WO2002046154A1 - Peroxisome proliferator activated receptor d activators - Google Patents

Abstract

Urea derivatives represented by the general formula (III) or salts thereof are useful as peroxisome proliferator activated receptor d (PPARδ) activators: (III) wherein Y0 is oxygen or sulfur; R?8 and R9¿ are each hydrogen or C¿1-8? alkyl; R is hydrogen or C1-8 alkyl; ... represents a single or double bond; R?6 and R7¿ are each C¿1-8? alkyl, C1-8 alkyl substituted with one to three halogen atoms, C6-10 aryl, arylalkyl, a heterocyclic group, or the like; and X?0¿ is C¿1-8? alkylene.

Description

 Description Activator of peroxisome proliferator-activated receptor Technical field

 The present invention relates to a peroxisome proliferator-activated receptor (5 activators).

 Peroxisomes are organelles found in cells of animals and plants, and their matrices contain various enzymes such as lipase.ぺ Zeroxisomers (eroX isome ro 1 iferator) is a substance that induces the growth of peroxisom, and is used in various forms such as antilipidemic drugs (fibrates), herbicides, and phthalate plasticizers. Compounds are known.

 A nuclear receptor activated by this peroxisome proliferator was identified by Isseman et al., And a peroxisome proliferator-responsive receptor (perox is ome prolifera rat or activat edreceptor) was identified. : PP AR). (Nat ur, 347, p 645-650, 1990)

PPARs, PPARa, and PPAR5 have been identified to date. (Proc. Natl. Ac ad. Sci. US A, 91, p 7335-7359, 1994)

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

 In addition, thiazolidinedione compounds (Troglitazone, Rostiglitazone, Pioglitazone), which are therapeutic agents for diabetes, are known as ligands of PPAR • χ.

PPAR (as a drug having J-activating action, for example, the following formula:

 GW— 2433 (Gl axo We l lcome) represented by the following formula,

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

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

 GW-2433 is described in WO 92 0468 for use as a prophylactic and therapeutic agent for atherosclerosis, L-165041 is described in WO 97/281 15 for use as a therapeutic agent for diabetes mellitus, and YM- Regarding 16638, WO 99/04815 describes that it has a serum cholesterol lowering effect and an LDL-cholesterol lowering effect. More recently, PPARd ligands have been reported to promote their use as anti-cancer and anti-inflammatory agents (JBC, 272 (6), p3406-3410, 1997; Cell, 99, p335-345, 1999). It has been done.

In the ゥ rea derivative represented by the following general formula (III), which is a compound of the present invention, WO 96/20925, JP-A-55-124758, JP-A-51-128965, Acta Pol. Pharm., Which describes a compound having an indoleoxyacetic acid moiety, which is one of the structural features. , 32 (5), 551-6 (1975) and Khim. Farm. Zh., 3 (9), 9-113 (1969)

) Etc. are known. However, the compounds described in these documents also do not have an urea portion which is a structural feature of the compound of the present invention. In addition, there is no suggestion in the literature relating the compound to PPARS.

 On the other hand, the above-mentioned GW-2433 and the compound of the present invention commonly have a rare moiety, but the side chain having a carboxyl group is bonded to a benzene ring in GW-2433, while the following general formula (III) This side chain is bonded to the indole ring in the urea derivative represented by, and the structure is clearly different.

An object of the present invention is to provide a urea derivative represented by the following general formula (I), a urea derivative represented by the following general formula (III) or a salt thereof, which has an activity of activating the peroxisome proliferator-activated receptor 5. Is to do. Disclosure of the invention

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

(In the formula, Y represents an oxygen atom or a sulfur atom,

η represents an integer from 0 to 4,

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 1 to 3 halogen atoms;

W is a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a sulfonic acid group Represents a phosphonic acid group, a cyano group, or a tetrazolyl group;

A double line consisting of a solid line and a broken line represents a single bond or a double bond,

And one of R ^a , R ^b and R ^e is a group represented by the following general formula (II), and the other two are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, and a carbon atom. An aryl group or an arylalkyl group represented by the formulas 6 to 10 (the aryl moiety has 6 to 10 carbon atoms, and the alkyl moiety has 1 to 8 carbon atoms).

R ² 0 R ³

Here, I 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 1 to 3 halogen atoms, and 1 carbon atom. Alkyl group having 1 to 8 carbon atoms, alkenyl group having 2 to 8 carbon atoms, alkynyl group having 2 to 8 carbon atoms, cycle alkyl having 3 to 7 carbon atoms, substituted with an alkoxy group having up to 8 carbon atoms Group, an alkyl group having 1 to 8 carbon atoms substituted with a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms, an arylalkyl group (carbon atom in the aryl moiety) The number is from 6 to 10, and the number of carbon atoms in the alkyl portion is 1 to 8), a heterocyclic group, or a heterocyclic alkyl group (the number of carbon atoms in the alkyl portion is 1 to 8), and X is a carbon atom. Represents an alkylene chain of numbers 1 to 8.

In the above R ^a , R ^b and R ^e , the aryl part of the aryl group and the arylalkyl group and the heterocyclic part of the heterocyclic group and the heterocyclic alkyl group have 1 to 8 carbon atoms. An alkyl group, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, a carbon atom Numbers 2 to 8 of acyl group, formyl group, hydroxyl group, halogen atom, nitro group, cyano group, amino group, alkylamino group (alkyl group has 1 to 8 carbon atoms), dialkylamino group (carbon of alkyl group The number of atoms may be 1 to 8), a phenyl group, or a substituted phenyl group. )

And a salt thereof. Further, the present invention provides the following general formula (III):

(Wherein, Y ^Q represents an oxygen atom or a sulfur atom,

R ⁸ and R ⁹ represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,

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

A double line consisting of a solid line and a broken line represents a single bond or a double bond,

R ⁶ and R ⁷ are an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or an alkoxy group having 1 to 8 carbon atoms. Alkyl group having 1 to 8 carbon atoms, alkenyl group having 2 to 8 carbon atoms, alkynyl group having 2 to 8 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, 3 to 7 carbon atoms An alkyl group having 1 to 8 carbon atoms substituted with a cycloalkyl group, an aryl group having 6 to 1 ◦ carbon atoms, an aryl alkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkyl moiety Represents 1 to 8), a heterocyclic group, or a heterocyclic alkyl group (the alkyl portion has 1 to 8 carbon atoms),

X ° represents an alkylene chain having 1 to 8 carbon atoms.

In the above R ′ ⁶ and R ⁷ , the aryl moiety of the aryl group and the arylalkyl group, and the heterocyclic moiety of the heterocyclic group and the heterocyclic alkyl group are an alkyl group having 1 to 8 carbon atoms, An alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, a formyl group, Hydroxyl group, halogen atom, nitro group, cyano group, amino group, alkylamino group (alkyl group has 1 to 8 carbon atoms), dialkylamino group (alkyl group has 1 to 8 carbon atoms), phenyl group or It may have a substituent selected from a substituted phenyl group (the substituent is selected from a halogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkoxy group having 1 to 8 carbon atoms). )

And a salt thereof. Furthermore, the present invention relates to a peroxisome proliferator-activated receptor containing a perea derivative represented by the above general formula (I), a perea derivative represented by the above general formula (III) or a salt thereof as an active ingredient. Activator of body d. Next, the present invention will be described in detail.

 The symbols in the above general formula (I) will be explained.

In the above general formula (I), the alkyl group having 1 to 8 carbon atoms of RR ² , R ³ , R ⁴ , R ⁵ , R ^a , R ^b and R ^e is a methyl group, an ethyl group, a propyl group. Isopropyl group, butyl group, i-butyl group, t-butyl group, pentyl group and the like.

Examples of the alkyl group having 1 to 8 carbon atoms substituted with a halogen atom represented by RRR ⁴ and R ⁵ include a methyl group and an ethyl group substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom or a bromine atom. Propyl group, isopropyl group, butyl group, t-butyl group and the like, and preferably trifluoromethyl group, chloromethyl group, 2-chloroethyl group, 2-bromoethyl group, and 2-fluoroethyl group. No.

Examples of the alkyl group having 1 to 8 carbon atoms substituted with an alkoxy group having 1 to 8 carbon atoms of R \ R ² and R ³ include a methyl group, an ethyl group, a methyl group substituted with a methoxy group, an ethoxy group, and the like. Propyl group or butyl group and the like.

Examples of the alkenyl group having 2 to 8 carbon atoms of RR ² and R ³ include an aryl group and a 3-methyl-2-butenyl group.

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

Examples of the cycloalkyl group having 3 to 7 membered carbon atoms of RR ² and R ³ include a cyclohexyl group and a cyclopentyl group.

Examples of the alkyl group having 1 to 8 carbon atoms substituted with a cycloalkyl group having 3 to 7 carbon atoms of RR ² and R ³ include a cyclopropylmethyl group and a cyclohexylmethyl group. ^{RR 2, R \ R \ R} b and R ^e carbon atoms from 6 to; the Ariru group L 0, and the like phenyl group or a naphthyl group.

RR ² , R ³ , R ^a ,: R ^b and R ^e arylalkyl groups (the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 8 carbon atoms) Or a phenethyl group.

The heterocyclic group of R \ R ² and R ^3, thienyl group, furyl group, thiazolyl group, Okisazoriru group, a pyridyl group, Imidazoriru group, quinolyl group, indolyl group, or include benzofuranyl group.

Examples of the heterocyclic alkyl group of RR ² and R ³ (the number of carbon atoms in the alkyl portion is 1 to 8) include a chenyl group, a furyl group, a thiazolyl group, an oxazolyl group, a pyridyl group, an imidazolyl group, a quinolyl group, an indolyl group, or Examples include a methyl group, an ethyl group, a propyl group, and a butyl group substituted with a heterocyclic group such as a benzofuranyl group.

Examples of the alkoxycarbonyl group having 2 to 8 carbon atoms of W include a methoxycarbonyl group and an ethoxycarbonyl group. In the above RR ² , RRR ^b and R ^e , the aryl group of the aryl group and the aryl alkyl group, and the heterocyclic group of the aryl group and the heterocyclic alkyl group of II ¹ : R ² and Among the preferable substituents, examples of the alkyl group having 1 to 8 carbon atoms include a methyl group, an ethyl group, a propyl group, a butyl group, an i-butyl group and a t-butyl group, and the like. Examples of the alkyl group having 1 to 8 carbon atoms substituted with an atom include a methyl group, an ethyl group, a propyl group, and an isopropyl group, which are substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom or a bromine atom. Or a butyl group, and the like. Examples of the alkoxy group having 1 to 8 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, or a butoxy group, and an alkoxycarbonyl group having 2 to 8 carbon atoms. Examples thereof include a methoxycarbonyl group and an ethoxycarbonyl group.Examples of the acetyl group having 2 to 8 carbon atoms include an acetyl group and a propionyl group.Examples of the halogen atom include a chlorine atom and a bromine atom. Is a fluorine atom, etc., an alkylamino group (the alkyl group has 1 to Examples of 8) include a methylamino group or an ethylamino group.Examples of a dialkylamino group (the alkyl group has 1 to 8 carbon atoms) include a dimethylamino group or an ethylamino group. Halogen atom (fluorine atom, chlorine atom, etc.), alkyl group having 1 to 8 carbon atoms (methyl group, ethyl group, propyl group, etc.), alkoxy group having 1 to 8 carbon atoms (methoxy group, ethoxy group) , A propyloxy group) and the like. The number of substituents which the above-mentioned heterocyclic group, phenyl group and the like may have is preferably 1 to 3. The symbols in the general formula (III) will be described.

In the general formula (III), examples of the alkyl group having 1 to 8 carbon atoms of R ⁶ , R ⁷ , R ⁸ , R ^9, and R include the alkyl groups exemplified in RR ^{2 and the} like in the general formula (I). Groups. An alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms of R ⁶ and R ⁷ , an alkyl group having 1 to 8 carbon atoms substituted with an alkoxy group having 1 to 8 carbon atoms, C1-C8 alkenyl group, C2-C8 alkynyl group, C3-C7 cycloalkyl group, C3-C7 cycloalkyl group substituted carbon atom1 Alkyl group of ~ 8, Aryl group of 6 ~ 10 carbon atoms, Arylalkyl group (The carbon number of aryl part is 6 ~ 10, the carbon number of alkyl part is 1 ~ 8), complex Also, a 璟 group or a heteroalkyl group (the number of carbon atoms in the alkyl portion is 1 to 8) is an alkyl group or an alkoxy group similarly substituted with a halogen atom as exemplified in II ¹ and R ² of the general formula (I). Alkyl, alkenyl, alkynyl, cycloalkyl substituted with Group, an alkyl group substituted with a cycloalkyl group, Ariru group, § reel alkyl group, a heterocyclic group, or a heterocyclic alkyl Le groups.

In R ⁶ and R ⁷ , among the aryl groups of the aryl group and the arylalkyl group and the substituents that the heterocyclic group of the heterocyclic group and the heterocyclic alkyl group may have, An alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, C2 to C8 acyl group, halogen atom, a Alkylamino group (number of carbon atoms of the alkyl group is 1-8), 1 ^ dialkylamino groups likewise formula also (number of carbon atoms ho 1-8 of § alkyl group) (I), those exemplified such as R ² Is mentioned. In and R ⁷ , when the substituent which the aryl group, heterocyclic group, and the like may have is a substituted phenyl group, the substituent of the phenyl group of the substituted phenyl group includes a bromine atom, a chlorine atom, and a fluorine atom. Examples thereof include halogen atoms such as atoms, alkyl groups having 1 to 8 carbon atoms such as methyl group, ethyl group and propyl group, and alkoxy groups having 1 to 8 carbon atoms such as methoxy group, ethoxy group and propoxy group. .

