JP2006232706A - Phenetylamine derivative and medicine by using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound having an excellent PPAR (peroxisome proliferator-activated receptor)α/γ agonistic activity and desirable properties as a medicine. <P>SOLUTION: This peroxisome proliferator-activated receptor α/γ agonist is expressed e.g. by formula (I), exhibits the excellent PPAR α/γ agonistic activity and is useful as a preventing or treating agent of diabetes. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a phenethylamine derivative, a salt thereof, or a solvate thereof effective as a prophylactic / therapeutic agent for diabetes. More specifically, the present invention relates to a peroxisome proliferator-activated receptor α / γ agonist (PPAR α / γ agonist).

Diabetes mellitus is a disease that causes a significant disorder in daily life by developing or developing various acute or chronic complications such as ischemic heart disease and cerebrovascular disorder. Therefore, it is necessary to prevent the onset and progression of these complications through early detection and strict glycemic control.
Diabetes mellitus is type 1 diabetes, in which the production and secretion of insulin that controls blood sugar is impaired, and the production and secretion of insulin is at a high level from the normal range, but the sensitivity is decreased in the target organ and tissue of insulin ( That is, it is classified as type 2 diabetes (in which insulin resistance is increased).
The main target organs and tissues of insulin are muscle, adipose tissue and liver, which promotes glucose uptake and glycogen synthesis in muscle, promotes glucose uptake and utilization in adipose tissue, and gluconeogenesis in liver Suppresses and promotes glycogen synthesis. Insulin not only controls sugar metabolism as described above, but is also involved in fat metabolism (facilitation of fat synthesis and inhibition of degradation) in adipose tissue.

  In recent years, thiazolidinedione derivatives (Non-patent Document 1) such as pioglitazone having the following structure have been developed as drugs for improving insulin resistance and are widely used for the treatment of type 2 diabetic patients, particularly type 2 diabetic patients with obesity. It is used.

  These thiazolidinedione derivatives have been shown to be agonists of peroxisome proliferator-activated receptor γ (PPARγ) (Non-patent Document 2). Although the mechanism by which PPARγ agonists improve insulin resistance has not been fully elucidated, apoptosis of hypertrophic adipocytes that produce and secrete free fatty acids that induce insulin resistance and differentiation from preadipocytes to adipocytes The promotion of free fatty acid uptake and storage by promotion is cited as a promising theory.

Pioglitazone, which is a PPARγ agonist, is administered to type 2 diabetic patients with obesity, and has a high therapeutic effect. On the other hand, weight gain and fluid retention have been observed in some patients (non-patent literature). 3). As mentioned above, since diabetes causes and develops complications such as ischemic heart disease and cerebrovascular disorder, such weight gain and fluid retention are not preferable. Recently, research on PPARα / γ agonists in which PPARα agonist activity is added to PPARγ agonists has been active, and it has been suggested that animal models exhibit properties as antidiabetic agents superior to PPARγ agonists. For example, in a test using db / db mice, it has been shown that the PPARα / γ agonist KRP-297 significantly suppresses the increase in body weight compared to pioglitazone (Non-patent Document 4). In addition, it has been shown that the PPARα / γ agonist LY465608 increases high-density lipoprotein (HDL) in a dose-dependent manner and decreases plasma triglycerides to reduce the risk of ischemic heart disease (Non-patent Document 5). ).
Representative PPARα / γ agonists include the following compounds (Non-patent Documents 6 and 7 and Patent Documents 1 and 2).

Chem. Pharm. Bull., 39, 1440-1445 (1991) J. Biol. Chem., 270, 12953-12956 (1995) Am. J. Med., 115 (8A), 111S-115S (2003) Am. J. Physiol., 284, E966-E971 (2003) Diabetes, 51, 1083-1087 (2002) Bioorg. Med. Chem. Lett., 9, 533-538 (1999) Chem. Pharm. Bull., 51, 138-151 (2003) WO2001-021602 WO 2004-000785

  An object of the present invention is to provide a compound having a chemical structure that is different from the aforementioned known PPARα / γ agonist, has an excellent PPARα / γ agonist activity, and has desirable properties as a pharmaceutical product.

As a result of various studies, the present inventor has found that a phenethylamine derivative represented by the following general formula (I) exhibits an excellent PPARα / γ agonist activity and is useful as a prophylactic / therapeutic agent for diabetes. Completed the invention.
That is, the general formula (I)

(In the above formula,
R ¹ and R ² are each independently a hydrogen atom, hydroxyl group, halogen atom, lower alkoxy group, cyano group, lower alkanoyl group, lower alkylcarbamoyloxy group, lower alkylsulfonyl group, lower alkylthio group, lower alkylsulfinyl group, substituted A lower alkyl group which may have a group, an amino group which may have a substituent, a carbamoyl group which may have a substituent, a lower alkylsulfonyloxy group which may have a substituent An arylsulfonyloxy group which may have a substituent, a sulfamoyl group which may have a lower alkyl group, a sulfamoyloxy group which may have a lower alkyl group, and a substituent. 5-6 membered saturated heterocyclic group which may have, 5-6 membered aromatic heterocyclic group which may have a substituent, A good aryloxy group, or an aryl group which may have a substituent,
R ³ represents a lower alkoxy group, an optionally substituted carbamoyl group, or an optionally substituted 5- to 6-membered aromatic heterocyclic group;
R ⁴ and R ⁵ each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, an optionally substituted lower alkyl group, or an optionally substituted amino group. Group,
R ⁶ and R ⁷ each independently represent a hydrogen atom or a lower alkyl group, or R ⁶ and R ⁷ together with the carbon atom to which they are substituted form a 3-6 membered aliphatic saturated ring. May form,
R ⁸ represents a hydrogen atom or a lower alkyl group,
m represents an integer of 1 to 3 (provided that when R ³ is a lower alkoxy group, m represents an integer of 2 to 3), and n represents an integer of 1 to 3. )
The compound represented by these, its salt, or those solvates are provided.

The present invention also provides a pharmaceutical comprising the compound represented by the above general formula (I), a salt thereof or a solvate thereof as an active ingredient.
The present invention also provides a pharmaceutical composition comprising a compound represented by the above general formula (I), a salt thereof or a solvate thereof and a pharmaceutically acceptable carrier.
Furthermore, the present invention provides use of the compound represented by the above general formula (I), a salt thereof or a solvate thereof for the production of a medicine.
Furthermore, the present invention provides a therapeutic agent for diseases caused by insulin resistance, comprising the compound represented by the above general formula (I), a salt thereof or a solvate thereof. is there.
Furthermore, this invention provides the therapeutic agent of diabetes characterized by containing the compound represented by the said general formula (I), its salt, or those solvates.

  The compound represented by the general formula (I) of the present invention exhibits an excellent PPARα / γ agonist action and is useful as a prophylactic / therapeutic agent for diabetes.

Below, each substituent in general formula (I) is demonstrated.
A halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. As the halogen atom, a fluorine atom, a chlorine atom and a bromine atom are preferable.

The lower alkoxy group means an alkoxy group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, such as methoxy group, ethoxy group, propoxy group, 1-methylethoxy group, butoxy group. Typical examples include a group, 1,1-dimethylethoxy group, 2-methylpropoxy group, pentoxy group, and cyclopentyloxy group. Among these, a methoxy group, an ethoxy group, a butoxy group, and a 1,1-dimethylethoxy group are preferable, and a methoxy group and a 1,1-dimethylethoxy group are more preferable.
The same applies to lower alkoxy groups used in the following description of various substituents.

  The lower alkanoyl group means a linear or branched alkanoyl group having 2 to 6 carbon atoms, such as ethanoyl group, propanoyl group, butanoyl group, 2-methylpropionyl group, pentanoyl group, and 3-methyl. A butanoyl group can be mentioned as a representative example. Among these, an ethanoyl group, a propanoyl group, and a butanoyl group are preferable, and an ethanoyl group is more preferable. The same applies to lower alkanoyl groups used in the description of various substituents below.

  The lower alkyl group means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and includes a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, and 1-methylethyl. Group, 1,1-dimethylethyl group, 1-methylpropyl group, 2-methylpropyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-methylbutyl group 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group 3,3-dimethylbutyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, cyclopropyl group, cyclobutyl group, Butyl group, a cyclohexyl group, a cyclopropylmethyl group, and cyclobutylmethyl group, and a cyclopentylmethyl group as a representative example. Among these, a methyl group, an ethyl group, and a propyl group are preferable. The same applies to lower alkyl groups used in the description of various substituents below.

  Examples of the lower alkylcarbamoyloxy group include carbamoyloxy groups having the above lower alkyl groups, and specific examples include methylcarbamoyloxy group, ethylcarbamoyloxy group, dimethylcarbamoyloxy group, and diethylcarbamoyloxy group. Can be mentioned.

  Examples of the lower alkylsulfonyl group include sulfonyl groups having the above-mentioned lower alkyl groups, and specifically include methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group, pentylsulfonyl group, hexylsulfonyl group, 1 -Methylethylsulfonyl group, 1,1-dimethylethylsulfonyl group, 1-methylpropylsulfonyl group, 2-methylpropylsulfonyl group, 1,1-dimethylpropylsulfonyl group, 1,2-dimethylpropylsulfonyl group, 2,2 -Dimethylpropylsulfonyl group, 1-methylbutylsulfonyl group, 2-methylbutylsulfonyl group, 3-methylbutylsulfonyl group, 1,1-dimethylbutylsulfonyl group, 1,2-dimethylbutylsulfonyl group, 1,3-dimethyl Butylsulfonyl group, , 2-dimethylbutylsulfonyl group, 2,3-dimethylbutylsulfonyl group, 3,3-dimethylbutylsulfonyl group, 1-methylpentylsulfonyl group, 2-methylpentylsulfonyl group, 3-methylpentylsulfonyl group, 4-methyl Typical examples include a pentylsulfonyl group, a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, a cyclohexylsulfonyl group, a cyclopropylmethylsulfonyl group, a cyclobutylmethylsulfonyl group, and a cyclopentylmethylsulfonyl group. Among these, a methylsulfonyl group, an ethylsulfonyl group, and a propylsulfonyl group are preferable, and a methylsulfonyl group is more preferable.

  Examples of the lower alkylthio group include thio groups having the above lower alkyl groups, and include methylthio group, ethylthio group, propylthio group, butylthio group, pentylthio group, hexylthio group, 1-methylethylthio group, 1,1-dimethylethyl group. Thio group, 1-methylpropylthio group, 2-methylpropylthio group, 1,1-dimethylpropylthio group, 1,2-dimethylpropylthio group, 2,2-dimethylpropylthio group, 1-methylbutylthio group 2-methylbutylthio group, 3-methylbutylthio group, 1,1-dimethylbutylthio group, 1,2-dimethylbutylthio group, 1,3-dimethylbutylthio group, 2,2-dimethylbutylthio group 2,3-dimethylbutylthio group, 3,3-dimethylbutylthio group, 1-methylpentylthio group, 2-methylpentylthio group, -Representative examples include methylpentylthio, 4-methylpentylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cyclopropylmethylthio, cyclobutylmethylthio, and cyclopentylmethylthio be able to. Among these, a methylthio group, an ethylthio group, and a propylthio group are preferable.

  Examples of the lower alkylsulfinyl group include sulfinyl groups having the above lower alkyl groups, such as methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, butylsulfinyl group, pentylsulfinyl group, hexylsulfinyl group, 1-methylethylsulfinyl group. 1,1-dimethylethylsulfinyl group, 1-methylpropylsulfinyl group, 2-methylpropylsulfinyl group, 1,1-dimethylpropylsulfinyl group, 1,2-dimethylpropylsulfinyl group, 2,2-dimethylpropylsulfinyl group 1-methylbutylsulfinyl group, 2-methylbutylsulfinyl group, 3-methylbutylsulfinyl group, 1,1-dimethylbutylsulfinyl group, 1,2-dimethylbutylsulfinyl group, 1,3- Methylbutylsulfinyl group, 2,2-dimethylbutylsulfinyl group, 2,3-dimethylbutylsulfinyl group, 3,3-dimethylbutylsulfinyl group, 1-methylpentylsulfinyl group, 2-methylpentylsulfinyl group, 3-methylpentyl Typical examples include sulfinyl group, 4-methylpentylsulfinyl group, cyclopropylsulfinyl group, cyclobutylsulfinyl group, cyclopentylsulfinyl group, cyclohexylsulfinyl group, cyclopropylmethylsulfinyl group, cyclobutylmethylsulfinyl group, and cyclopentylmethylsulfinyl group. be able to. Among these, a methylsulfinyl group, an ethylsulfinyl group, and a propylsulfinyl group are preferable.

  As the lower alkyl group which may have a substituent, in addition to the above lower alkyl group, a hydroxyl group, a halogen atom, an amino group, a lower alkylamino group, a di-lower alkylamino group, a lower alkoxy group, a carboxy group, Lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoylamino group, lower alkylcarbamoylamino group, di-lower alkylcarbamoylamino group, lower alkylsulfonylamino group, lower alkoxycarbonylamino group, and lower Examples include lower alkyl groups substituted with 1 to 3 groups selected from alkanoylamino groups, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, hydroxy Methyl group, 2-hydride Xylethyl group, 3-hydroxypropyl group, 2-fluoroethyl group, 2-chloroethyl group, 3-fluoropropyl group, aminomethyl group, 2-aminoethyl group, 3-aminopropyl group, methylaminomethyl group, 2-methyl Aminoethyl group, 3-methylaminopropyl group, dimethylaminomethyl group, 2-dimethylaminoethyl group, 3-dimethylaminopropyl group, methoxymethyl group, 2-methoxyethyl group, 3-methoxypropyl group, carboxymethyl group, 2-carboxyethyl group, 3-carboxypropyl group, methoxycarbonylmethyl group, 2-methoxycarbonylethyl group, 3-methoxycarbonylpropyl group, carbamoylmethyl group, 2-carbamoylethyl group, 3-carbamoylpropyl group, methylcarbamoylmethyl Group, 2-methyl Rubamoylethyl group, 3-methylcarbamoylpropyl group, ethylcarbamoylmethyl group, 2-ethylcarbamoylethyl group, 3-ethylcarbamoylpropyl group, dimethylcarbamoylmethyl group, 2-dimethylcarbamoylethyl group, 3-dimethylcarbamoylpropyl group, diethylcarbamoyl group Methyl group, 2-diethylcarbamoylethyl group, 3-diethylcarbamoylpropyl group, carbamoylaminomethyl group, 2-carbamoylaminoethyl group, 3-carbamoylaminopropyl group, methylcarbamoylaminomethyl group, 2-methylcarbamoylaminoethyl group, 3-methylcarbamoylaminopropyl group, ethylcarbamoylaminomethyl group, 2-ethylcarbamoylaminoethyl group, 3-ethylcarbamoylaminopropyl group, Dimethylcarbamoylaminomethyl group, 2-dimethylcarbamoylaminoethyl group, 3-dimethylcarbamoylaminopropyl group, diethylcarbamoylaminomethyl group, 2-diethylcarbamoylaminoethyl group, 3-diethylcarbamoylaminopropyl group, methylsulfonylaminomethyl group, 2-methylsulfonylaminoethyl group, 3-methylsulfonylaminopropyl group, methoxycarbonylaminomethyl group, 2-methoxycarbonylaminoethyl group, 3-methoxycarbonylaminopropyl group, ethoxycarbonylaminomethyl group, 2-ethoxycarbonylaminoethyl group Group, 3-ethoxycarbonylaminopropyl group, ethanoylaminomethyl group, 2-ethanoylaminoethyl group, and 3-ethanoylaminopropyl group It is possible to mention to.

