JP2006111553A - Sulfonyloxyindole derivative and medicinal composition containing the same - Google Patents

Sulfonyloxyindole derivative and medicinal composition containing the same Download PDF

Info

Publication number
JP2006111553A
JP2006111553A JP2004299077A JP2004299077A JP2006111553A JP 2006111553 A JP2006111553 A JP 2006111553A JP 2004299077 A JP2004299077 A JP 2004299077A JP 2004299077 A JP2004299077 A JP 2004299077A JP 2006111553 A JP2006111553 A JP 2006111553A
Authority
JP
Japan
Prior art keywords
group
lt
gt
sp
lower
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
JP2004299077A
Other languages
Japanese (ja)
Inventor
Hiroshi Harada
Shirou Kato
Kazuhiro Mizuno
Mayumi Oue
Masaaki Sawa
Hirotaka Tateishi
Hiroshi Tsujiuchi
博史 原田
まゆみ 大植
和弘 水野
匡明 澤
浩貴 立石
志朗 賀登
宏 辻内
Original Assignee
Dainippon Sumitomo Pharma Co Ltd
大日本住友製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dainippon Sumitomo Pharma Co Ltd, 大日本住友製薬株式会社 filed Critical Dainippon Sumitomo Pharma Co Ltd
Priority to JP2004299077A priority Critical patent/JP2006111553A/en
Publication of JP2006111553A publication Critical patent/JP2006111553A/en
Application status is Pending legal-status Critical

Links

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound which has excellent selectivity and a strong β<SB>3</SB>adrenalin receptor-stimulating action and is useful as an agent for preventing and treating obesity, diabetes, hyperlipemia, hypersensitive colon syndrome, acute or chronic diarrhea, pollakiuria, anischuria, urolithiasis and the like. <P>SOLUTION: This sulfonyloxyindole derivative represented by the general formula [I] (R<SP>1</SP>is H or the like; R<SP>3</SP>and R<SP>4</SP>are each H, a lower alkyl, or the like; R<SP>5</SP>is H, a lower alkyl, or the like; R<SP>6</SP>is a lower alkyl; R<SP>7</SP>is H or the like; R<SP>2</SP>is X<SP>1</SP>-R<SP>8</SP>, OSO<SB>2</SB>-R<SP>9</SP>or X<SP>2</SP>-A<SP>1</SP>-R<SP>10</SP>or the like; X<SP>1</SP>is O, S or NH; R<SP>8</SP>is a lower alkyl, or the like; R<SP>9</SP>is phenyl, naphthyl, a heteroaryl, or the like; X<SP>2</SP>is O, S, NH or SO<SB>2</SB>; A<SP>1</SP>is a lower alkylene moiety or the like; R<SP>10</SP>is phenyl, naphthyl or a heteroaryl) or its physiologically acceptable salt. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to a pharmaceutical, in particular to a novel sulfonyloxindole derivative having a β 3 adrenergic receptor stimulating action and a pharmaceutical composition containing the same.

It is known that there are two subtypes of β 1 and β 2 in the sympathetic β-adrenergic receptor. β 1 -adrenergic receptor agonists are useful as cardiac function enhancers or vasopressors, and β 2 adrenergic receptor agonists are useful as bronchodilators and are currently used clinically.

Β 3 -adrenergic receptor (β 3 receptor) (Non-patent Document 1) isolated as a third subtype different from these two subtypes is present in adipocytes and adheres to the subcutaneous or internal organs. It is considered to have a function of decomposing neutral fat of white adipose tissue and heat production in brown adipose tissue. Therefore, it is thought that a decrease in the function of β 3 adrenergic receptor causes accumulation of body fat, suggesting an association with obesity, and the occurrence of non-insulin dependent diabetes mellitus (type 2 diabetes) Relevance has also been reported. For these reasons, β 3 -adrenergic receptor agonists are expected as prophylactic / therapeutic agents for obesity and diabetes.

In addition, β receptor exists in bladder smooth muscle, and the bladder relaxes via β receptor by sympathetic nerve stimulation during urine accumulation. Recently, it has been found that human bladder is relaxed mainly through β 3 receptor among β receptors (Non-patent Document 2), and β 3 adrenergic receptor agonists are used to prevent frequent urination and urinary incontinence. It is also expected as a therapeutic agent. In addition, β 3 adrenergic receptor agonists are said to be useful as prophylactic / therapeutic agents for hyperlipidemia, irritable bowel syndrome, acute or chronic diarrhea, urinary calculus, and depression.

If the deviation from the β 1 or β 2 receptor stimulating action of the β 3 adrenergic receptor agonist is insufficient, tachycardia or tremor of the limbs may occur as a side effect, so β 3 adrenergic reception In order to develop a body agonist, a compound having a strong β 3 receptor stimulating action and not stimulating the β 1 and β 2 receptors or having a low activity even when stimulated is desired. In the present specification, a compound having such a strong β 3 receptor stimulating action and a large difference from the stimulating action of β 1 or β 2 receptor is expressed as “a compound having excellent selectivity”. Sometimes.

As a compound having a β 3 adrenergic receptor stimulating action, Patent Document 1 discloses 2- [3- (7-methoxyindol-3-yl) -2-propylamino] -1- (3- Chlorophenyl) ethanol and the like are described, and these compounds are described as having a β 3 adrenergic receptor stimulating action.

  However, none of the compounds described in Patent Document 1 has a sulfonic acid ester group at positions 4 to 7 of the indole ring, and the substituent on the benzene ring bonded to the ethanol moiety 1 position. The structure is completely different from the compounds of the present invention.

Patent Document 2 describes compounds represented by the following general formula 2 and describes that these compounds have a β 3 adrenergic receptor stimulating action.

[Wherein, R 1 is a substituted or unsubstituted lower alkyl group, or a formula: —X—R 1e —C (═O) NR 1a R 1b or the like (where X is a single bond or a formula: —O—, —S— , -N (R 1c) -, - N (R 1c) C (= O) -, - C (= O) N (R 1c) -, - N (R 1c) SO 2 -, = SO 2 N ( R 1c ) —, or —C (═O) NHSO 2 —)

R 2 represents a hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkyl group, etc .;

R 3 represents a hydrogen atom or a substituted or unsubstituted lower alkyl group, or a divalent group represented by the formula: —X—R 1e —C (═O) — in which R 1 and R 3 are combined. ;

R 4 , R 5 , R 6 , and R 7 are a hydrogen atom or an optionally substituted lower alkyl group;

R 8 represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkylsulfonyl, a substituted or unsubstituted lower alkylsulfonylamino group, or A substituted or unsubstituted benzenesulfonylamino group;

R 9 and R 10 are a hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkyl group, and the like;

Two of R 8 , R 9 and R 10 may be combined to form a methylenedioxy group, a group represented by the formula: —NR 8a C (═O) CR 8b ═CR 8c —. ]

  However, none of the compounds described in Patent Document 2 has a sulfonate group at positions 4 to 7 of the indole ring, and the structure is completely different from the compound of the present invention.

International Publication No. 96/16938 Pamphlet

International Publication No. 03/106418 Pamphlet

Emorine, L. J., "Science", 1989, Vol. 245, p. 1118-1121

Yamaguchi, "Urology", 2002, Vol. 59, Supplement 5A, p.25-29

An object of the present invention is to provide a novel sulfonyloxyindole derivative and a physiologically acceptable salt thereof which have a strong stimulating action on β 3 adrenergic receptors and are excellent in selectivity.

  The present invention relates to a novel sulfonyloxyindole derivative represented by the following general formula [I] or a physiologically acceptable salt thereof.

(Wherein R 1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a trifluoromethyl group, a benzyloxy group, a lower alkoxy group, a hydroxyl group, an amino group, or a mono- or di-substituted lower alkylamino group;

R 3 and R 4 are the same or different and each represents a hydrogen atom, a lower alkyl group, or a cyclic lower alkyl group in which R 3 and R 4 are combined;

R 5 represents a hydrogen atom or an optionally substituted lower alkyl group,
OSO 2 R 6 and R 7 are bonded to any of the 4-position, 5-position, 6-position or 7-position of the indole ring;

R 6 is an optionally substituted lower alkyl group, cyclic lower alkyl group, lower alkenyl group, lower alkynyl group, optionally substituted naphthyl group, optionally substituted phenyl group, or optionally substituted. Means a heteroaryl group, a mono- or di-substituted lower alkylamino group or a cyclic amino group;
Alternatively, when OSO 2 R 6 is bonded to position 7 of the indole ring, R 5 and R 6 may be combined to form a linear or branched lower alkylene moiety,

R 7 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group,

R 2 means a group represented by a trifluoromethoxy group, a difluoromethoxy group, a fluoromethoxy group, X 1 -R 8 , OSO 2 -R 9 or X 2 -A 1 -R 10 ;

X 1 represents an oxygen atom, a sulfur atom or NH,

R 8 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group,

R 9 is an optionally substituted lower alkyl group, a cyclic lower alkyl group, a lower alkenyl group, a lower alkynyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group, or optionally substituted. Means a heteroaryl group,

X 2 represents an oxygen atom, a sulfur atom, NH or SO 2 ,

A 1 means a linear or branched lower alkylene moiety, a linear or branched lower alkenylene moiety or a linear or branched lower alkynylene moiety,

R 10 is an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted heteroaryl group, a halogen atom, a lower alkoxy group, a cyclic lower alkyl group, a hydroxyl group, a nitro group, a cyano group. , Carboxyl group, lower alkoxycarbonyl group, carbamoyl group, mono- or di-substituted lower alkylaminocarbonyl group, cyclic aminocarbonyl group, phenylaminocarbonyl group, naphthylaminocarbonyl group, heteroarylaminocarbonyl group, amino group, mono- or di-substituted It means a lower alkylamino group or a cyclic amino group.

However, when A 1 is methylene, R 10 is a group other than a halogen atom, a hydroxyl group, a nitro group, an amino group, a mono- or di-substituted lower alkylamino group, or a cyclic amino group. )

  A physiologically acceptable salt means a physiologically acceptable acid addition salt, alkali metal salt, alkaline earth metal salt or organic base salt. Specifically, examples of the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, and oxalate, maleate, and fumarate. And organic acid salts such as malonate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, and gluconate. 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. Further, examples of the salt as an organic base include Examples thereof include salts with ammonia, methylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, dicyclohexylamine.

  Since the compound represented by the general formula [I] and physiologically acceptable salts thereof may exist in the form of hydrates and / or solvates, these hydrates and solvates may also be present. Included in the compounds of the present invention.

The compound represented by the general formula [I] has one or more asymmetric carbons. That is, when the carbon atom to which the hydroxyl group is bonded is an asymmetric carbon and R 3 and R 4 are different from each other, the carbon atom to which these groups are bonded is an asymmetric carbon. Therefore, two or more stereoisomers may exist in the general formula [I]. These stereoisomers and mixtures thereof are also included in the compounds of the present invention. The carbon atom to which the hydroxyl group is bonded preferably has an R configuration.

  Terms used in this specification are explained below.

  The “lower alkyl group” and the “lower alkyl” part mean a linear or branched alkyl group having 1 to 8 carbon atoms, and specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -Butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, octyl.

  “Cyclic lower alkyl group” means a cyclic alkyl group having 3 to 8 carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

  “Lower alkoxy group” and “lower alkoxy” moiety means a straight or branched alkoxy group having 1 to 6 carbon atoms, and specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, Examples include sec-butoxy and tert-butoxy.

  The “lower alkenyl group” means a carbon chain in which at least one of the carbon-carbon single bonds of the “lower alkyl group” having 2 to 8 carbon atoms is replaced with a double bond. , Allyl, 3-butenyl, isobutenyl, 1,4-heptadienyl.

  The “lower alkynyl group” means a carbon chain in which at least one of the carbon-carbon single bonds of the “lower alkyl group” having 2 to 8 carbon atoms is replaced with a triple bond. Specific examples include ethynyl, Examples include propargyl, 2-butynyl, 3-butynyl, 4-heptynyl.

  The “lower alkylene” moiety means a divalent carbon chain composed of a carbon-carbon single bond having 1 to 6 carbon atoms, and specific examples include methylene and ethylene.

  The “lower alkenylene” moiety means a divalent carbon chain in which at least one of the carbon-carbon single bonds having 2 to 8 carbon atoms is replaced with a double bond. Specific examples include vinylene and propenylene. Is mentioned.

  The “lower alkynylene” moiety means a divalent carbon chain in which at least one of the carbon-carbon single bonds having 2 to 8 carbon atoms is replaced with a triple bond, and specific examples include ethynylene and propynylene. .

  “Halogen atom” means fluorine, chlorine, bromine or iodine.

