WO2001079197A1 - ACTIVATORS FOR PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR δ (PPARδ) - Google Patents

Abstract

Benzisoxazole derivatives of the general formula (II) having a PPARδ-activating effect, or salts thereof, wherein A is O, S, or the like; R?1, R2 and R3¿ are each hydrogen, C¿1-8? alkyl, optionally substituted phenyl, or the like; X?1 and X2¿ are each O, S, a free valency, or the like; Y1 is an optionally substituted C¿1-8? alkylene chain; Z is O or S; and R?4 and R5¿ are each hydrogen, C¿1-8? alkyl, or the like.

Description

 Description Activator of peroxisome proliferator-activated receptor 5 '' Technical field

 The present invention relates to the activation scheme 1 of peroxisome proliferator-activated receptor d. Background art

 Peroxisomes are organelles found in the cells of animals and plants, and their matrices contain a variety of enzymes, including lipase. Peroxisome protosome (peroxisome prol if erator) is a substance that induces the growth of this phenolic isomer, a variety of substances such as antilipidemic drugs (fibrates), herbicides, and furate plasticizers. Compounds are known.

 A nuclear receptor activated by this peroxisome proliferator was identified by Isseman et al., And a peroxisomal proliferator-activated receptor (peroxisome proliferator or activated recept or: PPAR) Was named. (Nature, 347, p645—650, 1990)

The existence of three subtypes of PPAR has been confirmed to date: PPAR, PPARa and PPARd. (Proc. Natl. Acad. Sci. USA, 91, 7335-7359, 1994)

 The above-mentioned fibrate drugs have a ligand effect on PPARα, and a strong serum TG (triglyceride) lowering effect has been recognized in clinical practice.

 Also, thiazolidinedione compounds (Troglitazone, Rosiglitazone, Pioglitazone) which are therapeutic agents for diabetes are known as ligands of PPARy.

As a drug having PP AR 5 activating action, for example, the following formula:

GW— 2433 (Glaxo We lle ome) expressed by the following formula,

L— 165041 (Me r ck) represented by the following formula or

YM—16638 (Yamanouchi Pharmaceutical) and the like are known.

 GW-2433 is described in WO 92/10 468 for use as a preventive and therapeutic agent for atherosclerosis, L-165041 is described in WO 97/28115 for use as a therapeutic agent for diabetes mellitus, and an antiobesity agent, and YM-16638 is described in WO 99/04815 as having a serum cholesterol lowering effect and an LDL-cholesterol lowering effect. More recently, PPAR5 ligand has been reported to promote its application as an anticancer drug and an anti-inflammatory drug (J BC, 272 (6), p3406-3410, 1997; Ce 11, 99, p 335-345, 1999). I have. On the other hand, as a compound having a structure similar to the vesazol derivative represented by the following general formula (II) of the present compound,

Compound A (Patent No. 2581523),

Compound C (Japanese Unexamined Patent Publication No. Hei 8-311065),

Compound D (WO97 / 27 1990)

It has been known. All of the above compounds A, B, and C have a carboxyl group, a cyano group, or an ethoxy or propylthio group substituted on the right side of the benzisoxazole ring or benzofuran ring. Carboxyl groups are linked via an alkylene chain.

 On the other hand, the compound of the present invention is acetic acid or 2-alkylpropionic acid in which the right side of penzisoxazole is bonded by an ether or thioether bond, and has a structural difference from A, B and C described above.

 It has been reported that the compounds described in Compounds A, B and C above have an insulin resistance improving effect, a hypoglycemic effect, etc., but these compounds are useful as ligands of PPAR d. There is no specific description. On the other hand, Compound D above has a benzofuran ring bonded to the left side of the indole ring via an alkylene chain, and a thiazolyl ring-oxazole ring bonded to the left side of the benzixoxazole ring via an alkylene chain. Although it is structurally different from the compound of the present invention, and there is a statement that W0997 / 27190 has an ACAT (acyl coenzyme A-cholesterol acyltransferase) inhibitory action, There is no description that it is useful as a ligand for PPAR5. An object of the present invention is to provide a compound represented by the following general formula (I) or a penzisoxazole derivative represented by the following general formula (II), which has an activity of activating peroxisome proliferator-activated receptor 3. It is in. Disclosure of the invention

 That is, the present invention provides the following general formula (I):

(I)

(Where A represents 0, S or NR ⁶ ; Here, R ⁶ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms, and a alkenyl group having 2 to 8 carbon atoms, and an alkynyl group having 2 to 8 carbon atoms. An arylalkyl group which may have a substituent (carbon number of an aryl moiety is 6 to 10; carbon number of an alkyl moiety is 1 to 4); or a carbon atom which may have a substituent has 6 to 6 carbon atoms. Represents an aryl group or a bond of 10

R ¹ , R ² and R ³ are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by a halogen atom, a cycloalkyl group having 3 to 7 carbon atoms, An alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, and an arylalkyl group which may have a substituent (The aryl moiety has 6 to 10 carbon atoms, the alkyl moiety has 1 to 4 carbon atoms), an aryl group having 6 to 10 carbon atoms which may have a substituent, and 1 to 3 as ring-forming atoms. A 5- to 8-membered heterocyclic group consisting of a nitrogen atom, an oxygen atom or a sulfur atom, and a 5- to 8-membered ring consisting of the remaining carbon atoms, or a bond, or R ¹ and R ² are bonded And R ¹ and R ² may form a benzene ring together with the carbon atom to which they are bonded,

X ¹ and X ² represent 0, SC (= 0) NH, C (= 0), C (OH) or NR ⁷ , or a bond,

Here, R ⁷ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms,

Y ¹ represents an alkylene chain having 1 to 8 carbon atoms which may have a substituent,

B ¹ represents CW ¹ or N,

Here, W ¹ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or a bond,

B ² represents CW ² or N,

Here, W ² represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or a bond,

D represents ◦, S, NR ⁸ ;

Here, R ⁸ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an arylalkyl group which may have a substituent (the carbon number of the aryl portion is 6 to 10 and the carbon number of the alkyl portion is 1 to 10). ~ 4), or a bond,

 Z represents 0 or S,

Y ² represents an alkylene chain having 1 to 4 carbon atoms or a bond,

And are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, and a carbon atom substituted with a halogen atom. Represents an alkyl group of the numbers 1 to 8,

 E represents a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a sulfonic group, a phosphonic group, a cyano group, or a tetrazole group.

However, ^one of R ¹ , R ² ₃ R ³ and R ⁶ is a bond, and the rest is other than a bond, and this bond is bonded to X ¹ , and W ¹ , W ² And one of R ⁸ is a bond, and the rest is other than a bond, and this bond and X ² are bonded. ) Or a salt thereof. Further, the present invention provides the following general formula (11):

 (II)

(Where Α represents 0, S or NR ⁶ ;

Here, R ⁶ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a alkenyl group having 2 to 8 carbon atoms, An alkynyl group, an arylalkyl group which may have a substituent (an aryl moiety having 6 to 10 carbon atoms and an alkyl moiety having a carbon number of 1 to 4), or a carbon atom which may have a substituent Represents an aryl group or a bond of 6 to 10;

R ¹ , R ² and R ³ are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, a cycloalkyl group having 3 to 7 carbon atoms, An alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, and an arylalkyl group which may have a substituent (The aryl portion has 6 to 10 carbon atoms, and the alkyl portion has 1 to 4 carbon atoms), and may have a substituent. Aryl group having 6 to 10 carbon atoms, a heteroatom selected from a nitrogen atom, an oxygen atom or a sulfur atom as a ring-forming atom and a 5- to 8-membered ring composed of the remaining carbon atoms A group or a bond, or and and R ² may be bonded to form a benzene ring together with R ¹ and the carbon atom to which R ² is bonded;

X ¹ and X ² represent 0, S, C (= 0) NH, C (= 0), C (OH) or NR ⁷ , or a bond,

 Here, represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms,

Y ¹ represents an alkylene chain having 1 to 8 carbon atoms which may have a substituent,

 Z represents 0 or S,

R ⁴ and R ⁵ represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom.

However, ^one of R ¹ , R ² , and R ⁶ is a bond, and the rest is other than a bond, and this bond and X ¹ are bonded. ) Or a salt thereof.

 Furthermore, the present invention relates to a peroxisome proliferator-activated receptor δ containing, as an active ingredient, a compound represented by the above general formula (I) or a benzisoxazole derivative represented by the above general formula (II), or a salt thereof. Activator. BEST MODE FOR CARRYING OUT THE INVENTION

 Next, the present invention will be described in detail.

In the general formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , RRW ¹ and W ² may be a methyl group, an ethyl group, or a propyl group. Groups, isopropyl group, butyl group, i-butyl group, t-butyl group, pentyl group and hexyl group.

The alkyl Le group _{^{R 1, R 2, R 5}} R 4, R 5 and the carbon number is substituted with a halogen atom R ⁶ 1~ 8, 1~ 3 fluorine atoms, such as chlorine atom or bromine atom Examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and a t-butyl group substituted with a halogen atom, and preferably a trifluoromethyl group, a chloromethyl group, or a 2-alkyl group. A loroethyl group, a 2-bromoethyl group, a 2-fluoroethyl group and the like. ,

Examples of the cycloalkyl group having 3 to 7 carbon atoms represented by R ¹ , R ² and R ³ include a cyclopropyl group, a cyclopentyl group and a cyclohexyl group.

R ¹ , R ¹ , R ² and R ³ include a C ¹ to C 6 alkyl group substituted by a C ³ to C 7 cycloalkyl group such as a cyclohexylmethyl group and a cyclopentylmethyl group.

Examples of the alkenyl group having 2 to 8 carbon atoms for R ¹ , R ² , R ³ and R ⁶ include a vinyl group and an aryl group.

Examples of the alkynyl group having 2 to 8 carbon atoms for R ¹ , R ² , R ³ and include a propargyl group.

R ¹ , R ^z , R ₃ R and R ⁸ which may have a substituent may be an arylalkyl group (C 6 to C 10 in the aryl moiety and C 1 to C 4 in the alkyl moiety). An alkyl group having 1 to 6 carbon atoms (methyl group, ethyl group, propyl group, etc.), an alkoxy group having 1 to 6 carbon atoms (methoxy group, ethoxy group) or a halogen atom (fluorine atom, chlorine atom, bromine atom), etc. And a substituted or unsubstituted aryl group (a phenyl group or a naphthyl group), for example, a methyl group or an ethyl group, preferably a pendyl group, a benzhydryl group or a phenethyl group.

Examples of the aryl group having 6 to 10 carbon atoms which may have a substituent of 1, R ² , R ³ and R ⁶ include an alkyl group having 1 to 6 carbon atoms (a methyl group, an ethyl group, a propyl group). ), An alkyl group having 1 to 6 carbon atoms (trifluoromethyl group) substituted with a halogen atom, an alkoxy group having 1 to 6 carbon atoms (methoxy group, ethoxy group), a halogen atom (fluorine atom, chlorine atom, It has a substituent such as a bromine atom, an acyl group (an acetyl group, a benzoyl group), a nitro group, an amino group, a substituted amino group (a dimethylamino group), a carboxyl group, a hydroxyl group, a phenyl group, a benzyl group, or a phenyloxy group. A phenyl group or a naphthyl group which may be mentioned, and preferably a phenyl group, a 2-chlorophenyl group, a 2-methylphenyl group, a 3-chlorophenyl group, and a 2,3-dichlorophenyl Or 2, 4-dichlorophenyl group, and the like. As a ring-forming atom of R ¹ , R ² and R ^3, a 5- to 8-membered heterocyclic group comprising a heteroatom selected from 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms and the remaining carbon atoms, A pyridyl group, a cyenyl group, a furyl group, a thiazolyl group, a quinolyl group, and the like. These complex ring groups include an alkyl group having 1 to 6 carbon atoms (a methyl group and an ethyl group) and a carbon atom having a 1 to 6 carbon atoms. 6 may have a substituent such as an alkoxy group (methoxy group, ethoxy group), a halogen atom (fluorine atom, chlorine atom), a trifluoromethyl group, or a trifluoroethyl group.

The alkylene chain having 1 to 8 carbon atoms which may have a substituent of Y ¹ includes a methylene which may be substituted with a substituent such as an alkyl group having 1 to 6 carbon atoms (methyl group, ethyl group). , Ethylene and propylene.

Examples of the alkylene chain having 1 to 4 carbon atoms of Y ² include methylene and ethylene.

 Examples of the alkoxycarbonyl group having 2 to 8 carbon atoms of E include methoxycarbonyl and ethoxycarbonyl.

 The substitution position of Z is at the 4, 5, 6 or 7 position, preferably at the 5 or 6 position.

Further, among the compounds represented by the above general formula (I), a compound in which B ¹ is CW ¹ is preferable. Among the compounds represented by the above general formula (I), B ¹ is CW ¹ and Y ² is A compound that is a bond is preferable.

Further, among the compounds represented by the general formula (I), a compound in which B ¹ is CW ¹ , Y ² is a bond, and E is a carboxyl group is preferable. Further, among the compounds represented by the above general formula (I),

Gaben isoxazole ring, benzofuran II, benzothiophene II, or indole Compounds in which Y ² is a bond and Ε is a carboxyl group are preferred. Further, among the compounds represented by the above general formula (I), the benzodisoxazole derivative represented by the above general formula (II) of the present invention is preferable.

