyl acetate: ethanol = 10: 1) to give an Rf value = 0.44.
1.52 g of target compound having (silica gel thin layer chromatography; ethyl acetate: ethanol = 10: 1)
was gotten.

Production Example 10 5- {4- [2- (5- (3-chlorophenoxymethymethyene
) -2-oxooxazolidin-3-yl) propyl
Thio] benzyl} thiazolidine-2,4-dione (example
Compound No. 1-159) 5- {4- [2- (3- (3-chlorophenoxy) -2
-Hydroxypropylamino) propylthio] benzyl} thiazolidine-2,4-dione 300 mg, N,
Using 470 mg of N'-carbonyldiimidazole and 20 ml of anhydrous dimethylformamide, the reaction and post-treatment were carried out according to Production Example 4. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: n
-Hexane = 3: 2), the diastereomer becomes p
It was obtained by separating it into an olar and a less polar.
Reverse phase preparative high performance liquid chromatography (YMC-Pack ODS-A (trade name; manufactured by YMC); acetonitrile: water: acetic acid: triethylamine =
100: 100: 1: 1) and purified
From ar, 110 mg of the target compound having an Rf value of 0.15 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 1) was also added.
From ar, 120 mg of the desired compound having an Rf value of 0.25 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 1) was obtained.

Production Example 11 5- {4- [2- (R)-(5- (S)-(3-chloro
Phenoxymethyl) -2-oxooxazolidine-3-
Il) propoxy] benzyl} thiazolidine-2,4-
Dione (Exemplified Compound No. 1-94) 5- {4- [2- (R)-(5- (S)-(3-chlorophenoxymethyl) -2-oxooxazolidine-3-
(Yl) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione (0.96 g), methylene chloride (4 ml) and trifluoroacetic acid (4 ml) were used and the reaction and post-treatment were carried out according to Production Example 1 to give a melting point of 48. ° C to 53 ° C (softening point) and [α] _D = + 5
0.52 g of the target compound having 4.0 ° (methanol, C = 1.000) was obtained.

Production Example 12 5- {4- [2- (S)-(5- (R)-(3-chloro
Phenoxymethyl) -2-oxooxazolidine-3-
Il) propoxy] benzyl} thiazolidine-2,4-
Dione (Exemplified Compound No. 1-94) 5- {4- [2- (S)-(5- (R)-(3-chlorophenoxymethyl) -2-oxooxazolidine-3-
(Yl) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione (0.73 g), methylene chloride (4 ml) and trifluoroacetic acid (4 ml) were used and the reaction and post-treatment were carried out according to Preparation Example 1 to give a melting point of 55. ° C to 60 ° C (softening point) and [α] _D = -5
0.39 g of the target compound having 2.4 ° (methanol, C = 0.990) was obtained.

Production Example 13 5- {4- [2- (S)-(5- (S)-(3-chloro
Phenoxymethyl) -2-oxooxazolidine-3-
Il) propoxy] benzyl} thiazolidine-2,4-
Dione (Exemplified Compound No. 1-94) 5- {4- [2- (S)-(5- (S)-(3-chlorophenoxymethyl) -2-oxooxazolidine-3-
Yl) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione (286 mg), trifluoroacetic acid (1 ml) and methylene chloride (1 ml) were used and the reaction and post-treatment were carried out according to Preparation Example 1 to give a melting point of 54 ° C. The target compound having 56 ° C. and [α] _D = + 41.8 ° (methanol, C = 0.975) 15.
0 mg was obtained.

Production Example 14 5- {4- [2- (R)-(5- (R)-(3-chloro
Phenoxymethyl) -2-oxooxazolidine-3-
Il) propoxy] benzyl} thiazolidine-2,4-
Dione (Exemplified Compound No. 1-94) 5- {4- [2- (R)-(5- (R)-(3-chlorophenoxymethyl) -2-oxooxazolidine-3-
(Yl) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione (0.57 g), trifluoroacetic acid (2 ml) and methylene chloride (2 ml) were used and the reaction and post-treatment were carried out according to Production Example 1 to give a melting point of 52. ℃
To 280 mg of the target compound having a temperature of 53 ° C to [α] _D = -39.7 ° (methanol, C = 0.965).
was gotten.

Production Example 15 5- {4- [2- (3-benzyloxy-2-hydroxy)
Cypropylamino) propoxy] benzyl} thiazolidi
2,4-dione (Exemplified compound number 1-64) 3-benzyloxy-2-hydroxypropylamine
The reaction and post-treatment were carried out according to Preparation Example 2 using 545 mg, 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione 700 mg, sodium cyanoborohydride 470 mg and anhydrous methanol 60 ml. . The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: ethanol = 1).
The product obtained by subjecting it to 0: 1 → 5: 1) is further subjected to reverse phase preparative high performance liquid chromatography (YMC-Pack).
ODS-A (trade name; YMC); acetonitrile: water: acetic acid: triethylamine = 50: 50: 1:
When purified by subjecting to 1), Rf value = 0.16 (silica gel thin layer chromatography; ethyl acetate: ethanol =
10: 1) as a pale yellow glassy solid target compound
130 mg was obtained.

Production Example 16 5- {4- [2- (3- (5-phenylpentyloxy)
Ci) -2-Hydroxypropylamino) propoxy]
Nthyl} thiazolidine-2,4-dione (exemplary compound no.
No. 1-160) 3- (5-phenylpentyloxy) -2-hydroxypropylamine 820 mg, 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione 840 mg, sodium cyanoborohydride 540
Preparation Example 2 using mg and 80 ml of anhydrous methanol
The reaction and post-treatment were carried out according to The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:
The product obtained by subjecting to ethanol = 10: 1 → 5: 1) was further subjected to reverse phase preparative high performance liquid chromatography (Y).
MC-Pack ODS-A (trade name; manufactured by YMC);
Acetonitrile: water: acetic acid: triethylamine = 50:
When purified by subjecting to 50: 1: 1), Rf value = 0.35
Target compound in the form of a pale yellow oil having (silica gel thin layer chromatography; ethyl acetate: ethanol = 5: 1)
250 mg was obtained.

Production Example 17 5- {4- [2- (3- (3-phenylpropoxy)-
2-Hydroxypropylamino) propoxy] benzyl
Lu} thiazolidine-2,4-dione (exemplary compound number
1-74) 3- (3-phenylpropoxy) -2-hydroxypropylamine 720 mg, 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione 8
00 mg, sodium cyanoborohydride 540 mg
And 70 ml of anhydrous methanol were used to carry out the reaction and post-treatment according to Production Example 2. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: ethanol = 10: 1 to 5: 1), and the obtained product was further subjected to reverse phase preparative high performance liquid chromatography (YM.
C-Pack ODS-A (trade name; manufactured by YMC); acetonitrile: water: acetic acid: triethylamine = 50: 5
When purified by subjecting to 0: 1: 1), Rf value = 0.29
380 mg of the target compound was obtained as a pale yellow glassy solid having (silica gel thin layer chromatography; ethyl acetate: ethanol = 5: 1).

Production Example 18 5- {4- [2- (3- (2-phenylethoxy) -2]
-Hydroxypropylamino) propoxy] benzyl}
Thiazolidine-2,4-dione (Exemplified compound number 1-
69) 3- (2-phenylethoxy) -2-hydroxypropylamine 0.70g, 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione 1.
The reaction and post-treatment were carried out according to Production Example 2 using 00 g, 0.71 g of sodium cyanoborohydride and 20 ml of anhydrous methanol. The obtained crude product was purified by subjecting it to silica gel column chromatography (ethyl acetate) to obtain 0.92 g of the target compound having a melting point of 46 ° C to 49 ° C (softening point).

Production Example 19 5- {4- [2- (3- (4-phenylbutoxy) -2]
-Hydroxypropylamino) propoxy] benzyl}
Thiazolidine-2,4-dione (Exemplified compound number 1-
161) 3- (4-phenylbutoxy) -2-hydroxypropylamine 1.20 g, 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione 1.
The reaction and post-treatment were carried out according to Production Example 2 using 00 g, 0.71 g of sodium cyanoborohydride and 20 ml of anhydrous methanol. The obtained crude product was purified by subjecting it to silica gel column chromatography (ethyl acetate: ethanol = 8: 1) to obtain 1.34 g of the desired compound having a melting point of 32 ° C to 37 ° C (softening point).

Production Example 20 5- {4- [2- (3- (6-phenylhexyloxy)
Ci) -2-Hydroxypropylamino) propoxy]
Nthyl} thiazolidine-2,4-dione (exemplary compound no.
No. 1-162) 3- (6-phenylhexyloxy) -2-hydroxypropylamine 864 mg, 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione 800 mg, sodium cyanoborohydride 540
Preparation Example 2 using mg and 50 ml of anhydrous methanol
The reaction and post-treatment were carried out according to The obtained crude product was purified by silica gel column chromatography (ethyl acetate or ethyl acetate: ethanol = 5: 1) to give Rf value = 0.42 (silica gel thin layer chromatography; ethyl acetate: ethanol = 5). There was obtained 500 mg of the target compound as a pale yellow oil having the formula: 1).

Production Example 21 5- {4- [2- (3- (8-phenyloctyloxy)
Ci) -2-Hydroxypropylamino) propoxy]
Nthyl} thiazolidine-2,4-dione (exemplary compound no.
No. 1-163) 3- (8- phenyloctyloxy) -2-hydroxypropylamine 0.96 g, 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione 0.80 g, hydrogenated Sodium cyanoboron 0.5
Production Example 2 using 4 g and 50 ml of anhydrous methanol
The reaction and post-treatment were carried out according to The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:
Purification by ethanol = 10: 1 to 5: 1) gave 360 mg of the desired compound with Rf value = 0.43 (silica gel thin layer chromatography; ethyl acetate: ethanol = 5: 1).

Production Example 22 5- {4- [2- (5-benzyloxymethyl-2-o
Xoxooxazolidin-3-yl) propoxy] benzyl
Lu} thiazolidine-2,4-dione (exemplary compound number
1-164) 5- {4- [2- (3-benzyloxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione 200 mg, N, N'-carbonyldiimidazole 73 mg and anhydrous dimethylformamide. The reaction and post-treatment were carried out according to Production Example 4 using 20 ml. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 2:
When purified by subjecting to 1 → 3: 1), Rf value = 0.49
(Silica gel thin layer chromatography; ethyl acetate: n
-Less polar with -hexane = 3: 1) and po with Rf value = 0.38 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 3: 1).
160 mg of the target compound are obtained as a pale yellow glassy solid as a mixture of lars.

Production Example 23 5- {4- [2- (5- (2-phenylethoxymethyi)
) -2-oxooxazolidin-3-yl) propoxy
[Ci] benzyl} thiazolidine-2,4-dione (exemplified
Compound No. 1-165) 5- {4- [2- (3- (2-phenylethoxy) -2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione obtained in Production Example 18
700 mg, N, N'-carbonyldiimidazole 2
Using 50 mg and 10 ml of anhydrous dimethylformamide, the reaction and post-treatment were carried out according to Production Example 4. The obtained crude product was purified by subjecting it to silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain Rf value = 0.74 (silica gel thin layer chromatography; ethyl acetate) polar and Rf. Value = 0.80
650 mg of a less polar (silica gel thin layer chromatography; ethyl acetate) was obtained as a 1: 1 mixture of diastereomers.

Production Example 24 5- {4- [2- (5- (3-phenylpropoxymethyi
) -2-oxooxazolidin-3-yl) propoxy
[Ci] benzyl} thiazolidine-2,4-dione (exemplified
Compound number 1-166) 5- {4- [2- (3- (3-phenylpropoxy)-
2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione 600 mg, N,
Using 206 mg of N'-carbonyldiimidazole and 60 ml of anhydrous dimethylformamide, the reaction and post-treatment were carried out according to Production Example 4. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: n
-Hexane = 1: 1 to 3: 2), diastereomers were obtained by separation into polar and less polar. Reverse phase preparative high performance liquid chromatography (YMC-Pack ODS-A (trade name; Y
(Manufactured by MC Co., Ltd.); purified by subjecting to acetonitrile: water = 1: 1), and the target compound having Rf value = 0.46 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 2: 1) from polar. 98 mg, again le
Rf value = 0.52 from ss polar (silica gel thin layer chromatography; ethyl acetate: n-hexane =
189 mg of the target compound with 2: 1) were obtained.

Production Example 25 5- {4- [2- (5- (4-phenylbutoxymethytene
) -2-oxooxazolidin-3-yl) propoxy
[Ci] benzyl} thiazolidine-2,4-dione (exemplified
Compound No. 1-79) 5- {4- [2- (3- (4-phenylbutoxy) -2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione obtained in Production Example 19
550 mg, N, N'-carbonyldiimidazole 1
Using 80 mg and 10 ml of anhydrous dimethylformamide, the reaction and post-treatment were carried out according to Production Example 4. The obtained crude product was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 2: 1), and then reverse phase preparative high performance liquid chromatography (YMC-
Pack ODS-A (trade name; YMC); acetonitrile: water: acetic acid: triethylamine = 100: 10
(0: 1: 1), the diastereomer was separated into polar and less polar.
170 mg of the target compound having Rf value = 0.71 (silica gel thin layer chromatography; ethyl acetate) from r.
However, Rf value = 0.79 from less polar
160 mg of the target compound having (silica gel thin layer chromatography; ethyl acetate) are obtained.

Production Example 26 5- {4- [2- (5- (5-phenylpentyloxy
Methyl) -2-oxooxazolidin-3-yl) pro
Poxy] benzyl} thiazolidine-2,4-dione (eg
Compound No. 1-167) 5- {4- [2- (3- (5-phenylpentyloxy) -2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione 600 mg,
N, N′-carbonyldiimidazole 194.3 mg
Using 60 ml of anhydrous dimethylformamide, the reaction and post-treatment were carried out according to Production Example 4. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 1) to give R
f value = 0.61 (silica gel thin layer chromatography;
Less with ethyl acetate: n-hexane = 2: 1)
polar and Rf value = 0.52 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 2: 1)
520 mg of the target compound was obtained as a pale yellow oily mixture as a mixture of polar compounds.

Production Example 27 5- {4- [2- (5- (6-phenylhexyloxy
Methyl) -2-oxooxazolidin-3-yl) pro
Poxy] benzyl} thiazolidine-2,4-dione (eg
Compound No. 1-168) 5- {4- [2- (3- (6-phenylhexyloxy) -2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione 690 mg,
Using 217 mg of N, N′-carbonyldiimidazole and 20 ml of anhydrous dimethylformamide, the reaction and post-treatment were carried out according to Production Example 4. The resulting crude product was purified by subjecting it to silica gel column chromatography (ethyl acetate: n-hexane = 1: 1 to 3: 2) to give an Rf value = 0.63 (silica gel thin layer chromatography; ethyl acetate: 502 mg of the target compound as a pale yellow oil as a mixture of less polar with n-hexane = 3: 2) and polar with Rf value = 0.56 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 3: 2). was gotten.

Production Example 28 5- {4- [2- (5- (8-phenyloctyloxy
Methyl) -2-oxooxazolidin-3-yl) pro
Poxy] benzyl} thiazolidine-2,4-dione (eg
Compound number 1-169) 5- {4- [2- (3- (8- phenyloctyloxy) -2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione 660 mg,
Using 197 mg of N, N'-carbonyldiimidazole and 20 ml of anhydrous dimethylformamide, the reaction and post-treatment were carried out according to Production Example 4. The obtained crude product was purified by subjecting it to silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give an Rf value =
Po with 0.58 and 0.65 (silica gel thin layer chromatography; ethyl acetate: hexane = 3: 2)
550 mg of the target compound are obtained as a mixture of diastereomers of lar and less polar.

Production Example 29 5- {4- [2- (5- (7-phenylheptyloxy
Methyl) -2-oxooxazolidin-3-yl) pro
Poxy] benzyl} thiazolidine-2,4-dione (eg
Compound No. 1-170) 5- {4- [2- (3- (7-phenylheptyloxy) -2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione 590 mg,
Using 181 mg of N, N'-carbonyldiimidazole and 15 ml of anhydrous dimethylformamide, the reaction and post-treatment were carried out in the same manner as in Production Example 4. The obtained crude product was purified by subjecting it to silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give an Rf value =
Po with 0.29 and 0.37 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 1)
383 mg of the target compound were obtained as a diastereomeric mixture of lar and less polar.

Production Example 30 5- {4- [2- (5- (3-fluorophenoxymethytene
) -2-oxooxazolidin-3-yl) propoxy
[Ci] benzyl} thiazolidine-2,4-dione (exemplified
Compound No. 1-171) 5- {4- [2- (5- (3-fluorophenoxymethyl) -2-oxooxazolidin-3-yl) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4 -Dione 390 mg, trifluoroacetic acid 2
The reaction and post-treatment were carried out in the same manner as in Production Example 1 using 2 ml of methylene chloride and 2 ml of methylene chloride to obtain 200 mg of the target compound having a melting point of 50 ° C to 53 ° C.