Among them, methyl group, ethyl group, propyl group, trifluoromethyl group, hydroxymethyl group, 2-hydroxyethyl group, 2-fluoroethyl group, 2-chloroethyl group, aminomethyl group, 2-aminoethyl group, methylaminomethyl Group, 2-methylaminoethyl group, dimethylaminomethyl group, 2-dimethylaminoethyl group, methoxymethyl group, 2-methoxyethyl group, carboxymethyl group, 2-carboxyethyl group, methoxycarbonylmethyl group, 2-methoxycarbonyl Ethyl group, carbamoylmethyl group, 2-carbamoylethyl group, methylcarbamoylmethyl group, 2-methylcarbamoylethyl group, ethylcarbamoylmethyl group, 2-ethylcarbamoylethyl group, dimethylcarbamoylmethyl group, 2-dimethylcarbamoylethyl group, diethyl Carbamoylmethyl group, 2-diethylcarbamoylethyl group, carbamoylaminomethyl group, 2-carbamoylaminoethyl group, methylcarbamoylaminomethyl group, 2-methylcarbamoylaminoethyl group, ethylcarbamoylaminomethyl group, 2-ethylcarbamoylaminoethyl group Dimethylcarbamoylaminomethyl group, 2-dimethylcarbamoylaminoethyl group, diethylcarbamoylaminomethyl group, 2-diethylcarbamoylaminoethyl group, methylsulfonylaminomethyl group, 2-methylsulfonylaminoethyl group, methoxycarbonylaminomethyl group, 2 -Methoxycarbonylaminoethyl group, ethoxycarbonylaminomethyl group, 2-ethoxycarbonylaminoethyl group, ethanoylaminomethyl group, and 2-ethane Ylaminoethyl group is preferred, methyl group, ethyl group, propyl group, trifluoromethyl group, hydroxymethyl group, 2-hydroxyethyl group, 2-fluoroethyl group, aminomethyl group, 2-aminoethyl group, methylaminomethyl Group, 2-methylaminoethyl group, dimethylaminomethyl group, 2-dimethylaminoethyl group, methoxymethyl group, 2-methoxyethyl group, carbamoylmethyl group, 2-carbamoylethyl group, methylcarbamoylmethyl group, 2-methylcarbamoyl group Ethyl group, dimethylcarbamoylmethyl group, 2-dimethylcarbamoylethyl group, diethylcarbamoylmethyl group, carbamoylaminomethyl group, methylcarbamoylaminomethyl group, ethylcarbamoylaminomethyl group, dimethylcarbamoylaminomethyl group, diethyl A rucarbamoylaminomethyl group and a methylsulfonylaminomethyl group are more preferable, and a methyl group, an ethyl group, a propyl group, a trifluoromethyl group, a hydroxymethyl group, a 2-hydroxyethyl group, and a 2-fluoroethyl group are particularly preferable. The same applies to the alkyl group which may have a substituent, which is used in the description of the following various substituents.
As the amino group which may have a substituent, in addition to the unsubstituted amino group, a lower alkylamino group, a di-lower alkylamino group, a lower alkoxycarbonylamino group, a carbamoylamino group, a lower alkylcarbamoylamino group, Di-lower alkylcarbamoylamino group, lower alkylsulfonylamino group, lower alkanoylamino group, N-lower alkyl-N-lower alkanoylamino group, and N-lower alkyl-N-lower alkylsulfonylamino group, N-lower alkyl-N -Lower alkoxycarbonylamino group, for example, amino group, methylamino group, ethylamino group, propylamino group, butylamino group, pentylamino group, hexylamino group, 1-methylethylamino group, 1,1- Dimethylethylamino group, 1-methylpropiyl Amino group, dimethylamino group, diethylamino group, dipropylamino group, dibutylamino group, dipentylamino group, dihexylamino group, di (1-methylethyl) amino group, methylethylamino group, methoxycarbonylamino group, ethoxycarbonylamino Group, carbamoylamino group, methylcarbamoylamino group, ethylcarbamoylamino group, dimethylcarbamoylamino group, diethylcarbamoylamino group, methylsulfonylamino group, ethylsulfonylamino group, ethanoylamino group, propanoylamino group, butanoylamino group N-methyl-N-ethanoylamino group, N-methyl-N-methylsulfonylamino group, and N-methyl-N-methoxycarbonylamino group can be given as representative examples. Among them, amino group, methylamino group, ethylamino group, 1-methylethylamino group, dimethylamino group, diethylamino group, dipropylamino group, methylethylamino group, methoxycarbonylamino group, ethoxycarbonylamino group, methylcarbamoylamino Group, ethylcarbamoylamino group, dimethylcarbamoylamino group, diethylcarbamoylamino group, methylsulfonylamino group, ethylsulfonylamino group, ethanoylamino group, butanoylamino group, and N-methyl-N-methylsulfonylamino group are preferable. An amino group, an ethanoylamino group, a methylsulfonylamino group, and an N-methyl-N-methylsulfonylamino group are more preferable. The same applies to the amino group which may have a substituent, which is used in the description of the various substituents below.

  The lower alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms. For example, a vinyl group, an allyl group, and a butenyl group can be given as representative examples. Among these, a vinyl group is preferable. The same applies to lower alkenyl groups used in the description of various substituents below.

  The carbamoyl group which may have a substituent is selected from a hydroxyl group, a lower alkenyl group, a lower alkyl group which may have a substituent, and a lower alkoxy group in addition to the unsubstituted carbamoyl group. Or a carbamoyl group substituted by two groups, for example, a carbamoyl group, a hydroxycarbamoyl group, a vinylcarbamoyl group, a methylcarbamoyl group, an ethylcarbamoyl group, a dimethylcarbamoyl group, a diethylcarbamoyl group, a methoxycarbamoyl group, an ethoxycarbamoyl group Can be cited as a representative example. Among these, a methylcarbamoyl group, an ethylcarbamoyl group, a dimethylcarbamoyl group, and a methoxycarbamoyl group are preferable, and a methylcarbamoyl group is more preferable.

  As the arylsulfonyloxy group which may have a substituent, in addition to the unsubstituted arylsulfonyloxy group, one or two groups selected from a halogen atom, a lower alkyl group, and a lower alkoxy group are substituted. Arylsulfonyloxy group, for example, phenylsulfonyloxy group, chlorophenylsulfonyloxy group, dichlorophenylsulfonyloxy group, fluorophenylsulfonyloxy group, difluorophenylsulfonyloxy group, methylphenylsulfonyloxy group, ethylphenylsulfonyloxy group, propyl Phenylsulfonyloxy group, isopropylphenylsulfonyloxy group, dimethylphenylsulfonyloxy group, diethylphenylsulfonyloxy group, methoxyphenylsulfonyloxy group, etho Representative examples include a xyphenylsulfonyloxy group, a propoxyphenylsulfonyloxy group, a dimethoxyphenylsulfonyloxy group, and a diethoxyphenylsulfonyloxy group. Among them, phenylsulfonyloxy group, chlorophenylsulfonyloxy group, fluorophenylsulfonyloxy group, methylphenylsulfonyloxy group, ethylphenylsulfonyloxy group, methoxyphenylsulfonyloxy group, and ethoxyphenylsulfonyloxy group are preferable, and phenylsulfonyloxy group , A fluorophenylsulfonyloxy group, a methylphenylsulfonyloxy group, and a methoxyphenylsulfonyloxy group are more preferable.

The lower alkylsulfonyloxy group which may have a substituent is a lower alkylsulfonyl group substituted with 1 to 3 groups selected from a halogen atom and a lower alkoxy group in addition to an unsubstituted lower alkylsulfonyloxy group. Alkylsulfonyloxy group, for example, methylsulfonyloxy group, ethylsulfonyloxy group, propylsulfonyloxy group, trifluoromethylsulfonyloxy group, 2-fluoroethylsulfonyloxy group, 2-chloroethylsulfonyloxy group, 3- Fluoropropylsulfonyloxy group, methoxymethylsulfonyloxy group, 2-methoxyethylsulfonyloxy group, and 3-methoxypropylsulfonyloxy group can be given as representative examples. Among them, methylsulfonyloxy group, ethylsulfonyloxy group, propylsulfonyloxy group, trifluoromethylsulfonyloxy group, 2-fluoroethylsulfonyloxy group, 2-chloroethylsulfonyloxy group, methoxymethylsulfonyloxy group, and 2-methoxy Preferred are ethylsulfonyloxy groups, methylsulfonyloxy group, ethylsulfonyloxy group, propylsulfonyloxy group, trifluoromethylsulfonyloxy group, 2-fluoroethylsulfonyloxy group, methoxymethylsulfonyloxy group, and 2-methoxyethylsulfonyloxy group A group is more preferable, and a methylsulfonyloxy group, an ethylsulfonyloxy group, and a trifluoromethylsulfonyloxy group are particularly preferable.
Examples of the lower alkylsulfonyloxy group include sulfonyloxy groups having the above-mentioned lower alkyl groups, such as a methylsulfonyloxy group, an ethylsulfonyloxy group, a propylsulfonyloxy group, a butylsulfonyloxy group, a pentylsulfonyloxy group, and a hexylsulfonyloxy group. Group, 1-methylethylsulfonyloxy group, 1,1-dimethylethylsulfonyloxy group, 1-methylpropylsulfonyloxy group, 2-methylpropylsulfonyloxy group, 1,1-dimethylpropylsulfonyloxy group, 1,2- Dimethylpropylsulfonyloxy group, 2,2-dimethylpropylsulfonyloxy group, 1-methylbutylsulfonyloxy group, 2-methylbutylsulfonyloxy group, 3-methylbutylsulfonyloxy group, 1,1-dimethyl Rubutylsulfonyloxy group, 1,2-dimethylbutylsulfonyloxy group, 1,3-dimethylbutylsulfonyloxy group, 2,2-dimethylbutylsulfonyloxy group, 2,3-dimethylbutylsulfonyloxy group, 3,3- Dimethylbutylsulfonyloxy group, 1-methylpentylsulfonyloxy group, 2-methylpentylsulfonyloxy group, 3-methylpentylsulfonyloxy group, 4-methylpentylsulfonyloxy group, cyclopropylsulfonyloxy group, cyclobutylsulfonyloxy group, Typical examples include cyclopentylsulfonyloxy group, cyclohexylsulfonyloxy group, cyclopropylmethylsulfonyloxy group, cyclobutylmethylsulfonyloxy group, and cyclopentylmethylsulfonyloxy group. It is possible. Among these, a methylsulfonyloxy group, an ethylsulfonyloxy group, and a propylsulfonyloxy group are preferable, and a methylsulfonyloxy group is more preferable.

  Examples of the sulfamoyl group which may have a lower alkyl group include the sulfamoyl group having the above lower alkyl group in addition to the unsubstituted sulfamoyl group, a sulfamoyl group, a methylsulfamoyl group, a dimethylsulfamoyl group. , Ethylsulfamoyl group, diethylsulfamoyl group, propylsulfamoyl group, dipropylsulfamoyl group, butylsulfamoyl group, dibutylsulfamoyl group, pentylsulfamoyl group, dipentylsulfamoyl group, hexyl Sulfamoyl group, dihexylsulfamoyl group, 1-methylethylsulfamoyl group, 1,1-dimethylethylsulfamoyl group, 1-methylpropylsulfamoyl group, 2-methylpropylsulfamoyl group, 1 , 1-dimethylpropylsulfamoyl group, 1 2-dimethylpropylsulfamoyl group, 2,2-dimethylpropylsulfamoyl group, 1-methylbutylsulfamoyl group, 2-methylbutylsulfamoyl group, 3-methylbutylsulfamoyl group, 1,1 -Dimethylbutylsulfamoyl group, 1,2-dimethylbutylsulfamoyl group, 1,3-dimethylbutylsulfamoyl group, 2,2-dimethylbutylsulfamoyl group, 2,3-dimethylbutylsulfamoyl Group, 3,3-dimethylbutylsulfamoyl group, 1-methylpentylsulfamoyl group, 2-methylpentylsulfamoyl group, 3-methylpentylsulfamoyl group, 4-methylpentylsulfamoyl group, cyclo Propylsulfamoyl, cyclobutylsulfamoyl, cyclopentylsulfamoyl, cycl Hexyl sulfamoyl group, a cyclopropyl methylsulfamoyl group, cyclobutylmethyl sulfamoyl group, and a cyclopentylmethyl sulfamoyl group as a representative example. Among them, sulfamoyl group, methylsulfamoyl group, ethylsulfamoyl group, 1-methylethylsulfamoyl group, dimethylsulfamoyl group, diethylsulfamoyl group, dipropylsulfamoyl group, and methylethylsulfamoyl Group is preferable, and sulfamoyl group, methylsulfamoyl group, and ethylsulfamoyl group are more preferable.

