JP2001039948A - 3,7-disubstituted indole derivative and pharmaceutical composition containing the derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound consisting of a specific disubstituted indole derivative and useful as pharmaceuticals especially having β3 adrenaline receptor stimulating action. SOLUTION: The objective compound is expressed by formula I [X is O, NH or the like; R1 is hydroxy or the like; R2 and R3 are each H or a lower alkyl; R4 is H or OR7 (R7 is H, a lower alkyl or the like); R5 is H, a halogen or the like; R6 is H, a lower alkyl or the like; and (n) is 1-5], e.g. 3- (2R)-2-[3-(4 hydroxyphenoxy)-(2S)-2-hydroxypropylamino]propyl}indol-7yloxyacetic acid N,N-diethylamide. 1/2 oxalate. 1/2 hydrate of formula II. The compound of formula I can be produced by the addition reaction of a compound of formula III with the compound of formula IV. The reaction temperature is preferably 25-100 deg.C. The solvent to be used in the reaction is methanol, etc., and the reaction is carried out in the presence of a base such as sodium bicarbonate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a medicament, particularly to a novel 3,7-disubstituted indole derivative having a β ₃ adrenergic receptor stimulating action and a pharmaceutical composition containing the same.

[0002]

2. Description of the Related Art Sympathetic β-adrenergic receptors include β
It is known that there are three subtypes of ₁ , β ₂ and β ₃ . beta _1-adrenergic receptor agonists are useful as cardiac function enhancers or vasopressors, beta ₂ adrenergic receptor agonists are useful as bronchodilator, it is currently used, respectively clinical.

The β ₃ adrenergic receptor isolated as a _third subtype [Emorine, LJ et al .: Science, 245 ,
1118-1121 (1989)] is considered to have a function of degrading lipids of white adipose tissue attached to subcutaneous and internal organs and producing heat by being present in brown adipocytes. Thus, beta ₃ adrenergic receptor has been suggested association with one of the causes of obesity, also relevant to the pathogenesis of non-insulin dependent diabetes mellitus has also been reported.

[0004] β_ThreeAdrenergic receptor agonist β₁Or β
_TwoAlso acts as a side effect
Since tremor and the like may be expressed, β_ThreeAdrenaline
Β to develop receptor agonists_ThreeReceptor stimulating action
Is powerful, and β₁And β_TwoDoes not stimulate receptors
Or a compound that has a low degree of stimulation
ing. In the present specification, β_ThreeReceptor stimulating action
Is strong and β₁Or β _TwoNature with large deviation from the action of
Are expressed as "compounds with excellent selectivity".
Sometimes.

[0005] As a drug that stimulates β ₃ adrenergic receptor, for example, WO 98/03485 discloses
Are described.

[0006]

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Wherein R ₁ is a C _3-7 alkyl group or C _3-7
Represents a cycloalkyl group, R ₂ represents a hydrogen atom or an electron accepting group, and Alk represents a C _2-3 alkylene group. )

[0008] WO 96/16938 discloses that
Indole derivatives such as 2- [3- (7-methoxyindol-3-yl) -2-propylamino] -1- (3-chlorophenyl) ethanol represented by the following formula 3 are described. It is described as having a beta ₃ adrenergic receptor stimulating effect.

[0009]

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Further, US Pat. No. 4,806,655 discloses that
An indole derivative represented by the following chemical formula 4 has been described.
These compounds have an effect on the cardiovascular system,
α, β ₁And β_TwoDescribed as having an adrenergic effect
Have been. However, β _ThreeAdrenergic receptor
No effect is described or suggested.

[0011]

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(Wherein the C ^* atom is in the (R) or (S) configuration, X ₁ and X ₂ are each independently a hydrogen atom or lower alkyl, R ₁ and R ₂ are each independently a hydrogen atom Or a halogen atom, lower alkyl, lower alkoxy or formyl, or R ₁ and R ₂ together with the benzene ring to which they are attached represent an optionally substituted bicyclic nucleus; R ₃ and R ₄ each independently represent a hydrogen atom, a halogen atom, a lower alkyl or a lower alkoxy.)

Further, GB2141121 discloses that an indole derivative represented by the following formula (5) is useful as an antihypertensive agent due to a combination of an adrenergic receptor blocking and vasodilatory activity. This means that it has β ₁ and β ₂ adrenergic effects. However, no or suggested described at all action on beta ₃ adrenergic receptor.

[0014]

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Wherein _one of R ₁ and R ₂ is hydrogen;
And the other is hydrogen or C _1-4 alkyl; R ₃ and R
₄ is independently selected from hydrogen or C _1-4 alkyl; R ₅
Is halogen, hydrogen, hydroxy, or C _1-4 alkyl; the phenoxypropanol aminoalkyl side chain is attached to the indole ring at the 2- or 3-position; and the hydroxyl substituent is
It occupies the-, 5-, 6- or 7-position. )

[0016]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel 3,7-disubstituted indole derivative having excellent selectivity and a strong β ₃ adrenergic receptor stimulating action, and a salt thereof.

[0017]

The present invention provides a compound represented by the following formula [I]:
And a physiologically acceptable salt thereof.

[0018]

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Wherein X represents O, NH or S;
¹ is a hydroxy group, lower alkoxycarbonyl group, mono- or di-lower alkylaminocarbonyl group, carbamoyl group, cyclic aminocarbonyl group, carboxyl group, sulfamoyl group, mono- or di-lower alkylaminosulfonyl group, cyclic aminosulfonyl group, sulfonic acid group ,
Sulfonic acid ester group, phosphoric acid group, phosphoric acid ester group or substituted or unsubstituted phenyl group (the substituent is a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a nitro group) Group, a cyano group, an amino group and a mono- or di-lower alkylamino group.

