JPH08325250A - New substituted phenol derivative - Google Patents

Abstract

PURPOSE: To obtain a new highly safe compound having hypoglycemic action and blood lipid depressing action, but inducing no lactic acidosis or excessive hypoglycemia, thus useful as a preventive/therapeutic agent for diabetes and hyperlipemia, etc. CONSTITUTION: This new compound (salt) is expressed by formula I [R1 is OH, a lower alkoxyl, etc.; R2 is thiol, nitro, etc.; X-Y is CH2 -CH2 , CH=CH, etc.; (m) is 0-2; A is an aromatic heterocyclic group such as of formula II, III (R7 and R8 are each H, furyl, etc.; R9 is H or a lower alkyl,), etc.], e.g. 3- 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxyl-2-nitrophenyl}acrylic acid ethyl ester. The compound of formula I is obtained, for example, by hydrolyzing a benzaldehyde derivative followed by reacting the resultant hydrolyzate with an alkylating reagent of the formula A-(CH2 )m R11 (R11 is OH or an eliminable functional group) to form a 2,4-disubstituted benzaldehyde of formula IV which is then reacted with a Wittig reagent of the formula PPh3 =COR1 .

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel substituted phenol derivative, and more particularly, it has a hypoglycemic action and a hypolipidemic action, and is useful as a preventive and therapeutic drug for diabetes and hyperlipidemia. It relates to substituted phenol derivatives and their pharmaceutically acceptable salts.

[0002]

In the treatment of non-insulin-dependent diabetes mellitus (type II diabetes), insulin and oral hypoglycemic agents (sulfonylurea agents, biguanide agents) are generally administered in addition to diet therapy and exercise therapy. However, administration of a sulfonylurea agent is known to cause severe hypoglycemia due to its strong hypoglycemic effect. Further, the sulfonylurea agent may show a phenomenon of secondary ineffectiveness in which its effect is gradually weakened when it is used for a long period of time.
Furthermore, biguanide agents sometimes cause lactic acidosis, and it is necessary to exercise caution when administering them.

In recent years, a new therapeutic drug for diabetes has been attracting attention, which improves blood glucose by improving insulin resistance in peripheral tissues, which is one of the causes of non-insulin-dependent diabetes mellitus. As an example of such a type of therapeutic drug for diabetes, Japanese Patent Application Laid-Open No. 61-85372 discloses [5-
[4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyl] -2,4-thiazolidinedione] and the like, and in JP-A-60-51189, [(±)- 5- [4- (6-hydroxy-2,5,7,
It is described that thiazolidinedione derivatives such as 8-tetramethylchroman-2-ylmethoxybenzyl] -2,4-thiazolidinedione] have a hypoglycemic effect.

On the other hand, as an example of an effective compound having no thiazolidinedione or its related functional group, WO91 / 1
9702 has the following formula

Embedded image (In the formula, A is a bicyclic condensed ring containing a benzene ring, and X is
1 represents O, S, SO or SO ₂ ) and a compound having a hypoglycemic action is disclosed.

Further, in the WO93 / 21166, formula _{A 1 -X- (CH 2) n} -O-A 2 -A 3 -COR 2 ( wherein, A ₁ is an aromatic heterocyclic ring, A ₂ is a substituted group A is a benzene ring, A ₃ is-(CH ₂ ) m-CHR _1- , and R is
₁ is a halogen atom or a formula S (O) pA _{4 in which} p is 0 to 2
A compound having a hypoglycemic action represented by the formula (1) is disclosed.

Furthermore, the WO94 / 01420, wherein _{A 1 -X- (CH 2) n} -O-A 2 -A 3 -YR 2 ( wherein, A _1, A ₂ is as defined above, A ₃ is-(C
H ₂ ) m-CH (OR ₁ )-) having a hypoglycemic effect is disclosed.

In WO94 / 13650, the formula A ₁ -X- (CH ₂ ) -OA ₂ -CHR ₁ -CR ₂ R ₃ R ₄ (wherein A ₁ and A ₂ are the same as above) And R ₁ and R ₂ independently represent hydrogen, or R ₁ and R ₂ represent a bond, and R ₃ and R ₄ independently represent a nitrile group or —COR ₅ ) Compounds having action are disclosed.

Furthermore, the WO94 / 29302, formula _{A 1 -X- (CH 2) n} -O-A 2 - (CH 2) m-CHR 1 (C
OR ₂ ) (In the formula, A ₁ and A ₂ are the same as those described above, and R ₁ represents a substituted or unsubstituted 5-membered aromatic heterocyclic ring bonded to N.
However, compounds having a hypoglycemic action represented by this ring containing 1 to 3 nitrogen atoms are disclosed. These known compounds have been studied for variations of the substituent bonded to the α-carbon of the terminal carbonyl, but have not obtained satisfactory results.

[0009] Further, in the WO94 / twenty-nine thousand two hundred and eighty-five, wherein _{A 1 -X- (CH 2) -O} -A 2 - (CH 2) m-CHNR 1 R
A compound represented by ₂ (COR ₃ ) (in the formula, A ₁ and A ₂ are the same as above, R ₁ represents hydrogen or an alkyl group, and particularly R ₂ is an aryl group) has a hypoglycemic effect. Disclosed as having.

However, these antidiabetic agents are not yet satisfactory for practical use as medicines because of their weak core effects and side effects, and they are effective compounds without these difficulties. Development is desired.

[0011]

DISCLOSURE OF THE INVENTION As a result of intensive investigations by the present inventors to provide a novel compound useful as a therapeutic drug for diabetes and hyperlipidemia, the hypoglycemic action and blood lipid lowering action are strong. Then, they have found a novel substituted phenol derivative with extremely low toxicity and completed the present invention.

[0012]

The compound of the present invention is a novel substituted phenol derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof.

[Chemical 21] [Wherein R ₁ is substituted with a hydroxyl group, a lower alkoxy group, a phenyl lower alkoxy group, a phenoxy group, an amino group, a mono- or di-lower dialkylamino group, a pyrrolidino group, a piperidino group, a morpholino group, and 3 or less halogen atoms. Optionally represents a lower alkanesulfonylamino group or a benzenesulfonylamino group. R ₂ is a hydroxyl group, a thiol group, a nitro group, a halogen atom, a formyl group, a cyano group, a lower alkyl group optionally substituted with 3 or less halogen atoms, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkoxy group. , An amino group represented by NR ₃ R ₄ , a group represented by SO ₂ R ₅ , or -Q
It represents a group represented by (CH ₂ ) nZR ₆ . Where R ₃ ,
Each R ₄ is independently hydrogen, a lower alkyl group, an aralkyl group, a lower alkanoyl group, a benzoyl group, a nitro group or a benzoyl group substituted with a halogen atom, or a lower group which may be substituted with 3 or less halogen atoms. Represents an alkanesulfonyl group, and R ₅ represents a lower alkyl group which may be substituted with 3 or less halogen atoms, or a lower alkyl-substituted or unsubstituted phenyl group. Q is absent or represents an oxygen or sulfur atom or a carbonyl group, Z is an oxygen or sulfur atom, R ₆ is hydrogen, a hydroxyl group or a lower alkyl group or a lower alkoxy group, and n is 1, 2 or Or represents 3. X-Y is CH ₂ -C
H _2, CH = CH, represents O-CH ₂ or NH-CH _2,, m represents 0, 1 or 2. A is the formula (II), (II
I) or (IV)

[Chemical formula 22] Represents an aromatic heterocyclic group represented by, where L is oxygen,
It represents a nitrogen or sulfur atom, and R ₇ and R ₈ each independently represent hydrogen, a lower alkyl group, a phenyl group, a thienyl group, or a furyl group. R ₉ represents hydrogen or a lower alkyl group. ]

In the present specification, the lower alkoxy group means a linear or branched alkoxy group having 8 or less carbon atoms, and the phenyl lower alkoxy group means that the lower alkoxy moiety has the same meaning as described above. A lower alkyl group, a lower alkanesulfonyl group, or a lower alkanesulfonylamino group, which may be substituted with 3 or less halogen atoms, means a phenylalkoxy group, and a hydrocarbon moiety is a straight chain having 8 or less carbon atoms or Branched alkyl, which means that they may be substituted with up to 3 halogen atoms, for example trifluoromethyl group,
It means a methanesulfonyl, trifluoromethanesulfonyl, methanesulfonylamino, trifluoromethanesulfonylamino group or the like. The lower alkanoyl group or lower alkanoyloxy group has a hydrocarbon moiety of 7 carbon atoms.
The following straight-chain or branched alkanoyl group or alkanoyloxy group is meant, and the lower alkyl group means a straight-chain or branched alkyl group having 8 or less carbon atoms,
The mono- or di-lower alkylamino group means a monoalkylamino group or dialkylamino group in which each lower alkyl group has the same meaning as described above, and the lower alkyl-substituted or unsubstituted benzenesulfonyl group means a lower alkyl group. means mono-substituted benzenesulfonyl group having the same meaning as above, and the group represented by -Q (CH ₂₎ nZR _6, wherein _{- (CH 2) nOR 6,} -O (CH 2) nOR 6, - ( _{CH 2) nSR 6, -O (} CH 2) nSR 6, -S (CH 2) nOR 6, -S (CH 2) nSR 6 - (CH 2) nCOR 6, -O (CH 2) nCOR 6, - A group represented by S (CH ₂ ) nCOR _{6 and the} like, wherein R ₆ is hydrogen or a lower alkyl group, and n is 1, 2 or 3.