Production Example 31 5- {4- [2- (5- (4-methoxyphenoxymethythene
) -2-oxooxazolidin-3-yl) propoxy
[Ci] benzyl} thiazolidine-2,4-dione (exemplified
Compound number 1-173) (a) 5- {4- [2- obtained in Reference Example 78 (a)]
(5- (4-Methoxyphenoxymethyl) -2-oxooxazolidin-3-yl) propoxy] benzyl}-
Preparation Example 1 using 3-triphenylmethylthiazolidine-2,4-dione less polar 0.68 g, trifluoroacetic acid 2 ml and methylene chloride 2 ml.
When the reaction and post-treatment are performed according to
target compound having a melting point of 49 ° C to 52 ° C from ar
280 mg was obtained.

(B) 5-obtained in Reference Example 78 (b)
{4- [2- (5- (4-methoxyphenoxymethyl)
2-oxooxazolidin-3-yl) propoxy]
Benzyl} -3-triphenylmethylthiazolidine-
When 840 mg of 2,4-dione polar, 2 ml of trifluoroacetic acid and 2 ml of methylene chloride were used and the reaction and post-treatment were carried out according to Production Example 1, the target compound 440 having a melting point of 54 ° C. to 58 ° C.
mg was obtained.

Production Example 32 5- {4- [2- (3- (3-dimethylaminophenoxy)
Ci) -2-Hydroxypropylamino) propoxy]
Nthyl} thiazolidine-2,4-dione (exemplary compound no.
No. 1-176) 3- (3-Dimethylaminophenoxy) -2-hydroxypropylamine 1.20 g, 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione 1.81 g, hydrogenated Cyanoboron sodium 0.9
Production Example 2 using 6 g and 50 ml of anhydrous methanol
The reaction and post-treatment were carried out according to The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:
Purification by subjecting to ethanol = 20: 1) and recrystallization from ethanol gave 0.74 g of the desired compound having a melting point of 92.1 ° C to 98 ° C.

Production Example 33 5- {4- [2- (5- (3-dimethylaminophenoxy)
Cimethyl) -2-oxooxazolidin-3-yl) pre
Ropoxy] benzyl} thiazolidine-2,4-dione
(Exemplified Compound No. 1-177) 5- {4- [2- (3- (3-dimethylaminophenoxy) -2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione 500 mg,
Production Example 4 using 195 mg of N, N′-carbonyldiimidazole and 5 ml of anhydrous dimethylformamide.
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 applying hexane = 2: 1), the melting point is 55.5.
380 mg of the target compound having a temperature of -5 ° C to 57.1 ° C were obtained.

Production Example 34 5- {4- [2- (3- (4-phenylphenoxy)-
2-Hydroxypropylamino) propoxy] benzyl
Lu} thiazolidine-2,4-dione (exemplary compound number
1-179) 3- (4-phenylphenoxy) -2-hydroxypropylamine 1.00 g, 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione
1.46 g, sodium cyanoborohydride 0.52
g and 40 ml of anhydrous methanol were used to carry out the reaction and post-treatment according to Production Example 2. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: methanol = 1: 0 to 10: 1) and then subjected to reverse phase liquid chromatography (acetonitrile: water = 1: 1) according to Production Example 10. ) And a melting point of 7
174 mg of the target compound at 6.7 ° C to 80.3 ° C was obtained.

Production Example 35 5- {4- [2- (5- (4-phenylphenoxymethyi
) -2-oxooxazolidin-3-yl) propoxy
[Ci] benzyl} thiazolidine-2,4-dione (exemplified
Compound number 1-180) 5- {4- [2- (3- (4-phenylphenoxy)-
2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione 500 mg, N,
Using 195 mg of N'-carbonyldiimidazole and 10 ml of anhydrous dimethylformamide, the reaction and post-treatment were carried out according to Production Example 4. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 2) to give a melting point of 73.1 ° C.
0.44 g of the expected compound having a temperature of ˜75.4 ° C. is obtained.

Production Example 36 5- {4- [2- (5- (4-phenylphenoxymethyi
) -2-Thioxooxazolidin-3-yl) propo
[Xy] benzyl} thiazolidine-2,4-dione (exemplification
Compound No. 1-181) 5- {4- [2- (3- (4-phenylphenoxy)-
2-Hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione 218 mg of N, N'-thiocarbonyldiimidazole was added to a solution of 500 mg of anhydrous methylene chloride in 10 ml, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the extract was dried over anhydrous sodium sulfate, and ethyl acetate was evaporated. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 2: 3), and then purified by reverse phase liquid chromatography (acetonitrile: water = 60: 40) according to Production Example 10. Then, the melting point of polar was 58.7 ° C. to 60.
8 ° C, melting point 177.6 ° C from less polar
Each of the target compounds having a temperature of -180.3 ° C is 1
36 mg and 165 mg were obtained.

Production Example 37 5- {4- [2- (3-phenylthio-2-hydroxy)
Propylamino) propoxy] benzyl} thiazolidine
-2,4-dione (Exemplified compound number 1-182) 3-phenylthio-2-hydroxypropylamine
2.95 g, 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione 3 g, sodium cyanoborohydride 1.0 g and anhydrous methanol 100 ml were used and the reaction was carried out according to Preparation Example 2 and Work-up gave 1.74 g of the desired compound having a melting point of 176 ° C to 177 ° C.

Production Example 38 5- {4- [2- (5-phenylthiomethyl-2-oxy)
Sooxazolidin-3-yl) propoxy] benzyl}
Thiazolidine-2,4-dione (Exemplified compound number 1-
128) 5- {4- [2- (3-phenylthio-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione 1.2 g, N, N'-carbonyldiimidazole 0.52 g and anhydrous dimethyl. When 20 ml of formamide was used and the reaction and post-treatment were carried out according to Production Example 4, Rf value = 0.30 (polar) and Rf were obtained.
Value = 0.38 (less polar) (silica gel thin layer chromatography; ethyl acetate: n-hexane =)
1.15 g of the expected compound are obtained as a 1: 1 mixture of two diastereomers with 1: 1).

Production Example 39 5- {4- [2- (3- (N-methyl-N-phenylacrole
Mino) -2-hydroxypropylamino) propoxy]
Benzyl} thiazolidine-2,4-dione (exemplary compound
No. 1-183) 3- (N-methyl-N-phenylamino) -2-hydroxypropylamine 1.55 g, 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione 1.6 g , Sodium cyanoborohydride 0.4
g and 50 ml of anhydrous methanol, Production Example 2
The reaction and post-treatment were carried out in accordance with to give 1.39 g of the desired compound having a melting point of 115 ° C to 125 ° C.

Production Example 40 5- {4- [2- (5- (N-methyl-N-phenylacrole
Minomethyl) -2-oxooxazolidin-3-yl)
Propoxy] benzyl} thiazolidine-2,4-dione
(Exemplified Compound No. 1-184) 5- {4- [2- (3- (N-methyl-N-phenylamino) -2-hydroxypropylamino) propoxy]
Benzyl} thiazolidine-2,4-dione 0.9 g,
When the reaction and post-treatment were carried out according to Preparation Example 4 using 0.36 g of N, N′-carbonyldiimidazole and 20 ml of anhydrous dimethylformamide, Rf value = 0.
The target compound having 24 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 1).
6 g were obtained.

Production Example 41 5- {4- [2- (3- (3-chlorobenzyloxy)]
-2-Hydroxypropylamino) propoxy] benz
Lu} thiazolidine-2,4-dione (exemplary compound number
1-186) 3- (3-chlorobenzyloxy) -2-hydroxypropylamine 3.00 g (purity 57%), 5- [4-
(2-Oxopropoxy) benzyl] thiazolidine-
The reaction and post-treatment were carried out according to Preparation Example 2 using 2.00 g of 2,4-dione, 2.64 g of sodium cyanoborohydride and 100 ml of anhydrous methanol.
The obtained crude product is subjected to silica gel column chromatography (ethyl acetate: ethanol = 10: 1 to 4: 1).
After purification by reverse phase column chromatography (acetonitrile: water = 3: 7), the desired compound with a melting point (softening point) of 52 ° C. to 53 ° C.
g was obtained.

Production Example 42 5- {4- [2- (5- (3-chlorobenzyloxime
Tyl) -2-oxooxazolidin-3-yl) propo
[Xy] benzyl} thiazolidine-2,4-dione (exemplification
Compound No. 1-187) 5- {4- [2- (3- (3-chlorobenzyloxy))
2-Hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione 300 mg, N,
Using 115 mg of N'-carbonyldiimidazole and 5 ml of anhydrous dimethylformamide, the reaction and post-treatment were carried out according to Production Example 4. The crude product obtained was purified by subjecting it to silica gel column chromatography (ethyl acetate: hexane = 3: 2 to 2: 1) to give Rf.
Target compound 2 with value = 0.25 (silica gel thin layer chromatography; ethyl acetate: hexane = 2: 1)
Obtained 06 mg.

Production Example 43 5- {4- [2- (5- (3-chlorobenzyloxime
Cyl) -2-thioxooxazolidin-3-yl) pro
Poxy] benzyl} thiazolidine-2,4-dione (eg
Compound No. 1-188) 5- {4- [2- (3- (3-chlorobenzyloxy))
2-Hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione 300 mg, N,
Using 125 mg of N'-thiocarbonyldiimidazole and 5 ml of anhydrous dichloromethane, the reaction and post-treatment were carried out according to Production Example 36. The obtained crude product was purified by subjecting it to silica gel column chromatography (ethyl acetate: hexane = 2: 3) to give an Rf value = 0.35.
191 mg of the target compound having (silica gel thin layer chromatography; ethyl acetate: hexane = 2: 1) were obtained.

Production Example 44 5- {4- [2- (5- (3-chlorobenzyloxythiophene
Mel) -2-thioxooxazolidin-3-yl) pro
Poxy] benzyl} thiazolidine-2,4-dione.N
a salt (Exemplified Compound No. 1-189) 5- {4- [2- (5- (3-chlorobenzyloxymethyl) -2-thioxooxazolidin-3-yl) propoxy] benzyl} thiazolidine-2,4- Zeon 6
A solution prepared by dissolving 8 mg in 2 ml of methanol, 24 mg of sodium methoxide (28% methanol solution) diluted with 1 ml of methanol was added, and the mixture was stirred at room temperature for 1 hour. When the solvent is distilled off, the melting point is 238.7 ° C to 24
50 mg of the target compound at 0 ° C. (decomposition) was obtained.

Production Example 45 5- {4- [2- (5- (3-chlorophenoxymethymethyene
) -2-Thioxooxazolidin-3-yl) propo
[Xy] benzyl} thiazolidine-2,4-dione (exemplification
Compound No. 1-95) 5- {4- [2- (3- (3-chlorophenoxy) -2]
-Hydroxypropylamino) propoxy] benzyl}
Thiazolidine-2,4-dione 300 mg, N, N '
Using 127 mg of -thiocarbonyldiimidazole and 5 ml of anhydrous dimethylformamide, the reaction and post-treatment were carried out according to Production Example 36. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: hexane = 2: 3), and then according to Preparation Example 10, reverse phase column chromatography (acetonitrile: water = 1: 3).
When purified by subjecting to 1), the melting point was 50.3 from polar.
87 mg of the target compound having a temperature of 5 ° C to 52.8 ° C
In addition, 78 mg of the target compound having a melting point of 50.6 ° C. to 53.1 ° C. was obtained from the less polar.

Production Example 46 5- {4- [2- (3- (3-chlorophenoxy) -2]
-Hydroxypropylamino) butyloxy] benzyl
Lu} thiazolidine-2,4-dione (exemplary compound number
1-190) 3- (3-chlorophenoxy) -2-hydroxypropylamine 1.50 g , 5- [4- (2- oxobutyloxy) benzyl] thiazolidine-2,4-dione
2.61 g, sodium cyanoborohydride 1.40
g and 40 ml of anhydrous methanol were used to carry out the reaction and post-treatment according to Production Example 2. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: ethanol = 1: 0 to 10: 1), and then subjected to reverse phase column chromatography (acetonitrile: water = 3: 7) according to Preparation Example 10. (2) to give 2.97 g of the desired compound having a melting point (softening point) of 49.5 ° C to 52.8 ° C.

Production Example 47 5- {4- [2- (5- (3-chlorophenoxymethymethyene
Ru) -2-oxooxazolidin-3-yl) butyr
[Xy] benzyl} thiazolidine-2,4-dione (exemplification
Compound No. 1-191) 5- {4- [2- (3- (3-chlorophenoxy) -2]
-Hydroxypropylamino) butyloxy] benzyl} thiazolidine-2,4-dione 5.48 g, N,
Using 2.11 g of N'-carbonyldiimidazole and 60 ml of anhydrous dimethylformamide, the reaction and post-treatment were carried out according to Production Example 4. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: hexane = 2: 3 to 2: 1), and then Production Example 1 was performed.
Purified by reverse phase column chromatography (acetonitrile: water = 9: 11) according to 0,
1.91 g of the target compound having a melting point of 150.5 ° C. to 154.4 ° C. from r
As a result, 1.90 g of the desired compound having a melting point (softening point) of 54.4 ° C. to 55.4 ° C. was obtained.

Production Example 48 5- {4- [2- (5- (3-chlorophenoxymethyi
) -2-Thioxooxazolidin-3-yl) butyl
Oxy] benzyl} thiazolidine-2,4-dione (eg
Compound number 1-192) 5- {4- [2- (3- (3-chlorophenoxy) -2]
-Hydroxypropylamino) butyloxy] benzyl} thiazolidine-2,4-dione 250 mg, N,
Using 102 mg of N'-thiocarbonyldiimidazole and 5 ml of methylene chloride, the reaction and post-treatment were carried out according to Production Example 36. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: hexane =
2: 3) and then reverse phase column chromatography (acetonitrile: water = 1: 1) according to Preparation Example 10.
87 mg of the target compound having a melting point of 54.1 ° C. to 56.0 ° C. from polar, and a melting point of 57.7 ° C. to 5 from less polar.
85 mg of the target compound having a temperature of 9.0 ° C. were obtained.

Production Example 49 5- {4- [2- (5-phenoxymethyl-2-thioki
Sooxazolidin-3-yl) propoxy] benzyl}
Thiazolidine-2,4-dione (Exemplified compound number 1-
51) 5- {4- [2- (3-phenoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione obtained in Production Example 3 205 mg, N,
Preparation Example 36 using 95 mg of N'-thiocarbonyldiimidazole and 5 ml of anhydrous dimethylformamide.
The reaction and post-treatment were carried out according to The obtained crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give a melting point of 5
Target compound having 3 ° C. to 58 ° C. (softening point) 19
0 mg was obtained.

Production Example 50 5- {4- [2- (5- (3-chlorophenoxymethymethyene
Ru) -2-oxooxazolidin-3-yl) pentoki
[Ci] benzyl} thiazolidine-2,4-dione (exemplified
Compound number 1-193) (a) 5- {4- [2- (5 obtained in Reference Example 100
-(3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl) pentoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione les
s polar1.58g, trifluoroacetic acid 2ml
When the reaction and post-treatment were carried out in the same manner as in Production Example 1 using 4 ml of methylene chloride and methylene chloride, 516m of the target compound having a melting point of 50 ° C to 52 ° C from less polar
g was obtained.

(B) 5- {4 obtained in Reference Example 100
-[2- (5- (3-chlorophenoxymethyl) -2-
Oxooxazolidin-3-yl) pentoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-
1.45 g of dione polar, trifluoroacetic acid 2
ml and 4 ml of methylene chloride, the reaction and post-treatment were carried out according to Production Example 1, and the melting point was 5 from polar.
314 mg of the expected compound having a temperature of 3 ° C. to 55 ° C. were obtained.

Production Example 51 5- {4- [2- (5- (3-chlorophenoxymethyi
) -2-oxooxazolidin-3-yl) -3-me
Chilbutoxy] benzyl} thiazolidine-2,4-dio
(Exemplified Compound No. 1-195) (a) 5- {4- [2 obtained in Reference Example 103 (a)
-(5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl) -3-methylbutoxy] benzyl} -3-triphenylmethylthiazolidine-2,
Using 4-dione less polar 0.92 g, trifluoroacetic acid 2 ml and methylene chloride 4 ml,
When the reaction and post-treatment were carried out according to Production Example 1, less
145 mg of the target compound having a melting point of 51 ° C to 53 ° C was obtained from polar.

(B) 5 obtained in Reference Example 103 (b)
-{4- [2- (5- (3-chlorophenoxymethyl))
2-oxooxazolidin-3-yl) -3-methylbutoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione polar 1.18 g, trifluoroacetic acid 2 ml and methylene chloride 4 ml were used, Production Example 1 When the reaction and post-treatment are performed according to
177 mg of the target compound having a melting point of 57 ° C. to 58 ° C. was obtained from lar.

Production Example 52 5- {4- [2- (5- (3-chlorophenoxymethyi
) -2-oxooxazolidin-3-yl) -2-me
Cylpropoxy] benzyl} thiazolidine-2,4-di
ON (Exemplified Compound No. 1-197) 5- {4- [2- (5- (3-
Mixture of chlorophenoxymethyl) -2-oxooxazolidin-3-yl) -2-methylpropoxy] benzyl} thiazolidin-2-imino-4-one and thiourea
1.50 g and 6 N hydrochloric acid 15 ml, methanol 4
ml was added and the mixture was heated under reflux for 5 hours. After the reaction was completed, an aqueous sodium bicarbonate solution was added to the reaction solution for neutralization, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, the obtained residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 1), and further reversed phase preparative high performance liquid chromatography (YMC-Pack O).
DS-A (trade name; manufactured by YMC); acetonitrile: water = 1: 1) for purification, melting point 55 ° C. to 58 ° C.
454 mg of the target compound having a temperature of ℃ were obtained.