R ¹ in Benzuisokisazo Ichiru derivative represented by the general formula ^{(II), R 2, R} 3, R 4, R 5, alkyl group having 1 to 8 carbon atoms of R ⁶ and R ^7; R ^1, R ² R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ halogen atom-substituted alkyl groups having 1 to 8 carbon atoms; R ¹ , R ² and R ³ cycloalkyl groups having 3 to 7 carbon atoms; R ¹ An alkyl group having 1 to 6 carbon atoms, which is substituted with a cycloalkyl group having 3 to 7 carbon atoms of R ² , R ² and R ³ ; an alkenyl group having 2 to 8 carbon atoms of R ¹ , R ² , R ³ and R ⁶ ; R ¹ , R ² , R ³ and R ⁶ alkynyl groups having 2 to 8 carbon atoms; R ¹ , R ² , R ³ and R ⁶ arylalkyl groups which may have a substituent (aryl moiety) carbon number 6-10, and 1 to 4 carbon atoms in the alkyl moiety); R ^1, R ^2, Ariru groups R ³ and good carbon number 6-10 which may have a substituent group R ^6; R ¹ , 1 as ring-forming atoms of R ² and R ³ 3 nitrogen atoms, SansoHara child or sulfur atom Alkylene chain of Y ¹ which may have a substituent carbon prime 1-8 above general formula (I); heterocyclic group having from 5 to 8-membered ring comprising a heteroatom and the remaining carbon atoms selected from Examples are the same as those described for the compounds represented. Further, among the benzisoxazole derivatives represented by the general formula (II), a benzisoxazole derivative in which A is 0 or S is preferable.

Further, among the benzisoxazole derivatives represented by the general formula (II), a benzisoxazole derivative in which A is 0 or S, and X ¹ and X ² are a bond is preferable.

Also, among the benzisoxazole derivatives represented by the general formula (II), A is 0 or S, X ¹ and X ² are a bond; ¹ , R ² and R ³ are a hydrogen atom, C1-8 alkyl group substituted by halogen atom, C1-8 alkyl group substituted by halogen atom, C3-7 cycloalkyl group substituted by C3-7 cycloalkyl group Alkyl group, alkenyl group having 2 to 8 carbon atoms, alkynyl group having 2 to 8 carbon atoms, arylalkyl group which may have a substituent (alkyl having 6 to 10 carbon atoms in the aryl portion, Preferred are an aryl group, a pyridyl group, a phenyl group, a phenyl group, a phenyl group, a fenyl group, and a benzodisoxazole derivative which is a bond, having 1 to 4) carbon atoms in the moiety and 6 to 10 carbon atoms which may have a substituent. Furthermore, among the benzisoxazole derivatives represented by the general formula (II), A is 0 or S, X ¹ and X ² are a bond, and R ¹ , R ² and R ³ are a hydrogen atom, a carbon atom, An alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 6 carbon atoms as a substituent, an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, an acyl group Aryl having 6 to 10 carbon atoms which may have an atom or a group selected from a group, a nitro group, an amino group, a substituted amino group, a carboxyl group, a hydroxyl group, a phenyl group, a benzyl group and a phenyloxy group. Group, a viridyl group, a cyenyl group, a furyl group or an arylalkyl group (the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 4 carbon atoms), or a benzisoxazole derivative which is a bond . The compound represented by the general formula (I) or the benzisoxazole derivative represented by the general formula (II) may be a pharmacologically acceptable salt, for example, a sodium salt, a potassium salt, or the like. Metal salts. Next, a method for synthesizing the compound represented by the above general formula (I) or the benzisoxazole derivative represented by the above general formula (II) will be described. A synthesis scheme of the benzisoxazole derivative represented by the general formula (II) is shown below.

(V)

, K ₂ CO ₃

Hydrolysis

(VI)

(In the reaction formula, R represents a methyl group, the carbon number of 1 to 6 alkyl groups such as Echiru group, Q represents a leaving group such as chlorine atom, bromine atom, and _{^{R 1, R 2 5 RAX 1}} , Y ¹ , X ² , Z, R ⁴ and R ⁵ are the same as above.

Hydroxy (or mercapto) benzisoxazole derived from general formula (IV) The body is obtained by diazotizing the aminopenzisoxazole derivative represented by the general formula (III) with sodium nitrite or mineral acid (sulfuric acid) under ice-cooling, and sulfuric acid if Z is an oxygen atom. In the case where Z is a sulfur atom, it is obtained by heating with ethyl ethyl xanthogen tandem steam or the like and then heating.

 The benzisoxazole derivative of the present invention represented by the general formula (VI) is represented by the general formula (V) in the presence of a base such as potassium carbonate in the compound represented by the general formula (IV). It is obtained by the action of an acetate derivative.

Further, the benzisoxazole derivative of the present invention represented by the general formula (VII) can be obtained by converting the benzisoxazole derivative of the present invention represented by the general formula (VI) to lithium hydroxide, hydroxide rim, or the like. It can be obtained by subjecting it to a hydrolysis reaction in the presence. Further, the benzixoxazole derivative of the present invention can also be obtained by the following reaction scheme.

R ⁴ ,

GT, C0 ₂ R> ^K 2 ^C ° 3

Hydrolysis

(In the formula, A, R ¹ , R ² , R ³ , Z, R ⁴ , R ⁵ Q and R are the same as described above.) Further, the compound of the present invention can also be obtained by the following reaction scheme ₍ , K ₂ C0 ₃

Hydrolysis

D = NH, 0, S (In the reaction formula, D represents NH, 0 or S, and R, Q, R ¹ , R ^z ₅ R ³ , A, Z, R ⁴ and R ⁵ are the same as described above.) Starting materials in the above reaction scheme Can be obtained, for example, by the method described in WO 96/35688, EP 505322, and the like. Other compounds represented by the above general formula (I) can be obtained by the same method.

Tables 1 to 22 show examples of the compound of the present invention thus obtained.

 (1-1)

 The following general formula (a),

Wherein Y ¹ is ethylene, X ¹ and X ² are bonds, and the substitution positions of R ² , R ³ , R ⁴ , RZ and Z are listed in Tables 1 to 4. thing.

【table 1】

^{R 2 R 3 R 4 R 5} Z position it methyl phenyl HH 0 6-methyl phenyl methyl 0 6-methyl phenyl methyl 0 6 Echiru phenyl methyl 0 6 full ° opening arsenide ° Le phenyl methyl 0 6 off ⁰ Rohi ⁰ Le (2 - C1) phenyl methyl 0 6 off ,, chill phenyl methyl 0 6 to ⁰ pentyl phenyl methyl 0 off to 6 hexyl phenyl methyl 0 6. Tylphenylmethylmethyl06 octylphenylmethylmethyl06 irif. Phenyl phenyl methyl methyl methyl 0 6 Irif, tyl phenyl methyl methyl methyl 0 7

CF ₃ phenyl methyl methyl 0 7

CH ₂ CF ₃ phenyl methyl methyl 0 7

[Table 2] 2 R 3 R ⁴ R ⁵ Z position

CH ₂ CHF ₂ phenyl Echiru HS 7 phenyl full ⁰ [pi arsenide ⁰ Le HS 7 cyclohexyl phenyl methyl cyclohexane 0 7 Shikurofu. !] Hylphenylmethylmethyl S5 cycle. 11 h. Phenyl methyl methyl methyl 07 phenyl phenyl methyl methyl 06

(CH ₂ ) ₂ CH-CH ₂ phenylmethylmethyl07. rm. Phenyl, phenyl methyl methyl 0 6 phenyl phenyl methyl methyl 0 7

(2-C1),,, phenyl methyl methyl 0 7

(2-F),,,, phenyl methyl methyl ル 7

(2-F, 6-Cl,,, phenylmethyl methyl 0 7

To (2-CF ₃ ), si, le phenyl methyl methyl 0 7

(2-state Les)

[Table 3]

[Table 4]

(1-2)

A benzisoxazole derivative represented by the above general formula (a), wherein Y ¹ is ethylene, and the substitution positions of R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² , Z and Z are As shown in Table 5. [Table 5]

^{R 2 R3 R 4 5 z 117.} X 1 X 2 methyl 2-arsenide ⁰ Rishi ,, le H methyl 0 7 binding丰Echiru (2) 3-arsenide ° Rishi ,, methyl Echiru 0 7 bond Echiru ( 2-C1) - 3- Rishi ,, methyl off ⁰ Rohi ⁰ Le 0 7 C 0 bond τ kill (6- C1) one 3-arsenide. Rishi, Le Methylo. Le s 6 CO bond off, chill H off ⁰ Rohi. Le s 6 NHCO bond 3-h. Rishi,, methyl, methyl 0 6 Bond 0

4 ^{15 15} 、 ル メ チ ル 0 メ チ ル 6 — ェ 5 ェ ル ル

I-chill (6-C1) one-two. Remisi, methyl methyl 0 5 mouth s-ethyl 2-quinolyl methyl methyl 0 7 -ί 1 '' NH-ethyl 3-furyl methyl methyl 0 6 bond 0

T—kill 3-furyl methyl methyl s 6

 2-furyl methyl methyl 0 6 Bonding bond Bonding isof. Ethyl 3-thiermethylmethyl s 6 NH bond Isoph, tyl 2-thiermethylmethyl 06 Bond

(CH.). CHF. 3-indyl, ril methyl methyl s5 bond

 , -Cyl 2-yl methyl methyl methyl 0 7 / |, mouth bond methyl tonaphthyl methyl methyl 06

Λ hexyl (2-CD-3 -. Furylmethyl methyl 0 6 bond isophthalic ⁰卟cyclohexyl methyl to Le consequent Y 0 6 binding丰 Ethyl 2-,-,-,-,-,-,,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-and-Cynylmethylmethyl 06 Mouth.へ, ン, リ, furanyl methyl methyl 06 Rohi ⁰ Le (23-Cl) -4- arsenide. Rishi ,, methyl methyl 0 6 bond formation also full ⁰ necked Le (2,3-F) - 4- arsenide. Rishi, methyl, methyl, methyl 06 (2,3-Br) -4-H. Rishi, Le methyl engineering chill 06 (twenty one)

The following general formula (b),

In the benzisoxazole derivative represented by the formula, the substitution position of Z is the 6-position, and R ² , R ³ , X ¹ , X ² , YR ⁴ , R ⁵ and Z are those described in Table 6.

[Table 6]

(In the table, η η means a peroxy group.)

 (2-2)

In the benzisoxazole derivative represented by the general formula (b), when Z is 0, Substitution position is at the 7-position, and R ^2, those _{^{R 3 3 X 1, X \}} YR 4 and R ⁵ are as defined in Table 7

[Table 7]

(3— 1—) The following general formula (c :)

A benzisoxazole derivative represented by the following formula, wherein R ⁴ and R ⁵ are methyl groups, and the substitution positions of A, RRX ¹ , YX ² , Ζ and Ζ are shown in Table 8.

Ζ5 [Table 8]

(3-2)

In the benzisoxazole derivative represented by the general formula (c), Y ¹ is ethylene, the substitution position of Z is 7-position, and R ¹ , R ³ , X ¹ , X ² , R ⁴ and R ⁵ are Those described in Table 9. [Table 9]

 (4-1)

Wherein X ² is a bond, and the position of R ² R ³ R ⁴ R ⁵ B ² DZZ, X ¹ and Y ¹ are listed in Table 10.

[Table 10]

(In the table, Bn represents an,, or group.) (4-2)

In the compound represented by the above general formula (d), R ⁵ is a methyl group, Y ¹ is ethylene, and substitution positions of R ² , R ³ , R ⁴ , \ D, Z, Z, X ¹ and X ² is listed in Table 11

[Table 11]

(5-1)

Wherein Z is 0, Y ¹ is ethylene, and the positions of R ² , R \ R ⁴ R ⁵ , BD, Z, X ¹ and X ² are listed in Table 12. [Table 1 2]

(5-2)

In the compound represented by the general formula (e), R ⁴ and: R ⁵ is a methyl group, Z is S, and the substitution positions of R ² , R ³ , BD, Z, X ¹ , Y ¹ and X ² is also to in Table 1 3. [Table 13]

(6)

The following general formula Wherein R ¹ , R ² , X ¹ , X ² , Y ¹ and Z are listed in Tables 1 to 22.

[Table 14]

R ¹ R ² X ¹ Y ¹ X ² z

(2-C1) phenyl isopropyl compound CH ₂ CH ₂ ^ compound 0

(4-C1) phenyl blanking opening pill Mago寻CH ₂ CH ₂ i Gone 0

(2-C1) phenyl hexyl, gasoline CH ₂ CH ₂ i and others 0

(2-C1) phenyl benzene, CH ₂ CH ₂ combined 40

(2-Me) Phenyl Bubble Pill i Mine CH ₂ CH ₂ Mine 0

(2-C1) phenyl ethyl i CH ₂ CH ₂ , n 0

(2-N02) phenyl blanking opening building Magone CH ₂ CH ₂ or case 4 0

(2-C1) Fanyl Cyclopropyl Combined CH ₂ CH ₂ Combined 0 Cyclohexyl building mouth, Doo CH ₂ CH ₂ i Combined 0

(2-C1) phenylisobutyl, combined CH ₂ CH ₂ combined 0

(2-C1) phenyl t-butyl compound CH ₂ CH ₂ , ne 0

(2-F) full A Interview Le Lee Soburopiru, 4 CH ₂ CH ₂ Magone 0

(4- 1-butyl) fuunil isovrovir, ne CH ₂ CH ₂ , total 0

2-Naphthyl isoprovir imagoto CH ₂ CH ₂ , 寻 0

(2-OMe) Phenyl i Sopropyl Gasto CH ₂ CH ₂

(2,4-Cl) phenyl i-soprovir DOO CH ₂ CH ₂ , DOO 0

(2, 6-Cl) phenyl isopropyl i ₂ CH ₂ CH ₂ , 0

(2-CF3) phenyl bropir i ₂ CH ₂ CH ₂ , 0

(2-0H) phenyl isobrovir doo CH ₂ CH ₂ ^

(4 - butyl) off _A sulfonyl Isoburopiru i Magone CH ₂ CH ₂ 0 [Table 15]