(1) As the compound of the present invention, among the (1) rare derivatives represented by the above general formula (I), R ^a is a group represented by the general formula (II), R ^b and IT are a hydrogen atom, and C 1 to C 1. An alkyl group having 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aryl alkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkyl moiety has 1 to 8 carbon atoms). Or a salt thereof is preferred.

 (2) Further, as the compound of the present invention, among the urea derivatives represented by the above general formula (I) or the urea derivatives described in (2), urea wherein W is a carboxyl group or an alkoxycarbonyl group having 2 to 8 carbon atoms. Derivatives or salts thereof are preferred.

 (3) The compound of the present invention is preferably a urea derivative represented by the above general formula (I), or a urea derivative represented by the formula (I) above, or a urea derivative wherein is a hydrogen atom, or a salt thereof.

Further, as the compound of the present invention, among the urea derivatives represented by the above general formula (III), R ⁶ is substituted as a substituent by an alkyl group having 1 to 8 carbon atoms or by 1 to 3 halogen atoms. Alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, acyl groups having 2 to 8 carbon atoms, hydroxyl groups, halogen atoms, nitro groups, amino groups, alkylamino groups (alkyl The group has 1 to 8 carbon atoms), a dialkylamino group (the alkyl group has 1 to 8 carbon atoms), or a group selected from a phenyl group or a phenyl group which may have an atom, a naphthyl group, Preference is given to urea derivatives which are chenyl, furyl, thiazolyl, oxazolyl, pyridyl, imidazolyl, quinolyl, indolyl or benzofuranyl groups, or salts thereof. In addition, as the compound of the present invention, among the urea derivatives represented by the above general formula (III) or the urea derivatives described in ④, R ⁷ is an alkyl group having 1 to 8 carbon atoms, or a carbon atom as a substituent. An alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, A group or atom selected from a hydroxyl group, a halogen atom, a nitro group, an amino group, an alkylamino group (the alkyl group has 1 to 8 carbon atoms), or a dialkylamino group (the alkyl group has 1 to 8 carbon atoms) A perylene derivative which is a phenylalkyl group (the alkyl moiety has 1 to 8 carbon atoms) which may be possessed, or a salt thereof is preferable.

 化合物 Further, as the compound of the present invention, a urea derivative represented by the above general formula (II) or a urea derivative described in ④⑤, wherein a double line consisting of a solid line and a broken line is a double bond, or Its salts are preferred.

 化合物 In addition, as the compound of the present invention, a urea derivative represented by the above general formula (III) or a urea derivative described in 、, wherein a double line consisting of a solid line and a broken line is a single bond, or a derivative thereof Salts are preferred.

 {Furthermore, as the compound of the present invention, among the urea derivatives represented by the above general formula (III) or the urea derivatives described in the above items 1 to 4, urea derivatives wherein R is a carboxyl group, or salts thereof are preferable. The urea derivative (the compound of the present invention) represented by the above general formula (I) may also include cis and trans geometric isomers and optical isomers, and these isomers are also included in the present invention. It is.

 The compounds of the present invention also include pharmaceutically acceptable salts such as alkali metal salts such as sodium salt and potassium salt.

Furthermore, among the urea derivatives represented by the above general formula (I) or (III), in the case of a urea derivative in which a double line consisting of a solid line and a broken line is a single bond, the compound of the present invention contains hydrochloric acid. Salts and the like are also included. Next, a method for producing the perrea derivative represented by the above general formula (I), which is the compound of the present invention, will be described.

 (Synthesis method 1)

R ² = H 3 0 R ³

 , H II I

 R1-M = C = 0 HN-X- -N-C-N-X-L

 (a) (c)

(Where L is the following general formula (A) (B) or (C) (CH ₂ ) _N -CW

(Λ) (B) (is a group represented by: wherein R ^a , R ^b and R ^e are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or aryl. (the number of carbon atoms from 6 10 Ariru portion, the number of carbon atoms in the alkyl moiety 1-8) alkyl group is, and Y, n, ^4, R ^5, doublet consisting of W and the solid line and the broken line , And II ¹ , and X are the same as described above.) The urea derivative represented by the general formula (c) is prepared by mixing an amine (b) and an isocyanate (0 ° C to room temperature) in a solvent that does not participate in a reaction such as ethyl acetate. a) can be obtained by reacting

When W in L is a carboxyl group or the like, the above reaction is preferably performed after protecting these with a protecting group. The amine (b) as a raw material can be obtained, for example, by the method described below. (i) When the rare side chain is at position 1 of indole

Br-X-Br / base

/ Base (CH ₂ ) _n W 1

(In the reaction scheme, G ¹ and G ² represent a protecting group, Q represents a leaving group, and W ¹ represents a lower alkoxycarbonyl group, a cyano group, or PO ₃ R ₂ (R is a lower alkyl group). , And R ³ , R ⁴ , R ⁵ , R ^b , R \ n, X and Y are the same as above)

(ii) ゥ When the rare side chain is at position 2 or 3 of indole

12

Replacement paper (Rule 26) G,-

R

_v . b (or _R c) _G 1-Y Rb is _R C) / ^ _W 1 / base

G -Y,-is amino group protected ^G „JG ¹ ) Q- (CH ₂ )„ ^W

 ■ NHR °

R ^a R ^a

(Table in Reaction Scheme, G ¹ and G ² represents a protecting group, Q represents a leaving group, W ¹ is the low grade alkoxycarbonyl group, Shiano group or P 0 ₃ R ₂ a (R is a lower alkyl group) M represents 0 or 1, Z represents a chlorine atom or a hydroxyl group, X ¹ represents a bond or an alkylene chain having 1 to 7 carbon atoms, and R ³ , RR ⁵ , R \ R '\ R \ n, X and Y are the same as above)

(i i i) ゥ When the rare side chain is at position 1 of indlin

Deprotection

13

For replacement ¾ (rule 26) (In Reaction Scheme, G ² represents a protecting group, W ¹ is a lower alkoxycarbonyl group, Shiano group or P 0 ₃ R ₂ (R represents a lower alkyl ^{group), R 3, RR 5,} R \ R e, n, X and Y are the same as above)

 (Synthesis method 2)

R ² ≠ H

R ² -Q

0 R ³ (d) R ² 0

 . I II I

R ¹ -N-C- NXI R ¹ — N-C-N-X-

H.,

 (c) (e)

(Wherein Q represents a leaving group, and I ¹ , RRX and L are the same as described above). The urea derivative represented by the general formula (e) is represented by a compound represented by the following formula: 0 in a solvent such as THF, toluene, DMF or DMS0. The compound can be obtained by reacting the rare derivative (c) with the compound of the general formula (d) in the presence of a base such as sodium hydride at a temperature of from ° C to the reflux temperature of the solvent. Here, the leaving group Q is a halogen atom such as a bromine atom or a tosyloxy group. When W in L is a carboxyl group or the like, it is desirable to carry out the above reaction after protecting these with a protecting group.

 (Synthesis reaction 3)

 (f) (g)

(Wherein, R ^a , RRY, n, R ⁴ , R ⁵ and W are the same as described above.)

14

For replacement (Rule 26) The urea derivative represented by the general formula (g) can be obtained by reacting the compound represented by the general formula (f) with a reducing agent such as a borane-vilidine complex in a solvent such as acetic acid at room temperature to the reflux temperature of the solvent. Can be.

 (Synthesis method 4)

<>

R ^a -N

 .

 (h) (i)

(In the formula, when W ¹ is a lower alkoxycarbonyl group or a nitrile group, W ² represents a carboxyl group; when W ¹ is a phosphonate ester, W ² represents a phosphonic acid; and R ^a , R a ^{b, RY, η, R 4} , R 5 and double line consisting of solid and dotted lines are the same as before follow.)

In the above reaction, when W ¹ is a lower alkoxycarbonyl group, the perylene derivative (i) is converted into an ester form (h) at a temperature of 0 to 60 ° C in a solvent such as ethanol-water by sodium hydroxide, It can be obtained by reacting with lime or lithium hydroxide.

 The representative compounds of the present invention thus obtained are shown below.

 Compound Example I-a

(I-a)

15 For replacement (Rule 26) 【table 1】

 Y (replace

^{R 1 R 2 R 3 XR b} R 0 position) n R ⁴ R ⁵ w 3- cyclopropyl port phenyl Η off I Nechiru (GH HH 0 (5) 0 Me Me C0 2 Et, 3- shea ¹¹ Urorofeniru Η Fuene于Ru (CH ₂ ) ₂ HH 0 (5) 0 Me Me C0 ₂ H 3 Cyclo-phenyl Η phenyl (CH, HH 0 (4) 0 Me Me C0 ₂ H 3-Cyclo phenyl Η ,), HH 0 (6) 0 Me Me C0 ₂ H 3—Di π-open phenyl pentyl (GH HHS (5) 0 Me Me COjEt 3—Di clo-open phenyl Η ethylen Me Me C0 ₂ H 3 Chloromar Η, 、, '(GH HH 0 (5) 0 Me Me C0 ₂ H 3 シ シ ロ τ,' (GH HH 0 (5) 0 HH C0 ₂ H 3—square π-open failure イ ソ isofur (CH,), HH 0 (5) 0 Me Me C0 ₂ Et, 3-—cyclohexane phenyl イ ソ isophthyl (GH ₂ ) ₂ HH 0 (5) 0 Me Me G0 ₂ H, 3-cyclohexyl phenyl イ ソ isophthyl (CH ₂ ) ₃ HH 0 (5) 0 Me Me C0 ₂ H, 4-cyclohexyl phenyl イ ソ isoph 'chill _{(CH 2) 2 HH 0 (} 5) 0 Me Me C0 2 Et, 4- sheet "black hole off Cycloalkenyl Η isophthalic 'chill _{(GH 2) 2 HH 0 (} 5) 0 Me Me C0 2 H

[Table 2]

 Y (replace

R ¹ R ² R ³ XR ^b R ^c position) n R ⁴ R ⁵ w, 4-cyclohexane phenyl H isobutyl (CH ₂ ) ₂ HH 0 (4) 0 Me Me C0 ₂ H, 4—cyclo Mouth phenyl H isobutyl (CH,) ₃ HH 0 (6) 0 Me Me C0 ₂ H, 4-cyclocyclophenyl H isobutyl (CH ₂ ) ₄ HH 0 (5) 0 Me Me C0 ₂ H 4 — black hole phenyl H isophthalic 'chill (GH HH 0 (5) 0 Me Et C0 2 H 4 Shikurorofu:: nil H isophthalic' chill fCH,), HH 0 (5 ) 0 Me Bu C0 2 H4 over sheet Rorofeniru H isophthalic 'Chill (CH ₂ ) ₂ HH 0 (5) 0 H 2 Full age C0 ₂ H

4—ί / Chlo n nil H ily "'Ul H H 0 (5) o Me Me CN 4—Cyclolof: Enil H Irif'1000 H H 0 (5) o Me Me 5—Tetra

Solyl, 4-cyclophenyl H isobutyl (CH ₂ ) ₂ HH 0 (5) 0 HH P03H ₂ 4-cyclo ¹ ? HH

4-cyclo Π "7enyl Me isophthyl HH 0 (5) o Me Me cn„ H, 4, / phenyl hexyl isophthyl (GH,), HH, 0 (5) 0 Me Me C0 ₂ H

 V le

, 4-Dichloro phenyl H isophenyl (CH ₂ ) ₂ HH 0 (5) 1 HH G0 ₂ H, 4-Dicyclo phenyl H isophenyl (CH ₂ ) ₂ HH 0 (5) 3 HH CO _z H

[Table 3]

[Table 4]

 Y plate (, place IS. Holding Ji¾

R 1 R ² R 3 XR b R ^c position) R ⁴ R ⁵ w

2 4-shi 'ゥ Lolov :! : Nil Eta 3 3- Shi 'full silo (GH HH 0 (5) 0 Me Me C0 2 H full ° Rohi "" Le

2,4-cyclophenyl Η2-methoxyethyl (GH ₂ ) ₂ HH 0 (5) 0 Me Me C0 ₂ H

2,4—Black phenyl peryl (CH ₂ ) ₂ HH 0 (5) 0 Me Me C0 ₂ H

2 4—Si * Chlorov: £ Η Η H H HH 0 (5) o Me Me CO _z H

2 4-cyclocyclophenyl Ηphenyl (CH ₂ ) ₂ HH 0 (5) 0 Me Me C0 ₂ H

 / * Γ * ζ (, C M M) 0

 n2 on n ale)

9 4—, ゥ ^ 1 [3 っ:-ル Η 2— 2 s 1 / HH 0 (w5) o Me Me C0 ₂ H

 ) Ethyl

3 Black phenyl イ ソ isobutyl (GH HH 0 (5) o Me Me C0 ₂ H

4—Black Η Isofu ¹ "chill HH 0 (5) 0 Me Me GO Et

4- 1-butylphenyl イ ソ isotyl (CH ₂ ) ₂ HH 0 (5) 0 Me Me C0 ₂ H

2 6 ,,, know-J and Η Yili "^ thousand J Les, Li ^{1 1 2 HH 0 (5)} 0 Me Me C0 2 H

2 5 Black phenyl Η isophenyl (Hn) n HH 0 (5) o Me Me C0 ₂ H

2 Chloro 4-fu 'mouth ΐ ΐ iso-butyl (GH ₂ ) ₂ HH 0 (5) 0 Me Me G0 ₂ H nil

2-Acetylphenyl Η isotyl (CH ₂ ) ₂ HH 0 (5) 0 Me Me C0 ₂ H

[Table 5]

Compound Example I-b

[Table 6]