Production Example 53 5- {4- [3- (5-phenoxymethyl-2-oxo
Oxazolidin-3-yl) propoxy] benzyl} thi
Azolidine-2,4-dione (Exemplified Compound No. 1-4
9) 5- {4- [3- (5-phenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl}-
The reaction having the melting point of 41 ° C to 43 ° C when the reaction and post-treatment are carried out according to Preparation Example 1 using 1.98 g of 3-triphenylmethylthiazolidine-2,4-dione, 2 ml of trifluoroacetic acid and 4 ml of methylene chloride. 1.18 g of compound was obtained.

Production Example 54 5- {4- [4- (5- (3-chlorophenoxymethyi
Ru) -2-oxooxazolidin-3-yl) butoki
[Ci] benzyl} thiazolidine-2,4-dione (exemplified
Compound number 1-200) 5- {4- [4- (5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl) butoxy] benzyl} -3-triphenylmethylthiazolidine-2,4 -Dione 1.42 g, trifluoroacetic acid 2
ml and methylene chloride 4 ml, the reaction and post-treatment were carried out according to Preparation Example 1, melting point 40 ° C. to 42 ° C.
910 mg of the target compound having a temperature of ℃ were obtained.

Production Example 55 5- {4- [2- (2- (3-chlorophenoxymethyi
Le) morpholino) propoxy] benzyl} thiazolidine
-2,4-dione (Exemplified Compound 1-201) 5- {4- [2- (2- (3-chlorophenoxymethyl) morpholino) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione 1.24
g, trifluoroacetic acid 4 ml and methylene chloride 2
When the reaction and post-treatment are carried out in the same manner as in Production Example 1 using ml, the desired compound having a melting point of 51 ° C to 52 ° C is obtained.
1 mg was obtained.

Production Example 56 5- {4- [2- (3- (7-phenylheptyloxy)
Ci) -2-Hydroxypropylamino) propoxy]
Nthyl} thiazolidine-2,4-dione (exemplary compound no.
No. 1-204) 3- (7-phenylhelpyloxy) -2-hydroxypropylamine 836 mg, 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione 800 mg, sodium cyanoborohydride 54
When the reaction and post-treatment were carried out according to Preparation Example 2 using 0 mg and 50 ml of anhydrous methanol, the Rf value was 0.2.
1 (silica gel thin layer chromatography; ethyl acetate:
74 mg of the target compound with ethanol = 5: 1) were obtained.

Production Example 57 5- {4- [2- (N-3- (3-chlorophenoxy))
2-Hydroxypropyl-N-methylamino) propo
[Xy] benzyl} thiazolidine-2,4-dione (exemplification
Compound number 1-206) 5- {4- [2- (3- (3-chlorophenoxy) -2]
-Hydroxypropylamino) propoxy] benzyl}
To 20 ml of a mixed solution of thiazolidine-2,4-dione 300 mg of toluene: dioxane (1: 1), 180 mg of paraformaldehyde and 30 mg of p-toluenesulfonic acid were added, and the mixture was heated under reflux for 3 hours. After stirring for further 2 days, 180 mg of paraformaldehyde and 30 mg of p-toluenesulfonic acid were added, and the mixture was heated under reflux for 8 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure, an aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the resulting residue was subjected to reverse phase preparative high performance liquid chromatography (YMC-Pack ODS-A (trade name; Y
Purified by applying acetonitrile: water = 1: 1 to obtain 78 mg of the target compound having a melting point (softening point) of 64 ° C. to 67 ° C.

Production Example 58 5- {4- [2- (3- (4-phenylphenoxy)-
2-hydroxypropylamino) ethoxy] benzyl}
Thiazolidine-2,4-dione (Exemplified compound number 1-
207) 3- (4-phenylphenoxy) -2-hydroxypropylamine 0.42 g, anhydrous methanol 10 ml,
Sodium cyanoborohydride 0.21 g and 5-
[4- (2-Oxoethoxy) benzyl] thiazolidine-2,4-dione (0.52 g) was used and the reaction and post-treatment were carried out according to Production Example 2. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: methyl alcohol = 1: 0 → 3: 1) and further subjected to reverse phase preparative high performance liquid chromatography (YMC-Pack OD).
S-A (trade name; YMC); acetonitrile: water =
(3: 7 → 35: 65), the product has a melting point of 83 ° C.
222 mg of the target compound having a ˜86 ° C. were obtained.

Production Example 59 5- {4- [2- (5- (4-phenylphenoxymethyi
) -2-Thioxooxazolidin-3-yl) etoki
[Ci] benzyl} thiazolidine-2,4-dione (exemplified
Compound number 1-209) 5- {4- [2- (3- (4-phenylphenoxy)-
2-hydroxypropylamino) ethoxy] benzyl}
Thiazolidine-2,4-dione (50 mg), anhydrous methylene chloride (1 ml) and N, N'-thiocarbonyldiimidazole (22 mg) were used to carry out a reaction and a post-treatment according to Production Example 4. The obtained crude product was subjected to reverse phase preparative high performance liquid chromatography (YMC-Pack ODS-
A (trade name; manufactured by YMC); acetonitrile: water = 1:
Purification by 1 → 11: 9) yielded 42 mg of the desired compound having a melting point of 68 ° C. to 70 ° C.

Reference Example 1 3-chlorophenoxymethyloxirane 3-chlorophenol 35.70 g, potassium carbonate
47.67 g and anhydrous dimethylformamide 200
50 ml of anhydrous dimethylformamide solution containing 40.96 g of epibromohydrin was added dropwise to the mixture of 6 ml.
Heated at 2 ° C. for 3.5 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 further washed with brine and dried over anhydrous sodium sulfate. After distilling off ethyl acetate from the extract, the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to give an Rf value = 0.45.
43.43 g of the target compound having (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 4) was obtained.

Reference Example 2 5- (3-chlorophenoxymethyl) -3-t-butoki
2.18 g of sodium carbonyl oxazolidin-2-one hydride (55% by weight) was washed with n-hexane, 50 ml of dimethylformamide was added, and di-t-butyliminodicarboxylate 13.3 was added.
60 ml of a dimethylformamide solution of g was added dropwise under ice cooling, and 50 ml of dimethylformamide was further added.
The reaction mixture was stirred at the same temperature for 1 hour and then at room temperature for 2 hours. Add dimethylformamide 350 to the reaction mixture.
ml, and then 3-chlorophenoxymethyloxirane 9.2 g was added, and the mixture was stirred for 2 days and then at 70 ° C. for 3 days.
Heated for hours. After the reaction was completed, the reaction mixture was cooled to 2N under ice cooling.
The pH was adjusted to 4 by adding hydrochloric acid. The solvent was distilled off from the reaction mixture under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate: n-
When purified by subjecting to hexane = 1: 3 → 3: 1), the desired compound having a melting point of 116.2 ° C to 124.0 ° C is obtained.
9.80 g were obtained.

Reference Example 3 5- (3-chlorophenoxymethyl) -oxazolidine
2-one 5- (3-chlorophenoxymethyl) -3-t-butoxycarbonyloxazolidin-2-one 1.97 g of anhydrous tetrahydrofuran solution 4 ml was added with trifluoroacetic acid 4 ml under ice cooling and at room temperature for 1 hour. It was stirred. After completion of the reaction, tetrahydrofuran and trifluoroacetic acid were distilled off from the reaction mixture under reduced pressure to give an Rf value of 0.4.
3 (silica gel thin layer chromatography; ethyl acetate)
1.23 g of the target compound having is obtained.

Reference Example 4 2- [5- (3-chlorophenoxymethyl) -2-oxy
Sodium oxazolidin-3-yl] sodium propionate sodium hydride (55% by weight) (0.17 g) was washed with n-hexane, dimethylformamide (15 ml) was added, and 5- (3-chlorophenoxymethyl) -oxazolidine was added under ice cooling. 10 ml of a dimethylformamide solution of 1.85 g of 2-one was added dropwise, 50 ml of dimethylformamide was further added, and the mixture was stirred at room temperature for 2 hours. Then, to the reaction mixture was added ice-cooled ethyl 2-bromopropionate (1.76 g) in dimethylformamide solution (5 ml), and the mixture was stirred at room temperature for 1 hr. 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. Ethyl acetate was distilled off from the extract, and the resulting residue was subjected to silica gel chromatography (ethyl acetate: n-hexane = 1: 1).
Rf value = 0.38 (silica gel thin layer chromatography; ethyl acetate: n-hexane =
1.05 g of the target compound with 1: 1) was obtained.

Reference Example 5 2- [5- (3-chlorophenoxymethyl) -2-oxy
Sooxazolidin-3-yl] propanol (method a) 2- [5- (3-chlorophenoxymethyl)
25 ml of tetrahydrofuran solution of 2.95 g of ethyl-2-oxooxazolidin-3-yl] propionate
After adding 0.4 g of lithium borohydride under ice cooling, 0.37 ml of methanol and tetrahydrofuran 5
ml mixture was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, tetrahydrofuran was distilled off from the reaction mixture under reduced pressure, brine 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 obtained residue was recrystallized from ethyl acetate to obtain 0.93 g of the desired compound having a melting point of 114 ° C to 115 ° C.

(Method b) 3- (2-t-butyldimethylsilyloxy-1-methylethyl) -5- (3-chlorophenoxymethyl) oxazolidin-2-one 152
1 mg of anhydrous tetrahydrofuran solution was added to tetra-n-butylammonium fluoride (26 W / V) under ice cooling.
% Tetrahydrofuran solution) (1.2 ml) and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, saturated saline was added to the reaction mixture 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 obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol = 1: 0 → 20: 1) to obtain 97 mg of the target compound. It showed the same physicochemical properties as the compound obtained by the method.

Reference Example 6 5- {4- [2- (5- (3-chlorophenoxymethyi
) -2-oxooxazolidin-3-yl) propoxy
[C] benzyl} -3-triphenylmethylthiazolidine
2,4-dione tri -n- butyl phosphine 344 mg, anhydrous benzene 15ml, 5- (4- hydroxybenzyl) -3-
Triphenylmethyl thiazolidine-2,4-dione 6
54 mg and azodicarbonyldipiperidine 429
After stirring the mg mixture at room temperature for 30 minutes, 2- [5-
(3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propanol (500 mg) in a benzene solution (10 ml) was added, and the mixture was stirred overnight. After completion of the reaction, the solvent was concentrated from the reaction mixture under reduced pressure, and the insoluble material was filtered off.
The obtained filtrate is concentrated to dryness, and the obtained residue is purified by subjecting it to silica gel column chromatography (ethyl acetate: n-hexane = 2: 3) to have a melting point of 90.9 ° C. to 94.0 ° C. 0.33 g of the target compound was obtained.

Reference Example 7 2-Benzyloxycarbonylaminopropanol DL-alaninol A solution of 16.9 g of anhydrous tetrahydrofuran in 100 ml of triethylamine 31.3
ml was added, and 100 g of carbobenzyloxy chloride (30 to 35 W / V% toluene solution) was added dropwise under ice cooling. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, tetrahydrofuran 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. Ethyl acetate was distilled off from the extract, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 1) to have a melting point of 52.2 ° C to 56.6 ° C. 18.07 g of the target compound was obtained.

Reference Example 8 N- (2-t-butyldimethylsilyloxy-1-methyi)
Ru) Ethyl-O-benzylcarbamate 2-benzyloxycarbonylaminopropanol 1
To a mixture of 6.0 g, 12.39 g of imidazole and 150 ml of dimethylformamide, 50 ml of a dimethylformamide solution of 13.72 g of t-butyldimethylsilyl chloride was added dropwise under ice cooling, and the mixture was stirred at room temperature for 6.5 hours. After completion of the reaction, dimethylformamide was distilled off from the reaction mixture under reduced pressure, water was added to the obtained residue,
It was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 6) to have a melting point of 68.0 ° C to 70.2 ° C. 23.89 g of the target compound was obtained.

Reference Example 9 2-t-butyldimethylsilyloxy-1-methylethyi
Lumine N- (2-t-butyldimethylsilyloxy-1-methyl) ethyl-O-benzylcarbamate 4.0 g, 1
0% palladium-carbon 0.80 g, ethanol 40
Hydrogen was introduced to the mixture in ml for 1 hour. After purging with nitrogen, 10% palladium-carbon was filtered off from the reaction mixture, and the filtrate was concentrated to have an Rf value = 0.27 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 3). 1.88 g of compound was obtained.

Reference Example 10 1- (3-chlorophenoxymethyl) -2- (2-t-
Butyldimethylsilyloxy-1-methylethylami
No.) Ethanol 2-t-butyldimethylsilyloxy-1-methylethylamine 1.48 g, 3-chlorophenoxymethyloxirane 1.44 g, and a mixture of ethanol 16 ml were heated under reflux for 24 hours. After completion of the reaction, ethanol was distilled off from the reaction mixture under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol = 1: 0 → 10: 1) to give Rf value =
Target compound having 0.30 (silica gel thin layer chromatography; ethyl acetate: ethanol = 10: 1)
1.53 g was obtained.

Reference Example 11 3- (2-t-butyldimethylsilyloxy-1-methyi)
Ruethyl) -5- (3-chlorophenoxymethyl) oxy
Sazolidin-2-one 1- (3-chlorophenoxymethyl) -2- (2-t-
Butyldimethylsilyloxy-1-methylethylamino) ethanol 300 mg of dimethylformamide solution 5 ml of N, N′-carbonyldiimidazole 1
46 mg was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4).
Rf value = 0.30 and 0.17 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 3)
A compound having the formula (diastereomer mixture) 28
7 mg was obtained.

Reference Example 12 3- (3-chlorophenoxy) -2-hydroxypropyi
Ruazido 3-chlorophenoxymethyloxirane 0.37 g of methanol-water (8: 1) solution 12 ml was added with sodium azide 0.65 g and methyl formate 3 ml, and 50
The mixture was stirred for 9 hours under heating at ℃. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure, water was added to the obtained residue,
It was extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate and the solvent was distilled off from the extract, Rf value = 0.
0.40 g of the target compound was obtained as a colorless oil having 19 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 4).

Reference Example 13 3- (3-chlorophenoxy) -2-hydroxypropyi
Lumine 3- (3-chlorophenoxy) -2-hydroxypropyl azide 0.39 g in anhydrous tetrahydrofuran
To 5 ml, 0.19 g of lithium aluminum hydride was added little by little under a nitrogen stream under ice cooling. After stirring for 1.5 hours under the same conditions, excess lithium aluminum hydride was decomposed by adding water. After completion of the reaction, insoluble matter was removed from the reaction mixture by filtration through Celite, and the filtrate was dried over anhydrous sodium sulfate. When the solvent was distilled off from the reaction mixture under reduced pressure,
0.15 g of the target compound is obtained as white crystals with a melting point of 55 ° C. to 58 ° C.

Reference Example 14 3-phenoxy-2-hydroxypropyl azidophenoxymethyloxirane 1.00 g, sodium azide 1.94 g, methyl formate 10 ml and methanol-water (8: 1) 45 ml were used, and according to Reference Example 12. When the reaction and post-treatment were carried out, the target compound was obtained as a pale yellow oil having Rf = 0.26 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 4).
1.30 g was obtained.

Reference Example 15 3-phenoxy-2-hydroxypropylamine 3-phenoxy-2-hydroxypropyl acid 1.
Reference Example 1 using 17 g, lithium aluminum hydride 0.46 g and anhydrous tetrahydrofuran 20 ml.
The reaction and post-treatment were carried out according to 3, to obtain 1.09 g of the desired compound having a melting point of 82 ° C to 84 ° C.

Reference Example 16 3-Phenyl-2-hydroxypropyl azide (±)-(2,3-epoxypropyl) benzene 5
g, sodium azide 12.1 g, methyl formate 60 m
1, 270 ml of methanol-water (8: 1) was used and the reaction and post-treatment were carried out according to Reference Example 12, and Rf value =
6.03 g of the target compound is obtained as a colorless oil having 0.3 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 4).

Reference Example 17 3-phenyl-2-hydroxypropylamine 3-phenyl-2-hydroxypropyl azide 6.0
g, lithium aluminum hydride (2.6 g) and anhydrous tetrahydrofuran (300 ml) were used to carry out the reaction and post-treatment according to Reference Example 13 to give a melting point of 64 ° C. to 6 ° C.
5.26 g of the expected compound having a temperature of 6 ° C. are obtained.

Reference Example 18 5- [4- (2-oxopropylthio) benzyl] thia
1.28 g of sodium zolidine-2,4-dione hydride (55% by weight) was washed with toluene, 30 ml of dimethylformamide was added,
20 ml of a dimethylformamide solution containing 3.2 g of 5- (4-mercaptobenzyl) thiazolidine-2,4-dione was added dropwise under ice cooling, and the mixture was stirred at room temperature for 30 minutes. 1.69 ml of bromoacetone was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 2 hours. Furthermore, after leaving the reaction mixture overnight, dimethylformamide was distilled off under reduced pressure. Water was added to the obtained residue, the pH was adjusted to 2-3 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 2:
Purification by 3) gave 1.68 g of the desired compound having a melting point of 96 ° C to 102 ° C.