R ¹ R ² X ¹ Y ¹ X ² z

(2-0H, 4-Me) phenyl isovrovirene CH ₂ CH ₂ , alloy 0

(2,4-Me) phenyl isopropyl, combined CH ₂ CH ₂ 40

(2-0H, 3,4-Me) phenyl isopropyl compound cH ₂ m

(2-0H.4-CF3) F Anil Isopropyl Compound H ₂ CH ₂ i Compound 0

(2-Cl, 4-0 e) Fanyl isopropyl 4 CH ₂ CH ₂ , 0

(2-Cl, 4-0Ph) phenyl isopropyl 4 CH ₂ CH ₂ , alloy 0

1-Naphthyl i Sopropirene CH ₂ CH ₂ 4 0

2—quinolyl isopropir compound CH ₂ CH ₂ 0

8—Quinolyl isovrovir, total CH ₂ CH ₂ 40

3 quinoline isopropyl doo CH ₂ CH ₂ 4 0

2-pyrimidyl isopropyl ^ Chemical CH2CH2, Chemical 0

2-Chenyl isopropyl ^ CH ₂ CH ₂ M

2-midazolyl isobrovir CH ₂ CH ₂ 4 0

2—Ind ¹ ) Louisobrovir Total CH ₂ CH _{2 to} 0

2 -Venzocenyl i-sopropylene CH ₂ CH ₂ 4 0

2-benzimidazolyl isoprpropyl i ₂ CH ₂ CH ₂ , dip 0

(2-0H, 4-Me) phenyl Buchi pill Doo CH ₂ CH ₂ Doo 0

(2,4-Me) phenyl Buchiguchi Doo CH CHg 0

(2-0H) Funnel Bubble pill Doo CH ₂ CH ₂ Μ 4 0

(2-0H, 3,4-Me) Ferment CH ₂ CH ₂ 0

(2-0H.4-CF3) phenyl pill, combined CH ₂ CH ₂ 0

(2-Cl, 4-0me) off A sulfonyl blanking port building CH ₂ CH ₂寻0

(2-Cl, 4-0ph) phenyl blanking port building Ne CH ₂ CH ₂ Tewi 0 [Table 16]

R ¹ R ² X ¹ Y ¹ X ² z

1-Naphthyl pill pill, go CH, CH ₂ , go 40

2-Naphthyl-Buguchi Building, Ma-Gato GH. Hfl

2—Kino,) Lub mouth building MA ₂ CH ₂ CH, 0

8—Quinolyl pill, mat 4 CH ₂ CH ₂ i mat 0

3 Protective pill pill

2-Pirimisolve mouth building Total CH CH2, negative 0

2-Chenil Buchi Building Building CH2CH2, MAGOTO 0

2-furanyl pill, combined CH2CH2 combined 0

2-dimidazolyl

2—Indrilling sigma pill, combined CH ₂ CH ₂ combined 0

2-^ s Nzo handicraft Niruguchi pill Compound CH ₂ CH ₂ Gaso 0

2 Nzui imidazolyl blanking opening pill Gone CH ₂ CH ₂ Gone 0

(2-0H, 4- e) F A nilethyl compound CHgCHg compound 0

(2,4-Me) phenyl ethyl compound CHoCH compound 0

(2-0H) phenyl Koshu Le Goto CH ₂ CH ₂ Goto 0

(2-0H, 3,4-e) phenyl, combined CH ₂ CH ₂ combined 0

(2-0H.4-CF3) phenyl ethyl 4 CH9CH9 4 0

(2-Cl, 4-0me) Funil

(2-Cl, 4-0ph) phenylethyl CH _a CH ₂

1-Naphthyl ethyl ^ CH ₂ CH ₂

2-Naphthyl ethyl, CH ₂ CH ₂ or CH 0

2—quinolyl ethyl CH ₂ CH ₂

8—Kinori Rlechil Doo CH ₂ CH ₂ Ma Goto 0 [Table 17]

_D 1

 Π R γ1

 Λ Y X 7 L-^ Nori renal, moss or moss 0 2 11

—Hirinle ^ Chile, "people CH ₂ Cn ₂ " s people

 Including 0

2—Chinore thousand)] "Ma-jin: i" people

Π Π ₂ Π Π is mosquito 0

2 Js "People! *

 —Funi Renal i

Order CH ₂ CH ₂

2—Tasori 1

Renare ia containing CH ₂ CH ₂ , moss containing 0 rt 1 1 ϊ

 2 c 1 1

— Note ¹ J Renal it

CH ₂ CH ₂ s included 0

2 ¾ ¾ CH ₂ CH ₂ a containing 0

(2-OH 4 Me) Hue-Le Futil "People: *

, Ma containing ne i (! G n ₂ a mosquito 0

(2, 4 Me) Hue >> Leftil s containing CH. CH ₂ , including ^ "0

(2 i '-i "

— OH) phenyle futyl or moss containing CH ₂ CH ₂ , containing 0

(2-OH, 3 4 Me) phenyl containing CH ₂ CH ₂ 5 mosquito 0

(2-0H 4-CF3) ph-leftyl ¾ including CH ₂ CH ₂ , including mosquito 0

(2-C1, 4 Ome) phenyl phenyl s moss CH ₂ CH ₂ moss 0

(2-C1 4-Opn phenyl ha

Borderless Les s含孑CH "CH 11 _2, including 0

 r «i r« i

1 Naphuchi-re-buchi-s mosquito CH ₂ CHo mosquito 0

2-Sufu Lef, Chill

Shimo CHCH ₂ "people it

 , Φ mosquito 0

2 "people

— No / H / H CH ₂ then H ₂

 Mosquito 0

8 "people" people

^ Nori resole 孑 moss Pig レ n ₂ , 0-含

/ Narrative δ comb 11 ₂ shi 11 ₂ u

2-pyrimidyl butyl i-m CH ₂ CH ₂ , m 0

2-Chenyl butyl gas ₂ CH ₂ CH 0

2-furanyl butyl ヰ CH ₂ CH ₂ , total 40

2-imidazolyl butyl 寻 CH ₂ CH ₂ , alloy 0 [Table 18]

R ¹ R ² X ¹ Y ¹ X ² z

2-Ind 'J-Butyl DOO CH ₂ CH ₂ ^

2-benzothenyl butyl compound CH ₂ CH ₂ , compound 0-benzimidazole butyl 寻 CH ₂ CH _Z i

(2-C1) phenyl isopropyl i ₂ CH ₂ CH ₂ ^ containing S

(4-C1) Hu-nil-bu σ-building mating CH ₂ CH ₂ mating S

(2-C1) phenyl hexyl, conjugated CH ₂ CH ₂ , conjugated S

(2-C1) phenyl benzol CH ₂ CH ₂ doo S

(2 - Me) phenyl Bed σ building i Magone CH ₂ CH _2, Ne S

(2, 3—C1) phenyl ethyl CH ₂ CH _a , S

(2-C1) phenyl ethyl compound CH ₂ CH ₂ , S

(2-N02) Fuyuniru blanking port pills, Go寻CH ₂ CH ₂ Ma含Ne S

(2-C1) Phenyl cyclobutene pill 4 CH ₂ CH ₂ or S S cyclohexyl σ building 4 CH ₂ CH ₂ i or S

(2-C1) phenylisobutyl compound CH ₂ CH ₂ i compound S

(2-C1) F Anil t-Butyl CH ₂ CH ₂ ^ Compound S

(2-F) phenylisopropyl CH ₂ CH ₂ , S

(t-butyl) phenyl-isopropyl 4 CH ₂ CH ₂ F

2-decyl isopropyl, CH ₂ CH ₂ or S

(2-0Me) phenyl Lee an isopropyl ^ Gone CH ₂ CH ₂ Ne S

(2,4-Cl) phenyl isopropyl, combined CH ₂ CH ₂ ^ combined S

(2, 6-Cl) Fuyl Isoprovirene CH ₂ CH ₂ combined 4 S

(2-CF3) phenyl isobu σ building MA ₂ CH ₂ CH ₂ , MA S

(2-0H) phenyl isopropyl CH ₂ CH ₂ compound S [Table 19]

R ¹ R ² X ¹ Y ¹ X ² z

(4-butyl) phenyl isopropizole bond CH2CH2 ίΡπ PI key s

(2-OH, 4-Me) phenyl isopropyl bond CH2CH2 bond s

(2,4-Me) P: cnyl isopropynole bond CH2CH2 bond s

(2-OH, 3,4-Me) phenyl isopropizole bond CH2CH2 bond s

(2-OH, 4-CF3) phenyl isopropizole bond CH2CH2 bond s

(2-Gl, 4-OMe) phenyl isopropyl ;! D bond CH2CH2 bond s

(2-Gl, 4-OPh) phenyl isopropyl bond CH2CH2 bond s

1-naphthyl isopropizole bond CH2CH2 bond s

2-quinolyl isopropizole bond CH2CH2 bond s

8-quinolyl isopropizole bond CH2CH2 $ Π (= 3 -f ¹ s

3-quinolyl isopropyl bond CH2CH2 bond s

2-pyrimidyl isopropyle bond CH2CH2 bond s

2-Chenyl isopropyl bond CH2CH2 bond s

2-furanyl isopropizole bond CH2CH2 bond s

2-imidazolyl isopropyl bond CH2CH2 bond s

2-Indolyl Isopropizole Bond CH2CH2 Bond s

2-benzobenzoyl isopropyl clue pj hand CH2CH2 bond s

² -benzimidazolyl isopropyl bond F3 CH2CH2 bond s

(2-OH, 4-Me) phenyl propyl bond CH2CH2 bond s

(2,4-Me) phenyl propyl yarn. ia cow CH2CH2 thread. Cow s

(2-OH) phenyl propyl bond CH2CH2 bond s

(2-OH, 3,4-Me) phenyl propyl bond CH2CH2 bond s

(2-OH, 4-CF3) phenylpropyl bond CH2CH2 | * P f = l T- s [Table 20]

R ¹ R ² X ¹ Y ¹ X ² z

(2-Cl, 4-0Me) phenyl pill, Doo CH ₂ CH ₂ Gaso s

(2-Cl, 4-0Ph) phenyl CH ₂ CH ₂ compound S

1-Naphthyl bguchi Building i-Mate CH ₂ CH _2- Mate N

2-naphthyl pill conjugated CH, CH, mated 4 S

2-quinolyl butyl mouth joint CH CH9 i joint 4 S

8—Quinolyl Buchi Building Building CH0CH0 Gasto S

3—Kinolil Buchi Building i Go CH ₂ CH ₂ Go Go S

2-Pirimiru Pup pill ^ go CHijCHrt ^ go S

2-Chenyl

2-furanyl pill, combined CH ₂ CH ₂ combined S

2 ミ ゾ ダ ダ ビ ル CH ₂ CH ₂ i

2—In drill hole pill ^ go CHpCH, gogo S

2 one ^ - Nso "thienyl blanking opening building, Magone CH, CH _2, Magone S

2 Nzimi Mi Dazoril Bguchi Building i Maaito CH ₂ CH ₂ Maena S

(2-0H, 4-Me) file

(2,4-Me) phenylethyl CH ₂ CH, i

(2-0H) phenyl ethyl CH ₂ CH ₂

(2-0H, 3,4-e) phenyl ethyl or CH9CH5 or S

(2-0H, 4-CF3) Fuel 寻 CH ₂ CH ₂寻 S

(2-Cl, 4-0Me) phenyl 4 CH ₂ CH ₂ S

(2-Cl, 4-0Ph) phenyl CH ₂ CH ₂ D

1-Naphthyl ethyl CH ₂ CH ₂ i

2-naphthyl ethyl CH ₂ CH ₂ compound S [Table 21]

R, R ² X ¹ Y, X ² z

2—quinolyl ethyl CH ₂ H i

8—Kino ryl ethyl i MATO ₂ CH ₂ CH ₂ MANE S

3—quinoline ethyl i CH ₂ CH ₂ , D

2-Bi "missile", including plastic 4S

2-Handenyl CH ₂ H Compound S

2-furanylethyl, 4 in total, including S

2-mimi dazolyl ethyl, 4-mato S

2—Indolethyl, CH ₂ 0Hrt Gas S

2-benzocenylethyl, combined CH ₂ CHo

2-Benzi midazolyl ethyl, Gaso CH ₂ CH ₂ Ma Gaso S

(2-0H, 4-e) phenyl butyl is MCH CH ₂ CH ₂ i Mato S

(2, 4-Me) vinyl compound CH ₂ CH ₂ compound S

(2-0H) A

(2-0H, 3, 4-Me) Furbutyl, Gasoline CH ₂ CH ₂ , Ne S

(2-0H 4-CF3) Fe-butyl, combined CH ₂ CH ₂ combined S

(2-Cl 4-0me) phenyl butyl gas CH ₂ CH ₂ S

(2-Cl 4-0ph) phenyl butyl, combined CH ₂ CH ₂ combined S

1-naphthyl butyl, union CH ₂ CH ₂ N S

2-Naphthyl butyl, Ne CH ₂ CH ₂ D S

2—Quinolyl butyl 4 CH ₂ CH ₂ D S

8—Quinolyl butylene CH _a CH ₂ , containing S

3-quinolyl butyl ^ union CH ₂ CHo, Doo S

2-Pyrimyl butyl 4 CH ₂ CH ₂ヰ S [Table 22]

Next, the pharmacological effects of the present invention will be described.

 The compound of the present invention: The PPAR3 activating effect is obtained by receptor plasmid (GAL 4-hPPAR0-LBD), luciferase expression plasmid (UASx4-TK-LUC) and /?-Galactosidase (^ — GAL) After transfecting the expression plasmid with DMRI E-C and culturing for 40 hours in the presence of the compound of the present invention or L-165041, which is a comparative compound, the solubilized cells are luciferase and GAL-activated. It was determined by measuring.

 Incidentally, the luciferase activity was corrected by the /?-1 GAL activity, and the relative ligand activity was calculated with the luciferase activity of the cells treated with L-165041 as 100%. (Example 10 described later) As is clear from Table 23, the compounds of the present invention (Examples 1 to 7) exhibited a PPAR5 activating effect equivalent to or higher than that of L-165041.