  “Cyclic amino group” and “cyclic amino” moiety are nitrogen atoms fused to a 4- to 7-membered cyclic amine or benzene ring containing at least one nitrogen atom and optionally containing an oxygen atom and a sulfur atom. Is a 4- to 7-membered cyclic amine which may contain an oxygen atom and a sulfur atom, and specific examples thereof include azetidyl, pyrrolidyl, piperidyl, morpholyl, thiomorpholyl, hexahydroazepi. Nyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, 1-oxoisoindolyl, 1,3-dioxoisoindolyl.

  The “lower alkanoyl” moiety means a linear or branched alkanoyl group having 1 to 5 carbon atoms, and specific examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl and pivaloyl.

“Heteroaryl group” means an oxygen atom fused to a 5- or 6-membered unsaturated heterocycle or benzene ring containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms, Means a 5- or 6-membered unsaturated heterocycle containing 1 to 4 heteroatoms selected from sulfur and nitrogen atoms, for example thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, pyridyl , Pyrazyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, quinolinyl, isoquinolinyl.

The “optionally substituted lower alkyl group” is a halogen atom, lower alkoxy group, cyclic lower alkyl group, hydroxyl group, nitro group, cyano group, carboxyl group, lower alkoxycarbonyl group, carbamoyl group, mono- or di-substituted lower alkyl group. Means a lower alkyl group optionally substituted by 1 to 5 substituents selected from aminocarbonyl group, cyclic aminocarbonyl group, amino group, mono- or di-substituted lower alkylamino group, cyclic amino group, for example , Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, chloromethyl, methoxymethyl, 2-methoxyethyl, cyclopropylmethyl, hydroxymethyl, methoxycarbonylmethyl, hydroxycarbonylmethyl, carbamoylmethyl, 2-chloroethyl, -Bromoethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2-aminoethyl, 3-chloropropyl, 3-nitropropyl, 3-cyanopropyl, 3- (methylamino) propyl, 3- (Dimethylamino) propyl and 3- (1-pyrrolidyl) propyl are mentioned.

The “optionally substituted phenyl group” includes a halogen atom, a lower alkyl group, a phenyl group, a lower alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a lower alkylthio group, a hydroxyl group, a hydroxy lower alkyl group, a nitro group, A cyano group, a carboxyl group, a lower alkoxycarbonyl group, a benzyloxycarbonyl group, a carbamoyl group, a mono- or di-substituted lower alkylaminocarbonyl group, a cyclic aminocarbonyl group, an amino group, a mono- or di-substituted lower alkylamino group, a cyclic amino group, Lower alkylsulfonylamino group, benzenesulfonylamino group, lower alkanoylamino group, benzoylamino group, lower alkoxycarbonylamino group, carbamoylamino group, mono- or disubstituted lower alkylaminocarbonylamino group, cyclic It means a phenyl group which may be substituted with 1 to 5 substituents selected from a minocarbonylamino group, a sulfamoyl group, a mono- or di-substituted lower alkylaminosulfonyl group and a cyclic aminosulfonyl group. -, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-fluorophenyl, 2,4-dichlorophenyl, 2,3-dibromophenyl, 2,4-difluorophenyl 2-, 3- or 4-methylphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-aminophenyl, 4-methylaminophenyl, 4-trifluoromethylphenyl, 3-dimethyl Aminophenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-nitrophenyl, 4-biphenyl, 2 Trifluoromethoxyphenyl, 4-ethylthiophenyl, 2-, 3- or 4-hydroxyphenyl, 4-hydroxymethylphenyl, 4-carboxylphenyl, 4-methoxycarbonylphenyl, 2- (methanesulfonylamino) phenyl, 4- (Benzenesulfonylamino) phenyl, 2-, 3- or 4- (acetylamino) phenyl, 4- (benzoylamino) phenyl, 4- (ethoxycarbonylamino) phenyl may be mentioned.

The “optionally substituted naphthyl group” means a naphthyl group which may be substituted with 1 to 7 substituents selected from the substitutions described in the above “optionally substituted phenyl group”. And, for example, naphthalene, 2-, 3-, 4-, 5-, 6-, 7- or 8-chloronaphthyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-methyl Naphthyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-methoxynaphthyl, 6,7-dibromo-2-naphthyl, 3-acetylamino-1-naphthyl.

The “optionally substituted heteroaryl group” refers to a heteroaryl optionally substituted with 1 to 5 substituents selected from the substitutions described in the above “optionally substituted phenyl group” Means a group such as thienyl, furyl, benzothienyl, pyridyl, quinolinyl, indolyl, 2-chloro-3-thienyl, 3-methyl-2-thienyl, 2-methyl-3-indolyl, 4-methylamino-3 -Pyridyl, 6-cyano-2-isoquinolinyl.

  “Phenolic hydroxyl protecting group, hydroxyl protecting group, amino protecting group, and sulfonamide protecting group” are commonly used in the field of organic synthesis and can be easily removed by reduction or hydrolysis. In addition to a group, it means a substituent that can be removed enzymatically or non-enzymatically in vivo.

  Examples of the “protective group for phenolic hydroxyl group” include methyl group, ethyl group, isopropyl group, tert-butyl group, allyl group, benzyl group, diphenylmethyl group, triphenylmethyl group, methoxymethyl group, methoxyethoxymethyl group, Tetrahydropyranyl group, phenacyl group, acetyl group, propionyl group, pivaloyl group, benzoyl group, carbamoyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, allyloxycarbonyl group, isobutoxycarbonyl Group, tert-butoxycarbonyl group and benzyloxycarbonyl group.

  Examples of the “amino-protecting group” include methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, isobutoxycarbonyl group, allyloxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group , Vinyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, formyl group, acetyl group, propionyl group, benzoyl group, trifluoroacetyl group, p-toluenesulfonyl group, benzenesulfonyl group, methanesulfonyl group, benzyl group, diphenyl Examples thereof include a methyl group, a triphenylmethyl group, a pivaloyloxymethyl group, an acetoxymethyl group, an acetoxymethoxycarbonyl group, a 1-acetoxyethoxycarbonyl group, and an alanyl group.

  Examples of the “hydroxyl-protecting group” include silyl-based protective groups such as tert-butyldimesylsilyl group, tert-butyldiphenylsilyl group and triethylsilyl group in addition to the above-mentioned “phenolic hydroxyl group-protecting group”. .

  Examples of the “reactive ester residue of alcohol” include halogen atoms, lower alkylsulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy, and arylsulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy.

The compound of the present invention is represented by the general formula [I]. Preferred is a compound in which the steric configuration of the asymmetric carbon in which the benzene ring and the hydroxyl group are substituted in the general formula [I] is the R configuration, and R 1 is A compound which is a hydrogen atom, a hydroxyl group or an amino group, and R 7 is a hydrogen atom, and physiologically acceptable salts thereof.

A more preferred compound is a group in which, in the general formula [I], the configuration of the asymmetric carbon substituted with a benzene ring and a hydroxyl group is the R configuration, and OSO 2 R 6 is a group bonded to the 6-position or 7-position of the indole ring. R 1 is a hydrogen atom, a hydroxyl group or an amino group, R 3 and R 4 are the same or different and are a hydrogen atom or a methyl group, R 7 is a hydrogen atom, and R 5 is a hydrogen atom or a lower alkyl group. R 6 is a lower alkyl group, an optionally substituted phenyl group or an optionally substituted heteroaryl group, or R 5 and R 6 together form a linear or branched chain Compounds forming a lower alkylene moiety and physiologically acceptable salts thereof.

Further preferred compounds are those in which the configuration of the asymmetric carbon substituted with a benzene ring and a hydroxyl group is the R configuration, OSO 2 R 6 is a group bonded to the 7-position of the indole ring, and R 1 is a hydrogen atom, a hydroxyl group or An amino group, R 3 and R 4 are the same or different and are a hydrogen atom or a methyl group, R 7 is a hydrogen atom, R 5 is a hydrogen atom or a lower alkyl group, and R 6 is a lower alkyl group. Or a compound or a physiologically acceptable salt thereof in which R 5 and R 6 are combined to form a linear or branched lower alkylene moiety.

Particularly preferred compounds are those in which the configuration of the asymmetric carbon substituted with a benzene ring and a hydroxyl group is the R configuration, OSO 2 R 6 is a group bonded to the 7-position of the indole ring, and R 1 is a hydrogen atom, a hydroxyl group or An amino group, R 3 and R 4 are the same or different and are a hydrogen atom or a methyl group, R 7 is a hydrogen atom, R 5 is a hydrogen atom or a lower alkyl group, and R 6 is a lower alkyl group. Or R 5 and R 6 together form a linear or branched lower alkylene moiety, and R 2 is X 1 -R 8 , OSO 2 -R 9 or X 2 -A 1. -R 10 , R 8 is a lower alkyl group or a lower alkenyl group, and R 9 is an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted heteroaryl group. Yes, a 1 is a straight-chain or branched Lower alkylene moiety, or a straight-chain or lower alkenylene moiety of the branched, a phenyl group which may R 10 is optionally substituted, an optionally substituted naphthyl group, is a heteroaryl group which may be substituted A compound or a physiologically acceptable salt thereof.

  Specific examples of the most preferred compounds include the compounds in Tables 1 and 2 below, and stereoisomers or physiologically acceptable salts thereof.

Table IV) Abbreviations in the table have the following meanings.
Me = methyl

  Specific examples of the compound included in the present invention include the compounds shown in Table 3 below and the stereoisomers or physiologically acceptable salts thereof in addition to the compounds of Examples described later.

Table IV) Abbreviations in the table have the following meanings.
Me = methyl,
Et = ethyl,
i Pr = isopropyl,
Ph = phenyl,
Py = pyridyl

  The production method of the compound of the present invention is described below. The compound of the present invention represented by the general formula [I] can be produced, for example, by the following production methods 1 to 4.

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

(Wherein P 1 represents a protecting group for a hydroxyl group, Y 1 represents a reactive ester residue of an alcohol, and R 1 and R 2 are the same as described above.)
And a compound represented by the following general formula [III]

(In the formula, R 3 , R 4 , R 5 , R 6 and R 7 are the same as described above.)
In after the reaction with the compound represented by may be prepared by removal of the protecting group P 1.

The protecting group P 1 is preferably a group that can be easily and selectively removed. Examples of the protecting group P 1 include silyl-based protecting groups such as tert-butyldimesylsilyl group, tert-butyldiphenylsilyl group, triethylsilyl group, and tert-butyl group. A tetrahydropyranyl group is mentioned. These protecting groups are easily removed with acids such as formic acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like. Furthermore, in the case of a silyl-based protecting group, it can be easily removed by a fluorine anion generated from tetra-n-butylammonium fluoride, sodium fluoride or the like.

The reaction of the compound represented by the general formula [II] and the compound represented by the general formula [III] is performed in a suitable solvent or without solvent. The solvent to be used is appropriately selected according to the type of raw material compound, etc., but alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as dichloromethane and chloroform, diethyl ether, tetrahydrofuran, Examples include ethers such as dioxane, aromatic hydrocarbons such as benzene and toluene, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetonitrile, 1-methyl-2-pyrrolidone and the like. These solvents may be used alone or in combination of two or more. Used as a mixture. This reaction is carried out in the presence of a base. As the base, an alkali hydroxide such as sodium hydroxide or potassium hydroxide, an alkali bicarbonate such as sodium bicarbonate or potassium bicarbonate, an alkali carbonate such as sodium carbonate or potassium carbonate, or Examples include organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, etc., but it is also possible to use an excess of the compound of general formula [III] relative to the compound of general formula [II]. is there. In addition, in the compound of the general formula [II], when a compound in which Y 1 is chlorine, bromine or arylsulfonyloxy group is used, the reaction is smoothly carried out by adding an alkali metal iodide such as sodium iodide or potassium iodide. proceed. While the reaction temperature varies depending on the type of starting compound used, it is generally about 20 ° C to about 200 ° C. The compound of the general formula [III] used in this reaction can also be used in the form of an acid addition salt. In this case, the base added to the reaction is used in an amount for returning the compound of the general formula [III] to a free amine. Must be added. Examples of the acid addition salt include inorganic acid salts such as hydrochloride and hydrobromide and organic acid salts such as oxalate, maleate and fumarate.

Compound 4 in which Y 1 is chlorine or bromine in general formula [II] can be produced, for example, by the following production method (1A).

(In the formula, Y 2 represents chlorine or bromine, and R 1 , R 2 and P 1 are the same as described above.)

  Compound 2 can be synthesized by chlorinating or brominating the α-position of the carbonyl group of Compound 1. Examples of the chlorinating agent include chlorine, N-chlorosuccinimide, sulfuryl chloride, and cupric chloride. Examples of the brominating agent include bromine, N-bromosuccinimide, phenyltrimethylammonium tribromide, pyridinium hydrobromide dibromide, 2-pyrrolidone hydrotribromide, and cupric bromochloride.