R ² and R ³ are the same or different and each represents a hydrogen atom or a lower alkyl group; R ⁴ represents a hydrogen atom or OR ⁷ , wherein R ⁷ is a hydrogen atom, a lower alkyl group, a substituted or unsubstituted group; Substituted benzyl group (the substituent is selected from a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a nitro group, a cyano group, an amino group and a mono- or di-lower alkylamino group One or two types) or a lower alkanoyl group,

R ⁵ is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, a nitro group,
A cyano group, an amino group, a mono- or di-lower alkylamino group, a lower alkylsulfonylamino group or a lower alkylsulfonyl group, wherein R ⁶ is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, a nitro group; , Cyano group, amino group, formylamino group, phenylsulfonylamino group, mono- or di-lower alkylamino group, lower alkylsulfonylamino group or lower alkylsulfonyl group;
3, 4 or 5 is meant. ]

Physiologically acceptable salts mean physiologically acceptable acid addition salts, alkali metal salts, alkaline earth metal salts or salts with organic bases. Specifically, the acid addition salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and the like, oxalate, maleate, fumarate , Malonate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, gluconate and the like. Examples of the alkali metal salt include inorganic alkali salts such as sodium salt and potassium salt, examples of the alkaline earth metal salt include calcium salt and magnesium salt, and examples of the salt with an organic base include: For example, salts with ammonia, methylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, and dicyclohexylamine can be mentioned.

The compound represented by the formula [I] and a physiologically acceptable salt thereof may exist in the form of a hydrate or / and a solvate. The solvates are also included in the compounds of the present invention.

The compound represented by the formula [I] has one or two asymmetric carbons. That is, when the carbon atom to which the hydroxy group is bonded is an asymmetric carbon, and when R ² and R ³ are different groups, the carbon atom to which these groups are bonded is also an asymmetric carbon. Therefore, when R ² and R ³ are the same atom or group in the formula [I], there are two stereoisomers, and when R ² and R ³ are different groups, there are four stereoisomers. Can. These stereoisomers and mixtures are also included in the compounds of the present invention.

The terms used in this specification are described below.
The “lower alkyl group” and the “lower alkyl” portion mean a straight or branched alkyl group having 1 to 4 carbon atoms, and specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and sec. -Butyl and tert-butyl.

The "lower alkoxy group" and the "lower alkoxy" moiety mean a straight or branched chain alkoxy group having 1 to 4 carbon atoms, and specific examples include methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy.

"Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
A chlorine atom and a bromine atom are preferred.

The term "cyclic amino" refers to a 5- or 6-membered cyclic amine containing at least one nitrogen atom and optionally containing an oxygen atom, and specific examples include pyrrolidine, piperidine, morpholine and the like. Is mentioned.

"Lower alkanoyl group" means a straight or branched alkanoyl group having 1 to 5 carbon atoms, and specific examples include formyl, acetyl, propionyl, butyryl,
Isobutyryl, valeryl and pivaloyl.

The compounds of the present invention are represented by the general formula [I], and preferred are those represented by the following general formula [Ia] wherein X is O

[0031]

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(In the formula, R ^{1 to} R ⁶ and n are the same as described above.)
And a physiologically acceptable salt thereof.

More preferred compounds are those of the formula [Ia] wherein R ¹ is a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a cyclic aminocarbonyl group, a carboxyl group, a sulfamoyl group, a mono- or di-lower alkylaminosulfonyl group. A cyclic aminosulfonyl group, a sulfonic acid group or a substituted or unsubstituted phenyl group (the substituent is a halogen atom, a trifluoromethyl group,
One or two selected from a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a nitro group, a cyano group, an amino group and a mono- or di-lower alkylamino group), and R ² and R ³ is the same or different and is a hydrogen atom, a methyl group or an ethyl group;
A compound wherein R ⁴ is a hydrogen atom or OR ⁷ , R ⁷ is a hydrogen atom, a methyl group, a benzyl group or a lower alkanoyl group, and n is 1, 2 or 3, or a physiologically acceptable salt thereof; .

Further, the compounds of the present invention in which R ² and R ³ are different groups in the formulas [I] and [Ia] have two asymmetric carbon atoms and therefore have four kinds of stereoisomers. However, a compound in which the configuration of the carbon atom to which the hydroxy group is bonded is S-configuration, and the configuration of the carbon atom to which R ² and R ³ are bonded is R-configuration is particularly preferable.

Specific examples of the most preferred compounds include the following compounds and their stereoisomers or physiologically acceptable salts thereof. 3- [2- (3-phenoxy-2-hydroxypropylamino) propyl] indole-7-
Iloxyacetic acid, 3- [2- (3-phenoxy-2-hydroxypropylamino) propyl] -7-benzyloxyindole, 3- [2- (3-phenoxy-2-hydroxypropylamino) propyl] indole-7-
Methyl yloxyacetate, 3- [2- [3- (4
-Hydroxyphenoxy) -2-hydroxypropylamino] propyl] -7-benzyloxyindole, 3
-[2- [3- (4-hydroxyphenoxy) -2-hydroxypropylamino] propyl] -7-[(4-methoxycarbonylphenyl) methoxy] indole, 3
-[2- [3- (4-hydroxyphenoxy) -2-hydroxypropylamino] propyl] -7-[(4-carboxyphenyl) methoxy] indole, 3- [2-
[3- (4-hydroxyphenoxy) -2-hydroxypropylamino] propyl] indole-7-yloxyacetic acid, 3- [2- [3- (4-hydroxyphenoxy) -2-hydroxypropylamino] propyl] indole- 7-yloxyacetic acid-N, N-diethylamide, 3- [2- [3- (4-hydroxyphenoxy)-
2-hydroxypropylamino] propyl] indol-7-yloxyacetic acid methyl ester and 3- [2-
[3- (2-Chlorophenoxy) -2-hydroxypropylamino] propyl] indol-7-yloxyacetic acid.

Specific examples of the compounds contained in the compounds of the present invention include the compounds shown in Tables 1 and 2 below and the physiologically acceptable salts thereof, in addition to the compounds of the following Examples.

[0037]

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[0038]

[Table 1]

[0039]

[Table 2]

Tables Note) In Tables 1 and 2, the following abbreviations are used for simplification of the description.

Et: ethyl group, Ph: phenyl group. In R ¹ , for example, Ph-4-COOH refers to the phenyl group 4
In R ⁶ , for example, 3-OH means an OH group substituted at the 3-position of a phenyl group.

The method for producing the compound of the present invention is described below. The compound of the present invention can be produced according to the method described in US Pat. No. 4,806,655 or by the following production methods 1 and 2.