 In addition, Table 24 also shows that the compounds of the present invention described in Examples 9-11 to 9-22 also exhibited the same or higher PPAR5 activating action as compared to L-165041.

Therefore, the compound represented by the general formula (I) of the present invention has an excellent P PARS activating action. Because it has hypoglycemic agents, lipid-lowering agents, obesity, syndrome X, hypercholesterolemia, metabolic disorders such as hyperlipoproteinemia, hyperlipidemia, arteriosclerosis, cardiovascular disease, bulimia, Malignant tumors such as ischemic disease, lung cancer, breast cancer, colon cancer, colorectal cancer, ovarian cancer, Alzheimer's disease, inflammatory disease, and osteoporosis (Mano H. et.Al., (2000) J. Biol. Chem. , 275: 8126-8132), and is expected as a prophylactic or therapeutic agent for Graves' ophthalmopathy and adrenoleukodystrophy. The compound of the present invention can be administered to humans by an appropriate administration method such as general oral administration or parenteral administration.

 For formulation, it can be manufactured into tablets, granules, powders, capsules, suspensions, injections, suppositories and the like by usual methods in the technical field of formulation.

 These preparations employ conventional excipients, disintegrants, binders, lubricants, dyes, diluents, and the like. Here, the excipients include lactose, D-mannitol, crystalline cellulose, sucrose and the like, the disintegrants include starch and calcium carboxymethylcellulose (CMC-Ca), and the lubricants include stearin. Examples include magnesium acid and talc, and examples of the binder include hydroxypropylcellulose (HPC), gelatin, and polyvinylpyrrolidone (PVP).

 In general, the dosage for adults is about 0.1 mg / day to 100 mg / day of the compound of the present invention, which is an active ingredient in an injection, and 100 mg / day to 100 mg / day for oral administration. Can be increased or decreased. Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. Example

 Example 1

2-C [3 -— [2- (5-Methyl-2-phenyl-4-isoxazolyl) ethyl] —1, _2—benzisoxazolyl-6-yl “Loxy” 1-2-methylpropionic acid (1) 6-acetamido-3- [2- (5-methyl-2-phenyl-4-oxazolyl) ethyl] 1-1,2-benzisoxazole

6-acetamido-3-methyl-1,2-benzisoxazole (1.50 g, 7.89 mmol) was dissolved in dry THF (25 mL), and then dissolved under a nitrogen atmosphere. C, 2M LDA (9. OmL, 18. Ommol) was added dropwise over 10 minutes, and the mixture was further stirred under the same conditions for 10 minutes. Subsequently, a THF solution (1.90 g, 7.89 mmol 1/4. OmL) of 4-hydroxymethyl-5-methyl-2-phenyloxazole, which was synthesized according to a conventional method, was added dropwise over 5 minutes. The mixture was stirred under the conditions for 30 minutes. After confirming the completion of the reaction, the temperature was returned to room temperature, and a saturated aqueous solution of sodium chloride and ethyl acetate were added. The ethyl acetate layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and collected by filtration. After distilling off ethyl acetate under reduced pressure

The residue was subjected to silica gel column chromatography (black mouth form, black mouth form z

The title compound was obtained as white crystals (91 Omg).

(Yield 32%)

! H-NMR (CDC 1 ₃₅ 400 MHz) δ:

 2.14 (s, 3Η),

 2.19 (s, 3Η),

 3.02 (t, 2Η, J = 8Hz),

 3.32 (t, 2Η, J = 8Hz),

 7.35- 7.45 (m, 4Η),

 7.83 (br-s, 1Η),

 7. 9-8. 0 (m, 2Η),

 8. 08 (d, 1Η, J = ΙΗζ)

(2) 6-amino-3_ [2- (5-methyl-2-phenyl-4-oxazolyl) ethyl ") 1-1,2-benzisoxazole 6-acetamido-3- [2- (5-methyl-2-phenyl-4-oxazolyl) ethyl] -1,2-benzisoxazole (700 mg, 1.9 mmol) obtained by the above method was added to IN hydrochloric acid ( (9 mL), the reaction temperature was raised to 100 ° C, and the mixture was refluxed by heating for 6 hours.

After confirming the completion of the reaction, the temperature was returned to room temperature and a saturated aqueous solution of sodium carbonate was added to neutralize. After adding ethyl acetate, the organic layer was separated and washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to give the title compound as a white crystal (530 mg) in the residue. (86% yield) — NMR (CDC 1 ₃₅ 400 MHz) δ:

 2.15 (s, 3H),

 3.00 (t, 2Η, J = 8Hz),

 3.27 (t, 2H, J = 8Hz),

 4. 0 1 (br-s, 2H,),

6.54 (dd, 1 H ₅ J = 2, 9Hz),

 6.70 (d, 1 H, J = 2Hz),

 7. 2-7. 5 (m, 4H),

 8.0-8.2 (m, 2H).

(3) 6-Hydroxy-3— [2- (5-Methyl-2-phenyl-4-oxazolyl) ethyl] 1,1,2-benzisoxazole The 6-amino-3— [2- ( After suspending 5-methyl-2-phenyl-4-oxazolyl) ethyl] -1,2-pentisoxazole (2.14 g, 6.72 mmol 1) in 25% sulfuric acid (4 OmL), An aqueous sodium nitrite solution (487 mg / 2.5 mL) was added dropwise over 10 minutes while cooling on ice.

After stirring under the same conditions for 45 minutes, the mixture was added dropwise to a 75% aqueous sulfuric acid solution (3 OmL) under reflux for about 30 minutes. After the completion of the dropwise addition, the mixture was refluxed for 20 hours under the same conditions. After confirming the completion of the reaction, the mixture was returned to room temperature and poured into ice-cold water. After extraction with getyl ether (1 O OmL x 2), a 1N sodium hydroxide solution (200 mL x 3) was added to the ether solution to perform back extraction. Subsequently, the sodium hydroxide solution was acidified by adding 3 N hydrochloric acid under ice-cooling, and ethyl acetate was added thereto to separate an organic layer.

The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure to give the crude title compound as a brown solid (1.1 g). — NMR (CD C 1 ₃₅ 400 MHz) δ:

 2.23 (s, 3Η),

 3.02 (t, 2Η, J = 8Hz),

 3.26 (t, 2H, J = 8Hz),

6.71 (dd ₃₁ H, J = 2, 9Hz),

6. 90 (d, 1 H ₅ J = 2 Hz),

 7.26 (d, 1H, J = 9Hz),

 7. 4-7. 5 (m, 3H),

 7.59 (br—s, 1H),

 7. 9-8. 0 (m, 2H)

(4) 2-[[3- [2- (5-Methyl-2-phenyl-4,4-year-old oxazolyl) ethyl] -1-1,2-benzisoxazolyl-6-yl] oxy] —2-methylpropionic acid Ethyl

6-Hydroxy-3- (2- (5-Methyl-2-phenyl-4,4-year-old xazolyl) ethyl) -1,2-benzisoxazole (20 Omg, 0.60 mmol), 2-promo 2- After suspending ethyl methyl propionate (156 mg, 0.8 Ommo 1) and potassium carbonate (ll lmg, 0.8 Ommo 1) in methyl ethyl ketone (1 OmL), raise the reaction temperature to 80 ° C. Heated to reflux. 12 hours later, 2-ethyl 2-methylpropionate (156 mg, 0.8 Ommo 1) and potassium carbonate (11 mg, 0.8 Ommo 1) were further added, and the mixture was heated under reflux for 20 hours. After confirming the completion of the reaction, return to room temperature, The insoluble material was filtered, washed with methyl ethyl ketone, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2Z1) to give the above title compound as a colorless oil (23 Omg). (89% yield)

^ -NM (CDC 1 ₃₅ 400 MHz) δ:

 1.23 (t, 3H, J = 7Hz),

 1.64 (s, 6Η),

 2. 1 5 (s, 3 Η),

 3.02 (t, 2Η, J = 7Hz),

3.3 1 (t ₃ 2H ₅ J = 7Hz) ₃

 4.24 (q, 2H, J = 7Hz),

 6.80 (dd, 1H, J = 2, 9Hz),

 6.88 (d, 1 H, J = 2 Hz),

 7.38 (d, 1 H, J = 9Hz),

 7. 4-7. 5 (3H, m),

 7.9-8.0 (m, 2H).

(5) 2-[[3- [2- (5-Methyl-2-phenyl-1-oxazolyl) ethyl]-1,2-benzisoxazolyl-6-yl] oxy] —2-methylpropionic acid 2- [3- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethyl] -1,2-benzisoxazole-6-yloxy] ethyl 2-methylpropionate (22 Omg, 0.5 Immo 1) was dissolved in a mixed solvent of methanol ZTHF / ^ K (3 mLZ ImL / lmL), and lithium hydroxide monohydrate (lOOmg) was added. After stirring at room temperature for 20 hours, disappearance of the raw materials was confirmed. After cooling the reaction solution on ice, dilute hydrochloric acid was added. (About pH 4)

The precipitated crystals were separated, washed with water (40 mL), air-dried for 2 minutes, and dried under reduced pressure to obtain the title compound as white crystals (170 mg).

(83% yield) One _{NMR (DMSO - d 6, 40} OMHz) δ:

 1.77 (s, 6H),

 2.19 (s, 3H),

 2.96 (t, 2H, J = 7Hz),

 3.25 (t, 2H, J = 7Hz),

 6.86 (dd, 1H, J = 2, 9Hz),

6.96 (d, 1 H ₃ J = 2 Hz),

 7.45 -7.5 (m, 3H),

 7.71 (d, 1H, J = 9Hz),

 7.85-7.95 (m, 2H),

 13. 2 (br s, 1 H). Example 2

 2-[[3— [2 -— (5-ethyl-2-phenyl-4-oxazolyl) ethyl] —1,2, benzisoxazolu-1-yl] oxy] -12-methylpropionic acid The following intermediates and the title compound were obtained in a similar manner.

(1) 6-acetamide—3 -— [2- (5-ethyl-2-phenyl-4-oxazolyl) ethyl] —1,2-benzisoxazole yield 15%

— NMR (CDC 1 ₃₅ 40 OMHz) δ:

 1.08 (t, 3Η, J = 7Hz),

 2. 2 1 (s, 3Η),

 2.51 (q, 2Η, J = 7Hz),

 3.03 (t, 2Η, J = 7Hz),

 3.34 (t, 2Η, J = 7Hz),

7.09 (d, 1H, J = 1, 9Hz), 7. 41 (br- s, 1H),

 7. 4-7. 5 (m, 4H),

 7.95—8.00 (m, 2H),

8.07 (d, 1 H ₃ J = 1 Hz).

(2) 6-Amino-3— [2- (5-Ethyru2-Fuenru 41-year-old xazolyl) ethyl] — 1,2-Benzisoxazole Yield 96%

! H-NMR (CDC 1 ₃₅ 400 ΜΗζ) δ

 1. 01 (t, 3Η, J = 7Hz),

 2.51 (q, 2H, J = 7Hz),

 3.03 (t, 2H, J = 7Hz),

 3.27 (t, 2H, J = 7Hz),

 4.02 (br s, 2H),

 6.54 (dd, 1H, J = 2, 9Hz),

 6, 69 (1H, d, J = 2Hz),

 7.26 (d, 1 H, J = 9 Hz),

 7. 4-7. 5 (3H, m),

 7.95—8.00 (m, 2H)

(3) 6-Hyd mouth xy-3- (2- (5-Ethyl-2-phenyl-4-oxazolyl) ethyl) 1,2-benzisoxazole Yield 53%

! H-NMR (CD C 1 33 400MHz) δ:

 1.11 (t, 3H, J = 7Hz),

2.55 (q ₃ 2H ₅ J = 7Hz),

3. 03 (t, 2H, J = 7Hz), 3.29 (t, 2H, J = 7Hz),

 5. 95-6. 05 (br, 1H),

 6.72 (dd, 2H, J = 2.9Hz)

 6, 91 (d, 1 H, J = 2Hz),

7.31 (dd, 1 H ₅ J = 9Hz),

 7. 4-7. 5 (m, 3H),

 7.95—8.0 (m, 2H).

(4) 2 — [[3-—2- (5-Ethyl-2-phenyl—4 year old xazolyl) ethyl]-1,2—Benzisoxazoyl 6-yl] oxy] —2-methylpropionate 88% yield

One NMR (CDC 1 ₃₅ 400MHz) δ

 1. 07 (t, 3Η, J = 7Hz)

 1.23 (t, 3Η, J = 7Hz)

 1.64 (s, 6H),

 2.51 (q, 2H, J = 7Hz)

 3.02 (t, 2H, J = 7Hz)

 3.32 (t, 2H, J = 7Hz)

 4.23 (q, 2H, J = 7Hz)

 6.79 (dd, 2H, J = 2.9 Hz)

 6, 88 (d, 1 H, J = 2 Hz)

 7.37 (d, 1 H, J = 9 Hz)

 7. 4-7. 5 (m, 3H),

 7.95—8.0 (m, 2H).

(5) 2-[[3- [2- (5-Ethyl-2-phenyl-4-oxazolyl) ethyl] -1,1,2-benzisoxazolyl-6-yl] oxy] —2-methylpropionic acid 73% yield

One _{NMR (CDC1 3, 400MHz) δ} :

 1.3 (t, 3H, J = 7Hz),

 1.69 (s, 6H),

2.58 (q, 2H, J = 7Hz) ₃

 3.02 (t, 2H, J = 7Hz),

 3.22 (t, 2H, J = 7Hz),

6.79 (dd, 2H, J = 2, 9Hz) ₅

 7. 01 (1H, d, J = 2Hz),

 7.22 (1H, d, J = 9Hz),

 7. 4-7. 5 (m, 3H),

 7.95—8.0 (m, 2H) Example 3

 2-[[3- [2- (5-Propyl-2-phenyl-2-ethyloxazolyl) ethyl]-1,2-benzisoxazolyl 6-yl] oxy] —2-methylpropionic acid The following intermediates and the title compound were obtained in the same manner as in 1.