 Y (replace

^{R 1 R 2 R 3 XR a} R c ^{position) n R 4 R 5 W,} 3- shea * black port phenyl Η phenethyl HH 0 (5) 0 Me Me C0 2 Et, 3- cyclopropyl port phenyl Η phenethyl HH 0 ( 5) 0 Me Me C0 ₂ H, 3 -— * Black phenyl Η phenethyl GH, Me H 0 (5) 0 Me Me C0 ₂ H, 3-—1 ¹ Black phenyl エ phenyl CH ,, Le H 0 (5) 0 HH C0 ₂ H, 3-—cyclohexene phenyl phenethyl (CH,), Me H 0 (6) 0 Me Me C0 ₂ H, 3-cyclohexene phenyl Ηphenyl (CH ,), HH 0 (4) 0 Me Me C0 ₂ H 3—cyclomethyl phenyl Η phenethyl CH ₂ Me HS (5) 0 Me Me C0 ₂ H, 4-cyclohexylphenyl イ ソ isobutyl CH HH 0 ( 5) 0 Me Me C0 ₂ Et 4-'Phenyl phenyl Η isobutyl CH ₂ HH 0 (5) 0 Me Me CO _a H, 4-4 * Phenyl phenyl イ ソ isophenyl CH ₂ HHS (5) 0 Me Me C0 ₂ H, 4-cyclohexyl phenyl イ ソ isobutyl (CH ₂ ) ₂ Me H 0 (6) 0 Me Me C0 ₂ H, 4-cyclophenyl phenyl イ ソ isotyl (GH ₂ ) ₃ Me H 0 (6) 0 Me Me G0 ₂ H, 4— Black phenyl Η isobutyl (CH ₂ ) ₂ Me H 0 (6) 0 Me Et C0 ₂ H, 4—cyclo phenyl Me isobutyl CH ₂ Me H 0 (5) 0 Me Me C0 ₂ H

[Table 7]

 Y (replace

^{R 1 R 2 R 3 XR a} R c n R 4 R 5 W, 4- sheet 'black hole to phenyl' Nshi 'Le iso chill _{GH 2 Me H 0 (5)} 0 Me Me CO, H, 4- / Black mouth phenyl Me isophthalic 'chill CH ₂ to emissions' Le H 0 (5) 0 Me Me C0 2 H, 4- / black port phenyl H iso chill _{(CH 2) 2 Me H 0} (6) 1 HH C0 2 H, 4-Ci-chlorophenyl H isobutyl (CH ₂ ) _Z Me H 0 (6) 2 HH C0 ₂ H, 4-Cyclophenyl. H Isobutyl (CH ₂ ) ₂ H Me 0 (6) 0 Me Me C0 ₂ H, 4-Shi Rorofeniru H Isofuchiru (CH), Me Ph 0 ( 6) 0 Me Me G0 2 H, 4- sheet ¹ "black hole phenyl H n-off ° 13 heat - Le (CH,), Me H 0 (5) 0 Me Me C0 2 H, 4- cyclo port phenyl H 2-menu Bok Kishe (CHJ, HH 0 (5) 0 Me Me C0 2 H chill

One t- flop 'Chirufueniru H isophthalic' chill _{(CH 2) p Me H 0} (6) 0 Me Me C0 2 H - Asechirufueniru H isobutyl _{(CH 2), Me H 0} (6) 0 Me Me C0 2 H - isophthalic ° port arsenide Refeniru H iso chill _{(CH 2) 2 Me H 0} (6) 0 Me Me C0 2 H -. methoxyphenyl H isophthalic 'chill _{(CH 2) 2 Me H 0} (6) 0 Me Me C0 2 H -Naphthyl H isotyl (GH ₂ ) ₂ Me H 0 (6) 0 Me Me C0 ₂ H-Quinolyl H isotyl (CH ₂ ) ₂ Me H 0 (6) 0 Me Me C0 ₂ H

Compound Example I-c

(I-

[Table 8]

 Y (replace

R ¹ R ² R ³ XR ^a R ^b position) n R ⁴ R ⁵ w

2,3-Siphenyl phenyl H phenethyl JHO HH 0 (6) 0 Me Me C0 ₂ Et

2,3 Black phenyl H Phenyl HH 0 (6) 0 Me Me C0 ₂ H

2 3—S ¹ "Black phenyl Me Me phenethyl HH 0 (6) 0 Me Me C0 ₂ H

2,3-Siphenyl phenyl H phenethyl l Me H 0 (6) 0 Me Me C0 ₂ H

2,3-cyclocyclophenyl H phenethyl t Me HS (6) 0 Me Me C0 ₂ H

24 4-cis "phenyl phenyl H isophthyl CH ₂ Me H 0 (6) 0 Me Me C0 ₂ H

2,4-cyclophenyl phenyl H isotyl t Me H 0 (6) 0 Me Me C0 ₂ H

2,4 -— / cloth phenyl H isobutyl (GH ₂ ) ₂ HH 0 (6) 1 HH C0 ₂ H

2 4—CH 2 HH 0 (6) 2 HH C0 ₂ H

2,4-Silorophenyl Me Isotyl (GH ₂ ) ₂ Me H 0 (6) 0 HH .G0 ₂ H 4— n HH CO H

 , Sol

2 4—Chronenil H V V * ¹ "U J Re (GH 丄 Me H 0 (6) o H 2—Full age CO, H

 Mouth etil

2,4—cyclohexenyl phenyl H isobutyl (Gh ₂ Me H 0 (4) 0 Me Me C0 ₂ H

2,4-cyclohexenyl phenyl H isobutyl (CH ₂ ) ₂ Me H J3 (5) 0 Me Me C0 ₂ H

2,4 sheet ¹ "chlorophenyl H isobutyl _{(CH 2) 2 Me H 0} (7) 0 Me Me C0 2 H

[Table 9]

 Y (replace

R 1 R ² R ³ XR ^a R ^b position) n RR ⁵ w

2,4-Si * Black mouth phenyl H isobutyl (CH ₂ ) ₂ Me HS (5) 0 Me Me C0 ₂ H

2,4-cyclohexyl phenyl H isoflur (CHJ, Me Me 0 (6) 0 Me Me C0 ₂ H

2,4-cyclocyclophenyl H isophenyl (CH,) ₉ Me Ph 0 (6) 0 HH C0 ₂ H

2,4 -— * Black phenyl H isophthyl (GH Me H 0 (6) 0 Me Me C0 ₂ H

2,4-cyclocyclophenyl H isophthyl (GH '2 Me H 0 (6) 0 Me Me C0 ₂ H

2,4-cyclohexenyl phenyl H isotyl (CH ₂ ) ₂ Et H 0 (6) 0 Me Me G0 ₂ H

2 4—, ゥ 口 口 フ 酸 .. H V V: ^ 2 ン ン ぺ H H 0 (6) 0 Me Me C0 ₂ H

2 4—Chirolofère H n-7 ° nt ° JL (GH Me H 0 (6) o Me Me C0 ₂ H

9 4— ί Black mouth “Ale H 2—Methoxy z ェ 2 2 H 0 (6) o Me Me GO„ H

 Chill

2-Acetylphenyl H isobutyl (CH ₂ ) ₂ Me H 0 (6) 0 Me Me G0 ₂ H

2—Methoxyxie, Ile H Isofu * Chill i2 2 Me H 0 (6) o Me Me C0 ₂ H

2 6—Cifluorophenyl H Isophthyl Me H 0 (6) o Me Me C0 ₂ H

2 Kurorohi * phenylene Lou 4 one H isophthalic 'chill (CH,), Me H 0 (6) 0 Me Me C0 2 H I le

1 Naphthyl H Isophthyl (CH ₂ ) ₂ Me H 0 (6) 0 Me Me C0 ₂ H

2—Tialyl H Irif 'chill (CH ₂ ) ₂ Me H 0 (6) 0 Me Me C0 ₂ H

Compound Example I-d

 d-d)

[Table 10]

 Y (replace

R ¹ R ² R ³ XR ^b R ^c Standing) n R ⁴ R ⁵ W

2,3 Shi ,, click phenyl Η phenethyl _{(CH 2) 2 HH 0 (} 5) 0 Me Me C0 2 Et

2,3-Shi, black mouth fu ;: Leu phenethyl (CH _Z ) ₂ HH 0 (5) 0 Me Me C.0 ₂ H

2,3-Si, K UD phenyl Η phenyl (CH ₂ ) ₂ HHS (5) 0 Me Me C0 ₂ H

2, 3-si, ηπ phenyl Η, 、, シ, (CH ₂ ) ₂ HH 0 (5) 0 Me Me C0 ₂ H

2, 3-、, 而 ェ Η Η, リ フ (CH ₂ ) 2 HH 0 (5) 0 Me Me C0 ₂ Et

2, 3-Si ,, phenyl ク ロ リ フ, chill (CH ₂ ) 2 HH 0 (5) 0 Me Me C0 ₂ H

2, 3-si, diphenyl, nof, chill (CH ₂ ) ₃ HH. 0 (5) 0. Me Me C. 0 ₂ H

2,4-Si, kuroguchi fu ;: Le イ ソ isof, chill (CH ₂ ) 2 HH 0 (5) 0 Me Me C0 ₂ Et

2,4-Si,, diphenyl, rif, chill (CH ₂ ) ₂ HH 0 (5) 0 Me Me C0 ₂ H

2, 4-Si ,, black mouth fu :: Le Η isof, chill (CH ₂ ) 2 HH 0 (4) 0 Me Me C0 ₂ H

2,4-si, diphenyl isofur, chill (CH ₂ ) ₃ HH 0 (6) 0 Me Me G0 ₂ H

2,4-Si, phenyl rif, chill (CH ₂ ) ₄ HH 0 (5) 0 Me Me C0 ₂ H

[Table 1 1

 Y (replace

R ¹ R ² R ³ XR ^b R ^c n R ⁴ R ⁵ W

2,4- シ * Black phenyl H isobutyl (GH,) ₂ HH 0 (5) 0 Me Et C0 ₂ H

2,4-Si * Black phenyl H isobutyl HH 0 (5) 0 Me Bu C0 ₂ H

2,4 -— / H-phenyl H-isobutyl (CH ₂ ) ₂ HH 0 (5) 0 H 2 -Full-year C0 ₂ H

2,4-cyclophenyl phenyl H isobutyl (GH ₂ ) ₂ HH 0 (5) 0 Me Me CN

2,4 chlorophenyl H isobutyl (CH ₂ ) ₂ HH 0 (5) 0 Me Me 5—tetrasoaryl

2,4-SiH * Phenyl H Isophthyl (CH ₂ ) ₂ HH 0 (5) 0 HH P03H ₂

2,4-Siphenyl phenyl H isobutyl (GH ₂ ) ₂ HH 0 (5) 0 HH SOgH

• 2,4-—Chlorophenyl Me isobutyl (CH ₂ ) ₂ HH 0 (5) .0 Me Me C0 ₂ H

2,4 / Chlorophenyl phenyl isobutyl (CH ₂ ) ₂ HH 0 (5) 0 Me Me G0 ₂ H

2,4-Si: 'Black phenyl H isotyl (CH ₂ ) _Z HH 0 (5) 1 HH C0 ₂ H

2,4- シ * Black phenyl H isobutyl (CH ₂ ) ₂ HH 0 (5) 3 H .H C0 ₂ H

2,4-cyclohexyl phenyl H isophenyl (CH ₂ ) ₂ HHS (5) 0 Me Me C0 ₂ H

2,4-cyclocyclophenyl H isobutyl (CH ₂ ) ₂ Ph H 0 (5) 0 Me Me CO _a H

[Table 1 2]

[Table 13]

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

 The PPAR5 activating effect of the compound of the present invention is determined by the expression of chimeric receptor expression plasmid (GAL4-hPPARS LBD), repo overnight plasmid (UAS X4-TK-LUC) and CV-1 cells in CV-1 cells. After transfection of ^ -galactosidase (^ -GAL) expression plasmid with Lipofection reagent D MR IE-C (Life Technology), in the presence of the compound of the present invention or L-165041 which is a comparative compound After culturing for 40 hours, the solubilized cells were determined by measuring luciferase activity and / or GAL activity.

The luciferase activity was corrected by the G-AL activity, and the relative ligand activity was calculated by setting the luciferase activity of the cells treated with L-165041 as 100%. (Example 14 described later) As shown in Table 14, the compound of the present invention exhibited a PPAR d activating action equivalent to or higher than that of L-165041.

 Therefore, the urea derivative represented by the general formula (I) of the present invention has an excellent PPARi activating action, and is therefore a hypoglycemic agent, a lipid-lowering agent, obesity, syndrome X, hypercholesterolemia, and hyperliposome. Metabolic disorders such as proteinemia, hyperlipidemia, arterial sclerosis, cardiovascular disease, bulimia, ischemic disease, malignant tumors such as lung cancer, breast cancer, colon cancer, colon cancer, ovarian cancer, Alzheimer's disease, inflammatory diseases, osteoporosis (ManoH. Et. A.1, (2000) J. Biol. Chem., 275: 8126-8132), Graves' ophthalmopathy, adrenoleukodystrophy, etc. It is expected as a preventive or therapeutic agent. 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 a usual method in the technical field of formulation.