  Examples of the sulfamoyloxy group optionally having a lower alkyl group include the above-mentioned sulfamoyloxy groups having a lower alkyl group in addition to the unsubstituted sulfamoyloxy group. Group, methylsulfamoyloxy group, dimethylsulfamoyloxy group, ethylsulfamoyloxy group, diethylsulfamoyloxy group, propylsulfamoyloxy group, dipropylsulfamoyloxy group, butylsulfamoyloxy group , Dibutylsulfamoyloxy group, pentylsulfamoyloxy group, dipentylsulfamoyloxy group, hexylsulfamoyloxy group, dihexylsulfamoyloxy group, 1-methylethylsulfamoyloxy group, 1,1- Dimethylethylsulfamoyloxy group, 1-methyl Rupropylsulfamoyloxy group, 2-methylpropylsulfamoyloxy group, 1,1-dimethylpropylsulfamoyloxy group, 1,2-dimethylpropylsulfamoyloxy group, 2,2-dimethylpropylsulfa Moyloxy group, 1-methylbutylsulfamoyloxy group, 2-methylbutylsulfamoyloxy group, 3-methylbutylsulfamoyloxy group, 1,1-dimethylbutylsulfamoyloxy group, 1,2- Dimethylbutylsulfamoyloxy group, 1,3-dimethylbutylsulfamoyloxy group, 2,2-dimethylbutylsulfamoyloxy group, 2,3-dimethylbutylsulfamoyloxy group, 3,3-dimethylbutyl Sulfamoyloxy group, 1-methylpentylsulfamoyloxy group, 2-methyl Rupentylsulfamoyloxy group, 3-methylpentylsulfamoyloxy group, 4-methylpentylsulfamoyloxy group, cyclopropylsulfamoyloxy group, cyclobutylsulfamoyloxy group, cyclopentylsulfamoyloxy group Typical examples include cyclohexylsulfamoyloxy group, cyclopropylmethylsulfamoyloxy group, cyclobutylmethylsulfamoyloxy group, and cyclopentylmethylsulfamoyloxy group. Among them, sulfamoyloxy group, methylsulfamoyloxy group, ethylsulfamoyloxy group, 1-methylethylsulfamoyloxy group, dimethylsulfamoyloxy group, diethylsulfamoyloxy group, dipropylsulfamoyl group An oxy group and a methylethylsulfamoyloxy group are preferable, and a sulfamoyloxy group, a methylsulfamoyloxy group, and an ethylsulfamoyloxy group are more preferable.

  The 5- to 6-membered saturated heterocyclic group which may have a substituent is selected from a hydroxyl group, an oxo group, a lower alkyl group, and a lower alkoxy group in addition to an unsubstituted saturated heterocyclic group. And a saturated heterocyclic group substituted with at least one substituent. As used herein, the 5- to 5-membered saturated heterocycle means a 5- to 6-membered saturated heterocycle containing at least one heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom, and is a morpholine ring. Typical examples include a piperidine ring, a piperazine ring, a pyrrolidine ring, an azetidine ring, and a thiomorpholine ring. Examples of the 5- to 6-membered saturated heterocyclic group which may have a substituent include morpholinyl group, hydroxymorpholinyl group, oxomorpholinyl group, methoxymorpholinyl group, ethoxymorpholinyl group, methylmorpholine. Folinyl group, thiomorpholinyl group, hydroxythiomorpholinyl group, oxothiomorpholinyl group, methoxythiomorpholinyl group, ethoxythiomorpholinyl group, methylthiomorpholinyl group, piperidinyl group, hydroxypiperidinyl group, Oxopiperidinyl group, methoxypiperidinyl group, ethoxypiperidinyl group, methylpiperidinyl group, pyrrolidinyl group, hydroxypyrrolidinyl group, oxopyrrolidinyl group, methoxypyrrolidinyl group, ethoxypyrrolidinyl group , And methylpyrrolidinyl groups can be mentioned as representative examples. Among these, morpholinyl group, oxomorpholinyl group, thiomorpholinyl group, oxothiomorpholinyl group, piperidinyl group, and oxopiperidinyl group are preferable.

As the 5- to 6-membered aromatic heterocyclic group which may have a substituent, in addition to the unsubstituted 5- to 6-membered aromatic heterocyclic group, a hydroxyl group, a halogen atom, a lower alkoxy group, Lower alkyl group optionally having substituent, amino group optionally having substituent, phenyl group optionally having substituent (described later), and optionally having substituent Examples include 5 to 6-membered aromatic heterocyclic groups which may have 1 to 2 groups selected from 5 to 6-membered unsaturated heterocyclic groups (described later).
The term “5- to 6-membered aromatic heterocyclic group” as used herein means a 5- to 6-membered aromatic ring containing at least one heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom as a component of the ring structure. Specifically, pyrrolyl group, furyl group, thienyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, oxadiazolyl group, thiadiazolyl group, pyridyl group Groups, pyrimidinyl groups, pyridazinyl groups, and pyrazinyl groups can be mentioned as representative examples. Among them, a thiazolyl group, a triazolyl group, a furyl group, and an oxazolyl group are preferable.

  Specific examples of the 5- to 6-membered aromatic heterocyclic group which may have the above-described substituent include thiazolyl group, hydroxythiazolyl group, chlorothiazolyl group, methoxythiazolyl group, ethoxythiazolyl group Group, methylthiazolyl group, trifluoromethylthiazolyl group, ethanoylaminothiazolyl group, phenylthiazolyl group, methyl-phenylthiazolyl group, triazolyl group, hydroxytriazolyl group, chlorotriazolyl group, Methoxytriazolyl, ethoxytriazolyl, methyltriazolyl, trifluoromethyltriazolyl, ethanoylaminotriazolyl, phenyltriazolyl, methyl-phenyltriazolyl, furyl , Hydroxyfuryl group, chlorofuryl group, methoxyfuryl group, ethoxyfuryl group, methylfuryl group, Fluoromethylfuryl group, ethanoylaminofuryl group, phenylfuryl group, methyl-phenylfuryl group, oxazolyl group, hydroxyoxazolyl group, chlorooxazolyl group, methoxyoxazolyl group, ethoxyoxazolyl group, methyloxa Zolyl group, trifluoromethyloxazolyl group, ethanoylaminoxazolyl group, phenyloxazolyl group, methyl-phenyloxazolyl group, oxadiazolyl group, hydroxyoxadiazolyl group, chlorooxadiazolyl group, methoxy Typical examples are oxadiazolyl, ethoxyoxadiazolyl, methyloxadiazolyl, trifluoromethyloxadiazolyl, ethanoylaminoxazolyl, phenyloxadiazolyl, and methyl-phenyloxadiazolyl To mention Can. Among these, a furyl group, a thiazolyl group, a triazolyl group, an oxazolyl group, and a methyl-phenyloxazolyl group are more preferable.

  As the above-mentioned phenyl group which may have a substituent, in addition to the unsubstituted phenyl group, one or two groups selected from a lower alkyl group, a halogen atom, and a lower alkoxy group are substituted. A phenyl group is mentioned. Specifically, in addition to the unsubstituted phenyl group, examples of the mono-substituted phenyl group include methylphenyl group, ethylphenyl group, fluorophenyl group, chlorophenyl group, bromophenyl group, and methoxyphenyl group as representative examples. Specific examples of the di-substituted phenyl group include fluoro-methylphenyl group, chloro-methylphenyl group, difluorophenyl group, dichlorophenyl group, chloro-fluorophenyl group, fluoro-methoxyphenyl group, and chloro-methoxy. A phenyl group can be mentioned as a representative example. Preferred examples include phenyl group, methylphenyl group, methoxyphenyl group, fluorophenyl group, chlorophenyl group, bromophenyl group, fluoro-methylphenyl group, chloro-methylphenyl group, difluorophenyl group, dichlorophenyl group, chloro-fluorophenyl group. , A fluoro-methoxyphenyl group and a chloro-methoxyphenyl group are preferred, and a phenyl group, a methylphenyl group, a methoxyphenyl group, a fluorophenyl group, a difluorophenyl group, a dichlorophenyl group, and a chloro-fluorophenyl group are more preferred.

  Examples of the 5- to 6-membered unsaturated heterocyclic group which may have a substituent include thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl Group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group and other unsubstituted heterocyclic groups, and at least one selected from a hydroxyl group, a halogen atom, a lower alkyl group, and a lower alkoxy group Thienyl group, furyl group, pyranyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group Etc. Specifically, thienyl group, hydroxythienyl group, chlorothienyl group, fluorothienyl group, methylthienyl group, ethylthienyl group, propylthienyl group, methoxythienyl group, ethoxythienyl group, propoxythienyl group, furyl group, hydroxyfuryl group Chlorofuryl group, fluorofuryl group, methylfuryl group, ethylfuryl group, propylfuryl group, methoxyfuryl group, ethoxyfuryl group, propoxyfuryl group, pyranyl group, hydroxypyranyl group, chloropyranyl group, fluoropyranyl group, methylpyranyl group Group, ethylpyranyl group, propylpyranyl group, methoxypyranyl group, ethoxypyranyl group, propoxypyranyl group, pyrrolyl group, hydroxypyrrolyl group, chloropyrrolyl group, fluoropyrrolyl group, methylpyrrolyl group, ethylpyrrolyl group , Propylpyrrolyl group, methoxypyrrolyl group, ethoxypyrrolyl group, propoxypyrrolyl group, imidazolyl group, hydroxyimidazolyl group, chloroimidazolyl group, fluoroimidazolyl group, methylimidazolyl group, ethylimidazolyl group, propylimidazolyl group, methoxyimidazolyl group Group, ethoxyimidazolyl group, propoxyimidazolyl group, pyrazolyl group, hydroxypyrazolyl group, chloropyrazolyl group, fluoropyrazolyl group, methylpyrazolyl group, ethylpyrazolyl group, propylpyrazolyl group, methoxypyrazolyl group, ethoxypyrazolyl group, and propoxypyrazolyl group It can be mentioned as a representative example.

  As the aryl group which may have a substituent, in addition to the unsubstituted aryl group, a hydroxyl group, a halogen atom, a lower alkyl group, a lower alkoxy group, and an amino group which may have a substituent may be used. An aryl group substituted with 1 or 2 groups selected from For example, phenyl group, hydroxyphenyl group, chlorophenyl group, fluorophenyl group, methylphenyl group, ethylphenyl group, propylphenyl group, butylphenyl group, isopropylphenyl group, methoxyphenyl group, ethoxyphenyl group, propoxyphenyl group, methylamino Phenyl group, ethylaminophenyl group, propylaminophenyl group, butylaminophenyl group, pentylaminophenyl group, hexylaminophenyl group, 1-methylethylaminophenyl group, 1,1-dimethylethylaminophenyl group, 1-methylpropyl Aminophenyl group, dimethylaminophenyl group, diethylaminophenyl group, dipropylaminophenyl group, dibutylaminophenyl group, dipentylaminophenyl group, dihexylaminophenyl group, di ( -Methylethyl) aminophenyl group, methylethylaminophenyl group, methoxycarbonylaminophenyl group, ethoxycarbonylaminophenyl group, methylcarbamoylaminophenyl group, ethylcarbamoylaminophenyl group, dimethylcarbamoylaminophenyl group, diethylcarbamoylaminophenyl group, Methylsulfonylaminophenyl group, ethylsulfonylaminophenyl group, ethanoylaminophenyl group, propanoylaminophenyl group, butanoylaminophenyl group, N-methyl-N-ethanoylaminophenyl group, N-methyl-N-methylsulfonyl Aminophenyl group, N-methyl-N-methoxycarbonylaminophenyl group, naphthyl group, hydroxynaphthyl group, chloronaphthyl group, fluoronaphthyl group, methylnaphthyl group Tyl group, ethyl naphthyl group, propyl naphthyl group, butyl naphthyl group, isopropyl naphthyl group, methoxy naphthyl group, ethoxy naphthyl group, propoxy naphthyl group, methyl amino naphthyl group, ethyl amino naphthyl group, propyl amino naphthyl group, butyl amino naphthyl group Pentylaminonaphthyl group, hexylaminonaphthyl group, 1-methylethylaminonaphthyl group, 1,1-dimethylethylaminonaphthyl group, 1-methylpropylaminonaphthyl group, dimethylaminonaphthyl group, diethylaminonaphthyl group, dipropylaminonaphthyl group Group, dibutylaminonaphthyl group, dipentylaminonaphthyl group, dihexylaminonaphthyl group, di (1-methylethyl) aminonaphthyl group, methylethylaminonaphthyl group, methoxycarbonylamino Naphtyl group, ethoxycarbonylaminonaphthyl group, methylcarbamoylaminonaphthyl group, ethylcarbamoylaminonaphthyl group, dimethylcarbamoylaminonaphthyl group, diethylcarbamoylaminonaphthyl group, methylsulfonylaminonaphthyl group, ethylsulfonylaminonaphthyl group, ethanoylaminonaphthyl group , Propanoylaminonaphthyl group, butanoylaminonaphthyl group, N-methyl-N-ethanoylaminonaphthyl group, N-methyl-N-methylsulfonylaminonaphthyl group, and N-methyl-N-methoxycarbonylaminonaphthyl group. It can be mentioned as a representative example.

  As the aryloxy group which may have a substituent, in addition to the unsubstituted aryloxy group, a hydroxyl group, a halogen atom, a lower alkyl group, a lower alkoxy group, and an amino group which may have a substituent An aryloxy group substituted with 1 or 2 groups selected from among them. For example, phenoxy group, hydroxyphenoxy group, chlorophenoxy group, fluorophenoxy group, methylphenoxy group, ethylphenoxy group, propylphenoxy group, butylphenoxy group, isopropylphenoxy group, methoxyphenoxy group, ethoxyphenoxy group, propoxyphenoxy group, methyl Aminophenoxy group, ethylaminophenoxy group, propylaminophenoxy group, butylaminophenoxy group, pentylaminophenoxy group, hexylaminophenoxy group, 1-methylethylaminophenoxy group, 1,1-dimethylethylaminophenoxy group, 1-methyl Propylaminophenoxy group, dimethylaminophenoxy group, diethylaminophenoxy group, dipropylaminophenoxy group, dibutylaminophenoxy group, dipentyl Minophenoxy group, dihexylaminophenoxy group, di (1-methylethyl) aminophenoxy group, methylethylaminophenoxy group, methoxycarbonylaminophenoxy group, ethoxycarbonylaminophenoxy group, methylcarbamoylaminophenoxy group, ethylcarbamoylaminophenoxy group, Dimethylcarbamoylaminophenoxy group, diethylcarbamoylaminophenoxy group, methylsulfonylaminophenoxy group, ethylsulfonylaminophenoxy group, ethanoylaminophenoxy group, propanoylaminophenoxy group, butanoylaminophenoxy group, N-methyl-N-ethanoyl Aminophenoxy group, N-methyl-N-methylsulfonylaminophenoxy group, N-methyl-N-methoxycarbonylaminophenoxy group Group, naphthoxy group, hydroxynaphthoxy group, chloronaphthoxy group, fluoronaphthoxy group, methylnaphthoxy group, ethylnaphthoxy group, propylnaphthoxy group, butylnaphthoxy group, isopropylnaphthoxy group, methoxynaphthoxy group, ethoxynaphthoxy group, propoxy Naphthoxy group, methylaminonaphthoxy group, ethylaminonaphthoxy group, propylaminonaphthoxy group, butylaminonaphthoxy group, pentylaminonaphthoxy group, hexylaminonaphthoxy group, 1-methylethylaminonaphthoxy group, 1 , 1-dimethylethylaminonaphthoxy group, 1-methylpropylaminonaphthoxy group, dimethylaminonaphthoxy group, diethylaminonaphthoxy group, dipropylaminonaphthoxy group, dibutylaminonaphthoxy group, dipentylamino Nonanaphthoxy group, dihexylaminonaphthoxy group, di (1-methylethyl) aminonaphthoxy group, methylethylaminonaphthoxy group, methoxycarbonylaminonaphthoxy group, ethoxycarbonylaminonaphthoxy group, methylcarbamoylaminonaphthoxy group, ethyl Carbamoylaminonaphthoxy group, dimethylcarbamoylaminonaphthoxy group, diethylcarbamoylaminonaphthoxy group, methylsulfonylaminonaphthoxy group, ethylsulfonylaminonaphthoxy group, ethanoylaminonaphthoxy group, propanoylaminonaphthoxy group, butanoyl Aminonaphthoxy group, N-methyl-N-ethanoylaminonaphthoxy group, N-methyl-N-methylsulfonylaminonaphthoxy group, and N-methyl-N-methoxycarbonylaminonaphtho It can be mentioned sheet group as a representative example.