A preferred group of compounds of the present invention is the above-mentioned general formula (I), wherein R ₁ is a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, a benzyloxy group, a phenoxy group, an amino group,
A mono- or dialkylamino group having 1 to 4 carbon atoms, a pyrrolidino group, a piperidino group, a morpholino group, a methanesulfonylamino group, or a benzenesulfonylamino group, and R ₂ is a hydroxyl group, a thiol group, a nitro group, a halogen atom, or formyl. Group, cyano group, trifluoromethyl group,
Alkanoyl group having 1 to 5 carbon atoms, alkanoyloxy group having 1 to 5 carbon atoms, alkoxy group having 1 to 3 carbon atoms, NR ₃
Represents an amino group represented by R ₄ , a group represented by SO ₂ R ₅ , or a group represented by —Q (CH ₂ ) nZR ₆ , wherein:
R ₃ and R ₄ are each independently hydrogen, an alkyl group having 1 to 5 carbon atoms, an aralkyl group, an alkanoyl group having 1 to 5 carbon atoms, a benzoyl group, a nitro group or a benzoyl group substituted with a halogen atom, or methanesulfonyl. Represents a group or a trifluoromethanesulfonyl group. R ₅ is an alkyl group having 1 to ₅ carbon atoms, a trifluoromethyl group, a phenyl group, or p-
Represents a methylphenyl group, R ₆ is hydrogen or 1 carbon atom
Represents an alkyl group of 5 and Q and n have the same meaning as described above. m and XY have the same meanings as above, and A is of formula (II), (III), or (IV)

[Chemical formula 23] Wherein L has the same meaning as described above, R ₇ and R ₈ are each independently hydrogen, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a thienyl group. Represents a furyl group. R ₉ is hydrogen, a novel substituted phenol derivative having an alkyl group having 1 to 4 carbon atoms, or a pharmaceutically acceptable salt thereof.

Here, the alkoxy group having 1 to 3 carbon atoms is specifically a methoxy group, an ethoxy group, a normal propyloxy group or an isopropyloxy group, preferably an ethoxy group. Specific examples of the alkylamino group having 1 to 4 carbon atoms include methylamino group, ethylamino group, normal propylamino group, isopropylamino group, normal butylamino group, isobutylamino group, sec-butylamino group, tert-butyl group. An amino group, preferably a methylamino group or an ethylamino group. Similarly, carbon number 1-4
The dialkylamino group of is specifically a dimethylamino group, a diethylamino group, a dinormalpropylamino group,
Diisopropylamino group, dinormal butylamino group,
A diisobutylamino group, a di-sec-butylamino group and a di-tert-butylamino group are preferable, and a dimethylamino group and a diethylamino group are preferable. The halogen atom is fluorine, chlorine, bromine, iodine, preferably fluorine,
It is chlorine. The alkanoyl group having 1 to 5 carbon atoms is specifically a formyl group, acetyl group, propanoyl group, butanoyl group, pentanoyl group, isopropanoyl group, isobutanoyl group, preferably formyl group, acetyl group, propanoyl group, It is a butanoyl group. Carbon number 1
The alkanoyloxy group of 5 is specifically a formyloxy group, an acetyloxy group, a propanoyloxy group, a butanoyloxy group, a pentanoyloxy group, an isopropanoyloxy group, an isobutanoyloxy group, preferably A formyloxy group, an acetyloxy group, a propanoyloxy group and a butanoyloxy group. 1 to 5 carbon atoms
Specifically, the alkyl group of is a methyl group, an ethyl group, a normal propyl group, a normal butyl group, a normal pentyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, or a neopentyl group. Of these, a methyl group, an ethyl group, a normal propyl group and an isopropyl group are preferable. Specific examples of the aralkyl group include a benzyl group, a phenylethyl group, a phenylpropyl group, a naphthylmethyl group, a naphthylethyl group, a thienylmethyl group, a thienylethyl group, a furylmethyl group, a furylethyl group, and a quinonylmethyl group, and are preferable. Is a benzyl group.

A preferred compound group of the present invention is the compound of the above general formula (I) wherein m is 2 and R ₁ is a hydroxyl group, or a linear or branched lower alkoxy group having 8 or less carbon atoms, especially carbon atom. a number from 1 to 3 alkoxy groups, a X-Y is CH ₂ -CH ₂ or CH = substituted phenol derivative is a group represented by CH or pharmaceutically acceptable salts thereof.

A more preferred group of compounds is represented by the general formula (I)
In the formula (II)

[Chemical formula 24] [In the formula, L represents an oxygen, nitrogen or sulfur atom, and R ₇ ,
Each R ₈ independently represents hydrogen, a linear or branched lower alkyl group having 8 or less carbon atoms, particularly an alkyl group having 1 to 4 carbon atoms, a phenyl group, a thienyl group, or a furyl group. ] A novel substituted phenol derivative which is a group represented by or a pharmaceutically acceptable salt thereof.

Still another preferred group of compounds is the compound of the general formula (I) in which A is the formula (III)

[Chemical 25] [In the formula, R ₉ represents hydrogen, a linear or branched lower alkyl group having 8 or less carbon atoms, particularly an alkyl group having 1 to 4 carbon atoms. ] A novel substituted phenol derivative which is a group represented by or a pharmaceutically acceptable salt thereof.

Still another preferred compound group is a compound of the general formula (I) wherein A is the formula (IV)

[Chemical formula 26] [In the formula, L represents an oxygen, nitrogen or sulfur atom, R ₉ represents hydrogen, a linear or branched lower alkyl group having 8 or less carbon atoms, particularly an alkyl group having 1 to 4 carbon atoms. ] The above-mentioned novel substituted phenol derivative which is a group represented by or a pharmaceutically acceptable salt thereof.

A more particularly preferred group of compounds is the above formula (I) in which L is an oxygen atom, R ₇ is a phenyl group,
A novel substituted phenol derivative in which R ₈ is a methyl group, or a pharmaceutically acceptable salt thereof.

A further particularly preferred group of compounds is a novel substituted phenol derivative in which L is an oxygen atom and R ₉ is a methyl group in the above general formula (I), or a pharmaceutically acceptable salt thereof.

The compounds of the present invention which are particularly excellent are listed below. 3- {4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -2
-Nitrophenyl} acrylic acid ethyl ester; 3-
{2-chloro-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-bromo-4- [2- (5-
Methyl-2-phenyl-4-oxazolyl) ethoxy]
Phenyl} acrylic acid ethyl ester; 3- {2-fluoro-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-hydroxy-4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-acetoxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) Ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-formyl-4- [2- (5-methyl-
2-Phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-cyano-4
-[2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester;
3- {2-Acetyl-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-methoxy-4- [2
-(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester;

3- {4-Ethoxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {4- [2-
(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-trifluoromethylphenyl} acrylic acid ethyl ester; 3- {2-amino-4- [2- (5-
Methyl-2-phenyl-4-oxazolyl) ethoxy]
Phenyl} acrylic acid ethyl ester; 3- {2-methylamino-4- [2- (5-methyl-2-phenyl-4)
-Oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-ethylamino-4- [2- (5
-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-
Methanesulfonyl-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {4- [2- (5-methyl-
2-Phenyl-4-oxazolyl) ethoxy] -2-trifluoromethanesulfonylphenyl} acrylic acid ethyl ester; 3- {2-methoxymethoxy- {4- [2
-(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3-
{4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-ethoxymethoxyphenyl}
Acrylic acid ethyl ester; 3- {4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy]-
2-Methylthiomethoxyphenyl} acrylic acid ethyl ester;

3- {2-ethylthiomethoxy-4- [2
-(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3-
{-2-hydroxymethyl-4- [2- (5-methyl-
2-Phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-methoxymethyl-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester Ester; 3- {4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -2-nitrophenyl} propionic acid ethyl ester; 3- {2-chloro-
4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-bromo-4- [2- (5-methyl-2-
Phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-fluoro-4-
[2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-hydroxy-4- [2- (5-methyl-
2-Phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-acetoxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester 3- {2-formyl-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester;

3-{-2-Cyano-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-acetyl-4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-methoxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl } Propionic acid ethyl ester; 3- {2-ethoxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {4- [2- (5 -Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-trifluoromethylphenyl} propionic acid ethyl ester; 3- {2
-Amino-4- [2- (5-methyl-2-phenyl-4
-Oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-methylamino-4- [2-
(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3-
{2-Ethylamino-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-methanesulfonyl-4- [2- (5-methyl 2-Phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {4- [2- (5-methyl-2-phenyl-
4-Oxazolyl) ethoxy] -2-trifluoromethanesulfonylphenyl} propionic acid ethyl ester;
3- {2-methoxymethoxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester;