These preparations use conventional excipients, disintegrants, binders, lubricants, pigments, diluents, and the like. Here, the excipients include lactose, D-mannitol, crystalline cellulose, glucose, etc., the disintegrants include starch, carboxymethylcellulose-scalcium (CMC-Ca), and the lubricants. , Magnesium stearate, talc, and the like, and binders include hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like. The dosage is usually about 0.1 mg / day for the compound of the present invention, which is an active ingredient in an injection, and about 00 mg / L for oral administration, and 1 mg / day to 2000 mg / day for oral administration, but may vary depending on age, symptoms, etc. Can be. Next, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto. 【Example】

Example 1

 2-[1-[2-[[3-(2, 3-phenyl dichloro) 1-1-phenyl] ゥ raido] ethyl] indole-5-yl] oxy-1-methylpropionic acid

(1) 5-benzyloxy 11- (2-promoethyl) indole

 To a solution of 5-benzyloxyindole (1.60 g, 7.17 mmol) in 1,2-dibutene (30 mL) was added tetrabutylammonium bromide (23.1 g). , 0.717 mmo 1) and 28% aqueous sodium hydroxide (30 mL) were added, and the mixture was stirred at 50 ° C. for 54 hours. After cooling to room temperature, the organic layer was separated and the aqueous layer was extracted with toluene. The organic layers were combined, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (hexane / ethyl acetate = 5/1) to obtain 1.72 g (73%) of the title compound as white crystals.

 1 H NMR (CD C 1 "400 0 MHz)

 δ:

 3.60 (2H, t, J = 7Hz),

 4.45 (2 H, t, J = 7 H z),

 5.09 (2 H, s),

 6.4 2 (1 H, d d, J = l, 3 H z),

 6.97 (1H, dd, J = 2, 9Hz),

 7.08 (1H, d, J = 3Hz),

 7.17 (1 H, d, J = 2 H z),

 7.2 1 (1 H, d, J = 9 H z),

 7.3 1 (1 H, m),

 7.34-7.4 1 (2 H, m),

7.43-7.49 (2H, m). (2) 5-benzyloxy 1- [2- (phenethylamino) ethyl] India

A mixture of 5-benzyloxy-1- (2-bromoethyl) indole (66 Og, 2.00 mmo 1) and phenethylamine (0.75 mL, 6.0 Ommol) was subjected to a nitrogen atmosphere at 120 ° C. For 1 hour. After cooling to room temperature, ethyl acetate and aqueous sodium carbonate solution were added to the reaction mixture. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (form / form = 501) to give 745 mg (1%) of the title compound as a yellow oil. 0%).

1 H NMR (CD C ₁₃₃ 4 00 MHz)

 δ

 1 5 8 1 Η, b r s),

2 7 2 2 H ₅ ΐ, J = 7 H z),

2 8 5 2 H ₃ t, J = 7 H z),

 3 0 2 2 H, t, J = 6 H z),

 4 2 0 2 H, t, J = 6 H z),

 5 1 1 2 H, s),

 6 3 7 1 H, d, J = 3 H z),

 6 9 5 1 H, d d, J = 2, 9 H z),

 7 0 3 1 H, d, J = 3 H z),

 7 0 7-7.5 1 (1 2 H, m)

(3) 5—Hydroxy-1— [2- (Phenethylamino) ethyl] Window

5-Benzyloxy 1- [2- (phenethylamino) ethyl] Indole (745 mg, 2.0 mmol), 10% palladium-carbon (0.15 g) and ethanol (8 mL) were mixed at room temperature with 1 Contact hydrogenation was performed at atmospheric pressure for 6.5 hours. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to give the title compound as a pale brown oil (56 mg).

(100%). _{^{1 H NMR (CD C 1 3}} 4 0 0 MH z)

 ό ·

 2 73 (2 H, t J = 7 H z),

 2 8 6 (2 H, t J = 7 H z),

 3 0 3 (2 H, t J = 6 Hz),

 4 2 0 (2 H, t J = 6 H z),

 6 3 2 (1 H, d d, J = l, 3 H z),

 6 74 (1 H, d d, J = 2, 9 H z),

 6 9 8-7.26 (8H, m).

(4) 1- [2- (N-benzyloxycarbonyl-1-N-phenethylamino) ethyl] -1-5-hydroxydindole

5- arsenide Dorokishi 1- [2- (Fuenechiruamino) Echiru] Sodium bicarbonate acetate Echiru (4 mL) solution of Indoru _{(5 6 0 mg 5 2. 0} 0 mmo 1)

A solution of (210 mg, 2.50 mmo 1) in water (4 mL) was added. Next, benzyloxycarbonyl chloride (0.30 mL, 2.10 mmol) was added dropwise while the mixture was vigorously stirred. After stirring at room temperature for 2 hours, the organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (hexane / ethyl acetate = 3Z2) to obtain 719 mg (87%) of the title compound as a pale yellow oil.

 1 H NMR (CD C 1 "400 MHz)

 δ

2. 5 2, 2. 7 1 ( 2 H 5 eachbrt, J = 7 H z)

 3.00, 3.21 (2 H, e a c h b r t, J = 7 H z)

 3.34-3.48 (2 H, m),

 4.10, 4.20 (2 H, e a c h b r t)

 4.5 9 (1 H, b r s),

 5. 1 1, 5. 1 4 (2 H, e a c h b r s)

6. 2 8 - 6. 3 5 ( l H 5 m) 3 6.62-7.42 (14H, m).

(5) 2-[1-[2-(N-benzyloxycarbonyl-N-phenethylamino) ethyl] indyl-1-5-yl] oxy-1-methyl 2-ethylpropionate

 1— [2— (N-benzyloxycarbonyl N-phenethylamino) ethyl] —A solution of 5-hydroxyindole (709 mg, 1.71 mmo 1) in 2-butanone (5 mL) Potassium carbonate (0.71 g, 5.1 mmo 1) and ethyl 2-bromoisobutyrate (0.76 mL, 5.1 mmo 1) were added. After heating under reflux for 41 hours with stirring, the mixture was cooled to room temperature, and insoluble materials were separated by filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by flash column chromatography (hexane / ethyl acetate = 3/1) to obtain 58 Omg (64%) of the title compound as a pale yellow oil. . —

 1 H NMR (CD C 1 "400 MHz)

 δ:

 1.28 (3 Η, t, J = 7 Hz),

 1. 5 6 (6 H, s),

2. 5 1, 2.70 (2 H ₅ eachbrt),

2.98, 3.22 (2H, eachbrt) ₃

3.34-3.48 (2 H ₃ m),

 4.03, 4.20 (2 H, e a c h b r t),

 4.25 (2 H, q, J = 7 H z),

 5.11, 5.14 (2 H, e a c h b r s),

 6.30-6.38 (1 H, m),

 6.71-7.42 (14H, m).

(6) 2-Methyl-2-C [1- [2- (Phenethylamino) ethyl] Indole 5-yl] oxy] ethyl propionate

2- [1- [2 -— (N-benzyloxycarbonyl-1-N-phenethylamino) ethyl] indyl-5-yl] oxy-2-methylethyl propionate (32 _{4mg 3 0. 6 1 3 mmo l} ), 2 hours contact was hydrogenated in the mixture at room temperature 1 atm 1 0% palladium one-carbon (3 1 mg) and ethanol (3 mL). After the catalyst was separated by filtration, the solvent was distilled off under reduced pressure to obtain 24 l mg (100%) of the title compound as a pale yellow oil.

_{^{1 H NMR (CD C 1 3}} , 4 0 0 MH z)

 δ:

 1.30 (3 Η, t, J2 7 Η ζ),

 1. 4 6 (1 Η, b r s),

 1. 5 7 (6 Η, s),

 2.73 (2 Η, t, J = 7 Η ζ),

 2.85 (2Η, t, J = 7Η ζ),

 3.03 (2Η, t, J = 6Η ζ),

 4.19 (2 Η, t, J = 6 Η ζ),

 4. 2 7 (2 Η, q, J = 7 Η ζ),

 6. 3 6 (1 Η, d, J = 3 Η ζ),

 6. 8 6 (1, d d, J = 2, 9 Η ζ),

 7.03 (1 Η, d, J = 3 Η ζ),

 7 0 7-7.27 (7 Η, m).

(7) 2-[1-[2-C [3-(2, 3-diphenyl phenyl) 1-1-phenyl] ゥ raido] ethyl] indole-1-5-yl] oxy-1-2-methylpropionate

2-Methyl- 2-[[1- [2- (phenethylamino) ethyl] indole-5-yl] oxy] ethyl propionate (66 mg, 0.167 mmo 1) of ethyl acetate (1 mL) ) 2,3-Dichlorophenylisocyanate (38 mg, 0.2 Ommo 1) was added to the solution. After stirring at room temperature for 0.5 hour, methanol (0.3 mL) was added, and the mixture was further stirred for 1 hour, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography (hexane / ethyl acetate = 2/1) to give 9 Omg (93%) of the title compound as a colorless oil. ¹ H NMR (CD C 40 0 MHz)

 δ:

 1 2 8 3 H t, J = 7 H z)

 1 5 5 6 H s),

 2 652 Ht, J7Hz)

 3 0 1 2 H t J 7 H z)

 3 5 6 2 H t J 6 H z)

 4 2 5 2 H q J 7 H z)

 4 3 1 2 H t J 6 H z)

 6 3 9 1 H d J 3 H z)

 6 8 5 1 H, b rs),

 6 8 7 1 H, d d, J = 2, 9 H z),

 6 9 7-7.02 (3 H, m),

 7 1 1 1 H, d, J = 2 H z),

 7 1 4 1 H, d d, J = 2, 8 H z),

 7 16-7. 28 (5H, m),

 8 1 3 (1 H, d d, J = 2, 8 H z).

(8) 2—C 1 -C 2-[[3- (2,3-dichlorophenyl) 1-1-phenyl] perylene] indyl] 5-dyl] oxy—2-methylpropion

2 -— [1— [2-—3— (2,3-dichlorophenyl) -1-1-phenyl] ゥ rad] ethyl] indole—5-yl] oxy—2-methylpropionate (86 mg, An aqueous solution of sodium hydroxide (0.29 mL) was added to a solution of 0.148 mmo1) in ethanol (0.4 mL). After stirring at room temperature for 16 hours, 0.1 M hydrochloric acid (3.0 mL) was added under ice cooling. After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration and washed with water. After drying under reduced pressure, 82 mg (100%) of the title compound was obtained as a white powder.

Melting point 8 9— 9 2 ° C ¹ H NMR (CD C 400 MHz)

 δ:

 1 54 6 H, s),

 2 682 H, t, J = 7 Hz)

 3 0 6 2 H, t, J = 7 Hz)

 3 5 8 2 H, t, J = 6 H z)

 4 3 2 2 H, t, J = 6 H z)

 6 44 1 H, d, J = 3 H z)

 6 8 4 1 H, b r s),

 6 8 8 1 H, d d, J = 2, 9 H z)

 6 9 9-7.04 (2 H, m),

 7 0 6 1 H, d, J = 3 H z),

 7 1 4 1 H, d d, J = 1, 8 H z)

 7 1 6 7. 2 8 (7 H, m),

8 2 (1 H ₅ dd, J 8 H z) Example 2

2-[1 [2— “[3-— (2,3-dichlorophenyl) — 1——phenyl] ゥ laid] —ethyl] Indoline-5-yloxy-1-methylpropionic acid

(1) 2-[1-[2-(N-benzyloxycarbonyl-N-phenethylamino) ethyl Indoline-_5-yl, oxy-1-Methyl ethyl propionate

2- [1- [2 -— (N-benzyloxycarbonyl N-phenethylamino) ethyl] indole-5-yl] oxy-2-ethylmethyl ethyl propionate (159 mg, 0.30 A borane-pyridine complex (0.12 mL, 1.2 mmo 1) was added to a solution of mmo 1) in acetic acid (0.880 mL). After stirring at room temperature for 24 hours, the mixture was made basic by adding an aqueous solution of sodium carbonate under ice-cooling, and extracted twice with ethyl acetate. The organic layers were combined, concentrated under reduced pressure, 2 M hydrochloric acid (2 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hour. The mixture was made basic again by adding aqueous sodium carbonate solution. After that, extraction was performed with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the title compound as a pale yellow oil (155 mg, 97%).

_{lE NMR (CD C 1 3,} 400MH z)

 δ:

 1.28 (3 Η, t, J2 7 Hz),

 1.5 0 (6 Η, s),

2.76-3.60 (1 2 Η ₅ m),

 4.2 3 (2 Η, q, J = 7 Hz),

5. 1 2, 5. 1 6 (2 Η ₃ eachbrs),

6. 0 8, 6. 3 1 (1 H ₅ eachbrd),

 6.46-6.74 (2 H, m),

 7.04-7.42 (10H, m).

(2) 2-methyl-2-[[1-C2- (phenethylamino) ethyl] indolin-5-yl] oxy] ethyl propionate

 2— [1-[2— (N-benzyloxycarbonyl-N-phenethylamino) ethyl] indoline-5-yl] oxy-1-methylethyl propionate (155 mg, 0.292 mmo 1) The title compound was obtained as pale yellow semisolid (116 mg, 100%) in the same manner as in Example 1 (6).

1 H NMR (CD C 1 400 MHz)

 δ:

 1.29 (3 Η, t, J = 7 Hz),

 1.50 (6 H, s),

 2.85 (2H, t, J = 8Hz),

 2.90-2.98 (4 H, m),

 3.03 (2H, t, J = 7Hz),

 3.2 1 (2 H, t, J = 6 H z),

3.24 (2 H, t, J = 8 Hz), 4.2 3 (2 H ₃ q, J = 7 H z),

 6.39 (1H, d, J = 8Hz),

 6.62 (1 H, d d, J = 2, 8 H z)

 6.69 (1 H, d, J = 2 H z),

7. 1 6 - 7. 3 0 ( 5 H 3 m).