The following describes R ¹ to R ^8.
R ¹ and R ² are each independently a hydrogen atom, hydroxyl group, halogen atom, lower alkoxy group, cyano group, lower alkanoyl group, lower alkylcarbamoyloxy group, lower alkylsulfonyl group, lower alkylthio group, lower alkylsulfinyl group, substituted A lower alkyl group which may have a group, an amino group which may have a substituent, a carbamoyl group which may have a substituent, a lower alkylsulfonyloxy group which may have a substituent A sulfamoyl group optionally having a lower alkyl group, a sulfamoyloxy group optionally having a lower alkyl group, and a 5- to 6-membered saturated heterocyclic group optionally having a substituent Is preferred.

  Specifically, hydrogen atom, hydroxyl group, methoxy group, chlorine atom, methyl group, carbamoyl group, ethanoyl group, cyano group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, ethanoylamino group, 1, 1-dimethylethoxycarbonyl group, carbamoyloxy group, methylsulfonylamino group, N-methyl-N-methylsulfonylamino group, methylsulfonyloxy group, ethylsulfonyloxy group, trifluoromethylsulfonyloxy group, sulfamoyl group, sulfamoyl Preferred examples include oxy, methylthio, methyl sulfoxide, methylsulfonyl, morpholinyl, piperidyl, piperazyl, pyrrolidyl, azetidyl, azepyr, tetrahydrofuryl, and tetrahydropyranyl. Can.

Preferred examples of R ³ include methoxy group, ethoxy group, carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, methoxycarbamoyl group, furyl group, oxazolyl group, methyloxazolyl group, Preferred examples include methyl-phenyloxazolyl group, hydroxyoxadiazolyl group, methyloxadiazolyl group, thiazolyl group, thiadiazolyl group, and pyridinyl group, such as methoxy group, methoxycarbamoyl group, methylcarbamoyl group, ethyl More preferred examples include a carbamoyl group, a dimethylcarbamoyl group, a diethylcarbamoyl group, a furyl group, an oxazolyl group, a methyl-phenyloxazolyl group, and a thiazolyl group.

R ⁴ and R ⁵ are each independently preferably a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkoxy group, and a lower alkyl group which may have a substituent. Specifically, each independently represents a hydrogen atom. , A hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a methoxy group, and a methyl group are preferable.

Specifically, R ⁶ and R ⁷ are each independently preferably a hydrogen atom, a methyl group, or an ethyl group, and are formed together with a carbon atom to which R ⁶ and R ⁷ are bonded. A 6-membered saturated ring is also preferred. R ⁶ and R ⁷ are each independently more preferably a hydrogen atom and a methyl group, and particularly preferably a methyl group.
Specifically, R ⁸ is preferably a hydrogen atom, a methyl group, an ethyl group, or a 1,1-dimethylethyl group, and particularly preferably a hydrogen atom.
Although n is an integer of 1-3, 1-2 are preferable.
m is an integer of 1 to 3, but 1 is preferable. However, when R ³ is a lower alkoxy group, m is preferably 2.

  The compound represented by the general formula (I) of the present invention may have stereoisomers or optical isomers derived from asymmetric carbon atoms. These stereoisomers, optical isomers, and mixtures thereof Any of these are included in the present invention.

  The salt of the compound represented by the general formula (I) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, hydrochloride, hydrobromide, hydroiodic acid Mineral salts such as salts, phosphates, nitrates and sulfates, benzoates, methanesulfonates, organic sulfonates such as 2-hydroxyethanesulfonate and p-toluenesulfonate, and acetates, propane And organic carboxylates such as acid salt, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, malate and mandelate.

  In addition, when the compound represented by the general formula (I) has an acidic group, it may be a salt of an alkali metal ion or an alkaline earth metal ion. The solvate is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include hydrates and ethanol solvates.

  Below, the typical synthesis | combining method of the compound represented by general formula (I) of this invention is demonstrated.

  Compound (3) can be synthesized by reacting aldehyde (1) and amine (2) in the presence of a reducing agent. In the presence or absence of an acid such as acetic acid, a Schiff base is produced from aldehyde (1) and amine (2), and then a reducing agent is allowed to act to obtain compound (3). In this case, compound (3) can also be synthesized by dissolving aldehyde (1) and amine (2) in a solvent and allowing a reducing agent to act without confirming the formation of a Schiff base. Usually, an equimolar amount or an excess molar amount of amine (2) is used with respect to aldehyde (1). Examples of the reducing agent include metal hydride complexes such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc., and are usually equimolar or excess, preferably equimolar to aldehyde (1). 5 times moles of reducing agent is used. Examples of the reaction solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, and halogenated alkanes such as dichloromethane and chloroform. The reaction temperature is from −20 ° C. to the boiling point of the solvent used, preferably 0 ° C. to 50 ° C., and the reaction time is 15 minutes to 24 hours, preferably about 30 minutes to 10 hours.

Synthesis of compound (Ia) from compound (3) can be carried out by allowing compound (4) to act on compound (3). The compound (4) is allowed to act on the compound (3) in an equimolar to excess molar amount, preferably equimolar to 2 molar in the presence of a base, and if necessary, a reaction accelerator such as tetrabutylammonium iodide or potassium iodide. Can be used. As the base, equimolar to excess molar amounts of tertiary amines such as triethylamine and carbonates such as potassium carbonate and cesium carbonate are used. Examples of the solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, and solvents such as N, N-dimethylformamide and acetonitrile. The reaction temperature is from 0 ° C. to the boiling point of the solvent used, preferably from room temperature to 100 ° C., and the reaction time is from 1 hour to 7 days, preferably from 1 hour to 48 hours.

The synthesis of compound (Ib) from compound (Ia) varies depending on the type of ester, but the method described in the literature [Protective Groups in Organic Synthesis, 2nd edition, T.R. W. Green (T. W. Green), P.M. G. M.M. See P. GM M. Wuts, John Wiley & Son (1991)] or a method analogous thereto. Examples thereof include a hydrolysis reaction using an acid or a base, a hydrogenation reaction performed in the presence of a catalyst such as palladium-carbon, and a method using trifluoroacetic acid. For example, in a hydrolysis reaction using a base, a metal hydroxide salt such as lithium hydroxide or sodium hydroxide or a carbonate salt such as sodium carbonate or potassium carbonate is allowed to act on compound (Ia) in an equimolar to excess molar manner. Do. Examples of the solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, water, and mixed solvents thereof. The reaction temperature is 0 ° C to 100 ° C, preferably 0 ° C to 60 ° C. While the reaction time varies depending on the type of ester, it is generally 1 hour to 72 hours, preferably about 1 hour to 24 hours. When R8 of compound (Ia) is a tert-butyl group, it can be carried out by a method in which an acid such as trifluoroacetic acid or hydrochloric acid is allowed to act. Trifluoroacetic acid and hydrochloric acid are used in excess moles. Examples of the solvent include solvents such as dichloromethane and dioxane. The reaction temperature is from 0 ° C. to the boiling point of the solvent used, preferably 0 ° C. to 30 ° C., and the reaction time is 1 hour to 48 hours, preferably 1 hour to 24 It's time.

Said compound (Ia) can also be manufactured by the method shown to the following synthesis method 1-2 or the synthesis method 1-3.

Compound (Ia) can be synthesized by reacting amine (3) and aldehyde (5) in the presence of a reducing agent. Compound (Ia) is produced by generating a Schiff base from amine (3) and aldehyde (5) in the presence or absence of an acid such as acetic acid and then reacting with a reducing agent.
Get. In this case, compound (Ia) can also be synthesized by dissolving amine (3) and aldehyde (5) in a solvent and allowing a reducing agent to act without confirming the formation of a Schiff base. Usually, the aldehyde (5) is used in an equimolar amount or an excess molar amount relative to the amine (3). Examples of the reducing agent include metal hydride complexes such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc. Among them, sodium triacetoxyborohydride is preferable, and usually for aldehyde (5). Molar or excess molar, preferably equimolar to 5-fold molar reducing agent is used. Examples of the reaction solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, and halogenated alkanes such as dichloromethane and chloroform. The reaction temperature is from −20 ° C. to the boiling point of the solvent used, preferably 0 ° C. to 50 ° C., and the reaction time is 15 minutes to 24 hours, preferably about 30 minutes to 10 hours.

Compound (Ia) is an amine (3) and a compound (6) meaning carboxylic acid or acid chloride.
The amide compound (7) derived from) can also be derived by a reduction reaction.
The synthesis of the amide compound (7) from the compound (3) is performed by reacting the compound (3) with the carboxylic acid (6) in the presence of a condensing agent when the compound (6) is a carboxylic acid derivative, ie, Y is a hydroxyl group. It can be carried out. For example, equimolar to excess molar amount of amine (3) with respect to compound (6) is −50 ° C. to the boiling point of the solvent used in the reaction, preferably 0 to 30 ° C. in the presence of a condensing agent. It is done by acting on. The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 12 hours. Examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate, benzotriazolyloxy-tris [pyrrolidino] -phosphonium hexafluorophosphate, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate and the like can be mentioned, and equimolar to excess molar, preferably equimolar to the compound (6). Use ~ 5 times mole. Examples of the inert solvent include solvents such as dichloromethane, N, N-dimethylformamide, tetrahydrofuran, and ethyl acetate, or a mixture thereof. If necessary, the reaction can be carried out in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine. Further, N-hydroxy compounds such as 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, etc. or 4-nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol, pentachlorophenol, etc. A phenolic compound can be added as a reaction accelerator.

  In addition, the synthesis of the amide compound (7) from the compound (3) is carried out by reacting the compound (3) with an acid chloride (6) in the presence of a base when the compound (6) is an acid chloride, that is, Y is a chlorine atom. Can be done. For example, compound (6) with respect to amine (3) is used in an equimolar to excess molar amount in an inert solvent at −50 ° C. to the boiling point of the solvent used in the reaction, preferably at 0 ° C. to 30 ° C. in the presence of a base. This is done by acting. The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 12 hours. As the base, an equimolar or excess molar amount of tertiary amine such as triethylamine, carbonate such as potassium carbonate or cesium carbonate, or pyridine is used. Examples of the inert solvent include solvents such as dichloromethane, N, N-dimethylformamide, tetrahydrofuran, and ethyl acetate, or a mixture thereof.

Synthesis of compound (Ia) from compound (7) can be carried out by a reduction reaction. As the reducing agent, a borane complex such as borane-tetrahydrofuran complex or borane-dimethyl sulfide complex is usually used, and equimolar or excess molar amount relative to compound (7) is 0 ° C. in the inert solvent or the boiling point of the solvent used for the reaction. Up to preferably 90 ° C. to 90 ° C. The reaction time is about 30 minutes to 48 hours, preferably about 30 minutes to 12 hours. Examples of the inert solvent include ether solvents such as tetrahydrofuran and diethyl ether.

The above compound (Ia) can also be synthesized by synthesis methods 2-1 to 2-3 via compound (9) as shown below.

The synthesis of compound (9) from compound (1) and compound (8) and the synthesis of compound (9) from compound (10) and compound (5) are carried out by compound (1) and compound (2) in synthesis method 1-1. Can be carried out under the same conditions as in the synthesis of compound (3).
Compound (Ia) is synthesized from compound (9) and compound (11) under the same conditions as in the case of synthesizing compound (Ia) from compound (3) and compound (4) in Synthesis Method 1-1. it can.

The compound (Ia) is synthesized from the compound (9) and the compound (12) under the same conditions as in the case of synthesizing the compound (Ia) from the compound (3) and the compound (5) in Synthesis Method 1-2. it can.

The compound (14) is synthesized from the compound (9) and the compound (13) (carboxylic acid or acid chloride) when the compound (7) is synthesized from the compound (3) and the compound (6) in Synthesis Method 1-3. It can be performed under similar conditions.
Compound (Ia) can be synthesized from compound (14) by reduction of amide in the same manner as compound (Ia) is synthesized from compound (7) in Synthesis Method 1-3.

The above compound (Ia) can also be synthesized by synthesis methods 3-1 to 3-3 via compound (13) as shown below.

The synthesis of compound (15) from compound (5) and compound (2) and the synthesis of compound (15) from compound (8) and compound (12) are carried out by compound (1) and compound (2) in Synthesis Method 1-1. Can be carried out under the same conditions as in the synthesis of compound (3).
The compound (Ia) is synthesized from the compound (15) and the compound (16) under the same conditions as in the case of synthesizing the compound (Ia) from the compound (3) and the compound (4) in Synthesis Method 1-1. it can.

Compound (Ia) is synthesized from compound (15) and compound (1) under the same conditions as in the case of compound (Ia) is synthesized from compound (3) and compound (5) in Synthesis Method 1-2. it can.

The compound (18) is synthesized from the compound (15) and the compound (17) (carboxylic acid or acid chloride) when the compound (7) is synthesized from the compound (3) and the compound (6) in Synthesis Method 1-3. It can be performed under similar conditions.
Compound (Ia) can be synthesized from compound (18) under the same conditions as in the case of synthesizing compound (Ia) from compound (7) in Synthesis Method 1-3.
Compound (Ia) synthesized by the above synthesis methods 1-2 to 3-3 can be led to compound (Ib) under the conditions described in synthesis method 1-1.