Reference Example 19 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 obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to give an Rf value = 0.46.
(Silica gel thin layer chromatography; ethyl acetate: n
600 mg of target compound having -hexane = 1: 2)
was gotten.

Reference Example 20 5- [4- (2-oxoethoxy) benzyl] thiazoli
Gin-2,4-dione 5- [4- (2,2-diethoxyethoxy) benzyl]
Thiazolidine-2,4-dione 10.07 g was dissolved in tetrahydrofuran 80 ml, then 6N hydrochloric acid 2
0 ml was added and left overnight at room temperature. 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 subjecting it to silica gel column chromatography (ethyl acetate: n-hexane = 3: 2) to give Rf
5.92 g of the expected compound with a value = 0.37 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 2: 1) were obtained.

Reference Example 21 2- [5- (3-chlorophenoxymethyl) -2-oxy
Soxazolidin-3-yl] propanol 3- (2-t-butyldimethylsilyloxy-1-methylethyl) -5- (3-chlorophenoxymethyl) oxazolidin-2-one 152 mg tetrahydrofuran solution 1 ml tetrabutyl fluoride 1.2 ml of a tetrahydrofuran solution (1.0 M) of ammonium was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, water and sodium chloride were added to the reaction mixture, and the mixture was extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, ethyl acetate was distilled off from the extract. The obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol = 1: 0 → 20: 1) to give Rf = 0.
97 mg of the target compound having 28 (silica gel thin layer chromatography; ethyl acetate) were obtained.

Reference Example 22 5.22 g of diethyl azodicarboxylate was added dropwise to a mixture of (S) -3-chlorophenoxymethyloxirane 3-chlorophenol 2.57 g, triphenylphosphine 7.86 g and anhydrous benzene 30 ml at room temperature. It was stirred for 1 hour. Next, 2.01 g of (R) -glycidol was added dropwise, and the mixture was allowed to stand at room temperature for 14 hours. Benzene was distilled off from the reaction mixture, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) to give an Rf value = 0.42.
(Silica gel thin layer chromatography; ethyl acetate: n
3.11 g of the target compound having -hexane = 1: 3)
was gotten.

Reference Example 23 (R) -2 -Benzoxycarbonylaminopropanol D-alaninol 5.00 g, potassium carbonate 18.
To a mixture of 49 g, 15 ml of ethyl acetate and 15 ml of water, 11.42 g of carbobenzoxylcolide was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and concentrated. The precipitated crude crystals are collected by filtration and washed with n-hexane to give the target compound 1 having a melting point of 78 ° C to 80 ° C.
3.68 g was obtained.

Reference Example 24 N-2-t-butyldimethylsilyloxy-1- (R)
-Methylethyl -O-benzylcarbamate (R) -2-benzyloxycarbonylaminopropanol 12.54 g, t-butyldimethylsilyl chloride 9.97 g, imidazole 4.90 g and anhydrous dimethylformamide 150 ml were used according to Reference Example 8. When the reaction and the post-treatment are carried out, Rf value = 0.54.
(Silica gel thin layer chromatography; ethyl acetate: n
16.43 with hexane = 1: 4)
g was obtained.

Reference Example 25 2-t-butyldimethylsilyloxy-1- (R) -me
Cylethylamine N-2-t-butyldimethylsilyloxy-1- (R)
-Methylethyl-O-benzyl carbamate 16.4
g and 10% palladium-carbon (3.5 g) and ethanol (100 ml) were used, and the reaction and post-treatment were carried out according to Reference Example 9, Rf value = 0.27 (silica gel thin layer chromatography; ethyl acetate: n-hexane =). 1: 3)
And [α] _D = -10.1 ° (methanol, C = 1.
This gave 8.55 g of the desired compound having 155).

Reference Example 26 1- (S)-(3-chlorophenoxymethyl) -2-
(2-t-butyldimethylsilyloxy-1- (R)-
Methylethylamino) ethanol 2-t-butyldimethylsilyloxy-1- (R) -methylethylamine 1.48 g, (S) -3-chlorophenoxymethyloxirane 0.72 g, and anhydrous ethanol 10 ml were used, and Reference Example 10 was used. When the reaction and the post-treatment are carried out according to the same manner, Rf value = 0.24 (silica gel thin layer chromatography; ethyl acetate) and [α] _D = −1.
1.00 g of the target compound having 4.3 ° (methanol, C = 1.025) are obtained.

Reference Example 27 3- (2-t-butyldimethylsilyloxy-1-)
(R) -Methylethyl) -5- (S)-(3-chlorophenyl)
Enoxymethyl) oxazolidin-2-one 1- (S)-(3-chlorophenoxymethyl) -2-
(2-t-butyldimethylsilyloxy-1- (R)-
Methylethylamino) ethanol 0.92 g, N,
Reference example 11 using 0.48 g of N'-carbonyldiimidazole and 10 ml of anhydrous dimethylformamide.
When the reaction and post-treatment are carried out according to, Rf value = 0.25
(Silica gel thin layer chromatography; ethyl acetate: n
-Hexane = 1: 2) and [α] _D = + 34.1 °
Target compound having (methanol, C = 0.960)
0.92 g was obtained.

Reference Example 28 2- (R)-[5- (S)-(3-chlorophenoxime
Cyl) -2-oxooxazolidin-3-yl] propa
Nol 3- (2-t-butyldimethylsilyloxy-1-)
(R) -Methylethyl) -5- (S)-(3-chlorophenoxymethyl) oxazolidin-2-one 0.88
g, tetra-n-butylammonium fluoride (26 W /
V% tetrahydrofuran solution) 6.6 ml and anhydrous tetrahydrofuran 10 ml were used and the reaction and post-treatment were carried out according to Reference Example 5. Rf value = 0.45 (silica gel thin layer chromatography; ethyl acetate) and [α] _D = + 45.6 ° (methanol, C = 1.00)
0.58 g of the target compound having 0) was obtained.

Reference Example 29 5- {4- [2- (R)-(5- (S)-(3-chloro
Phenoxymethyl) -2-oxooxazolidine-3-
Il) propoxy] benzyl} -3-triphenylmethyl
Lthiazolidine-2,4-dione 2- (R)-[5- (S)-(3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propanol 0.52 g, 5- (4-hydroxybenzyl) )
-3-Triphenylmethylthiazolidine-2,4-dione 1.01 g, tri-n-butylphosphine 0.4
Using 4 g, 0.55 g of azodicarbonyldipiperidine and 30 ml of anhydrous benzene and performing the reaction and post-treatment according to Reference Example 6, Rf value = 0.26 (silica gel thin layer chromatography; ethyl acetate: n-hexane). =
1: 1) and [α] _D = + 35.9 ° (methanol,
1.02 g of the target compound having C = 1.000) was obtained.

Reference Example 30 (R) -3-Chlorophenoxymethyloxirane 3-chlorophenol (5.14 g), (S) -glycidol (4.44 g), triphenylphosphine (15.7)
When 2 g, diethyl azodicarboxylate 10.44 g and anhydrous benzene 50 ml were used and the reaction and post-treatment were carried out according to Reference Example 22, Rf value = 0.42 (silica gel thin layer chromatography; ethyl acetate: n-hexane =). 6.43 g of the target compound with 1: 3) were obtained.

Reference Example 31 (S) -2-Benzyloxycarbonylaminopropano
Lumpur L- alaninol 14.55 g, carbobenzoxy chloride (30~35W / V% toluene solution) 126m
The reaction and post-treatment were carried out according to Reference Example 7 using 1 and 29.6 ml of triethylamine and 100 ml of anhydrous tetrahydrofuran to obtain 8.15 g of the target compound having a melting point of 79 ° C to 80 ° C.

Reference Example 32 N-2-t-butyldimethylsilyloxy-1- (S)
-Methylethyl -O-benzylcarbamate (S) -2-benzyloxycarbonylaminopropanol 7.00 g, t-butyldimethylsilyl chloride 6.03 g, imidazole 5.45 g and anhydrous dimethylformamide 100 ml were used according to Reference Example 8. After the reaction and post-treatment, 10.52 g of the desired compound having an Rf value of 0.48 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 7) was obtained.

Reference Example 33 2-t-butyldimethylsilyloxy-1- (S) -me
Cylethylamine N-2-t-butyldimethylsilyloxy-1- (S)
-Methylethyl-O-benzyl carbamate 10.2
When 2 g, 10% palladium-carbon (2.00 g) and 80 ml of ethanol were used for the reaction and post-treatment according to Reference Example 9, Rf value = 0.27 (silica gel thin layer chromatography; ethyl acetate: n-hexane =). 1:
3) and [α] _D = + 9.7 (methanol, C = 1.
540) was obtained as the desired compound (5.69 g).

Reference Example 34 1- (R)-(3-chlorophenoxymethyl) -2-
(2-t-butyldimethylsilyloxy-1- (S)-
Methylethylamino) ethanol 2-t-butyldimethylsilyloxy-1- (S) -methylethylamine 1.51 g, (R) -3-chlorophenoxymethyloxirane 0.74 g and absolute ethanol 10 ml were used, and Referential Example 10 was used. When the reaction and the post-treatment are carried out according to the same manner, Rf value = 0.24 (silica gel thin layer chromatography; ethyl acetate) and [α] _D = + 1.
0.88 g of the target compound having 5.1 ° (methanol, C = 1.075) was obtained.

Reference Example 35 3- (2-t-butyldimethylsilyloxy-1-)
(S) -Methylethyl) -5- (R)-(3-chlorophenyl)
Enoxymethyl) oxazolidin-2-one 1- (R)-(3-chlorophenoxymethyl) -2-
(2-t-butyldimethylsilyloxy-1- (S)-
Methylethylamino) ethanol 0.82 g, N,
Using N'-carbonyldiimidazole 0.43 g and anhydrous dimethylformamide 10 ml, Reference Example 11
When the reaction and post-treatment are carried out according to, Rf value = 0.25
(Silica gel thin layer chromatography; ethyl acetate: n
-Hexane = 1: 2) and [α] _D = -33.4 °
Target compound having (methanol, C = 1.040)
0.85 g was obtained.

Reference Example 36 2- (S)-[5- (R)-(3-chlorophenoxime
Cyl) -2-oxooxazolidin-3-yl] propa
Nol 3- (2-t-butyldimethylsilyloxy-1-)
(S) -Methylethyl) -5- (R)-(3-chlorophenoxymethyl) oxazolidin-2-one 0.78
g, tetra-n-butylammonium fluoride (26 W /
V% tetrahydrofuran solution) 5.85 ml and anhydrous tetrahydrofuran 10 ml were used and the reaction and post-treatment were carried out according to Reference Example 5, melting point 92 ° C. to 94 ° C.
C and [α] _D = -47.8 ° (methanol, C =
0.52 g of the target compound having 0.980) are obtained.

Reference Example 37 5- {4- [2- (S)-(5- (R)-(3-chloro
Phenoxymethyl) -2-oxooxazolidine-3-
Il) propoxy] benzyl} -3-triphenylmethyl
Lthiazolidine-2,4-dione 2- (S)-[5- (R)-(3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propanol 0.46 g, 5- (4-hydroxybenzyl) )
-3-Triphenylmethylthiazolidine-2,4-dione 0.90 g, tri-n-butylphosphine 0.3
When 9 g, 0.49 g of azodicarbonyldipiperidine and 30 ml of anhydrous benzene were used and the reaction and post-treatment were carried out according to Reference Example 6, Rf value = 0.26 (silica gel thin layer chromatography; ethyl acetate: n-hexane). =
1: 1) and [α] _D = -35.3 ° (methanol,
0.79 g of the target compound having C = 1.015) was obtained.

Reference Example 38 1- (S)-(3-chlorophenoxymethyl) -2-
(2-t-butyldimethylsilyloxy-1- (S)-
Methylethylamino) ethanol 2-t-butyldimethylsilyloxy-1- (S) -methylethylamine (2.00 g), (S) -3-chlorophenoxymethyloxirane (1.92 g) and ethanol (20 ml) were used according to Reference Example 10. After the reaction and work-up, the Rf value = 0.24 (silica gel thin layer chromatography; ethyl acetate) and [α] _D = + 14.
2.22 g of the target compound having 7 ° (methanol, C = 0.995) are obtained.

Reference Example 39 3- [2-t-butyldimethylsilyloxy-1-
(S) -Methylethyl] -5- (S)-(3-chlorophenyl
Enoxymethyl) oxazolidin-2-one 1- (S)-(3-chlorophenoxymethyl) -2-
(2-t-butyldimethylsilyloxy-1- (S)-
Methylethylamino) ethanol 2.06 g, N,
Using N'-carbonyldiimidazole 1.07 g and anhydrous dimethylformamide 20 ml, Reference Example 11
When the reaction and post-treatment are carried out according to, the Rf value = 0.18.
(Silica gel thin layer chromatography; ethyl acetate: n
-Hexane = 1: 4) and [α] _D = + 51.7 °
Target compound having (methanol, C = 1.03)
2.11 g was obtained.

Reference Example 40 2- (S)-[5- (S)-(3-chlorophenoxime
Cyl) -2-oxooxazolidin-3-yl] propa
Nol 3- [2-t-butyldimethylsilyloxy-1-
(S) -Methylethyl] -5- (S)-(3-chlorophenoxymethyl) oxazolidin-2-one 2.00
g, tetra-n-butylammonium fluoride (26 W /
V% tetrahydrofuran solution) (15 ml) and anhydrous tetrahydrofuran (20 ml) were used to carry out the reaction and post-treatment according to Reference Example 5 (b), and the melting point was 67 ° C to 7 ° C.
0 ° C. and [α] _D = + 57.0 ° (methanol, C =
0.85 g of the target compound having 1.055) are obtained.

Reference Example 41 5- {4- [2- (S)-(5- (S)-(3-chloro
Phenoxymethyl) -2-oxooxazolidine-3-
Il) propoxy] benzyl} -3-triphenylmethyl
Thiazolidine-2,4-dione tri -n- butyl phosphine 405 mg, anhydrous benzene 25ml, 2- (S) - [5- (S) - (3- chlorophenoxy) -2-oxo-oxazolidine -3
-Yl] propanol 700 mg, azodicarbonyldipiperidine 505 mg and 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,
Using 745 mg of 4-dione and carrying out the reaction and post-treatment according to Reference Example 6, melting point 80 ° C. to 84 ° C. and [α] _D = + 25.9 ° C. (methanol, C = 0.96)
340 mg of the target compound having

Reference Example 42 1- (R)-(3-chlorophenoxymethyl) -2-
(2-t-butyldimethylsilyloxy-1- (R)-
Methylethylamino) ethanol 2-t-butyldimethylsilyloxy-1- (R) -methylethylamine 3.00 g, (R) -3-chlorophenoxymethyloxirane 2.95 g and ethanol 30 ml were used according to Reference Example 10. After the reaction and the post-treatment, the Rf value = 0.23 (silica gel thin layer chromatography; ethyl acetate) and [α] _D = -15.
3.73 g of the target compound having 6 ° (methanol, C = 0.990) were obtained.

Reference Example 43 3- [2-t-butyldimethylsilyloxy-1-
(R) -Methylethyl] -5- (R)-(3-chlorophenyl
Enoxymethyl) oxazolidin-2-one 1- (R)-(3-chlorophenoxymethyl) -2-
(2-t-butyldimethylsilyloxy-1- (R)-
Methylethylamino) ethanol 3.45 g, N,
Using N'-carbonyldiimidazole 1.78 g and anhydrous dimethylformamide 30 ml, Reference Example 11
When the reaction and the post-treatment are carried out according to, the Rf value = 0.74.
(Silica gel thin layer chromatography; ethyl acetate: n
-Hexane = 1: 1) and [α] _D = -53.3 °
Target compound having (methanol, C = 1.020)
3.52 g was obtained.

Reference Example 44 2- (R)-[5- (R)-(3-chlorophenoxime
Cyl) -2-oxooxazolidin-3-yl] propa
Nol 3- [2-t-butyldimethylsilyloxy-1-
(R) -Methylethyl] -5- (R)-(3-chlorophenoxymethyl) oxazolidin-2-one 3.25
g, tetra-n-butylammonium fluoride (26 W /
V% tetrahydrofuran solution) 24 ml and anhydrous tetrahydrofuran 30 ml were used to carry out the reaction and post-treatment according to Reference Example 5 (b), and the melting point was 76 ° C. to 7 ° C.
8 ° C. and [α] _D = -65.4 ° (methanol, C =
2.28 g of the expected compound having 1.060) are obtained.

Reference Example 45 5- {4- [2- (R)-(5- (R)-(3-chloro
Phenoxymethyl) -2-oxooxazolidine-3-
Il) propoxy] benzyl} -3-triphenylmethyl
Thiazolidine-2,4-dione tri -n- butyl phosphine 526 mg, anhydrous benzene 25ml, 2- (R) - [5- (R) - (3- chlorophenoxy) -2-oxo-oxazolidine -3
-Yl] propanol 900 mg, azodicarbonyldipiperidine 656 mg and 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,
When 1.21 g of 4-dione was used and the reaction and post-treatment were carried out according to Reference Example 6, the melting point was 74 ° C. to 81 ° C. and [α] _D = −29.0 ° (methanol, C = 1.00).
0.65 g of the target compound having 0) was obtained.