(1) 6-acetamide—3— [2- (5-propyl-1-2-phenyl—4-oxazolyl) ethyl] 1-1,2-benzisoxazole

! H-NMR (CDC 1 ₃₃ 400ΜΗζ) δ

0.87 (t, 3H ₅ J = 7Hz),

 1. 55- 1.70 (m, 2H),

 2.22 (s, 3H),

 2.49 (t, 2H, J = 7Hz),

3.04 (t, 2H, J = 7Hz), 3.35 (t, 2H, J = 7Hz),

 7.12 (dd, 1 H, J = l, 9Hz),

 7. 2-7. 6 (m, 5H),

 7.95-8.05 (m, 2H),

 8.01 (d, 1H, J = l Hz)

(2) 6-amino-3— [2- (5-propyl-1-2-phenyl-4,1-year-old xazolyl) ethyl] 1,1,2-penzisoxazole

Two-step yield 41%

— NMR (CDC 1 ₃₅ 400MHz) δ

 0.87 (t, 3H, J = 7Hz),

 55- 1 70 (m, 2H),

 2 49 (t 2H, J = 7Hz),

 3 01 (t 2H, J = 7Hz),

 3 26 (t 2H, J = 7Hz),

 4 00 (br-s, 2H),

 6 55 (dd, 1 H, J = 2.9 Hz)

 6 70 (d, 1H, J = 2Hz),

 7 30 (d, 1 H, J = 9Hz),

 7 4-7. 45 (m, 3H),

 7 95—8.05 (m, 2H).

(3) 6-Hydroxy 3— [2- (5-Propyl-2-phenyl-4-oxazolyl) ethyl] — 1,2-Penzisoxazole yield 53%

! H-NMR (CDC 1 ₃₃ 400 ΜΗζ) δ:

0.91 (t, 3H, J = 7Hz), 1. 55— 1.70 (m, 2H),

2.56 (t, 2H ₅ J = 7Hz),

 3.02 (t, 2H, J = 8Hz),

 3.25 (t, 2H, J = 8Hz),

6.74 (dd ₃ 1H, J = 2, 9Hz),

6.91 (d ₃ 1H ₃ J = 2Hz) ₅

 7.28 (d, 1H, J = 9Hz),

 7. 4— 7. 45 (m, 3H),

 7.95—8.00 (m, 2H),

 8.15 (br-s, 1 H).

(4) 2-[[3- [2-(5-Probi-1--2-phenyl-4-oxazolyl) ethyl]]-1,2-benzisoxazo'-l-6-yl] oxy] -l-methylpropionic acid Ethyl yield 70%

One _{NMR (CDC 1 3, 40 ΟΜΗζ} ) δ:

 0.85 (t, 3Η, J = 7Hz),

 1.23 (t, 3H, J = 7Hz),

 1.5-1.60 (m, 2H),

 1.64 (s, 6H),

 2.48 (t, 2H, J = 7Hz),

 3.02 (t, 2H, J = 8Hz),

 3.32 (t, 2H, J = 8Hz),

 4.23 (q, 2H, J = 7Hz),

 6.80 (dd, 1H, J = 2, 9Hz),

 6.88 (d, 1 H, J = 2Hz),

 7.40 (d, 1 H, J = 9 Hz),

7.40- 7.50 (m, 3H) ₃ 7.95-8.00 (m, 2H).

(5) 2 — [[3— [2- (5-Propyl-1-2-phenyl-4,1-xazolyl) ethyl] —1,2-Penzisoxazolyl-6-yl] oxy] -1-2-methylpropion Acid yield 94%

1 H-NMR (CD C 1 3, 400 MHz) δ:

0.85 (t, 3H ₃ J = 7Hz),

 1. 5- 1.65 (m, 2Η),

 1.64 (s, 6Η),

 2.55 (t, 2H, J = 7Hz),

 3.03 (t, 2H, J = 8Hz),

_{3. 19 (t 3 2H, J} = 8Hz),

 6.76 (dd, 1 H, J = 2.9 Hz),

 7.00 (d, 1 H, J = 2Hz),

7.20 (d ₃ 1H, J = 9Hz),

 7.40- 7.50 (m, 3H),

 7.95-8.00 (m, 2H) .Example 4

 2-C [3 -— [2 -— (5-propyl-1- (2-chlorophenyl) -14-oxazolyl) ethyl] —1,2-benzisoxazole-6-yl] oxy] 1-2 —Methylpropionic acid The following intermediates and the title compound were obtained in the same manner as in Example 1.

(1) 6-acetamide 3- [2- (5-propyl-1- (2-chlorophenyl) -14-oxazolyl) ethyl] — 1,2-benzisoxazole 14% yield

_{^ -NMR (CDC 1 33 40 OMHz} ) δ:

 0.85 (t, 3H, J = 7Hz),

 1.45- 1.60 (m, 2H),

 2.22 (s, 3H),

 2.46 (t, 2H, J = 7Hz),

3.06 (t, 2H ₃ J = 7Hz),

 3.36 (t, 2E, J = 7 z),

 7.12 (dd, 1 H, J = l, 9Hz),

 7. 3-7. 4 (m, 3 H),

 7. 4-7. 6 (m, 2H),

 7. 9-8. 0 (m,, 2H),

8.07 (d, 1H ₅ J = 1Hz)

(2) 6-amino-3- (2- (5-propyl-1- (2-chlorophenyl) -14-oxazolyl) ethyl) 1,2-benzisoxazole yield 80%

! H-NMR (CDC 1 ₃₅ 40 OMHz) δ:

0.87 (t ₃ 3H ₅ J = 7Hz),

 1.45—1.60 (m, 2H),

 2.49 (t, 2H, J = 7Hz),

 3.03 (t, 2H, J = 7Hz),

 3.29 (t, 2H, J = 7Hz),

 4.00 (br—s, 2H),

 6. 56 (dd, 1 H, J = 2.9Hz),

 6.70 (d, 1H, J = 2Hz),

 7.28 (d, 1H, J = 9Hz),

7. 5-7. 6 (m, 2H), 7. 4-7. 6 (m, 1H),

 7. 9-8. 0 (m, 1H)

(3) 6-Hydroxyl 3- (2- (5-Propyl-2- (2-chlorophenyl) -14-oxazolyl) ethyl) — 1,2-Penzisoxazolyl Yield 34%

_{^{! H-NMR (CDC 1 3}} , 40 OMHz) δ:

 0.87 (t, 3H, J = 7Hz),

 1.45- 1.60 (m, 2H),

 2.5 1 (t, 2H, J = 7Hz),

 3.10 (t, 2H, J = 7Hz),

 3.3 1 (t, 2H, J = 7Hz),

 6. 1-6. 2 (b r, 1 H),

6.74 (dd, 1H, J = ₂₅ 9 Hz),

 6.91 (d, 1H, J = 2Hz),

 7. 3-7. 4 (m, 3H),

 7. 4-7. 5 (m, 1 H),

 7. 9-8. 0 (m, 1 H)

(4) 2-[[3- [2- (5-Propyl-2- (2-chlorophenyl) -14-oxazolyl) ethyl] —1,2-benzisoxazolyl-6-yl] oxy] —2 —Ethyl methyl propionate 63% yield

_{- NMR (CD C 1 33 40} ΟΜΗζ) δ:

 0.87 (t, 3H, J = 7Hz),

 1.23 (t, 3H, J = 7Hz),

1.45- 1.60 (m, 2H), 1.64 (s, 6H),

 2.48 (t, 2H, J = 7Hz),

 3.05 (t, 2H, J = 7Hz),

 3.33 (t, 2H, J = 7Hz),

 4.24 (q, 2H, J = 7Hz),

 6.80 (dd, 1 H, J = 2, 9Hz),

 6.88 (d, 1H, J = 2Hz),

 7. 3-7. 4 (m, 3H),

 7. 4-7. 5 (m, 1 H),

 7. 9—8.0 (m, 1 H)

(5) 2-[[3- [2 -— (5-Propyl-2- (2-chlorophenyl) 14-oxazolyl) ethyl] —1,2-Benzisoxazolyl-6-yl] oxy] —2—Methyl propionic acid Yield 80%

iH—NMR (CDC 1 ₃₅ 40 OMHz) δ:

 0.86 (t, 3Η, J = 7Hz),

 1.45- 1.60 (m, 2Η),

 1.66 (s, 6H),

 2.52 (t, 2Η, J = 7Hz),

 3.04 (t, 2H, J = 7Hz),

 3.29 (t, 2Η, J = 7Hz),

_{4. 24 (q 5 2Ε, J} = 7Hz),

 6.82 (dd, 1H, J = 2, 9Hz)

 7.00 (d, 1H, J = 2Hz),

 7. 3-7. 4 (m, 3H),

 7. 4-7. 5 (m, 1H),

7.9-8.0 (m, 1H). Example 5

 2—C [3 -— [2- (5-butyl-2-phenyl-4-oxazolyl) ethyl] —1,2-benzisoxazolu-1-yl] oxy] —2-methylpropionic acid The following intermediates and the title compound were obtained in a similar manner.

(1) 6-acetamide—3— [2- (5-butyl-2-phenyl-4-oxazolyl) ethyl] —1,2-benzisoxazolyl Yield 13%

_{^ -NMR (CDC 1 33 400 MHz} ) δ:

 0.87 (t, 3H, J = 7Hz),

 1.22- 1.30 (m, 2H),

 1. 4—1.5 (m, 2H),

 2.21 (s, 3H),

 2.49 (t, 2H, J = 7Hz),

 3.03 (t, 2H, J = 7Hz),

 3.34 (t, 2H, J = 7Hz),

 7.10 (dd, 1 H, J = l, 9Hz),

 7. 3-7. 5 (m, 5H),

 7.95- 8.05 (m, 2H),

 8.01 (d, 1H, J = 1Hz)

(2) 6-amino-3- [2- (5-butyl-2-phenyl-1-oxazolyl) ethyl] 1-1,2-penzisoxazole Yield 86%

— NMR (CDC 1 ₃₅ 400 MHz) δ: 0.87 (t, 3H, J = 7Hz),

 1. 2-1. 35 (m, 2H),

 1.40- 1.50 (m, 2H),

 2.50 (t, 2H, J = 7Hz),

 3.01 (t, 2H, J = 7Hz),

 3.26 (t, 2H, J = 7Hz),

 4. 03 (b r-s, 2H),

 6.54 (dd, 1H, J = 2, 9Hz),

 6.70 (d, 1 H, J = 2Hz),

 7.29 (d, 1 H, J = 9Hz),

 7. 4-7. 45 (m, 3H),

 7.95-8.5 (m, 2H).

(3) 6-Hydroxoxy 3 -— [2- (5-butyl-2-phenyl 4-oxazolyl) ether] —1, 2-benzisoxazolyl Yield 34%

! H-NMR (CDC 1 ₃₅ 400MHz) δ:

 0.89 (t, 3Η, J = 7Hz),

 1. 2-1. 40 (m, 2Η),

 1.40- 1.50 (m, 2Η),

 2.55 (t, 2Η, J = 7Hz),

 3. 02 (t, 2 Η, J = 7 Η ζ),

 6.91 (d, 1Η, J = 2Hz),

 7.29 (d, 1Η, J = 9Hz),

 7. 4-7. 45 (m, 3Η),

7.9-8.0 (m, 2Η). (4) 2-[[3- [2- (5-butyl-5-phenyl-4-xazolyl) ethyl] —1,2-benzisoxazolyl-6-yl] oxy] —2-methylpropion Acid ethyl yield 76%

NMR (CDC 1 ₃₅ 400MHz) δ:

0.87 (t ₃ 3H, J = 7Hz),

 1.33 (t, J = 7Hz),

 1.2-1.3 (m, 2H),

 1.4-1.5 (m, 2H),

 1.64 (s, 6 H),

 2.50 (t, 2H, J = 7Hz),

 3.02 (t, 2H, J = 7Hz),

 3.32 (t, 2H, J = 7Hz),

 4.23 (q, 2H, J = 7Hz),

6.79 (dd ₅ 1H, J = 2, 9Hz),

 6.88 (d, 1 H, J = 2Hz),

 7.39 (d, 1H, J = 9Hz),

 7.40—7.50 (m, 3H),

 7.9-8.00 (m, 2H).

(5) 2-[[3-—2- (5-butyl-2-phenyl-4-isoxazolyl) ethyl]-1,2-pentisoxazolyl 6-yl] oxy] -12-methylpropionic acid Yield 82%

^ -NMR (CDC 1 ₃₅ 40 OMHz) δ:

 0.88 (t, 3Η, J = 7Hz),

1. 2-1.4 (m, 2H), 1.45- 1.6 (m, 2H),

 1.64 (s, 6H),

2.56 (t, 2H ₃ J = 7Hz),

 3.01 (t, 2H, J = 7Hz),

 3.22 (t, 2H, J = 7Hz),

 6.79 (dd, 1 H, J = 2, 9Hz),

 7.00 (d, 1 H, J = 2 Hz),

 7.24 (d, 1 H, J = 9 Hz),

7.40- 7.50 (m ₃ 3H),

 7. 9 -8. 05 (m, 2H). Example 6

 2-[[3 -— [2- (2,5-Diphenyl-2-4-oxazolyl) ethyl] —1,2-benzisoxazole-1-yl] oxy] —2-methylpropionic acid The following intermediates and the title compound were obtained in the same manner as in 1.