(3) 2-C 1-[2-C [3-(2, 3-dichlorophenyl) 1-1-phenyl] perethyl] indolin-5-yl] oxy-1-2-methylpropionate

 Example 1 (2-methyl-1-2-[[1- [2- (phenethylamino) ethyl] indoline-5-yl] oxy] ethyl propionate (112 mg, 0.282 mmo 1) was used. In the same manner as in 7), 125 mg (76%) of the title compound was obtained as a colorless oil.

_{^{1 H NMR (CD C 1 3}} , 40 0 MH z)

 δ:

 1.2 8 (3 Η, t, J 7 Hz)

 1. 5 1 (6 Η, s)

 2.90 (2 Η, t, J 8 Hz)

 3.02 (2Η, t, J7Hz)

 3.2 0 (2 Η, t, J 6 Hz)

 3.3 7 (2 Η, t, J 8 Hz)

 3.5 1 (2 Η, t, J 6 H z)

 3.63 (2Η, t, J7Hz)

 4.2 3 (2 Η, q, J 7 Hz)

 6. 3 5 (1 Η, d, J 8 H z)

6.64 (1 Η ₅ dd, J 2 2, 8 Hz),

 6. 7 2 (1 Η, d, J 2 H z)

 7.07 (1Η, d d, J = 1, 8 Hz)

7.14 (1Η, t, J8Hz) 7.20—7.35 (5H, m),

8.0 (IH ₅ br),

 8.03 (1 H, d d, J = 1, 8 H z)

(4) 2— [l— [2 — [[3— (2,3-dichlorophenyl) -1-1-phenyl 1 ureido Ίethyl チ ル indoline-5-yl] oxy-1-2-methylpropion

2— [1— [2— [3— (2,3-dichlorophenyl) -1-1-phenyl] ゥ reido] ethyl] indolin-5-yl] oxy-1-2-methylpropionate (125 mg , 0.214 mmo 1) in the same manner as in Example 1 (8) to obtain 107 mg (90%) of the title compound as a slightly brown powder.

Melting point 1 15—1 17 ° C (decomposition)

_{^{1 H NMR (CD C 1 3}} , 4 0 0 MH z)

 δ:

 1 5 0 6 s s),

 2 9 3 2 Η t, J = 8 Η ζ),

 3 0 2 2 Η t, J = 7 Η ζ),

 3 2 2 2 Η t, J = 6 Η ζ),

 3 4 2 2 Η t, J = 8 Η ζ),

 3 5 1 2 Η t, J = 6 Η ζ),

 3 6 3 2 Η t, J = 7 Η ζ),

 6 3 7 1 Η d, J = 8 Η ζ),

 6 7 0 1 Η d d, J = 2, 8 Η ζ),

 6 7 6 1 Η ά, J = 2 Η ζ),

 7 0 8 1 Η d d, J = l, 8 Η ζ),

 7 1 5 1 Η t, J = 8 Η ζ),

 7 2 0-7. 3 6 (5 Η, m),

 7 8 5 I Η b r s),

8 0 5 1 Η dd, J = 1, 8 Η). Example 3

 2- [1-[2 — [[332, —3-dichlorophenyl) -1-_1-isobutyl-1_ ゥ] ethyl] indole-5-yl] oxy-1-2-methylpropionic acid

(1) 5-benzyloxy- [2- (isobutylamino) ethyl

 Using 5- (benzyloxy) indole (402 mg, 1.22 mmo 1) and isobutylamine (1.2 mL, 12 mmo 1), as in Example 1 (2), The title compound was obtained as a yellow oil (392 nig (100)).

NMR (CDC.l ₃ , 400MHz)

 δ:

0 84 (6 H ₃ d, J = 6 H z)

 1 66 (1 H, m),

 2 39 (2H, d, J = 7 Hz),

 3 00 (2H, t, J = 6Hz),

 4 21 (2 H, t, J = 6 Hz),

 5 10 (2H, s),

 40 (1 H, dd, J = 1, 3 H z)

 95 (1H, dd, J2, 9Hz)

 1 1 (1 H, d, J = 3 H z),

 17 (1 H, d, J = 2 H z),

 27 (1 H, d, J = 9 H z),

 31 (1 H, m),

 34-7. 41 (2H, m),

 44-7.49 (2H, m).

(2) 5—Hydroxy-1 11 _ [2 -— (Isoptylamino) ethyl] indole 5-Benzyloxy 1- [2- (isobutylamino) ethyl] Indole (392 mg, 1.22 mmo 1) was used to convert the title compound to a brown oil in the same manner as in Example 1 (3). 283 mg (100%) was obtained.

(3) 1- [2- (N-benzyloxycarbonyl-N-isobutylamino) ethyl] —5-hydroxyindole

 The title compound was converted to a colorless oil by using 5-hydroxy-1- [2- (isobutylamino) ethyl] indole (283 mg, 1.22 mmo 1) in the same manner as in Example 1 (4). 1 mg (97%) was obtained.

_{H NMR (CD C 1 3,} 40 0 MH z)

 δ

 0 7 3, 0 836 H, e a c h b r d, J = 6 H z),

 6 2-1 9 2 1 H, m),

 2 65, 2 88 2 H, e a c h b r d, J = 7 H z),

 3 48-3 62 2 H, m),

 4 1 6, 4 3 0 2 H, e a c h b r t),

 4 6 3 (1 Η, b r s),

 5 1 0, 5.16 2 H, e a c h b r s),

 6 3 0-6 3 6 1 H, m),

 6 64, 6 74 1 H, e a c h b r d, J = 8 H z),

 6 8 6-7 04 2 H, m),

 7 2 0-7 42 6 H, m).

(4) 2-C1- [2- (N-benzyloxycarbonyl-N-isobutylamino) ethyl] India-5-yl] oxy-2-ethylethyl propionate

1— [2 -— (N-benzyloxycarbonyl-N-isobutylamino) ethyl] —5-hydroxyindole (4.16 mg, 1.14 mmol 1) was used in the same manner as in Example 1 (5). This gave 456 mg (84%) of the title compound as a colorless oil. _{^{1 H NM (CD C 1 3}} , 40 0 MH z)

 6

 0.70, 0.81 (6 H, e a c h b r d, J = 6 H z)

 1.29 (3 H, t, J = 7 H z),

 1. 5 5 (6 H, s),

 1.6-1.9 (1 H, m),

 2.61, 2.86 (2 H, e a c h b r d, J = 7 H z)

 3.46-3.62 (2 H, m),

 4.15, 4.30 (2 H, e a c h m)

 4.26 (2 H, q, J = 7 H z),

 5.11, 5.16 (2H, e a c h b r s)

 6.32-6.38 (1 H, m),

 6.70-7.42 (9H, m).

(5) 2-C1- [2- (isobutylamino) ethyl] indole-5-yloxy-2-ethyl methylpropionate

 2 -— [1— [2 -— (N-benzyloxycarbonyl N-isobutylamino) ethyl] indole-5-yl] oxy-1-ethylethyl 2-methylpropionate (90 mg, 0.19mmo 1) In the same manner as in Example 1 (6), 65 mg (100%) of the title compound was obtained as a pale yellow oil.

_{lE NMR (CD C 1 33 4} 00 MH z)

 ό-:

 0.83 (6 Η, d, J = 7 Hz),

 1.29 (3 H, t, J = 7 H z),

 4 5 (1 H b rs),

 5 7 (6 H s),

 1 6 6 (1 H m),

 2 4 0 (2 H d, J = 7 H z),

3 0 0 (2 H t, J = 6 H z), 4.20 (2 H ₃ t, J = 6 H z),

 4.26 (2 H, q, J = 7 H z),

 6.39 (1 H, d, J = 3 H z),

 6.86 (1 H, d d, J 2 2, 9 H z)

 7.10 (1 H, d, J = 3H z),

 7. 1 2 (1 H, d, J = 2 H z),

 7.2 2 (1 H, d, J = 9 Hz).

(6) 2— _ [1—— [2 — [[3- (2,3-dichlorophenyl) isobutyl] peridol] indole-5-yl] oxy-1-2-methylpropionate

 Example 1 using 2- [1- [2- (isobutylamino) ethyl] indole-5-yl] oxy-2-ethylethyl propionate (65 mg, 0.19 mmo 1) In a similar manner to (7), 85 mg (85%) of the title compound was obtained as a colorless oil.

_{NMR (CD C 1 3, 400MH} z)

 δ:

 0.8 2 (6 H, J 6 H z),

 1.29 (3 H, t, J 7 H z),

 1.5 5 (6 H, s)

 1.84 (1 H, m)

 2.55 (2H, d, J8Hz),

 3.69 (2 H, t, J 6 H z),

 4.26 (2H, q, J7Hz),

 4.38 (2 H, t, J 6 H z),

 6. 4 1 (1 H, J 3 H z),

 6.85 (1 H, d d J = 2, 9 H z),

 6.96 (1 H, b r s),

7. 04 (1 H, J 3 H z), 7.13 (1 H, d, J = 2 H z),

7. 14 (1 H, dd, J = l 5 8 H z),

 7.2 1 (1 H, t, J = 8 H z),

 7.25 (1 H, d, J = 9 Hz),

 8.22 (1 H, d d, J = l, 8 H z).

(7) 2-[1-[2-C [3-(2, 3-dichlorophenyl) 1-1-isobutyl] peridol] ethyl] indole 1-5-yl 1-oxy-1-2-methylpropion

2— [1— [2— [3— (2,3-dichlorophenyl) -1-1-isobutyl] ゥ reido] ethyl] indole-5-yl] oxy-1-2-methyl propionate (82 mg, 0 Using 15 mmo 1), 78 mg (100%) of the title compound was obtained as a white amorphous substance in the same manner as in Example 1 (8).

_{^{1 H NMR (CD C 1 3}} , 400 MH z)

 δ

 0.84 (6Η, d, J7Hz),

 1. 54 (6 Η, s),

 1.86 (1 Η, m),

 2.62 (2Η, d, J7Hz),

 3.70 (2Η, t, J6Hz),

 4.40 (2Η, t, J6Hz),

6. 45 (1 Η ₃ d, J 3 H z),

 6. 8 8 (1 Η, d d, J = 2, 9 H z),

 6. 9 6 (1 Η, b r s),

 1, 09 (1Η, d, J 3 H z),

 7.14 (1 Η, d d, J = 1, 8 Hz),

7.2 1 (1 Η ₅ t, J 8 Hz),

 7.22 (1 Η, d, J 2 H z),

7.3 1 (1 Η, d, J 9 Hz), 8.20 (1 H, dd, J = l, 8 H z). Example 4

 2 -— [1— [2 -— [[3- (2,4-dichlorophenyl) -1-1-isobutyl] ゥ reido] ethyl] indole-5-yl] oxy-1-2-methylpropionic acid

(1) 2— [1-[2— [[3- (2,4-dichlorophenyl) 1-1-isobutyl] ゥ reido] ethyl] quinone-5-yl] oxy-1-methylpropion Acid ethyl

 2— [1— [2— (Isoptylamino) ethyl] indole—5-yl] oxyl 2-methylethyl propionate (78 mg, 0.23 mmo 1) and 2,4-dichlorophenylisocyanate (47 mg. In the same manner as in Example 1 (7), 10 Omg (83%) of the title compound was obtained as a colorless oil.

_{^{1 H NMR (CD C 1 3}} , 400 MHz)

 δ:

 0.82 (6 Η, d, J 6 Hz),

1.29 (3Η, t, J 7Hz) ₅

 1.55 (6 Η, s)

 1.82 (1 Η, m)

 2.54 (2 Η, d, J 8H z),

3.68 (2 Η, t, J 6 Hz) ₅

 4.26 (2Η, q, J 7Hz),

 4.37 (2Η, t, J 6Hz),

6.40 (1 Η, d, J 3 H z) ₃

 6. 81 (1 Η, b r S),

 6.85 (1 Η, d d, J = 2, 9Hz),

 7. 04 (1 Η, d, J 3 H z),

7, 12 (1 Η, d, J 2 H z), 7.24 (1 H, d, J = 9 H z),

 7.25 (1 H, d d, J = 2, 9 H z)

 7.35 (1H, d, J = 2Hz),

 8.23 (1 H, d, J = 9 Hz).

(2) 2— [1— [2 — [[3— (2,4-dichlorophenyl) -1-1-isobutyl Ί ゥ ray ド de] ethyl Ί indole _5-yl] oxy-1 2-methylpropion _

2— [1— [2— [3— (2,4-dichlorophenyl) 1-11-isobutyl) ゥ reido] ethyl] indole—5-yl] oxy-1-ethyl 2-methylpropionate (96 In the same manner as in Example 1 (8), 91 mg (100%) of the title compound was obtained as a pale yellow amorphous.

¹ H NMR (CD C ₁₃₅ 4 00 MHz)

 6:

 0.84 (6 H, d, J 7 H z),

 1. 54 (6 H, s),

 1.84 (1 H, m),

 2.60 (2 H, d, J 8 H z),

 3.69 (2 H, t, J 6 H z),

 4.39 (2H, t, J6Hz),

6. 4 5 (1 H, d, J 3 H z) ₅

 6.8 1 (1 H, b rs),

 6.88 (1 H, d d, J = 2, 9 H z)

 7.09 (1 H, d, J 3 H z),

 7.2 2 (1 H, d, J 2 H z),

 7.24 (1 H, d d, J = 2, 9 H z)

 7.30 (1 H, d, J 9 H z),

 7.3.5 (1 H, d, J 2 H z),

8.2 2 (1 H, d, J 9 H z). Example 5

 2-[1-[2-[[3- (4-chlorophenyl) -1- 1-isobutyl] ureido_ethyl] -indyl-5-yl] -oxy-1--2-methylpropionic acid

(1) 2-C1-C2-C3- (4-chlorophenyl) 1-isobutyl] 一 Reid] ethyl] indyl 5-yl] oxy-2-methylpropionate

 2- [1- [2- (Isoptylamino) ethyl] indole-5-yl] oxy-2-ethylethyl propionate (78 mg, 0.23 mm o 1). And 4-chlorophenyliso Using the cyanate (39 mg, 0.25 mmo 1), 96 mg (85%) of the title compound was obtained as a colorless oil in the same manner as in Example 1 (7). .