  Compound 3 can be synthesized by reducing the carbonyl group of compound 2. Examples of the reducing agent to be used include diborane, sodium borohydride, lithium aluminum hydride and its alkoxy complex or transition metal salt, and trialkylsilane. Further, the optical isomers of Compound 3 are (+)-or (-)-B-chlorodiisopinocanphenylborane, (R)-or (S) -B-diisopinoccanphenyl-9-borabicyclo. An asymmetric reducing agent such as [3,3,1] nonane is used, or (R)-or (S) -tetrahydro-1-methyl-3,3-diphenyl-1H, 3H-pyrrolo [1,2- c] [1,3,2] can be synthesized by reduction of borane in the presence of an asymmetric catalyst such as oxazaborol.

Compound 4 can be synthesized by introducing a protecting group P 1 into the hydroxyl group of compound 3.

Of the compounds of the general formula [III], the following general formula [IIIa] wherein R 5 is a hydrogen atom

(In the formula, R 3 , R 4 , R 6 and R 7 are the same as described above.)
For example, the compound represented by the following general formula [IIIb]

(In the formula, R 6 and R 7 are the same as described above.)
By introducing a —CH 2 —C (R 3 ) (R 4 ) —NH 2 group (wherein R 3 and R 4 are the same as described above) into the 3-position of the indole ring of the compound represented by Can be manufactured.

The —CH 2 —C (R 3 ) (R 4 ) —NH 2 group is, for example, J. Org. Chem., 25 , 1548-1558 (1960), J. Org. Chem., 51 , 4294-4295 (1986). ), And can be introduced at the 3-position of the indole ring by applying the method described in JP-A-11-255743 or WO00 / 44721.

In addition, among the compounds of the general formula [III], the following general formula [IIIc], in which R 5 is an optionally substituted lower alkyl group

(In the formula, R 5a means an optionally substituted lower alkyl group, and R 3 , R 4 , R 6 and R 7 are the same as described above.)

Is produced by, for example, protecting the NH 2 group of the general formula [IIIa] with an amino-protecting group P 2 , introducing an R 5a group at the 1-position of the indole, and then removing P 2. can do. The protecting group P 2 is preferably a group that can be easily and selectively removed, and examples thereof include a tert-butoxycarbonyl group and an acetyl group. These protecting groups are easily removed with acids such as formic acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like.

The compound of general formula [III] has one asymmetric carbon when R 3 and R 4 are groups different from each other. The enantiomer can be produced by applying the method described in, for example, Japanese Patent Application Laid-Open No. 2000-319256 or Japanese Patent Application Laid-Open No. 11-255743.

Production method 2 :
The compound of the present invention represented by the general formula [I] is represented by the following general formula [IV]

(In the formula, R 1 , R 2 , R 3 , R 5 , R 7 and P 2 are the same as described above.)
And a compound represented by the general formula [V]

(In the formula, R 6 is the same as described above.)
In after reacting the compound represented by may be prepared by removing the protecting group P 2.

  The reaction between the compound represented by the general formula [IV] and the compound represented by the general formula [V] is carried out in an appropriate solvent, and the solvent used is a ketone such as acetone or methyl ethyl ketone, or a halogenated compound such as dichloromethane or chloroform. Examples include hydrocarbons, ethers such as diethyl ether, tetrahydrofuran, and dioxane, aromatic hydrocarbons such as benzene and toluene, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine, and the like. A mixture of two or more types is used. This reaction is preferably carried out in the presence of a base. As the base, an alkali hydroxide such as sodium hydroxide or potassium hydroxide, an alkali bicarbonate such as sodium bicarbonate or potassium bicarbonate, or a carbonate such as sodium carbonate or potassium carbonate. Examples include alkali or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine and the like. When pyridine is used as a solvent, no new base is required because pyridine also serves as a base. The reaction temperature is usually about −20 ° C. to about 100 ° C.

  The compound represented by the general formula [IV] includes, for example, the compound represented by the above general formula [II] and the following general formula [VI].

(In the formula, P 3 means a protecting group for a phenolic hydroxyl group, and R 3 , R 4 , R 5 and R 7 are the same as described above.)

The compound represented by is reacted in the same manner as described in Production Method 1, after removal of the protecting group of the hydroxyl group, the following formula by introducing a new protecting group P 2 to 2 amino group (VII)

(In the formula, R 1 , R 2 , R 3 , R 5 , R 7 , P 2 and P 3 are the same as described above.)

And finally, the protective group P 3 of the compound represented by the general formula [VII] is removed to produce the compound. The combination of the protecting group P 3 for the phenolic hydroxyl group and the protecting group P 2 for the amino group is appropriately selected so that the protecting group P 3 can be selectively removed in the final step.

Production method 3 :
Among the compounds of the present invention, R 2 in the general formula [I] is a group represented by X 3 -R 11 , X 3 is an oxygen atom, a sulfur atom, or NH, and R 11 is a lower alkyl group, cyclic a lower alkyl group, a lower alkenyl group, lower alkynyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted heteroaryl group or group represented by A 2 -R 12 A 2 is a linear or branched lower alkylene moiety, a linear or branched lower alkenylene moiety or a linear or branched lower alkynylene moiety, and R 12 is a cyclic lower alkyl group, substituted An optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted heteroaryl group, a phenylaminocarbonyl group, a naphthylaminocarbonyl group or a heteroaryl The following general formula is Lumpur aminocarbonyl group (Ia)

(Wherein X 3 represents an oxygen atom, a sulfur atom or NH, and R 11 represents a lower alkyl group, a cyclic lower alkyl group, a lower alkenyl group, a lower alkynyl group, an optionally substituted phenyl group, or a substituted one. Means an optionally substituted naphthyl group, an optionally substituted heteroaryl group or a group represented by A 2 -R 12 , wherein A 2 is a linear or branched lower alkylene moiety, linear or branched Or a linear or branched lower alkynylene moiety, R 12 is a cyclic lower alkyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted heteroaryl group, phenylaminocarbonyl group, refers to naphthyl amino group or heteroarylamino group, R 1, R 3, R 4, R 5, R 6及R 7 are the same as cited above.)
For example, the compound represented by the following general formula [VIII]

(In the formula, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , X 3 and P 2 are the same as described above.)
The compound represented by the following general formula [IX]

(In the formula, Y 3 represents a reactive ester residue of alcohol, and R 11 is the same as described above.)
In represented by conducting a reaction with the compound, it can be prepared by removing the protecting group P 2.

  The reaction of compound [VIII] and compound [IX] is carried out in a suitable solvent or without solvent. Solvents used include alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as diethyl ether, tetrahydrofuran and dioxane, and aromatic carbonization such as benzene and toluene. Examples thereof include hydrogens, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine and the like, and these solvents are used alone or in combination of two or more. This reaction is preferably carried out in the presence of a base. As the base, an alkali hydroxide such as sodium hydroxide or potassium hydroxide, an alkali bicarbonate such as sodium bicarbonate or potassium bicarbonate, or a carbonate such as sodium carbonate or potassium carbonate. Examples include alkali or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine and the like. When pyridine is used as a solvent, no new base is required because pyridine also serves as a base. The reaction temperature is usually about 0 ° C to about 150 ° C.

Compound 9 in which X 3 is NH in the general formula [VIII] can be produced, for example, by the following production method (3A).

(Wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , Y 2 and P 2 are the same as described above.)

  Compound 7 is obtained by reacting Compound 6 obtained from Compound 5 with an alkali hydroxide such as sodium hydroxide or potassium hydroxide or an alkali bicarbonate such as sodium bicarbonate or potassium bicarbonate by the method described in Production Method (1A). Can be synthesized. Examples of the solvent include alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, water, dimethylformamide, dimethyl sulfoxide, and 1-methyl-2-pyrrolidone. These solvents may be used alone or in combination of two or more. Used as a mixture. The reaction temperature is generally about 0 ° C to about 150 ° C, preferably about 20 ° C to about 80 ° C.

  The reaction from compound 7 and compound [III] to compound 8 is carried out in a suitable solvent or without solvent. Solvents include alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as diethyl ether, tetrahydrofuran and dioxane, and aromatic carbonization such as benzene and toluene. Examples thereof include hydrogens, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetonitrile, 1-methyl-2-pyrrolidone and the like, and these solvents are used alone or in combination of two or more. The reaction temperature is generally about 0 ° C to about 200 ° C, preferably about 20 ° C to about 120 ° C. Further, trimethylsilylacetamide and bistrimethylsilylacetamide may be added to this reaction.

Compound 9 can be synthesized by introducing a protecting group P 2 into the secondary amino group of Compound 8 and then reducing the nitro group. The nitro group can be reduced by using a reducing agent such as zinc dust, reduced iron, tin dust, stannous chloride, titanium chloride, a method using a hydrogen donor such as hydrazine in the presence of Raney nickel, Raney nickel, palladium carbon. And catalytic hydrogen reduction or catalytic hydrogen transfer reduction in the presence of a catalyst such as palladium hydroxide or platinum oxide.

Production method 4 :
Of the compounds represented by the general formula [Ia] described in Production Method 3, X 3 is NH, R 11 is CH 2 -R 13 , R 13 is a lower alkyl group, a cyclic lower alkyl group, A lower alkenyl group, a lower alkynyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted heteroaryl group or a group represented by A 3 -R 14 ; 3 is a linear or branched lower alkylene moiety, a linear or branched lower alkenylene moiety or a linear or branched lower alkynylene moiety, R 14 is a cyclic lower alkyl group, The following general formula [Ib], which is a good phenyl group, an optionally substituted naphthyl group or an optionally substituted heteroaryl group

(Wherein R 13 is a lower alkyl group, a cyclic lower alkyl group, a lower alkenyl group, a lower alkynyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted heteroaryl. Or a group represented by A 3 -R 14 , wherein A 3 is a linear or branched lower alkylene moiety, a linear or branched lower alkenylene moiety, or a linear or branched lower alkynylene. R 14 represents a cyclic lower alkyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted heteroaryl group, R 1 , R 3 , R 4 , R 5 , R 6 and R 7 are the same as described above.)
Can be produced, for example, from the aforementioned compound 9 by the following production method (4A) or production method (4B).

(In the formula, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 13 and P 2 are the same as described above.)

  Compound 11 described in the production method (4A) can be synthesized by subjecting compound 9 and compound 10 to an amidation reaction in an appropriate solvent in the presence of a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, diphenylphosphoryl azide, 1,1′-carbonyldiimidazole, ethyl chlorocarbonate, and the like. Dicyclohexylcarbodiimide, 1- When using ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or the like, N-hydroxysuccinimide, 1-hydroxybenzotriazole or the like may be added and reacted. Examples of the solvent include ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, ethyl acetate, Examples thereof include dimethylformamide, dimethyl sulfoxide, acetonitrile and the like, and these solvents are used alone or in combination of two or more. The reaction temperature is usually about 0 ° C to about 50 ° C.

After removal of the protecting group P 2 of the compound 11 can be prepared a compound [Ib] by reducing the amide group. Addition of diborane, lithium aluminum hydride and its alkoxy complexes or transition metal salts, aluminum chloride, boron trifluoride, phosphorus oxychloride or carboxylic acids (eg acetic acid, trifluoroacetic acid) as reducing agents used in amide reduction reactions And sodium borohydride. This reduction reaction is carried out in a solvent such as ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane and diglyme and aromatic hydrocarbons such as benzene and toluene, and is appropriately selected depending on the reducing agent used. The reaction temperature varies depending on the type of reducing agent and the like, but is usually about 0 ° C to about 160 ° C.

  Compound 13 described in the production method (4B) can be produced in one step by subjecting compound 9 and compound 12 to a condensation / reduction reaction under a reducing condition in a suitable solvent. The reducing conditions in this reaction are the presence of a reducing agent that can reduce only the imine moiety formed in the middle without affecting the substituents such as carbonyl group, carboxyl group and benzyl group present in other parts. Alternatively, it means under catalytic hydrogen reduction conditions. 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 0 ° C to about 100 ° C. When this reaction is carried out under catalytic hydrogen reduction conditions, palladium, platinum oxide or the like is used as a catalyst. The reaction temperature is usually about 0 ° C. to about 100 ° C., and preferred solvents include alcohols such as methanol and ethanol.

In the above production methods 1 to 4, in the general formula [I], any one of R 1 , R 2 , R 5 , R 6 and R 7 is a carboxyl group, a hydroxyl group, an amino group, a mono-substituted lower alkylamino group or a group thereof. In the case of producing a compound containing a containing group, after using a compound in which the corresponding site is protected with an appropriate protecting group, a deprotection reaction is carried out in the final step or in the middle of the process, whereby the desired compound [ I] can be produced. The protective group to be used is appropriately selected depending on the type of the functional group to be protected, the production method, and the balance with the protective group used in other places.

  The introduction and deprotection of protecting groups such as carboxyl groups, phenolic hydroxyl groups, hydroxyl groups, and amino groups used in the above production methods 1 to 4 are described in, for example, “Protective Groups in Organic Synthesis” by Jon Wiley & Sons by TW Green, PGM Muts. , Inc, Second Edition, 1991., etc.

  The compounds produced in production methods 1 to 4 can be isolated and purified by conventional methods such as chromatography, recrystallization and reprecipitation.