3- {2-ethoxymethoxy-4- [2-
(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3-
{4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-methylthiomethoxyphenyl} propionic acid ethyl ester; 3- {2-ethylthiomethoxy-4- [2- (5- Methyl-2-phenyl-
4-Oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-hydroxymethyl-4-
[2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-methoxymethyl-4- [2- (5-methyl-2-phenyl-4-oxazolyl ) Ethoxy] phenyl} propionic acid ethyl ester; 3- {4- [2-
(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-nitrophenyl} acrylic acid; 3- {2-
Formyl-4- [2- (5-methyl-2-phenyl-4]
-Oxazolyl) ethoxy] phenyl} acrylic acid; 3
-{2-cyano-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid; 3- {4- [2- (5-methyl-2-phenyl-4)
-Oxazolyl) ethoxy] -2-trifluoromethylphenyl} acrylic acid; 3- {2-methoxymethoxy-
4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid;

3- {4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -2-nitrophenyl} propionic acid; 3- {2-formyl-4- [2-
(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid; 3- {2-cyano-4
-[2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid; 3- {4-
[2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-trifluoromethylphenyl} propionic acid; 3- {4- [2- (5-methyl-2-phenyl-4-oxazolyl) Ethoxy] -2-methoxymethoxyphenyl} propionic acid; 3- {4- [2- (2
-Benzoxazolylmethylamino) ethoxy)]-2
-Nitrophenyl} acrylic acid ethyl ester; 3-
{-2-Formyl-4- [2- (2-benzoxazolylmethylamino) ethoxy)] phenyl} acrylic acid ethyl ester; 3-{-2-cyano-4- [2- (2-
Benzoxazolylmethylamino) ethoxy)] phenyl} acrylic acid ethyl ester; 3- {4- [2- (2
-Benzoxazolylmethylamino) ethoxy)]-2
-Trifluoromethylphenyl} acrylic acid ethyl ester; 3- {4- [2- (2-benzoxazolylmethylamino) ethoxy)]-2-methoxymethoxyphenyl} acrylic acid ethyl ester; 3- {4- [ 2- (2
-Benzoxazolylmethylamino) ethoxy)]-2
-Nitrophenyl} propionic acid ethyl ester;

3- {2-Formyl-4- [2- (2-benzoxazolylmethylamino) ethoxy)] phenyl} propionic acid ethyl ester; 3-{-2-cyano-4- [2- (2 -Benzoxazolylmethylamino)
Ethoxy)] phenyl} propionic acid ethyl ester;
3- {4- [2- (2-benzoxazolylmethylamino) ethoxy)]-2-trifluoromethylphenyl}
Propionic acid ethyl ester; 3- {4- [2- (2-
Benzoxazolylmethylamino) ethoxy)]-2-
Methoxymethoxyphenyl} propionic acid ethyl ester; {4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-nitrophenoxy} acetic acid ethyl ester; {4- [2- (5-Methyl 2-Phenyl-4-oxazolyl) ethoxy] -2-nitrophenylamino} acetic acid ethyl ester, a novel substituted phenol derivative or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable salt may be any salt as long as it forms a non-toxic salt with the substituted phenol derivative represented by the above general formula (I). For example, examples of forming a salt with an acidic functional group of a substituted phenol derivative include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium and magnesium, ammonium, trimethylamine, triethylamine, pyridine salt and picoline salt. Examples thereof include amino acid salts such as organic base salts, lysine salts, and arginine salts. on the other hand,
Examples of forming a salt with a basic functional group of a substituted phenol derivative include salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, and phosphate, acetate, succinate, citrate, and apple. Examples thereof include organic acid salts such as acid salts, oxalates, maleates, and methanesulfonates. However, any of the above salts is not limited to these.

The compound of the present invention has a strong hypoglycemic action and hypolipidemic action, and is not only useful as a prophylactic and therapeutic drug for diabetes and hyperlipidemia, but also expected to be used as a prophylactic drug for arteriosclerosis. it can. When the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt is used as a pharmaceutical preparation comprising an active ingredient, it is usually a known pharmacologically acceptable carrier, excipient,
Diluents, extenders, disintegrants, stabilizers, preservatives, buffers, emulsifiers, fragrances, coloring agents, sweeteners, thickeners, flavoring agents, solubilizing agents, other additives, specifically water. , Alcohols such as vegetable oils, ethanol, or benzyl alcohol, carbohydrates such as polyethylene glycol, glycerol triacetate, gelatin, lactose, starch, magnesium stearate, talc, lanolin,
Mixed with petrolatum etc., tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, troches,
It can be administered orally or parenterally in the form of an aerosol, an exyl, a suspension, an emulsion, a syrup and the like. The dose may vary depending on the kind and degree of the disease, the compound to be administered and the administration route, the age, sex, body weight of the patient, etc., but in the case of oral administration, the compound (I) is usually 0.1 to 1000 mg per adult per day. It is particularly preferable to administer 1 to 100 mg.

The compound represented by the general formula (I) is XY
When CH represents CH = CH, there exist geometrical isomers of E-form and Z-form formed by a benzene ring following X and a carboxyl equivalent functional group following Y. A mixture of either one of the isomers and both the E and Z isomers in any ratio is also within the scope of the present invention.

The compound of the present invention can be produced, for example, by the following method when XY in the general formula (I) is CH = CH or CH2-CH2. However, it goes without saying that the method for producing the compound of the present invention is not limited to these.

The compound (I) of the present invention can be produced, for example, by the following several routes. Manufacturing route 1 formula (B)

[Chemical 27] A 4-hydroxy-2-substituted benzaldehyde compound (B) represented by the formula A- (CH ₂ ) m-R ₁₁
- (CH ₂₎ is reacted with m groups introduced alkylating reagent (T), or, alkanol represented corresponding 4 halogen-2-substituted benzaldehyde compound (D) by the formula A- (CH ₂₎ m-OH The compound represented by the general formula (C) is reacted with the derivative (S).

[Chemical 28] In the represented by 2,4-disubstituted benzaldehyde compounds, the aldehyde compound (C) a further formula PPh ₃ = C
By reacting with a Wittig reagent represented by OR, general formula (E)

[Chemical 29] By further reducing the double bond of the acrylic acid moiety in the acrylic acid type product (E), wherein the objective substituted phenol derivative represented by the formula (X-Y is CH = CH) , General formula (F)

Embedded image A propionic acid type (X—Y is CH ₂ —CH ₂ ) objective substituted phenol derivative represented by [However,
In the formula, R ₁₁ represents a functional group such as a hydroxyl group, a halogen atom, a p-toluenesulfonyloxy group and a methanesulfonyloxy group, which is a good leaving group in the nucleophilic reaction, and other symbols have the same meanings as described above. Have. ]

More specifically, the target substituted phenol derivative (E) or (F) contained in the general formula (I) can be produced by the steps described below.

[Chemical 31] (Step a) For example, the corresponding benzaldehyde derivative (A) (R ₁₀ is a lower alkyl group such as ethyl and methyl) is added to, for example, dimethylformamide, tetrahydrofuran, dioxane, chloroform, methylene chloride, methanol,
Obtained by hydrolysis with hydrogen bromide-acetic acid, hydrochloric acid, trimethylsilyl iodide, boron trifluoride-ether, lithium chloride at room temperature or under heating using ethanol, acetic acid, trifluoroacetic acid, water or the like as a solvent. 4-hydroxy - benzaldehyde compound (B) was prepared, (step b) the compound (B) with an alkylating reagent compound (T), when R ₁₁ is a hydroxyl group, Mitsunobu reaction conditions [organic reactions ( Organic Reaction
s), vol. 42, p. 335], for example, in a solution of the raw material compound such as methylene chloride, tetrahydrofuran, benzene, toluene, ether, dimethylformamide, dioxane, etc., 1 to 3 equivalents of triphenylphosphine and dialkyl azobiscarboxylate, respectively. (Dimethyl, diethyl, diisopropyl) or azobiscarboxylic acid amide and an alkylating reagent are added at −50 ° C. to room temperature, and the reaction is carried out as it is or at a temperature corresponding to the boiling point of the solvent.
When R ₁₁ is a leaving functional group, sodium hydroxide,
In the presence of a base such as potassium hydroxide or sodium hydride, for example, water, dimethylformamide, benzene, toluene or the like is used as a solvent to react at −30 ° C. to a temperature corresponding to the boiling point of each solvent to give a 4-alkoxy-benzaldehyde compound ( C) can be obtained.

(Step c) Further, this compound (C) is
-Halogeno-benzaldehyde compound (D) (wherein hal
Represents a halogen atom such as fluorine, bromine and chlorine) and an alkylating reagent (S) such as dimethylformamide and tetrahydrofuran as a solvent, and sodium hydride,
It can also be obtained by reacting in the presence of a base such as sodium hydroxide, potassium hydroxide or potassium carbonate at -30 ° C to a temperature corresponding to the boiling point of each solvent.

(Step d) The compound (C) thus obtained is a reaction reagent capable of forming a carbon-carbon double bond, for example, a Wittig reaction reagent represented by the formula (U), for example, carboethoxymethylene. By reacting with triphenylphosphorane, the target acrylic acid type substituted phenol derivative (E) can be obtained.