Production method 1 : The compound of the present invention represented by the formula [I] is prepared by the following formula [II]

[0044]

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(Wherein R ⁴ , R ⁵ and R ⁶ are the same as described above) and the following formula [III]

[0046]

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(Wherein R ¹ , R ² , R ³ , X and n are the same as those described above), and can be produced by an addition reaction.

The reaction temperature varies depending on the kind of the starting compound used and the like, but is usually about 20 ° C. to about 150 ° C., preferably about 25 ° C.
C to about 100C. The reaction between the compound of the formula [II] and the compound of the formula [III] is carried out in a suitable solvent or without a solvent.
The solvent to be used is appropriately selected according to the type of the raw material compounds, etc., but alcohols such as methanol, ethanol, isopropyl alcohol, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as methylene chloride and chloroform, diethyl ether, Examples thereof include ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, ethyl acetate, dimethylformamide, dimethylsulfoxide, and acetonitrile. These solvents may be used alone or as a mixture of two or more.

The compound of the formula [III] used in this reaction can be used in the form of an acid addition salt. As acid addition salts,
Inorganic acid salts such as hydrochloride and hydrobromide, and organic acid salts such as oxalate, maleate and fumarate are exemplified. When such a salt is used or when R ¹ is a carboxyl group in the compound of the formula [III], the reaction is carried out in the presence of a base, and sodium bicarbonate,
Alkali bicarbonate such as potassium bicarbonate, sodium carbonate,
Alkali carbonate such as potassium carbonate or triethylamine, tributylamine, diisopropylethylamine,
Organic bases such as N-methylmorpholine are exemplified.

In the present production method, when the starting compounds [II] and [III] have an asymmetric carbon, the configuration of the asymmetric carbon is retained in the product of the compound of the formula [I]. I have. For example, a racemic compound of formula (II)
And a compound of the formula [III] wherein R ² and R ³ are the same group to obtain a racemic compound of the formula [I] wherein R ² and R ³ are different groups. The compound of formula [I], which is a mixture of diastereomers, is obtained from the compound of formula [III]. Formula (II) having a specific configuration
From the compound of the formula [III] and the compound of the formula [III], a compound of the formula [I] in which the configuration is maintained can be obtained.

The enantiomer of the compound of the formula [II] is Kl
under, JM et al. [J. Org. Chem., 54 , 1295-1304]
(1989)] or the method according to Reference Example 1 described later. Enantiomers of the compound of formula (III) are described, for example, in Repke, DB and Ferguson, W.
J. Method [J. Heterocycl. Chem., 13 , 775-778 (197
6)].

Compound 4 in which at least one of R ^{2 and} R ³ in formula [III] is a hydrogen atom can be produced, for example, by the following production method (1A) or (1B).

[0053]

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(In the formula, R ^{2a ′} represents a hydrogen atom or a lower alkyl group, and R ¹ , X and n are the same as described above.)

Compound 4 can be produced by subjecting compound 1 and compound 2 to a condensation reaction in the presence of a base to give compound 3, followed by reduction.

As the base in the condensation reaction, alkali bicarbonate such as sodium bicarbonate and potassium bicarbonate, alkali carbonate such as sodium carbonate and potassium carbonate, or organic base such as triethylamine, tributylamine, diisopropylethylamine and N-methylmorpholine. No. The reaction temperature varies depending on the type of the starting compound used, but is usually about -15 ° C to about 150 ° C, preferably about 0 ° C to about 1 ° C.
00 ° C.

This reaction is carried out in a suitable solvent or without a solvent. The solvent to be used is appropriately selected depending on the kind of the raw material compounds and the like. For example, alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as methylene chloride and chloroform, tetrahydrofuran, dioxane and the like Examples include ethers, aromatic hydrocarbons such as benzene and toluene, ethyl acetate, dimethylformamide, dimethylsulfoxide, acetonitrile, and the like. These may be used alone or as a mixture of two or more.

In the reduction reaction from compound 3 to compound 4, a reducing agent capable of reducing a nitro group and a double bond at a time is used as a reducing agent, and examples thereof include lithium aluminum hydride and its alkoxy complex. This reduction reaction can also be performed by catalytic hydrogen reduction using palladium or Raney-nickel as a catalyst.

In this reaction, when a reducing agent is used, ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane, aromatic hydrocarbons such as benzene and toluene, and halogen hydrocarbons such as methylene chloride and chloroform are used as solvents. Etc. are used, and are appropriately selected depending on the type of the reducing agent. In the case of catalytic hydrogen reduction, alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene and toluene, acetonitrile,
Ethyl acetate, dimethylformamide and the like are used. The reaction temperature varies depending on the reduction method, but is usually about 0 ° C. to about 15 ° C.
0 ° C.

[0060]

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(In the formula, R ¹ , R ^{2a ′} , X and n are the same as described above.)

Compound 4 can also be produced by subjecting compound 5 and compound 6 to an addition reaction in a suitable solvent to give compound 7, followed by reduction.

The addition reaction is carried out in a suitable solvent, and may be carried out in the presence of a base. Examples of the base include sodium hydride, alkali alkoxides such as sodium methoxide and potassium tert-butoxide, alkyl magnesium halides (Grignard reagent) such as methyl magnesium chloride and ethyl magnesium bromide, n-butyl lithium,
Examples thereof include alkyllithium such as methyllithium, lithium dialkylamide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide. The reaction temperature varies depending on the type of the starting compound used or the type of the base used, but is usually about -10 ° C to about 180 ° C, preferably about 0 ° C to about 150 ° C.

The solvent to be used is appropriately selected depending on the kind of the starting compound and the kind of the base to be used.
Alcohols such as ethanol, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as diethyl ether and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, ethyl acetate and dimethyl Formamide, dimethyl sulfoxide, acetonitrile and the like can be mentioned.
These solvents are used alone or in combination of two or more.

The reduction reaction from compound 7 to compound 4 can be carried out under the same conditions as the reduction reaction from compound 3 to compound 4 in production method (1A).