  Moreover, although the compound of this invention manufactured by the manufacturing methods 1-4 is obtained in the form of a salt, a free acid, or a free base by reaction conditions, these compounds are desired salt, a free acid, or a free base by a conventional method. Can be converted to

In the production methods 1 to 4, the starting compound represented by the general formula [II], [III], [IV], [V], [VI], [VII], [VIII] or [IX] is asymmetric carbon. The configuration of the asymmetric carbon is also retained in the compound of the general formula [I] as a product. For example, in the production method 1, a compound of the general formula [I] which is a racemate is isolated from a compound of the general formula [II] which is a racemate and a compound of the general formula [III] where R 3 and R 4 are the same group. A compound is obtained, and a compound of general formula [I] which is a mixture of diastereomers is obtained from a compound of general formula [III] in which R 3 and R 4 are different groups. In addition, the compound of the general formula [II] having the specific configuration and the compound of the general formula [III] yield a compound of the general formula [I] that retains the configuration.

  In addition, when the compound of the present invention or the raw material compound produced by the production methods 1 to 4 is a racemate or a diastereomer mixture, each steric structure can be obtained by applying a method such as fractional crystallization or column chromatography. Isomers can be separated.

Pharmacological tests :
The representative compounds of the present invention were examined for their action on human β-adrenergic receptors.

The method for preparing human β 3 and human β 2 adrenergic receptor-expressing cell lines is described in WO 96/16938, and the method for preparing human β 1 adrenergic receptor-expressing cell lines is WO 2000/44721. Prepared according to

For the expression of the beta-adrenergic receptors in humans, beta 3 adrenergic receptors are underexpressed in predominantly white adipose tissue, beta 1 adrenergic receptors are mainly highly expressed in heart, beta 2 adrenergic receptors are mainly skeletal muscle It is speculated that the expression is high. Therefore, in order to establish an expression cell line reflecting each receptor expression ratio in human tissues in this test, the human β 3 adrenergic receptor expression cell line is a low expression cell line CHO / pKREX10-24. -1A (13,000 receptor / cell), human β 1 adrenergic receptor expressing cell line is expressed in high expression cell line CHO / pKREX23-30-2C (320,000 receptor / cell), human β 2 adrenergic receptor expressing cell line is expressed A high quantity cell line CHO / pKREX21-109-3 (600,000 receptor / cell) was selected and used for the following tests.

Test example : stimulating action of human β-adrenergic receptor

Human β 3 adrenergic receptor expressing cell line CHO / pKREX10-24-1A in 10% fetal bovine serum and 200 μg / ml G-418 in MEM-Dulbecco medium at 37 ° C., 5% CO 2 for 2 to 3 days Incubated below. After removing the medium, the medium was washed once with phosphate buffered saline (without calcium and magnesium), and 37 ° C in phosphate buffered saline with 0.5 mM EDTA (without calcium and magnesium). The cells were detached by standing for 5 minutes in the presence of 5% CO 2 . CHO / pKREX10-24-1A cells are collected by centrifugation to approximately 5 × 10 5 cells / ml in Hank's balanced salt solution containing 20 mM HEPES, 1 mM ascorbic acid and 0.5 mM 3-isobutyl-1-methylxanthine. So that it was suspended. 100 μl of this suspension was mixed with 500 μl of the test compound in the same balanced salt solution and reacted at 37 ° C. for 30 minutes, and then the reaction was stopped by boiling for 5 minutes. After centrifuging the reaction solution, the amount of cyclic AMP in the supernatant was measured using cAMP EIA System (manufactured by Bioscience).

Further, instead of the human β 3 adrenergic receptor expressing cell line CHO / pKREX10-24-1A, the human β 1 adrenergic receptor expressing cell line CHO / pKREX23-30-2C or the human β 2 adrenergic receptor expressing cell line CHO / pKREX21 The same operation was performed using −109-3, and the amount of cyclic AMP was measured.

The cyclic AMP amount when 10-6 M (-)-isoproterenol is added or not added is 100% and 0%, respectively, and the relative value of the cyclic AMP amount when the compound of the present invention is added is the intrinsic activity (I A.). 30% or more of I.V. A. For the compounds that showed values, the concentration (EC 50 ) causing 50% cyclic AMP accumulation was also calculated from the concentration-response curve of each compound by the least square method. The test results are shown in Table 4.

Table IV) * Test compound 10 -6 Relative value of cyclic AMP amount upon addition of M; ** means the compound of Example 58; *** Cannot be calculated due to low intrinsic activity; *** (- ) -Isoproterenol.

In this test, the EC 50 value is low and I.V. A. A compound having a high value is evaluated as having a strong stimulating effect on its receptor. Therefore, as is clear from Table 4, the compounds of the present invention have a strong stimulating action on human β 3 adrenergic receptors, but the stimulating action on human β 1 and human β 2 adrenergic receptors is very weak. there were. From the above results, the compound of the present invention is expected to be effective as a human β 3 adrenergic receptor agonist with excellent selectivity.

The compound of the present invention is used as a β 3 adrenergic receptor agonist to prevent obesity, diabetes, hyperlipidemia, irritable bowel syndrome, acute or chronic diarrhea, frequent urination, urinary incontinence, urinary calculus, depression, etc. It is useful as a therapeutic agent. The compound of the present invention is also useful as a remedy for 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, patient symptom / age, treatment mode (prevention or therapy), etc., but is usually 10 ng / kg / day to 10 mg / kg / day, preferably 0.1 μg / kg / day to 1 mg. / kg / day, more preferably 1 μg / kg / day to 100 μg / kg / day.

  The compound of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier. As a pharmaceutical carrier, a substance which 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 aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, 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, lauryl Sodium sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin Polysorbate, macrogol, vegetable oils, waxes, nonionic surfactants, 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 dissolved or suspended in water or other appropriate medium at the time of use. Tablets and granules may be coated by a known method. In the case of an injection, it is prepared by dissolving a physiologically acceptable salt of the compound represented by the general formula [I] in water, but an isotonic agent may be dissolved if necessary. Further, a pH adjusting agent, a buffering agent or a preservative may be added.

  These preparations can contain the compound of the present invention in an amount of 0.01% by weight or more, preferably 0.05 to 70% by weight. These formulations may also contain other therapeutically effective ingredients.

Since the compound of the present invention has excellent selectivity and strong β 3 adrenergic receptor stimulating action, obesity, diabetes, hyperlipidemia, irritable bowel syndrome, acute or chronic diarrhea, frequent urination, urinary incontinence, urinary tract It is useful as a preventive and therapeutic agent for stones and depression.

The present invention will be described more specifically with reference examples and examples, but the present invention is not limited to these examples. The compound was identified by hydrogen nuclear magnetic resonance absorption spectrum ( 1 H-NMR), liquid chromatography mass spectrometry (LC-MS) and the like.

Table 16 shows the LC-MS m / z (MH + ) and LC retention time for the compounds obtained in the examples.
LC-MS measurement conditions Ionization; Atmospheric pressure chemical ionization (APCI) separation column; Chromolith SpeedROD RP-18e (diameter 4.6 mm x 50 mm, manufactured by Merck)
Mobile phase; CH 3 CN: 0.05% trifluoroacetic acid aqueous solution = 80:20 unless otherwise noted
Flow rate: 1.0 ml / min Detection wavelength: 254 nm

  In the following, in order to simplify the description of the present specification, the following abbreviations may be used.

Me: methyl,
i Pr: Isopropyl,
t Bu: tert-butyl,
Boc: tert-butoxycarbonyl
THF: tetrahydrofuran,
DMF: dimethylformamide,
DMSO: dimethyl sulfoxide,
J: coupling constant,
s: single line,
d: double line,
dd: two double lines,
t: Triple line,
br: Broad,
m: multiple line.

(R) -3- (2-aminopropyl) -7-benzyloxy-1H-indole used as a raw material compound in Reference Examples or Examples was prepared according to the method described in JP-A No. 2000-319256. 2-Amino-2-methylpropyl) -7-benzyloxy-1H-indole is prepared according to the method described in J. Am. Chem. Soc., 69 , 3140-3142 (1947). Carbonyl) amino] benzyl bromide is obtained by the method described in Tetrahedron, 54 , 3999-4012 (1998), and 3-acetylbenzenethiol is obtained by the method described in Helv. Chim. Acta., 22 , 360-364 (1939). 2-formyl-1H-indole was prepared according to the method described in J. Am. Chem. Soc., 71 , 3541-3542 (1949), and 7-formylquinoline was converted into J. Med. Chem., 36 , 3308. -3320 (1993), respectively.

Reference Example 1 : Production of (R) -3- (2-aminopropyl) -7-methanesulfonyloxy-1H-indole

(First step)
After dissolving 112 g of (R) -3- (2-aminopropyl) -7-benzyloxy-1H-indole in 800 ml of ethyl acetate, a solution of 105 g of di-tert-butyl dicarbonate in 200 ml of ethyl acetate was added, and the mixture was stirred at room temperature for 3 hours. Stir. After evaporating the solvent under reduced pressure, 400 ml of hexane was added to the residue, and the insoluble solid was collected by filtration and dried to give (R) -7-benzyloxy-3- [2- (tert-butoxycarbonylamino) propyl] -1H-indole. 146 g was obtained.

(Second step)
To 60 g of the product of the first step, 500 ml of methanol and 6 g of 5% palladium carbon (containing about 50% water) were added and hydrogenated at room temperature and normal pressure for 3 hours. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure, 250 ml of hexane was added to the residue, the insoluble solid was collected by filtration and dried to give (R) -3- [2- (tert-butoxycarbonylamino) propyl] -7-. 46 g of hydroxy-1H-indole was obtained as crystals. Melting point 164 ~ 166 ℃

(Third step)
20.4 g of the product of the second step was dissolved in 150 ml of ethyl acetate, 13.3 ml of triethylamine was added, and 6.5 ml of methanesulfonyl chloride was added dropwise with stirring with ice cooling. After stirring at room temperature for 1.5 hours, the reaction solution was washed with water, 10% aqueous citric acid solution, water, 10% aqueous potassium carbonate solution and saturated brine in this order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (100: 1, v: v) to give (R) -3- [2- (tert-butoxycarbonylamino) propyl] -7-methanesulfonyl. 23.6 g of oxy-1H-indole was obtained as an amorphous solid.

(4th process)
After adding 35 ml of ethanol to 23.6 g of the product of the third step, 70 ml of 4 mol / l hydrogen chloride-ethyl acetate solution was added dropwise under ice cooling. After stirring at room temperature for 1.5 hours, the solvent was distilled off under reduced pressure, and 200 ml of ethyl acetate and 100 ml of 10% aqueous potassium carbonate solution were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 16.3 g of the title compound as crystals. Melting point 135-137 ° C

1 H-NMR (DMSO-d 6 , δppm): 0.99 (3H, d, J = 6.2 Hz), 1.80 (2H, br), 2.65 (2H, d, J = 6.6 Hz), 3.09 (1H, m) , 3.40 (3H, s), 6.99-7.09 (2H, m), 7.22 (1H, s), 7.52 (1H, d, J = 8.1 Hz), 11.25 (1H, s).

Reference Examples 2 to 4 :

  Instead of (R) -3- (2-aminopropyl) -7-benzyloxy-1H-indole and / or methanesulfonyl chloride in Reference Example 1, the corresponding tryptamine derivative and / or pyridine-3-sulfonyl chloride were used. The reaction and treatment were conducted in the same manner as in Reference Example 1 to obtain the compounds shown in Table 5.

Reference Example 5 : Production of 2-bromomethyl-6-chlorobenzothiazole

(First step)
After dissolving 4.86 g of 2,4-dichloroaniline in 50 ml of chloroform, 2.67 ml of pyridine and 3.11 ml of acetic anhydride were added and stirred at room temperature for 16 hours. The reaction solution was washed with water, diluted hydrochloric acid, water, 10% aqueous potassium carbonate solution and saturated brine in that order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 50 ml of diisopropyl ether was added to the residue, the insoluble solid was collected by filtration and dried to obtain 6 g of 2,4-dichloroacetanilide as crystals.

(Second step)
To 3 g of the product in the first step, 30 ml of toluene and 2 g of diphosphorus pentasulfide were added and stirred at 90 ° C. for 2 hours. The reaction solution was cooled to room temperature, and insoluble solids were removed by decantation, followed by extraction with a 10% aqueous sodium hydroxide solution. The mixture was neutralized with 10% hydrochloric acid under ice cooling, and extracted with ethyl acetate. The extract was washed with water, 10% aqueous potassium carbonate solution and saturated brine in that order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.31 g of 2,4-dichlorothioacetanilide as an oil, which was used for the next reaction without purification.