_{^{1 H NMR (CD C 1 3}} , 40 0 MH z)

 δ:

 0.84 (6Η, J = 7 Hz),

 1.29 (3 Η, t, J = 7 Hz), '

 1.56 (6Η, s)

 1.83 (1 Η, m)

 2.63 (2Η, d, J = 7Hz),

 3.67 (2 Η, t, J = 6 Hz),

 4.25 (2Η, q, J = 7Hz),

 4.34 (2Η, t, J = 6Hz),

 5. 7 6 (1 Η, b rs),

 6.4 1 (1Η, d, J = 3Hz),

 6.87 (1 Η, d d, J 2 2, 9 Hz),

 7.00-7.06 (3 H, m),

 7.13 (1Η, d, J = 2Hz),

7.16-7.26 (3H, m). (2) 2— [1— [2 — [“3- (4-chlorophenyl)-1-isobutyl-reido] ethyl] indyl 5-yl] oxy-1-methylpropionic

 2— [1— [2— [3— (4-chlorophenyl) 1-1—isobutyl] ureido] ethyl] indole-5—yl] oxy-1-ethyl 2-methylpropionate (9 l mg, Using 0.18 mmo 1), 86 mg (100%) of the title compound was obtained as a pale yellow amorphous in the same manner as in Example 1 (8).

_{1 H NMR (CD C 1 3} 5 40 0MH z)

 δ

 0 8 5 6 E, d, J = 7 H z),

1 5 5 6 H ₅ s),

 1 8 3 1 H, m),

 2 6 8 2 H, d J = 7 H z),

 3 6 8 2 H, t, J = 6 Hz),

 4 3 6 2 H, t, J = 6 Hz),

 5 8 5 1 H, b r s),

 6 4 5 1 H, d, J = 3 H z),

 6 9 0 1 H, d d, J = 2, 9 H z)

 7 0 5 7.1 1 1 (3 H, m),

 7 1 7 7.24 (3 H, m),

 7 3 0 (1 H, d, J = 9 Hz) Example 6

 2— [1— [2— [[1-butyl-3— (2,3-dichlorophenyl)] uredoethyl] _indole-5-yl 1-oxy-2-methylpropionic acid

(1) 5-benzyloxy 1- [2- (butylamino) ethyl] indole

Using 5-pentyloxy 1- (2-promoethyl) indole (66 1 mg, 2.00 mmo 1) and n-butylamine (1.0 mL, 10 mmo 1), proceed in the same manner as in Example 1 (2). To give the title compound as a yellow oil, 645 mg (10 0%).

_{1 H NMR (CD C 1 3} , 40 0 MH z)

 δ

 0 8 7 (3 H, t, J = 7 H z),

 1 2—1.6 (5 H, m),

 2 5 8 2 H, t, J = 7 H z),

 3 0 1 2 H, t, J = 6 H z),

 4 2 3 2 H, t, J = 6 H z),

 5 1 1 2 H, s),

 6 40 1 H, d, J = 3 H z),

 6 9 5 1 H, d d, J = 2, 9 H z),

 7 1 1 1 H, d, J = 3 H z),

 7 1 7 1 H, d, J = 2 H z),

 7 2 5-7.5 1 (6 H, m)

(2) 1- [2- (Butylamino) ethyl] —5-Hydroxyindole

 Using the 5-benzyloxy 1 _ [2- (butylamino) ethyl] indole (64 Omg, 1.98 mmo 1), the title compound was converted to a brown oil in the same manner as in 46 Omg (1 0%).

(3) 1- [2- (N-benzyloxycarbonyl-N-butylamino) ethyl] — 5-hydroxyindole

Using 1- [2- (butylamino) ethyl] —5-hydroxyindole (460 mg, 1.98 mmo 1), the title compound was converted to a colorless oil in the same manner as in Example 1 (4). 66 mg (91%) was obtained.

¹ H NMR (CD C 1 "400 0 MHz)

 δ:

0.76, 0.85 (3 H ₅ eachbrt, J = 7 H z), 1. 04- 1 46 (4 H, m),

2 82, 3 03 (2H _{5 each} ach brt)

 3 45-3 60 (2 H, m),

 4 16, 4.28 (2H, e ach b r t)

 4 94 (1 H, b r s),

 5 09, 5.17 (2H, e ach b r s)

 6 33 (1 H, b r s),

 6 6 1 -7. 40 (9H, m).

(4) 2- [1- [2-((N-benzyloxycarbonyl-N-butylamino) ethyl] indole-5-yl] oxy-1-ethyl 2-methylpropionate

 Example 1 using 1- [2-((N-benzyloxycarbonyl) -N-butylamino) ethyl] -5-hydroxyindole (646 mg, 1.76 mmo 1)

In a similar manner to (5), 775 mg (9 1%) of the title compound was obtained as a colorless oil.

¹ H NMR (CD C 1 "400 MHz)

 δ:

 0 74, 0.84 (3Η, each brt, J = 7Hz)

 02-1.46 (4H, m),

 29 (3Η, t, J = 7Hz),

 1 55 (6 H, s),

 2 79, 3.03 (2 H, e ach b r t)

 3 48-3.58 (2 H, m),

4 16, 4. 30 (2H _{3 each} m)

 4 26 (2H, q, J = 7Hz),

5 10, 5. 16 (2H _{3 each} brs)

6 36 (1 H ₅ brd),

6 70-7.42 (9H, m). (5) 2-[1-"2-Mino) ethyl] Indole-5-yl] Oxy 2-methyl ethyl propionate

 2- [1-[2 -— (N-benzyloxycarbonyl N-butylamino) ethyl] indole-5-yl] oxy-2-ethylethyl propionate (127 mg, 0.2 Using 64 mmo 1), 86 mg (94%) of the title compound was obtained as a pale yellow oil in the same manner as in Example 1 (6).

_{^{1 H NMR (CD C 1 3}} , 4 0 0 MH z)

 6:

 0.87 (3 H, t, J = 7 H z),

 1.2 2-1.45 (5 H, m),

 1.30 (3 Η, t, J 7 Hz),

 1. 5 7 (6 Η, s),

 2. 5 8 (2 Η, t, J 7 H z),

 3. 0 1 (2 Η, t, J 6 H z),

 4.2 1 (2 Η, t, J 6 H z),

 4.26 (2Η, q, J7Hz),

 6. 3 9 (1 Η, d, J 3 H z),

 6.86 (1 Η, d d, J = 2, 9 Hz),

7.10 (1 Η, d, J 3 H z) ₅

7.1 2 (1 Η, d, J 2 H z) ₃

 7.2 2 (1st, d, J 9 Hz).

(6) 2-[1-1 [2-C [1 butyl-3 _ (2, 3-dichlorophenyl)] ゥ rad] ethyl] indole 5-yl] oxy-2-methyl propionate

 2-[1 1 [2 1 (butyl), no.] India-Lou 5

Using ethyl 2-ethylpropionate (79 mg, 0.23 mmo 1), in the same manner as in Example 1 (7), 113 mg (93%) of the title compound was obtained as a colorless oil. NMR (CD C 1 ₃ 400 MHz) n 8 1 C 3 HJ 7 H z ^ ノ

 1 1 g (2 H

1 2 Q (, 3 Ht 3 J 7 Hz ¹ )

 1 Q Q C H m)

1 C fi H ^ΰノ

 ? , † J 7 (H 7, no j

 Q V, J j

 4 9 R q, J 7 Vi)

 4 (o H t J no

 4 n (V, .1 H d, J H 7,

 R uQ a (1 Η d d j = 9 Q H 7, no

 4 (1 Η b r no,

 7 n w s (, 1 Η d, J no

 7 1 9 (1 Η d, J no

 7.14 (1 h, d d, J = 1, 8 H z ヽ),

 7.2 1 (1 H, t, J 8 H z),

 7.24 (1 H d J 9 H z),

 8.20 (1 Hd d, J = 18 Hz).

(7) 2-Γ 1-[2-丄 [1-butyl-3-(2,3-dichlorophenyl)] ureido-deethyl] indone-luni 5-yl] oxy-1-methylpropion i

2— [1— [2- [1-butyl-1-3- (2,3-dichlorophenyl)] ゥ reido] ethyl] indole—5-yl] oxy-2-ethylethyl propionate (104 mg, 0 In the same manner as in Example 1 (8) using .195mmo 1), 96 mg (97%) of the title compound was obtained as slightly yellowish white crystals.

_{^{1 H NMR (CD C 1 3}} , 400 MHz)

6: 0.8 3 (3 H, t, J = 7 H z),

 ヽ

 1.2 1 (2 H, m)

 ヽ

 1.4 1 (2 H, m)

 ヽ

1.5 5 (6 H ₃ s)

 丄

 2.83 (2H, t, J = Hz),

 3.68 (2 H, t, J = 6 H z),

 4.39 (2H, t, J = 6Hz),

 6.45 (1 H, d, J = 3 H z),

 6.88 (1 H, d d, J = 2, 9 H z),

 6.90 (1 H, b r s),

 7.10 (1H, d, J = 3Hz),

 7. .14 (1 H, d d, J = 1, 8 H z),

 7.2 1 (1 H, t, J = 8 Hz),

 7.2 2 (1 H, d, J = 2 H z),

7.30 (1 H ₃ d, J = 9 H z),

 8.19 (1H, dd, J = 1, 8Hz).

F AB -M S m / z 5 0 7, 5 0 5 Example 7

2-[1 [2— “[3- (2,3-dichlorophenyl) 1-1-isobutyl] ゥ reido] ethyl, indoline-5-yl] oxy-1-2-methylpropionic acid

(1) 2-[I 2-(N-benzyloxycarbonyl-N-isoptylano) ethyl] indoline-1-5-yl] oxy-1-methylethyl propionate 2-[1-[2-(N- Using benzyloxycarbonyl-1-N-isobutylamino) ethyl] indole-5-yl] oxy-2-methylpropionate (144 mg, 0.3 Ommo 1) in the same manner as in Example 2 (1) The title compound was obtained as pale yellow oil (144 mg, 99%). 'Ε NMR (CD C 400 MHz)

 6

 0.86, 0.90 (6 H, e a c h b r d, J = 6 H z)

 1.29 (3 H, t, J = 7 H z),

 1.50 (6 H, s),

 1. 94 (1H, m),

 2.78-2.93 (2 H, m),

 3.06—3.52 (8H, m),

 4.2 3 (2 H, q, J = 7 H z),

 5. 1 4 (2 H, b r s),

 6.10, 6.35 (1 H, e a c b r d, J = 8 H z)

 6.4 6-6.72 (2 H, m),

 7.26-7.41 (5H, m)

(2) 2-C1- [2- (isobutylamino) ethyl] indoline-5-yl] oxy-2-ethylethyl methylpropionate

 2 -— [1- [2- (N-benzyloxycarbonyl-N-isobutylamino) ethyl] indrin-1-yl] oxy-1-ethylethyl 2-methylpropionate (14 Omg, 0.290 mmo 1) In the same manner as in Example 1 (6), 10 lmg (100%) of the title compound was obtained as a pale yellow oily substance.

_{1 H NMR (CD C 1 3} , 4 00 MH z)

 δ

 0.91 (6 H, d, J = 7 Hz)

 1.29 (3 H, t, J = 7 H z)

 1.50 (6 H, s),

 1.59 (1H, brs),

 1.76 (1 H, m),

 2.47 (2 H, d, J = 7 H z)

2.82 (2H, t, J = 6Hz) 2.90 (2 H, t J = 8 H z),

 3 1 3 (2 H, t J = 6 Hz),

 3 3 0 (2 H, t J = 8 Hz),

 4 2 3 (2 H, q J = 7 H z),

 6 3 7 (1 H, d J = 8 H z),

 6 6 3 (1 H, d d, J = 2, 8 H z)

 6 7 0 (1H, d, J = 2Hz).

(3) 2-C 1-[2-C [3--(2,3-dichlorophenyl) -1-1-isobutyl] perylene] ethyl] indoline-5-yl] oxy-1 2-methylpropionate

 .2— [1_ [2- (isobutylamino) ethyl] indoline-1-yl] oxyl 2-methylpropionate (95 mg, 0.27 mmo 1) In the same manner as in Example 1 (7), 138 mg (94%) of the title compound was obtained as a colorless oil.

¹ H NMR (CD C 1 "400 MHz)

 δ:

 1. 0 0 (6 Η, J 7 H z),

 1.28 (3Η, t, J7Hz),

 1. 5 6 (6 Η, s)

 2. 1 0 (1Η, m)

 2.92 (2Η, t, J8Hz),

 3.23 (2Η, d, J7Hz),

3.2 7 (2 Η, t ₃ J 6 Hz),

 3.42 (2 Η, t, J 8 H z),

 3.60 (2 Η, t, J 6 H z),

 4.24 (2Η, q, J7Hz),

 6. 3 9 (1 Η, J 8 H z),

6 · 6 5 (1, dd, J = 2, 88 Hz) 6. 7 2 (1 H ₃ d, J = 2 H z),

 7.07 (1 H, d d, J = l, 8 H z)

 7.14 (1 H, t, J = 8 Hz),

 7.83 (I H, b r s),

 8.08 (1 H, d d, J 2 1, 8 H z)

(4) 2— 丄 1—— [2— _ [[3- (2,3 nitrochlorophenyl) isobutyl] perethyl] ethyl 1 indoline _5—yl] oxy 1 2-methylpropion

2— [1— [2— [3— (2,3-dichlorophenyl) -1-1-isobutyl] ゥ reido] ethyl] indoline-5-yl] oxy-2-ethyl methylpropionate (1 Using 22 mg, 0.246 mmo 1), 122 mg (98%) of the title compound was obtained as a white powder in the same manner as in Example 1 (8).