Production method 2 : A compound in which at least one of R ^{2 and} R ³ in the formula [I] is a hydrogen atom is represented by the following formula [I
V]

[0067]

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(Wherein R ⁴ , R ⁵ and R ⁶ are the same as described above) and the following formula [V]

[0069]

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(Wherein, R ^{2 ″} represents R ² or R ³ described above. R ¹ , X and n are the same as those described above). -It can be produced in one step by a reduction reaction.

The reducing condition in this reaction is that only the imine moiety (compound of the formula [VI] to be described later) is reduced without affecting the carbonyl group, carboxyl group and benzyl group of other substituents. In the presence of a reducing agent or under conditions of catalytic hydrogen reduction.

Examples of the reducing agent include sodium cyanoborohydride, borane dimethylamine complex, borane trimethylamine complex, borane triethylamine complex, and borane pyridine complex. This reaction is carried out in a suitable solvent, and suitable solvents include alcohols such as methanol and ethanol. The reaction temperature is usually about 20
C to about 80C.

When this reaction is carried out under catalytic hydrogen reduction conditions,
As the catalyst, palladium, platinum oxide or the like is used. The reaction temperature is usually about 10 ° C. to about 25 ° C., and preferred solvents include alcohols such as methanol and ethanol.

In the formula [I], a compound in which at least one of R ^{2 and} R ³ is a hydrogen atom can be obtained by converting a compound of the formula [IV] and a compound of the formula [V] into a suitable solvent in the presence of a catalytic amount of an acid. Under the dehydration condensation reaction, once, the following formula (VI)

[0075]

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Where R ¹ , R ^{2 ″} , R ⁴ , R ⁵ , R ⁶ , X
And n are the same as above. ), And then reducing the product to produce the compound in two steps.

Examples of the acid in the condensation reaction include p-toluenesulfonic acid and pyridine salt of p-toluenesulfonic acid, and the solvent is preferably an aromatic hydrocarbon such as benzene and toluene. The reaction temperature is usually from about 80 ° C to about
150 ° C.

The reduction reaction can be performed under the same reducing conditions as described above. As a reducing agent, sodium borohydride is used in addition to the above-mentioned reducing agents.

In the compound of the present invention wherein R ¹ is a carboxyl group, a phenyl group substituted by a carboxyl group or a sulfonic acid group in the formula [I] produced by the above production methods 1 and 2, the corresponding R ¹ is lower. Alkoxycarbonyl group, carbamoyl group, mono- or dialkylaminocarbonyl group, cyclic aminocarbonyl group, sulfamoyl group,
It can also be produced by hydrolyzing a compound which is a mono- or dialkylaminosulfonyl group, a cyclic aminosulfonyl group or a phenyl group substituted by a lower alkoxycarbonyl group in a suitable solvent under acid or alkaline conditions.

As the acid, for example, a mineral acid such as hydrochloric acid, sulfuric acid, or hydrobromic acid is used, and as the alkali, for example, an alkali hydroxide such as sodium hydroxide or potassium hydroxide is used. The reaction temperature varies depending on the type of the raw materials and the like, but is usually about 10 ° C to about 200 ° C, preferably about 25 ° C to about 150 ° C. Examples of the solvent include alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone,
A mixed solvent of water and a solvent such as dioxane, acetonitrile, ethylene glycol, dimethylformamide, dimethylsulfoxide, dimethoxyethane, dioxane, diglyme is used.

In the compounds of the present invention wherein R ⁴ is OH in the formula [I], except that n = 1 and R ¹ is a substituted or unsubstituted phenyl group, the corresponding R ⁴ is OR
⁷ , R ⁷ is a substituted or unsubstituted benzyl group (the substituent is a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group,
A carboxyl group, a nitro group, a cyano group, an amino group, and a mono- or di-lower alkylamino group). . Hydrogenolysis is performed using palladium, palladium hydroxide, platinum oxide or the like as a catalyst, and is performed in the presence of hydrogen or a hydrogen donor such as ammonium formate or cyclohexene. The reaction temperature is usually about 10 ° C. to about 80 ° C., and preferred solvents include alcohols such as methanol and ethanol, ethyl acetate, and the like.
Acetonitrile, acetic acid, water, dimethylformamide and the like can be mentioned, and these solvents are used alone or in combination of two or more.

In the production methods 1 and 2, the substituent R ¹ , R ⁵ , R ⁶ or R ⁷ of the compound used contains an amino group, a carboxyl group, a hydroxy group, a sulfonic acid group or a phosphoric acid group. In such a case, the desired target compound can be efficiently produced by protecting the substituent with a commonly used protecting group in advance and removing the protecting group after the reaction.

The compounds produced in Production Methods 1 and 2 can be isolated and purified by conventional methods such as chromatography, recrystallization and reprecipitation.

The compounds of the present invention produced by the production methods 1 and 2 can be obtained in the form of a salt, a free acid or a free base depending on the reaction conditions. Or it can be converted to the free base form.

When the compound of the present invention or the starting compound produced by Production Methods 1 and 2 is a racemate or a mixture of diastereomers, a conventional method or
For example, each stereoisomer can be separated according to the method described in European Patent Application Publication No. 455006.

[0086]

[Pharmacological test] The effects of representative compounds of the present invention on human β-adrenergic receptor were examined.

A cell line highly expressing human β ₃ and β ₂ adrenergic receptors was prepared according to the method described in WO 96/16938.

Test Example : Human β-Adrenergic Receptor Stimulating Action

The cell line CHO / pKREX10-36, which highly expresses human β ₃ adrenergic receptor, was obtained by adding 10% fetal bovine serum, 11.5 μg / ml.
-Dulbe containing proline and 200 μg / ml G-418
After culturing in a cco medium for 3 days, the medium was removed, and the cells were detached by leaving still at 37 ° C. for 10 minutes in a phosphate buffered saline containing 0.5 mM EDTA. CHO / pK by centrifugation
REX10-36 cells were collected and 1 mM ascorbic acid and 1 mM 3
-Suspended in Hanks' balanced salt solution containing 1-isobutyl-1-methylxanthine (ICN Biomedicals) to about 2 × 10 ⁶ cells / ml. 100 µl of this suspension and the test compound were mixed in 500 µl of the same balanced salt solution, reacted at 37 ° C for 30 minutes, and then stopped by boiling for 5 minutes. After centrifuging the reaction solution, the amount of cyclic AMP in the supernatant was measured using cAMP EIA.
It was measured using the System (Amersham).