  The prophylactic / therapeutic agent for diabetes of the compound (I) of the present invention is orally administered using various preparations. The compound (I) of the present invention used for the preparation may be a free form, a salt, or a hydrate or solvate thereof. Examples of the oral preparation containing the compound (I) of the present invention include tablets, fine granules, powders, granules, and capsules, and tablets and capsules are preferred. These oral preparations contain pharmaceutically acceptable additives and require, for example, fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents, lubricants, etc. It can be selected and used according to.

  The dosage is preferably 0.1 mg to 1500 mg per person per day, particularly preferably 1 mg to 500 mg. This dose may be once a day or divided into 2 to 3 times.

[Reference Example 1]
(1) 2- (4-Formyl-2,6-dimethylphenoxy) -2-methylpropanoic acid ethyl ester

  3,5-dimethyl-4-hydroxybenzaldehyde (5.0 g) was dissolved in N, N-dimethylformamide (20 ml), and cesium carbonate (10 g) and 2-bromo-2-methylpropanoic acid ethyl ester (10 ml) were added. The mixture was further stirred at 80 ° C. for 12 hours. After returning to room temperature, ethyl acetate (200 ml) and water (40 ml) were added for liquid separation. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (6.2 g) as a solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (3H, t, J = 7.2 Hz), 1.50 (6H, s), 2.31 (6H, s), 4.30 (2H , Q, J = 7.2 Hz), 7.52 (2H, s), 9.85 (1H, s).
(2) Ethyl 2- [4-[[(furan-2-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionate

  The compound of Reference Example 1- (1) (2.0 g) and furfurylamine (0.70 ml) were dissolved in ethanol (20 ml), sodium sulfate was added, and the mixture was heated and stirred at 80 ° C. for 4.5 hours. The reaction mixture was cooled with ice water, sodium borohydride (286 mg) was added, and the mixture was stirred at room temperature for 14 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to give the title compound (2.13 g) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (3H, t, J = 7.1 Hz), 1.46 (6H, s), 2.18 (6H, s), 3.66 (2H , S), 3.79 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 6.18 (1H, d, J = 3.2 Hz), 6.32 (1H, dd) , J = 1.7, 3.2 Hz), 6.92 (2H, s), 7.37 (1H, d, J = 1.7 Hz).
MS m / z: 346 (M + H) ^<+> .

[Reference Example 2]
(1) 2- [4-[[Furan-2-ylmethyl- [2- (4-hydroxyphenyl) acetyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

The compound of Reference Example 1- (2) (250 mg), 4-hydroxyphenylacetic acid (121 mg) and 1-hydroxybenzotriazole hydrate (133 mg) were dissolved in N, N-dimethylformamide (5 ml), and 1- ( 3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (166 mg) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (354 mg) as a colorless oil.
MS m / z: 480 (M + H) ^<+> .

(2) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonyloxyphenyl) acetyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

Reference compound 2- (1) compound (350 mg) was dissolved in dichloromethane (5 ml), and triethylamine (0.12 ml) and methanesulfonyl chloride (0.061 ml) were added while cooling with ice water, and the temperature was gradually raised to room temperature. The mixture was stirred for 4 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (346 mg) as a colorless oil.
MS m / z: 558 (M + H) ^<+> .

[Reference Example 3]
2- [4-[[2- (4-Hydroxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

  The compound of Reference Example 1- (1) (2.0 g) and tyramine (1.04 g) were dissolved in ethanol (30 ml), sodium sulfate was added and the mixture was stirred at 80 ° C. for 3.5 hours. After cooling the reaction solution to room temperature, sodium borohydride (286 mg) was added under ice water cooling. After 4.5 hours, saturated brine was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 94: 6) to give the title compound (2.36 g) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.34 (3H, t, J = 7.1 Hz), 1.44 (6H, s), 2.14 (3H, s), 2.75 (2H , T, J = 6.6 Hz), 2.86 (2H, t, J = 6.6 Hz), 3.68 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6 .67 (2H, d, J = 8.3 Hz), 6.84 (2H, s), 6.97 (2H, d, J = 8.3 Hz).
MS m / z: 386 (M + H) ^<+> .

[Reference Example 4]
(1) 2- (4-Formyl-2,6-dimethylphenoxy) -2-methylpropionic acid tert-butyl ester

In the same manner as in Reference Example 1- (1), 3,5-dimethyl-4-hydroxybenzaldehyde (15.0 g) and 2-bromo-2-methylpropanoic acid tert-butyl ester (75.6 ml) were used to give the title compound (75.6 ml). 5.69 g) was obtained as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41 (6H, s), 1.47 (9H, s), 2.25 (6H, s), 7.48 (2H, s), 9. 83 (1H, s).

(2) 2- [4-[[2- (4-hydroxyphenyl) ethylamino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid tert-butyl ester

In the same manner as in Reference Example 3, the title compound (1.41 g) was obtained as a colorless oil from the compound of Reference Example 4- (1) (1.0 g) and tyramine (0.47 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41 (6H, s), 1.51 (9H, s), 2.18 (6H, s), 2.75 (2H, d, J = 7) .1 Hz), 2.85 (2H, d, J = 7.1 Hz), 3.67 (2H, s), 6.70 (2H, d, J = 8.3 Hz), 6.85 (2H, s) ), 7.00 (2H, d, J = 8.3 Hz).
MS m / z: 414 (M + H) ^<+> .

[Reference Example 5]
(1) 2- (4-Formylphenoxy) -2-methylpropionic acid ethyl ester

  In the same manner as in Reference Example 1- (1), the title compound (8.91 g) was obtained as a pale yellow oily substance from 4-hydroxybenzaldehyde (10 g) and 2-bromo-2-methylpropanoic acid ethyl ester (18 ml). .

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.21 (3H, t, J = 7.1 Hz), 1.67 (6H, s), 4.23 (2H, q, J = 7.1 Hz) 6.90 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz), 9.88 (1H, s).
(2) 2- [4-[[(Furan-2-ylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid ethyl ester

In the same manner as in Reference Example 1- (2), the title compound (12.9 g) was obtained by treating the compound of Reference Example 5- (1) (10 g) and furfurylamine (4.1 ml) with sodium borohydride. Was obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25 (3H, t, J = 7.4 Hz), 1.58 (6H, s), 3.71 (2H, s), 3.79 (2H , S), 4.23 (2H, q, J = 7.4 Hz), 6.17 (1H, d, J = 2.9 Hz), 6.31 (1H, dd, J = 2.0, 2. 9 Hz), 6.80 (2H, d, J = 8.8 Hz), 7.19 (2H, d, J = 8.8 Hz), 7.37 (1H, d, J = 2.0 Hz).
MS m / z: 318 (M + H) ^<+> .

(3) 2- [4-[[Furan-2-ylmethyl- [2- (4-hydroxyphenyl) acetyl] amino] methyl] phenoxy] -2-methylpropionic acid ethyl ester

In the same manner as in Reference Example 2- (1), the title compound (903 mg) was obtained as a colorless oil from the compound of Reference Example 5- (2) (635 mg) and 4-hydroxyphenylacetic acid (364 mg).
MS m / z: 452 (M + H) ^<+> .

(4) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonyloxyphenyl) acetyl] amino] methyl] phenoxy] -2-methylpropionic acid ethyl ester

  In the same manner as in Reference Example 2- (2), the title compound was obtained from the compound of Reference Example 5- (3) (900 mg) and used in the next reaction without purification.

[Reference Example 6]
(1) 2- (4-Formyl-2-methoxyphenoxy) -2-methylpropionic acid ethyl ester

In the same manner as in Reference Example 1- (1), the title compound (6.3 g) was solidified from 4-hydroxy-3-methoxybenzaldehyde (5.0 g) and 2-bromo-2-methylpropanoic acid ethyl ester (10 ml). Got as.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.23 (3H, t, J = 7.1 Hz), 1.66 (6H, s), 3.90 (3H, s), 4.24 (2H , Q, J = 7.1 Hz), 6.85 (1H, d, J = 8.3 Hz), 7.35 (1H, dd, J = 8.3, 1.9 Hz), 7.42 (1H, d, J = 1.9 Hz), 9.85 (1H, s).

(2) 2- [4-[[(Furan-2-ylmethyl) amino] methyl] -2-methoxyphenoxy] -2-methylpropionic acid ethyl ester

In the same manner as in Reference Example 1- (2), the title compound (1.11 g) was obtained as a colorless oil from the compound of Reference Example 6- (1) (850 mg) and furfurylamine (0.31 ml).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1 Hz), 1.55 (6H, s), 3.72 (2H, s), 3.78 (2H , S), 3.81 (3H, s), 4.24 (2H, q, J = 7.1 Hz), 6.18 (1H, d, J = 3.2 Hz), 6.32 (1H, dd) , J = 2.0, 3.2 Hz), 6.74 (1H, dd, J = 2.0, 8.1 Hz), 6.82 (1H, d, J = 8.1 Hz), 6.88 ( 1H, d, J = 2.0 Hz), 7.37 (1H, d, J = 2.0 Hz).
MS m / z: 348 (M + H) ^<+> .

(3) 2- [4-[[Furan-2-ylmethyl- [2- (4-hydroxyphenyl) acetyl] amino] methyl] -2-methoxyphenoxy] -2-methylpropionic acid ethyl ester

In the same manner as in Reference Example 2- (1), the title compound (299 mg) was obtained as a pale yellow oil from the compound of Reference Example 6- (2) (272 mg) and 4-hydroxyphenylacetic acid (119 mg).
MS m / z: 482 (M + H) ^<+> .

(4) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonyloxyphenyl) acetyl] amino] methyl] -2-methoxyphenoxy] -2-methylpropionic acid ethyl ester

  In the same manner as in Reference Example 2- (2), the title compound was obtained from the compound of Reference Example 6- (3) (295 mg) and used in the next reaction without purification.

[Reference Example 7]
(1) 2- [4-[(Furan-2-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid tert-butyl ester

In the same manner as in Reference Example 1- (2), the title compound (2.68 g) was obtained as a colorless oil from the compound of Reference Example 4- (1) (2.1 g) and furfurylamine (0.73 ml).
¹ H-NMR (CDCl ₃ ) δ: 1.42 (6H, s), 1.51 (9H, s), 2.21 (6H, s), 3.66 (2H, s), 3.78 ( 2H, s), 6.18 (1H, d, J = 3.2 Hz), 6.32 (1H, dd, J = 2.0, 3.2 Hz), 6.91 (2H, s), 7. 37 (1H, d, J = 2.0 Hz).
MS m / z: 374 (M + H) ^<+> .

(2) 2- [4-[[Furan-2-ylmethyl- [2- (4-hydroxyphenyl) propionyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid tert-butyl ester

In the same manner as in Reference Example 2- (1), the title compound (473 mg) was obtained as a colorless oil from the compound of Reference Example 7- (1) (373 mg) and 4-hydroxyphenylpropionic acid (166 mg).
MS m / z: 521 (M + H) ^<+> .

(3) tert-Butyl 2- [4-[[furan-2-ylmethyl- [2- (4-methanesulfonyloxyphenyl) propionyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionate ester

  In the same manner as in Reference Example 2- (2), the title compound was obtained from the compound of Reference Example 7- (2) (468 mg) and used in the next reaction without purification.

[Reference Example 8]
2- [4-[[[2- (4-Ethansulfonyloxyphenyl) acetyl] -furan-2-ylmethylamino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

  The compound of Reference Example 2- (1) (500 mg) was dissolved in dichloromethane (7 ml), triethylamine (0.188 ml) and ethanesulfonyl chloride (0.118 ml) were added while cooling with ice water, and the mixture was stirred at the same temperature for 2 hours. . An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound, which was used in the next reaction without purification.

[Reference Example 9]
(1) 2- [4-[[Furan-2-ylmethyl- [2- (3-hydroxyphenyl) acetyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

In the same manner as in Reference Example 2- (1), the title compound (733 mg) was obtained as a colorless oil from the compound of Reference Example 1- (2) (518 mg) and 3-hydroxyphenylacetic acid (228 mg).
MS m / z: 480 (M + H) ^<+> .

(2) 2- [4-[[Furan-2-ylmethyl- [2- (3-methanesulfonyloxyphenyl) acetyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

  In the same manner as in Reference Example 2- (2), the title compound was obtained from the compound of Reference Example 9- (1) (730 mg) and used in the next reaction without purification.

[Reference Example 10]
2- [4-[[Furan-2-ylmethyl- [2- (4-methoxyphenyl) acetyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

The compound of Reference Example 1- (2) (350 mg) was dissolved in dichloromethane (6 ml), sodium hydrogen carbonate (102 mg) and 4-methoxyphenylacetyl chloride (0.17 ml) were added with cooling with ice water, and the mixture was stirred for 1 hour. . An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound (420 mg) as a colorless oil.
MS m / z: 494 (M + H) ^<+> .

[Reference Example 11]
(1) 2- [4-[[[2- (4-tert-butylcarbonylaminophenyl) acetyl] furan-2-ylmethylamino] methyl] -2,6-dimethylphenoxy] -2-methylpropionate ethyl ester

In the same manner as in Reference Example 2- (1), the title compound (1.08 g) was colorless from the compound of Reference Example 1- (2) (691 mg) and 4-1,1-dimethylethoxycarbonylaminophenylacetic acid (502 mg). Obtained as an oil.
MS m / z: 601 (M + Na) ^<+> .

(2) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonylaminophenyl) acetyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

The compound of Reference Example 11- (1) (1.08 g) was dissolved in dichloromethane (8 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 ml), 2,6-lutidine (0.435 ml) and methanesulfonic anhydride (650 mg) were added with cooling with ice water, and the mixture was stirred at room temperature for 2 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 2) to give the title compound (917 mg) as a colorless oil.
MS m / z: 557 (M + H) ^<+> .

[Reference Example 12]
2- [2,6-Dimethyl-4- [2- (4-sulfamoylphenyl) ethylamino] methyl] phenoxy] -2-methylpropionic acid ethyl ester

In the same manner as in Reference Example 3, the title compound (1.26 g) was obtained as a colorless solid from the compound of Reference Example 5- (1) (1.0 g) and 4- (2-aminoethyl) benzenesulfonamide (757 mg). It was.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (3H, t, J = 7.1 Hz), 1.45 (6H, s), 2.17 (6H, s), 2.88-2 .92 (4H, m), 3.67 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.86 (2H, s), 7.33 (2H, d, J = 8.1 Hz), 7.84 (2H, d, J = 8.1 Hz).
MS m / z: 449 (M + H) ^<+> .