(1) 6-acetamido-3- [2- (2,5-diphenyl-4-oxazolyl) ethyl] 1-1,2-benzisoxazole yield 21%

_{- NMR (CDC 1 3, 400MHz} ) δ:

 2.2 1 (s, 3H),

 3.35—3.50 (m, 4H),

 7.15 (dd, 1H, J = 2, 9Hz),

 7. 3 -7. 4 (m, 2H),

7. 4-7. 55 (m ₅ 5 H),

 7.55 (d, 1H, J = 9Hz),

7.60 (dd, 2H, J = l, 9Hz), 8.04 (d, 1 H, J = 1Hz),

 8.05-8.15 (m, 2H).

(2) 6-amino-3- [2- (2,5-diphenyl-1-4-oxazolyl) ethyl] 1,2-benzisoxazole yield 84%

¹ H-NMR (CD C ₁₃₃ 400 MHz) δ:

 3.35—3.45 (m, 4H),

 4. 01 (s, 2H),

 6.58 (dd, 1H, J = 2, 9Hz),

 6.70 (d, 1H, J = 2Hz),

 7.3-7. 6 (m, 7H),

 7. 6-7. 65 (m, 2H),

 8. 1 -8. 1 5 (m, 2H).

(3) 6 _Hyd mouth 3- (2- (2,5-diphenyl 4-oxazolyl) ethyl) — 1, 2-benzisoxazole yield 34%

'H-NMR (CD C 1 3, 400MHz) δ:

 3.35-3.45 (m, 4H),

 6. 3 (br s, 1 H),

 6.76 (dd, 1 H, J = 2, 9Hz),

6. 9 1 (d, 1 H 5 J = 2Hz),

 7. 3-7. 6 (m, 7H),

 7.62 (dd, 2H, J = 2, 9 H z.),

8. 1—8.15 (m, 2H). (4) 2- [3- [2- (2,5-Diphenyl-4-one-year-old xazolyl) ethyl] —1,2—pentisoxazole-6-yloxy] ethyl 2-ethylpropionate 55% yield '

! H-NMR (CDC 1 ₃₅ 400 MHz) δ:

 1.22 (t, 3Η, J = 7Hz),

 1.64 (s, 6Η),

 3.35—3.50 (m, 4Η),

 4.23 (q, 2Η, J = 7Hz),

 6.82 (dd, 1H, J = 2.9Hz),

 6.87 (d, 1H, J = 2Hz),

 7. 3-7. 55 (m, 7H),

 7. 55-7. 6 (m, 2H),

 8.05—8.15 (m, 2H).

(5) 2 — [[3- [2- (2,5-Diphenyl-4-4-oxazolyl) ethyl] —1,2-pentisoxazolyl 6-yl] oxy] —2-methylpropionic acid Yield Quantitative

_{^ -NMR (CDC 1 3, 400MHz} ) δ:

 1.67 (s, 6H),

 3.35- 3.45 (m, 4H),

 6.85 (dd, 1H, J = 2.9Hz),

 7.00 (d, 1 H, J = 2Hz),

 7.37-55 (m, 7H),

 7. 55-7. 6 (m, 2H),

8. 05-8. 1 5 (m ₃ 2H). Example 7 2-C [3- [2- [5-Methyl-2-phenyl 4-thiazolyl) ethyl] — 1,2-Penzisoxazolu-6-yl] oxy] -12-Methylpropionic acid Same as in Example 1. The following intermediates and the title compound were obtained by the procedure described above.

(1) 6-acetamido-3- [2- (5-methyl-2-phenyl-1-4-thiazolyl) ethyl] — 1,2-benzisoxazolyl Yield 2 1%

'H-NMR (CD C 1 3, 40 OMHz) δ:

 2.2 1 (s, 3 H),

 2.22 (s, 3 H),

 3.2 1 (t, 2 H, J = 8Hz),

 3.41 (t, 2 H, J = 8Hz),

_{7. 07 (dd 5 1H, J} = 2 3 9 Hz),

 7.34 (d, 1 H, J = 9Hz),

 7.35- 7.50 (m, 4H),

 7.85-7.9 (m, 2H),

 8.06 ((d, 1H, J = lHz)

(2) 6-Amino-3- [2- (5-Methyl-1-phenyl-4-thiazolyl) ethyl]-1,2-benzisoxazole yield 89%

_{^ -NMR (CD C 1 35 40} OMHz) 6:

 2.24 (s, 3H),

 3.22 (t, 2Η, J = 7Hz),

 3.37 (t, 2H, J = 7Hz),

6.54 (dd ₃ 1H, J = 2, 9Hz), 6.69 (1H ₅ d, J = 2Hz),

 7.22 (d, 1H, J = 9Hz),

 7. 4-7. 55 (m, 3H),

 7. 9—8.0 (m, 2H).

(3) 6-Hydroxyl 3- [2- (5-Methyl-2-phenyl-14-thiazolyl) ethyl] 1-1,2-Benzisoxazolyl Yield 44%

— NMR (CDC 1 ₃₅ 400MHz) δ:

 2.24 (s, 3Η),

 3.25 (t, 2H, J = 7Hz),

 3.36 (t, 2H, J = 7Hz),

 6.74 (d, 1H, J = 9Hz),

 6.91 (s, 1H),

 7.29 (d, 1 H, J = 9 Hz),

 7.35- 7.45 (m, 3H),

 7.8-7. 9 (m, 2H).

(4) 2 — [[3 -— [2 -— (5-Methyl-2-phenyl-4_thiazolyl) ethyl] -1,1,2-benzisoxazolu-1-yl] oxy] — 2-methylpropionate Yield 71%

 1.23 (t, 3H, J = 7Hz),

 1.64 (s, 6H),

 2. 24 (s, 3H),

 3.21 (t, 2H, J = 7Hz),

3.39 (t, 2H, J = 7Hz), 4.24 (q, 2H, J = 7Hz),

 6.79 (d, 1H, J = 2, 9Hz),

6.88 (d, 1 H ₅ J = 2Hz),

 7.30 (d, 1 H, J = 9Hz),

 7.35- 7.45 (m, 3H),

 7.85- 7.90 (m, 2H).

(5) 2 — [[3— [2— (5-Methyl-1-phenyl-4-thiazolyl) ethyl] —1,2-benzisoxazolu-6-yl] oxy] —2-methylpropionic acid 64% rate

! H-NMR (CDC 1 ₃₃ 400 MHz) δ:

 1. 66 (s, 6Η),

 2.27 (s, 3H),

 3.21 (t, 2Η, J = 7Hz),

 3.36 (t, 2H, J = 7Hz),

 6.81 (d, 1H, J = 2, 9 Hz),

 7.01 (d, 1H, J = 2Hz),

 7.28 (d, 1H, J = 9Hz),

 7.35- 7.45 (m, 3H),

7.85-7.90 (m ₅ 2H). Example 8

 [[3- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethyl]] — 1,2-benzisoxazo-1-yl 6-yl] oxy] acetic acid

(1) [[3- [2- (5-Methyl-1-phenyl-4-year-old oxazolyl) ethyl] -1,2-benzisoxazolyl 6-yl] oxy] ethyl acetate Synthetic intermediate of Example 1 6-Hydroxy-3- (2- (5-methyl-2-phenyl-14-oxazolyl) ethyl) —1,2-benzisoxazole (200 mg, 0.60 mmo 1), Promo After suspending ethyl acetate (134 mg, 0.8 Ommo 1) and potassium carbonate (1 lmg, 0.8 Ommo 1) in methyl ethyl ketone (10 mL), raise the reaction temperature to 80 ° C. The mixture was refluxed for 5 hours.

After confirming the completion of the reaction, the insolubles were filtered, further washed with methyl ethyl ketone, and the solvent was distilled off. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 2/1) to give the above title compound as a colorless oil.

 (99% yield)

1 H-NMR (CDC 1 ₃₅ 400MHz) δ:

 1.26 (t, 3H, J = 7Hz),

 2.15 (s, 3Η),

 3.02 (t, 2H, J = 7Hz),

 3.32 (t, 2E, J = 7Hz),

 4.29 (q, 2H, J = 7Hz),

 4.67 (s, 2H),

 6. 9-7. 0 (m, 2H),

 7.35-7.5 (m, 4H),

 7.95—8.00 (m, 2H).

(2) [[3- [2- (5-Methyl-2-phenyl-4-year-old xazolyl) ethyl] -1-1,2-benzisoxazolu-1-yl] oxy] acetic acid Titled in the same manner as in Example 1. The compound was obtained.

Yield 64% — NMR (DMSO-d ₆₅ 40 ΟΜΗζ) δ:

 2.18 (s, 3Η),

2.96 (t, 2Η, J = 7Hz), 3.25 (t, 2H, J = 7Hz),

 4.73 (s, 2H),

6.94 (dd, 1 H ₃ J = 2 ₃ 9 Hz),

 7.16 (d, 1 H, J = 2Hz),

 7. 45—7.5 (m, 3H),

 7.09 (d, 1H, J = 9Hz),

 7. 85-7. 9 (2H, m). Example 9

 The following compounds were obtained in the same manner as in Example 1. (Example 9-1)

 2 — [[3-—2— [2 -— (2-chlorophenyl) _5—isopropyl-1-oxazolyl] ethyl] — 1,2-pentisoxazolyl-6-yl] oxy——2— Methyl propionic acid white crystals

mp. 100- 105 ° C

iH—NMR (CDC 1 ₃₅ 400MHz) δ;

 1.13 (6H, d, J = 7Hz)

 1.63 (6H, s)

 2. 9-3. 0 (1H, m)

 3.04 (2H, t, J = 7Hz)

3.27 (2H, t, J = 7Hz)

 6.80 (1H, dd, J = 2.9Hz)

 6.99 (1H, d, J = 2Hz)

 7.24 (1H, d, J = 9Hz)

7. 3-7. 4 (2H, m)

7.35-7.50 (1H ₅ m) 7.80 -7.95 (1 H,

IR (KBr) cm-

3000, 2950, 2900, 1720. 1700, 1620, 1610, 15

60, 1520, 1500, 1475, 1460, 1440, 1400, 1380, 1280, 1180, 1 140, 1120, 1040, 1020, 980, 840,

780, 740.

(Example 9-1-2)

 2-C [3— [2— [2 -— (4-chlorophenyl) -1-5-propyl-14-oxazolyl] ethyl] —1,2-Benzisoxazo-1-yl 6-yl] oxy] -1— Methylpropionic acid ■ White crystal

mp 156-158 ° C

ί ί NMR (CDC 1 ₃₅ 40 OMHz) δ

 0.88 (3H, t, J = 7Hz)

 1. 52-1. 61 (2H, m)

 69 6H, s)

2 53 2H ₃ t, J = 7Hz)

3 00 2H, t, J = 7Hz)

(3 20 2H, t, J = 7Hz)

(6 79 1H, dd, J = 2, 8Hz)

(6 99 1H, d, J = 2Hz)

7 23 1H, d ₃ J = 8Hz)

(7 42 2H, d, J = 8Hz)

7 92 2H, d, J = 8Hz)

R (KBr) cm ― 1 2873, 1620, 1518, 1497, 1479, 1392, 1385, 12 82, 1188, 1144, 1095, 984, 843, 835,

 816, 742

(Example 9-3)

 2—C [3— [2- [2 -— (2-chlorophenyl) -1-5-hexyl-4-oxazolyl] ethyl] -1-1,2-benzisoxazolyl-6-yl] oxy] 1 2 —Methylpropionic acid colorless oil

_{! H-NMR (CDC1 3)} δ;

0.86 (3H, t, J = 7Hz),

 1.2-: L. 3 (6H, m,),

 1.45 to 1.55 (2H, m),

 1.66 (6H, s),

 2.55 (2H, t, J = 7Hz),

 3.20 (2H, t, J = 8Hz),

3.25 (2H, t, J = 8Hz),

6.80 (1 H ₅ dd ₅ J = 3 and 10Hz),

 6.98 (1H, d, J = 3Hz),

 7.2 to 7.4 (3H, m),

 7.50 (1H, d, J = 3Hz),

7.90 (1 H, dd ₅ J = 3 and 9Hz).

(Example 9-1-4)

2-C [3-[2-[5-benzyl-2- (2-chlorophenyl) -14-oxazolyl] ethyl] _1,2-benzisoxazolyl-6-yl] oxy] -1-2-methylpro Pionic acid Colorless oil

_{iH- NMR (CDC 1 3) δ} ;

 1.66 (6Η, s)

3.07 (2H, t, J = 7Hz)

3.26 (2H, t, J = 7Hz)

3.93 (2H, s)

 6.80 (1H, dd, J = 3 and 9 Hz)

 6.97 (1 H, d, J = 3 Hz)

7.15 to 7.40 (8H, m)

 7.47 (1 H, d, J = 9 Hz)

 7.86 (1 H, dd, J = 2 and 8 Hz)

(Example 9-5)

 2-[[3- [2- [2- (2-Methylphenyl) -1-5-propyl-4-oxazolyl] ethyl] —1,2-benzisoxazolyl-6-yl] oxy] —2-methylpropione Acid

Yellow oil

_{- NMR (CDC 1 3) δ} ;

0.87 (3H ₃ t, J = 7Hz)

 1.55 (2H, t q, J = 7Hz, 7Hz)

 1.66 (6H, s)

2.52 (2H ₃ t, J = 7Hz)

 2.61 (3H, s)

3.02 (2H ₅ t, J = 7Hz)

 3.28 (2H, t.J = 7Hz)

6.82 (1H ₃ dd, J = 2Hz, 8Hz)

 7.01 (1H, d, J = 2Hz)

7.2-7.4 (4H, m) 7.89 (1H, d, J = 7Hz).