[0090] Further, instead of the highly expressing cell line CHO / pKREX10-36 human beta ₃ adrenergic receptor, the same operation using the human beta ₂ adrenoreceptor highly expressing cell line CHO / pKREX21-8, Sai The click AMP amount was measured.

When 10 ^-5 M (-)-isoproterenol was added or not added, the amount of cyclic AMP was 100
% And 0%, and the relative value of the maximum cyclic AMP amount when the compound of the present invention was added was calculated as the intrinsic activity (IA). Further, the concentration (EC ₅₀ ) that caused 50% cyclic AMP accumulation was calculated from the concentration-response curve of each compound by the least squares method. Table 3 shows the results.

[0092]

[Table 3]

Table ^* ) ^* means the compound of Example 1; ^**
(-)-Isoproterenol; ^*** Calculation not possible due to low intrinsic activity.

In this test, the EC ₅₀ value was low and I.
A. A high value compounds are evaluated with strong stimulatory effect on human beta ₃ or beta ₂ adrenergic receptors. Accordingly, as it is clear from Table 3, the present invention compound is observed a strong stimulatory effect on human beta ₃ adrenergic receptors, stimulating effect on human beta ₂ adrenergic receptor is not substantially observed.

From the above results, the compounds of the present invention are expected to be effective as human β ₃ adrenergic receptor agonists having excellent selectivity.

The compound of the present invention can be used as a β ₃ -adrenergic receptor agonist to prevent obesity, diabetes, hyperlipidemia, irritable bowel syndrome, acute or chronic diarrhea, pollakiuria, urinary incontinence, urinary calculus and the like. Useful as a therapeutic. Further, the compound of the present invention is also useful as an agent for ameliorating symptoms such as abdominal pain, nausea, vomiting, and upper abdominal discomfort associated with peptic ulcer, acute or chronic gastritis, biliary dyskinesia, cholecystitis and the like.

When the compound of the present invention is used as a β ₃ adrenergic receptor agonist, it may be administered orally, parenterally or rectally, but oral administration is preferred. The dose varies depending on the administration method, the patient's symptoms and age, the type of treatment (prevention or treatment), etc.
It is 20 mg / kg / day, preferably 0.05-10 mg / kg / day.

The compound of the present invention is usually administered in the form of a preparation prepared by mixing with a preparation carrier. As the pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, for example, lactose, glucose, mannitol, dextrin, starch,
Sucrose, magnesium metasilicate aluminate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, calcium carboxymethylcellulose, ion exchange resin,
Methylcellulose, gelatin, gum arabic, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, Examples include sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, nonionic surfactant, propylene glycol, water and the like.

Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, gels, injections and the like. These preparations are prepared according to a conventional method. In the case of a liquid preparation, it may be in the form of being dissolved or suspended in water or another appropriate medium at the time of use. Tablets and granules may be coated by a known method. In the case of an injection, a physiologically acceptable acid addition salt of the compound represented by the formula [I] is prepared by dissolving the same in water. Alternatively, a pH adjuster, a buffer or a preservative may be added.

These preparations contain 0.01% of the compound of the present invention.
As described above, the content can be preferably 0.05 to 70%. These formulations may also contain other therapeutically effective ingredients.

[0101]

The compound of the present invention has excellent selectivity and a strong β ₃ -adrenergic receptor stimulating action, and thus is useful as an agent for preventing and treating obesity and diabetes.

[0102]

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples. Compound elemental analysis, was identified by like hydrogen nuclear magnetic resonance absorption spectrum ⁽¹ H-NMR).

In the description of ¹ H-NMR, the following abbreviations are used for simplification.

J: coupling constant, s: singlet, d: doublet, dd: double doublet, t: triplet, q: quadruple, m: multiplet.

In the following reference examples, the following abbreviations may be used for simplification of the description.

Fmoc: 9-fluorenylmethoxycarbonyl group, Ala: alanine residue.

Reference Example 1 Production of (S) -3- (4-benzyloxyphenoxy) -1,2-epoxypropane

60 ml of dimethylformamide was added under ice-cooling and stirring.
After adding 1.6 g of sodium hydride (mineral oil), 7.21 g of p-benzyloxyphenol was added little by little. further
After stirring for 10 minutes, 7.77 g of (S)-(+)-glycidyl 3-nitrobenzenesulfonate was added little by little. After stirring at room temperature for 30 minutes, the reaction solution was poured into ice water and extracted with toluene. The organic layer was washed successively with water, an aqueous sodium hydroxide solution and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the residue, and the precipitated crystals were collected by filtration to obtain 7.72 g of the pale yellow title compound.

¹ H-NMR spectrum (CDCl ₃ , δppm): 2.73
(1H, dd, J = 5 Hz, J = 3 Hz), 2.88 (1H, dd, J = 5 H
z, J = 5 Hz), 3.33 (1H, m), 3.90 (1H, dd, J = 11 H
z, J = 6 Hz), 4.16 (1H, dd, J = 11 Hz, J = 3 Hz),
5.01 (2H, s), 6.80-6.96 (4H, m), 7.30-7.47 (5H,
m)

Reference Example 2 : Production of indole-7-yloxyacetic acid-N, N-diethylamide

7-hydroxyindole (13.3 g, 100 m
mol) in acetone (100 ml) solution, potassium carbonate (16.6 g),
Chloroacetic acid-N, N-diethylamide (16.5 g, 110 mmol)
And potassium iodide (1.66 g) were added and the mixture was refluxed for 3 hours. After cooling with ice, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. Chloroform (200 ml) and water (100 ml) were added to the residue and stirred. The chloroform layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, isopropyl ether (100 ml) was added to the residue, and the precipitated crystals were collected by filtration and dried to give 22 g of the title compound as colorless crystals. Melting point 121 ° C

¹ H-NMR spectrum (300 MHz, CDCl ₃ , δpp
m): 1.17 (3H, t, J = 7.1 Hz), 1.21 (3H, t, J = 7.
1 Hz), 3.34 (2H, q, J = 7.1 Hz), 3.44 (2H, q, J =
7.1 Hz), 4.80 (2H, s), 6.52 (1H, dd, J = 3.1 Hz,
J = 2.2 Hz), 6.68 (1H, d, J = 7.7 Hz), 6.99 (1H,
t, J = 7.9 Hz), 7.20 (1H, t, J = 2.7 Hz), 7.32 (1
H, d, J = 7.9 Hz), 9.49 (1H, s).