(Third step)
To 2.31 g of the product of the second step, 10 ml of 1-methylpyrrolidone and 3.68 g of 1,1,3,3-tetramethylguanidine were added and stirred at 150 ° C. for 2 hours. The reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with water, 5% aqueous sodium hydroxide solution, water and saturated brine in this order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane / ethyl acetate (3: 1, v: v) to give 1.33 g of 6-chloro-2-methylbenzothiazole as crystals.

1 H-NMR (CDCl 3 , δppm): 2.83 (3H, s), 7.40 (1H, dd, J = 8.7, 2.1 Hz), 7.80 (1H, d, J = 2.1 Hz), 7.85 (1H, d, J = 8.7 Hz).

(4th process)
To a solution of 1.28 g of the product of the third step in 30 ml of carbon tetrachloride, 0.1 g of 2,2-azobisisobutyronitrile and 2.14 g of N-bromosuccinimide were added, followed by heating under reflux for 16 hours. After cooling the reaction solution to room temperature, the insoluble solid was filtered off, and the filtrate was washed with water and then saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with hexane / ethyl acetate (3: 1, v: v) to obtain 0.59 g of the title compound as crystals.

1 H-NMR (CDCl 3 , δ ppm): 4.79 (2H, s), 7.46 (1H, dd, J = 8.6, 2.1 Hz), 7.86 (1H, d, J = 2.1 Hz), 7.92 (1H, d, J = 8.6 Hz).

Reference Examples 6 to 13 :

  In place of 2,4-dichloroaniline in the first step of Reference Example 5, reaction and treatment were performed in the same manner as in Reference Example 5 using 2,3-dichloroaniline to obtain the compound of Reference Example 6 shown in Table 6. . Further, instead of 5-chloro-2-methylbenzothiazole in the fourth step of Reference Example 5, the corresponding methyl compound was used for the reaction and treatment in the same manner as in the fourth step of Reference Example 5, and the references shown in Table 6 were used. The compounds of Examples 7-13 were obtained.

Reference Example 14 : Production of 3-chlorocinnamilk chloride

(First step)
After dissolving 7.3 g of 3-chlorocinnamic acid in 60 ml of THF, 5.42 ml of triethylamine was added, and 3.82 ml of ethyl chloroformate was added dropwise with stirring under ice cooling. After stirring for 10 minutes, the precipitated solid was filtered off, and a solution of 3.78 g of sodium borohydride in 30 ml of water was added dropwise to the filtrate under ice cooling. After stirring at room temperature for 3 hours, the reaction solution was ice-cooled and neutralized by adding 10% hydrochloric acid. After extraction with diisopropyl ether, the mixture was washed with a 5% aqueous sodium hydroxide solution and saturated brine in this order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 6.5 g of 3-chlorocinnamyl alcohol as an oil.

(Second step)
To a solution of 1.69 g of the product in the first step in 40 ml of dichloromethane were added 4.02 g of triphenylphosphine and 4.97 g of carbon tetrabromide under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with hexane / ethyl acetate (3: 1, v: v) to give 3.43 g of the title compound as an oil.

1 H-NMR (CDCl 3 , δppm): 4.12 (2H, d, J = 7.5 Hz), 6.39 (1H, m), 6.57 (1H, d, J = 15.5 Hz), 7.21-7.27 (3H, m) , 7.36 (1H, s).

Reference Examples 15 and 16 :

  Instead of 3-chlorocinnamic acid in the first step of Reference Example 14, the corresponding carboxylic acid was used for reaction and treatment in the same manner as in Reference Example 14 to obtain the compounds shown in Table 7.

Reference Example 17 : Preparation of 3-[[N- (tert-butoxycarbonyl) -N-methyl] amino] benzyl bromide

  After dissolving 1 g of 3-[(tert-butoxycarbonyl) amino] benzyl bromide in 15 ml of DMF, 0.21 g of 60% sodium hydride (containing mineral oil) and 5 g of methyl iodide were added with stirring under ice cooling, and the mixture was stirred at room temperature for 14 hours. did. The reaction mixture was ice-cooled, water was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane / ethyl acetate (8: 1, v: v) to give 0.96 g of the title compound as an oil.

1 H-NMR (CDCl 3 , δ ppm): 1.46 (9H, s), 3.26 (3H, s), 4.43 (2H, s), 7.08-7.31 (4H, m).

Reference Example 18 : Production of (R) -3-benzyloxy- [2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] benzene

(First step)
To a 180 ml THF solution of 14.2 g of 3-benzyloxyacetophenone, 21.6 g of phenyltrimethylammonium tribromide was added and stirred at room temperature for 15 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. Diisopropyl ether was added to the residue, washed twice with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with hexane / ethyl acetate (5: 1, v: v) to give 20 g of 3-benzyloxyphenacyl bromide as an oil.

(Second step)
In a solution of 17.5 g of the first step and 3 g of (R) -tetrahydro-1-methyl-3,3-diphenyl-1H, 3H-pyrrolo [1,2-c] [1,3,2] oxazaborol in 100 ml of THF Then, a 1 molar THF solution of borane-THF complex was slowly added dropwise with stirring at room temperature. After stirring for 1 hour, 100 ml of saturated aqueous ammonium chloride solution was added dropwise under ice cooling, and THF was distilled off under reduced pressure. The obtained aqueous solution was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with chloroform to obtain 15 g of (R) -3-benzyloxy- (2-bromo-1-hydroxyethyl) benzene as an oil.

(Third step)
11 g of tert-butyldimethylsilyl chloride was added to a solution of 15 g of the second step and 5 g of imidazole in 150 ml of DMF under stirring with ice cooling. After stirring at room temperature for 15 hours, diisopropyl ether and water were added for liquid separation, and the diisopropyl ether layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane / ethyl acetate (20: 1, v: v) to obtain 18.8 g of the title compound as an amorphous solid.

1 H-NMR (CDCl 3 , δppm): -0.09 (3H, s), 0.10 (3H, s), 0.89 (9H, s), 3.41-3.49 (2H, m), 4.81 (1H, m), 5.02 -5.10 (2H, m), 6.89-6.93 (2H, m), 6.98 (1H, m), 7.25 (1H, m), 7.30-7.45 (5H, m).

Reference Example 19 : (R)-[2-Bromo-1- (tert-butyldimethylsilyloxy) ethyl] -3-trifluoromethoxybenzene Instead of 3-benzyloxyacetophenone in Reference Example 18, 3-trifluoromethoxy The reaction and treatment were conducted in the same manner as in Reference Example 18 using acetophenone to obtain the title compound.

Reference Example 20 : Production of (R) -3-benzylthio- [2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] benzene

To a solution of 3.9 g of 3-acetylbenzenethiol in 30 ml of DMF, 1.4 g of potassium carbonate and 2 ml of benzyl bromide were added and stirred with heating at 60 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with hexane / diethyl ether (2: 1, v: v) to give 1.52 g of 3- (benzylthio) acetophenone. Obtained.
The reaction and treatment were conducted in a similar manner to Reference Example 18 using 3- (benzylthio) acetophenone instead of 3-benzyloxyacetophenone in Reference Example 18, and the title compound was obtained as an oil.

Reference Example 21 Production of (R) -3- (3-nitrobenzylthio)-[2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] benzene In place of benzyl bromide in Reference Example 20, 3- The reaction and treatment were carried out in the same manner as in Reference Example 20 using nitrobenzyl bromide to obtain the title compound as an oil.

Reference Example 22 : Production of (R) -3-benzylsulfoxy- [2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] benzene

  To a solution of 0.44 g of (R) -3-benzylthio- [2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] benzene obtained in Reference Example 20 in 10 ml of dichloromethane was added 0.52 g of metachloroperbenzoic acid. For 16 hours. Water was added to the reaction solution, extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with hexane / ethyl acetate (5: 1, v: v) to give 0.45 g of the title compound as an oil.

1 H-NMR (CDCl 3 , δ ppm): -0.13 (3H, s), 0.08 (3H, s), 0.87 (9H, s), 3.22-3.38 (2H, m), 4.30 (2H, s), 4.81 (1H, dd, J = 6.6, 5.1 Hz), 7.04 (2H, d, J = 7.0 Hz), 7.18-7.34 (3H, m), 7.43 (1H, m), 7.50-7.70 (3H, m).

Reference Example 23 : Production of (R)-[2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] -3-methoxybenzene

(First step)
50 g of ethanol and 5% palladium carbon (containing about 50% water) in 5 g of (R) -3-benzyloxy- [2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] benzene obtained in Reference Example 18 0.5 g was added and hydrogenated at room temperature and normal pressure for 3 hours. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to obtain 3.5 g of an oily substance containing (R)-[2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] -3-hydroxybenzene, which was purified. Used in the second step without.

(Second step)
To a solution of 0.4 g of the product of the first step in 10 ml of DMF, 0.06 g of 60% sodium hydride (containing mineral oil) was added with stirring under ice cooling, and then 0.26 g of methyl iodide was added dropwise. After stirring at room temperature for 3 hours, 20 ml of 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to medium pressure silica gel column chromatography and eluted with hexane / ethyl acetate (30: 1, v: v) to give 0.38 g of the title compound as an oil.

1 H-NMR (CDCl 3 , δppm): -0.08 (3H, s), 0.11 (3H, s), 0.93 (9H, s), 3.45 (2H, d, J = 6.0 Hz), 3.81 (3H, s ), 4.83 (1H, t, J = 6.0 Hz), 6.82 (1H, m), 6.89-6.92 (2H, m), 7.24 (1H, m).

Reference Examples 24-38 :
Instead of methyl iodide in Reference Example 23, the corresponding halide was used and reacted and treated in the same manner as in Reference Example 23 to obtain the compounds shown in Table 8.

Reference Example 39 : (R)-[2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] -3- (2-phenylethoxy) benzene

(First step)
(R)-[2-Bromo-1- (tert-butyldimethylsilyloxy) ethyl] -3-hydroxybenzene 0.5 g, triphenylphosphine 0.79 g, 2-phenylethanol 0.37 g in THF 20 ml solution was stirred with ice cooling. Lower diethyl azodicarboxylate 0.55g was dripped. After stirring at room temperature for 18 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. This solution was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane / ethyl acetate (50: 1, v: v) to give 0.55 g of the title compound as an oil.

1 H-NMR (CDCl 3 , δppm): -0.08 (3H, s), 0.10 (3H, s), 0.89 (9H, s), 3.10 (2H, t, J = 7.1 Hz), 3.40-3.45 (2H , m), 4.17 (2H, t, J = 7.1 Hz), 4.80 (1H, m), 6.81 (1H, m), 6.89-6.91 (2H, m), 7.20-7.35 (6H, m).

Reference Example 40 : Production of (R) -4-benzyloxy- [2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] -3-methanesulfonyloxybenzene

(First step)
After adding 17.8 ml of benzyl bromide and 43.5 ml of diisopropylethylamine to a DMF 10 ml solution of 3,4-dihydroxyacetophenone 15.2 g, the mixture was heated to reflux for 78 hours. After cooling the reaction solution to room temperature, 600 ml of toluene was added, washed with water, 1N hydrochloric acid, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. Toluene was distilled off under reduced pressure to about 100 ml, and the solid precipitated by ice cooling was collected by filtration. After washing with toluene / hexane (1: 1, v: v) and drying, 12.3 g of 4-benzyloxy-3-hydroxyacetophenone was obtained.

(Second step)
The product of the first step was brominated in the same manner as in the first step of Reference Example 19 to obtain 4-benzyloxy-3-hydroxyphenacyl bromide as a solid.

(Third step)
To a solution of 2.1 g of the product in the second step and 1 g of triethylamine in 50 ml of dichloromethane was added dropwise a solution of 0.82 g of methanesulfonyl chloride in 10 ml of dichloromethane, followed by stirring at room temperature for 15 hours. The reaction mixture was washed with water, 1N hydrochloric acid and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane / ethyl acetate (5: 1-3: 1, v: v) to give 1.47 g of 4-benzyloxy-3-methanesulfonyloxyphenacyl bromide as a solid. It was.

(4th process, 5th process)
Using the product of the third step, a reduction reaction and a silylation reaction were carried out in the same manner as in the second step and the third step of Reference Example 19 to obtain 1.8 g of the title compound as an oil.

1 H-NMR (CDCl 3 , δ ppm): -0.05 (3H, s), 0.11 (3H, s), 0.89 (9H, s), 3.06 (3H, s), 3.50 (1H, dd, J = 11.1, 4.7 Hz), 3.56 (1H, dd, J = 11.1, 7.3 Hz), 4.77 (1H, dd, J = 7.3, 4.7 Hz), 5.11 (2H, s), 7.04 (1H, d, J = 8.6 Hz) , 7.24 (1H, m), 7.33-7.46 (6H, m).

Reference Example 41 Production of (R) -3-benzenesulfonyloxy-4-benzyloxy- [2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] benzene

  The reaction and treatment were conducted in the same manner as in Reference Example 40 using benzenesulfonyl chloride in place of methanesulfonyl chloride in the third step of Reference Example 40, and the title compound was obtained as an oil.