[Reference Example 13]
2- [4-[[2- (3,4-Dimethoxyphenyl) ethylamino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

In the same manner as in Reference Example 3, the title compound (1.48 g) was obtained from the compound of Reference Example 1- (1) (1.0 g) and 2- (3,4-dimethoxyphenyl) ethylamine (0.638 ml) as a colorless solid. Got as.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (3H, t, J = 7.1 Hz), 1.45 (6H, s), 2.17 (6H, s), 2.78 (2H , T, J = 6.6 Hz), 2.87 (2H, t, J = 6.6 Hz), 3.67 (2H, s), 3.858 (3H, s), 3.861 (3H, s) ), 4.28 (2H, q, J = 7.1 Hz), 6.73-6.75 (2H, m), 6.80 (1H, d, J = 8.3 Hz), 6.86 (2H) , S).
MS m / z: 430 (M + H) ^<+> .

[Reference Example 14]
2- [4-[[Carboxymethyl- [2- (4-hydroxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid tert-butyl ester

  The compound of Reference Example 4- (2) (1.09 g) was dissolved in a mixture of dichloromethane (15 ml) and methanol (5 ml), and glyoxylic acid (364 mg) and sodium triacetoxyborohydride (1.17 g) were added. And stirred at room temperature overnight. A 10% aqueous citric acid solution and ethyl acetate were added to the reaction mixture, and the mixture was concentrated under reduced pressure to obtain a crude product of the title compound, which was directly used in the next reaction.

[Example 1]
(1) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonyloxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

The compound of Reference Example 2- (2) (340 mg) was dissolved in tetrahydrofuran (6 ml), borane-dimethyl sulfide complex (0.12 ml) was added with cooling with ice water, and the mixture was stirred at 60 ° C. for 4 hours, and then borane-dimethyl sulfide. The complex (0.12 ml) was added and the mixture was further stirred for 4 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (243 mg) as a colorless oil.
MS m / z: 544 (M + H) ^<+> .

(2) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonyloxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid

  The compound of Example 1- (1) (235 mg) was dissolved in a mixed solvent of tetrahydrofuran (2 ml) and ethanol (2 ml), 5N aqueous sodium hydroxide solution (0.173 ml) was added, and the mixture was stirred at room temperature for 23 hours. . Concentrated hydrochloric acid (0.072 ml) was added to the reaction solution, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 95: 5) and then purified by preparative thin phase silica gel chromatography (developed with dichloromethane: methanol = 95: 5) to give the title compound (66 mg) as colorless Obtained as a solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.31 (6H, s), 2.12 (6H, s), 2.57 (2H, t, J = 7.1 Hz), 2.76 (2H, t, J = 7.1 Hz), 3.34 (2H, s), 3.49 (2H, s), 3.66 (2H, s), 6.28 (1H, d, J = 2) .9 Hz), 6.40 (1 H, dd, J = 1.7, 2.9 Hz), 6.84 (2 H, s), 7.22 (4 H, s), 7.61 (1 H, d, J = 1.7 Hz).
MS m / z: 516 (M + H) ^<+> .

[Example 2]
(1) 2- [4-[[Furan-2-ylmethyl- [2- (4-hydroxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

  The compound of Reference Example 3 (2.36 g) and furfural (0.61 ml) were dissolved in dichloromethane (25 ml), sodium triacetoxyborohydride (1.95 g) was added, and the mixture was stirred at room temperature for 19 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (2.67 g) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (3H, t, J = 7.1 Hz), 1.46 (6H, s), 2.16 (6H, s), 2.60-2 .65 (2H, m), 2.69-2.73 (2H, m), 3.52 (2H, s), 3.71 (2H, s), 4.28 (2H, q, J = 7) .1 Hz), 6.17 (1H, d, J = 3.2 Hz), 6.32 (1H, dd, J = 2.0, 3.2 Hz), 6.71 (2H, d, J = 8. 3 Hz), 6.89 (2H, s), 6.96 (2H, d, J = 8.6 Hz), 7.38 (1H, d, J = 2.0 Hz).
MS m / z: 466 (M + H) ^<+> .

(2) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonyloxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

In the same manner as in Reference Example 2- (2), the title compound (2.68 g) was obtained as a pale yellow oil from the compound (2.67 g) of Example 2- (1).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 1.46 (6H, s), 2.17 (6H, s), 2.66 (2H , T, J = 6.6 Hz), 2.78 (2H, t, J = 6.6 Hz), 3.12 (3H, s), 3.53 (2H, s), 3.69 (2H, s) ), 4.29 (2H, q, J = 7.1 Hz), 6.15 (1H, d, J = 2.9 Hz), 6.33 (1H, dd, J = 2.0, 2.9 Hz) 6.89 (2H, s), 7.15 (4H, s), 7.39 (1 H, d, J = 2.0 Hz).
MS m / z: 544 (M + H) ^<+> .

[Example 3]
(1) 2- [4-[[[2- (4-Hydroxyphenyl) ethyl] thiazol-2-ylmethylamino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid tert-butyl ester

In the same manner as in Example 2- (1), the compound of Reference Example 4- (2) (325 mg) and thiazole-2-carboxaldehyde (0.083 ml) are treated with sodium triacetoxyborohydride (333 mg). Gave the title compound (332 mg) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41 (6H, s), 1.51 (9H, s), 2.20 (6H, s), 2.72 (4H, s), 3. 60 (2H, s), 3.97 (2H, s), 6.70 (2H, q, J = 8.6 Hz), 6.92 (2H, s), 6.93 (2H, d, J = 8.6 Hz), 7.26 (1H, d, J = 3.2 Hz), 7.68 (1H, d, J = 3.2 Hz).
MS m / z: 510 (M + H) ^<+> .

(2) 2- [4-[[[2- (4-Methanesulfonyloxyphenyl) ethyl] thiazol-2-ylmethylamino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid tert-butyl ester

The title compound (354 mg) was obtained as a colorless oil by treating the compound of Example 3- (1) (325 mg) with methanesulfonyl chloride (0.059 ml) in the same manner as in Reference Example 2- (2). It was.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42 (6H, s), 1.51 (9H, s), 2.20 (6H, s), 2.73-2.84 (4H, m ), 3.12 (3H, s), 3.62 (2H, s), 3.96 (2H, s), 6.92 (2H, s), 7.11 (2H, ABq, J = 8. 8 Hz), 7.15 (2H, ABq, J = 8.8 Hz), 7.25 (1H, d, J = 3.2 Hz), 7.67 (1H, d, J = 3.2 Hz).
MS m / z: 589 (M + H) ^<+> .

(3) 2- [4-[[[2- (4-Methanesulfonyloxyphenyl) ethyl] thiazol-2-ylmethylamino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid

The compound (403 mg) of Example 3- (2) was dissolved in dichloromethane (5 ml), 4N hydrochloric acid-dioxane (1 ml) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 93: 7) to give the title compound (213 mg) as a colorless amorphous solid. This was crystallized from aqueous methanol to give the title compound as a colorless solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.32 (6H, s), 2.12 (6H, s), 2.68 (2H, t, J = 6.6 Hz), 2.82 (2H, t, J = 6.6 Hz), 3.34 (3H, s), 3.57 (2H, s), 3.95 (2H, s), 6.90 (2H, s), 7. 22 (4H, s), 7.60 (1H, d, J = 3.2 Hz), 7.70 (1H, d, J = 3.2 Hz).
Elemental analysis value Calculated as C ₂₆ H ₃₂ N ₂ O ₆ S ₂ : C, 58.63; H, 6.05; N, 5.26; S, 12.04.
Found: C, 58.50; H, 5.98; N, 5.22; S, 11.97.
MS m / z: 533 (M + H) ^<+> .

[Example 4]
(1) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonyloxyphenyl) ethyl] amino] methyl] phenoxy] -2-methylpropionic acid ethyl ester

The title compound (607 mg) was obtained as a colorless oil by treating the compound obtained in Reference Example 5- (4) with borane-dimethyl sulfate complex in the same manner as in Example 1- (1).
MS m / z: 516 (M + H) ^<+> .

(2) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonyloxyphenyl) ethyl] amino] methyl] phenoxy] -2-methylpropionic acid

  The compound of Example 4- (1) (600 mg) was dissolved in a mixed solvent of ethanol (3 ml) and tetrahydrofuran (3 ml), 1N aqueous lithium hydroxide solution (2.33 ml) was added, and the mixture was stirred overnight at room temperature. . A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5) and then by preparative thin phase silica gel chromatography (developed with chloroform: methanol = 95: 5) to give the title compound (314 mg) as a colorless solid. Obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.48 (6H, s), 2.58 (2H, t, J = 6.9 Hz), 2.77 (2H, t, J = 6. 9 Hz), 3.34 (3 H, s), 3.54 (2 H, s), 3.65 (2 H, s), 6.28 (1 H, d, J = 3.2 Hz), 6.40 (1 H , Dd, J = 2.0, 3.2 Hz), 6.75 (2H, d, J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.23 (4H, s), 7.60 (1H, d, J = 2.0 Hz).
Elemental analysis _{C 25 H 29 NO 7 S ·} 3 / 4H 2 O Calculated: C, 59.92; H, 6.14 ; N, 2.80; S, 6.40.
Found: C, 59.68; H, 5.67; N, 2.73; S, 6.37.
MS m / z: 488 (M + H) ^<+> .

[Example 5]
(1) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonyloxyphenyl) ethyl] amino] methyl] -2-methoxyphenoxy] -2-methylpropionic acid ethyl ester

In the same manner as in Example 1- (1), the title compound (169 mg) was obtained as a colorless oil by treating the compound obtained in Reference Example 6- (4) with borane-dimethyl sulfide complex.
MS m / z: 546 (M + H) ^<+> .

(2) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonyloxyphenyl) ethyl] amino] methyl] -2-methoxyphenoxy] -2-methylpropionic acid

In the same manner as in Example 4- (2), the title compound (31 mg) was obtained as a colorless solid from the compound (165 mg) of Example 5- (2).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.32 (6H, s), 2.12 (6H, s), 2.19 (3H, s), 3.48 (2H, s), 3.645 (2H, s), 3.652 (2H, s), 6.36 (1H, d, J = 2.9 Hz), 6.44 (1H, dd, J = 1.7, 2.9 Hz) ), 6.92 (2H, s), 6.96 (1H, s), 7.33-7.37 (1H, m), 7.52 (2H, t, J = 8.3 Hz), 7. 64 (1H, d, J = 1.7 Hz), 7.93 (2H, d, J = 8.3 Hz).
MS m / z: 489 (M + H) ^<+> .

[Example 6]
(1) 2- [4-[[Furan-2-ylmethyl- [2- (4-hydroxybenzyl) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

  The compound of Reference Example 1- (2) (360 mg) and 4-hydroxybenzaldehyde (127 mg) were dissolved in dichloromethane (6 ml), sodium triacetoxyborohydride (331 mg) was added, and the mixture was stirred overnight at room temperature. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (386 mg) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (3H, t, J = 7.1 Hz), 1.46 (6H, s), 2.19 (6H, s), 3.46 (2H , S), 3.49 (2H, s), 3.58 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.16 (1H, d, J = 3.2 Hz). ), 6.33 (1H, d, J = 1.7, 3.2 Hz), 6.78 (2H, d, J = 8.6 Hz), 6.96 (2H, s), 7.23 (2H) , D, J = 8.6 Hz), 7.39 (1H, d, J = 1.7 Hz).

(2) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonyloxybenzyl) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

In the same manner as in Reference Example 2- (2), the title compound (409 mg) was obtained as a colorless oil from the compound of Example 6- (1) (380 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (3H, t, J = 7.1 Hz), 1.57 (6H, s), 2.19 (6H, s), 3.13 (3H , S), 3.49 (2H, s), 3.57 (2H, s), 3.59 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.16 ( 1H, d, J = 2.9 Hz), 6.33 (1H, dd, J = 1.7, 2.9 Hz), 6.96 (2H, s), 7.23 (2H, d, J = 8) .6 Hz), 7.40 (1H, d, J = 1.7 Hz), 7.43 (2H, d, J = 8.6 Hz).
MS m / z: 530 (M + H) ^<+> .

(3) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonyloxybenzyl) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid

In the same manner as in Example 4- (2), the title compound (225 mg) was obtained as a colorless solid from the compound (400 mg) of Example 6- (2).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.33 (6H, s), 2.16 (6H, s), 3.36 (3H, s), 3.44 (2H, s), 3.54 (2H, s), 3.55 (2H, s), 6.30 (1H, d, J = 2.9 Hz), 6.41 (1H, dd, J = 1.7, 2.9 Hz) ), 6.98 (2H, s), 7.31 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.6 Hz), 7.63 (1H, d, J = 1.7 Hz).
Elemental analysis _{C 26 H 31 NO 7 S ·} 1 / 2H 2 O Calculated: C, 61.16; H, 6.32 ; N, 2.74; S, 6.28.
Found: C, 61.07; H, 6.10; N, 2.62; S, 6.11.
MS m / z: 502 (M + H) ^<+> .

[Example 7]
(1) 2- [4-[[Furan-2-ylmethyl- [3- (4-methanesulfonyloxyphenyl) propyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid tert-butyl ester

In the same manner as in Example 1- (1), the title compound (409 mg) was obtained as a colorless solid by treating the compound obtained in Reference Example 7- (3) with a borane-dimethyl sulfide complex.
MS m / z: 586 (M + H) ^<+> .

(2) 2- [4-[[Furan-2-ylmethyl- [3- (4-methanesulfonyloxyphenyl) propyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid

In the same manner as in Example 3- (3), the title compound (137 mg) was obtained as a colorless solid from the compound (400 mg) of Example 7- (1).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.33 (6H, s), 1.73 (2H, t, J = 7.3 Hz), 2.15 (6H, s), 2.37 (2H, t, J = 7.3 Hz), 2.56 (2H, t, J = 7.3 Hz), 3.33 (3H, s), 3.43 (2H, s), 3.58 (2H , S), 6.24 (1H, d, J = 3.2 Hz), 6.39 (1H, dd, J = 2.0, 3.2 Hz), 6.93 (2H, s), 7.20. (2H, ABq, J = 9.1 Hz), 7.23 (2H, ABq, J = 9.1 Hz), 7.59 (1H, d, J = 2.0 Hz).
Elemental analysis _{C 28 H 35 NO 7 S ·} 1 / 2H 2 O Calculated: C, 62.43; H, 6.74 ; N, 2.60; S, 5.95.
Found: C, 62.09; H, 6.39; N, 2.51; S, 5.82.
MS m / z: 530 (M + H) ^<+> .