Reference Example 46 4.03 g of sodium benzyloxymethyloxirane sodium hydride (55% by weight) was washed with n-hexane to give anhydrous dimethylformamide (200 m).
20 g of anhydrous benzyl alcohol was added dropwise under ice cooling. After stirring at room temperature for 1 hour, 15.2 ml of epibromohydrin was added dropwise to the reaction mixture under ice cooling, stirred for 1.5 hours, and left overnight. 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 further washed with brine and dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off from the extract, the resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 6 → 1: 5) to give Rf value =
Target compound 1 having 0.39 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 5)
3 g were obtained.

Reference Example 47 3-Benzyloxy-2-hydroxypropylazido Benzyloxymethyloxirane 4.92 g, methanol-water (8: 1) solution 160 ml, sodium azide 9.75 g and methyl formate 40 ml were used. When the reaction and post-treatment are carried out according to 12, Rf value =
There was obtained 5.7 g of the target compound in the form of a pale yellow oil having 0.22 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 5).

Reference Example 48 3-benzyloxy-2-hydroxypropylamine 3-benzyloxy-2-hydroxypropyl azide
When 5.7 g, 2.09 g of lithium aluminum hydride and 250 ml of anhydrous tetrahydrofuran were used for the reaction and post-treatment according to Reference Example 13, the melting point was 72 ° C.
3.5 g of white crystalline target compound having a temperature of ˜74 ° C.
was gotten.

Reference Example 49 5-phenylpentyloxymethyloxirane 5-phenyl-1-pentanol 5 g, epibromohydrin 4.99 ml, sodium hydride (55% by weight) 1.31 g and anhydrous dimethylformamide 8
The reaction and post-treatment were carried out according to Reference Example 46 using 0 ml. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 6) to give Rf value = 0.49 (silica gel thin layer chromatography; ethyl acetate: n-hexane =). 1:
4.2 g of the target compound is obtained as a colorless oil having 4).

Reference Example 50 3- (5-Phenylpentyloxy) -2-hydroxy
Propyl azide 5-phenylpentyloxymethyloxirane 4.0
g, sodium azide 5.9 g, methanol-water (8:
1) When 160 ml of the solution and 40 ml of methyl formate were used for the reaction and post-treatment according to Reference Example 12, R
f value = 0.25 (silica gel thin layer chromatography;
4.5 g of the target compound was obtained as a pale yellow oil having ethyl acetate: n-hexane = 1: 4).

Reference Example 51 3- (5-Phenylpentyloxy) -2-hydroxy
Propylamine 3- (5-phenylpentyloxy) -2-hydroxypropyl azide 4.5 g, lithium aluminum hydride 1.3 g and anhydrous tetrahydrofuran 250 ml
Was used and the reaction and post-treatment were carried out according to Reference Example 13, Rf value = 0.09 (silica gel thin layer chromatography; ethyl acetate: ethanol: triethylamine = 1).
0: 2: 1) as a pale yellow oily target compound 4.3
g was obtained.

Reference Example 52 3 -phenylpropoxymethyloxirane 3-phenyl-1-propanol 8 g, epibromohydrin 9.64 ml, sodium hydride (55% by weight) 2.56 g and anhydrous dimethylformamide 1
The reaction and post-treatment were carried out according to Reference Example 46 using 00 ml. The obtained crude product was purified by subjecting it to silica gel column chromatography (ethyl acetate: n-hexane = 1: 6) to give an Rf value = 0.36 (silica gel thin layer chromatography; ethyl acetate: n-hexane =). 1:
7.2 g of the colorless oily target compound containing 5) were obtained.

Reference Example 53 3- (3-phenylpropoxy) -2-hydroxyprop
Pyrazide 3-phenylpropoxymethyloxirane 5.77
g, sodium azide 9.75 g, methanol-water (8: 1) solution 160 ml and methyl formate 40 ml
When the reaction and the post-treatment are carried out in accordance with Reference Example 12 using the above compound, the target compound is a pale yellow oily substance having an Rf value = 0.27 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 5). 0.6 g was obtained.

Reference Example 54 3- (3-phenylpropoxy) -2-hydroxyprop
Pyramine 3- (3-phenylpropoxy) -2-hydroxypropyl azide 6.5 g, lithium aluminum hydride
When 2.1 g and 250 ml of anhydrous tetrahydrofuran were used for the reaction and post-treatment according to Reference Example 13,
Rf value = 0.09 (silica gel thin layer chromatography; ethyl acetate: ethanol: triethylamine = 1)
6 g of the target compound are obtained, which is a pale yellow oil with 0: 2: 1).

Reference Example 55 2-phenylethoxymethyloxirane 2-phenylethanol 4.28 g, sodium hydride (55% by weight) 1.68 g, epibromohydrin
4.1 ml and 100 ml of anhydrous dimethylformamide
Was used for the reaction and post-treatment according to Reference Example 46. The obtained crude product was purified by subjecting it to silica gel chromatography (n-hexane: ethyl acetate = 8: 1) to give an Rf value = 0.77 (silica gel thin layer chromatography; n-hexane: ethyl acetate = 2). 1.68 g of the target compound is obtained as a colorless oil having 1).

Reference Example 56 3- (2-Phenylethoxy) -2-hydroxypropyi
Luzide 2-phenylethoxymethyloxirane 4.50 g,
When 8.20 g of sodium azide, 45 ml of methyl formate and 180 ml of methanol-water (8: 1) were used for the reaction and post-treatment according to Reference Example 12, Rf value =
5.49 g of the target compound is obtained as a colorless oil having 0.70 (silica gel thin layer chromatography; n-hexane: ethyl acetate = 2: 1).

Reference Example 57 3- (2-phenylethoxy) -2-hydroxypropyi
Lumine 3- (2-phenylethoxy) -2-hydroxypropyl azide 5.30 g, lithium aluminum hydride
When 1.85 g and 120 ml of anhydrous tetrahydrofuran were used and the reaction and post-treatment were carried out according to Reference Example 13,
4.47 g of the colorless oily target compound having an Rf value = 0.09 (silica gel thin layer chromatography; ethyl acetate: methanol = 10: 1) were obtained.

Reference Example 58 4-phenylbutoxymethyloxirane 4-phenyl-1-butanol 5.00 g, sodium hydride (55% by weight) 1.58 g, epibromohydrin 3.9 ml and anhydrous dimethylformamide 1
The reaction and post-treatment were performed according to Reference Example 46 using 10 ml. The obtained crude product was purified by subjecting it to silica gel column chromatography (n-hexane: ethyl acetate = 8.1) to give an Rf value = 0.77 (silica gel thin layer chromatography; n-hexane: ethyl acetate =). 2:
3.83 g of the colorless oily target compound containing 1) were obtained.

Reference Example 59 3- (4-phenylbutoxy) -2-hydroxypropyi
Luazido 4-phenylbutoxymethyloxirane 3.70 g,
When the reaction and post-treatment were carried out according to Reference Example 12 using sodium azide (5.83 g), methyl formate (37 ml) and methanol-water (8: 1) (135 ml), Rf value =
There was obtained 4.46 g of the target compound as a colorless oil having 0.67 (silica gel thin layer chromatography; n-hexane: ethyl acetate = 2: 1).

Reference Example 60 3- (4-phenylbutoxy) -2-hydroxypropyi
Lumine 3- (4-phenylbutoxy) -2-hydroxypropyl azide 4.30 g, lithium aluminum hydride
Using 1.31 g and 120 ml of anhydrous tetrahydrofuran and carrying out the reaction and post-treatment according to Reference Example 13,
3.70 g of the target compound is obtained as a colorless oil with Rf value = 0.08 (silica gel thin layer chromatography; ethyl acetate: methanol = 10: 1).

Reference Example 61 6-phenylhexyloxymethyloxirane 6-phenyl-1-hexanol 5 g, epibromohydrin 4.6 ml, sodium hydride (55% by weight)
1.23 g and anhydrous dimethylformamide 80 ml
Was used for the reaction and post-treatment according to Reference Example 46. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 7) to give Rf value = 0.60 (silica gel thin layer chromatography; ethyl acetate: n-hexane =). 4.35 g of the target compound are obtained as a colorless oil having 1: 5).

Reference Example 62 3- (6-phenylhexyloxy) -2-hydroxy
Propyl azide 6-phenylhexyloxymethyloxirane 4 g,
Sodium azide 5.5 g, methanol-water (8: 1)
Using 100 ml of solution and 25 ml of methyl formate,
When the reaction and the post-treatment were carried out according to Reference Example 12, 4.5 g of the objective compound as a light yellow oil having an Rf value = 0.39 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 5) was obtained. Was obtained.

Reference Example 63 3- (6-phenylhexyloxy) -2-hydroxy
Propylamine 3- (6-phenylhexyloxy) -2-hydroxypropyl azide 4.5 g, lithium aluminum hydride 1.23 g and anhydrous tetrahydrofuran 150 m
The reaction and post-treatment were carried out according to Reference Example 13 using 1 to give Rf value = 0.12 (silica gel thin layer chromatography; ethyl acetate: ethanol: triethylamine =).
5: 1: 1) as a pale yellow oily target compound 3.1
4 g were obtained.

Reference Example 64 8- phenyloctyloxymethyloxirane 8-phenyloctyl alcohol 4 g, epibromohydrin 3.18 ml, sodium hydride (55% by weight) 0.85 g and anhydrous dimethylformamide 8
When 0 ml was used and the reaction and post-treatment were carried out according to Reference Example 46, 2.42 g of the desired compound having an Rf value = 0.51 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 6) was obtained. It was

Reference Example 65 3- (8-Phenyloctyloxy) -2-hydroxy
Propyl azide 8-phenyloctyloxymethyloxirane 2.4
g, sodium azide 2.97 g, methyl formate 20 m
The reaction and post-treatment were carried out according to Reference Example 12 using 80 ml of a mixed solution of 1 and methanol: water = 8: 1.
f value = 0.29 (silica gel thin layer chromatography;
Target compound having ethyl acetate: hexane = 1: 5)
2.7 g were obtained.

Reference Example 66 3- (8-Phenyloctyloxy) -2-hydroxy
Propylamine 3- (8-phenyloctyloxy) -2-hydroxypropyl azide 2.6 g, lithium aluminum hydride 0.65 g and anhydrous tetrahydrofuran 80 ml
The target compound having a melting point of 50 ° C. to 54 ° C. is obtained by carrying out the reaction and post-treatment according to Reference Example 13 using
11 g were obtained.

Reference Example 67 7-phenylheptyloxymethyloxirane 7-phenylheptyl alcohol 2 g, epibromohydrin 1.7 ml, sodium hydride (55% by weight)
0.44 g and anhydrous dimethylformamide 50 ml
Was subjected to the reaction and post-treatment according to Reference Example 46 to give 1.15 g of the desired compound having an Rf value = 0.49 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 6). .

Reference Example 68 3- (7-Phenylheptyloxy) -2-hydroxy
Propyl azide 7-phenylheptyloxymethyloxirane 1.1
g, sodium azide 1.4 g, methyl formate 15 ml
And 60 ml of a mixed solution of methanol and water = 8: 1 were used to carry out the reaction and post-treatment according to Reference Example 12, and R
f value = 0.45 (silica gel thin layer chromatography;
Target compound having ethyl acetate: hexane = 1: 3)
1.27 g was obtained.

Reference Example 69 3- (7-Phenylheptyloxy) -2-hydroxy
Propylamine 3- (7-phenylheptyloxy) -2-hydroxypropyl azide 1.1 g, lithium aluminum hydride 0.287 g and anhydrous tetrahydrofuran 50 m
The reaction and post-treatment were carried out according to Reference Example 13 using 1 to give Rf value = 0.12 (silica gel thin layer chromatography; ethyl acetate: ethanol: triethylamine =).
0.82 g of the expected compound with 5: 1: 1) was obtained.

Reference Example 70 3-Fluorophenoxymethyloxirane 3-fluorophenol 4.00 g, sodium hydride (55% by weight) 1.88 g, epibromohydrin
Using 6.66 g and 50 ml of anhydrous dimethylformamide and carrying out the reaction and post-treatment according to Reference Example 46,
5.33 g of the expected compound having an Rf value = 0.48 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 4) was obtained.

Reference Example 71 1- (3-Fluorophenoxymethyl) -2- (2-t
-Butyldimethylsilyloxy-1-methylethylami
No.) Ethanol 2-t-butyldimethylsilyloxy-1-methylethylamine 2.00 g, 3-fluorophenoxymethyloxirane 1.77 g and ethanol 20 ml were used to carry out a reaction and a post-treatment according to Reference Example 10, and R
f value = 0.17 (silica gel thin layer chromatography;
2.13 g of the target compound having (ethyl acetate) are obtained.

Reference Example 72 3- (2-t-butyldimethylsilyloxy-1-methyi)
Ruethyl) -5- (3-fluorophenoxymethyl) o
Xazolidin-2-one 1- (3-fluorophenoxymethyl) -2- (2-t
-Butyldimethylsilyloxy-1-methylethylamino) ethanol (2.00 g), anhydrous dimethylformamide (20 ml) and N, N'-carbonyldiimidazole (1.09 g) were used and the reaction and post-treatment were carried out according to Reference Example 11, 0.74 g of the target compound having Rf value = 0.29 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 3) was obtained from polar.
The melting point is 54 ℃ to 58 ℃ from less polar.
1.03 g of the target compound having is obtained.

Reference Example 73 2- [5- (3-fluorophenoxymethyl) -2-o
Xoxooxazolidin-3-yl] propanol 3- (2-t-butyldimethylsilyloxy-1-methylethyl) -5- (3-fluorophenoxymethyl) oxazolidin-2-one 0.93 g, anhydrous tetrahydrofuran 9 ml and fluorinated Tetra-n-butylammonium (26 W / V% tetrahydrofuran solution)
The desired compound having an Rf value of 0.18 (silica gel thin layer chromatography; ethyl acetate) was obtained by the reaction and post-treatment according to Reference Example 5 (b) using 7.2 ml.
0.63 g was obtained.

Reference Example 74 5- {4- [2- (5- (3-fluorophenoxymethyi
) -2-oxooxazolidin-3-yl) propoxy
Cy] benzyl} -3-triphenylmethylthiazolidine
2,4-dione tri -n- butyl phosphine 364 mg, anhydrous benzene 5ml, 5- (4- hydroxybenzyl) -3-triphenylmethyl-thiazolidine-2,4-dione 69
8 mg, azodicarbonyldipiperidine 454 mg and 2- [5- (3-fluorophenoxymethyl) -2
-Oxooxazolidin-3-yl] propanol 4
The target compound having a melting point of 70 ° C. to 77 ° C. is obtained by the reaction and post-treatment according to Reference Example 6 using 89 mg.
0.52 g was obtained.

Reference Example 75 1- (4-methoxyphenoxymethyl) -2- (2-t
-Butyldimethylsilyloxy-1-methylethylami
No.) Ethanol 2-t-butyldimethylsilyloxy-1-methylethylamine 3.22 g, 4-methoxyphenoxymethyloxirane 3.00 g and ethanol 30 ml were used and the reaction and post-treatment were carried out according to Reference Example 10,
3.58 g of the expected compound with an Rf value = 0.15 (silica gel thin layer chromatography; ethyl acetate) are obtained.

Reference Example 76 3- (2-t-butyldimethylsilyloxy-1-methyi)
Ruethyl) -5- (4-methoxyphenoxymethyl) o
Xazolidin-2-one 1- (4-methoxyphenoxymethyl) -2- (2-t
-Butyldimethylsilyloxy-1-methylethylamino) ethanol 3.36 g, N, N'-carbonyldiimidazole 1.78 g and anhydrous dimethylformamide 30 ml were used and the reaction and post-treatment were carried out according to Reference Example 11, From polar, 1.42 g of the target compound having Rf value = 0.41 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 2)
1.62 g of the target compound having a melting point of 81 ° C. to 85 ° C. was obtained from the less polar.

Reference Example 77 2- [5- (4-methoxyphenoxymethyl) -2-o
Xoxooxazolidin-3-yl] propanol (a) 3- (2-t-butyldimethylsilyloxy-1-methylethyl) -5- (4- obtained in Reference Example 76
Methoxyphenoxymethyl) oxazolidin-2-one less polar 1.52 g, fluorinated tetra-n
-Butyl ammonium (26 W / V% tetrahydrofuran solution) 12 ml and anhydrous tetrahydrofuran 1
When 0 ml was used and the reaction and post-treatment were carried out according to Reference Example 5 (b), 1.20 g of the desired compound having a melting point of 80 ° C. to 88 ° C. was obtained from the less polar.

(B) 3- (2-obtained in Reference Example 76)
t-butyldimethylsilyloxy-1-methylethyl)
Using 5- (4-methoxyphenoxymethyl) oxazolidin-2-one polar 1.26 g, tetra-n-butyl ammonium fluoride (26 W / V% tetrahydrofuran solution) 9.6 ml and anhydrous tetrahydrofuran 10 ml, Reference Example 5 ( According to b),
0.86 g of the target compound having a melting point of 62 ° C. to 67 ° C. was obtained from polar.