(Step e) This compound (E) is further treated with, for example, ethanol, methanol, tetrahydrofuran,
The target propionate-type substituted phenol is obtained by catalytic reduction reaction in the presence of a reducing catalyst such as palladium carbon, palladium, platinum oxide, or Raney nickel in a hydrogen atmosphere at atmospheric pressure to 5 atm using dioxane, ethyl acetate, dimethylformamide or the like as a solvent. The derivative (F) can be obtained. Further, this compound (F) can be obtained by the method of [Angewante, Chemie., International Edition], 4
Vol. 271 (1965)], a reduction reaction with a diimide, for example, a reaction of hydroxylamine-O-sulfonic acid with sodium hydroxide in the presence of hydroxylamine sulfate in a mixture of water and acetonitrile. The compound (E) can also be obtained by a reduction reaction with a diimide.

In the above manufacturing route 1, R ₂ is —OH,
In the case of —SH, the compounds (G) and (H) contained in the general formula (I) can be produced as follows. Production Route 2 When R ₂ in the acrylic acid type (E) or propionic acid type (F) product obtained by the above method is a hydroxyl group or a thiol group, these products are further reacted with a reagent for introducing the group R _12. Then, the group R ₂ is converted into the group ZR ₁₂ to obtain the desired substituted phenol derivative represented by the general formula (G) or (H). [In the formula, R ₁₂ represents lower alkanoyl, lower alkyl, or — (CH ₂ ) nZR ₆ , and other symbols have the same meanings as described above. ]

This will be described in more detail. The R ₂ groups of the compounds (E) and (F) contained in the general formula (I) can be produced by converting as follows.

Embedded image (Step f) When R ₂ is —OH or —SH, the acrylic acid type substituted phenol derivative (E) is treated with, for example, methylene chloride, chloroform, tetrahydrofuran, dioxane, acetonitrile, benzene, toluene, acetone, pyridine,
Water or a mixed solution thereof is used as a solvent in the presence of a base such as triethylamine, pyridine, N, N-diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium hydrogencarbonate at -30 ° C. ~ At the temperature corresponding to the boiling point of each solvent, the group R ₁₂
The compound (G) in which the group R ₂ is replaced with the group ZR ₁₂ can be obtained by reacting with an introducing reagent of, for example, an active reagent such as halide.

(Step g) The corresponding ZR ₁₂ -substituted propionic acid type compound (H) can be obtained from the compound (F) by the same procedure as in the above step f. (Step h) The compound (H) can also be obtained by reducing the ZR ₁₂ with the substituted acrylic acid type compound (G) by the same procedure as described in Step e of Production Example 1 above.

Manufacturing Route 3 Even if steps b and d in Manufacturing Route 1 are reversed, the desired substituted phenol derivatives (E) and (F) are similarly obtained.
Can be obtained. The desired propionic acid type substituted phenol derivative (F) is obtained by hydrolyzing the intermediate compound (J) to give 4-hydroxy-phenylacrylic acid (K) which is once free, and then the double bond of the acrylic acid moiety is converted. After reduction (L) and esterification or amidation again to introduce the group R ₁ into the carboxy group (M), the formula A- (C
It can also be obtained by reacting with an A- (CH ₂ ) m group-introduced alkylating reagent represented by H ₂ ) mR ₁₁ .

More specifically, the acrylic acid type substituted phenol derivative (E) and the propionic acid type substituted phenol derivative (F) contained in the general formula (I) can be produced as follows.

[Chemical 33] (Step i) The intermediate compound (J) can be obtained from the compound (B) and the Wittig reaction agent (U) by the same procedure as the step d described above. (Step j) The acrylic acid type compound (E) can be obtained from the intermediate compound (J) and the alkylating reagent (T) by the same procedure as in the step b described above. (Step k) The propionic acid type compound (F) can be obtained from the compound (E) by the same procedure as in the step e described above.

(Step l) The compound (K) is obtained by converting the above intermediate compound (J) into, for example, methanol, ethanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, acetic acid, trifluoroacetic acid, ethyl acetate, chloroform, methylene chloride, water. Etc. or a mixed solution thereof as a solvent, to which acids such as hydrochloric acid, sulfuric acid and trifluoroacetic acid, and an aqueous solution of a base such as sodium hydroxide, potassium hydroxide and potassium carbonate are added and reacted at room temperature or under heating. Can be done. Further, when R ₁ is a benzyloxy group, the compound (K) can be obtained under the reducing reaction conditions described in step e.

(Step m) The compound (L) can be obtained by reducing the compound (K) by the same procedure as in the step e described above. (Step n) The compound (M) can be obtained by esterifying or amidating the compound (L) according to a conventional method. (Step o) The compound (M) thus obtained can be reacted with the alkylating reagent (T) in the same manner as in the step b described above to obtain the desired propionic acid type substituted phenol derivative.

Further, the free carboxylic acid type objective substituted phenol release in which R ₁ is a hydroxyl group in the general formula (I) can also be produced by the following production routes 4 to 6. Manufacturing route 4

Embedded image (Step p) The corresponding free carboxylic acid compound (N) can be obtained by hydrolyzing the acrylic acid type compound (E) in the same procedure as in step 1 described above. (Step q) This compound (N) can also be obtained by reacting the compound (K) with an alkylating reagent (T) in the same procedure as in the step b described above.

Manufacturing route 5

Embedded image (Step r) The propionic acid type compound (F) can be hydrolyzed in the same manner as in the step 1 described above to obtain the corresponding free carboxylic acid type compound (O). (Step s) This compound (O) can also be obtained by reacting the compound (L) with an alkylating reagent (T) in the same procedure as in the step b described above.

Manufacturing route 6

Embedded image (Step t) The acrylic acid type compound (G) can be hydrolyzed in the same procedure as in step l described above to obtain the corresponding free carboxylic acid type compound (P). (Step u) Further, the corresponding free carboxylic acid type compound (Q) can be obtained by hydrolyzing the propionic acid type compound (H) in the same procedure as in the step 1 described above.
The compound obtained in each of these steps can be isolated and purified by a known separation and purification means, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization or chromatography.

[0048]

EXAMPLES The present invention will be described in more detail below with reference to examples. Example 1 (E) -3- {2-hydroxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester (Step 1) 4- [2- ( 5-methyl-2-phenyl-4
Synthesis of 2-oxazolyl) ethoxy] -2-hydroxybenzaldehyde 2- (5-methyl-2-phenyl-4-oxazolyl)
Ethanol 2.03 g (10 mM), 2,4-dihydroxybenzaldehyde 1.38 g (10 mM) and triphenylphosphine 2.79 g (10.7 mM) were dissolved in tetrahydrofuran 100 ml, and dimethyl azodicarboxylate 1.57 g (10 0.7 mM) was added dropwise. After stirring overnight at room temperature, the solvent was distilled off under reduced pressure and the obtained oily product was subjected to silica gel chromatography (hexane: ethyl acetate = 4: 1).
The title compound having the following properties was obtained as a white crystalline substance (2.2 g, yield 65%). ¹ HNMR (CDCl ₃ , δ) 2.38 (s, 3H) 3.0
2 (t, 2H, J = 6.6) 4.34 (t, 2H, J =
6.93) 7.0 (d, 2H, J = 8.91) 7.41-
7.45 (m, 3H) 7.82 (d, 2H, J = 8.5
7) 7.95-7.99 (m, 2H) 9.87 (s, 1
H)

(Step 2) Synthesis of (E) -3- {2-hydroxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester 4- [2 2.8 g (8.2 mM) of-(5-methyl-2-phenyl-4-oxazolyl) ethoxy] -2-hydroxybenzaldehyde and 3.48 g (10 mM) of carboethoxymethylenetriphenylphosphorane were added to 100 ml of toluene.
And was stirred overnight at room temperature. The precipitated solid was filtered off to obtain 2.6 g (yield 81%) of the title compound having the following properties as white crystals. ¹ HNMR (DMSO-d ₆ , δ) 1.23 (t, 3H,
J = 7.1Hz) 2.37 (s, 3H) 2.93 (t, 2)
H, J = 6.6 Hz) 4.14 (q, 2H, J = 7.0H
z) 4.20 (t, 2H, J = 6.6 Hz) 6.47-6.
41 (m, 3H) 7.53-7.47 (m, 4H) 7.7
7 (d, 1H, J = 15.8 Hz) 7.93-7.89
(M, 2H) EI-MS m / z; 393 IR (KBr, cm ^-1 ) 1704, 1610, 129
9,1184,1130

Example 2 3- {2-hydroxy-4- [2- (5-methyl-2-
Phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester (E) -3- {2-hydroxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester Ester (Compound of Example 1)
2.9 g (7.3 mM) was dissolved in 200 ml of tetrahydrofuran and 700 mg of 10% palladium carbon was added. After stirring at room temperature for 6 hours under hydrogen (3 atm), the solvent was distilled off under reduced pressure from the filtrate obtained by filtering off 10% palladium carbon, and the title compound having the following properties was obtained as white crystals.2.
7 g (yield 94%) was obtained. ¹ HNMR (CDCl ₃ , δ) 1.22 (t, 3H, J =
7.3 Hz) 2.37 (s, 3H) 2.65 (t, 2H,
J = 5.9Hz) 2.81 (t, 2H, J = 5.9Hz)
2.95 (t, 2H, J = 6.6 Hz) 4.13 (q, 2)
H, J = 7.26 Hz) 4.18 (t, 2H, J = 6.7)
6 Hz) 6.48-6.40 (m, 2H) 6.94 (d,
2H, J = 8.25Hz) 7.38-7.44 (m, 3
H) 7.51 (br, 1H) 7.95-7.99 (m, 2
H) EI-MS m / z; 395 IR (KBr, cm ^-1 ) 1741, 1618, 116.
8,1118