Reference Example 3 Production of (R) -3- (2-aminopropyl) indol-7-yloxyacetic acid-N, N-diethylamide oxalate

(First step) Fmoc-D-Ala-OH (4.67 g, 15
mmol), methylene chloride (50 ml) and dimethylformamide (0.08 ml) in a suspension at room temperature with stirring.
(1.40 ml, 16 mmol) was added dropwise, and the mixture was further stirred for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain an oil containing Fmoc-D-Ala-Cl, which was used for the next reaction without further purification.

(Second step) Indole obtained in Reference Example 2
7-yloxyacetic acid-N, N-diethylamide (2.46
g, 10 mmol) in methylene chloride (25 ml), the inside of the reaction system was purged with argon, cooled to -20 to -5 ° C, and treated with a 3 mol solution of methylmagnesium bromide / diethyl ether (1
1.7 ml, 35.1 mmol) was added dropwise. After completion of the dropwise addition, the mixture was further stirred at -20 ° C for 1 hour. After the reaction solution was cooled to -20 to -10 ° C, a solution of Fmoc-D-Ala-Cl obtained in the first step in methylene chloride (30 ml) was added dropwise, and the mixture was further stirred at -20 ° C for 3 hours. The temperature was raised to about 0 ° C, added to 5% hydrochloric acid (25 ml), and further stirred for 30 minutes. The organic layer was separated, washed with water (25 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and an oil containing (R) -3- [2- (9-fullerenylmethoxycarbonyl) amino] propionylindol-7-yloxyacetic acid-N, N-diethylamide 9.92
g was used in the next reaction without further purification.

(Third Step) To a mixed solution of the oil obtained in the second step in acetonitrile (40 ml) -2-propanol (2.3 ml) was added sodium borohydride (1.13 g, 3 ml) at room temperature with stirring.
(0 mmol) was added little by little, and the mixture was refluxed for 5 hours. After cooling the reaction solution to room temperature, methanol (80 ml) was added dropwise.
The reaction mixture was concentrated to dryness under reduced pressure. Chloroform in residue
(200 ml) and water (100 ml) were added and stirred. The organic layer was separated, washed with water (100 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 2-propanol (70
oxalic acid (0.9 g, 10 mmol).
-A solution of propanol (9 ml) was added. The precipitated crystals were collected by filtration and dried to give the title compound (1.35 g) as colorless crystals. Melting point 158-163 ° C

¹ H-NMR spectrum (300 MHz, CDCl ₃ , δpp
m): 1.04 (3H, t, J = 7.1 Hz), 1.15 (3H, d, J = 6.
8 Hz), 1.16 (3H, t, J = 7.1 Hz), 2.80 (1H, dd, J =
14.1Hz, J = 9.0 Hz), 3.02 (1H, dd, J = 14.1 Hz, J
= 5.1 Hz), 3.35 (1H, m), 3.30 (2H, q, J = 7.1 Hz),
3.39 (2H, q, J = 7.1 Hz), 4.90 (2H, s), 6.53 (1H,
d, J = 7.7 Hz), 6.89 (1H, t, J = 7.7 Hz), 7.14 (1
H, s), 7.15 (1H, d, J = 7.5 Hz), 11.09 (1H, s).

Reference Example 4 Production of (S) -3- (2-chlorophenoxy) -1,2-epoxypropane

5.0 ml of 2-chlorophenol was dissolved in 50 ml of dimethylformamide, and 2.38 g of 60% sodium hydride (mineral oil) was added little by little under ice-cooling and stirring. After further stirring for 15 minutes, 11.34 g of (S)-(+)-glycidyl 3-nitrobenzenesulfonate was added little by little. 2.5 at room temperature
After stirring for an hour, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to medium pressure silica gel column chromatography, eluted with hexane-ethyl acetate (20: 1, v: v), and the fraction containing the desired product was concentrated under reduced pressure (S) 5.51 g of a crude product of -3- (2-chlorophenoxy) -1,2-epoxypropane was obtained as a colorless oil.

Example 1 : 3-[(2R) -2- [3-
Production of (4-hydroxyphenoxy)-(2S) -2-hydroxypropylamino] propyl] indol-7-yloxyacetic acid-N, N-diethylamide 1/2 oxalate 1/2 hemihydrate

[0121]

Embedded image

(First step) (R) -3- (2-aminopropyl) indole-7- produced from Reference Example 3
To a solution of 1.79 g of iloxyacetic acid-N, N-diethylamide in 10 ml of ethanol, 1.26 g of (S) -3- (4-benzyloxyphenoxy) -1,2-epoxypropane was added.
The mixture was heated under reflux for 3 hours. After the reaction solution was concentrated to dryness under reduced pressure, the residue was subjected to medium pressure silica gel column chromatography, eluted with chloroform-methanol (20: 1, v: v), and the fraction containing the desired product was concentrated under reduced pressure. Te 3-[(2
R) -2- [3- (4-Benzyloxyphenoxy)-
(2S) -2-hydroxypropylamino] propyl]
1.38 g of indole-7-yloxyacetic acid-N, N-diethylamide were obtained as a brown oil.