 Melting point 1 24— 1 27 ° C (decomposition)

¹ H NMR (CD C 1 "400 MHz)

 δ:

 1. 0 1 (6 Η, d, J 6 H z),

 1. 5 0 (6 Η, s)

 2.1 0 (1 Η, m)

 2.95 (2 Η, t, J 8 Hz),

 3.2 3 (2 Η, d, J 8 Hz),

 3.30 (2 Η, t, J 6 H z),

 3.46 (2Η, t, J8Hz),

 3.6 1 (2 Η, t, J 6 Hz),

 6.42 (1Η, d, J8Hz),

 6. 7 1 (1 Η, d d, J = 2, 8 H z),

 6. 7 5 (1 Η, b r S),

 7. 08 (1 Η, d d, J = 1, 8 Hz),

7. 1 5 (1 Η, t, J 8 H z), 7.67 (IH, brs),

 8. 10 (1H, dd, J = l, 8 Hz).

 2— [3— [2-[[3 (2, —3—_dichlorophenyl) -1-_1-phenyl] ゥ raid] ethyl ン indole-6-yl] oxy-2-methylpropionic acid

(1) 6-Benzyloxy-3-indoleglyoxylyl cue

 Under ice-cooling, oxalyl chloride (0.28 mL, 3.2 mmol) was added dropwise to a solution of 6-benzyloxyindole (590 mg, 2.64 mmol) in anhydrous ether (8 mL). After stirring at room temperature for 0.5 hour, the precipitated crystals were collected by filtration and washed several times with ether. Drying under reduced pressure gave 482 mg (58%) of the title compound as brown crystals.

_{NMR (CDC l 3 / DMSOd 6} = 10 / l 5 400 MH z) δ:

 5.12 (2 H, s),

 6.99 (1 H, dd, J two 2, 9 H z),

 7.03 (1H, d, J = 2 Hz),

 7.29-7.49 (5H, m),

 8.21 (1 H, d, J = 9 Hz),

 8.42 (1 H, d, J = 3 H z),

 1 1.64 (1 H, b rs).

(2) 6-Penzyloxy-3-Indole-N-Phenethylglyoxylam

Under ice cooling, a solution of phenethylamine (100 mg, 0.825 mmo 1) and triethylamine (115 L, 0.82 mmo 1) in methylene chloride (6 mL) was added to a solution of 6-pentyloxy-3-indoleglyoxylyl chloride. (236 mg, 0.752 mmo 1) was added. Stir at 5 ° C for 1 hour and at room temperature for 17 hours to precipitate crystals. The crystals were collected by filtration and washed several times with methylene chloride. The crystals were dried under reduced pressure to give the title compound as yellow crystals (263 mg, 88%).

_{1 H NMR (CD C 1 3} / DM S 0 d 6 = 1 0/1 5 4 00 MH z)

 ό ":

 2.91 (2Η, t, J = 7 Hz),

 3.60 (2 H, d t, J = 6, 7 H Z),

5.1 2 (2 H, s) ₃

 6.97 (1 H, d d, J = 2, 9 H z),

 7. 0 2 (1 H, d, J = 2 H z),

 7.19-7.49 (10H, m),

8.08 (1 H ₃ brt, J = 6 H z),

 8. 1 9 (l H, d, J = 9 H z),

 8.8 2 (1 H, d, J = 3 H z),

 1 1.60 (1 H, b rs).

(3) 6-Benzyloxy-3- (2- (phenethylamino) ethyl) 6-Penzyloxy-3 in a suspension of lithium aluminum hydride (7 Omg, 1.8 mmo 1) in anhydrous THF (3 mL) —Indone-l-N-phenethylglycoxysilamide (244 mg, 0.612 mmo 1) was added, and the mixture was heated under reflux for 23 hours with stirring. After cooling in an ice bath, aqueous sodium sulfate was added until the reaction mixture separated into a clear solution and a solid, and the insolubles were filtered and washed with THF. The filtrate and the washing were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography (form: chloroform / methanol: 15/1) to give 7 l mg (31%) of the title compound as a brown oil.

_{^{1 H NMR (CD C 1 3}} , 40 0 MH z)

 6:

_{2. 0 7 (1 H 3 brs} ), 2.75 (2 H, t, J = 7 Hz)

2. 84-2.96 (6H ₃ m) ₅

 5.05 (2 H, s),

 6.75 (1 H, d, J = lHz)

 6. 8 1—6.88 (2H, m),

 7.07-7.47 (1 1 H, m)

 8.09 (1H, brs).

(4) 6-benzyloxy-3- 3- [2- (N-tert-butoxycarbonyl-N-phenethylamino) ethyl] indole

 6-Benzyloxy-3- (2- (phenethylamino) ethyl) Indole (71 mg, 0.19 mmo 1) in THF (1 mL) was added to water (1 mL) and triethylamine (53 L), followed by A solution of di-t-butyldicarbonate (50 mg, 0.23 mmo 1) in THF (1 mL) was added. After stirring at room temperature for 2 hours, water

(5 mL) and extracted twice with ethyl acetate. The extracts were combined, washed with a 10% aqueous solution of citric acid, water and saturated saline, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained residue was purified by flash column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a brown oil (59 mg)

(65%).

¹ H NMR (CD C 1 "400 MHz)

 ό ·:

 1. 4 1, 1.45 (9 Η, each br s)

 2.65—3.00 (4H, m),

 3.25-3.50 (4Η, m),

 5. 05 (2 H, s),

 6.75-6.90 (3H, m),

 7. 06— 7.50 (1 1 H, m),

8.06 (1 H ₅ brs). (5) 3- [2- (N-te rt-butoxycarbonyl-N-phenethylamino) ethyl] — 6-hydroxyindole

 6-benzyloxy 3- (2- (N-tert-butoxycarbonyl N-phenethylamino) ethyl) indole (59 mg, 0.13 mmo 1), 10% palladium on carbon (18 mg) and ethanol (2 mL) Was catalytically hydrogenated at room temperature and 1 atmospheric pressure for 23 hours. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (hexane / ethyl acetate = 3/2) to give the title compound as a tan oil (28 mg, 59 mg). %) Obtained.

_{^{1 H NMR (CD C 1 3}} , 400 MHz)

 δ:

 1.40, 1.46 (9Η, e a ch b r s)

 2. 6-3.0. (4 Η, m)

 3.2-3.6 (4H, m)

 5.9 (1 H, b r),

 6. 6—6.8 (3 H, m)

 7.0-7.5 (6 H, m)

 7.84 (1 H, b r s)

(6) 2-[3— [2— (N—t ert—butoxycarbonyl—N-phenethylamino) ethyl] India 6-yl] oxy-12-methylpropionate) _

 3- (2- (N-tert-butoxycarbonyl N-phenethylamino) ethyl] — 6-hydroxyindole (28 mg, 0.074 mmo 1) was used in the same manner as in Example 1 (5). The title compound was obtained as a yellow oil (19 mg, 52%). '

^J H NMR (CD C 1 ₃₅ 400 MHz)

 ό ":

 1.27 (3Η, t, J = 7 Hz),

1.38 ₅ 1.45 (9H, ea ch brs), 1. 5 8 (6 H, s),

 2.63-3.00 (4 H, m),

 3.25-3.52 (4 H, m),

 4.25 (2 H, q, J = 7 Hz),

 6.75 (1 H, d d, J = 2, 9 H z).

 6.82-6.96 (2 H, m),

 7.05—7.31 (5H, m),

 7.4.3 (1 H, b r),

 7.86 (1 H, b rs).

(7) 2-Methyl-1-2-[[3- [2- (phenethylamino) ethyl] indole-6-yl] oxy] ethyl propionate

 2— [3— [2- (N-tert-butoxycarbonyl N-phenethylamino) ethyl] indole-6-yl] oxy-1-ethyl 2-methylpropionate (19 mg, 0.03 To a solution of 8 mmo 1) in ethyl acetate (0.3 mL) was added 4 M hydrogen chloride Z-dioxane solution (0.3 mL). After stirring at room temperature for 1.5 hours, saturated aqueous sodium hydrogen carbonate (6 mL) and ethyl acetate (6 mL) were added to the reaction mixture, the organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 15 mg (100%) of the title compound as a yellow oily substance.

1 H NMR (CD C ₁₃₃ 4 00 MHz)

 δ:

 1.28 (3 Η, t, J = 7 Hz),

 1.59 (6 H, s),

 1. 6 9 (1 H, b r s),

 2.78 (2H, t, J = 7Hz),

 2. 8 7— 2. 9 9 (6 H, m),

 4.26 (2 H, q, J = 7 H z),

6. 74 (1 H, dd ₃ J = 2, 9 H z),

6.85 (l H, d, J = 2 H z), 6.87 (1 H, d, J = 2 H z),

 7.10-7.27 (5H, m),

 7.42 (1 H, d, J = 9 H z),

 7.83 (1 H, b rs).

(8) 2— [3— [2 — [[3 -— (2,3-Dichlorophenyl) -1-1-phenyl] ゥ Reid] ethyl] Etil

 Example 1 (2-methyl-1-[[3- [2- (phenylethylamino) ethyl] indole-6-yl] oxy] ethyl propionate (16 mg, 0.038 mmo 1) In the same manner as in 7), 18 mg (80%) of the title compound was obtained as a pale yellow oil.

_{^{1 H NMR (CD C 1 3}} , 4 0 0 MH)

 δ:

 2 7 3 Η t, J = 7 Η ζ),

 5 9 6 Η s)

 2 9 1 2 Η t, J = 8 Hz)

 3 0 3 2 Η t, J = 7 H z)

 3 5 2 2 Η t, J = 8 H z)

 3 5 7 2 Η t, J = 7 H z)

 4 2 6 2 Η q, J = 7 Hz)

 6 7 8 1 Η d d, J = 2, 9 H z),

 6 8 8 1 Η d, J = 2 H z),

 6 9 4 2 Η b r s),

 7 0 6 7. 3 3 (7 H, m),

 7 4 3 1 Η d, J = 9 Hz),

 7 9 1 1 Η b r s),

8 1 5 1 Η dd, J = 1 ₃ 8 Hz). (9) 2-C 3-[2-[[3-(2,3-dichloro-phenyl) 1-1-phenyl] ゥ raido] ethyl] indole-6-yl] oxy-2-methylpropionic acid

 2 -— [3 -— [2-[[3- (2,3-dichlorophenyl) -1-1-phenyl] -reido] ethyl] indole-6-yl] oxy-1-ethyl 2-methylpropionate (18 mg, 0 Using 0.33 mmo 1), 16 mg (92%) of the title compound was obtained as pale yellow-brown crystals in the same manner as in Example 1 (8).

_{1 H NMR (CD C 1 3} , 40 0MH z)

 δ:

 1. 5 7 (6 Η, s),

 2.92 (2 Η, t, J = 8 Hz),

 3. 0 5 (2Η, t, J = 7Hz),

 3.5 3 (2 Η, t, J = 8 Hz),

 3.5 8 (2 Η, t, J = 7 Hz),

 6.83 (1 Η, d d, J = 2, 9 H z),

 6. 9 1 (1 Η, b r s),

 6.96 (1 Η, d, J = 2 Hz),

 7. 0 1 (1 Η, d, J = 2 Hz),

 7.09 (1 Η, d d, J = 1, 8 Hz),

 7. 1 2--7. 3 3 (6 Η, m),

 7.5 0 (1 H, d, J = 9 H z),

 7.95 (1 H, b r s),

 8.1 4 (1 H, d d, J = l, 8 H z).

 2_ [1— “2— [“ 3— (2,4-dichloropheninole) • propyl] ureido perethyl] India:

-Ru-5-yl] oxy-2-methylpropionic acid The title compound was obtained in the same manner as described in Example 1. Light brown amorphous

One _{NMR (CDC1 3, 400MHz) δ} :

 0.83 (3Η, t, J = 7Hz),

 1.20-1.40 (2H, m),

 1.54 (6H, s),

 2.81 (2H, t, J = 7Hz),

 3.68 (2H, t, J = 7Hz),

 4.39 (2H, t, J = 7Hz),

 6.46 (1H, d, J = 3Hz),

 6.80 (1H, brs),

 6.88 (1H, dd, J = 2.9Hz),

 7.11 (1H, d, J = 3Hz),

 7.23 (1H, d, J = 2Hz),

 7.25 (1H, dd, J = 2, 9Hz),

 7.31 (1H, d, J = 9Hz),

 7.35 (1H, d, J = 2Hz),

 8.20 (1H, d, J = 9Hz). Example 10

 2— [1— [2 — [[3- (2,6-Dichroic phenol) -1-isobutyl] ureido] ethyl] indole—5-yl] oxy-1-2-methylpropionic acid The title compound was obtained in the same manner as described in 1.

 Light brown amorphous

400MHz) δ:

 0.84 (6Η, d, J = 7Hz),

 1.55 (6H, s),

 1.86 (1H, m),

2.65 (2H, d, J = 7Hz), 3.70 (2H, t, J = 6Hz),

 4.42 (2H, t, J = 6Hz),

 6.00 (1H, brs)

 6.46 (1H, d, J = 3Hz),

 6.89 (1H, dd, J = 2, 9Hz),

 7.12 (1H, d, J = 8Hz),

 7.15 (1H, d, J = 3Hz),

 7.23 (1H, d, J = 2Hz),

 7.3—7.4 (3H, m)

Light brown amorphous Example 11

 2- [1- [2 _ [[1-Isobutyl-3- (2-methoxyphenyl)] perido] ethyl] indole 5-yl] oxy-1-methylpropionic acid By a method similar to that described in Example 1. The title compound was obtained.