Example 3 (E) -3- {2-acetoxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester (E) -3- { 2-Hydroxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester (Compound of Example 1)
1 g (2.5 mM) was dissolved in 100 ml of dichloromethane, acetic anhydride (0.5 ml) and pyridine (0.5 ml) were added, and the mixture was stirred at room temperature overnight. After the solvent was distilled off under reduced pressure, water was added and the mixture was extracted with ethyl acetate and washed with a 1N hydrochloric acid solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained oily substance was crystallized from hexane / ethyl acetate to obtain 250 mg (yield 23%) of the title compound having the following properties as white crystals. ¹ HNMR (CDCl ₃ , δ) 1.32 (t, 3H, J =
7.3) 2.35 (s, 3H) 2.36 (s, 3H) 2.9
8 (t, 2H, J = 6.6) 4.24 (q, 2H, J =
7.3) 4.27 (t, 2H, J = 6.6) 6.31 (d,
1H, J = 15.8) 6.65 (d, 1H, J = 2.6)
6.81 (dd, 1H, J = 2.3 & 8.6) 7.39-
7.45 (m, 3H) 7.54 (d, 1H, J = 8.6)
7.65 (d, 1H, J = 16.2) 7.95-7.99
(M, 2H) EI-MS m / z; 435 IR (KBr, cm ^-1 ) 1762, 1714, 129.
6,1211,1178

Example 4 (E) -3- {2-acetoxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester (E) -3- { 2-Acetoxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester (Compound of Example 3)
Was catalytically reduced in the same manner as in Example 2 to obtain a white crystal (yield 77%) of the title compound having the following properties. ¹ HNMR (CDCl ₃ , δ) 1.23 (t, 3H, J =
7.26) 2.30 (s, 3H) 2.36 (s, 3H) 2.
52 (t, 1H, J = 6.59) 2.77 (t, 1H, J
= 7.3) 3.00 (t, 2H, 6.62) 4.11 (q,
2H, 7.23) 6.60 (d, 1H, 2.3) 6.73
(Dd, 1H, J = 2.65 & 8.59) 7.12 (d,
1H, 8.56) 7.39-7.43 (m, 3H) 7.95
-7.99 (m, 2H) EI-MS m / z; 437 IR (KBr, cm ^-1 ) 1739, 1506, 122
8, 1209, 1153, 1105

Example 5 (E) -3- {4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-methoxymethoxyphenyl} propionic acid ethyl ester (E) -3- {2-Hydroxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) -ethoxy]-
Phenyl} propionic acid ethyl ester (the compound of Example 2) 0.50 g (1.3 mM) and chloromethyl methyl ether 0.10 g (1.3 mM) were added to dichloromethane 30 ml.
Dissolved in N, N-diisopropylethylamine 0.1
3 g (1.3 mM) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with a 1N aqueous hydrochloric acid solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained oily substance was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to give 0.35 g of the title compound having the following properties as white crystals.
(Yield 63%) was obtained. ¹ HNMR (CDCl ₃ , δ) 1.23 (t, 3H, J =
7.3) 2.37 (s, 3H) 2.55 (t, 2H, J =
7.8) 2.88 (t, 2H, J = 7.8) 2.96 (t,
2H, J = 6.6) 3.47 (s, 3H) 4.11 (q,
2H, J = 7.0) 4.20 (t, 2H, J = 6.6) 5.
17 (s, 2H) 6.48 (dd, 1H, J = 2.3 &
8.2) 6.66 (d, 1H, J = 2.3) 7.03 (d,
1H, J = 8.6) 7.40-7.43 (m, 3H) 7.9
5 (m, 2H) EI-MS m / z; 439 IR (KBr, cm ^-1 ) 1728, 1182, 112.
2,1070,1028

Example 6 (E) -3- {4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-trifluoromethylphenyl} acrylic acid ethyl ester (Step 1) 4 -[2- (5-methyl-2-phenyl-4
-Oxazolyl) -ethoxy] -2-trifluoromethyl-benzaldehyde synthesis 2- (5-methyl-2-phenyl-4-oxazolyl)
0.96 g (5.0 mM) of ethanol was dissolved in 50 ml of dimethylformamide, cooled to 0 ° C. and sodium hydride (60% in oil) was added. In the reaction solution, after stirring at 0 ° C. for 1 hour until the generation of hydrogen was completed, 4-fluoro-2-trifluoromethylbenzaldehyde was added to 0
Dropwise at ° C. The reaction solution was returned to room temperature and stirred overnight. Water was added to the reaction solution, which was extracted and washed with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting oily matter was subjected to silica gel chromatography (hexane:
The product was purified with ethyl acetate = 9: 1) and crystallized from hexane / ethyl acetate to give 0.70 g (yield 37%) of the title compound having the following properties. ¹ HNMR (CDCl ₃ , δ) 2.39 (s, 3H) 3.0
3 (t, 2H, J = 6.6) 4.38 (t, 2H, J = 6.6)
6) 7.15 (dd, 1H, J = 2.0 & 8.9) 7.24
(D, 1H, J = 2.3) 7.41-7.45 (m, 3
H) 7.95-7.99 (m, 3H) 8.10 (d, 1
H, J = 8.6) 10.24 (s.1H)

(Step 2) (E) -3- {4- [2- (5
-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-trifluoromethylphenyl} acrylic acid ethyl ester 0.70 g (1.9 mM) of the aldehyde compound obtained in Step 1 and carboethoxymethylenetriphenylphosphorane 0.6
4 g (1.9 mM) was dissolved in 50 ml of toluene and boiled under reflux overnight. The reaction mixture was cooled and the solvent was evaporated under reduced pressure to give an oily substance which was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) and further crystallized from hexane / ethyl acetate to give the title compound having the following properties. As white crystals, 0.30 g (36%) was obtained. ¹ HNMR (CDCl ₃ , δ) 1.33 (t, 3H, J =
7.10) 2.39 (s, 3H) 3.01 (t, 2H, J
= 6.8) 4.26 (q, 2H, J = 6.9) 4.32
(T, 2H, J = 6.8) 6.31 (d, 1H, J = 1
5.8) 7.06 (dd, 1H, J = 2.6 & 8.6) 7.
20 (d, 2H, 2.6) 7.40-7.45 (m. 3H)
7.50 (d, 1H, J = 8.9) 7.94-8.00
(M.3H) EI-MS m / z; 445 IR (KBr, cm ^-1 ) 1710, 1305, 115
9,1114

Example 7 3- {4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-trifluoromethylphenyl} propionic acid ethyl ester (E) -3- {4- Catalytic reduction of [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -2-trifluoromethylphenyl} acrylic acid ethyl ester (product compound of Example 6) in the same manner as in Example 2 The title compound having the following properties was obtained. (Yield 97%) ¹ HNMR (CDCl ₃ , δ) 1.24 (t, 3H, J =
7.1) 2.38 (s, 3H) 2.56 (t, 2H, J =
7.9) 2.95-3.07 (m, 4H) 4.13 (q, 2)
H, J = 7.3) 4.25 (t, 2H, J = 6.8) 6.9
9 (dd, 1H, J = 2.6 & 8.3) 7.14 (d, 1
H, J = 2.6) 7.23 (d, 1H, J = 8.6) 7.3
9-7.47 (m, 3H) 7.95-7.99 (m, 2
H) EI-MS m / z; 447 IR (KBr, cm ^-1 ) 1722, 1504, 142
9, 1330, 1315, 1296, 1230, 115
5,1112

Example 8 (E) -3- {4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-nitrophenyl} acrylic acid ethyl ester (Step 1) (E) Synthesis of 3- (4-hydroxy-2-nitro-phenyl) acrylic acid ethyl ester By reacting with 4-hydroxy-2-nitrobenzaldehyde and treating with Wittig reagent in the same manner as in Step 2 of Example, the following properties are obtained. The title compound was obtained. ¹ HNMR (CDCl ₃ , δ) 1.33 (t, 3H, J =
7.26) 4.26 (q, 2H, J = 7.26) 6.27
(D, 1H, 15.8) 7.10 (dd, 1H, 2.0 &
8.6) 7.47-7.52 (m, 2H) 7.99 (d, 1
H, 15.8) 9.6 (Br, 1H)