Reference Example 42 : 3-[(2R) -2- [N-[(2R) -2- (3-aminophenyl) -2-hydroxyethyl] -N- (tert-butoxycarbonyl) amino] propyl] -7 -Production of methanesulfonyloxy-1H-indole

(First step)
A solution of 24.4 g of 3-nitrophenacyl bromide and 4.2 g of (R) -tetrahydro-1-methyl-3,3-diphenyl-1H, 3H-pyrrolo [1,2-c] [1,3,2] oxazaborol in 200 ml of THF A 1 molar THF solution of borane-THF complex was slowly added dropwise thereto while stirring at room temperature. After stirring for 1 hour, 200 ml of a saturated aqueous ammonium chloride solution was added dropwise under ice cooling, and THF was distilled off under reduced pressure. The obtained aqueous solution was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and 100 ml of hexane / diisopropyl ether (3: 2, v: v) was added to the crystals obtained by elution with chloroform, followed by stirring. Insoluble crystals were collected by filtration and dried to obtain 18.7 g of (R) -3-nitro- (2-bromo-1-hydroxyethyl) benzene.
(Second step)
To a solution of 12.0 g of the product of the first step in 49 ml of THF, 98 ml of 2N aqueous sodium hydroxide solution was added and stirred at room temperature for 1 hour. To the reaction solution was added 700 ml of ethyl acetate, and the mixture was separated, and the organic layer was washed with water and then saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 8.2 g of crude (R)-(3-nitrophenyl) oxirane as an oil, which was used in the next reaction without purification.

(Third step)
(R) -3- (2-aminopropyl) -7-methanesulfonyloxy-1H-indole (17.0 g) was added to a solution of 8.2 g of the product of the second step in DMF (65 ml), and the mixture was stirred at 90 ° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, 600 ml of ethyl acetate was added, and the mixture was washed with water and saturated brine in this order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluting with chloroform / methanol (40: 1, v: v) to give 3-[(2R) -2- 18.1 g of [[(2R) -2-hydroxy-2- (3-nitrophenyl) ethyl] amino] propyl] -7-methanesulfonyloxy-1H-indole was obtained as an amorphous solid.

(4th process)
10.9 g of di-tert-butyl dicarbonate was added to a solution of 18.1 g of the product of the third step in 350 ml of chloroform and stirred at room temperature for 16 hours. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with chloroform / methanol (60: 1, v: v) to give 3-[(2R) -2- [N- 20.5 g of [(2R) -2-hydroxy-2- (3-nitrophenyl) ethyl] -N- (tert-butoxycarbonyl) amino] propyl] -7-methanesulfonyloxy-1H-indole was obtained as an amorphous solid. .

(5th process)
To a mixture consisting of 8 g of reduced iron, 2 g of ammonium chloride, 100 ml of ethanol and 50 ml of water, 20.5 g of the product of the fourth step was added and heated to reflux for 2 hours. The reaction solution was allowed to cool to room temperature, insoluble material was removed by filtration, and ethanol in the filtrate was distilled off under reduced pressure. The resulting aqueous solution was made basic by adding a 5% aqueous sodium hydroxide solution, and then extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude product was subjected to silica gel column chromatography and eluted with chloroform / methanol (100: 1, v: v) to obtain 17.6 g of the title compound as an amorphous solid.

1 H-NMR (CDCl 3 , δppm): 1.20 (9H, s), 1.27 (3H, d, J = 6.8 Hz), 2.68-2.90 (2H, m), 3.10-3.19 (4H, m), 3.35- 3.98 (3H, m), 4.27 (1H, m), 4.59 (1H, m), 6.53-6.76 (3H, m), 6.85-7.14 (4H, m), 7.51 (1H, m), 8.82 (1H, s).

Reference Example 43 : (R) -3- [2- [N- [2- (3-aminophenyl) -2-hydroxyethyl] -N- (tert-butoxycarbonyl) amino] ethyl] -7-methanesulfonyloxy Of 1H-indole

  Instead of (R) -3- (2-aminopropyl) -7-methanesulfonyloxy-1H-indole in the second step of Reference Example 42, 3- (2-aminoethyl) -7-methanesulfonyloxy-1H Reaction was performed in the same manner as in Reference Example 42 using indole to obtain the title compound.

Reference Example 44 : 3-[(2R) -2- [N-[(2R) -2-hydroxy-2- (3-hydroxyphenyl) ethyl] -N- (tert-butoxycarbonyl) amino] propyl] -7 -Production of methanesulfonyloxy-1H-indole

  Instead of (R) -3- (2-aminopropyl) -7-benzyloxy-1H-indole in Reference Example 1, 3-[(2R) -2-[[(2R) 2- (3-Benzyloxyphenyl) -2-hydroxyethyl] amino] propyl] -7-methanesulfonyloxy-1H-indole was reacted and treated in the same manner as in the first step and the second step of Reference Example 1. The title compound was obtained.

Example 1 : Preparation of 3-[(2R) -2-[[(2R) -2- (3-benzyloxyphenyl) -2-hydroxyethyl] amino] propyl] -7-methanesulfonyloxy-1H-indole

(First step)
(R) -3-Benzyloxy- [2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] benzene (2.53 g) and (R) -3- (2-aminopropyl) -7-methanesulfonyloxy-1H -After adding 2.41 g of indole, 0.93 g of diisopropylethylamine and 60 ml of acetonitrile, the mixture was heated to reflux for 18 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in 60 ml of ethyl acetate and washed with water and saturated brine in this order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluting with chloroform / methanol (50: 1, v: v) to give 3-[(2R) -2- 3.2 g of [[(2R) -2- (3-benzyloxyphenyl) -2- (tert-butyldimethylsilyloxy) ethyl] amino] propyl] -7-methanesulfonyloxy-1H-indole was obtained as an amorphous solid. .

(Second step)
75 ml of 4 mol / l hydrogen chloride-ethyl acetate solution was added dropwise to a solution of 3.2 g of the product of the first step in 25 ml of ethanol under ice cooling. After stirring at room temperature for 2 hours, the solvent was evaporated under reduced pressure, and 60 ml of ethyl acetate and 20 ml of 10% aqueous potassium carbonate solution were added to the residue and stirred. After liquid separation, the ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with chloroform / methanol (10: 1, v: v) to obtain 2.14 g of the title compound as an amorphous solid.

Example 2 : Preparation of 3-[(2R) -2-[[(2R) -2-hydroxy-2- (3-hydroxyphenyl) ethyl] amino] propyl] -7-methanesulfonyloxy-1H-indole

20 ml of ethanol and 0.1 g of 5% palladium carbon (containing about 50% water) were added to 0.31 g of the compound of Example 1, and hydrogenated at room temperature and normal pressure for 18 hours. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform / methanol (10: 1, v: v) to obtain 0.2 g of the title compound as an amorphous solid. .
Examples 3 to 21 :
(R) -3-Benzyloxy- [2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] benzene and / or (R) -3- (2-aminopropyl) -7-methane in Example 1 Instead of sulfonyloxy-1H-indole, the corresponding benzene compound and / or indole derivative was used for reaction and treatment in the same manner as in Example 1 to obtain the compounds shown in Table 9 as an amorphous solid.

Example 22 3-[(2R) -2-[[(2R) -2- [3- (benzenesulfonyloxy) phenyl] -2-hydroxyethyl] amino] propyl] -7-methanesulfonyloxy-1H- Indole manufacturing

(First step)
3-[(2R) -2- [N-[(2R) -2-hydroxy-2- (3-hydroxyphenyl) ethyl] -N- (tert-butoxycarbonyl) amino] propyl] -7-methanesulfonyloxy To a solution of 0.62 g of -1H-indole and 0.19 g of triethylamine in 15 ml of dichloromethane was added 0.26 g of benzenesulfonyl chloride. After stirring at room temperature for 18 hours, the reaction mixture was washed with 1N hydrochloric acid and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography eluting with ethyl acetate / hexane (5: 1, v: v) to give 3-[(2R) -2- [N-[(2R) -2- [3- 0.66 g of (benzenesulfonyloxy) phenyl] -2-hydroxyethyl] -N- (tert-butoxycarbonyl) amino] propyl] -7-methanesulfonyloxy-1H-indole was obtained as an amorphous solid.

(Second step)
0.66 g of the product of the first step was dissolved in 10 ml of 4 mol / l hydrogen chloride-ethyl acetate solution and stirred at room temperature for 2 hours. The reaction solution was made alkaline by adding 10 ml of 10% aqueous potassium carbonate solution, and the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform / methanol (10: 1, v: v) to obtain 0.38 g of the title compound as an amorphous solid.

Examples 23-29 :
Instead of the benzenesulfonyl chloride in Example 22, the corresponding various sulfonyl chloride derivatives were used for reaction and treatment in the same manner as in Example 22 to obtain the compounds shown in Table 10 as an amorphous solid.

Example 30 3-[(2R) -2-[[(2R) -2- (3-aminophenyl) -2-hydroxyethyl] amino] propyl] -7- (3-pyridine) sulfonyloxy-1H- Indole manufacturing

(First step)
Instead of (R) -3- (2-aminopropyl) -7-methanesulfonyloxy-1H-indole in the second step of Reference Example 42, (R) -3- (2-aminopropyl) -7- ( 3-Pyridinyl) sulfonyloxy-1H-indole was reacted and treated in the same manner as in Reference Example 42 to give 3-[(2R) -2- [N-[(2R) -2- (3-aminophenyl)- 2-Hydroxyethyl] -N- (tert-butoxycarbonyl) amino] propyl] -7- (3-pyridine) sulfonyloxy-1H-indole was obtained.

(Second step)
The product of the first step was reacted and treated in the same manner as in the second step of Example 22 to remove Boc, and then the crude product was subjected to silica gel column chromatography (eluent: chloroform / methanol, 10: 1, Purification using v: v) gave the title compound as an amorphous solid.

Example 31 Production of (R) -3- [2-[[2- (3-aminophenyl) -2-hydroxyethyl] amino] ethyl] -7-methanesulfonyloxy-1H-indole

  (R) -3- [2- [N- [2- (3-aminophenyl) -2-hydroxyethyl] -N- (tert-butoxycarbonyl) amino] ethyl] -7- which is the compound of Reference Example 43 Using methanesulfonyloxy-1H-indole, the reaction and treatment were carried out in the same manner as in the second step of Example 22 to remove Boc, and then the crude product was subjected to silica gel column chromatography (eluent: chloroform / methanol, 10: 1, v: v) to give the title compound as an amorphous solid.

Example 32 3-[(2R) -2-[[(2R) -2- (4-hydroxy-3-methanesulfonyloxyphenyl) -2-hydroxyethyl] amino] propyl] -7-methanesulfonyloxy- Production of 1H-indole production

  Instead of (R) -3-benzyloxy- [2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] benzene in Example 1, (R) -4-benzyloxy which is the compound of Reference Example 40 3-[(2R) -2-obtained by reacting and treating in the same manner as in Example 1 using-[2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] -3-methanesulfonyloxybenzene After dissolving 0.2 g of [[(2R) -2- (4-benzyloxy-3-methanesulfonyloxyphenyl) -2-hydroxyethyl] amino] propyl] -7-methanesulfonyloxy-1H-indole in 10 ml of ethanol, 0.2 g of 20% palladium hydroxide carbon was added and hydrogenated at 50 ° C. and normal pressure for 1.5 hours. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure, and the crude product was purified using silica gel column chromatography (eluent: chloroform / methanol, 10: 1, v: v) to give 0.12 g of the title compound as an amorphous solid. Got as.

Example 33 3-[(2R) -2-[[(2R) -2- (3-benzenesulfonyloxy-4-hydroxyphenyl) -2-hydroxyethyl] amino] propyl] -7-methanesulfonyloxy- Production of 1H-indole production

  Instead of (R) -4-benzyloxy- [2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] -3-methanesulfonyloxybenzene in Example 32, (R) -3-benzenesulfonyloxy The reaction and treatment were conducted in the same manner as in Example 32 using -4-benzyloxy- [2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] benzene to obtain 0.12 g of the title compound as an amorphous solid.

Example 34 3-[(2R) -2-[(2R) -2-hydroxyethyl-2- [3- (2-naphthylmethylamino) phenyl] amino] propyl] -7-methanesulfonyloxy-1H- Indole manufacturing

(First step)
3-[(2R) -2- [N-[(2R) -2- (3-aminophenyl) -2-hydroxyethyl] -N- (tert-butoxycarbonyl) amino] propyl] -7-methanesulfonyloxy After dissolving 0.3 g of -1H-indole in 5 ml of DMF, 0.084 g of potassium carbonate and 0.132 g of naphthylmethyl bromide were added, and the mixture was heated and stirred at 80 ° C. for 5 hours. The reaction mixture was allowed to cool to room temperature, the solvent was evaporated under reduced pressure, the residue was dissolved in 30 ml of ethyl acetate, and washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography eluting with hexane / ethyl acetate (3: 1, v: v) to give 3-[(2R) -2- [N-[(2R) -2-hydroxyethyl-2]. -[3- (2-Naphtylmethylamino) phenyl]]-N- (tert-butoxycarbonyl) amino] propyl] -7-methanesulfonyloxy-1H-indole was obtained as an amorphous solid.