[Example 8]
(1) 2- [4-[[2- (4-ethanesulfonyloxyphenyl) ethyl] furan-2-ylmethylamino] methyl] 2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

In the same manner as in Example 1- (1), the title compound (318 mg) was obtained as a colorless solid by treating the compound obtained in Reference Example 8 with borane-dimethyl sulfide complex.
MS m / z: 558 (M + H) ^<+> .

(2) 2- [4-[[2- (4-ethanesulfonyloxyphenyl) ethyl] furan-2-ylmethylamino] methyl] 2,6-dimethylphenoxy] -2-methylpropionic acid

In the same manner as in Example 4- (2), the title compound (79 mg) was obtained as a colorless oil from the compound of Example 8- (1) (312 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.32 (6H, s), 1.36 (3H, t, J = 7.4 Hz), 2.12 (6H, s), 2.57 (2H, t, J = 6.9 Hz), 2.76 (2H, t, J = 6.9 Hz), 3.45-3.50 (4H, m), 3.66 (2H, s), 6 .28 (1H, d, J = 2.9 Hz), 6.41 (1H, dd, J = 1.7, 2.9 Hz), 6.84 (2H, s), 7.18-7.26 ( 4H, m), 7.61 (1H, d, J = 1.7 Hz).
MS m / z: 530 (M + H) ^<+> .

[Example 9]
(1) 2- [4-[[Furan-2-ylmethyl- [2- (3-methanesulfonyloxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

In the same manner as in Example 1- (1), the title compound (474 mg) was obtained as a colorless oil by treating the compound obtained in Reference Example 9- (2) with borane-dimethyl sulfide complex.
MS m / z: 544 (M + H) ^<+> .

(2) 2- [4-[[Furan-2-ylmethyl- [2- (3-methanesulfonyloxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid

In the same manner as in Example 4- (2), the title compound (161 mg) was obtained as a colorless solid from the compound of Example 9- (1) (470 mg). This was crystallized from water-methanol to obtain colorless crystals.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.32 (6H, s), 2.11 (6H, s), 2.59 (2H, t, J = 7.1 Hz), 2.78 (2H, t, J = 7.1 Hz), 3.34 (3H, s), 3.48 (2H, s), 3.66 (2H, s), 6.28 (1H, d, J = 3) .2 Hz), 6.40 (1 H, dd, J = 2.0, 3.2 Hz), 6.82 (2 H, s), 7.12-7.17 (3 H, m), 7.35 (1 H) , T, J = 7.6 Hz), 7.60 (1H, d, J = 2.0 Hz).
Elemental analysis C ₂₇ H ₃₃ NO ₇ S Calculated: C, 62.89; H, 6.45 ; N, 2.72; S, 6.22.
Found: C, 62.75; H, 6.20; N, 2.74; S, 6.26.
MS m / z: 516 (M + H) ^<+> .

[Example 10]
(1) 2- [4-[[Furan-2-ylmethyl- [2- (4-methoxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

In the same manner as in Example 1- (1), the compound of Reference Example 10 (410 mg) was treated with borane-dimethyl sulfide complex to give the title compound (324 mg) as a colorless oil.
MS m / z: 480 (M + H) ^<+> .

(2) 2- [4-[[Furan-2-ylmethyl- [2- (4-methoxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid

In the same manner as in Example 1- (2), the title compound (238 mg) was obtained as a colorless solid from the compound of Example 10- (1) (320 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.33 (6H, s), 2.11 (6H, s), 2.48-2.51 (2H, m), 2.65 (2H , T, J = 6.6 Hz), 3.48 (2H, s), 3.66 (2H, s), 3.70 (3H, s), 6.29 (1H, d, J = 2.9 Hz). ), 6.41 (1H, dd, J = 1.7, 2.9 Hz), 6.80 (2H, d, J = 8.8 Hz), 6.84 (2H, s), 7.01 (2H) , D, J = 8.8 Hz), 7.61 (1H, d, J = 1.7 Hz).
Elemental analysis _{C 27 H 33 NO 5 · 1} / 4H 2 O Calculated: C, 71.11; H, 7.40 ; N, 3.07.
Found: C, 70.96; H, 7.42; N, 3.13.
MS m / z: 452 (M + H) ^<+> .

[Example 11]
(1) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonylaminophenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

In the same manner as in Example 1- (1), the compound of Reference Example 11- (2) (910 mg) was treated with borane-dimethyl sulfide complex to give the title compound (438 mg) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 (3H, t, J = 7.1 Hz), 1.46 (6H, s), 2.17 (6H, s), 2.65 (2H , Dd, J = 5.9, 9.3 Hz), 2.75 (2H, dd, J = 5.9, 9.3 Hz), 2.98 (3H, s), 3.52 (2H, s) , 3.70 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 6.16 (1H, d, J = 3.2 Hz), 6.33 (1H, dd, J = 1.7, 3.2 Hz), 6.35 (1 H, s), 6.88 (2 H, s), 7.10 (4 H, s), 7.39 (1 H, d, J = 1.7 Hz) .
MS m / z: 543 (M + H) ^<+> .

(2) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonylaminophenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid

In the same manner as in Example 1- (2), the title compound (103 mg) was obtained as a colorless solid from the compound of Example 11- (1) (210 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.33 (6H, s), 2.12 (6H, s), 2.50-2.55 (2H, m), 2.69 (2H , T, J = 6.4 Hz), 2.92 (3H, s), 3.48 (2H, s), 3.65 (2H, s), 6.27 (1H, d, J = 3.2 Hz) ), 6.40 (1H, dd, J = 2.0, 3.2 Hz), 6.86 (2H, s), 7.06 (2H, ABq, J = 8.8 Hz), 7.09 (2H) , ABq, J = 8.8 Hz), 7.61 (1H, s).
Elemental analysis _{C 27 H 34 N 2 O 6} S · 1 / 4H 2 O Calculated: C, 62.47; H, 6.70 ; N, 5.40; S, 6.18.
Found: C, 62.37; H, 6.64; N, 5.35; S, 6.18.
MS m / z: 515 (M + H) ^<+> .

[Example 12]
(1) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonylmethylamino) phenyl] ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionate ethyl ester

  The compound of Example 11- (1) (210 mg) was dissolved in tetrahydrofuran (5 ml), methanol (0.078 ml), triphenylphosphine (152 mg) and azodicarboxylic acid diisopropyl ester (0.114 ml) were added while cooling with ice water. And stirred for 8 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound (215 mg) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 (3H, t, J = 7.1 Hz), 1.46 (6H, s), 2.18 (6H, s), 2.65-2 .69 (2H, m), 2.76-2.80 (2H, m), 2.83 (3H, s), 3.30 (3H, s), 3.54 (2H, s), 3. 70 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 6.16 (1H, d, J = 3.2 Hz), 6.33 (1H, dd, J = 1.7) , 3.2 Hz), 6.91 (2H, s), 7.12 (2H, d, J = 8.3 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.39 (1H) , D, J = 1.7 Hz).
MS m / z: 557 (M + H) ^<+> .

(2) 2- [4-[[Furan-2-ylmethyl- [2- (4-methanesulfonylmethylamino) phenyl] ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid

In the same manner as in Example 1- (2), the title compound (120 mg) was obtained as a colorless solid from the compound of Example 12- (1) (216 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.32 (6H, s), 2.13 (6H, s), 2.57 (2H, t, J = 6.9 Hz), 2.74 (2H, t, J = 6.9 Hz), 2.90 (3H, s), 3.20 (3H, s), 3.50 (2H, s), 3.66 (2H, s), 6. 28 (1H, d, J = 2.9 Hz), 6.41 (1H, dd, J = 1.7, 2.9 Hz), 6.88 (2H, s), 7.14 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.61 (1H, d, J = 1.7 Hz).
Elemental analysis _{C 28 H 36 N 2 O 6} S · H 2 O Calculated: C, 61.52; H, 7.01 ; N, 5.12; S, 5.87.
Found: C, 61.63; H, 6.69; N, 5.05; S, 5.72.
MS m / z: 529 (M + H) ^<+> .

[Example 13]
(1) 2- [4-Furan-2-ylmethyl- [2- (4-sulfamoylphenyl) ethyl] amino] methyl] phenoxy] -2-methylpropionic acid ethyl ester

  The compound of Reference Example 12 (350 mg) was dissolved in a mixed solvent of dichloromethane (5 ml) and methanol (2 ml), furfural (0.097 ml) and sodium triacetoxyborohydride (331 mg) were added, and the mixture was stirred overnight at room temperature. . An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound (328 mg) as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 1.44 (6H, s), 2.14 (6H, s), 2.68 (2H , T, J = 7.1 Hz), 2.79 (2H, t, J = 7.1 Hz), 3.49 (2H, s), 3.72 (2H, s), 4.28 (2H, q , J = 7.1 Hz), 4.89 (2H, s), 6.18 (1H, d, J = 2.9 Hz), 6.34 (1H, dd, J = 1.7, 2.9 Hz) , 6.81 (2H, s), 7.22 (2H, d, J = 8.3 Hz), 7.40 (1H, d, J = 1.7 Hz), 7.76 (2H, d, J = 8.1 Hz).
MS m / z: 529 (M + H) ^<+> .

(2) 2- [4-Furan-2-ylmethyl- [2- (4-sulfamoylphenyl) ethyl] amino] methyl] phenoxy] -2-methylpropionic acid

In the same manner as in Example 1- (2), the title compound (258 mg) was obtained as a colorless solid from the compound of Example 13- (1) (320 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.30 (6H, s), 2.12 (6H, s), 2.58 (2H, t, J = 7.4 Hz), 2.80 (2H, t, J = 7.4 Hz), 3.48 (2H, s), 3.66 (2H, s), 6.29 (1H, d, J = 2.9 Hz), 6.41 (1H , Dd, J = 1.7, 2.9 Hz), 6.82 (2H, s), 7.26 (2H, s), 7.29 (2H, d, J = 8.3 Hz), 7.61 (1H, d, J = 1.7 Hz), 7.69 (2H, d, J = 8.3 Hz).
MS m / z: 501 (M + H) ^<+> .

[Example 14]
(1) 2- [4-[[[2- (3,4-Dimethoxyphenyl) ethyl] furan-2-ylmethylamino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

In the same manner as in Example 13- (1), the title compound (361 mg) was obtained as a pale yellow oil from the compound of Reference Example 13 (350 mg) and furfural (0.101 ml).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (3H, t, J = 7.1 Hz), 1.45 (6H, s), 2.17 (6H, s), 2.65-2 .69 (2H, m), 2.73-2.76 (2H, m), 3.53 (2H, s), 3.70 (2H, s), 3.84 (3H, s), 3. 85 (3H, s), 4.28 (2H, q, J = 7.1 Hz), 6.16 (1H, d, J = 3.2 Hz), 6.32 (1H, dd, J = 2.0) 3.2 Hz), 6.65 (1 H, d, J = 2.0, 8.1 Hz), 6.68 (1 H, d, J = 2.0 Hz), 6.76 (1 H, d, J = 8.1 Hz), 6.90 (2H, s), 7.38 (1 H, d, J = 2.0 Hz).
MS m / z: 509 (M + H) ^<+> .

(2) 2- [4-[[[2- (3,4-Dimethoxyphenyl) ethyl] furan-2-ylmethylamino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid

In the same manner as in Example 1- (2), the title compound (299 mg) was obtained as a colorless solid from the compound of Example 14- (1) (355 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.32 (6H, s), 2.11 (6H, s), 2.54 (2H, t, J = 7.6 Hz), 2.66 (2H, t, J = 7.6 Hz), 3.48 (2H, s), 3.66 (2H, s), 3.69 (3H, s), 3.70 (3H, s), 6. 28 (1H, d, J = 3.2 Hz), 6.41 (1H, dd, J = 1.7, 3.2 Hz), 6.61 (1H, dd, J = 2.0, 8.1 Hz) , 6.73 (1H, d, J = 2.0 Hz), 6.80 (1H, d, J = 8.1 Hz), 6.85 (2H, s), 7.60 (1H, d, J = 1.7 Hz).
Elemental analysis _{C 28 H 36 N 2 O 6} S · 3 / 4H 2 O Calculated: C, 67.93; H, 7.43 ; N, 2.83.
Found: C, 67.74; H, 7.38; N, 2.74.
MS m / z: 481 (M + H) ^<+> .

[Example 15]
(1) 2- [4-[[Furan-2-ylmethyl- [2- (hydroxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid tert-butyl ester

In the same manner as in Example 2- (1), the title compound (323 mg) was obtained by treating the compound of Reference Example 4- (2) (308 mg) and furfural (0.093 ml) with sodium triacetoxyborohydride. Obtained as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42 (6H, s), 1.51 (9H, s), 2.20 (6H, s), 2.61-2.64 (2H, m ), 2.69-2.73 (2H, m), 3.52 (2H, s), 3.70 (2H, s), 6.16 (1H, d, J = 3.2 Hz), 6. 32 (1H, dd, J = 2.0, 3.2 Hz), 6.71 (2H, d, J = 8.3 Hz), 6.89 (2H, s), 6.97 (2H, d, J = 8.3 Hz), 7.39 (1H, d, J = 2.0 Hz).
MS m / z: 494 (M + H) ^<+> .

(2) 2- [4-[[Furan-2-ylmethyl- [2- (4-trifluoromethanesulfonyloxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid tert- Butyl ester

  The compound of Example 15- (1) (320 mg) was dissolved in dichloromethane, and 2,6-lutidine (0.113 ml) and trifluoromethanesulfonic anhydride (0.16 ml) were added while cooling with dry ice-acetone. Stir at the same temperature for 1 hour. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6) to give the title compound (236 mg) as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42 (6H, s), 1.51 (9H, s), 2.19 (6H, s), 2.65-2.69 (2H, m ), 2.77-2.80 (2H, m), 3.52 (2H, s), 3.68 (2H, s), 6.13 (1H, d, J = 3.2 Hz), 6. 32 (1H, dd, J = 2.0, 3.2 Hz), 6.86 (2H, s), 7.13 (2H, ABq, J = 9.1 Hz), 7.17 (2H, ABq, J = 9.1 Hz), 7.38 (1H, d, J = 2.0 Hz).
MS m / z: 626 (M + H) ^<+> .