(Step 2) (E) -3- {4- [2- (5
Synthesis of -Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-nitrophenyl} acrylic acid ethyl ester (E) -3- (4-hydroxy-2-) obtained in Step 1 above.
Nitro-phenyl) acrylic acid ethyl ester 0.80 g
(3.4 mM), 2- (5-methyl-2-phenyl-4-)
0.69 g (3.4 mM) of oxazolyl) ethanol and 1.04 g (4 mM) of triphenylphosphine were dissolved, 0.57 g (4 mM) of dimethyl azodicarboxylate was added dropwise, and the mixture was stirred overnight. After the reaction was completed, the solvent was distilled off under reduced pressure and the obtained oily product was purified by column chromatography (chloroform: methanol = 99: 1) to obtain 1.2 g of the title compound having the following properties as a white crystalline product (yield: 84%). ¹ HNMR (CDCl ₃ , δ) 1.33 (t, 3H, J =
6.9) 2.39 (s, 3H) 3.01 (t, 2H, J =
6.6) 4.27 (q, 2H.J = 6.9) 4.35 (t,
2H, J = 6.6) 6.80 (d, 1H, J = 16.0)
7.17 (dd, 1H, J = 2.6 & 8.9) 7.41-
7.45 (m, 3H) 7.51 (d, 1H, J = 2.6
2) 7.55 (d, 1H, J = 8.9) 7.95-7.97
(M, 2H) 8.01 (d, 1H, J = 15.7) EI-MS m / z; 422 IR (KBr, cm ^-1 ) 1709 1529 1269.
1253

Example 9 (E) -3- {4- [2- (5-methyl-2-phenyl-4-oxazolyl) -ethoxy] -2-nitrophenyl} acrylic acid The product compound of Example 8 (E ) -3- {4- [2- (5-
Methyl-2-phenyl-4-oxazolyl) ethoxy]
2-Nitrophenyl} acrylic acid ethyl ester 2.
4 g (5.7 mM) was dissolved in 100 ml of methanol, 10 ml of 2N sodium hydroxide aqueous solution was added, and the mixture was refluxed and boiled for 4 hours. 100 ml of 0.5N hydrochloric acid aqueous solution was added to the reaction solution, and the precipitated solid was filtered off to obtain 2.2 g (yield 98%) of the title compound having the following properties as white crystals. ¹ HNMR (DMSO-d ₆ , δ) 2.37 (s, 3H)
2.97 (t, 2H, J = 6.6) 4.37 (t, 2H,
J = 6.6) 6.48 (d, 2H, J = 15.5) 7.31
−7.59 (m, 5H) 7.70 (d, 1H, J = 15.
8) 7.89-7.92 (m, 3H) EI-MS m / z; 394 IR (KBr, cm ^-1 ) 1695, 1610, 153.
5,1359,1226

Example 10 3- {4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-nitrophenyl} propionic acid ethyl ester (Step 1) (E) -3- ( Synthesis of 4-hydroxy-2-nitro-phenyl) acrylic acid 1.2 g (E) -3- (4-hydroxy-2-nitro-phenyl) acrylic acid ethyl ester obtained in step 1 of Example 8 1 mM) in 50 ml of methanol and 2N
8 ml of an aqueous sodium hydroxide solution was added, and the mixture was refluxed and boiled for 3 hours. A 0.5N aqueous hydrochloric acid solution was added to the reaction solution, the mixture was extracted with dichloromethane and washed with water, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and 0.95 g (92%) of the title compound having the following properties was obtained as yellow crystals. ¹ HNMR (DMSO-d ₆ , δ) 6.42 (d, 1H,
J = 15.5) 7.14 (dd, 1H, J = 2.6 & 8.
6) 7.36 (d, 1H, J = 2.3) 7.63 (d, 1
H, J = 15.8) 7.83 (d, 2H, J = 8.9)

(Step 2) Synthesis of 3- (4-hydroxy-2-nitrophenyl) propionic acid 0.95 g of (E) -3- (4-hydroxy-2-nitro-phenyl) acrylic acid obtained in Step 1 (4.5 mM), hydroxyamine-O-sulfonic acid 25.7 g (227.0 m)
M) and hydroxyamine sulfate 18.9 g (113.5 mM)
Is dissolved in a mixed solution of 50 ml of water and 50 ml of acetonitrile,
The reaction solution was neutralized with 40% sodium hydroxide and then stirred at room temperature overnight. A 1N aqueous hydrochloric acid solution was added to the reaction solution, the mixture was extracted and washed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The oily substance obtained by distilling off the solvent was subjected to silica gel chromatography (chloroform: methanol = 19:
Purified in 1), 0.50 g (52%) of the title compound having the following properties was obtained as yellow crystals. ¹ HNMR (DMSO, δ) 2.51 (t, 2H, J =
7.6) 2.93 (t, 2H, J = 7.6) 7.05 (d
d, 1H, J = 2.6 & 8.6) 7.27-7.33 (m,
2H) EI-MS m / z; 202

(Step 3) Synthesis of 3- (4-hydroxy-2-nitrophenyl) propionic acid ethyl ester 0.5 g of 3- (4-hydroxy-2-nitrophenyl) propionic acid obtained in Step 2 (2. 5mM) ethanol 50m
It was dissolved in 1 l, 0.1 ml of concentrated sulfuric acid was added, and the mixture was refluxed and boiled overnight. The solvent of the reaction solution was evaporated under reduced pressure, water was added, the mixture was extracted and washed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound having the following properties as a brown oil (0.52 g, yield 88%). ¹ HNMR (CDCl ₃ , δ) 1.25 (t, 3H, J =
6.9) 2.70 (t, 2H, J = 7.3) 3.16 (t,
2H, J = 7.3) 4.14 (q, 2H, J = 7.0) 6.
04 (br, 1H) 6.99 (dd, 1H, J = 2.6 &
8.6) 7.24 (d, 1H, J = 8.2) 7.41 (d,
1H, J = 2.6) EI-MS m / z; 239

(Step 4) 3- {4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -2-
Synthesis of nitrophenyl} propionic acid ethyl ester 0.50 g (2.1 m) of 3- (4-hydroxy-2-nitrophenyl) propionic acid ethyl ester obtained in Step 3
M), 2- (5-methyl-2-phenyl-4-oxazolyl) ethanol 0.43 g (2.1 mM) and triphenylphosphine 0.66 g (2.4 mM) were dissolved, and diethyl azodicarboxylate 0.44 g ( 2.4 mM) was added dropwise, and the mixture was stirred overnight at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure and the obtained oily product was purified by silica gel column chromatography (hexoic acid: ethyl acetate = 3: 1). (Yield 8
1%) was obtained. ¹ HNMR (CDCl ₃ , δ) 1.22 (t, 3H, J =
7.3) 2.38 (s, 3H) 2.65 (t, 2H, J =
7.6) 2.99 (t, 2H, J = 6.6) 3.14 (t,
2H, J = 7.5) 4.11 (q, 2H, J = 7.2) 4.
29 (t, 2H, J = 6.8) 7.07 (dd, 1H, J
= 2.6 & 8.5) 7.28 (d, 1H, J = 8.6) 7.
39-7.48 (m, 4H) 7.95-7.99 (m, 2
H) EI-MS m / z; 424 IR (KBr, cm ^-1 ) 1718, 1531, 134.
8,1244,1207

Example 11 3- {4- [2- (2-benzoxazolylmethylamino) ethoxy)]-2-nitrophenyl} propionic acid ethyl ester 2- (2-benzoxazolylmethylamino) ethanol 0.41 g (2.1 mM) and 3 obtained in step 3 of Example 10
0.51 g (2.1 mM) of ethyl 4- (4-hydroxy-2-nitrophenyl) propionate was reacted with an alkylating reagent in the same manner as in Step 4 of Example 10 to give a white crystal of the title compound having the following properties ( Yield 80%) was obtained. ¹ HNMR (CDCl ₃ , δ) 1.22 (t, 3H, J =
6.9) 2.66 (t, 2H, J = 7.4) 3.14 (t,
2H, J = 7.4) 3.35 (s, 3H) 3.97 (t,
2H, J = 5.3) 4.11 (q, 2H, 7.J = 7.3)
4.31 (t, 2H, J = 5.3) 6.99-7.38
(M, 6H) 7.49 (d, 1H, J = 2.6) EI-MS m / z; 413 IR (KBr, cm-1) 1724, 1583, 137.
7,1197,1145

Pharmacological test of the compound of the present invention Test example In the experiment, non-insulin-dependent diabetic mice "KK-Ay / Ta Jcl" (male, CLEA Japan, 10 weeks old, 1 group = 3) were used. Mice were bred by free ingestion of powdered feed "CE-2" (CLEA Japan) from 5 days before the start of the test. On the first day of the test, the animals were fasted from 9 am to 1 pm, and then heparin was collected from the tail vein (50 μL), and the body weight was measured. The blood was kept on ice and centrifuged (10,000 rpm, 5 minutes), and the glucose and triglyceride concentrations in the obtained plasma were measured by glucose C-II test Wako and triglyceride E test Wako (Wako Pure Chemical Industries, Ltd., respectively). ) Was used for the measurement. After grouping so that the average blood glucose level (about 400 mg / dL) of each group was equal, the compound of the present invention was mixed with powdered feed [CE-2] at a ratio of 0.020% or 0.005%. And kept for 4 days. The estimated dose (mg / kg / day) was calculated from the mouse body weight and food intake. On the fifth day of the test, blood was collected in the same manner as on the first day, and the glucose and triglyceride concentrations in plasma were measured. still,
A group fed with a feed not containing the compound of the present invention was used as a control group, and pioglitazone represented by the formula (N) (feeding ratio: 0.020%) was used as a positive control compound. The rate of change (%) in blood glucose and blood triglyceride levels in each group was calculated by the following formula, and the results are shown in Table 1.