¹ H-NMR spectrum (CDCl ₃ , δppm): 1.14
1.26 (9H, m), 2.73-2.93 (4H, m), 3.08 (1H, dd, J =
13.0, 6.2 Hz), 3.35 (2H, q, J = 7.1 Hz), 3.44 (2
H, q, J = 7.0 Hz), 3.87-3.95 (3H, m), 4.80 (2H, s),
5.01 (2H, s), 6.67 (1H, d, J = 7.7 Hz), 6.78-7.06
(6H, m), 7.22-7.43 (6H, m), 9.52 (1H, s)

(Second step) To a solution of 1.38 g of the above compound in 30 ml of methanol were added 0.32 g of ammonium formate and 0.2 g of 10% palladium on carbon, and the mixture was heated under reflux for 2 hours. After cooling to room temperature, the catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was subjected to medium pressure silica gel column chromatography, eluted with chloroform-methanol (20: 1, v: v), and the fraction containing the desired product was concentrated under reduced pressure. After dissolving the residue in 3 ml of ethanol, 0.22 g of oxalic acid was added, and the mixture was allowed to stand at about 4 ° C. for 16 hours.
The precipitated crystals were collected by filtration and dried to give the title compound (0.8 g) as white crystals. Melting point 149-151 ° C

¹ H-NMR spectrum (DMSO-d ₆ , δppm): 1.04
-1.19 (9H, m), 2.71 (1H, dd, J = 13.2, 8.8 Hz), 2.
85-3.05 (3H, m), 3.21 (1H, m), 3.31 (2H, q, J = 6.
9 Hz), 3.40 (2H, q, J = 6.9 Hz), 3.85 (2H, d, J =
5.1 Hz), 3.99 (1H, m), 4.89 (2H, s), 6.51 (1H, d, J
= 7.7 Hz), 6.67 (2H, d, J = 7.8 Hz), 6.74 (2H, d,
J = 7.8 Hz), 6.86 (1H, dd, J = 7.7 Hz, J = 7.7 H
z), 7.09 (1H, s), 7.15 (1H, d, J = 7.7 Hz), 10.96
(1H, s)

Example 2 : (S) -3- [2- [3- (4
-Hydroxyphenoxy) -2-hydroxypropylamino] ethyl] indol-7-yloxyacetic acid-N,
Production of N-diethylamide oxalate hemihydrate

(R) -3- (2-Aminopropyl) indol-7-yloxyacetic acid-N, N
The reaction and treatment were conducted in a similar manner to Example 1 using 3- (2-aminoethyl) indol-7-yloxyacetic acid-N, N-diethylamide instead of -diethylamide, and the title compound was obtained. 94-97 ° C

Example 3 3-[(2RS) -2- [3-
Production of (4-hydroxyphenoxy)-(2S) -2-hydroxypropylamino] propyl] -7-benzyloxyindole 1/2 oxalate 1/4 hydrate

In Example 1, (R) -3- (2-aminopropyl) indol-7-yloxyacetic acid-N, N
The reaction and treatment were carried out in the same manner as in Example 1 using (±) -3- (2-aminopropyl) -7-benzyloxyindole instead of -diethylamide, to obtain the title compound. Melting point 167-169 ° C

Example 4 : 3-[(2R) -2- [3-
Production of (4-hydroxyphenoxy)-(2S) -2-hydroxypropylamino] propyl] indol-7-yloxyacetic acid 1/4 hydrate

3-[(2R) -2- [3- (4-hydroxyphenoxy)-(2S) -2-hydroxypropylamino] propyl] indol-7-yloxyacetic acid
To a solution of 0.3 g of N, N-diethylamide in 6 ml of ethanol was added a solution of 0.2 g of potassium hydroxide in 3 ml of water, and the mixture was refluxed for 4 hours. After allowing to cool to room temperature, 0.25 ml of acetic acid was added to neutralize.
The precipitated crystals were collected by filtration and dried to give 0.24 g of the colorless title compound. Melting point 257-259 ℃

¹ H-NMR spectrum (DMSO-d ₆ , δppm): 0.95
(3H, d, J = 6.2 Hz), 1.5-3.5 (7H, m), 3.84 (2H, d,
J = 5.1 Hz), 4.03 (1H, m), 4.51 (2H, s), 6.47 (1
H, d, J = 7.3 Hz), 6.65-6.80 (5H, m), 6.96-7.01 (2
H, m), 11.06 (1H, s)

Example 5 : (S) -3- [2- [3- (4
-Hydroxyphenoxy) -2-hydroxypropylamino] ethyl] indol-7-yloxyacetic acid / 1
Manufacture of tetrahydrate

Example 4 was repeated using (S) -3- [2- [3- (4-hydroxyphenoxy) -2-hydroxypropylamino] ethyl] indol-7-yloxyacetic acid-N, N-diethylamide. The reaction and treatment were performed in the same manner to obtain the colorless title compound. Melting point 222-224 ° C

Example 6 : 3-[(2RS) -2- (3-
Phenoxy- (2S) -2-hydroxypropylamino) propyl] indol-7-yloxyacetic acid

The procedure of Example 1 was repeated using (±) -3- (2-aminopropyl) indol-7-yloxyacetic acid-N, N-diethylamide and (S) -3-phenoxy-1,2-epoxypropane. Reaction and treatment as in the first step,
3-[(2RS) -2- (3-phenoxy- (2S)-
2-hydroxypropylamino) propyl] indol-7-yloxyacetic acid-N, N-diethylamide,
This was reacted and treated in the same manner as in Example 4 to obtain the colorless title compound. Melting point 156 ~ 160 ℃

Example 7 : 3-[(2R) -2- [3-
Production of (2-chlorophenoxy)-(2S) -2-hydroxypropylamino] propyl] indol-7-yloxyacetic acid-N, N-diethylamide

(R) -3- (2) produced from Reference Example 3
-Aminopropyl) indole-7-yloxyacetic acid-
To a solution of 1.00 g of N, N-diethylamide in 8 ml of ethanol was added 0.62 g of the crude (S) -3- (2-chlorophenoxy) -1,2-epoxypropane obtained in Reference Example 4, and the mixture was heated under reflux for 3 hours. After the reaction solution was concentrated to dryness under reduced pressure, the residue was subjected to medium pressure silica gel column chromatography, and eluted with chloroform-methanol (30: 1, v: v).
The fraction containing the desired compound was concentrated under reduced pressure to obtain 1.14 g of the title compound as a brown oil.