Reference Example 78 5- {4- [2- (5- (4-methoxyphenoxymethyi
) -2-oxooxazolidin-3-yl) propoxy
Cy] benzyl} -3-triphenylmethylthiazolidine
-2,4-dione (a) 2- [5- (4- obtained in Reference Example 77 (a)
Methoxyphenoxymethyl) -2-oxooxazolidin-3-yl] propanol less polar 8
00 mg, tributylphosphine 688 mg, anhydrous benzene 30 ml, 5- (4-hydroxybenzyl)-
1.30 g of 3-triphenylmethylthiazolidine-2,4-dione and azodicarbonyldipiperidine 8
When 58 mg was used and the reaction and post-treatment were carried out according to Reference Example 6, the melting point was 60 ° C. to 6 ° C. from the less polar.
0.75 g of the target compound having a temperature of 6 ° C. was obtained.

(B) 2-obtained in Reference Example 77 (b)
[5- (4-Methoxyphenoxymethyl) -2-oxooxazolidin-3-yl] propanol polar
0.85 g, tri-n-butylphosphine 0.73
g, 50 ml of anhydrous benzene, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,
When 1.68 g of 4-dione and 0.91 g of azodicarbonyldipiperidine were used and the reaction and post-treatment were carried out according to Reference Example 6, the melting point was 85 ° C. to 9 ° C. from polar.
0.93 g of the target compound having a temperature of 4 ° C. was obtained.

Reference Example 79 3-Dimethylaminophenoxymethyloxirane 3-dimethylaminophenol 4.00 g, epibromohydrin 4.5 ml, sodium hydride (55% by weight) 1.53 g and dimethylformamide 50 ml.
Was used for the reaction and post-treatment according to Reference Example 46. The obtained crude product was purified by subjecting it to silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give an Rf value = 0.36 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 4). 4.18 g of the target compound having is obtained.

Reference Example 80 3- (3-Dimethylaminophenoxy) -2-hydroxy
Cypropyl azide 3-dimethylaminophenoxymethyloxirane 1.
0 g, sodium azide 3.25 g, methyl formate 2
When 0 ml and 90 ml of a mixture of methanol: water = 8: 1 were used and the reaction and post-treatment were carried out according to Reference Example 12,
2.34 g of the expected compound having an Rf value = 0.35 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 4) was obtained.

Reference Example 81 3- (3-Dimethylaminophenoxy) -2-hydroxy
Cypropylamine 3- (3-dimethylaminophenoxy) -2-hydroxypropyl azide 2.41 g, lithium aluminum hydride 0.76 g and anhydrous tetrahydrofuran 50
When the reaction and the post-treatment were carried out according to Reference Example 13 using ml, 1.80 g of the target compound having an Rf value = 0.9 (silica gel thin layer chromatography: ethyl acetate: ethanol = 4: 1) was obtained. It was

Reference Example 82 4-phenylphenoxymethyloxirane 4-phenylphenol 4.00 g, epibromohydrin 3.97 g, sodium hydride (55% by weight)
When 1.27 g and 80 ml of anhydrous dimethylformamide were used for the reaction and post-treatment according to Reference Example 46,
Target compound having a melting point of 80.2 ° C to 82.9 ° C
4.43 g was obtained.

Reference Example 83 3- (4-phenylphenoxy) -2-hydroxypro
Pyrazide 4-phenylphenoxymethyloxirane 3.00
g, sodium azide 4.23 g, methyl formate 15 m
The reaction and post-treatment were carried out according to Reference Example 12 using 90 ml of a mixed solution of 1 and methanol: water = 8: 1, and the desired compound having a melting point of 72.2 ° C to 73.9 ° C was obtained.
3.09 g was obtained.

Reference Example 84 3- (4-phenylphenoxy) -2-hydroxypro
Pyramine 3- (4-phenylphenoxy) -2-hydroxypropyl azide 2.94 g, 10% palladium-carbon
Hydrogen was bubbled through a mixture of 0.3 g and 60 ml of ethanol for 3 hours. The insoluble matter is filtered off, the filtrate is concentrated and the melting point is 1
Target compound having 37.7 ° C to 146.8 ° C
2.84 g was obtained.

[0506] Reference Example 85 phenylthiomethyl oxirane epibromohydrin 6 ml, sodium hydroxide 5.
A solution of thiophenol 5.0 g in 1,4-dioxane in a mixture of 45 g and 1,4-dioxane 30 ml.
30 ml was added dropwise at room temperature, and the mixture was stirred at room temperature for 36 hours. After completion of the reaction, insoluble solid matter was removed by filtration, and then 1, 4 was collected from the filtrate.
-Dioxane was distilled off, 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. Ethyl acetate was distilled off from the extract, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to give Rf value = 0.60 (silica gel thin layer chromatography). 6.78 g of the target compound was obtained as a colorless oil having ethyl acetate: n-hexane = 1: 10).

Reference Example 86 3-Phenylthio-2-hydroxypropylazido Phenylthiomethyloxirane 7.2 g, sodium azide 14 g, methyl formate 65 ml and methanol-water (8: 1) 270 ml were used according to Reference Example 12. After reaction and work-up, the colorless oily target compound with Rf value = 0.23 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 10).
8.33 g was obtained.

Reference Example 87 3-phenylthio-2-hydroxypropylamine 3-phenylthio-2-hydroxypropyl azide 8
g, lithium aluminum hydride (2.9 g) and anhydrous tetrahydrofuran (400 ml), and used in Reference Example 13
When the reaction and post-treatment were carried out according to (1), 6.8 g of the desired compound having a melting point of 57 ° C. to 61 ° C. was obtained.

Reference Example 88 N-methyl-N-phenylaminomethyloxirane N-methylaniline 5 g, epibromohydrin 7.
65 ml, sodium hydride (55% by weight) 2.44
g and 100 ml of anhydrous dimethylformamide, the reaction and post-treatment were carried out according to Reference Example 46 to give R
f value = 0.33 (silica gel thin layer chromatography;
1.67 g of the target compound are obtained as a pale yellow oil having ethyl acetate: n-hexane = 1: 10).

Reference Example 89 3- (N-methyl-N-phenylamino) -2-hydro
Xypropyl azide N-methyl-N-phenylaminomethyl oxirane
1.65 g, sodium azide 3.29 g, methyl formate 15 ml and methanol: water (8: 1) 63 ml
When the reaction and the post-treatment are carried out in accordance with Reference Example 12 using the above compound, a pale yellow oily target compound having an Rf value = 0.09 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 15). 0.9 g was obtained.

Reference Example 90 3- (N-methyl-N-phenylamino) -2-hydro
Propyl amine 3- (N- methyl -N- phenylamino) -2-hydroxypropyl azide 1.85 g, 10% palladium - hydrogen was introduced for 1.5 hours to a mixture of carbon 0.9g and ethanol 30 ml. After purging with nitrogen, 10% palladium-carbon catalyst was filtered off from the reaction mixture, and the filtrate was concentrated to obtain 1.6 g of the objective compound which decomposes at 136 ° C.

Reference Example 91 3-chlorobenzyloxymethyloxirane 3-chlorobenzyl alcohol 5.00 g, sodium hydride (55% by weight) 1.83 g, epibromohydrin 3.45 ml and anhydrous dimethylformamide.
The reaction and post-treatment were carried out according to Reference Example 46 using 60 ml to give 5.45 g of the desired compound having an Rf value = 0.31 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 6). It was

Reference Example 92 3- (3-chlorobenzyloxy) -2-hydroxyp
Ropyrazide 3-chlorobenzyloxymethyloxirane 4.73
g, sodium azide 7.80 g, methyl formate 24 m
l, methanol: water = 8: 1 mixed solution (135 ml) and water (10 ml) were used to carry out the reaction and post-treatment according to Reference Example 12, and Rf value = 0.29 (silica gel thin layer chromatography; ethyl acetate: hexane =) 5.74 g of the target compound having 1: 4) are obtained.

Reference Example 93 3- (3-chlorobenzyloxy) -2-hydroxyp
Ropyramine 3- (3-chlorobenzyloxy) -2-hydroxypropyl azide 6.22 g, lithium aluminum hydride 1.97 g and anhydrous tetrahydrofuran 120 m
When 1 was used and the reaction and post-treatment were carried out according to Reference Example 13, 3.37 g of the desired compound having an Rf value of 0.03 (silica gel thin layer chromatography; ethyl acetate) was obtained.

Reference Example 94 5- [4- (2-oxobutyloxy) benzyl] -3
-Triphenylmethylthiazolidine- 2,4-dione 1-bromo-2-butanone 7.37 ml, 5- (4-
Hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 20.0 g, cesium carbonate
A mixture of 21.18 g and 200 ml of anhydrous acetone was stirred at room temperature for 3 hours. Acetone was distilled off under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off, and the residue was recrystallized with a mixed solvent of ethyl acetate, ethyl ether and isopropyl ether to obtain 19.36 g of the desired compound having a melting point of 155.2 ° C to 156.4 ° C.

Reference Example 95 5- [4- (2-oxobutyloxy) benzyl] thia
Zolidine-2,4-dione 5- [4- (2- oxobutyloxy ) benzyl] -3
-Triphenylmethylthiazolidine-2,4-dione
50 ml of trifluoroacetic acid was added to a solution of 19.3 g of dichloromethane in 100 ml, the mixture was stirred at room temperature for 1.5 hours, and concentrated under reduced pressure. Water was added to the residue and the mixture was neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, the extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 2) and then recrystallized from a mixed solvent of ethyl acetate and isopropyl ether to give a melting point of 141.5 ° C. 145.7 ° C
9.55 g of the target compound having

Reference Example 96 2- [5- (3-chlorophenoxymethyl) -2-oxy
Soxazolidin-3-yl] pentanoic acid ethyl sodium hydride (55% by weight) 1.35 g, 5-
(3-Chlorophenoxymethyl) -oxazolidine-2
-One 6.00 g, anhydrous dimethylformamide 100
The reaction and post-treatment were carried out according to Reference Example 4 using ml and ethyl 2-bromovalerate (6.48 g). When the obtained crude product was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 3), diastereomers were obtained by separation into polar and less polar. 4.5 g of the target compound having an Rf value of 0.58 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 1) from polar, and the target compound having a melting point of 43 ° C. to 49 ° C. from less polar 4 0.47 g was obtained.

Reference Example 97 2- [5- (3-chlorophenoxymethyl) -2-oxy
Sooxazolidin-3-yl] pentanol (a) 2- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-, obtained in Reference Example 96
Il] ethyl pentanoate less polar 4.38
g, anhydrous tetrahydrofuran 40 ml, lithium borohydride 0.39 g and anhydrous methanol 0.29 g
And the reaction and post-treatment according to Reference Example 5,
From the less polar, 2.22 g of the desired compound having a melting point of 79 ° C to 81 ° C was obtained.

(B) 2- [5- obtained in Reference Example 96
Ethyl (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] pentanoate polar 4.
31 g, anhydrous tetrahydrofuran 40 ml, lithium borohydride 0.42 g and anhydrous methanol 0.
When 31 g was used and the reaction and post-treatment were carried out according to Reference Example 5, 2.03 g of the desired compound having a melting point of 98 ° C. to 102 ° C. was obtained from polar.

Reference Example 98 5- {4- [2- (5- (3-chlorophenoxymethyi
Ru) -2-oxooxazolidin-3-yl) pentoki
Cy] benzyl} -3-triphenylmethylthiazolidine
-2,4-dione (a) 2- [5- (3- obtained in Reference Example 97 (a)
Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] pentanol less polar 1.
00g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 1.07
g, triphenylphosphine 0.74 g, diethyl azodicarboxylate 0.49 g and anhydrous tetrahydrofuran 30 ml were used and the reaction and post-treatment were carried out according to Reference Example 6, Rf value = 0.6 from the less polar.
(Silica gel thin layer chromatography; ethyl acetate: n
-1.58 g of the target compound having -hexane = 1: 1)
was gotten.

(B) 2-obtained in Reference Example 97 (b)
[5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] pentanol polar
1.00 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 0.
When 88 g, triphenylphosphine 0.73 g, anhydrous tetrahydrofuran 30 ml and diethyl azodicarboxylate 0.49 g were used and the reaction and post-treatment were carried out according to Reference Example 6, Rf value = 0.57 from polar.
(Silica gel thin layer chromatography; ethyl acetate: n
1.22 g of the target compound with -hexane = 1: 1)
was gotten.

Reference Example 99 2- [5- (3-chlorophenoxymethyl) -2-oxy
Sooxazolidin-3-yl] -3-methylbutanoic acid
Sodium chill hydride (55 wt%) 0.92 g, anhydrous dimethylformamide 80 ml, 5-a (3-chloro-phenoxymethyl) oxazolidin-2-one 4.10g and 2-bromoisobutyrate methyl 4.16g using Reference Example 4 Reaction and post-treatment were carried out according to. The obtained crude product was purified by subjecting it to silica gel column chromatography (ethyl acetate: n-hexane = 1: 3 → 1: 2) to obtain Rf value = 0.39 from polar (silica gel thin layer chromatography; acetic acid. Ethyl: n-hexane = 1:
1.05 g of the target compound having 1)
1.23 g of the target compound having Rf value = 0.48 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 1) was obtained from lar.

Reference Example 100 2- [5- (3-chlorophenoxymethyl) -2-oxy
Sooxazolidin-3-yl] -3-methylbutanol (a) 2- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-, obtained in Reference Example 99
Ill] -3-methylbutanoic acid methyl lesspola
r 1.14 g, lithium borohydride 144 mg,
When 12 ml of anhydrous tetrahydrofuran and 105 mg of anhydrous methanol were used to carry out the reaction and post-treatment according to Reference Example 5, Rf value = 0.
Target compound having 26 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 1).
02 g were obtained.

(B) 2- [5- obtained in Reference Example 99
Methyl (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] -3-methylbutanoate pol
ar 0.93 g, lithium borohydride 118 mg,
When 10 ml of anhydrous tetrahydrofuran and 87 mg of anhydrous methanol were used and the reaction and post-treatment were performed according to Reference Example 5, Rf value = 0.48 from polar (silica gel thin layer chromatography; ethyl acetate: n-hexane = 2: 1). 0.47 g of the target compound having is obtained.

Reference Example 101 5- {4- [2- (5- (3-chlorophenoxymethyi
) -2-oxooxazolidin-3-yl) -3-me
Tylbutoxy] benzyl} -3-triphenylmethylthio
Azolidine-2,4-dione (a) 2- [5- (3 obtained in Reference Example 100 (a)
-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] -3-methylbutanol less po
lar 800 mg, triphenylphosphine 656
mg, anhydrous tetrahydrofuran 20 ml, 5- (4-
Hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione (791 mg) and diethyl azodicarboxylate (435 mg) were used to carry out the reaction and post-treatment according to Reference Example 6 to give a melting point of 60 ° C to 66 ° C from a less polar. Target compound having 0.92
g was obtained.

(B) 2 obtained in Reference Example 100 (b)
-[5- (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] -3-methylbutanol p
olar 0.90 g, triphenylphosphine 0.
76 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 0.88
g, anhydrous tetrahydrofuran (20 ml) and diethyl azodicarboxylate (0.49 g) were used and the reaction and post-treatment were carried out in accordance with Reference Example 6 to obtain an Rf value of polar =
Target compound having 0.55 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 1)
1.22 g was obtained.

Reference Example 102 2-benzyloxycarbonylamino-2-methylpro
Panol 2-amino-2-methylpropanol 7.00 g, carbobenzyloxy chloride 13.47 g, potassium carbonate 13.13 g, ethyl acetate 35 ml and water.
When the reaction and post-treatment were carried out according to Reference Example 7 using 35 ml, 17.59 g of the desired compound having an Rf value = 0.72 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 3: 1) was obtained. Was obtained.

Reference Example 103 N-2-t-butyldimethylsilyloxy-1,1-di
Methylethyl- O-benzylcarbamate 2-benzyloxycarbonylamino-2-methylpropanol 10.00 g, imidazole 7.35 g,
When 150 ml of anhydrous dimethylformamide and 8.14 g of t-butyldimethylsilyl chloride were used for the reaction and post-treatment according to Reference Example 8, Rf value = 0.7.
3 (silica gel thin layer chromatography; ethyl acetate:
Target compound having n-hexane = 1: 4) 14.6
8 g were obtained.

Reference Example 104 2-t-butyldimethylsilyloxy-1,1-dimethyl
Ruethylamine N-2-t-butyldimethylsilyloxy-1,1-dimethylethyl-O-benzylcarbamate 8.00
g, 10% palladium-carbon 1.60 g, and ethanol 80 ml, the reaction and post-treatment were carried out according to Reference Example 9 to obtain the target compound having Rf value = 0.14 (silica gel thin layer chromatography; ethyl acetate).
4.02 g was obtained.