[0066]

[Equation 1]

Embedded image

[0067]

[Table 1]

Acute Toxicity Test “Jcl / ICR” mice (male, CLEA Japan, 6 weeks old, 1 group = 5) were used in the experiment. 250 mg / kg of the compound of the present invention shown in Table 1 was intraperitoneally administered to these and observed for one week, but all survived.

As is clear from the above test results (Table 1), the compound of the present invention showed excellent blood glucose lowering action and blood triglyceride lowering action even when compared with the positive control compound.
The compound of the present invention did not cause lactic acidosis, nor did it cause excessive hypoglycemia. From this, the compound of the present invention is not only useful for treating diabetes, but also useful as various complications of diabetes and blood lipid lowering agents. Moreover, all are highly safe compounds with less toxicity than the effective dose.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Kazuhiro Watanabe 4-53-3 Kitahama, Chuo-ku, Osaka-shi, Osaka Sumitomo Metal Industries, Ltd.

Claims (20)

[Claims] 1. A compound of the general formula (I) [Wherein R ₁ is substituted with a hydroxyl group, a lower alkoxy group, a phenyl lower alkoxy group, a phenoxy group, an amino group, a mono- or di-lower dialkylamino group, a pyrrolidino group, a piperidino group, a morpholino group, and 3 or less halogen atoms. Optionally represents a lower alkanesulfonylamino group or a benzenesulfonylamino group. R ₂ is a hydroxyl group, a thiol group, a nitro group, a halogen atom, a formyl group, a cyano group, a lower alkyl group optionally substituted with 3 or less halogen atoms, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkoxy group. , An amino group represented by NR ₃ R ₄ , a group represented by SO ₂ R ₅ , or -Q
It represents a group represented by (CH ₂ ) nZR ₆ . Where R ₃ ,
Each R ₄ is independently hydrogen, a lower alkyl group, an aralkyl group, a lower alkanoyl group, a benzoyl group, a nitro group or a benzoyl group substituted with a halogen atom, or a lower group which may be substituted with 3 or less halogen atoms. Represents an alkanesulfonyl group, and R ₅ represents a lower alkyl group which may be substituted with 3 or less halogen atoms, or a lower alkyl-substituted or unsubstituted phenyl group. Q is absent or represents an oxygen or sulfur atom, Z is an oxygen or sulfur atom or a carbonyl group, R ₆ is hydrogen, a hydroxyl group, a lower alkyl group or a lower alkoxy group, and n is 1, 2 or Or represents 3. X-Y is CH ₂ -C
H _2, CH = CH, represents O-CH ₂ or NH-CH _2,, m represents 0, 1 or 2. A is the formula (II), (II
I) or (IV) Represents an aromatic heterocyclic group represented by, where L is oxygen,
It represents a nitrogen or sulfur atom, and R ₇ and R ₈ each independently represent hydrogen, a lower alkyl group, a phenyl group, a thienyl group, or a furyl group. R ₉ represents hydrogen or a lower alkyl group. ] The novel substituted phenol derivative represented by these, or those pharmaceutically acceptable salts. 2. The compound according to claim 1, wherein m is 2, R ₁ is a hydroxyl group or a lower alkoxy group, and XY is CH ₂ —CH ₂ , or CH═CH. 3. A is of the formula (II): [In the formula, L represents oxygen, nitrogen, or sulfur, and R ₇ and R ₈ each independently represent hydrogen, a lower alkyl group, a phenyl group, a thienyl group, or a furyl group. ] The compound of Claim 2 which is a group shown by these. 4. A is of the formula (III): [In the formula, R ₉ represents hydrogen or a lower alkyl group. ]
The compound according to claim 2, which is a group represented by: 5. A is of formula (IV) [In the formula, L represents an oxygen, nitrogen or sulfur atom, and R ₉ represents hydrogen or a lower alkyl group. ] The compound of Claim 2 which is a group shown by these. 6. The compound according to claim 3, wherein L is an oxygen atom, R ₇ is a phenyl group, and R ₈ is a methyl group. 7. L is an oxygen atom and R ₉ is a methyl group,
The compound according to claim 5. 8. 3- {4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-nitrophenyl} acrylic acid ethyl ester; 3- {2-chloro-4- [2 -(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-bromo-4- [2- (5-methyl-2-
Phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-fluoro-4-
[2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester;
3- {2-hydroxy-4- [2- (5-methyl-2-
Phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-acetoxy-4-
[2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester;
3- {2-Formyl-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-cyano-4- [2-
(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2
-Acetyl-4- [2- (5-methyl-2-phenyl-
4-Oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-methoxy-4- [2- (5-
Methyl-2-phenyl-4-oxazolyl) ethoxy]
Phenyl} acrylic acid ethyl ester; 3- {2-ethoxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {4- [2- ( 5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-trifluoromethylphenyl} acrylic acid ethyl ester; 3- {2-
Amino-4- [2- (5-methyl-2-phenyl-4-
Oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-methylamino-4- [2- (5-
Methyl-2-phenyl-4-oxazolyl) ethoxy]
Phenyl} acrylic acid ethyl ester; 3- {2-ethylamino-4- [2- (5-methyl-2-phenyl-4)
-Oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {2-methanesulfonyl-4- [2-
(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {4
-[2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-trifluoromethanesulfonylphenyl} acrylic acid ethyl ester; 3- {2-methoxymethoxy- {4- [2- (5-methyl 2-Phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {4- [2- (5-methyl-2-
Phenyl-4-oxazolyl) ethoxy] -2-ethoxymethoxyphenyl} acrylic acid ethyl ester; 3-
{4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-methylthiomethoxyphenyl} acrylic acid ethyl ester; 3- {2-ethylthiomethoxy-4- [2- (5- Methyl-2-phenyl-4
-Oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3-{-2-hydroxymethyl-4- [2
-(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3-
{2-methoxymethyl-4- [2- (5-methyl-2-
Phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid ethyl ester; 3- {4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -2
-Nitrophenyl} propionic acid ethyl ester; 3-
{2-chloro-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-bromo-4- [2- (5
-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2
-Fluoro-4- [2- (5-methyl-2-phenyl-
4-Oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-hydroxy-4- [2-
(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3-
{2-acetoxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-formyl-4- [2
-(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3-
{-2-Cyano-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-acetyl-4- [2-
(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3-
{2-Methoxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-ethoxy-4- [2-
(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3-
{4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-trifluoromethylphenyl} propionic acid ethyl ester; 3- {2-amino-
4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-methylamino-4- [2- (5-methyl-2-phenyl-4) -Oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-ethylamino-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- { 2-Methanesulfonyl-4- [2-
(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3-
{4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-trifluoromethanesulfonylphenyl} propionic acid ethyl ester; 3- {2-
Methoxymethoxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-ethoxymethoxy-
4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {4- [2- (5-methyl-2-phenyl-4)
-Oxazolyl) ethoxy] -2-methylthiomethoxyphenyl} propionic acid ethyl ester; 3- {2-ethylthiomethoxy-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid Ethyl ester; 3- {2-hydroxymethyl-
4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {2-methoxymethyl-4- [2- (5-methyl-2-phenyl-4) -Oxazolyl) ethoxy] phenyl} propionic acid ethyl ester; 3- {4- [2-
(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-nitrophenyl} acrylic acid; 3- {2-
Formyl-4- [2- (5-methyl-2-phenyl-4]
-Oxazolyl) ethoxy] phenyl} acrylic acid; 3
-{2-cyano-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid; 3- {4- [2- (5-methyl-2-phenyl-4)
-Oxazolyl) ethoxy] -2-trifluoromethylphenyl} acrylic acid; 3- {2-methoxymethoxy-
4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} acrylic acid; 3- {4-
[2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -2-nitrophenyl} propionic acid;
3- {2-formyl-4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid; 3- {2-cyano-4- [2- (5-methyl-2) -Phenyl-4-oxazolyl) ethoxy] phenyl} propionic acid; 3- {4- [2- (5-methyl-2)
-Phenyl-4-oxazolyl) ethoxy] -2-trifluoromethylphenyl} propionic acid; 3- {4-
[2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -2-methoxymethoxyphenyl} propionic acid; 3- {4- [2- (2-benzoxazolylmethylamino) ethoxy)]- 2-Nitrophenyl} acrylic acid ethyl ester; 3-{-2-formyl-4-
[2- (2-benzoxazolylmethylamino) ethoxy)] phenyl} acrylic acid ethyl ester; 3-{-
2-Cyano-4- [2- (2-benzoxazolylmethylamino) ethoxy)] phenyl} acrylic acid ethyl ester; 3- {4- [2- (2-benzoxazolylmethylamino) ethoxy)] -2-Trifluoromethylphenyl} acrylic acid ethyl ester; 3- {4- [2-
(2-benzoxazolylmethylamino) ethoxy)]
2-Methoxymethoxyphenyl} acrylic acid ethyl ester; 3- {4- [2- (2-benzoxazolylmethylamino) ethoxy)]-2-nitrophenyl} propionic acid ethyl ester; 3- {2-formyl -4-
[2- (2-Benzoxazolylmethylamino) ethoxy)] phenyl} propionic acid ethyl ester; 3-