(Second step)
0.6 ml of a 4 mol / l hydrogen chloride-ethyl acetate solution was added to a solution of 0.112 g of the product of the first step in 0.2 ml of ethanol, followed by stirring at room temperature for 2 hours. To the reaction solution, 10 ml of ethyl acetate and 5 ml of 10% potassium carbonate aqueous solution were added and stirred. The ethyl acetate layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with chloroform / methanol (10: 1, v: v) to obtain 0.074 g of the title compound as an amorphous solid.

Examples 35-75 :
3-[(2R) -2- [N-[(2R) -2- (3-aminophenyl) -2-hydroxyethyl] -N- (tert-butoxycarbonyl) amino] propyl] -7 in Example 34 Instead of methanesulfonyloxy-1H-indole and / or naphthylmethyl bromide, (R) -3- [2- [N- [2- (3-aminophenyl) -2-hydroxyethyl] -N- (tert -Butoxycarbonyl) amino] ethyl] -7-methanesulfonyloxy-1H-indole and / or the corresponding bromo form or chloro form, reaction and treatment in the same manner as in Example 34, and compounds shown in Tables 11 and 12 Was obtained as an amorphous solid.

Example 76 3-[(2R) -2-[(2R) -2-hydroxyethyl-2- [3-[(1-methyl-1H-indol-2-yl) methylamino] phenyl] amino] propyl ] -7 Production of methanesulfonyloxy-1H-indole (first step)
3-[(2R) -2- [N-[(2R) -2- (3-aminophenyl) -2-hydroxyethyl] -N- (tert-butoxycarbonyl) amino] propyl] -7-methanesulfonyloxy After adding 40 μl of acetic acid and 0.3 g of 2-formyl-1-methyl-1H-indole to a THF 3 ml solution of 0.3 g of 1H-indole, 0.073 g of sodium cyanoborohydride was added under ice cooling. After stirring at room temperature for 64 hours, the mixture was stirred at 50 ° C. for 6 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 30 ml of ethyl acetate, and then washed with a 10% aqueous potassium carbonate solution, water and saturated brine in this order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography eluting with hexane / ethyl acetate (3: 2, v: v) to give 3-[(2R) -2- [N-[(2R) -2-hydroxyethyl-2]. -[3-[(1-Methyl-1H-indol-2-yl) methylamino] phenyl]]-N- (tert-butoxycarbonyl) amino] propyl] -7-methanesulfonyloxy-1H-indole Obtained as an amorphous solid.

(Second step)
After 0.28 g of the product of the first step was reacted and treated in the same manner as in the second step of Example 34 to de-Boc, the crude product was subjected to silica gel column chromatography (eluent: chloroform / methanol, 50 : 1-9: 1, v: v) to give 0.12 g of the title compound as an amorphous solid.

Examples 77-88 :
3-[(2R) -2- [N-[(2R) -2- (3-aminophenyl) -2-hydroxyethyl] -N- (tert-butoxycarbonyl) amino] propyl] -7 in Example 76 Instead of methanesulfonyloxy-1H-indole and / or 2-formyl-1-methyl-1H-indole, (R) -3- [2- [N- [2- (3-aminophenyl) -2- Hydroxyethyl] -N- (tert-butoxycarbonyl) amino] ethyl] -7-methanesulfonyloxy-1H-indole and / or the corresponding aldehyde were reacted and treated in the same manner as in Example 76, and are shown in Table 13. The compound was obtained as an amorphous solid.

Example 89 3-[(2R) -2-[(2R) -2-hydroxyethyl-2- [3-[(indoline-4-yl) methylamino] phenyl] amino] propyl] -7-methanesulfonyl Production of oxy-1H-indole (first step)
3-[(2R) -2- [N-[(2R) -2- [3-[(4-Indolyl) methylamino] phenyl] -2-hydroxyethyl] -N obtained as an intermediate in Example 83 -(Tert-Butoxycarbonyl) amino] propyl] -7-methanesulfonyloxy-1H-indole A solution of 250 mg of acetic acid in 1 ml was added with sodium cyanoborohydride (74 mg) and stirred at room temperature for 2 hours. To the reaction solution was added 10 ml of 10% aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography eluting with hexane / ethyl acetate (3: 2, v: v) to give 3-[(2R) -2- [N-[(2R) -2- [3- 152 mg of [(Indoline-4-yl) methylamino] phenyl] -2-hydroxyethyl] -N- (tert-butoxycarbonyl) amino] propyl] -7-methanesulfonyloxy-1H-indole was obtained as an amorphous solid.

(Second step)
The product of the first step, 152 mg, was reacted and treated in the same manner as in the second step of Example 34 to remove Boc, and then the crude product was subjected to silica gel column chromatography (eluent: chloroform / methanol, 12: 1-6: 1, v: v) to give 100 mg of the title compound as an amorphous solid.

Examples 90, 91 :
3-[(2R) -2-[(2R) -2-hydroxyethyl-2- [3- (4-indolylmethylamino) phenyl] amino] propyl] -7-methanesulfonyloxy-1H in Example 89 -The reaction and treatment were performed in the same manner as in Example 89 using the corresponding indole instead of the indole, and the compounds shown in Table 14 were obtained as an amorphous solid.

Example 92 Preparation of (R) -3- [2-[[2- [3-[(3-hydroxybenzyl) amino] phenyl] -2-hydroxyethyl] amino] ethyl] -1H-indole

  1.19 ml of a 1 molar solution of boron tribromide in dichloromethane 15 ml was added dropwise to a solution of the compound of Example 52 in 273 mg of dichloromethane 15 ml. After stirring at room temperature for 15 hours, 2 ml of methanol was added to the reaction solution under ice cooling, and then neutralized with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with chloroform / methanol (10: 1 to 7: 1, v: v) to obtain 140 mg of the title compound as an amorphous solid.

Example 93 : 3-[(2R) -2-[[(2R) -2- [3-[(3-hydroxybenzyl) amino] phenyl] -2-hydroxyethyl] amino] propyl] -1H-indole Manufacturing

  3-[(2R) -2-[[(2R) -2- [3-[(3-methoxybenzyl) amino] phenyl] -2-hydroxyethyl] amino] propyl] -1H-indole (of Example 64 The compound was used in the same manner as in Example 92 to obtain the title compound as an amorphous solid.

Example 94 3-[(2R) -2-[[(2R) -2- [3- (3-aminobenzyloxy) phenyl] -2-hydroxyethyl] amino] propyl] -7-methanesulfonyloxy- Production of 1H-indole

(First step)
Instead of (R) -3-benzyloxy- [2-bromo-1- (tert-butyldimethylsilyloxy) ethyl] benzene in Example 1, (R)-[2-bromo-1- (tert-butyl) Dimethylsilyloxy) ethyl] -3- (3-nitrobenzyloxy) benzene (compound of Reference Example 32) was used for the reaction and treatment in the same manner as in the first step of Example 1, and 3-[(2R) -2 -[[(2R) -2- (tert-butyldimethylsilyloxy) -2- [3- (3-nitrobenzyloxy) phenyl] ethyl] amino] propyl] -7-methanesulfonyloxy-1H-indole is obtained. It was.

(Second step)
To a mixture consisting of 283 mg of reduced iron, 126 mg of ammonium chloride, 12 ml of ethanol and 6 ml of water, 541 mg of the product of the first step was added and heated to reflux for 2 hours. The reaction solution was allowed to cool to room temperature, insoluble material was removed by filtration, and ethanol in the filtrate was distilled off under reduced pressure. The resulting aqueous solution was made basic by adding a 5% aqueous sodium hydroxide solution, and then extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude product was subjected to silica gel column chromatography and eluted with chloroform / methanol (70: 1, v: v) to give 3-[(2R) -2-[[(2R) -2- [3- ( 491 mg of 3-aminobenzyloxy) phenyl] -2- (tert-butyldimethylsilyloxy) ethyl] amino] propyl] -7-methanesulfonyloxy-1H-indole was obtained.

(Third step)
The product of the first step, 152 mg, was reacted and treated in the same manner as in the second step of Example 1 for desilylation, and then the crude product was subjected to silica gel column chromatography (eluent: chloroform / methanol, 12: 1-6: 1, v: v) to give 323 mg of the title compound as an amorphous solid.

Examples 95-99 :

  (R)-[2-Bromo-1- (tert-butyldimethylsilyloxy) ethyl] -3- (3-nitrobenzyloxy) benzene and / or (R) -3- (2-aminopropyl) in Example 94 ) Instead of -7-methanesulfonyloxy-1H-indole, the corresponding nitro compound and / or tryptamine derivative was used for reaction and treatment in the same manner as in Example 94 to obtain the compounds shown in Table 15 as an amorphous solid.

Example 100 3-[(2R) -2-[[(2R) -2- [3-[(3-aminobenzene) sulfonyloxy] phenyl] -2-hydroxyethyl] amino] propyl] -7-methane Production of sulfonyloxy-1H-indole

(First step)
The reaction and treatment were conducted in the same manner as in the first step of Example 22 using (3-nitrobenzene) sulfonyl chloride instead of benzenesulfonyl chloride in Example 22, and 3-[(2R) -2- [N-[( 2R) -2-Hydroxy-2- [3-[(3-nitrobenzene) sulfonyloxy] phenyl] ethyl] -N- (tert-butoxycarbonyl) amino] propyl] -7-methanesulfonyloxy-1H-indole is obtained. It was.

(Second step)
40 ml of ethanol and 40 mg of 10% palladium carbon were added to 384 mg of the product of the first step, and hydrogenated at room temperature and normal pressure for 4 hours. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure, and 3-[(2R) -2- [N-[(2R) -2- [3-[(3-aminobenzene) sulfonyloxy] phenyl] -2- Hydroxyethyl] -N- (tert-butoxycarbonyl) amino] propyl] -7-methanesulfonyloxy-1H-indole was obtained.
(Third step)
The product of the second step, 685 mg, was reacted and treated in the same manner as in the second step of Example 22 to remove Boc, and then the crude product was subjected to silica gel column chromatography (eluent: chloroform / methanol, 10: 1). , V: v) to give 250 mg of the title compound as an amorphous solid.

Example 101 : (R) -3- [2-[[2- [3-[(3-aminobenzyl) amino] phenyl] -2-hydroxyethyl] amino] ethyl] -7-methanesulfonyloxy-1H- Indole manufacturing

  To a mixture of 1 g of reduced iron, 250 mg of ammonium chloride, 10 ml of ethanol and 5 ml of water, (R) -3-[-2-[[2-hydroxy-2- [3-[(3-nitrobenzyl) amino] phenyl] 200 mg of [ethyl] amino] ethyl] -7-methanesulfonyloxy-1H-indole (the compound of Example 36) was added, and the mixture was heated to reflux for 3 hours. The reaction solution was allowed to cool to room temperature, insoluble material was removed by filtration, and ethanol in the filtrate was distilled off under reduced pressure. The resulting aqueous solution was made basic by adding saturated aqueous sodium hydrogen carbonate, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude product was subjected to silica gel column chromatography and eluted with chloroform / methanol / triethylamine (100: 10: 1, v: v: v) to give 120 mg of the title compound as an amorphous solid.

Example 102 3-[(2R) -2-[[(2R) -2- [3-[(3-aminobenzyl) amino] phenyl] -2-hydroxyethyl] amino] propyl] -7-methanesulfonyl Production of oxy-1H-indole

  Instead of 3- (2-aminoethyl) -7-methanesulfonyloxy-1H-indole in Example 36, (R) -3- (2-aminopropyl) -7-methanesulfonyloxy-1H-indole was used. The resulting 3-[(2R) -2- [N-[(2R) -2-hydroxy-2- [3-[(3-nitrobenzene) sulfonyloxy] phenyl] ethyl] -N- (tert-butoxycarbonyl ) Amino] propyl] -7-methanesulfonyloxy-1H-indole was subjected to nitro group reduction in the same manner as in Example 101 to obtain the title compound as an amorphous solid.

Formulation example : (Tablet manufacturing method)

  In accordance with a conventional method, the compound of Example 1, lactose, corn starch and hydroxypropyl cellulose are granulated according to a conventional method, to which crystalline cellulose, light anhydrous silicic acid and magnesium stearate are added and mixed, compression molded, One tablet of 100 mg was prepared.

Since the compound of the present invention has excellent selectivity and strong β 3 adrenergic receptor stimulating action, obesity, diabetes, hyperlipidemia, irritable bowel syndrome, acute or chronic diarrhea, frequent urination, urinary incontinence, urinary tract It is useful as a preventive and therapeutic agent for stones and depression.