(Example 9-6)

 2— Γ [3- [2- “2- (2,3-Dichlorophenyl) -1-5-ethyl-_4-oxazolyl] ethyl] 2-benzisoxazolyl-6-yl] oxy] 2-methylpropionic acid Colorless oil

_{- NMR (CDC 1 3) ό} ·;

 1.10 (3Η, t, J = 8Hz),

 1.67 (6H, s),

 2.57 (2H, t, J = 8Hz),

 3.03 (2H, t, J = 8Hz),

3.27 (2H, t, J = 8Hz),

 6.82 (1H, dd, J = 2 and 9Hz),

 6.99 (1H, d, J = 2Hz),

 7.25 to 7.30 (2H, m),

 7.55 (1H, dd, J = 2 and 8Hz),

7.79 (1 H, dd, J = 2 and 8 Hz)

(Example 9-1 7)

 2-C [3 -— [2- [2- (2-chlorophenyl) —5-ethyl-14-oxazolyl] ethyl] —1,2-Benzisoxazolyl-6-yl] oxy] —2— Methylpropionic acid White amorphous

— NMR (CDC 1 ₃₃ 400MHz) δ;

1.1 1 (3Η, t, J = 7Hz)

1.66 (6H, s) 2.57 (2H, q, J = 7Hz)

 3.02 (2H, t, J = 7Hz)

 3.25 (2H, t, J = 7Hz) '6.80 (1H, dd, J = 2, 8Hz)

 6.98 (1H, d, J = 2Hz)

 7.23 (1H, d, J = 8Hz)

7. 32- 7.50 (3H, m)

 7.89 (1 H, m)

IR (KB r) cm- ¹ : ''

 298 1, 2939, 2519, 1697, 1622, 1572, 1543, 15 18, 1497, 1462, 1441, 1419, 1392, 1385, 1350, 1284, 1282, 1205, 1 178, 1 144, 1088, 1055, 984, 943, 858, 839, 812, 754, 750,

 735, 688, 604, 586

(Example 9-8)

 2 — [[3— [2— [2- (2-Nitrophenyl) —5—Provyl—4-oxazolyl] ethyl] 1,1,2-Penzisoxazolyl-6-yl] oxy] —2-methylpropione Acid

m 1 14-1 16 ° C

_{! H-NMR (CDC 1 3} ) ό ";

0.82 (3Η, t, J = 7Hz)

1.46 (2H, t q, J = 7Hz 7Hz)

1.67 (6H, s)

 2.45 (2H, t, J = 7Hz)

3.01 (2H, t, J = 7Hz) 3.27 (2H, t.J = 7Hz)

 6.86 (1 H, dd, J = 2 Hz, 9 Hz)

6.99 (1H ₃ d, J = 2 Hz)

 7.33 (1 H, d, J = 9 Hz)

7.5-7. 7 (2H, m)

 7.81 (1H, dd, J = 1Hz, 8Hz)

 7.97 (1H, dd, J = lHz, 8Hz).

IR (KB r) cm "¹;

 2970, 2931, 2873, 1701, 1624, 1 560, 1533, 14 98, 1470, 1446, 1439, 1419, 1394, 1352, 1282, 1203, 1 174, 1 142, 1090, 984, 841,

 812, 785, 752, 729, 604, 584.

(Example 9-9)

 2 — [[3— [2— [2 -— (2-chlorophenyl) -1-5-cyclopropyl-1-oxosazolyl] ethyl] —1,2-benzisoxazole-6-yl] oxy] —2 —Methylpropionic acid colorless oil

- NMR (CDC1 ₃₎ δ;

 1.7 to: L. 9 (4Η, m)

 1.67 (6H, s)

 1.7 to 1.8 (1H, m)

 3.10 (2H, t, J = 7Hz)

 3.29 (2H, t, J = 7Hz)

 6.81 (1 H, dd, J = 2 and 9 Hz)

 7.00 (iH, d, J = 2Hz)

7.25 to 7.9 (5H, m). (Examples 9 and 10)

 2 -— [[3 -— [2 -— (2-cyclohexyl-5-propyl-1-4-oxazolyl) ethyl] —1,2-benzisoxazo-1-yl 6-yl] oxy] —2-methylpropionic acid Colorless Oil

Ichi匪_{R (CD C 1 3) δ} ;

 0.83 (3H, t, J = 7Hz)

 1.2 to 2.1 (10H, m)

 1.45-: L. 55 (2H, m)

 1.71 (6H, s)

 2.44 (2H, t, J = 7Hz)

 2.8 to 2.9 (3H, m)

 3.0 to 3.1 (2H, m)

 6.72 (1H, dd, J = 2 and 9Hz)

6. 95 (1 H, d, J = 2 Hz)

6.99 (1H, d, J = 9Hz).

(Example 9-11)

 2-[[3— [2— [2— (2-chlorophenyl) —5-isobutyryl 4-xazolyl] ethyl] —1,2-benzisoxazolyl-6-yl] oxy] 1 2— Methylpropionic acid White crystals

mp 118-120 ° C

_{^ -NMR (CDC1 3, 400MHz)} δ;

 0.87 (6H, d, J = 6Hz)

 1.66 (6H, s)

1. 90 (1 H ₅ m) 2.44 (2H, d, J = 7Hz)

 3. 03 (2H, t, J = 7Hz)

3.28 (2H, t, J = 7Hz)

 6.82 (1 H, dd, J = 2.8 Hz)

6.99 (1 H ₅ d, J = 2 Hz)

 7. 3 1-7. 39 (3H, m)

7.48-7.50 (1H, m)

7.89 -7.92 (1 H,

IR (KB r) cm ' ¹ :

 3433, 2960, 2931, 2870, 2530, 1707, 1620, 15 52, 1518, 1497, 1473, 1417, 1385, 1381, 1277, 1 180, 1 138, 1088, 1053, 978, 843,

 820, 768, 742, 606, 584, 47 1

(Example 9-12)

 2-[[3— [2— [2 -— (2-chlorophenyl) —5—te rt—butyl—4-oxazolyl] ethyl] —1,2-Benzisoxazolyl 6-yl] oxy] — 2-Methyl propionic acid white crystals

mp 127-129 ° C

_{^ -NMR (CD C 1 33 40} OMHz) δ;

 1.26 (9H, s)

 1.65 (6H, s)

 3.17 (2H, t, J = 7Hz)

 3.3 1 (2H, t, J = 7Hz)

 6.81 (1H, dd, J = 2, 8Hz)

7.00 (1H ₃ d, J = 2Hz) 7.28 (1H, d, J = 8Hz)

 7. 34-7. 37 (2H, m)

 7.50 (1 H, m)

 7.93 (1H, m)

IR (KBr) cm ' ¹

 3855, 3737 3433, 2978, 2974, 2872, 2347

 1707, 1703 1620, 1572, 1549, 1522,

 1498, 142 1 1383, 1367, 1346, 1284, 1 184

 1 146, 1055 982, 837, 8 16, 768, 744, 739,

 609

(Examples 9-13)

 2-C [3- [2- [2- (2-fluorophenyl) -1-5-isopropyl-14-oxosazolyl] ethyl] — 1,2-benzisoxazolyl-6-yl] oxy] —2— Methylpropionic acid pale yellow amorphous

_{! H-NMR (CDC 1 3} ) 6;

 1.15 (6H, d, J = 7Hz)

 1.67 (6H, s)

 2.95-3.00 (1H, m)

 3.04 (2H, t, J = 7Hz)

3.24 (2H, t, J = 7Hz)

 6.80 (1H, dd, J = 2 and 8Hz)

 7.00 (1H, d, J = 2Hz)

7015-7.25 (3H, m)

7.40 to 7.45 (1 H, m) 7.95-8.00 (1H, m).

(Example 9-14)

 2—C [3— [2— [2- (4-tert-butylphenyl) -1-5-isopropyl-14-oxazolyl] ethyl] —1,2-benzisoxazolyl—6-yl] oxy] —2— Methylpropionic acid pale yellow amorphous

_{- NMR (CDC 1 3) δ} ;

 1.16 (6H, d, J = 7Hz)

 1.36 (9H, s)

 1.70 (6H, s)

 2.95-3.05 (3H, m)

 3.17 (2H, t, J = 8Hz)

6.76 (1H, dd ₅ J = 2 and 8 Hz)

 7.00 (1H, d, J = 2Hz)

7.15 (1H, d, J = 8Hz)

 7.47 (2H, d, J2 8Hz)

7.93 (2H, d, J = 8Hz).

(Example 9-15)

 2-[[3-[2-[5-Isopropyl-1- (2-naphthyl) -14-year-old xazolyl] ethyl] -1,2-benzisoxazole-1-6-yl] oxy] —2-methylpropion Acid slightly brown amorphous

_{'H-NMR (CDC 1 3} ) δ;

1.20 (6Η, d, J = 7Hz) 3.00 (1H, qq, J = 7Hz, 7Hz)

3.07 (2H, t, J = 7Hz)

3.30 (2H, t, J = 7Hz),

6.80 (1H, dd, J = 2Hz ₅ 9Hz)

 7.02 (1H, d, J = 2Hz)

 7.30 (1H, d, J = 9 Hz)

 7.5-7. 6 (2H, m)

 7. 8-8. 0 (3H, m),

 8.08 (1 H, dd, J = 2 Hz, 9 Hz)

8.49 (1 H, s).

IR (KB r) cm— ¹ ;

 2972, 2929, 2872, 1707, 1701, 1620, 1560,

1516, 1498, 1466, 1417, 1392, 1383, 1365, 1284, 1184, 1144, 1088, 1053, 982, 893,

 858, 835, 816, 754, 607, 471.

(Example 9-16)

 2 — [[3— [2— [5-Isoprobiyl-2- (2-methoxyphenyl) -14-oxazolyl] ethyl] —1,1,2-benzisoxazolyl—6-yl] oxy 1-Methylpropionic acid White crystals

m 123-125 ° C

One NMR (CDC 1 ₃₎ δ;

 1.17 (6H, d, J = 7Hz)

 1.67 (6H, s)

 2. 9-3. 1 (3H, m)

3.1-3. 2 (2H, m) 3.93 (3H, s)

 6.73 (1H, dd, J = 2Hz, 9Hz)

 6.96 (1H, d, J = 2Hz)

 7. 0-7. 1 (2H, m)

 7.13 (1H, d, J = 9Hz)

 7.43 (1H, m),

7.83 (1H, dd ₃ J = 2Hz, 8Hz).

IR (KB r) cm- ¹ ;

 2999, 2927, 1709, 1622, 1620, 1554, 15 18,

1497, 1468, 1419, 1389, 1363, 128 1, 1259, 1 186, 1 1 38, 1096, 1053 ₃ 1026, 978, 833,

 802, 752, 744, 715, 604, 584.

(Example 9-17)

 2-C [3 -— [2 -— [2- (2,4-dichlorophenyl) -5-isopropyl-14-oxazolyl] ethyl] —1,2-benzisoxazolyl-6-yl] oxy] —2-methyl Propionic acid white crystals

mp 102- 104 ° C

One _{NMR (CDC 1 3, 400MHz)} δ;

 1.13 (6Η, d, J = 7Hz)

 1.66 (6H, s)

 2.95 (1H, m)

 3. 04 (2H, ΐ, J = 7Hz)

3.27 (2H, t, J = 7Hz)

 6.82 (1H, dd, J = 2, 8Hz)

6.99 (1H, d, J = 2Hz) 7.28 (1H, d, J = 8Hz)

 7.32 (1H, dd, J = 2, 8Hz)

 7.51 (1 H, d, J = 2 Hz)

 7.87 (1H, d, J = 8Hz)

IR (KB r) cm— ¹ :

 3535, 2939, 1705, 1618, 1562, 1498 466 1460, 1385, 138 1, 1286, 1 184, 1 147

 1 107, 1053, 976, 841, 816, 417

(Example 9-18)

 2-C [3-[2-[2-(2, 6-dichloro phenyl) 1-5-isoprovir-1 4-oxazolyl] ethyl]-1,2-benzisoxazolyl 6 -yl] oxy] 1 -methyl Propionic acid

White crystals

mp 161-1 63 ° C

^ -NMR (CDC 1 ₃₅ 400MHz) δ;

1.08 (6H, d, J = 7Hz)

1.63 (6H, s)

 2.92 (1 H, m)

 3.07 (2H, t, J = 7Hz)

3.31 (2H, t, J = 7Hz)

6.81 (1H, dd ₃ J = 2, 8Hz)

 6.99 (1H, d, J = 2Hz)

 7. 31-7. 41 (4H, m)

IR (KBr) cm- ¹ :

3467, 2976, 2873, 2521, 1722, 1624, 1605, 1560, 1518, 1498, 1468, 1433, 385, 1383, 1367, 1340, 1321, 1271, 1200, 176, 1130, 1095, 1041, 974, 933, 883, 839 793, 771,

 750, 600, 569, 482

(Examples 9-19)

 2- [1- [3- [2 [-5-isopropyl-1-2- (2-trifluoromethylphenyl)

) 1-4-oxazolyl] -ethyl] — 1,2-benzisoxazolyl-6-yl] oxy] —2-methylpropionic acid

_{! H-NMR (CDC 1 3} ) δ;

 1. 1 1 (6Η, d, J = 7Hz),

 1.65 (6Η, s),

 2. 9 ~ 3.0 (1 Η, m),

 3. 04 (2Η, t, J = 7Hz),

3.28 (2Η, t, J = 7Hz),

 6.18 (1Η, dd, J = 2 and 8Hz),

 7.00 (1H, d, J = 2Hz),

7.26 (1H, d, J = 8Hz) ₅

 7.5 to 7.7 (2H, m),

 7.80 (1 H, d, J = 8 Hz),

 8.02 (1 H, d, J = 8 Hz).

(Examples 9-20)

2-C [3 -— [2-—2- (2-hydroxyphenyl) -1-5-isopropyl-14-oxazolyl] ethyl] — 1,2-benzisoxazolyl-6-yl] oxy] —2 —Methylpropionic acid Colorless oil

One NMR (CDC 1 ₃₎ δ;

 1.16 (6Η, ά, J = 7Hz)

 1.66 (6H, s)

2. 97 (1H, qq, J = 7Hz 3 7Hz)

3.06 (2H ₃ t, J = 7Hz)

3.31 (2H ₃ t, J = 7Hz)

 6. 8-7. 1 (4H, m)

7.32 (1 H ₃ m)

 7.40 (1H, d, J = 9Hz)

 7.76 (1H, dd, J = lHz, 8Hz).