{-2-Cyano-4- [2- (2-benzoxazolylmethylamino) ethoxy)] phenyl} propionic acid ethyl ester; 3- {4- [2- (2-benzoxazolylmethylamino) ethoxy )]-2-Trifluoromethylphenyl} propionic acid ethyl ester; 3- {4
-[2- (2-Benzoxazolylmethylamino) ethoxy)]-2-methoxymethoxyphenyl} propionic acid ethyl ester; {4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] 2-Nitrophenoxy} acetic acid ethyl ester; {4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy]-
The novel substituted phenol derivative according to claim 1 selected from 2-nitrophenylamino} acetic acid ethyl ester or a pharmaceutically acceptable salt thereof. 9. A compound represented by the general formula (I): A process for producing a substituted phenol derivative represented by: or a pharmaceutically acceptable salt thereof, which comprises a compound represented by the general formula (C): The 2,4-disubstituted benzaldehyde compound represented by
Reacting with a Wittig reagent of the formula PPh ₃ = COR ₁ to give an acrylic acid type product or further reducing the double bond of the acrylic acid moiety of this product to the corresponding propionic acid type product, Furthermore, if necessary, the above-mentioned product is converted into a pharmaceutically acceptable salt thereof by a conventional method. [Wherein R ₁ is a hydroxyl group, a lower alkoxy group, a phenyl lower alkoxy group, a phenoxy group, an amino group, a mono- or di-lower dialkylamino group, a pyrrolidino group, a piperidino group, a morpholino group, 3
Represents a lower alkanesulfonylamino group which may be substituted with up to 4 halogen atoms, or a benzenesulfonylamino group. R ₂ is a hydroxyl group, a thiol group, a nitro group, a halogen atom, a formyl group, a cyano group, or a lower alkyl group which may be substituted with 3 or less halogen atoms,
Lower alkanoyl group, lower alkanoyloxy group, lower alkoxy group, amino group represented by NR ₃ R ₄ , SO ₂ R ₅
In represents a group represented by or -Q (CH ₂₎ groups represented by NZr _6,. Here, R ₃ and R ₄ are each independently substituted with hydrogen, a lower alkyl group, an aralkyl group, a lower alkanoyl group, a benzoyl group, a nitro group or a benzoyl group substituted with a halogen atom, or 3 or less halogen atoms. Represents an optionally substituted lower alkanesulfonyl group, and R ₅ represents a lower alkyl group optionally substituted with 3 or less halogen atoms, or a lower alkyl-substituted or unsubstituted phenyl group. Q is absent or represents an oxygen or sulfur atom, Z is an oxygen or sulfur atom or a carbonyl group, R ₆ is hydrogen, a hydroxyl group, a lower alkyl group or a lower alkoxy group, and n is 1, 2 or Or represents 3.
X-Y represents _{CH 2 -CH 2, CH = CH} , the O-CH ₂ or NH-CH _2,, m represents 0, 1 or 2. A
Is of formula (II), (III), or (IV) Represents an aromatic heterocyclic group represented by, where L is oxygen,
It represents a nitrogen or sulfur atom, and R ₇ and R ₈ each independently represent hydrogen, a lower alkyl group, a phenyl group, a thienyl group, or a furyl group. R ₉ represents hydrogen or a lower alkyl group. ] 10. The 2,4-disubstituted benzaldehyde compound represented by the general formula (C) is obtained by converting the corresponding 4-hydroxy-2-substituted benzaldehyde compound (B) into the formula A- (C
H ₂ ) m-R ₁₁ is reacted with an A- (CH ₂ ) m group-introduced alkylating reagent, or the corresponding 4-halogen-2-substituted benzaldehyde compound (D) is represented by the formula A-
The production method according to claim 9, which is obtained by reacting with an alkanol derivative represented by (CH ₂ ) m-OH.
[In the formula, R ₁₁ represents a functional group serving as a leaving group in the nucleophilic reaction, and the other symbols have the same meanings as described above. ] 11. When R ₂ in the acrylic acid type or propionic acid type product obtained by the method of claim 9 or 10 is a hydroxyl group or a thiol group, the product is further introduced with a group R _{12 as} a reagent. Reacting with the group R ₂ to give a group ZR ₁₂
Method according to claim 9 or 10, characterized in that [In the formula, Z represents an oxygen atom or a sulfur atom, R ₁₂ represents a lower alkanoyl, a lower alkyl, or-(CH ₂ ).
nZR ₆ and other symbols have the same meanings as described above. ] 12. A compound represented by the general formula (I): A process for producing a substituted phenol derivative represented by: or a pharmaceutically acceptable salt thereof, comprising a 4-hydroxy-2-substituted benzaldehyde compound (B) represented by the general formula (B): Is reacted with a Wittig reagent of the formula PPh ₃ = COR ₁ to give the intermediate 4-hydroxy-2-substituted phenylacrylic acid compound of the formula (J) And the intermediate compound (J) is represented by the formula A- (CH ₂ ) mR ₁₁
In indicated by A- (CH ₂₎ was reacted with m groups introduced alkylating reagent or an acrylic acid type product (E), or,
Further, the double bond of the acrylic acid moiety of the product (E) is reduced to give the corresponding propionic acid type product (F), or the intermediate compound (J) is hydrolyzed to give a carboxy group. After freeing, and then reducing the double bond of the acrylic acid moiety, and further esterifying or amidating to reintroduce the group R ₁ into the carboxy group, the above A- (C
H ₂ ) m group-introduced alkylating reagent is reacted to give a propionic acid type product (F), and if necessary, these products (E) and (F) are pharmaceutically acceptable by a conventional method. A method characterized by changing to a possible salt. [Wherein the symbols have the same meanings as described above] 13. A compound represented by the general formula (I-OH): A process for producing a substituted phenol derivative represented by: or a pharmaceutically acceptable salt thereof, comprising the following general formulas (E), (F),
(G) or (H) By hydrolyzing the compound represented by the general formula (K) or (L) The compound represented by the formula (I) is reacted with an A- (CH ₂ ) m group-introduced alkylating reagent represented by the formula A- (CH ₂ ) mR ₁₁ and, if necessary, the product is pharmaceutically acceptable by a conventional method. A method characterized by changing to a possible salt. [In the formula,
The symbols have the same meanings as above] 14. A compound represented by the general formula (I): [Wherein R ₁ is substituted with a hydroxyl group, a lower alkoxy group, a phenyl lower alkoxy group, a phenoxy group, an amino group, a mono- or di-lower dialkylamino group, a pyrrolidino group, a piperidino group, a morpholino group, and 3 or less halogen atoms. Optionally represents a lower alkanesulfonylamino group or a benzenesulfonylamino group. R ₂ is a hydroxyl group, a thiol group, a nitro group, a halogen atom, a formyl group, a cyano group, a lower alkyl group which may be substituted with 3 or less halogen atoms, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkoxy group. , An amino group represented by NR ₃ R ₄ , a group represented by SO ₂ R ₅ , or -Q
It represents a group represented by (CH ₂ ) nZR ₆ . Where R ₃ ,
Each R ₄ is independently hydrogen, a lower alkyl group, an aralkyl group, a lower alkanoyl group, a benzoyl group, a nitro group or a benzoyl group substituted with a halogen atom, or a lower group which may be substituted with 3 or less halogen atoms. Represents an alkanesulfonyl group, and R ₅ represents a lower alkyl group which may be substituted with 3 or less halogen atoms, or a lower alkyl-substituted or unsubstituted phenyl group. Q is absent or represents an oxygen or sulfur atom, Z is an oxygen or sulfur atom or a carbonyl group, R ₆ is hydrogen, a hydroxyl group, a lower alkyl group or a lower alkoxy group, and n is 1, 2 or Or represents 3. X-Y is CH ₂ -C
H _2, CH = CH, represents O-CH ₂ or NH-CH _2,, m represents 0, 1 or 2. A is the formula (II), (II
I) or (IV) Represents an aromatic heterocyclic group represented by, where L is oxygen,
It represents a nitrogen or sulfur atom, and R ₇ and R ₈ each independently represent hydrogen, a lower alkyl group, a phenyl group, a thienyl group, or a furyl group. R ₉ represents hydrogen or a lower alkyl group. ] The pharmaceutical composition for diabetes and / or hyperlipidemia prevention treatment which comprises the effective amount of the substituted phenol derivative shown by these, or its pharmaceutically acceptable salt. 15. m is 2, R ₁ is a hydroxyl group or a lower alkoxy group, and XY is CH ₂ —CH ₂ or C.
The pharmaceutical composition according to claim 14, which is a group represented by H = CH. 16. A is of formula (II): [In the formula, L represents oxygen, nitrogen, or sulfur, and R ₇ and R ₈ each independently represent hydrogen, a lower alkyl group, a phenyl group, a thienyl group, or a furyl group. ] The composition of Claim 14 which is a group shown by these. 17. A is of formula (III): [In the formula, R ₉ represents hydrogen or a lower alkyl group. ] The composition of Claim 14 which is a group shown by these. 18. A is of formula (IV) [In the formula, L represents an oxygen, nitrogen or sulfur atom, and R ₉ represents hydrogen or a lower alkyl group. ] The composition of Claim 14 which is a group shown by these. 19. L is an oxygen atom, R ₇ is a phenyl group, and R ₈
15. The composition according to claim 14, wherein is a methyl group. 20. The composition according to claim 14, wherein L is an oxygen atom and R ₉ is a methyl group.