Reference Example 105 1- (3-chlorophenoxymethyl) -2- (2-t-
Butyldimethylsilyloxy-1,1-dimethylethyl
Amino) ethanol 2-t-butyldimethylsilyloxy-1,1-dimethylethylamine 3.36 g, 3-chlorophenoxymethyloxirane 3.05 g and ethanol 30 ml.
Was subjected to the reaction and post-treatment according to Reference Example 10 to give 4.54 g of the desired compound having a melting point of 70.5 ° C to 77.3 ° C.

Reference Example 106 3- (2-t-butyldimethylsilyloxy-1,1-
Dimethylethyl) -5- (3-chlorophenoxymethyi)
) Oxazolidin-2-one 1- (3-chlorophenoxymethyl) -2- (2-t-
When butyldimethylsilyloxy-1,1-dimethylethylamino) ethanol (5.13 g), anhydrous dimethylformamide (50 ml) and N, N′-carbonyldiimidazole (2.59 g) were used and the reaction and post-treatment were carried out according to Reference Example 11. , Rf value = 0.33 (silica gel thin layer chromatography; ethyl acetate: n-hexane =
5.27 g of the target compound having 1: 4) are obtained.

Reference Example 107 5- (3-chlorophenoxymethyl) -3- (2-hydr)
Roxy-1,1-dimethylethyl) oxazolidine-2
-One 3- (2-t-butyldimethylsilyloxy-1,1-
Dimethylethyl) -5- (3-chlorophenoxymethyl) oxazolidin-2-one (3.84 g) in acetonitrile (40 ml) was added dropwise with 5% hydrogen fluoride in acetonitrile (7 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure to give 2.71 g of the desired compound having a melting point of 81 ° C to 82 ° C.
was gotten.

Reference Example 108 5- (3-chlorophenoxymethyl) -3- [2- (4
-Nitrophenoxy) -1,1-dimethylethyl] oxy
Sazolidin-2-one 5- (3-chlorophenoxymethyl) -3- (2-hydroxy-1,1-dimethylethyl) oxazolidine-2
200 mg of 4-one and 288 mg of 4-fluoronitrobenzene were dissolved in 5 ml of dimethylformamide, and sodium hydride (55% by weight) 35 m was obtained under ice cooling.
g was added in three times, and the mixture was stirred at the same temperature for 30 minutes. After stirring at room temperature for 7 hours, the solvent 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 further washed with brine and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off from the extract, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 3) to give the target compound 2 having a melting point of 108 ° C to 112 ° C.
62 mg was obtained.

Reference Example 109 3- [2- (4-aminophenoxy) -1,1-dimethyi]
Ruethyl] -5- (3-chlorophenoxymethyl) oxy
Sazolidin-2-one 5- (3-chlorophenoxymethyl) -3- [2- (4
-Nitrophenoxy) -1,1-dimethylethyl] oxazolidin-2-one 2.34 g of ethyl acetate: t-
Stannous chloride in 70 ml of butanol (9: 1) solution
6.32 g of dihydrate was added, 0.11 g of sodium borohydride was further added on an oil bath at 66 ° C., and the mixture was stirred at the same temperature for 6 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure, an aqueous sodium bicarbonate solution was added to the residue for neutralization, the precipitated insoluble matter was filtered, and the filtrate was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. When ethyl acetate was distilled off from the extract,
1.96 g of the expected compound having an Rf value = 0.34 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 4: 1) were obtained.

Reference Example 110 2-Bromo-3- {4- [2- (5- (3-chlorophene
Nonoxymethyl) -2-oxooxazolidin-3-i
) -2-Methylpropoxy] phenyl} propionic acid
n-Butyl 3- [2- (4-aminophenoxy) -1,1-dimethylethyl] -5- (3-chlorophenoxymethyl) oxazolidin-2-one 2.20 g acetone solution 2
47% aqueous hydrogen bromide solution (4.82 g) under ice-cooling to 5 ml.
Was added dropwise, and then 2 ml of an aqueous solution of 462 mg of sodium nitrite was added dropwise. After stirring for 15 minutes at the same temperature, 7.18 g of n-butyl acrylate was added, and 157 mg of cuprous oxide was further added at room temperature. After stirring at room temperature for 2.5 hours, the solvent was distilled off from the reaction mixture under reduced pressure, an aqueous sodium bicarbonate solution was added to the residue for neutralization, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract,
The obtained residue was purified by subjecting it to silica gel column chromatography (ethyl acetate: n-hexane = 1: 3 → 1: 1) to give an Rf value = 0.44 (silica gel thin layer chromatography; ethyl acetate: n-). Hexane = 1: 2)
2.24 g of the target compound having

Reference Example 111 5- {4- [2- (5- (3-chlorophenoxymethyi
) -2-oxooxazolidin-3-yl) -2-me
Cylpropoxy] benzyl} thiazolidine-2-imino
-4-one 2-bromo-3- {4- [2- (5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl) -2-methylpropoxy] phenyl} propionate n-butyl 2 30 ml of methanol solution of 0.07 g
To the above, add 0.5 g of thiourea and add sodium acetate.
0.49g was added. After heating under reflux for 5 hours, the solvent was distilled off from the reaction mixture under reduced pressure, saturated brine was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and ethyl acetate was distilled off. The obtained residue was purified by subjecting it to silica gel column chromatography (ethyl acetate: tetrahydrofuran = 1: 0 → 3: 1).
1.50 g of a mixture of the target compound with an Rf value = 0.19 (silica gel thin layer chromatography; ethyl acetate) and thiourea were obtained.

Reference Example 112 5-phenoxymethyloxazolidin-2-one 3-phenoxy-2-hydroxypropylamine 50
A solution of 0 mg of anhydrous dimethylformamide in 5 ml of N, N'-carbonyldiimidazole (422 mg) under ice cooling.
And stirred at room temperature overnight. After completion of the reaction, the solvent was concentrated from the reaction mixture under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract,
The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give 490 mg of the target compound having a melting point of 110 ° C to 111 ° C.

Reference Example 113 3- (5-phenoxymethyl-2-oxooxazolidi
(N-3-yl) ethyl propionate sodium hydride (55% by weight) 113 mg, anhydrous dimethylformamide 10 ml, 5-phenoxymethyloxazolidin-2-one 420 mg and ethyl 3-bromopropionate 471 mg were used according to Reference Example 4. After the reaction and post-treatment, 463 mg of the desired compound having an Rf value of 0.34 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 2: 1) was obtained.

Reference Example 114 3- (5-phenoxymethyl-2-oxooxazolidi
(N-3-yl) propanol Ethyl 3- (5-phenoxymethyl-2-oxooxazolidin-3-yl) propionate (1.64 g), anhydrous tetrahydrofuran (15 ml), lithium borohydride (244 mg) and anhydrous methanol (179 mg) were used, and Reference Example 5 was used. When the reaction and post-treatment were carried out according to (a), 1.41 g of the desired compound having an Rf value = 0.28 (silica gel thin layer chromatography; ethyl acetate) was obtained.

Reference Example 115 5- {4- [3- (5-phenoxymethyl-2-oxo
Oxazolidin-3-yl) propoxy] benzyl}-
3 triphenylmethyl-2,4-dione tri -n- butyl phosphine 1.29 g, anhydrous benzene 30ml, 5- (4- hydroxybenzyl) -3-
Triphenylmethyl thiazolidine-2,4-dione
2.98 g, azodicarbonyldipiperidine 1.61
g and 3- (5-phenoxymethyl-2-oxooxazolidin-3-yl) propanol 1.33 g, the reaction and post-treatment according to Reference Example 6 were carried out to give the target compound having a melting point of 70 ° C. to 73 ° C. 2.04 g was obtained.

Reference Example 116 4- [5- (3-chlorophenoxymethyl) -2-oxy
Soxazolidin-3-yl] butyric acid ethyl sodium hydride (55% by weight) 0.52 g, anhydrous dimethylformamide 30 ml, 5- (3-chlorophenoxymethyl) oxazolidin-2-one 2.00 g and ethyl 4-bromobutyrate 2 Using .34 g, Reference Example 4
When the reaction and post-treatment are carried out according to, Rf value = 0.39
(Silica gel thin layer chromatography; ethyl acetate: n
1.50 g of the target compound with -hexane = 2: 1)
was gotten.

Reference Example 117 4- [5- (3-chlorophenoxymethyl) -2-oxy
Soxazolidin-3-yl] butanol Ethyl 4- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] butyrate 1.43
g, sodium borohydride 183 mg, anhydrous tetrahydrofuran 20 ml and anhydrous methanol 135
By using mg and performing the reaction and post-treatment according to Reference Example 5, 1.26 g of the desired compound having an Rf value = 0.31 (silica gel thin layer chromatography; ethyl acetate) was obtained.

Reference Example 118 5- {4- [4- (5- (3-chlorophenoxymethyi
Ru) -2-oxooxazolidin-3-yl) butoki
Cy] benzyl} -3-triphenylmethylthiazolidine
2,4-dione tri -n- butyl phosphine 647 mg, anhydrous benzene 20ml, 5- (4- hydroxybenzyl) -3-
Triphenylmethyl thiazolidine-2,4-dione
1.49 g, azodicarbonyldipiperidine 807 m
g and 4- [5- (3-chlorophenoxymethyl)-
2-oxooxazolidin-3-yl] butanol 8
The target compound having a melting point of 68 ° C to 72 ° C was obtained by the reaction and post-treatment according to Reference Example 6 using 00 mg.
1.49 g was obtained.

Reference Example 119 2-Chloroacetylamino-1- (3-chlorophenoxy)
Dimethyl) ethanol 3- (3-chlorophenoxy) -2-hydroxypropylamine 300 mg anhydrous tetrahydrofuran solution
To 4 ml, 1 ml of an anhydrous tetrahydrofuran solution containing 0.24 ml of triethylamine was added under ice cooling, and 1 ml of an anhydrous tetrahydrofuran solution containing 192 mg of chloroacetyl chloride was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate: n-
Purification by subjecting to hexane = 3: 2) gave 310 mg of the desired compound having a melting point of 74 ° C to 77 ° C.

Reference Example 120 2- [6- (3-chlorophenoxymethyl) -3-oxy
Sodium morpholin-4-yl] ethyl propionate sodium hydride (55% by weight) To 2.49 g of dimethylformamide solution 170 ml, 2-chloroacetylamino-1- (3-chlorophenoxymethyl) ethanol 5.50 g of dimethylformamide solution 110 ml
Was added dropwise on an oil bath at 65 ° C. Reaction mixture at the same temperature 1
After stirring for an hour, 5.25 g of ethyl 2-bromopropionate was added dropwise to the reaction mixture under ice cooling, and the mixture was stirred for 1 day. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 → 3: 2) to give Rf value =
4.23 g of the target compound having 0.39 (silica gel thin layer chromatography; ethyl acetate) are obtained.

Reference Example 121 2- [2- (3-chlorophenoxymethyl) morpholyl
No] propanol 0.51 g of lithium aluminum hydride 20 ml of anhydrous tetrahydrofuran suspension was added to 2- [6-
10 ml of an anhydrous tetrahydrofuran solution containing 1.50 g of ethyl (3-chlorophenoxymethyl) -3-oxomorpholin-4-yl] propionate was added dropwise. After stirring at room temperature for 2.5 hours, excess lithium aluminum hydride was decomposed by adding sodium sulfate decahydrate. After completion of the reaction, insoluble matter was filtered from the reaction mixture through Celite, and the solvent was distilled off from the filtrate under reduced pressure to give Rf value = 0.19 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 3: 1). 0.97 g of the target compound having is obtained.

Reference Example 122 5- {4- [2- (2- (3-chlorophenoxymethyi
Le) morpholino) propoxy] benzyl} -3-trif
Phenylmethylthiazolidine-2,4-dionetriphenylphosphine 1.21 g, anhydrous tetrahydrofuran 20 ml, 5- (4-hydroxybenzyl)
-3-Triphenylmethylthiazolidine-2,4-dione 1.77 g, diethyl azodicarboxylate 0.81
g and 2- [2- (3-chlorophenoxymethyl) morpholino] propanol 1.32 g were used, and Reference Example 6 was used.
When the reaction and post-treatment were carried out according to (1), 1.32 g of the desired compound having a melting point of 48 ° C. to 53 ° C. was obtained.

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 a glucose analyzer (GL-101, Mitsubishi Chemical Corporation) was used.
Blood glucose level was measured with a Gluco loader (manufactured by Shino Test 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.

[0549]

[Table 29] Table 8 ───────────────────────────────── Manufacturing Example No. Dose (mg / kg) Blood glucose Descent rate (%) ───────────────────────────────── 1 1 28.5 6 1 19.2 7 1 36.3 11 1 24.3 13 1 29.9 15 1 19.1 18 1 10.5 19 1 15.8 20 1 37.9 22 1 14.3 28 1 13.6 29 1 18.1 31 ( less polar) 1 21.6 35 1 13.5 36 (polar) 1 13.7 41 1 1 18.2 45 (polar) 1 23.9 45 (less polar) 1 27.2 47 (polar) 1 34.7 50 (less polar) 1 17.5 51 (polar) 1 20.8 ────────────────────────────────── From Table 8 the compounds of the present invention are excellent It showed the blood sugar effect.

Example 2. Aldose reductase inhibitory action S. Hyman and JH are aldose reductases of bovine lens.
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 Table 9.

[0552]

[Table 30] Table 9 ───────────────────────────────── Manufacturing Example No. IC ₅₀ inhibition at a concentration of 5 μg / ml Rate (%) (μg / ml) ────────────────────────────────── 1 89.6 0.11 2 63.2 2.8 4 84.5 1.1 8 67.2 2.2 10 (less polar) 60.1
2.0 10 (polar) 88.3 0.40 16 59.2 3.3 19 56.1 3.9 20 69.1 1.8 21 58.7 2.5 22 22 70.1 1.7 23 70 .7 1.6 24 (less polar) 71.7 0.98 25 (less polar) 57.1 2.0 25 (polar) 82.0 0.22 26 74.2 0.55 27 54.9 1. 9 30 68.6 1.8 31 (less polar) 67.8 1.9 31 (polar) 88.1 0.42 32 54.6 2.9 33 85.5 0.32 34 62.0 1.9 37 55.2 3.9 38 80.1 0.71 40 80.9 0.87 41 57.4 3.2 42 74.0 0.95 43 65.9 0.61 46 61 2.9 47 (less polar) 57.6 1.6 47 (polar) 86.6 0.23 49 77.8 0.49 50 ──── 0.32 5 2 72.8 0.94 53 77.6 1.1 54 69.1 1.0 55 62.7 1.4 ──────────────────────── ─────────── Example 3. Toxicity test Male F344 rats were used as experimental animals. Five groups were used for the experiment. 50 mg / test compound for each animal
The body weight of ml was orally administered for 2 weeks. The test compounds used were Production Examples 20 and 45 (polar, less po).
lar) and 47 (polar). Animals were observed for two weeks after dosing. During that period, no abnormality due to the test compound was observed. In hematological examination, le obtained in Production Example 45 was used.
There was only a slight decrease in red blood cells, which was probably due to ss polar. In terms of the effective dose for each animal, a mortality of 0 indicates that the compound of the invention is very toxic.