¹ H-NMR spectrum (CDCl ₃ , δppm): 1.12
1.26 (9H, m), 2.81-3.06 (5H, m), 3.35 (2H, q, J =
7.1 Hz), 3.45 (2H, q, J = 7.1 Hz), 3.94-4.01 (3H,
m), 4.79 (2H, s), 6.65 (1H, d, J = 7.7 Hz), 6.87-
7.04 (4H, m), 7.17-7.36 (3H, m), 9.67 (1H, s)

Example 8 : 3-[(2R) -2- [3-
Production of (2-chlorophenoxy)-(2S) -2-hydroxypropylamino] propyl] indol-7-yloxyacetic acid

The 3-[(2R) -2- [3
-(2-chlorophenoxy)-(2S) -2-hydroxypropylamino] propyl] indol-7-yloxyacetic acid-N, N-diethylamide 1.01 g of ethanol 3
To the ml solution was added a solution of 0.57 g of potassium hydroxide in 3 ml of water, and 7.5
Heated to reflux for an hour. After allowing to cool to room temperature, 0.64 ml of acetic acid was added to neutralize. The precipitated crystals were collected by filtration and dried to give 0.71 g of the colorless title compound. 188-194 ° C

¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 0.92
(3H, d, J = 6.1 Hz), 2.40-3.50 (7H, m), 3.96-4.15
(3H, m), 4.52 (2H, s), 6.46 (1H, d, J = 7.9 Hz),
6.76 (1H, dd, J = 7.7 Hz, J = 7.7 Hz), 6.94-7.30
(5H, m), 7.42 (1H, dd, J = 1.3Hz, J = 7.9Hz), 11.03
(1H, s)

Formulation Example : (Tablet Production Method)

According to a conventional method, the respective components shown in Table 4 below are mixed, granulated, and compression-molded to obtain a tablet of 100 mg per tablet.
Tablets were prepared.

[0145]

[Table 4]

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/00 613 A61K 31/00 613 643 643D 31/40 607 31/40 607 (72) Inventor Kazu Kawashima F-term (reference) 4C086 AA01 AA02 AA03 BC13 MA04 NA14 ZA66 ZA68 ZA81 ZC33 ZC35 ZC41 4C204 BB01 CB03 DB13 EB02 FB01 GB25 GB29 GB32

Claims (6)

[Claims] 1. A 3,7-disubstituted indole derivative represented by the following formula [I] or a physiologically acceptable salt thereof. Embedded image [Wherein X represents O, NH or S, and R ¹ represents a hydroxy group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a carbamoyl group, a cyclic aminocarbonyl group, a carboxyl group, a sulfamoyl group, Or a di-lower alkylaminosulfonyl group,
A cyclic aminosulfonyl group, a sulfonic acid group, a sulfonic ester group, a phosphoric acid group, a phosphoric ester group or a substituted or unsubstituted phenyl group (the substituent is a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group,
R ² and R ³ are the same or different and are hydrogen or lower alkoxycarbonyl, carboxyl, nitro, cyano, amino and mono- or di-lower alkylamino. An atom or a lower alkyl group, R ⁴ represents a hydrogen atom or OR ⁷ ,
Here, R ⁷ is a hydrogen atom, a lower alkyl group, a substituted or unsubstituted benzyl group (the substituent is a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a nitro group, One or two selected from a cyano group, an amino group and a mono- or di-lower alkylamino group) or a lower alkanoyl group, and R ⁵ is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy Group, nitro group, cyano group, amino group, mono- or di-lower alkylamino group, lower alkylsulfonylamino group or lower alkylsulfonyl group, and R ⁶ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, Hydroxy, nitro, cyano, amino, formylamino, Sulfonyl sulfonylamino group, a mono- or di-lower alkylamino group, a lower alkylsulfonylamino group or a lower alkylsulfonyl group means, n
Means 1, 2, 3, 4 or 5. ] 2. The compound according to claim 1, wherein X is O, or a physiologically acceptable salt thereof. 3. R¹Is a lower alkoxycarbonyl group,
Or di-lower alkylaminocarbonyl groups,
Minocarbonyl group, carboxyl group, sulfamoyl
A mono- or di-lower alkylaminosulfonyl group,
Cyclic aminosulfonyl, sulfonic acid, or substituted
Is an unsubstituted phenyl group (the substituent is a halogen atom,
Fluoromethyl group, lower alkyl group, lower alkoxy group,
Lower alkoxycarbonyl group, carboxyl group, nitro
Group, cyano group, amino group and mono- or di-lower alkyl
Or two or more selected from the group consisting of
R ^TwoAnd R^ThreeIs the same or different and is a hydrogen atom, a methyl group or
An ethyl group,^FourIs a hydrogen atom or OR⁷And R⁷
Is hydrogen, methyl, benzyl or lower alkanoy
3. The compound according to claim 2, wherein n is 1, 2 or 3.
Or a physiologically acceptable salt thereof. 4. 3- [2- (3-phenoxy-2-hydroxypropylamino) propyl] indol-7-yloxyacetic acid, 3- [2- (3-phenoxy-2-hydroxypropylamino) propyl] -7 -Benzyloxyindole, 3- [2- (3-phenoxy-2-hydroxypropylamino) propyl] indole-7-yloxyacetic acid methyl ester, 3- [2- [3- (4-hydroxyphenoxy) -2-
Hydroxypropylamino] propyl] -7-benzyloxyindole, 3- [2- [3- (4-hydroxyphenoxy) -2-
Hydroxypropylamino] propyl] -7-[(4-
Methoxycarbonylphenyl) methoxy] indole, 3- [2- [3- (4-hydroxyphenoxy) -2-
Hydroxypropylamino] propyl] -7-[(4-
Carboxyphenyl) methoxy] indole, 3- [2
-[3- (4-hydroxyphenoxy) -2-hydroxypropylamino] propyl] indol-7-yloxyacetic acid, 3- [2- [3- (4-hydroxyphenoxy) -2-
[Hydroxypropylamino] propyl] indole-7
-Yloxyacetic acid-N, N-diethylamide, 3- [2- [3- (4-hydroxyphenoxy) -2-
[Hydroxypropylamino] propyl] indole-7
-Yloxyacetic acid methyl ester and 3- [2- [3-
(2-Chlorophenoxy) -2-hydroxypropylamino] propyl] indol-7-yloxyacetic acid or a physiologically acceptable salt thereof. 5. A β containing the compound according to claim 1 or a physiologically acceptable salt thereof as an active ingredient.
₃ Adrenergic receptor agonists. 6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a physiologically acceptable salt thereof.