(Example 9-21)

2- C [3- [2- [2- phenyl - 5-propyl one 4- Okisazoriru] Echiru] I Ndoru -. 6-I le] Okishi] -2-methylpropionic Lactobiono acid ^l E NMR (CD C 1 ₃ , 40 OMHz) δ;

0.82 (3Η, t, J = 7Hz)

 1.40- 1.55 (2H, m)

 1.57 (6H, s)

 2.41 (2H, t, J = 7Hz)

2.87 (2H, t, J = 7Hz)

3.10 (2H, t, J = 7Hz)

6.76 (1H, dd, J = 1, 9Hz)

6.92 (1H, s)

 6.96 (1H, d, J = 1 Hz)

7. 4-7. 5 (4H, 7.85 (1H, brs,)

7. 95— '8. 05 (2 H, m)

(Examples 9 to 22)

 2-[[3- [2- [5-Isopropyl-2- (4-butylphenyl) -1-oxazolyl] ethyl] —1,2-benzisoxazolu-l-6-yl] oxy] —2-methylpropionic acid Colorless oil

NMR (CD C 1 ₃₅ 400 MHz) δ:

0.94 (t, 3H, J = 7Hz),

1.16 (d ₃ 6Η ₅ J = 7Hz),

 1.35—1.45 (m, 2Η),

 1 60-1 70 (m, 2Η),

 68 (s 6Η),

 2 66 (t 2Η),

 2.95-3 05 (m, 3Η),

 3.21 (t 2Η, J = 7Hz),

7.00 (d, 1 Η, J = 2Hz),

 7.20 (d, 1Η, J = 8Hz),

7.25 (d, 2Η, J = 8Hz),

7.90 (d, 2H, J = 8Hz). Example 10 Pharmacological experiment

 . Measuring method

 (1) Measurement of PPAR activation

Test compound [Example :! ~ 7 and known: L-1655041 of P PAR 5 agonist (Berger, J. et al., (1999) J. Biol. Chem., 274: 6718-6. 725)] was measured as follows.

 1) Material

 African green monkey kidney fibroblasts (CV-1 cells) were obtained from Sen-ichi Medical Cell Resource Center, Institute of Aging Medicine, Tohoku University. All test compounds were dissolved in dimethyl sulfoxide (DMSO) and used in the test at a final DMSO concentration of 0.1%.

 2) Plasmid

 Receptor expression plasmid (GAL4-hPPARS LBD), luciferase-expressing plasmid (UASx4-TK-LUC), and galactosidase-expressing plasmid (? GAL) are (Kli ewer, SA et al., (1992) Nature, 358 : 771 — The same as 774) was used.

3) Transfection

CV-1 cells are seeded on a 24-well culture plate at a cell concentration of 2 x 10 ⁵ cells / well and incubated for 24 hours with 4% fetal serum serum (FCS). After culturing the cells in dl um (Liie Technologies 500 1 / well), the cells were washed with serum-free OPT I-MEM, and the DNA-containing solution [1 µl (250 µl added solution) Contains the following components: 0.03 g of GAL4—hPPARS LBD, 0.25 g of UAS x 4—TK—LUC, 0.35 g of 5GAL, 2〃1 lipofection reagent DMR IE—C (Lifte Technologies), which were dissolved in 0 PTI-MEM and allowed to stand at room temperature for 30 minutes], and cultured at 37 ° C for 5 hours.

 4) Cell treatment by adding test compound

Except for DNA-containing solution, the test compound (final concentration: 10- ⁴ M or ^10-5 such that M obtained by dissolving in 100% DMSO) newly exchanged to 4% FCS- OPT I- MEM 500 1 including For another 40 hours at 37 ° C.

 5) Measurement of gene level of repo overnight

± except咅地, washed twice with PBS, and subjected once freezing and thawing, per Ueru, Rushifu gill Ichize activity measurement solubilization buffer _{(25mM Tr i s-P0 4} (pH 7. 8) , 1 5% v / v Glys ero l, 2% CHAPS, l% Le cit hin, 1% BSA , 4mM EGTA (pH 8. 0) , with the addition of _{8 mM MgC 1 2, 1 mM} DTT) 100 〃1, allowed to stand for 10 minutes at room temperature. 2 μl of the mixture was collected on a 96-well measuring plate, and 100 μl of luciferase substrate solution (Pitka Gene; manufactured by Futsubone Co., Ltd.) was added. The amount of luminescence (luciferase activity) per second was determined using a laser (Corona Electric Co., Ltd.). The expression level of the activity due to the introduction of GAL into cells was measured, and the change in luciferase activity due to the addition of the compound was corrected by the transfection efficiency of the transgene. To determine β-galactosidase activity, 50 1 of the solubilized sample was separated into another 96-well plate, and 100 µl of ONPG (2-nitrophenyl /?-D-galactoviranoside) solution was added. 1 was added and incubated at room temperature for 5 minutes. A reaction stop solution (1 M sodium carbonate solution) (50〃1) was added, and the absorbance at 414 nm was measured. DMSO used as solvent

(0.1% concentration) treated only with Lucifera Ichize activity of cells (control value) to 0%, Lucifera Ichize activity of cells treated with L-165041 in 10- ⁴ M to 1 ◦ 0% And the relative ligand activity was calculated.

I I. Test results

Table 23 shows the test results.

[Table 23]

(PPARd activity 10 - ⁵ relative activity value of M) As is clear from Table 23, Example compounds compared to the L 65041, showed activation effect of equal or more potent PP AR ά. Example 11

GAL4—hPPAR LBD, GAL4-hPPA Rr LBD, and GAL4-hPPAR0-LBD were used as receptor expression plasmids, and PPAR: 10 " ⁴ M WY-165041, PPARr: 10" ⁵ M Ros iglitazone, PPARd as control drugs the L-165041 using the 10- ⁴ M, the method same as a method of example 10 described was measured PPAR activity to a compound described in example 9.

Table 24 shows the PPAR activities of the test compounds. [Table 24] Test compound PPARa PPARr PPAR <5 Example 9-1-1 12 ± 1 22 ± 1 91 ± 6 Example 9-2 91 ± 10 34 ± 1 99 ± 12 Example 9-3 95 ± 9 61 ± 6 97 ± 2 Example 9-4 46 ± 2 18 ± 1 26 ± 1 Example 9-5 22 ± 6 21 ± 0.5 86 ± 15 Example 9-6 72 ± 2 24 ± 4 101 ± 10 Example 9 — 7 25 ± 0.1 1 17 ± 3 87 ± 3 Example 9-9 12 13 60 Example 9-11 10 15 62 Example 9-14 74 86 86 Example 9-15 82 ± 16 81 ± 5 105 ± 16 Example 9-16 1 19 25 Example 9-17 63 ± 4 22 ± 3 111 ± 4 Example 9-19 28 21 43 Example 9-20 28 25 61 Example 9-22 94 78 111

L-165041 2 ± 1 1 ± 0.03 32 ± 15 PPAR activity: relative value a of the test compound 10- ⁵ M when the control drug was 100%: the 10- ⁴ M WY- 14643

7: 10- ^5] 1 \ osi gl it az one

6: 10- ⁴ As is apparent from M of L-165041 Table 24, compared Example 9 one 1 to Example 9-22 Compounds according to L one 16 5041, equal to or more active strong PPARd Showed a chemical effect. In addition, Examples 9-1, 5, 6, 7, 9, 11, 15, 17, 20, 22, etc. have selectivity of the activating effect on PPARs 1, 2, and 5 similar to L-165041. Became clear.

Claims

1. The following general formula (I)

(I) Ki blue

(Where A represents 0, S or NR ⁶ ;

 of

Where R ⁶ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkenyl group having 2 to 8 carbon atoms, and a 2 to 8 carbon atoms. Alkynyl group

An arylalkyl group which may have a substituent (carbon number of the aryl moiety is 6 to 10; carbon number of the alkyl moiety is 1 to 4); Represents an aryl group or a bond of 10

R ¹ , R ² and R are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, a cycloalkyl group having 3 to 7 carbon atoms, An alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an arylalkyl group which may have a substituent (aryl) 6 to 10 carbon atoms in the alkyl moiety, 1 to 4 carbon atoms in the alkyl moiety), an aryl group having 6 to 10 carbon atoms which may have a substituent, and 1 to 3 ring-forming atoms. A 5- to 8-membered heterocyclic group consisting of a heteroatom selected from a nitrogen atom, an oxygen atom or a sulfur atom and the remaining carbon atom, or a bond, or R ¹ and R ² are bonded, R ¹ and R ² may form a benzene ring together with the carbon atom to which they are bonded,

X ¹ and X ² represent 0, S, C (= 0) NH, C (= 0), C (OH) or NR ⁷ , or a bond,

Here, R ⁷ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms,

Y ¹ represents an alkylene chain having 1 to 8 carbon atoms which may have a substituent,

Represents CW ¹ or N, Here, W ¹ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or a bond,

B ² represents CW ² or N,

Here, W ² represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or a bond,

D represents 0, S, NR ⁸ ,

Here, R ⁸ may be a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or a substituent, or an arylalkyl group (where the carbon number of the aryl portion is 6 to 10 and the carbon number of the alkyl portion is 1 to 10). 4), or represents a bond,

 Z represents 0 or S,

Y ² represents an alkylene chain having 1 to 4 carbon atoms or a bond,

R ⁴ and R ⁵ represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom,

 E represents a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a sulfonic acid group, a phosphonic acid group, a cyano group, or a tetrazo 'group.

However, one of RR ² , R ³ and R ⁶ is a bond, and the rest is other than a bond, and this bond and X ¹ are combined, and W ¹ , W ² and R ⁸ One of them is a bond, and the rest is other than a bond, and this bond and X ² are connected. )

 Or a salt thereof.

2. The compound or a salt thereof according to claim ¹ , wherein B ¹ is CW ¹ .

3. The compound according to claim ¹ , wherein B ¹ is CW ¹ and Y ² is a bond, or a salt thereof.

4. The compound according to claim ¹ , wherein B ¹ is CW ¹ , Y ² is a bond, and E is a carboxyl group.

 Five .

Is a condensed ring selected from a benzisoxazole ring, a benzofuran ring, a benzothiophene ring, or an indole ring; Y ² is a bond; and E is a carboxyl group. Or a salt thereof.

 6. The following general formula (1 1),

 (Π)

(Where A represents 0, S or NR ⁶ ;

Here, R ⁶ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms. An arylalkyl group which may have a substituent (carbon number of the aryl moiety is 6 to 10; carbon number of the alkyl moiety is 1 to 4); or a carbon atom which may have a substituent has 6 to 6 carbon atoms. Represents an aryl group or a bond of 10;

R ¹ , R ² and R ³ are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, a cycloalkyl group having 3 to 7 carbon atoms, An alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, and an arylalkyl group which may have a substituent (Where the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 4 carbon atoms), an aryl group having 6 to 10 carbon atoms which may have a substituent, as a ring-forming atom; ! to 3 nitrogen atoms, oxygen atoms or heteroatoms and the remaining heterocyclic group 5-8 membered ring consisting of carbon atoms selected from sulfur atom, the young properly represents a bond, or R ¹ and R ² R ¹ and R ² may form a benzene ring together with the carbon atom to which they are bonded,

X ¹ and X ² represent 0, S, C (= 0) NH, C (= 0), C (OH) or NR ⁷ , or a bond,

Here, R ⁷ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms,

Y ¹ represents an alkylene chain having 1 to 8 carbon atoms which may have a substituent, Z represents 0 or s,

R ⁴ and R ⁵ represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom.

However, any one of R ¹ , R ² , R ³ and R ⁶ is a bond, and the rest is other than a bond, and this bond and X ¹ are bonded. )

Or a salt thereof.

 7. The benzisoxazole derivative or the derivative thereof according to claim 6, wherein A is 0 or S.

8. The benzisoxazole derivative or a salt thereof according to claim 6, wherein Α is 0 or S, and X ¹ and X ² are a bond.

9. A is 〇 or S, X ¹ and X ² are a bond, and R ¹ , R ² and R ³ are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, and a carbon atom having 1 to 8 carbon atoms substituted with a halogen atom. Alkyl group having 8 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, alkyl group having 1 to 6 carbon atoms substituted with cycloalkyl group having 3 to 7 carbon atoms, alkenyl group having 2 to 8 carbon atoms, 2 to carbon atoms 8, an alkynyl group, an arylalkyl group which may have a substituent (an aryl moiety having 6 to 10 carbon atoms and an alkyl moiety having a carbon number of 1 to 4), and a carbon atom which may have a substituent. 7. The benzisoxazole derivative or a salt thereof according to claim 6, which is an aryl group, a pyridyl group, a phenyl group, or a furyl group represented by Formula 6 to 10, or a bond.

10. A is 0 or S, X ¹ and X ² are a bond, and R ¹ , R ² and R ³ are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or a carbon atom having 1 to 6 carbon atoms as a substituent. Alkyl group having 1 to 6 carbon atoms substituted with halogen atom, alkoxy group having 1 to 6 carbon atoms, halogen atom, acyl group, nitro group, amino group, substituted amino group, carboxyl group, hydroxyl group, phenyl , A benzyl group or a phenyloxy group, which may have an atom or a group selected from the group consisting of an aryl group, a pyridyl group, a phenyl group, a phenyl group, a phenyl group, a furyl group and an arylalkyl group, 7. The penzisoxazolyl derivative or a salt thereof according to claim 6, wherein the moiety has 6 to 10 carbon atoms, the alkyl moiety has 1 to 4 carbon atoms) or a bond.

 11. An activator of peroxisome proliferator-activated receptor 5, comprising the compound according to any one of claims 1 to 10 or a salt thereof as an active ingredient.