[0553]

The drug containing the aromatic compound of the present invention as an active ingredient is hyperlipidemia, hyperglycemia, gestational diabetes, obesity, glucose intolerance, insulin resistance, diabetic complications, arteriosclerosis. It also improves polycystic ovary syndrome and has an aldose reductase inhibitory action. Thus, for example, hyperlipidemia, hyperglycemia, obesity, glucose intolerance, insulin resistance non-glucose intolerance, hypertension, osteoporosis, cachexia,
It is useful as a preventive and / or therapeutic drug for fatty liver, diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.), arteriosclerosis, etc. It is useful as a preventive and / or therapeutic agent for diseases caused by insulin resistance such as diabetes and polycystic ovary disease.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/535 ABX A61K 31/535 ABX 31/54 ABU 31/54 ABU C07D 263/44 ACV C07D 263/44 ACV 271/06 271/06 413/12 213 413/12 213 263 263 473 417/12 213 417/12 213 263 263 265 265 265 417/14 213 417/14 213 419/12 419/12 // C07C 275/64 9451- 4H C07C 275/64 (C07D 413/12 263: 44 265: 28) (C07D 413/12 213: 77 263: 44) (C07D 417/12 263: 20 277: 34) (C07D 417/12 263: 16 277) : 34) (C07D 417/12 265: 28 277: 34) (C07D 417/12 213: 77 277: 34) (C07D 417/12 213: 70 277: 34) (C07D 417/14 213: 77 263: 20) 277: 34) (C07D 417/14 213: 77 263: 16 277: 34) (C07D 417/14 213: 77 265: 28 277: 34) (C07D 419/12 277: 34 291: 04) (C07D 419 / 12 277: 34 291: 06) (C07D 419/12 271 : 06 291: 06) (72) Inventor Hiroaki Yanagisawa 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Toshihiko Fujiwara 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo In stock company (72) Inventor Hokoshi Ono Sankyo 1-25-258, Shinagawa-ku, Tokyo Sankyo Stock company (72) Inventor Minoru Oguchi 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo In stock company (72) Inventor Kunio Wada 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock company

Claims (45)

[Claims] 1. A compound of the general formula (I) A pharmaceutical containing an aromatic compound having the formula (1), a pharmaceutically acceptable salt thereof or an ester thereof as an active ingredient. However, in the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms. Alternatively, R ¹ and R ² together represent a group — (CH ₂ ) _k — (wherein k represents an integer of 2 to 6). R ³ is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, 1 carbon atom
A linear or branched alkoxy group having 4 to 4, a halogen atom or a hydroxy group. A and B are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, an aralkyl group having 7 to 11 carbon atoms, or 1 to 11 carbon atoms. Having a linear or branched aliphatic acyl group, an araliphatic acyl group having 8 to 12 carbon atoms, an aromatic acyl group having 7 to 11 carbon atoms, a carbamoyl group or a total of 2 carbon atoms A substituted carbamoyl group having from 1 to 12 is shown. Alternatively, A and B together are Is shown. X is the formula ^{_{W- (CH 2) m -X 1}} - [ In the formula, W is C 6 -C may have to 1 I identical or different five substituents described below (a) An aryl group having 10; 5 to 6 containing 1 to 3 oxygen, sulfur or / and nitrogen atoms, which may be the same or different and may have 1 to 4 of the following substituents (a) A membered-ring unsaturated heterocyclic group containing 1 to 3 oxygen, sulfur or / and nitrogen atoms which may be the same or different and may have 1 to 4 of the following substituents (a) 5
To 6-membered ring saturated heterocyclic group or a condensation containing 1 to 3 oxygen, sulfur or / and nitrogen atoms which may be the same or different and may have 1 to 4 of the following substituents (a): Indicates a heterocyclic group. X ¹ is a bond, an oxygen atom, a sulfur atom or a group (In the formula, R ⁴ is a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, an aralkyl group having 7 to 11 carbon atoms or 6 to 10 carbon atoms.
Is shown having an aryl group. ). m represents an integer of 0 to 8. Here, as the above-mentioned substituent (a), 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 straight-chain or branched haloalkyl group having 1 to 4 carbon atoms, a halogen atom, a phenyl group, a hydroxy group, a nitro group or an amino group optionally having 1 or 2 substituents (b). (The substituent (b) is a linear or branched alkyl group having 1 to 8 carbon atoms, an aralkyl group having 7 to 11 carbon atoms, 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 .) ]. Y represents a formula — (CH ₂ ) _n —Y ¹ — (wherein, Y ¹ represents a bond, an oxygen atom or a sulfur atom. N is 1
Is an integer from 5 to 5. ). Z is (In the group, R ⁵ is a hydrogen atom, a linear or branched carboxyalkyl group having 2 to 5 carbon atoms, a linear or branched alkanoyloxy group having 2 to 12 carbon atoms. Alkyl group, cycloalkyl-containing linear or branched alkanoyloxyalkyl group having 6 to 12 carbon atoms, 5 to 17 carbon atoms
A straight-chain or branched-chain cycloalkylcarbonyloxyalkyl group having 3 carbon atoms, a straight-chain or branched-chain alkoxycarbonyloxyalkyl group having 3 to 17 carbon atoms, and a 6-carbon group having cycloalkyl A linear or branched alkoxycarbonyloxyalkyl group having 17 or 5 to 17 carbon atoms
Represents a linear or branched cycloalkyloxycarbonyloxyalkyl group having 1 or 2. ), Embedded image Is shown. 2. The method according to claim 1, wherein R ¹ and R ^{2 are}
Are the same or different and each is a hydrogen atom or has 1 to 6 carbon atoms.
A pharmaceutical comprising an aromatic compound, which is a linear or branched alkyl group having 1 or more, a pharmacologically acceptable salt thereof or an ester thereof, as an active ingredient. 3. In [Claim 1], R ³ is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a methoxy group, an ethoxy group, a propoxy group or a halogen atom. A pharmaceutical containing an aromatic compound, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient. 4. The method according to claim 1, wherein A and B are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and 1 to 6 carbon atoms. Has an aliphatic acyl group or a carbamoyl group, or A and B together form a group -C (= O)
-, group -C (= S) -, group _{-CH 2 C (= O) -} , group -
A pharmaceutical composition comprising an aromatic compound of CH ₂ CH ₂ — or a group —SO ₂ —, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient. 5. In [claim 1], W is the same or different and is an aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents (a), and X is
¹ is a bond, oxygen atom, sulfur atom or formula -NR ⁴ '-
(In the formula, R ⁴ 'represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.)
Wherein m is an integer of 0 to 8, and a pharmaceutical agent containing a pharmacologically acceptable salt or ester thereof as an active ingredient. 6. In [Claim 1], Z is Which is an aromatic compound, a pharmaceutically acceptable salt thereof or an ester thereof as an active ingredient. 7. The method according to claim 1, wherein R ¹ and R ^{2 are}
Are the same or different and each is a hydrogen atom or has 1 to 6 carbon atoms.
A straight-chain or branched alkyl group having 1 to 4, R ³ is a hydrogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a methoxy group, an ethoxy group, and propoxy. Group or halogen atom, A and B being the same or different and having 1 to 4 carbon atoms, straight-chain or branched-chain alkyl group, straight-chain or branched chain having 1 to 6 carbon atoms A linear acyl acyl group or a carbamoyl group, or A and B together form a group -C (= O)-, a group -C (= S)-, a group -C.
_{H 2 C (= O) -} , group -CH ₂ CH ₂ - or a group -S
O ₂ —, W is the same or different and is an aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents (a), and X ¹ is a bond or an oxygen atom. ,
Sulfur atom or the formula -NR ⁴ '- (. Wherein, R ^4' is from 1 number hydrogen atom or a carbon a linear or branched alkyl group having 4), and, Z is embedded 7] Which is an aromatic compound, a pharmaceutically acceptable salt thereof or an ester thereof as an active ingredient. 8. The method according to claim 1, wherein R ¹ and R ^{2 are}
Are the same or different and each is a hydrogen atom or has 1 to 4 carbon atoms.
A pharmaceutical comprising an aromatic compound, which is a linear or branched alkyl group having 1 or more, a pharmacologically acceptable salt thereof or an ester thereof, as an active ingredient. 9. The aromatic compound of claim 1, wherein R ³ is a hydrogen atom, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom, a pharmacologically acceptable salt thereof, or a salt thereof. A drug containing an ester as an active ingredient. 10. In [claim 1], A and B are the same or different and each is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an acetyl group, a propionyl group, a butyryl group or a carbamoyl group, or A and B B together based -C (= O) -, group -C (= S) - or a group -CH ₂ CH ₂ - in which an aromatic compound, an active ingredient a pharmacologically acceptable salt or ester thereof Contained as a medicine. 11. The [claim 1], wherein W is the same or different and is a phenyl group optionally having 1 to 3 substituents (a), and X ¹ is a bond, an oxygen atom or sulfur. Or an —NR ⁴ ″ — (wherein R ⁴ ″ represents a hydrogen atom, a methyl group, an ethyl group or a propyl group) and m is an integer of 0 to 6, and its pharmacology. A medicament containing the above-accepted salt or its ester as an active ingredient. 12. A pharmaceutical composition containing an aromatic compound, wherein Y ¹ is an oxygen atom or a sulfur atom, a pharmacologically acceptable salt thereof or an ester thereof according to [claim 1] as an active ingredient. 13. In [Claim 1], Z is Which is an aromatic compound, a pharmaceutically acceptable salt thereof or an ester thereof as an active ingredient. 14. The method according to claim 1, wherein R ¹ and R
² is the same or different and is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R ³ is a hydrogen atom, a methyl group, an ethyl group, a methoxy group, an ethoxy group, or fluorine. Atom or chlorine atom, A
And B are the same or different and are a hydrogen atom, a methyl group, an ethyl group, a propyl group, an acetyl group, a propionyl group, a butyryl group or a carbamoyl group, or A and B are taken together to form a group -C (= O). -, Group -C (=
S) - or a group -CH ₂ CH ₂ - and is, W is the same or different one to three substituents (phenyl group that may have a a), X ¹ is a bond, an oxygen atom , A sulfur atom or —NR ⁴ ″ — (in the formula, R ⁴ ″ represents a hydrogen atom, a methyl group, an ethyl group or a propyl group), m is an integer of 0 to 6, and Y ¹ is It is an oxygen atom or a sulfur atom, and Z is Which is an aromatic compound, a pharmaceutically acceptable salt thereof or an ester thereof as an active ingredient. 15. The method according to claim 1, wherein R ¹ and R
^An aromatic compound in which ² are both hydrogen atoms or one of which is a hydrogen atom and the other is a linear or branched alkyl group having 1 to 4 carbon atoms; A drug containing a salt or an ester thereof as an active ingredient. 16. A medicine comprising an aromatic compound, a pharmacologically acceptable salt thereof or an ester thereof, wherein R ³ is a hydrogen atom, a methyl group, a methoxy group or a chlorine atom in [claim 1] as an active ingredient. 17. In [Claim 1], A and B are the same or different and each is a hydrogen atom, a methyl group, an ethyl group, an acetyl group, a propionyl group or a carbamoyl group, or A and B are combined. Group -C (= O)
-, group -C (= S) - or a group -CH ₂ CH ₂ - in which aromatic compounds, medicaments containing a pharmacologically acceptable salt or ester thereof as an active ingredient. 18. The phenyl group according to claim 1, wherein W is the same or different and may have 1 to 3 substituents (a ′) (wherein the substituents (a ′) are halogens. An atom, a methyl group, an ethyl group, a hydroxy group, a phenyl group, an amino group, a dimethylamino group, a methoxy group or an ethoxy group), and X ¹ is a bond, an oxygen atom,
Sulfur atom, a group -NH- or a group -N (CH ₃₎ - and is, m is an aromatic compound which is an integer of from 0 6, medicaments containing a pharmacologically acceptable salt or ester thereof as an active ingredient. 19. The aromatic compound according to claim 1, wherein Y ¹ is an oxygen atom or a sulfur atom, and n is an integer of 1 to 3, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient. Pharmaceuticals contained. 20. In [claim 1], Z is Which is an aromatic compound, a pharmaceutically acceptable salt thereof or an ester thereof as an active ingredient. 21. In Claim 1, R ¹ and R
² are both hydrogen atoms, or either is a hydrogen atom, and the other is a linear or branched alkyl group having 1 to 4 carbon atoms, R ³ is a hydrogen atom,
A methyl group, a methoxy group or a chlorine atom, and A and B are the same or different and are a hydrogen atom, a methyl group, an ethyl group, an acetyl group, a propionyl group or a carbamoyl group, or a group in which A and B are taken together -C
(= O) -, group -C (= S) - or a group -CH ₂ CH ₂
And a phenyl group in which W is the same or different and may have 1 to 3 substituents (a ′) (wherein the substituents (a ′) are a halogen atom, a methyl group, an ethyl group, A hydroxy group, a phenyl group, an amino group, a dimethylamino group, a methoxy group or an ethoxy group.)
¹ is a bond, an oxygen atom, a sulfur atom, a group —NH— or a group —N (CH ₃ ) —, m is an integer of 0 to 6, Y ¹ is an oxygen atom or a sulfur atom, and n is Is an integer from 1 to 3 and Z is Which is an aromatic compound, a pharmaceutically acceptable salt thereof or an ester thereof as an active ingredient. 22. In Claim 1, R ¹ and R
^An aromatic compound in which ² are both hydrogen atoms or one of which is a hydrogen atom and the other is a methyl group, an ethyl group, a propyl group or an isopropyl group, a pharmacologically acceptable salt thereof or an ester thereof is an active ingredient. Contained as a medicine. 23. A pharmaceutical composition comprising the aromatic compound of claim 1, wherein R ³ is a hydrogen atom, a methyl group or a chlorine atom, a pharmacologically acceptable salt thereof or an ester thereof, as an active ingredient. 24. In [claim 1] A is a hydrogen atom and B is a hydrogen atom, a methyl group, an ethyl group or an acetyl group, or A and B are taken together.
A pharmaceutical comprising an aromatic compound of group -C (= O)-or group -C (= S)-, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient. 25. In [claim 1], W is a halogenated phenyl group, a phenylphenyl group, a methoxyphenyl group or a phenyl group, X ¹ is an oxygen atom or a sulfur atom, and m is an integer of 0 to 6. Which is an aromatic compound, a pharmaceutically acceptable salt thereof or an ester thereof as an active ingredient. 26. In [claim 1], Y is a group -CH.
₂ -O- or a group -CH ₂ CH ₂ -O- in which aromatic compounds, medicaments containing a pharmacologically acceptable salt or ester thereof as an active ingredient. 27. In [claim 1], R ¹ and R
² are both hydrogen atoms, or either is a hydrogen atom, the other is a methyl group, an ethyl group, a propyl group or an isopropyl group, R ³ is a hydrogen atom, a methyl group or a chlorine atom, and A is A hydrogen atom, B is a hydrogen atom, a methyl group, an ethyl group or an acetyl group, or A and B together are a group -C (= O)-or a group -C (= S)-. , W is a halogenated phenyl group, a phenylphenyl group, a methoxyphenyl group or a phenyl group, X ¹ is an oxygen atom or a sulfur atom, m is an integer of 0 to 6, and Y is a group —CH ₂ —O.
- or a group -CH ₂ CH ₂ -O-, Z is embedded image Which is an aromatic compound, a pharmaceutically acceptable salt thereof or an ester thereof as an active ingredient. 28. In Claim 1, R ¹ and R
A medicament containing as an active ingredient an aromatic compound in which ² are both hydrogen atoms or one of which is a hydrogen atom and the other is a methyl group or an ethyl group, a pharmacologically acceptable salt thereof or an ester thereof. 29. A medicament comprising the aromatic compound of claim 1, wherein R ³ is a hydrogen atom, a pharmacologically acceptable salt thereof or an ester thereof, as an active ingredient. 30. In [claim 1] A is a hydrogen atom and B is a hydrogen atom or a methyl group, or A and B are taken together to form a group -C (= O)-or
A pharmaceutical comprising an aromatic compound of group -C (= S)-, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient. 31. In [claim 1], W is phenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3
An aromatic compound, a methoxyphenyl group, a 4-methoxyphenyl group or a 4-phenylphenyl group, X ¹ is an oxygen atom, and m is an integer of 0 to 6, a pharmacologically acceptable salt thereof or an ester thereof. A medicament containing as an active ingredient. 32. In [claim 1], Y is a group -CH.
A medicament containing an aromatic compound which is _2- O-, a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient. 33. In [claim 1], R ¹ and R
² are both hydrogen atoms, or either is a hydrogen atom and the other is a methyl group or an ethyl group, R ³
Is a hydrogen atom, A is a hydrogen atom, B is a hydrogen atom or a methyl group, or A and B together form a group -C (= O)-or a group -C (= S)-. And W is a phenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group or a 4-phenylphenyl group, X
¹ is an oxygen atom, m is an integer of 0 to 6, and Y
Is a group —CH ₂ —O—, and Z is Which is an aromatic compound, a pharmaceutically acceptable salt thereof or an ester thereof as an active ingredient. 34. In [claim 1], 5- {4- [2- (3-phenyl-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-
2,4-dione, 5- {4- [2- (5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl) ethoxy] benzyl} thiazolidine-2,4-dione, 5- {4 -[2- (5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidine-2,4-dione, 5- {4- [2- (5- (3- Chlorophenoxymethyl) -2-thioxooxazolidin-3-yl) propoxy] benzyl} thiazolidine-2,4-dione, 5- {4- [2- (3- (6-phenylhexyloxy) -2-hydroxypropyl] Amino) propoxy] benzyl} thiazolidine-2,4-dione or 5- {4
-[2- (5- (3-chlorophenoxymethyl) -2-
A medicine containing oxooxazolidin-3-yl) butoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient. 35. Due to insulin resistance, the aromatic compound, pharmacologically acceptable salt or ester thereof according to any one of [claim 1] to [claim 34] is contained as an active ingredient. A therapeutic and / or preventive agent for diseases. 36. A therapeutic agent for hyperglycemia, comprising the aromatic compound according to any one of [1] to [34], a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient, and / Or prophylactic. 37. A therapeutic agent for diabetic complications, which comprises the aromatic compound according to any one of [1] to [34], a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient, and / Or prophylactic. 38. A therapeutic agent for arteriosclerosis containing the aromatic compound according to any one of [1] to [34], a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient, and / Or prophylactic. 39. A therapeutic agent for hyperlipidemia, comprising the aromatic compound according to any one of [1] to [34], a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient. And / or prophylactic drugs. 40. A remedy for obesity, which comprises the aromatic compound according to any one of [1] to [34], a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient, and / or Or prophylactic drug. 41. A therapeutic agent for impaired glucose tolerance, which comprises the aromatic compound according to any one of [1] to [34], a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient, and / Or prophylactic. 42. A therapeutic agent for hypertension, comprising the aromatic compound according to any one of [1] to [34], a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient, and / or Or prophylactic drug. 43. A therapeutic agent for polycystic ovary syndrome containing the aromatic compound according to any one of [1] to [34], a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient. And / or prophylactic drugs. 44. A therapeutic drug for gestational diabetes, which comprises the aromatic compound according to any one of [1] to [34], a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient, and / or Or prophylactic drug. 45. Insulin-resistant non-glucose tolerance containing the aromatic compound according to any one of [1] to [34], a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient. Defective and / or prophylactic drugs.