 Slightly yellow amorphous

_{- NMR (CDC1 3, 400MHz)} δ:

 0.83 (6Η, d, J = 7Hz),

 1.54 (6H, s),

 1.82 (1H, m),

 2.61 (2H, d, J = 7Hz),

 3.68 (2H, t, J = 7Hz),

 3.85 (3H, s),

 4.40 (2H, t, J = 7Hz),

 6.45 (1H, d, J = 3Hz),

 6.8-6.9 (2H, m),

 6. 9-7.0 (2H, m),

7.04 (1H, brs), 7.12 (1H, d, J = 3Hz),

 7.22 (1H, d, J = 2Hz),

 7.34 (1H, d, J = 9Hz),

 8.1 1—8.2 (1H, m).

 2-"-[1- [2-[[1-Isobutyl] -3- (2-^-f-propylphenyl)] ureido] ethyl] indole-5-yl] oxy-1-2-methylpropionic acid The title compound was obtained in a similar manner.

 Light brown crystal

aH-NMR (CDCl ₃ , 400 MHz) δ:.

 0.83 (6Η, d, J = 7Hz),

 1.24 (6H, d ,, J = 7Hz),

 1.54 (6H, s),

 1.80 (1H, m),

 2.58 (2H, d, J = 7Hz),

 2.92 (1H, dq, J = 7Hz, J = 7Hz),

 3.69 (2H, t, J = 7Hz),

 4.40 (2H, t, J = 7Hz),

 6.01 (1H, brs),

 6.45 (1H, d, J = 3Hz),

 6.88 (1H, dd, J = 2.9Hz),

 7.11 (1H, d, J = 3Hz),

 7.15— 7.30 (4H, m)

 7.34 (1H, d, J2 9Hz),

7.57 (1H, dd, J = l, 8Hz). Example of 2- [l- [2-[[3- (2,4-dichlorophenyl) -1-1-isobutyl-3-methyl] ureido] ethyl] indole-5-yl] oxy-12-methylpropionic acid The title compound was obtained in the same manner as described in 1.

 Pale yellow crystal

One NMR (CDC1 _3, 400MHz) δ

 0.74 (6Η, d, J = 7Hz),

 1.56 (6H, s),

 1.75 (1H, m),

 2.57 (2H, d, J = 7Hz),

 3.01 (3H, s),

 3.52 (2H, t, J = 7Hz),

 4.21 (2H, t, J = 7Hz),

 6.44 (1H, d, J = 3Hz),

 6.88 (1H, d, J = 8Hz),

 6.90 (1H, dd, J = 2, 8Hz)

 6.98 (1H, dd, J = 2, 8Hz)

 7.07 (1H, d, J = 3Hz),

 7.23 (1H, d, J = 2Hz),

 7.28 (1H, d, J = 8Hz),

 7.44 (1H, d, J = 2Hz). Example 14

 (Pharmacological experiment)

I. Measurement method

 (1) Measurement of P PAR 5 activation

Test compounds [Examples 2, 3, 4, 6 and 7 and known PPAR agonist L-165041 (Berger ₃ J. et al., (1999) J. Biol. Cem., 274: 6718- 6725)] of PPAR (5 It was measured.

1) Material

 African green monkey kidney fibroblasts (〇-1 cells) were obtained from Senyuichi Medical Cell Resource Center, Tohoku University Aging Medicine Laboratory. All test compounds were dissolved in dimethyl sulfoxide (DMSO) and final; used in the test at a DMSO concentration of 0.1%.

2) Plasmid

 Receptor expression plasmid (GAL 4— hPPARS LBD), luciferase expression plasmid (UASX 4— TK— LUC), and ^ —galactosidase expression plasmid (GAL) are Klieware, SA and others. ((1992) Natur II, 358: 771-774).

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 added with 4% fetal bovine serum (FCS) for 24 hours. 0 PTI—MEM I Reduced Se rum Medium Life technologies) 5001 / we11. After that, wash the cells with 0 PTI-MEM without serum and add the following components per DNA-containing solution [1 µl (250 µl added solution); 0.03 µg of GAL 4-hPP AR5 LBD , 0. 25 g UASx4—TK—LUC, 0. /? GAL, and

2〃1 lipofection reagent DMR IE-C (Lift 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

Remove the DNA-containing solution, replace with a 4% FCS-SPTI-MEM 500〃1 containing the test compound (dissolved in 100% DMSO to a final concentration of 10 ： ^5— ), and replace with another 40%. Incubated at 37 ° C for hours.

5) Measurement of gene level of repo overnight The medium was removed, washed twice with PB S, performed once freezing and thawing, 1 per Uweru, Rushifuweraze activity measurement for solubilization buffer _{(25mM Tr i s-P0 4} (H 7. 8), 15% v / v Glys erol, 2% CHAPS , 1 L ecithin, 1% BSA, 4mM E GT a (pH 8. 0), with the addition of _{8 mM Mg C 1 2, ImM} DTT) 10 OI, left for 10 minutes at room temperature did. Twenty-one of them are dispensed into a 96-well plate for measurement, and luciferase substrate solution 1001 (Pi Force Gene; manufactured by Nippon Gene Co., Ltd.) is added thereto. The amount of luminescence per second (luciferase activity) was determined using an electric company. The expression level of the activity due to the introduction of GAL into the cells, which was added simultaneously with the addition of the luciferase gene, was measured, and the change in luciferase activity due to the addition of the compound was corrected by the transfection efficiency of the transgene. ^ The method for measuring galactosidase activity is as follows. One hundred and fifty solubilized samples are collected on another 96-well plate, and the ONPG (2-nitrophenyl-15-D-galactobilanoside) solution 100 1 was added and incubated at room temperature for 5 minutes. A reaction stop solution (1M sodium carbonate solution) 50/1 was added, and the absorbance at 414 nm was measured. Rushifuwera Ichize activity of DM SO (0. 1% concentration) only treated cells that had use as solvent (Control value) 0%, fine treated with control drug (10- ⁴ M of L-165041) The relative ligand activity was calculated with the luciferase activity value of the vesicle as 100%.

I. Test results

Table 14 shows the test results 76

[Table 14]

(P PAR activity 1 0 ⁴ Kino relative value and defined as 100% L 6 504 1 activity in M) Example 2: 2- [1- [2 - [[3- (2, 3-dichloro Phenyl) 1-phenylene] -reido] ethyl] indrin-5-yl-2-oxy-2-methylpropionic acid Example 3: 2-[1-[2-[[3-(2,3-dichlorophenyl) 1-Soptyl] ureido] ethyl] indole-5-yloxy-2-methylpropionic acid Example 4: 2-[1— [2 — [[3- (2,4-dichlorophenyl) —] 1-Soptyl] 'ゥ Reid] Ethyl] indole-5-yl] oxy-2-methylpropionic acid Example 6: 2— [1— [2 — [[1—butyl—3— (2,3— Diclo mouth)) [Reid] ethyl] India 1-5-yl] Oxy-12-methylpropionic acid Example 7: 2— [1— [2 — [[3 -— (2,3-dichlorophenyl) —1-soptyl] perylene] ethyl] indolin-5-yl] oxy-1-2-methylpropionic acid Example 9: 2- [1-1- [2-[[3- (2,4-dichloromethyl) -1-1-propyl] ureido] ethyl] indole-5- ^ fur] oxy-1--2-methylpropionic acid As is evident from Table 14, it was found that the compound of the example exhibited a stronger or more potent PPAR3 activating effect than L-1655041.

Claims

The scope of the claims

1. The following general formula (I),

(I)

(In the formula, Y represents an oxygen atom or a sulfur atom,

η represents an integer from 0 to 4,

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 1 to 3 halogen atoms;

 W is a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a sulfonic acid group

Represents a phosphonic acid group, a cyano group, or a tetrazolyl group;

A double line consisting of a solid line and a broken line represents a single bond or a double bond,

And one of R ^a , R ^b and R ^e is a group represented by the following general formula (II), and the other two are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, and a carbon atom. An aryl group or an arylalkyl group of the number 6 to 10 (the aryl moiety has 6 to 10 carbon atoms, and the alkyl moiety has 1 to 8 carbon atoms).

R ² 0 R ³

R ¹ -NCNX- (II) wherein I ¹ , R ² and R ³ are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, and 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. An alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, substituted with an alkoxy group having 1 to 8 carbon atoms. 3 to 7 cycloalkyl groups, 1 to 8 carbon atoms substituted with a 3 to 7 cycloalkyl alkyl group, 6 to 10 carbon atom aryl group, aryl alkyl group (

73

Corrected form (Rule 91) The aryl moiety has 6 to 10 carbon atoms, the alkyl moiety has 1 to 8 carbon atoms, a heterocyclic group, or a heterocyclic alkyl group (the alkyl moiety has 1 to 8 carbon atoms), X represents an alkylene chain having 1 to 8 carbon atoms.

In the above R ^a , R ^b and IT, the aryl part of the aryl group and the arylalkyl group, and the heterocyclic part of the heterocyclic group and the heterocyclic alkyl group are an alkyl group having 1 to 8 carbon atoms, Alkyl group having 1 to 8 carbon atoms, alkoxy group having 1 to 8 carbon atoms, alkoxycarbonyl group having 2 to 8 carbon atoms, acyl having 2 to 8 carbon atoms substituted with 3 halogen atoms Group, formyl group, hydroxyl group, halogen atom, nitro group, cyano group, amino group, alkylamino group (the alkyl group has 1 to 8 carbon atoms), dialkylamino group (the alkyl group has 1 to 8 carbon atoms) ), A phenyl group, or a substituted phenyl group. )

 Or a salt thereof represented by the formula:

2. A group R ^a is represented by the general formula (II), R ^b and R ^e is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, Ariru group having a carbon number of 6-1 0, or Ariru 2. The perylene derivative according to claim 1, which is an alkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkyl moiety has 1 to 8 carbon atoms), or a salt thereof.

 3. The paraderivative according to claim 1 or 2, wherein W is a carboxyl group or an alkoxycarbonyl group having 2 to 8 carbon atoms, or a salt thereof.

4. The urea derivative according to claims 1 to 3, wherein R ² is a hydrogen atom, or i-plate o

 5. The following general formula (I I I),

(In the formula, Y ^fl represents an oxygen atom or a sulfur atom,

R ⁸ and R ⁹ represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,

R represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, A double line consisting of a solid line and a broken line represents a single bond or a double bond,

R ⁶ and R ⁷ are an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or an alkoxy group having 1 to 8 carbon atoms. Alkyl group having 1 to 8 carbon atoms, alkenyl group having 2 to 8 carbon atoms, alkynyl group having 2 to 8 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, 3 to carbon atoms An alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms substituted with a cycloalkyl group (7 to 10 carbon atoms in the aryl group) Wherein the alkyl moiety represents 1 to 8 carbon atoms, a heterocyclic group, or a heteroalkyl group (the alkyl moiety has 1 to 8 carbon atoms),

And X. Represents an alkylene chain having 1 to 8 carbon atoms.

In the above R ⁶ and R ⁷ , the aryl moiety of the aryl group and the arylalkyl group, and the heterocyclic moiety of the heterocyclic group and the heterocyclic alkyl group are an alkyl group having 1 to 8 carbon atoms, and 1 to 3 halogen atoms. C1-C8 alkyl group, C1-C8 alkoxy group, C2-C8 alkoxycarbonyl group, C2-C8 acyl group, formyl group, hydroxyl group substituted with an atom , Halogen atom, nitro group, cyano group, amino group, alkylamino group (alkyl group has 1 to 8 carbon atoms), dialkylamino group (alkyl group has 1 to 8 carbon atoms), phenyl group or substitution Fuweniru group (the substituent is a halogen atom, carbon atom 1 to ^8:. alkyl group, or selected from an alkoxy group having carbon atom number 1-8 in) may have a substituent group selected from. )

 Or a salt thereof represented by the formula: .

6.R ⁶ is an alkyl group having 1 to 8 carbon atoms as a substituent, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms, C2 to C8 acyl group, hydroxyl group, halogen atom, nitro group, amino group, alkylamino group (alkyl group has 1 to 8 carbon atoms), dialkylamino group (alkyl group has 1 to 8) a phenyl group, a naphthyl group, a phenyl group, a phenyl group, a phenyl group, a thienyl group, a thiazole group, a thiazolyl group, an oxazolyl group, a pyridyl group, an imidazolyl group, a quinolyl group, or an indolyl group, which may have an atom. Or the benzoyl group, or a benzofuranyl group. Is its salt.

7. R ⁷ is an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms as a substituent, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. An alkoxy group having 1 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, a hydroxyl group, a halogen atom, a nitro group, an amino group, an alkylamino group (the alkyl group has 1 to 8 carbon atoms), or A phenylalkyl group (the alkyl portion has 1 to 8 carbon atoms) which may have a group or atom selected from a dialkylamino group (the alkyl group has 1 to 8 carbon atoms). Item 6. The dielectric conductor according to Item 5 or 6, or a salt thereof.

 8. The urea derivative according to claims 5 to 7, wherein the double line consisting of a solid line and a dashed line is a double bond, or a salt thereof.

 9. The rare earth derivative or the salt thereof according to claim 5, wherein a double line consisting of a solid line and a broken line is a single bond.

 10. The urea derivative according to claims 5 to 9, wherein R is a carboxyl group, or a salt thereof.

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