(3) 2- [4-[[Furan-2-ylmethyl- [2- (4-trifluoromethanesulfonyloxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid

In the same manner as in Example 3- (3), the title compound (168 mg) was obtained as a light brown solid from the compound (230 mg) of Example 15- (2).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.32 (6H, s), 2.10 (6H, s), 2.58 (2H, t, J = 7.1 Hz), 2.79 (2H, t, J = 7.1 Hz), 3.48 (2H, s), 3.66 (2H, s), 6.26 (1H, d, J = 3.2 Hz), 6.40 (1H , Dd, J = 2.0, 3.2 Hz), 6.81 (2H, s), 7.30 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8. 8 Hz), 7.60 (1H, d, J = 2.0 Hz).
Elemental analysis _{C 27 H 30 F 3 NO 7} S · 1 / 4H 2 O Calculated: C, 56.49; H, 5.35 ; F, 9.93; N, 2.44; S, 5. 59. Found: C, 56.57; H, 5.30; F, 9.63; N, 2.41; S, 5.51.
MS m / z: 570 (M + H) ^<+> .

[Example 16]
(1) 2- [4-[[[2- (4-Hydroxyphenyl) ethyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid tert-butyl ester

  The compound (400 mg) obtained in Reference Example 14 was dissolved in N, N-dimethylformamide (7 ml), and methylamine (2N tetrahydrofuran solution, 4.2 ml), 1- (3-dimethylaminopropyl) -3- Ethylcarbodiimide hydrochloride (195 mg) and 1-hydroxybenzotriazole hydrate (156 mg) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5) to give the title compound (244 mg) as a pale brown oil.

¹ H-NMR (CDCl ₃ ) δ: 1.42 (6H, s), 1.51 (9H, s), 2.20 (6H, s), 2.54 (3H, d, J = 4.9 Hz) ), 2.68-2.71 (4H, m), 3.04 (2H, s), 3.55 (2H, s), 6.62 (1H, br s), 6.79 (2H, s) ), 6.81 (2H, d, J = 8.3 Hz), 6.99 (2H, d, J = 8.3 Hz).
MS m / z: 485 (M + H) ^<+> .

(2) tert-Butyl 2- [4-[[[2- (4-ethanesulfonyloxyphenyl) ethyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenoxy] -2-methylpropionate

  The compound of Example 16- (1) (240 mg) was dissolved in dichloromethane (3 ml), and triethylamine (0.090 ml) and ethanesulfonyl chloride (0.056 ml) were added under ice water cooling, followed by stirring for 2 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 96: 4) to give the title compound (198 mg) as a pale brown oil.

¹ H-NMR (CDCl ₃ ) δ: 1.43 (6H, s), 1.51 (9H, s), 1.55 (3H, t, J = 7.4 Hz), 2.21 (6H, s ), 2.60 (3H, d, J = 4.9 Hz), 2.74-2.79 (4H, m), 3.08 (2H, s), 3.29 (2H, q, J = 7) .4 Hz), 3.56 (2 H, s), 6.58 (1 H, br s), 6.78 (2 H, s), 7.15 (2 H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.6 Hz).
MS m / z: 577 (M + H) ^<+> .

(3) 2- [4-[[[2- (4-ethanesulfonyloxyphenyl) ethyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid

  The compound of Example 16- (2) (193 mg) was dissolved in dichloromethane (1.5 ml), 4N hydrochloric acid dioxane solution (1 ml) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 90: 10) to give the title compound (132 mg) as a colorless oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.33 (6H, s), 1.36 (3H, t, J = 7.4 Hz), 2.13 (6H, s), 2.52 (3H , D, J = 4.9 Hz), 2.64 (2H, t, J = 6.9 Hz), 2.79 (2H, t, J = 6.9 Hz), 3.01 (2H, s), 3 .48 (2H, q, J = 7.4 Hz), 3.56 (2H, s), 6.90 (2H, s), 7.21-7.29 (5H, m).
MS m / z: 521 (M + H) ^<+> .

[Example 17]
(1) 2- [4-[[Dimethylcarbamoylmethyl- [2- (4-hydroxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid tert-butyl ester

In the same manner as in Example 16- (1), the title compound (111 mg) was obtained as a pale brown oil from the compound (400 mg) obtained in Reference Example 14 and dimethylamine (2N tetrahydrofuran solution, 4.2 ml). It was.
¹ H-NMR (CDCl ₃ ) δ: 1.40 (6H, s), 1.51 (9H, s), 2.15 (6H, s), 2.73 (3H, s), 2.77 ( 2H, t, J = 7.1 Hz), 2.86 (3H, s), 3.06 (2H, t, J = 7.1 Hz), 3.49 (2H, s), 3.83 (2H, s), 6.74 (2H, d, J = 8.6 Hz), 6.90 (4H, s).
MS m / z: 499 (M + H) ^<+> .

(2) 2- [4-[[Dimethylcarbamoylmethyl- [2- (4-ethanesulfonyloxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid tert-butyl ester

In the same manner as in Example 16- (2), the title compound (92 mg) was obtained as a colorless oil from the compound of Example 17- (1) (105 mg) and ethanesulfonyl chloride (0.024 ml).
MS m / z: 591 (M + H) ^<+> .

(3) 2- [4-[[Dimethylcarbamoylmethyl- [2- (4-ethanesulfonyloxyphenyl) ethyl] amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid

In the same manner as in Example 16- (3), the title compound (50 mg) was obtained as a colorless oil from the compound of Example 17- (2) (87 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 1.32 (6H, s), 1.36 (3H, t,
J = 7.4 Hz), 2.12 (6H, s), 2.68 (3H, s), 2.71 (3H, s), 2.71-2.75 (4H, m), 3.20. (2H, s), 3.47 (2H, q, J = 7.4 Hz), 3.54 (2H, s), 6.85 (2H, s), 7.19-7.24 (4H, m ).
MS m / z: 535 (M + H) ^<+> .

[Example 18]
(1) 2- [4-[[[2- (4-Hydroxyphenyl) ethyl]-(5-methyl-2-phenyloxazol-4-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] -2 -Methylpropionic acid tert-butyl ester

In the same manner as in Example 2- (1), the compound of Reference Example 4- (2) (67 mg) and 5-methyl-2-phenyloxazole-4-carbaldehyde (30 mg) were mixed with sodium triacetoxyborohydride (51 mg). ) To give the title compound (60 mg) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41 (6H, s), 1.52 (9H, s), 2.19 (6H, s), 2.22 (3H, s), 2. 77 (4H, br s), 3.57 (2H, s), 3.58 (2H, s), 6.70 (2H, d, J = 8.5 Hz), 6.90 (2H, s), 6.99 (2H, d, J = 8.3 Hz), 7.40-7.45 (3H, m), 7.9-8.01 (2H, m).
MS m / z: 585 (M + H) ^<+> .

(2) 2- [4-[[[2- (4-Methanesulfonyloxyphenyl) ethyl]-(5-methyl-2-phenyloxazol-4-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] -2-Methylpropionic acid tert-butyl ester

In the same manner as in Reference Example 2- (2), the title compound (54 mg) was obtained as a colorless oil from the compound of Example 18- (1) (60 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41 (6H, s), 1.52 (9H, s), 2.19 (6H, s), 2.20 (3H, s), 2. 83-2.84 (4H, m), 3.10 (3H, s), 3.57 (4H, s), 6.90 (2H, s), 7.15 (4H, dd, J = 15. 6Hz, 8.8Hz), 7.42-7.44 (3H, m), 7.99-8.01 (2H, m).
MS m / z: 663 (M + H) ^<+> .

(3) 2- [4-[[[2- (4-Methanesulfonyloxyphenyl) ethyl]-(5-methyl-2-phenyloxazol-4-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] -2-Methylpropionic acid hydrochloride

The compound (50 mg) of Example 18- (2) was dissolved in dichloromethane (5.0 ml), 4N hydrochloric acid-dioxane solution (2 ml) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by preparative thin layer silica gel chromatography (chloroform: methanol = 9: 1), and then 4N hydrochloric acid-dioxane solution was added and concentrated under reduced pressure. The residue was freeze-dried to give the title compound (38 mg) as a colorless amorphous solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.35 (6H, s), 2.16 (6H, s), 2.41 (3H, s), 3.21-3.70 (11H M), 7.28-7.37 (6H, m), 7.56-7.58 (3H, m), 7.96-7.99 (2H, m).
MS m / z: 607 (M + H) ^<+> .
Elemental analysis _{C 33 H 39 ClN 2 O 7} S · 2H 2 O · HCl Calculated: C, 58.35; H, 6.38 ; N, 4.12.
Found: C, 58.62; H, 6.38; N, 3.64.

[Test Example 1]
GAL4-hPPAR transactivation assay (a) Plasmid GAL4 DNA-binding region-PPAR ligand-binding region fusion protein expression plasmids pFA-hPPARα / GAL4 and pFA-hPPARγ / GAL4, respectively, contain LBD cDNAs of hPPARα and hPPARγ under the CMV promoter. It was obtained by integrating into a commercially available expression vector (pFA trans-Activator plasmids, STRATAGENE) having a yeast GAL4 DNA binding region (GAL4 DBD). As the reporter protein expression plasmid, a commercially available plasmid (pFR-SEAP, STRATAGENE) having a GAL4 response region (GAL4 UAS) upstream of cDNA of secretory alkaline phosphatase (SEAP) was used.
(B) Cell culture and transactivation assay HEK293T cells are suspended in high glucose Dulbecco's conditioned Eagle's medium (DMEM) containing 10% fetal bovine serum (Hyclone), 100 units / mL penicillin G and 100 mg / mL streptomycin sulfate. It became cloudy and was seeded in 24-well cell culture plates at a density of 8 × 10 4 cells / well. After incubation for 24 hours at 37 ° C. in a humidified atmosphere of 5% CO ₂ , transfer under serum-free conditions using Lipofectamine (Lipofectamine, Invitrogen) and Plus Reagent (Plus Reagent, Invitrogen) according to the manufacturer's instructions. Was performed. That is, in a 225 μL transfection medium (OPTI-MEM, Invitrogen) containing lipofectamine 0.48 μL, pFA-PPAR / GAL4 expression plasmid 0.030 μg, and pFR-SEAP 0.13 μg, in a 5% CO ₂ atmosphere. Cells were incubated for 5 hours at 37 ° C. Next, an equal volume of fresh high glucose DMEM containing 10% fetal bovine serum, 100 units / mL penicillin G and 100 mg / mL streptomycin sulfate and the specified 2-fold concentration of test compound was added, and the cells were incubated for about 48 hours. . Since the compounds were solubilized in DMSO, control cells were incubated with an equivalent concentration of DMSO. The final DMSO concentration is 0.1% or less, and it has been revealed that the concentration does not affect the transactivation activity. After completion of the incubation, the culture supernatant was collected, and SEAP activity was measured using a kit (Reporter assay kit-SEAP, TOYOBO) according to the manufacturer's instructions. That is, an equal volume of an endogenous alkaline phosphatase inhibitor was added to 5 μL of the culture supernatant and incubated at 37 ° C. for 30 minutes, and then 100 μL of a chemiluminescent substrate (Lumiphos PLUS, Lumigen) was added and incubated at 37 ° C. for 15 minutes. Later, luminescence was measured using a multi-label counter (ARVOsx, PerkinElmer). The relationship between the value obtained by the above operation and the concentration of the test compound was plotted, and the EC ₅₀ value was determined.
<Test results>
As shown in the table below, the compounds of the present invention showed potent GAL4-hPPAR transactivation activity.

Claims (13)

Formula (I)

(In the above formula,
R ¹ and R ² are each independently a hydrogen atom, hydroxyl group, halogen atom, lower alkoxy group, cyano group, lower alkanoyl group, lower alkylcarbamoyloxy group, lower alkylsulfonyl group, lower alkylthio group, lower alkylsulfinyl group, substituted A lower alkyl group which may have a group, an amino group which may have a substituent, a carbamoyl group which may have a substituent, a lower alkylsulfonyloxy group which may have a substituent An arylsulfonyloxy group which may have a substituent, a sulfamoyl group which may have a lower alkyl group, a sulfamoyloxy group which may have a lower alkyl group, and a substituent. 5-6 membered saturated heterocyclic group which may have, 5-6 membered aromatic heterocyclic group which may have a substituent, A good aryloxy group, or an aryl group which may have a substituent,
R ³ represents a lower alkoxy group, an optionally substituted carbamoyl group, or an optionally substituted 5- to 6-membered aromatic heterocyclic group;
R ⁴ and R ⁵ each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, an optionally substituted lower alkyl group, or an optionally substituted amino group. Group,
R ⁶ and R ⁷ each independently represent a hydrogen atom or a lower alkyl group, or R ⁶ and R ⁷ together with the carbon atom to which they are substituted form a 3-6 membered aliphatic saturated ring. May form,
R ⁸ represents a hydrogen atom or a lower alkyl group,
m represents an integer of 1 to 3 (provided that when R ³ is a lower alkoxy group, m represents an integer of 2 to 3), and n represents an integer of 1 to 3. )
Or a salt or a solvate thereof. R ¹ and R ² are each independently a hydrogen atom, a hydroxyl group, a lower alkoxy group, an optionally substituted amino group, a lower alkylsulfonyl group, or an optionally substituted lower alkylsulfonyloxy group. Or a sulfamoyl group optionally having a lower alkyl group, or a 5- or 6-membered saturated heterocyclic group optionally having a substituent, or a salt thereof or a solvent thereof. Japanese products. R ³ is A compound according to claim 1 or 2 lower alkoxy groups, a salt thereof, or a solvate. R < ³ > is the carbamoyl group which may have a substituent, The compound of Claim 1-2, its salt, or those solvates. R ³ is a furyl group, an oxazolyl group, a thiazolyl group, or an oxadiazolyl group, and these groups are optionally substituted lower alkyl groups and optionally substituted phenyl groups. The compound according to claim 1 or 2, a salt thereof or a solvate thereof, which may be substituted with one or two groups which may be the same or different, selected from among them. R ⁴ and R ⁵ are each independently a hydrogen atom or a lower alkyl group which may have a substituent, The compound according to claim 1, a salt thereof, or a solvate thereof. Independently R ⁶ and R ⁷ are each A compound according to claims 1 to 6 is a lower alkyl group, a salt thereof, or a solvate. R < ⁸ > is a hydrogen atom, The compound, its salt, or those solvates of Claims 1-7. A medicament comprising the compound represented by formula (I) according to claim 1, a salt thereof or a solvate thereof. A pharmaceutical composition comprising the compound represented by formula (I) according to claim 1, a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier. Use of the compound represented by the general formula (I) according to claim 1, a salt thereof or a solvate thereof for the production of a medicament. A therapeutic agent for diseases caused by insulin resistance, comprising the compound represented by formula (I) according to claim 1, a salt thereof, or a solvate thereof. A therapeutic agent for diabetes comprising the compound represented by the general formula (I) according to claim 1, a salt thereof, or a solvate thereof.