Claims (15)

  1. A sulfonyloxyindole derivative represented by the following formula [I] or a physiologically acceptable salt thereof.
    (Wherein R 1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a trifluoromethyl group, a benzyloxy group, a lower alkoxy group, a hydroxyl group, an amino group, or a mono- or di-substituted lower alkylamino group;
    R 3 and R 4 are the same or different and each represents a hydrogen atom, a lower alkyl group, or a cyclic lower alkyl group in which R 3 and R 4 are combined;
    R 5 represents a hydrogen atom or an optionally substituted lower alkyl group,
    OSO 2 R 6 and R 7 are bonded to any of the 4-position, 5-position, 6-position or 7-position of the indole ring;
    R 6 is an optionally substituted lower alkyl group, cyclic lower alkyl group, lower alkenyl group, lower alkynyl group, optionally substituted naphthyl group, optionally substituted phenyl group, or optionally substituted. Means a heteroaryl group, a mono- or di-substituted lower alkylamino group or a cyclic amino group;
    Alternatively, when OSO 2 R 6 is bonded to position 7 of the indole ring, R 5 and R 6 may be combined to form a linear or branched lower alkylene moiety,
    R 7 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group,
    R 2 means a group represented by a trifluoromethoxy group, a difluoromethoxy group, a fluoromethoxy group, X 1 -R 8 , OSO 2 -R 9 or X 2 -A 1 -R 10 ;
    X 1 represents an oxygen atom, a sulfur atom or NH,
    R 8 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group,
    R 9 is an optionally substituted lower alkyl group, a cyclic lower alkyl group, a lower alkenyl group, a lower alkynyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group, or optionally substituted. Means a heteroaryl group,
    X 2 represents an oxygen atom, a sulfur atom, NH or SO 2 ,
    A 1 means a linear or branched lower alkylene moiety, a linear or branched lower alkenylene moiety or a linear or branched lower alkynylene moiety,
    R 10 is an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted heteroaryl group, a halogen atom, a lower alkoxy group, a cyclic lower alkyl group, a hydroxyl group, a nitro group, a cyano group. , Carboxyl group, lower alkoxycarbonyl group, carbamoyl group, mono- or di-substituted lower alkylaminocarbonyl group, cyclic aminocarbonyl group, phenylaminocarbonyl group, naphthylaminocarbonyl group, heteroarylaminocarbonyl group, amino group, mono- or di-substituted It means a lower alkylamino group or a cyclic amino group.
    However, when A 1 is methylene, R 10 is a group other than a halogen atom, a hydroxyl group, a nitro group, an amino group, a mono- or di-substituted lower alkylamino group, or a cyclic amino group. )
  2.   The compound or a physiologically acceptable salt thereof according to claim 1, wherein the configuration of the asymmetric carbon substituted with a benzene ring and a hydroxyl group is an R configuration.
  3. The compound or a physiologically acceptable salt thereof according to claim 2, wherein R 1 is a hydrogen atom, a hydroxyl group or an amino group, and R 7 is a hydrogen atom.
  4. The compound according to claim 3, wherein R 3 and R 4 are the same or different and are a hydrogen atom or a methyl group, and OSO 2 R 6 is a group bonded to the 6- or 7-position of the indole ring, or a physiologically acceptable compound thereof Salt.
  5. 5. The compound according to claim 4, wherein R 5 is a hydrogen atom or a lower alkyl group, and R 6 is a lower alkyl group, an optionally substituted phenyl group or an optionally substituted heteroaryl group, or a physiologically physiological compound thereof. Acceptable salt.
  6. 5. The compound according to claim 4, wherein OSO 2 R 6 is a group bonded to the 7-position of the indole ring, and R 5 and R 6 are combined to form a linear or branched lower alkylene moiety. Physiologically acceptable salt.
  7. 6. The compound according to claim 5, or a physiologically acceptable salt thereof, wherein OSO 2 R 6 is a group bonded to the 7-position of the indole ring, and R 6 is a lower alkyl group.
  8. The compound according to claim 7 or a physiologically acceptable salt thereof, wherein R 2 is a group represented by X 1 -R 8 or X 2 -A 1 -R 10 .
  9. R 2 is a group represented by X 2 -A 1 -R 10 , and R 10 is an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted heteroaryl group. A compound according to claim 8 or a physiologically acceptable salt thereof.
  10. The compound or a physiologically acceptable salt thereof according to claim 9, wherein X 2 is NH, and A 1 is a linear or branched lower alkylene moiety or a linear or branched lower alkenylene moiety.
  11. Is a group R 2 is represented by OSO 2 -R 9, phenyl group optionally R 9 is substituted, may be substituted naphthyl group, claims a heteroaryl group which may be substituted 7. The compound according to 7, or a physiologically acceptable salt thereof.
  12. R 2 is a group represented by X 2 -A 1 -R 10 , A 1 is a linear or branched lower alkylene moiety or a linear or branched lower alkenylene moiety, and R 10 is substituted. The compound according to claim 6 or a physiologically acceptable salt thereof, which is a phenyl group which may be substituted, a naphthyl group which may be substituted, or a heteroaryl group which may be substituted.
  13.   The pharmaceutical composition containing the compound as described in any one of Claims 1-12, or its physiologically acceptable salt.
  14. A β 3 adrenergic receptor agonist comprising the compound according to any one of claims 1 to 12 or a physiologically acceptable salt thereof as an active ingredient.
  15.   Obesity, diabetes, hyperlipidemia, irritable bowel syndrome, acute or chronic, characterized by comprising as an active ingredient the compound according to any one of claims 1 to 12 or a physiologically acceptable salt thereof. Prophylactic / therapeutic agent for diarrhea, pollakiuria, urinary incontinence, urinary calculus or depression
JP2004299077A 2004-10-13 2004-10-13 Sulfonyloxyindole derivative and medicinal composition containing the same Pending JP2006111553A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2004299077A JP2006111553A (en) 2004-10-13 2004-10-13 Sulfonyloxyindole derivative and medicinal composition containing the same

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2004299077A JP2006111553A (en) 2004-10-13 2004-10-13 Sulfonyloxyindole derivative and medicinal composition containing the same

Publications (1)

Publication Number Publication Date
JP2006111553A true JP2006111553A (en) 2006-04-27

Family

ID=36380366

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2004299077A Pending JP2006111553A (en) 2004-10-13 2004-10-13 Sulfonyloxyindole derivative and medicinal composition containing the same

Country Status (1)

Country Link
JP (1) JP2006111553A (en)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008017381A1 (en) 2006-08-08 2008-02-14 Sanofi-Aventis Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
WO2008058341A1 (en) * 2006-11-15 2008-05-22 Cytopia Research Pty Ltd Inhibitors of kinase activity
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
US20100093865A1 (en) * 2008-09-05 2010-04-15 Acucela, Inc. Sulphur-linked compounds for treating ophthalmic diseases and disorders
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
WO2011023754A1 (en) 2009-08-26 2011-03-03 Sanofi-Aventis Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
CN102381988A (en) * 2010-08-31 2012-03-21 凯瑞斯德生化(苏州)有限公司 Method for preparing intermediate compound of Rivastigmine and intermediate compound
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120050A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120058A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120057A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120051A1 (en) 2011-03-08 2012-09-13 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof
EP2567959A1 (en) 2011-09-12 2013-03-13 Sanofi 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
AU2013273769B2 (en) * 2006-11-15 2016-05-12 Ym Biosciences Australia Pty Ltd Inhibitors of Kinase Activity
US9815815B2 (en) 2013-01-10 2017-11-14 Pulmokine, Inc. Non-selective kinase inhibitors
US9925184B2 (en) 2013-10-11 2018-03-27 Pulmokine, Inc. Spray-dry formulations
US10231966B2 (en) 2016-10-27 2019-03-19 Pulmokine, Inc. Combination therapy for treating pulmonary hypertension

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008017381A1 (en) 2006-08-08 2008-02-14 Sanofi-Aventis Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
JP2015164925A (en) * 2006-11-15 2015-09-17 ワイエム・バイオサイエンスィーズ・オーストラリア・ピーティーワイ・リミテッドYM Biosciences Australia Pty Ltd Inhibitors of kinase activity
JP2014065713A (en) * 2006-11-15 2014-04-17 Ym Biosciences Australia Pty Ltd Inhibitors of kinase activity
AU2007321719B2 (en) * 2006-11-15 2013-11-21 Ym Biosciences Australia Pty Ltd Inhibitors of kinase activity
JP2010509375A (en) * 2006-11-15 2010-03-25 サイトピア・リサーチ・ピーティーワイ・リミテッド Inhibitor of kinase activity
US8461161B2 (en) 2006-11-15 2013-06-11 Ym Biosciences Australia Pty Ltd Substituted pyrazines as inhibitors of kinase activity
AU2013273769B2 (en) * 2006-11-15 2016-05-12 Ym Biosciences Australia Pty Ltd Inhibitors of Kinase Activity
WO2008058341A1 (en) * 2006-11-15 2008-05-22 Cytopia Research Pty Ltd Inhibitors of kinase activity
US9029386B2 (en) 2006-11-15 2015-05-12 Gilead Sciences, Inc. Pyridine derivatives useful as kinase inhibitors
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
US20100093865A1 (en) * 2008-09-05 2010-04-15 Acucela, Inc. Sulphur-linked compounds for treating ophthalmic diseases and disorders
KR101395952B1 (en) 2008-09-05 2014-05-21 어큐셀라 인코포레이티드 Sulfur-linked compounds for treating opthalmic diseases and disorders
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
WO2011023754A1 (en) 2009-08-26 2011-03-03 Sanofi-Aventis Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
CN102381988A (en) * 2010-08-31 2012-03-21 凯瑞斯德生化(苏州)有限公司 Method for preparing intermediate compound of Rivastigmine and intermediate compound
CN102381988B (en) 2010-08-31 2014-05-28 凯瑞斯德生化(苏州)有限公司 Method for preparing intermediate compound of Rivastigmine and intermediate compound
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120051A1 (en) 2011-03-08 2012-09-13 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120058A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120050A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120057A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
EP2567959A1 (en) 2011-09-12 2013-03-13 Sanofi 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
US9815815B2 (en) 2013-01-10 2017-11-14 Pulmokine, Inc. Non-selective kinase inhibitors
US10246438B2 (en) 2013-01-10 2019-04-02 Pulmokine, Inc Non-selective kinase inhibitors
US9925184B2 (en) 2013-10-11 2018-03-27 Pulmokine, Inc. Spray-dry formulations
US10231966B2 (en) 2016-10-27 2019-03-19 Pulmokine, Inc. Combination therapy for treating pulmonary hypertension

Similar Documents

Publication Publication Date Title
JP3692034B2 (en) Imidazopyridine derivatives that inhibit gastric acid secretion
EP0611003B1 (en) Substituted phenyl sulfonamides as selective B3 agonists for the treatment of diabetes and obesity
EP0783486B1 (en) Novel prostaglandin synthase inhibitors
AU765919B2 (en) Beta2-adrenoceptor agonists
CN1043893C (en) Pharmaceuticals
JP3545461B2 (en) Bicyclic heterocycles containing sulfonamide derivative
US7087635B2 (en) 3-substituted oxindole β3 agonists
AU2004275757B2 (en) 1,1,1-trifluoro-4-phenyl-4-methyl-2-(1H-pyrrolo [2,3-C]pyridin-2-ylmethyl)pentan-2-ol Derivatives and related compounds as glucocorticoid ligands for the treatment of inflammatory diseases and diabetes.
EP0673937B1 (en) Bicyclic heterocyclic sulfonamide and sulfonic ester derivatives
JP4192268B2 (en) 1H-indole derivatives as inhibitors of cyclooxygenase-2 with excellent selectivity
JP2007525482A (en) Amide compounds and their use as ion channel ligands
AU2003239609B2 (en) 2-Furancarboxylic acid hydrazides and pharmaceutical compositions containing the same
US7183294B2 (en) Indole derivatives useful for the treatment of diseases
RU2479577C2 (en) Heterocyclic compounds as positive modulators of metabotropic glutamate receptor 2 (mglu2 receptor)
NL1028948C2 (en) Ortho substituted aryl or heteroarylamide compounds.
JP3149186B2 (en) Selective beta ▲ under 3 ▼ substituted sulfonamide as agents for the treatment of diabetes and obesity
US20050020617A1 (en) 3-substituted oxindole beta3 agonists
JP5191497B2 (en) S1P receptor modulating compounds and uses thereof
ES2265447T3 (en) Oxindol-3-replaced beta-3 receiver agonists.
KR101985044B1 (en) Modulators of atp-binding cassette transporters
US20070232681A1 (en) Compounds Having Crth2 Antagonist Activity
US6380238B1 (en) Indoline derivatives as 5-HT2B and or 5-HTC receptor ligands
US20070099938A1 (en) Antistress drug and medical use thereof
EP1519915B1 (en) Tricyclic steroid hormone nuclear receptor modulators
JP3224372B2 (en) Heterocyclic carboxamide